To examine birth outcomes between children conceived with in vitro fertilization (IVF) or intrauterine insemination (IUI) and sibling births from unassisted conceptions. Retrospective sibling cohort. Live born children conceived via IVF, with or without intracytoplasmic sperm injection, or IUI at the Utah Center for Reproductive Medicine, 1999-2018, and sibling births from unassisted conceptions (born 1985-2018). The main analysis included singleton births (460 IVF, 666 IUI, and 1,579 unassisted siblings). In vitro fertilization, with or without intracytoplasmic sperm injection, or IUI. Preterm birth, low birth weight, small for gestational age, large for gestational age (LGA), and major congenital anomalies. Compared with unassisted siblings, singleton children conceived via IVF had gestational ages shorter by nearly half a week (95% confidence interval [CI], -0.6 to -0.3), birth weights of 72.1 g lower (95% CI, -118.8 to -25.4), and higher proportions of preterm birth (IVF, 11.1%; IUI, 8.7%; unassisted siblings, 6.8%), LGA (IVF, 9.1%; IUI, 4.5%; unassisted siblings, 5.9%), and major congenital anomalies (IVF, 3.7%; IUI, 2.0%; unassisted siblings, 1.4%). Models adjusted for maternal age, infant sex, infant birth year, previous pregnancy, and birth order showed that children conceived via IVF were more likely to be preterm (adjusted risk ratio [aRR], 1.6; 95% CI, 1.2-2.2; absolute difference, 4.3%) and LGA (aRR, 1.8; 95% CI, 1.2-2.5; absolute difference, 3.2%). Children conceived via IVF had a higher risk of major congenital anomalies than unassisted siblings adjusted for maternal age, infant sex, and birth order (aRR, 1.9; 95% CI, 1.0-3.8; absolute difference, 2.3%). Children conceived via IUI had birth weights 55.8 g lower (95% CI, -95.6 to -15.9) than unassisted siblings. We observed an increased risk of preterm birth, low birth weight, LGA, and major congenital anomalies among singleton children conceived with IVF compared with that among unassisted siblings; however, absolute differences remain small. For children conceived via IUI, lower birth weights were observed. These results suggest that treatment-related factors in addition to underlying subfertility may contribute to adverse birth outcomes.
General OB/GYNUterine Closure TechniqueHysterotomy RepairCesarean Scar Complications
Bujold E et al., 2026·American Journal of Obstetrics and Gynecology
Normal uterine function depends on cyclical regeneration and the capacity to sustain pregnancy. A cesarean incision represents an injury to this remarkable organ. Although the uterus possesses exceptional healing potential, cesarean delivery increases the risk of secondary infertility, pelvic pain, uterine rupture, and abnormal placentation in subsequent pregnancies. The two most important determinants of successful hysterotomy healing after cesarean delivery are the location of the incision and the surgical technique used for closure. The anatomic site of entry-whether the corpus, lower uterine segment, or cervix-defines the tissue composition, vascularity, and contractility at the wound margins, which in turn influence how the scar remodels and withstands subsequent pregnancies. Surgical technique is also important. A robust body of experimental and clinical evidence demonstrates that restoring anatomic integrity by reapproximating uterine layers while excluding the endometrium produces stronger scars and reduces late complications. The rationale for excluding the endometrium is to prevent displacement of endometrial tissue into the myometrium and to avoid mucosal tearing against a foreign body (i.e. suture material), both of which predispose to defective healing. When the endometrium is incorporated, healing is often impaired, leading to niches or isthmoceles, adenomyosis, and endometriosis at the scar site. Over time, these defects have been recognized as contributors to abnormal bleeding, pelvic pain, infertility, uterine rupture, and placenta accreta spectrum disorders. Despite this evidence, single-layer closures that incorporate endometrium became widely adopted because of their speed and simplicity, while their long-term sequels were initially underappreciated. This has prompted renewed scrutiny of closure techniques, including comparisons of single-layer vs double-layer closure, locking vs nonlocking sutures, type of sutures, and the direction of suture. Collectively, the data show that optimal closure respects uterine anatomy, restores the natural alignment of tissues, and achieves hemostasis without compromising perfusion or strangulating tissues. Building on these principles, we herein describe a refined 3-layer closure. The first layer approximates decidua and junctional myometrium while excluding surface endometrium to prevent tissue entrapment and bacterial contamination. The second layer restores anatomic wall integrity by reapproximating the bulk of the myometrium, thereby reinforcing strength and distributing tension across the scar. The third layer reapproximates superficial myometrium and serosa, smoothing the uterine surface and reducing adhesions. This technique is not simply a return to traditional double-layer methods or an extension of single-layer practice, but rather a refinement that integrates lessons from visceral surgery and contemporary obstetric data. Its rationale is to restore anatomy, secure hemostasis without ischemia, and preserve long-term uterine function. While short-term safety appears comparable across closure methods, evidence increasingly indicates that long-term reproductive outcomes depend on how closure respects tissue biology. We argue that appropriate repair is more meticulous restoration of uterine anatomy should take precedence over operative speed. The enduring success of a hysterotomy repair depends on the surgical technique employed, as it directly affects women's future reproductive health.
NaProTECHNOLOGYPregnancy RatesRestorative MedicineCohort Studies
Open Access
Sánchez-Méndez JI et al., 2025·Front Reprod Health
Assisted reproductive technologies (ART) are widely used to address infertility; however, they are costly, associated with medical risks, and often yield suboptimal clinical outcomes. Natural Procreative Technology, also known as NaProTechnology (NPT), provides a systematic and integrative approach to infertility by thoroughly identifying and treating underlying medical conditions to restore the couple's natural fertility potential. Despite its promise, real-world data on NPT effectiveness remain limited. The objective of this study is to evaluate the take-home baby rate in a large population of infertile couples treated with NPT and to synthesize findings from previously published studies. A retrospective cohort study was conducted involving 1,310 infertile couples treated at a specialized fertility clinic in Spain over a 5-year period. Participants presented with primary or secondary infertility or recurrent pregnancy loss. Clinical data, diagnoses, and outcomes were analyzed, including surgical interventions and treatment duration. The mean age of women and men was 35.0 (SD 4.4) and 36.9 (SD 5.3) years, respectively. Primary infertility was the most common subtype (73.5%), the median infertility duration was 24 months, and prior ART attempts were recorded in 27.5% of couples. Mean number of diagnoses per couple was 2.5 (SD 1.3). The crude take-home baby rate was 35.3% (N = 463). Independent predictors of successful take-home baby included female age, recurrent pregnancy loss as the reason for consultation, duration of infertility, and the presence of endometriosis, hormonal dysfunction, male factor, and endometrial disorders as diagnoses. Considering a median duration of NPT of 10.9 months (range 8.1-17.0), the adjusted cumulative take-home baby rate was 62.1%. Rates varied significantly by female age, with higher success 83.7% at 18-30 years, 53.3% at 36-40 years, and 24.4% over 40 years. A sensitivity analysis was performed to assess the impact of dropout assumptions on cumulative pregnancy rates. Nearly one-third of patients underwent surgery, most commonly hysteroscopy and/or laparoscopy. In this cohort, NPT was associated with a notably high take-home baby rate in an infertile population with unfavorable prognostic factors, including advanced maternal age, prolonged duration of infertility, or previous failed attempts at conventional ART procedures.
InfertilityIVF Regulation and OversightOutcomes and StatisticsClinic Regulation
Recently, editorials have been published in reproductive medical journals that have misunderstood and misrepresented the origin and meaning of “restorative reproductive medicine” (RRM).1,2 This term was first used in 2000 when a group of physicians established the International Institute for Restorative Reproductive Medicine (IIRRM, iirrm.org ). I am a founding member and am currently president of the IIRRM.
The IIRRM was founded as a secular, not a faith-based organization. We adhere to time-honoured medical principles to understand and treat underlying factors responsible for infertility. We are always seeking to improve our diagnosis and treatment of those factors, the training of clinicians who offer RRM, and the quality of clinical practice of RRM. We believe that in the clinical realm, in vitro fertilization (IVF) is often offered quickly without sufficient efforts first made to help couples conceive naturally.
IVF was originally developed to treat patients with bilateral tubal occlusion who could not conceive through sexual intercourse. Most patients who undergo IVF today do not have blocked fallopian tubes. Intracytoplasmic Sperm Injection (ICSI) was developed for patients with severe male factor infertility. Most patients who undergo ICSI today do not have severe male factor infertility. Remarkably, the most recent Cochrane review of IVF indicates ongoing uncertainty about whether IVF improves the live birth rate compared to expectant management for previously untreated couples with “unexplained” subfertility.3
I am an active RRM clinician since 1998 and I have treated thousands of couples. When patients present for fertility treatment, I do not ask them what religion, political view, or philosophy they support, because that is irrelevant to people who want a solution for their infertility. If they have a condition that is better treated by IVF, I tell them that at the first appointment. If natural conception is possible with RRM, I explain what is involved and outline the treatment process which can take up to 12 cycles (most often less) to reach a healthy ongoing pregnancy, or a full course of treatment.
RRM honours patient autonomy. We do not seek to prohibit patient access to IVF. Patients seek us out. RRM expands their choices and options. Many of my patients were previously seen in fertility clinics that offer IVF. Patients repeatedly tell me they did not receive the same depth of investigation or non-IVF treatment in the IVF clinics. I recently received these comments from patients, “RRM empowered us in our fertility journey. It provided a personalised approach. We are so grateful.” And “even if we didn’t conceive, we’d never regret trying RRM as my health improved immeasurably…”
The World Health Organization states that “Infertility is a disease of the male or female reproductive system defined by the failure to achieve a pregnancy after 12 months or more of regular unprotected sexual intercourse”.4 As RRM physicians, we respectfully suggest a slight “Infertility is a medical condition defined by failure to achieve a pregnancy after 12 months or more of regular sexual intercourse without contraception, which is caused by one or more underlying diseases and conditions involving the male or female reproductive system.” This definition indicates that infertility is not a singular condition to be treated solely by treatments to generate a pregnancy and birth. Rather, it is “a canary in the coal mine” for human health, indicating the need to identify and address underlying health concerns. 5,6
As RRM physicians and clinicians we have training and backgrounds that allow us to treat infertility patients with a focus on treatments and approaches that restore and optimize natural function. The specialty of reproductive endocrinology and infertility has extensive training with a particular focus on IVF and treatments to improve the success of IVF. But we can and should be in agreement to offer patients evidence-based information and treatments that meet the needs and preferences of patients.
Further research is needed and is currently ongoing on patient-relevant questions, How does an RRM evaluation differ in process and results from a fertility evaluation before initiating IVF? How do the outcomes of RRM and IVF compare on multiple levels including live birth rates, premature delivery, patient satisfaction, health improvement, and repeat successful births?7
For the sake of our patients with infertility, let us strive to be objective about the scientific facts, and meet all patients with respect. Surely as we challenge and learn from one another and strive for excellence, the patients will be the ultimate beneficiaries.
InfertilityRRM vs IVF ComparisonLive Birth RatesPrematurity and Birth Weight
Open Access
Restorative reproductive medicine (RRM) is an emerging approach that can be used to treat infertility. Our goal was to compare RRM to IVF outcomes in 2019.
We conducted a retrospective clinic-based analysis and referenced it against publicly available data from IVF registries, as published by the Centers for Disease Control and Prevention (CDC) or the Society for Assisted Reproductive Technology (SART) in the USA, and the Human Fertilization and Embryology Authority (HFEA), in the UK. Data from 2019 was collected from routine medical records following treatment at one clinic in Dublin, Ireland during 2019. We defined the demographics, diagnoses, and treatments and then calculated the crude percentages of conception, live birth, multiple pregnancy, prematurity, and low birth weight. These results were benchmarked against data reported in IVF databases. 249 couples had at least one RRM consultation, 187 committed to the RRM treatment program and met the inclusion criteria. The average female age for all included patients was 36.4 years and couples were trying to conceive for a mean of 32.2 months. Of the 187 patients/couples who underwent treatment, 28% had a previous live birth, 30% had a previous miscarriage, and 42% had never conceived;19% (35/187) had previously had IVF, 2.3 + 1.6 IVF cycles per couple. Of the 187 couples, 52% (98/187) conceived, 41% (77/187) had a documented live birth. There were 75 singletons and 2 sets of twins, producing 79 babies. Time to conception for live birth patients averaged 12 + 8 months. The average birth weight was 3422g (7lb 9oz) and average weeks’ gestation at delivery was 39 + 1.5 weeks. 4.0% (3/75) of singleton babies were premature (33-37 weeks) and none were very premature (< 32 weeks). 5.3% (4/75) of singleton babies had low birth weight (< 2,500g). When we compared births across age groups, the RRM percentages with live birth were comparable to those in a single cycle of IVF with multiple subsequent embryo transfers, and greater than a single cycle of IVF with a single embryo transfer. Furthermore, RRM babies had fewer multiple pregnancies, and singleton RRM pregnancies had less than half as many premature deliveries compared to IVF, (6.5% RRM all pregnancies or 4.0% RRM, singleton pregnancies vs 14.4% SART, all pregnancies or 11.8% CDC, singleton pregnancies). 74% (26/35) of couples who remained in contact with us and tried for another pregnancy had a repeat successful live birth. In our clinic, a comprehensive RRM assessment and treatment followed by up to 12 optimal cycles of timed intercourse resulted in a 41% live birth rate (crude rate). We propose that using RRM may improve a couple’s chance of having a healthy pregnancy and reduce the demand for IVF. Furthermore, RRM reduces the risk of multiple pregnancy, low birth weight and premature delivery compared to IVF. The majority of couples who sought a second live birth were successful.
Limitations This is a retrospective analysis with a small number of RRM patients, compared to large IVF databases of patients using one cycle of IVF, including all transfers made from the IVF retrieval. While useful for benchmarking, conclusions are limited by sample size, and the lack of relevant prognostic data (other than female age) for the IVF patients. Larger prospective studies with full prognostic data are needed to make a proper comparison of RRM and IVF outcomes.
AndrologyAir PollutionMorphology and MotilityEnvironmental Exposures
Open Access
Prior studies have observed impacts of air pollution on semen quality, but timing of exposure during developmental windows of spermatogenesis and impacts of low-to-moderate air pollution is less well understood. We examined the relation between air pollution and semen quality in the Folic Acid and Zinc Supplementation Trial (2013-2018), which enrolled male partners of couples seeking infertility treatment in the Salt Lake City, Utah region (n = 2015). Semen quality parameters were assessed at baseline, 2-, 4-, and 6-months follow-up. Measures of daily air pollutants at each participant's residence were abstracted from Community Multiscale Air Quality models (fine PM2.5, sulfur dioxide, nitrogen dioxide, O3), linked to participants' residential addresses, and averaged across the 74-day spermatogenesis window prior to the sample collection date for each study visit, and across four developmental windows of spermatogenesis (mitosis, meiosis I-II, spermiogenesis, and spermiation). Generalized linear mixed models considered four repeated semen sample measures per participant and adjusted for co-pollutants, age, season, and income. In multi-pollutant models, O3 during early-to-mid spermatogenesis (meiosis I+II and spermiogenesis) was related to lower percent normal morphology (% difference -6.73, 95 % CI -9.82, -3.54 and % difference -3.83, 95 % CI -7.51, 0.00, respectively). Additionally, PM2.5 and O3 during late spermatogenesis (spermiation) were associated with lower count and concentration, and PM2.5 with lower progressive motility. These findings suggest that exposure to low-to-moderate levels of air pollution may negatively impact semen quality and indicate that exposure to O3 during meiosis and spermiogenesis may particularly affect normal sperm morphological development.
Fertility AwarenessPopulation StudiesMisconceptionsReproductive Education
Open Access
Fertility rates in the UK are at an all-time low, with infertility affecting approximately 1 in 7 couples. Despite the rising demand for fertility services, fertility awareness, specifically knowledge of ovulation and the fertile window, remains low among women of reproductive age. Most existing studies offer a broad perspective, lacking focus on women actively trying to conceive (TTC). This study aims to assess the level of understanding surrounding the fertile window among women TTC, identifying factors associated with knowledge gaps. A retrospective, cross-sectional analysis of 97,414 women actively TTC who answered an online health assessment was conducted. Participants provided information on menstrual cycle characteristics, previous pregnancies, and fertility knowledge, including the timing of the fertile window. Frequencies, percentages were calculated and chi-squared tests performed to assess differences in categorical data. Logistic regression models were used to calculate odds ratios (ORs) to better understand factors significantly associated with not knowing the fertile window. Out of the total respondents (97,414), over a third (33,756, 41%) could not accurately identify the fertile window, with substantial misconceptions observed across all age groups and ethnicities. Women with previous pregnancies were more likely to correctly identify the fertile window (OR = 1.45, 97.5% CI: 1.20-1.75, p < 0.001). However, knowledge was significantly lower among those with irregular cycles, non-White ethnicities, younger age groups and longer time TTC. Additionally, misconceptions about cycle regularity were apparent, of 60,322 women describing their cycles as regular 10% did not know their cycle length (66,95) and a further 2.9% fell outside of the clinically regular 21-35 day range. These misconceptions followed a similar trend with younger age groups, non-white ethnicities and longer time TTC having significantly increased rates of misidentifying regular cycles. This further increased the odds of not knowing their fertile window (OR = 2.99, 97.5% CI: 2.83-3.17, p < 0.001). The findings reveal gaps in fertility awareness among women actively TTC. Addressing these knowledge gaps through targeted educational interventions could potentially reduce time-to-pregnancy and the reliance on assisted reproductive technologies. Improved fertility education focusing on cycle tracking and ovulation timing is essential to assist women with accurate information during their TTC journey.
Bulletti FM et al., 2025·Clin Med�Insights�Reprod�Health
Infertility affects around 17.5% of reproductive-aged individuals worldwide, posing significant personal and public health challenges. Although Medically Assisted Reproduction and Assisted Reproductive Technology (ART; e.g., in vitro fertilization) have advanced outcomes, many couples fail to conceive due to unaddressed pelvic, uterine, or systemic factors. We aim to (1) define the current usage of Restorative Reproduction Medicine (RRM) in clinical practice, (2) compare RRM outcomes with conventional ART, and (3) propose an integrated model of RRM plus ART for optimal fertility care.
A systematic review following PRISMA guidelines was conducted (INPLASY registration no. INPLASY2024110069). We searched PubMed, Scopus, and Web of Science (January 1995–October 2024), combining terms such as “restorative reproductive medicine,” “intrauterine adhesions,” “myomas,” “polyps,” “hydrosalpinx,” “endometritis,” “BMI,” “thyroid dysfunction,” “microbiome,” and “assisted reproductive technology.” studies on uterine/systemic factors affecting infertility, focusing on surgical/pharmacological RRM interventions and ART limitations. male-only infertility, case reports, narrative reviews, non-English publications. Quality assessment employed the Newcastle-Ottawa Scale and the Cochrane Risk of Bias Tool. We also briefly noted potential publication bias due to language and study-type restrictions. From >25,000 initial titles, 3 sequential screenings yielded 145 key articles addressing uterine (septum, myomas, polyps, adhesions) and systemic (body mass index (BMI) extremes, thyroid dysfunction, microbiome imbalance) factors. Surgical corrections (e.g., hysteroscopic removal of polyps/myomas, salpingectomy for hydrosalpinx) significantly improved natural conception and ART success (⩾20%–40% increase in clinical pregnancy). Chronic endometritis treatment, endometrial microbiome modulation, and BMI/thyroid optimization further improved pregnancy rates by 15%–20%. Comparisons of RRM versus ART alone indicated that RRM often lowers overall cost and may reduce miscarriage, while ART offers immediate embryo transfer. Combining RRM to correct pathologies prior to ART can boost implantation and live birth rates (⩾40%–70% improvement in some studies). Restorative Reproductive Medicine comprehensively addresses pelvic and systemic abnormalities, thereby enhancing fertility outcomes and complementing ART. A proposed integrated model—RRM diagnostics/interventions followed by ART if needed—maximizes success, reduces time/cost, and emphasizes holistic reproductive health. Further multicenter trials are warranted to standardize protocols and fully realize RRM’s potential in modern fertility care.
InfertilityVaccine and Medication EffectsEnvironmental ExposuresPopulation-Level Analysis
Adverse effects of COVID-19 vaccination on human menstrual cycle characteristics have been observed, but limited data are available on the relationship between COVID-19 vaccination status and birth rates. Therefore, we used nationwide data from the Czech Republic to examine rates of successful conceptions (SCs), that is, conceptions leading to live births 9 months later, for women who were either vaccinated or unvaccinated against COVID-19 before SC. Summary monthly COVID-19 vaccination and birth data for women in the Czech Republic aged 18-39 years were retrieved for the period from January 2021 to December 2023. The numbers of SCs per month per 1000 women were calculated for preconception-vaccinated or unvaccinated women, respectively, as well as the number of SCs per month per 1000 women for all women aged 18-39 years. During the study period, there were approximately 1,300,000 women aged 18-39 years in the Czech Republic, and the proportion of COVID-19-vaccinated women increased from January 2021 until reaching a steady state of around 70% by the end of 2021. At least from June 2021, SCs per 1000 women were considerably lower for women who were vaccinated, compared to those that were unvaccinated, before SC. Furthermore, SC rates for the vaccinated group were much lower than expected based on their proportion of the total population. In the Czech Republic, SC rates were substantially lower for women vaccinated against COVID-19 before SC than for those who were not vaccinated. These hypothesis-generating and preliminary results call for further studies of the potential influence of COVID-19 vaccination on human fecundability and fertility.
InfertilityIVF Outcomes and StatisticsFrozen Embryo TransferPopulation-Level Data
Human Fertilisation and Embryology Authority, 2025
# Fertility treatment 2023: Preliminary UK statistics for IVF and DI treatment, storage, June 2025
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[Download the underlying dataset as Excel Worksheet](https://www.hfea.gov.uk/media/3qip3kon/fertility-treatment-2023-trends-and-figures-underlying-dataset.xlsx "Download the underlying dataset for the ‘Fertility treatment 2023: trends and figures’ report")
## - [Main points](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2023-trends-and-figures/#main-points)
- [Note on preliminary data](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2023-trends-and-figures/#note-on-preliminary-data)
- [Section 1: More babies born from IVF in the UK](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2023-trends-and-figures/#section-1)
- [Section 2: IVF pregnancy and birth rates using fresh embryo transfers increased over the years, though lower for Black patients](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2023-trends-and-figures/#section-2)
- [Section 3: Average pregnancy and birth rates using frozen embryo transfers increased in 2023](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2023-trends-and-figures/#section-3)
- [Section 4: Multiple births rate from IVF is one of the lowest in the world](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2023-trends-and-figures/#section-4)
- [Section 5: Most treatment types have increased across the UK since 2019](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertili...
Reproductive EndocrinologyVaccine EffectsCOVID-19 VaccinationAMH and AFC
Open Access
This study aimed to elucidate the effects of messenger RNA (mRNA) and inactivated coronavirus disease 2019 (COVID-19) vaccines on ovarian histology and reserve in rats. Thirty female Wistar albino rats, aged 16-24 weeks, were randomly divided into three groups (n = 10): control, mRNA vaccine, and inactivated vaccine groups. Each vaccine group received two doses (on day 0 and day 28) at human-equivalent doses. Four weeks post-second vaccination, ovarian tissues were harvested for analysis. Immunohistochemical analysis was performed to evaluate the expression of transforming growth factor beta-1 (TGF-β1), vascular endothelial growth factor (VEGF), caspase-3, and anti-Müllerian hormone (AMH) in ovarian follicles. Both vaccines induced significant increases in TGF-β1, VEGF, and caspase-3 expression, with more pronounced effects in the mRNA vaccine group. Conversely, AMH expression in the granulosa cells of primary, secondary, and antral follicles showed marked reductions (p < 0.001). The counts of primordial, primary, and secondary follicles decreased significantly in the inactivated vaccine group relative to controls and further in the mRNA vaccine group compared to the inactivated group (p < 0.001). Additionally, the mRNA vaccine group exhibited a decrease in antral and preovulatory follicles and an increase in atretic follicles compared to the other groups (p < 0.05). The serum AMH level was diminished with the mRNA vaccination in comparison with the control and inactivated groups. Our findings suggest that both mRNA and inactivated COVID-19 vaccines may detrimentally impact ovarian reserve in rats, primarily through accelerated follicular loss and alterations in apoptotic pathways during folliculogenesis. Given these observations in a rat model, further investigations into the vaccines' effects on human ovarian reserve are needed.
PCOSGestational DiabetesMetabolic DisordersPCOS and Pregnancy Risk
The objective of this study is to test the association between preconception polycystic ovary syndrome (PCOS) and gestational diabetes mellitus (GDM) using Utah's Pregnancy Risk Assessment Monitoring System (2016-2021). In addition, pre-pregnancy hypertension will be tested as a potential effect moderator. This cross-sectional study utilizes data from Phase 8 of the Utah Pregnancy Risk Assessment Monitoring System (PRAMS) survey (2016-2021). The association between PCOS and GDM was tested using Poisson regression to generate adjusted prevalence ratios and 95% confidence intervals. PCOS was associated with higher prevalence of GDM in all models, regardless of whether the outcome data (GDM) came from the infant's birth certificate, the PRAMS survey, or the combined measure. When adjusting for sociodemographic characteristics, lifestyle factors, reproductive history, and comorbidities, women with PCOS were 1.50 (1.16-1.95) times as likely to have GDM (reported on birth certificate and/or survey) compared to women without PCOS. Pre-pregnancy hypertension was not found to be a statistically significant effect moderator. The findings from this study were consistent with the majority of research indicating that women with PCOS have increased risk for GDM. This is also the first known study to test pre-pregnancy hypertension as an effect moderator between PCOS and GDM. More research is needed on the role of comorbidities such as chronic hypertension as effect modifiers between PCOS and GDM.
These findings show that women with PCOS are at high risk for GDM, among a population-based sample of mothers. Interventions to reduce the risk of GDM among women with PCOS need to be developed and evaluated.
SurgeryExcision TechniquesSurgical ManagementFertility Outcomes
Open Access
Restorative reproductive surgery has emerged to become an exciting and promising field of surgery that can transform the way that we treat patients, especially regarding fertility. As a prime example of this type of surgery, restorative reproductive surgery for endometriosis, a common and debilitating disease that can lead to infertility and pelvic pain, offers a root cause treatment to remove the actual disease and to optimize the reproductive anatomy, for best patient outcomes. Optimal excision of endometriosis and prevention of pelvic adhesions has been shown to lead to reduce symptoms, to lead to high natural fertility rates, and to lead to very low rates of the need for repeat surgery. Patients have improved symptoms and quality of life, in addition to improved fertility chances for one and subsequent pregnancies (if desired), demonstrating the link between wellness and fertility.
There is an urgent need for more resources, training, advocacy, research and publication for this exciting area of restorative reproductive surgery. Its time has come.
NaProTECHNOLOGYFoundational PrinciplesClinical ApplicationRestorative Approaches
Open Access
In 1972, a seminal article was published demonstrating that women, adequately trained, could detect the approach of ovulation in the fertile window of their menstrual cycle. It was demonstrated that the symptoms perceived by women at the vulva correlate closely with changes in steroid hormone levels associated with folliculogenesis and the luteal phase. The fertility charting performed by women trained to recognize vulvar symptoms associated with hormonal changes serves as an instrument for detecting potential pathologies and monitoring the effects of treatment These findings established the biological foundations of a tool of fertility awareness tracking that has facilitated the development of restorative reproductive medicine (RRM): an approach that can be applied to identify and treat the underlying causes of infertility/subfertility.
Several core characteristics—or foundational pillars—of the RRM approach to fertility can be identified. a commitment to respecting healthy physiological processes, comprehensive health care for both the couple and the potential embryo, and the provision of education and continuous support throughout the therapeutic process.
This commentary aims to elucidate the interplay of these foundational pillars by drawing upon evidence from peer-reviewed biomedical literature. Finally, the challenges faced by RRM in strengthening its scientific foundations, engaging with the broader scientific community, and promoting the dissemination of this approach are described.
Human Fertilisation and Embryology Authority, 2025
# National Patient Survey 2024
Survey 2 September - 9 October 2024
March 2025
[Download the underlying dataset as .xlsx](https://www.hfea.gov.uk/media/vf5bxixp/national-patient-survey-2024-underlying-dataset.xlsx "Download the underlying dataset for the ‘National Patient Survey 2024’ report")
## - [Main points](https://www.hfea.gov.uk/about-us/publications/research-and-data/national-patient-survey-2024/#main-points)
- [Introduction](https://www.hfea.gov.uk/about-us/publications/research-and-data/national-patient-survey-2024/#introduction)
- [Section 1: Over 70% of patients were satisfied with treatment](https://www.hfea.gov.uk/about-us/publications/research-and-data/national-patient-survey-2024/#section-1)
- [Section 2: Almost 80% of patients spoke to a GP before treatment](https://www.hfea.gov.uk/about-us/publications/research-and-data/national-patient-survey-2024/#section-2)
- [Section 3: 73% had used an additional test, treatment or emerging technology](https://www.hfea.gov.uk/about-us/publications/research-and-data/national-patient-survey-2024/#section-3)
- [Section 4: Around a quarter of respondents had used donor eggs, sperm, or embryos](https://www.hfea.gov.uk/about-us/publications/research-and-data/national-patient-survey-2024/#section-4)
- [Section 5: 40% of those able to donate would be willing to donate to research](https://www.hfea.gov.uk/about-us/publications/research-and-data/national-patient-survey-2024/#section-5)
- [Section 6: Familiarity with the HFEA increased to 68%](https://www.hfea.gov.uk/about-us/publications/research-and-data/national-patient-survey-2024/#section-6)
- [Qualitative summary](https://www.hfea.gov.uk/about-us/publications/research-and-data/national-patient-survey-2024/#qualitative-summary)
- [About our data](https://www.hfea.gov.uk/about-us/publications/research-and-data/national-patient-survey-2024/#about-our-data)
## - Fertility patients’ satisfaction with most ...
InfertilityChronic EndometritisEndometritis Management
Open Access
Chronic endometritis (CE), frequently asymptomatic, is associated with female infertility. Fallopian tube obstruction (FTO) is also one of the factors contributing to female infertility. More than 90% of cases of proximal FTO can be successfully treated after fallopian tubal recanalization (FTR) and the spontaneous pregnancy rate of treated women after FTR is only about 30%. Potential factors affecting the success rate of FTR remain unclear. We speculate that CE may be one of the reasons affecting the recanalization of the fallopian tubes. To identify the correlation between CE and FTO, as well as the influence of CE on pregnancy outcomes following FTR.
Retrospective observational study. We retrospectively analyzed 498 women of childbearing age who underwent laparoscopy and hysteroscopy surgery for infertility. Endometrial samples were collected during surgery for CD138 immunohistochemistry staining for the diagnosis of CE. Based on the results of the tubal patency test, they the fallopian tubal patency group and the proximal FTO group. The prevalence of CE was compared between these two groups. All women with FTO underwent FTR during the operation until successful treatment was achieved. Pregnancy outcomes were assessed after a 12-month follow-up period following the procedures. Logistic regression was used to analyze factors that might affect pregnancy after FTR. The prevalence of CE in women with tubal obstruction was 30.5%, which was significantly higher than that in the fallopian tubal patency group (10.75%), p < 0.001. After FTR, the prevalence of CE in non-pregnant women was 40.18%, which was higher than that in pregnant women (40.18% vs 13.11%), and the difference was significant (p < 0.001). Multiple regression analysis showed that CE was a significant risk factor for FTO (OR: 2.54, 95% CI: 1.368-4.717, p < 0.05). In addition, CE was identified as a risk factor for infertility after FTR (OR: 4.730, 95% CI: 2.012-11.122). The presence of CE seems to decrease the likelihood of achieving spontaneous pregnancy following FTR. This observation underscores the clinical importance of early detection and treatment of CE, emphasizing the necessity for immediate intervention to prevent potential fertility complications.
The prevalence of uterine isthmocele, also known as a uterine niche, has risen in parallel with increasing cesarean section (CS) rates, affecting approximately 60% of women depending on their history of cesarean deliveries. This condition, now categorized as cesarean scar disorder (CSD) by the "Delphi consensus," is characterized by one primary or two secondary symptoms. Diagnosis can be made through transvaginal ultrasound, sonohysterography, hysteroscopy, or magnetic resonance imaging (MRI). Management of isthmocele may involve pharmacological or surgical interventions. This review aims to provide a thorough analysis of the surgical management options, focusing on postoperative symptom relief, intraoperative and postoperative complications, length of hospital stay, and impact on secondary infertility. PubMed was comprehensively searched for observational studies from inception to 07.08.2024. Surgical treatments include hysteroscopic resection, laparoscopic procedures, and vaginal approaches, all of which offer comparable symptom relief. However, the vaginal approach is associated with a longer hospital stay. The robotic-assisted approach shows promising results but lacks extensive data. Among surgical options, hysteroscopic treatment has the fewest complications but is generally avoided when residual myometrial thickness (RMT) is less than 3 mm. While many CSDs remain asymptomatic, and some women with uterine isthmocele may not wish to conceive, symptomatic patients or those desiring to conceive may benefit from surgical intervention. The choice of procedure should be based on individual patient characteristics, particularly RMT, to define the most appropriate surgical approach.
InfertilityPreconception HealthResearch AgendaHealth Optimization
Open Access
How should premature/primary ovarian insufficiency (POI) be diagnosed and managed based on the best available evidence from published literature?Summary answerThe current guideline provides 145 recommendations on symptoms, diagnosis, causation, sequelae, and treatment of POI. Premature ovarian insufficiency (POI) presents a significant challenge to women's health, with far-reaching implications, both physically and emotionally. The potential implications include adverse effects on quality of life; fertility; and bone, cardiovascular, and cognitive health. Although hormone therapy (HT) can mitigate some of these effects, many questions still remain regarding the optimal management of POI.Study design size durationThe guideline was developed according to the structured methodology for development of ESHRE guidelines. Key questions were determined by a group of experts and informed by a scoping survey of women and health care professionals. Literature searches and assessments were then performed. Papers published up to 30 January 2024 and written in English were included in the guideline. An integrity review was conducted for the randomized controlled trials (RCTs) on POI included in the guideline. Participants/materials setting methodsBased on the collected evidence, recommendations were formulated and discussed within the guideline development group until consensus was reached. Women with lived experience of POI informed the recommendations in general, and particularly on those on provision of care. A stakeholder review was organized after finalization of the draft. The final version was approved by the guideline development group and the ESHRE Executive Committee. s and the role of chanceNew data indicate a higher prevalence of POI, 3.5%, than was previously thought. This guideline aims to help health care professionals to apply best practice care for women with POI. The recent update of the POI guideline covers 40 clinical questions on diagnosis of the condition, the different sequelae, including bone, cardiovascular, neurological and sexual function, fertility and general well-being, and treatment options, including HT. The list of clinical questions was expanded from the previous iteration of the guideline (2015) based on the scoping survey and appreciation of emerging knowledge of POI. Questions were added on the role of anti-Müllerian hormone (AMH) in the diagnosis of POI, fertility preservation, muscle health, and specific considerations for HT in iatrogenic POI. Additionally, the topic on complementary treatments was extended with specific focus on non-hormonal treatments and lifestyle management options. Significant changes from the previous 2015 guideline include the recommendations that only one elevated FSH >25 IU is required for diagnosis of POI, and guidance that AMH testing, repeat FSH measurement, and/or AMH may be required where there is diagnostic uncertainty. Recommendations were also updated regarding genetic testing, estrogen doses and regimens, use of the combined oral contraceptive and testosterone therapy. Women with lived experience of POI informed the recommendations on provision of care. Limitations reasons for cautionThe guideline describes different management options, but it must be acknowledged that for most of these options, supporting evidence is limited for POI. s of the findingsThe guideline provides health care professionals with clear advice on best practice in POI care, based on the best evidence currently available. In addition, a list of research recommendations is provided to guide further studies in POI.Study funding/competing interestsThe guideline was developed and funded by ESHRE, American Society for Reproductive Medicine (ASRM), Centre for Research Excellence in Women's Health in Reproduction Life (CRE-WHiRL), and International Menopause Society (IMS), covering expenses associated with the guideline meetings, literature searches, and dissemination of the guideline. The guideline group members did not receive payments. N.P. declared grants from Bayer Pharma (research and consultancy) and NIHR-research POISE; consulting fees from Abbott, Astellas, Bayer, Besins, Lawley, Mithra, Theramex, Viatris; honoraria from Astellas, Bayer, Besins, Gedeon Richter, Theramex, Viatris; support for attending meetings and/or travel from Astellas, Bayer, Theramex, Viatris; President, International Menopause Society, Medical Advisory Committee member, British Menopause Society, Patron Daisy Network. A.J.V. declared grants from Amgen Australia, Australian NHMRC, and Australian MRFF; consulting fees from IQ Fertility; honoraria from the Australasian Menopause Society; participation on a Data Safety Monitoring Board or Advisory Board of Astellas; Board Member of the International Menopause Society (2020 to current) and Past president of the Australasian Menopause Society (2017-2019); R.A.A. declared grants from Roche (Research support, to institution), and participation on a Data Safety Monitoring Board of Bayer. M.C. declared grants from NHI; payments or honoraria from Up-to-Date (as editor/reviewer); Board Member of American Society of Reproductive Medicine, and of American Gynecological and Obstetrical Society. M.D. declared (NIHR-HTA NIHR133461; NIHR128757; Action GN2818) consulting fees from a small personal medical practice, support for attending meetings and/or travel from ESHRE, Bayer and UCLH special Trustees; Participation on the Advisory Board of the British Menopause Society, UKSTORE project, the Progress Educational Trust, and the Turner Syndrome Support Society UK; Leadership or fiduciary roles in the British Fertility Society (Trustee), Elizabeth Garrett Anderson Hospital Charity (chair of Trustees), and the Essex Wynter charitable trust (Trustee). C.E. declared being Chair of a SIG from the Royal Australian College of General Practitioners Integrative Medicine Specific Interest Group and Program Lead for Next Practice Western Sydney Integrative Health. C.H.G. declared grants from Novo Nordisk Foundation (Nos. NNF15OC0016474 and NNF20OC0060610), sygesikringen danmark (No 2022-0189), and the Independent Research Fund Denmark (Nos. 0134-00406 and 0134-00130B); consulting fees from Novo Nordisk, Merck, and Astra Zeneca. S.K. declared grants from Roche diagnostics. A.K. declared grants from NIH R01 5R01HD101475; consulting fees as Medical Reviewer for Flo and for Healthline; honoraria as Medical Consultant for Summus; support for attending meetings from the Reproductive Scientist Development Program; Society for Reproductive Investigation Council Member and Society for Assisted Reproduction Registry/Validation Chair; R.E.N. declared consulting fees from Astellas, Bayer Pharma, Besins Healthcare, Fidia, Theramex; honoraria from Abbott, Astellas, Exeltis, Fidia, Gedeon Richter, Merck & Co, Novo Nordisk, Shionogi Limited, Theramex, Viatris; payment for expert testimony from Vichy Laboratories; Participation in Data Safety Monitoring Board of Advisory board from Astellas and Bayer Healthcare; President elect of the International Menopause Society (IMS). H.T. declared a grant from NHMRC Centre for Research Excellence for women's health in reproductive life. A.B. declared being chair of the Daisy Network Charity. The other authors have no conflicts of interest to declare.DisclaimerThis guideline represents the views of ESHRE, ASRM, CRE-WHiRL, and IMS, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant stakeholders has been obtained. Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgement to each individual presentation, nor variations based on locality and facility type. The collaborating societies make no warranty, expressed or implied, regarding the clinical practice guidelines and specifically exclude any warranties of merchantability and fitness for a particular use or purpose. (Full disclaimer available at www.eshre.eu/guidelines.).
InfertilityIVF Statistics and TrendsFamily Formation DemographicsNHS Fertility Funding
Human Fertilisation and Embryology Authority, 2024
# Family formations in fertility treatment 2022
Preliminary UK family type statistics for IVF and DI treatment, storage, November 2024
[Download the underlying dataset as .xlsx](https://www.hfea.gov.uk/media/zpjlvhnd/family-formations-in-fertility-treatment-2022-underlying-dataset.xlsx "Download the underlying dataset for the ‘Family formations in fertility treatment 2022’ report")
## - [Main points](https://www.hfea.gov.uk/about-us/publications/research-and-data/family-formations-in-fertility-treatment-2022/#main-points)
- [Introduction](https://www.hfea.gov.uk/about-us/publications/research-and-data/family-formations-in-fertility-treatment-2022/#introduction)
- [Section 1: The proportion of female same-sex couples and single patients having fertility treatment has changed](https://www.hfea.gov.uk/about-us/publications/research-and-data/family-formations-in-fertility-treatment-2022/#section-1)
- [Section 2: IVF birth rates highest among female same-sex couples](https://www.hfea.gov.uk/about-us/publications/research-and-data/family-formations-in-fertility-treatment-2022/#section-2)
- [Section 3: Single patients are starting IVF younger than previous years](https://www.hfea.gov.uk/about-us/publications/research-and-data/family-formations-in-fertility-treatment-2022/#section-3)
- [Section 4: Patient population changes between those storing eggs and thawing them](https://www.hfea.gov.uk/about-us/publications/research-and-data/family-formations-in-fertility-treatment-2022/#section-4)
- [Section 5: Average IVF multiple birth rate decreased across all family types](https://www.hfea.gov.uk/about-us/publications/research-and-data/family-formations-in-fertility-treatment-2022/#section-5)
- [Section 6: Female same-sex couples and single patients had the lowest levels of NHS funding](https://www.hfea.gov.uk/about-us/publications/research-and-data/family-formations-in-fertility-treatment-2022/#section-6)
- [Section 7: Up to two-thirds o...
To compare outcomes of vaginal surgery in women with moderate or severe symptomatic cesarean scar defect (with or without residual myometrium).
Retrospective cohort study.
Gynecology department of a teaching hospital. Fifty-three women, between January 2014 and December 2019, underwent vaginal surgery for symptomatic 20 women with moderate defect (with residual myometrium) and 33 with severe defect (without residual myometrium). Vaginal surgical approach to repair cesarean scar defect. MAIN surgery by comparing the myometrial residual thickness before and after surgery. The secondary objectives were evaluation of vaginal surgery efficacy on symptoms resolution, per and postoperative courses, and subsequent fertility. Failure rate was evaluated as the need for a second surgery. After vaginal surgery, the residual myometrium significantly increased from 2.4 mm ± 0.9 mm to 6.6 mm ± 2.4 mm (p <.01) in the moderate group and from 0 mm to 4.4 mm ± 2.2 mm (p <.01) in the severe group. The prevalence of abnormal uterine bleeding was significantly reduced after surgery in both groups (p <.01). Pelvic pain was significantly reduced only in the moderate group (p <.01). The rate of complications (5% vs 9.1%) and second surgery (15% vs 24.2%) were not significantly different between moderate and severe groups, respectively. The median time to conceive (7 months vs 12 months); pregnancy rates (84.6% vs 68.2%); and live birth rates (76.9% vs 50%) were not statistically significant in the moderate and severe groups respectively, with 90% of pregnancies occurring naturally. Women delivered by cesarean section at 38 weeks of gestation in both groups, and no uterine rupture was reported. Despite the absence of residual myometrium, vaginal repair of severe cesarean scar defect was effective in increasing myometrial thickness, in relieving bleeding symptoms, and in allowing to achieve pregnancy.
No standard criteria exist for how to perform a diagnostic laparoscopy. This case series provides evidence of the importance of standardized, reproducible techniques. A single non-oncologic gynecologic surgeon used Near-Contact Laparoscopy (NCL) and Systematic Mapping of the Abdomen and Pelvis (S-MAP) techniques, resulting in the incidental finding and curative treatment of 4 rare cancers over 3 years. Three were neuroendocrine tumors of the appendix (incidence 0.95/100,000; probability of 3 0.0000000001). The fourth was a 2 mm well-differentiated papillary mesothelioma (WDPM). All 4 were cured. 3 of 3 infertile patients subsequently achieved pregnancy. The NCL technique was originally coined by Dr. Redwine (PMID: 3190209). The S-MAP method was described in the NaProTechnology textbook by Dr. Thomas Hilgers, and the S-MAP term coined by this author. Case D used robotic-assisted laser excision. Standardization should be incorporated as the gold standard.
General OB/GYNUK OversightClinic Safety and ComplianceFertility Treatment Governance
Human Fertilisation and Embryology Authority, 2024
# State of the fertility sector 2023/24
Annual publication (1st April 2023 – 31st March 2024)
1st October 2024
[Download the underlying dataset as .xlsx](https://www.hfea.gov.uk/media/cjwjns5j/state-of-the-fertility-sector-2023-2024-underlying-dataset.xlsx "State of the fertility sector 2023-2024 - underlying dataset")
## - [How we regulate](https://www.hfea.gov.uk/about-us/publications/research-and-data/state-of-the-fertility-sector-2023-2024/#how-we-regulate)
- [1\. Inspections in 2023/24](https://www.hfea.gov.uk/about-us/publications/research-and-data/state-of-the-fertility-sector-2023-2024/#section-1)
- [2\. There were 226 non-compliances identified at inspection in 2023/24](https://www.hfea.gov.uk/about-us/publications/research-and-data/state-of-the-fertility-sector-2023-2024/#section-2)
- [3\. In 2023/24, 135 clinics were licensed by the HFEA to provide fertility treatment, storage and/or research](https://www.hfea.gov.uk/about-us/publications/research-and-data/state-of-the-fertility-sector-2023-2024/#section-3)
- [4\. Total incidents reduced by 8% compared to the previous financial year](https://www.hfea.gov.uk/about-us/publications/research-and-data/state-of-the-fertility-sector-2023-2024/#section-4)
- [5\. Fewer Ovarian hyperstimulation syndrome (OHSS) incidents were reported in 2023/24](https://www.hfea.gov.uk/about-us/publications/research-and-data/state-of-the-fertility-sector-2023-2024/#section-5)
- [6\. Patient complaints in 2023/24 were consistent with the previous financial year](https://www.hfea.gov.uk/about-us/publications/research-and-data/state-of-the-fertility-sector-2023-2024/#section-6)
- [About our data](https://www.hfea.gov.uk/about-us/publications/research-and-data/state-of-the-fertility-sector-2023-2024/#about-our-data)
## The Human Fertilisation and Embryology Authority (HFEA) is the independent regulator of fertility treatment and human embryo research in the United Ki...
InfertilityEndometrial PolypsVitamin D and Reproductive HealthEndometrial Pathology Detection
Are serum vitamin D levels associated with the incidence of endometrial polyps (EPs) in infertile patients? Serum 25(OH)D levels were nonlinearly correlated with the incidence of EPs in infertile women. EPs are a common condition that may affect the receptivity of the endometrium in women of reproductive age. Vitamin D regulates cell proliferation and differentiation, apoptosis, angiogenesis, anti-inflammation, and immunomodulation, in addition to its well-known functions in balancing calcium and phosphorus. Previous studies have shown that vitamin D concentrations are associated with reproductive outcomes, and that low vitamin D levels are associated with the incidence of colorectal polyps and nasal polyps. There is little evidence regarding the relationship between EPs and serum vitamin D levels. STUDY DESIGN, SIZE, We conducted a cross-sectional study using data from Guangdong Women and Children Hospital from January 2019 to October 2023, enrolling 3107 patients. PARTICIPANTS/MATERIALS, SETTING, A total of 3107 infertile patients who underwent hysteroscopy were included in this study; 642 patients had endometrial polyps and 2465 had a normal uterine cavity. Hysteroscopy findings included risk of EPs, polyp size, percentage of multiple polyps, and incidence of chronic endometritis (CE). Serum vitamin D were assessed by measuring total 25(OH)D using chemiluminescence. According to international guideline recommendations for vitamin D deficiency, patients the <50 nmol/l group and the ≥50 nmol/l group. Univariable and multivariable logistic regression models, stratified analyses, and smooth curve fitting were used to examine the relationship between serum 25(OH)D levels and risk of EPs. MAIN Of all patients, 23.8% (740/3107) were vitamin D deficient (<50 nmol/l). The incidence of EPs was significantly higher in the 25(OH)D < 50 nmol/l group than in the ≥50 nmol/l group (24.9% vs 19.3%; P = 0.001). However, there were no differences in polyp size, proportion of multiple polyps, and presence of CE between the two groups. After controlling for confounders, 25(OH)D ≥ 50 nmol/l (compared with <50 nmol/l) was negatively associated with risk of EPs (adjusted OR, 0.733; 95% CI, 0.598-0.898). Other variables that had an impact on polyp incidence included BMI, type of infertility, CA125, and CD138-positive plasma cells. In addition, a linear regression model between age and serum 25(OH)D levels showed a positive linear association. Subgroup analyses were performed for different age groups, and the risk of EPs was significantly higher in the 25(OH)D < 50 nmol/l group than in the ≥50 nmol/l group, both in the younger subgroup (23.8% vs 19.1%) and in the older subgroup (28.0% vs 19.9%). The smooth curve fitting model showed a nonlinear correlation between 25(OH)D levels and risk of EPs (nonlinear P-value = 0.020), with an optimal threshold of 51.8 nmol/l for 25(OH)D levels. Moreover, subgroup smooth curve fitting models showed a nonlinear correlation between 25(OH)D levels and polyp risk in patients aged <35 years (nonlinear P-value = 0.010), whereas a linear correlation between 25(OH)D levels and polyp risk was found in patients aged ≥35 years (nonlinear P-value = 0.682). LIMITATIONS, Caution should be exercised in interpreting our findings as this is a correlational study and causality cannot be inferred from our results. In addition, because of strict inclusion and exclusion criteria, our results may not be generalizable to unselected populations, including premenopausal women or women of other races. This study demonstrated for the first time that vitamin D deficiency is an independent risk factor for the incidence of EPs in infertile patients. Identifying modifiable risk factors (e.g. vitamin D deficiency) can help in the development of new strategies for treating polyps or to protect against polyp development. Further clinical intervention trials and laboratory studies are needed to evaluate the effect of vitamin D on the development of EPs and to elucidate the mechanisms. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the National Natural Science Foundation of China (82101718) and Natural Science Foundation of Guangdong Province, China (2022A1515010776). No competing interest was involved in this study. N/A.
PregnancyPharmacological TreatmentImmunomodulationMulticenter French
Open Access
What are the outcomes of pregnancies exposed to hydroxychloroquine (HCQ) in women with a history of recurrent pregnancy loss (RPL), and what factors predict the course of these pregnancies beyond the first trimester? In our cohort of pregnancies in women with a history of RPL exposed to HCQ early in pregnancy, we found that the only factor determining the success of these pregnancies was the number of previous miscarriages. Dysregulation of the maternal immune system plays a role in RPL. HCQ, with its dual immunomodulating and vascular protective effects, is a potential treatment for unexplained RPL. STUDY DESIGN, SIZE, The FALCO (Facteurs de récidive précoce des fausses couches) registry is an ongoing French multicenter infertility registry established in 2017 that includes women (aged from 18 to 49 years) with a history of spontaneous RPL (at least three early miscarriages (≤12 weeks of gestation (WG)) recruited from several university hospitals. PARTICIPANTS/MATERIALS, SETTING, Spontaneous pregnancies enrolled in the FALCO registry with an exposure to HCQ (before conception or at the start of pregnancy) were included. Pregnancies concomitantly exposed to tumor necrosis factor inhibitors, interleukin-1 and -2 inhibitors, intravenous immunoglobulin, and/or intravenous intralipid infusion, were excluded. Concomitant treatment with low-dose aspirin (LDA), low-molecular weight heparin (LMWH), progesterone, and/or prednisone was allowed. All patients underwent the recommended evaluations for investigating RPL. Those who became pregnant received obstetric care in accordance with French recommendations and were followed prospectively. The main endpoint was the occurrence of a pregnancy continuing beyond 12 WG, and the secondary endpoint was the occurrence of a live birth. MAIN One hundred pregnancies with HCQ exposure in 74 women were assessed. The mean age of the women was 34.2 years, and the median number of previous miscarriages was 5. Concomitant exposure was reported in 78 (78%) pregnancies for prednisone, 56 (56%) pregnancies for LDA, and 41 (41%) pregnancies for LMWH. Sixty-two (62%) pregnancies ended within 12 WG, the other 38 (38%) continuing beyond 12 WG. The risk of experiencing an additional early spontaneous miscarriage increased with the number of previous miscarriages, but not with age. The distributions of anomalies identified in RPL investigations and of exposure to other drugs were similar between pregnancies lasting ≤12 WG and those continuing beyond 12WG. The incidence of pregnancies progressing beyond 12 WG was not higher among pregnancies with at least one positive autoantibody (Ab) (i.e. antinuclear Ab titer ≥1:160, ≥1 positive conventional and/or non-conventional antiphospholipid Ab, and/or positive results for ≥1 antithyroid Ab) without diminished ovarian reserve (18/51, 35.3%) than among those without such autoantibody (18/45, 40.0%) (P = 0.63). Multivariate analysis showed that having ≤4 prior miscarriages was the only factor significantly predictive for achieving a pregnancy > 12 WG, after adjustment for age and duration of HCQ use prior to conception (adjusted odds ratio (OR) = 3.13 [1.31-7.83], P = 0.01). LIMITATIONS, Our study has limitations, including the absence of a control group, incomplete data for the diagnostic procedure for RPL in some patients, and the unavailability of results from endometrial biopsies, as well as information about paternal age and behavioral factors. Consequently, not all potential confounding factors could be considered. Exposure to HCQ in early pregnancy for women with a history of RPL does not seem to prevent further miscarriages, suggesting limited impact on mechanisms related to the maternal immune system. STUDY FUNDING/COMPETING INTEREST(S): The research received no specific funding, and the authors declare no competing interests. clinicaltrial.gov NCT05557201.
InfertilityIVF Success Rates and TrendsEgg and Embryo Freezing StatisticsUK Fertility Data
Human Fertilisation and Embryology Authority, 2024
# Fertility treatment 2022: Preliminary UK statistics for IVF and DI treatment, storage, July 2024
[Download the underlying dataset as .xlsx](https://www.hfea.gov.uk/media/5jfpm1cw/fertility-treatment-2022-preliminary-trends-and-figures-underlying-dataset.xlsx "Fertility treatment 2022: preliminary trends and figures - underlying dataset")
## - [Main points](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2022-preliminary-trends-and-figures/#main-points)
- [Note on preliminary data](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2022-preliminary-trends-and-figures/#note-on-preliminary-data)
- [Section 1: Average IVF pregnancy rate using fresh embryo transfers increased](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2022-preliminary-trends-and-figures/#section-1)
- [Section 2: Average IVF pregnancy and birth rates using frozen embryo transfers similar to previous years](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2022-preliminary-trends-and-figures/#section-2)
- [Section 3: Average age at first IVF treatment increased above 35 years of age for first time](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2022-preliminary-trends-and-figures/#section-3)
- [Section 4: New egg and sperm donors increased by 21% from 2019 to 2022](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2022-preliminary-trends-and-figures/#section-4)
- [Section 5: Egg storage fastest growing treatment, but accounted for 5% of all cycles in 2022](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2022-preliminary-trends-and-figures/#section-5)
- [Section 6: Multiple births from IVF at lowest UK average yet of 4%](https://www.hfea.gov.uk/about-us/publications/research-and-data/fe...
General OB/GYNUterine NicheCesarean Scar Niche DetectionCesarean Scar Defect and Fertility
Open Access
The increasing prevalence of cesarean section (CS) deliveries globally has sparked apprehension regarding potential long-term complications, notably the emergence of uterine niches. CS results in a scar that in certain patients, inadequate healing of that scar results in the development of a uterine niche. While most small niches show no symptoms, large cesarean scar niches in nonpregnant women can give rise to cesarean scar disorder syndrome. This syndrome is characterized by abnormal uterine bleeding, dysmenorrhea, and secondary infertility. In pregnant women, the presence of substantial niches may be linked to potentially life-threatening complications, including cesarean scar dehiscence, uterine rupture, placenta accreta spectrum disorders, placenta previa, and cesarean scar ectopic pregnancy.
Given the potential dangers associated with uterine niche occurrence, numerous studies in recent years have delved into the concept of cesarean scar niche, exploring its risk factors, diagnostic approaches, and treatment options. Various diagnostic modalities, such as twoor three-dimensional transvaginal ultrasonography, twoand three-dimensional sono-hysterography, hysterosalpingography, hysteroscopy, or magnetic resonance imaging, can be employed to detect uterine niches. However, none of these diagnostic methods is universally accepted as the “gold standard,” and there remains a lack of unequivocal guidelines on certain aspects related to the diagnosis of cesarean scar niche. These niches, characterized by hypoechoic regions within the myometrium at the site of a previous CS scar, pose diagnostic complexities and provoke inquiries into their prevalence, factors influencing their development, clinical presentations, and appropriate therapeutic approaches.
As CS rates rise, this review aims to understand and address uterine niches and mitigate their impact on maternal health and reproductive outcomes.
EndometriosisLaparoscopic Surgery OutcomesEndometriosis-Related InfertilityPrognostic Factors
Open Access
Zhang J et al., 2024·Eur J Obstet Gynecol Reprod Biol
To analyze the factors that might influence the pregnancy rate in patients with infertility related to endometriosis (EMs) after undergoing laparoscopic surgery, providing guidance for our clinical diagnostic and therapeutic decision-making. A retrospective analysis was conducted on clinical records and 1-year postoperative pregnancy outcomes of 335 patients diagnosed with endometriosis-related infertility via laparoscopic surgery, admitted to our department from January 2018 to December 2020. The overall pregnancy rate for patients with endometriosis (EMs) related infertility 1-year post-surgery was 57.3 %, with the highest pregnancy rate observed between 3 to 6 months after surgery. Factors such as Body Mass Index (BMI) (P = 0.515), presence of dysmenorrhea (P = 0.515), previous pelvic surgery (P = 0.247), type of EMs pathology (P = 0.893), and preoperative result of serum carbohydrate antigen 125 (CA125)（P = 0.615）had no statistically significant effect on postoperative pregnancy rates. The duration of infertility (P = 0.029), coexistence of adenomyosis (P = 0.042), surgery duration (P = 0.015), intraoperative blood loss (P = 0.050), preoperative result of serum anti-Müllerian hormone (AMH) (P = 0.002) and age greater than 35 (P = 0.000) significantly impacted postoperative pregnancy rates. The post-surgery pregnancy rate in patients with mild (Stage I-II) EMs was notably higher than those with moderate to severe (Stage III-IV) EMs (P = 0.009). Age (P = 0.002), EMs stage (P = 0.018), intraoperative blood loss (P = 0.010) and adenomyosis (P = 0.022) were the factors that affected the postoperative live birth rate. For patients with EMs-related infertility undergoing laparoscopic surgery, factors such as age > 35 years, infertility duration > 3 years, concurrent adenomyosis, severe EMs, surgery duration ≥ 2 h, intraoperative blood loss ≥ 50 ml, and low AMH before surgery are detrimental for the pregnancy rate within the first postoperative year. However, BMI, dysmenorrhea, past history of pelvic surgery, EMs pathology types (ovarian, peritoneal, deep infiltrating),and preoperative result of serum CA125 barely show any statistical difference in their effect on postoperative pregnancy rates. In terms of postoperative live birth rate, age > 35 years, severe EMs, intraoperative blood loss ≥ 50 ml, and adenomyosis were adverse factors.
InfertilityIsthmoceleCesarean Scar Defect RepairScar Niche
Open Access
Isthmocele is a gynecological condition characterized by a disruption in the uterine scar, often associated with prior cesarean sections. This anatomical anomaly can be attributed to inadequate or insufficient healing of the uterine wall following a cesarean incision. It appears that isthmocele may impact a woman's quality of life as well as her reproductive capacity. The incidence of isthmocele can range from 20% to 70% in women who have undergone a cesarean section. This review aims to sum up the current knowledge about the effect of isthmocele on fertility and the possible therapeutic strategies to achieve pregnancy. However, currently, there is not sufficiently robust evidence to indicate the need for surgical correction in all asymptomatic patients seeking fertility. In cases where surgical correction of isthmocele is deemed necessary, it is advisable to evaluate residual myometrial thickness (RMT). For patients with RMT >2.5-3 mm, hysteroscopy appears to be the technique of choice. In cases where the residual tissue is lower, recourse to laparotomic, laparoscopic, or vaginal approaches is warranted.
AndrologyOverview and EvaluationCauses and TreatmentSemen Analysis
Infertility is usually defined as the inability of a couple to conceive even after 1 year of unprotected, frequent sexual intercourse. It affects about 15% of all couples in the United States and at least 180 million couples worldwide. Male infertility is defined by the World Health Organization (WHO) as the inability of a male to make a fertile female pregnant for a minimum of at least 1 year of regular unprotected intercourse. The male is solely responsible for about 20% of cases and is a contributing factor in another 30% to 40% of all infertility cases. As male and female causes often co-exist, it is essential that both partners are investigated for infertility and managed together. Overall, the male factor substantially contributes to about 50% of all cases of infertility. There are several reasons for male fertility, including both reversible and irreversible conditions. Other factors can influence each partner, including age, medications, surgical history, exposure to environmental toxins, genetic problems, and systemic diseases. The key purpose for evaluating a male for infertility is to identify his contributing factors, offer treatment for those that are reversible, determine if he is a candidate for assisted reproductive techniques (ART), and provide counseling for irreversible and untreatable conditions. Up to 6% of men evaluated for male infertility will be found to have more serious underlying pathology, such as cancer. This is an additional reason to do a comprehensive evaluation of the male partners of infertile couples so that any significant, underlying medical conditions can be identified and treated.
EndometriosisPrevalence in Unexplained InfertilityEndometriosis AssociationEndometriosis Detection
Open Access
Endometriosis, a systemic ailment, profoundly affects various aspects of life, often eluding detection for over a decade. This leads to enduring issues such as chronic pain, infertility, emotional strain, and potential organ dysfunction. The prolonged absence of diagnosis can contribute to unexplained obstetric challenges and fertility issues, necessitating costly and emotionally taxing treatments. While biopsy remains the gold standard for diagnosis, emerging noninvasive screening methods are gaining prominence. These tests can indicate endometriosis in cases of unexplained infertility, offering valuable insights to patients and physicians managing both obstetric and non-obstetric conditions. In a retrospective cross-sectional study involving 215 patients aged 25 to 45 with unexplained infertility, diagnostic laparoscopy was performed after unsuccessful reproductive technology attempts. Pathology results revealed tissue abnormalities in 98.6% of patients, with 90.7% showing endometriosis, confirmed by the presence of endometrial-like glands and stroma. The study underscores the potential role of endometriosis in unexplained infertility cases. Although the study acknowledges selection bias, a higher than previously reported prevalence suggests evaluating endometriosis in patients who have not responded to previous reproductive interventions may be justified. Early detection holds significance due to associations with ovarian cancer, prolonged fertility drug use, pregnancy complications, and elevated post-delivery stroke risk.
InfertilityNeonatal MortalityART and Socioeconomic StatusInfant Health Outcomes
Open Access
To determine the association between fertility treatment, socioeconomic status (SES), and neonatal and post-neonatal mortality. Retrospective cohort study of all births (19,350,344) and infant deaths from 2014-2018 in the United States. The exposure was mode of conception-spontaneous vs fertility treatment. The outcome was neonatal (<28d), and post-neonatal (28d-1y) mortality. Multivariable logistic models were stratified by SES. The fertility treatment group had statistically significantly higher odds of neonatal mortality (high SES OR 1.59; CI [1.5, 1.68], low SES OR 2.11; CI [1.79, 2.48]) and lower odds of post-neonatal mortality (high SES OR 0.87, CI [0.76, 0.996], low SES OR 0.6, CI [0.38, 0.95]). SES significantly modified the effect of ART/NIFT on neonatal and post-neonatal mortality. Fertility treatment is associated with higher neonatal and lower post-neonatal mortality and SES modifies this effect. Socioeconomic policies and support for vulnerable families may help reduce rates of infant mortality.
AndrologyDNA FragmentationSperm DNA IntegrityOffspring Safety
Open Access
The role of sperm DNA fragmentation index (DFI) in investigating fertility, embryonic development, and pregnancy is of academic interest. However, there is ongoing controversy regarding the impact of DFI on pregnancy outcomes and the safety of offspring in the context of Assisted Reproductive Technology (ART). In this study, we conducted an analysis of clinical data obtained from 6330 patients who underwent in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) at the reproductive medical center of The First People's Hospital of Shangqiu and The Affiliated Hospital of Zhengzhou University. The patients was stratified IVF group and ICSI group, Within each group, patients were further classified into three subgroups. group A (< 15%) included 3123 patients, group B (15-30%) included 561 patients, and group C (≥ 30%) included 46 patients. group A (< 15%) included 1967 patients, group B (15-30%) included 462 patients, and group C (≥ 30%) included 171 patients. Data were collected and subjected to statistical analysis. There were no significant differences in the basic characteristics among the three groups, and the sperm DFI did not significantly affect the fertilization rates, pregnancy rates, stillbirth rates and the number of birth defects. However, the incidences of miscarriage rates in IVF/ICSI groups with DFI > 30% and DFI 15-30% were significantly higher than those in IVF/ICSI groups with DFI < 15%, and the miscarriage rates in ICSI group with DFI > 30% were significantly higher than DFI 15-30% group, the smooth fitting curve shows that there is a positive correlation between miscarriage rates and sperm DFI (OR 1.095; 95% CI 1.068-1.123; P < 0.001). The birth weight of infants in the IVF/ICSI groups with DFI > 30% and DFI 15-30% exhibited a statistically significant decrease compared to those in the IVF/ICSI groups with DFI < 15%. Furthermore, the birth weight of infants in the ICSI group with DFI > 30% was lower than that of the DFI 15-30% group. The smooth fitting curve analysis demonstrates a negative association between birth weight and sperm DFI (OR 0.913; 95% CI 0.890-0.937; P < 0.001). Sperm DFI has an impact on both miscarriage rates and birth weight in assisted reproductive technology. The smooth fitting curve analysis reveals a positive correlation between miscarriage rates and DFI, while a negative correlation is observed between birth weight and DFI.
Intrauterine adhesion (IUA), a major cause of uterine infertility, is pathologically characterized by endometrial fibrosis. Current treatments for IUA have poor efficacy with high recurrence rate, and restoring uterine functions is difficult. We aimed to determine the therapeutic efficacy of photobiomodulation (PBM) therapy on IUA and elucidate its underlying mechanisms. A rat IUA model was established via mechanical injury, and PBM was applied intrauterinely. The uterine structure and function were evaluated using ultrasonography, histology, and fertility tests. PBM therapy induced a thicker, more intact, and less fibrotic endometrium. PBM also partly recovered endometrial receptivity and fertility in IUA rats. A cellular fibrosis model was then established with human endometrial stromal cells (ESCs) cultured in the presence of TGF‐β1. PBM alleviated TGF‐β1‐induced fibrosis and triggered cAMP/PKA/CREB signaling in ESCs. Pretreatment with the inhibitors targeting this pathway weakened PBM's protective efficacy in the IUA rats and ESCs. Therefore, we conclude that PBM improved endometrial fibrosis and fertility via activating cAMP/PKA/CREB signaling in IUA uterus. This study sheds more lights on the efficacy of PBM as a potential treatment for IUA.
InfertilityRegistry and SurveillanceEuropean ART RegistriesData Harmonization
Pregnancy rates after the placement of expanded polytetrafluoroethylene (ePTFE, trade name Gore-Tex®) for adhesion prevention following cystectomy of endometriomas ≥3 cm and excision of endometriosis were analyzed in this pilot study. A prospective cohort study was performed at a single tertiary care center. 56 women qualified for the study and underwent surgery. Expanded polytetrafluoroethylene placement around affected ovaries was self-selected. Inclusion criteria for analysis were pathology-confirmed endometrioma ≥3 cm, no hysterectomy at time of surgery, ≥1 year of postoperative survey completion, and absence of strategies to avoid pregnancy. 18 women in the ePTFE group and 11 women in the control group met inclusion criteria for analysis. 16 of the 18 women in the ePTFE group and 7 of the 11 women in the control group were affected by infertility. Absolute pregnancy rates and cumulative 4-year pregnancy rates, which are based on survival analysis using lifetables and adjust for varying follow-up times, were calculated for all women as well as for women with infertility only. High cumulative 4-year pregnancy rates were observed for women with expanded polytetrafluoroethylene compared to women without (85% vs. 65%, p = 0.69). High cumulative 4-year pregnancy rates for women with infertility prior to surgery were observed for women with expanded polytetrafluoroethylene compared to women without (83% vs. 33%, p = 0.89). There are consistent trends, although not statistically significant, seen in pregnancy rates for women with ePTFE compared to women without, particularly in those with a history of infertility prior to ePTFE use. This is the first study examining how adhesion prevention strategy targeting the adnexa during surgery for endometriosis affects pregnancy rates. The trend towards increased pregnancy rates with expanded polytetrafluoroethylene use, particularly in patients with a history of infertility, is promising and warrants further study with larger groups.
General OB/GYNRegulatory OversightIVF Clinic RegulationFertility Treatment Regulation
Human Fertilisation and Embryology Authority, 2023
# State of the fertility sector 2022/23
Annual publication (1st April 2022 – 31st March 2023)
12th September 2023
[Download the underlying dataset as .xlsx](https://www.hfea.gov.uk/media/2znoxhqv/state-of-the-fertility-sector-2022-2023-underlying-dataset.xlsx "State of the fertility sector 2022-2023 - underlying dataset")
## - [About this report](https://www.hfea.gov.uk/about-us/publications/research-and-data/state-of-the-fertility-sector-2022-2023/#about-this-report)
- [1\. There were 85 inspections undertaken in 2022/23](https://www.hfea.gov.uk/about-us/publications/research-and-data/state-of-the-fertility-sector-2022-2023/#section-1)
- [2\. Critical non-compliances have decreased to 2%](https://www.hfea.gov.uk/about-us/publications/research-and-data/state-of-the-fertility-sector-2022-2023/#section-2)
- [3\. In 2022/23, 107 clinics were licensed by the HFEA to provide fertility treatment](https://www.hfea.gov.uk/about-us/publications/research-and-data/state-of-the-fertility-sector-2022-2023/#section-3)
- [4\. No Grade A incidents since 2020/21, and severe/critical OHSS incidents remained consistent with previous years](https://www.hfea.gov.uk/about-us/publications/research-and-data/state-of-the-fertility-sector-2022-2023/#section-4)
- [5\. Patient complaints decreased in 2022/23](https://www.hfea.gov.uk/about-us/publications/research-and-data/state-of-the-fertility-sector-2022-2023/#section-5)
- [About our data](https://www.hfea.gov.uk/about-us/publications/research-and-data/state-of-the-fertility-sector-2022-2023/#about-our-data)
## The Human Fertilisation and Embryology Authority (HFEA) is the independent regulator of fertility treatment and human embryo research in the United Kingdom (UK). We aim to ensure that everyone receives high quality care in a licenced fertility clinic. We do this by licensing, monitoring, and inspecting fertility clinics and research centres [i](https://www.hfea.go...
PCOSPlatelet-Rich PlasmaPRP Ovarian RejuvenationNovel Approaches
Open Access
The use of platelet-rich plasma (PRP) has become popular as an adjunct to fertility treatment for women with infertility, particularly those with low ovarian reserve and premature ovarian insufficiency. Recent data in a polycystic ovary syndrome (PCOS) animal model demonstrated that intraovarian PRP administration improved folliculogenesis, ovarian antioxidant potential, and serum hormonal imbalance, suggesting that PRP could be considered a novel technique to alleviate PCOS-induced pathogenesis. With injection of PRP into the ovaries, it has been hypothesized that the infusion of cytokines and growth factors may exhibit a local effect that changes the expression of genes important in folliculogenesis and steroidogenesis, decreases inflammation, and partially restores normal ovarian function. This report is the first to present a case of a long-term amenorrheic woman with PCOS who has been trying to conceive, who resumed spontaneous ovulatory cycles, and had improvement in several aspects of her hormonal imbalance following intraovarian PRP administration. The purpose of this case report is to increase awareness regarding the possible benefits of intraovarian PRP injections for women with PCOS. There is a clear need for larger prospective studies to properly elucidate the effect of intraovarian PRP administration on both the reproductive and metabolic dysfunctions observed in women with PCOS.
To present a case of concurrent uterine arteriovenous malformation (AVM) and isthmocele, treated with ethylene vinyl alcohol copolymer (EVAC) embolization of the AVM followed by robotic isthmocele repair.
A stepwise video demonstration with narration.
A tertiary care academic hospital. Patient is a 37-year-old with one previous cesarean section who presented with persistent heavy vaginal bleeding after a dilation and evacuation procedure. Imaging showed evidence of an isthmocele and an iatrogenic uterine AVM secondary to the dilation and evacuation procedure. Both entities are morbid conditions associated with significant operative blood loss. Embolization of the acquired AVM was first performed to stabilize bleeding. In addition, owing to the extensive uterine defect and history of infertility, surgical repair of the isthmocele was recommended. A multidisciplinary approach combining interventional radiology and gynecologic surgery expertise, implementing several strategies 1. Image-guided uterine AVM embolization with EVAC [1] 2. Hysteroscopic identification of isthmocele and residual EVAC in the cavity, with fluorescence transillumination to clearly delineate isthmocele borders 3. Robot-assisted laparoscopic approach for bladder flap creation, as well as retroperitoneal space dissection to skeletonize uterine arteries 4. Transient occlusion of uterine arteries using vascular clamps to minimize operative blood loss given the isthmocele size and its proximity to the left uterine artery 5. Resection of the isthmocele and removal of residual intracavitary EVAC 6. Multilayer, bidirectional hysterotomy closure and vascular Successful multidisciplinary treatment of concurrent uterine AVM and isthmocele. Cesarean delivery at 36 to 37 weeks' gestational age was recommended for future deliveries.
Reproductive EndocrinologyThyroid Autoimmunity and IVFIVF Outcomes and Thyroid FunctionTSH Thresholds in Fertility
Open Access
This study aimed to investigate the impact of thyroid autoantibodies and serum TSH levels on clinical IVF outcomes. This study included 260 Korean women scheduled for their first IVF between 2013 and 2017. Serum levels of thyroid hormone, TSH, and antibody for thyroid peroxidase and thyroglobulin were measured just before the first ovarian stimulation. Clinical pregnancy rate (PR), ongoing PR, and miscarriage rate were analyzed according to thyroid autoimmunity and serum TSH levels. The primary outcome was ongoing PR beyond 12 weeks of gestation. The ongoing PR and miscarriage rates were similar between women with positive (n = 29) and negative autoantibodies (n = 186). In women with subclinical hypothyroidism (serum TSH ≥4.2 μIU/mL), ongoing PR was significantly lower than euthyroid women (22.2%, vs. 44.7%, p = 0.045), but miscarriage rate was similar. The group with serum TSH ≥3.4 μIU/mL showed a significantly lower ongoing PR (23.9% vs. 46.7%, p = 0.005) and significantly higher miscarriage rate (38.9% vs. 14.1%, p = 0.020). In multivariate logistic regression analysis, serum TSH ≥3.4 μIU/mL was an independent unfavorable predictor for ongoing PR (odds ratio 0.375, p = 0.013). Thyroid autoantibodies did not affect clinical IVF outcomes, but women with serum TSH ≥3.4 μIU/mL demonstrated poor IVF outcomes.
Endometriosis is a common finding among women with infertility, and women who are diagnosed with endometriosis are almost twice as likely to experience infertility. Mechanisms by which endometriosis causes infertility remain poorly understood. In this review, we evaluate the current literature on the impact of endometriosis on oocyte and embryo quality. The presence of endometriosis evidently reduces ovarian reserve, oocyte quality, and embryo quality; however, this does not appear to translate to a clear clinical impact. Analysis of data from large assisted reproduction technology registries has shown that women with endometriosis have a lower oocyte yield but no reduction in reproductive outcomes. There is a need for future studies in the form of well-designed randomized controlled trials to further evaluate the role of surgical and medical treatment options in women with endometriosis undergoing assisted conception.
Ovarian rejuvenation is an innovative procedure intended to restore ovarian fertility and development during the climacteric and has been used to enhance fertility in women with premature ovarian insufficiency (POI). This retrospective study was conducted to determine the effects of an intraovarian platelet-rich plasma (PRP) injection on ovarian stimulation outcomes in women referred to an in vitro fertilisation centre. This was a retrospective observational study, and the inclusion criteria included women of reproductive age with at least one ovary with a history of infertility, hormonal abnormalities, an absence of a menstrual cycle, and premature ovarian failure. During the patient's first consultation, a detailed reproductive history was recorded, a pelvic scan for ovarian size was conducted, and hormonal analysis for follicle-stimulating hormone (FSH), anti-Müllerian hormone (AMH), estradiol (E2), and luteinizing hormone (LH) was conducted. In the study, 469 women with a history of infertility, hormonal abnormalities, an absence of a menstrual cycle, and premature ovarian failure had hormonal levels recorded up to four months after treatment, and these were included in the study. The volume of peripheral blood required to prepare 6-8 mL of PRP for administration was 40-60 mL. The initial concentration of platelets in the peripheral blood sample was about 25000/µL, whereas the prepared PRP had a concentration of 900.000/µL. A volume of approximately 2-4 mL per ovary, depending on the ovarian volume, was used for the intraovarian injection. PRP intervention had significant effects on FSH concentration at the α = 0.05 level. Statistically significant increases in normal values of FSH and E2were observed for months three and four after the PRP intervention for all age groups. The results of our observational study revealed that a PRP intraovarian injection is associated with improved ovarian tissue and function. Future randomised clinical trials are needed to shed light on the use of PRP in ovarian rejuvenation before offering it routinely in clinical practice.
To assess the effect of randomization to FertilityFriend.com, a mobile computing fertility-tracking app, on fecundability.
Parallel non-blinded randomized controlled trial nested within the Pregnancy Study Online (PRESTO), a North American preconception cohort. PATIENT(S): Female participants aged 21 to 45 years attempting conception for ≤6 menstrual cycles at enrolment (2013-2019). Randomization (1:1) of 5532 participants to receive a premium Fertility Friend (FF) subscription. MAIN OUTCOME MEASURE(S): Fecundability (per-cycle probability of conception). Participants completed bimonthly follow-up questionnaires until pregnancy or a censoring event, whichever came first. We first performed an intent-to-treat analysis of the effect of FF randomization on fecundability. In secondary analyses, we used a per-protocol approach that accounted for adherence in each trial arm. In both analyses, we used proportional probabilities regression models to estimate fecundability ratios (FR) and 95% confidence intervals (CI) comparing those randomized vs. not randomized and applied inverse probability weights to account for loss-to-follow-up (intent-to-treat and per-protocol analyses) and adherence (per-protocol analyses only). Using life-table methods, 64% of the 2775 participants randomized to FF and 63% of the 2767 participants not randomized to FF conceived during 12 cycles; these respective percentages were each 70% among those with 0-1 cycles of attempt time at enrolment. Of those randomized to FF, 72% were defined as adherent (68% of observed menstrual cycles). In intent-to-treat analyses, there was no appreciable association overall (FR = 0.97; 95% CI, 0.90-1.04) or within strata of pregnancy attempt time at enrolment, age, education, or other characteristics. In per-protocol analyses, we observed little association overall (FR = 1.06; 95% CI, 0.99-1.14), but weak-to-moderate positive associations among participants who had longer attempt times at enrolment (FR = 1.15; 95% CI, 0.98-1.35 for 3-4 cycles; FR = 1.14; 95% CI, 0.87-1.48 for 5-6 cycles), were aged <25 years (FR = 1.29; 95% CI, 1.01-1.66), had ≤12 years of education (FR = 1.32; 95% CI, 0.92-1.89), or were non-users of hormonal contraception within 3 months before enrolment (FR = 1.10; 95% CI, 1.02-1.19). No appreciable associations were observed in intent-to-treat analyses. In secondary per-protocol analyses that accounted for adherence, randomization to FF was associated with slightly greater fecundability among selected subgroups of participants; however, these results are susceptible to unmeasured confounding.
Human Fertilisation and Embryology Authority, 2023
# Fertility treatment 2021: Preliminary UK statistics for IVF and DI treatment, storage, June 2023
[Download the underlying dataset as .xlsx](https://www.hfea.gov.uk/media/5zzh25zw/fertility-treatment-2021-preliminary-trends-and-figures-underlying-dataset.xlsx "Fertility treatment 2021: preliminary trends and figures - underlying dataset")
## - [Main points](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2021-preliminary-trends-and-figures/#main-points)
- [Note on preliminary data](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2021-preliminary-trends-and-figures/#note-on-preliminary-data)
- [Section 1. Average IVF pregnancy rates using fresh embryo transfers increased for all ages](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2021-preliminary-trends-and-figures/#section-1)
- [Section 2. Average IVF pregnancy and birth rates using frozen embryo transfers increased over the past 30 years](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2021-preliminary-trends-and-figures/#section-2)
- [Section 3. Fertility treatments have returned to pre-pandemic levels](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2021-preliminary-trends-and-figures/#section-3)
- [Section 4. Multiple births from IVF at lowest UK average yet of 5%](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2021-preliminary-trends-and-figures/#section-4)
- [Section 5. Egg and embryo storage cycles continued to increase](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2021-preliminary-trends-and-figures/#section-5)
- [Section 6. Average age of IVF patients increased to 36 years](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2021-preliminary-trends-a...
RRM MethodsTeachingProfessional TrainingUnexplained
Open Access
Natural Procreative Technology (NaProTechnology) is a system of management of infertility and other reproductive health issues which requires the application of a woman’s observation and record of key events throughout her menstrual cycle. The study assessed the knowledge, awareness, and perception of NaProTechnology as well as the effect of an educational intervention among pharmacy undergraduate students at University of Nigeria, Nsukka. It was a cross-sectional, questionnaire-based study. The ethical approval was obtained from the research ethics committee of the Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka. At baseline, the knowledge, awareness and perception of the students were assessed. Followed by the administration of an educational video on NaProTechnology. Then a post intervention survey was done to assess the effect of the educational intervention. s
There were 410 and 350 students in the preand post-intervention surveys respectively with relatively equal number of males and females. Majority were between 18 and 29 years old. Less than 5% were married while the highest proportion of the respondents were from 300 level The knowledge, awareness, and positive perception of NaProTechnology among the pharmacy students prior to intervention were poor but improved markedly post intervention (P < 0.001).
A video intervention was effective in improving the short-term knowledge, awareness and positive perception of NaProTechnology among pharmacy students. s
What is already known on this topic?
Natural Procreative Technology (NaProTechnology) is a system of management of infertility based on the observation and record of fertility biomarkers by a woman. s?
The level of knowledge, awareness, and positive perception of NaProTechnology among the pharmacy undergraduates students were poor prior to a video intervention but How this study might affect research, practice or policy?
This study would lead to the public health system approach of informing, educating and communicating NaProTechnology to pharmacy students to achieve long-term effects by using well-designed courses and curriculum implementation.
Objective Complicated grief reactions follow some pregnancy outcomes, like miscarriage, stillbirth, neonatal death, infant death, selective reduction, or termination of pregnancy. Stigma can delay treatment and worsen outcomes. Screening tools such as the Edinburgh Postnatal Depression Scale detect complicated grief poorly, and specific tools for prolonged or complicated grief after a reproductive loss are cumbersome. In this study, a five-item questionnaire to detect complicated grief after reproductive loss of any type was designed and preliminary validated. Methods A questionnaire patterned after the extensively validated Brief Grief Questionnaire (BGQ) was created by a group of physicians and lay advocates to employ non-traumatic but specific language related to grief after miscarriage, stillbirth, neonatal death, infant death, selective reduction, or termination of pregnancy. One hundred and forty women at a large academic center were recruited in person and via social media to validate the questionnaire with well-studied instruments for anxiety (7-item Panic Disorder Severity Scale, PDSS), trauma (22-item Impact of Events Scale), and reproductive grief and depressive symptoms (33-item Perinatal Grief Scale [PGS]). Results The response rate was 74.9%. Of the 140 participants, 18 (12.8%) experienced their loss during high-risk pregnancies, and 65 (46.4%) were recruited via social media. Seventy-one (51%) respondents had a score > 4, a positive screen for the BGQ. On average, women experienced their loss 2 years prior to participation (IQR 1-5 years). Cronbach's alpha was 0.77 (95% CI: 0.69-0.83). The goodness of fit indices of the model met Fornell and Larker criteria (RMSEA = 0.167, CFI = 0.89, SRMR = 0.06). The AVE was 0.42 and the CR 0.78. Conclusions This investigator-created screening tool is internally consistent and meets preliminary criteria for discriminant validity. This tool can be refined prior to testing for sensitivity and specificity in screening for complicated grief after a reproductive loss.
Infertility is a world-wide problem, defined as failure to achieve pregnancy after 12 months of regular unprotected sexual intercourse. There are multiple causes for infertility involving both male and female factors. Fallopian tube occlusion is a common reason for female infertility. The initial attempts to treat proximal obstruction involved the use of a whalebone bougie positioned in the uterine cornua to dilate the proximal tube by Smith as early as 1849. Fluoroscopic fallopian tube recanalization for the treatment of infertility was first described in 1985. Since that time, there have been over 100 papers describing various methods for recanalization of occluded fallopian tubes. Fallopian tube recanalization is a minimally invasive procedure which is performed on an outpatient basis. It should be a first line therapy for patients with proximal occlusion of fallopian tubes.
General OB/GYNPelvic Inflammatory DiseasePID-Related Tubal DamageChlamydia and Gonorrhea
Pelvic inflammatory disease (PID) is defined as an inflammation of the upper genital tract due to an infection in women. The disease affects the uterus, fallopian tubes, and/or ovaries. It is typically an ascending infection, spreading from the lower genital tract. The majority of cases of PID are related to a sexually transmitted infection. The diagnosis of PID is primarily clinical and should be suspected in female patients with lower abdominal or pelvic pain and genital tract tenderness. During the patient’s evaluation, other etiologies of pain, including ectopic pregnancy, should be considered and ruled out. PID is treated with antibiotics to cover the primary pathogens, including Neisseria gonorrhoeae and Chlamydia trachomatis. Short-term complications include tubo-ovarian or pelvic abscess. Long-term complications include ectopic pregnancy, infertility, and chronic pelvic pain. Early diagnosis and treatment can potentially prevent complications.
SurgeryModern Role and EvolutionSurgical vs ARTFertility Preservation
For years, reproductive surgery was the mainstay of reproductive care. With the evolution and ultimate success of in vitro fertilization (IVF), reproductive surgery became an adjuvant therapy, indicated mainly for severe symptoms or to enhance success rates with assisted reproductive technologies. As success rates for IVF have plateaued, and emerging data rekindles the enormous benefits of surgically correcting reproductive pathologies, there is renewed interest among reproductive surgeons in reviving research and surgical expertise in this area. In addition, new instrumentation and surgical techniques to preserve fertility have gained traction and will solidify the need to have skilled reproductive endocrinology and infertility surgeons in our practice.
General OB/GYNChronic Disease PopulationsCystic FibrosisCounseling and Education
As survival and health improve in people with cystic fibrosis (CF), more women with CF (wwCF) are considering their sexual and reproductive health (SRH). This study compared SRH experiences, behaviors, and care utilization of wwCF to the general population and defined CF-impacted considerations and care preferences. We surveyed wwCF aged ≥25 years regarding SRH and compared results to the US National Survey of Family Growth (NSFG;n = 4357) and friend controls(n = 123). We used descriptive statistics and chi-squared/Fisher's exact testing and linear regression for comparisons. A total of 460 wwCF (mean age 36.1 years) completed the survey. WwCF were less likely to report current contraceptive use (43%vs76% NSFG, p<0.001;60% friends, p = 0.005). Nearly 25% of wwCF reported worsened CF symptoms during their menstrual cycles, 50% experienced urinary incontinence, and 80% vulvovaginal candidiasis. WwCF were significantly less likely to be parents (46%vs62% friends, p = 0.015) and to have experienced pregnancy (37%vs78% NSFG, p<0.001;58% friends, p = 0.002). More wwCF required medical assistance to conceive (29%vs12% NSFG, p<0.001 and 5% friends, p<0.001). Eighty-four percent of wwCF view their CF doctor as their main physician and 41% report no primary care provider (vs19% friends; p<0.001). WwCF report suboptimal rates of contraceptive and preconception counseling/care and are less likely to have received HPV vaccination (42%vs55%friends, p = 0.02). Despite desiring SRH conversations with their CF team, <50% report discussing SRH topics. WwCF have significantly different SRH experiences than non-CF peers. They report suboptimal SRH care compared to their preferences highlighting an urgent need to encourage SRH counseling/care in the CF model.
Primary ovarian insufficiency (POI) is a common gynecological disease with serious ramifications including low pregnancy rate and low estrogen symptoms. Traditional Chinese medicine is regarded as an effective treatment for POI. However, the therapeutic mechanism of it is unclear. In this study, a mouse model of primary ovarian insufficiency was established by intraperitoneal injection of cyclophosphamide (CTX) and He's Yang Chao Recipe (HSYC) concentrate was used for intragastric administration. Serum hormone levels (Anti-Müllerian Hormone, Estradiol, Progesterone, Luteinizing Hormone and Follicle Stimulating Hormone) and Oxidative Stress (OS) related products, superoxide dismutase (SOD), GSH-Px, and malondialdehyde (MDA) were measured by enzyme-linked immunosorbent assay. Pathological changes in ovarian tissue were evaluated by hematoxylin and eosin staining, and flow cytometry was used to determine reactive oxygen species content and mitochondrial membrane potential levels in granulosa cells. Mitochondrial distribution and morphology were investigated using immunofluorescence staining. The level of mitophagy was evaluated by LC3 immunofluorescence staining and autophagosome counts using electron microscopy. Western blotting and qPCR were used to detect the expression of proteins and genes related to mitophagy and the NLRP3 inflammasome. After HSYC treatment, the ovarian damage was milder than in the CTX group. Compared with the CTX group; SOD, GSH-Px, and the total antioxidant capacity were significantly increased, while MDA and ROS were decreased in the HSYC treatment groups. Furthermore, mitochondrial distribution and membrane potential levels were improved after HSYC treatment compared to the CTX group. After the HSYC treatment, the LC3 fluorescent intensity and autophagosome counts were decreased. Similarly, mitophagy related markers PINK1, Parkin, LC3, and Beclin1 were decreased, while p62 was significantly increased, compared with the CTX groups. The mRNA and protein expression of NLRP3 inflammasome, NLRP3, caspase-1, GSDMD, IL-18, and IL-1β were significantly decreased in the HSYC treatment groups. This is the first study in molecular mechanisms underlying HSYC against granulosa cell injury in POI. HSYC protects ovaries from CTX-induced ovarian damage and oxidative stress. HSYC enhanced ovarian function in mice with primary ovarian insufficiency by inhibiting PINK1-Parkin mitophagy and NLRP3 inflammasome activation.
The number of sperm that reaches the oocytes in mammalian species is limited. In mice, 8-10 oocytes are ovulated, a similar number of sperm reaches the oocytes, and nearly all oocytes are fertilized via natural mating. Meanwhile, our improved superovulation technique (ultrasuperovulation: administration of inhibin antiserum and equine chorionic gonadotropin [IASe]) produced 100 oocytes from a single female C57BL/6 mouse but resulted in only approximately 20 fertilized oocytes via mating. We hypothesized that sperm shortage in the ampulla might cause this low fertilization rate. Mice were mated in the proestrus stage or after hormone injection, but ovulation timing was not considered. In clinical application, the rhythm method supports fertilization by testing the ovulation period and synchronizing the ovulation and copulation timings. Therefore, this study examined the effects of ovulation and copulation timings on in vivo fertilization in female mice with IASe. Synchronization of the ovulation and copulation timings increased fertilization efficiency in female mice with ultrasuperovulation. The number of embryos obtained post ovulation was three times higher than that obtained pre ovulation. This study suggests that synchronized ovulation and copulation timings improve the efficiency of in vivo fertilization in IASe-treated female mice. This technique can be used to produce genetically modified mice and develop technologies for infertility treatment.
Dominguez JA et al., 2023·Ultrasound Obstet Gynecol
The purpose of this State-of-the-Art Review was to provide a strategic analysis, in terms of strengths, weaknesses, opportunities and threats (SWOT analysis), of the current evidence regarding the management of uterine isthmocele (Cesarean scar defect). Strengths include the fact that isthmocele can be diagnosed on two-dimensional transvaginal ultrasound, and that surgical repair may restore natural fertility potential and prevent secondary infertility, as well as reduce the risk of miscarriage and other obstetric complications. However, there is a lack of high-quality evidence regarding the best diagnostic method and criteria, as well as the potential benefits of surgical repair with respect to fertility. There is a need for experienced surgeons skilled in the various isthmocele repair techniques. Isthmocele repair does not prevent the need for Cesarean delivery in subsequent pregnancies. There is increasing awareness regarding the accuracy of transvaginal ultrasound in diagnosing isthmocele. This may lead to surgical correction and prevention of obstetric and perinatal complications in subsequent pregnancies, including Cesarean scar pregnancy. Regarding threats, the existence of different surgical techniques means that there is a risk of selecting an inadequate approach if the type of isthmocele and the patient's characteristics are not considered. There is a risk of overtreatment when asymptomatic defects are repaired surgically. Finally, there is an absence of cost-effectiveness analyses to justify routine repair. Thus, while there are many data suggesting that isthmocele has an adverse effect on both natural fertility and the outcome of assisted reproduction techniques, high-quality evidence to support surgical isthmocele repair in all asymptomatic patients desiring future fertility are lacking. There is increasing agreement to recommend hysteroscopic repair of isthmocele as a first-line approach as long as the residual myometrial thickness is at least 2.5-3.0 mm.
We sought to better understand factors associated with ovarian aging in women with HIV (WWH).
HIV has been associated with diminished fertility, younger age at menopause, and shorter leukocyte telomere length (LTL), a marker of cellular aging. We herein examine cross-sectional and longitudinal associations between LTL, anti-Müllerian hormone (AMH), and HIV. We included WWH and HIV-negative women 12-50 years of age in the CARMA cohort with one or more study visit(s). LTL and AMH were measured by qPCR and ELISA, respectively. Women were analyzed in peak reproductive (<35 years) vs. late reproductive (≥35 years) life phases. Using multivariable mixed-effect linear or logistic regressions, we assessed factors associated with AMH and ΔAMH/year while adjusting for relevant confounders. WWH had shorter LTL and lower AMH levels compared to HIV-negative controls despite being of similar age. After adjusting for relevant factors, HIV was associated with 20% lower AMH levels in women under 35 years of age and shorter LTL was associated with AMH levels below 2 ng/ml among women aged 35 years or older. Longitudinally, ΔAMH/year was largely related to initial AMH level among older women, and to age in younger women. Factors associated with AMH change across women's reproductive lifespan. Lower AMH among peak reproductive aged WWH suggests that HIV may have an initial detrimental effect on ovarian reserve, an observation that may warrant counseling around pregnancy planning. In women aged 35 years or older, the association between shorter LTL and lower AMH suggests that the immune and reproductive aging connections are more important in this age group.
InfertilityIVF Outcomes by EthnicityRacial and Ethnic DisparitiesPopulation-Level Data
Human Fertilisation and Embryology Authority, 2023
# Ethnic diversity in fertility treatment 2021
Preliminary UK ethnicity statistics for IVF and DI treatment, storage, December 2023
[Download the underlying dataset as .xlsx](https://www.hfea.gov.uk/media/5rgnpqsr/ethnic-diversity-in-fertility-treatment-2021-underlying-dataset.xlsx "Ethnic diversity in fertility treatment 2021 - underlying dataset")
## - [Main points](https://www.hfea.gov.uk/about-us/publications/research-and-data/ethnic-diversity-in-fertility-treatment-2021/#main-points)
- [Introduction](https://www.hfea.gov.uk/about-us/publications/research-and-data/ethnic-diversity-in-fertility-treatment-2021/#introduction)
- [Note on preliminary and ethnicity data](https://www.hfea.gov.uk/about-us/publications/research-and-data/ethnic-diversity-in-fertility-treatment-2021/#note-on-preliminary-and-ethnicity-data)
- [Section 1. IVF birth rates increased across all ethnic groups, though disparities remain](https://www.hfea.gov.uk/about-us/publications/research-and-data/ethnic-diversity-in-fertility-treatment-2021/#section-1)
- [Section 2. Black patients started fertility treatment later than other ethnic groups](https://www.hfea.gov.uk/about-us/publications/research-and-data/ethnic-diversity-in-fertility-treatment-2021/#section-2)
- [Section 3. DI predominantly used by White patients](https://www.hfea.gov.uk/about-us/publications/research-and-data/ethnic-diversity-in-fertility-treatment-2021/#section-3)
- [Section 4. Imported donor sperm and eggs vary by ethnicity](https://www.hfea.gov.uk/about-us/publications/research-and-data/ethnic-diversity-in-fertility-treatment-2021/#section-4)
- [Section 5. Multiple birth rate decreased in all ethnic groups, but remain highest for Black patients](https://www.hfea.gov.uk/about-us/publications/research-and-data/ethnic-diversity-in-fertility-treatment-2021/#section-5)
- [Section 6. Use of egg storage was similar across all ethnic groups](https://www.hfea.gov.uk/about-us/publications/res...
Is sequential letrozole/human menopausal gonadotrophin (HMG) superior to letrozole alone in ovulation induction and pregnancy promotion among infertile women with polycystic ovary syndrome (PCOS)?
This open-label randomized controlled trial comparing sequential letrozole/HMG and letrozole alone included 174 participants enrolled from August 2019 to January 2020 at the Union Hospital of Tongji Medical College, Huazhong University of Science and Technology. Infertile women aged between 18 and 40 years who met Rotterdam criteria for PCOS and without other known causes of infertility were selected for this study. Patients were randomly assigned at a 1:1 ratio to receive 2.5 mg letrozole on cycle days 3-7 (n = 87) or 2.5 mg letrozole on cycle days 3-7 with a sequential injection of 75 IU HMG on cycle days 8-10 for one treatment cycle (n = 87). The pregnancy outcome was recorded after one treatment cycle.
Women receiving sequential treatment achieved a significantly higher ovulation rate than those in the letrozole group (90.8% versus 70.1%, P = 0.001) and the live birth rate of the sequential group was significantly higher than that of the letrozole protocol (23.0% versus 10.3%, P = 0.025); there was no statistical variation with respect to adverse events. The data suggest that the sequential letrozole/HMG protocol may be superior to the letrozole alone protocol in terms of ovulation induction and pregnancy promotion among infertile women with PCOS.
Endocrine disorders negatively influence the ovarian function, and increasing incidence of endocrine diseases with age may have further negative effects on pregnancy rate. Prospective cohort study of 231 consecutively enrolled patients underwent IVF treatment. In patients with known endocrine disorders, the laboratory parameters were corrected before IVF treatment. One hundred sixty one patients (69.7%) had at least one known and treated endocrine disorder (study group), and 70 patients were endocrine negative (control group). Endocrine disorders diagnosed were thyroid disorders (32.5%), diminished ovarian reserve (23.8%), insulin resistance (22.5%), PCOS (15.2%), hyperprolactinaemia (13.4%), obesity (12.1%), hypogonadotropic hypogonadism (0.8%) and congenital adrenal hyperplasia (0.2%). Before the IVF treatment, systematic endocrine laboratory examinations were performed in all patients. Higher age, BMI and FSH were found in the study group, while AMH level was lower. There were no differences in LH, E2, prolactin, TSH, FT3, FT4, TT, DHEAS, androstendione, 17-OHP and SHBG level between the study and control groups. The study group had higher baseline glucose, baseline insulin, 120-min glucose and 120-min insulin level after oral glucose tolerance test. With no difference in the IVF cycles performed, pregnancy rate was lower in the study group (61.43% vs. 34.16%; p = 0.003), and this difference (p = 0.0151) remained in age-corrected rates, as well. The analyses were also performed in individual endocrinology groups. The prevalence of endocrine disorders is high in females participating in IVF programs, and they are often accompanying each other. Even after proper correction, the presence of the endocrine disorder negatively influences the pregnancy rate in IVF treatment.
With the increasing offer of fertility treatment by a largely privatised sector, which has involved the proliferation of treatment add-ons lacking evidence of effectiveness, In-Vitro Fertilisation (IVF) patients are expected to make informed choices on what to include in their treatment. Drawing on interviews with 51 individuals undergoing fertility treatment, this article explores patients' approaches to medical evidence interpretation and its role in their decisions to include add-ons. While most IVF patients share understandings of what counts as medical evidence, our findings show how their approaches also differ. Our analysis focuses on how patients negotiate the notion of medical evidence and its relation to other forms of experience or knowledge. We present four different (1) delegating evaluations of evidence to experts; (2) critically assessing available evidence; (3) acknowledging the process of making evidence; and (4) contextualising evidence in their lived experience of infertility. We suggest that patients' choice to include add-ons is not due to a lack of information on or understanding of evidence, but rather should be interpreted as part of the complexity of patients' experiences of infertility.
This systematic review and meta-analysis aims to evaluate the impact of chronic endometritis (CE) and its therapy on in vitro fertilization (IVF) outcome. Additionally, we aim to investigate whether various degrees of CE severity may exert a different effect on IVF outcome. Ongoing-pregnancy rate/live-birth-rate (OPR/LBR), clinical-pregnancy rate (CPR), and miscarriage rate (MR) were calculated. A total number of 4145 patients (from ten studies) were included. Women with CE had lower OPR/LBR (OR 1.97, p = 0.02) and CPR (OR 2.28, p = 0.002) compared to those without CE. CE cure increased OPR/LBR (OR 5.33, p < 0.0001) and CPR (OR 3.64, p = 0.0001). IVF outcome was comparable between women with cured CE and those without CE (OPR/LBR, p = ns). Women with severe CE had lower OPR/LBR (OR 0.43, p = 0.003) and CPR (OR 0.40, p = 0.0007) compared to those mild CE. Mild CE showed no influence on the IVF outcome as compared to women without CE (OPR/LBR, p = ns). Based on this data analysis, CE significantly reduces OPR/LBR and CPR in women undergoing IVF. Importantly, CE resolution after antibiotic therapy may improves IVF outcome, leading to similar OPR/LBR and CPR as compared to unaffected patients. The negative effects of CE on IVF outcome may be restricted to severe disease, whereas mild CE may have no influence on IVF success.
InfertilityNatural Cycle ManagementReceptor Up-RegulationProgesterone Support
Open Access
Many infertility specialists advise women with diminished oocyte reserve (DOR) that their remaining oocytes probably are of poor quality similar to women of advanced reproductive age. There have been studies, especially employing in vitro fertilization-embryo transfer (IVF-ET), showing very poor live delivered pregnancy rates despite the transfer of morphologically normal embryos in women even with mild DOR. However, other data suggests that the low pregnancy rates are related to the use of high dosages of follicle stimulating hormone (FSH) drugs which down-regulate some key FSH dependent enzymes, cytokines, or proteins required for proper embryo implantation. Some studies have shown that techniques that favor FSH receptor up-regulation, rather than down-regulation, can provide the chance of live delivery 80% as well in women ≤ 35 with DOR, 70% for women 36-39, and 50% for women 40-42. Though some infertility specialists will encourage women whose only infertility issue is DOR, who reject the initial suggestion to consider donor oocytes, to proceed immediately with IVF-ET to maximize success, pregnancies are quite possible with natural conception. Thus, it seems imprudent to make couples undergo the financial burden of IVF-ET in the absence of a significant tubal or male factor problem. Not only have live deliveries occurred in women with DOR, using the principle described to achieve a mature dominant follicle followed by proper luteal phase support, with serum FSH levels over 100 mIU/mL, but also serum Anti-Mullerian Hormone (AMH) levels that were undetectable. This even applies to women in overt menopause where FSH up-regulation was achieved by negative feedback to the pituitary using ethinyl estradiol inhibiting FSH release, or down-regulation of hypothalamic-pituitary stimulation of FSH production by using gonadotropin releasing hormone agonists or antagonists.
What is the association between perceived stress during peri-conception and early pregnancy and pregnancy loss among women who have experienced a prior pregnancy loss? Daily perceived stress above the median is associated with over a 2-fold risk of early pregnancy loss among women who have experienced a prior loss. WHAT IS KNOWN ALREADY? Women who have experienced a pregnancy loss may be more vulnerable to stress while trying to become pregnant again. While prior research has indicated a link between psychological stress and clinically confirmed miscarriages, research is lacking among a pre-conceptional cohort followed prospectively for the effects of perceived stress during early critical windows of pregnancy establishment on risk of both hCG-detected pregnancy losses and confirmed losses, while considering important time-varying confounders. STUDY DESIGN, SIZE, Secondary data analysis of the EAGeR trial (2007-2011) among women with an hCG-detected pregnancy (n = 797 women). PARTICIPANTS/MATERIALS, SETTING, Women from four US clinical centers enrolled pre-conceptionally and were followed ≤6 cycles while attempting pregnancy and, as applicable, throughout pregnancy. Perceived stress was captured via daily diaries and end-of-month questionnaires. Main outcome measures include hCG-detected and clinically recognized pregnancy losses. MAIN Among women who had an hCG-confirmed pregnancy, 188 pregnancies (23.6%) ended in loss. Women with high (>50th percentile) versus low (≤50th percentile) peri-implantation or early pregnancy weekly perceived stress had an elevated risk of experiencing any pregnancy loss (hazard ratio (HR): 1.69, 95% CI: 1.13, 2.54) or clinical loss (HR: 1.58, 95% CI: 0.96, 2.60), with higher risks observed for women experiencing an hCG-detected loss (HR: 2.16, 95% CI: 1.04, 4.46). Models accounted for women's age, BMI, employment, marital status, income, education, race, parity, prior losses, exercise and time-varying nausea/vomiting, caffeine, alcohol and smoking. LIMITATIONS, We were limited in our ability to clearly identify the mechanisms of stress on pregnancy loss due to our sole reliance on self-reported perceived stress, and the lack of biomarkers of different pathways of stress. This study provides new insight on early pregnancy perceived stress and risk of pregnancy loss, most notably hCG-detected losses, among women with a history of a prior loss. Our study is an improvement over past studies in its ability to account for time-varying early pregnancy symptoms, such as nausea/vomiting, and lifestyle factors, such as caffeine, alcohol and smoking, which are also risk factors for psychological stress and pregnancy loss. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (Contract HHSN267200603423, HHSN267200603424, HHSN267200603426, HHSN275201300023I). Additionally, K.C.S. was supported by the National Institute on Aging of the National Institutes of Health under Award Number K01AG058781. The authors have no conflicts of interest to disclose. #NCT00467363.
Zhao Y et al., 2022·Evid Based Complement Alternat Med
To evaluate the effects of He's Yangchao Recipe (HSYC) on ameliorating ovarian oxidative stress of aging mice under consecutive superovulation. An 8-month-old C57BL/6 female mouse was chosen to establish an aging model under ovarian hyperstimulation. Mice were randomly R1 as the control group, R4 as the model group, NR4 with N-acetyl-L-cysteine (NAC) administration, and TR4 with HSYC administration. Oocyte collection, in vitro fertilization, and embryo culture were performed. The serum hormone levels were measured by enzyme-linked immunosorbent assays (ELISA); the reactive oxygen species (ROS) level of oocytes, the number of growing follicles, corpus luteum, ovulated oocytes, and developing embryos at each stage, along with the proportions of fragmented oocytes and abnormal mitochondria in granulosa cells (GCs) and the apoptosis rate of GCs were calculated; the mRNA and protein levels of JNK, P53, BAX were detected by real-time PCR and the Simple Western System. HSYC enhanced estradiol, progesterone, and inhibin-B levels and increased growing follicle and corpus luteum and ovulated egg counts compared to the R4 group (P < 0.05), whereas it decreased the proportions of fragmented oocytes (P < 0.01); Meanwhile, embryos from mice subjected to four superovulation cycles with HSYC treated had a higher hatching potential. The ROS level of oocytes is downregulated by HSYC (P < 0.01) and the percentage of abnormal mitochondrial in ovaries of the TR4 group was also significantly declined compared to the R4 group (P < 0.05); the most TUNEL-positive cells proportion was detected in the R4 group; nevertheless, HSYC effectively attenuated this detrimental effect (P < 0.05). The mRNA and protein expressions of JNK and P53 in ovary tissues were reduced in the TR4 group while these genes were upregulated by repeated superovulation (P < 0.05). HSYC exerted promising effects on promoting the diminished ovarian reserve and decreased oocyte quality induced by both aging and consecutive ovarian superovulation, potentially via the ROS/JNK/p53 pathway.
Ranisavljevic N et al., 2022·Front Endocrinol (Lausanne)
Progesterone plays a key role in implantation. Several studies reported that lower luteal progesterone levels might be related to decreased chances of pregnancy. This systematic review was conducted using appropriate key words, on MEDLINE, EMBASE, and the Cochrane Library, from 1990 up to March 2021 to assess if luteal serum progesterone levels are associated with ongoing pregnancy (OP) and live birth (LB) rates (primary outcomes) and miscarriage rate (secondary outcome), according to the number of corpora lutea (CLs). Overall 2,632 non-duplicate records were identified, of which 32 relevant studies were available for quantitative analysis. In artificial cycles with no CL, OP and LB rates were significantly decreased when the luteal progesterone level falls below a certain threshold (risk ratio [RR] 0.72; 95% confidence interval [CI] 0.62-0.84 and 0.73; 95% CI 0.59-0.90, respectively), while the miscarriage rate was increased (RR 1.48; 95% CI 1.17-1.86). In stimulated cycles with several CLs, the mean luteal progesterone level in the no OP and no LB groups was significantly lower than in the OP and LB groups [difference in means 68.8 (95% CI 45.6-92.0) and 272.4 (95% CI 10.8-533.9), ng/ml, respectively]. Monitoring luteal serum progesterone levels could help in individualizing progesterone administration to enhance OP and LB rates, especially in cycles without corpus luteum. //www.crd.york.ac.uk/prospero/display_record.php?RecordID=139019, identifier 139019.
To analyze outcomes and postoperative complications in patients undergoing robot-assisted isthmocele repair. This retrospective cohort study included 33 patients who had robot-assisted laparoscopic surgical management of an isthmocele between September 2013 and August 2020 in two French university hospitals. All charts were reviewed to identify patient characteristics, preoperative and postoperative anatomical findings, complications, and postoperative fertility and symptoms. Patients who had undergone this procedure were asked to complete a telephone questionnaire about their treatment satisfaction and symptoms. The isthmocele was discovered most often as a result of subfertility (57.6%), but also ectopic pregnancy (18.2%), pelvic pain (15.2%), and postmenstrual bleeding (9.1%). Robot-assisted repair of the isthmocele significantly improved myometrial thickness (from 1.55 mm before surgery to 4.26 mm after surgery [mean difference 2.71; 95% confidence interval, 1.91-3.51], P = 0.0005). Among 20 patients who still desired a child after surgery, 15 became pregnant and 14 had full-term live births. Among the nine patients who had surgery for disabling symptoms, five had no persistent symptoms, three reported global improvement, and one had the same gynecologic discomfort. Seventeen patients agreed to complete the questionnaires (51.5%), and all stated that they would choose to have this surgery again. Robot-assisted repair of an isthmocele is a viable minimally invasive procedure.
Coccia ME et al., 2022·Int J Environ Res Public Health
Laparoscopic surgery was originally considered the gold standard in the treatment of endometriosis-related infertility. Assisted reproductive technology (ART) was indicated as second-line treatment or in the case of male factor. The combined approach of surgery followed by ART proved to offer higher chances of pregnancy in infertile women with endometriosis. However, it was highlighted how pelvic surgery for endometriosis, especially in cases of ovarian endometriomas, could cause iatrogenic damage due to ovarian reserve loss, adhesion formation (scarring), and ischemic damage. Furthermore, in the last few years, the trend to delay the first childbirth, recent technological advances in ultrasound diagnosis, and technological progress in clinical and laboratory aspects of ART have certainly influenced the approach to infertility and endometriosis with, ART assuming a more relevant role. Management of endometriosis should take into account that the disease is chronic and involves the reproductive system. Consequently, treatment and counselling should aim to preserve the chances of pregnancy for the patient, even if it is not associated with infertility. This review will analyse the evolution of the management of infertility associated with endometriosis and propose an algorithm for treatment decision-making based on the most recent acquisitions.
Male infertility is an increasing and serious medical concern, though the mechanism remains poorly understood. Impaired male reproductive function affects approximately half of infertile couples worldwide. Multiple factors related to the environment, genetics, age, and comorbidities have been associated with impaired sperm function. Present-day clinicians rely primarily on standard semen analysis to diagnose male reproductive potential and develop treatment strategies. To address sperm quality assessment bias and enhance analysis accuracy, the World Health Organization (WHO) has recommended standardized sperm testing; however, conventional diagnostic and therapeutic options for male infertility, including physical examination and semen standard analysis, remain ineffective in relieving the associated social burden. Instead, assisted reproductive techniques are becoming the primary therapeutic approach. In the post-genomic era, multiomics technologies that deeply interrogate the genome, transcriptome, proteome, and/or the epigenome, even at single-cell level, besides the breakthroughs in robotic surgery, stem cell therapy, and big data, offer promises towards solving semen quality deterioration and male factor infertility. This review highlights the complex etiology of male infertility, especially the roles of lifestyle and environmental factors, and discusses advanced technologies/methodologies used in characterizing its pathophysiology. A comprehensive combination of these innovative approaches in a global and multi-centric setting and fulfilling the suitable ethical consent could ensure optimal reproductive and developmental outcomes. These combinatorial approaches should allow for the development of diagnostic markers, molecular stratification classes, and personalized treatment strategies. Since lifestyle choices and environmental factors influence male fertility, their integration in any comprehensive approach is required for safe, proactive, cost-effective, and noninvasive precision male infertility theranostics that are affordable, accessible, and facilitate couples realizing their procreation dream.
Streit-Ciećkiewicz D et al., 2022·Int J Environ Res Public Health
Regenerative medicine combines elements of tissue engineering and molecular biology aiming to support the regeneration and repair processes of damaged tissues, cells and organs. The most commonly used preparation in regenerative medicine is platelet rich plasma (PRP) containing numerous growth factors present in platelet granularities. This therapy is increasingly used in various fields of medicine. This article is a review of literature on the use of PRP in gynecology and obstetrics. There is no doubt that the released growth factors and proteins have a beneficial effect on wound healing and regeneration processes. So far, its widest application is in reproductive medicine, especially in cases of thin endometrium, Asherman's syndrome, or premature ovarian failure (POF) but also in wound healing and lower urinary tract symptoms (LUTS), such as urinary incontinence or recurrent genitourinary fistula auxiliary treatment. Further research is, however, needed to confirm the effectiveness and the possibility of its application in many other disorders.
de Ligny W et al., 2022·Cochrane Database Syst Rev
The inability to have children affects 10% to 15% of couples worldwide. A male factor is estimated to account for up to half of the infertility cases with between 25% to 87% of male subfertility considered to be due to the effect of oxidative stress. Oral supplementation with antioxidants is thought to improve sperm quality by reducing oxidative damage. Antioxidants are widely available and inexpensive when compared to other fertility treatments, however most antioxidants are uncontrolled by regulation and the evidence for their effectiveness is uncertain. We compared the benefits and risks of different antioxidants used for male subfertility. To evaluate the effectiveness and safety of supplementary oral antioxidants in subfertile men. The Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, AMED, and two trial registers were searched on 15 February 2021, together with reference checking and contact with experts in the field to identify additional trials.
We included randomised controlled trials (RCTs) that compared any type, dose or combination of oral antioxidant supplement with placebo, no treatment, or treatment with another antioxidant, among subfertile men of a couple attending a reproductive clinic. We excluded studies comparing antioxidants with fertility drugs alone and studies that included men with idiopathic infertility and normal semen parameters or fertile men attending a fertility clinic because of female partner infertility.
We used standard methodological procedures recommended by Cochrane. The primary review outcome was live birth. Clinical pregnancy, adverse events and sperm parameters were secondary outcomes. We included 90 studies with a total population of 10,303 subfertile men, aged between 18 and 65 years, part of a couple who had been referred to a fertility clinic and some of whom were undergoing medically assisted reproduction (MAR). Investigators compared and combined 20 different oral antioxidants. The evidence was of 'low' to 'very low' the main limitation was that out of the 67 included studies in the meta-analysis only 20 studies reported clinical pregnancy, and of those 12 reported on live birth. The evidence is current up to February 2021. antioxidants may lead to increased live birth rates (odds ratio (OR) 1.43, 95% confidence interval (CI) 1.07 to 1.91, P = 0.02, 12 RCTs, 1283 men, I(2) = 44%, very low-certainty evidence). Results in the studies contributing to the analysis of live birth rate suggest that if the baseline chance of live birth following placebo or no treatment is assumed to be 16%, the chance following the use of antioxidants is estimated to be between 17% and 27%. However, this result was based on only 246 live births from 1283 couples in 12 small or medium-sized studies. When studies at high risk of bias were removed from the analysis, there was no evidence of increased live birth (Peto OR 1.22, 95% CI 0.85 to 1.75, 827 men, 8 RCTs, P = 0.27, I(2) = 32%). antioxidants may lead to increased clinical pregnancy rates (OR 1.89, 95% CI 1.45 to 2.47, P < 0.00001, 20 RCTs, 1706 men, I(2) = 3%, low-certainty evidence) compared with placebo or no treatment. This suggests that, in the studies contributing to the analysis of clinical pregnancy, if the baseline chance of clinical pregnancy following placebo or no treatment is assumed to be 15%, the chance following the use of antioxidants is estimated to be between 20% and 30%. This result was based on 327 clinical pregnancies from 1706 couples in 20 small studies. only six studies reported on this outcome and the event rate was very low. No evidence of a difference in miscarriage rate was found between the antioxidant and placebo or no treatment group (OR 1.46, 95% CI 0.75 to 2.83, P = 0.27, 6 RCTs, 664 men, I(2) = 35%, very low-certainty evidence). The findings suggest that in a population of subfertile couples, with male factor infertility, with an expected miscarriage rate of 5%, the risk of miscarriage following the use of an antioxidant would be between 4% and 13%. antioxidants may lead to an increase in mild gastrointestinal discomfort when compared with placebo or no treatment (OR 2.70, 95% CI 1.46 to 4.99, P = 0.002, 16 RCTs, 1355 men, I(2) = 40%, low-certainty evidence). This suggests that if the chance of gastrointestinal discomfort following placebo or no treatment is assumed to be 2%, the chance following the use of antioxidants is estimated to be between 2% and 7%. However, this result was based on a low event rate of 46 out of 1355 men in 16 small or medium-sized studies, and the certainty of the evidence was rated low and heterogeneity was high. We were unable to draw conclusions from the antioxidant versus antioxidant comparison as insufficient studies compared the same interventions. AUTHORS' In this review, there is very low-certainty evidence from 12 small or medium-sized randomised controlled trials suggesting that antioxidant supplementation in subfertile males may improve live birth rates for couples attending fertility clinics. Low-certainty evidence suggests that clinical pregnancy rates may increase. There is no evidence of increased risk of miscarriage, however antioxidants may give more mild gastrointestinal discomfort, based on very low-certainty evidence. Subfertile couples should be advised that overall, the current evidence is inconclusive based on serious risk of bias due to poor reporting of methods of randomisation, failure to report on the clinical outcomes live birth rate and clinical pregnancy, often unclear or even high attrition, and also imprecision due to often low event rates and small overall sample sizes. Further large well-designed randomised placebo-controlled trials studying infertile men and reporting on pregnancy and live births are still required to clarify the exact role of antioxidants.
Caffeine is the most frequently used psychoactive substance in the United States and >90% of reproductive-age women report some amount of intake daily. Despite biological plausibility, previous studies on caffeine and fecundability report conflicting results. Importantly, prior studies measured caffeine exposure exclusively by self-report, which is subject to measurement error and does not account for factors that influence caffeine metabolism. Our objective was to examine associations between preconception serum caffeine metabolites, caffeinated beverage intake, and fecundability. Participants included 1228 women aged 18-40 y with a history of 1-2 pregnancy losses in the EAGeR (Effects of Aspirin in Gestation and Reproduction) trial. We prospectively evaluated associations of preconception caffeine metabolites (i.e., caffeine, paraxanthine, and theobromine) measured from 1191 serum samples untimed to a specific time of day, self-reported usual caffeinated beverage intakes at baseline, and time-varying cycle-average caffeinated beverage intake, with fecundability. Using Cox proportional hazards models, we estimated fecundability odds ratios (FORs) and 95% CIs according to each metabolite. Follow-up was complete for 89% (n = 1088) of participants. At baseline, 85%, 73%, and 91% of women had detectable serum caffeine, paraxanthine, and theobromine, respectively. A total of 797 women became pregnant during ≤6 cycles of preconception follow-up. After adjusting for potential confounders, neither serum caffeine [tertile (T)3 compared with T1 0.87; 95% CI: 0.71, 1.08], paraxanthine (T3 compared with T1 0.92; 95% CI: 0.75, 1.14), nor theobromine (T3 compared with T1 1.15; 95% CI: 0.95, 1.40) were associated with fecundability. Baseline intake of total caffeinated beverages was not associated with fecundability (>3 compared with 0 0.99; 95% CI: 0.74, 1.34), nor was caffeinated coffee (>2 compared with 0 0.93; 95% CI: 0.45, 1.92) or caffeinated soda (>2 0.92; 95% CI: 0.71, 1.20). Our findings are reassuring that caffeine exposure from usual low to moderate caffeinated beverage intake likely does not influence fecundability.This trial was registered at clinicaltrials.gov as NCT00467363.
In vitro fertilization (IVF) births contribute to a considerable proportion of preterm birth (PTB) each year. However, there is no formal surveillance of adverse perinatal outcomes for less invasive fertility treatments. The study objective was to describe associations between fertility treatment (in vitro fertilization, intrauterine insemination, usually with ovulation drugs (IUI), or ovulation drugs alone) and preterm birth, compared to no treatment in subfertile women. The Fertility Experiences Study (FES) is a retrospective cohort study conducted at the University of Utah between April 2010 and September 2012. Women with a history of primary subfertility self-reported treatment data via survey and interviews. Participant data were linked to birth certificates and fetal death records to asses for perinatal outcomes, particularly preterm birth. A total 487 birth certificates and 3 fetal death records were linked as first births for study participants who completed questionnaires. Among linked births, 19% had a PTB. After adjustment for maternal age, paternal age, maternal education, annual income, religious affiliation, female or male fertility diagnosis, and duration of subfertility, the odds ratios and 95% confidence intervals (CI) for PTB were 2.17 (CI 0.99, 4.75) for births conceived using ovulation drugs, 3.17 (CI 1.4, 7.19) for neonates conceived using IUI and 4.24 (CI 2.05, 8.77) for neonates conceived by IVF, compared to women with subfertility who used no treatment during the month of conception. A reported diagnosis of female factor infertility increased the adjusted odds of having a PTB 2.99 (CI 1.5, 5.97). Duration of pregnancy attempt was not independently associated with PTB. In restricting analyses to singleton gestation, odds ratios were not significant for any type of treatment. IVF, IUI, and ovulation drugs were all associated with a higher incidence of preterm birth and low birth weight, predominantly related to multiple gestation births.
The aim of the current study was to characterize ovarian reserve parameters and IVF outcomes in women with a history of poor ovarian response (POR) treated with intraovarian injection of autologous platelet rich plasma (PRP). Reproductive age women (N=510; age range 30-45yo) diagnosed with POR based on Poseidon criteria were included in the study. PRP treatment resulted in higher AFC, higher serum AMH, lower serum FSH, and a higher number of mature oocytes and cleavage and blastocyst stage embryos. After PRP injection, 22 women (4.3%) conceived spontaneously, 14 (2.7%) were lost to follow up, and 474 (92.9%) attempted IVF. Among women who attempted IVF, 312 (65.8%) generated embryos and underwent embryo transfer, 83 (17.5%) achieved a pregnancy, and 54 (11.4%) achieved sustained implantation/live birth (SI/LB). In total, of the 510 women with POR and mean age of 40.3, PRP resulted in improvement of ovarian reserve parameters, a pregnancy rate of 20.5% and SI/LB rate of 12.9%. Our findings suggest that PRP treatment may be considered in women with POR. For wider clinical application, its clinical efficacy will need to be demonstrated in prospective randomized clinical trials.
To investigate the association of infertility with atherosclerotic cardiovascular disease (ASCVD) among postmenopausal participants in the Women's Health Initiative (WHI). We hypothesized that nulliparity and pregnancy loss may reveal more extreme phenotypes of infertility, enabling further understanding of the association of infertility with ASCVD.
Prospective cohort study.
Forty clinical centers in the United States. PATIENT(S): A total of 158,787 postmenopausal participants in the Women's Health Initiative cohort. INTERVENTION(S): Infertility, parity, and pregnancy loss. MAIN OUTCOME MEASURE(S): The primary outcome was risk of ASCVD among women with and without a history of infertility, stratified by history of live birth and pregnancy loss. Cox proportional-hazards models were adjusted for demographics and risk factors for ASCVD. RESULT(S): Among 158,787 women, 25,933 (16.3%) reported a history of infertility; 20,427 (80%) had at least 1 live birth; and 9,062 (35%) had at least 1 pregnancy loss. There was a moderate overall association between infertility and ASCVD (adjusted hazard ratio, 1.02; 95% confidence interval [CI], 0.99-1.06) over 19 years of follow-up. Among nulliparous women, infertility was associated with a 13% higher risk of ASCVD (95% CI, 1.04-1.23). Among nulliparous women who had a pregnancy loss, infertility was associated with a 36% higher risk of ASCVD (95% CI, 1.09-1.71). CONCLUSION(S): Women with a history of infertility overall had a moderately higher risk of ASCVD compared with women without a history of infertility. Atherosclerotic cardiovascular disease risk was much higher among nulliparous infertile women and among nulliparous infertile women who also had a pregnancy loss, suggesting that in these more extreme phenotypes, infertility may be associated with ASCVD risk.
At present infertility is affecting about 15% of couples and male factor is responsible for almost 50% of infertility cases. Oxidative stress, due to enhanced Reactive Oxygen Species (ROS) production and/or decreased antioxidants, has been repeatedly suggested as a new emerging causative factor of this condition. However, the central roles exerted by ROS in sperm physiology cannot be neglected. On these bases, the present review is focused on illustrating both the role of ROS in male infertility and their main sources of production. Oxidative stress assessment, the clinical use of redox biomarkers and the treatment of oxidative stress-related male infertility are also discussed.
NaProTECHNOLOGYComparison with ARTAssisted Reproduction AlternativesNatural Procreative Technology
Open Access
La progresiva medicalización de la infertilidad en las últimas tres décadas se corresponde con una creciente difusión de las Tecnologías de Reproducción Asistida (TRA), que han dejado en la sombra, casi por completo, otros enfoques más fisiológicos del tratamiento de la infertilidad, que tienen menos riesgos, son más económicos y, a la vez, igualmente efectivos. Este trabajo presenta un enfoque sistemático e la NaProTecnología (NPT), que tiene como objetivo optimizar las condiciones fisiológicas en cada ciclo menstrual, para permitir, de esta forma, una concepción por métodos naturales. Este método se postula como una mejor solución para el tratamiento de la infertilidad, desde un punto de vista que no sólo es más ético, sino que, además, es compatible con otros puntos de vistas religiosos, médicos, sociales, legales y ambientales. Los gobiernos deberían promover y financiar la NPT y, al mismo tiempo, las sociedades médicas y científicas deberían diseñar estudios para comparar de una manera justa la tasa de éxito, los costos y las complicaciones de la NPT en contraposición al método TRA tradicional.
Human Fertilisation and Embryology Authority, 2022
# National Patient Survey 2021
Survey of UK fertility patients, 2 November – 7 December 2021
April 2022
The key findings are published on this page with a statistical appendix available for download. A separate [Quality & Methodology report](https://www.hfea.gov.uk/about-us/publications/research-and-data/national-patient-survey-2021/patient-survey-2021-quality-and-methodology-report) provides details on survey methodology and patient profile.
[Download the underlying dataset as Excel Worksheet](https://www.hfea.gov.uk/media/lqwnb4lp/2022-04-07-national-patient-survey-underlying-data.xlsx "National Patient Survey Underlying Data").
## - [Main points](https://www.hfea.gov.uk/about-us/publications/research-and-data/national-patient-survey-2021/#main-points)
- [1\. Introduction](https://www.hfea.gov.uk/about-us/publications/research-and-data/national-patient-survey-2021/#introduction)
- [2\. Recent experience of fertility treatment](https://www.hfea.gov.uk/about-us/publications/research-and-data/national-patient-survey-2021/#recent-experience-of-fertility-treatment)
- [3\. Experience of speaking to a GP about fertility concerns](https://www.hfea.gov.uk/about-us/publications/research-and-data/national-patient-survey-2021/#experience-of-speaking-to-a-gp-about-fertility-concerns)
- [4\. Multiple embryo transfers](https://www.hfea.gov.uk/about-us/publications/research-and-data/national-patient-survey-2021/#multiple-embryo-transfers)
- [5\. Use of donor eggs, sperm, or embryos](https://www.hfea.gov.uk/about-us/publications/research-and-data/national-patient-survey-2021/#use-of-donor-eggs-sperm-or-embryos)
- [6\. Treatment add-ons](https://www.hfea.gov.uk/about-us/publications/research-and-data/national-patient-survey-2021/#treatment-add-ons)
- [7\. Knowledge of HFEA & Information/support sources](https://www.hfea.gov.uk/about-us/publications/research-and-data/national-patient-survey-2021/#knowledge-of-hfea-information-support-sources)
- [About ou...
Mankato Family Medicine Residency, University of Minnesota, Mankato, MN The corresponding author is Robert D. Jeske; [email protected]. The authors declare no conflicts of interest.
InfertilityGamete and Embryo DonationUK Fertility RegulationDonor Conception
Human Fertilisation and Embryology Authority, 2022
# Trends in egg, sperm and embryo donation 2020
Statistics on donation November 2022
[Download the underlying dataset as .xlsx](https://www.hfea.gov.uk/media/ycjb2gnm/trends-in-egg-sperm-and-embryo-donation-2020-underlying-dataset.xlsx "Trends in egg, sperm and embryo donation 2020 - underlying dataset")
## - [Main points](https://www.hfea.gov.uk/about-us/publications/research-and-data/trends-in-egg-sperm-and-embryo-donation-2020/#main-points)
- [Foreword](https://www.hfea.gov.uk/about-us/publications/research-and-data/trends-in-egg-sperm-and-embryo-donation-2020/#foreword)
- [Section 1. Use of donor eggs, sperm and embryos has increased](https://www.hfea.gov.uk/about-us/publications/research-and-data/trends-in-egg-sperm-and-embryo-donation-2020/#section-1)
- [Section 2. Donor registrations have increased, though access to donors of ethnic minority backgrounds varies](https://www.hfea.gov.uk/about-us/publications/research-and-data/trends-in-egg-sperm-and-embryo-donation-2020/#section-2)
- [Section 3. Treatments using donor eggs, sperm and embryos less commonly funded by NHS](https://www.hfea.gov.uk/about-us/publications/research-and-data/trends-in-egg-sperm-and-embryo-donation-2020/#section-3)
- [Section 4. Donor eggs can increase birth rates for older patients](https://www.hfea.gov.uk/about-us/publications/research-and-data/trends-in-egg-sperm-and-embryo-donation-2020/#section-4)
- [Section 5. From 2023, donor-conceived people will be able to access information on their donors](https://www.hfea.gov.uk/about-us/publications/research-and-data/trends-in-egg-sperm-and-embryo-donation-2020/#section-5)
- [Section 6. Characteristics of egg and sperm donors have changed over time](https://www.hfea.gov.uk/about-us/publications/research-and-data/trends-in-egg-sperm-and-embryo-donation-2020/#section-6)
- [About our data](https://www.hfea.gov.uk/about-us/publications/research-and-data/trends-in-egg-sp...
Ethics/PhilosophyProcreation and InfertilityRestorative vs Assisted ReproductionNatural Procreative Methods
Infertility is a worldwide problem today. The more conventional approach of medicine would be to diagnose the causes and correct them, so that the fertility potential of the couple would permit them to conceive naturally. However, since the advance of Assisted Reproductive Technologies, it has become a lucrative industry that seek to help anyone to procure a child. Lately, natural procreative processes such as NaProTechnology have arisen that can restore couples’ fertility potential through proper diagnosis and treatment. The Catholic Church prefers these latter approaches not only because they are truer to the nature of medical practice, but because they are more consistent with a healthy vision of human sexuality, procreation, and marriage.
Chronic endometritis (CE) and endometrial polyps (EPs) are common conditions in reproductive age women. CE is an infectious disorder of the endometrium characterized by signs of chronic inflammation at hysteroscopic and histological analyses. EPs are abnormal endometrial growths containing glands, stroma and blood vessels projecting from the lining of the uterus. During the last years, different authors have investigated the correlation between CE and EPs, with controversial results. The aim of this study was to summarize available evidence on the potential correlation between CE and EPs.
Systematic literature review and meta-analysis. Observational-studies were identified by searching electronic databases from their inception to September 2021. Only studies on pre-menopausal women were included. Statistical analysis was performed using MedCalc 16.4.3 (Ostend, Belgium) and Review Manager version 5.3 (Nordic Cochrane Centre, Cochrane Collaboration). The summary measures were reported as pooled proportion or odds ratio (OR) with 95% confidence interval (CI). The primary outcome was to evaluate the prevalence of CE in women with EPs. The secondary outcome was to determine the prevalence of CD-138-positive EPs among EPs. Tertiary outcomes were to compare the prevalence of CE in women with EPs versus women with a non-polypoid endometrium and to compare the prevalence of CE in women with a single EP versus women with multiple EPs. Eight observational studies (n = 3225 patients) were included in quantitative synthesis. Pooled prevalence of CE among women with EPs was 51.35% (95% CI, 27.24-75.13%). Pooled proportion of CD-138-positive EPs among EPs was 70.73% (95% CI, 55.73-83.68%). Women with EPs showed higher prevalence of CE compared to women without EPs (OR 3.07, 95% CI 1.59-5.95). Women with ≥3 EPs had higher prevalence of CE then women with a single EP (OR 3.43, 95% CI 1.83-6.46). In pre-menopausal women, CE and EPs may have a dependent relationship and may represent two consequent steps of a common pathological process.
Uterine isthmocele or uterine niche is a late complication of cesarean deliveries and causes chronic pelvic pain, menorrhagia or postmenstrual spotting, and infertility. As the number of cesarean sections are constantly increasing, it is important to be aware of this entity so as to make an early diagnosis. This would enable the clinicians to manage these patients efficiently. We present three patients of uterine isthmocele who were evaluated and managed at our institution.
InfertilityPCOSReproductive Endocrinology
Open Access
Metabolic risk factors such as obesity are considered major obstacles to female fertility. Chronic infertility imposes psychological and social burdens on women because infertility violates societal gender roles. Although the prevalence of obesity among women is expected to increase in the future, the relevance of metabolic status for fertility is still underestimated. However, the assessment of metabolic risk factors is highly relevant for understanding fertility disorders and improving infertility treatment. This narrative review discusses the associations of metabolic risk factors (e.g. obesity, female athlete triad, oxidative stress) with significant infertility. An electronic search was conducted for studies published between 2006 and 2020 in Cumulative Index to Nursing and Allied Health Literature, ScienceDirect, PubMed, Scopus, Google Scholar and related databases. In total, this search identified 19,309 results for polycystic ovary syndrome, 28,969 results for endometriosis, and only 1611 results for idiopathic and/or unknown infertility. For the present narrative review, 50 19 studies were on obesity, 24 studies investigated the female athlete triad, and seven studies addressed other risk factors, including reactive oxygen species. This narrative review confirms the direct impact of obesity on female infertility, while the effect of other risk factors needs to be confirmed by large-scale population studies.
General OB/GYNUK Fertility RegulationIndustry StatisticsFertility Sector Oversight
Human Fertilisation and Embryology Authority, 2021
# State of the fertility sector 2020/21
**Annual publication on HFEA licensed clinics**
November 2021
[**Download the underlying dataset as .xlsx**](https://www.hfea.gov.uk/media/5czb4k2o/2024-02-26-state-of-the-sector-underlying-data.xlsx "State of the Sector 2020/21 underlying dataset").
## - [About this report](https://www.hfea.gov.uk/about-us/publications/research-and-data/state-of-the-fertility-sector-2020-2021/#about-this-report)
- [HFEA regulatory response to COVID-19](https://www.hfea.gov.uk/about-us/publications/research-and-data/state-of-the-fertility-sector-2020-2021/#hfea-regulatory-response-to-covid-19)
- [Maintaining regulatory oversight](https://www.hfea.gov.uk/about-us/publications/research-and-data/state-of-the-fertility-sector-2020-2021/#maintaining-regulatory-oversight)
- [There were 77 inspections undertaken in 2020/21, taking a hybrid inspection approach](https://www.hfea.gov.uk/about-us/publications/research-and-data/state-of-the-fertility-sector-2020-2021/#there-were-77-inspections-undertaken-in-2020-21-taking-a-hybrid-inspection-approach)
- [In 2020/21, 103 clinics were licensed by the HFEA to provide fertility treatment](https://www.hfea.gov.uk/about-us/publications/research-and-data/state-of-the-fertility-sector-2020-2021/#in-2020-21-103-clinics-were-licensed-by-the-hfea-to-provide-fertility-treatment)
- [The number of incidents in 2020/21 is broadly consistent with previous years](https://www.hfea.gov.uk/about-us/publications/research-and-data/state-of-the-fertility-sector-2020-2021/#the-number-of-incidents-in-2020-21-is-broadly-consistent-with-previous-years)
- [The number of severe incidents of OHSS reported declined in 2020/21](https://www.hfea.gov.uk/about-us/publications/research-and-data/state-of-the-fertility-sector-2020-2021/#the-number-of-severe-incidents-of-ohss-reported-declined-in-2020-21)
- [A total of 88 patient complaints were received about licensed clinics in 2...
Couple infertility is a pathology with an absolute number of cases growing markedly over the last decade in connection mainly with the increased age of couples wishing to conceive. Platelet-rich plasma (PRP) is an alternative treatment used for several years for experimental purposes. Yet, this method is not yet defined as a standard therapeutic option in the infertility protocol for poor responders in assisted human reproduction procedures. Thus, the present study is a retrospective study conducted between February 2019 and February 2020 to evaluate the effect of ovarian PRP injection in patients with a poor ovarian response (POR) to ovarian stimulation. Women (n=20; age 31-44 years) diagnosed with POR based on the European Society of Human Reproduction and Embryology criteria underwent ovarian injection with autologous PRP injection. Markers of ovarian reserve before, during the following two menstrual cycles, and at six months after treatment were followed as well as stimulation and fertilisation parameters before and post-treatment. PRP treatment resulted in increased antral follicle count and serum anti-Mullerian hormone, while levels of serum follicle-stimulating hormone and luteinising hormone were decreased. These changes were more pronounced during the 2nd menstrual cycle following treatment. By six months following the injection, their values return to pre-treatment levels and any small differences were not considered statistically significant. The average dose of gonadotropin used and duration remained statistically unchanged, but a significant increase in estradiol achieved by the day of the human chorionic gonadotropin trigger day was achieved. The cancellation rate decreased following PRP treatment while the number of collected oocytes, number of oocytes in metaphase II rose. The number of embryos (of A and B quality) resulting also increased but fell short of the significance level set (α=0.073). Following the PRP injection, two singleton pregnancies were achieved, resulting in live births at term without complications during pregnancy. Another pregnancy was achieved spontaneously 45 months following the PRP and a failed assisted human reproduction procedure. Although the group included a small number of women, the results indicate the potential benefits of an ovarian autologous PRP injection in women with POR. Positive results appear to be short-term for 2-6 months after the procedure.
PregnancyInfertilityReproductive Endocrinology
Open Access
Does the OPtimization of Thyroid function, Thrombophilia, Immunity, and Uterine Milieu (OPTIMUM) treatment strategy, developed for treating repeated implantation failure (RIF), contribute to improving pregnancy outcomes in patients with a history of recurrent pregnancy loss (RPL)? Between 2018 and 2019, women with RPL after two or more clinical pregnancy losses underwent RPL testing. We treated chronic endometritis with antibiotics, high Th1/Th2 cell ratios with vitamin D and/or tacrolimus, overt/subclinical hypothyroidism with levothyroxine, and thrombophilia with low-dose aspirin. Of 168 consecutive women aged ≤43 years, 115 underwent RPL testing. We compared 100 pregnancies (90 women) and 46 pregnancies (41 women) with and without the OPTIMUM treatment strategy, respectively. RPL testing identified intrauterine abnormalities in 66 (57.4%), elevated Th1/Th2 cell ratios in 50 (43.5%), thyroid dysfunction in 33 (28.7%), and thrombophilia in 33 (28.7%). The live birth rate in the OPTIMUM group was significantly higher than that in the control group among women aged <40 years (78.1% and 42.3%, respectively; p = 0.002), but no significant difference was observed in women aged ≥40 years (55.6% and 30.0%, respectively; p = 0.09). The OPTIMUM treatment strategy improved pregnancy outcomes in patients with not only RIF but also RPL.
Time to pregnancy (TTP) is a biomarker of fecundability and has been associated with behavioral and environmental characteristics; however, these associations have not been examined in a large population-based sample of application (app) users. This observational study followed 5,376 women with an age range of 18 to 45 years who used an app to identify their fertile window. We included women who started trying to conceive between September 30, 2017 and August 31, 2018. TTP was calculated as the number of menstrual cycles from when the user switched to "Plan" mode up to and including the cycle in which they logged a positive pregnancy test. We examined associations with several characteristics, including age, gravidity, body mass index, cycle length and cycle length variation, frequency of sexual intercourse, and temperature measuring frequency. Discrete time fecundability models were used to estimate fecundability odds ratios. For the complete cohort the 6-cycle and 12-cycle cumulative pregnancy probabilities were found to be 61% (95% confidence interval [CI]: 59-62) and 74% (95% CI: 73-76), respectively. The median TTP was four cycles. The highest fecundability was associated with an age of less than 35 years, with cycle length variation <5 days and logging sexual intercourse on at least 20% of days added (the proportion of days in which intercourse was logged) (11.5% [n = 613] of entire sample). This group achieved a 6and 12-cycle cumulative pregnancy probability of 88% (95% CI: 85-91) and 95% (95% CI: 94-97), respectively, and a TTP of 2 cycles. Natural Cycles was an effective method of identifying the fertile window and a noninvasive educational option for women planning a pregnancy. Women under age 35 with regular cycles showed a high pregnancy rate.
Restorative reproductive medicine (RRM) seeks to identify and correct underlying causes and factors contributing to infertility and reproductive dysfunction. Many components of RRM are highly suitable for primary care practice. We studied the outcomes amongst couples who received restorative reproductive medicine treatment for infertility in a primary care setting. Two family physicians in Massachusetts trained in a systematic approach to RRM (natural procreative technology, or NaProTechnology) treated couples with infertility. We retrospectively reviewed the characteristics, diagnoses, treatments, and outcomes for all couples treated during the years 1989 to 2014. We compared pregnancy and live birth by clinical characteristics using Kaplan-Meier analysis. We employed the Fleming-Harrington weighted Renyi test or the logrank test to compare the cumulative proportion with pregnancy or with live birth. Among 370 couples beginning treatment for infertility, the mean age was 34.8 years, the mean prior time trying to conceive was 2.7 years, and 27% had a prior live birth. The mean number of diagnoses per couple was 4.9. Treatment components included fertility tracking with the Creighton Model FertilityCare System (80%); medications to enhance cervical mucus production (81%), to stimulate ovulation (62%), or to support the luteal phase (75%); and referral to female laparoscopy by a surgeon specializing in endometriosis (46%). The cumulative live birth rate at 2 years was 29% overall; this was significantly higher for women under age 35 (34%), and for women with body mass index < 25 (40%). There were 2 sets of twins and no higher-order multiple gestations. Of the 63 births with data available, 58 (92%) occurred at term. Family physicians can provide a RRM approach for infertility to identify underlying causes and promote healthy term live births. Younger women and women with body mass index < 25 are more likely to have a live birth.
Ethics/PhilosophyCatholic BioethicsEthical Alternative to ARTNaProTECHNOLOGY
Open Access
This paper looks at the ethics of assisted reproductive technology (ART) from the perspective of the Catholic Church. The three criteria of evaluation of the ethics of ART are the right to life and physical integrity of human beings, the unity of marriage, and the value of human sexuality. The paper examines the arguments based on these criteria carefully, as they apply to in vitro fertilization which is the most common ART method. It concludes that most ART methods would be unacceptable, but there are new alternatives like NaProTechnology that is promising for infertile couples.
InfertilityIVF Success RatesPopulation StatisticsNational Registry Data
Human Fertilisation and Embryology Authority, 2021
# Fertility treatment 2019: UK statistics for IVF and DI treatment, storage, May 2021
Fertility trends is our annual statistical release. The key findings are published on this page with a statistical appendix available for download.
[**Download the underlying dataset as .xlsx**](https://www.hfea.gov.uk/media/jvqloejj/2021-05-13-fertility-treatment-2019-trends-and-figures-underlying-data.xlsx "2021 05 Fertility Treatment 2019 Trends and Figures Underlying Data").
## - [Main points](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2019-trends-and-figures/#mainpoints)
- [30 years of the Human Fertilisation and Embryology Authority (HFEA)](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2019-trends-and-figures/#introduction)
- [Section 1. IVF birth rates in 2019 were three times higher than in 1991](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2019-trends-and-figures/#Section1)
- [Section 2. Great progress has been made in the reduction of multiple births, which now stands at 6%](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2019-trends-and-figures/#Section2)
- [Section 3. Single embryo transfer is now common practice](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2019-trends-and-figures/#Section3)
- [Section 4. Frozen embryo transfers have increased in use](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2019-trends-and-figures/#Section4)
- [Section 5. The use of donor eggs and sperm has increased](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2019-trends-and-figures/#Section5)
- [Section 6. Fertility treatment has enabled more people to have families later](https://www.hfea.gov.uk/about-us/publications/research-and-dat...
To synthesize the literature on fertility knowledge and fertility-awareness among women seeking pregnancy. The search terms "fertility-awareness OR fertility knowledge AND women AND subfertile OR infertile OR seeking pregnancy OR trying to conceive OR pre-conception OR conception NOT contraception NOT birth control" were used via CINAHL, PubMed, and Web of Science. Primary research studies were considered in the search parameters. Searches yielded 116 studies published between 1978 and 2020. After screening, 43 full-text studies were assessed for eligibility, 35 of which were omitted as not relevant. Nine quantitative studies using cross-sectional designs met this review's inclusion criteria. Studies were reviewed for information on the relationship between fertility knowledge/fertility-awareness and pregnancy intention. Studies examining the results of fertility-awareness based method (FABM) efficacy, FABMs for contraception, and provider knowledge regarding FABMs were omitted. Analysis showed low knowledge regarding the identification of the fertile window in the menstrual cycle to optimize pregnancy. There was moderate general knowledge on fertility (e.g., infertility definition, age of fertility decline, etc.). Use of an FABM and education regarding FABMs were infrequent, yet participants recognized that it would be beneficial to use and learn when trying to conceive. Women seeking pregnancy have low to moderate fertility knowledge. More research is necessary on the relationship between fertility knowledge/fertility-awareness and unexplained infertility. Nurses, nurse practitioners, and nurse-midwives should provide education on FABMs to women when they first report difficulty achieving pregnancy. Clinicians' approaches toward FABM education for women and how to implement FABM education into the preconception visit are important areas for future research.
The aim of this study was to determine predictive factors for pregnancy and assess the cumulative pregnancy rate (CPR) and live birth rate (CLBR) in subfertile couples undergoing timed intercourse (TI) using ultrasound. This retrospective cohort study included 285 women (854 cycles) who started TI with ultrasound between January 2017 and October 2019. The overall clinical pregnancy rate was 28.1% (80/285) per couple and 9.4% (80/854) per cycle. Pregnant women had a higher body mass index (BMI), higher percentage of irregular menstrual cycles, a shorter duration of subfertility, lower serum follicle-stimulating hormone levels, and higher anti-Müllerian hormone levels than non-pregnant women. A longer duration of subfertility (≥24 months vs. <12 months; 0.193; 95% 0.043-0.859) and endometriosis (vs. ovulatory factors; 0.282; 95% 0.106-0.746) as causes of subfertility were unfavorable factors that independently affected clinical pregnancy. In subgroup analysis, old age ≥ 35 years [vs. < 35 years; 0.279; 95% 0.083-0.938), a longer duration of infertility ≥24 months (vs. <24 months; 0.182; 95% 0.036-0.913) and a higher BMI ≥ 25 kg/m(2)(vs. >25 kg/m(2); 3.202; 95% 1.020-10.046) in couples with ovulatory factor and a longer duration of infertility ≥24 months (vs. <24 months; 0.185; 95% 0.042-0.819) in couples with non-ovulatory factors were significant independent predictive factors for pregnancy. No significant differences were found in the cycle characteristics between pregnant and non-pregnant women. The CPR substantially increased during the first three cycles and significantly increased until the sixth cycle. No significant increase was observed in the CPR after the sixth cycle. The CLBRs substantially increased during the first three cycles and significantly increased until the fourth cycle. No significant increase was observed in the CLBRs after the fifth cycle. When comparing CPRs and CLBRs according to subfertile causes, CRPs was significantly different and CLBRs was different with borderline significance. Our findings may indicate that women with a longer duration of subfertility or subfertility due to endometriosis have poor outcomes during TI with ultrasound. Women who failed to achieve conception by the fourth or fifth cycle of TI with ultrasound may be encouraged to consider advancing to the next treatment strategy.
To evaluate the efficacy of surgical management for isthmoceles in patients presenting with secondary infertility. A systematic search was performed in MEDLINE, EMBASE, and Cochrane Library databases from inception to May 2020. The search was limited to studies published in English. After the removal of duplicates, 3380 articles were screened for inclusion independently by 2 authors. These 2 authors assessed for studies which focused on women of reproductive age with a diagnosed isthmocele and secondary infertility who underwent any surgical intervention for defect repair with at least 1 of the goals being fertility restoration. TABULATION, INTEGRATION, A total of 13 studies, comprising of 1 randomized controlled trial, 6 prospective case series, and 6 retrospective case series describing 234 patients who underwent surgical management for an isthmocele and secondary infertility were included. The methodologic quality of the included studies was assessed independently by both reviewers. Next, the data extraction was performed independently and then compared to ensure no discrepancies. A total of 188 patients were treated by hysteroscopy, 36 by laparoscopy, 7 by laparotomy, and 3 through a vaginal approach. In total, 153 of the 234 patients (65.4%) achieved pregnancy across all studies within their respective study periods. Pregnancy rates in the randomized controlled trial were 21 of 28 (75%) for those treated by hysteroscopy compared with 9 of 28 (32%) for those untreated. Among the studies reporting pregnancy outcomes, 101 of 116 (87.1%) pregnancies resulted in a live birth. The incidence of adverse events was 2%, including the risk of reoperation. The results of this systematic review suggest that the surgical treatment of an isthmocele, particularly through hysteroscopy, in patients with residual myometrial thickness of at least 2.5 mm, may be effective in treating isthmocele-associated secondary infertility with a relatively low complication rate. Further high-quality studies are needed because of the small sample sizes and observational nature of most available data.
Platelet-rich plasma (PRP) has become a novel treatment in various aspects of medicine including orthopedics, cardiothoracic surgery, plastic surgery, dermatology, dentistry, and diabetic wound healing. PRP is now starting to become an area of interest in reproductive medicine more specifically focusing on infertility. Poor ovarian reserve, menopause, premature ovarian failure, and thin endometrium have been the main areas of research. The aim of this article is to review the existing literature on the effects of autologous PRP in reproductive medicine providing a summation of the current studies and assessing the need for additional research. A literature search is performed using PubMed, MEDLINE, and CINAHL Plus to identify studies focusing on the use of PRP therapy in reproductive medicine. Articles were divided into 3 PRP in thin lining, PRP in poor ovarian reserve, and PRP in recurrent implantation failure. In women with thin endometrium, the literature shows an increase in endometrial thickness and increase in chemical and clinical pregnancy rates following autologous PRP therapy. In women with poor ovarian reserve, autologous intraovarian PRP therapy increased anti-Mullerian hormone (AMH) levels and decreased follicle-stimulating hormone (FSH), with a trend toward increasing clinical and live birth rates. This trend was also noted in women with recurrent implantation failure. Limited literature shows promise in increasing endometrial thickness, increasing AMH, and decreasing FSH levels, as well as increasing chemical and clinical pregnancy rates. The lack of standardization of PRP preparation along with the lack of large randomized controlled trials needs to be addressed in future studies. Until definitive large RCTs are available, PRP use should be considered experimental.
InfertilityMultiple BirthsEmbryo Transfer PolicyFertility Treatment Outcomes
Human Fertilisation and Embryology Authority, 2021
# Multiple births in fertility treatment 2019
UK multiple February 2022
[Download the underlying dataset as Excel Worksheet](https://www.hfea.gov.uk/media/ikninm5o/2022-01-25-multiple-births-in-fertility-treatment-underlying-supplementary-data-tables.xlsx "2022 01 25 Multiple Births In Fertility Treatment Underlying Supplementary Data Tables").
## - [Main points](https://www.hfea.gov.uk/about-us/publications/research-and-data/multiple-births-in-fertility-treatment-2019/#main-points)
- [History of multiple births in the UK](https://www.hfea.gov.uk/about-us/publications/research-and-data/multiple-births-in-fertility-treatment-2019/#history-of-multiple-births-in-the-uk)
- [Section 1. Multiple births reduced following cross-sector collaborative efforts](https://www.hfea.gov.uk/about-us/publications/research-and-data/multiple-births-in-fertility-treatment-2019/#section-1)
- [Section 2. Single embryo transfers increased most among young patients](https://www.hfea.gov.uk/about-us/publications/research-and-data/multiple-births-in-fertility-treatment-2019/#section-2)
- [Section 3. Largest improvements in multiple birth rate among youngest and oldest patients](https://www.hfea.gov.uk/about-us/publications/research-and-data/multiple-births-in-fertility-treatment-2019/#section-3)
- [Section 4. Multiple embryo transfers put younger patients at greatest risk of multiple birth](https://www.hfea.gov.uk/about-us/publications/research-and-data/multiple-births-in-fertility-treatment-2019/#section-4)
- [Section 5. Greater risk of multiple births when using donor eggs](https://www.hfea.gov.uk/about-us/publications/research-and-data/multiple-births-in-fertility-treatment-2019/#section-5)
- [Section 6. Multiple birth rates higher among Black patients](https://www.hfea.gov.uk/about-us/publications/research-and-data/multiple-births-in-fertility-treatment-2019/#section-6)
- [Section 7. Higher multiple birth rate...
InfertilityCOVID-19 ImpactTreatment Trends and StatisticsPandemic Effects on Fertility Services
Human Fertilisation and Embryology Authority, 2021
# Impact of COVID-19 on fertility treatment 2020
UK statistics for IVF and DI treatment, May 2022
[Download the underlying dataset as Excel Worksheet](https://www.hfea.gov.uk/media/rhih4yyx/impact-of-covid-19-on-fertility-treatment-2020-underlying-dataset.xlsx "Impact of COVID-19 on fertility treatment 2020 - Underlying dataset").
## - [Main points](https://www.hfea.gov.uk/about-us/publications/research-and-data/impact-of-covid-19-on-fertility-treatment-2020/#main-points)
- [Foreword](https://www.hfea.gov.uk/about-us/publications/research-and-data/impact-of-covid-19-on-fertility-treatment-2020/#foreword)
- [HFEA regulatory response to the COVID-19 pandemic](https://www.hfea.gov.uk/about-us/publications/research-and-data/impact-of-covid-19-on-fertility-treatment-2020/#hfea-regulatory-response-to-the-covid-19-pandemic)
- [1\. NHS-funded IVF treatment slower to recover](https://www.hfea.gov.uk/about-us/publications/research-and-data/impact-of-covid-19-on-fertility-treatment-2020/#section-1)
- [2\. Treatments decreased by 20% from 2019 to 2020](https://www.hfea.gov.uk/about-us/publications/research-and-data/impact-of-covid-19-on-fertility-treatment-2020/#section-2)
- [3\. Greater decrease in IVF cycles among younger patients and patients in heterosexual relationships](https://www.hfea.gov.uk/about-us/publications/research-and-data/impact-of-covid-19-on-fertility-treatment-2020/#section-3)
- [4\. Egg donor registrations decreased by 23% from 2019 to 2020](https://www.hfea.gov.uk/about-us/publications/research-and-data/impact-of-covid-19-on-fertility-treatment-2020/#section-4)
- [5\. Impact of COVID-19 varied by nation and English region](https://www.hfea.gov.uk/about-us/publications/research-and-data/impact-of-covid-19-on-fertility-treatment-2020/#section-5)
- [6\. COVID-19 caused delays in GP appointments and fertility treatment](https://www.hfea.gov.uk/about-us/publications/research-and-data/impact-of-covid-19-on-fertil...
NaProTECHNOLOGYEffectiveness and EthicsDiagnostic Applications
NaProTECHNOLOGY – a chance for offspring or fraud? In the media space in Poland, you can meet the concept of Naprotechnology as an alternative to the in vitro procedure. Often, many myths and untruths appear in the discussion regarding this method of treatment. Naprotechnology is a new look at the health of women and men created by prof. Thomas Hilgers. It takes into account natural fertility biomarkers thanks to observation with the Creighton Model based on the female mucus. At every stage of diagnosis and treatment, Naprotechnology respects human life from the moment of conception and the mutual dignity of the spouses. It also does not use assisted reproductive procedures for ethical reasons. Naprotechnology is part of the broader scientific discipline of restorative medicine in infertility. Thanks to the accurate diagnosis and observation of the cycle, it is possible to correctly diagnose the cause of infertility. A proper diagnosis is the starting point for the implementation of specialized pharmacological and surgical treatment for both women and men. Properly used Naprotechnology and restorative medicine are highly effective in treating marital infertility. W przestrzeni medialnej w Polsce można spotkać pojęcie Naprotechnologii jako alternatywy dla procedury in vitro. Często w dyskusji pojawia się wiele mitów i nieprawdy dotyczących takiego sposobu leczenia. Naprotechnologia, stworzona przez prof. Thomasa Hilgersa, jest nowym spojrzeniem na zdrowie kobiety i mężczyzny. Uwzględnia ona naturalne biomarkery płodności dzięki obserwacji za pomocą Modelu Creighton bazującego na kobiecym śluzie. Na każdym etapie diagnostyki i leczenia Naprotechnologia szanuje ludzkie życie od samego poczęcia oraz wzajemną godność małżonków. Nie stosuje ona też procedur wspomaganego rozrodu z powodów etycznych. Naprotechnologia jest częścią szerszej dyscypliny naukowej, jaką jest przyczynowe leczenie niepłodności. Dzięki dokładnej diagnostyce i obserwacji cyklu możliwe jest postawienie prawidłowej diagnozy dotyczącej przyczyny niepłodności. Właściwa diagnoza jest punktem wyjścia dla wdrożenia specjalistycznego leczenia farmakologicznego i chirurgicznego zarówno wobec kobiety, jak i mężczyzny. Prawidłowo stosowana Naprotechnologia i przyczynowe leczenie niepłodności cechują się wysoką skutecznością leczenia niepłodności małżeńskiej.
To examine potential risk factors associated with the success rate following fallopian tube recanalization (FTR) in infertile women with obstruction of the proximal fallopian tube. We retrospectively studied patients who underwent FTR for tubal obstructive infertility between January 2016 and December 2018 at the Third Affiliated Hospital of Guangzhou Medical University. FTR was performed using a catheter and guidewire system to clear tubal obstruction. Predictive factors potentially associated with the success rate were assessed by logistic regression. A total of 762 patients were included. Multivariable analysis showed that age (odds ratio [OR] = 2.38, 95% confidence interval [CI]: 1.24-4.58), infertility type (OR = 2.82, 95% CI: 1.36-6.21), history of ectopic pregnancy (OR = 7.87, 95% CI: 4.05-15.81), history of abdominal surgery (OR = 4.30, 95% CI: 2.22-8.60), history of artificial abortion curettage (OR = 4.08, 95% CI: 2.12-8.03), and duration of infertility (OR = 2.03, 95% CI: 1.06-3.85) were independently associated with postoperative tubal patency. Our findings suggest that risk factors, such as age ≥35 years, secondary infertility, duration of infertility ≥5 years, and histories of ectopic pregnancy, abdominal surgery, and artificial abortion curettage, affect the success rate of FTR. These factors may also predict surgical success in treating tubal obstructive infertility.
Infertility affects one in 16 married women in the United States where 12.7% of these seek treatment. The stress of infertility and treatment is known to impact marital satisfaction, which can be further complicated by personal and religious beliefs regarding the ethics of some assistive reproductive technologies. A morally acceptable approach to infertility diagnosis and treatment is natural procreative technology or NaProTECHNOLOGY (NPT) using the Creighton Model FertilityCare™ System. A quantitative, descriptive study utilizing demographic surveys and the Index of Marital Satisfaction found that couples using NPT reported marital satisfaction.
While we agree with many of the points stated by Dyer et al. in their recent commentary inRBMO(Dyer et al., 2020), we believe their conclusions are focused too narrowly. Limiting the indicator of access to, and utilization of, fertility treatment to assisted reproductive technology (ART) excludes information that is of key importance for subfertile couples, populations, and policymakers. Even in countries where access to ART is widespread, there are more births in subfertile couples through non-ART treatment than through ART (Stanford et al., 2016).
While ART is necessary for some couples to have a child, it is not required for many subfertile couples, and overuse of ART may potentially be harmful (Annual Capri Workshop Group 2019). Focusing solely on ART as a metric may unnecessarily encourage overutilization (Boltz et al., 2017).
We believe the focus on ART and its outcomes for national and international registries of fertility treatment has stunted the scientific development of non-ART treatments, including those which seek to address underlying health conditions (Boyle et al., 2018). There is a pressing and critical need to develop robust registries of couples treated with non-ART treatments, for the improvement of outcomes and the promotion of robust consumer choice. (Spandorfer, 2020).
The ultimate measure of access to fertility care should be determined by the proportion of those with a desire for fertility who achieve a healthy live birth, whether or not ART is required to do so (Mascarenhas et al., 2012). Therefore, notwithstanding methodologic challenges, registry assessments should be developed and supported for all fertility treatments, not only ART.
Infertility affects \~20% of the couples in the world. Assisted reproductive technologies (ARTs) are currently the most common treatment option for infertility. Nevertheless, ARTs may be associated with complications for mothers and/or offspring. Natural procreative technology (NaProTechnology) is a natural treatment which minimizes these risks by seeking to identify the causes of infertility to enable better treatments. This narrative review summarizes the complications related to ARTs and clarifies how the NaProTechnology approach can help ARTs to achieve better results or be used in alternative to ARTs. Data in the literature indicate that NaProTechnology is a natural approach for treating infertility. The percentage of live births obtained by NaProTechnology is similar to that of ARTs. An extensive search for the genetic defects causing infertility or subfertility through genetic testing can help both ARTs and NaProTechnology to achieve successful pregnancies. By discovering the underlying causes of infertility, genetic tests enable better family counseling, like the implications of transmitting risk- and disease-alleles to future generations.
We herein summarise the evidence concerning the impact of sperm DNA fragmentation in various clinical infertility scenarios and the advances on sperm DNA fragmentation tests. The collected evidence was used to formulate 41 recommendations. Of these, 13 recommendations concern technical aspects of sperm DNA fragmentation testing, including pre-analytical information, clinical thresholds and interpretation of results. The remaining 28 recommendations relate to indications for sperm DNA fragmentation testing and clinical management. Clinical scenarios like varicocele, unexplained infertility, idiopathic infertility, recurrent pregnancy loss, intrauterine insemination, in vitro fertilisation/intracytoplasmic sperm injection, fertility counselling for men with infertility risk factors and sperm cryopreservation have been contemplated. The bulk evidence supporting the recommendations has increased in recent years, but it is still of moderate to low quality. This guideline provides clinicians with advice on best practices in sperm DNA fragmentation testing. Also, recommendations are provided on possible management strategies to overcome infertility related to sperm DNA fragmentation, based on the best available evidence. Lastly, we identified gaps in knowledge and opportunities for research and elaborated a list of recommendations to stimulate further investigation.
DeVilbiss EA et al., 2020·Paediatr Perinat Epidemiol
Attaining pregnancy is conditional upon a series of complex processes, including adequately timed intercourse, ovulation, fertilisation, and implantation. Anovulation is a first-line treatment target for couples with difficulty conceiving and is frequently examined in studies of fecundability. To identify whether sporadic anovulation is an important determinant of cumulative pregnancy rates and time to pregnancy among fertile women with regular menstrual cycles. We simulated cumulative pregnancy rates and time to pregnancy for 12 consecutive menstrual cycles among 100 000 women based on data-driven probabilities of implantation, fertilisation, ovulation, and intercourse occurring in the fertile window. We assumed anovulation probabilities of 1%, 8%, or 14.5% and intercourse averaging once per week, every other day, or daily. The model incorporated reductions in implantation and fertilisation rates for successive cycles of non-pregnancy. After 12 cycles, a reduction in the per cycle incidence of anovulation from 14.5% to 1% resulted in a 4.0% higher cumulative pregnancy rate (86.7% vs 90.7%) and similar time to pregnancy (1-cycle median difference). In contrast, increasing mean unscheduled sexual intercourse frequency from weekly to every other day was associated with a 5-cycle median reduction in time to pregnancy (weekly: 7 cycles; 2 cycles) and a 28.9% increase in the cumulative pregnancy rate (weekly: 59.9%, 88.8%; 91.6%). In presumed fertile women with regular menstrual cycles, routine investigation of anovulation may not be an informative outcome in studies of fecundability, and routine testing to ensure ovulation and treatment of anovulation are unlikely to be medically necessary. While biomarkers or cervical fluid may help time intercourse to the fertile window, time to pregnancy can also be improved through increasing the frequency of unscheduled intercourse. These findings need corroboration in large preconception time to pregnancy studies.
To investigate the association between pre-pregnancy body mass index (BMI) and subfertility within a population-based cohort, exploring Hispanic ethnicity as a potential effect modifier. We used cross-sectional study data from the Utah Pregnancy Risk Assessment Monitoring System from 2012-2015. Relationships between maternal pre-pregnancy BMI and subfertility were evaluated via Poisson regression models with robust error variance, accounting for the stratified survey sampling. Preconception BMI was analyzed continuously and categorically. Women's subfertility was defined 1) time trying to achieve pregnancy; and 2) report of using fertility-related drugs/medical procedures. The median age was 27.0; 18.8% were obese, and 15.9% were Hispanic. Women with preconception obesity (BMI>30kg/m(2)), compared to normal weight women (18.4kg/ m(2)<BMI<25kg/m(2)) had a 1.85 (95% CI 1.43, 2.38) higher adjusted prevalence ratio (aPR) for having subfertility defined by time trying and a 1.73 (95% CI 1.20, 2.32) higher aPR for receiving fertility-enhancing drugs/medical procedures. Continuous models indicated a linear relationship between BMI and subfertility (aPR 1.04, 95% CI 1.03, 1.06 for time trying; and 1.06, 95% CI 1.03, 1.10 for receiving fertility-enhancing drugs/medical procedures). Obese women, but not underweight or overweight women, reported higher subfertility than normal-weight women. Findings among this cohort of at-risk new mothers, oversampled on low education and birth weight and comprised of higher than the national average of Hispanics, indicated a dose-response relationship between obesity and subfertility.
Our findings highlight the importance of population-oriented obesity prevention for at-risk women with intentions to conceive.
To what extent does the use of mobile computing apps to track the menstrual cycle and the fertile window influence fecundability among women trying to conceive? After adjusting for potential confounders, use of any of several different apps was associated with increased fecundability ranging from 12% to 20% per cycle of attempt. Many women are using mobile computing apps to track their menstrual cycle and the fertile window, including while trying to conceive. STUDY DESIGN, SIZE, The Pregnancy Study Online (PRESTO) is a North American prospective internet-based cohort of women who are aged 21-45 years, trying to conceive and not using contraception or fertility treatment at baseline. PARTICIPANTS/MATERIALS, SETTING, We restricted the analysis to 8363 women trying to conceive for no more than 6 months at baseline; the women were recruited from June 2013 through May 2019. Women completed questionnaires at baseline and every 2 months for up to 1 year. The main outcome was fecundability, i.e. the per-cycle probability of conception, which we assessed using self-reported data on time to pregnancy (confirmed by positive home pregnancy test) in menstrual cycles. On the baseline and follow-up questionnaires, women reported whether they used mobile computing apps to track their menstrual cycles ('cycle apps') and, if so, which one(s). We estimated fecundability ratios (FRs) for the use of cycle apps, adjusted for female age, race/ethnicity, prior pregnancy, BMI, income, current smoking, education, partner education, caffeine intake, use of hormonal contraceptives as the last method of contraception, hours of sleep per night, cycle regularity, use of prenatal supplements, marital status, intercourse frequency and history of subfertility. We also examined the impact of concurrent basal body temperature, cervical fluid, cervix position and/or urine LH. MAIN Among 8363 women, 6077 (72.7%) were using one or more cycle apps at baseline. A total of 122 separate apps were reported by women. We designated five of these apps before analysis as more likely to be effective (Clue, Fertility Friend, Glow, Kindara, Ovia; hereafter referred to as 'selected apps'). The use of any app at baseline was associated with 20% increased fecundability, with little difference between selected apps versus other apps (selected apps FR (95% CI): 1.20 (1.13, 1.28); all other apps 1.21 (1.13, 1.30)). In time-varying analyses, cycle app use was associated with 12-15% increased fecundability (selected apps FR (95% CI): 1.12 (1.04, 1.21); all other apps 1.15 (1.07, 1.24)). When apps were used at baseline with one or more fertility indicators, there was higher fecundability than without fertility indicators (selected apps with indicators FR (95% CI): 1.23 (1.14, 1.34) versus without indicators 1.17 (1.05, 1.30); other apps with indicators 1.30 (1.19, 1.43) versus without indicators 1.16 (1.06, 1.27)). In time-varying analyses, results were similar when stratified by time trying at study entry (<3 vs. 3-6 cycles) or cycle regularity. For use of the selected apps, we observed higher fecundability among women FR 1.33 (1.05-1.67). LIMITATIONS, Neither regularity nor intensity of app use was ascertained. The prospective time-varying assessment of app use was based on questionnaires completed every 2 months, which would not capture more frequent changes. Intercourse frequency was also reported retrospectively and we do not have data on timing of intercourse relative to the fertile window. Although we controlled for a wide range of covariates, we cannot exclude the possibility of residual confounding (e.g. choosing to use an app in this observational study may be a marker for unmeasured health habits promoting fecundability). Half of the women in the study received a free premium subscription for one of the apps (Fertility Friend), which may have increased the overall prevalence of app use in the time-varying analyses, but would not affect app use at baseline. Most women in the study were college educated, which may limit application of results to other populations. Use of a cycle app, especially in combination with observation of one or more fertility indicators (basal body temperature, cervical fluid, cervix position and/or urine LH), may increase fecundability (per-cycle pregnancy probability) by about 12-20% for couples trying to conceive. We did not find consistent evidence of improved fecundability resulting from use of one specific app over another. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by grants, R21HD072326 and R01HD086742, from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, USA. In the last 3 years, Dr L.A.W. has served as a fibroid consultant for AbbVie.com. Dr L.A.W. has also received in-kind donations from Sandstone Diagnostics, Swiss Precision Diagnostics, FertilityFriend.com and Kindara.com for primary data collection and participant incentives in the PRESTO cohort. Dr J.B.S. reports personal fees from Swiss Precision Diagnostics, outside the submitted work. The remaining authors have nothing to declare. N/A.
Fertility AwarenessMobile ApplicationsFertile Window IdentificationDigital Tools
Open Access
To characterize mobile fertility tracking applications (apps) to determine the use of such apps for women trying to conceive by identifying the fertile window.
An exploratory cross-sectional audit study was conducted of fertility tracking applications. Ninety out of a possible total 200 apps were included for full review. The main outcome measures were the underlying app method for predicting ovulation, the fertile window, or both, price to download and use the app, disclaimers and cautions, information and features provided and tracked, and app marketing strategies.
All the apps except one monitored the women's menstrual cycle dates. Most apps only tracked menstrual cycle dates (n = 49 [54.4%]). The remainder tracked at least one fertility-based awareness method (basal body temperature, cervical mucus, LH) (n = 41 [45.6%]). Twenty-five apps measured dates, basal body temperature, LH and cervical mucus (27.8%). Seventy-six per cent of apps were free to download with free apps having more desirable features, tracking more measures and having more and better quality educational insights than paid apps. Seventy per cent of apps were classified as feminine apps, 41% of which were pink in colour. Mobile fertility tracking apps are heterogenous in their underlying methods of predicting fertile days, the price to obtain full app functionality, and in content and design. Unreliable calendar apps remain the most commonly available fertility apps on the market. The unregulated nature of fertility apps is a concern that could be addressed by app regulating bodies. The possible benefit of using fertility apps to reduce time to pregnancy needs to be evaluated.
Showell MG et al., 2020·Cochrane Database Syst Rev
M.G. Showell, R. Mackenzie‐Proctor, V. Jordan, and R.J. Hart, “Antioxidants for Female Subfertility,” Cochrane Database of Systematic Reviews, no. 8 (2020): CD007807, //doi.org/10.1002/14651858.CD007807.pub4 This Editorial Note is for the above article, published online on August 27, 2020, in Cochrane Library (cochranelibrary.com), and has been issued by the Publisher, John Wiley & Sons Ltd, in agreement with Cochrane. The Editorial note has been agreed due to concerns discovered by the Cochrane managing editor regarding the retraction of six studies in the Review (Badawy et al. 2006, 10.1016/j.fertnstert.2006.02.097; El Refaeey et al. 2014, 10.1016/j.rbmo.2014.03.011; El Sharkwy & Abd El Aziz 2019a, //doi.org/10.1002/ijgo.12902; Gerli et al. 2007, //doi.org/10.26355/eurrev_202309_33752, //europepmc.org/article/MED/18074942; Ismail et al. 2014, //dx.doi.org/10.1016/j.ejogrb.2014.06.008; Hashemi et al. 2017, //doi.org/10.1080/14767058.2017.1372413). In addition, expressions of concern have been published for two studies (Jamilian et al. 2018, //doi.org/10.1007/s12011-017-1236-3; Zadeh Modarres 2018, //doi.org/10.1007/s12011-017-1148-2). The retracted studies will be moved to the Excluded Studies table, and their impact on the review findings will be investigated and acted on accordingly in a future update. Initial checks indicate that removal of the six retracted studies did not make an appreciable difference to the results. Likewise, the studies for which Expressions of Concern were issued will be moved to the Awaiting classification table; they did not report any review outcomes, so removal will have no impact on the review findings.
A couple may be considered to have fertility problems if they have been trying to conceive for over a year with no success. This may affect up to a quarter of all couples planning a child. It is estimated that for 40% to 50% of couples, subfertility may result from factors affecting women. Antioxidants are thought to reduce the oxidative stress brought on by these conditions. Currently, limited evidence suggests that antioxidants improve fertility, and trials have explored this area with varied results. This review assesses the evidence for the effectiveness of different antioxidants in female subfertility. To determine whether supplementary oral antioxidants compared with placebo, no treatment/standard treatment or another antioxidant improve fertility outcomes for subfertile women. We searched the following databases (from their inception to September 2019), with no Cochrane Gynaecology and Fertility Group (CGFG) specialised register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and AMED. We checked reference lists of relevant studies and searched the trial registers.
We included randomised controlled trials (RCTs) that compared any type, dose or combination of oral antioxidant supplement with placebo, no treatment or treatment with another antioxidant, among women attending a reproductive clinic. We excluded trials comparing antioxidants with fertility drugs alone and trials that only included fertile women attending a fertility clinic because of male partner infertility.
We used standard methodological procedures expected by Cochrane. The primary review outcome was live birth; secondary outcomes included clinical pregnancy rates and adverse events. We included 63 trials involving 7760 women. Investigators compared oral antioxidants, combinations of antioxidants, N-acetylcysteine, melatonin, L-arginine, myo-inositol, carnitine, selenium, vitamin E, vitamin B complex, vitamin C, vitamin D+calcium, CoQ10, and omega-3-polyunsaturated fatty acids versus placebo, no treatment/standard treatment or another antioxidant. Only 27 of the 63 included trials reported funding sources. Due to the very low-quality of the evidence we are uncertain whether antioxidants improve live birth rate compared with placebo or no treatment/standard treatment (odds ratio (OR) 1.81, 95% confidence interval (CI) 1.36 to 2.43; P < 0.001, I(2) = 29%; 13 RCTs, 1227 women). This suggests that among subfertile women with an expected live birth rate of 19%, the rate among women using antioxidants would be between 24% and 36%. Low-quality evidence suggests that antioxidants may improve clinical pregnancy rate compared with placebo or no treatment/standard treatment (OR 1.65, 95% CI 1.43 to 1.89; P < 0.001, I(2) = 63%; 35 RCTs, 5165 women). This suggests that among subfertile women with an expected clinical pregnancy rate of 19%, the rate among women using antioxidants would be between 25% and 30%. Heterogeneity was moderately high. Overall 28 trials reported on various adverse events in the meta-analysis. The evidence suggests that the use of antioxidants makes no difference between the groups in rates of miscarriage (OR 1.13, 95% CI 0.82 to 1.55; P = 0.46, I(2) = 0%; 24 RCTs, 3229 women; low-quality evidence). There was also no evidence of a difference between the groups in rates of multiple pregnancy (OR 1.00, 95% CI 0.63 to 1.56; P = 0.99, I(2) = 0%; 9 RCTs, 1886 women; low-quality evidence). There was also no evidence of a difference between the groups in rates of gastrointestinal disturbances (OR 1.55, 95% CI 0.47 to 5.10; P = 0.47, I(2) = 0%; 3 RCTs, 343 women; low-quality evidence). Low-quality evidence showed that there was also no difference between the groups in rates of ectopic pregnancy (OR 1.40, 95% CI 0.27 to 7.20; P = 0.69, I(2) = 0%; 4 RCTs, 404 women). In the antioxidant versus antioxidant comparison, low-quality evidence shows no difference in a lower dose of melatonin being associated with an increased live-birth rate compared with higher-dose melatonin (OR 0.94, 95% CI 0.41 to 2.15; P = 0.89, I(2) = 0%; 2 RCTs, 140 women). This suggests that among subfertile women with an expected live-birth rate of 24%, the rate among women using a lower dose of melatonin compared to a higher dose would be between 12% and 40%. Similarly with clinical pregnancy, there was no evidence of a difference between the groups in rates between a lower and a higher dose of melatonin (OR 0.94, 95% CI 0.41 to 2.15; P = 0.89, I(2) = 0%; 2 RCTs, 140 women). Three trials reported on miscarriage in the antioxidant versus antioxidant comparison (two used doses of melatonin and one compared N-acetylcysteine versus L-carnitine). There were no miscarriages in either melatonin trial. Multiple pregnancy and gastrointestinal disturbances were not reported, and ectopic pregnancy was reported by only one trial, with no events. The study comparing N-acetylcysteine with L-carnitine did not report live birth rate. Very low-quality evidence shows no evidence of a difference in clinical pregnancy (OR 0.81, 95% CI 0.33 to 2.00; 1 RCT, 164 women; low-quality evidence). Low quality evidence shows no difference in miscarriage (OR 1.54, 95% CI 0.42 to 5.67; 1 RCT, 164 women; low-quality evidence). The study did not report multiple pregnancy, gastrointestinal disturbances or ectopic pregnancy. The overall quality of evidence was limited by serious risk of bias associated with poor reporting of methods, imprecision and inconsistency. AUTHORS' In this review, there was lowto very low-quality evidence to show that taking an antioxidant may benefit subfertile women. Overall, there is no evidence of increased risk of miscarriage, multiple births, gastrointestinal effects or ectopic pregnancies, but evidence was of very low quality. At this time, there is limited evidence in support of supplemental oral antioxidants for subfertile women.
Does sexual intercourse in the implantation time window (5-9 days after ovulation) reduce fecundability? After adjustment for intercourse in the fecund window and clustering by couple, there was no association between intercourse in the implantation time window and fecundity. Previous research has suggested an association between intercourse in the peri-implantation time window (5-9 days after estimated ovulation) and reduced fecundability. STUDY DESIGN, SIZE, We used data from the FERTILI study, a prospective observational study conducted in five European countries, with data collected from 1992 to 1996. PARTICIPANTS/MATERIALS, SETTING, Women who were experienced in fertility awareness tracking kept a daily diary of cervical mucus observations, basal body temperature measurements, coitus and clinically identified pregnancy. We estimated the day of ovulation as cycle length minus 13 days. From 661 women, 2606 cycles had intercourse during the fecund window (from 5 days before to 3 days after the estimated day of ovulation), resulting in 418 pregnancies (conception cycles). An established Bayesian fecundability model was used to estimate the fecundability ratio (FR) of peri-implantation intercourse on fecundability, while adjusting for each partner's age, prior pregnancy, the couple's probability of conception and intercourse pattern(s). We conducted sensitivity analyses estimating ovulation as cycle length minus 12 days, or alternatively, as the peak day of estrogenic cervical mucus. MAIN There was no effect of peri-implantation adjusted FR for three or more acts of peri-implantation 1.00, 95% 0.76-1.13. Results were essentially the same with sensitivity analyses. There was an inverse relationship between frequency of intercourse in the fecund window and intercourse in the peri-implantation window. LIMITATIONS, Women with known subfertility were excluded from this study. Many couples in the study were avoiding pregnancy during much of the study, so 61% of otherwise eligible cycles in the database were not at meaningful risk of pregnancy and did not contribute to the analysis. Some couples may not have recorded all intercourse. We believe the current balance of evidence does not support a recommendation for avoiding intercourse in the peri-implantation period among couples trying to conceive. STUDY FUNDING/COMPETING INTEREST(S): No external funding. The authors have no potential competing interests. N/A.
Numerous evidences have alerted on the toxic effects of the exposure to glyphosate on living organisms. Glyphosate is the herbicide most used in crops such as maize and soybean worldwide, which implies that several non-target species are at a high risk of exposure. Although the Environmental Protection Agency (EPA-USA) has reaffirmed that glyphosate is safe for users, there are controversial studies that question this statement. Some of the reported effects are due to exposure to high doses; however, recent evidences have shown that exposure to low doses could also alter the development of the female reproductive tract, with consequences on fertility. Different animal models of exposure to glyphosate or glyphosate-based herbicides (GBHs) have shown that the effects on the female reproductive tract may be related to the potential and/or mechanisms of actions of an endocrine-disrupting compound. Studies have also demonstrated that the exposure to GBHs alters the development and differentiation of ovarian follicles and uterus, affecting fertility when animals are exposed before puberty. In addition, exposure to GBHs during gestation could alter the development of the offspring (F1 and F2). The main mechanism described associated with the endocrine-disrupting effect of GBHs is the modulation of estrogen receptors and molecules involved in the estrogenic pathways. This review summarizes the endocrine-disrupting effects of exposure to glyphosate and GBHs at low or "environmentally relevant" doses in the female reproductive tissues. Data suggesting that, at low doses, GBHs may have adverse effects on the female reproductive tract fertility are discussed.
Male infertility secondary to oligozoospermia is surprisingly common. Although a majority of cases are idiopathic, oligozoospermia can be caused by endocrine dysfunction, anatomic abnormalities, medications, or environmental exposures. The work-up includes excluding reversible factors such as hormonal deficiency, medication effects, and retrograde ejaculation and identifying any underlying genetic syndrome and treating reversible medical causes. If no reversible cause is found, appropriate referrals to urology and assisted reproductive technology should be initiated. Lastly, clinicians should be aware of and respond to the psychological and general health ramifications of a diagnosis of oligozoospermia as part of the comprehensive care of men and couples struggling with a diagnosis of infertility.
Human Fertilisation and Embryology Authority, 2020
# Fertility treatment 2018: **UK statistics for IVF and DI treatment, storage, and donation**
30 June 2020
Fertility trends is our annual statistical release. The key findings are published on this page with a statistical appendix available for download.
[**Download the underlying data set in .xlsx (151kb)**](https://www.hfea.gov.uk/media/3293/underlying-data-tables-fertility-trends-2018.xlsx "download the data as .xlsx").
[**Download a PDF version of this report (1.04mb)**](https://www.hfea.gov.uk/media/3158/fertility-treatment-2018-trends-and-figures.pdf "Fertility treatment 2018: trends and figures").
## - [Main points](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2018-trends-and-figures/#mainpoints)
- [Section 1. IVF birth rates have increased for patients under 43 years](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2018-trends-and-figures/#birthrates)
- [Section 2. Birth rates were above 20% per embryo transferred on average in the first three cycles](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2018-trends-and-figures/#birthrates2)
- [Section 3. Using donor eggs can result in high birth rates for older patients, but they are not widely used](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2018-trends-and-figures/#donoreggs)
- [Section 4. The multiple birth rate decreased further to 8% in 2018](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2018-trends-and-figures/#multiplebirths)
- [Section 5. Transferring more than one embryo could result in a multiple birth rate over 30%](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2018-trends-and-figures/#multiplebirths2)
- [Section 6. Embryo and egg storage have increased as freezing becomes more common](https://www.hfea...
To estimate the association between physical activity and risk of subclinical and clinical pregnancy loss among women with a history of pregnancy loss.
Prospective cohort study as a secondary analysis of the Effects of Aspirin in Gestation and Reproduction randomized controlled trial of preconception-initiated low-dose aspirin among women with one or two prior pregnancy losses.
Four U.S. clinical centers, 2007-2011. PATIENT(S): Women with confirmed pregnancy (n = 785) as determined from hCG testing in longitudinally collected biospecimens. MAIN OUTCOME MEASURE(S): Subclinical loss of pregnancy detected only by hCG testing and clinically recognized loss. RESULT(S): Among 785 women (mean [SD] age, 28.7 [4.6] years) with an hCG-confirmed pregnancy, 188 (23.9%) experienced pregnancy loss. In multivariable models adjusted for confounders, compared with the first tertile of physical activity (median = 7.7 metabolic equivalent of task hours/week), there was a roughly twofold higher risk of subclinical loss in the second (risk ratio = 2.06; 95% confidence interval, 1.03-4.14) and third tertiles (risk ratio = 1.92; 95% confidence interval, 0.94-3.90), with median metabolic equivalent of task hours/week of 27.8 and 95.7, respectively. No relations were observed between physical activity and clinically recognized loss. CONCLUSION(S): Risk related to physical activity is different for pregnancy failure close to the time of implantation compared with that for later, clinical pregnancy loss. Higher physical activity levels were associated with an elevated risk of subclinical loss (i.e., pregnancies detected only by hCG, n = 55); however, no relationship was observed with clinically recognized loss. Further work is required to confirm these findings, assess generalizability to women without prior losses, and evaluate mechanisms. Each participating center's Institutional Review Board approved the study, and participants provided written informed consent. The trial was registered on ClinicalTrials.gov (NCT00467363), and a Data Safety and Monitoring Board provided oversight. : Estimar la asociación entre la actividad física y el riesgo de pèrdida gestacional subclínica y clínica entre mujeres con historia de pèrdida gestacional. DISEÑO:: Estudio prospectivo de cohortes como análisis secundario de un estudio aleatorizado de los efectos de aspirina en la gestación y la reproducción, utilizando bajas dosis de aspirina desde la preconcepción entre mujeres con una o dos pèrdidas gestacionales previas. : Cuatro clínicas en Estados Unidos, entre 2007–2011. : Mujeres con embarazo confirmado (n= 785) determinado por pruebas de hCG en muestras biológicas recogidas longitudinalmente. PRINCIPALES MEDIDAS DE RESULTADO(S):: Pérdida gestacional subclínica detectada sólo por la prueba de hCG y la reconocida clínicamente. : Entre 785 mujeres (media de edad [Deviación standard], 28,7 [4,6] años) con una gestación confirmada con hCG, 188 (23.9%) que tuvieron pérdida gestacional. En un modelo multivariante ajustado para factores de confusión comparado con el primer tercil de actividad física (media= 7,7 equivalentes metabólicos de trabajo horas/semana) hubo un riesgo bruto dos veces mayor de pérdida subclínica en el segundo (relación de riesgo= 2,06; Intervalo de confianza 95%, 1,03–4,14) y el tercer tercil (Relación de riesgo = 1,92 Intervalo de confianza 95%, 0,94–3,9) con una media metabólica equivalente de trabajo horas/semana de 27,8 y 95,7 respectivamente. No hubo relación entre actividad física y pérdidas gestacionales clínicas. : El riesgo asociado a actividad física es diferente para fallo gestacional próximo al momento de la implantación comparado con el más tardío de pérdida gestacional clínica. Niveles mayores de actividad física estuvieron asociados con un riesgo elevado de pérdida subclínica (por ejemplo, embarazos detectados solo por hCG, n=55); sin embargo, no se observó relación con pérdida clínicamente reconocida. Se necesitan más trabajos para confirmar estos hallazgos, evaluando de forma general mujeres sin pérdidas gestacionales previas, y evaluar sus mecanismos. APROBACIÓN ÉTICA:: El comité de revisión institucional de cada centro participante aprobó el estudio y los participantes dieron por escrito su consentimiento informado. El ensayo fue registrado en ClinicalTrial.gov (NCT00467363), y el comité de seguridad y monitorización de los datos dio su aprobación
InfertilityInfant MortalityCryopreserved Embryo Transfer OutcomesProspective Cohort Studies
To assess infant (<1 year) and childhood (1-18 years) mortality in singletons conceived through assisted reproductive techniques (ART) versus naturally conceived singletons.
Nationwide prospective study.
Sweden. PATIENT(S): All singleton liveborn infants born from 1983 to 2012 in Sweden identified using the Medical Birth Register (N = 2,847,108), of whom 43,506 were conceived through ART treatments including in vitro fertilization with and without intracytoplasmic sperm injection. INTERVENTION(S): None. MAIN OUTCOME MEASURES(S): Infant (<1 year) and childhood (1-18 years) mortality. RESULT(S): Data on ART treatment and covariates were retrieved from population-based registers using the unique personal identity number assigned to all permanent residents in Sweden. Cox proportional hazards models estimated the hazard ratios (HRs) with 95% confidence intervals (CIs) as measures of association between ART treatments and death. The analyses were adjusted for maternal characteristics, infertility, child sex, and birth cohort and were restricted to individuals with complete information on covariates for fully adjusted analysis. Compared with naturally conceived singletons, higher infant mortality risks were seen in infants conceived through ART (adjusted HR 1.45; 95% CI, 1.19-1.77), especially after transfer of cryopreserved embryos (adjusted HR 2.30; 95% CI, 1.46-3.64). Early neonatal mortality risk (deaths during the first week) was increased in children born after transfer of blastocysts (HR 2.40; 95% CI, 1.05-5.48). No increased mortality risk was observed between the ages of 1 and 18 years. CONCLUSION(S): Singletons conceived through ART had an increased risk of infant mortality from birth up to 1 year of life, predominantly in the early neonatal period and in pregnancies after transfer of frozen and thawed embryos.
Despite great advances in assisted reproductive technology, poor ovarian response (POR) is still considered as one of the most challenging tasks in reproductive medicine. The aim of this systemic review is to evaluate the role of different adjuvant treatment strategies on the probability of pregnancy achievement in poor responders undergoing IVF. Randomized controlled trials (RCTs) comparing 10 adjuvant treatments [testosterone, dehydroepiandrosterone (DHEA), letrozole, recombinant LH, recombinant hCG, oestradiol, clomiphene citrate, progesterone, growth hormone (GH) and coenzyme Q10 (CoQ10)] were included. Relevant studies published in the English language were comprehensively selected using PubMed, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) until 11 July 2018. We included studies that investigated various adjuvant agents, including androgen and androgen-modulating agents, oestrogen, progesterone, clomiphene citrate, GH and CoQ10, during IVF treatment and reported subsequent pregnancy outcomes. The administration of GnRH analogs and gonadotrophins without adjuvant treatment was set as the control. We measured study quality based on the methodology and categories listed in the Cochrane Collaboration Handbook. This review protocol was registered with PROSPERO (CRD42018086217). Of the 1124 studies initially identified, 46 trials reporting on 6312 women were included in this systematic review, while 19 trials defining POR using the Bologna criteria reporting 2677 women were included in the network meta-analysis. Compared with controls, DHEA and CoQ10 treatments resulted in a significantly higher chance of clinical pregnancy [odds ratio (OR) 2.46, 95% CI 1.16 to 5.23; 2.22, 1.08-4.58, respectively]. With regard to the number of retrieved oocytes, HCG, oestradiol and GH treatments had the highest number of oocytes retrieved [weighted mean difference (WMD) 2.08, 0.72 to 3.44; 2.02, 0.23 to 3.81; 1.72, 0.98 to 2.46, compared with controls, respectively]. With regard to the number of embryos transferred, testosterone and GH treatment led to the highest number of embryos transferred (WMD 0.72, 0.11 to 1.33; 0.67, 0.43 to 0.92; compared with controls, respectively). Moreover, GH resulted in the highest oestradiol level on the HCG day (WMD 797.63, 466.45 to 1128.81, compared with controls). Clomiphene citrate, letrozole and GH groups used the lowest dosages of gonadotrophins for ovarian stimulation (WMD 1760.00, -2890.55 to -629.45; -1110.17, -1753.37 to -466.96; -875.91, -1433.29 to -282.52; compared with controls, respectively). CoQ10 led to the lowest global cancelation rate (OR 0.33, 0.15 to 0.74, compared with controls). For patients with POR, controlled ovarian stimulation protocols using adjuvant treatment with DHEA, CoQ10 and GH showed better clinical outcomes in terms of achieving pregnancy, and a lower dosage of gonadotrophin required for ovulation induction. Furthermore, high-level RCT studies using uniform standards for POR need to be incorporated into future meta-analyses.
Delayed childbearing is currently a major challenge in reproductive medicine as increased age has an important impact on successful conception, both in natural and in assisted reproduction. There is a lack of knowledge about the impact of age on fertility, even in highly educated populations. A number of initiatives have been taken to increase fertility awareness. Health care providers have been encouraged to talk with patients about their reproductive life plan (RLP) for almost a decade based on recommendations from the Centres for Disease Control and Prevention. This concept has been explored successfully in Swedish contraception counselling. A growing number of online interventions aim to raise fertility awareness. These websites or interactive tools provide relevant information for individuals and couples as they consider whether they want children, when they should have them, and how many they may wish to have. These interventions are important, because research depicts that knowledge helps people in their decision-making process. With new fertility preservations such as egg freezing now available, additional education is needed to be sure that women and couples are well informed about the cost and low success rates of this intervention.
Dietary supplements marketed for male fertility commonly contain folic acid and zinc based on limited prior evidence for improving semen quality. However, no large-scale trial has examined the efficacy of this therapy for improving semen quality or live birth. To determine the effect of daily folic acid and zinc supplementation on semen quality and live birth.Design, setting, and participantsThe Folic Acid and Zinc Supplementation Trial was a multicenter randomized clinical trial. Couples (n = 2370; men aged ≥18 years and women aged 18-45 years) planning infertility treatment were enrolled at 4 US reproductive endocrinology and infertility care study centers between June 2013 and December 2017. The last 6-month study visit for semen collection occurred during August 2018, with chart abstraction of live birth and pregnancy information completed during April 2019. Men were block randomized by study center and planned infertility treatment (in vitro fertilization, other treatment at a study site, and other treatment at an outside clinic) to receive either 5 mg of folic acid and 30 mg of elemental zinc (n = 1185) or placebo (n = 1185) daily for 6 months.Main outcomes and measuresThe co-primary outcomes were live birth (resulting from pregnancies occurring within 9 months of randomization) and semen quality parameters (sperm concentration, motility, morphology, volume, DNA fragmentation, and total motile sperm count) at 6 months after randomization. Among 2370 men who were randomized (mean age, 33 years), 1773 (75%) attended the final 6-month study visit. Live birth outcomes were available for all couples, and 1629 men (69%) had semen available for analysis at 6 months after randomization. Live birth was not significantly different between treatment groups (404 [34%] in the folic acid and zinc group and 416 [35%] in the placebo group; risk difference, -0.9% [95% CI, -4.7% to 2.8%]). Most of the semen quality parameters (sperm concentration, motility, morphology, volume, and total motile sperm count) were not significantly different between treatment groups at 6 months after randomization. A statistically significant increase in DNA fragmentation was observed with folic acid and zinc supplementation (mean of 29.7% for percentage of DNA fragmentation in the folic acid and zinc group and 27.2% in the placebo group; mean difference, 2.4% [95% CI, 0.5% to 4.4%]). Gastrointestinal symptoms were more common with folic acid and zinc supplementation compared with placebo (abdominal 66 [6%] vs 40 [3%], respectively; 50 [4%] vs 24 [2%]; 32 [3%] vs 17 [1%]). Conclusions and relevanceAmong a general population of couples seeking infertility treatment, the use of folic acid and zinc supplementation by male partners, compared with placebo, did not significantly improve semen quality or couples' live birth rates. These findings do not support the use of folic acid and zinc supplementation by male partners in the treatment of infertility. ClinicalTrials.gov NCT01857310.
InfertilityIVF OutcomesEthnic and Racial InequalitiesUK Registry Data
Human Fertilisation and Embryology Authority, 2020
# Ethnic diversity in fertility treatment 2018
UK ethnicity March 2021
[**Download the underlying dataset as .xlsx (27kb)**](https://www.hfea.gov.uk/media/3348/2021-03-03-bame-report-suppl_mental-underlying-data-final.xlsx "download the underlying data as .xlsx").
## - [Main points](https://www.hfea.gov.uk/about-us/publications/research-and-data/ethnic-diversity-in-fertility-treatment-2018/#mainpoints)
- [Introduction](https://www.hfea.gov.uk/about-us/publications/research-and-data/ethnic-diversity-in-fertility-treatment-2018/#introduction)
- [Section 1. IVF birth rates lowest for patients of Black ethnicities](https://www.hfea.gov.uk/about-us/publications/research-and-data/ethnic-diversity-in-fertility-treatment-2018/#Section1)
- [Section 2. Multiple birth rate higher on average for Black patients](https://www.hfea.gov.uk/about-us/publications/research-and-data/ethnic-diversity-in-fertility-treatment-2018/#Section2)
- [Section 3. White egg donors most commonly used across all ethnic groups](https://www.hfea.gov.uk/about-us/publications/research-and-data/ethnic-diversity-in-fertility-treatment-2018/#Section3)
- [Section 4. Fewer Asian egg and sperm donors compared to UK Asian population](https://www.hfea.gov.uk/about-us/publications/research-and-data/ethnic-diversity-in-fertility-treatment-2018/#Section4)
- [Section 5. Asian patients represent a larger proportion of IVF users](https://www.hfea.gov.uk/about-us/publications/research-and-data/ethnic-diversity-in-fertility-treatment-2018/#Section5)
- [Section 6. Variation in NHS-funded IVF cycles between cycles in larger in younger age groups](https://www.hfea.gov.uk/about-us/publications/research-and-data/ethnic-diversity-in-fertility-treatment-2018/#Section6)
- [Section 7. Black patients start IVF later than other ethnic groups](https://www.hfea.gov.uk/about-us/publications/research-and-data/ethnic-diversit...
Mirkes R, 2020·The National Catholic Bioethics Quarterly
This How does the Catholic Church guide infertile couples to exercise their right to build a family? Part One examines the principal tenets of Catholic social teaching on human rights in general. Part Two focuses in particular on the Church’s guidelines regarding the right to family planning for infertile couples. And Part Three contrasts NaProTechnology protocols for infertility with in vitro fertilization and concludes that NaPro provides infertile couples not only a responsible means of conceiving a baby that remedies the injustice of in vitro fertilization but also a medical embodiment of the Church’s teaching on the right to family planning.
Contraception/ComparisonFamily Formation PatternsIVF and Donor Insemination StatisticsFamily Diversity in ART
Human Fertilisation and Embryology Authority, 2020
# Family formations in fertility treatment 2018
UK IVF and DI statistics for heterosexual, 22 September 2020
[**Download the underlying data set in .xlsx (144KB)**](https://www.hfea.gov.uk/media/3294/family-formations-2018-complete-underlying-data-tables.xlsx).
[**Download a PDF version of this report (976KB)**](https://www.hfea.gov.uk/media/3234/family-formations-in-fertility-treatment-2018.pdf "Family formations 2018").
## - [Main points](https://www.hfea.gov.uk/about-us/publications/research-and-data/family-formations-in-fertility-treatment-2018/#mainpoints)
- [Section 1. In vitro fertilisation (IVF) increasingly used over donor insemination (DI) for single patients and patients in female same-sex relationships](https://www.hfea.gov.uk/about-us/publications/research-and-data/family-formations-in-fertility-treatment-2018/#Section1)
- [Section 2. IVF birth rates increased most for patients in female same-sex relationship as average age declined](https://www.hfea.gov.uk/about-us/publications/research-and-data/family-formations-in-fertility-treatment-2018/#Section2)
- [Section 3. DI birth rates lowest for single patients due to higher average age](https://www.hfea.gov.uk/about-us/publications/research-and-data/family-formations-in-fertility-treatment-2018/#Section3)
- [Section 4. Egg freezing most used by single patients](https://www.hfea.gov.uk/about-us/publications/research-and-data/family-formations-in-fertility-treatment-2018/#Section4)
- [Section 5. NHS-funded cycles were more common for patients in heterosexual relationships](https://www.hfea.gov.uk/about-us/publications/research-and-data/family-formations-in-fertility-treatment-2018/#Section5)
- [Section 6. Patients in female same-sex relationships used cost-reducing egg share programme at the highest rate](https://www.hfea.gov.uk/about-us/publications/research-and-data/family-formations-in-fertility-treatment-2018/#...
Contraception/ComparisonOvarian Reserve EffectsAMH and AFCContraceptive Impact on Markers
Landersoe SK et al., 2019·Eur J Contracept Reprod Health Care
The aim of the study was to assess whether the ovarian reserve markers anti-Müllerian hormone (AMH) and antral follicle count (AFC) were lower among women using the progestin-only pill (POP) or levonorgestrel-releasing intrauterine system (LNG-IUS) and similar to the decrease observed in combined oral contraceptive (COC) pill users. This retrospective study comprised 565 hormonal contraceptive users (COC, POP, LNG-IUS or contraceptive vaginal ring) and 983 non-hormonal contraceptive users, who were seen in two Danish fertility assessment and counselling clinics between 2015 and 2019. Adjusted multiple regression analysis was used to examine the differences in AMH and AFC between hormonal and non-hormonal contraceptive users. Compared with non-hormonal contraceptive users, AMH was 31.1% lower among COC users [95% confidence interval (CI) -39.6%, -25.9%; p < 0.001], 35.6% lower among POP users (95% CI -49.0%, -18.6%; p < 0.001) and 17.1% lower among LNG-IUS users (95% CI -31.4%, 0.002%; p = 0.052); no significant differences were seen among vaginal ring users. Compared with non-hormonal contraceptive users, AFC was 31.3% lower among COC users (95% CI -35.0%, -25.3%; p < 0.001) and 29.7% lower among POP users (-39.1%, -17.9%; p < 0.001); no significant differences were seen among LNG-IUS or vaginal ring users. Ovarian volume was more than 50% reduced among COC and vaginal ring users (p < 0.001) but was unchanged among POP and LNG-IUS users. Assessment of ovarian reserve markers among users of all types of hormonal contraception should be interpreted cautiously and the type of contraceptive method considered.
To quantify the frequency of use of selected fertility awareness indicators and to assess their influence on fecundability. Web-based prospective cohort study. Not applicable. PATIENT(S): Female pregnancy planners, aged 21-45 years, attempting conception for ≤6 cycles at study entry. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): We ascertained time to pregnancy, in menstrual cycles, with bimonthly questionnaires. We estimated adjusted fecundability ratios (FRs) and confidence intervals (CIs) using proportional probabilities models, controlling for age, income, education, smoking, intercourse frequency, and other lifestyle and reproductive factors. RESULT(S): A total of 5,688 women were analyzed, with a mean age of 29.9 years and mean time trying of 2.1 cycles at baseline; 30% had ever been pregnant. At baseline, 75% were using one or more fertility indicators (counting days or charting menstrual cycles [71%], measuring basal body temperature [BBT, 21%], monitoring cervical fluid [39%], using urine LH tests [32%], or feeling for changes in position of the cervix [12%]). Women using any fertility indicator at baseline had higher subsequent fecundability (adjusted FR 1.25, 95% CI 1.16-1.35) than those not using any fertility indicators. For each individual indicator, adjusted FRs ranged from 1.28-1.36, where 1.00 would indicate no relation with fecundability. The adjusted FR for women using a combination of charting days, cervical fluid, and urine LH was 1.48 (95% CI 1.31-1.67) relative to women using no fertility indicators. CONCLUSION(S): In a North American preconception cohort study, use of fertility indicators indicating the fertile window was common, and was associated with greater fecundability.
Chronic endometritis (CE) is a poorly investigated pathology which has been related to adverse reproductive outcomes, such as implantation failure and recurrent miscarriage. In this paper, we aim to provide an overview of diagnosis, etiology, pathophysiology and treatment of CE, its impact on endometrial microenvironment and its association with infertility. We present a narrative review of the current literatures, synthesizing the findings retrieved from searches of computerized databases. CE is more prevalent in infertile patients. Effective antibiotic treatment of CE seems to improve the pregnancy and live birth rate in patients with unexplained recurrent pregnancy loss (RPL), and increase ongoing pregnancy rate in patients with recurrent implantation failure. In order to increase the diagnostic accuracy, immunohistochemistry is recommended besides the conventional histology. In addition, hysteroscopy could be considered as gold standard tool for diagnosis, considering its high correlation with histological findings. CE, as the chronic inflammation of endometrium, is usually asymptomatic and probably underestimated. Interaction of bacteria with endometrial microenvironment promotes changes in leukocyte population, cytokine production and growth factors which support its negative impact on endometrial receptivity. Nevertheless, standardization of the criteria for histopathological diagnosis and immunohistochemistry technique needs to be defined.
Women who experience pregnancy loss are especially prone to high stress, though the effects of stress on reproductive outcomes in this vulnerable population are unknown. We assessed relationships between perceived stress and hormones, anovulation, and fecundability among women with prior loss. One thousand two hundred fourteen women with 1-2 prior losses were followed for ≤6 cycles while attempting pregnancy and completed end-of-cycle stress assessments. For cycles 1 and 2, women also collected daily urine and completed daily perceived stress assessments. We assessed anovulation via. an algorithm based on human chorionic gonadotropin (hCG), pregnanediol-3-glucuronide (PdG), luteinizing hormone (LH), and fertility monitor readings. Pregnancy was determined via. hCG. Adjusted weighted linear mixed models estimated the effect of prospective phase-varying (menses, follicular, periovulatory, and luteal) perceived stress quartiles on estrone-1-glucuronide (E1G), PdG, and LH concentrations. Marginal structural models accounted for time-varying confounding by hormones and lifestyle factors affected by prior stress. Poisson and Cox regression estimated risk ratios and fecundability odds ratios of cycle-varying stress quartiles on anovulation and fecundability. Models were adjusted for age, race, body mass index (BMI), parity, and time-varying caffeine, alcohol, smoking, intercourse, and pelvic pain. Women in the highest versus lowest stress quartile had lower E1G and PdG concentrations, a marginally higher risk of anovulation [1.28; 95% confidence interval (CI) = 1.00, 1.63], and lower fecundability (0.71; 95% CI = 0.55, 0.90). Preconception perceived stress appears to adversely affect sex steroid synthesis and time to pregnancy. Mechanisms likely include the effects of stress on ovulatory function, but additional mechanisms, potentially during implantation, may also exist.
Contraception/ComparisonIndustry ReportsNational Data UK
Is pre-conception 25(OH)D associated with the per cycle probability of conception, i.e fecundability, in a prospective cohort study? There are suggestive associations of high 25(OH)D (at least 50 ng/ml) with increased fecundability and low 25(OH)D (<20 ng/ml) with reduced fecundability, but the estimates were imprecise. Vitamin D has been associated with reproductive function and fertility in animal studies, but few human studies exist. STUDY DESIGN, SIZE, This community-based prospective cohort study included 522 women attempting to become pregnant between 2010 and 2016. The women completed online daily and monthly diaries until a positive home pregnancy test was observed or 12 months had elapsed. PARTICIPANTS/MATERIALS, SETTING, The study included women from central North Carolina who were aged 30-44 with no history of infertility, with no more than 3 months of attempt time at recruitment. Women recorded vaginal bleeding so that the ongoing number of attempt cycles could be counted and used to quantify a woman's pregnancy attempt time. Blood collected at the study entry was analysed for 25(OH)D using liquid chromatography tandem mass spectrometry. Associations with fecundability were estimated with a log-binomial discrete time-to-event model. MAIN Among 522 women, 257 conceived during the study. The mean age was 33 years and the mean 25(OH)D was 36 ng/ml. There was an estimated 10% higher fecundability with each 10 ng/ml increase in 25(OH)D (fecundability ratio (FR) 1.10, 95% CI: 0.96, 1.25). The suggestive dose-response association with the continuous measure of 25(OH)D was driven by women in the lowest and the highest categories of 25(OH)D. Compared to women with 25(OH)D of 30-40 ng/ml, women below 20 ng/ml had an estimated 45% reduction in fecundability (FR (CI): 0.55 (0.23, 1.32)), and women with at least 50 ng/ml had an estimated 35% increase in fecundability (FR (CI): 1.35 (0.95, 1.91)). Across these three categories (25(OH)D of <20 ng/ml, 30-40 ng/ml and > 50 ng/ml), the probability of taking longer than 6 months to conceive was, respectively, 51% (17%, 74%), 28% (17%, 39%) and 15% (10%, 37%). LIMITATIONS, While the distribution of 25(OH)D was wide, the number of observed cycles with high 25(OH)D (N = 107) or low 25(OH)D (N = 56) was small. Our findings are consistent with prior reports of reduced fertility in women with 25(OH)D concentrations below the clinically defined deficiency level (20 ng/ml). Further studies are needed to evaluate the possible reproductive benefits of considerably higher 25(OH)D concentration (>50 ng/ml). STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH) under award numbers R00HD079659 and R01HD067683 and supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences, under projects ES103086, ES049003 and ES044003. ClearBlue ovulation predictor kits were generously donated to AMZJ and AJW by Swiss Precision Diagnostics. Drs Wilcox and Jukic report non-financial support from Swiss Precision Diagnostics during the conduct of the study; Dr Jukic reports non-financial support from Theralogix, LLC, outside the submitted work. Otherwise there are no competing interests. N/A.
Women wishing to conceive are largely unaware of fertility symptoms at the time of ovulation. This study investigated the effectiveness of fertility-awareness in achieving pregnancy, particularly fertile mucus pattern, in the context of infertility. The 384 eligible participants were taken from consecutive women desiring pregnancy who attended 17 Australian Billings Ovulation Method(®) clinics from 1999-2003. This cohort included couples with infertility ≥12 months (51%) and female age >35 years (28%). Under fertility-awareness instruction, pregnancy was achieved by 240 couples (62.5%) after maximum follow-up of two years. Mucus symptom observations effectively stratified 'low pregnancy-potential' (35.2%) and 'high pregnancy-potential' groups. Pregnancy rates were ∼30% higher in the latter group (44.4% versus 72.3%) in addition to consistent effects observed on pregnancy achievements within subgroups defined by prognostic factors such as duration of infertility (p = 0.001) and increasing female age (p = 0.04). Fertile symptoms were also associated with significantly shorter time to conception (4.2 versus 6.4 months) in a survival analysis (p = 0.003). Billings Ovulation Method(®) observations strongly predicted successful conception. This has the capacity to provide a rapid, reliable and cost-effective approach to stratifying fertility potential, including directing timely and targeted investigations/management, and is accessible for women who may be remote from primary or specialist care.
Reproductive EndocrinologyHistological DatingNoyes CriteriaEndometrial Dating
Thyroid autoantibodies, specifically thyroid peroxidase antibodies, have been associated with miscarriage and pre-term birth in women with a normal thyroid function. Small randomised controlled trials have found that treatment with levothyroxine may reduce such adverse outcomes in pregnancy. The Thyroid AntiBodies and LEvoThyroxine (TABLET) trial was conducted to explore the effects of levothyroxine in euthyroid women with thyroid peroxidase antibodies. This was a randomised, double-blind, placebo-controlled, multicentre study conducted in 49 hospitals across the UK between 2011 and 2016. Euthyroid women who tested positive for thyroid peroxidase antibodies, were aged between 16 and 41 years and were trying to conceive either naturally or through assisted conception were eligible. Participants were randomised to levothyroxine at a dose of 50 mcg daily or placebo. The primary outcome was live birth at >= 34 completed weeks of gestation. Of the 19,556 women screened, 1420 were eligible and 952 were randomised. The live birth rate was 37% in the levothyroxine group and 38% in the placebo group (relative risk 0.97, 95% CI 0.83 to 1.14; p = 0.74). Levothyroxine therapy in a dose of 50 mcg per day does not improve live birth rate in euthyroid women with thyroid peroxidase antibodies.
Prior studies among women with impaired fecundity have consistently demonstrated a positive association between daily perceived stress and the ability to conceive. However, the effects of daily stress on time to pregnancy (TTP) among women with proven fertility is not known. One hundred and forty-three women ages 18-35, in a relationship of proven fertility, who desired to conceive were included in the analysis. Daily diaries recording perceived stress (scale 0-10) were completed for up to 7 menstrual cycles or until pregnancy. Cox proportional hazards regression models were used to estimate the association between time-varying perceived stress tertiles (high [>4.1-7.2], moderate [>2.7-4.1], and low [0.1-2.7]) and adjusted fecundability odds ratio (aFOR), 95% confidence intervals (CI), after taking into account age, parity, education, time-varying caffeine and alcohol intake, fertility awareness tracking, and cycle intent to conceive. Among the 111 participants who completed daily diaries, 90 (81.1%) conceived. Women reporting high or moderate stress, versus low stress, had no difference in probability of achieving pregnancy (aFOR: 1.11 [95% CI: 0.58, 2.14]; 1.37 [0.71, 2.67]), respectively. Additional adjustment for intercourse frequency during narrow fertile window, or narrowing exposure focus to pre-ovulatory or pre-implantation stress did not appreciably alter the estimates. Daily perceived stress was not adversely associated with TTP among women with proven fertility. While a growing body of evidence supports adverse effects of more severe stressful life events on female reproductive function, moderate psychological stress, commonly referred to as eustress, among relatively healthy women with proven fertility does not appear to adversely impact TTP.
Costello MF et al., 2019·Aust N Z J Obstet Gynaecol
Polycystic ovary syndrome (PCOS) is complex with reproductive, metabolic and psychological features. Infertility is a prevalent presenting feature of PCOS with approximately 75% of these women suffering infertility due to anovulation, making PCOS by far the most common cause of anovulatory infertility. Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. This review paper aims to provide a brief update on the best available and most current research evidence supporting the treatment of PCOS which informed the recommendations in the assessment and treatment of infertility section of the international evidence-based guideline on PCOS 2018. International evidence-based guideline development engaged professional societies and consumer organisations with multidisciplinary experts and women with PCOS directly involved at all stages. Lifestyle change alone is considered the first-line treatment for the management of infertile anovulatory PCOS women who are overweight or obese. Letrozole should now be considered first-line pharmacological treatment for ovulation induction to improve fertility outcomes. Clomiphene citrate alone and metformin alone could also be used as first-line pharmacological therapy, although both are less effective than letrozole and metformin is less effective than clomiphene citrate in obese women. Gonadotrophins or laparoscopic ovarian surgery are usually second-line ovulation induction therapies. In the absence of an absolute indication for in vitro fertilisation (IVF) / intracytoplasmic sperm injection, women with PCOS and anovulatory infertility could be offered IVF as third-line therapy where firstor second-line ovulation induction therapies have failed. This review provides the best available evidence informing recommendations (along with clinical expertise and consumer preference) which provide clinicians with clear advice on best practice for the management of infertile women with PCOS.
Bisphenol A (BPA) is a non-persistent endocrine-disrupting chemical with nearly ubiquitous, involuntary exposure. Previous studies have shown that BPA causes reproductive dysfunction in animal models, but there are limited data regarding the effects of BPA exposure on time to pregnancy (TTP) in humans. To evaluate whether peri-conceptional BPA exposure of women and men is associated with couples' TTP. A total of 164 heterosexual couples (164 women; 163 men) who have available BPA information as well as time to pregnancy from the Home Observation of Peri-conceptional Exposures (HOPE) Study were included and were followed up to 12 months. Women collected first-morning urine samples starting at the beginning of the fertile window and continued until the onset of menses or 18 days after the estimated day of ovulation (EDO+18 days). The time to pregnancy (TTP) after the enrolment was self-reported and used for the analysis. Discrete-time Cox proportional hazards models were performed to generate fecundability odds ratio (FOR) between BPA and TTP after adjusting for education and age, accounting for right censoring and prior number of cycles trying to conceive. Among 164 couples, 125 couples became pregnant during the study. There was no association between TTP and peri-conceptional BPA exposure for both men (FOR 1.02, 95% CI 0.72, 1.47) and women (FOR 1.07, 95% CI 0.75, 1.53) after adjusting for education and age. No association was found between peri-conceptional BPA exposure and fecundability in this preconception cohort of relatively young, healthy pregnancy planners.
Different sizes of uterine septum between infertile women and patients with abortions may have a clinical relevance in reproductive performance after surgery. This study aimed to assess if the fecundity of women after surgical correction of the uterine septum is associated with septum size.A retrospective, single-center, cohort study was conducted in Peking Union Medical College Hospital using patients aged between 21 and 37 years. Hysteroscopic metroplasty was performed on 121 patients with a uterine septum. The septum size was assessed by ultrasonography and hysteroscopy. The subjects were divided into 3 Group A consisted of 35 women with complete uterine septum (mean ± standard deviation (SD) age 28.29 ± 3.53; group B consisted of 48 women with uterine septum >2.5 cm (mean ± SD age 28.85 ± 3.63); and group C consisted of 48 women with uterine septum ≤2.5 cm (mean ± SD age 28.79 ± 3.74). Age and body mass index (BMI) were not significantly different among the 3 groups.No serious hysteroscopic complications occurred. However, uterine septa were observed in 4 cases after surgery and 6 cases of intrauterine adhesions were observed after long-term follow-up. The abortion rate decreased, and term delivery rate increased significantly in the 3 groups after hysteroscopic metroplasty. The infertility rate was significantly lower in group C after surgery. However, no significant difference was observed in the infertility rate between groups A and B. The recurrent abortion rate was significantly lower in group A than in groups B and C before surgery. After surgery, the infertility rate was significantly higher in group A than in group B (28.57% and 10.53%, respectively; P = .048). After at least 12-months of follow-up, the pregnancy rate in group A was significantly lower than that in group C (71.43% and 89.47%, respectively; P = .048).Uterine septum resection improves obstetrical outcomes. After surgery, the infertility rate was significantly higher in patients with complete uterine septum than in those with a large partial uterine septum, and the pregnancy rate in patients with complete uterine septum was lower than that in the patients with a small partial uterine septum.
Since the introduction of autologous platelet-rich plasma (PRP) in medical practice, various studies have documented that implementing PRP can enhance healing and the anti-aging process, employing angiogenesis regeneration due to the multiple growth factors and cytokines involved. Numerous reports have shown promising results with the use of PRP in ovarian treatment, regarding ovarian regeneration and reactivation of folliculogenesis. This case series reports on two women with premature ovarian failure (POF) aged 40 and 27 years, respectively, and one menopausal woman aged 46 years. All patients presented with lack of menstrual cycle for over a year. The women reported previous failed in vitro fertilization (IVF) attempts, and, after rejecting the option of oocyte donation, they opted for the approach of autologous ovarian PRP treatment. Following PRP treatment, the three patients were invited to conceive naturally. The primary outcome was the restoration of menstruation following autologous ovarian PRP treatment, as well as an improvement in hormonal profile, a decrease in follicle-stimulating hormone (FSH) levels, and a concurrent increase in anti-Müllerian hormone (AMH) levels. Further to that, our patients achieved pregnancy through natural conception within 2-6 months following PRP treatment, resulting in currently ongoing complication-free clinical pregnancies - a first report in the literature for menopausal and POF patients. Implementation of PRP should be further investigated through randomized controlled trials (RCTs), as it may hold the key to successful treatment for a certain cohort of patients exploring reproductive treatment options following menopause.
NaProTECHNOLOGYFollicular MonitoringOvulation DefectsFollicular Development
Some authorities have found that, when the mean follicular diameter is >25 mm, the follicle is considered large, and these authorities are convinced that large follicles are biomarkers to ovarian pathology. Several studies have been carried out to determine the optimal maximum follicular size (MFS) that will be adequate before the use of human chorionic gonadotropin trigger to induce ovulation. None of these studies have considered the woman's age as a factor. An in vitro fertilization-based study has also shown that large leading follicles did not result in higher percentage of matured oocytes, and they even result in a lower live birth rate; however, we note that the ages of the women were not specifically mentioned in connection with the problems of large follicle. We set out in this study to evaluate the relationship between the MFS and the woman's age both in our control group (fertile women) Group (A) and in the women attending fertility clinic Group (B). Using the Creighton Model Fertility Care System and NaProTECHNOLOGY, it was possible to determine when to start follicular tracking and also determine ultrasound diagnosis of ovulation by recording the MFS and the reduced size. In both Group A and Group B, we discovered that the MFS reduces as woman's age increases. We also discovered that the average MFS in the Group B was higher for age compared with the Group A (P = 0.0043). There was also an association between these bigger follicles for age and low mid-luteal progesterone. This is probably the first study that describes the association of follicular size and woman's age and its possible link with ovulation defects. We have proposed that this phenomenon of large matured maximum follicle for age could be a contributory factor to infertility and miscarriages. We propose further studies to verify this hypothesis. Despite the high percentage of complete rupturing of follicles in the AB cycles in the Group (B) there are very high proportion having low mid luteal (P+7) Progesterone. This may be due to pathologies associated with big follicles for woman's age. The E2/Pg ratio study in luteal phase strongly suggested that the women in Group (B) that may have fertility challenge are those in subgroup of AB in Group (B). Therefore matured follicular size should be considered with the woman's age. If the follicles grows bigger away from the range for a woman's age it may be the marker for infertility or reproductive health challenges.
Thyroid disease is the second most common endocrine disorder affecting women of reproductive age. Subclinical hypothyroidism is diagnosed by an elevated thyroid-stimulating hormone concentration with a normal concentration of free thyroxine hormone. Autoimmune thyroid disease (ATD) is diagnosed by the presence of thyroid autoantibodies, regardless of thyroid hormone levels. Thyroxine may be a useful treatment for subfertile women with these two specific types of thyroid disease for improving pregnancy outcomes during assisted reproduction. To evaluate the efficacy and harms of levothyroxine replacement in subfertile women with subclinical hypothyroidism or with normal thyroid function and thyroid autoimmunity (euthyroid autoimmune thyroid disease, or euthyroid ATD) undergoing assisted reproduction. We searched the Cochrane Gynaecology and Fertility (CGF) Group specialised register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and two trials registers together with reference checking and contact with study authors and experts in the field to identify studies. We searched for all published and unpublished randomised controlled trials (RCTs) comparing thyroxine with no treatment or placebo, without language restrictions, from inception to 8 April 2019, and in consultation with the Cochrane CGF Information Specialist. We included women undergoing assisted reproduction treatment, meaning both in vitro fertilisation and intracytoplasmic sperm injection, with a history of subfertility and with subclinical hypothyroidism or with euthyroid ATD. We excluded women with a previously known clinical hypothyroidism or already taking thyroxine or tri-iodothyronine. RCTs compared thyroxine (levothyroxine) with either placebo or no treatment. We used standard methodological procedures expected by Cochrane. Our primary review outcomes were live birth and adverse events of thyroxine; our secondary outcomes were clinical pregnancy, multiple pregnancy and miscarriage. The review included four studies with 820 women. The included studies were of overall low risk of bias. Using GRADE methodology, we assessed the quality of evidence for the primary outcomes of this review to be very low- to low-quality evidence. Evidence was downgraded for imprecision as it was based on single, small trials with wide confidence intervals (CI). We were able to include data from three of the four included studies.In one study of women with both subclinical hypothyroidism and positive or negative anti-TPO antibodies (autoimmune disease), the evidence suggested that thyroxine replacement may have improved live birth rate (RR 2.13, 95% CI 1.07 to 4.21; 1 RCT, n = 64; low-quality evidence) and it may have led to similar miscarriage rates (RR 0.11, 95% CI 0.01 to 1.98; 1 RCT, n = 64; low-quality evidence). The evidence suggested that women with both subclinical hypothyroidism and positive or negative anti-TPO antibodies would have a 25% chance of a live birth with placebo or no treatment, and that the chance of a live birth in these women using thyroxine would be between 27% and 100%.In women with normal thyroid function and thyroid autoimmunity (euthyroid ATD), treatment with thyroxine replacement compared with placebo or no treatment may have led to similar live birth rates (risk ratio (RR) 1.04, 95% CI 0.83 to 1.29; 2 RCTs, number of participants (n) = 686; I(2) = 46%; low-quality evidence) and miscarriage rates (RR 0.83, 95% CI 0.47 to 1.46, 2 RCTs, n = 686, I(2) = 0%; low-quality evidence). The evidence suggested that women with normal thyroid function and thyroid autoimmunity would have a 31% chance of a live birth with placebo or no treatment, and that the chance of a live birth in these women using thyroxine would be between 26% and 40%.Adverse events were rarely reported. One RCT reported 0/32 in the thyroxine replacement group and 1/32 preterm births in the control group in women diagnosed with subclinical hypothyroidism and positive or negative anti-TPO antibodies. One RCT reported 21/300 preterm births in the thyroxine replacement group and 19/300 preterm births in the control group in women diagnosed with positive anti-TPO antibodies. None of the RCTs reported on other maternal pregnancy complications, foetal complications or adverse effects of thyroxine. AUTHORS' We could draw no clear conclusions in this systematic review due to the very low to low quality of the evidence reported.
To investigate the rate of sperm DNA fragmentation in male partners of women with recurrent pregnancy loss and fertile control women.
Systematic review and meta-analysis.
Not applicable. PATIENT(S): A total of 579 male partners of women with recurrent pregnancy loss and 434 male partners fertile control women. INTERVENTION(S): Prospective studies were identified through a Pubmed search. Recurrent pregnancy loss was defined as two or more previous pregnancy losses. Fertile control women had a history of a live birth or ongoing pregnancy. MAIN OUTCOME MEASURE(S): The primary outcome was the rate of sperm DNA fragmentation. The summary measures were reported as mean difference with 95% confidence interval (CI). RESULT(S): Fifteen prospective studies were included in a qualitative review. Pooled data from 13 studies with sufficient data for meta-analysis suggest that male partners of women with a history of recurrent pregnancy loss have a significantly higher rate of sperm DNA fragmentation compared to the partners mean difference 11.91, 95% CI 4.97-18.86. CONCLUSION(S): These findings support an association between sperm DNA fragmentation and recurrent pregnancy loss. However, given the significant heterogeneity between studies and lack of prospective pregnancy outcome data, further large prospective studies are needed.
Almasi-Hashiani A et al., 2019·BMC Pregnancy Childbirth
The objective of this systematic review and meta-analyses was to assess the risk of preeclampsia among women who conceived with assisted reproductive technology (ART). We searched the ISI Web of Knowledge, Medline/PubMed, Scopus, and Embase (from inception to May 2017) for English language articles using a list of key words. In addition, reference lists from identified studies and relevant review articles were also searched. Data extraction was performed by two authors, and the study quality was assessed using the Newcastle-Ottawa Scale. Random-effects model meta-analysis was applied to pool the relative risks (RR) across studies. A total of 48 studies (5 case-control studies and 43 cohort studies) were included in this meta-analysis. The Cochran Q test and I(2) statistics revealed substantial heterogeneity (Q = 26,313.92, d.f. = 47, p < 0.001 and I(2) = 99.8%). Meta-analysis showed a significant increase in preeclampsia in women who conceived by ART compared with those who conceived spontaneously (RR = 1.71, 95% CI = 1.11-2.62, p = 0.015). The findings of this systematic review indicate that the use of ART treatment is associated with a 1.71-fold increase in preeclampsia.
The relation between excessive prolactin and endometriosis-related infertility is debatable. Anovulation or defective luteal phase occurs frequently due to hyperprolactinemia in subfertile women. In this investigation, we evaluated the association between serum prolactin levels and the severity of endometriosis. This retrospective cohort study carried out at the Babol Infertility Research Center looked into the baseline serum prolactin levels of 114 infertile women with endometriosis and compared them to the levels seen in 101 infertile women without endometriosis (controls). Statistical analysis included independent t-test, chi-square, Welch test and ROC curve analysis. Infertile women with endometriosis had significantly higher serum prolactin levels than infertile women without endometriosis (p=0.003). A significant difference was detected between controls and individuals with endometriosis stages III/IV (p-value=0.009). Prolactin was found to have diagnostic value to detect endometriosis stages III/IV vs. stages I/II in AUC=0.65, 95% CI (0.55, 0.76). Prolactin values with a cut off set at 20.08 ng/mL had a sensitivity of 0.74 and specificity of 0.54 in detecting disease stages III/IV vs. I/II. The prognostic capability of prolactin in detecting endometriosis in cases vs. controls by ROC curve analysis had an AUC=+0.67, 95% CI (0.60, 0.74). Prolactin values with a cut off set at 17.5 ng/mL had a sensitivity of 0.64 and specificity of 0.63 in segregating subjects with and without endometriosis. Higher prolactin levels were observed in infertile women with more severe endometriosis when compared to infertile women without endometriosis. Prolactin levels act as a probable prognostic biomarker to detect endometriosis stages III/IV vs. I/II and segregate infertile women with endometriosis from subjects without endometriosis.
NaProTECHNOLOGYMidwifery RoleOpinions on CareReproductive Health Disorders
Open Access
Background. Infertility is a disease of the reproductive system manifesting with the inability to get pregnant within a minimum of 12 months. In diagnosing infertility and the therapeutic process, pharmacotherapy, surgery and assisted reproductive technology are used. In Poland, the NaProTechnology program is also available, which is a diagnostic and therapeutic method of reproductive health disorders without utilizing assisted reproduction. The midwife can play an important role in the care of the infertile couple.
InfertilityUltrasound SafetyBioeffects and SafetyUltrasound Exposure
Abramowicz JS, 2019·Ultrasound Imaging in Reproductive Medicine
Ultrasound is a form of energy with effects in tissues it traverses (bioeffects). The major bioeffects are a rise in temperature (thermal effects) and some effects secondary to the alternating positive and negative pressures of the ultrasound wave (nonthermal or mechanical effects). Two on-screen indices, the thermal index (TI) and the mechanical index (MI), give the end user an indication of possible thermal and nonthermal changes occurring in real time during the ultrasound scan. No harmful effects have been described in epidemiological studies in humans, but some deleterious results have been demonstrated in animals. While intensities produced by B-mode, gray-scale ultrasound are, most likely, safe, the use of Doppler involves much higher levels of energy. In addition, the very early fetus is known to be very vulnerable to external influences or insults. Information on susceptibility of the ovum, preor postfertilization, is virtually inexistent. In addition, knowledge regarding bioeffects and safety of ultrasound by clinical end users is grossly inadequate. In vivo exposure to ultrasound at spatial average intensities below 1 W/cm2, which is, arguably, almost always the case in ART as well as early gestation, does not adversely affect oocytes/embryos/fetuses. It is advocated to utilize ultrasound only when medically indicated, for the shortest time and at the lowest intensity compatible with accurate diagnosis. The TI and MI should be kept below 1. Further prospective studies on ultrasound safety in ART and pregnancy are highly recommended, as is education of the end users.
InfertilityPlatelet-Rich Plasma TreatmentExperimental RejuvenationFertility Restoration
Open Access
This report presents the case of a woman aged 40 who has experienced premature menopause from the age of 35. Having rejected oocyte donation, she opted for intraovarian injection of autologous platelet-rich plasma with the aim to rejuvenate the ovarian tissue and enable the employment of her own gametes through in-vitro fertilization. Six weeks following the autologous platelet-rich plasma treatment, a significant reduction in the patient's follicle-stimulating hormone (FSH) levels were noted. A natural in-vitro fertilization cycle led to a biochemical pregnancy, resulting in a spontaneous abortion at the 5th week of pregnancy. This is the first report of a successful autologous platelet-rich plasma application leading to pregnancy in menopause. This report uniquely contributes to the medical knowledge and challenges current practice in the context of infertility. The efficiency and safety of this treatment with regard to the reproductive system merits further investigation.
Contraception/ComparisonIndustry ReportsEpidemiology and Trends
A reductive reading of Humanae vitae seeks to limit its appeal to a ban on contraception. In truth, however, it offers a vision of human sexuality and conjugal love with broad and enduring relevance. In setting forth the intrinsic complementarity and irreducibility of the unitive and procreative dimensions of the conjugal act, Paul VI has given us a hermeneutical key for assessing many contemporary ethical dilemmas in human reproductive medicine. From this perspective, this article seeks to apply the logic of Humanae vitae to several real-life scenarios confronted by medical practitioners, educators, and ethicists working in the field of fertility and reproductive health. These include a consideration of the ethics of prescribing hormonal contraceptives, the possibilities of investigating male infertility, issues of cooperation in counseling and assisting conception in same-sex relationships, the ethics pertaining to assisted reproductive technology (ART), the contested case of prenatal adoption, and the application of double-effect reasoning.
On the occasion of the fiftieth anniversary of the promulgation of Pope Paul VI's encyclical Humanae vitae, this article seeks to defend its enduring relevance to modern-day society, through application of its reasoning to contemporary dilemmas in reproductive medicine. It considers real cases of the ethics of prescribing hormonal contraceptives, of investigating male infertility, of cooperating in counseling and assisting conception in same-sex relationships, of ART, of prenatal adoption, and the application of double-effect reasoning.
Contraception/ComparisonEgg Freezing TrendsOocyte CryopreservationUK Regulation and Statistics
To determine the live birth rate for patients who chose to undergo treatment with Restorative Reproductive Medicine (RRM) after previous IVF (includes ICSI). To look at birth outcomes with RRM after IVF, particularly rates of twin and higher order pregnancies, premature birth, low birth weight, and potential cost savings achieved with RRM. Two outpatient clinics in Ireland providing advanced RRM treatment of infertility. All patients presenting between January 2004 and January 2010, with a history of infertility and previous IVF treatment were included if they proceeded beyond the initial consultation and began treatment. Main outcome is live birth per couple calculated using life table analysis. 403 patients met the study criteria, among which 74 had a subsequent live birth. These women had significant negative predictive characteristics for advanced reproductive age (average 37.2 years), an average of 5.8 years of infertility with 2.1 (range 1-9) previous IVF attempts, with only 5% having previously had a live birth from IVF. Despite these undesirable prognostic indicators, the overall RRM live birth rate was 32.1% (crude 18.4%). Women aged 35-38 had a live birth rate of 37.5% (crude 23.6%) and older women over 40 had a live birth rate of 27.4% (crude 16.0%). The average birth weight was 3374g (7lb 7oz) with 92% being born at 37+ weeks and no very low birth weight babies. There was only one twin pregnancy in the study population; the potential health care savings for avoidable multiple pregnancies in these patients was estimated at £205 672 (USD$284 915). Patients who have already tried IVF can achieve comparable live birth outcomes with RRM compared to another cycle of IVF. RRM has a low risk of twin or multiple births, and very good neonatal outcomes with a potential cost savings to the health care system.
AndrologyInsulin Resistance and Testicular FunctionMale Insulin SensitivityMetabolic Syndrome Hormonal Effects
Open Access
A cohort of 141 males (18-80 yo, 42.9 ± 12.9) strongly suspected of being Insulin Resistant (IR) was prospectively studied by determining their insulin sensitivity (Pancreatic Suppression Test, PST) and testicular function (total testosterone and SHBG). The subjects were labeled as IR when the Steady State Plasma Glucose (SSPG) was ≥150 mg/dL and Non-Insulin Resistant (NIR) when SSPG was <150 mg/dl; similarly, the subjects were labeled as Hypogonadal (HYPOG) when total testosterone was ≤3.0 ng/mL and Eugonadal (EUG) when total testosterone was >3.0 ng/mL. Two out of three subjects turned out to be IR, while around one in four subjects were HYPOG. Contingency analysis indicated a significant interdependence between insulin resistance and hypogonadism (chi-square was 4.69, p = 0.0303). Age (>43 yo) predicted hypogonadism (AUROC 0.606, p = 0.0308). Twice as many HYPOG subjects were IR as compared with EUG subjects. Also, HYPOG subjects exhibited higher SSPG values as compared with EUG subjects. Statistically, neither Weight nor BMI predicted hypogonadism, while Waist Circumference (>110 cm) was only a mediocre predictor (AUROC 0.640, p = 0.009). SSPG (>224 mg/dL) on the other hand, was the best predictor of hypogonadism (AUROC 0.709, p = 0.002), outperforming Waist Circumference (half of the subjects with an SSPG >224 mg/dL were HYPOG). Age did not predict insulin resistance, while Weight (>99 kg), BMI (>29), and especially, Waist Circumference (>99 cm, AUROC 0.812, p < 0.0001) were all predictors of insulin resistance. Almost 90% of the subjects with a waist circumference >99 cm was IR. As a logical consequence of the selection criteria (various clues suggesting insulin resistance), most subjects with normal weight in this cohort were IR (53.3%) while 20% were HYPOG. On the other hand, 13.6% of the obese subjects were NIR, and 2 out of 3 of them were both NIR and EUG. In conclusion, Waist Circumference predicted both insulin resistance (>99 cm) and hypogonadism (>110 cm), suggesting that the first hit of abdominal obesity is insulin resistance and the second hit is male hypogonadism. Normal weight did not protect from IR, while a relevant proportion of obese subjects were NIR (with 2/3 being also EUG).
InfertilityPlatelet-Rich Plasma in GynecologyPRP TherapyPRP Clinical Applications
Open Access
The purpose of this paper is to review the current clinical uses of platelet-rich plasma (PRP) in the field of gynecology. All relevant articles published from January 2000 to December 2017 were reviewed and analyzed. The articles on PRP in the field of gynecology were mainly case series, pilot studies, or case reports. PRP is currently considered a new therapeutic modality for some disorders that are refractory to conventional drugs.
Menstrual CycleDietary Minerals and Ovulatory FunctionMicronutrient InfluenceDietary Mineral Deficiency
Although minerals are linked to several reproductive outcomes, it is unknown whether dietary minerals are associated with ovulatory function. We hypothesised that low intakes of minerals would be associated with an increased risk of anovulation. We investigated associations between dietary mineral intake and both reproductive hormones and anovulation in healthy women in the BioCycle Study, which prospectively followed up 259 regularly menstruating women aged 18-44 years who were not taking mineral supplements for two menstrual cycles. Intakes of ten selected minerals were assessed through 24-h dietary recalls at up to four times per cycle in each participant. Oestradiol, progesterone, luteinising hormone (LH), follicle-stimulating hormone (FSH), sex-hormone-binding globulin and testosterone were measured in serum up to eight times per cycle. We used weighted linear mixed models to evaluate associations between minerals and hormones and generalised linear models for risk of anovulation. Compared with Na intake ≥1500 mg, Na intake <1500 mg was associated with higher levels of FSH (21·3 %; 95 % CI 7·5, 36·9) and LH (36·8 %; 95 % CI 16·5, 60·5) and lower levels of progesterone (-36·9 %; 95 % CI -56·5, -8·5). Na intake <1500 mg (risk ratio (RR) 2·70; 95 % CI 1·00, 7·31) and Mn intake <1·8 mg (RR 2·00; 95 % CI 1·02, 3·94) were associated with an increased risk of anovulation, compared with higher intakes, respectively. Other measured dietary minerals were not associated with ovulatory function. As essential minerals are mostly obtained via diet, our results comparing insufficient levels with sufficient levels highlight the need for future research on dietary nutrients and their associations with ovulatory cycles.
InfertilityPhysical Activity and FecundabilityEAGeR Trial Secondary AnalysisExercise and Conception Rates
Open Access
Is physical activity (PA) associated with fecundability in women with a history of prior pregnancy loss? Higher fecundability was related to walking among overweight/obese women and to vigorous PA in women overall. PA may influence fecundability through altered endocrine function. Studies evaluating this association have primarily utilized Internet-based recruitment and self-report for pregnancy assessment and have yielded conflicting results. STUDY DESIGN, SIZE, This is a secondary analysis of the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial (2007-2011), a multisite, randomized controlled trial of preconception-initiated low-dose aspirin. PARTICIPANTS/MATERIALS, SETTING, Healthy women (n = 1214), aged 18-40 and with 1-2 prior pregnancy losses, were recruited from four US medical centers. Participants were followed for up to six menstrual cycles while attempting pregnancy and through pregnancy for those who became pregnant. Time to hCG detected pregnancy was assessed using discrete-time Cox proportional hazard models to estimate fecundability odds ratios (FOR) adjusted for covariates, accounting for left truncation and right censoring. Main The association of walking with fecundability varied significantly by BMI (P-interaction = 0.01). Among overweight/obese women, walking ≥10 min at a time was related to improved fecundability (FOR = 1.82, 95% CI: 1.19, 2.77). In adjusted models, women reporting >4 h/wk of vigorous activity had significantly higher fecundability (FOR = 1.69, 95% CI: 1.24, 2.31) compared to no vigorous activity. Associations of vigorous activity with fecundability were not significantly different by BMI (P-interaction = 0.9). Moderate activity, sitting, and International Physical Activity Questionnaire (IPAQ) categories were not associated with fecundability overall or in BMI-stratified analyses. LIMITATIONS, Some misclassification of PA levels as determined by the short form of the IPAQ is likely to have occurred, and may have led to non-differential misclassification of exposure in our study. Information on diet and change in BMI was not collected and may have contributed to some residual confounding in our results. The generalizability of our results may be limited as our population consisted of women with a history of one or two pregnancy losses. These findings provide positive evidence for the benefits of PA in women attempting pregnancy, especially for walking among those with higher BMI. Further study is necessary to clarify possible mechanisms through which walking and vigorous activity might affect time-to-pregnancy. STUDY FUNDING/COMPETING INTEREST(S): This work was funded by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors report no conflicts of interest in this work. #NCT00467363.
InfertilityPreconception Carotenoid Intake and FecundabilityAntioxidant MicronutrientsEAGeR Trial Micronutrient Analysis
Although maternal nutrition may affect fecundity, associations between preconception micronutrient levels and time to pregnancy (TTP) have not been examined. We assessed the relationship between preconception fat-soluble micronutrient concentrations and TTP among women with 1-2 prior pregnancy losses. This was a prospective cohort study of 1,228 women set within the Effects of Aspirin in Gestation and Reproduction (EAGeR) Trial (United States, 2007-2011), which assessed the association of preconception-initiated daily low-dose aspirin with reproductive outcomes. We measured preconception levels of zeaxanthin, cryptoxanthin, lycopene, αand β-carotene, and αand γ-tocopherol in serum. We used discrete Cox regression models, accounting for left-truncation and right-censoring, to calculate fecundability odds ratios and 95% confidence intervals. The models adjusted for age, body mass index, race, smoking, alcohol, physical activity, income, vitamin use, cholesterol, treatment arm, and study site. Serum α-carotene levels (per log unit (μg/dL) increase, fecundability odds ratio (FOR) = 1.17, 95% confidence interval (CI): 1.00, 1.36) and serum α-carotene concentrations at or above the US average (2.92 μg/dL) versus below the average (FOR = 1.21, 95% CI: 1.02, 1.44) were associated with shorter TTP. Compared with levels below the US average (187 μg/dL), γ-tocopherol concentrations at or above the average were associated with longer TTP (FOR = 0.83, 95% CI: 0.69, 1.00). The potential for these nutrients to influence fecundability deserves further exploration.
InfertilityTamoxifen for Thin EndometriumEndometrial Thickness ImprovementClomiphene Alternative Approaches
Open Access
Gonadotropin stimulation is used as the second line of treatment in patients with thin endometrium following clomiphene citrate (CC) administration, which is associated with higher cost, multiple births, and ovarian hyperstimulation syndrome. Tamoxifen (TMX), a selective estrogen receptor modulator, acts as an agonist on the endometrium. The objective of the present study was to compare the efficacy of low-dose CC, TMX, and gonadotropins in women with thin endometrium (<7 mm) following Clomiphene in intrauterine insemination (IUI) cycles. A prospective observational study between December 2011 and June 2013 was carried out in a tertiary infertility center. Women (n = 502) undergoing IUI with endometrium <7 mm after 100 mg CC were included in the study and divided into three treatment groups. Women in Group A (n = 182, cycles = 364) received clomiphene (50 mg/day from day 3 to 7), Group B (n = 179, cycles = 342) received TMX (40 mg/day from day 3 to 7), and Group C (n = 141, cycles = 226) received continuous urine-derived follicle-stimulating hormone 75-150 IU from day 3 onward until human chorionic gonadotropin injection. Endometrial thickness (ET), pregnancy rate, and live birth rate were considered as main outcome measures. Multiple comparisons using one-way ANOVA and Schiff's test were performed. Pregnancy and live birth rate were significantly higher (P < 0.004) in TMX and gonadotropin groups compared to clomiphene. A number of follicles in the TMX group were found to be lower (P < 0.001) compared to other two groups. In polycystic ovary syndrome patients, ovulation induction with TMX resulted in inadequate response in more than half of the cycles. TMX can improve ET and live birth rate in patients with thin endometrium after clomiphene.
Reports on clinical uses of platelet-rich plasma (PRP) have dramatically increased in the last decade. Indications for PRP therapy range from muscle and skeletal injuries to hair re-growth. More recently evidences have shown its positive effects in promoting endometrial and follicular growth and gestation in assisted reproduction cycles. We discuss the putative role of PRP on endometrial receptivity, with a brief history of its applications in research and clinical therapies. Despite its widespread uses in medicine, the mechanisms through which PRP exerts its regenerative effects are only postulated, not based on scientific data. There is an unmet need for advanced research to corroborate present findings in the clinical scenario.
Chronic endometritis is a persistent inflammation of the endometrial mucosa caused by bacterial pathogens such as Enterobacteriaceae, Enterococcus, Streptococcus, Staphylococcus, Mycoplasma, and Ureaplasma. Although chronic endometritis can be asymptomatic, it is found in up to 40% of infertile patients and is responsible for repeated implantation failure and recurrent miscarriage. Diagnosis of chronic endometritis is based on hysteroscopy of the uterine cavity, endometrial biopsy with plasma cells being identified histologically, while specific treatment is determined based on microbial culture. However, not all microorganisms implicated are easily or readily culturable needing a turnaround time of up to 1 week. We sought to develop a molecular diagnostic tool for chronic endometritis based on real-time polymerase chain reaction equivalent to using the 3 classic methods together, overcoming the bias of using any of them alone. Endometrial samples from patients assessed for chronic endometritis (n = 113) using at least 1 or several conventional diagnostic methods namely histology, hysteroscopy, and/or microbial culture, were blindly evaluated by real-time polymerase chain reaction for the presence of 9 Chlamydia trachomatis, Enterococcus, Escherichia coli, Gardnerella vaginalis, Klebsiella pneumoniae, Mycoplasma hominis, Neisseria gonorrhoeae, Staphylococcus, and Streptococcus. The sensitivity and specificity of the molecular analysis vs the classic diagnostic techniques were compared in the 65 patients assessed by all 3 recognized classic methods. The molecular method showed concordant results with histological diagnosis in 30 samples (14 double positive and 16 double negative) with a matching accuracy of 46.15%. Concordance of molecular and hysteroscopic diagnosis was observed in 38 samples (37 double positive and 1 double negative), with an accuracy of 58.46%. When the molecular method was compared to microbial culture, concordance was present in 37 samples (22 double positive and 15 double negative), a matching rate of 56.92%. When cases of potential contamination and/or noncultivable bacteria were considered, the accuracy increased to 66.15%. Of these 65 patients, only 27 patients had consistent histological + hysteroscopic diagnosis, revealing 58.64% of nonconcordant results. Only 13 of 65 patients (20%) had consistent histology + hysteroscopy + microbial culture results. In these cases, the molecular microbiology matched in 10 cases showing a diagnostic accuracy of 76.92%. Interestingly, the molecular microbiology confirmed over half of the isolated pathogens and provided additional detection of nonculturable microorganisms. These results were confirmed by the microbiome assessed by next-generation sequencing. In the endometrial samples with concordant histology + hysteroscopy + microbial culture results, the molecular microbiology diagnosis demonstrates 75% sensitivity, 100% specificity, 100% positive and 25% negative predictive values, and 0% false-positive and 25% false-negative rates. The molecular microbiology method describe herein is a fast and inexpensive diagnostic tool that allows for the identification of culturable and nonculturable endometrial pathogens associated with chronic endometritis. The results obtained were similar to all 3 classic diagnostic methods together with a degree of concordance of 76.92% providing an opportunity to improve the clinical management of infertile patients with a risk of experiencing this ghost endometrial pathology.
InfertilityUnited States 2015 National OutcomesCDC ART Reporting SystemMultiple Birth and Preterm Delivery Rates
Open Access
Since the first U.S. infant conceived with assisted reproductive technology (ART) was born in 1981, both the use of ART and the number of fertility clinics providing ART services have increased steadily in the United States. ART includes fertility treatments in which eggs or embryos are handled in the laboratory (i.e., in vitro fertilization [IVF] and related procedures). Although the majority of infants conceived through ART are singletons, women who undergo ART procedures are more likely than women who conceive naturally to deliver multiple-birth infants. Multiple births pose substantial risks for both mothers and infants, including obstetric complications, preterm delivery (<37 weeks), and low birthweight (<2,500 g) infants. This report provides state-specific information for the United States (including the District of Columbia and Puerto Rico) on ART procedures performed in 2015 and compares birth outcomes that occurred in 2015 (resulting from ART procedures performed in 2014 and 2015) with outcomes for all infants born in the United States in 2015. 2015. In 1995, CDC began collecting data on ART procedures performed in fertility clinics in the United States as mandated by the Fertility Clinic Success Rate and Certification Act of 1992 (FCSRCA) (Public Law 102-493 [October 24, 1992]). Data are collected through the National ART Surveillance System, a web-based data collection system developed by CDC. This report includes data from 52 reporting areas (the 50 states, the District of Columbia, and Puerto Rico).
In 2015, a total of 182,111 ART procedures (range: 135 in Alaska to 23,198 in California) with the intent to transfer at least one embryo were performed in 464 U.S. fertility clinics and reported to CDC. These procedures resulted in 59,334 live-birth deliveries (range: 55 in Wyoming to 7,802 in California) and 71,152 infants born (range: 68 in Wyoming to 9,176 in California). Nationally, the number of ART procedures performed per 1 million women of reproductive age (15-44 years), a proxy measure of the ART utilization rate, was 2,832. ART use exceeded the national rate in 13 reporting areas (California, Connecticut, Delaware, the District of Columbia, Hawaii, Illinois, Maryland, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, and Virginia). Nationally, among ART transfer procedures in patients using fresh embryos from their own eggs, the average number of embryos transferred increased with increasing age of the woman (1.6 among women aged <35 years, 1.8 among women aged 35-37 years, and 2.3 among women aged >37 years). Among women aged <35 years, the national elective single-embryo transfer (eSET) rate was 34.7% (range: 11.3% in Puerto Rico to 88.1% in Delaware). In 2015, ART contributed to 1.7% of all infants born in the United States (range: 0.3% in Puerto Rico to 4.5% in Massachusetts). ART also contributed to 17.0% of all multiple-birth infants, 16.8% of all twin infants, and 22.2% of all triplets and higher-order infants. The percentage of multiple-birth infants was higher among infants conceived with ART (35.3%) than among all infants born in the total birth population (3.4%). Approximately 34.0% of ART-conceived infants were twins and 1.0% were triplets and higher-order infants. Nationally, infants conceived with ART contributed to 5.1% of all low birthweight infants. Among ART-conceived infants, 25.5% had low birthweight, compared with 8.1% among all infants. ART-conceived infants contributed to 5.3% of all preterm (gestational age <37 weeks) infants. The percentage of preterm births was higher among infants conceived with ART (31.2%) than among all infants born in the total birth population (9.7%). Among singletons, the percentage of ART-conceived infants who had low birthweight was 8.7% compared with 6.4% among all infants born. The percentage of ART-conceived infants who were born preterm was 13.4% among singletons compared with 7.9% among all infants. Multiple births from ART contributed to a substantial proportion of all twins, triplets, and higher-order infants born in the United States. For women aged <35 years, who are typically considered good candidates for eSET, the national average of 1.6 embryos was transferred per ART procedure. Of the four states (Illinois, Massachusetts, New Jersey, and Rhode Island) with comprehensive mandated health insurance coverage for ART procedures (i.e., coverage for at least four cycles of IVF), three (Illinois, Massachusetts, and New Jersey) had rates of ART use exceeding 1.5 times the national rate. This type of mandated insurance coverage has been associated with greater use of ART and likely accounts for some of the difference in per capita ART use observed among states. Twins account for the majority of ART-conceived multiple births. Reducing the number of embryos transferred and increasing use of eSET when clinically appropriate could help reduce multiple births and related adverse health consequences for both mothers and infants. State-based surveillance of ART might be useful for monitoring and evaluating maternal and infant health outcomes of ART in states with high ART use.
InfertilityCRP and FecundabilityInflammation-Mediated AnovulationEAGeR Trial Inflammation Analysis
To assess systemic inflammation in relation to fecundability and anovulation.
Prospective cohort study among participants in the Effects of Aspirin in Gestation and Reproduction trial who were assigned to the placebo.
Academic medical centers. PATIENT(S): Healthy eumenorrheic women (n = 572), 18-40 years of age, with one or two pregnancy losses, attempting spontaneous pregnancy. INTERVENTION(S): Baseline serum high-sensitivity C-reactive protein (hsCRP) values <10 mg/L were categorized into tertiles. MAIN OUTCOME MEASURE(S): Discrete Cox proportional hazards models estimated the fecundability odds ratio (FOR) and 95% confidence interval (CI) and adjusted for potential confounders. Log-binomial regression estimated the risk ratio (RR) and 95% CI of anovulation. The algorithm to define anovulation used data on urinary concentrations of hCG, pregnanediol-3-glucuronide, and LH as well as fertility monitor readings. RESULT(S): Higher hsCRP was associated with reduced fecundability but not with an increased risk of anovulation. CONCLUSION(S): Among healthy women attempting pregnancy after one or two pregnancy losses, we found preliminary evidence that systemic inflammation is associated with reduced fecundability, but not independently from adiposity. Sporadic anovulation did not appear to drive this association. Trial ClinicalTrials.gov: NCT00467363.
InfertilityOocyte RetrievalProcedural SafetyIVF Procedural Risks
Open Access
The most common complication during oocyte retrieval is vaginal bleeding, which is largely controlled by buffer application. In conclusion, the oocyte retrieval process can be considered a safe procedure.
Fertility AwarenessFertile Window IdentificationPrimary Care Pregnancy AchievementNatural Fertility Indicator Effectiveness
Open Access
To determine the effectiveness of achieving pregnancy with focused intercourse in the fertile window identified using natural fertility indicators. 24-cycle prospective effectiveness study.
A North American web-based fertility monitoring service. 256 North American women aged 20-43 (mean age 29.2 years) seeking to achieve pregnancy. Participants identified their fertile window with either electronic hormonal fertility monitoring or cervical mucus monitoring, or both, and recorded their observations on an online fertility tracking system. Pregnancies were validated by nurses with an online self-assessed pregnancy evaluation form. Survival analysis was used to determine pregnancy rates. There were 150 pregnancies among the 256 participants with an overall pregnancy rate of 78 per 100 women over 12 menstrual cycles. There were 54 pregnancies (68%) among the 80 women using the fertility monitor, 11 pregnancies (46%) among the 24 women using mucus monitoring, and 90 (63%) among the 143 women using both mucus and monitor. The 12-cycle pregnancy rates per 100 women were 83 (monitor group), 72 (mucus group), and 75 (mucus and monitor group). Pregnancy rates reached 100% at 24 cycles of use for those women using the hormonal fertility monitor. Use of the hormonal fertility monitor alone seems to offer the best natural estimate of the fertile phase of the menstrual cycle for women wishing to achieve a pregnancy. Focusing intercourse through 24 menstrual cycles can be beneficial for achieving pregnancy.
Orouji Jokar T et al., 2017·J Clin Endocrinol Metab
Unexplained infertility (UI), defined as the inability to conceive after 12 months of unprotected intercourse with no diagnosed cause, affects 10% to 30% of infertile couples. An improved understanding of the mechanisms underlying UI could lead to less invasive and less costly treatment strategies. Abnormalities in thyroid function and hyperprolactinemia are well-known causes of infertility, but whether thyrotropin (TSH) and prolactin levels within the normal range are associated with UI is unknown. To compare TSH and prolactin levels in women with UI and women with a normal fertility evaluation except for an azoospermic or severely oligospermic male partner. DESIGN, SETTING, Cross-sectional study including women evaluated at a large academic health system between 1 January 2000 and 31 December 2012 with normal TSH (levels within the normal range of the assay and ≤5 mIU/L) and normal prolactin levels (≤20 ng/mL) and either UI (n = 187) or no other cause of infertility other than an azoospermic or severely oligospermic partner (n = 52). TSH and prolactin. Women with UI had significantly higher TSH levels than controls [UI: TSH 1.95 mIU/L, (1.54, 2.61); TSH 1.66 mIU/L, (1.25, 2.17); P = 0.003]. This finding remained significant after we controlled for age, body mass index, and smoking status. Nearly twice as many women with UI (26.9%) had a TSH ≥2.5 mIU/L compared with controls (13.5%; P < 0.05). Prolactin levels did not differ between the groups. Women with UI have higher TSH levels compared with a control population. More studies are necessary to determine whether treatment of high-normal TSH levels decreases time to conception in couples with UI.
InfertilityInternational Consensus Glossary 2017Reproductive Medicine DefinitionsFertility Care Terminology
Can a consensus and evidence-driven set of terms and definitions be generated to be used globally in order to ensure consistency when reporting on infertility issues and fertility care interventions, as well as to harmonize communication among the medical and scientific communities, policy-makers, and lay public including individuals and couples experiencing fertility problems? A set of 283 consensus-based and evidence-driven terminologies used in infertility and fertility care has been generated through an inclusive consensus-based process with multiple stakeholders. In 2006 the International Committee for Monitoring Assisted Reproductive Technologies (ICMART) published a first glossary of 53 terms and definitions. In 2009 ICMART together with WHO published a revised version expanded to 87 terms, which defined infertility as a disease of the reproductive system, and increased standardization of fertility treatment terminology. Since 2009, limitations were identified in several areas and enhancements were suggested for the glossary, especially concerning male factor, demography, epidemiology and public health issues. STUDY DESIGN, SIZE, Twenty-five professionals, from all parts of the world and representing their expertise in a variety of sub-specialties, were organized clinical definitions; outcome measurements; embryology laboratory; clinical and laboratory andrology; and epidemiology and public health. Assessment for revisions, as well as expansion on topics not covered by the previous glossary, were undertaken. A larger group of independent experts and representatives from collaborating organizations further discussed and assisted in refining all terms and definitions. PARTICIPANTS/MATERIALS, SETTING, Members of the working groups and glossary co-ordinators interacted through electronic mail and face-to-face in international/regional conferences. Two formal meetings were held in Geneva, Switzerland, with a final consensus meeting including independent experts as well as observers and representatives of international/regional scientific and patient organizations. MAIN A consensus-based and evidence-driven set of 283 terminologies used in infertility and fertility care was generated to harmonize communication among health professionals and scientists as well as the lay public, patients and policy makers. Definitions such as 'fertility care' and 'fertility awareness' together with terminologies used in embryology and andrology have been introduced in the glossary for the first time. Furthermore, the definition of 'infertility' has been expanded in order to cover a wider spectrum of conditions affecting the capacity of individuals and couples to reproduce. The definition of infertility remains as a disease characterized by the failure to establish a clinical pregnancy; however, it also acknowledges that the failure to become pregnant does not always result from a disease, and therefore introduces the concept of an impairment of function which can lead to a disability. Additionally, subfertility is now redundant, being replaced by the term infertility so as to standardize the definition and avoid confusion. LIMITATIONS, All stakeholders agreed to the vast majority of terminologies included in this glossary. In cases where disagreements were not resolved, the final decision was reached after a vote, defined before the meeting as consensus if passed with 75%. Over the following months, an external expert group, which included representatives from non-governmental organizations, reviewed and provided final feedback on the glossary. Some terminologies have different definitions, depending on the area of medicine, for example demographic or clinical as well as geographic differences. These differences were taken into account and this glossary represents a multinational effort to harmonize terminologies that should be used worldwide. None. N/A.
EndometriosisMiscarriage RiskMild vs SevereEndometriosis-Related Pregnancy Loss
To investigate the prevalence of miscarriage in women with endometriosis (WwE) compared with disease-free control women (CW).
Cross-sectional analysis nested in a retrospective observational study (n = 940).
Hospitals and associated private practices. PATIENT(S): Previously pregnant women (n = 268) within reproductive age in matched pairs. INTERVENTION(S): Retrospective analysis of surgical reports and self-administered questionnaires. MAIN OUTCOME MEASURE(S): Rate of miscarriage, subanalysis for fertility status (≤12 vs. >12 months' time to conception), endometriosis stages (revised American Society of Reproductive Medicine classification [rASRM] I/II vs. III/IV) and phenotypic localizations (superficial peritoneal, ovarian, and deep infiltrating endometriosis). RESULT(S): The miscarriage rate was higher in WwE (35.8% [95% confidence interval 29.6%-42.0%]) compared with CW (22.0% [16.7%-27.0%]); adjusted incidence risk ratio of 1.97 (95% CI 1.41-2.75). This remained significant in subfertile WwE (50.0% [40.7%-59.4%]) vs. CW (25.8% [8.5%-41.2%]) but not in fertile WwE (24.5% [16.3%-31.6%]) vs. CW (21.5% [15.9%-26.8%]). The miscarriage rate was higher in women with milder forms (rASRM I/II 42.1% [32.6%-51.4%] vs. rASRM III/IV 30.8% [22.6%-38.7%], compared with 22.0% [16.7%-27.0%] in CW), and in women with superficial peritoneal endometriosis (42.0% [32.0%-53.9%]) compared with ovarian endometriosis (28.6% [17.7%-38.7%]) and deep infiltrating endometriosis (33.9% [21.2%-46.0%]) compared with CW (22.0% [16.7%-27.0%]). CONCLUSION(S): Mild endometriosis, as in superficial lesions, is related to a great extent of inflammatory disorder, possibly leading to defective folliculogenesis, fertilization, and/or implantation, presenting as increased risk of miscarriage. TRIAL NCT02511626.
Despite lack of evidence of their utility, biomarkers of ovarian reserve are being promoted as potential markers of reproductive potential. To determine the associations between biomarkers of ovarian reserve and reproductive potential among women of late reproductive age. DESIGN, SETTING, Prospective time-to-pregnancy cohort study (2008 to date of last follow-up in March 2016) of women (N = 981) aged 30 to 44 years without a history of infertility who had been trying to conceive for 3 months or less, recruited from the community in the Raleigh-Durham, North Carolina, area. Early-follicular-phase serum level of antimüllerian hormone (AMH), follicle-stimulating hormone (FSH), and inhibin B and urinary level of FSH. The primary outcomes were the cumulative probability of conception by 6 and 12 cycles of attempt and relative fecundability (probability of conception in a given menstrual cycle). Conception was defined as a positive pregnancy test result. A total of 750 women (mean age, 33.3 [SD, 3.2] years; 77% white; 36% overweight or obese) provided a blood and urine sample and were included in the analysis. After adjusting for age, body mass index, race, current smoking status, and recent hormonal contraceptive use, women with low AMH values (<0.7 ng/mL [n = 84]) did not have a significantly different predicted probability of conceiving by 6 cycles of attempt (65%; 95% CI, 50%-75%) compared with women (n = 579) with normal values (62%; 95% CI, 57%-66%) or by 12 cycles of attempt (84% [95% CI, 70%-91%] vs 75% [95% CI, 70%-79%], respectively). Women with high serum FSH values (>10 mIU/mL [n = 83]) did not have a significantly different predicted probability of conceiving after 6 cycles of attempt (63%; 95% CI, 50%-73%) compared with women (n = 654) with normal values (62%; 95% CI, 57%-66%) or after 12 cycles of attempt (82% [95% CI, 70%-89%] vs 75% [95% CI, 70%-78%], respectively). Women with high urinary FSH values (>11.5 mIU/mg creatinine [n = 69]) did not have a significantly different predicted probability of conceiving after 6 cycles of attempt (61%; 95% CI, 46%-74%) compared with women (n = 660) with normal values (62%; 95% CI, 58%-66%) or after 12 cycles of attempt (70% [95% CI, 54%-80%] vs 76% [95% CI, 72%-80%], respectively). Inhibin B levels (n = 737) were not associated with the probability of conceiving in a given cycle (hazard ratio per 1-pg/mL increase, 0.999; 95% CI, 0.997-1.001). Among women aged 30 to 44 years without a history of infertility who had been trying to conceive for 3 months or less, biomarkers indicating diminished ovarian reserve compared with normal ovarian reserve were not associated with reduced fertility. These findings do not support the use of urinary or blood follicle-stimulating hormone tests or antimüllerian hormone levels to assess natural fertility for women with these characteristics.
InfertilityUterine and Upper Tract BacteriaFemale Reproductive Tract ContinuumMicrobiome Association
Open Access
Reports on bacteria detected in maternal fluids during pregnancy are typically associated with adverse consequences, and whether the female reproductive tract harbours distinct microbial communities beyond the vagina has been a matter of debate. Here we systematically sample the microbiota within the female reproductive tract in 110 women of reproductive age, and examine the nature of colonisation by 16S rRNA gene amplicon sequencing and cultivation. We find distinct microbial communities in cervical canal, uterus, fallopian tubes and peritoneal fluid, differing from that of the vagina. The results reflect a microbiota continuum along the female reproductive tract, indicative of a non-sterile environment. We also identify microbial taxa and potential functions that correlate with the menstrual cycle or are over-represented in subjects with adenomyosis or infertility due to endometriosis. The study provides insight into the nature of the vagino-uterine microbiome, and suggests that surveying the vaginal or cervical microbiota might be useful for detection of common diseases in the upper reproductive tract.Whether the female reproductive tract harbours distinct microbiomes beyond the vagina has been a matter of debate. Here, the authors show a subject-specific continuity in microbial communities at six sites along the female reproductive tract, indicative of a non-sterile environment.
InfertilityAffordability and AccessFertility TreatmentComparison with ART
The literature on the relationship between diet and human fertility has greatly expanded over the last decade, resulting in the identification of a few clear patterns. Intake of supplemental folic acid, particularly at doses higher than those recommended for the prevention of neural tube defects, has been consistently related to lower frequency of infertility, lower risk of pregnancy loss, and greater success in infertility treatment. On the other hand and despite promising evidence from animal models, vitamin D does not appear to exert an important role in human fertility in the absence of deficiency. Antioxidant supplementation does not appear to offer any benefits to women undergoing infertility treatment, but it appears to be beneficial when it is the male partner who is supplemented. However, the available evidence does not allow discerning which specific antioxidants, or at which doses, are responsible for this benefit. Long-chain omega-3 fatty acids appear to improve female fertility, although it remains unclear to what extent contamination of shared food sources, such as fish with high levels of environmental toxicants, can dampen this benefit. Lastly, adherence to healthy diets favoring seafood, poultry, whole grains, fruits, and vegetables are related to better fertility in women and better semen quality in men. The cumulative evidence has also piled against popular hypotheses. Dairy and soy, once proposed as reproductive toxicants, have not been consistently related to poor fertility. In fact, soy and soy supplements appear to exert a beneficial effect among women undergoing infertility treatment. Similarly, because data from large, high-quality studies continue to accumulate, the evidence of a potentially deleterious effect of moderate alcohol and caffeine intake on the ability to become pregnant seems less solid than it once did. While a complete picture of the role of nutrition on fertility is far from complete, much progress has been made. The most salient gaps in the current evidence include jointly considering female and male diets and testing the most consistent findings in randomized trials.
PCOSMyo-Inositol and D-Chiro-Inositol SupplementationInositol TherapyNon-Pharmaceutical Ovulation Restoration
Open Access
Polycystic ovary syndrome (PCOS)’s rate is about 6% to10% among the reproductive aged women; it is characterized by menstrual cycle irregularity with oligo-anovulation, hyperandrogenism, insulin resistance, and compensatory hyperinsulinemia. Despite the fact that the last two elements are present in a large percentage of PCOS women, they are not mandatory for the diagnosis; in order to explain the pathogenesis in these patients, it was supposed that ovarian theca cells got higher insulin sensitivity probably related to the mechanism of intracellular signalling transduction (1). Corroborating this view, it was previously demonstrated that diazoxid, which has the well-known effect of decreasing insulin levels, reduced hyperandrogenism in lean women affected by PCOS, even in the cases of normal insulin level and insulin sensitivity (2). Based on the detrimental role of insulin resistance, several insulin sensitizer drugs have been used to ameliorate PCOS symptoms and signs. Although metformin has represented the landmark of PCOS therapy in the recent past, to date several studies have tested the efficacy of Inositols, a carbocyclic polyols. Two stereoisomers, in particular Myo-inositol (MI) and D-Dhiro-inositol (DCI) showed a clinical efficacy and safety during PCOS. MI is converted in DCI by epimerase, an enzyme regulated also by insulin action. In the form of inositol-phosphoglycans (IPGs), they are involved in a non-classical insulin receptor is coupled by G-protein which can activate phospholipase, allowing the release of second messengers (DCI-glycan), which is able to stimulate pyruvate dehydrogenase and glycogen synthase activities, the enzyme involved in the oxidative and the non-oxidative glucose metabolism (3). On one hand, MI-IPG is able to inhibit cyclic adenosine monophosphate (cAMP) kinase and adenylyl cyclase, both involved in free fatty acid metabolism. On the other hand, DCI-IPG play a pivotal role during the binding of insulin to its receptor on cell membrane where it stimulates IPG release and starts signalling cascade. In addition, Inositols are incorporated in membrane phospholipids as phosphoinositides. Phosphatidylinositol 4, 5 bisphosphate (PtdIns-4, 5P) and phosphatidylinositol 4P (PtdIns-4P), in particular, are involved in the regulation of the cytoskeleton structure and in the regulation of cellular motility, which account also the beneficial effects of Inositol administration on sperm parameters. PtdIns-4, 5P plays a key role in controlling calcium-mediated intracellular signalling which is mandatory to address the oocytes maturation and fecundation (4).
Reproductive EndocrinologyDisease Mechanism ReviewROS in Health and DiseaseGamete Quality and Reproductive Impact
Open Access
Oxidative stress is a phenomenon caused by an imbalance between production and accumulation of oxygen reactive species (ROS) in cells and tissues and the ability of a biological system to detoxify these reactive products. ROS can play, and in fact they do it, several physiological roles (i.e., cell signaling), and they are normally generated as by-products of oxygen metabolism; despite this, environmental stressors (i.e., UV, ionizing radiations, pollutants, and heavy metals) and xenobiotics (i.e., antiblastic drugs) contribute to greatly increase ROS production, therefore causing the imbalance that leads to cell and tissue damage (oxidative stress). Several antioxidants have been exploited in recent years for their actual or supposed beneficial effect against oxidative stress, such as vitamin E, flavonoids, and polyphenols. While we tend to describe oxidative stress just as harmful for human body, it is true as well that it is exploited as a therapeutic approach to treat clinical conditions such as cancer, with a certain degree of clinical success. In this review, we will describe the most recent findings in the oxidative stress field, highlighting both its bad and good sides for human health.
Menstrual CycleFolate Homocysteine and Ovulatory FunctionOvarian Cycle EffectsB-Vitamin Status and Anovulation
How are concentrations of plasma homocysteine and serum folate associated with reproductive hormones and anovulation in regularly menstruating women? Higher homocysteine was associated with sporadic anovulation and hormonal changes that may be indicative of impaired ovulatory function, but higher serum folate was associated only with higher luteal phase progesterone. Higher folate levels as well as some variants in genes relevant to one-carbon metabolism, are associated with improved reproductive outcomes and responses to fertility treatment, but only a few small studies have explored the relationship between markers of one-carbon metabolism and menstrual cycle characteristics. STUDY DESIGN, SIZE, The BioCycle Study (2005-2007) is a prospective, longitudinal cohort of 259 regularly menstruating women not using hormonal contraceptives or dietary supplements who were followed for up to two menstrual cycles. PARTICIPANTS/MATERIALS, SETTING, Serum folate and reproductive hormones were measured up to eight times per cycle and plasma homocysteine up to three times. Linear mixed models were used to estimate associations between serum folate or plasma homocysteine and log-transformed reproductive hormone levels while accounting for multiple observations and cycles per woman. Generalized estimating equations were used to examine risk of sporadic anovulation. All models were adjusted for age, race, body mass index, cigarette and alcohol use, and energy and fiber intake. Main Higher plasma homocysteine concentrations were associated with lower total estradiol across the cycle (adjusted percent change per unit increase in homocysteine [aPC] -2.3%, 95% CI: -4.2, -0.03), higher follicle stimulating hormone around the time of expected ovulation (aPC 2.4%, 95% CI: 0.2, 4.7) and lower luteal phase progesterone (aPC -6.5%, 95% CI: -11.1, -1.8). Higher serum folate concentrations were associated with higher luteal phase progesterone (aPC per unit increase in folate 1.0%, 95% CI: 0.4, 1.6). Higher homocysteine concentrations at expected ovulation were associated with a 33% increased risk of sporadic anovulation. We observed no risk associated with decreased folate concentrations, but a higher ratio of folate to homocysteine at ovulation was associated with a 10% decreased risk of anovulation. LIMITATIONS, Our results are generalizable to healthy women with adequate serum folate levels. The independent influence of homocysteine should be confirmed in larger cohorts and among women with folate deficiency or increased risks of anovulation. If these findings are confirmed, it is possible that lowering homocysteine with B-vitamins through diet or supplementation could improve ovulatory function in some women. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (Contract HHSN275200403394C, HHSN275201100002I and Task one HHSN27500001). None of the authors has any conflicts of interest to disclose.
Malaria is prevalent in Nigeria, and artemether + lumefantrine (artemisinin-based combination therapy [ACT]) is drug of choice in treatment of uncomplicated cases. ACT is contraindicated in early pregnancy. They release-free radicals that can compromise female fertility. Infertility and its associated complications such as miscarriages, abnormal gestation, and unstable marriages seem to be on the increase. This study aims at evaluating the effect of ACT on female fertility. The significance of this research is to draw the attention of fertility care givers to this possible cause of infertility and fertility challenges. Creighton Model FertilityCare System and NaProTECHNOLOGY are simply technologies that can be used to assess female fertility. They are used in this study to assess the effect of ACT administered at different stages of menstrual cycles of three selected fertile adult females. The results are interpreted on the background of standard Creighton model chart. This study has shown that ACT has a significant fertility deteriorating effect on the women. It caused ovulation defect and diagnosed as partial rupture syndrome in the very cycle of use and in the first cycle after use. It also significantly reduced cervical mucus production and significantly reduced luteal phase progesterone production with an associated significant increase of luteal phase estrogen production. ACT use as antimalarial may be a possible cause of infertility and fertility challenges in women.
InfertilityContaminant Exposure and FertilityBPA Phthalate Pesticide EffectsSemen Quality and Chemical Exposure
This review article summarizes the epidemiological findings published between 2011 and 2016 concerning bisphenol A (BPA), phthalates, dioxins, pesticides, air pollution, fracking chemicals, triclosan, and parabens and fertility parameters in men (i.e., semen volume, sperm concentration, sperm motility, and sperm morphology) as well as fertility parameters in women (i.e., cyclicity, fertility treatment outcomes), pregnancy outcomes (i.e., preterm birth,miscarriage), and reproductive disorders (i.e., polycystic ovary syndrome, endometriosis, and uterine fibroids). Overall, this review indicates that several environmental toxicants are significantly associated with reduced fertility parameters in men and women as well as several reproductive disorders in women. Although many studies reported that the selected exposures are associated with adverse fertility outcomes, several studies reported null associations. Thus, future studies are still needed to better elucidate the associations and potential mechanisms between these environmental chemicals and fertility outcomes in men and women.
Late preterm infants are at risk for short-term morbidities. We report that late preterm singletons conceived with fertility treatment have increased risk for admission to the neonatal intensive care unit and respiratory support compared with spontaneously conceived infants. Fertility treatment may be a risk factor to consider in managing late preterm infants.
Pregnancy rates among infertile women have been reported to increase after hysterosalpingography, but it is unclear whether the type of contrast medium used (oil-based or water-soluble contrast) influences this potential therapeutic effect. We performed a multicenter, randomized trial in 27 hospitals in the Netherlands in which infertile women who were undergoing hysterosalpingography were randomly assigned to undergo this procedure with the use of oil-based or water-based contrast. Subsequently, couples received expectant management or the women underwent intrauterine insemination. The primary outcome was ongoing pregnancy within 6 months after randomization. Outcomes were analyzed according to the intention-to-treat principle. A total of 1119 women were randomly assigned to hysterosalpingography with oil contrast (557 women) or water contrast (562 women). A total of 220 of 554 women in the oil group (39.7%) and 161 of 554 women in the water group (29.1%) had an ongoing pregnancy (rate ratio, 1.37; 95% confidence interval [CI], 1.16 to 1.61; P<0.001), and 214 of 552 women in the oil group (38.8%) and 155 of 552 women in the water group (28.1%) had live births (rate ratio, 1.38; 95% CI, 1.17 to 1.64; P<0.001). Rates of adverse events were low and similar in the two groups. Rates of ongoing pregnancy and live births were higher among women who underwent hysterosalpingography with oil contrast than among women who underwent this procedure with water contrast. (Netherlands Trial Register number, NTR3270 .).
Are maternal preconception lipid levels associated with fecundability?Summary answerFecundability was reduced for all abnormal female lipid levels including total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and total triglyceride levels. Subfecundity affects 7-15% of the population and lipid disorders are hypothesized to play a role since cholesterol acts as a substrate for the synthesis of steroid hormones. Evidence illustrating this relationship at the mechanistic level is mounting but few studies in humans have explored the role of preconception lipids in fecundity.Study design, size, durationA secondary analysis of the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial (2007-2011), a block-randomized, double-blind, placebo-controlled trial. Participants/materials, setting, methodsA total of 1228 women, with 1-2 prior pregnancy losses and without a diagnosis of infertility, attempting pregnancy for up to six menstrual cycles were recruited from clinical sites in Utah, New York, PA and Colorado. Time to pregnancy was the number of menstrual cycles to pregnancy as determined by positive hCG test or ultrasound. Individual preconception lipoproteins were measured at baseline, prior to treatment randomization and dichotomized based on clinically accepted cut-points as total cholesterol ≥200 mg/dl, LDL-C ≥130 mg/dl, HDL-C Main results and the role of chanceThere were 148 (12.3%) women with elevated total cholesterol, 94 (7.9%) with elevated LDL-C, 280 (23.2%) with elevated triglycerides and 606 (50.7%) with low HDL-C. The fecundability odds ratio (FOR) was reduced for all abnormal lipids before and after confounder adjustment, indicating reduced fecundability. Total cholesterol ≥200 mg/dl was associated with 24% (For: 0.76, 95% CI: 0.59, 0.97) and 29% (For: 0.71, 95% CI: 0.55, 0.93) reduced fecundability for hCG-detected and ultrasound-confirmed pregnancy, respectively, compared with total cholesterol Limitations, reasons for cautionAlthough the FOR is a measure of couple fecundability, we had only measures of female lipid levels and can therefore not confirm the findings from a previous study indicating the independent role of male lipids in fecundity. The attenuated estimates and decreased precision after adjustment for central adiposity and obesity indicate the complexity of potential causal lipid pathways, suggesting other factors related to obesity besides dyslipidemia likely contribute to reduced fecundability. s of the findingsOur results are consistent with one other study relating preconception lipid concentrations to fecundity and expand these findings by adding critically important information about individual lipoproteins. As lipid levels are modifiable they may offer an inexpensive target to improve female fecundability.Study funding and competing interest(s)This study was funded by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors have declared that no conflicts of interest exist.Trial registration number#NCT00467363.
Inflammation is linked to causes of infertility. Low-dose aspirin (LDA) may improve reproductive success in women with chronic, low-grade inflammation. To investigate the effect of preconception-initiated LDA on pregnancy rate, pregnancy loss, live birth rate, and inflammation during pregnancy.
Stratified secondary analysis of a multicenter, block-randomized, double-blind, placebo-controlled trial.
Four US academic medical centers, 2007 to 2012. Healthy women aged 18 to 40 years (N = 1228) with one to two prior pregnancy losses actively attempting to conceive. Preconception-initiated, daily LDA (81 mg) or matching placebo taken up to six menstrual cycles attempting pregnancy and through 36 weeks' gestation in women who conceived. Confirmed pregnancy, live birth, and pregnancy loss were compared between LDA and placebo, stratified by tertile of preconception, preintervention serum high-sensitivity C-reactive protein (hsCRP) (low, <0.70 mg/L; middle, 0.70 to <1.95 mg/L; high, ≥1.95 mg/L). Live birth occurred in 55% of women overall. The lowest pregnancy and live birth rates occurred among the highest hsCRP tertile receiving placebo (44% live birth). LDA increased live birth among high-hsCRP women to 59% (relative risk, 1.35; 95% confidence interval, 1.08 to 1.67), similar to rates in the lower and mid-CRP tertiles. LDA did not affect clinical pregnancy or live birth in the low (live 59% LDA, 54% placebo) or midlevel hsCRP tertiles (live 59% LDA, 59% placebo). In women attempting conception with elevated hsCRP and prior pregnancy loss, LDA may increase clinical pregnancy and live birth rates compared with women without inflammation and reduce hsCRP elevation during pregnancy.
To explore the relationship between the type of clinician (generalist vs subspecialist) initially seen by infertile women, the treatment received, and the time to pregnancy. We analyzed mixed-mode questionnaire data from 867 women with primary infertility enrolled into a retrospective cohort through population- and fertility clinic-based sampling. We compared women presenting first to generalist providers with women presenting first to fertility subspecialists, with the main outcomes of receiving in vitro fertilization (IVF), time to pregnancy, and live birth. The first contact for most (84%) women with infertility was a generalist provider. Only 8% of women sought care first from a fertility subspecialist, and these women were older and had been trying longer to conceive. Women who presented first to a generalist provider were less likely to receive IVF (adjusted odds ratio, 0.48; 95% confidence interval, 0.28-0.82), were equally likely to achieve pregnancy, and had similar times to pregnancy (adjusted hazard ratio, 1.11; 95% confidence interval, 0.80-1.53) compared with women who presented first to a subspecialist. Generalist providers are frequently the first point of care for women with difficulty conceiving and are uniquely positioned to promote the balanced management of infertility.
Tamoxifen has played a vital role in endocrine therapy for the treatment of estrogen receptor-positive breast cancer. We examined the effect of tamoxifen in patients with a thin endometrium in frozen-thawed embryo transfer (FET) cycles and compared the improvement in endometrial thickness (EMT) and pregnancy outcomes stratified by different etiologies of thin endometrium. A total of 226 women were recruited for a new tamoxifen protocol; all had an EMT of less than 7.5 mm in previous cycles, including natural cycle (NC), hormone replacement treatment (HRT), and ovulation induction (OI) cycles. Compared with previous cycles, tamoxifen cycles showed a significantly increased EMT (from 6.11 ± 0.98 mm to 7.87 ± 1.48 mm in the NC group, from 6.24 ± 1.01 mm to 8.22 ± 1.67 mm in the HRT group, and from 6.34 ± 1.03 mm to 8.05 ± 1.58 mm in the OI group; all P < .001). Patients were further divided into 3 groups based on the causes (1) history of intrauterine adhesion (n = 34), (2) history of uterine curettage (n = 141), and (3) polycystic ovary syndrome (PCOS; n = 51). Patients with PCOS obtained the thickest EMT (9.31 ± 1.55 mm), the lowest cycle cancellation rate (11.76%), and the highest rate of clinical pregnancy (60%) and live birth (55.56%) per transfer ( P < .001). Multivariable regression analysis showed that EMT was related to live birth (odds 1.487; 95% 1.172-1.887). A tamoxifen protocol improves EMT in patients after NC, HRT, and OI cycles during FET. Patients with PCOS show the most benefit from tamoxifen and achieve better pregnancy outcomes.
This Committee Opinion provides practitioners with suggestions for optimizing the likelihood of achieving pregnancy in couples/individuals attempting conception who have no evidence of infertility. This document replaces the document of the same name previously published in 2013, Fertil Steril 2013;100(3):631-7.
To report on the presence and rate of endometriosis in hydatid cysts of Morgagni found at the time of excision surgery for endometriosis and to describe any association of endometriosis in hydatid cysts of Morgagni with preoperative or operative factors.
A retrospective cohort study (Canadian Task Force Classification II-2).
The Center for Endometriosis at Saint Louis University, a tertiary referral center for endometriosis. Women who underwent optimal excision surgery for suspected endometriosis because of chronic pelvic pain and/or infertility and who also had hydatid cysts of Morgagni removed at the time of surgery when found. Preoperative and operative data were collected prospectively. The rate of endometriosis in hydatid cysts of Morgagni. Secondary measures included are the rate of hydatid cysts of Morgagni in patients with pelvic pain or infertility with and without endometriosis in the cysts. The overall prevalence of endometriosis in hydatid cysts of Morgagni was 11.3%. Patients with pelvic pain had a higher rate (although not statistically significant) of hydatid cysts of Morgagni compared with those without pain (21.1% vs 12.5 %, p = .54). Patients with infertility had a higher rate of hydatid cysts of Morgagni compared with those without infertility (38.1% vs 16.7%, p < .001), and there was a higher rate of endometriosis in the hydatid cysts of Morgagni in patients with infertility compared with those without (11.1% vs 0.0%, p < .001). This study is the first known report of endometriosis found within hydatid cysts of Morgagni. With a rate of 11.3% of cysts of Morgagni having endometriosis within them, this study supports a practice of removing hydatid cysts of Morgagni at the time of surgery in order to achieve optimal excision of endometriosis. The rates of hydatid cysts of Morgagni and of endometriosis found within hydatid cysts of Morgagni were higher in patients with infertility. Further studies are needed to evaluate whether excising cysts of Morgagni affects clinical outcomes.
To analyze cumulative pregnancy rates of subfertile couples after fertility awareness training. A prospective observational cohort study followed 187 subfertile women, who had received training in self-observation of the fertile phase of the menstrual cycle with the Sensiplan method, for 8 months. The women, aged 21-47 years, had attempted to become pregnant for 3.5 years on average (range 1-8 years) before study entry. Amenorrhea, known tubal occlusion and severe male factor had been excluded. An additional seven women, who had initially been recruited, became pregnant during the cycle immediately this is taken to be the spontaneous pregnancy rate per cycle in the cohort in the absence of fertility awareness training. The cumulative pregnancy rate of subfertile couples after fertility awareness training was 38% (95% CI 27-49%; 58 pregnancies) after eight observation months, which is significantly higher than the estimated basic pregnancy rate of 21.6% in untrained couples in the same cohort. For couples who had been seeking to become pregnant for 1-2 years, the pregnancy rate increased to 56% after 8 months. A female age above 35 (cumulative pregnancy rate 25%, p = 0.06), couples who had attempted to become pregnant for more than 2 years (cumulative pregnancy rate 17%, p < 0.01), all significantly reduce the chances of conceiving naturally at some point. Training women to identify their fertile window in the menstrual cycle seems to be a reasonable first-line therapy in the management of subfertility.
Chronic endometritis (CE) is a condition involving the breakdown of the peaceful co-existence between microorganisms and the host immune system in the endometrium. A majority of CE cases produce no noticeable signs or mild symptoms, and the prevalence rate of CE has been found to be approximately 10%. Gynecologists and pathologists often do not focus much clinical attention on CE due to the time-consuming microscopic examinations necessary to diagnose CE, its mild clinical manifestations, and the benign nature of the disease. However, the relationship between CE and infertility-related conditions such as repeated implantation failure and recurrent miscarriage has recently emerged as an area of inquiry. In this study, we reviewed the literature on the pathophysiology of CE and how it may be associated with infertility, as well as the literature regarding the diagnosis and treatment of CE. In addition, we discuss the value of hysteroscopic procedures in the diagnosis and treatment of CE.
InfertilityDelayed ChildbearingPrevalence in Specific PopulationsCareer and Fertility
Female physicians may experience unique challenges regarding fertility and family planning. We sought to determine childbearing patterns and decision-making among American female physicians. In 2012-2013, we surveyed a random sample of 600 female physicians who graduated medical school between 1995 and 2000. Primary outcome measures included fertility and childbearing history, reflections regarding decision-making, perceptions of workplace support, and estimations of childbearing potential. Response rate was 54.5% (327/600). A majority (82.0%) of the sample were parents, 77.4% had biological children with an average of 2.3 children. Average age at medical school graduation was 27.5 years, at completion of training (completion of medical school, residency, and/or fellowship) was 31.6 years, and at first pregnancy was 30.4 years. Nearly one quarter (24.1%) of respondents who had attempted conception were diagnosed with infertility, with an average age at diagnosis of 33.7 years. Among those with infertility, 29.3% reported diminished ovarian reserve. When asked what they would do differently in retrospect, most respondents (56.8%) would do nothing differently regarding fertility/conception/childbearing, 28.6% would have attempted conception earlier, 17.1% would have gone into a different specialty, and 7.0% would have used cryopreservation to extend fertility. Fewer of those whose first pregnancy was in medical school perceived substantial workplace support (68.2%) than those whose first pregnancies followed training (88.6%). A substantial proportion of female physicians have faced infertility or have regrets about family planning decisions and career decision-making. Combining a medical career with motherhood continues to pose challenges, meriting further investigation and targeted support.
Endometriosis is a complex, inflammatory disease that affects 6-10% of reproductive-aged women. Almost half of the women with endometriosis experience infertility. Despite the excessive prevalence, the pathogenesis of endometriosis and its associated infertility is unknown and a cure is not available. While many theories have been suggested to link endometriosis and infertility, a consensus among investigators has not emerged. In this extensive review of the literature as well as research from our laboratory, we provide potential insights into the role of immune dysfunction in endometriosis associated infertility. We discuss the implication of the peritoneal inflammatory microenvironment on various factors that contribute to infertility such as hormonal imbalance, oxidative stress and how these could further lead to poor oocyte, sperm and embryo quality, impaired receptivity of the endometrium and implantation failure.
Buck Louis GM et al., 2016·J Womens Health (Larchmt)
Endometriosis is a gynecologic disease reported to be associated with infertility and, possibly, adverse pregnancy outcomes. While considerable research focuses on pregnancy outcomes following diagnosis and/or treatment, few data actually describe women's reproductive history before diagnosis for a more complete understanding of endometriosis and reproduction. The study sample comprised 473 women (aged 18-44 years) undergoing laparoscopies or laparotomies, irrespective of surgical indication at 14 clinical sites, during the period 2007-2009. Upon enrollment and before surgery, women were queried about pregnancy intentions and the time required to become pregnant for planned pregnancies. Endometriosis was defined as surgically visualized disease. Using discrete time survival analysis, we estimated fecundability odds ratios (FORs) and 95% confidence intervals (CIs) to assess time to pregnancy (TTP) after adjusting for potential confounders (age, body composition, cigarette smoking, site). Generalized estimating equations accounted for multiple pregnancy attempts per woman. FORs ResultsApproximately 66% and 69% of women with and without endometriosis, respectively, reported having a planned pregnancy before surgery, respectively. After adjustment, an endometriosis diagnosis was associated with ≈29% reduction in fecundity or a longer TTP across all pregnancy-trying attempts (adjusted FOR = 0.71; 95% CI 0.46-1.10). While FORs were consistently ConclusionsWomen with endometriosis had a longer TTP than unaffected women, irrespective of disease severity, although the findings did not achieve significance. Prior reproductive history may be informative for predicting fecundity and pregnancy outcomes following diagnosis/treatment.
Pelvic inflammatory disease (PID) and more specifically salpingitis (visually confirmed inflammation) is the primary cause of tubal factor infertility and is an important risk factor for ectopic pregnancy. The risk of these outcomes increases following repeated episodes of PID. We developed a homogenous discrete-time Markov model for the distribution of PID history in the UK. We used a Bayesian framework to fully propagate parameter uncertainty into the model outputs. We estimated the model parameters from routine data, prospective studies, and other sources. We estimated that for women aged 35-44 years, 33·6% and 16·1% have experienced at least one episode of PID and salpingitis, respectively (diagnosed or not) and 10·7% have experienced one salpingitis and no further PID episodes, 3·7% one salpingitis and one further PID episode, and 1·7% one salpingitis and ⩾2 further PID episodes. Results are consistent with numerous external data sources, but not all. Studies of the proportion of PID that is diagnosed, and the proportion of PIDs that are salpingitis together with the severity distribution in different diagnostic settings and of overlap between routine data sources of PID would be valuable.
The use of 2 × 2000 mg myoinositol + 2 × 200 μg folic acid per day is a safe and promising tool in the effective improvement of symptoms and infertility for patients with a polycystic ovary syndrome (PCOS). Using a questionnaire an observational study was performed under German gynecologists to collect data on ovulation and pregnancy rates in PCOS patients with infertility. In this observational study, 3602 infertile women used myoinositol and folic acid between 2 and 3 months in a dosage of 2 × 2000 mg myoinositol + 2 × 200 μg folic acid per day. In a subgroup of 32 patients, hormonal values for testosterone, free testosterone, and progesterone were analyzed before and after 12 weeks of treatment. The mean time of use was 10.2 weeks. During this time 70% of these women had a restored ovulation, and 545 pregnancies were obtained. This means a pregnancy rate of 15.1% of all the myoinositol and folic acid users. In 19 cases a concomitant medication with clomiphene or dexamethasone was used. One twin pregnancy was documented. Testosterone levels changed from 96.6 ng/ml to 43.3 ng/ml and progesterone from 2.1 ng/ml to 12.3 ng/ml (p < 0.05) after 12 weeks of treatment. No relevant side effects were present among the patients. This study could show that a new treatment option for patients with a PCOS and infertility is available. The achieved pregnancy rates are at least in an equivalent or even superior range than those reported by the use of metformin.
InfertilityOvarian Hyperstimulation Syndrome PreventionOHSS Risk ReductionSafety Protocols
Open Access
Ovarian hyperstimulation syndrome is a potentially life-threatening, but preventable iatrogenic complication of in vitro fertilisation treatment. In recent years, new strategies have been developed to minimise the risk of ovarian hyperstimulation syndrome after in vitro fertilisation, including better at-risk patient identification prior to starting treatment, the use of a lower human chorionic gonadotrophin dose or alternative medication instead of human chorionic gonadotrophin to induce final oocyte maturation such as gonadotrophin-releasing hormone agonist and kisspeptin in antagonist cycles, cryopreservation of all embryos and delayed embryo transfer, and the use of oral dopamine agonists after oocyte retrieval. In this article, the advantages and limitations of those new developments are discussed and future directions towards establishment of an ovarian hyperstimulation syndrome–free in vitro fertilisation clinic are explored.
Contraception/ComparisonIVF SafetyIVF ProceduresEmbryo Protection
Open Access
Wdowiak A et al., 2016·Videosurgery and Other Miniinvasive Techniques
In vitro fertilization (IVF) is a method of treatment for infertility in selected indications. Recent years have brought dynamic development of technologies related to IVF. This article presents problems pertaining to the safety of technology with respect to the patient, as well as the embryo, based on an analysis of scientific reports and our own experience. Invasiveness of the IVF procedure for the woman and the embryo varies on an individual basis. Minimization of the invasiveness of IVF requires experience of the staff performing the procedure, especially with respect to the assessment of risk for an individual patient. Technologies related to IVF are constantly being improved, and the effectiveness of the selected individual treatment methods is not always scientifically confirmed.
SurgeryCesarean Scar Defect RepairScar Defect ManifestationsCesarean Scar Defect and Fertility
The objective of this study was to evaluate the prevalence of cesarean scar defects and its clinical manifestations in reproductive-aged women. We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement using keywords of "cesarean scar defect, uterine scar defect, uterine diverticulum niche, isthmocele, pouch, or sacculation" and their combination. Thirty-two trials met the inclusion criteria. Cesarean scar defects are commonly found on ultrasound examination (24%-88%). Their presence could be asymptomatic or related to postmenstrual spotting, postmenstrual bleeding, or infertility. The prevalence of this condition is related to the number of cesarean deliveries. Hysteroscopic repair of a cesarean scar defect or isthmoplasty is associated with an improvement in uterine bleeding in 59% to 100% of cases and a pregnancy rate of 77.8% to 100%. An improvement in uterine bleeding after vaginal repair occurred in 89% to 93.5% of cases. Laparoscopic repair led to uterine bleeding improvement in 86% of cases and a pregnancy rate of 86%. The association between cesarean scar defect and infertility, pelvic pain, and dysmenorrhea require more studies. Treatment of uterine scar defects should be performed after eliminating other causes of postmenstrual bleeding or infertility. Hysteroscopic isthmoplasty appears to be the most popular treatment. However, in the absence of randomized trials, the efficacy of different surgical approaches remains to be seen. Until we have concrete evidence, the treatment should be reserved for selective cases.
The aim of this study was to evaluate the association between menstrual cycle characteristics in early life and adulthood and fecundability. Pregnancy Study Online (PRESTO) is an Internet-based preconception cohort study of pregnancy planners from the United States and Canada. During the preconception period, we enrolled 2189 female pregnancy planners aged 21-45 years who had been attempting conception for ≤6 cycles. Women self-reported menstrual cycle characteristics via an online baseline questionnaire, and pregnancy status was ascertained through bimonthly follow-up questionnaires. Proportional probabilities models were used to estimate fecundability ratios (FRs) and 95% confidence intervals (CIs), adjusting for potential confounders. Compared with usual menstrual cycle lengths of 27-29 days, cycle lengths of <25 (FR = 0.81, 95% CI: 0.54-1.22) and 25-26 days (FR = 0.92, 95% CI: 0.75-1.14) were associated with reduced fecundability. Compared with women who reached menarche at the age of 12-13 years, those who reached menarche at <12 years had reduced fecundability (FR = 0.87, 95% CI: 0.76-0.99). Women whose cycles never regularized after menarche (FR = 0.93, 95% CI: 0.81-1.06) had slightly reduced fecundability compared with women whose cycles regularized within 2 years of menarche. Bleed length and heaviness of bleeding were not appreciably associated with fecundability. Menstrual cycle characteristics, specifically cycle length and age at menarche, may act as markers of fertility potential among pregnancy planners.
Of the 237 women, 92 (38.8%) had experienced both a normal and a toxaemic pregnancy, and 72 (78%) contrasted the sense of well-being associated with a normal pregnancy with the malaise and minor symptoms characteristic of the toxaemic condition. The striking feature of these early minor symptoms of toxaemia was their close resemblance to those of premenstrual syndrome noted in an earlier investigation (Greene and Dalton, 1953), most patients confirming that the minor symptoms during their toxaemic pregnancy were similar, though of increased severity, to those experienced in the premenstruum, irrespective of whether the onset of premenstrual syndrome had preceded or followed the toxaemic pregnancy.
More than 70 million couples suffer from infertility worldwide. The aim of this study was to evaluate the fertility outcomes after laparoscopic fimbrioplasty and neosalpingostomy in female infertility. Laparoscopic distal tuboplasty was carried out for 402 cases at the Gynecological Endoscopic Surgery and Human Reproductive Teaching Hospital in Yaoundé-Cameroon in Central Africa from December 2002 to December 2007. Laparoscopic fimbrioplasty and neosalpingostomy were done using bipolar electrocoagulation and conventional endoscopic instruments. Log-rank test was used to compare cumulative rate curves of intrauterine pregnancy with respect to the tubal stages. P<0.05 was considered statistically significant. The mean age of the patients was 31.6±5.45 years. Secondary infertility was the most frequent type of infertility (70.14%). The laparoscopic tubal surgery done consisted of fimbrioplasty in 185(46%) cases and neosalpingostomy in 217 (54%) cases. Of 260 women followed up after tuboplasty, there were overall 74 (28.48%) pregnancies; 68(26.1%) intrauterine pregnancies and 6(2.3%) ectopic pregnancies. Pregnancy rates were significantly associated to the tubal stage (63% in stage 1, 15% in stage 3 and 00% in stage 4; p<0.001) and the adnexal adhesion scores (73.91% in the absence of adnexal adhesions and 8.8% in the case of a severe adnexal adhesion score). Of the 68 intrauterine pregnancies, there were 60(88%) live births and 8(12%) spontaneous abortions. It is believed that laparoscopic fimbrioplasty and neosalpingostomy should be the preferred choice when faced with tubal distal occlusion in a context of female infertility. This implies that training in endoscopic surgery should be regarded as an important issue in developing countries.
Reproductive EndocrinologyAMH and Vitamin DVitamin D and FecundabilitySecondary Analysis
Vitamin D is associated with markers of ovarian reserve in women of in studies suggest that vitamin D may influence anti‐mullerian hormone (AMH). Higher vitamin D levels are also associated with improved IVF outcomes in some studies. However, less is understood regarding associations with ovarian reserve or time to pregnancy among younger women or women without a history of infertility. Our purpose was to assess the relationships between vitamin D and AMH and fecundability among women with proven fecundity.
Secondary analysis of the EAGeR Trial, a multicenter, block‐randomized, double‐blind, placebo‐controlled clinical trial to evaluate the effect of preconception‐initiated daily low dose aspirin on reproductive outcomes in women with a history of pregnancy loss and normal fecundity. Participants were attempting pregnancy, aged 18–40 years, with 1–2 prior pregnancy losses and no history of infertility. We assessed 25‐OH vitamin D and AMH in serum at baseline (not pregnant) among 1185 women. AMH levels were log‐transformed for normality. Linear regression was used to estimate associations between vitamin D and AMH concentrations adjusting for age, body mass index, race, season, physical activity, and number of prior losses. Time to hCG detected pregnancy was assessed using Cox proportional hazard regression models for discrete survival time, accounting for left truncation and right censoring, to estimate fecundability odds ratios (FOR), adjusting for the same factors. A total of 163 women (13.8%) had deficient vitamin D levels (<20 ng/mL). Overall, vitamin D levels were not associated with AMH (percent change −1.6, 95% confidence interval [CI] −5.3%, 2.3% per 10 ng/mL). Vitamin D deficiency was also not associated with AMH (deficient: adjusted geometric mean AMH 2.51, 95% CI 2.20, 2.85 vs. 2.74, 95% CI 2.60, 2.89). There also were no significant associations observed between overall vitamin D levels or deficiency and fecundability (FOR 1.09, 95% CI 0.84, 1.42 comparing deficient vs. inadequate/sufficient) after adjustment. Vitamin D was not associated with AMH, time to pregnancy, or fecundability among women with proven fecundity. These results suggest that vitamin D is not associated with ovarian reserve or fecundability and that vitamin D supplementation may offer little clinical benefit for improving markers of ovarian reserve and fecundity.
Intramural Research Program, DIPHR, NICHD, NIH
To evaluate if antimüllerian hormone (AMH) is associated with pregnancy loss.
Prospective cohort study within a block-randomized, double-blind, placebo-controlled trial of low-dose aspirin.
Not applicable. PATIENT(S): Women (n = 1,228) were of ages 18-40 years with a history of one to two pregnancy losses and were actively attempting pregnancy without fertility treatment. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Pregnancy loss. RESULT(S): Relative risks (and 95% confidence interval [CIs]) of human chorionic gonadotropin (hCG)-detected and clinical pregnancy loss were assessed with the use of log binomial models with robust variance and inverse probability weights adjusted for age, race, body mass index, income, trial treatment assignment, parity, number of previous losses, and time since most recent loss. low (<1.00 ng/mL; n = 124), normal (referent; 1.00-3.5 ng/mL; n = 595), and high (>3.5 ng/mL; n = 483). Of the 1,202 women with baseline AMH data, 19 (17.3%) with low AMH experienced a clinical loss, compared with 61 (11.4%) with normal AMH and 50 (11.8%) with high AMH levels. Low or high AMH levels, compared with normal AMH, were not associated with clinical loss. Results for hCG-detected pregnancy loss mirrored those of clinical loss. CONCLUSION(S): AMH values were not associated with hCG-detected or clinical pregnancy loss in unassisted conceptions in women with a history of one to two previous losses. Our data do not support routine AMH testing for prediction of pregnancy loss. Trial NCT00467363.
Sanders JN et al., 2016·Paediatr Perinat Epidemiol
Most cohort-based research for subfertility has been conducted in clinic-based cohorts, which may differ from population-based cohorts. We retrospectively recruited parallel one by sampling two specialty fertility clinics in Utah, and one by population-based sampling based on marriage and birth records. The index date (of first clinic visit or subfertility status) was between 2000 and 2009, and we linked the women recruited to subsequent birth certificate records through December 2010. We enrolled 459 women through clinic-based sampling and 501 women through population-based sampling. Clinic-based women were older, had higher annual household income and more likely to have had a most intensive treatment of intrauterine insemination (31%) or in vitro fertilisation (46%) than women from population recruitment (19% and 14% respectively). Conversely, they were less likely to have received no medical treatment (9%) compared to women from population recruitment (41%). For both types of sampling, prior to eligibility screening, non-responders were less likely to link to a 51% vs. 58% for clinic-based, and 69% vs. 76% for the population-based with an index date in 2004. Population-based sampling for subfertility cohort research identifies women who were more likely to have had less intensive treatment or no treatment. However, in both clinic-based and population-based sampling, women who have had a live birth are more likely to respond to retrospective recruitment.
Is bilateral tubotubal anastomosis a successful treatment in an outpatient patient population? For women wanting children after tubal sterilization, bilateral tubotubal anastomosis is an effective outpatient treatment. With the current emphasis in reproductive medicine on high technology procedures, the effectiveness of female surgical sterilization reversal is often overlooked. Previous clinical studies of tubal sterilization reversal have been mostly retrospective analyses of small patient populations. STUDY DESIGN, SIZE, A cohort of women who underwent outpatient bilateral tubotubal anastomosis from January 2000 to June 2013 was followed prospectively until December 2014 to determine the proportions of women undergoing the procedure who became pregnant and who had live births. Data were collected at the time of pregnancy. Differences in pregnancy rates and live birth rates associated with age, race and sterilization method were evaluated. PARTICIPANTS/MATERIALS, SETTING, A total of 6692 women, aged 20-51 years, underwent outpatient bilateral tubotubal anastomosis. MAIN The crude overall pregnancy rate was 69%. The crude overall birth rate was 35%. Results varied according to age at sterilization reversal and the method of sterilization. Women under 30 years of age at reversal of ring/clip sterilizations had an 88% pregnancy rate and 62% birth rate. Pregnancy and birth rates declined as age increased at sterilization reversal. Coagulation sterilization reversals resulted in the lowest rates of pregnancies and births. Ligation/resection reversals had intermediate success rates. LIMITATIONS, Limitations of our study include probable underreporting of pregnancies based on patient-initiated reports; possible errors in the reporting of pregnancies or early miscarriages that may have been based solely on home pregnancy tests; and probable over-reporting of the diagnosis of ectopic pregnancies. We identified age and sterilization method as being associated with subsequent pregnancy, however, in order to be considered predictive, the associations would need to be validated in an independent second prospectively studied group of representative patients. Finally, we also included patients in the study population who had additional surgical procedures performed at the time of tubotubal anastomosis (e.g. uterine myomectomy, fimbrioplasty, ovarian cystectomy and adhesiolysis), factors that could result in differences in pregnancy statistics in our study versus other patient populations. The results of this study can help inform patients and clinicians about this low technology alternative to IVF. None. N/A.
Petousis S et al., 2016·J Matern Fetal Neonatal Med
To compare the expression of progesterone receptors (A + B) and type-B progesterone receptors in the epithelial and stromal cells of fertile and infertile women. Women were divided into two groups, the group of fertile controls (group 1) and the group of infertile women (group 2) and were set on regular ultrasound imaging in order to detect ovulation. An endometrial biopsy was obtained on the seventh or eighth post-ovulatory day. Immunohistochemistry was performed to measure percentage of positive nuclei, intensity of staining and h-score for progesterone receptors (PgR) (A + B) as well as type-B progesterone receptors in epithelial and stromal cells. Secondary outcomes included endometrial tissue dating, the rate of tissues being out-of-phase and endometrial thickness. Endometrial issue was obtained from 15 fertile and 30 infertile women. Expression of PgR (A + B) and PgR type-B was significantly lower in the epithelial cells of infertile women. PgR (A + B) h-score was 220.0 ± 18.5 for fertile versus 147.3 ± 18.0 for infertile women (p = 0.02). PgR type-B h-score in epithelial cells was 166.8 ± 30.7 for fertile versus 90.8 ± 20.6 for infertile (p = 0.04). No significant difference was observed in stromal cells. Expression levels of PgR (A + B) as well as type-B receptors are significantly lower in the epithelial cells of infertile women during implantation window.
What is the association between daily preconception-initiated low-dose aspirin (LDA) treatment and very early pregnancy losses or euploid (chromosomally normal) losses among women with one to two prior losses? Daily LDA initiated preconception was not associated with the rate or type of pregnancy loss among women with a history of one to two prior pregnancy losses. LDA is often used to treat recurrent pregnancy loss with reductions in pregnancy loss generally only observed among women with antiphospholipid antibodies, and null associations observed among women without antiphospholipid antibodies. We previously evaluated the association between LDA and pregnancy loss overall among women with one to two prior losses in the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial and found no association, though did not distinguish between potential effects at different stages of pregnancy loss, including implantation failure, or between euploid and aneuploid losses. STUDY DESIGN, SIZE, The EAGeR trial was a multi-site prospective block-randomized double-blind placebo-controlled trial. In total, 1228 women were randomized to daily LDA (81 mg/day) plus folic acid (400 mcg/day), or placebo plus folic acid. Participants were assigned study drug for less than or equal to six menstrual cycles or if they conceived, throughout pregnancy with study drug discontinued at 36 weeks gestation. This analysis includes additional outcome information obtained from chart abstractions after the completion of the trial, as well as testing of stored urine for measurement of hCG and detection of very early pregnancy losses, and karyotyping of the products of conception for assessment of aneuploidy of the losses. PARTICIPANTS, SETTING, Women aged 18-40 with a history of one to two prior losses and actively trying to conceive were randomized (n = 615 LDA and n = 613 placebo) at four clinical centers in the USA (2007-2011). Log-binomial regression was used to estimate risk ratios under the intent-to-treat approach. Main Daily LDA initiated preconception was not associated with clinically recognized pregnancy losses or implantation failures among women with proved fecundity and a history of one to two prior losses. Specifically, 1088 (88.6%) women completed the trial with 797 having an hCG detected pregnancy (64.9%). Overall there were 133 clinical losses (12.7% LDA versus 11.8% placebo, P = 0.71) and 55 implantation failures (5.2% LDA versus 4.9% placebo, P = 0.89). No differences were found in rate of euploid losses (RR 1.11, 95% 0.99, 1.26). LIMITATIONS, Generalizability of these findings is limited to women with a history of one to two prior losses, and may further be limited to women of white race with higher socioeconomic status as given the rigors of the study protocol participants tended to be white and have higher incomes and more education. We were also missing karyotype information on approximately one-third of the clinically recognized pregnancy losses, which may limit our power to detect effects on euploid losses, though detailed sensitivity analysis showed similar results. Our data do not support the general use of LDA to decrease pregnancy loss and further demonstrate no increased risk of loss for women on LDA treatment. This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (Contract Nos. HHSN267200603423, HHSN267200603424, HHSN267200603426). The authors have no conflicts of interest. The trial was registered at ClinicalTrials.gov #NCT00467363. 27 April 2007. DATE OF FIRST PATIENT'S 15 June 2007.
PregnancyInterpregnancy IntervalPost-MiscarriagePregnancy Loss Guidelines
The article raises the issue of today’s application of assisted (artificial) reproduction methods, which are incom-patible with human dignity. The authors articulate the principles of human dignity, which are formulated as an evaluation tool of criteria and them revealing system of indicators in the assessed object. The article compares Naprotechnology as a contemporary holistic method of diagnosis and treatment of infertility, which comprises therapeutic, surgical and fertility awareness method, with methods of assisted reproduction and identifies their medical and ethical differences. The project of the Assisted Reproduction Law of the Republic of Lithuania is evaluated in the aspect of human dignity as well.
Flores R, 2016·Scholars Academic Journal of Biosciences
The latest retrievable data about infertility in the Philippines was made available to the public by Merck Serono, a private pharmaceutical company who commissioned the survey in 2011. The survey was conducted by Synovate in 100 participating households in the Philippines, particularly in key cities located in Luzon, Visayas and Mindanao. The survey results revealed that one out of ten Filipino couples are suffering from infertility. And these couples are not seeking treatment (1) financial constraints; (2) time constraints; and (3) the patient’s belief. Of all these, financial constraints, at 86%, is the primary reason why infertile couples are not seeking treatment. In addition to this data, the Chief of The Medical City’s Reproductive Medicine, Infertility and Gynecologic Endoscopy, Dr. Marc Anthony Ancheta, further reveals that “some 35 to 40% of a couple’s inablity to conceive a child are due to female factors; while the other 35 to 40% could be attributed to male factors.” While male factor infertility is also deserving of proper attention, it is the female factor infertility that should receive greater attention and focus in terms of treatment. Why? Because, primarily, the female’s reproductive cycle is very complex and would need months and/or years to partially identify the underlying reason/s of infertility; and second, the female’s ability to conceive naturally will fall by 50% when she reached the age of 35. Therefore, there should be urgency in treating female factor infertility in an efficient, ethical and affordable way. And these conditions can be achieved by the use of NaPro Technology.
To evaluate the relationship between epigenetic patterns in sperm and fecundity.
Prospective study.
Academic andrology and in vitro fertilization laboratory. PATIENT(S): Twenty-seven semen samples from couples who conceived within 2 months of attempting a pregnancy and 29 semen samples from couples unable to achieve a pregnancy within 12 months. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Genomewide assessment of differential sperm DNA methylation and standard semen analysis. RESULT(S): We analyzed DNA methylation alterations associated with fecundity in 124 semen samples, and identified regions of interest in 27 semen samples from couples who conceived within 2 months of attempting a pregnancy and a total of 29 semen samples from couples who were unable to achieve a pregnancy within 12 months. No differences in sperm count, sperm morphology, or semen volume were observed between the patients achieving a pregnancy within 2 months of study time and those not obtaining a pregnancy within 12 months. However, using data from the human methylation 450k array analysis we did identify two genomic regions with statistically significantly decreased (false discovery rate <0.01) methylation and three genomic regions with statistically significantly increased methylation in the failure-to-conceive group. The only two sites where decreased methylation was associated with reduced fecundity are at closely related genes known to be expressed in sperm, HSPA1L and HSPA1B. CONCLUSION(S): Our data suggest that there are genomic loci where DNA methylation alterations are associated with decreased fecundity. We have thus identified candidate loci for future study to verify these results and investigate the causative or contributory relationship between altered sperm methylation and decreased fecundity.
Progesterone is essential for the maintenance of pregnancy. However, whether progesterone supplementation in the first trimester of pregnancy would increase the rate of live births among women with a history of unexplained recurrent miscarriages is uncertain. We conducted a multicenter, double-blind, placebo-controlled, randomized trial to investigate whether treatment with progesterone would increase the rates of live births and newborn survival among women with unexplained recurrent miscarriage. We randomly assigned women with recurrent miscarriages to receive twice-daily vaginal suppositories containing either 400 mg of micronized progesterone or matched placebo from a time soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) through 12 weeks of gestation. The primary outcome was live birth after 24 weeks of gestation. A total of 1568 women were assessed for eligibility, and 836 of these women who conceived naturally within 1 year and remained willing to participate in the trial were randomly assigned to receive either progesterone (404 women) or placebo (432 women). The follow-up rate for the primary outcome was 98.8% (826 of 836 women). In an intention-to-treat analysis, the rate of live births was 65.8% (262 of 398 women) in the progesterone group and 63.3% (271 of 428 women) in the placebo group (relative rate, 1.04; 95% confidence interval [CI], 0.94 to 1.15; rate difference, 2.5 percentage points; 95% CI, -4.0 to 9.0). There were no significant between-group differences in the rate of adverse events. Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with a history of unexplained recurrent miscarriages. (Funded by the United Kingdom National Institute of Health Research; PROMISE Current Controlled Trials number, ISRCTN92644181.).
Luteinized unruptured follicle (LUF) syndrome is considered a cause of ovulation failure and a subtle cause of infertility. Preovulatory injection of human chorionic gonadotropin (HCG) prevents or treats LUF syndrome, but it has also occurred after the induction of ovulation with clomiphene/HMG and HCG. This study was designed for evaluation and comparison of LUF incidence in eligible infertile women undergoing two stimulation protocols (clomiphene + HMG and letrozole + HMG) in addition to intrauterine insemination (IUI). Some related factors were compared between LUF and non-LUF cycles as secondary outcomes. The study was designed as a prospective randomized controlled trial. Patients were randomized using a table of random numbers into two equal protocol groups. For group A, (n = 90) clomiphene citrate was administrated orally in doses of 100 mg/day, and group B (n = 90) orally received letrozole 5 mg/day from day 3 to 7 of the menstrual cycle. Then HMG 75IU/day was administered intramuscularly in both groups on day 8 of the menstrual cycle and the dose was adjusted on the basis of ovarian response. The optimum size of preovulatory follicles for the injection of HCG (10,000 IU) was considered 18-23 mm. The number and size of preovulatory follicles were assessed by vaginal ultrasound 12 h before HCG (D0). Endometrial thickness was measured as well. IUI was performed on all patients 38-40 h after HCG. The second ultrasound examination was performed to observe the evidence of oocyte releasing at the time of IUI (D1). If the follicles were unruptured, a third sonography was performed on day 7 after HCG (D7) to observe LUF syndrome. There was a significant difference between clomiphene-HMG and letrozole-HMG in LUF (p = 0.021) and pregnancy (p = 0.041). The complete LUF in letrozole-HMG was lower than the alternative group and the pregnancy rate was higher. The patients in the non-LUF group had higher midluteal progesterone and a thicker endometrium compared to LUF cycles (p = 0.039) and (p < 0.001). The results of our multivariate logistic regression indicate that size 18-19.9 mm leads to the complete LUF less than ≥22 mm [AOR: 0.25, P = 0.005], and in size 20- 21.9 mm as well [AOR: 0.17, P = 0.002]. Letrozole, with lower incidences of LUF, is more effective than clomiphene citrate for the induction of ovulation in IUI cycles. In our study, we illustrated that larger follicles of ≥22 mm diameter were associated with higher incidences of LUF. We recommend that further studies investigate and focus on the relationship between follicular size and/or full hormonal profiles and LUF.
The objective of the study was to evaluate whether anti-Müllerian hormone (AMH) is associated with fecundability among women with proven fecundity and a history of pregnancy loss.
This was a prospective cohort study within a multicenter, block-randomized, double-blind, placebo-controlled clinical trial ( clinicaltrials.gov , number NCT00467363).
The study was conducted at four US medical centers (2006-2012). Participating women were aged 18-40 years, with a history of one to two pregnancy losses who were actively attempting pregnancy. Time to human chorionic gonadotropin detected and clinical pregnancy were assessed using Cox proportional hazard regression models to estimate fecundability odds ratios (fecundability odds ratios with 95% confidence interval [CI]) adjusted for age, race, body mass index, income, low-dose aspirin treatment, parity, number of previous losses, and time since most recent loss. Analyses examined low (<1.00 ng/mL, n = 124); normal (referent 1.00-3.5 ng/mL, n = 595); and high (>3.5 ng/mL, n = 483). Of the 1202 women with baseline AMH levels, 82 women with low AMH (66.1%) achieved an human chorionic gonadotropin detected pregnancy, compared with 383 with normal AMH (65.2%) and 315 with high AMH level (65.2%). Low or high AMH levels relative to normal AMH (referent) were not associated with fecundability (low fecundability odds ratios 1.13, 95% CI 0.85-1.49; FOR 1.04, 95% CI 0.87-1.24). Lower and higher AMH values were not associated with fecundability in unassisted conceptions in a cohort of fecund women with a history of one or two prior losses. Our data do not support routine AMH testing for preconception counseling in young, fecund women.
Chronic endometritis (CE) is a local inflammatory disease characterized by unusual plasmacyte infiltration in the endometrial stromal areas. CE has been neglected in gynecologic practice, as it is a less symptomatic benign disease that requires demanding and time-consuming histopathologic examinations for the definite diagnosis. Recent studies, however, suggest the association of CE with infertility and obstetric and neonatal complications. In this review article, we aimed to update the knowledge on epidemiology, etiology, and pathogenesis of CE as well as discuss its clinical management from diagnosis to treatment.
Thyroid autoimmunity with normal thyroid function is associated with recurrent miscarriage (RM), but the association with live birth is less clear. Therefore, we determined the association between thyroid peroxidase antibodies (TPO-Ab) and live-birth rate (LBR) in a retrospective cohort of euthyroid women with unexplained RM. We included 202 women of which 28 were TPO-Ab positive (13.9%) and 174 were TPO-Ab negative. TPO-Ab positive women (n = 10) without levothyroxine treatment had a lower LBR (29%) compared to TPO-Ab negative women (51%) (HR 0.23, 0.07-0.72, p = 0.012). The LBR in women with TPO-Ab receiving levothyroxine was not different compared women without TPO-Ab (60% versus 51%, p = 0.50). In conclusion, TPO-Ab are associated with a lower LBR in euthyroid women with unexplained RM and these women may benefit from treatment with levothyroxine.
NaProTECHNOLOGYAlternative to IVFEugenics and IVFNaProTECHNOLOGY vs IVF
Open Access
In vitro fertilization (IVF) is a method known almost all over the world, by which modern man is trying to cope with the problem of infertility. The aim of this article is to show the eugenic roots of in vitro and to attempt to reconciliate the supporters and opponents of this controversial procedure at a NaProTechnological plane. In order to achieve this, the author characterizes IVF from the technical, medical and legal point of view. Then, the article shows the relationship between the in vitro procedure and eugenic thought. The third section contextualizes the problem of artificial insemination in the contemporary, human uncritical faith in technological progress. The last part of this article directs the reader's attention towards NaProTechnology – a method of infertility treatement which can engage both the supporters and the opponents of IVF.
Many women throughout the world have history of subfertility (resolved or unresolved), but much remains unknown about services and treatments chosen. We developed a mixed-mode fertility experiences questionnaire (FEQ) in 2009 through literature review and iterative pilot work to optimize question format and mode of administration. The focus of the FEQ is to collect data retrospectively on time at risk for pregnancy, fertility treatments received and declined, pregnancy, time to pregnancy and pregnancy outcomes. We conducted a validation of key elements of the FEQ with comparison to medical records in 2009 and 2010. The validation sample was selected from women initially seen at a specialized fertility treatment center in Utah in 2004. The FEQ was 1) written (paper or web-based), self-administered, followed by 2) telephoneadministered questions. In 63 patients analyzed, high levels of correlation were identified between patient self-report and medical records for the use of intrauterine insemination and assisted reproductive technology, pregnancy and live birth histories, time at risk for pregnancy and time to pregnancy. There was low correlation between medical records and self-report for the use of oral ovulation drugs and injectable ovulation drugs. Compared to the medical record, the FEQ was over 90% sensitive for all elements, except injectable ovulation drugs (70% sensitivity). The FEQ accurately captured elements of fertility treatment history at 5-6 years after the first visit to a specialty clinic.
To investigate perinatal outcomes associated with fertility treatments, including assisted reproductive technology (ART), intrauterine insemination with ovulation stimulation (IUI), and ovulation stimulation alone (OS). Population-representative cross-sectional survey of women with live births, 2004-2008. Florida, Maryland, and Utah, USA. 21 803 women, weighted to represent 1 022 597 women. Survey and birth certificate data were analysed with logistic regression models adjusted for age, education, race, income, and parity, using separate models for singletons and all births. (1) women who never used fertility treatment and (2) subfertile women conceiving without treatment. Preterm birth (<37 weeks), very preterm birth (<34 weeks), low birthweight (<2500 g), and very low birthweight (<1500 g). Referent group 1: In singletons, ART was associated with preterm birth (OR 3.28; 95% CI 1.74, 6.20) and low birthweight (OR 2.91; 95% CI 1.99, 4.26). OS was also associated with low birthweight (OR 1.62; 95% CI 1.19, 2.19). Including all births, treatment was associated with preterm ART (OR 6.21; 95% CI 4.21, 9.16 and OR 6.51; 95% CI 4.85, 8.73); IUI (OR 2.10; 95% CI 1.24, 3.56 and OR 2.41; 95% CI 1.54, 3.76); OS (OR 1.40; 95% CI 1.01, 1.94 and OR 2.10; 95% CI 1.60, 2.75), respectively. Referent group 2: ART was associated with both outcomes in all births, but not singletons. Preterm birth and low birthweight associated with fertility treatments are largely attributable to multiple gestation, but are also related to underlying subfertility. Preterm birth is associated with subfertility, and with fertility treatments through multiple gestation.
The aim of the present study was to assess the efficacy of endoscopic repair for secondary infertility caused by post-cesarean scar defect (PCSD). Our investigation focused on the validity of new diagnostic criteria and selection methods. The subjects were 22 women with secondary infertility due to PCSD with retention of bloody fluid in the uterine cavity. Women with a residual myometrial thickness of ≥ 2.5 mm and an anteflexed or straight uterus underwent hysteroscopic surgery, while all others underwent laparoscopic repair. Hysteroscopic surgery involved resection and coagulation of scarred areas, whereas laparoscopic surgery involved removal of scarred areas combined with hysteroscopy, followed by resuturing. Fourteen of the 22 women (63.6%) who were followed up for ≥ 1 year after surgery achieved pregnancy. Pregnancies occurred in all four women (100%) who underwent hysteroscopic surgery and in 10 of the 18 women (55.6%) who underwent laparoscopic surgery. Three out of four women who underwent hysteroscopic surgery had term deliveries. Among the women who underwent laparoscopic surgery, five had term deliveries. No cases of uterine rupture were experienced, and the delivery method was cesarean section in all cases. We propose that infertility associated with PCSD, cesarean scar syndrome, is caused by the retention of bloody fluid in the uterine cavity and scarring. Endoscopic treatment, such as hysteroscopy or laparoscopy, was effective for cesarean scar syndrome.
Female infertility is a complex issue encompassing a wide variety of diagnoses, many of which are caused or affected by adhesions. The study intended to examine the rates of successful treatment of infertile women using a protocol of manual physical therapy to address underlying adhesive disease leading to infertility. Methods • The research team designed a retrospective chart review.
The study took place in a private physical therapy clinic. Participants were 1392 female patients who were treated at the clinic between the years of 2002 and 2011. They had varying diagnoses of infertility, including occluded fallopian tubes, hormonal dysfunction, and endometriosis, and some women were undergoing in vitro fertilization (IVF). Intervention • All patients underwent whole-body, patient-centered treatments that used a protocol of manual physical therapy, which focused on restoring mobility and motility to structures affecting reproductive function. Improvements demonstrated in the condition(s) causing infertility were measured by improvements in tubal patency and/or improved hormone levels or by pregnancy. Results • The results included a 60.85% rate of clearing occluded fallopian tubes, with a 56.64% rate of pregnancy in those patients. Patients with endometriosis experienced a 42.81% pregnancy rate. The success rate was 49.18% for lowering elevated levels of follicle stimulating hormone (FSH), with a 39.34% pregnancy rate in that group, and 53.57% of the women with polycystic ovarian syndrome (PCOS) achieved pregnancy. The reported pregnancy rate for patients who underwent IVF after the therapy was 56.16%. The results also suggested that the treatment was effective for patients with premature ovarian failure (POF). The manual physical therapy represented an effective, conservative treatment for women diagnosed as infertile due to mechanical causes, independent of the specific etiology.
SurgeryTubal Repair vs IVFTreatment OptionsFallopian Tube Restoration
American Society for Reproductive Medicine, 2015·Fertil Steril
This document reviews surgical options for achieving patency in obstructed fallopian tubes and the factors that must be considered when deciding between surgical repair and IVF. This document replaces the document of the same name, last published in 2012 (Fertil Steril 2012;97:539–45).
Schisterman EF et al., 2015·J Clin Endocrinol Metab
The objective was to determine the effect of preconception-initiated daily low-dose aspirin (LDA; 81 mg/day) treatment on time to pregnancy in women with a history of pregnancy loss.
This was a multicenter, block-randomized, double-blind, placebo-controlled trial. Participants were block-randomized by center and eligibility stratum.
The study was conducted at four U.S.A. medical centers (2007-2012). Participants women aged 18-40 years actively attempting pregnancy, stratified the "original" stratum, women with one loss <20 weeks' gestation during the previous year; and the "expanded" stratum, women with one or two previous losses of any gestational age regardless of time since loss. Daily LDA was compared with matching placebo for up to six menstrual cycles of attempting pregnancy. Time to hCG detected pregnancy and clinically confirmed pregnancy, analyzed by intention-to-treat, was measured. Of the 1228 women randomly assigned to LDA (n = 615) or placebo (n = 613), 410 (67%) women receiving LDA achieved pregnancy compared to 382 (63%) receiving placebo, corresponding to a fecundability odds ratio (FOR) of 1.14 (95% CI: 0.97, 1.33). Among women in the original stratum (n = 541), LDA was associated with increased fecundability compared to placebo (For: 1.28; 95%CI: 1.02, 1.62). Preconception-initiated LDA treatment resulted in a nonsignificant increase in fecundability of 14% in women with a history of 1-2 pregnancy losses, and a significant increase of 28% in women with a history of only one pregnancy loss of <20 weeks' gestation in the preceding year. Preconception-initiated LDA may increase fecundability in certain women with a recent early pregnancy loss.
To determine whether in vitro fertilization with preimplantation genetic screening (IVF/PGS) is cost effective compared with expectant management in achieving live birth for patients with unexplained recurrent pregnancy loss (RPL). Decision analytic model comparing costs and clinical outcomes. Academic recurrent pregnancy loss programs. PATIENT(S): Women with unexplained RPL. INTERVENTION(S): IVF/PGS with 24-chromosome screening and expectant management. MAIN OUTCOMES MEASURE(S): Cost per live birth. RESULT(S): The IVF/PGS strategy had a live-birth rate of 53% and a clinical miscarriage rate of 7%. Expectant management had a live-birth rate of 67% and clinical miscarriage rate of 24%. The IVF/PGS strategy was 100-fold more expensive, costing $45,300 per live birth compared with $418 per live birth with expectant management. CONCLUSION(S): In this model, IVF/PGS was not a cost-effective strategy for increasing live birth. Furthermore, the live-birth rate with IVF/PGS needs to be 91% to be cost effective compared with expectant management.
We sought to assess the relationship between a short interpregnancy interval (IPI) following a pregnancy loss and subsequent live birth and pregnancy outcomes. A secondary analysis of women enrolled in the Effects of Aspirin in Gestation and Reproduction trial with a human chorionic gonadotropin-positive pregnancy test and whose last reproductive outcome was a loss were included in this analysis (n = 677). IPI was defined as the time between last pregnancy loss and last menstrual period of the current pregnancy and categorized by 3-month intervals. Pregnancy outcomes include live birth, pregnancy loss, and any pregnancy complications. These were compared between IPI groups using multivariate relative risk estimation by Poisson regression. Demographic characteristics were similar between IPI groups. The mean gestational age of prior pregnancy loss was 8.6 ± 2.8 weeks. The overall live birth rate was 76.5%, with similar live birth rates between those with IPI ≤3 months as compared to IPI >3 months (adjusted relative risk [aRR], 1.07; 95% confidence interval [CI], 0.98-1.16). Rates were also similar for periimplantation loss (aRR, 0.95; 95% CI, 0.51-1.80), clinically confirmed loss (aRR, 0.75; 95% CI, 0.51-1.10), and any pregnancy complication (aRR, 0.88; 95% CI, 0.71-1.09) for those with IPI ≤3 months as compared to IPI >3 months. Live birth rates and adverse pregnancy outcomes, including pregnancy loss, were not associated with a very short IPI after a prior pregnancy loss. The traditional recommendation to wait at least 3 months after a pregnancy loss before attempting a new pregnancy may not be warranted.
To assess the effects of both male and female body mass index (BMI), individually and combined, on IVF outcomes.
Prospective cohort study.
University fertility center. PATIENT(S): All couples undergoing first fresh IVF cycles, 2005-2010, for whom male and female weight and height information were available (n = 721 couples). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Embryologic parameters, clinical pregnancy, and live birth incidence. RESULT(S): The average male BMI among the study population was 27.5 ± 4.8 kg/m(2) (range, 17.3-49.3 kg/m(2)), while the average female BMI (n = 721) was 25.2 ± 5.9 kg/m(2) (range, 16.2-50.7 kg/m(2)). Neither male nor female overweight (25-29.9 kg/m(2)), class I obese (30-34.9 kg/m(2)), or class II/III obese (≥35 kg/m(2)) status was significantly associated with fertilization rate, embryo score, or incidence of pregnancy or live birth compared with normal weight (18.5-24.9 kg/m(2)) status after adjusting for male and female age, partner BMI, and parity. Similar null findings were found between combined couple BMI categories and IVF success. CONCLUSION(S): Our findings support the notion that weight status does not influence fecundity among couples undergoing infertility treatment. Given the limited and conflicting research on BMI and pregnancy success among IVF couples, further research augmented to include other adiposity measures is needed.
Endometriosis is defined as the presence of endometrial-like tissue (glands or stroma) outside the uterus, which induces a chronic inflammatory reaction. Although endometriosis impairs fertility, it does not usually completely prevent conception. The question of evidence based-medicine guidelines in endometriosis-associated infertility is weak in many situations. Therefore, we will highlight in this issue where the challenges are.
Luteal phase deficiency (LPD), while commonly observed and managed in stimulated in-vitro fertilisation cycles, is a more contentious phenomenon in natural cycles. The challenge arises in the definition and diagnosis of LPD. Controversy regarding the clinical significance of LPD is due in part to the lack of a reliable test to diagnose the disorder.2 Jones first described LPD based on temperature criteria, urinary pregnanediol studies and histological appearance of the endometrium in 1949. 3 In current practice, timing of the luteal phase from which an evaluation of its length and hormonal parameters can be made are problematic. Ovulation and thereby the length of the luteal phase can reliably and reproducibly be determined by teaching women to identify their Peak Symptom Day (PSD) of cervical mucus (the last day of any mucus discharge that is clear, stretchy, or lubricative). 4 There is an abrupt and dramatic change in the characteristic fertile pattern of pre-ovulatory mucus that is due to the effects of progesterone post-ovulation. Correlation with ultrasound and hormonal evaluation indicates that the mucus observation occurs within 2 days of ovulation. Using such a fertility awareness based method, the American Academy of Fertility Care Professionals has defined a luteal phase deficiency as a deficiency in the length of the luteal phase, or a deficiency of the hormones progesterone and oestradiol that occurs during the luteal phase. Women presenting with infertility or recurrent miscarriages to the Fertility Assessment and Research Clinic of the Mater Mothers' Hospital (Brisbane, Australia) were instructed in the Sympto-Thermal Method. This allowed for accurate documentation of ovulation and the luteal phase. Luteal phase hormone levels were collected 5, 7 and 9 days after ovulation. Women were allocated a luteal phase status using the definition below for luteal phase defect. This data is part of the recruitment phase of the Pregnancy Achieving Trials (Mater Health Services HREC no. 1618M). By the definition above, a luteal phase deficiency exists in 36% (100) of 279 infertile couples who presented to our clinic, in preparation for involvement in the Pregnancy Achieving Trials. Of 16 infertile women who had previously experienced both a miscarriage and an ectopic pregnancy, 75% (12) met the criteria for a luteal phase deficiency. Ectopic pregnancy is known to be associated with infectious history, smoking, age, previous spontaneous miscarriage, history of infertility, previous use of an intrauterine device and prior history of medical termination of pregnancy (mifepristone + misoprostol). Previous research has suggested an association between luteal phase defect (LPD) and ectopic pregnancy in subfertile couples." All stimulated cycles of in-vitro fertilisation have abnormal luteal phases.' There exists a high rate of ectopic pregnancy among women undergoing in-vitro fertilization. The high proportion of ectopic pregnancies among women who fall pregnant on progestogen-only contraceptives also suggests an hormonal association." Women who are heavy smokers, another risk factor associated with ectopic pregnancy, has been shown to have lower urinary progesterone metabolite levels in the luteal phase compared with non-smokers. 10 There appears to be an association between prior miscarriage, prior ectopic pregnancy and luteal phase deficiency in subfertile couples. Could luteal phase deficiency, an hormonal disorder, be useful in the definition of ectopic pregnancy risk?
Fertility awareness based methods (FABMs) can be used to ameliorate the likelihood to conceive. A literature search was performed to evaluate the relationship of cervical mucus monitoring (CMM) and the day-specific -pregnancy rate, in case of subfertility. A MEDLINE search revealed a total of 3331 articles. After excluding articles based on their relevance, 10 studies and were selected. The observed studies demonstrated that the cervical mucus monitoring (CMM) can identify the days with the highest pregnancy rate. According to the literature, the quality of the vaginal discharge correlates well with the cycle-specific probability of pregnancy in normally fertile couples but less in subfertile couples. The results indicate an urgent need for more prospective randomised trials and -prospective cohort studies on CMM in a subfertile population to evaluate the effectiveness of CMM in the subfertile couple.
PCOSOvulation InductionLetrozole vs ClomipheneRandomized Controlled Trial
The Creighton Model FertilityCare System (CrMS) teaches women to identify days when intercourse is likely to result in pregnancy. We sought to assess the impact of the CrMS on time to pregnancy (TTP), via per-cycle pregnancy rates (fecundability). We conducted a parallel randomised trial at the University of Utah School of Medicine, 2003-06. Women ages 18-35 years, in a relationship of proven fertility, who desired to conceive, were block-randomised and stratified for age, with allocation concealment by opaque sequentially numbered sealed envelopes. The control group received the advice to have intercourse 2-3 times per week, and the intervention group received CrMS instruction. All women were asked to begin trying to conceive starting the second cycle in the study and were followed actively up to seven cycles, without blinding of research personnel. We calculated descriptive statistics and fecundability, and estimated Cox models for TTP. (Clinicaltrials.gov NCT00161395). There were 143 71 to the control group (all analysed) and 72 to the CrMS group (69 analysed). The adjusted hazard ratio for the influence of CrMS on TTP was 0.86 [95% confidence interval (CI): 0.53, 1.38]. Fecundability in cycles with intent to conceive was 31% in controls and 36% with CrMS (P = 0.32). By the first cycle, fecundability was 17% in controls, and 4% with CrMS (P = 0.02). No adverse events were reported. We found no significant impact of CrMS on TTP or fecundability, but fewer of the women receiving CrMS conceived by the first cycle.
Knowledge regarding the role of the cervix in fertility has expanded considerably over the past 20 years and in this article, we propose that it is now time for its function to be reappraised. First, we review the anatomy of the cervix and the vaginal ecosystem that it inhabits. Then, we examine the physiology and the role of the cervical mucus. The ongoing mystery of the exact mechanism of the sperm-cervical mucus interaction is reviewed and the key players that may unlock this mystery in the future are discussed. The soluble and cellular biomarkers of the lower female genital tract which are slowly being defined by contemporary research are reviewed. Attempts to standardize these markers, in this milieu, are hindered by the changes that may be attributed to endogenous age, hormonal changes during the menstrual cycle, ectropion, infection, smoking and exposure to semen during sexual intercourse. We review what is known about the immunology of the cervix. With the widespread use of large loop excision of the transformation zone (LLETZ) for treatment of cervical intraepithelial neoplasia, the anatomy of the cervix is changing for many women. While LLETZ surgery has had very positive effects in the fight against cervical cancer, we debate the impact it could have on a woman's fertility.
InfertilityPrevalence and TrendsAge-Related Fertility DeclinePopulation-Based Estimates
This report presents nationally representative estimates and trends for infertility and impaired fecundity-two measures of fertility problems-among women aged 15-44 in the United States. Data are also presented on a measure of infertility among men aged 15-44. Data for this report come primarily from the 2006-2010 National Survey of Family Growth (NSFG), which consisted of 22,682 interviews with men and women aged 15-44, conducted from June 2006 through June 2010. The response rate for women in the 2006-2010 NSFG was 78%, and for men was 75%. Selected trends are shown based on prior NSFG years. The percentage of married women aged 15-44 who were infertile fell from 8.5% in 1982 (2.4 million women) to 6.0% (1.5 million) in 2006-2010. Impaired fecundity among married women aged 15-44 increased from 11% in 1982 to 15% in 2002, but decreased to 12% in 2006-2010. Among all women, 11% had impaired fecundity in 2006-2010. Both infertility and impaired fecundity remain closely associated with age for nulliparous women. Among married, nulliparous women aged 35-44, the percentage infertile declined from 44% in 1982 to 27% in 2006-2010, reflecting greater delays in childbearing over this period. Among married women in 2006-2010, non-Hispanic black women were more likely to be infertile than non-Hispanic white women. Some form of infertility (either subfertility or nonsurgical sterility) was reported by 9.4% of men aged 15-44 and 12% of men aged 25-44 in 2006-2010, similar to levels seen in 2002.
Bentov Y et al., 2014·Clin Med�Insights�Reprod�Health
The age-related reduction in live-birth rate is attributed to a high rate of aneuploidy and follicle depletion. We showed in an animal model that treatment with Coenzyme Q10 (CoQ10) markedly improved reproductive outcome. The aim of this study was to compare the post-meiotic oocyte aneuploidy rate in in vitro fertilization (IVF) and intra cytoplasmic sperm injection (ICSI) patients treated with CoQ10 or placebo.
We conducted a double blind placebo controlled randomized trial that included IVF-ICSI patients 35-43 years of age. The patients were treated with either 600 mg of CoQ10 or an equivalent number of placebo caps. We compared the post-meiotic aneuploidy rate using polar body biopsy (PBBX) and comparative genomic hybridization (CGH). According to the power calculation, 27 patients were needed for each arm.
Owing to safety concerns regarding the effects of polar body biopsy on embryo quality and implantation, the study was terminated before reaching the target number of participants. A total of 39 patients were evaluated and randomized (17 CoQ10, 22 placebo), 27 were given the study medication (12 CoQ10, 15 placebo), and 24 completed an IVF-ICSI cycle including PBBX and embryo transfer (10 CoQ10, 14 placebo). Average age, base line follicle stimulating hormone (FSH), peak estradiol and progesterone serum level, as well as the total number of human menopausal gonadotropin (hMG) units-did not differ between the groups. The rate of aneuploidy was 46.5% in the CoQ10 group compared to 62.8% in the control. Clinical pregnancy rate was 33% for the CoQ10 group and 26.7% for the control group.
No significant differences in outcome were detected between the CoQ10 and placebo groups. However, the final study was underpowered to detect a difference in the rate of aneuploidy.
EndometriosisMenstrual Symptoms as BiomarkersPremenstrual Spotting AssociationPremenstrual Spotting Predictive Value
The purpose of this study was to assess the prevalence of endometriosis in women with premenstrual spotting and to determine the predictive value of this symptom in the diagnosis of endometriosis. We conducted a retrospective cohort study of 80 consecutive women who presented to the infertility clinic for evaluation and who subsequently underwent laparoscopic assessment for infertility with or without pelvic pain. Our main outcome measure was the presence or absence of histologically confirmed endometriosis in women with and without premenstrual spotting. Endometriosis was significantly more prevalent in subfertile women who reported premenstrual spotting for ≥2 days relative to women without this symptom (89% [34/38 women] vs 26% [11/42 women]; P < .0001). Multinomial logistic regression analysis demonstrated the presence of premenstrual spotting for ≥2 days to be associated significantly with the presence of endometriosis (odds ratio, 16; 95% confidence interval, 3.9-65.4; P < .01) and red vesicular lesion type (odds ratio, 52.6; 95% confidence interval, 8.6-323.1; P < .001). In this cohort of women with infertility, premenstrual spotting of ≥2 days was associated strongly with histologically confirmed endometriosis and a better predictor than dysmenorrhea or dyspareunia of finding endometriosis at laparoscopy. Premenstrual spotting of at least 2 days was also associated strongly with both higher stage disease and the red vesicular peritoneal endometriosis phenotype.
This report updates CDC's 2002 recommendations regarding screening tests to detect Chlamydia trachomatis and Neisseria gonorrhoeae infections (CDC. Screening tests to detect Chlamydia trachomatis and Neisseria gonorrhoeae infections-2002. MMWR 2002;51[No. RR-15]) and provides new recommendations regarding optimal specimen types, the use of tests to detect rectal and oropharyngeal C. trachomatis and N. gonorrhoeae infections, and circumstances when supplemental testing is indicated. The recommendations in this report are intended for use by clinical laboratory directors, laboratory staff, clinicians, and disease control personnel who must choose among the multiple available tests, establish standard operating procedures for collecting and processing specimens, interpret test results for laboratory reporting, and counsel and treat patients. The performance of nucleic acid amplification tests (NAATs) with respect to overall sensitivity, specificity, and ease of specimen transport is better than that of any of the other tests available for the diagnosis of chlamydial and gonococcal infections. Laboratories should use NAATs to detect chlamydia and gonorrhea except in cases of child sexual assault involving boys and rectal and oropharyngeal infections in prepubescent girls and when evaluating a potential gonorrhea treatment failure, in which case culture and susceptibility testing might be required. NAATs that have been cleared by the Food and Drug Administration (FDA) for the detection of C. trachomatis and N. gonorrhoeae infections are recommended as screening or diagnostic tests because they have been evaluated in patients with and without symptoms. Maintaining the capability to culture for both N. gonorrhoeae and C. trachomatis in laboratories throughout the country is important because data are insufficient to recommend nonculture tests in cases of sexual assault in prepubescent boys and extragenital anatomic site exposure in prepubescent girls. N. gonorrhoeae culture is required to evaluate suspected cases of gonorrhea treatment failure and to monitor developing resistance to current treatment regimens. Chlamydia culture also should be maintained in some laboratories to monitor future changes in antibiotic susceptibility and to support surveillance and research activities such as detection of lymphogranuloma venereum or rare infections caused by variant or mutated C. trachomatis.
Although adequate luteal hormone production is essential for establishing pregnancy, luteal phase deficiency (LPD) is poorly characterized among eumenorrheic women. We assessed the prevalence and overlap of two established short luteal phase duration less than10 days (clinical LPD) and suboptimal luteal progesterone of 5 ng/mL or less (biochemical LPD) and their relationship with reproductive hormone concentrations.
Design, Setting, We conducted a prospective study in western New York (2005-2007) following 259 women, aged 18-44 years, for up to two menstrual cycles. Among ovulatory cycles with recorded cycle lengths (n = 463), there were 41 cycles (8.9%) with clinical LPD, 39 cycles (8.4%) with biochemical LPD, and 20 cycles (4.3%) meeting both criteria. Recurrent clinical and biochemical LPD was observed in eight (3.4%) and five (2.1%) women, respectively. Clinical and biochemical LPD were each associated with lower follicular estradiol (both P ≤ .001) and luteal estradiol (P = .03 and P = .02, respectively) after adjusting for age, race, and percentage body fat. Clinical, but not biochemical, LPD was associated with lower LH and FSH across all phases of the cycle (P ≤ .001). Clinical and biochemical LPD were evident among regularly menstruating women. Estradiol was lower in LPD cycles under either criterion, but LH and FSH were lower only in association with shortened luteal phase (ie, clinical LPD), indicating that clinical and biochemical LPD may reflect different underlying mechanisms. Identifying ovulation in combination with a well-timed luteal progesterone measurement may serve as a cost-effective and specific tool for LPD assessment by clinicians and researchers.
To evaluate the association between endometriosis and chronic endometritis. Endometrial specimens were obtained from 71 patients, 34 with endometriosis (endometriosis group) and 37 without endometriosis (non-endometriosis group), who underwent hysterectomy, and the specimens were immunostained for the plasmacyte marker CD138. The rate of chronic endometritis was compared between the endometriosis group and the non-endometriosis group. Furthermore, the 71 patients were also divided into two groups, 28 with chronic endometritis (chronic endometritis group) and 43 without chronic endometritis (non-chronic endometritis group). Logistic regression analysis was performed with variables including age, body mass index (BMI), gravidity and parity, and diagnoses of leiomyoma, adenomyosis, and endometriosis on pathology to examine the independent effect of each variable on chronic endometritis. Patients suffering from cervical invasive carcinoma, endometrial carcinoma, and endometrial polyps or treated with gonadotropin-releasing hormone agonists, progestins, or oral contraceptives before surgery were excluded. Chronic endometritis was identified in 52.94% of the endometriosis group and 27.02% of the non-endometriosis group (p<0.05). Logistic regression analysis revealed that endometriosis was associated with chronic endometritis. This result suggests a strong association between endometriosis and chronic endometritis.
PregnancyLubricant Effects on SpermMotility AssessmentLubricant Selection
To evaluate the effects of coital lubricants and oils on sperm motility. Comparative prospective in vitro study. University Andrology laboratory. PATIENT(S): Twenty-two normozoospermic donors. INTERVENTION(S): Semen samples were incubated in modified human tubal fluid (mHTF) control and in 10% Pre-Seed, Astroglide, and KY products (Sensitive, Warming, and Tingling) and baby, canola, sesame, and mustard oils. Total and progressive sperm motility was evaluated before and at 5, 30, and 60 minutes of incubation. MAIN OUTCOME MEASURE(S): Sperm motility. RESULT(S): Control samples exhibited no significant decrease in sperm motility. Pre-Seed showed a slight (∼4%) but significant drop in progressive motility after 30 minutes. Total and progressive sperm motility significantly declined under Astroglide, KY products (Sensitive, Warming, and Tingling) and sesame oil incubation. Canola oil significantly decreased total motility after 30 minutes and progressive motility after 5 minutes of incubation. Similarly, baby oil decreased total motility after 60 minutes and progressive motility after 5 minutes. After initial decline, total and progressive sperm motility under Pre-Seed and canola and baby oils remained high. Exposure to mustard oil caused persistent hyperactivation of sperm in each sample with no decrease in motility. CONCLUSION(S): Sesame oil and synthetic coital lubricants impaired sperm motility and may hamper fertility. Pre-Seed and canola, mustard, and baby oils showed no deleterious effect and may be considered sperm-friendly coital lubricants. Mustard oil exposure resulted in hyperactivation of sperm and needs to be studied further.
Infertility is a relatively common health condition, affecting nearly 7% of all couples. Clinically, it is a highly heterogeneous pathology with a complex etiology that includes environmental and genetic factors. It has been estimated that nearly 50% of infertility cases are due to genetic defects. Hundreds of studies with animal knockout models convincingly showed infertility to be caused by gene defects, single or multiple. However, despite enormous efforts, progress in translating basic research findings into clinical studies has been challenging. The genetic causes remain unexplained for the vast majority of male or female infertility patients. A particular difficulty is the huge number of candidate genes to be studied; there are more than 2,300 genes expressed in the testis alone, and hundreds of those genes influence reproductive function in humans and could contribute to male infertility. At present, there are only a handful of genes or genetic defects that have been shown to cause, or to be strongly associated with, primary infertility. Yet, with completion of the human genome and progress in personalized medicine, the situation is rapidly changing. Indeed, there are 10-15 new gene tests, on average, being added to the clinical genetic testing list annually.
Contraception/ComparisonSafety ProfilesClinic StandardsComplications and Risks
To compare pregnancy rates when women have intercourse on self-estimated high and peak fertile days and when they only have intercourse on low fertile days during the fertile window (FW). We used a prospective observational cohort study design. Our convenience sample included 124 women who utilized our online charting Web sites to achieve pregnancy from January 2010 to November 2012. Participants used an electronic hormonal fertility monitor (EHFM) or self-observed cervical mucus or both to determine fertility during the estimated FW. Pregnancy rates were determined with Kaplan-Meier survival analysis. Chi square analysis was used to evaluate the efficacy of achieving pregnancy between two different intercourse patterns. The pregnancy rate was 87 per 100 women at 12 months when intercourse happened on high or peak days and 5 per 100 when intercourse occurred only on low days of the FW. Chi square analysis showed a greater proportion of pregnancies with intercourse on high and peak fertile days of the menstrual cycle (x2 = 40.2, p < .001, df = 1). Focusing intercourse on high or peak fertile days during the estimated FW enhances the probability of achieving a desired pregnancy. Fertility awareness-based online charting system is effective in helping women to determine their FW and target intercourse accordingly to achieve pregnancy.
Recurrent miscarriage (RM) is defined as 3 or more miscarriages before 20 weeks' pregnancy. In recent years, interest has been focused on chronic endometritis (CE), a subtle inflammation thought to be associated with RM. We aimed to evaluate the relationships between CE and RM. The records of 360 women with unexplained RM were retrospectively analyzed. Data from hysteroscopy, endometrial histology, endometrial culture, and polymerase chain reaction for chlamydia, performed before and after antibiotic treatment for CE, were analyzed. The occurrence of successful pregnancies within 1 year after treatment was also evaluated. Results showed that 208 (57.8%) women with RM showed CE at hysteroscopy; 190 (91.3%), positive at hysteroscopy, were also positive at histology, and 142 (68.3%) had positive cultures. Common bacteria were found in 110 (77.5%) patients. Mycoplasma and Ureaplasma were found in 36 (25.3%) patients and Chlamydia in 18 patients (12.7%). In 102 (71%) women, antibiogram-based antibiotic treatment normalized hysteroscopy, histology, and cultures (group 1); while in 40 (28.2%) patients, CE was still present at hysteroscopy (group 2). In 16 of the 66 patients positive at hysteroscopy, but not at cultures, the hysteroscopy becomes normal (group 3) after a Centers for Disease Control and Prevention-based therapy; while in 50 women, CE was still present (group 4). One year after treatment, group 1 showed a significantly higher number of pregnancies (78.4%) compared to group 2 (17.5%; P < .001) and group 4 (15.3%; P = .005). The CE is frequent in women with RM. Antibiotic treatment seems to be associated with an improved reproductive outcome.
Schisterman EF et al., 2013·Paediatr Perinat Epidemiol
Low-dose aspirin (LDA) has been proposed to improve pregnancy outcomes in couples experiencing recurrent pregnancy loss. However, results from studies of LDA on pregnancy outcomes have been inconsistent, perhaps because most studies evaluated LDA-initiated post-conception. The purpose of the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial was to determine whether preconception-initiated LDA improves livebirth rates in women with one to two prior losses. We performed a multicentre, block randomised, double-blind, placebo-controlled trial. Study participants were recruited using community-based advertisements and physician referral to four university medical centres in the US (2006-12). Eligible women were aged 18-40 years actively trying to conceive, with one to two prior losses. Participants were randomised to receive daily LDA (81 mg/day) or a matching placebo, and all were provided with daily 400-mcg folic acid. Follow-up continued for ≤6 menstrual cycles while attempting to conceive. For those who conceived, treatment was continued until 36 weeks gestation. The primary outcome was the cumulative livebirth rate over the trial period. There were 1228 women randomised (615 LDA, 613 placebo). Participants had a mean age of 28.7, were mostly white (95%), well educated (86% more than high school education), and employed (75%) with a household income >$100 000 annually (40%). The characteristics of those in the treatment and placebo arms were well balanced. We describe the study design, recruitment, data collection, and baseline characteristics of participants enrolled in EAGeR, which aimed to determine the effect of LDA on livebirth and other pregnancy outcomes in these women.
NaProTECHNOLOGYConception OptimizationNatural Procreative TechnologyNatural vs Invasive Treatment
L’auto-osservazione e il follow-up grafico del ciclo mestruale in caso di presunta sterilita, aiutano a diagnosticare e trattare certe alterazioni ginecologiche, al fine di attuare il rapporto sessuale finalizzato ad ottimizzare concepimento. Attraverso queste procedure naturali (naprotecnologia), prive di aspetti negativi da un punto di vista etico, possiamo ottenere tassi di natalita che sono paragonabili, o addirittura superiori, a quelle ottenute con trattamenti invasivi. ---------- Self-observation and the graphic follow-up of the menstrual cycle in cases of supposed infertility, help to diagnose and treat certain gynaecological alterations in order to carry out the sexual intercourse focused on optimising conception. Through these natural procedures (Naprotechnology), with no ethical drawbacks, we can obtain birth rates that are comparable, or even higher, to those obtained with invasive treatments.
According to the World Health Organization, infertility, associated with metabolic syndrome, has become a global issue with a 10%-20% incidence worldwide. An accumulating body of evidence has shown that the renin-angiotensin system is involved in the fertility problems observed in some populations. Moreover, alterations in the expression of angiotensin-converting enzyme-1, angiotensin-converting enzyme-2, and angiotensin-converting enzyme-3 might be one of the most important mechanisms underlying both female and male infertility. However, as a pseudogene in humans, further studies are needed to explore whether the abnormal angiotensin-converting enzyme-3 gene could result in the problems of human reproduction. In this review, the relationship between angiotensin-converting enzymes and fertile ability is summarized, and a new procedure for the treatment of infertility is discussed.
To assess the use of cervical mucus monitoring (CMM) in women trying to conceive and determine whether monitoring is associated with increased cycle-specific probability of conception (fecundability). Time-to-pregnancy cohort study. Population-based cohort. PATIENT(S): Three hundred thirty-one women trying to conceive, ages 30 to 44 years, without known infertility. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): CMM prevalence and fecundability. RESULT(S): During the first cycle of the study, CMM was performed consistently (checked on >66% of pertinent cycle days) by 20 women (6%), inconsistently (34% to 66% of days) by 60 women (18%), infrequently (≤33% of days) by 73 women (22%), and not performed by 178 women (54%). Cycles in which CMM was consistently performed were statistically significantly more likely to result in conception after adjusting for age, race, previous pregnancy, body mass index, intercourse frequency, and urinary luteinizing hormone (LH) monitoring. Fecundability also increased with increasing consistency of CMM. CONCLUSION(S): Among women trying to conceive, CMM is uncommon, but our study suggests that CMM-a free, self-directed method to determine the fertile window-is associated with increased fecundability independent of intercourse frequency or use of urinary LH monitoring.
Does unilateral volume-adjusted laparoscopic diathermy increase the chances of ovulation in women with polycystic ovary syndrome (PCOS)? Although unilateral laparoscopic ovarian drilling (ULOD) using adjusted thermal doses was more efficient than bilateral laparoscopic ovarian drilling (BLOD) using fixed doses, the chances of ovulation were improved in patients irrespective of the technique used. The adjustment of the thermal dose to ovarian volume in BLOD increases ovulation and pregnancy rates compared with fixed-dose treatment, but BLOD causes the formation of adhesions, particularly on the left ovary, and increases the risk of damage to ovarian tissue. In contrast, ULOD with a fixed thermal dose minimizes the risk of ovarian tissue damage, and can increase the activity in both right and left ovaries, although this varies in humans and in other species. STUDY DESIGN, SIZE, This prospective, longitudinal, study, between September 2009 and January 2013, included 96 infertile women with PCOS who were unresponsive to clomiphene citrate treatment and had underwent either ULOD or BLOD. After surgery, the groups were followed up for 6 months to assess ovulatory response. PARTICIPANTS/MATERIALS, SETTING, Patients were assigned to two groups; one group underwent laparoscopic ovarian drilling of the right ovary alone, while both ovaries were treated in the second group. The ULOD group (n = 49) received thermal doses adjusted to the volume of the right ovary (60 J/cm³). The BLOD group (n = 47) received fixed doses of 600 J per ovary, regardless of its volume. The two treatment groups were matched by the number of participants, age and baseline parameters. MAIN The ovulation rate during the first menstrual cycle after LOD was significantly higher in the ULOD group than in the BLOD group [73 versus 49%; absolute risk reduction (ARR), -0.25; 95% confidence interval (CI), -0.44 to -0.03; P = 0.014]. Treatment with ULOD on the right ovary significantly increased the chances of ovulation in patients with a larger right ovary compared with those who had a smaller right ovary (100 versus 36%; ARR, -0.64; 95% CI, -0.84 to -0.37; P = 0.004). Interestingly, the chances of ovulation were also significantly higher in patients in the BLOD group who had a larger right ovary compared with those who had a smaller right ovary (88 versus 33%; ARR, -0.55; 95% CI, -0.73 to -0.28; P = 0.002). The pregnancy rate was also significantly higher in patients with a larger right ovary compared with those with a smaller right ovary, regardless of the treatment group. LIMITATIONS, The 6-month follow-up was too short to demonstrate any long-term differences in the ovulation rates. Future research should therefore extend the follow-up beyond 6 months. Another limitation is that ULOD was used to treat only the right ovary. Future studies should investigate whether ULOD treatment of the larger ovary, whether left or right, would significantly increase the ovulation rate. This study represents an advance in the determination of the optimal laparoscopic treatment for women with PCOS, as it was shown that improved results can be achieved using less thermal energy in volume-adjusted ULOD.
Oxidative stress can contribute to impairment in spermatogenesis leading to male-factor infertility. The effectiveness of various antioxidants (such as carnitine, vitamin C, vitamin E, selenium, carotenoids, glutathione, N-acetylcysteine, zinc, folic acid, and coenzyme Q10) is variable with respect to improving semen parameters and pregnancy rates. A recent Cochrane review determined that men taking antioxidants had a statistically significant increase in both live birth rates and pregnancy rates. For those undergoing assisted reproduction, the odds ratio that antioxidant use would improve pregnancy rates was 4.18, with a 4.85-fold improvement in live birth rate also noted. Further investigation with randomized, controlled clinical trials is needed to confirm the safety and efficacy of antioxidant supplementation in the medical management and treatment of male infertility.
Porpora MG et al., 2013·Evid Based Complement Alternat Med
Urged by the unmet medical needs in endometriosis treatment, often with undesirable side effects, and encouraged by N-acetylcysteine (NAC) efficacy in an animal model of endometriosis and by the virtual absence of toxicity of this natural compound, we performed an observational cohort study on ovarian endometriosis. NAC treatment or no treatment was offered to 92 consecutive Italian women referred to our university hospital with ultrasound confirmed diagnosis of ovarian endometriosis and scheduled to undergo laparoscopy 3 months later. According to patients acceptance or refusal, NAC-treated and untreated groups finally comprised 73 and 72 endometriomas, respectively. After 3 months, within NAC-treated patients cyst mean diameter was slightly reduced (-1.5 mm) versus a significant increase (+6.6 mm) in untreated patients (P = 0.001). Particularly, during NAC treatment, more cysts reduced and fewer cysts increased their size. Our results are better than those reported after hormonal treatments. Twenty-four NAC-treated patients-versus 1 within controls-cancelled scheduled laparoscopy due to cysts decrease/disappearance and/or relevant pain reduction (21 cases) or pregnancy (1 case). Eight pregnancies occurred in NAC-treated patients and 6 in untreated patients. We can conclude that NAC actually represents a simple effective treatment for endometriosis, without side effects, and a suitable approach for women desiring a pregnancy.
We sought to identify risk factors for endometriosis and their consistency across study populations Natural History, Diagnosis, and Outcomes (ENDO) Study. In this prospective matched, exposure cohort design, 495 women aged 18-44 years undergoing pelvic surgery (exposed to surgery, operative cohort) were compared to an ageand residence-matched population cohort of 131 women (unexposed to surgery, population cohort). Endometriosis was diagnosed visually at laparoscopy/laparotomy or by pelvic magnetic resonance imaging in the operative and population cohorts, respectively. Logistic regression estimated the adjusted odds ratios (AORs) and 95% confidence intervals (CIs) for each cohort. The incidence of visualized endometriosis was 40% in the operative cohort (11.8% stage 3-4 by revised criteria from the American Society for Reproductive Medicine), and 11% stage 3-4 in the population cohort by magnetic resonance imaging. An infertility history increased the odds of an endometriosis diagnosis in both the operative (AOR, 2.43; 95% CI, 1.57-3.76) and population (AOR, 7.91; 95% CI, 1.69-37.2) cohorts. In the operative cohort only, dysmenorrhea (AOR, 2.46; 95% CI, 1.28-4.72) and pelvic pain (AOR, 3.67; 95% CI, 2.44-5.50) increased the odds of diagnosis, while gravidity (AOR, 0.49; 95% CI, 0.32-0.75), parity (AOR, 0.42; 95% CI, 0.28-0.64), and body mass index (AOR, 0.95; 95% CI, 0.93-0.98) decreased the odds of diagnosis. In all sensitivity analyses for different diagnostic subgroups, infertility history remained a strong risk factor. An infertility history was a consistent risk factor for endometriosis in both the operative and population cohorts of the ENDO Study. Additionally, identified risk factors for endometriosis vary based upon cohort selection and diagnostic accuracy. Finally, endometriosis in the population may be more common than recognized.
To determine patterns of usage of clomiphene citrate (CC) by primary care providers (obstetrician-gynecologists, family physicians, and other providers) within University of Utah Community Clinics. We performed a retrospective chart review (n = 79) and followup telephone survey of patients (n = 43) who were prescribed CC in the University of Utah Community Clinics in 2006. Most women who were prescribed CC had appropriate indications for therapy (65% with a diagnosis related to irregular menses and 33% with a diagnosis of female infertility), but there was variable and inconsistent monitoring of ovulation (much of which was apparently initiated by the patients). In the interview, 24 of the women (56%) said they would be fine having twins, and 14 (33%) said they would prefer to have twins if possible. In this primary care setting, clomiphene was prescribed for appropriate indications, but the monitoring of treatment could be improved. The preference of some patients for twin gestations represents a challenge for optimum clinical care and public health.
InfertilityTreatment Utilization PatternsOvulation MonitoringTiming and Appropriateness
The purpose of this study was to compare the utilization of medical help for fertility among women who reported up to a year versus more than a year of trying to become pregnant and to describe the characteristics of those women seeking early treatment. Data from the 2004-2008 Pregnancy Risk Assessment Monitoring System (PRAMS) survey were used to assess attempt duration and use of fertility treatments in a sample of 9,517 women who had a recent live birth in Utah. PRAMS respondents who were trying to become pregnant at the time of conception were asked questions about fertility treatments (sampling n = 5,238; representative n = 153,036). Univariate and bivariate analyses were used to describe and compare characteristics of women who sought treatment after attempting pregnancy for a year or less and women who waited at least a year to seek treatment. Among women who were trying to become pregnant, 9.5 % reported using some medical assistance to conceive. Among the women trying to become pregnant, 89.3 % had been trying for ≤12 months and 10.7 % reported having tried >12 months. 5.2 % of those trying to become pregnant for up to a year reported use of fertility treatment, compared with 45.8 % of those trying for a year or more. Women who had previous live births were significantly more likely to use early treatment than nulliparous women (aOR = 2.4, 95 % CI = 1.5, 3.9). The use of fertility drugs and other treatments were more common than ART among recipients of early treatment (aOR = 3.7, 95 % CI = 1.7, 7.9). Some women may be receiving fertility treatment before it is clinically indicated. Instead of invasive treatment, these women may benefit from preconception counseling on folic acid, healthy prepregnancy weight and use of ovulation monitoring to time intercourse.
Above-ground and underground nuclear weapon detonation at the Nevada Test Site (1951-1992) has resulted in radioiodine exposure for nearby populations. Although the long-term effect of environmental radioiodine exposure on thyroid disease has been well studied, little is known regarding the effect of childhood radioiodine exposure on subsequent fertility. We investigated early childhood thyroid radiation exposure from nuclear testing fallout (supplied predominantly by radioactive isotopes of iodine) and self-reported lifetime incidence of male or female infertility or sterility. Participants were members of the 1965 Intermountain Fallout Cohort, schoolchildren at the time of exposure who were reexamined during two subsequent study phases to collect dietary and reproductive histories. Thyroid radiation exposure was calculated via an updated dosimetry model. We used multivariable logistic regression with robust sandwich estimators to estimate odds ratios for infertility, adjusted for potential confounders and (in separate models) for a medically confirmed history of thyroid disease. Of 1,389 participants with dosimetry and known fertility history, 274 were classified as infertile, including 30 classified as sterile. Childhood thyroid radiation dose was possibly associated with infertility [adjusted odds ratio (AOR) = 1.17; 95% CI: 0.82, 1.67 and AOR = 1.35; 95% CI: 0.96, 1.90 for the middle and upper tertiles vs. the first tertile of exposure, respectively]. The odds ratios were attenuated (AOR = 1.08; 95% CI: 0.75, 1.55 and AOR = 1.29; 95% CI: 0.91, 1.83 for the middle and upper tertiles, respectively) after adjusting for thyroid disease. There was no association of childhood radiation dose and sterility. Our findings suggest that childhood radioiodine exposure from nuclear testing may be related to subsequent adult infertility. Further research is required to confirm this.
Human uterus transplantation (UTx) is currently under investigation as a treatment for uterine infertility. Without a uterus transplant, the options available to women with uterine infertility are adoption or surrogacy; only the latter has the potential for a genetically related child. UTx will offer recipients the chance of having their own pregnancy. This procedure occurs at the intersection of two assisted reproductive technologies (ART) and organ transplantation. In relation to organ transplantation, UTx lies with composite tissue transplants such as face and limb grafts, and shares some of the ethical concerns raised by these non-life saving procedures. In relation to ART, UTx represents one more avenue by which a woman may seek to meet her reproductive goals, and as with other ART procedures, raises questions about the limits of reproductive autonomy. This paper explores the ethical issues raised by UTx with a focus on the potential gap between women's desires and aspirations about pregnancy and the likely functional outcomes of successful UTx.
The current approach to infertility of assisted reproductive technology (ART) completely misses and then bypasses the evaluation and treatment of cervical factor infertility. In contrast, the Creighton Model Fertility Care System (CrMS), a method of fertility awareness that has the unique ability to quantify cervical mucus observations, and natural procreative technology (NaProTECHNOLOGY or NPT) directly evaluate and treat cervical factor infertility. The ART treatment of choice for cervical factor infertility--intrauterine insemination (IUI)--is also morally disparate from while the latter genuinely assists the infertile couple's act of sexual union to achieve its natural end of pregnancy, IUI replaces the natural act, depriving human conception of the one context worthy of the dignity of human life and procreation, a reciprocal self-gifting act of love between husband and wife. A renewed interest and focus on the direct evaluation and treatment of cervical factor infertility is needed.
AndrologyObesity and FertilityIVF OutcomesPaternal BMI
Infertility is a significant and constantly increasing individual and social problem. It is estimated that at present it affects approx. 15 to 20 percent of couples. Inability to conceive a child elicits a range of unfavourable implications in the scope of emotional experiences, in the partner’s relationship and in a broader social perspective. Making a decision on undergoing diagnostics and infertility treatment is a difficult and often postponed moment for many couples. This is an expression of the escape model of dealing with a situation that threatens with a fall of self-esteem. However, if a couple reacts in a task-oriented way and participates in the diagnostic and therapeutic procedure, new doubts appear connected with the medical, psychological, social and ethical sphere. Infertility treatment sometimes prompts fear connected with the stripping of intimacy, loss of control over one’s body, possible complications and unsuccessful therapy. This article is an analysis of the medical and the other aspects of struggling with infertility with reference to two extremely different methods NaProTechnology as a process of assisting natural procreation and assisted reproductive techniques with a special consideration of in vitro fertilization.
InfertilityEvaluation GuidelinesRecurrent MiscarriageRecurrent Pregnancy Loss Workup
The majority of miscarriages are sporadic and most result from genetic causes that are greatly influenced by maternal age. Recurrent pregnancy loss (RPL) is defined by two or more failed clinical pregnancies, and up to 50% of cases of RPL will not have a clearly defined etiology.
To study the outcomes of women with infertility or miscarriage treated with natural procreative technology (NaProTechnology or NPT), a systematic medical approach to promoting conception in vivo; and to compare the outcomes with those previously published from a general practice in Ireland. Retrospective cohort study. An urban Canadian primary care practice in which the physician had a part-time practice in NPT. Couples with infertility or recurrent miscarriage who received treatment in the practice between August 2000 and July 2006. All couples were taught to identify the fertile time of their menstrual cycles using the Creighton Model FertilityCare System (CrMS) and completed a standard NPT evaluation. Many also received additional medical treatment to enhance conception in vivo. Live birth was the primary outcome; secondary outcomes included conceptions, multiple births, low birth weight, and prematurity. A total of 108 couples received NPT and were included in the analysis, of which 19 (18%) reported having 2 or more previously unexplained miscarriages. The average female age was 35.4 years. Couples had been attempting to conceive for a mean of 3.2 years. Twentytwo participants (20%) had previously given birth; 24 (22%) had previous intrauterine insemination; and 9 (8%) had previous assisted reproductive technology. The cumulative adjusted proportion of first live births for those completing up to 24 months of NPT treatment was 66 per 100 couples, and the crude proportion was 38%. The cumulative adjusted proportion of first conceptions was 73 per 100 couples, and the crude proportion was 47%. Of the 51 couples who conceived, 12 couples (24%) conceived with CrMS instruction alone, 35 (69%) conceived with CrMS and NPT medical treatment, and 4 (8%) conceived after additional surgical treatment. All births were singleton births; 54% were born at 37 weeks' gestation or later; and 78% had birth weights of 2500 g or greater. Natural procreative technology in a family physician's office was effective in treating infertility and miscarriage with outcomes that were comparable to those in an NPT general practice in Ireland. Larger multicentre prospective studies to compare NPT directly to other forms of infertility treatment are warranted.
Infertility affects 9% of couples in the UK. Most couples who visit their GP because they are worried about their fertility will ultimately conceive, but a few will not. Treatment usually happens in secondary care, but GPs can have an invaluable role in starting investigations, referring, and giving support throughout treatment and beyond. To inform clinical practice by exploring primary care experiences of infertility treatment among females and males, and discussing findings with a reference group of GPs to explore practice experience. A qualitative patient interview and GP focus group study. Interviews were conducted in patients homes in England and Scotland; the focus group was held at a national conference. An in-depth interview study was conducted with 27 females and 11 males. A maximum variation sample was sought and interviews were transcribed for thematic analysis. Results were discussed with a focus group of GPs to elicit their views. Feeling that they were being taken seriously was very important to patients. Some felt that their concerns were not taken seriously, or that their GP did not appear to be well informed about infertility. The focus group of GPs highlighted the role of protocols in their management of patients who are infertile, as well as the difficulty GPs faced in communicating both reassurance and engagement. Simple things that GPs say and do, such as describing the 'action plan' at the first consultation, could make a real difference to demonstrating that they are taking the fertility problem seriously.
To describe the characteristics of women seeking infertility treatment and the types of fertility treatment sought within a population-based sample. We analyzed data from the cross-sectional Pregnancy Risk Assessment Monitoring System (PRAMS) of women with a live birth using data from seven states. Logistic regression was used to determine factors associated with infertility treatment utilization. Infertility treatment was reported by 10.5% of women who were trying to become pregnant. The most common treatment reported was fertility enhancing drugs (29%), followed by assisted reproductive technology including in vitro fertilization (21%), and artificial insemination together with fertility enhancing drugs (15%). Some women reported using other types of treatment (23%). The PRAMS data provide insights into the use of infertility treatment among women giving birth in the United States. Further research is needed to understand the true prevalence of infertility, factors that influence treatment choices, and the longitudinal impact of infertility treatment on outcomes.
In vitro fertilisation (IVF) is a widely accepted treatment for unexplained infertility (NICE 2004), which affects up to a third of all infertile couples. With estimated live birth rates (LBRs) per cycle varying from 33.1% in women aged under 35 years down to 12.5% in women aged between 40 and 42 years (HFEA 2011), its effectiveness has not been rigorously evaluated in comparison with other treatments. With increasing awareness of the role of expectant management, less-invasive procedures such as intrauterine insemination (IUI), and concerns about multiple pregnancies and costs associated with IVF, it is important to evaluate the effectiveness of IVF against other treatment options in couples with unexplained infertility. To evaluate the effectiveness and safety of IVF compared to expectant management, clomiphene citrate, IUI alone and intrauterine insemination plus controlled ovarian stimulation (IUI+SO). Cochrane Menstrual Disorders and Subfertility Group Trials Register (searched July 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, first quarter), MEDLINE (1970 to July 2011), EMBASE (1985 to July 2011) and reference lists of articles were searched. Relevant conference proceedings were handsearched. Authors were contacted.
Randomised controlled trials (RCTs) were included. LBR per woman was the primary outcome.
Two review authors independently assessed eligibility and quality of trials. Six RCTs were included in the final analysis. LBR per woman was significantly higher with IVF (45.8%) than expectant management (3.7%) (odds ratio (OR) 22.00, 95% confidence interval (CI) 2.56 to 189.37, 1 RCT, 51 women). There were no comparative data for clomiphene citrate. There was no evidence of a significant difference in LBR between IVF and IUI alone (OR 1.96, 95% CI 0.88 to 4.36, 1 RCT, 113 women), 40.7% with IVF versus 25.9% with IUI. In studies comparing IVF versus IUI+SO, LBR per woman did not differ significantly between the groups among treatment-naive women (OR 1.09, 95% CI 0.74 to 1.59, 2 RCTs, 234 women) but was significantly higher in a large RCT of women pretreated with IUI + clomiphene citrate (OR 2.66, 95% CI 1.94 to 3.63, 1 RCT, 341 women). These three studies could not be pooled due to high heterogeneity (I(2) = 84%). There was no evidence of a significant difference in multiple pregnancy rate (MPR) or ovarian hyperstimulation syndrome (OHSS) between the two treatments (OR 0.64, 95% CI 0.31 to 1.29, 3 RCTs, 351 women; OR 1.53, 95% CI 0.25 to 9.49, 1 RCT, 118 women, respectively). AUTHORS' IVF may be more effective than IUI+SO. Due to paucity of data from RCTs the effectiveness of IVF for unexplained infertility relative to expectant management, clomiphene citrate and IUI alone remains unproven. Adverse events and the costs associated with these interventions have not been adequately assessed.
Reproductive EndocrinologyInfertilityDiagnostics
Open Access
A reliable indirect measure of ovarian reserve for the individual woman remains a challenge for reproductive specialists. Using descriptive statistics from a large-scale study of ovarian volumes, we have developed a normative model for healthy females for ages 25 through 85. For average values, this model has a strong and positive correlation (r = 0.89) with our recent model of nongrowing follicles (NGFs) in the human ovary for ages 25 through 51. When both models are log-adjusted, the correlation increases to r = 0.99, over the full range of ovarian volume. Furthermore we can deduce that an ovary of 3 cm(3) volume (or less) contains approximately 1000 NGF (or fewer). These strong correlations indicate that ovarian volume is a useful factor in the indirect estimation of human ovarian reserve for the individual woman.
Use of selective salpingography (SS) and fallopian tube catheterization (TC) has revolutionized the diagnosis and treatment of proximal tubal infertility. To evaluate results of women treated for proximal tubal obstruction by selective salpingography and tubal catherization. Selective salpingography was performed in women with proximal bilateral tubal obstructions. Follow-up ranged from 4 to 12 months. twelve patients had been shown to have bilateral proximal obstruction of the fallopian tube. After SS/TC, patency was achieved in 8 cases. Spontaneous conceptions occurred in 4 women. SS and TC should be used more widely because it is simple and effective in case of proximal tubal blockage.
To review the treatments of the cesarean-induced isthmocele in restoring infertility, associated techniques, and the risks of complications associated with their use.
Isthmocele is a reservoir-like pouch defect on the anterior wall of the uterine isthmus located at the site of a previous cesarean delivery scar. The flow of menstrual blood through the cervix may be slowed by the presence of isthmocele, as the blood may accumulate in the niche because of the presence of fibrotic tissue, causing pelvic pain in the suprapubic area. Moreover, persistence of the menstrual blood after menstruation in the cervix may negatively influence the mucus quality and sperm quality, obstruct sperm transport through the cervical canal, interfere with embryo implantation, leading to secondary infertility. The removal of the local inflamed tissue may be performed by laparoscopic, combined laparoscopic-vaginal, or vaginal surgery, and operative hysteroscopy, a minimally invasive approach to improve symptoms and restore fertility.
Isthmocele occurs after cesarean section, a common method of delivery and one of the most frequent surgical procedures, so that its upward incidence appears likely to continue in the near future. Because of its minimal invasiveness, resectoscopy may be the better choice for treatment, yielding good therapeutic results.
AndrologyACE Inhibitors for OligospermiaIdiopathic Oligospermia TreatmentMale Infertility
The outcomes of drug treatment for male infertility remain conjectural, with controversial study results. Our pilot study employed a randomized, placebo-controlled, crossover methodology with intention-to-treat analysis. Thirty-three men with idiopathic oligospermia were randomized to start either daily oral lisinopril 2.5 mg (n = 17) or daily oral placebo (n = 16). Lisinopril was found to cause a normalization of seminal parameters in 53.6% of the participants. Although the mean ejaculate volume was unchanged (P ≥ 0.093), the total sperm cell count and the percentage of motile sperm cells increased (P ≤ 0.03 and P < 0.001, respectively), whereas the percentage of sperm cells with abnormal morphology decreased (P ≤ 0.04). The pregnancy rate was 48.5%, and there was no serious adverse drug event. It is concluded, albeit cautiously, that prolonged treatment with 2.5 mg/day of oral lisinopril may be well tolerated in normotensive men with idiopathic oligospermia, may improve sperm quantity and quality, and may enhance fertility in approximately half of those treated.
InfertilitySperm-Oviduct InteractionElectron Microscopy Reproductive TractSperm Transport and Reservoir
The oviduct is an important organ for successful mammalian reproduction. In this work, human oviducts were inseminated and their explants analyzed using scanning electron microscopy in order to study, at a finer ultrastructual level, the interaction between spermatozoon and oviduct in vitro. Results show unequivocally a spermatozoon tightly attached through the acrosomal region of its head to several cilia of the human tubal epithelial cells. This finding proves that spermatozoa do indeed adhere to the endosalpinx, a fact of utmost relevance for the physiology of the reproductive process, since it supports the idea of a spermatozoa reservoir being formed in the oviduct, which is also briefly discussed.
To investigate the impact of antithyroid antibody on pregnancy outcome following the in vitro fertilization and embryo transfer (IVF-ET). A total of 90 patients (156 cycles) positive for antithyroid antibody (ATA+ group) and 676 infertile women (1062 cycles) negative for antithyroid antibody (ATAgroup) undergoing IVF/ICSI from August 2009 to August 2010 were retrospectively analyzed. There was no significant difference in the days of ovarian stimulation, total gonadotropin dose, serum E2 level of HCG day and number of oocytes retrieved between the two groups. The fertilization rate, implantation rate and pregnancy rate following IVF-ET were significantly lower in women with antithyroid antibody than in control group (64.3% vs 74.6%, 17.8% vs 27.1% and 33.3% vs 46.7%, respectively), but the abortion rate was significantly higher in patients with antithyroid antibody (26.9% vs 11.8%). Patients with antithyroid antibody showed significantly lower fertilization rate, implantation rate and pregnancy rate and higher risk for abortion following IVF-ET when compared with those without antithyroid antibody. Thus, the presence of antithyroid antibody is detrimental for the pregnancy outcome following IVF-ET.
SurgeryFalloposcopic TuboplastyProximal Tubal OcclusionAlternatives to IVF
To assess the clinical effectiveness of falloposcopic tuboplasty in tubal infertility.
Retrospective cohort study (Canadian Task Force classification II-3).
Infertility clinic. Three hundred forty-five infertile patients (≥2y) with a diagnosis of proximal tubal occlusion, either bilateral or unilateral, between January 2005 and January 2011. Falloposcopic tuboplasty. MAIN Medical records for 345 patients with a diagnosis of proximal tubal occlusion were reviewed. Of the 345 patients, 304 underwent falloposcopic tuboplasty, with successful recanalization achieved in 248 patients (81.6%). Ninety-one of the 304 patients (29.9%) became pregnant. Of these, 18 patients (19.8%) miscarried, and 4 (4.4%) had ectopic pregnancies in the recanalized tube. At 1-, 3-, 6-, and 9-month follow-up, the cumulative probability of conception was 23.1%, 50.6%, 73.6%, and 82.4%, respectively. Related complications included postsurgical infection (0.3%), perforation of the fallopian tube (1.3%), and accidental breakage of the catheter (4.9%) or the falloposcope (1.3%). Falloposcopic tuboplasty is safe and effective for treatment of tubal infertility. The pregnancy rate after falloposcopic tuboplasty is comparable to that after in vitro fertilization, which suggests that it can be an alternative to in vitro fertilization in women with tubal infertility.
Administration of nonsteroidal antiinflammatory drugs (NSAIDs) may impair fertility. The occurrence of the luteinized unruptured follicle (LUF) syndrome was assessed in women with inflammatory arthropathies exposed to NSAIDs and compared to that in nonexposed women. Fourteen patients with inflammatory rheumatic disease, 29 women with noninflammatory musculoskeletal conditions, and 449 women not exposed to NSAIDs were studied by intravaginal ultrasound monitoring for follicular development and ovulation in 1 or more menstrual cycles. Disease activity was assessed in inflammatory rheumatic disease. In 59 monitored cycles of patients with continuous NSAID exposure, 35.6% of LUF syndromes occurred compared to 3.4% of LUF syndromes in untreated women (P < 0.001). Etoricoxib was responsible for 75% of LUF syndromes in patients exposed continuously, whereas diclofenac generated 15% of LUF syndromes. An ibuprofen dosage of 1,600 mg/day did not induce LUF syndrome either at continuous periovulatory or discontinuous exposure. Interestingly, the frequency of LUF syndrome was 46.2% in patients with inactive inflammatory disease compared to 15% in patients with active disease (P = 0.023). Etoricoxib generated LUF syndrome in 94.2% of the cases with inactive disease versus 28.6% in patients with active disease (P = 0.003). NSAIDs increased the risk of the LUF syndrome, particularly in patients with inactive disease. The selective cyclooxygenase 2 (COX-2) inhibitor etoricoxib was a more potent inductor of LUF syndrome than nonselective COX inhibitors. Continuous periovulatory exposure to NSAIDs should be avoided when planning a pregnancy in patients with rheumatic diseases.
SurgeryTechniques and OutcomesSurgical TreatmentTubal Reconstruction
The diminished role of tubal surgery in infertile women following widespread access to IVF is now being reviewed as more patients and surgeons today consider tubal surgery as an effective alternative to assisted reproduction treatment in certain circumstances. The limitations of and lack of patient acceptance of assisted reproduction treatment for ethical and moral reasons have contributed to this change as well as advances in surgical techniques and instrument technology, notably developments in endoscopic surgery. Strategies in tubal surgery are largely unchanged but the mini-invasive nature of the endoscopic approach has added value because of less tissue trauma, better visualization of the operative field and more rapid healing, which make surgery using today's techniques an integral part of the treatment strategy in infertile couples.
Boyle PC et al., 2011·Biomedicina (Sveikatos Mokslai/Health Sciences)
Infertility is usually a consequence of multiple chronic conditions rather than a single acute condition. We propose that it is erroneous to apply acute medical interventions to a condition that is chronic in nature.
Retrospective analysis of 3 case studies which demonstrate the multifactorial and chronic nature of infertility that were previously managed unsuccessfully with acute intervention using IVF (in Vitro Fertilisation) or ART (Assisted Reproductive Technology).
Demonstration of the multifactorial approach and 3 successful singleton live births using NPT (Natural Procreative Technology or NaProTechnology). Infertility can be treated successfully with a multifactorial approach which takes into account the chronic nature of infertility and targets treatment to manage multiple factors responsible for the condition. Infertility is not a diagnosis but is often the expression of several underlying ill health conditions which if diagnosed and treated correctly will result in restoration of normal reproductive function. Physicians ought to consider broader diagnostic possibilities in their evaluation of infertile couples. A multifactorial treatment strategy for the chronic condition of infertility may be more effective than the widespread acute strategy employed by ART. Further study is required to investigate this possibility in more detail. Future studies looking at NPT and ART outcomes must be cohort studies comparing populations with similar patient characteristics.
AndrologyAcrosome ReactionFertilization MechanismsSperm Function
Open Access
Spermatozoon acrosome reaction is an exocytotic event of the utmost importance for the development of mammalian fertilisation. Current evidence shows that the triggering of the acrosome reaction (AR) could be regulated by the action of diverse compounds, namely, metabolites, neurotransmitters and hormones. The aim of the present review is to describe the modulating effects of several compounds that have been classified as inductors or inhibitors of acrosome reaction. Among AR inductors, it is necessary to mention progesterone, angiotensin II, atrial natriuretic peptide, cathecolamines, insulin, leptin, relaxin and other hormones. Regarding the inhibitors, oestradiol and epidermal growth factor are among the substances that retard AR. It is worth mentioning that gamma-aminobutyric acid, a neurotransmitter known to be an inhibitor in the central nervous system, has been shown to induce AR. The multiple hormones located in the fluids of the female reproductive tract are also likely to act as subtle regulators of AR, constituting a fundamental aspect for the development of successful fertilisation. Finally, it is necessary to emphasise that the study of regulation exerted by hormones and other compounds on AR is essential for further understanding of mammalian reproductive biology, especially spermatozoon physiology.
The paper presents the main concepts of NaProTECHNOLOGY. Such problems as family planning effectiveness, targeted hormonal assessment of the menstrual cycle, ovarian hormone and target organ dysfucntion, disorders of human ovulation, cooperative progesterone replacement therapy, premustrual syndrome, postpartum depression, unusual bleeding, infertility and antiadhesion therapy are discussed.
NaProTECHNOLOGYComprehensive Women's HealthAlternative to IVFClinical Outcomes
Dr. Thomas W. Hilgers draws on decades of medical experience to provide educational and revolutionary insights into the world of women's health. The NaPro Technology Revolution provides real solutions to real problems such as infertility, repetitive miscarriage, menstrual cramps, postpartum depression, PMS, prematurity prevention, ovarian cysts, hormonal abnormalities, irregular/abnormal bleeding, chronic discharges, polycystic ovarian disease, and family planning. Hilgers sheds light on abnormal ovarian function, an issue that millions of women unknowingly suffer from. His methods have proven to assist infertile couples nearly three times more successfully than those who use In Vitro Fertilization, without the dangers of early abortions, frozen embryos, or high rates of multiple pregnancy. The NaProTechnology Prematurity Prevention Program cuts the rate from the national 12.7% to 7%. The NaPro Technology Revolution discusses what every woman has a right to know about her body, her health, and her future!
Reproductive EndocrinologyThyroid and Reproductive FunctionThyroid Disease in PregnancyThyroid Dysfunction and Sperm Quality
Via its interaction in several pathways, normal thyroid function is important to maintain normal reproduction. In both genders, changes in SHBG and sex steroids are a consistent feature associated with hyper- and hypothyroidism and were already reported many years ago. Male reproduction is adversely affected by both thyrotoxicosis and hypothyroidism. Erectile abnormalities have been reported. Thyrotoxicosis induces abnormalities in sperm motility, whereas hypothyroidism is associated with abnormalities in sperm morphology; the latter normalize when euthyroidism is reached. In females, thyrotoxicosis and hypothyroidism can cause menstrual disturbances. Thyrotoxicosis is associated mainly with hypomenorrhea and polymenorrhea, whereas hypothyroidism is associated mainly with oligomenorrhea. Thyroid dysfunction has also been linked to reduced fertility. Controlled ovarian hyperstimulation leads to important increases in estradiol, which in turn may have an adverse effect on thyroid hormones and TSH. When autoimmune thyroid disease is present, the impact of controlled ovarian hyperstimulation may become more severe, depending on preexisting thyroid abnormalities. Autoimmune thyroid disease is present in 5-20% of unselected pregnant women. Isolated hypothyroxinemia has been described in approximately 2% of pregnancies, without serum TSH elevation and in the absence of thyroid autoantibodies. Overt hypothyroidism has been associated with increased rates of spontaneous abortion, premature delivery and/or low birth weight, fetal distress in labor, and perhaps gestation-induced hypertension and placental abruption. The links between such obstetrical complications and subclinical hypothyroidism are less evident. Thyrotoxicosis during pregnancy is due to Graves' disease and gestational transient thyrotoxicosis. All antithyroid drugs cross the placenta and may potentially affect fetal thyroid function.
EndometriosisEndometriosis Fertility IndexFertility Outcomes After Surgical TreatmentPrognosis and Prediction Tools
To develop a clinical tool that predicts pregnancy rates (PRs) in patients with surgically documented endometriosis who attempt non-IVF conception.
Prospective data collection on 579 patients and comprehensive statistical analysis to derive a new staging system--the endometriosis fertility index (EFI)--from data rather than a priori assumptions, followed by testing the EFI prospectively on 222 additional patients for correlation of predicted and actual outcomes.
Private reproductive endocrinology practice.
PATIENT(S): A total of 801 consecutively diagnosed and treated infertile patients with endometriosis.
INTERVENTION(S): Surgical diagnosis and treatment followed by non-IVF fertility management.
MAIN OUTCOME MEASURE(S): The EFI and life table PRs.
RESULT(S): A statistically significant variable used to create the EFI was the least function score (i.e., the sum of those scores determined intraoperatively after surgical intervention that describe the function of the tube, fimbria, and ovary on both sides). Sensitivity analysis showed that the EFI varies little, even with variation in the assignment of functional scores, and predicted PRs.
CONCLUSION(S): The EFI is a simple, robust, and validated clinical tool that predicts PRs after endometriosis surgical staging. Its use provides reassurance to those patients with good prognoses and avoids wasted time and treatment for those with poor prognoses.
Endometriosis is a debilitating condition characterized by high recurrence rates. The etiology and pathogenesis remain unclear. Typically, endometriosis causes pain and infertility, although 20-25% of patients are asymptomatic. The principal aims of therapy include relief of symptoms, resolution of existing endometriotic implants, and prevention of new foci of ectopic endometrial tissue. Current therapeutic approaches are far from being curative; they focus on managing the clinical symptoms of the disease rather than fighting the disease. Specific combinations of medical, surgical, and psychological treatments can ameliorate the quality of life of women with endometriosis. The benefits of these treatments have not been entirely demonstrated, particularly in terms of expectations that women hold for their own lives. Although theoretically advantageous, there is no evidence that a combination medical-surgical treatment significantly enhances fertility, and it may unnecessarily delay further fertility therapy. Randomized controlled trials are required to demonstrate the efficacy of different treatments.
Ethics/PhilosophyEmbryo Adoption and Moral StatusDignitas Personae and Reproductive TechnologyFertility Industry Cooperation and Scandal
The Congregation of the Doctrine of the Faith’s Dignitas personae doesnotofferadefinitiverejectionofthepracticeofhumanembryoadoptionas intrinsicallyevil,butneitherdoesitsimplyleavethematteran“openquestion.” The document does indeed oppose the practice, but its reasons for doing so are notclearlystatedandseemtobeintensionwithitsownaffirmationsofthe personal dignity of embryos and the goodness of adoption. The Congregation’s opposition is therefore best read as a prudential judgment that embryo adoption cannotbejustifiedinthepresentcircumstancesduetothepotentialforscandal and the cooperation with the fertility industry which it involves. National Catholic Bioethics Quarterly 10.2(Summer2010):307–328.
InfertilityAutoimmune and Systemic DiseasesCeliac Disease and ReproductionSecondary Amenorrhea
Celiac disease is an intestinal inflammatory disease that is triggered by gluten in the diet. Patients present with a wide array of symptoms due to malabsorption that include diarrhea, abdominal pain, bloating and weight loss. In women, this disease may have implications on menstrual and reproductive health. The symptom complex includes delayed menarche, early menopause, secondary amenorrhea, infertility, recurrent miscarriages and intrauterine growth restriction. These women benefit from early diagnosis and treatment. Therefore, celiac disease should be considered and screening tests performed on women presenting with menstrual and reproductive problems and treated accordingly. The objective of this article is to review the current literature on celiac disease and its association with the above-mentioned disorders.
Progesterone is essential for endometrial receptivity and successful establishment of pregnancy. Either an insufficient progesterone concentration or an insufficient response to progesterone, therefore can lead to infertility and pregnancy loss. Assessment of the role that either progesterone insufficiency or inadequate progesterone response plays in human reproductive failure has been difficult to assess because serum progesterone concentrations fluctuate markedly, limiting the ability to characterize sufficiency of progesterone, and there are no highly reliable markers of endometrial function available. Recent evidence demonstrates exquisite sensitivity of normal endometrium to very low levels of progesterone stimulation, suggesting that progesterone insufficiency should not be a common cause of reproductive failure. Further evidence suggests that women with endometriosis, and possibly polycystic ovarian syndrome, have an altered progesterone response, which may explain some of the clinical features of these disorders and supports the hypothesis that progesterone resistance underlies some cases of human reproductive failure.
Chronic plasmacytic endometritis (CPE) is an infectious or reactive process with multiple etiologies. The lesion is reportedly often associated with pelvic inflammatory disease and intermenstrual bleeding. However, the clinical significance of the diagnosis when found incidentally and whether particular pathologic findings are associated with clinically important CPE have not been evaluated. We reviewed 105 chronic endometritis cases that had been diagnosed earlier and 130 controls to examine the pathologic and clinical associations in a diverse population.A pathology database was searched for endometrial biopsies diagnosed as CPE, and 105 cases were found. Systematic randomized sampling identified 130 control cases (biopsies not diagnosed as CPE). Slides were carefully reviewed to assess 10 histopathologic features. Clinical records were reviewed for 15 clinical parameters. Analysis was performed using chi tests and SAS software.Few patients (3%) received antibiotics or further clinical intervention after the diagnosis of CPE was rendered. The clinical data trended toward fewer menstrual abnormalities as plasma cells increased. The intensity of inflammation showed no association with patient age or symptom duration. Evaluation of controls revealed 17 cases with missed diagnosis of CPE, representing an overall 16% underdiagnosis rate.In CPE, there are no specific clinical features that correlate with the intensity of pathologic findings; the most specific histologic feature is the presence of plasma cells, and it is predominantly identified in weakly proliferative endometrium. There is a clinically insignificant 16% pathologic underdiagnosis rate. In contrast to the findings of past studies, only a small percentage of patients had pelvic inflammatory disease (4%).
Recent studies have shown that both female and male obesity may delay time-to-pregnancy (TTP). Little is known about central adiposity or weight gain and fecundability in women. We examined the association between anthropometric factors and TTP among 1651 Danish women participating in an internet-based prospective cohort study of pregnancy planners (2007-2008). We categorized body mass index (BMI = kg/m(2)) as underweight (<20), normal weight (20-24), overweight (25-29), obese (30-34) and very obese (> or =35). We used discrete-time Cox regression to estimate fecundability ratios (FRs) and 95% confidence intervals (CI), controlling for potential confounders. We found longer TTPs for overweight (FR = 0.83, 95% CI = 0.70-1.00), obese (FR = 0.75, 95% CI = 0.58-0.97), and very obese (FR = 0.61, 95% CI = 0.42-0.88) women, compared with normal weight women. After further control for waist circumference, FRs for overweight, obese, and very obese women were 0.72 (95% CI = 0.58-0.90), 0.60 (95% CI = 0.42-0.85) and 0.48 (95% CI = 0.31-0.74), respectively. Underweight was associated with reduced fecundability among nulliparous women (FR = 0.82, 95% CI = 0.63-1.06) and increased fecundability among parous women (FR = 1.61, 95% CI = 1.08-2.39). Male BMI was not materially associated with TTP after control for female BMI. Compared with women who maintained a stable weight since age 17 (-5 to 4 kg), women who gained > or =15 kg had longer TTPs (FR = 0.72, 95% CI = 0.59-0.88) after adjustment for BMI at age 17. Associations of waist circumference and waist-to-hip ratio with TTP depended null associations were observed before adjustment for BMI and weakly positive associations were observed after adjustment for BMI. Our results confirm previous studies showing reduced fertility in overweight and obese women. The association between underweight and fecundability varied by parity.
Dehydroepinadrosterone (DHEA) supplementation improves pregnancy chances in women with diminished ovarian reserve (DOR), by possibly reducing aneuploidy. Since a large majority of spontaneous miscarriages are associated with aneuploidy, one can speculate that DHEA supplementation may also reduce miscarriage rates. We retroactively compared, utilizing two independent statistical models, miscarriage rates in 73 DHEA supplemented pregnancies at two independent North American infertility centers, age-stratified, to miscarriages reported in a national U.S. in vitro fertilization (IVF) data base. After DHEA supplementation the miscarriage rate at both centers was 15.1% (15.0% and 15.2%, respectively). For DHEA supplementation Mantel-Hänszel common odds ratio (and 95% confidence interval), stratified by age, was significantly lower, relative to odds of miscarriage in the general IVF control population [0.49 (0.25-0.94; p = 0.04)]. Miscarriage rates after DHEA were significantly lower at all ages but most pronounced above age 35 years. Since DOR patients in the literature are reported to experience significantly higher miscarriage rates than average IVF patients, the here observed reduction in miscarriages after DHEA supplementation exceeds, however, all expectations. Miscarriage rates after DHEA not only were lower than in an average national IVF population but were comparable to rates reported in normally fertile populations. Low miscarriage rates, comparable to those of normal fertile women, are statistically impossible to achieve in DOR patients without assumption of a DHEA effect on embryo ploidy. Beyond further investigations in infertile populations, these data, therefore, also suggest the investigations of pre-conception DHEA supplementation in normal fertile populations above age 35 years.
Contraception/ComparisonFertility ReturnContraceptive History
This review will address the current understanding of the relationship between prolactin (PRL) and endometriosis-associated infertility. Although the exact mechanisms of action of hyperprolactinemia in patients with endometriosis-associated infertility have not been clearly established, this report reviews results from relevant studies in the literature. These include serum PRL levels in endometriosis-associated infertility, PRL receptors in ectopic endometriotic tissues, basal PRL levels after TSH and Danazol (isoxazolic derivative of the synthetic steroid 5alpha-ethinyl-testosterone) therapy, peritoneal fluid and nocturnal serum PRL levels in endometriosis, infertility, and luteal phase PRL concentrations in patients with endometriosis. Obstetricians & Gynecologists, Family Physicians. After completion of this article, the reader should be able to explain the relationship between prolactinand endometriosis-associated infertility, relate endometriosis with infertility, and summarize two ways in which prolactin and endometriosis may be linked in the pathophysiology of infertility.
Contraception/ComparisonIVF Access and UtilizationAssisted Reproductive Technology DemographicsPublic Health Data
To characterize the demographic correlates of IVF availability and utilization.
Demographic analysis of public data.
Each of the 50 states in the United States was used as a unit of analysis. PATIENT(S): Patients undergoing IVF, as demographically estimated. INTERVENTION(S): Publicly available data were collected through the Society for Assisted Reproductive Technology and the Centers for Disease Control. The US Census Bureau data were collected by using software available from the Centers for Disease Control. MAIN OUTCOME MEASURE(S): The number of physicians performing IVF and the number of IVF cycles per 100,000 reproductive-age women were used to estimate IVF availability and utilization. RESULT(S): In 2005, 1,031 providers performed 98,242 fresh IVF cycles in 430 centers. Overall availability was 2.5 IVF physicians per 100,000, and utilization was 236 IVF cycles per 100,000. Availability and utilization of IVF were highly correlated. Mean IVF availability and utilization were significantly higher in states with IVF insurance coverage. In adjusted analyses, IVF availability correlated positively with mandated insurance coverage, percentage of single persons, and median income. Utilization of IVF correlated with IVF availability, percentage urbanization, and percentage of individuals >or=25 years of age who had a bachelor's degree. CONCLUSION(S): Lower rates of IVF utilization in some states are correlated with a lack of insurance coverage and decreased availability of physicians providing this service.
InfertilityConservative vs Assisted ReproductionCumulative Pregnancy ProbabilitySimulation Study
To model the cumulative probability of pregnancy among couples with subfertility without a definitive diagnosis, according to different treatment strategies. A beta distribution of fecundity was fitted that reproduced the cumulative probability of pregnancy in prospective studies of natural fertility, and this distribution was applied to simulated cohorts starting with one million couples each. Probabilities of pregnancy were generated for each cycle of each couple. Simulation study. PATIENT(S): Hypothetic subfertile population. INTERVENTION(S): After 2 or 4 years of attempting pregnancy and diagnostic evaluation to exclude anovulation, tubal obstruction, and severe male factor, simulated treatments were applied to the remaining nonpregnant couples, with treatment effects based on published literature. MAIN OUTCOME MEASURE(S): Simulated cumulative probability of pregnancy. RESULT(S): Initially, the cumulative probability of pregnancy was highest for early treatment with IVF, but over time, conservative treatment or frequent intercourse approached the same cumulative probability. CONCLUSION(S): In couples without clear indications for IVF, the main benefit of early IVF may be to shorten time to pregnancy, a benefit that must be weighed against costs and potential adverse outcomes. Couples should be encouraged to maintain regular intercourse to maximize chances of pregnancy, even after unsuccessful treatment attempts.
To examine whether thin endometria can be improved by increasing uterine radial artery (uRA) blood flow. A prospective observational study. University hospital and city general hospital. PATIENT(S): Sixty-one patients with a thin endometrium (endometrial thickness [EM] <8 mm) and high radial artery-resistance index of uRA (RA-RI >or=0.81). INTERVENTION(S): Vitamin E (600 mg/day, n = 25), l-arginine (6 g/day, n = 9), or sildenafil citrate (100 mg/day, intravaginally, n = 12) was given. MAIN OUTCOME MEASURE(S): EM and RA-RI were assessed by transvaginal color-pulsed Doppler ultrasound. RESULT(S): Vitamin E improved RA-RI in 18 (72%) out of 25 patients and EM in 13 (52%) out of 25 patients. L-arginine improved RA-RI in eight (89%) out of nine patients and EM in six (67%) patients. Sildenafil citrate improved RA-RI and EM in 11 (92%) out of 12 patients. In the control group (n = 10), who received no medication to increase uRA-blood flow, only one (10%) patient improved in RA-RI and EM. The effect of vitamin E was histologically examined in the endometrium (n = 5). Vitamin E improved the glandular epithelial growth, development of blood vessels, and vascular endothelial growth factor protein expression in the endometrium. CONCLUSION(S): Vitamin E, l-arginine, or sildenafil citrate treatment improves RA-RI and EM and may be useful for the patients with a thin endometrium.
Pregnancy could be associated with a state of oxidative stress that could initiate and propagate a cascade of changes that may lead to pregnancy wastage. This process of oxidative stress may be suppressed by the antioxidant effect of N-acetyl cysteine (NAC). The current study aimed to evaluate the effect of NAC therapy in patients diagnosed with unexplained recurrent pregnancy loss (RPL). The study was a prospective controlled study performed in the Women's Health Centre, Assiut University, Egypt. A group of 80 patients with history of recurrent unexplained pregnancy loss were treated with NAC 0.6 g + folic acid 500 microg/day and compared with an aged-matched group of 86 patients treated with folic acid 500 microg/day alone. NAC + folic acid compared with folic acid alone caused a significantly increased rate of continuation of a living pregnancy up to and beyond 20 weeks [P < 0.002, relative risk (RR) 2.9, 95% confidence interval (CI) 1.5-5.6]. NAC + folic acid was associated with a significant increase in the take-home baby rate as compared with folic acid alone (P < 0.047, RR 1.98, 95% CI 1.3-4.0). In conclusion, NAC is a well-tolerated drug that could be a potentially effective treatment in patients with unexplained RPL.
NaProTECHNOLOGYClinical OutcomesLive Birth RatesGeneral Practice Setting
We evaluated outcomes in couples treated for infertility with natural procreative technology (NaProTechnology [corrected] NPT), a systematic medical approach for optimizing physiologic conditions for conception in vivo, from an Irish general practice. All couples receiving treatment from 2 NPT-trained family physicians between February 1998 and January 2002 were studied. The main outcome was live birth, and secondary outcomes included conceptions and multiple births. Crude proportions and adjusted life-table proportions were calculated per 100 couples. A total of 1239 couples had an initial consult for NPT, of which 1072 had been trying for at least a year to conceive and initiated treatment. The average female age was 35.8 years, the mean duration of attempting to conceive was 5.6 years, 24% had a prior birth, and 33% had previously attempted treatment with assisted reproductive technology (ART). All couples were taught to identify the fertile days of the menstrual cycle with the Creighton Model FertilityCare System, and most received additional medical treatment, including clomiphene (75%). In life-table analysis, the cumulative proportion of first live births for those completing up to 24 months of NPT treatment was 52.8 per 100 couples. The crude proportion was 25.5. Younger couples and couples without previous ART attempts had higher rates of live birth. Among live births, there were 4.6% twin births. NPT provided by trained general practitioners had live birth rates comparable to cohort studies of more invasive treatments, including ART. Further studies are warranted to compare NPT directly to other treatments.
Over the past decade, significant advances have occurred in the diagnosis and treatment of reproductive disorders. In this review, we discuss the routine testing performed to diagnose unexplained infertility. We also discuss additional testing, such as assessment of ovarian reserve, and the potential role of laparoscopy in the complete workup of unexplained infertility. Finally, we outline the available therapeutic options and discuss the efficacy and the cost-effectiveness of the existing treatment modalities. The optimal treatment strategy needs to be based on individual patient characteristics such as age, treatment efficacy, side-effect profile, and cost considerations.
To determine the effect of luteinized unruptured follicle (LUF) cycles on frozen thawed embryo transfer (FET).
A retrospective analysis comparing the clinical outcomes after FET among 144 cases of luteinized unruptured follicle (LUF) cycles and 866 cases of ovulation cycles.
Reproductive medical center, Beijing China. Chinese infertile women who underwent FET. None. Clinical pregnancy rate (PR), implantation rate. The implantation rate, clinical pregnancy rate, on-going pregnancy rate and live birth rate in LUF group were 12.76% (49/384), 27.78% (40/144), 24.31% (35/144) and 19.44% (28/144), respectively, and in ovulation group, 14.74% (332/2251), 31.29% (271/866), 28.29% (245/866) and 22.23% (193/866), respectively (p > 0.05). LUF does not affect the clinical outcomes of FET. Patients of LUF should be included in FET treatment.
In vitro fertilization used in combination with intracytoplasmic sperm injection allows otherwise sterile couples to become parents. Despite recent studies on the safety of these technologies, there is still only an incomplete picture of the risks associated with the usage of these assisted reproductive techniques to offspring. The risk of multiple gestations continues to be of major concern because of its association with low birth weight, preterm delivery, and increased perinatal mortality. This article outlines the risks associated with in vitro fertilization/intracytoplasmic sperm injection as a well-defined treatment for couples with severe male factor infertility.
Reproductive EndocrinologyInflammatory MechanismsLuteinized Unruptured FollicleG-CSF in Reproduction
In 1980, Espey proposed a famous hypothesis that mammalian ovulation is comparable to an inflammatory reaction and many researches have proved the validity of his hypothesis in the last three decades. For example, interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)- alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF) and other inflammatory cytokines presence was proven in the preovulatory follicle. Since granulocyte is the major leukocyte and it plays a very important role during inflammation, the importance of granulocyte and its related cytokine, granulocyte colony-stimulating factor (G-CSF) in the mechanism of human ovulation is easily predictable. G-CSF is one of the hemopoietic cytokines and it has strong positive effects on granulocytes. G-CSF increases the number of granulocytes and it improves the function of granulocytes. In this review, the participation of leukocytes in the ovulation mechanism is demonstrated first. Second, the participation of G-CSF is shown in comparison with the above mentioned cytokines. Finally, since G-CSF has been used for more than 20 years as a medicine without severe side effects in the field of oncology, the clinical application of G-CSF for the treatment of an ovulation disorder, luteinized unruptured follicle (LUF), will be discussed.
In the light of similarities between premenstrual syndrome and toxaemia, and the fact that treatment of the former with progesterone not only relieved the symptoms (Greene and Dalton, 1953) but also prevented the development of edema, hypertension, and albumin
AndrologyMetabolic SyndromeObesity and Hormonal DysfunctionSystemic Disease Impact
Metabolic syndrome (MetS) is highly prevalent, affecting more than 47 million US residents. This condition is also multifaceted, potentially leading to significant disturbance of numerous physiologic processes. This review article evaluates the literature regarding metabolic syndrome and male reproductive health. Links between obesity, dyslipidemia, hypertension, and insulin resistance are each examined with regard to their associated detrimental effects on male fertility. At the end of this manuscript, we propose a new MetS/male infertility paradigm. Additional studies specifically addressing the components of MetS and their impact on male reproduction will enhance our understanding of the underlying pathophysiology. These studies may also help clarify the role for therapeutic intervention.
InfertilityTransport and CapacitationCapacitation MechanismsSperm Preparation
It is well understood that a myriad of complex steps occur between the time of ejaculation and the union of the haploid number of chromosomes from each partner that results in the final process of fertilization. Consequently, it is easy to imagine the numerous potential problems that can occur at each step, and thus may prevent a successful pregnancy. Often overlooked are the complexities of sperm transport and the steps that must occur in the sperm, a process known as capacitation, before fertilization can occur. These processes of sperm delivery and potentiation are addressed in detail in this chapter.
Oligomenorrhea and polycystic ovaries in women are one of the most important causes of the high incidence of ovulation failure. This is linked, perhaps, to insulin resistance and related metabolic features. A small number of reports show that myo-inositol improves ovarian function, but in these trials the quality of evidence supporting ovulation is suboptimal. Furthermore, few of them have been placebo-controlled. The aim of our study was to use a double-blind, placebo-controlled approach with detailed assessment of ovarian activity (two blood samples per week) to assess the validity of this therapeutic approach in this group of women. Of the 92 patients randomized, 47 received 400 mcg folic acid as placebo, and 45 received myo-inositol plus folic acid (4 g myo-inositol plus 400 mcg folic acid). The ovulation frequency assessed by the ratio of luteal phase weeks to observa-tion weeks was significantly (P < 0.01) higher in the treated group (25%) compared with the placebo (15%), and the time to first ovulation was significantly (P < 0.05) shorter [24.5 d; 95% confidence interval (CI), 18, 31; compared with 40.5 d; 95% CI, 27, 54]. The number of patients failing to ovulate during the placebo-treatment period was higher (P < 0.05) in the placebo group, and the majority of ovulations were characterized by normal progesterone concentrations in both groups. The effect of myo-inositol on follicular maturation was rapid, because the E2 circulating concentration increased over the first week of treatment only in the myo-inositol group. A significant increase in circulating high-density lipoprotein was observed only in the myo-inositol-treated group. Metabolic risk factor benefits of myo-inositol treatment were not observed in the morbidly obese subgroup of patients (body mass index > 37). After 14-wk myo-inositol or placebo therapy, no change in fasting glucose concentrations, fasting insulin, or insulin responses to glucose challenge was recorded. There was an inverse relationship between body mass and treatment efficacy. In fact a significant weight loss (and leptin reduction) (P < 0.01) was recorded in the myo-inositol group, whereas the placebo group actually increased weight (P < 0.05). These data support a beneficial effect of myo-inositol in women with oligomenorrhea and polycystic ovaries in improving ovarian function.
AndrologyLubricant Effects on MotilityVaginal Lubricant ImpactDNA Fragmentation
To evaluate the effect of vaginal lubricants Pre-Seed, FemGlide, Astroglide, and Replens on human sperm motility and chromatin integrity. Prospective, comparative, in vitro study. Andrology laboratory at tertiary care hospital. PATIENT(S): Thirteen normozoospermic donors. INTERVENTION(S): Semen samples from 13 subjects were incubated in human tubal fluid media (HTF) controls and 10% (vol/vol) of Pre-Seed, FemGlide, Astroglide, and Replens lubricants. After 30 minutes, progressive sperm motility was assessed by light microscopy. Semen samples of 12 patients were placed in positive control (HTF), negative control (10% K-Y Jelly lubricant), and 10% vol/vol Pre-Seed and FemGlide lubricants. After 4 hours culture, spermatozoa were analyzed for percent DNA fragmentation index with use of the acridine orange-based sperm chromatin structure assay. MAIN OUTCOME MEASURE(S): Sperm motility and percent DNA fragmentation index. Percent motility did not differ significantly between HTF controls and Pre-Seed, whereas FemGlide, Replens, and Astroglide lubricants demonstrated a significant decrease in motility. There was no significant difference in percent DNA fragmentation index between the HTF controls and Pre-Seed, but a significant decline in sperm chromatin quality occurred with FemGlide and K-Y Jelly. Pre-Seed does not cause a significant decrease in progressive sperm motility or chromatin integrity in contrast to other lubricants used by couples.
The period in each menstrual cycle during which sexual intercourse can result in conception is called the "fertile window". Although the fertile window closes on the day of ovulation, little is known about the moment it opens. We defined the first day of normal sperm-mucus interaction as the opening of the fertile window. We hypothesized that length of the fertile window varies between couples and that the number of days the fertile window is "open" is related to the time to spontaneous conception. METHODS Serial post-coital tests and sperm-mucus penetration tests were performed to detect the first normal sperm-mucus interaction day. Ovulation was confirmed by serial ultrasound. Using Cox' regression analysis, we determined whether the fertile window length was associated with time to ongoing pregnancy. This association was expressed in fecundability ratios (FR). RESULTS The fertile window length was determined in 410 subfertile couples. The fertile window length varied among couples from <1 to >5 days. The FR increased with increasing fertile window length and varied between 0.11 (95% CI: 0.03-0.45) for a fertile window of 1 day, to 2.4 (95% CI: 1.1-5.2) for a fertile window of 5 days or more. CONCLUSIONS The longer the fertile window in subfertile couples, the higher is the probability of spontaneously conceiving an ongoing pregnancy.
InfertilityStress and DistressPsychosocial InterventionsPatient Dropout
Cousineau TM et al., 2007·Best Practice & Research Clinical Obstetrics & Gynaecology
The inability to conceive children is experienced as a stressful situation by individuals and couples all around the world. The consequences of infertility are manifold and can include societal repercussions and personal suffering. Advances in assisted reproductive technologies, such as IVF, can offer hope to many couples where treatment is available, although barriers exist in terms of medical coverage and affordability. The medicalization of infertility has unwittingly led to a disregard for the emotional responses that couples experience, which include distress, loss of control, stigmatization, and a disruption in the developmental trajectory of adulthood. Evidence is emerging of an association between stress of fertility treatment and patient drop-out and pregnancy rates. Fortunately, psychological interventions, especially those emphasizing stress management and coping-skills training, have been shown to have beneficial effects for infertility patients. Further research is needed to understand the association between distress and fertility outcome, as well as effective psychosocial interventions.
To compare clomiphene citrate plus N-acetyl cysteine versus clomiphene citrate for inducing ovulation in patients with polycystic ovary syndrome.
Prospective cross-over trial.
University teaching hospital and a private practice setting. Five hundred and seventy-three patients were treated with clomiphene citrate for one menstrual cycle among which 470 patients were treated with clomiphene citrate plus N-acetyl cysteine for another cycle. All women suffered from polycystic ovary syndrome. Patients had clomiphene citrate 50-mg tablets twice daily alone or with N-acetyl cysteine 1,200 mg/day orally for 5 days starting on day 3 of the menstrual cycle. Primary outcomes were number of mature follicles, serum E2, serum progesterone, and endometrial thickness. Secondary outcome was the occurrence of pregnancy. Ovulation rate improved significantly after the addition of N-acetyl cysteine (17.9% versus 52.1%). Although the number of mature follicles was more in the N-acetyl cysteine group (2.1+/-0.88 versus 3.2+/-0.93), the difference was not statistically significant. The mean E2 levels (pg/ml) at the time of human chorionic gonadotropine injection, serum progesterone levels (ng/ml) on days 21-23 of the cycle, and the endometrial thickness were significantly improved in the N-acetyl cysteine group. The overall pregnancy rate was 11.5% in the N-acetyl cysteine group. Insulin resistance occurred in 260 patients (55.4%). There was no significant difference between the insulin resistance group (n = 260) and non-insulin resistance group (n = 210) as regards ovulation rate, number of follicles, serum E2 (pg/ml), serum progesterone (ng/ml), endometrial thickness (mm), or pregnancy rate. N-Acetyl cysteine is proved effective in inducing or augmenting ovulation in polycystic ovary patients.
Fertility AwarenessFecundability EstimationTime to Pregnancy StudiesIntercourse Pattern Effects
Time to pregnancy, typically defined as the number of menstrual cycles required to achieve a clinical pregnancy, is widely used as a measure of couple fecundity in epidemiologic studies. Time to pregnancy studies seldom utilize detailed data on the timing and frequency of sexual intercourse and the timing of ovulation. However, the simulated models in this paper illustrate that intercourse behavior can have a large impact on time to pregnancy and, likewise, on fecundability ratios, especially under conditions of low intercourse frequency or low fecundity. Because intercourse patterns in the menstrual cycles may vary substantially among groups, it is important to consider the effects of sexual behavior. Where relevant and feasible, an assessment should be made of the timing and frequency of intercourse relative to ovulation. Day-specific probabilities of pregnancy can be used to account for the effects of intercourse patterns. Depending on the research hypothesis, intercourse patterns may be considered as a potential confounder, mediator, or outcome.
Women with polycystic ovary syndrome (PCOS) are considered to be at increased risk of miscarriage. Since metformin has beneficial effects on the risk factors contributing to first-trimester abortion in PCOS patients, we hypothesized that metformin - owing to its metabolic, endocrine, vascular and anti-inflammatory effects - may reduce the incidence of first-trimester abortion in PCOS women. A prospective cohort study was set up to determine the beneficial effects of metformin on PCOS patients during pregnancy. Two hundred non-diabetic PCOS patients were evaluated while undergoing assisted reproduction. One hundred and twenty patients became pregnant while taking metformin, and continued taking metformin at a dose of 1000-2000 mg daily throughout pregnancy. Eighty women who discontinued metformin use at the time of conception or during pregnancy comprised the control group. Both groups were similar with respect to all background characteristics (age, body mass index, waist/hip ratio, follicle-stimulating hormone, luteinizing hormone, estradiol and dehydroepiandrosterone sulfate levels). Rates of early pregnancy loss in the metformin group were 11.6% compared with 36.3% in the control group (p < 0.0001; odds ratio = 0.23, 95% confidence interval 0.11-0.42). Administration of metformin throughout pregnancy to women with PCOS was associated with a marked and significant reduction in the rate of early pregnancy loss.
SurgerySalpingectomy for HydrosalpinxIVF OptimizationSurgical Recommendations
Clinically a couple is considered to be infertile after at least one year without contraception and without pregnancy. There was scant knowledge about the prevalences of infertility, involuntary childlessness and the seeking of fertility treatment and only few longitudinal studies about the psychosocial consequences of infertility and its treatment. This thesis is about the epidemiological aspects of infertility; the conceptualization and measurement of important psychosocial aspects of infertility; and a medical sociological analysis of the associations between these psychosocial variables among Danish women and men in fertility treatment. The thesis is based on nine papers. (i) to review critically, population based studies of infertility and medical care seeking in industrialised countries. Further, to examine these prevalences and subsequent motherhood among women in former assisted reproduction in a Danish population. (ii) To develop measures of psychosocial fertility problem stress, marital benefit, communication, coping strategies, attitudes to and evaluation of fertility treatment. (iii) To examine these phenomena and to analyse their interrelations among Danish women and men in fertility treatment. The thesis is based (i) The Women and Health Survey, a cross-sectional population-based study among 15-44 year old women (n=907, 25-44 year old) in Copenhagen County, 1989. (ii) The Psychosocial Infertility Interview Study, a qualitative interview study among 16 couples (n=2 participants) infertility treatment at The Fertility Clinic, Herlev University Hospital,1992. (iii) The Infertility Cohort, a longitudinal cohort study consecutively including all couples (n=250 participants) beginning anew fertility treatment period at one of four public (Braedstrup, Herlev, Odense, Rigshospitalet) and one private fertility clinic (Trianglen),2000-2002. (iv) The Communication and Stress Management Training Programme, an intervention study among couples(n=74 participants) in fertility treatment at The Fertility Clinic, The Juliane Marie Centre, Rigshospitalet, 2001-2003. Included is also a literature review of population-based infertility studies from industrialised countries. Data from (iii) and (iv) are studies from The Copenhagen Multi-centre Psychosocial Infertility (COMPI) Research Programme (www.compipro.dk). Epidemiological and demographic studies investigating the prevalences of infertility differed in how they defined the numerator (the infertile participants) and the denominator (the population at risk). It was important to calculate reliable estimates of the infertility prevalence by including only women who had tried to have at least one child in the population at risk, as a notable proportion of women in the fertile ages had not (yet) attempted to become a mother. The lifetime prevalence of infertility in the representative population-based study was 26.4%. In the age group 35 to 44 years 5.8% were primarily involuntarily in fecund (involuntarily childless). Even in a country with access to fertility treatment in a public health-care system without self-payment lower education was a predictor of lower treatment seeking. In the cohort study (2000-2002)of couples starting a new period of assisted reproduction treatment 62.6% reported a treatment-related pregnancy at the one-year follow-up. In total 32.4% reported a treatment-related delivery. In total 24.2% reported a current continuing pregnancy and spontaneous pregnancies accounted for 2.7% of these. We developed measures of fertility problem stress, marital benefit(that infertility has brought the partners closer together and strengthened their marriage), partner communication, infertility related communication, coping strategies, attitudes to fertility treatment and evaluation of care. The medical sociological analyses showed that the variables of psychosocial consequences of infertility and treatment are interwoven with each others in a complex pattern, a pattern that both differed and was similar when comparing women and men. The infertility-related communication strategy (secrecy, formal, open-minded)identified in the qualitative interviews was later confirmed in the COMPI Infertility Cohort. Using the formal strategy and not talking about the emotional aspects of infertility and its treatment suggested high fertility problem stress. The coping strategies studied showed significant social differences and active-avoidance coping was a significant predictor of high fertility problem stress. A positive effect of infertility on the marriage, marital benefit was common. Men using the secrecy communication strategy had increased risk of low marital benefit. Difficult partner communication was a significant predictor of high fertility problem stress and among men, of low marital benefit. The intervention study showed that it was possible for the participants to change their communication with partner and other people close to them and that participants achieved an increased awareness of what, how much and when to discuss with others. High fertility problem stress and high marital benefit were associated with high importance ratings of patient-centred care and intentions to use professional psychosocial services. Among women, high fertility problem stress was a predictor of lower satisfaction ratings with fertility treatment. High marital benefit was a predictor of high satisfaction ratings of both medical and patient-centred care. In conclusion, infertility is a common experience among couples attempting to become parents. Assisted reproduction in the public health-care system in Denmark has high success rates, i.e. pregnancies,deliveries and high patient satisfaction. A large minority of people in fertility treatment experience high fertility problem stress,and some use communication and coping strategies that predicts high stress. Developing and evaluating different psychosocial interventions are necessary to offer the psychosocial support needed for this minority of fertility patients.
Thyroid disease in general, and hypothyroidism in particular, are very common in women. In the USA, the most common cause of primary thyroid deficiency is on an autoimmune basis due to lymphocytic (Hashimoto) thyroiditis. Because there are thyroid hormone receptors in virtually every tissue of the body, the manifestations of hypothyroidism are varied, but problems with abnormal menses, conception, fertility, and pregnancy can be especially troubling in young women. The single most important diagnostic test is measurement of serum thyrotropin (TSH). The overwhelming majority of patients with hypothyroidism are treated with a single daily dose of synthetic levothyroxine with the goal of therapy being restoration of a normal metabolic state with return of the TSH level down to the range of 0.5 to 1.5 mlU/L. "Subclinical" hypothyroidism refers to those patients with early or mild thyroid hypofunction manifested as slight elevations of thyrotropin (approximately 4-10 mlU/L) although serum thyroxine (T4) and triiodothyronine (T3) levels are within their reference ranges. The entity is somewhat controversial in regard to its consequences if left untreated, and whether or not we should be screening patients, at least susceptible populations, for the condition. Reports indicate an association between subclinical hypothyroidism and poor outcomes of pregnancy, as well as dyslipidemias, atherogenesis, and increased mortality in the long term. We believe these consequences are sufficiently compelling to warrant screening and treatment with levothyroxine when found to halt progression to overt hypothyroidism, and improve symptoms, pregnancy outcomes, lipid abnormalities, and cardiovascular function. Obstetricians & Gynecologists, Family Physicians. After completion of this article, the reader should be able to recall that hypothyroidism is a common disease in women, has many protean manifestations, and can be successfully diagnosed and treated; explain that the condition of subclinical hypothyroidism can be diagnosed and if treated can prevent many untoward complications; and state that there should be heightened awareness of the disease so that proper screening tests can be performed.
With the collaboration of Italian centres providing services on natural family planning, a prospective study collected data on 2755 menstrual cycles of 193 women. A database was constructed using information on the daily characteristics of cervical mucus and episodes of intercourse. Taking the day of peak mucus as a conventional marker of ovulation, the database identified the length (12 days) and location of a 'window' of potential fertility, the highest level of conception probability being confined to the central five to six days. Univariate analysis provided evidence of the impact on fecundability of the woman's age and the basic infertile pattern of a cycle. Several analytical approaches highlighted the relationship between daily mucus characteristics and levels of fecundability
Effective tubal transport of ova, sperm and embryos is a prerequisite for successful spontaneous pregnancy. Although there is much yet to be discovered about the mechanisms involved, it is evident that tubal transit is a far more complicated process than initially thought. Propulsion of gametes and embryos is achieved by complex interaction between muscle contractions, ciliary activity and the flow of tubal secretions. Evidence is accumulating of the important and possibly pre-eminent role of ciliary motion in this process; and this review describes current knowledge about ciliary activity and its physiological regulation. There is also a description of the effects on ciliary function of cigarette smoking and various pathological states, including endometriosis and microbial infection, with consideration given as to how altered ciliary activity may impact upon fertility.
Assessing the psychological acceptability of technologies designed to assist couples in achieving pregnancy is complex. The current study developed measures relating to the impact of one such technology on 52 couples' relationships, their feelings relating to pregnancy status and their feelings about the technology itself. Pregnancy status and daily logs of sexual activity were recorded for four menstrual cycles, in addition to the completion of acceptability questionnaires. Baseline acceptability measures were more favorable among couples eventually achieving pregnancy. For couples not becoming pregnant, acceptability declined over time and relationships became more strained. Behavioral data clearly indicated a "targeting" and focusing of sexual activity in response to the information displayed by the monitor. Expectations of success, couple disagreements about prior failure and partner communication patterns appear to be related to pregnancy success when using such technology.
Fertility AwarenessBasal Body TemperatureOvulation DetectionClinical Counseling
Advanced practice nurses in primary care settings are often asked to give appropriate advice to couples seeking pregnancy. This article examines the issue of basal body temperature (BBT), a time-honored way to establish the presence of ovulatory cycles, and asks if BBT is an outdated recommendation. The article also reviews the benefits and limitations of recommending BBT to couples seeking pregnancy in light of recent fecundity research.
The objective of the present paper is to review the main results of recent European cycle databases on ovulation detection and determination of the fertile window performed by the women themselves. The ongoing German Long-term Cycle Database currently comprises 32788 prospectively collected cycle charts of 1551 women, the I European Cycle Database (10 countries) 1328 women/19048 cycles, the II European Cycle Database (six countries) 782 women/6724 cycles, and the World Health Organization Database (one European country) 234 women/2808 cycles. The women record cycle parameters (cervical mucus changes, temperature rise, etc.), family planning intention and sexual behavior. With the symptothermal method of natural family planning it has become possible to determine the fertile window in order to avoid pregnancy with a method effectiveness of 0.3%. According to a small sub-study, the ovulation time observed by the women themselves correlates closely with ovulation detected by ultrasound and measurement of luteinizing hormone (correlation within 1 day in 89% of the 62 cycles). Fertility awareness methods can be integrated into the management of sub-fertility. They seem to shorten the time to pregnancy. Self-observation of the fertile window puts women into a position to develop a high level of reproductive competence that could be used much more in different areas than is currently the case.
To analyze IVF outcomes in patients with a history of one or more elevations in basal FSH who have a normal basal FSH at the start of their IVF cycle, compared with the general IVF population.
Retrospective clinical study.
University hospital. PATIENT(S): General IVF patient population. INTERVENTION(S): Patients received standard IVF gonadotropin protocols, oocyte retrieval, and embryo transfer. MAIN OUTCOME MEASURE(S): Oocyte yield, fertilization, implantation, clinical pregnancy, and cancellation rate. RESULT(S): Oocyte yields were lower in patients with a history of elevated basal FSH, for all age groups, and showed an age-dependent decline in all patients. Over the age of 40 years, both implantation and clinical pregnancy rates were lower in these patients, with no significant difference observed in patients under the age of 40 years. No pregnancies were observed in patients with a history of three or more elevated FSH levels, regardless of age. CONCLUSION(S): A history of elevated basal FSH levels in patients under the age of 40 years predicts a lower oocyte yield in IVF cycles with normal basal FSH levels but does not translate to either lower pregnancy or implantation rates. Patients aged >40 years with prior elevations in basal FSH levels have both compromised ovarian response and compromised embryo quality relative to those with normal FSH levels, as illustrated by lower oocyte yield, higher cancellation rates, and lower implantation and pregnancy rates.
Chen TH et al., 2004·Human reproduction (Oxford, England)
Little is known about the prevalence of specific depressive and anxiety disorders in women before a new course of assisted reproductive technology treatment. Few studies have adopted the proper psychiatric diagnostic procedures.
All consecutive women visiting the assisted reproduction clinic of a university-affiliated medical centre, with the intention of starting a new assisted reproduction treatment course, were recruited. A psychiatrist made a diagnosis of psychiatric disorders using a structured interview, the Mini-International Neuropsychiatric Interview (MINI).
Of a total of 112 participants, 40.2% had a psychiatric disorder. The most common diagnosis was generalized anxiety disorder (23.2%), followed by major depressive disorder (17.0%), and dysthymic disorder (9.8%). Participants with a psychiatric morbidity did not differ from those without in terms of age, education, income, or years of infertility. Women with a history of previous assisted reproduction treatment did not differ from those without in depression or anxiety.
Depressive and anxiety disorders were highly prevalent among women who visited an assisted reproduction clinic for a new course of the treatment. Demographic features and a history of previous assisted reproduction treatment were not risk factors for these psychiatric morbidities in the assisted reproduction clinic.
The new third generation aromatase inhibitors are extremely potent and specific oral inhibitors of estrogen production. We reported the success of using aromatase inhibitors for induction of ovulation in World Health Organization (WHO) type II anovulatory patients. Promising pregnancy rates were associated with the use of aromatase inhibitors for induction of ovulation in these women. In addition, the use of aromatase inhibition in conjunction with gonadotropin injection was associated with a significant reduction in the gonadotropin dose required for optimum controlled ovarian hyperstimulation. We believe that these oral agents are efficient and safe and have many advantages compared with clomiphene citrate (CC). We propose that aromatase inhibitors will replace CC in the future as the new primary treatment for ovulation induction. In this review, we present an update on the use of aromatase inhibitors for induction of ovulation and we discuss several new areas of potential interest regarding the use of aromatase inhibitors, either alone or together with recombinant follicle-stimulating hormone (FSH) for infertility treatment. Further research in these areas may demonstrate an expanded role in assisted reproductive technologies.
Fertility AwarenessMucus Quality and ConceptionDay-Specific Probability of ConceptionIntercourse Timing
Intercourse results in a pregnancy essentially only if it occurs during the 6-day fertile interval ending on the day of ovulation. The strong association between timing of intercourse within this interval and the probability of conception typically is attributed to limited sperm and egg life times. A total of 782 women recruited from natural family planning centres in Europe contributed prospective data on 7288 menstrual cycles. Daily records of intercourse, basal body temperature and vaginal discharge of cervical mucus were collected. Probabilities of conception were estimated according to the timing of intercourse relative to ovulation and a 1-4 score of mucus quality. There was a strong increasing trend in the day-specific probabilities of pregnancy with increases in the mucus score. Adjusting for the mucus score, the day-specific probabilities had limited variability across the fertile interval. Changes in mucus quality across the fertile interval predict the observed pattern in the day-specific probabilities of conception. To maximize the likelihood of conception, intercourse should occur on days with optimal mucus quality, as observed in vaginal discharge, regardless of the exact timing relative to ovulation.
A surprising set of recent observations suggests a link between assisted reproductive technology (ART) and epigenetic errors--that is, errors involving information other than DNA sequence that is heritable during cell division. An apparent association with ART was found in registries of children with Beckwith-Wiedemann syndrome, Angelman syndrome, and retinoblastoma. Here, we review the epidemiology and molecular biology behind these studies and those of relevant model systems, and we highlight the need for investigation (1) large-scale case-control studies of ART outcomes, including long-term assessment of the incidence of birth defects and cancer, and (2) investigation of the relationship between epigenetic errors in both offspring and parents, the specific methods of ART used, and the underlying infertility diagnoses. In addition, the components of proprietary commercial media used in ART procedures must be fully and publicly disclosed, so that factors such as methionine content can be assessed, given the relationship in animal studies between methionine exposure and epigenetic changes.
This study was undertaken to determine proportions of very-low-birth-weight (VLBW) multiple birth infants receiving neonatal intensive care whose mothers received various types of infertility treatment and to evaluate infertility treatment-associated morbidity and mortality. Study infants were multiples with birth weight 401 to 1500 g cared for in Cincinnati neonatal intensive care units from January 1996 to December 2000. Data were obtained retrospectively from the National Institute for Child Health and Human Development Neonatal Research Network registry. Use of infertility treatment (in vitro fertilization, injection or oral ovulation, and intrauterine insemination) was determined by maternal interview or chart review. The generalized estimating equation approach to logistic regression was used. The study included 382 infants of 212 201=spontaneous conception (53%), 93=in vitro fertilization (24%), 55=injection (14%), 15=oral (4%), and 18=intrauterine insemination (5%). Neither gestational age nor birth weight differed between groups. More female (58%, P=.003) and white infants (95%, P<.001) resulted from infertility treatment-induced pregnancies than from spontaneous pregnancies. Advancing gestational age significantly decreased odds for all outcomes. Of VLBW multiples receiving neonatal intensive care, 47% are associated with infertility treatment. Infertility treatment does not influence outcomes in VLBW multiples.
General OB/GYNEpidemiology and PreventionSexually Transmitted InfectionsSTD Risk Factors
Sexually transmitted diseases (STDs) constitute a major health burden in the United States, causing pelvic inflammatory disease, ectopic pregnancy, infertility, chronic pelvic pain, genital lesions, genital neoplasms, adverse pregnancy outcomes, immune system dysfunction, liver disease, and even death. STDs disproportionately affect adolescents and young adults. Of the estimated 15 million STDs that occur annually each year in the United States, 4 million are among adolescents and 6 million among young adults. The current epidemic is complicated by the high asymptomatic carrier state associated with most STDs and the inadequate protection of condoms in preventing transmission. Sexually active individuals, particularly adolescents, must be educated on the ramifications of early onset of sexual activity and the health consequences of multiple sexual partners.
Andrology/Male FactorCriteria and ClassificationMedical TreatmentSurgical Correction
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY
Male infertility plays a clinically significant role in a large share of couples who struggle to conceive, yet standard laboratory criteria for semen analysis were designed primarily to predict success with assisted reproduction, not natural fertility. NaProTECHNOLOGY approaches male factor as a diagnosable condition with identifiable root causes, applying medical and surgical options aimed at restoring sperm function and combining that work with fertility-awareness charting to maximize the couple's chances of natural conception.
Thomas W. Hilgers, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY
Medical protocols in NaProTECHNOLOGY are cycle-phase-targeted regimens — covering ovulation induction, luteal phase hormonal support, hyperprolactinemia management, thyroid optimization, and pre-conceptual supplementation — derived from the biomarker-defined diagnosis rather than empirical stimulation. Consolidating these protocols in a single reference enables practitioners to apply evidence-based, individualized treatment sequences that address root hormonal pathology while supporting natural conception.
NaProTECHNOLOGYFertilityCare Practitioner RoleMedical Consultant Referral LetterLong-Distance Consultation Model
Hilgers TW et al., 2004·The Medical and Surgical Practice of NaProTECHNOLOGY
The FertilityCare Practitioner (FCP) is the trained educator and coach who teaches the Creighton Model FertilityCare System to clients, standardizes charting methodology, and serves as the primary data interface between the patient and the NaProTECHNOLOGY physician. Accurate, consistent chart data from FCPs directly determines the quality of biomarker interpretation, targeted intervention timing, and longitudinal outcome assessment throughout medical and surgical care.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY
Serial transvaginal ultrasound monitoring of follicular dynamics -- growth, rupture, corpus luteum formation, and free fluid -- forms the basis of a systematic classification of human ovulation disorders, including anovulation, luteinized unruptured follicle (LUF), follicular arrest, premature luteinization, and PCOS-type patterns. Anchoring sonographic findings to the CrMS Peak day allows precise correlation between ultrasound events and cervical mucus biomarkers, creating a reproducible diagnostic taxonomy that drives targeted medical and surgical treatment within the NaProTECHNOLOGY framework.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY
A CrMS-synchronized hormone sampling protocol is detailed in which progesterone, estradiol, and other reproductive hormones are drawn at cycle-phase-specific time points defined by the charted Peak Day rather than by fixed cycle day, producing a targeted hormone profile that accurately reflects luteal and follicular function. This Peak Day-referenced approach substantially improves the diagnostic sensitivity for luteal phase deficiency, follicular dysfunction, and other endocrine abnormalities that fixed-day sampling routinely misclassifies.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY
Infertility is not merely a reproductive inconvenience but frequently signals systemic or hormonal pathology — including polycystic ovarian disease, endometriosis, thyroid dysfunction, and immune abnormalities — each carrying independent health risks beyond failure to conceive. Identifying and treating these underlying conditions reduces long-term morbidity and reframes infertility evaluation as a form of preventive medicine rather than a terminal bypass decision.
InfertilityFemale Age and FecundabilityMale Age and FertilityProspective Fecundability Studies
Dunson DB et al., 2004·Obstetrics & Gynecology
To estimate the effects of aging on the percentage of outwardly healthy couples who are sterile (completely unable to conceive without assisted reproduction) or infertile (unable to conceive within a year of unprotected intercourse).
A prospective fecundability study was conducted in a sample of 782 couples recruited from 7 European centers for natural family planning. Women aged 18-40 years were eligible. Daily intercourse records were used to adjust for timing and frequency of intercourse when estimating the per-menstrual-cycle probability of conception. The number of menstrual cycles required to conceive a clinical pregnancy and the probability of sterility and infertility were derived from the estimated fecundability distributions for men and women of different ages.
Sterility was estimated at about 1%; this percent did not change with age. The percentage infertility was estimated at 8% for women aged 19-26 years, 13-14% for women aged 27-34 years and 18% for women aged 35-39 years. Starting in the late 30s, male age was an important factor, with the percentage failing to conceive within 12 cycles increasing from an estimated 18-28% between ages 35 and 40 years. The estimated percentage of infertile couples that would be able to conceive after an additional 12 cycles of trying varied from 43-63% depending on age.
Increased infertility in older couples is attributable primarily to declines in fertility rates rather than to absolute sterility. Many infertile couples will conceive if they try for an additional year.
NaProTECHNOLOGYFamily Practice ModelFertilityCare Practitioner and OB/GYN ConsultCreighton Model Charting and Timed Hormone Profiling
Hilgers TW et al., 2004·The Medical and Surgical Practice of NaProTECHNOLOGY
Family physicians trained in NaProTECHNOLOGY serve as primary coordinators of medical management — prescribing targeted hormone support, monitoring biomarker trends, and triaging surgical referrals — within a collaborative care model. Their longitudinal relationship with patients and ability to integrate reproductive medicine into whole-person primary care is a structural advantage of the NaProTECHNOLOGY delivery system over specialist-only models.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY
Selective hysterosalpingography combined with transcervical fallopian tube catheterization allows both precise diagnosis and non-surgical correction of proximal tubal occlusion, distinguishing true anatomical obstruction from tubal spasm or mucous plugging. In NaProTECHNOLOGY practice, this minimally invasive approach restores tubal patency without laparotomy, preserving natural conception potential in appropriately selected patients.
NaProTECHNOLOGYInfertilityOvarian and Target Organ DysfunctionCervical Mucus
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY
Ovarian dysfunction — encompassing luteal insufficiency, abnormal folliculogenesis, and anovulation — is treated in NaProTECHNOLOGY with cycle-timed interventions including HCG trigger, progesterone supplementation, clomiphene, and thyroid optimization, guided by prospective CrMS charting rather than protocol-driven stimulation. This approach normalizes endogenous hormonal patterns rather than overriding them, preserving uterine receptivity and reducing multiple gestation risk.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY
Pelvic adhesions from prior infection, surgery, or endometriosis restrict tubal motility, occlude the fimbriae, and distort ovarian-tubal relationships, constituting a primary mechanical barrier to natural conception. Microsurgical adhesiolysis performed under NaProTECHNOLOGY protocols achieves tubal patency and restores anatomical relationships, enabling natural pregnancy in a substantial proportion of cases that would otherwise be directed to IVF.
InfertilityMultifactorial DiagnosisCycle Classification and Hormonal CorrelationLuteinized Unruptured Follicle and Serial Ultrasound
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY
NaProTECHNOLOGY applies the standardized biomarkers of the Creighton Model FertilityCare System to identify the specific pathophysiological causes of infertility in each couple, then directs targeted medical or surgical intervention against those causes. Published pregnancy rates demonstrate outcomes comparable to or exceeding IVF in many diagnostic categories, without the ethical, financial, or obstetric risks associated with assisted reproduction.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY
The PEARS (Pelvic Endoscopic Adhesion-Related Surgery) procedure for peritoneal and ovarian endometriosis combines near-contact laser vaporization, adhesiolysis, and ovarian cystectomy under strict anti-adhesion protocols to achieve comprehensive disease eradication while preserving ovarian reserve. Outcomes data demonstrate superior fertility and pain resolution compared to incomplete surgical approaches, establishing PEARS as the operative standard within NaProTECHNOLOGY.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY
Uterine fibroids contribute to abnormal uterine bleeding, dysmenorrhea, recurrent pregnancy loss, and implantation failure, making myomectomy a central NaProTECHNOLOGY surgical intervention for women seeking conception. PEARS myomectomy technique prioritizes uterine preservation, meticulous layered closure of the myometrial defect, and hemostasis strategies that minimize adhesion formation and support subsequent pregnancy.
Research MethodologyInfertilityPregnancy
Open Access
The determinants of successful human reproduction and development may act as early as periconceptionally, underscoring the need to capture exposures during these critical windows when assessing potential toxicants. To identify such toxicants, couples must be studied longitudinally prior to conception without regard to a couple's ability to ascertain a clinically recognized pregnancy. We examined the utility and feasibility of prospective pregnancy study designs by conducting a systematic review of the literature to summarize relevant information regarding the planning, implementation, and success of previously published prospective pregnancy studies. Information concerning design elements and participation was abstracted from 15 eligible studies (from a total of 20 identified studies) using a standardized form. The primary author of each study was contacted to review our summary of their work and obtain missing information. Our findings confirm the ability to recruit women/couples from diverse populations using a variety of recruitment strategies. Among the studies we reviewed, 4-97% of eligible individuals were successfully contacted, with enrollment rates ranging from 42 to 100%. Length of follow-up varied from 3 to 12 months. A high percentage of women provided urine (57-98%) and blood (86-91%) specimens and most male partners (94-100%) provided semen samples. These data support the feasibility of this design.
InfertilityPharmacological AgentsOvarian StimulationOvulation Induction vs Superovulation
To compare the effects of letrozole and clomiphene citrate in the rat in terms of number of ovarian follicles; endometrial thickness; and serum levels of E2, FSH, LH, and T. Controlled prospective study. University research laboratory. ANIMAL(S): Thirty sexually mature female Wistar-Albino rats that were 20 weeks of age. INTERVENTION(S): Letrozole, 5 mg/kg of body weight daily (10 rats); clomiphene citrate, 100 microg/kg daily (10 rats); or saline solution, 2 mL/d (10 rats). After 2 days, rats were euthanized and ovariectomized. MAIN OUTCOME MEASURE(S): Number of mature follicles, endometrial thickness, and serum levels of hormones. RESULT(S): Mean levels of FSH, LH, E2, and T; number of mature follicles; and ovary size differed among the groups, whereas the mean endometrial thickness did not differ. CONCLUSION(S): In rats, the effect of letrozole on follicular maturation is similar to that of clomiphene citrate.
InfertilityAromatase InhibitorsMechanism of ActionLetrozole Applications
The third-generation aromatase inhibitors were initially introduced to treat postmenopausal breast cancer. We now realize that many other potential indications for aromatase inhibitors exist, especially in the field of gynecology. Preliminary data were suggestive that aromatase inhibitors could be used to treat endometriosis and uterine leiomyomata and induce or augment ovulation.
Aromatase inhibitors promote ovulation, most likely by increasing endogenous FSH production owing to decreased estrogen biosynthesis in the ovary and extraovarian tissues, including the brain. Aromatase inhibitors differ from the estrogen antagonist clomiphene citrate in that they do not exert a direct unfavorable effect on endometrial growth and development during the menstrual cycle.
Healey et al. (1) report important findings on the effects of the addition of an aromatase inhibitor to gonadotropin injections for superovulation. A relatively large number of patients and a control group were studied, and several clinically useful outcomes including pregnancy rates were reported.
The addition of letrozole to an ovulation induction regimen using injectable gonadotropins in a mixed population of patients with infertility does not seem to offer any benefits over gonadotropin-only cycles, because the decreased gonadotropin dose (the only apparent benefit) was offset by increased complexity of the treatment. Further randomized clinical trials using a similar design and patient sample may not provide clinically useful data. On the other hand, optimization of this regimen (gonadotropin plus aromatase inhibitor) in poor responders may offer an alternative in this subset of women (2).
From the existing literature, it appears that use of an aromatase inhibitor alone to induce or augment ovulation will continue to be an exciting area of research future (3, 4). In particular, the dosing and timing of administration (late luteal versus early follicular) of an aromatase inhibitor for ovulation induction should be optimized. Defining the hormonal profiles of the women who will benefit the most from aromatase inhibition may further increase the success of treatment.
In summary, Healey et al. (1) should be congratulated for conducting this interesting work. Carefully designed randomized studies on the use of aromatase inhibitors for ovulation induction or augmentation are warranted.
InfertilityLetrozoleOvarian StimulationControlled Ovulation vs Superovulation
To assess the effectiveness of metformin in improving clinical and biochemical features of polycystic ovary syndrome. Systematic review and meta-analysis. Randomised controlled trials that investigated the effect of metformin compared with either placebo or no treatment, or compared with an ovulation induction agent. 13 trials were included for analysis, including 543 women with polycystic ovary syndrome that was defined by using biochemical or ultrasound evidence. Pregnancy and ovulation rates. Secondary outcomes of clinical and biochemical features of polycystic ovary syndrome. Meta-analysis showed that metformin is effective in achieving ovulation in women with polycystic ovary syndrome, with odds ratios of 3.88 (95% confidence interval 2.25 to 6.69) for metformin compared with placebo and 4.41 (2.37 to 8.22) for metformin and clomifene compared with clomifene alone. An analysis of pregnancy rates shows a significant treatment effect for metformin and clomifene (odds ratio 4.40, 1.96 to 9.85). Metformin has an effect in reducing fasting insulin concentrations, blood pressure, and low density lipoprotein cholesterol. We found no evidence of any effect hip ratio. Metformin was associated with a higher incidence of nausea, vomiting, and other gastrointestinal disturbance. Metformin is an effective treatment for anovulation in women with polycystic ovary syndrome. Its choice as a first line agent seems justified, and there is some evidence of benefit on variables of the metabolic syndrome. No data are available regarding the safety of metformin in long term use in young women and only limited data on its safety in early pregnancy. It should be used as an adjuvant to general lifestyle improvements and not as a replacement for increased exercise and improved diet.
This review addresses questions related to medicosocial concerns surrounding the care of women with multiple births and their infants. Relevant articles and texts on twin and triplet pregnancies were reviewed. Population-based data were selected for inclusion whenever possible. Relevant tables were simplified from original sources. The review clarifies obstetric and perinatal questions in a manner that is helpful to clinicians and their patients.
Fertility AwarenessTime to PregnancySubfertility DefinitionSurvival Analysis
The likelihood of spontaneous conception in subsequent cycles is important for a balanced management of infertility. Previous studies on time to pregnancy are mostly retrospective and biased because of exclusion of truly infertile couples. The study aim was to present a non-parametric estimation of cumulative probabilities of conception (CPC) in natural family planning (NFP) users illustrating an ideal of human fertility potential. A total of 346 women was observed who used NFP methods to conceive from their first cycle onwards. The couples practising NFP make optimal use of their fertility potential by timed intercourse. The CPC were estimated for the total group and for couples who finally conceived by calculating Kaplan-Meier survival rates. A total of 310 pregnancies occurred among the 346 women; the remaining 36 women (10.4%) did not conceive. Estimated CPC for the total group (n = 340 women) at one, three, six and 12 cycle(s) were 38, 68, 81 and 92% respectively. For those who finally conceived (truly fertile couples, n = 304 women), the respective pregnancy rates were 42, 75, 88 and 98% respectively. Although the numbers of couples in both groups were similar, the impact of age on time to conception, as judged by the Wilcoxon test, was less in the truly fertile than in the total group. Most couples conceive within six cycles with timed intercourse. Thereafter, every second couple is probably either subfertile or infertile. CPC decline with age because heterogeneity in fecundity increases. In the subgroup of truly fertile couples, an age-dependent decline in CPC is statistically less obvious because of high homogeneity, even with advancing age.
EndometriosisUterine and Ovarian FunctionEndometriosis-Related InfertilityImplantation Defects
Although numerous studies have attempted to elucidate the implication of endometriosis for infertility, this matter still remains unexplained. Diverse clinical approaches based on assisted reproduction techniques have produced conflicting results on this issue. Nevertheless, impairment of implantation and pregnancy rates seems to affect women who suffer from endometriosis. Whether this effect is due to alteration of the oocyte/embryo or the endometrium still remains to be elucidated, although actual data allude to deficiencies in both. Infertility due to poor quality embryos derived from impaired oocytes obtained from malfunctioning ovaries have been described by some groups. Endometrial defects have been argued by others. Adding more confusion to this topic, the influence of peritoneal fluid in women with endometriosis and/or mixed causes also needs to be considered. The aim of this review is to describe the current situation in the endometriosis-related infertility literature.
EndometriosisSubfertility RelationshipEndometriosis Staging and OutcomesSurgical Excision Fertility Outcomes
There are many arguments to support the hypothesis that there is a causal relationship between the presence of endometriosis and subfertility. These arguments are reviewed (1) an increased prevalence of endometriosis in subfertile women compared with women of proven fertility; (2) a reduced monthly fecundity rate (MFR) in baboons with mild to severe (spontaneous or induced) endometriosis compared with those with minimal endometriosis or a normal pelvis; (3) a trend toward a reduced MFR in infertile women with minimal to mild endometriosis compared with women with unexplained infertility; (4) a a negative correlation between the r-AFS stage of endometriosis and the monthly fecundity rate and crude pregnancy rate; (5) a reduced monthly fecundity rate and cumulative pregnancy rate after donor sperm insemination in women with minimal-mild endometriosis compared with those with a normal pelvis; (6) a reduced MFR after husband sperm insemination in women with minimal to mild endometriosis compared with those with a normal pelvis; (7) a reduced implantation rate per embryo after IVF in women with moderate to severe endometriosis compared with women with a normal pelvis; and (8) an increased monthly fecundity rate and cumulative pregnancy rate after surgical removal of minimal to mild endometriosis.
InfertilityEndometrial Biopsy AbnormalitiesEndometrial Carcinoma RiskHyperplasia and Carcinoma
To analyze retrospectively the frequency, long-term prognosis and pregnancy rate in infertile women diagnosed with endometrial hyperplasia or carcinoma by endometrial biopsy. From 1989 to 2000, endometrial biopsies were performed on 2,573 patients to investigate the cause of infertility. The main outcome measures were frequency, long-term prognosis and pregnancy rate for patients with each type of endometrial abnormality. Twenty-four patients (0.93%) were diagnosed with an endometrial abnormality. Of them, 10 were diagnosed with simple hyperplasia, 7 with complex hyperplasia, 3 with complex hyperplasia with atypia and 4 with endometrial carcinoma. All 4 patients (0.16%) with endometrial carcinoma were infertile as a result of complications arising from polycystic ovary syndrome. Two of them underwent hysterectomies. High-dose medroxyprogesterone acetate therapy combined with assisted reproductive technology resulted in pregnancy in 1 of the 2 patients with endometrial carcinoma. Of infertile women, 0.93% have endometrial abnormalities, and those with polycystic ovary syndrome have a high risk of endometrial carcinoma. Assisted reproductive technology combined with high-dose medroxyprogesterone acetate may be effective means of overcoming infertility, allowing women with endometrial carcinoma to readily achieve pregnancy.
Contraception/ComparisonFetal and Neonatal RisksAdverse OutcomesConfounders in ART Studies
Treatment for infertility using assisted reproductive technologies (ART) is highly successful and has been used to help a steadily growing number of couples worldwide. In 1999, in the United States, more than 86,000 treatment cycles were performed resulting in the birth of more than 30,000 babies. Despite this widespread application, few follow-up studies of children conceived through ART have been performed, and more rigorous investigation of this important issue has clearly been needed. In recent months, three studies linking ART with several complications have been published in high profile and widely Schieve et al. (1) reported that singletons conceived using ART were at an increased risk for low birth weight, whereas Hansen et al. (2) suggested an increased risk of major birth defects. Finally, Stromberg et al. (3) concluded that children conceived through IVF have an increased risk of neurological problems, especially cerebral palsy.
The importance of these studies is obvious as they provide clues of possible risks associated with ART. However, they are all retrospective analyses of data collected through registries and therefore are vulnerable to biases inherent to such study design. We must be careful not to overinterpret the data by concluding that the use of ART, whether from gamete or embryo manipulation or use of medications, is the direct cause of the complications—the observed associations may simply be explained by one or more confounders, such as an underlying infertility-related condition in the treated women. This short communication is an attempt to place these three articles in proper perspective for the clinician and to provide the impetus for conducting further studies to determine the true nature of the described associations.
At the outset, it should be stated that a major weakness of all three studies is the lack of proper controls. If the aim of a study is to determine whether a cause and effect relationship exists between the process of IVF and a specific outcome (i.e., low birth weight, major birth defects, neurological problems), the appropriate control population is that of babies born to infertile women achieving pregnancies by methods other than IVF. None of the three studies specifically included such a control population.
NaProTECHNOLOGYCervical Mucus ObservationsCreighton ModelDay-Specific Conception Probability
To assess the day-specific and cycle-specific probabilities of conception leading to clinical pregnancy, in relation to the timing of intercourse and vulvar mucus observations. This was a retrospective cohort study of women beginning use of the Creighton Model Fertility Care System in Missouri, Nebraska, Kansas, and California. Data were abstracted from Creighton Model Fertility Care System records, including women's daily standardized vulvar observations of cervical mucus discharge, days of intercourse, and clinically evident pregnancy (conception). Established statistical models were used to estimate day-specific probabilities of conception. Data were analyzed from 1681 cycles with 81 conceptions from 309 normally fertile couples (initially seeking to avoid pregnancy) and from 373 cycles with 30 conceptions from 117 subfertile couples (who were initially trying to achieve pregnancy). The highest probability of pregnancy occurred on the peak day of vulvar mucus observation (.38 for normally fertile couples and.14 for subfertile couples). The probability of pregnancy was greater than.05 for normally fertile couples from 3 days before to 2 days after the peak, and for subfertile couples from 1 day before to 1 day after the peak. The cycle-specific probability of conception correlated with the quality of mucus discharge in normally fertile couples but not in subfertile couples. Standardized vulvar observations of vaginal mucus discharge identify the days with the greatest likelihood of conception from intercourse in normal fertility and subfertility and provide an indicator of the overall potential for conception in a given menstrual cycle in normal fertility.
To confirm that hCG levels in follicular fluid and serum would be comparable between i.m. and s.c. administration of purified hCG. In a prospective study, serum and follicular fluid levels of hCG after an i.m. or s.c. injection of 10,000 IU of hCG were evaluated 36 hours after injection, that is, at the time of oocyte retrieval. This study was carried out in a university-affiliated IVF program. PATIENT(S): Forty women undergoing oocyte retrieval were entered into the study at the time of egg retrieval, that is, 36 hours after hCG administration. INTERVENTION(S): S.c. or i.m. injection of hCG. MAIN OUTCOME MEASURE(S): Serum and follicular fluid concentrations of hCG were evaluated 36 hours after injection at the time of oocyte retrieval. RESULT(S): There was a significantly higher serum hCG level in the s.c. group (348.6 +/- 98 IU/L) vs. the i.m. group (259.0 +/- 115 IU/L) and a significantly higher follicular fluid hCG level in the s.c. vs. the i.m. group (233.5 +/- 85 vs. 143.4 +/- 134 IU/L). CONCLUSION(S): After purified hCG administration via the s.c. route, both serum and follicular fluid levels are greater compared with the i.m. route.
To review the use of hCG and to describe the clinical benefit of recombinant hCG (r-hCG) based on the published results of prospective, randomized studies. Review of published articles. Tertiary infertility care center.None.None. Oocyte number and quality, luteal phase progesterone, pregnancy and OHSS rate, and local tolerability. The published data consistently show that single doses of 250 microg r-hCG and 5,000 IU urinary (u)-hCG produce similar clinical outcomes when used in infertility treatment cycles for timed intercourse, IUI, and IVF in terms of the number of oocytes retrieved, number of mature oocytes harvested, and fertilization and pregnancy rates attained. Single doses of 10,000 IU u-hCG also gave results comparable to single doses of 250 microg r-hCG. P levels in the midluteal phase were significantly higher with the use of r-hCG compared with u-hCG, and local injection site adverse effects were significantly less frequent, demonstrating the higher purity of the recombinant product. A single 500-microg dose of r-hCG led to a higher rate of ovarian hyperstimulation syndrome compared with a 250-microg dose, with no significant improvement in pregnancy rates.A single dose of 250 microg r-hCG was at least as effective as single doses of 5,000 or 10,000 IU u-hCG but offered the advantages associated with local injection site adverse effects were significantly less frequent with r-hCG than with u-hCG.
Ethics/PhilosophyCryopreserved Embryo DispositionIVF Embryo StorageART Practice Surveys
To determine the number of embryos stored at assisted reproductive technology (ART) clinics in the United States and their current disposition. A targeted survey instrument sent by the SART-RAND team to all medical practices providing in vitro fertilization services in the United States. The SART-RAND team surveyed all 430 ART practices in the United States. Of these practices, 340 returned surveys for analysis. The data from these surveys were merged with data taken from the 1999 SART dataset, which contains information about practice size and success rates. Responding clinics reported a total of 396,526 embryos in storage as of April 11, 2002. The vast majority of the embryos (88.2%) were targeted for patient use. Small numbers of embryos were available for research, donation, destruction, quality assurance, or other uses. Nearly 400,000 embryos are stored in the United States, the majority of which (88.2%) are targeted for patient use. Few are available for research (2.8%), limiting possible conversion into embryonic stem cell lines.
Yildirim M et al., 2003·Eur J Obstet Gynecol Reprod Biol
To determine the effects of ovarian wedge resection by minilaparotomy in infertile patients with polycystic ovarian syndrome (PCOS). One hundred and thirty-four anovulatory patients with PCOS, who were previously treated with clomiphene citrate and gonadotropins and did not conceive were operated via minilaparotomy with microsurgical principles and ovarian wedge resection was performed on each subject. Pregnancy rates and adhesion formation were investigated retrospectively. A total of 121 pregnancies were achieved in 2 years (90%). One hundred and four patients conceived within the first 6 months (78%) and the remaining 17 patients conceived within 2 years (13%) following the operation. Sixty-eight patients had a second pregnancy later. In the post-operative period, 24 patients had cesarean delivery and 20 had diagnostic laparoscopy. Out of these 44 patients, only 5 of them were found to have minimal adhesions. This technique offers high pregnancy rates and minimal adhesion formation. Ovarian wedge resection by minilaparotomy might be an alternative treatment approach in patients with PCOS who did not conceive with standard ovulation induction protocols.
To determine the efficacy of L-carnitine therapy in selected cases of male factor infertility.
Placebo-controlled, double-blind, crossover trial.
University tertiary referral center. One hundred infertile patients (ages 20-40 years) with the following baseline concentration, 10-20 x 10(6)/mL; total motility, 10%-30%; forward motility, <15%; atypical forms, <70%; velocity, 10-30 micro/s; linearity, <4. Eighty-six patients completed the study. Patients underwent L-carnitine therapy 2 g/day or placebo; the study design was 2 months of washout, 2 months of therapy/placebo, 2 months of washout, and 2 months placebo/therapy. Variation in sperm parameters used in the patients selection criteria, in particular, sperm motility. Excluding outliers, a statistically significant improvement in semen quality, greater than after the placebo cycle, was seen after the L-carnitine therapy for sperm concentration and total and forward sperm motility. The increase in forward sperm motility was more significant in those patients with lower initial values, i.e., <5 x 10(6) or <2 x 10(6) of forward motile sperm/ejaculate or sperm/mL. Based on a controlled study of efficacy, L-carnitine therapy was effective in increasing semen quality, especially in groups with lower baseline levels. However, these results need to be confirmed by larger clinical trials and in vitro studies.
To review the effectiveness of metformin in restoring regular menstrual cycles and ovulation and achieving pregnancy in women with polycystic ovary syndrome (PCOS). Systematic review of pertinent studies identified using the bibliographic databases MEDLINE and EMBASE. References of selected articles identified were hand-searched for additional relevant citations. PATIENT(S): Women with PCOS undergoing treatment with metformin alone, metformin combined with other methods of ovulation induction such as clomiphene citrate (CC) or gonadotropin injections, or metformin combined with in vitro fertilization (IVF). RESULT(S): Thirty published studies were included in the overall review. Studies consisted of 12 randomized controlled trials, two cohort studies, and 16 uncontrolled descriptive studies. Due to a strong variability in the use of metformin according to study population, exposure, and outcome of interest, it was not possible to combine the data of the 12 randomized controlled trials to perform a meta-analysis. Limited data on predominately obese PCOS patients demonstrate that metformin alone improves both restoration of regular menses and spontaneous ovulation, but there are no data supporting an improvement in pregnancy rate. The addition of metformin to CC results in an improved ovulation and pregnancy rate in both unselected and CC-resistant PCOS women. There are insufficient data to make any conclusions on the effect of metformin on FSH ovulation induction or IVF. CONCLUSION(S): The effectiveness and role of metformin in the treatment of PCOS anovulatory infertility in clinical practice is difficult to assess from currently available research. Further well-designed prospective, perhaps multicenter, randomized controlled trials with the primary end point of pregnancy or live-birth rate are required.
The incidence of Chlamydia trachomatis (Ct) infection and the possible correlation between couples presenting with first-trimester spontaneous abortions and active Ct infection was assessed. Additionally, the ability of Ct to infect zona-free hamster oocytes was explored by incubating the oocytes with spermatozoa from infected patients. A total of 961 women and 750 men consulting our reproductive medicine centre were screened for Ct using direct immunofluorescence. The general incidence of Ct infection was 9.4% in females (90 of 961) and 13.9% in males (104 of 750). In women with spontaneous abortions the incidence of Ct was 21.0% (14 of 66) compared with 8.9% (23 of 59) for women without spontaneous abortions and term pregnancies (chi-square, P < 0.05). When both partners of the couples were considered (one or both partners infected), the incidence rose to 68.8% (22 of 32) (chi-square, P < 0.001). In vitro studies using electron microscopy demonstrated the presence of Ct on the surface of and inside the oocyte. These results indicate a correlation between an active Ct infection and spontaneous abortion. Electron microscopy studies suggested the possibility of direct oocyte infection by Ct. Two models are proposed for the pathogenesis (i) direct zygote infection, and (ii) immune response to heat shock proteins expressed by the zygote and triggered by previous Ct infections.
Physicians who counsel women for preconception concerns are in an excellent position to give advice to couples regarding the optimal timing of intercourse to achieve pregnancy. The currently available evidence suggests that methods that prospectively identify the window of fertility are likely to be more effective for optimally timing intercourse than calendar calculations or basal body temperature. There are several promising methods with good scientific bases to identify the fertile window prospectively. These include fertility charting of vaginal discharge and a commercially available fertility monitor. These methods identify the occurrence of ovulation clinically and also identify a longer window of fertility than urinary luteinizing hormone kits. Prospectively identifying the full window of fertility may lead to higher rates of conception. Proper information given early in the course of trying to achieve pregnancy is likely to reduce time to conception for many couples, and also to reduce unnecessary intervention and cost.
PregnancyAdvanced Maternal AgePreeclampsia and Gestational DiabetesOocyte Donation Outcomes
As a result of oocyte donation, women in their sixth decade of life are now able to conceive and carry pregnancies to term. However, little is known about pregnancy outcomes in this population. To describe pregnancy outcomes in women aged 50 years or older who conceived after in vitro fertilization with donor oocytes. Retrospective analysis of cycles conducted at a US university assisted reproduction program during calendar years 1991-2001. Seventy-seven postmenopausal women with no chronic medical conditions (mean [SD] age, 52.8 [2.9] years; range, 50-63 years) who underwent 121 embryo transfer procedures (89 fresh and 32 frozen). Pregnancy outcomes were ascertained by chart review and telephone follow-up. Maternal and neonatal outcomes. There were 55 clinical pregnancies for a total pregnancy rate of 45.5%. The live birth rate was 37.2%. Of the 45 live births, 31 were singletons, 12 were twins, and 2 were triplets, for which the mean (SD) gestational ages at delivery were 38.4 (2.1) weeks, 35.8 (2.8) weeks, and 32.2 weeks, respectively. Mean (SD) birth weights were 3039 g (703 g), 2254 g (581 g), and 1913 g, respectively. Apgar scores at 1 and 5 minutes were 8.2 (0.9) and 9.1 (0.5), respectively. Of singletons, 68% were delivered by cesarean, and all multiples were delivered by cesarean. Mild preeclampsia was noted in 25% of patients and severe preeclampsia in 10%. Gestational diabetes required diet modification in 17.5%, and 2.5% required insulin. Appropriately screened women aged 50 years or older can successfully conceive via oocyte donation and experience similar pregnancy rates, multiple gestation rates, and spontaneous abortion rates as younger recipients. During pregnancy, they appear at increased risk of preeclampsia and gestational diabetes. A majority can expect to deliver via cesarean. However, there does not appear to be any definitive medical reason for excluding these women from attempting pregnancy on the basis of age alone.
To compare the efficacy of low-dose aspirin alone versus low-dose aspirin plus low molecular weight heparin in pregnant women with antiphospholipid syndrome and recurrent miscarriage as prophylaxis against pregnancy loss. From a regional miscarriage clinic, 119 consecutive women with persistently positive tests for lupus anticoagulant and/or anticardiolipin immunoglobulin G and M antibody were invited to participate in a randomized, controlled trial between 1997 and 2000. After ethical approval and adherence to a written protocol, 12 women were unwilling to participate, five failed exclusion/inclusion criteria, and four were nonpregnant. Laboratory analysis was performed by Sheffield University Coagulation Department, electronically generated randomization by Manchester University Centre for Cancer Epidemiology, and data collection and analysis by a research officer at Leeds University. Viability ultrasound every 2 weeks was provided until 12 weeks' gestation before transfer to the pregnancy support antenatal clinic. Ninety-eight women were randomized before 12 weeks' gestation. Forty-seven received low-dose aspirin 75 mg daily (group A), and 51 received low-dose aspirin plus low molecular weight heparin 5000 U subcutaneously daily (group B) throughout pregnancy. There were 13 pregnancy losses and 34 live births in group A and 11 losses and 40 live births in group B. The live-birth rate was 72% in group A and 78% in group B (odds ratio 1.39, 95% confidence interval 0.55, 3.47). There were no cases of maternal thrombosis in either group. A high success rate is achieved when low-dose aspirin is used for antiphospholipid syndrome in pregnancy. The addition of low molecular weight heparin does not significantly improve pregnancy outcome.
InfertilityInsulin ResistanceInsulin Resistance and PregnancyFasting Insulin and Glucose
To determine whether insulin resistance is associated with recurrent pregnancy loss (RPL). Single center, case-controlled, prospective study. University-associated reproductive endocrinology clinical practice. PATIENT(S): Seventy-four nonpregnant, nondiabetic women with RPL. Controls were 74 fertile, nonpregnant, nondiabetic women without RPL who had at least one live infant, and were matched by age, race, and body mass index (BMI). INTERVENTION(S): Both groups consented to obtaining fasting insulin and glucose levels. MAIN OUTCOME MEASURE(S): Insulin resistance was defined as a fasting insulin level >20 microU/mL or a fasting glucose to insulin ratio of <4.5. RESULT(S): Among the 74 women with RPL, 20 (27.0%) demonstrated insulin resistance, whereas only 7 of 74 (9.5%) of the matched controls were insulin resistant (odds ratio 3.55; 95% confidence interval 1.40-9.01). The RPL and control groups were similar with respect to age, ethnicity, and BMI. The RPL and control groups had similar fasting glucose levels and glucose-to-insulin ratios. However, fasting insulin levels > or =20 microU/mL were statistically different between the two groups (odds ratio 3.92). CONCLUSION(S): Women with RPL have a significantly increased prevalence of insulin resistance when compared with matched fertile controls.
To prove that several days of low-dose hCG alone can be used to stimulate folliculogenesis, complete FSH-initiated follicle/oocyte maturation, and achieve pregnancy in assisted reproduction technology. Case report. Reproductive endocrinology center at an academic institution. PATIENT(S): A 35-year-old female patient and her partner with male-related infertility. INTERVENTION(S): After an 8-day priming with hMG (225 IU/d), we administered low-dose hCG (200 IU/d) alone for 5 days in one GnRH-agonist suppressed patient until proper follicle development was obtained and intracytoplasmic sperm injection was performed. MAIN OUTCOME MEASURE(S): Daily serum levels of LH, FSH, hCG, E(2), P, and T; measurements of follicle number and size; oocytes retrieved and fertilized; pregnancy. RESULT(S): Although FSH levels rapidly declined after hMG discontinuation, E(2) and large follicles increased during hCG-only administration. Several good quality oocytes were retrieved and fertilized by intracytoplasmic sperm injection; three embryos were transferred and a twin pregnancy ensued. CONCLUSION(S): Replacement of FSH with low-dose hCG for several days in the late ovulation induction stages of assisted reproduction [1] continued growth of large ovarian follicles and E(2); [2] an optimal preovulatory follicle pattern consisting of many large and few medium and small follicles; and [3] reproductively competent oocytes and pregnancy.
To examine the cumulative conception rate and live birth rate in women undergoing IVF and to assess the influence of prognostic factors on cumulative conception rate and discontinuation of treatment. Retrospective analysis of data from couples undergoing IVF. Assisted conception unit of a university hospital. PATIENT(S): Two thousand fifty-six patients undergoing 2708 cycles of IVF from April 1992 to March 1999. MAIN OUTCOME MEASURE(S): Cumulative conception rate by age, number of oocytes retrieved, and embryos transferred, and the influence of these factors on dropout rates. RESULT(S): The cumulative conception rate and cumulative live birth rate after four attempts were 75% and 66%, respectively. The cumulative conception rate differed significantly between women 35 years of age or younger and those older than 35 years who had five or more oocytes retrieved (83% vs. 63%). When fewer than five oocytes were retrieved in women 35 years of age or younger, the cumulative conception rate decreased to 33%. Overall, 36% of patients continued treatment after the first attempt; these patients were more likely to have more than five oocytes retrieved and more than two embryos available for transfer. The cumulative conception rate was greater when the female partner was 35 years of age or younger and had more than five oocytes retrieved and more than two embryos were available for transfer. These factors influenced dropout rates.
EndometriosisIVF OutcomesEndometriosis and IVFReproductive Outcomes
To investigate the IVF outcome for patients with endometriosis. Meta-analysis. Academic research center. PATIENT(S): A MEDLINE search and review of the literature were performed. Patients were classified by level of endometriosis, and controls were classified according to the indication for IVF. INTERVENTION(S): Bivariate analysis and multivariate logistic regression was used to estimate overall effect and control for confounding. MAIN OUTCOME MEASURE(S): Pregnancy rates, fertilization rate, implantation rates, and numbers of oocytes retrieved. RESULT(S): Twenty-two published studies were included in the overall analysis. The chance of achieving pregnancy was significantly lower for endometriosis patients (odds ratio, 0.56; 95% confidence interval, 0.44-0.70) when compared with tubal factor controls. Multivariate analysis also demonstrated a decrease in fertilization and implantation rates, and a significant decrease in the number of oocytes retrieved for endometriosis patients. Pregnancy rates for women with severe endometriosis were significantly lower than for women with mild disease (odds ratio, 0.60; 95% confidence interval, 0.42-0.87). CONCLUSION(S): Patients with endometriosis-associated infertility undergoing IVF respond with significantly decreased levels of all markers of reproductive process, resulting in a pregnancy rate that is almost one half that of women with other indications for IVF. These data suggest that the effect of endometriosis is not exclusively on the receptivity of the endometrium but also on the development of the oocyte and embryo.
PregnancyTriplet PregnanciesPreterm Birth and Infant MortalityMultiple Birth Complications
To more precisely understand the changes in triplet births in recent years. Analysis of recent government and medical publications pertaining to triplets. Triplet births are at much greater risk than singletons of poor birth outcomes. More than 9 of 10 triplet births are born preterm (< 37 completed weeks of gestation) as compared with < 1 of 10 singleton infants. The average weight of a triplet newborn (1,698 g) is one-half that of a singleton newborn (3,358 g). The infant death rate for triplet and other higher-order multiple births is 12 times higher than that for singletons (93.7 as compared with 7.8 infant deaths per 1,000 live births). Based on their frequency of preterm birth, low birth weight and infant death rate, it is appropriate to characterize all triplet pregnancies as high risk.
To evaluate the effect of an antifibrotic treatment by a combination of pentoxifylline (PTX) and tocopherol (vitamin E) in patients with a thin endometrium who were enrolled in an oocyte donation programme. Eighteen oocyte recipients who failed to develop a pre-ovulatory endometrial thickness of at least 6 mm after receiving vaginal micronized estradiol were enrolled in the study. The patients received a combination of PTX (800 mg/day) and vitamin E (1000 IU/day) for 6 months. The main outcome measurements were the change in endometrial thickness and the pregnancy and delivery rates after treatment. Endometrial thickness increased significantly (P <0.001), with a mean of (+/-SD) 4.9 +/-0.6 mm before and 6.2 +/- 1.4 mm after treatment, with 72% (13/18) of patients being good responders. Five patients either did not respond to the treatment or responded only slightly. Three patients, of which two had received previous radiotherapy, became spontaneously pregnant, and two became pregnant after embryo transfer. Three patients did not have embryo transfer. A total of four babies were delivered. The pregnancy rate was thus 33% and the delivery rate 27%. Treatment by combination of PTX and vitamin E appears to improve the pregnancy rate in patients with a thin endometrium by increasing the endometrial thickness and improving ovarian function. This was especially noticeable in patients who had previously received total body irradiation.
To examine the use of the aromatase inhibitor letrozole with FSH for ovarian stimulation in poor responders undergoing ovarian superovulation and IUI. Observational cohort study as a prospective clinical trial in patients with unexplained infertility and a low response to ovarian stimulation with FSH. Two tertiary referral infertility clinics associated with the Reproductive Sciences Division, University of Toronto. PATIENT(S): Twelve patients with unexplained infertility undergoing IUI who received FSH alone in 25 prior cycles with poor response (less than three dominant follicles). INTERVENTION(S): Patients were offered letrozole, 2.5 mg/day from day 3-7 of the menstrual cycle with FSH (50-225 IU/day) starting on day 5-7. hCG (10,000 IU) was given when two leading follicles were >/=2 cm followed by IUI. MAIN OUTCOME MEASURE(S): Number of mature follicles (>1.8 cm), FSH dose, endometrial thickness, and pregnancy rate. RESULT(S): Improved response to FSH stimulation with letrozole co-treatment was evidenced by the significantly lower FSH dose associated with significantly higher number of mature follicles. During letrozole plus FSH stimulation cycles, clinical pregnancy was achieved in three cycles (21%). CONCLUSION(S): In this preliminary report, we demonstrate a potential benefit of aromatase inhibition for improving ovarian response to FSH in poor responders.
InfertilityLH Activity ProtocolsFSH and LH InteractionsOvarian Stimulation Safety
Intensive FSH stimulation is a key tool of assisted reproduction technology but can cause severe complications through the development of an excessive number of small ovarian follicles. We tested the hypothesis that, in the late stages of ovulation induction, LH activity in the form of low-dose human CG (hCG) can stimulate and selectively modulate ovarian follicle function and growth, independently of FSH administration. Four groups of GnRH agonist-suppressed normoovulatory women (10 each group) received recombinant human FSH (r-hFSH) (150 IU/d) for 7 d group A, r-hFSH 150 IU/d alone; group B, r-hFSH 50 IU/d and hCG 50 IU/d; group C, r-hFSH 25 IU/d and hCG 100 IU/d; group D, hCG 200 IU/d alone. Despite several days of lowered or absent r-hFSH administration, 70% of hCG-treated patients successfully completed treatment. In these subjects, preovulatory E2 levels and large (>14 mm diameter) ovarian follicle development were not reduced; conversely, the number of small (<10 mm diameter) ovarian follicles was significantly decreased in groups B-D vs. group A. Low-dose hCG administration did not cause follicle luteinization. We conclude that, following FSH priming, 1) stimulate folliculogenesis for several days, in spite of rapidly declining FSH levels; and 2) hasten small follicle demise. Therefore, LH activity administration could be used to design radically novel ovulation induction regimens that, by partly or completely replacing mid-/late follicular phase FSH administration, may reduce costs and improve safety of assisted reproduction technology.
It is not known whether infants conceived with use of intracytoplasmic sperm injection or in vitro fertilization have a higher risk of birth defects than infants conceived naturally. We obtained data from three registries in Western Australia on births, births after assisted conception, and major birth defects in infants born between 1993 and 1997. We assessed the prevalence of major birth defects diagnosed by one year of age in infants conceived naturally or with use of intracytoplasmic sperm injection or in vitro fertilization. Twenty-six of the 301 infants conceived with intracytoplasmic sperm injection (8.6 percent) and 75 of the 837 infants conceived with in vitro fertilization (9.0 percent) had a major birth defect diagnosed by one year of age, as compared with 168 of the 4000 naturally conceived infants (4.2 percent; P<0.001 for the comparison between either type of technology and natural conception). As compared with natural conception, the odds ratio for a major birth defect by one year of age, after adjustment for maternal age and parity, the sex of the infant, and correlation between siblings, was 2.0 (95 percent confidence interval, 1.3 to 3.2) with intracytoplasmic sperm injection, and 2.0 (95 percent confidence interval, 1.5 to 2.9) with in vitro fertilization. Infants conceived with use of assisted reproductive technology were more likely than naturally conceived infants to have multiple major defects and to have chromosomal and musculoskeletal defects. Infants conceived with use of intracytoplasmic sperm injection or in vitro fertilization have twice as high a risk of a major birth defect as naturally conceived infants.
The increased risk of low birth weight associated with the use of assisted reproductive technology has been attributed largely to the higher rate of multiple gestations associated with such technology. It is uncertain, however, whether singleton infants conceived with the use of assisted reproductive technology may also have a higher risk of low birth weight than those who are conceived spontaneously. We used population-based data to compare the rates of low birth weight (less-than-or-equal 2500 g) and very low birth weight (<1500 g) among infants conceived with assisted reproductive technology with the rates in the general population. We studied 42,463 infants who were born in 1996 and 1997 and conceived with assisted reproductive technology and used as a comparison group 3,389,098 infants born in the United States in 1997. Among singleton infants born at 37 weeks of gestation or later, those conceived with assisted reproductive technology had a risk of low birth weight that was 2.6 times that in the general population (95 percent confidence interval, 2.4 to 2.7). The use of assisted reproductive technology was associated with an increased rate of multiple gestations; however, its use was not associated with a further increase in the risk of low birth weight in multiple births. Among twins, the ratio of the rate of low birth weight after the use of assisted reproductive technology to the rate in the general population was 1.0 (95 percent confidence interval, 1.0 to 1.1). Infants conceived with assisted reproductive technology accounted for 0.6 percent of all infants born to mothers who were 20 years of age or older in 1997, but for 3.5 percent of low-birth-weight and 4.3 percent of very-low-birth-weight infants. The use of assisted reproductive technology accounts for a disproportionate number of low-birth-weight and very-low-birth-weight infants in the United States, in part because of absolute increases in multiple gestations and in part because of higher rates of low birth weight among singleton infants conceived with this technology.
PregnancyICSI vs IVF ComparisonICSI SafetyCongenital Malformations
To evaluate the safety of ICSI, this study compared data of IVF and ICSI children by collecting data on neonatal outcome and congenital malformations during pregnancy and at birth. The follow-up study included agreement to genetic counselling and eventual prenatal diagnosis, followed by a physical examination of the children after 2 months, after 1 year and after 2 years. 2840 ICSI children (1991-1999) and 2955 IVF children (1983-1999) were liveborn after replacement of fresh embryos. ICSI was carried out using ejaculated, epididymal or testicular sperm. In the two cohorts, similar rates of multiple pregnancies were observed. ICSI and IVF maternal characteristics were comparable for medication taken during pregnancy, pregnancy duration and maternal educational level, whereas maternal age was higher in ICSI and a higher percentage of first pregnancies and first children born was observed in the ICSI mothers. Birthweight, number of neonatal complications, low birthweight, stillbirth rate and perinatal death rate were compared between the ICSI and the IVF groups and were similar for ICSI and IVF. Prematurity was slightly higher in the ICSI children (31.8%) than in the IVF children (29.3%). Very low birthweight was higher in the IVF pregnancies (5.7%) compared with ICSI pregnancies (4.4%). Major malformations (defined as those causing functional impairment or requiring surgical correction), were observed at birth in 3.4% of the ICSI liveborn children and in 3.8% of the IVF children (P = 0.538). Malformation rate in ICSI was not related to sperm origin or sperm quality. The number of stillbirths (born > or =20 weeks of pregnancy) was 1.69% in the ICSI group and 1.31% in the IVF group. Total malformation rate taking into account major malformations in stillborns, in terminations and in liveborns was 4.2% in ICSI and 4.6% in IVF (P = 0.482). The comparison of ICSI and IVF children taking part in an identical follow-up study did not show any increased risk of major malformations and neonatal complications in the ICSI group.
To estimate the relationship of assisted reproductive technologies and ovulation-inducing drugs with preeclampsia in multiple gestations. This historical cohort study was conducted on 528 multiple gestations from a Colorado health maintenance organization. Using univariate and logistic regression analysis, we determined if women who conceived a multiple gestation as a result of assisted conception were at a greater risk of preeclampsia than those who conceived spontaneously. Between January 1994 and November 2000, there were 330 unassisted and 198 assisted multiple gestations. Sixty-nine multiple gestations followed assisted reproductive technologies (in vitro fertilization and gamete intrafallopian transfer). Human menopausal gonadotropins and clomiphene citrate were associated with 38 and 91 of the multiple gestations, respectively. Compared with unassisted multiple gestations, the relative risk of mild or severe preeclampsia among mothers who received assisted reproductive technologies was 2.7 (95% confidence interval [CI] 1.7, 4.7) and 4.8 (CI 1.9, 11.6), respectively. Adjusted for maternal age and parity, women who received assisted reproductive technologies were two times more likely to develop preeclampsia (odds ratio 2.1, CI 1.1, 4.1) compared with those who conceived spontaneously. The adjusted odds ratios of nulliparity and maternal age for preeclampsia were 2.1 (CI 1.3, 3.4) and 1.1 (CI 1, 1.1), respectively. Although the incidence of preeclampsia was greater in mothers who received clomiphene citrate and human menopausal gonadotropins, this association did not reach statistical significance at the P <.05 level. Women who conceive multiple gestations through assisted reproductive technologies have a 2.1-fold higher risk of preeclampsia than those who conceive spontaneously.
InfertilityLong-term Child OutcomesNeurological SequelaeChild Development
There is an absence of population-based long-term studies on the risk of neurological sequelae in children born after in-vitro fertilisation (IVF). Our aim was to compare the frequency of such problems between IVF-born children and controls. We did a population-based retrospective cohort study in which we compared development of neurological problems in 5680 children born after IVF, with 11360 matched controls. For 2060 twins born after IVF, a second set of controls (n=4120), all twins, were selected. We obtained data on neurological problems from the records of the Swedish habilitation centres. Children born after IVF are more likely to need habilitation services than controls (odds ratio 1.7, 95% CI 1.3-2.2). For singletons, the risk was 1.4 (1.0-2.1). The most common neurological diagnosis was cerebral palsy, for which children born after IVF had an increased risk of 3.7(2.0-6.6), and IVF singletons of 2.8 (1.3-5.8). Suspected developmental delay was increased four-fold (1.9-8.3) in children born after IVF. Twins born after IVF did not differ from control twins with respect to risk of neurological sequelae. Low-birthweight and premature infants were more likely to need habilitation than fullterm babies. Maternal age did not affect risk. Our study suggests that children born after IVF have an increased risk of developing neurological problems, especially cerebral palsy. These risks are largely due to the high frequency of twin pregnancies, low birthweight, and prematurity among babies born after IVF. To limit these risks, we recommend that only one embryo should be transferred during IVF.
InfertilityOvarian Cancer RiskOvarian Cancer EpidemiologyLong-term Safety
Controversy surrounds the relations among infertility, fertility drug use, and the risk of ovarian cancer. The authors pooled interview data on infertility and fertility drug use from eight case-control studies conducted between 1989 and 1999 in the United States, Denmark, Canada, and Australia. Odds ratios and 95% confidence intervals were calculated, adjusting for age, race, family history of ovarian cancer, duration of oral contraception use, tubal ligation, gravidity, education, and site. Included in the analysis were 5,207 cases and 7,705 controls. Among nulligravid women, attempts for more than 5 years to become pregnant compared with attempts for less than 1 year increased the risk of ovarian cancer 2.67-fold (95% confidence interval (CI): 1.91, 3.74). Among nulliparous, subfertile women, neither any fertility drug use (odds ratio (OR) = 1.60, 95% CI: 0.90, 2.87) nor more than 12 months of use (OR = 1.54, 95% CI: 0.45, 5.27) was associated with ovarian cancer. Fertility drug use in nulligravid women was associated with borderline serous tumors (OR = 2.43, 95% CI: 1.01, 5.88) but not with any invasive histologic subtypes. Endometriosis (OR = 1.73, 95% CI: 1.10, 2.71) and unknown cause of infertility (OR = 1.19, 95% CI: 1.00, 1.40) increased cancer risk. These data suggest a role for specific biologic causes of infertility, but not for fertility drugs in overall risk for ovarian cancer.
To compare the efficacy of Crinone 8% intravaginal progesterone gel vs. IM progesterone for luteal phase and early pregnancy support after IVF-ET. Randomized, open-label study. Academic medical center. PATIENT(S): Two hundred and one women undergoing IVF-ET. INTERVENTION(S): Women were randomized to supplementation with Crinone 8% (90 mg once daily) or IM progesterone (50 mg once daily) beginning the day after oocyte retrieval. MAIN OUTCOME MEASURE(S): Pregnancy, embryo implantation, and live birth rates. RESULT(S): The women randomized to luteal phase supplementation with IM progesterone had significantly higher clinical pregnancy (48.5% vs. 30.4%; odds ratio [OR], 2.16; 95% confidence interval [CI], 1.21, 3.87), embryo implantation (24.1% vs. 17.5%; OR, 1.89; 95% CI, 1.08, 3.30), and live birth rates (39.4% vs. 24.5%; OR, 2.00; 95% CI, 1.10, 3.70) than women randomized to Crinone 8%. CONCLUSION(S): In women undergoing IVF-ET, once-a-day progesterone supplementation with Crinone 8%, beginning the day after oocyte retrieval, resulted in significantly lower embryo implantation, clinical pregnancy, and live birth rates compared with women supplemented with IM progesterone.
Reproductive EndocrinologyLuteal Phase SupplementationLuteal Phase SupportPreclinical Pregnancy Loss
Kaider AS et al., 2001·Early Pregnancy (Cherry Hill)
The role of luteal phase estrogen in pregnancy outcome has been a matter of considerable debate. In order to evaluate the effectiveness of estrogen supplementation in gonadotropin releasing hormone agonist (GnRHa)/human menopausal gonadotropin (hMG)-stimulated cycles associated with low luteal estrogen concentration, a study was performed comparing the ongoing pregnancy rates in cycles with serum concentrations of estradiol (E2) <100 pg/ml 11 days post embryo transfer (p-ET), treated with luteal phase progesterone (P4) vs. E2 and P4 supplementation. Among 1106 serum samples studied, 951 were from women receiving GnRHa and follicle stimulating hormone (FSH) prior to oocyte retrieval and P4 (50 mg-100 mg IM daily) as luteal phase supplementation beginning day 11 after retrieval. The remaining 155 were from women receiving both E2 (2 mg-6 mg estrace orally each day) and P4 during the luteal phase. Significantly greater frequencies of preclinical losses were observed among women with human chorionic gonadotropin (hCG) concentrations>5 mIU/ml and concurrent E2 concentrations <100 pg/ml compared with E2 >100 pg/ml (p<0.00001). Among the 128 women who had hCG concentrations >5 mIU/ml and E2 concentrations <100 pg/ml, 102 received P4 only during the luteal phase and 26 were treated with estrace 2 mg-6 mg daily, as well as P4 during the luteal phase. The frequency of preclinical pregnancy losses among the 102 women with hCG >5 mIU/ml and E2 <100 pg/ml who did not receive luteal E2 supplementation was 72%, compared with 50% who received luteal E2 supplementation (p=0.04) The increase in preclinical pregnancy loss rates among women not receiving luteal E2 resulted in a decrease in ongoing pregnancy rate (8%), compared to those receiving luteal E2 supplementation (31%) (p=0.002). Our results indicated that a subset of women losing pregnancies preclinically after GnRHa and FSH stimulation due to low luteal phase serum E2 level may benefit from luteal estrogen supplementation. More sensitive and specific markers are needed to identify prospectively women in this risk group.
Gleicher N et al., 2001·Early Pregnancy (Cherry Hill)
Innumerable studies have attempted to demonstrate that hormonal support of the luteal phase during ovulation induction cycles improves pregnancy rates. None has, however, so far been able to confirm the validity of such treatment conclusively, possibly because most studies only utilized progesterone substitution. Since luteal phase endometrium also requires estradiol support, this study attempted to investigate whether hormone substitution with progesterone and estradiol would be more successful in improving pregnancy rates. Amongst approximately 7500 consecutive ovulation induction cycles were identified prospectively which were characterized by a precipitous drop of luteal phase serum estradiol levels by more than 50% over a 48 hour period within 10 days from hCG administration. Those cycles were prospectively randomized to oral micronized estradiol substitution (Group I) or not (Group II), while both groups received routine progesterone substitution of the luteal phase. Cycles were then evaluated in regards to the occurrence of chemical, ectopic and clinical pregnancies. One hundred sixty-three Group I cycles resulted in 34 pregnancies (20.9%), which compared favorably to 21 pregnancies in 167 Group II patients (12.6%) (x2[1] = 4.06; p < 0.04). The advantage for Group I cycles (29/95 pregnancies, 31%) vs. Group II cycles (16/105, 15%) became even more pronounced when only women up to age 35 years were evaluated. Estradiol substitution maintained a significant advantage until age 38 (x2 [1] = 6.87; p < 0.009). While gravidity did not affect pregnancy success, estradiol substitution in Group I benefited nulliparous (23% pregnancy rate) over multiparous women (12% pregnancy rate) (x2 [2] = 6.86; p< 0.03). This association was, however, age-dependent. A combined estradiol and progesterone substitution of the luteal phase of ovulation induction cycles increases the overall pregnancy rate. Since estradiol substitution was initiated in this study only once a precipitous drop in serum estradiol levels had already taken place, an even larger improvement in pregnancy rates could conceivably be possible if earlier estradiol substitution of the luteal phase is initiated. A further expansion of investigations of similar protocols for routine ovulation induction and in vitro fertilization (IVF) cycles may be indicated, especially in women below age 38 years and in nulliparous females.
To determine the metabolic and reproductive effectiveness of rosiglitazone in polycystic ovary syndrome (PCOS). Case report. Academic clinical practice and General Clinical Research Center. PATIENT(S): A 25-year-old woman with PCOS. INTERVENTION(S): Rosiglitazone maleate, 4 mg daily for 5 months until conception. MAIN OUTCOME MEASURE(S): Insulin sensitivity by steady-state plasma glucose technique; serum androgens, progesterone, and hCG; and pelvic ultrasound images. RESULT(S): Rosiglitazone treatment for 5 months improved insulin sensitivity, lowered serum free testosterone, and resulted in spontaneous ovulation and conception. CONCLUSION(S): Rosiglitazone is a promising insulin sensitizer for treatment of PCOS. Clinical trials are warranted.
PCOSIn Vitro MaturationIn Vitro Oocyte MaturationMaturation and Fertilization
To investigate differences in immature oocyte maturation, fertilization, and pregnancy rates among women with unstimulated normal ovaries, polycystic ovaries (PCOs), or PCOS. Prospective observational study. University fertility clinic. PATIENT(S): One hundred forty-four women undergoing 180 in vitro oocyte maturation treatment cycles. INTERVENTION(S): Transvaginal immature oocyte recovery from unstimulated ovaries 36 hours after hCG priming. In vitro oocyte maturation and fertilization. Fresh embryo transfer. MAIN OUTCOME MEASURE(S): Immature oocytes collected, metaphase II oocytes, and embryos produced. Implantation and pregnancy rates. RESULT(S): The overall oocyte maturation and fertilization rates attained were 80.3% (1,222 of 1,522) and 76.5% (935 of 1,222), respectively. Significantly fewer immature oocytes were retrieved from normal ovaries (5.1 +/- 3.7) compared with the PCO (10.0 +/- 5.1) or PCOS (11.3 +/- 9.0) groups. Fertilization and cleavage rates were comparable among the three groups. The implantation, pregnancy, and live birth rates per transfer for normal ovaries were 1.5%, 4.0%, and 2.0%, respectively; for PCOs 8.9%, 23.1%, 17.3%, respectively; and for women with PCOS 9.6%, 29.9%, and 14.9%, respectively. CONCLUSION(S): Immature oocytes retrieved from normal ovaries, PCOs, or women with PCOS, when using hCG priming before oocyte retrieval, have a similarly high maturation, fertilization, and cleavage potential. In vitro maturation is a useful treatment option, particularly for women with PCOs.
Polycystic ovary syndrome (PCOS) is a common disorder affecting women of reproductive age. Its cardinal features are hyperandrogenism, chronic anovulation, and infertility. Some of the most important pathogenic associations of PCOS are insulin resistance and compensatory hyperinsulinemia (1, 2, 3). The hyperinsulinemia in turn stimulates ovarian androgen production. Several clinical studies have demonstrated that a reduction in the insulin level results in decreased ovarian androgen production (4, 5, 6).
Metformin is a biguanide used extensively in type 2 diabetes. It inhibits hepatic gluconeogenesis and increases peripheral insulin sensitivity and glucose uptake but does not cause hypoglycemia (6, 7, 8). The correction of the hyperinsulinemia by metformin in PCOS patients is accompanied by normalization of the elevated serum LH and ovarian androgen levels, leading to resumption of spontaneous ovulatory cycles, or responsiveness to ovulation induction by clomiphene citrate (CC) (1, 4, 5, 6, 8, 9). Clinical use of this agent for ovulation induction in CC-resistant PCOS patients has increased with little knowledge of the possible effect on early embryo development. We sought to assess whether metformin was embryotoxic using a mouse embryo model.
During controlled clinical trials, plasma metformin levels do not exceed 5 μg/mL, even at maximum doses (10). Metformin hydrochloride (N, N-dimethylimidodicarbonimidic diamide hydrochloride; Sigma, St. Louis, MO) was dissolved in human tubal fluid (HTF) media (Irvine Scientific, Santa Ana, CA) to give working concentrations of 5, 25, and 100 μg. The culture dishes containing 1 mL of media at each concentration were incubated for overnight equilibration at 37°C and 5% CO2.
Thawed two-cell mouse embryos (Embryotech, Wilmington, MA) were pooled and randomly distributed into the culture dishes containing the various concentrations of metformin. The control consisted of HTF media alone (group 1). Groups 2, 3, and 4 were supplemented with metformin (5, 25, and 100 μg/mL). There were 40 embryos in each group. The embryos were incubated in an atmosphere of 5% CO2 at 37°C for 72 hours. The blastocyst development rate (BDR) was then calculated by dividing the number of embryos reaching the blastocyst stage by the total number of embryos cultured.
The relationship between BDR and concentration was assessed with repeated measures logistic regression using generalized estimated equation (GEE) methodology with a compound symmetry correlation structure. The sample size was sufficient to detect whether a specific concentration reduced the odds of development by a factor of 2.5. Statistical significance was assessed using two-tailed P<.05. Statistical computations were performed with SAS version 8.1 (SAS Institute Inc, Cary, NC). . .
Assisted reproductive technologies (ART) pregnancy rates improve with the replacement of multiple embryos. The specific number of embryos to be transferred (typically between two and four) is based on a patient's age and past history and a morphologic assessment of embryo quality. Superovulation, with the goal of multifollicular recruitment and the harvest of multiple preovulatory oocytes, is therefore an integral aspect of in vitro fertilization and related techniques. Given the considerable interindividual variability in response to superovulation, the selection of an appropriate ovarian stimulation protocol is critical both for the safety and success of ART. Specific superovulation strategies have therefore been developed for treatment of abnormal response patients as well as for patients expected to manifest a "normal" response to ovulation inducing agents.
To evaluate the effect of supernumerary preovulatory follicular reduction as an approach to avoid multiple pregnancies in ovulation induction or superovulation cycles. Retrospective study. Tertiary referral center. PATIENT(S): In 26 cycles, 24 patients underwent ovulation induction or superovulation with either clomiphene citrate or hMG. INTERVENTION(S): Selective follicle aspiration was performed before hCG administration. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate and numbers of multiple pregnancies. RESULT(S): A mean number of 4.5 follicles with a diameter > or =15 mm and a mean number of 4.5 follicles with a diameter < or =14 mm were observed before hCG administration. A mean number of 2.3 follicles with a diameter > or =15 mm and a mean number of 1.8 follicles with a diameter < or =14 mm were aspirated before the hCG administration. Seven singleton pregnancies (26.9% per cycle) ensued from the treatment. CONCLUSION(S): Aspiration of supernumerary follicles after ovulation induction or superovulation seems to be a valid approach to avoid multiple pregnancies without affecting pregnancy rate.
Intravenous immune globulin (IVIG) is approved for use in a number of conditions that may occur in obstetrical patients, including autoimmune thrombocytopenia and immune deficiency syndromes. IVIG also is widely used in obstetrics for nonapproved indications, such as fetal-neonatal alloimmune thrombocytopenia, antiphospholipid syndrome, and recurrent miscarriage. This review critically analyzes the use of IVIG for these indications based on the best available information. The authors conclude IVIG is effective in the management of fetal-neonatal alloimmune thrombocytopenia. IVIG appears promising as a treatment for severe fetal-neonatal alloimmune hemolysis due to antierythrocyte antibodies. A prospective multicenter trial should be undertaken. IVIG is no more effective than heparin and low-dose aspirin in the treatment of pregnancies complicated by antiphospholipid syndrome but has not been adequately evaluated in refractory cases. Finally, pending convincing studies, IVIG is not effective and should not be used for the management of recurrent miscarriage.
PCOSOvulation Induction and FertilityNeuroendocrine and Opioid DysfunctionHormone Therapy and Pharmacotherapy
The aim of the present study was to analyze the opioid influence on LH pulsatility in polycystic ovary syndrome (PCOS) patients and to evaluate the effectiveness of a long-term opioid antagonist (naltrexone) treatment in improving the pulsatile GnRH therapy which is successful in this syndrome. Ten obese women affected by PCOS participated in the study. Patients were hospitalized during the early follicular phase and underwent an oral glucose tolerance test (OGTT) with 75 g of glucose and a pulse pattern study followed by a GnRH test (100 pg i.v.). All patients were then treated for ovulation induction with pulsatile administration of GnRH (5 microg/bolus every 90 min). Since pregnancies did not occurr in any patient, after spontaneous or progestin-induced menstrual cycles, all patients received naltrexone at a dose of 50 mg/day orally for 8 weeks and during treatment repeated the basal protocol study and the ovulation induction cycle with the same modalities. The naltrexone treatment significantly reduced the insulin response to OGTT and the LH response to GnRH bolus, whereas it did not affect the FSH and LH pulsatility patterns. Concerning the ovulation induction by pulsatile GnRH, naltrexone treatment was able to improve, although not significantly, the ovulation rate (60% pre-treatment vs 90% post-treatment). Furthermore, the maximum diameter of the dominant follicle and the pre-ovulatory estradiol concentration were higher after long-term opioid blockade (follicular diameter 19.5+/-1.76 mm pre-treatment vs 21.6+/-2.19 mm post-treatment, p<0.001; maximum estradiol level 728.7+/-288.5 pmol/l pre-treatment vs 986.4+/-382.1 pmol/l post-treatment, p<0.05). During the naltrexone-pulsatile GnRH co-treatment two pregnancies occurred. In conclusion, our data show that naltrexone-pulsatile GnRH co-treatment is able to improve the ovarian responsiveness to ovulation induction in obese PCOS patients when compared to pulsatile GnRH alone. This action seems to be related to a decrease of insulin secretion. Further randomized studies should be performed in order to obtain significant conclusions on the possible clinical application.
To compare clinical accuracy and ease of use for several of the new rapid one-step home urinary LH detection kits compared with the preexisting OvuQuick brand LH detection kit (designated as the standard).
Prospective cohort study.
University-based infertility clinic. PATIENT(S): All women undergoing intrauterine inseminations at the clinic, regardless of infertility diagnosis, were offered enrollment during a 28-month study period. INTERVENTION(S): Each participant was supplied three one-step test kits (OvuQuick One-Step, ClearPlan Easy, and SureStep) in addition to a multistep OvuQuick test kit and instructed to run the tests in parallel on the same urine sample and to record the results. Urine testing was performed every 12 hours, beginning 3 days before the anticipated onset of an LH surge, and continued with the one-step kits every 12 hours for 48 hours after the surge was first detected by OvuQuick. Subjects also completed questionnaires evaluating the use of each test kit. MAIN OUTCOME MEASURE(S): Correlation of LH surge detection by one-step kits in comparison to surge detection by OvuQuick. Satisfaction and ease of use questionnaires. RESULT(S): Sixty-three volunteers returned useable data, from which 81 evaluable cycles were analyzed. The majority of patients found the newer one-step kits to be easier to use and less time consuming than OvuQuick. The three one-step kits detected the LH surge within +/- one testing period (+/-12 hours) of detection by OvuQuick 68%-84% of the time. OvuQuick One-Step, with modified instructions allowing for an equal color intensity in the test and reference areas, had the highest correlation with OvuQuick (84%). However, with a study power (alpha = 0.05, beta = 0.10) sufficient to detect a 10% difference between Ovuquick and each one-step kit, all one-step kits were statistically equivalent to each other. There was no cycle in which a one-step kit detected a positive LH surge but OvuQuick did not. CONCLUSION(S): One-step urinary LH kits are easier for patients to use than a multistep home urinary LH kit and have reasonable correlation with the multistep kit when used clinically for timing artificial inseminations.
To compare the effectiveness of i.m. P and 17alpha-hydroxyprogesterone caproate (17-HPC) for luteal phase support, in patients undergoing IVF-ET cycles. Prospective, randomized study. Patients undergoing IVF-ET in our Centers. PATIENT(S): The inclusion criteria were the use of GnRH down-regulation and aged <40 years. INTERVENTION(S): A total of 300 cycles were randomly treated with either 17-HPC (341 mg every 3 days) or P (50 mg daily). MAIN OUTCOME MEASURE(S): The outcomes of IVF in both study groups were evaluated for biochemical pregnancy, miscarriage, clinical pregnancy, and ongoing pregnancy. RESULT(S): No difference was found in the main outcome parameters considered. CONCLUSION(S): Although the results of the study encourage the use of 17-HPC for luteal phase support in patients undergoing IVF-ET program, more studies are necessary to support the hypothesis that it can replace i.m. P-in-oil.
Despite the widespread use of clomiphene citrate (CC) for ovulation induction, the pregnancy rates (PRs) in women who take CC are less than expected based on ovulation rates. The causes of this discrepancy between the PRs and ovulation rates have been explained by the antiestrogenic effects on cervical mucus and endometrial differentiation (1). Despite these adverse effects, CC therapy is so simple and safe that it is widely administered even to normally ovulatory women in the expectation of inducing multiple ovulation and increasing the chances of conception.
On the other hand, cyclofenil, which has been reported to exert less antiestrogenic activity than CC (2), is also used to treat infertile women with not only anovulatory cycles but normal ovulatory cycles. The purpose of this study was to assess whether administration of CC or cyclofenil to women with normal ovulatory cycles is beneficial.
One hundred fifty-five normally ovulatory women who received treatment for infertility at Shiga University of Medical Science from June 1998 to June 1999 were recruited for this study. Patients with ovulatory disorders, such as irregular cycles, hypothalamic or pituitary amenorrhea, polycystic ovary syndrome, premature ovarian failure, and hyperprolactinemia, were excluded from the study. Patients with bilateral tubal obstruction or azoospermia were also excluded.
Administration of CC or cyclofenil was withheld for a period of 3 months after the first visit while the timing of coitus was advised. Patients were advised to have sexual intercourse within 24 hours after confirmation of a positive urinary LH with a urinary LH surge detection kit (Gold-sign LH, Morinaga Nyugyo, Tokyo, Japan).
Then the patients who did not conceive were sequentially a CC-treated group, a cyclofenil-treated group, and a group with no administration. Briefly, the first patient enrolled in the study was assigned to a CC-treated group, the second patient was assigned to a cyclofenil-treated group, and the third patient was assigned to a group with no administration. Then the fourth patient was assigned to the CC-treated group, and so forth.
To compare the karyotype of babies conceived through ICSI with that of naturally conceived babies. Prospective controlled study. The Egyptian IVF-ET Center, Cairo, Egypt. PATIENT(S): Four hundred and thirty babies conceived through ICSI and 430 babies conceived naturally. INTERVENTION(S): ICSI and karyotyping. MAIN OUTCOME MEASURE(S): Abnormal karyotype. RESULT(S): Four hundred and thirty consecutive babies conceived through ICSI who were delivered in one hospital had 15 abnormal karyotypes (3.5%). Of the 15 babies, 7 were of female phenotype and 8 of male phenotype. Six babies had sex chromosome anomalies, 8 had autosomal anomalies, and 1 had combined sex chromosome and autosomal anomalies. A control group of 430 consecutive babies conceived naturally who were delivered in one hospital had no abnormal karyotype. The difference between the two groups was significant (P<.001). CONCLUSION(S): ICSI carries a small but significant increased risk of abnormal karyotyping to the offspring. This risk appears to be equally distributed between autosomal and sex chromosome anomalies.
There have been reports suggesting that children born after in-vitro fertilisation by intracytoplasmic sperm injection (ICSI) are at increased risk of neurodevelopmental delay. We have undertaken a case-control study of this issue. We studied 208 singleton children conceived by ICSI and a control group of 221 normally conceived singleton children. Children were recruited from 22 fertility centres and local nurseries throughout the UK. Controls were selected to match cases as closely as possible for social class, maternal educational attainment, region, sex, and race. The primary outcome measure was neurodevelopmental scoring; secondary measures were perinatal outcomes, postnatal health, and congenital abnormalities. A single examiner assessed all the children. A follow-up rate of 90% for the ICSI group was achieved at a mean age of 17 months. No difference between the study children and controls was found in mean neurodevelopmental scores (98.08 [SD 10.93] vs 98.69 [9.99]) or any subscales on the Griffiths' scales of mental development. Perinatal outcome was similar apart from a higher rate of caesarean section (73 [35.1%] vs 53 [24.0%], p=0.015) and a lower mean birthweight (3163 [SD 642] vs 3341 [606] g, p=0.013) in the study group. Rates of major congenital abnormality were also similar overall (ten [4.8%] study vs ten [4.5%] control), although there were significantly more congenital anomalies among children born to fathers with oligozoospermia than in other children. This population study did not show any significant difference between children conceived after ICSI and their naturally conceived peers in terms of physical health and development.
Transvaginal ultrasonic follicle puncture has now become the method of choice for oocyte retrieval among most in vitro fertilization (IVF) units. The procedure, which involves puncture then aspiration of ovarian follicles, inevitably results in damage to the fine vascular network of blood vessels on the ovarian surface and theca interna layer, and tends to produce varying degrees of blood loss. The transvaginal ultrasonically guided retrieval of oocytes can be considered noncomplicated when the procedure does not result in injury to iliac vessels, trauma to pelvic viscera, or iatrogenic pelvic infections (1, 2), which would necessitate laparoscopy and or laparotomy. The aim of our study was to quantify the amount of blood loss that should be considered “normal” after noncomplicated transvaginal ultrasonically guided retrieval of oocytes, to characterize the factors that are related to the amount of blood loss, and to identify the patients who have the highest risk of hemorrhage.
Before beginning our study, we performed a power analysis of potential participants. We established the sample size after evaluating the number of women of fertile age in our area, and we used the previous years’ data to calculate the prevalence of sterility problems and the percentage of women who had undergone in vitro fertilization. Thus, our prospective study was based on a sample of 220 women, 25 to 42 years old, who underwent assisted reproduction from January 1998 to May 1999. We excluded the women who had mild or severe ovarian hyperstimulation syndrome or thrombocytopenia, those who were taking anticoagulant drugs, and those who were overweight (body mass index 25 to 30) or obese (body mass index greater than 30). The study was approved by the local hospital ethics committee and all of the participants gave written informed consent.
Reproductive EndocrinologyEmbryo-Endometrial SignalinghCG Role in Endometrial ReceptivityGrowth and Differentiation Factor
Recent evidence suggests that human chorionic gonadotropin (hCG), in addition to its well-known endocrine effects on the corpus luteum, may act as a growth and differentiation factor during pregnancy. According to experimental results, its mode of action may be divided into three sequential phases. During the first phase, which begins at the blastocyst stage and lasts until the occurrence in the serum, hCG acts preferentially in a juxtacrine manner. We have used an intrauterine microdialysis system developed in our laboratory to administer low concentrations of hCG to the endometrium of women in the luteal phase of the menstrual cycle. HCG administration provoked profound effects on paracrine parameters of differentiation (IGFBP-1, prolactin) and implantation (LIF, M-CSF). VEGF, a cytokine important for neoangiogenesis, was significantly stimulated by hCG (P < .01), suggesting a role for hCG in the control of endometrial vascularization and placentation. The investigation of endometrial parameters of tissue remodeling revealed a significant increase of MMP-9 (P < .05) but not of TIMP-1 following hCG infusion. The second, endocrine, phase of hCG action is marked by the appearance of hCG in the maternal serum. Rising systemic hCG levels cause a very rapid elevation of serum progesterone reflecting the rescue of the corpus luteum. Other endocrine functions of hCG include its intrinsic thyrotropic activity as well as modulation of fetal testicular, ovarian, and adrenal function. The third phase may be characterized by the expression of full-length hCG/LH receptors on the trophoblasts themselves. Before the ninth week of gestation, human villous trophoblasts express a truncated hCG/LH receptor isoform (50 kDa) and are probably not responsive to hCG. Later, the expression pattern is switched to the full-length receptor (80 kDa), allowing hCG also to modulate the differentiation of the trophoblasts themselves. A special feature is the self-regulation of hCG biosynthesis that may in part explain the unique secretion profile of the hormone with peak levels during the first trimester followed by a rapid decline after the tenth week of gestation. In summary, hCG seems to have a variety of local and systemic functions in and outside the embryo-endometrial microenvironment.
Reproductive EndocrinologyEndometrial EffectshCG and Endometrial ReceptivityGonadotropin Direct Effects
Human chorionic gonadotropin (hCG) is widely used as a surrogate to luteinizing hormone (LH) to trigger ovulation in controlled ovarian hyperstimulation (COH). Yet this molecule may exert direct effects on the endometrium. These effects, not mediated by ovarian hormones, are probably a consequence of stimulation of endometrial hCG/LH receptors. Because the half-life of hCG differs markedly from that of LH, possible pharmacological effects of hCG on the endometrium could alter endometrial receptivity in COH. Arguments supporting a clinical action of gonadotropins, and hCG in particular, on the endometrium abound. Notably, evidence has been reported of decidualization of stromal cells of the human endometrium in vitro as a result of exposure to gonadotropins, including hCG. The present article discusses, from a clinical standpoint, the main basis supporting the hypothesis that hCG administration as commonly used in infertility treatments may exert direct effects in vivo on endometrial histology and partake in endometrial transformations of the luteal phase. Preliminary results suggest that endometrial effects of hCG exist in vivo and should be taken into account when assessing the endometrial effects of hormones.
InfertilityProgesterone SupplementationClinical Use in FertilityLuteal Phase Support
Progesterone, supplied in a variety of formulations, is commonly used in assisted reproduction. However, even the commonly accepted uses of progesterone in fertility care are believed to be largely empirical, as are the current available treatment options. While a critical balance of estrogen and progesterone is necessary for successful embryo implantation, achieving that balance is subject to differences in prescribing practice. In evaluating recommendations for the use of progesterone, discussion of its role in assisted-reproduction procedures must distinguish between known therapeutic benefits and empirical benefits.
General OB/GYNPsychological Impact of IVFMarital RelationshipsAnxiety in Reproductive Medicine
To compare the psychopathology, personality features, and marital relationships of women undergoing in vitro fertilization (IVF) with those of control patients, and to compare IVF inductees with program veterans. Cross-sectional clinical study. A university hospital. PATIENT(S): One hundred and one women undergoing IVF treatment. INTERVENTION(S): Psychometric tests were administered at first visit (baseline) of index treatment cycle. MAIN OUTCOME MEASURE(S): Achievement of pregnancy. RESULT(S): Women undergoing IVF show higher levels of anxiety and emotional tension than do controls. Although the infertile women showed no abnormal personality dimensions, the IVF group did have a particular psychological profile and a different marital relationship pattern when compared with the control participants. Between IVF veterans and inductees, there are significant differences with respect to psychopathology, psychological dimensions, and couple dynamics. The achievement of pregnancy is not associated with any special psychopathological, personality, or marital characteristics among the IVF women. CONCLUSION(S): The most crucial period in IVF procedures may immediately follow the end of the first cycle because of the high risk of patients dropping out of the program. To determine the most effective supporting therapies for women undergoing fertilization procedures it could be useful to consider the psychological and relational differences between veterans and inductees.
InfertilityEmbryo Transfer OptimizationUterine ContractilityLuteal Phase Support
To investigate whether uterine contractility at the time of embryo transfer (ET) can be reduced by early onset of luteal support with progesterone administered vaginally. Prospective analysis. Assisted reproduction unit. PATIENT(S): Eighty-four women undergoing 84 GnRH-a and FSH/hCG cycles for IVF-ET were studied. INTERVENTION(S): Vaginal progesterone was randomly started on the day of oocyte retrieval (group A, n = 43) or on the evening of ET (group B, n = 41). On the day of hCG administration and just before ET, 2-minute sagittal uterine scans were obtained by ultrasound and digitized with an image analysis system for assessing uterine contraction frequency. MAIN OUTCOME MEASURE(S): Uterine contraction frequency. RESULT(S): Whereas uterine contraction frequency was similar in both groups on the day of hCG (4.6 +/- 0.3 and 4.5 +/- 0.3 contractions per minute, respectively), only women in group A showed decreased uterine contraction frequency on the day of ET (2.8 +/- 0.2 vs. 4.2 +/- 0.3 contractions per minute). CONCLUSION(S): Vaginal progesterone administration starting on the day of oocyte retrieval induced a decrease in uterine contraction frequency on the day of ET as compared with preovulatory values. Uterine relaxation before ET is likely to improve IVF-ET outcome by avoiding the displacement of embryos from the uterine cavity.
To compare the rates of ovulation and pregnancy after tamoxifen citrate (TMX) or clomiphene citrate (CC) among anovulatory women with infertility. Prospective randomized trial. Infertility clinic in a university teaching hospital. PATIENT(S): Eighty-six anovulatory women under 40 years of age undergoing ovulation induction. INTERVENTION(S): The women were assigned randomly to receive either TMX or CC on cycle days 5-9. MAIN OUTCOME MEASURE(S): Rates of ovulation and pregnancy for the two treatment modalities. RESULTS(S): The overall rate of ovulation in the TMX group was 50 of 113 (44.2%) and in the CC group, 41 of 91 (45.1%). There were 10 pregnancies in the TMX group and 6 pregnancies in the CC group. The cycle fecundity per ovulatory cycle was 20.0% in the TMX group and 14.6% in the CC group. CONCLUSION(S): The overall rate of ovulation and pregnancy were similar with TMX and CC. TMX is a suitable alternative agent to CC in the management of anovulatory infertility.
To compare subcutaneous (SC) and intramuscular (IM) hCG administration and their association with body mass index (BMI) in women undergoing IVF-ET using hMG and ICSI. Prospective, randomized controlled trial. Private infertility clinic. PATIENT(S): Twenty-one ovulatory women, 29-39 years, were enrolled. Treatment of one patient who failed to respond to hMG was canceled. INTERVENTION(S): A standard IVF-ET treatment plan using an initial dose of 300 U of hMG was followed. Patients were randomly assigned to receive 10,000 IU hCG, either IM in the gluteal region or SC in the lower abdomen. Exactly 12 hours later, serum for hCG determination was obtained. All oocytes were fertilized using ICSI technology. MAIN OUTCOME MEASURE(S): Human chorionic gonadotropin levels 12 hours after injection, BMI, and oocyte maturity. RESULT(S): No significant differences in hCG levels were found, with mean levels of 225 +/- 24 mIU/mL for SC injection versus 213 +/- 26 mIU/mL for IM injection. No differences were observed in the percentage of mature oocytes. A significant negative correlation was found between BMI and hCG levels in all patients, regardless of route of administration. CONCLUSION(S): The highest levels of hCG were measured in women with the lowest BMI. Patients' body size, rather than route of hCG delivery, appears to determine circulating levels of hCG.
Zuppa AA et al., 2001·Eur J Obstet Gynecol Reprod Biol
Over the last 10 years, diffusion of assisted reproduction techniques (ovarian stimulation, IVF, GIFT) has led to an increased incidence of multiple pregnancies and consequently, of the related obstetric-neonatal problems. In this study, multiple births have been studied, with particular reference to the twin births occurring in the Gemelli hospital, Rome. The hospital is also a reference centre for obstetric pathologies and infertility treatment. In particular, attention has been focused on neonatal outcome, comparing twins born from spontaneous and assisted pregnancies. 228 neonates from spontaneous twin pregnancies and 32 from assisted twin pregnancies were taken into premature birth, low birth-weight, intrauterine growth retardation, weight discordance, Apgar score, major neonatal diseases, and mortality. Results showed a significant higher incidence of prematurity and low birth-weight, as well as a significant lower gestational age, occurring more frequently in twins resulting from assisted pregnancies than in twins from spontaneous pregnancies. Furthermore, the incidence of severe depression at birth and respiratory disease was significantly higher in twins from assisted pregnancies than in those from spontaneous pregnancies, despite similar gestational age and birth-weight.
To use aromatase inhibition for induction of ovulation in women in whom clomiphene citrate (CC) treatment was unsuccessful. Prospective trial in infertility patients treated with CC. Two tertiary-referral infertility clinics associated with the Division of Reproductive Sciences, University of Toronto. PATIENT(S): Twelve patients with anovulatory polycystic ovary syndrome (PCOS) and 10 patients with ovulatory infertility, all of whom had previously received CC with an inadequate outcome (no ovulation and/or endometrial thickness of < or =0.5 cm). INTERVENTION(S): The aromatase inhibitor letrozole was given orally in a dose of 2.5 mg on days 3-7 after menses. MAIN OUTCOME MEASURE(S): Occurrence of ovulation, endometrial thickness, and pregnancy rates. RESULT(S): With CC treatment in patients with PCOS, ovulation occurred in 8 of 18 cycles (44.4%), and all ovulatory cycles for the women included in this study had endometrial thickness of < or =0.5 cm. In 10 ovulatory patients, 15 CC cycles resulted in a mean number of 2.5 mature follicles, but all cycles had endometrial thickness of < or =0.5 cm on the day of hCG administration. With letrozole treatment in the same patients with PCOS, ovulation occurred in 9 of 12 cycles (75%) and pregnancy was achieved in 3 patients (25%). In the 10 patients with ovulatory infertility, letrozole treatment resulted in a mean number of 2.3 mature follicles and mean endometrial thickness of 0.8 cm. Pregnancy was achieved in 1 patient (10%). CONCLUSION(S): Oral administration of the aromatase inhibitor letrozole is effective for ovulation induction in anovulatory infertility and for increased follicle recruitment in ovulatory infertility. Letrozole appears to avoid the unfavorable effects on the endometrium frequently seen with antiestrogen use for ovulation induction.
PCOSMetforminClomiphene CitrateCombined Medical Therapy
To determine whether metformin treatment increases the ovulation and pregnancy rates in response to clomiphene citrate (CC) in women who are resistant to CC alone. Randomized, double-blind, placebo-controlled trial. Multicenter environment. PATIENT(S): Anovulatory women with the polycystic ovary syndrome (PCOS) who were resistant to CC. INTERVENTION(S): Participants received placebo or metformin, 500 mg three times daily, for 7 weeks. Information on reproductive steroids, gonadotropins, and oral glucose tolerance testing was obtained at baseline and after treatment. Metformin or placebo was continued and CC treatment was begun at 50 mg daily for 5 days. Serum P level > or =4 ng/mL was considered to indicate ovulation. With ovulation, the daily CC dose was not changed, but with anovulation it was increased by 50 mg for the next cycle. Patients completed the study when they had had six ovulatory cycles, became pregnant, or experienced anovulation while receiving 150 mg of CC. MAIN OUTCOME MEASURE(S): Ovulation and pregnancy rates. RESULT(S): In the metformin and placebo groups, 9 of 12 participants (75%) and 4 of 15 participants (27%) ovulated, and 6 of 11 participants (55%) and 1 of 14 participants (7%) conceived, respectively. Comparisons between the groups were significant. CONCLUSION(S): In anovulatory women with PCOS who are resistant to CC, metformin use significantly increased the ovulation rate and pregnancy rate from CC treatment.
InfertilityMultiple PregnanciesMaternal and Neonatal MorbidityMultiple Gestation
To investigate the contributions of ovulation-inducing drugs and assisted reproductive technologies to multiple birth. This historic prospective study was conducted in a cohort of 13,151 women who delivered after 20 weeks' gestation between October 1996 and December 1999. The study setting was a Colorado health maintenance organization. Cases were women who were pregnant as a result of exposure to treatment with either assisted reproductive technologies or ovulation induction in the absence of assisted reproductive technologies. The main outcome measure was multiple birth. There was a significant association between assisted conception and multiple birth. Compared with women with naturally conceived pregnancies, there was a 25-fold likelihood (95% confidence interval 18, 35, P <.001) of multiple birth among women exposed to any of those treatments. In the total cohort the proportion of multiple births attributable to those treatments was 33%. After adjusting for the use of assisted conception and other covariates, we found no association between advanced maternal age and multiple birth. In this cohort, assisted reproductive interventions were strongly associated with multiple birth. Although a higher proportion of older women sought assisted reproductive technologies, we did not find an independent relationship between advanced maternal age and multiple birth. The increasing number of multiple births attributable to assisted conception raises public health concerns regarding multiple gestation-related maternal and infant morbidities.
To assess the reliability of the most widely used clinical methods for predicting or confirming ovulation. We monitored spontaneous cycles in 101 infertile women using basal body temperature (BBT), transvaginal ultrasound, a urinary stick system for LH surge, and three serum progesterone measurements in the midluteal phase. Transvaginal ultrasound monitoring was standard for ovulation detection and sensitivity. We calculated specificity and accuracy of each method compared with that standard. Follicular development and ultrasound evidence of ovulation were confirmed in 97 of 101 cycles (96%). Urinary LH surge preceded follicular rupture assessed by ultrasonography in all cycles and showed concordance with ultrasound-evidenced ovulation in 98 of 101 cases. The timing of BBT nadir had wide variability, and BBT and ultrasonography agreed in a similar percentage of cases (74%). Midluteal serum progesterone assessments showed ovulatory values in 93 subjects, and ovulation was concordant with ultrasonography in 90 subjects. Urinary LH was accurate in predicting ovulation with ultrasonography as the standard for detection, but time varied widely. The nadir of BBT predicted ovulation poorly. The BBT chart was less accurate for confirming ovulation, whereas a single serum progesterone assessment in midluteal phase seemed as effective as repeated serum progesterone measures.
To compare the incidence of pregnancy-induced hypertension in patients with and without polycystic ovary disease (PCOD). We conducted a retrospective, case-control analysis of patients who achieved singleton pregnancies with human menopausal gonadotropin (hMG) therapy. Twenty-two PCOD patients were compared to 27 infertility patients without PCOD who were pregnant after hMG therapy. Non-PCOD patients received hMG for superovulation as part of superovulation/intrauterine insemination or in vitro fertilization/embryo transfer. PCOD patients were receiving hMG for simple ovulation induction. Pregnancy-induced hypertension was defined as late pregnancy blood pressure > 140/90 mm Hg on two readings six hours apart and return to normal blood pressure by four to six weeks postpartum. There were no differences between PCOD and non-PCOD patients with reference to age, body mass index, parity or other pregnancy-induced hypertension risk factors (i.e., chronic hypertension, diabetes or chronic renal disease). Pregnant PCOD patients had a much higher incidence of pregnancy-induced hypertension, 31.8% (7/22), versus non-PCOD patients, who only had a pregnancy-induced hypertension incidence of 3.7% (1/27) (P = .016, OR = 12.1, 95% CI = 1.3-566.8). PCOD patients are at very high risk of pregnancy-induced hypertension when pregnant after ovulation induction.
The potential risk of transmitting chromosomally abnormal spermatozoa from infertile males into oocytes through intracytoplasmic sperm injection (ICSI) has prompted us to investigate the male pronuclei of tripronuclear zygotes (3PN) obtained after ICSI. To specify the type of anomalies, we used triple colour fluorescent in-situ hybridization (FISH) with three specific probes for chromosomes X, Y and 18. From a total of 163 paternal complements of ICSI-3PN zygotes, 90 (55.2%) had Y-chromosome signals. Eighty-three of these were normal, four had the disomy XY and three were diploid. In the remaining 73 ICSI-3PN zygotes without Y-chromosome signals, the origin of paternal pronuclei was extrapolated through chromosome constitution of the first polar body. Five anomalies were found in this group of zygotes, giving a total rate of numerical chromosome aberrations for fertilizing spermatozoa of 7.4%. In contrast to ICSI, only two disomies (1.5%) were found in the control group of IVF-3PN zygotes. Compared with the incidence of chromosome anomalies between paternal-derived
Reproductive EndocrinologyMenstrual DisturbancesThyroid DysfunctionThyroid Disease and Reproduction
To review the menstrual function and fertility in thyroid disease, mainly in hyperthyroidism and hypothyroidism. Also to register the consequences of (131)I therapy, which is used widely in the treatment of Graves' disease and thyroid cancer, on subsequent pregnancies and on fertility in these patients. A MEDLINE computer search was used to identify relevant studies. The type of menstrual disturbances and the status of fertility were recorded from all the studies found. Also, the fertility and genetic hazard of female patients with Graves' disease and thyroid cancer who were treated with (131)I were registered. RESULT(S): Both hyperthyroidism and hypothyroidism may result in menstrual disturbances. Menstrual abnormalities are less common now than in previous series. In a recent study, we found that only 21.5% of 214 thyrotoxic patients had some type of menstrual disturbance, compared to 50 to 60% in some older series. The most common manifestations are hypomenorrhea and oligomenorrhea. According to the results of endometrial biopsies, most thyrotoxic women remain ovulatory. Moreover, the genetic hazard incident to radioiodine therapy in Graves' disease and thyroid carcinoma is very small; exposure to (131)I does not cause reduced fecundity, and the risk of loss of fertility is not a contraindication for its use in these patients. mIn hypothyroidism, the frequency of menstrual irregularities has very recently been reported to be 23.4% among 171 hypothyroid patients studied. This is much less than that reported in previous studies, which showed that 50 to 70% of hypothyroid female patients had menstrual abnormalities. The most common manifestation is oligomenorrhea. Severe hypothyroidism is commonly associated with failure of ovulation. Ovulation and conception can occur in mild hypothyroidism. These pregnancies are, however, often associated with abortions, stillbirths, or prematurity. The latter may be of greater clinical importance in infertile women with unexplained infertility. CONCLUSION(S): These new data, mainly concerning menstrual abnormalities in hyperthyroidism and hypothyroidism, are inconsistent with what is generally believed and written in the classic thyroid textbooks and indicate that such opinions should be revised.
The purpose of this study was to assess the association between subfertility and spontaneous abortion. A total of 1572 women in New York and Vermont reported 3269 pregnancies between 1980 and 1990 and were able to provide an estimate of the waiting time to conception for 2967. Subfertility was defined as a delay of 1 year or more before a recognized conception was achieved. Rates of spontaneous abortion were determined among women with and without subfertility, and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated via multiple logistic regression. Spontaneous abortion rates were 23.0% in pregnancies preceded by subfertility and 14.0% in pregnancies without impaired fertility (adjusted OR = 1.71, 95% CI = 1.26, 2.94). The attributable risk of spontaneous abortion associated with subfertility was 6.2%. Subfertile women evidence an increased number of spontaneous abortions.
InfertilityDrug-Induced InfertilityMedication ModificationNSAIDs and Reproductive Outcomes
To highlight the possible association between infertility and treatment with long-term non-steroidal anti-inflammatory drug (NSAIDs). NSAIDs act mainly through the inhibition of cyclooxygenase, the enzyme that catalyses the synthesis of prostaglandins, which are essential mediators of ovulation, implantation and placentation of the conceptus. Case reports of four women suffering from severe arthritis, on long-term NSAIDs and undergoing extensive investigation and treatment for infertility. During the last 2 yr, four out of five women with severe arthritis and difficulty conceiving were counselled to stop NSAIDs, and they successfully conceived shortly after the withdrawal of NSAIDs. NSAIDs, used largely for the treatment of rheumatological conditions, may be responsible for some cases of infertility.
PregnancyEpidemiology and TrendsNeonatal OutcomesMultiple Pregnancy Risk
Multiple births (of all orders) increased in epidemic proportions in the years 1971-1997. Twins increased 53%, 32%, 31%, and 83% in white, Afro-American, Native American and Mexican American women, respectively. Triplet, quadruplet, and quintuplet+ births increased >400%, >1,100%, and >500%, respectively, in the same years. The principal causes of these changes are related to the increasing age of the maternal cohort and an increasing incidence of fertility-inhibiting diseases and conditions in association with advancing maternal age. Major immediate consequences of these changes include disproportionately large numbers of infants born at <33 weeks' gestation (1.7% for singletons vs. 41.2% for triplets) and at <1,500 g birth weight (1.1% for singletons vs. 31.9% for triplets). Additional short-term consequences include an almost 2,000% increase in infant deaths (per 1,000 live births) among triplets compared with singletons (190.4 vs. 11.2). Long-term risks include a 300% increase in the relative risk of handicap in triplets compared with singletons (2.9 vs. 1.0), and a 650% increase in the rate of cerebral palsy per 1,000 live births in triplets compared with singletons (26.6 vs. 1.6). Peripartum costs relate to prematurity rather than plurality, as do lifetime survivorship costs, which relate to morbidities and subsequent health-related problems.
Contraception/ComparisonEmbryo DispositionStatus of EmbryosEmbryo Transfer Practices
Contemporary practice in assisted reproductive technologies (ART) compensates for the attrition that occurs at each phase of the cycle. Every follicle does not yield an egg, nor does every egg fertilize. Of those that do, many fail to properly develop, and even fewer implant. Nevertheless, ART cycles usually result in more embryos than are needed for transfer. With clinical and laboratory advances in the field and the undeniable need to reduce the incidence of multiple gestation, we must focus increased attention on these “spare” or “extra” embryos and their fate.
The relative quality of extra embryos clearly influences their disposition. Although the pregnancy potential of any single embryo is always uncertain, a fragmented embryo from a patient over the age of 40 generally has less potential than a morphologically normal one from an egg donor. Data from 1996 SART registry (1) suggests that only 4% of transferred embryos from patients 39 years and older result in a child, whereas this number is approximately 12% in women under 35. Because most programs choose the highest quality embryos for transfer, potential implantation rates for spare embryos would be lower.
Registry data are invaluable to track progress in the field, but they do little to guide decisions concerning individual patients, because the implantation rate of any given embryo of reasonable morphology is either zero or 100%. In the absence of more reliable markers of implantation potential, we must assume that all transferred embryos can implant. . .
InfertilityUnderlying Disease IdentificationInfertility as SymptomRoot Cause Diagnosis of Infertility
In an otherwise excellent editorial that appeared in this journal concerning the problems created by failure of the Health Insurance Industry to provide coverage for infertility, the author, a noted academician and clinician, repeatedly referred to infertility as a disease (1). The mistaken idea that infertility is a disease is commonplace among not only academicians and clinicians but also among third-party payers and the general public and is one of the reasons that infertility is not covered by most insurance plans.
The facts are that infertility and its frequent companion, anovulation, are not diseases; they are symptoms of underlying, sometimes serious disease in one or both marital partners. One result of considering infertility and anovulation as diseases rather than as symptoms is that unnecessarily powerful and expensive treatments may be used to obtain an immediate pregnancy, whereas chronic disease that may affect lifelong health is overlooked.
Just as the symptoms chronic headache, chronic stomach pain, and chronic chest pain may be caused by underlying disease, so may infertility be caused by underlying disease. Endometriosis, uterine fibroids, benign ovarian tumors, and pelvic adhesive disease are causes of infertility that can be treated by laparoscopy, if detected early, but may require more extensive surgery later if they remain undiagnosed. Anovulation may be due to insulin resistance that can result in diabetes or cardiovascular disease later in life (2) or any of a number of other endocrine disorders with lifelong effects.
A 1991 study from the Centers for Disease Control and prevention (CDC) found that the lifetime risk of developing endometrial cancer was increased not only in patients with polycystic ovary syndrome but also in infertile patients with hypothyroidism, uterine fibroids, and endometriosis (3). Infertile women with any of these conditions who conceived a term pregnancy did not have an increased risk of endometrial cancer.
A major obstacle to the treatment of infertility as a symptom by the Health Insurance Industry is the way it is characterized in the International Classification of Diseases, Volume 9 (ICD). In the ICD, female infertility (Code 628.0) and male infertility (606.0) are classified as diseases but are clearly treated as symptoms. Female infertility is listed as “associated with,” “due to,” or “having its origin in” 30 other conditions. Similarly, male infertility is listed as “due to” 12 other conditions. Anovulation is given the same diagnostic code number as female infertility (628.0) and is not classified further as to its underlying causes. Health insurers have taken advantage of this to deny coverage for endocrine evaluation of patients with anovulation on the basis that it is synonymous with infertility.
The ICD needs to be revised according to modern understanding of anovulation and the causes of female and male infertility, as was done in the 1999 edition for complications of pregnancy and childbirth. Health insurers must acknowledge that anovulation is a symptom separate from infertility that requires diagnosis and treatment irrespective of a desire to become pregnant. All of us, practicing physicians and academicians, should make establishment of an accurate and complete diagnosis our first goal when presented with an infertile couple.
InfertilityDiagnostic LaparoscopyLaparoscopic Detection in Infertile WomenLaparoscopy in Unexplained Infertility
Corson SL et al., 2000·J Am Assoc Gynecol Laparosc
To determine the prevalence of reproductive pathology in a group of infertile women thought to be at low risk for altered pelvic anatomy. Retrospective chart review and follow-up (Canadian Task Force classification II-2). Academic-affiliated, private reproductive endocrinology practice. One hundred infertile women. Diagnostic and/or therapeutic laparoscopy. MAIN Of 100 patients with a negative reproductive work-up up to the point of laparoscopy, 68 intrinsic tubal disease 24, peritubal adhesive disease 34, and endometriosis 43, some in combination. Laparoscopy was especially helpful in establishing treatment protocols for older women, who were referred for assisted reproductive techniques earlier than otherwise might have been the case. Women conceived after hormone therapy and after operative intervention. Although the hysterosalpingogram was read as normal in all women, tubal disease was diagnosed laparoscopically, independent of endometriosis, in 27 patients, with 2 having complete obstruction. Endometriosis stage I-II was found in 22 patients, stage III in 13, and stage IV in 6. Even in women thought to be at low risk for significant pelvic pathology affecting reproduction, the yield was high. Although some pregnancies were achieved after operative intervention, frequently laparoscopy was helpful in making a decision to go to assisted reproductive technology, particularly when infertility had been of long duration and in older women. Frequently the degree of pathology was such that a full operating suite was necessary to provide adequate instrumentation and anesthesia for operative intervention, which would not have been the case with office laparoscopy.
InfertilityMultiple Pregnancy OutcomesEpidemiology and TrendsPreterm Birth
In the United States, pregnancies associated with assisted reproductive technology (ART) or ovulation-inducing drugs are more likely to result in multiple births than spontaneously conceived pregnancies (1). In addition, triplet and higher-order multiple births are at greater risk than singleton births to be preterm (< or = 37 completed weeks' gestation), low birthweight (LBW) (i.e., < or = 2500 g), or very low birthweight (i.e., < 1500 g), resulting in higher infant morbidity and mortality (2). Because preterm and LBW infants often require costly neonatal care and long-term developmental follow-up, the continuing increase in triplet and higher-order multiple births causes concern among health-care providers and policymakers (3). This report provides estimates of the contribution of ART and ovulation-inducing drugs to these birth outcomes for 1996 and 1997, and summarizes trends during 1980-1997, which indicate that the ratio of triplet and higher-order multiple births has more than quadrupled and that a large proportion of this increase can be attributed to ART or the use of ovulation-inducing drugs.
Contraception/ComparisonMultiple Birth PreventionEmbryo Transfer StrategiesMultiple Pregnancy Reduction
To maximize pregnancy rates, physicians who perform IVF, often transfer multiple embryos, which increases the multiple birth risk. Multiple birth infants are at significant risk for a number of adverse outcomes including preterm delivery, low birth weight, congenital malformations, fetal and infant deaths and long term morbidity and disability among survivors. Since the ultimate goal for an IVF treatment is the birth of a healthy infant, an important issue for all kinds of assisted reproductive technologies (ART) must be the reduction or elimination of multiple pregnancies. In this article, different strategies to avoid multiple births in ART are discussed.
To quantify the contribution of in vitro fertilization (IVF) on changes in the rates of low birth weight (LBW), preterm delivery, very low birth weight, and multiple births during the past 3 years. Data on IVF pregnancies from 1994 to 1996 within Alberta were reviewed. Population data were obtained from the Provincial notice of a live or stillbirth. The IVF component of increased LBW rate in the province was 17.8% for infants <2500 g and 43.5% for those born <1500 g. IVF accounted for 10.5% of the provincial rate increase in deliveries <37 weeks' gestation and 66.2% of those <30 weeks' gestation. IVF accounted for 21.4% of the twins and all of the sets of triplets in the province. During a 3-year period IVF has affected the incidence of LBW, preterm delivery, and multiple birth. IVF is a substantial contributor to changes in very low birth weight and delivery before 30 weeks, which is partly related to multiple births.
Pelvic adhesions can be the result of inflamation, endometriosis or surgical trauma. Prevention of postoperative adhesions (either new or reoccurance) has been postulated by using barriers to prevent two surfaces being in contact. When pelvic surgery is being undertaken strategies to reduce pelvic adhesions occurring may be undertaken and these include barrier agents which are placed between the pelvic structures. Two synthetic barriers with differential characteristics oxidised regenerated cellulose (Interceed) and polytetrafluoroethylene (PTFC) (GoreTex). The objective of this review was to assess the effect of mechanical barriers (materials interposed between pelvic structures to prevent adherence of serosal surfaces) used during pelvic surgery in women of reproductive age on pregnancy rates, pelvic pain, or postoperative adhesion reformation.
The Cochrane Menstrual Disorders and Subfertility Group specialised register of controlled clinical trials was undertaken. In addition, companies were contacted for unpublished trials.
Randomised controlled trials or controlled clinical trials of barriers versus no treatment or other barriers in women undergoing fertility preserving pelvic surgery. Reviewers assessed eligibility and trial quality. 15 randomised controlled trials were included. Five trials randomised patients while the remainder randomised pelvic organs. Laparoscopy was the primary surgical technique in six trials while the remaining trials were laparotomy. Indications for surgery included myomectomy (five trials), ovarian surgery (four trials), pelvic adhesions (six trials), endometriosis (two trials) and mixed (one trial). Thirteen trials assessed Interceed versus no treatment, two assessed Interceed versus Gore-Tex, one trial assessed Gore-Tex versus no treatment, and one trial assessed Seprafilm versus no treatment. No study reported pregnancy or reduction in pain as an outcome. The use of Interceed in women was associated with reduced incidence of pelvic adhesion formation, both new formation and re-formation following laparoscopic surgery and after laparotomy. Gore-Tex was more effective than no barrier or Interceed in preventing adhesion formation. There was limited evidence that Seprafilm was effective in preventing adhesion formation in women following myomectomy. REVIEWER'S The absorbable adhesion barrier Interceed reduces the incidence of adhesion formation, both new formation and re-formation, at laparoscopy and laparotomy, but there are insufficient data to support its use to improve pregnancy rates. Gore-Tex may be superior to Interceed in preventing adhesion formation but its usefulness is limited by the need for suturing and later removal. There was no evidence of effectiveness of Seprafilm in preventing adhesion formation.
InfertilityICSI Pregnancy OutcomesART-Related ComplicationsICSI Outcomes by Sperm Source
The aim of this study was to report the outcome of all clinical pregnancies obtained after intracytoplasmic sperm injection (ICSI) performed during a 5 year period at two fertility clinics, with special reference to delivery outcome associated with different sperm origin and quality and the transfer of fresh or frozen-thawed pre-embryos. A total of 1293 clinical pregnancies was analysed. Deliveries occurred in 75.9% (n = 982) and early spontaneous abortion, late spontaneous abortion and ectopic pregnancy in 21.4, 1.0 and 1.2% respectively. Multiple birth occurred in 21.3% (208 sets of twins and one set of triplets) of the deliveries, with the highest incidence in the epididymal sperm group (30.2%) and lowest in the cryopreserved group (13.7%). A total of 1192 infants was born. Preterm birth occurred in 15.7% of all deliveries. Preterm birth was not related to sperm origin or quality but was related to multiple birth. The prematurity rate was 8.4%, 42.3% and 100% for singletons, twins and triplets respectively. Singleton infants born after cryopreservation as embryos had a significantly higher birthweight than the ejaculated sperm group with fresh embryo transfer. The perinatal mortality rate was 11.7 per 1000 born infants. Eighty-seven of the 1192 infants (7.3%) had a malformation, 40 of which were minor. The perinatal mortality rate and the malformation rate were similar in the different subgroups. Prenatal karyotyping was performed on 149 fetuses (12.5%) and abnormal results were found in four cases (2.7%). In conclusion, obstetric outcome of ICSI pregnancies was similar to that of conventional IVF and was not influenced by sperm origin or quality. The high incidence of multiple births is still the major concern.
Different routes of natural progesterone supplementation have been tried as luteal phase support in infertility treatments. Orally administered progesterone is rapidly metabolized in the gastrointestinal tract and its use has proved to be inferior to i.m. and vaginal routes. Progesterone i.m. achieves serum progesterone values that are within the range of luteal phase and results in sufficient secretory transformation of the endometrium and satisfactory pregnancy rates. The comparison between i.m. and vaginal progesterone has led to controversial results as regards the superiority of one or the other in inducing secretory endometrial transformation. However, there is increasing evidence in the literature to favour the use of vaginal progesterone. Vaginally administered progesterone achieves adequate endometrial secretory transformation but its pharmacokinetic properties are greatly dependent on the formulation used. After vaginal progesterone application, discrepancies have been detected between serum progesterone values and histological endometrial features. Vaginally administered progesterone results in adequate secretory endometrial transformation, despite serum progesterone values lower than those observed after i.m. administration, even if they are lower than those observed during the luteal phase of the natural cycle. This discrepancy is indicative of the first uterine pass effect and therefore of a better bioavailability of progesterone in the uterus, with minimal systematic undesirable effects.
Ovarian granulosa cell tumour (GCT) is a rare malignancy, which has been linked to both infertility and infertility treatment with ovulation inducers. The reproductive features were analysed of 146 women with GCT diagnosed between 1956 and 1996. During the study period no changes were found in the mean age (53 years), menopausal status (59% postmenopausal), parity (32% nulliparous) or tumour size or stage at diagnosis. The clinical features in women with GCT at fertile age were compared with GCT diagnosed later in life and to population-based data. Nulliparity (50%) and history of infertility (22%) were more frequent if the tumour occurred at fertile age (n = 50). Of the 12 infertile cases, seven had anovulatory infertility (58%); 11 occurred during the era of ovulation inducers, but only five had used these drugs (clomiphene citrate in five patients, gonadotrophins in two, and tamoxifen in one patient) and no patient had undergone in-vitro fertilization. Endometrial hyperplasia was associated with GCT at all ages, while endometrial cancer was found solely after the age of 45 years. In conclusion, GCT at fertile age is associated with nulliparity and with a clinical presentation of anovulatory infertility, while GCT later in life is associated with a more normal average fertility pattern and with occurrence of endometrial cancer.
The present study was designed to evaluate the prognostic value of salpingoscopy in patients undergoing tubal laparoscopic surgery for infertility due to periadnexal adhesion or distal tubal occlusion. In addition, the clinical value of salpingoscopy was compared with a current classification system of adnexal adhesions and distal tubal occlusion. A total of 51 patients with either adnexal adhesions (24 patients) or hydrosalpinx (27 patients) were prospectively evaluated. Salpingoscopy was performed concomitantly with salpingo-ovariolysis or salpingoneostomy at the time of operative laparoscopy. There was no significant correlation between salpingoscopic classes and the classification system used for both the salpingo-ovariolysis and the salpingoneostomy groups of patients. The patients had a mean follow-up of 33 months. Patients with a normal tubal mucosa (salpingoscopic classes I and II) had a 71% cumulative term pregnancy rate in the salpingo-ovariolysis group and a 64% cumulative term pregnancy rate in the salpingoneostomy group. No intrauterine pregnancies were obtained in patients with intratubal damage (salpingoscopic classes III to V). There was a statistically significant correlation between the occurrence of a term pregnancy and the salpingoscopic classes, but not with the classification system used. These results suggest that patients with tubal infertility should be offered operative laparoscopy with salpingoscopy as the first step of treatment.
To assess the value of laparoscopy in infertile women with normal hysterosalpingograms, with and without risk factors suggesting pelvic disease. We retrospectively reviewed 1,022 consecutive charts from a tertiary infertility practice. In 265 women, laparoscopies were performed after normal hysterosalpingograms. Laparoscopies were normal in 136 (51%) women, whereas 129 (49%) had one or more abnormal laparoscopic findings, including minimal or mild endometriosis (n = 85), moderate or severe endometriosis (n = 11), adnexal adhesions (n = 27), subserosal myomas (n = 17), ovarian neoplasms (n = 5), distal phimosis (n = 1) and salpingitis isthmica nodosa (n = 1). Only 7% of cases had findings that might require standard operative laparoscopy or laparotomy, although not all were causally related to infertility. A history of dysmenorrhea or dyspareunia increased the likelihood of detecting endometriosis from 41% to 64% and 69%, respectively. The presence of both symptoms increased the likelihood to 83%. In the presence of a normal hysterosalpingogram, laparoscopy identified other pelvic disease in about half of patients. Because most abnormalities were mild, this knowledge can be used to plan a micro-laparoscopic approach for many women, reserving traditional or operative laparoscopy for women with an abnormal hysterosalpingogram or extensive disease following micro-laparoscopy. Alternately, knowledge of the nature and severity of the expected laparoscopic findings might lead to bypassing laparoscopy in favor of assisted reproduction when the perceived benefit of surgical intervention is small.
InfertilityIVF Live Birth RatesMultiple Birth RiskMultiple Pregnancy
To maximize birth rates, physicians who perform in vitro fertilization (IVF) often transfer multiple embryos, but this increases the multiple-birth risk. Live-birth and multiple-birth rates may vary by patient age and embryo quality. One marker for embryo quality is cryopreservation of extra embryos (if embryos are set aside for cryopreservation, higher quality embryos may have been available for transfer). To examine associations between the number of embryos transferred during IVF and live-birth and multiple-birth rates stratified by maternal age and whether extra embryos were available (ie, extra embryos cryopreserved). Retrospective cohort of 300 US clinics reporting IVF transfer procedures to the Centers for Disease Control and Prevention in 1996. A total of 35554 IVF transfer procedures. Live-birth and multiple-birth rates (percentage of live births that were multiple). A total number of 9873 live births were reported (multiple births from 1 pregnancy were counted as 1 live birth). The number of embryos needed to achieve maximum live- birth rates varied by age and whether extra embryos were cryopreserved. Among women 20 to 29 years and 30 to 34 years of age, maximum live-birth rates (43 % and 36%, respectively) were achieved when 2 embryos were transferred and extra embryos were cryopreserved. Among women 35 years of age and older, live-birth rates were lower overall and regardless of whether embryos were cryopreserved, live-birth rates increased if more than 2 embryos were transferred. Multiple-birth rates varied by age and the number of embryos transferred, but not by whether embryos were cryopreserved. With 2 embryos transferred, multiple-birth rates were 22.7%, 19.7%, 11.6%, and 10.8% for women aged 20 to 29, 30 to 34, 35 to 39, and 40 to 44 years, respectively. Multiple-birth rates increased as high as 45.7% for women aged 20 to 29 years and 39.8% for women aged 30 to 34 years if 3 embryos were transferred. Among women aged 35 to 39 years, the multiple-birth rate was 29.4% if 3 embryos were transferred. Among women 40 to 44 years of age, the multiple-birth rate was less than 25% even if 5 embryos were transferred. Based on these data, the risk of multiple births from IVF varies by maternal age and number of embryos transferred. Embryo quality was not related to multiple birth risk but was associated with increased live-birth rates when fewer embryos were transferred.
InfertilityCost of TreatmentInsurance Coverage AnalysisCost Analysis
To assess the total costs of infertility coverage, determine the proportion of healthcare costs related to infertility, compare infertility costs to those of other diseases, and calculate a per member per month cost of an infertility benefit. Historical prospective analysis. A university-based, self-insured, fee-for-service healthcare plan. PATIENT(S): Healthcare policy members from January 1993 through December 1995. INTERVENTION(S): General and infertility-specific healthcare that included diagnostic tests for infertility, induction of ovulation, artificial insemination, donor gametes, in vitro fertilization, gamete intrafallopian transfer, zygote intrafallopian transfer, microsurgical epididymal sperm aspiration, embryo cryopreservation, and frozen embryo transfer. MAIN OUTCOME MEASURE(S): Healthcare costs, as calculated from the International Classification of Diseases, Volume 9 codes. RESULT(S): Total healthcare and infertility-specific costs of the university healthcare plan over a 3-year period were $86,445,642 and $680,921, respectively. Therefore, infertility accounted for 0.79% of the total university healthcare costs. The mean total and infertility-specific per member per month healthcare costs were $86.15 and $0.67, respectively. CONCLUSION(S): These data reveal that infertility costs account for only a small fraction of the total healthcare costs and can be attained at a nominal monthly fee.
InfertilityFetal Loss RiskRecurrent Pregnancy LossPredictors of Outcome
The aim of this study was to examine the separate and joint effects of previous pregnancy history, year of pregnancy outcome, maternal age, height, smoking and fertility on risk of fetal death. Data were available from a study of female radiographers. Analyses were carried out on 3053 women with a total of 6993 pregnancies. Women reporting problems with conception or previous fetal losses had an increased risk of a pregnancy ending in a fetal death. In particular, women with primary or secondary infertility had an approximately fourfold increase in risk compared with women who reported no difficulties [odds ratio (OR): 3.92; 95% confidence interval (CI): (3.02, 5.07)]. This relationship was independent of pregnancy order and pregnancy history and was more marked in older maternal ages. The effect of pregnancy history was cumulative and possibly multiplicative in effect, with a threefold increase in the risk of losing a third pregnancy following two previous losses [OR: 3.19; 95% CI: (1.60, 6.35)]. There were no consistent patterns of risk associated with year of pregnancy outcome, maternal age, height or smoking status. These results suggest that previous pregnancy outcomes and problems with conception may be the strongest determinants of fetal loss in subsequent pregnancies.
Doctors love conventions. They have them in exotic places and they frequently use them to defend what would otherwise be inexplicable calculations. Thus 38 weeks of true gestation is, of course, 40 weeks of amenorrhoea, which may also be viewed as 38–40 weeks of pregnancy if timing is based on a “conventional” menstrual cycle. Even if this leaves the outside world to wonder, the clinicians understand. Many of the proponents of such ambiguity have moved away from obstetrics into reproductive medicine but have carried with …
PregnancyHypertensive DisordersDonor Gamete OutcomesImmunological Factors in Preeclampsia
Pregnancies achieved from oocyte, sperm or embryo donation are unique, since they have resulted from donor gametes that are immunologically foreign to the mother. Thus, studying the obstetric outcome of such pregnancies may shed some light on the pathophysiology of preeclampsia, particularly in women conceiving with donated embryos, since the entire fetal genome is allogenic in these pregnancies. In this retrospective cohort study, a total of 144 women were studied. Of these, 72 were infertility patients who had conceived as a result of sperm, ovum or embryo donation and the other 72 women were age- and parity-matched control patients who became pregnant with their own gametes, either spontaneously, or following intrauterine insemination with their partner's spermatozoa. Study patients were divided into three groups depending on the origin of the donated gametes. Group 1 consisted of pregnancies achieved by intrauterine insemination with washed donor spermatozoa (n = 33). Group 2 included women who conceived using donated oocytes (n = 27) and group 3 consisted of women who conceived as a result of embryo donation (n = 12). The incidence of pregnancy-induced hypertension in the donated gametes study group was 12.5% (9/72) compared with 2.8% (2/72) in the control group. In addition, pre-eclampsia was diagnosed in 18.1% (13/72) of the donated gametes study group compared to 1.4% (1/72) in the age- and parity-matched controls. The increased incidence of gestational hypertension in pregnancies resulting from donated gametes gives evidence for a maternal genetic component, with an equally strong fetal influence, in the complicated aetiology of gestational hypertension, and pre-eclampsia in particular.
InfertilityOvarian Cancer RiskOvarian Cancer Genetics
A genetic mechanism may be responsible for the increased incidence of ovarian cancer in some infertile women (ie, those who failed to conceive despite treatment).
To assess the intratubal pressure (ITP) and patency status of the fallopian tubes before and after transcervical catheterization of the fallopian tubes (TCFT). Prospective procedural assessment. Pope Paul VI Institute for the Study of Human Reproduction. PATIENT(S): Two hundred thirty-four women with either primary or secondary infertility. INTERVENTION(S): Patients underwent selective hysterosalpingography and, in some cases, TCFT with measurement of the ITP before and after the procedure. MAIN OUTCOME MEASURE(S): The ITP before and after TCFT. RESULT(S): The mean (+/-SD) ITP in freely patent tubes was 0.53 +/- 0.06 atm, that in partially obstructed tubes was 1.23 +/- 0.52 atm, and that in completely obstructed tubes was 2.79 +/- 1.40 atm. After TCFT, the mean (+/-SD) ITP in partially obstructed tubes decreased to 0.64 +/- 0.31 atm and that in completely obstructed tubes decreased to 1.86 +/- 1.35 atm. The ITP was normalized in 76% of partially obstructed tubes and in 29.5% of completely obstructed tubes. In all cases of complete obstruction in which surgical correction was attempted, organic pathology was identified. CONCLUSION(S): The procedure described is a safe and easy means of obtaining reliable and significant information on the status of the proximal fallopian tube.
InfertilityL-Arginine SupplementationTreatment StrategiesUterine and Follicular Blood Flow
The objective of the present study was prospectively and randomly to evaluate the role of L-arginine in improving uterine and follicular Doppler flow and in improving ovarian response to gonadotrophin in poor responder women. A total of 34 patients undergoing assisted reproduction was divided in two groups according to different (i) flare-up gonadotrophin-releasing hormone analogue (GnRHa) plus elevated pure follicle stimulating hormone (pFSH) (n = 17); and (ii) flare-up GnRHa plus elevated pFSH plus oral L-arginine (n = 17). During the ovarian stimulation regimen, the patients were submitted to hormonal (oestradiol and growth hormone), ultrasonographic (follicular number and diameter, endometrial thickness) and Doppler (uterine and perifollicular arteries) evaluations. Furthermore, the plasma and follicular fluid concentrations of arginine, citrulline, nitrite/nitrate (NO2-/NO3-), and insulin-like growth factor-1 (IGF-1) were assayed. All 34 patients completed the study. In the L-arginine treated group a lower cancellation rate, an increased number of oocytes collected, and embryos transferred were observed. In the same group, increased plasma and follicular fluid concentrations of arginine, citrulline, NO2-/NO3-, and IGF-1 was observed. Significant Doppler flow improvement was obtained in the L-arginine supplemented group. Three pregnancies were registered in these patients. No pregnancies were observed in the other group. It was concluded that oral L-arginine supplementation in poor responder patients may improve ovarian response, endometrial receptivity and pregnancy rate.
Reproductive EndocrinologyRoutes of AdministrationClinical ApplicationsVaginal Progesterone
Progesterone is the natural progestagen produced by the corpus luteum during the luteal phase. It is absorbed when administered orally, but is greater than 90% metabolized during the first hepatic pass. This greatly limits the efficacy of once-daily administration and also results in unphysiologically high levels of progesterone metabolites, particularly those reduced at the 5-a position. These metabolites can cause dizziness and drowsiness to the point of preventing the operation of a motor vehicle. Synthetic progestins, such as medroxyprogesterone acetate and norethindrone acetate (NETA), have been specifically designed to resist enzymatic degradation and remain active after oral administration. However, these compounds exert undesirable effects on the liver and often cause severe psychological side effects. The permeability of the skin does not allow for administration of progesterone in the quantities normally produced by the corpus luteum, i.e., up to 25 mg/day during the mid-luteal phase. To avoid this problem, synthetic progestins such as NETA have been administered transdermally. These compounds, though, just like synthetic estrogens administered non-orally, retain undesirable hepatic effects even when administered transdermally. Transvaginal administration of progesterone is a practical non-oral route available for administering progesterone. Early experience was gained with vaginal suppositories, which lack manufacturing controls. Recently, a new progesterone gel formulation has been designed for vaginal use. The clinical acceptability of this product has been enhanced by the bioadhesive characteristics of its polycarbophil-based gel, which conveys controlled and sustained-released properties. Investigations have shown that because of local direct vagina-to-uterus transport, which results in a preferential uterine uptake of progesterone, this formulation given in conjunction with physiological amounts of estradiol produces endometrial changes similar to those seen in the luteal phase, despite plasma progesterone levels that remain subphysiologic. Studies in infertility show that vaginal progesterone in this form allows secretory transformation of the endometrium and the development of pregnancy despite providing low systemic progesterone concentrations. Fewer side effects occur when used for hormone replacement than typically encountered with progestins and oral progesterone. Uses in patients with infertility and hypoestrogenism and secondary amenorrhea are reviewed.
InfertilityHydrosalpinx Impact on IVFPregnancy and Implantation RatesReproductive Outcomes
This meta-analysis was intended to evaluate differences in pregnancy rates after in-vitro fertilization (IVF) in tubal fertility with and without hydrosalpinx. It examined nine published retrospective comparative series and five series published as abstracts for which additional information was obtained. In all, these studies involved 5592 patients (1004 with hydrosalpinx and 4588 with tubal infertility without hydrosalpinx). The main outcome measures were rates of pregnancy, implantation, live delivery, and early pregnancy loss. Pregnancy rates were significantly lower in 31.2% for the tubal sterility group without hydrosalpinx and 19.7% for the group with hydrosalpinx (odds 0.64; 95% 0.56, 0.74). Similarly, the implantation rate and the delivery rate per transfer in the hydrosalpinx group were only slightly more than half those of the non-hydrosalpinx group (implantation: 8.5 and 13.7%, respectively; 13.4 and 23.4%). The incidence of early pregnancy loss was also higher in the hydrosalpinx group (43.7%) than in the control group (31.1%). This meta-analysis makes it clear that hydrosalpinx present during IVF-embryo transfer has negative consequences on the rates of pregnancy, implantation, live delivery, and early pregnancy loss. It would be premature, nonetheless, to conclude that routine salpingectomy should be performed on all patients with hydrosalpinx.
To review the physiology, pathology, and treatment of proximal tubal disease. Relevant reports on the pathophysiology of proximal tubal disease were reviewed. All studies in English of microsurgery and macrosurgery, and of radiographic and hysteroscopic cannulation in women with proximal tubal blockage were identified through MEDLINE searches. All studies of therapy for proximal blockage that included pregnancy rates were considered. Series of sterilization reversals, series of unilateral or combined procedures, and series in which the location of tubal blockage was not given were excluded from the data analyses. Raw data were assessed for homogeneity, then standardized and pooled. Total and ongoing pregnancy rates after microsurgery and macrosurgery, as well as radiographic and hysteroscopic transcervical cannulation, were compared by the chi2 test. Relative risks for total and ongoing pregnancies were calculated for all treatment methods. RESULT(S): This meta-analysis suggests that, overall, microsurgical anastomosis results in higher total and ongoing pregnancy rates than macrosurgery or radiographic tubal cannulation. However, pregnancy rates in selected series of transcervical tubal cannulation are similar to those reported for microsurgery. CONCLUSION(S): Ongoing intrauterine pregnancy rates near 50% can be achieved in patients with proximal blockage of the fallopian tube. Selective salpingography and transcervical cannulation under fluoroscopic guidance are effective at establishing patency in appropriately selected patients and are less invasive and costly than the surgical alternatives.
InfertilityCancer Risk from Fertility DrugsBreast Cancer Risk FactorsLong-term Follow-up
To investigate a possible linkage between the use of fertility drugs for infertility and the risk of breast and ovarian cancers. Long-term, historic-prospective study. Fertility clinic in a university hospital. PATIENT(S): Files of 1,197 infertile women with a mean (+/- SD) follow-up of 17.9+/-5 years (21,407 person-years) were reviewed. Diagnoses, number of courses, and dosage of fertility drugs were extracted from the files. INTERVENTION(S): Cancers were identified by record linkage to the National Cancer Registry. Histopathologic reports and data on estrogen and progesterone receptors in breast cancer tissue were also reviewed. MAIN OUTCOME MEASURE(S): Standardized incidence ratio with 95% confidence interval (CI) were used for risk assessment. RESULT(S): Of 20 breast cancers (standardized incidence ratio, 1.40 [95% CI, 0.83-2.10]), 16 were detected among 780 women who had been exposed to 3,978 cycles of clomiphene citrate (CC) and/or hMG (standardized incidence ratio, 1.65 [95% CI, 0.94-2.68]). The standardized incidence ratio for this cancer was significantly increased only in patients with one or two CC treatments and a dose of < or =1,000 mg (2.6 [1.19-5.0] and 2.52 [1.21-4.64], respectively). Two cases of ovarian cancer (1 patient unexposed) were observed with no evidence of excessive risk. Six of the eight patients with data on estrogen and progesterone receptors were exposed to CC, and all tested positive for these receptors. CONCLUSION(S): An association between the use of fertility drugs and an increased risk of breast and ovarian cancers has not been confirmed.
InfertilityLuteal Phase SupportRoute of AdministrationIVF Protocols
To evaluate the efficacy of oral micronized progesterone compared with IM progesterone in oil for luteal support in patients undergoing IVF who are treated with a GnRH agonist. Randomized prospective clinical trial. University-based IVF center. PATIENT(S): Women <40 years of age who were undergoing IVF with luteal GnRH pituitary down-regulation. INTERVENTION(S): Patients were randomized to receive either oral micronized progesterone (200 mg three times daily) or IM progesterone (50 mg daily). MAIN OUTCOME MEASURE(S): Progesterone levels at standardized days 21 and 28, and pregnancy and embryo implantation rates. RESULT(S): Day 21 progesterone levels were 77.6+/-13.2 ng/mL in the IM group and 81.5+/-16.2 ng/mL in the oral group. Day 28 progesterone levels were 76.3+/-15.0 ng/mL in the IM group and 53.6+/-10.1 ng/mL in the oral group. The clinical pregnancy rates were 57.9% and 45.8% for the IM and oral groups, respectively. The implantation rate per embryo was significantly higher in the IM group (40.9%) than in the oral group (18.1%). CONCLUSION(S): When used according to our protocols, oral progesterone and IM progesterone result in comparable levels of circulating progesterone. However, oral progesterone results in a reduced implantation rate per embryo.
To investigate whether the timing of administration of clomiphene citrate (CC) affects hormone levels, follicular recruitment, reproductive end organs, and pregnancy rates. Prospective, randomized, double-blind trial. Academic center. PATIENT(S): Twenty-three patients with unexplained infertility. INTERVENTION(S): Twenty-three patients with unexplained infertility underwent 45 cycles of CC and IUI. For each cycle, patients were randomized either to receive 100 mg of CC on days 1-5 and placebo on days 5-9 (study group), or placebo on days 1-5 and CC on days 5-9 (control group). MAIN OUTCOME MEASURE(S): The difference in uterine artery PI, number of follicles, endometrial thickness, and pregnancy rates. RESULT(S): Gonadotropins and E2 levels, as well as uterine artery pulsatility index, were significantly higher in the study group on day 5. In addition, in the study group, a longer time interval existed between finishing CC and IUI (8 versus 6 days; MD = 2 days; 95% CI = 1-3) and the pregnancy rate was higher than in the control group (6 versus 0; OR = 15.1; 95% CI = 1.1-72.4). CONCLUSION(S): Clomiphene citrate commenced on day 1 of the menstrual cycle, rather than day 5, results in more rapid follicular growth, a longer CC-free period before IUI, and higher pregnancy rates. Although methodologically sound, our results should be taken with some degree of caution because they are based on a relatively small number of patients.
A variety of embryo-based technologies used in farm animal reproduction, including embryo culture, nuclear transfer, embryo-somatic cell co-culture and asynchronous embryo transfer can lead to the production of large offspring; the so-called large calf/lamb syndrome. In some cases, abnormalities in the fetus and newborn are apparent. The nature of these associations is explored with emphasis on the biological differences between in-vivo- and in-vitro-produced embryos. A unifying framework and research programme aimed at explaining anomalies in early embryo development is then proposed in terms of the response of somatic cells and embryos to cellular stress. The review concludes with a caution against developments in assisted conception technologies, in man and domestic animals, being determined too much by the needs of commerce at the expense of research on the molecular, biochemical and physiological basis of early mammalian development.
Menstrual CycleCycle Length VariabilityMenstrual Cycle BiomarkersProspective Cohort Study
To characterize how the menstrual cycle pattern relates to fertility regardless of potential biases caused by inappropriate coital timing during the menstrual cycle or early embryonal loss. Prospective follow-up study. Healthy couples recruited throughout Denmark. PATIENT(S): Two hundred ninety-five couples who were planning their first pregnancy were followed up from the discontinuation of birth control until a pregnancy was recognized within six menstrual cycles. Early embryonal losses were detected by changes in urinary hCG levels. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The probability of pregnancy occurring within one menstrual cycle (fecundity). RESULT(S): In women who had a cycle length that differed by >10 days from the usual cycle length, fecundity was approximately 25% that of women who had no variation (odds ratio 0.25, 95% confidence interval 0.09-0.68). When the combined effect of cycle variation and cycle length was assessed, cycle variation was a persistent strong predictor of fecundity. CONCLUSION(S): The mechanisms of the present findings probably are female functional disturbances in ovulation, conception, implantation, or sustained pregnancy, linked with variable menstrual cycle length. Thus, identification of medical and environmental causes of abnormal menstrual cycle patterns may provide clues to the causes of infertility. Moreover, the menstrual cycle pattern also should be taken into consideration in the clinical decision-making process.
To determine whether IVF or a standard infertility treatment algorithm results in better outcome and/or lower cost when used as first-line therapy for couples with infertility. Prospective, randomized clinical study. University-affiliated infertility clinic. PATIENT(S): Couples with newly diagnosed infertility and no prior treatment. INTERVENTION(S): Couples were randomized to undergo either IVF (group 1, n = 46) or a standard infertility treatment algorithm (group 2, n = 50) as initial therapy for infertility. MAIN OUTCOME MEASURE(S): Pregnancy rates and costs per couple, per month of treatment, and per pregnancy. RESULT(S): Pregnancy rates were higher in group 2 than in group 1. Costs per couple were not statistically different, although a trend toward higher costs was apparent in group 1, reflected by a higher median cost per clinical pregnancy established and a higher cost per month of treatment. Whereas cost differences between the groups diminished over time, pregnancy rates remained the same. CONCLUSION(S): In vitro fertilization currently does not represent an appropriate first-line treatment option for couples with infertility. The use of a standard infertility treatment algorithm results in a higher pregnancy rate and lower cost and therefore should be the preferred treatment approach.
Ethics/PhilosophyGamete DonationCommodification of ReproductionOocyte Donation
There is a growing threat to the practice of oocyte donation in the United States and all of us should take careful notice. This threat is posed by the escalating fees paid to young women for providing these services. I was shocked by the decision of St. Barnabas Medical Center in Livingston, New Jersey to double the compensation from the community standard of $2,500 to a startling $5,000 per cycle. These new fees were aggressively advertised throughout New Jersey and Manhattan in strategic periodicals, newspapers, and magazines. I was even more dismayed to see physicians and “ethicists” justifying the increase to the media (1) stating “there is nothing inherently wrong with bidding for human eggs.”
For years, I have advocated compensation to oocyte donors based upon time, effort, and risk of involvement. I have addressed this topic at speaking engagements and in position papers, typically defending the belief that physicians are capable of responsible restraint (2, 3). However, I have been increasingly concerned over the encroachment upon the traditional practice by both commercial enterprises and physician-led groups who have inflated the cost of donor compensation 500% in the past decade.
In most countries it is illegal to provide any compensation for oocyte donors. Many believe payment is inappropriate and many more agree that excessive compensation is ethically unacceptable, since it potentially exploits or even coerces young women to participate. Even if one considers the time spent traveling to the local office and waiting for an ultrasound exam to be “work,” donors now will be earning in excess of $300 per hour. I find it hard to believe that anyone thinks this “reasonable compensation” according to the recommendations of the Ethics Committee of the American Society for Reproductive Medicine (4).
If we are truly not guilty of “pimping for patients” (5) and if donors are not “selling eggs,” then we cannot justify another doubling of the compensation. I believe this is a flagrant violation of the Ethical Considerations of Assisted Reproductive Technologies issued in 1994 (4). What is most disappointing is that this violation comes from a highly respected group led by physicians held in esteem within our subspecialty, who stated in The New York Times “I’m not sure $5,000 is enough.” (1) I would ask them, “How much is enough?” Where does this stop and at what price to our patients and our profession? Inevitably, all of us will be forced to raise our compensation rates to meet this challenge. Most importantly, and most unfortunately, these expenses will have to be passed on directly to our patients, who are already spending considerable sums of money to seek this procedure.
I have always opposed government regulation and intervention, and I have often taken a public stand in defending our right to administer our own practices. However, for the first time in my career I am rethinking my position. If physicians are forced to drastically modify their practices to keep pace with commercial ventures or to compete with doctors whose modus operandi is “what the market will bear,” an approach to medicine so flagrantly greedy as to threaten the existence of the field, then I do believe it is time for regulation. These are truly sad events, and if we stand by and allow these changes to become standard operating procedure then we as professionals deserve the public criticism that will inevitably follow.
InfertilityGrief and DepressionCounseling InterventionsCoping Strategies
To identify the levels of grief and depression and the coping mechanisms of women with infertility problems who participated in in vitro fertilization (IVF) or ovulation-induction medication. Pretest and post-test data were obtained from 50 IVF and 50 ovulation-induction medication patients receiving treatment at two urban infertility centers. Both groups of women experienced measurable levels of grief and depression before, during, and after treatment. Higher scores on the Grief Experience Inventory were found for both groups of women when pregnancy did not occur. Age, reproductive problems, years infertile, financial impact, and number of past IVF cycles were not found to influence the reported grief or depression levels. Women in the IVF and ovulation-induction medication groups used isolation coping behaviors such as self-talk and sleep. Because of moderate to high levels of grief and depression, therapeutic counseling may be more effective if initiated before the infertility treatment. Women's present levels of distress and coping strategies should be assessed prior to initiating infertility treatment to provide the patients with opportunities to learn and practice new adaptive behaviors that could enhance their ability to cope with infertility and the associated medical procedures.
Hull MG et al., 1999·Endocrinol Metab Clin North Am
This article has provided outcome-based evidence using easily understood graphic representation of cumulative pregnancy rates whenever possible for the methods used to investigate and treat female infertility. A scheme of basic routine investigations in specialist practice is developed and clear guidance provided on the choice of treatment for each couple.
InfertilityOvarian CancerOvarian Cancer Risk FactorsCancer Risk
The possibility that ovulation induction increases the risk of ovarian cancer remains unproven. However, recent studies suggest that both infertility and endometriosis may be independent risk factors. Despite the various case reports and epidemiological studies performed the association between the use of infertility drugs and ovarian cancer remains weak. The fact that the women who were the first to use ovulation agents are now reaching mid-life means that future studies should show whether any association exists. Hence, there is a need now for large prospective trials to be performed to establish whether an association between ovulation induction agents and ovarian cancer truly exists.
American Society for Reproductive Medicine, 1998·J Assist Reprod Genet
A large part of infertility treatment involves the use of exogenous gonadotropins. The last decade has seen a progressive switch from human menopausal gonadotropin (hMG), the original gonadotropin product, to progressively more costly products, primarily or exclusively containing follicle-stimulating hormone (FSH). Though obviously at least in part driven by marketing efforts of pharmaceutical companies, this switch has received relatively little scrutiny despite its obvious cost implications. We therefore investigated whether a switch back to a generic or less costly hMG-driven ovulation induction protocol would affect patient outcome after ovulation induction and, by implications, with other assisted reproductive technologies. We prospectively studied clinical pregnancy rates in a large number of consecutive ovulation induction cycles in a well-defined patient population (group 1) which, after October of 1997, had been switched from a predominantly FSH to an hMG-driven protocol, based on an institutional formulary change. Until a transition period (between July and September 1997), this patient population had been on a primarily FSH-driven protocol (between July 1996 and June 1997). In parallel, we evaluated a second patient population (group 2), which was managed by the same physicians outside of formulary requirements and remained almost exclusively on principally FSH-driven ovulation induction cycles. FSHand hMG-driven ovulation induction protocols did not differ in pregnancy outcome during the prospective study period. Group 1 patients, however, demonstrated a significant increase in pregnancy rates after the switch from FSH to hMG stimulation had taken place (P = 0.02), while group 2 patients demonstrated no change in pregnancy rate during the same time period. Generic hMG products do not adversely affect pregnancy rates in comparison to more costly FSH products in routine ovulation induction cycles and should be considered an appropriate alternative to more expensive FSH products.
To investigate the incidence of complications in the use of assisted reproductive technology in the management of infertile couples. Retrospective study. The Egyptian IVF & ET Center, Maadi, Cairo, Egypt. PATIENT(S): Two thousand nine hundred twenty-four patients underwent IVF-ET or intracytoplasmic sperm injection (ICSI) in 3,500 cycles. INTERVENTION(S): IVF-ET, ICSI, ejaculate sperm, epididymal sperm aspiration, and testicular sperm extraction. MAIN OUTCOME MEASURE(S): Complications of the procedure and complications of pregnancy in 702 patients. RESULT(S): Fifteen hundred ovum pickups for IVF-ET and 2,000 ovum pickups for ICSI were performed. Clinical pregnancy occurred in 1,078 patients (30.8%). Four groups of complications were identified. Complications of the procedure occurred in 291 patients (8.3%). Complications of pregnancy included ectopic pregnancy in 1.9%, heterotopic pregnancy in 0.2%. abortion in 20.6%, multiple pregnancy in 28%, pregnancy-induced hypertension in 10%, preterm labor in 21.5%, low birth weight in 30.5%, and intrauterine death in 2%. Coincidental complications occurred in five patients (0.15%). Other complications that were difficult to measure included psychological breakdown and socioeconomic problems. CONCLUSION(S): Assisted reproductive technology is effective for the management of infertility and has an acceptable incidence of complications. Complications rarely endanger the life of the patient. When this line of treatment is offered, the indications should be definitive. Patients should be monitored properly and measures should be taken to minimize the incidence of complications.
InfertilityIVF OutcomesICSI vs Conventional IVFFollicular Development
Ovarian stimulation for in-vitro fertilization (IVF) causes development of several cohorts of follicles. At the time of oocyte collection, oocytes are thus retrieved from a wide range of follicles of different sizes and developmental stages. A relationship between size of follicles and pregnancy rates has earlier been demonstrated. The aim of the present study was to compare fertilization, cleavage and pregnancy rates between oocytes retrieved from large and small follicles in conventional IVF and intracytoplasmic sperm injection (ICSI). A total of 200 conventional IVF patients and 175 ICSI patients underwent oocyte retrieval where oocytes from both large and small follicles were collected. A follicle with a volume of > or = 2 ml, corresponding to a follicular diameter > or = 16 mm as determined by ultrasound, was regarded as a large follicle. Only one cycle from each patient was included. Fertilization and cleavage rates were calculated per patient for oocytes from large and small follicles. The mean fertilization and cleavage rates for conventional IVF and ICSI cycles were calculated. Comparison of pregnancy rates was performed for patients receiving embryos derived from oocytes of only large or only small follicles. For conventional IVF patients, fertilization rates were 71.4 and 58.1% (P < 0.01, Wilcoxon paired test) for oocytes of large and small follicles respectively. The corresponding cleavage rates were 95.4 and 93.9% respectively. The pregnancy rate for the two groups was 47% (60/127) and 15% (2/13) (P < 0.05, chi2 test). For ICSI patients the fertilization rate was 72.0 and 71.1% for oocytes of large and small follicles respectively. The corresponding cleavage rate was 93.0 and 91.1%. The pregnancy rate in the two groups was 41% (46/113) and 42% (5/12). The results show that oocytes from smaller follicles also yield fertilization and pregnancies, although in conventional IVF to a lesser extent than oocytes from larger follicles. For IVF cycles, a higher proportion of immature oocytes (which are normally not included in the ICSI procedure) in the group of oocytes from small follicles is most probably the explanation for the lower fertilization rate. The decrease in pregnancy rate with oocytes from small follicles in the IVF cycles was not observed in the ICSI cycles. The possibility of evaluating the degree of oocyte maturation prior to fertilization may be an advantage of the ICSI technique. This suggests that the disadvantages of oocytes from small follicles might be overcome by means of ICSI.
InfertilityPrevalence ProjectionsUnited States TrendsPopulation Estimates
Open Access
To project the number of infertile women aged 15-44 every 5 years from 2000 to 2025. Data are used from Cycle 5 of the National Survey of Family Growth conducted by the National Center for Health Statistics. Population projections prepared by the U.S. Bureau of the Census are used as the base population for 2000-2025. Prospective demographic projections are used to estimate the number of infertile women. The National Survey of Family Growth (Cycle 5) interviewed 10,847 women aged 15-44 in 1995. MAIN OUTCOME MEASURE(S): Number of infertile women. RESULT(S): The number of women experiencing infertility will range from 5.4-7.7 million in 2025, with the most likely number to be just under 6.5 million. CONCLUSION(S): This is a substantial revision (upward) in the number of infertile women, largely a result of the increase in the observed percentage of infertile women in 1995. This is the base population of concern to providers; of particular interest is the percentage of infertile women who seek medical treatment.
InfertilityCancer RiskEndometrial CancerOvarian and Endometrial Cancer
Among 2,496 infertile Israeli women treated between 1964 and 1974, 143 cancer cases were observed as compared with 116.1 expected (standardized incidence ratio (SIR) = 1.2, 95% confidence interval (CI) 1.0-1.5) through 1991. Site-specific analysis revealed 12 ovarian cancers versus 7.2 expected (SIR = 1.6, 95% CI 0.8-2.9), 21 endometrial cancers versus 4.3 expected (SIR = 4.85, 95% CI 3.0-7.4), and 59 breast cancers versus 46.6 expected (SIR = 1.3, 95% CI 0.96-1.6). Sensitivity analysis revealed that confounding was unlikely to explain the raised risk of endometrial cancer, but nulliparity might explain the increased risk of ovarian cancer. The excess of endometrial cancer was prominent among patients with normal estrogen production but progesterone deficiency (SIR = 9.4, 95% CI 5.0-16.0). The risk for ovarian cancer was similar among the total groups of treated and untreated patients (SIR = 1.7 vs. 1.6). The standardized incidence ratio for endometrial cancer was higher among the treated group than the untreated group, although not significantly. Treatment with ovulation-inducing drugs does not appear to increase the risk for ovarian cancer, but its role cannot be completely excluded.
InfertilityInsurance and Managed CareInfertility CoverageReproductive Technology Access
The birth of the McCaughey septuplets in Iowa in November 1997 brought issues of fertility assistance and their potential outcomes to worldwide attention. This Pergonal-stimulated multiple pregnancy ended successfully, but not without health hurdles and economic consequences for the new siblings and their family. This article reviews the general situation surrounding infertility services and, within the current debate of epidemiological, economic, legal and social issues, posits that managed care may be able to make greater strides than the present fee-for-service system in providing more accessible and comprehensive care to the 5.3 million US citizens at risk for infertility. Our conclusions suggest that managed care plans for infertility can aid in assuring quality and decreasing unnecessary costs. Managed care organizations should take the lead in providing infertile couples with an organized, humanistic approach that is mindful of the attending social issues. On May 5, 1997, a US District court in Chicago ruled that infertility fits the definition of a disability, and thus is subject to the antidiscrimination enforcement under the Americans with Disabilities Act.
Houston JG et al., 1998·Cardiovasc Intervent Radiol
To evaluate the technical success and outcome of fallopian tube recanalization (FTR) in salpingitis isthmica nodosa (SIN). SIN is a well-recognized pathological condition affecting the proximal fallopian tube and is associated with infertility and ectopic pregnancy. We reviewed the presentations, films, and case records of all patients attending for FTR for infertility from 1990 to 1994. Technical success and total, intrauterine, and ectopic pregnancy rates at follow-up were determined. SIN was observed in 22 of 349 (6%) patients. FTR was attempted in 34 tubes in these 22 patients. Technical success was achieved in 23 of 34 (68%) tubes affected by SIN. In 5 of the 11 failed recanalizations, failure was due to distal obstruction. At least one tube was patent on selective postprocedural salpingography in 17 of 22 (77%) patients. There were no recorded perforations or complications. At follow-up (mean 14 months), total, intrauterine, and ectopic pregnancy rates were 23%, 18%, and 4.5%, respectively. FTR in SIN is technically successful and, compared with previously reported results in unselected infertility patients, is associated with only a slightly less favorable intrauterine pregnancy rate and a comparable ectopic pregnancy rate. The findings of SIN at FTR should not discourage attempted fluoroscopic transcervical recanalization.
InfertilityPopulation Trends in FecundityAge and Delayed ChildbearingNational Survey of Family Growth
The 1995 National Survey of Family Growth (NSFG) provides new nationally representative data to test the accuracy of the commonly held assumption that impaired fecundity has been rising in the United States over the past decade. Using data from the 1982, 1988 and 1995 rounds of the NSFG, trends in both the proportions and numbers of women with impaired fecundity and of those who received infertility services were examined. Multiple logistic regressions were carried out to estimate the effects of demographic characteristics on the likelihood of currently having impaired fecundity and of ever having received medical help for infertility. The proportion of U.S. women aged 15-44 who reported some form of fecundity impairment rose from 8% in 1982 and 1988 to 10% in 1995, an increase in absolute numbers from 4.6 million to 6.2 million women. Although the proportion of fecundity-impaired women who had ever sought medical help did not change between 1988 and 1995 (44%), the absolute numbers of such women grew by nearly 30%, from 2.1 million to 2.7 million. Women who had ever sought help for fertility problems were older and had a higher income than those who had not, and were more likely to be married. The dramatic increase in the numbers of U.S. women with impaired fecundity occurred because the large baby-boom cohort, many of whom delayed childbearing, had reached their later and less fecund reproductive years. This increase in both rates and numbers occurred across almost all age, parity, marital status, education, income, and race and ethnicity subgroups.
To evaluate the expression of alpha6 and beta4 integrin subunits on surface and glandular endometrium throughout the menstrual cycle and during early pregnancy. Second Department of Obstetrics and Gynecology, University of Catania, Catania, Italy. PATIENT(S): Thirty-two women. Nineteen of the women regularly menstruated in different phases of the cycle, and 13 were in the sixth to ninth week of gestation and required voluntary abortion. INTERVENTION(S): Endometrial specimens collected during endometrial biopsy, hysterectomy, or voluntary abortion. MAIN OUTCOME MEASURE(S): Immunohistochemical staining for alpha6 and beta4 integrin subunits in endometrial tissues. RESULT(S): Both subunits (poorly expressed in preimplantation days) reached a significant peak on the endometrial surface during the implantation window, which tended to disappear in the postimplantation phase. On glandular endometrium they exhibited an opposite trend, showing high levels in the preimplantation and postimplantation days, whereas their expression decreased during the implantation window. The two subunits tended to disappear in early pregnancy. CONCLUSION(S): alpha6 and beta4 integrin subunits are uniformly distributed and highly expressed on the endometrial surface during the implantation window; they decreased dramatically in the postimplantation phase. These results could suggest involvement of integrin-extracellular matrix components in blastocyst-endometrium interaction during the early stages of implantation.
Neonatal outcome of in vitro fertilization (IVF) pregnancies has been described by different authors, but several issues have yet to be resolved. The aim of the present study was to evaluate neonates conceived in vitro and to direct special attention to neonatal morbidity and prevalence of minor abnormalities. The information that has been accumulated so far is scant. The first 100 babies conceived in vitro, and subsequently born in our institute, were investigated and compared with the general, spontaneously conceived newborn population. All infants were examined by a senior neonatologist, and the data that were recorded included gestational age at delivery, birth weight, gender, major malformations, minor congenital abnormalities, neonatal mortality, and neonatal morbidity (including asphyxia, jaundice, meconium aspiration, hypoglycemia, and hypocalcemia). The data indicate that the IVF neonates assessed had a higher rate of low birth weight (37%), twinning (30%), and preterm birth (20%) in comparison with the general reference population (p < 0.05). However, no differences were encountered either in the rate of small for gestational age infants or the incidence of major malformations and minor abnormalities between these groups of newborns. The overall neonatal morbidity in IVF babies was found to exceed that of the general population. Nevertheless, at birth, there were no clinical pathognomonic signs typical of IVF babies, although more detailed metabolic, endocrine, and neurobehavioral studies are still required to confirm that newborns conceived in vitro do not differ from those conceived spontaneously in any of these respects.
To assess the effect of insulin-lowering treatment on menstrual cyclicity in polycystic ovary syndrome (PCOS). Forty oligoamenorrheic women with PCOS were recruited in a prospective clinical study to receive metformin for a minimum period of 6 months. Twenty-two women completed the study. Serum LH, FSH, free testosterone, and glucose and insulin response to oral glucose load were measured both before and after 8 weeks of metformin treatment. Menstrual cyclicity and serum progesterone levels at the midluteal phase were assessed at the 30th week of metformin treatment. Twenty-one of 22 women had restoration of menstrual cyclicity (95.7%). Four of these women (19%) became pregnant within the 6th and 7th months of treatment. All four of the pregnant women delivered, and the infants were healthy. Thirteen of 15 women who had regular menses demonstrated a serum progesterone level within the ovulatory range (3.1-28 ng/mL). Fasting (P < .001) and the integrated insulin response to the glucose load decreased (P < .001) after 8 weeks of metformin treatment. This was accompanied by significant decreases in serum LH (P < .001) and free testosterone (P < .001) levels and LH/FSH ratio (P < .001). There was a small but significant reduction in body mass index after 8 weeks of metformin treatment (P < .001). A 6-month course of metformin may improve menstrual cyclicity and fertility in women with the PCOS. Insulin-sensitizing agents provide a rational approach to the treatment of the metabolic and endocrine abnormalities in PCOS women.
Reports suggest that there is an increased incidence of preeclampsia after a previously normal pregnancy if there is a change in paternity. We hypothesize that there is a higher incidence of preeclampsia (proteinuric hypertension) in women conceiving by intrauterine insemination with donor sperm versus intrauterine insemination with partner sperm. This was a retrospective cohort study. In women with primary infertility all pregnancies achieved by either partner or donor intrauterine insemination carried to birth of a fetus (> 20 weeks) were identified. The medical records were examined for the maternal and pregnancy outcome data. The relative risk and 95% confidence interval were calculated for the risk of preeclampsia. The baseline data were compared with t tests, chi 2 analysis and Fisher's exact test where appropriate. Forty-four patients in the partner intrauterine insemination group and 37 in the donor insemination group were identified as having primary infertility. Three cases of mild preeclampsia were found in the partner insemination program and nine cases of preeclampsia (five severe, four mild) in the donor insemination program (relative risk 1.85, 95% confidence interval 1.20 to 2.85). There is a higher incidence of preeclampsia in women conceiving by intrauterine insemination with washed donor sperm compared with intrauterine insemination with washed partner sperm. This supports, indirectly, an immunologic basis for preeclampsia. The antigenic factor would appear to be located on the sperm as opposed to the seminal fluid itself.
Body LiteracyFertility Awareness KnowledgeFertile Window UnderstandingConception Timing Knowledge
Eighty women attending for consultation at a tertiary referral fertility unit over a 3-month period were surveyed for their knowledge of fertility awareness and how they used this information to enhance their chances of conception. It was hypothesized that less than 50% of the subjects had an adequate understanding of when the fertile time occurred in their menstrual cycle. A questionnaire was completed anonymously by each subject and these were scored in 3 categories for fertility awareness by 2 independent Natural Family Planning teachers. Scores ranged from 0 for women who had no concept of fertility awareness, to 6 for women who were highly aware. The results showed that 26% (N = 21) of subjects had a score of 4 or greater which was considered as having an adequate understanding. The hypothesis was accepted, giving reason for concern about the effectiveness of consumer education at all levels of fertility investigation.
Patients suffering from normogonadotrophic anovulation and infertility are initially treated with clomiphene citrate. Those who do not respond to clomiphene citrate usually receive gonadotrophin treatment which is labour-intensive, expensive, and associated with an increased risk of multiple pregnancies and ovarian hyperstimulation syndrome. We treated 22 patients with clomiphene resistant normogonadotrophic anovulation with naltrexone (an opioid receptor blocker) alone or naltrexone in combination with an antioestrogen. In 19 patients ovulation and resumption of a regular menstrual cycle was achieved and in 12 out of 19 a singleton pregnancy was observed. In conclusion, ovulation can be induced successfully using naltrexone alone or naltrexone in combination with an anti-oestrogen in clomiphene citrate resistant anovulatory patients. Compared to gonadotrophin induction of ovulation, this method is safe, simple and inexpensive.
InfertilitySexually Transmitted InfectionsSexually Transmitted DiseasesSTD Detection and Treatment
The worldwide incidence of sexually transmitted diseases (STDs) including the human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) continues to increase and represents a major public health problem especially in the developing world causing infertility and ectopic pregnancy. Prevention of the spread of STDs, along with early detection and appropriate therapy has the potential to minimize the reproductive tract damage of these infections and simultaneously improve the health of women in all areas of the world.
EndometriosisLaparoscopic AssessmentPelvic Pain AssociationEndometriosis and Pelvic Pathology
Thornton JG et al., 1997·Eur J Obstet Gynecol Reprod Biol
To measure the relationship between laparoscopically detected pelvic pathology and pelvic pain or infertility. Women undergoing diagnostic laparoscopy either for the investigation of pelvic pain, for sterilisation or for the investigation of infertility were studied. The indication for surgery was recorded before laparoscopy. At operation a series of 35-mm slide photographs were taken of the pelvis and later scored by two independent assessors without knowledge of the indication for surgery. Satisfactory photographs were obtained in 298 women. Minimal endometriosis was not associated with pain (adjusted OR 1.3; 0.5-2.8), although moderate disease was non-significantly so (2.5; 0.4-7.1). Severe disease was significantly more common and never occurred in patients being sterilised (P = 0.02). The odds of pain were not increased in the presence of dilated veins > 9 mm diameter (OR 1.1; 0.4-3.2) or adhesions (OR 0.6; 0.2-4.7). The odds of infertility were non-significantly increased in the presence of minimal and moderate endometriosis (OR 2.0; 0.8-5.3, and OR 4.2; 0.6-25 respectively) and again significantly more common in the presence of advanced disease (P = 0.002). The odds of infertility tended to be lower in the presence of severely dilated veins (OR 0.2; 0.032-1.2). There was no clear effect of adhesions (OR 0.9; 0.1-5.9). The long established associations between severe endometriosis and pelvic pain, and between endometriosis in general and infertility are confirmed. However there is little or no association between minimal endometriosis, pelvic adhesions or dilated pelvic veins and pain. Previously reported associations may have been an artefact of the surgeon's knowledge of the indication for operation when assessing the pelvis.
Menstrual CycleThyroid-Related Menstrual DisturbancesEffects on MenstruationThyroid Dysfunction and Anovulation
Both hyperand hypothyroidism may result in menstrual disturbances. In hyperthyroidism, amenorrhea was described as early as 1840 by von Basedow. The most common manifestation is simple oligomenorrhea (decreased menstrual flow). Anovulatory cycles are very common. Increased bleeding may occur, but is rare in hyperthyroidism. Nowadays hyperthyroidism is diagnosed earlier than it once was, and so the clinical picture is generally milder. So, menstrual disorders are less common than in previous series. In a recent paper, 21.5% of 214 patients had disturbances in their cycle, compared to 50% in some older series. In hypothyroidism, on the contrary, polymenorrhea (increased menstrual bleeding) is more common. Defects in hemostasis may contribute to this. Anovulation may be represent. Fertility is reduced in both hyperand hypothyroidism, and the outcome of pregnancy is more often abnormal than in euthyroid women. It is of interest that in juvenile hypothyroidism precocious puberty has been described. This is probably due to a "spillover" effect TSH,
Progesterone is a known immunosupressant in humans and may be important in treatment regimens for women with immunological and endocrinological reproductive failure. The molecular mechanism of progesterone-mediated immunosuppression remains controversial. We used the reverse transcriptase polymerase chain reaction (RT-PCR) technique to detect progesterone receptor RNA in human peripheral blood mononuclear cells (PBMCs). No expression could be documented in PBMCs from men or women representing various reproductive states. We also used the glucocorticoid receptor antagonist RU 43044 to address the hypothesis that progesterone exerts immunomodulatory effects via interactions with the glucocorticoid receptor. Both hydrocortisone (10(-6) and 10(-7) M) and progesterone (10(-5), 10(-6) and 10(-7) M) inhibited phytohaemagglutinin-induced lymphocyte proliferation in a dose-dependent fashion. RU 43044 (10(-5) M) significantly reversed the immunosuppressive effect od hydrocortisone but not that of progesterone. These studies indicate that human PBMCs do not express the classical progesterone receptor. Our results further suggest that progesterone does not mediate its immunomodulatory effects via interaction with the glucocorticoid receptor. Interaction with other members of the steroid and thyroid hormone receptor superfamily, local conversion to other steroid substances or non-classical receptor-mediated mechanisms may be involved.
To determine whether singleton IVF pregnancies carry adverse maternal or fetal outcome when compared with naturally conceived gestations. An analysis of the obstetric outcome of singleton IVF pregnancies in comparison with matched, naturally conceived singleton controls. In vitro fertilization unit and obstetric service at a tertiary medical center. PATIENT(S): Two hundred sixty consecutive singleton IVF pregnancies and 260 naturally conceived singleton controls matched 1:1 for maternal age, parity, ethnic origin, and location and date of delivery. INTERVENTION(S): In vitro fertilization-ET. MAIN OUTCOME MEASURE(S): The rate of antenatal obstetric complications, nonvertex presentation, cesarean section, preterm labor, low birth weight, small and very small for gestational age, neonatal intensive care unit admissions, and perinatal mortality. RESULT(S): The rates of most antenatal complications were similar in both groups. Urinary tract infection was the only complication diagnosed significantly more frequently after IVF (7.3% versus 1.2%); however, the rates of severe urinary tract infection necessitating hospitalization were similar. The incidence of nonvertex presentation was also similar. The cesarean section rate was significantly higher among IVF patients (41.9% versus 15.5%). The rates of preterm labor, low birth weight, small and very small for gestational age, neonatal intensive care unit admissions, and perinatal mortality were comparable. CONCLUSION(S): When controlling for maternal age, parity, ethnic origin, and location and date of delivery, singleton IVF pregnancies do not carry an increased risk for prematurity, low birth weight, or maternal or fetal complications. Still, these pregnancies are associated with a high rate of cesarean sections.
To evaluate effectiveness and safety of a regimen of extended clomiphene citrate (CC) and prednisone for patients who fail treatment with CC alone. Retrospective observational analysis. University-based tertiary infertility center. PATIENT(S): Twenty-four anovulatory patients who failed to ovulate after CC 150 mg administered for 5 days. INTERVENTION(S): Treatment consisted of CC given on cycle days 3 through 9 (extended) at a starting dose of 100 to 150 mg/d. Additionally, patients were given prednisone 5 mg orally each night throughout the cycle. MAIN OUTCOME MEASURE(S): Ovulation was confirmed by luteal serum P. Pregnancy was confirmed by rising hCG levels and transvaginal ultrasound. RESULT(S): A total of 60 cycles were available for review. Forty-four of these cycles were ovulatory (73%) and 11 patients (46%) conceived on this therapy. Logistic (two-parameter) pregnancy occurrence over time (cycles) revealed a maximum pregnancy probability of 0.66 and a cycle fecundity of 0.36. No complications of therapy were noted. CONCLUSION(S): Clomiphene citrate-resistant anovulatory patients have high rates of ovulation and pregnancy after treatment with extended CC and prednisone. This therapy offers a potential reduction in cost and risk and should be considered in this group of patients before gonadotropin stimulation or surgery.
To test whether subfertile women may be at higher risk of preterm delivery. We used data from two population-based cohort studies on risk factors and pregnancy outcome for approximately 20,000 deliveries in three major Danish obstetric departments. The Aalborg-Odense study comprised all pregnant women attending routine antenatal care at two obstetric departments from 1984 to 1987. In all, 11,850 women (86%) filled in a questionnaire at about 36 weeks' gestation. The Aarhus study addressed women at the routine visit near 16 weeks' gestation from 1989 to 1991; a study questionnaire was returned by 6857 (80%). Both studies excluded women with chronic illnesses, multiple fetuses, and inability to speak Danish. Only women with planned pregnancies were included in the analysis. In all, 8855 and 3985 women from Aalborg-Odense and Aarhus, respectively, were eligible for the analyses. In both cohorts, women were categorized according to their waiting time to pregnancy (0-6 months, 7-12 months, and greater than 1 year) and according to examination or treatment for infertility (yes, no). Preterm delivery was defined as birth before 37 completed weeks. Compared with women who tried for 6 months or less before they conceived, women who tried for 7-12 months had 1.3 times (95% confidence interval [CI] 0.8, 2.1) the adjusted risk of preterm delivery in both cohorts, and women with a time to pregnancy of greater than 12 months had adjusted relative risks for preterm delivery of 1.6 (95% CI 1.1, 2.2) for Aalborg-Odense and 1.7 (95% CI 1.1, 2.6) for Aarhus. The results remained similar after excluding women with infertility treatment. Pregnant women with subfertility and clinically defined infertility are more prone to preterm delivery, even in the absence of infertility treatment.
PCOSUltrasound vs Endocrine CriteriaTransvaginal UltrasoundNormogonadotropic Oligomenorrhea
To investigate the predictive value of polycystic ovaries for endocrine signs of polycystic ovary syndrome (PCOS). Controlled descriptive study. Academic tertiary care fertility clinic. PATIENT(S): Normogonadotropic (FSH levels between 1 and 10 mIU/mL conversion factor to SI unit, 1.0) oligomenorrheic or amenorrheic women visiting our fertility clinic and a control group of regularly cycling, healthy, normal weight volunteers recruited by advertisement. INTERVENTION(S): Single blood samples and transvaginal sonography were performed. MAIN OUTCOME MEASURE(S): Serum levels of FSH, LH, androstenedione (A), and T and ovarian volume, ovarian stroma density, and follicle number. RESULT(S): In control women, the 95th percentile was calculated for ovarian volume, follicle number, and stroma count as well as endocrine parameters. The use of these upper limits of normal in the study group resulted in 217 (66%) patients with polycystic ovaries on ultrasound (defined as increased mean ovarian volume and/or mean follicle number per ovary), whereas only 120 (36%) patients exhibited elevated serum androgens (increased A and/or T concentrations) and 155 (47%) showed elevated LH levels. Sensitivity and specificity of single or combined sonographic parameters for prediction of elevated serum LH or androgen concentrations were limited. CONCLUSION(S): In the study group of normogonadotropic oligomenorrhea or amenorrheic infertile women, we set strict cutoff levels for various criteria used in the literature for defining PCOS. Groups defined by sonographic or endocrine PCOS criteria did overlap, but sonographic parameters had limited predictive value for abnormal hormone serum levels.
To evaluate the luteal phase in women with rigorously defined unexplained infertility. Prospective study. National Center for Infertility Research at Michigan. PATIENT(S): Evaluation of 1,885 women with infertility identified 12 women who met the rigorously defined criteria [1] infertility of > or = 24 months duration, with no male factor, anatomic-functional disorders of the reproductive tract, or immunologic infertility; [2] normal body mass index (BMI); [3] ovulatory cycles ranging from 26 to 32 days; [4] normal luteal phase determined by endometrial biopsy; and [5] normal baseline hormonal profile. Controls (n = 12) were healthy, parous women with normal ovulatory cycles, normal hormonal screen, and were matched for age and BMI to patients. MAIN OUTCOME MEASURE(S): Pattern of follicular growth rate and luteal phase hormonal profile. RESULT(S): Women with unexplained infertility did not differ in menstrual cycle characteristics, follicular growth rate or mean preovulatory follicle diameter, or endometrial biopsy dating. The mean levels of P tended to be lower in the unexplained infertility group throughout the luteal phase, but only the midluteal interval reached statistical significance. Luteal phase mean integrated P or urinary PDG levels of unexplained infertility women did not differ from those of fertile controls. The ratio of integrated E2:P also was significantly greater in women with unexplained infertility than in fertile controls. CONCLUSION(S): Women with rigorously defined unexplained infertility have subtle hormonal anomalies during the luteal phase when compared with fertile controls.
InfertilityDiagnostic Testing PatternsReproductive EndocrinologyClinical Practice Variation
To determine how board-certified reproductive endocrinologists vary in their approach to the clinical tests performed on the infertile couple. A cross-sectional study to assess differences in the approach to evaluating the infertile couple. A population-based national survey. PARTICIPANT(S): United States board-certified reproductive endocrinologists. MAIN OUTCOME MEASURE(S): The frequency of clinical tests and evaluation procedures by physician age, sex, size and setting of practice, institutional affiliation, and geographic location. RESULT(S): The overall response rate was 84%. Although the majority of practitioners routinely order a semen analysis (99.9%), an assessment of ovulation (98%), a hysterosalpingogram, (HSG; 96%), laparoscopy (89%), and a postcoital test (PCT, 79%), there was less agreement regarding hormonal testing (range, 22% [LH] to 66% [PRL]), use of pelvic ultrasounds (55%), hysteroscopy (53%), cervical cultures (range, 24% to 54%), and antisperm antibody testing (24%). Compared with male colleagues, female physicians order two to three times more cervical cultures and endometrial biopsies. Serum hormonal testing was two to three times more commonly ordered by younger (< 40 years) compared with older physicians, and physicians in private practice twice as frequently ordered hormonal testing, cervical cultures, PCTs, and antisperm antibody studies compared with their academic-affiliated colleagues. Western U.S. physicians order hormonal tests and cervical cultures 50% less often than their midwest and eastern counterparts. CONCLUSION(S): Trained specialists rely heavily on five "traditional" semen analysis, an assessment of ovulation, HSG, laparoscopy, and PCT. With regard to additional modes of testing, there is marked variability by physician sex, age, type of practice, and geographic location.
InfertilityHysterosalpingographyRadiation Exposure SafetySelective Salpingography and Catheterization
To evaluate the risk of radiation exposure to infertility patients during a gynecoradiologic procedure. Retrospective clinical study. Medical school-affiliated infertility center. PATIENT(S): Three hundred thirty-two consecutive infertility patients undergoing a gynecoradiologic procedure. INTERVENTION(S): Patients underwent a gynecoradiologic procedure as part of their infertility workup and the fluoroscopic exposure time was analyzed. MAIN OUTCOME MEASURE(S): The fluoroscopic exposure (rad time) during gynecoradiologic procedures, including hysterosalpingogram (HSG), selective salpingography, tubal catheterization, and others. RESULT(S): The rad time (mean +/- SD) was 63 +/- 54 seconds for normal HSG (n = 94, range 17 to 404 seconds), 100 +/- 61 seconds for abnormal HSG (n = 53, range 28 to 272 seconds), 111 +/- 57 seconds for unilateral selective salpingography (n = 36, range 31 to 324 seconds), 142 +/- 74 seconds for bilateral selective salpingography (n = 87, range 40 to 430 seconds), 176 +/- 77 seconds for unilateral tubal catheterization (n = 27, range 70 to 342 seconds), and 239 +/- 82 seconds for bilateral tubal catheterization (n = 30, range 110 to 381 seconds). Five patients had other procedures, such as lysis of intrauterine adhesions (n = 2) and resection of an uterine septum (n = 3), for which the rad time was in a range of 180 to 300 seconds. CONCLUSION(S): The radiation exposure of patients during a gynecoradiologic procedure, using previously described standard techniques, is well within established margins of safety.
To study the effects of clomiphene citrate (CC) on the endometrium by ultrasound and to reveal the echogenic difference between the control cycle and the CC cycle. Retrospective study of patients before and during a CC treatment. Department of Obstetrics and Gynecology, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan. PATIENT(S): Seventy-nine infertile women who had a spontaneous ovulation and a normal luteal function. INTERVENTION(S): Patients received 50 mg/d CC between days 5 and 9 of the menstrual cycle. MAIN OUTCOME MEASURE(S): Endometrial thickness, echogenic pattern of the endometrium, serum E2 content, and E2 and P receptor contents in the endometrium. RESULT(S): Endometrial thickness was significantly thinner during the CC cycle (7.6 +/- 1.4 mm, mean +/- SD, n = 79) than during the control cycle (8.5 +/- 1.7 mm, n = 79) on late proliferative days, but there was no significant difference on midsecretory days (10.8 +/- 2.2 mm during the CC cycle, n = 79; 11.2 +/- 2.2 mm during the control cycle, n = 79). The echogenic patterns, however, were different between the two cycles on midsecretory days. Moreover, the incidence in which patients showed a grade 3 endometrium on midsecretory days was significantly higher during the conceived CC cycle compared with the not-conceived CC cycle. Serum E2 levels were significantly higher, but E2 receptor contents in the endometrium were significantly lower during the CC cycle (67 +/- 46 fmol/mg, n = 13) compared with the control cycle (123 +/- 89 fmol/mg, n = 15) on late proliferative days. CONCLUSION(S): Clomiphene citrate affected the echogenic pattern of the endometrium, and most of the endometrium showed a grade 3 pattern on midsecretory days during the conceived CC cycle. Under the CC treatment, the comfortable endometrium for embryos might be different from the control cycle.
To determine whether treatment with low dose aspirin and heparin leads to a higher rate of live births than that achieved with low dose aspirin alone in women with a history of recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies), lupus anticoagulant, and cardiolipin antibodies (or anticardiolipin antibodies). Randomised controlled trial. Specialist clinic for recurrent miscarriages. 90 women (median age 33 (range 22-43)) with a history of recurrent miscarriage (median number 4 (range 3-15)) and persistently positive results for phospholipid antibodies. Either low dose aspirin (75 mg daily) or low dose aspirin and 5000 U of unfractionated heparin subcutaneously 12 hourly. All women started treatment with low dose aspirin when they had a positive urine pregnancy test. Women were randomly allocated an intervention when fetal heart activity was seen on ultrasonography. Treatment was stopped at the time of miscarriage or at 34 weeks' gestation. Rate of live births with the two treatments. There was no significant difference in the two groups in age or the number and gestation of previous miscarriages. The rate of live births with low dose aspirin and heparin was 71% (32/45 pregnancies) and 42% (19/45 pregnancies) with low dose aspirin alone (odds ratio 3.37 (95% confidence interval 1.40 to 8.10)). More than 90% of miscarriages occurred in the first trimester. There was no difference in outcome between the two treatments in pregnancies that advanced beyond 13 weeks' gestation. Twelve of the 51 successful pregnancies (24%) were delivered before 37 weeks' gestation. Women randomly allocated aspirin and heparin had a median decrease in lumbar spine bone density of 5.4% (range -8.6% to 1.7%). Treatment with aspirin and heparin leads to a significantly higher rate of live births in women with a history of recurrent miscarriage associated with phospholipid antibodies than that achieved with aspirin alone.
InfertilityImmunological FactorsCytokines in MiscarriageEndocrine Factors
Recurrent miscarriage remains an enigma. The main aetiologies are endocrinological, immunological and unexplained. With the growth in molecular biology, it is now possible to look at the effect of these aetiologies in more detail, allowing greater understanding of the underlying pathogenesis.
Two progesterone presentations, a vaginal application of 90 mg progesterone per day (Crinone) or 300 mg progesterone administered orally (Utrogestan), were compared for luteal phase support of patients undergoing an in-vitro fertilization (IVF) procedure. A total of 283 patients were randomly allocated to either treatment. The treatment started within 24 h after the embryo transfer procedure and continued until day 30 in cases of implantation. Efficacy was assessed using the pregnancy and delivery rates. Safety was assessed through specific symptoms and usual safety monitoring. The pregnancy rates per transfer were not significantly different in the Crinone and Utrogestan groups at days 12 (Crinone 35.3%, Utrogestan 29.9%, P = 0.55), 30 (Crinone 28.5%, Utrogestan 25.0%, P = 0.61) and 90 (Crinone 25.9%, Utrogestan 22.9%, P = 0.69). No differences in the spontaneous abortion rates were seen thereafter. The delivery rates (number of deliveries per patient; Crinone 23.0%, Utrogestan 22.2%, P = 1.00), as well as the ratio of newborn babies per embryo transferred (Crinone 11.7%, Utrogestan 11.1%, P = 0.91), were not significantly different. Safety parameters were similar in both groups, except for drowsiness, which was more significantly frequent in the oral progesterone group than in the Crinone group at all time points. No serious adverse events were recorded in this study. The fact that Crinone matches the efficacy of the larger doses of progesterone used orally reflects an advantage of the transvaginal route of administration which avoids the metabolic inactivation of progesterone during its first liver pass.
The optimal timing of sexual intercourse in relation to the day of ovulation in order for pregnancy to result is a topic of broad interest. Of obvious relevance to fecundability, on the one hand, a...
General OB/GYNDonor InseminationDonor Conception DisclosureTherapeutic Donor Insemination
To compare single women, lesbian couples, and heterosexual couples receiving therapeutic donor insemination (TDI). Chart review followed by anonymous mail questionnaires to donor insemination recipients and their partners. Infertility clinic in a university hospital. One hundred fifteen women receiving donor insemination were identified by chart review. Too few single women responded for reliable comparison. Lesbian women were similar to married women in age, education, duration, and outcome of donor insemination. When considering alternatives to TDI, married women were more likely to consider adoption and lesbians were most likely to consider using a known semen donor or having intercourse with a man aware of their desire to have a child. Married couples were less likely to tell others, including the child, about conception by donor insemination. They were also less likely to support disclosing identifying data about the donor to the child. Lesbians were more likely to report stress in their relationships as a result of TDI. Married men were most likely to support mandatory counseling before TDI initiation.
InfertilityClomiphene CitrateAge-Related OutcomesMaternal Age
To evaluate the influence of female age on clomiphene citrate (CC) with IUI therapy and to compare the efficacy of this therapy between patients with ovulatory and anovulatory infertility. A university fertility clinic. Six hundred sixty-four CC with IUI cycles from 290 women aged 22 to 48 years. Cumulative and clinical pregnancy rates (PRs). Both cumulative and clinical PRs declined substantially in women > 35 years when compared with those < or = 35 years. In addition, no difference in these parameters was noted between patients with ovulatory and anovulatory infertility diagnoses. The vast majority of pregnancies occurred within the first four treatment cycles, irrespective of age or ovulatory versus anovulatory infertility diagnoses. The age-related decline in clinical PR is most rapid beginning at the age of 35 years. For any given age group, CC with IUI therapy has similar cumulative and clinical PRs for both ovulatory and anovulatory infertility diagnoses. This therapy usually should not extend beyond four cycles. Couples should be counseled about the dramatic fall in PRs occurring beyond the age of 35 years.
To investigate whether luteal and endometrial abnormalities occur more frequently in an infertile population and thus contribute to infertility. Prospective controlled clinical study. Outpatient clinic in an academic research institution. Thirty-three fertile controls and 31 infertile women without ovulatory disorders, tubal disease, or male factors. All women underwent an endometrial biopsy 9 days after the LH surge followed by an IM injection of 5,000 IU hCG. Blood samples were drawn immediately before hCG administration for serum P and placental protein 14 (PP14) measurements, at 6 hours after hCG stimulation for serum P concentrations, and on day 5 after hCG administration for serum PP14 levels. Histologic dating of the endometrium and serum P and PP14 measurements. Abnormal endometrial biopsies occurred more frequently in infertile (43%) than in fertile women (9%). Except for one case, these specimens were not associated with low hCG-stimulated P levels. Serum PP14 measurements varied widely and did not discriminate subjects with abnormal endometrial development. Disruption of endometrial maturation without a concomitant defect of the corpus luteum occurs more frequently in an infertile population and thus may contribute to infertility.
To compare the expression of endometrial P receptors (PR) levels with markers of endometrial receptivity during the window of implantation. Prospective, controlled study to examine endometrial PR and three cycle-specific integrins in endometrial biopsies obtained during the window of implantation. An academic teaching hospital. One hundred seventy-five endometrial biopsies from regularly cycling women with luteal phase defect (LPD; group 1; n = 80), medically treated LPD (group 2; n = 16), minimal and mild endometriosis with aberrant alpha v beta 3 expression (group 3; n = 21), fertile controls (group 4; n = 26), and infertile controls (group 5; n = 32). Immunohistochemical staining intensity of each antigen using the semi-quantitative grading system (HSCORE), compared using analysis of variance with Scheffe's correction. Among the five groups studied, nuclear PR expression was significantly elevated in glandular epithelial cells from tissue samples with histologic delay > or = 3 days consistent with luteal phase deficiency (LPD; group 1). Failure of PR down-regulation was associated with aberrant alpha v beta 3 integrin expression. Medical correction of LPD was associated with return of normal endometrial histology, normal integrin expression, and the loss of epithelial PR, similar to controls. The other two cycle-dependent integrin markers, alpha 1 beta 1 and alpha 4 beta 1, were not different between groups. In women with aberrant alpha v beta 3 and "in phase" endometrium, epithelial PR expression was not different from controls. The establishment of normal endometrial receptivity appears to be tightly associated with the down-regulation of epithelial PR. Histologic delay, consistent with LPD, is associated with a failure of PR down-regulation and the lack of normal markers of endometrial receptivity. Occult uterine receptivity defects (aberrant beta 3 expression in otherwise normal histology) are regulated differently, suggesting alternate mechanisms also exist which influence endometrial receptivity.
The pulsatile release pattern of LH during the entire menstrual cycle is well defined; however, the response of corpora lutea to these LH pulses in patients suffering from corpus luteum insufficiencies (CLI) is largely unknown. Patients suffering from CLI were selected from infertile patients on the basis of low progesterone (P < 25 nmol/L) in a blood sample withdrawn during a monitoring cycle. During the next cycle, nine blood samples were collected during the follicular and luteal phase and follicular development was assessed by vaginal sonography. Of 109 patients who had a CLI in the monitoring cycle, 55 had a CLI again, and 38 women agreed to undergo assessment of pulsatile hormone secretion. These women again had P < 25 nmol/L at days 6 and 7 of the luteal phase and blood samples were withdrawn through antecubital vein catheters from 0900-1700 h at 10-min intervals on days 7, 8, or 9 following ovulation. From 38 patients with such defined CLI, 16 (42%) had no LH episode and significantly lower basal LH levels in comparison with 14 control subjects. Thirteen (34%) of the patients had normal appearing LH episodes despite too low P and E2 concentrations, but their CL did not react to the LH episodes. The remaining 9 patients (24%) had normal LH episodes; their CL reacted to these episodes, but their basal P levels were too low. In all blood samples LH was not only determined using an immunoassay but also by the mouse Leydig cell testosterone production bioassay. It could be established that no CLI exists, which is due to the release of bioinactive LH. It is anticipated that the differentiation of three different types of CLI, one of hypothalamic and two of ovarian origin, may allow the development of differential diagnostic and therapeutic tools in the future.
To assess the efficacy of IVP-ET in infertile women with the polycystic ovary syndrome (PCOS) and to provide a comprehensive review of contemporary therapeutic options and their complications as reflected in the current literature. Pertinent studies in medical literature identified through computerized bibliographic search and via manual review of relevant scientific publications. In vitro fertilization and ET is an effective therapy for PCOS patients who are refractory to ovulation induction in vivo or who have coexisting infertility factors. The use of GnRH agonist (GnRH-a) is associated with significant reductions in the incidence of pregnancy loss and may improve fertilization and cleavage rates. In the PCOS patient, the use of purified FSH preparations does not appear to improve pregnancy rates nor other clinical parameters when compared with hMG. Severe ovarian hyperstimulation syndrome (OHSS) is an important consideration when PCOS patients undergo superovulation protocols. Strategies for OHSS prevention include the use of intravenous albumin immediately after oocyte retrieval, triggering of ovulation with a GnRH-a, or withholding menotropin therapy for several days before hCG administration. Cryopreservation of all embryos for future transfer in an artificial cycle has also proven to be an effective alternative in PCOS patients at high risk for severe OHSS. Pregnancy rates for PCOS patients undergoing IVF-ET are comparable with those for women with tubal factor infertility. Therefore, IVF-ET should be offered to patients with PCOS who are refractory to conventional infertility modalities.
Fertility AwarenessTiming of IntercourseConception ProbabilityUrinary Hormone Metabolites
The timing of sexual intercourse in relation to ovulation strongly influences the chance of conception, although the actual number of fertile days in a woman's menstrual cycle is uncertain. The timing of intercourse may also be associated with the sex of the baby. We recruited 221 healthy women who were planning to become pregnant. At the same time the women stopped using birth-control methods, they began collecting daily urine specimens and keeping daily records of whether they had sexual intercourse. We measured estrogen and progesterone metabolites in urine to estimate the day of ovulation. In a total of 625 menstrual cycles for which the dates of ovulation could be estimated, 192 pregnancies were initiated, as indicated by increases in the urinary concentration of human chorionic gonadotropin around the expected time of implantation. Two thirds (n = 129) ended in live births. Conception occurred only when intercourse took place during a six-day period that ended on the estimated day of ovulation. The probability of conception ranged from 0.10 when intercourse occurred five days before ovulation to 0.33 when it occurred on the day of ovulation itself. There was no evident relation between the age of sperm and the viability of the conceptus, although only 6 percent of the pregnancies could be firmly attributed to sperm that were three or more days old. Cycles producing male and female babies had similar patterns of intercourse in relation to ovulation. Among healthy women trying to conceive, nearly all pregnancies can be attributed to intercourse during a six-day period ending on the day of ovulation. For practical purposes, the timing of sexual intercourse in relation to ovulation has no influence on the sex of the baby.
Rossi AM et al., 1995·Eur J Obstet Gynecol Reprod Biol
The outcome of 103 pregnancies in 64 women with constant hyperprolactinemia was evaluated. Seventy-eight pregnancies had been induced with bromocriptine and 25 occurred without any treatment. In all, 66% of the pregnancies ended in delivery, 17% in miscarriage, 10% in tubal pregnancy and 7% in induced abortion. The pregnancy of women with untreated hyperprolactinemia was more frequently ectopic when compared to those in women treated by bromocriptine. Obstetric complications as well as signs of tumoral enlargement during pregnancy were rare in hyperprolactinemic women treated or untreated with bromocriptine. Untreated hyperprolactinemia as a risk factor in tubal pregnancy is proposed.
To evaluate the effectiveness of the oxidized regenerated cellulose absorbable barrier (Interceed, TC7) in the prevention of de-novo adhesion formation after laparoscopic myomectomy, a prospective and randomized study was performed at the Department of Obstetrics and Gynaecology of the University of Cagliari, Cagliari, Italy. A total of 50 pre-menopausal non-pregnant women, aged 23-42 years, who submitted to laparoscopic myomectomy from January 1993 to June 1994, were randomized to surgery alone (control group, n = 25) or surgery and oxidized regenerated cellulose barrier (Interceed group, n = 25). Neither group received any other treatment for adhesion prevention. A second-look laparoscopy was performed 12-14 weeks after laparoscopic myomectomy. The incidence of adhesion-free patients was assessed at second-look laparoscopy by an investigator not informed of the treatment. The numbers of adhesion-free patients were three out of 25 (12%) in the control group and 15 out of 25 (60%) in the treatment group (P < 0.05). In conclusion, the oxidized regenerated cellulose absorbable barrier significantly reduced de-novo adhesion formation after laparoscopic myomectomy.
Sahmay S et al., 1995·Int J Fertil Menopausal Stud
Endometrial biopsy has been an important way of assessing infertile couples for several years. In this review of a wide-ranging series of endometrial biopsies of infertile couples in the Turkish population it was our aim to find the distribution of results according to the years 1956-1966, 1967-1980, 1981-1992. University hospital. 12,949 endometrial biopsies, referred to our gynecological pathology laboratory for infertility investigation between 1956 and 1992. Patient report files from pathology laboratory data, analyzed retrospectively. The assessment of the biopsies is made by the same pathologist. 78.8% of cases had primary infertility, 21.2% secondary. Most of them were in the age group 26-35 years (48.8%). 37.58% of cases were found to show normal secretory endometrium, 20.95% proliferative endometrial changes, and 28.22% signs of luteal phase defect (LPD). Other local endometrial factors were also encountered, but in 1.79% the sample was considered insufficient for diagnosis. Moreover, in nine cases, malignancy was diagnosed with the help of endometrial biopsy. During the study period, cases of normal secretory endometrium and tuberculous endometritis were observed to decrease and LPD to increase significantly. It is worthy to note that in only 28 (0.21%) cases had endometrial biopsies been performed during a pregnancy cycle. We conclude that endometrial biopsy not only shows the hormonal response of endometrium but gives additional information about the local factors of endometrium concerning atrophy, specific and non-specific infections, and malignancy.
SurgerySalpingoneostomy and Salpingo-ovariolysisSalpingoscopic AssessmentSalpingoscopy Prognostic Value
To compare the prognostic value of salpingoscopy with a current classification system of adnexal adhesions and distal tubal occlusion in patients with tubal infertility undergoing reconstructive tubal surgery. Prospective clinical study. Department of Obstetrics and Gynecology of the Catholic University, a tertiary care University Center in Rome, Italy. Fifty-five infertile patients with either adnexal adhesions (29 patients) or hydrosalpinx (26 patients) undergoing reconstructive tubal surgery. Salpingoscopy performed concomitantly to salpingo-ovariolysis or salpingoneostomy at the time of either operative laparoscopy or laparotomy using microsurgical techniques. Salpingoscopic findings were compared with a current classification system of adnexal adhesions and distal tubal occlusion. The patients were followed for a mean follow-up of 49 months; the pregnancy rates achieved were correlated with the salpingoscopic findings and the classification system used. There was a significant correlation between the salpingoscopic grade and the occurrence of a term pregnancy for both the salpingo-ovariolysis and salpingoneostomy groups of patients. There was no significant correlation between the classification system used and the occurrence of a term pregnancy for both groups of patients. Salpingoscopy plays an important role in selecting the patients who may benefit the most from reconstructive tubal surgery.
InfertilityCancer Risk After Fertility TreatmentLong-term Health OutcomesCancer Registry Linkage
Concern has been expressed that exposure to fertility drugs might be associated with a risk of ovarian cancer. We have examined the incidence of breast and ovarian cancer in a cohort of 10,358 women referred for in-vitro fertilisation (IVF) treatment in Victoria, Australia, between 1978 and 1992. The "exposed" group (n = 5564) had had ovarian stimulation to induce multiple folliculogenesis and the "unexposed" group (n = 4794) had been referred for IVF but were untreated or had had "natural cycle" treatment without ovarian stimulation. Duration of follow-up ranged from 1 to 15 years. Cases of cancer were determined by record linkage with data from population-based cancer registries. 34 cases of invasive breast cancer and 6 of invasive ovarian cancer were observed. A comparison with the expected numbers, derived by applying age-standardised general population rates to the cohort gave standardised incidence ratios (SIR) for breast cancer of 0.89 (95% CI 0.55-1.46) in the exposed group and 0.98 (0.62-1.56) in the unexposed group, and for ovarian cancer SIRs were 1.70 (0.55-5.27) and 1.62 (0.52-5.02), respectively. Rates of all cancers were not significantly different from general population rates. The relative risk (RR) of cancer, adjusted for age and infertility type, was, in the treated group compared with the untreated group, 1.11 (95% CI 0.56-2.20) for breast cancer and 1.45 (0.28-7.55) for ovarian cancer. The risk of body of uterus cancer was increased in the exposed and unexposed groups combined (SIR 2.84 [1.18-6.81]). Women with unexplained infertility, independent of IVF exposure, had significantly increased risks of ovarian cancer (RR = 19.19 [2.23-165.0]) and body of uterus cancer (RR = 6.34 [1.06-38.0]) compared with women with known causes of infertility. This relatively short-term follow-up suggests that ovarian stimulation with IVF is not associated with an increased risk of breast cancer. Although there was no significantly increased risk of ovarian cancer after ovarian stimulation with IVF the small number of cases limits the conclusions that can be drawn. Longer-term follow-up of large cohorts of women who have been in IVF programmes will be necessary.
InfertilityPregnancy and Birth ComplicationsMultiple Pregnancy RiskIVF-Related Prematurity
To describe the characteristics of pregnancies and children at birth resulting from IVF-ET and to assess whether they differ from those after natural conception. Prospective multicenter survey. A national registry, representing 80% of all French IVF-ET activity for the period 1986 to 1990. Data on 7,024 pregnancies, 5,371 deliveries, and 6,879 newborn infants. A form is completed for every clinical pregnancy. Spontaneous abortion, ectopic pregnancy, multiple pregnancy, prematurity, hypotrophy, perinatal and neonatal mortality, and congenital malformations rates. The spontaneous abortion and ectopic pregnancy rates were, respectively, 17.6% and 5.8%. More than a quarter (26.8%) of the deliveries were multiple births. The preterm birth rate (29.3%), the low birth weight rate (36.2%), and the perinatal and neonatal mortality rates were higher than the national average. The rate of malformations (2.8%) was comparable with the general population (2.1%). Assisted conception frequently results in multiple pregnancy, and this is the main determinant of pregnancy outcome. Nevertheless, it is not the only risk factor for prematurity, which is also more frequent among IVF singleton newborn. The prevalence of congenital malformations is not higher than after natural conception.
DiagnosticsDoppler Assessment of Corpus LuteumNoninvasive DiagnosisBlood Flow Assessment
To determine whether color flow pulsed Doppler analysis of corpus luteum blood flow in normal cycles differs from cycles with a luteal phase defect. A prospective study of natural ovarian cycles. The University of Vermont Reproductive Endocrinology and Infertility Service. Ten women with regular menstrual cycles and at risk for luteal phase defect (LPD) four with unexplained infertility, two with recurrent abortion, and four with age > 35 years. All women were examined by transvaginal color flow pulsed Doppler during the early follicular, late follicular, early luteal, midluteal, and late luteal phase of the menstrual cycle. Venous blood for P concentration was drawn on each day of Doppler exam. Urine testing for LH surge and endometrial biopsy during the late luteal phase were performed on each patient. Lowest resistance index associated with the highest amplitude signal from intraovarian vessels of each ovary, dated endometrial biopsies, serum P. Mean resistance indexes in LPD patients (n = 3) were significantly higher compared with normal women (n = 6) throughout the follicular and luteal phases. One patient remained anovulatory and was excluded from statistical analysis. Although systolic and diastolic velocities generally were observed to be lower in LPD patients compared with normal women, these differences were not statistically significant. High correlations were observed between P and resistance index within each luteal time point, achieving its highest value during the midluteal phase. This initial study provides evidence that color flow pulsed Doppler analysis of blood flow impedance to the corpus luteum may aid in assessing luteal phase adequacy.
InfertilityClomiphene Citrate EffectsEndometrial Thickness and Echo PatternClomiphene Impact
To determine whether successive cycles of clomiphene citrate affect endometrial thickness. Thirty-four women presenting for treatment of anovulation, oligoovulation, or follicle maturation defects were given the smallest dose of clomiphene citrate necessary to attain a mature follicle. If no pregnancy ensued, the same dose was continued if a follicle 18-24 mm in diameter and a serum estradiol (E2) level greater than 200 pg/mL were achieved. Ethinyl E2 was supplemented for poor cervical mucus only. Endometrial thickness and echo patterns were measured each cycle at peak follicular maturation. There was no difference in mean endometrial thickness during the first six cycles of therapy, nor was there a trend for thickness to increase or decrease with successive cycles with or without the addition of ethinyl E2. There was no change in the distribution of echo patterns with successive cycles of clomiphene citrate. Post-treatment measures of thickness and echo pattern did not differ from baseline pre-treatment values. The homogeneous hyperechogenic pattern was the rarest. Mean serum E2 and progesterone levels at mid-cycle did not change with successive cycles. One proposed mechanism for the dichotomy between ovulation and pregnancy rates after clomiphene citrate therapy is that the drug adversely affects the endometrium. If clomiphene citrate does affect implantation adversely, the mechanism does not seem to be related to thinning the endometrium or causing an echo pattern that indicates a poor prognosis. The data also suggest that estrogen supplementation does not influence endometrial thickness and would best be used exclusively for hostile cervical mucus.
To evaluate the efficacy of Interceed (TC7) Absorbable Adhesion Barrier, an oxidized regenerated cellulose fabric, as a barrier to the development of postsurgical ovarian adhesions after surgery involving the ovaries. In a multicenter randomized study, 55 patients with bilateral ovarian disease were treated at initial laparotomy. At the end of the procedure, one ovary was assigned randomly to be wrapped with Interceed and the other was left uncovered. A second-look laparoscopy was performed 10-98 days later to evaluate the occurrence and severity of adhesions and the raw ovarian surface area exposed after lysis of adhesions. At second-look laparoscopy, 26 of 55 Interceed-treated ovaries were free of adhesions, compared with 14 of 55 untreated control ovaries, a statistically significant difference (P = .028, Fisher exact test). At second-look laparoscopy, ovaries treated with Interceed formed adhesions less extensively (1.66 +/- 0.34 cm2) than did untreated ovaries (2.75 +/- 0.60 cm2) and with a greater reduction of raw ovarian surface area (difference in area differential -1.89 +/- 0.96 cm2; P = .055, paired t test). Adhesion scores at second-look laparoscopy were reduced significantly for ovaries treated with Interceed compared with untreated ovaries (P = .02, Wilcoxon signed-rank test). No adverse events were recorded during the course of the study. Treatment of ovaries with Interceed significantly reduced the occurrence and severity of postsurgical ovarian adhesions.
One of the major postoperative complications of reproductive surgery is the formation of adhesions. 1, 2 Over the past several decades a number of methods have been explored to solve this problem, g, 4 Recently there has been renewed interest in covering the damaged peritoneal surface with an absorbable or nonabsorbable barrier as a means of preventing adhesions after fertility-enhancing surgery. Currently, two barriers are commercially Interceed Absorbable Adhesion Barrier (Ethicon, Somerville, NJ), which is composed of oxidized regenerated cellulose, and the Gore-Tex Surgical Membrane (W. L. Gore & Associates, Inc., Flagstaff, AZ), constructed of expanded polytetrafluoroethylene (e-PTFE). Interceed has been investigated both experimentally and clinically and has proved effective in some circumstances. 5,6 Studies also report on the laparoscopic application of Interceed in fertility-enhancement procedures.7, 8 Recent reports, however, have questioned the product's degree of effectiveness and raised concern about possible residual effects it may have on peritoneal tissue? 11 Gore-Tex Surgical Membrane has been indicated for use in peritoneal reconstruction since 1983, and experimental and clinical reports describe its effectiveness in preventing adhesion formation. 12-14
Interceed is an absorbable material that is phagocytized by macrophages within 1 month. Gore-Tex Surgical Membrane is nonabsorbable and is intended to be a permanent implant. Since all published reports on the clinical application of the Gore-Tex membrane discuss implantation by laparotomy, ~g, 14 the ease of use of this product in laparoscopic surgery is of particular interest. Moreover, because of its permanence, its long-term safety and effectiveness merit examination. A prospective, multicenter clinical study was undertaken to evaluate the ease of using Gore-Tex Surgical Membrane laparoscopically.
InfertilityFecundabilityIVF OutcomesFertility Probability Models
The last decade has transformed the physician's approach to infertility. The development of IVF for its treatment has so improved our capacity to overcome this most distressing of disabilities that we now need to revise many of our working ideas on how it can come about. This is not because new causes have been discovered. Rather, an appreciation has been gained of how apparently minor disturbances can combine to cause a major disruption in the expectation of pregnancy.
At the best of times-and sometimes, no doubt, at the worst of times getting pregnant is a matter of chance. The parameter that describes this chance is the monthly probability of conception, known among epidemiologists as fecundability (f) (probability of achieving pregnancy in one menstrual cycle), and is similar to "monthly fecundity" (monthly probability of a live birth in one cycle exposed to the risk of pregnancy) (1). Like every statistic in biology, fecundability has a wide distribution of values in the population (modeled in Fig. 1). Figure 1 also illustrates a group of couples with a fecundability value of zero-meaning complete infertility, or sterility, which affects perhaps 5% of couples attempting to achieve a pregnancy.
Vaginal progesterone suppositories are an accepted treatment for infertility attributed to luteal phase defects. Although oral micronized progesterone may be preferable to suppositories for many patients, there are no studies on its use for patients with luteal phase defects. This study evaluated the efficacy of oral micronized progesterone for the treatment of luteal phase defects. Seven women with luteal phase defects previously corrected by vaginal suppositories were administered oral micronized progesterone (200 mg by mouth three times a day). Endometrial biopsies were performed to evaluate treatment efficacy. Questionnaires were used to assess side effects, including sedation. On oral micronized progesterone, all patients had in-phase endometrial biopsies. Despite complaints of drowsiness, the majority of patients preferred the oral formulation over the vaginal route of administration. We conclude that oral micronized progesterone is efficacious in the treatment of luteal phase defects.
InfertilityDiagnostic AssessmentAccuracy and LimitationsTubal Patency Testing
To determine whether the diagnostic accuracy and prognostic value of hysterosalpingography (HSG) could be improved if routine spot films were replaced by an on-line recorded gynecoradiologic study.
Medical school-affiliated private infertility center.
In 1992, a review of 152 infertile women with infertility who demonstrated a normal HSG, by standard criteria of spot film evaluation, in 117 (77%). They were further investigated by gynecoradiologic study if the HSG revealed asymmetrical tubal filling, an increased perfusion pressure, and/or evidence for abnormal tubal spill. In 1993, 47 women with normal HSG by spot film criteria underwent bilateral selective salpingography and were subdivided into those with normal (group I, n = 23) and abnormal (group II, n = 24) tubal perfusion pressures. Patients in both study groups then were treated for their infertility independently of pressure perfusion measurements.
Clinical pregnancy rates (PRs) over the ensuing 6 to 10 months. Among 117 women with apparently normal spot film HSG, 64 (55%) demonstrated asymmetrical tubal filling, 32 (27%) demonstrated abnormal spillage into the peritoneal cavity, and 55 (47%) demonstrated abnormally elevated injection pressures. Among 98 women who underwent bilateral selective salpingography, 43 (44%) demonstrated bilaterally normal tubal perfusion pressures and 55 (56%) showed an abnormally elevated pressure in at least one oviduct. Of 47 women that were followed prospectively in 1993, patients with normal perfusion pressure (group I) demonstrated a significantly higher PR than women with elevated tubal pressure (group II) from 2 months and on after the procedure. Routine spot film HSG is of limited value in assessing tubal status beyond the determination of tubal patency. Especially with regard to fertility potential, HSG should be replaced by gynecoradiologic study.
Reproductive EndocrinologyEstradiol and Pregnancy OutcomeGIFT OutcomesHormonal Predictors
To correlate luteal estradiol (E2) levels with pregnancy outcome, 36 consecutive conceptions resulting from gamete intrafallopian transfer in gonadotropin releasing hormone agonist/human menopausal gonadotropin (GnRH-a/hMG) cycles were analyzed. GnRH-a was initiated during the preceding luteal phase. HMG was adjusted individually. Human chorionic gonadotropin (hCG), 5,000 IU, was administered when E2 was > 500 pg/mL and the leading follicle > 17 mm (day 0). The luteal phase was supported by (1) hCG, 1,500 IU in three doses from day 5 and (2) progesterone (P) from day 7. E2 and P levels were analyzed normally progressing pregnancy (NPP), abortion (AB) and preclinical abortion (PAB). No significant differences in mean E2 levels were seen between the groups from day 0 through day 5 after hCG. Midluteal E2 levels were significantly different between the groups (P < .05). Late luteal E2 values were significantly higher for NPP than for either AB or PAB (P < .05). There were no significant differences in luteal P values between the NPP, AB and PAB groups. Decreased luteal E2 appears to be associated with early pregnancy wastage; this may be due to inadequate endometrial support.
To examine the role of steroid hormone receptor compartmentalization in infertile women with "in-phase" or "out-of-phase" endometrium. Nonrandomized prospective clinical study. A university clinic. Twenty-nine infertile patients without evidence of endometriosis, tubal factor, male factor, galactorrhea, or hyperandrogenism were enrolled. Sixteen patients had in-phase endometrium and a P level > or = 10 ng/mL (conversion factor to SI unit, 3.18) (group A). Four patients had out-of-phase endometrium and a P level > 10 ng/mL (group B). Four patients had in-phase endometrium and a P level < 10 ng/mL (group C), and five patients had out-of-phase endometrium and a P level < 10 ng/mL (group D). Each patient underwent determination of serum P and endometrial sampling on postovulatory days 6 to 9 based on serum LH measurement. Dating according to endometrial histology and biochemical assessment of estrogen receptor (ER) and P receptor (PR) were performed on each sample. The level of cytosol ER was significantly lower in out-of-phase endometrium regardless of serum P level. There were no significant differences in the levels of cytosol PR and nuclear ER and PR among groups. In a long-term follow-up study, 6 of 29 patients became pregnant. PR ratio in these patients was found to fit a single straight regression line (y = 0.34x - 2.2). Out-of-phase endometrium probably depends on inadequate cytosol ER. PR ratio may be important to become pregnant.
We describe the epidemiologic characteristics of conception, including subclinical early pregnancy loss, in a population of healthy women volunteers who had heterogeneous fertility experiences, and we describe the conception experience of women within this group who had evidence of impaired fertility. This was a prospective observational study of a cohort of women employed in two semiconductor manufacturing facilities. A total of 148 volunteers completed interviews and daily diaries and collected daily urine specimens for an average of 7 months. Conception, including subclinical losses and clinical pregnancies, was determined with a highly sensitive and specific assay for urinary human chorionic gonadotropin, and ovulation was determined with assays of urinary ovarian steroid hormones. There were 679 menstrual cycles at risk for pregnancy contributed by 124 (84%) of the 148 women. Women with evidence of subfertility before or during the study period had a rate of early pregnancy loss of 70% compared with 21% in women without fertility problems (relative risk 2.6, 95% confidence interval 1.8 to 3.8). The risk of pregnancy loss associated with subfertility increased with age and remained the same in women treated with clomiphene citrate. These results suggest that subfertile women have increased subclinical pregnancy losses regardless of fertility treatment and that the association between reduced fertility and advancing age may be related, in part, to early subclinical pregnancy loss.
InfertilityClomiphene Citrate Side EffectsVisual DisturbanceFertility Drug Complications
To identify a distinctive constellation of persistent visual abnormalities secondary to treatment with clomiphene citrate. Description of the clinical findings in three patients with visual disturbance secondary to clomiphene treatment. A neuro-ophthalmology referral center. Three women aged 32 to 36 years treated for infertility with clomiphene for 4 to 15 months. All three patients experienced prolonged afterimages (palinopsia), shimmering of the peripheral field, and photophobia while undergoing treatment with clomiphene. The results of the neuro-ophthalmologic examination and electrophysiologic studies were normal in all three patients. Unlike previously reported cases, visual symptoms did not resolve on cessation of treatment. Patients remain symptomatic from 2 to 7 years after discontinuing treatment with the medication. Treatment with clomiphene can cause prolonged visual disturbance. Patients who develop such symptoms should be advised that continued administration may cause irreversible changes. Women with characteristic visual symptoms should be questioned about past use of clomiphene.
To investigate the role of transcervical tubal catheterization in diagnosis and treatment of proximal tubal obstruction associated with salpingitis isthmica nodosa. Retrospective case study. University hospital and outpatient radiology practice. Fifty-two women with proximal tubal obstruction associated with salpingitis isthmica nodosa. Selective salpingography and catheter recanalization using fluoroscopic guidance. The number of tubes visualized to the fimbria as a percentage of the tubes with proximal tubal obstruction on the initial hysterosalpingogram was determined as a measure of diagnostic efficacy. To evaluate the treatment potential of catheter recanalization, the patients were grouped according to tubal status at the conclusion of the procedure and subsequent pregnancies were evaluated. Forty-seven of 65 tubes (72%) with proximal tubal obstruction were recanalized successfully. Among the 19 women who were able to conceive only via a recanalized salpingitis isthmica nodosa tube, there were 6 live births (32%) and two tubal pregnancies (10%). Selective salpingography allows complete tubal diagnosis in almost three fourths of patients with proximal tubal obstruction and salpingitis isthmica nodosa. The radiographic diagnosis of salpingitis isthmica nodosa may be pressure dependent. Intrauterine pregnancies occur via recanalized salpingitis isthmica nodosa tubes, therefore catheter recanalization may be attempted before tubal microsurgery or IVF in patients with proximal tubal obstruction and associated salpingitis isthmica nodosa.
Nordic Adhesion Prevention Study Group, 1995·Fertil Steril
To evaluate the efficacy of Interceed as an adjuvant in the prevention of postoperative adhesion reformation to the ovary, fallopian tube, and fimbria when used together with microsurgical techniques. Prospective, randomized, multicenter, controlled clinical study. Normal human volunteers in an academic research environment. Sixty-six women suffering from infertility due at least in part to bilateral tubal disease with bilateral adhesions attached to ovaries, fallopian tubes, and fimbriae. Adhesiolysis bilaterly through laparotomy with microsurgical techniques, application of Interceed on one of the sides randomly assigned not known by the surgeon before application, follow-up laparoscopy 4 to 10 weeks postoperatively, with each patient serving as her own control. Adhesion severity scores at all sites and number of adhesion free organs after laparotomy and follow-up laparoscopy. When the initial scores registered at the operation for fertility were compared with those registered at the second-look laparoscopy, the results indicated that gentle microsurgical techniques resulted in a significant reduction of postoperative adhesions. Adnexa, which were covered with Interceed, had significantly lower adhesion scores than the control adnexa, representing an improvement of 39% compared with microsurgery alone (control) in reducing adhesion reformation scores. When combined with microsurgical techniques, Interceed reduced adhesion reformation scores by 70%. The number of ovaries, fallopian tubes, and fimbriae without adhesions at the time of second-look laparoscopy was significantly increased by approximately twofold when organs were covered with Interceed. In a prospective, randomized, multicenter, controlled clinical study using a protocol in which other adjuvants have been shown not to be efficacious, Interceed was shown to reduce significantly the incidence and severity of adhesion reformation to the ovary, fallopian tube, and fimbria after infertility surgery.
Myomectomy Adhesion Multicenter Study Group, 1995·Fertil Steril
To evaluate the effects of the expanded polytetrafluoroethylene barrier (PTFE), Gore-Tex Surgical Membrane, in reducing postmyomectomy adhesion formation. Multicenter randomized clinical trial. Twenty-seven women having myomectomy with at least two incisions on the uterine fundus and posterior uterine wall of similar length were enrolled in the study. At laparotomy, the two incision sites were randomly assigned to be covered with PTFE or were left uncovered. A second-look laparoscopy to evaluate adhesion formation and to lyse adhesions was done from 2 to 6 weeks after the myomectomy. Adhesions were scored using a 0- to 11-point scoring system. At laparoscopy, 15 of 27 incisions covered with PTFE (55.6%) and only 2 of 27 uncovered sites (7.4%) were completely free of adhesions. The mean adhesion score at the PTFE sites was significantly lower (1.88 +/- 0.46; SEM) than at the control sites (7.55 +/- 0.57). The PTFE barrier is effective in reducing postmyomectomy adhesion formation.
To assess uterine receptivity in women with unexplained infertility using integrin cell adhesion molecules as markers. Prospective, controlled study design. Eighty-seven nulliparous women with unexplained infertility and 32 fertile and infertile parous controls. Immunohistochemical staining for alpha 1, alpha 4, and beta 3 integrin subunits in endometrial biopsies obtained during the window of implantation (days 20 to 24), using the semiquantitative HSCORE by two observers in a blinded fashion. All endometrial biopsies from parous controls contained positive immunostaining for the alpha 1, and beta 3 integrin subunits in glandular epithelium. Some samples from parous controls were missing the alpha 4 subunit. In contrast, compared with parous controls, biopsies from women with unexplained infertility had reduced significantly beta 3 expression, with similar expression of alpha 1 and alpha 4. Two distinct defects in integrin "out-of-phase" samples that lacked beta 3 because of histologic lag (type I defects) and "in-phase" endometrium that still failed to express this integrin (type II defects). These subclassifications accounted for 26% and 39% of the total unexplained infertility group, respectively. Abnormal endometrial integrin expression was a frequent finding in women with unexplained infertility. These data suggest that defective uterine receptivity may be an unrecognized cause of infertility in this population of women.
PCOSOvulation Induction StrategiesEndometrial Cancer RiskAntiestrogen Resistant PCOS
Women with hyperandrogenic disorders represent a unique group among those with infertility due to anovulation. Although antiestrogens are effective in restoring ovulation in most women, it remains unclear whether these treatments restore fecundability per ovulatory cycle and the ability to maintain pregnancy in these individuals. Moreover, antiestrogens are ineffective in restoring ovulation in some hyperandrogenic anovulatory women, whose condition poses unique and vexing challenges for the infertility therapist. Gonadotropin treatment in antiestrogen-resistant women often leads to ovarian hyperstimulation syndrome, which has been addressed by modification of dosing schedules (e.g., low-dose administration), pretreatment with gonadotropin-releasing hormone (GnRH) analogs, and elimination of luteinizing hormone from the administered gonadotropins. Surgical reduction in ovarian volume has met with some success, although there may be a risk of inducing surgical adhesions of the adnexa. The second major reproductive adversity facing these patients is their elevated risk of endometrial cancer. Unopposed estrogen exposure probably contributes to this risk, but hyperandrogenicity and hyperinsulinism may act independently or in concert with estrogen to amplify the risk in these women. While the risks and strategies for preventive care in these women need to be better defined, reproductive health specialists are urged to continue using presently accepted measures, including education, to maintain these women's reproductive health.
To determine whether luteal phase defect (LPD) may be an etiologic factor in ectopic pregnancy (EP). All patients who were seen over a 6-year period with the chief complaint of infertility underwent an extensive infertility workup and were followed prospectively. The diagnoses of the causes of infertility were assigned retrospectively. Two hospital-based tertiary care reproductive endocrine-infertility units. A total of 1,077 infertility patients were evaluated. Of the 633 who became pregnant, the infertility had been due to LPD in 51 and to anovulation in 210. All the infertility patients who became pregnant were followed to determine whether they miscarried, developed an EP, or had a viable birth. The incidence of EP and miscarriage in the patients whose infertility was found to be due to LPD were compared with a control group in whom the infertility was due to anovulation. The EP rate in the patients with LPD was significantly higher than in a control group whose infertility was due to anovulation (6 of 51 pregnancies versus 6 of 210 pregnancies, respectively). The spontaneous abortion rate in LPD cases also was highly significantly greater than in the control group (19 of 51 pregnancies versus 12 of 210 pregnancies, respectively). The EP and spontaneous abortion rates also were higher in patients with LPD who were untreated than in those who were treated. This study suggests that there is a significantly increased incidence of tubal EP in patients with LPD and that when patients with LPD become pregnant early ultrasound should be performed to rule out EP. The study also indicated that spontaneous abortion occurs in a significantly high percentage of LPD cases.
InfertilityClomiphene Cancer RiskOvarian Tumor EpidemiologyInfertility Treatment Outcomes
Case reports and the results of a recent case-control study have raised questions about the potential neoplastic effects of medications used as treatment for infertility. We examined the risk of ovarian tumors in a cohort of 3837 women evaluated for infertility between 1974 and 1985 in Seattle. Computer linkage with a population-based tumor registry was used to identify women in whom tumors were diagnosed before January 1, 1992. Data on infertility testing and treatment were abstracted from the medical records of women who had ovarian cancer and those of a randomly selected comparison group. The risk of ovarian tumors associated with exposure to ovulation-inducing medications was assessed through an age-standardized comparison with the rate of ovarian tumors in the general population, and Cox regression analysis was used to compare the risk of cancer among women who received these medications with the risk among infertile women who did not receive them. There were 11 invasive or borderline malignant ovarian tumors, as compared with an expected number of 4.4 (standardized incidence ratio, 2.5; 95 percent confidence interval, 1.3 to 4.5). Nine of the women in whom ovarian tumors developed had taken clomiphene; the adjusted relative risk among these women, as compared with that among infertile women who had not taken this drug, was 2.3 (95 percent confidence interval, 0.5 to 11.4). Five of the nine women had taken the drug during 12 or more monthly cycles. This period of treatment was associated with an increased risk of ovarian tumors among both women with ovarian abnormalities and those without apparent abnormalities (relative risk, 11.1; 95 percent confidence interval, 1.5 to 82.3), whereas treatment with the drug for less than one year was not associated with an increased risk. Prolonged use of clomiphene may increase the risk of a borderline or invasive ovarian tumor.
To investigate the efficacy of hCG in the management of recurrent early pregnancy loss. A prospective, randomized, controlled trial. Miscarriage Clinic, Women's Hospital, Liverpool, United Kingdom. Eighty-one women attending the miscarriage clinic with idiopathic recurrent pregnancy loss were randomized to receive hCG supplementation or placebo in early pregnancy. The success rate or live birth rate. In women with regular menstrual cycles it was found that hCG had no beneficial effect, the pregnancy success rate being 86% in both groups. However, women with oligomenorrhea had a pregnancy success rate of 40% in the placebo group but a statistically significant improvement to 86% if hCG was given. Human chorionic gonadotropin can be recommended for idiopathic recurrent pregnancy loss in women with oligomenorrhea.
To determine pharmacokinetic and endometrial effects of vaginally delivered micronized P. Functionally agonadal estrogen-replacement recipients received either micronized P administered vaginally or bi-daily IM injections of P. Hourly blood samples were obtained, from baseline to 6 hours after the initial dose of P and again on simulated cycle day 21 when transvaginal ultrasound (US) measurements and tissue samples of the endometrium were performed. Blood and tissue samples were assayed for P. Endometrial histology, estrogen receptor (ER) and P receptor (PR) contents were evaluated. University of Southern California School of Medicine, Los Angeles, California. Twenty functionally agonadal and four normally ovulating women. Delivery differences were assessed by [1] endometrial P concentrations; [2] USs; [3] histologic datings; [4] ER and PR contents, and [5] serum P levels. Endometrial P concentrations were higher with vaginally administered P than endometrial concentrations observed in normal ovulatory women or women who consistently had the highest serum P after IM administration (11.50 +/- 2.60 versus 1.40 +/- 0.40 versus 0.30 +/- 0.10 ng/mg protein [36.56 +/- 8.27 versus 4.45 +/- 1.27 versus 0.95 +/- 0.32 nmol/L], respectively). After 7 days of P, no differences between either treatment regimen and control groups were detected by histologic, ultrasonographic, or immunocytochemical receptor analyses. Vaginal micronized P enhances P delivery to the uterus compared with a standard IM regimen and results in a synchronous secretory endometrial histology in agonadal women preparing for embryo donation.
AndrologyEjaculation Frequency and Sperm QualityCoital Timing OptimizationSequential Ejaculation Effects
To clarify how often infertile men should have intercourse to achieve conception, the effect of sequential ejaculation on total motile sperm counts was investigated.
Case-control study.
Infertility and IVF unit, tertiary care center. Five hundred seventy-six men who produced two closely spaced sequential ejaculates.
The total motile sperm counts of the second ejaculates were compared with the total motile sperm counts of the first ejaculates. In normospermic men (n = 359), the total motile sperm counts decreased significantly from 93 (18 to 601) (median [minimum to maximum] x 10(6)) in the first ejaculate to 42 (1.2 to 387) in the second ejaculate, produced 24 hours later. In contrast to the normospermic men, in the asthenospermic group (24 hours difference, n = 81) and in both oligospermic groups, (1 to 4 hours difference, n = 27; and 24 hours difference, n = 45), there were no significant changes in the total motile sperm counts (24 [5.9 to 229] versus 30 [0.8 to 150], 6 [0.8 to 18] versus 3.6 [0.1 to 63] and 13 [2.5 to 32] versus 10 [0.1 to 66], respectively). Moreover, in both oligoasthenospermic groups (1 to 4 hours difference, n = 23; and 24 hours difference, n = 41) the total motile sperm counts increased significantly (3.2 [0.6 to 7.9] versus 8 [0.4 to 48] and 4 [0.2 to 13] versus 4 [0.1 to 101], respectively). In all groups, pooling sequential ejaculates significantly increased the total motile sperm counts, over and above that of the first ejaculate, by 49% in the normospermic group, 95% in the asthenospermic group, 67% and 75% in the oligospermic groups (1 to 4 hours and 24 hours difference, respectively), and 233% and 139% in the oligoasthenospermic groups (1 to 4 hours and 24 hours difference, respectively). Sequential ejaculation may overcome the impaired sperm transport causing low total motile sperm counts observed in some oligospermic and/or asthenospermic men. Most of these infertile men may significantly increase their fertility potential, assessed by the total motile sperm counts, either by pooling sequential ejaculates for IUI, GIFT, and IVF, or by having intercourse every day or even twice a day, at the time of ovulation.
To determine the ability of luteal phase length determined by basal body temperature (BBT) pattern and a midluteal serum progesterone level to predict the result of an endometrial biopsy in a subsequent cycle. We performed a retrospective analysis of 141 women with a history of infertility who were being evaluated for luteal function. The luteal phase length determined from a BBT chart of one menstrual cycle was compared to a single midluteal serum progesterone level from a second menstrual cycle. These findings were compared to a luteal phase endometrial biopsy performed in a third menstrual cycle. Subjects were divided into four groups depending upon luteal phase length (normal 11 or more days) and serum progesterone level (normal at least 10 ng/mL). The four groups were designated "normal," "short luteal phase," "low progesterone," and "abnormal," depending upon the results of the two tests. The frequency of in- and out-of-phase endometrial biopsy results in the four groups was compared. There was no difference in the occurrence of an in- or out-of-phase endometrial biopsy when the four groups were compared. Neither luteal phase length nor a single midluteal serum progesterone level was predictive of subsequent in-phase or out-of-phase endometrial biopsy.
InfertilityPregnancy Outcome AssociationMiscarriage Risk FactorsSubfertility Association
To examine the relationship of subfertility with miscarriage, low birth weight, and preterm delivery. Comparison of time to pregnancy distributions between pregnancies that had different outcomes. (a) miscarriages with live births; within live births, (b) low birth weight infant (up to 2,500 grams) or not low birth weight; (c) preterm birth (37 weeks or less) or not preterm. Cox regression was used to adjust for covariates. All first pregnancies were analyzed from the National Child Development Study, a large survey of young adults aged 33 years, which is nationally representative of the British-born population. The distribution of the time taken to conceive (time to pregnancy), miscarriage, birth weight, and preterm delivery. Pregnancies that ended in miscarriage tended to take 23% longer to conceive, after adjustment for the other variables. Pregnancies that resulted in preterm delivery tended to take 15% longer to conceive. There was no statistically significant association with low birth weight. Delay in time to conception is a risk factor for poor obstetric outcome, irrespective of medical intervention.
To examine whether luteal E2 is obligatory for obtaining an adequately developed endometrium. Survey of women with premature ovarian failure (POF) in a prospective, controlled, randomized study. In vitro fertilization unit in a tertiary care university medical center. Fourteen amenorrheic women with POF, candidates for oocyte donation, were divided into two distinct groups with seven women in each subgroup. Endometrial priming with a fixed dose of oral micronized E2, 4 mg/d for 14 days, was similarly performed in the study and the control groups. Progesterone replacement during the luteal phase was also identical in the two groups and was accomplished by IM P in oil, 50 mg/d for another 14 days. Only the control group continued to have the same E2 regimen during the luteal phase. Follicular phase mean E2 levels as well as luteal phase mean P levels were similar in both groups. However, luteal E2 levels differed significantly between the study and the control groups (21 +/- 5 and 692 +/- 199 pg/mL, respectively; conversion factor to SI units, 3.671). Nevertheless, histologic evaluation of endometrial biopsies on days 21 and 26 were similar for both groups. Endometrial gland dating, using light microscopy in the study and the control groups, on day 21, was 19.1 +/- 0.8 and 18.4 +/- 0.5, respectively, and on day 26, 25.4 +/- 0.8 and 25.9 +/- 0.5, respectively. Dating of the stroma in the two biopsies was also similar in both groups. Moreover, transmission electron microscopy performed in two patients of the study group showed typical characteristics of a secretory endometrium. Luteal E2 depletion in the human does not seem to adversely affect the morphological developmental capacity of the endometrium. Our results suggest that E2 secretion by the corpus luteum in the human does not appear to be obligatory for the development of a normal secretory endometrium. The actual receptivity of the endometrium after such preparation needs to be evaluated.
Reproductive EndocrinologyDiagnostic AccuracySensitivity and SpecificityLuteal Phase Defect Detection
To assess the sensitivity and specificity of common clinical tests used for the diagnosis of luteal phase defect (LPD). The sensitivity and specificity of these tests for predicting low integrated P levels over the luteal phase were calculated. Outpatient reproductive endocrinology and infertility clinic at a university medical center. Fifty-eight strictly defined normal women were used to determine normal integrated luteal phase P levels. The study population was a separate 34 women who either were normal (n = 15) or were being evaluated for infertility or recurrent abortion (n = 19). These 34 study subjects all had the following tests performed daily reproductive hormone levels, daily assessment of preovulatory follicle size, late luteal endometrial biopsies, and BBT charts. Basal body temperature, maximum preovulatory follicle size, dated endometrial biopsies, and serum P levels (single and multiple) were used in an attempt to predict which patients had low integrated P levels. Unacceptably low sensitivity and/or specificity levels were appearance of BBT charts, luteal phase length, and preovulatory follicle diameter. Timed endometrial biopsy was found to have marginally acceptable sensitivity and specificity levels whether dated by next menstrual period or midcycle events. The best test for the prediction of low integrated P was a single serum P level from the midluteal phase that was < 10 ng/mL (31.8 nmol/L) or a sum of three random serum P measurements that was < 30 ng/mL (95.4 nmol/L) (also obtained in the midluteal phase). Luteal phase defect is a relatively uncommon but important cause of infertility and/or habitual abortion. The recommended test for the determination of LPD is a midluteal phase single serum P level < 10 ng/mL or the sum of three serum P levels that is < 30 ng/mL. The endometrial biopsy is a second line test that is only recommended when LPD needs to be evaluated in a treated cycle (ovulation induction or supplemental P).
To follow-up and expand discussion on the action mechanisms of antisperm antibodies in human infertility, the etiology and control of antisperm antibody induction, sperm antigens involved in immunoinfertility, and strategies for therapy.
A review of the recent literature with an emphasis on female immunoinfertility. The role of antisperm antibodies in clinical infertility continues to be defined. Through assisted reproductive technologies, antisperm antibodies were shown to exert detrimental effects on different prefertilization and possibly postfertilization events. The female reproductive tract is part of the common mucosal immune system and is able to mount effective immune responses against infectious agents, foreign antigens, and, occasionally, sperm cells. Sperm membranes and constituents contain numerous antigenic components foreign to the human body, and yet antisperm antibodies become problematic in few women exposed to semen. Semen and sperm cells contain immunosuppressive factors capable of inhibiting different immune cells. Fertile women apparently produce antisperm antibodies but also possess neutralizing serum anti-idiotypic antibodies that are lacking in virgin and immunoinfertile women. Antisperm antibodies can affect adversely human fertility but normally may be controlled by anti-idiotypic antibodies, which along with immunosuppressor factors in semen prevent their induction to a significant degree. This balance between detrimental and "beneficial" immune response to sperm may be shifted toward an antisperm antibody response by stimulatory factors such as infection. Therapies may be devised to stimulate the anti-idiotypic antibody system, to induce immune tolerance to sperm antigens, and to use antigens to adsorb antisperm antibodies from spermatozoa.
To determine whether the use of luteal phase support improves pregnancy rate (PR) in infertility. A meta-analysis of randomized trials of luteal phase support. Search of the National Library of Medicine MEDLINE data base from 1971 using the words luteal, pregnancy, human, and comparative. Bibliography of relevant articles, reviews, and abstracts of scientific meetings were hand searched. All randomized controlled trials of luteal phase support in infertility were included. Luteal phase support for recurrent abortion and nonrandomized trials were excluded. The common odds ratio was calculated for each intervention using the Mantel-Haentzel test. Homogeneity of treatment effect was evaluated using the Breslow-Day test. Pregnancy per cycle, rate of spontaneous abortion, and ovarian hyperstimulation syndrome rate. Eighteen trials met the above criteria. Human chorionic gonadotropin improved PRs in IVF when GnRH agonist (GnRH-a) was used (n = 151) and was superior to P (n = 352). Its benefit in all IVF cycles, however, was not established because of significant heterogeneity of treatment effect. Progesterone improved the PR in all IVF cycles (n = 457). No significant reduction in spontaneous abortion was noted with luteal support (n = 200). Ovarian hyperstimulation syndrome occurred in 5% of patients with hCG. Combination of data from trials of luteal support with other infertility therapies was not possible because of the differences in patient populations. The meta-analysis supports the routine use of hCG in IVF cycles using a GnRH-a. Progesterone was also beneficial for luteal phase support in IVF. For other infertility therapy, however, further research is needed to evaluate the role of luteal phase support.
To characterize ampullary endosalpingeal findings in women with occlusive or nonocclusive salpingitis isthmica nodosa. Prospective case study. Obstetrics and Gynecology Department of a University Hospital. Twenty women (38 tubes) with occlusive or nonocclusive salpingitis isthmica nodosa were studied. Salpingoscopy was performed during diagnostic laparoscopy in 20 women (38 tubes) with hysterosalpingographic evidence of salpingitis isthmica nodosa. Salpingoscopic findings were recorded and the patients were managed accordingly. Of the 38 tubes 10 appeared radiographically and laparoscopically normal. Two tubes were occluded distally. Of the 26 tubes with occlusive or nonocclusive salpingitis isthmica nodosa, 5 (19.2%) showed varying degrees of endosalpingeal abnormality. Patients with abnormal salpingoscopy were regarded as having bipolar tubal disease and were referred for assisted conception. The remaining patients were scheduled for microsurgical tubal reconstruction. One in five patients with proximal tubal disease may have ampullary endosalpingeal damage of varying degrees. However, the significance of this finding in relation to subsequent management strategies and fertility outcome is yet to be characterized.
To determine the relationship between some reproductive variables and infertility caused by tubal obstruction. A retrospective, case-control study. A tertiary care university hospital that is a referral center for infertility patients. Subjects were interviewed between March 1990 and December 1991. Cases were 215 consecutively recruited infertile women with either evidence of tubal obstruction found at laparoscopy or hydrosalpinx diagnosed by hysterosalpingography. Women with a history of surgical sterilization were excluded. Controls, selected in the same hospital, were women in the puerperium who had no history of infertility. Two controls were matched by age at the time of tubal obstruction diagnosis to each case. History of pelvic surgery and use of alcohol were significantly associated with the risk of infertility caused by tubal obstruction. The use of barrier, oral, and medroxyprogesterone acetate (MPA) contraceptives was associated with a protective effect. When only women with secondary infertility were analyzed, history of pelvic surgery and number of lifetime sexual partners were significant risk factors, and the previous use of oral contraceptives was the only protective factor. History of pelvic surgery was the most important risk factor for tubal infertility. All precautions must be taken to avoid infection and adhesion formation when pelvic surgery is performed. In addition, women can be protected from tubal infertility by using barrier, oral, or MPA contraceptive methods.
To (1) review the events leading to peritoneal adhesion formation; (2) review traditional adhesion prevention adjuvants; (3) overview studies for adhesion prevention barriers including a perspective for their use; and (4) look toward the future of adhesion prevention. A great deal of effort has been dedicated to reduce adhesion formation because of the morbidity associated with adhesions and the associated economic burden, which considering only hospital costs and surgeons' fees, was $1,180 million in the United States. To understand the role of adhesion barriers in gynecological surgery, an appreciation of the cellular cascade and temporal nature of peritoneal repair is necessary. Evidence indicates that areas denuded of peritoneum will heal satisfactorily and that suturing of the peritoneum may increase adhesion formation. Physical barriers, including both mechanical and viscous solutions, are widely used to prevent adhesion formation by limiting tissue apposition during the critical stages of mesothelial repair. Clinical studies do not support the use of intraperitoneal, dextran for adhesion prevention. Theoretical considerations of peritoneal fluid dynamics indicate that crystalloid instillates should not prevent adhesion formation because of their short intraperitoneal residence. This prediction is consistent with clinical observation. The availability of Interceed (Johnson and Johnson Medical, Inc., Arlington, TX) and Gore-Tex Surgical Membrane (W.L. Gore, Flagstaff, Arizona) barriers provides substantial progress in postsurgical adhesion prevention. Although many investigators are incorporating adhesion prevention barriers into their routine clinical situations, physician acceptance is constrained by technical difficulties.
To evaluate further the safety and efficacy of selective ostial salpingography combined with transcervical wire recanalization for the diagnosis and treatment of proximal tubal obstruction. Prospective study. Division of Reproductive Endocrinology and Department of Radiology at Harbor-University of California Los Angeles (UCLA) Medical Center, a tertiary care academic institution. Twenty-eight infertile patients diagnosed with proximal tubal obstruction by hysterosalpingogram (HSG) or by chromopertubation at laparoscopy (total of 46 obstructed tubes). After antibiotic prophylaxis and IV analgesia a conventional HSG was performed. If proximal tubal obstruction was confirmed, selective salpingography was done under fluoroscopic guidance. If proximal tubal obstruction was still present, wire recanalization using a new prototype cannula was then performed. If recanalization was successful, contrast media was injected to confirm tubal patency. Proximal tubal patency, complete tubal patency, pregnancies. Eleven of 46 tubes (23.9%) were patent by HSG. Ostial salpingography of the remaining 35 tubes revealed 6 patent tubes (13%). Nine of the 29 obstructed tubes (31%) had successful wire recanalization, and 8 of these were patent distally. There were 4 intrauterine pregnancies (IUPs) and 1 ectopic pregnancy after recanalization and 2 IUPs after ostial salpingography. Selective salpingography should be considered at the time of an HSG showing proximal tubal obstruction. If indicated, wire recanalization can also be attempted. Selective ostial salpingography combined with wire recanalization is a safe and effective procedure for the diagnosis and treatment of PTO.
NaProTECHNOLOGYOvulation MonitoringUltrasoundClassification Systems
To compare the effect of fertility drugs and IVF on the outcome of triplet pregnancies. Prospective clinical study. A single university medical center. One hundred six consecutive triplet pregnancies treated from 1984 through 1992. The frequency of pregnancy loss, livebirths, and antenatal and neonatal complications was compared in spontaneous, clomiphene citrate (CC), menotropins, and IVF triplet pregnancies. Eighty-one of the 106 (76.4%) triplet pregnancies progressed beyond 25 weeks, comprising 6 of 7 (85.7%) spontaneous pregnancies, 13 of 16 (81.2%) CC induced, 44 of 56 (78.6%) menotropin induced, and 18 of 27 (66.6%) IVF gestations. There were no significant differences in the stillbirth and neonatal mortality rates according to the mode of conception. The mean gestational ages and the mean birth weights were similar in the four groups. The frequency of premature contractions, premature rupture of membranes, cesarean section, and neonatal complications were similar in the ovulation induction and IVF pregnancies. Triplet pregnancies after ovulation induction and IVF have a similar outcome.
To examine and discuss the pathology, diagnosis, incidence, and patient profile of salpingitis isthmica nodosa and to question its natural history, propose management strategies, and identify areas of promising research. Over 50 studies were reviewed, evaluated, and compared to offer the clinician a foundation on which to generate treatment plans. Salpingitis isthmica nodosa is diagnosed by the pathological presence of isthmic diverticula and may be suggested by characteristic changes on hysterosalpingogram. Its incidence in healthy, fertile women ranges from 0.6% to 11%, but it is significantly more common in the setting of ectopic pregnancy and infertility. There are no studies, retrospective or prospective, that clearly dictate appropriate therapy. Given its progressive nature and probable deleterious effects on fertility, we propose that microtubal surgery be the definitive treatment for qualified women who have salpingitis isthmica nodosa.
To assess the outcome of pregnancy following assisted conception. Cohort descriptive study. Unit of Reproductive Medicine, Ninewells Hospital and Medical School. One hundred and forty-eight consecutive assisted conceptions. Patient characteristics and outcome of pregnancy. Seventy-nine percent of mothers were aged between 26 and 35 years (mean 31.4). The main causes of infertility were tubal (48%), unexplained (35%), anovulatory (8%) and male factor (8%). Primary infertility accounted for 61% of cases and 82% of pregnancies occurred within 3 treatment cycles. Thirty-five (24%) pregnancies miscarried before 14 weeks and 7 (5%) between 15 and 24 weeks gestation. One hundred and three pregnancies resulted in 136 liveborn infants. There was one neonatal death. Thirty-five babies were admitted to SCBU. Antenatally, 13% of patients were admitted to hospital with hypertension and 8% with APH; 50% of multiple and 13% of singleton pregnancies were delivered prematurely, 68% following preterm labour. There were 28 sets of twins (four miscarried at less than 24 weeks) and four sets of triplets. Multiple pregnancy was not associated with cause of infertility, treatment, age or ovarian hyperstimulation syndrome. Seventy-eight per cent of singletons and 50% of multipara were delivered vaginally. Our data confirm the high incidence of pregnancy loss and preterm delivery associated with assisted conception once allowing for the high rate of multiple pregnancies. The effect of assisted conception programme on health services is discussed.
Mårtensson O et al., 1993·Acta Obstet Gynecol Scand
In 25 women with primary or secondary infertility, primary hysterosalpingography (HSG) or laparoscopy with chromopertubation indicated 33 proximal and 2 distal tubal obstructions. Four salpingectomies had been performed earlier. All patients were considered for transcervical catheter salpingoplasty (TCSP) to reconstruct tubal patency. Secondary examination with repeat HSG or selective osteal salpingography confirmed 26 proximal and 3 distal tubal occlusions while 17 tubes were patent. Selective osteal salpingography was performed successfully in 32 of 33 (97%) tubes. Sixteen of 26 (61.5%) proximally occluded tubes were successfully recanalized by coaxial catheter and guidewire technique while two of three distally occluded tubes were reopened by forceful flushing of contrast medium. So far, one ectopic and five intrauterine pregnancies were achieved in ten patients with observation time more than four months. Three patients have had normal deliveries. The favorable results, lack of complications and low costs seem to justify the recommendation to use selective salpingography and fallopian tube recanalization as the first intervention in patients with obstruction of the proximal fallopian tube.
Adhesion re-formation after a reproductive operation, particularly involving the pelvic sidewall, is a prominent cause of failure in the surgical treatment of infertility. This study was done to evaluate the impact of standard microsurgery through laparotomy and the additional benefit of an oxidized regenerated cellulose adhesion barrier (INTERCEED [TC7] Absorbable Adhesion Barrier [Ethicon Inc.]), in reducing pelvic sidewall adhesion re-formation. One hundred and thirty-four patients with bilateral pelvic sidewall adhesions undergoing adhesiolysis by standard microsurgical techniques through laparotomy were treated during a prospective randomized trial involving 13 centers. After adhesiolysis, the deperitonealized surface of one pelvic sidewall was randomly assigned to be covered with INTERCEED Barrier, the contralateral sidewall serving as control. A second-look laparoscopy was performed ten days to 14 weeks postoperatively. Microsurgical adhesiolysis alone resulted in 24 percent of the sidewalls becoming free of adhesions and a 55.6 percent reduction in the area of adherent peritoneum. With microsurgery alone, 60 and 39 percent of adhesions initially characterized as filmy or severe, respectively, were not seen at second-look laparoscopy. The use of INTERCEED Barrier increased the incidence of adhesion-free sidewalls twofold. The treatment was also associated with a statistically significant reduction in the area of peritoneum affected by adhesion re-formation, compared with the control wall. Of the adhesions originally graded as severe, 61 percent of those treated with INTERCEED Barrier did not re-form at all. When evaluated on filmy adhesions, the use of the barrier was associated with a 72 percent reduction in adhesion re-formation. A measurable reduction in adhesion re-formation was found, depending on the initial adhesion type, with microsurgery alone. The addition of INTERCEED Barrier further reduced the incidence, extent and severity of postoperative adhesion re-formation. In this study, 90 percent of the patients benefited from the use of INTERCEED Barrier.
To evaluate publications that introduced novel diagnostic and therapeutic transcervical procedures on the fallopian tubes. Major studies that conceptually changed the therapeutic approach to the fallopian tubes were reviewed. Minor publications were also included if they introduced a new concept or contributed to the topic. Clinical publications were selected if they involved transcervical diagnosis and treatment of fallopian tubes. Transcervical tubal catheterization procedures for diagnosis of tubal disease, tubal obliteration, tubal recanalization, and tubal medication are minimally invasive procedures that can improve our understanding and diagnostic accuracy of tubal disease. These procedures allow transcervical treatment of proximal tubal occlusion. Further improvements in equipment and methodology are promising. Transcervical tubal occlusion, gamete and embryo deposition, and treatment of ectopic pregnancy may all be performed using the transcervical approach. Transcervical tubal catheterization can replace microsurgery and IVF in selected patients with proximal tubal occlusion, improve the diagnostic accuracy of tubal disease, and deliver medications to the fallopian tubes. Cumulative knowledge suggests that transcervical tubal catheterization should become a universally accepted, taught, and practiced approach in the diagnosis and treatment of the fallopian tubes.
To evaluate the incidence and extent of periovarian adhesion formation subsequent to laparoscopic electrocoagulation of the ovarian surface in infertility patients with polycystic ovarian disease (PCOD). From a total of 199 PCOD patients treated with ovarian electrocautery, 50 cases of laparoscopy and 12 cesarean sections served as second-look investigation. A subgroup of 30 patients had abdominal lavage and artificial ascites after surgery; they underwent "early" second-look (2 to 14 days after laparoscopy). All patients were referred to our fertility outpatient clinic affiliated with the university hospital. Infertility patients with polycystic ovarian reaction to hormonal stimulation therapy underwent laparoscopic electrocoagulation of the ovarian surface. Adhesion formation was detected in 19.3%; the incidence reduced to 16.6% with the use of abdominal lavage. The adhesions found were obviously due to bleeding of the ovarian capsule caused by electrocautery. Adhesiolysis was easily possible during "early" second-look. The incidence of de novo adhesion formation caused by laparoscopic electrocoagulation of the ovarian surface seems to be lower than after ovarian wedge resection; it can be reduced by abdominal lavage and artificial ascites.
InfertilityService UtilizationSociodemographic DisparitiesNational Survey of Family Growth
To examine the characteristics of women in the 1988 National Survey of Family Growth who reported having obtained medical services for impaired fecundity. From a national sample of 8450 women between the ages of 15-44, drawn from the civilian, noninstitutionalized population of the entire United States in 1988, we estimated the use of infertility services in the United States. Multivariate statistical modeling was used to identify the characteristics associated with use of infertility services among the 770 women who reported impaired fecundity in this survey. Of all women with impaired fecundity, 43% had obtained some form of infertility service and 24% had obtained specialized infertility treatment--ovulation drugs, treatment of fallopian tubes, artificial insemination, or in vitro fertilization. Older, white, married women of higher socioeconomic status were most likely to have obtained specialized services, and a history of endometriosis was also strongly associated with having received such services. Most women with impaired fecundity had not obtained infertility services. Use of specialized services was strongly associated with certain sociodemographic variables or a history of endometriosis.
To assess the endocrinologic and clinical outcome after laparoscopic ovarian electrocautery because of polycystic reaction to ovarian stimulation in anovulatory infertility patients. Between 1986 and 1989, 133 patients with polycystic ovarian disease underwent laparoscopic electrocoagulation of the ovarian surface in an outpatient clinic after conventional ovarian stimulation had led to polycystic reaction. All patients were referred to our outpatient clinic affiliated with the university hospital. The reduction of androgen levels and normalization of cycle length were highly significant. The overall pregnancy rate was 70% (73 of 104), ranging from 27% in smokers to 94% in nonsmoking couples. In 26 second-look operations de novo adhesions were found in 26.9% of the patients. Laparoscopic coagulation of the ovarian surface is an effective tool to reduce elevated androgen levels and to improve the intraovarian mechanism of selecting a dominant follicle. A postoperative complication may be adhesion formation.
EndometriosisPeritoneal FluidAngiogenesis and Growth FactorsPeritoneal Factor
To review and evaluate published studies that have examined the role of peritoneal fluid (PF) in the development of endometriosis. Important studies related to this topic have been identified through a computerized bibliographical search (MEDLINE), as well as by manually scanning the published literature of major reproductive journals over the last several years. Studies that examined the effect of PF or its components on the pathophysiology of endometriosis are discussed. These include reported effects on the histogenesis, maintenance and proliferation of endometriosis, as well as related actions on infertility. The majority of investigations into the role PF plays in the pathogenesis of endometriosis have evaluated how it may adversely affect fertility. Suggestive but inconclusive data in the literature indicate that degenerating endometrial tissue may release a biochemical factor(s) into the peritoneal environment that is capable of inducing ectopic endometrium formation. Peritoneal fluid itself contains growth factor that may play a role in the implantation and maintenance of the ectopic endometrium. The PF of women with endometriosis has been shown to contain angiogenic as well as other growth factors. These compounds may contribute to the proliferation of the ectopic endometrium.
InfertilityClomiphene Citrate Side EffectsClomiphene EffectsDrug-Induced Changes
To analyze the effects of clomiphene citrate (CC) on cervical mucus (CM) and endometrial morphology independently of hormonal changes encountered when CC is administered for ovulation induction. Volunteers whose ovarian functions were temporarily suppressed (n = 18) by a long-acting GnRH agonist and 6 women of similar age suffering from premature ovarian failure (POF) received E2 and P. Half of the women also received CC (50 mg/d, days 2 to 6). Tertiary University Institution, Hôpital A. Béclère. PATIENTS, Eighteen volunteers suffering from infertility not related to a uterine cause and 6 women of similar age suffering from POF. Plasma gonadotropins, E2, and P were measured at baseline to confirm that the ovaries were inactive and twice weekly during physiological E2 and P replacement. Cervical mucus was analyzed on day 14 and scored from 0 to 15. Endometrial biopsies were obtained on replacement days 20 and 24 for conventional histology and immunocytochemistry analysis of estrogen receptors and progesterone receptors (PR). Premature ovarian failure women whose results have been previously published served as controls for day 20 biopsies. Cervical mucus scored lower in women who received CC (5.5 +/- 3.2) than in controls (13.6 +/- 4.7, mean +/- SEM). On day 20, endometrial findings were similar in women treated with CC and in controls. On day 24, specimens showed a significant delay in endometrial maturation in women treated with CC. On day 24, only staining for PR selectively persisted in endometrial stroma, and no difference was observed between women who received CC and controls. Our results indicate that CC significantly alters CM quality and late luteal phase endometrial morphology despite physiological levels of plasma E2 and P. Hence, clinicians should monitor E2 levels when using CC, and caution should be exerted when supraphysiological levels of E2 are not present to counterbalance the effects of CC on the CM and the endometrium.
Induction of ovulation is indicated for anovulatory and amenorrheic women as well as for women who have an inadequate luteal phase. It is also indicated as a strategy for recruiting multiple follicles for women with unexplained infertility and those who are undergoing assisted reproductive technologies. The use of various agents and detection of ovulation are described. This includes a discussion of clomiphene citrate, bromocriptine, human menopausal gonadotropins, urinary follicle stimulating hormone and pulsatile gonadotropin releasing hormone therapy. Regimens, success rates and potential complications of each form of therapy are reviewed. Also discussed is the use of combination therapy and partial ovarian destruction.
Ovarian laparoscopic resection was applied to 23 sterile patients affected with polycystic ovarian disease (PCOD) resistant to different pharmacological treatments, in order to induce ovulation. After resection, 56% of the patients had spontaneous ovulatory cycles and 13 pregnancies arose. Ten of the pregnancies were spontaneous and three followed treatment with clomiphene. Hormone changes were assessed in 15 patients, including five with spontaneous menstruation but without ovulation and five with persistent amenorrhoea for 3 months after resection. A significant decrease in both androstenedione and testosterone levels occurred in all patients. These decreases were not related to the clinical results of resection. Luteinizing hormone (LH) did not vary greatly in any group after resection. Mean values and mean pulsatility of follicle stimulating hormone (FSH) increased significantly only in pregnant patients or those with spontaneous ovulatory cycles. The results of gonadotrophin-releasing hormone (GnRH) assays did not change after resection. The mechanisms involved in the resumption of cyclic function of the hypophyseal-ovarian axis after resection are discussed briefly.
InfertilityPsychosocial FactorsStress and ReproductionInfertility Risk Factors
An adaptive model for the evolution of reproductive failure predicted psychosocial stress to increase as anatomic causes of infertility decrease. The nonanatomic infertility group in our study reported greater psychosocial stress than intermediate (P < 0.008) or anatomic groups (P < 0.0005). Controls, women with nonanatomic etiologies who were not attempting pregnancy, also reported higher psychosocial stress than the anatomic group (P < 0.007). Results are consistent with the hypothesis that psychosocial distress contributes significantly to the etiology of some forms of infertility.
To investigate the correlation between opacification and perfusion pressures during hysterosalpingography (HSG) and selective salpingography under the assumption that the latter may add to the diagnostic capabilities of the procedures. Perfusion pressures were uniformly evaluated by standardizing injection volume per time interval of contrast medium and the delivery system. Pressures were measured in a closed system through a digital manometer and recorded on tracing paper. Fully ambulatory gynecoradiology suite at academically affiliated infertility center. Thirty infertility patients. Hysterosalpingography and selective salpingography for diagnostic purposes. Correlation between opacification patterns and perfusion pressures. The evaluation of perfusion pressures during HSG is unreliable because they may be affected by uterine factors and will only reflect the oviduct of least resistance. In contrast, perfusion pressures during selective salpingography are reflective of only the investigated tube. They appear to lie within a functionally normal range of up to 350 mm Hg. Tubes by opacification judged as normal exhibited a pressure range of 429 +/- 376 mm Hg, which was significantly lower than that of abnormally appearing oviducts (957 +/- 445 mm Hg; P = 0.001). The concomitant performance of perfusion pressure studies during selective salpingography further enhances the diagnostic capability of selective salpingography over HSG in the diagnostic evaluation of fallopian tubes.
General OB/GYNOvarian Cancer Risk FactorsCancer RiskFertility Drug Safety
Data collected from 2,197 white ovarian cancer patients and 8,893 white controls in 12 US case-control studies conducted in the period 1956-1986 were used to evaluate the relation of invasive epithelial ovarian cancer to reproductive and menstrual characteristics, exogenous estrogen use, and prior pelvic surgeries. Clear trends of decreasing risk were evident with increasing number of pregnancies (regardless of outcome) and increasing duration of breast feeding and oral contraceptive use. Ovarian dysfunction leading to both infertility and malignancy is an unlikely explanation for these 1) The trends were evident even among the highly parous; 2) risk among nulliparous women did not vary by marital status or gravidity; and 3) risk among ever-married women showed little relation to length of longest pregnancy attempt or history of clinically diagnosed infertility. Risk was increased among women who had used fertility drugs and among women with long total duration of premenopausal sexual activity without birth control; these associations were particularly strong among the nulligravid. No consistent trends in risk were seen with age at menarche, age at menopause, or duration of estrogen replacement therapy. A history of tubal ligation or of hysterectomy with ovarian conservation was associated with reduced ovarian cancer risk. These observations suggest that pregnancy, breast feeding, and oral contraceptive use induce biological changes that protect against ovarian malignancy, that, at most, a small fraction of the excess ovarian cancer risk among nulliparous women is due to infertility, and that any increased risk associated with infertility may be due to the use of fertility drugs.
NaProTECHNOLOGYPregnancy AchievementCreighton Model SystemFertility-Focused Intercourse
Fifty consecutive clients achieved pregnancy using a standardization modification of the Billings ovulation method (the Creighton Model Natural Family Planning System). Of 50 clients followed, 38 (76%) achieved pregnancy in the first cycle of fertility-focused intercourse, 45 of 50 (90%) achieved pregnancy by the third cycle and 49 of 50 achieved pregnancy by the sixth cycle (98%).
To compare the obstetric outcome of in vitro fertilization pregnancies with normally conceived pregnancies. The obstetric outcome of in vitro fertilization pregnancies achieved in 763 British residents at two in vitro fertilization clinics resulting in the births of 961 babies were compared by means of the relative risk statistic with a control group of naturally conceived primiparous pregnancies matched by maternal age and multiplicity of pregnancy. Twenty-five percent of in vitro fertilization pregnancies were multiple pregnancies. The incidence of singleton term breech presentation was similar to that among controls. As compared with controls there was an increased incidence among in vitro fertilization pregnancies of vaginal bleeding and hypertension requiring hospitalization (p less than 0.001) and cesarean births (p less than 0.001) and, among in vitro fertilization singleton pregnancies, an increased incidence of intrauterine growth retardation (p less than 0.05), placenta previa (p less than 0.05), and preterm delivery (p less than 0.001). The congenital malformation, stillbirth, and perinatal mortality rates were comparable with maternal age-standardized national rates. Although the majority of in vitro fertilization pregnancies have a satisfactory obstetric outcome, there are a number of increased obstetric risks that may reflect the history of infertility, the relatively high incidence of poor obstetric history, and the lower threshold for obstetric intervention in in vitro fertilization patients.
The null hypothesis of this study is that the patterns of steroid secretion exhibited by the human corpus luteum in response to exogenous human chorionic gonadotropin stimulation are independent of corpus luteum age at the time of treatment. Twenty-five normally cycling women in whom the midcycle urinary luteinizing hormone surge (luteal day 0) was identified and from whom blood samples were obtained daily from cycle day 11 until menses were prospectively randomized to receive no treatment (group I, n = 5) or exogenous human chorionic gonadotropin 5000 IU administered intramuscularly on luteal day 0 (group II, n = 5), +4 (group III, n = 5), +8 (group IV, n = 5), or +12 (group V, n = 5). Serum concentrations of estrone, estradiol, progesterone, 17-hydroxyprogesterone, and androstenedione were measured by specific radioimmunoassays in all subjects; serum human chorionic gonadotropin concentrations were determined by immunoradiometric assay in treated subjects. Serum human chorionic gonadotropin levels (mean +/- SEM) were virtually identical among treatment groups (p greater than 0.05). Luteal phase duration (mean +/- SEM) was prolonged (p less than 0.05) only in group V (18.4 +/- 0.5 days) compared with untreated subjects (group I 13.8 +/- 0.7 days). In all groups estrone and 17-hydroxyprogesterone concentrations closely paralleled those of estradiol and progesterone, respectively. Steroid data and progesterone/estradiol ratios (mean +/- SEM) in groups I and II were indistinguishable and were combined (control, n = 10). Group III subjects exhibited patterns of steroid secretion similar to groups I and II, although progesterone was moderately increased after human chorionic gonadotropin treatment. In groups IV and V, progesterone increased (p less than 0.05) 1 day after human chorionic gonadotropin and remained elevated for 5 to 6 days; a 4-day rise (p less than 0.05) in estradiol began 3 days after treatment, and androstenedione rose modestly in parallel. Progesterone/estradiol ratios in groups III through V increased (p less than 0.05) approximately twofold after human chorionic gonadotropin treatment and remained elevated for 4 to 5 days. The human corpus luteum exhibits distinct age-dependent patterns of steroid secretion in response to exogenous human chorionic gonadotropin stimulation, an observation that may have clinical implications regarding the empirical use of exogenous human chorionic gonadotropin in support of luteal function.
Pregnancies of 112 patients who had conceived after a history of a minimum of 2 years of infertility were compared to an equal number of matching controls without prior infertility to find out any risk of increased pregnancy complications. These patients were at a significantly higher risk of developing first trimester bleeding, antepartum haemorrhage and intrauterine fetal death. Also there were higher rates of preterm delivery and Caesarean section. The patients in the study group had a significantly higher number of stillborn babies. The incidence of other complications such as ectopic pregnancy, multiple pregnancy, and medical complications was also higher in these patients but the difference was not statistically significant.
To investigate the local natural killer (NK) activity of the peritoneal fluid mononuclear cells (PFMC). In a prospective way, the NK activity (K562-assay) was measured in peripheral blood (PB) and peritoneal fluid (PF) of 44 women who underwent a laparoscopy for infertility and/or pain at the University Hospital of Gasthuisberg, Leuven, Belgium. The NK activity of peripheral blood mononuclear cells and PFMC, the number and concentration of PFMC, the percentage of lymphocytes versus macrophages by May-Grünwald-Giemsa staining and the estradiol and progesterone concentration of the PF were correlated together and with the severity of endometriosis. We demonstrated that there is a significant NK activity in PF and that this activity is decreased in women with endometriosis. This defect was more pronounced in the follicular phase of the cycle compared with the postovulatory phase. In PB of the same 44 women, the decreased NK activity correlated with the severity of the disease. This confirms our previous report on another 34 women. The NK activity is decreased in women with endometriosis and correlated significantly with the severity of the disease in both the PB and PF of women with endometriosis.
EndometriosisGlucocorticoid TherapyEmbryotoxicity and AutoimmunityImmunological Factors
To investigate the effect of short-term glucocorticoid administration on embryotoxicity of sera from infertile patients with mild to moderate endometriosis. Prospective longitudinal study. SETTING, Eight infertile patients with mild to moderate endometriosis and a control group of eight infertile patients with tubal infertility were selected on the basis of laparoscopic examination. Basal (B) serum collection and day 1 (T1), day 3 (T2), day 6 (T3), and day 12 (T4) serum drawn after a 3-day glucocorticoid treatment in endometriosis patients. Embryotoxicity of endometriosis sera, before and after glucocorticoid treatment, was investigated using a bioassay performed on two-cell mouse embryos. Interleukin 1 alpha (IL-1 alpha) and antismooth muscle, antimitochondrial, and antinuclear autoantibodies were also tested in these sera. At 50% concentration, endometriosis serum is embryotoxic in comparison with control; 0% versus 61% of the embryos reached the blastocyst stage at 72 hours, respectively (basal versus control, P less than 0.001). However, this embryotoxicity significantly decreases 12 days after glucocorticoid treatment in comparison with untreated sera; 32.4% versus 0% of the embryos reached blastocyst stage at 72 hours, respectively (T4 versus basal, P less than 0.001), although they did not reach nontoxic levels (greater than 50%). Interleukin 1 alpha was undetectable in all samples analyzed. In endometriosis sera, antismooth muscle antibody was detected. At 50% concentration, serum from infertile patients with minimal to moderate endometriosis appears to be embryotoxic to the in vitro development of two-cell mouse embryos. However, this embryotoxicity significantly decreases 12 days after a 3-day treatment with glucocorticoids.
To elucidate the role of peritoneal macrophages in infertility, we investigated how the presence of peritoneal macrophages would affect fecundity in mice. Moreover, we also studied the effects of interleukin-1 on embryonic development. Mice were administered OK-432 intraperitoneally to induce macrophage infiltration of the peritoneal cavity; ovulation was then induced and animals were mated. On day 13 of gestation, fetuses were counted. After injection of OK-432 or interleukin-1, the mice were mated. Three days later, embryos were collected and the stage of embryo development was determined. In mice given OK-432 (n = 33), four (12%) became pregnant and the mean litter number was 6.0 +/- 3.6, whereas in the control group 23 of 30 mice (77%; p < 0.01) became pregnant and the litter number was 14.1 +/- 5.3 (p < 0.01). OK-432 and interleukin-1 administered intraperitoneally significantly suppressed embryo development (p < 0.01). Increased numbers of peritoneal macrophages negatively affect fecundity, probably by suppressing embryonic development.
EndometriosisPeritoneal EnvironmentDanazol and GnRH AgonistsCytokine Mediated
Our aim was to examine the relationship between the levels of cytokines in peritoneal fluid and its embryo toxicity. The levels of interleukin-1 and tumor necrosis factor were measured in peritoneal fluid from infertile women who did not have endometriosis (n = 21), who had untreated endometriosis (n = 19), and who had undergone medical treatment for endometriosis (n = 10). Embryo toxicity was investigated in mouse two-cell embryos cocultured with the oviducts in culture media that contained various concentrations of peritoneal fluid. The levels of cytokines were significantly higher in the peritoneal fluid from women who had untreated endometriosis than in women who did not have endometriosis, but they were extremely low in women who had undergone medical treatment with either danazol or buserelin. The peritoneal fluid from women who had untreated endometriosis adversely affected the cleavage of mouse two-cell embryos. After medical treatment the embryo toxicity of the peritoneal fluid was almost undetectable. These results offer some theoretic bases in support of medical treatment to improve reproductive performance in infertile women who have endometriosis.
To determine if repetitive administration of hCG causes decreased pregnancy wastage rates in patients who are at a high risk of luteal inadequacy. Ovulation induction using human menopausal gonadotropin (hMG)/human chorionic gonadotropin (hCG) or clomiphene citrate (CC) is associated with luteal phase defects that may cause increased pregnancy wastage. An increased risk of abortion exists also in pregnancies in patients with previous repeated miscarriage, women older than 37 years, and various causes of infertility such as hyperprolactinemia. Because the presumed common denominator to the increased rate of pregnancy wastage in all these cases is luteal dysfunction, repetitive hCG administration, 2,500 U two times weekly, was carried out between the 4th and 8th week of gestation in 249 cases of ovulation induction and/or previous abortions, whereas 198 gestations served as controls (no hCG administration). In the hCG treatment group, 43 ended in miscarriage (17.3%) versus 97 abortions in the control group (49%, P less than 0.01). In 160 cases of hMG/hCG generated gestations, 94 received hCG and 66 did not. The pregnancy wastage rates were 21.3% and 42.4%, respectively (P less than 0.05). In 144 cases of CC/hCG-induced pregnancies, 95 received hCG and 49 served as controls. The respective abortion rates were 15.8% and 44.8% (P less than 0.01). The remaining 143 spontaneous conceptions occurred in infertile patients with previous repeated abortions. In 60 of these conceptions, hCG was administered during the first 4 weeks of gestation and 83 cases served as control. The pregnancy wastage rates were 13.3% versus 56.6%, respectively (P less than 0.001). Repetitive administration of hCG during the early gestation in cases that are at high risk of luteal inadequacy may significantly decrease the pregnancy wastage rate.
From 1960 10 1984, 2,501 women underwent diagnostic laparoscopy (index laparoscopy) because of a clinical suspicion of acute pelvic inflammatory disease (PID). Of these women, 1,844 had abnormal laparoscopic findings (patients) and 657 had normal findings (control subjects). The reproductive events after index laparoscopy of 1,732 patients and 601 control subjects were followed. The patients and control subjects were followed for a total of 13,400 and 3,958 woman-years, respectively. During the follow-up period, 1,309 (75.6%) of the patients and 451 (75.0%) of the control subjects attempted to conceive. Of these women, 209 (16.0%) of the patients and 12 (2.7%) of the control subjects failed to conceive. A total of 141 (10.8%) of the patients and 0 (0%) of the control subjects had confirmed tubal factor infertility, 21 (1.6%) of the patients and 3 (0.7%) control subjects had other causes of infertility, and 47 (3.6%) patients and 9 (2.0%) control subjects did not have a complete infertility evaluation. Additional information on tubal morphology (hysterosalpingography, laparoscopy, or laparotomy) in women from couples for whom evaluation was incomplete indicated that 165 (12.2%) patients and 4 (0.9%) of the control subjects had abnormal tubal function or morphology after index laparoscopy. Tubal factor infertility after PID was associated with number and severity of PID episodes. The ectopic pregnancy rate for first pregnancy after index laparoscopy was 9.1% among the patients and 1.4% among control subjects.
The empty follicle syndrome was assessed using transvaginal ultrasonography in a group of 152 consecutive women with unmedicated menstrual cycles being studied because of primary or secondary infertility or repetitive miscarriage. The overall frequency of the empty follicle syndrome was found to be 43.4%. The frequency increased with age but was independent of gravidity. The empty follicle syndrome may be a significant etiologic factor in infertility or other reproductive abnormalities, and transvaginal ultrasound represents a good, non-invasive means of evaluating it.
To review, evaluate, and synthesize current published reports assessing the value of abdominal myomectomy in infertile women and those desiring to preserve fertility potential. Major studies dealing with myomectomy were identified through Medline Searches. Those papers reporting the results of myomectomy, factors influencing them, and potential future innovations were obtained. More than half of women not previously pregnant and undergoing myomectomy to preserve childbearing capacity for treatment of recurrent pregnancy wastage or previous infertility conceive. The long duration of infertility before surgery, absence of other factors to explain their not conceiving, and short time interval subsequent to surgery in which conception occurs suggests myomectomy has value in treatment of patients with leiomyomata and otherwise unexplained infertility. The operation carries acceptable risk. Approximately 25% of women undergoing myomectomy have recurrent leiomyomata, but most recurrences are sufficiently delayed to allow adequate opportunity for conception. Abdominal myomectomy is an appropriate alternative to hysterectomy for most women who wish to preserve childbearing potential or enhance it. For the future, myomectomy by endoscopic techniques may hold similar potential.
EndometriosisLuteal Phase FunctionHormonal AssessmentEndometriosis Association
Our purpose was to determine whether infertile patients who have endometriosis show luteal phase defects. The luteal function in 24 infertile patients who had endometriosis was compared with the luteal function in 20 patients who had unexplained infertility and did not have endometriosis (control). In both groups serum luteinizing hormone, follicle-stimulating hormone, progesterone, and estradiol were assayed every day throughout the menstrual cycle. Endometrial biopsy specimens were obtained from eight patients of the endometriosis group for histologic dating of the endometrium. No significant differences in progesterone levels were observed between these two groups during the mid and late luteal phase. Seven of the eight patients who underwent histologic dating showed a luteal phase pattern, whereas only one patient was out of phase. Infertile patients who have endometriosis do not always have luteal phase defects.
InfertilityLuteal Phase SupportMiscarriage PreventionSupplementation in Early Pregnancy
A prospective and randomized study was performed to investigate the effect of supportive hormones on the development and outcome of early pregnancies following in vitro fertilization and embryo transfer. Immediately after pregnancies were confirmed endocrinologically on day 15 after oocyte collection, 17 alpha-hydroxyprogesterone caproate and oestradiol valerate (PC/EV) was administered to half of the patients in a randomly controlled trial. One group received supportive treatment until the twelfth week of gestation, whereas the other group received no treatment at all. Both groups were followed up by measurements of serum levels of human chorionic gonadotrophin (HCG), oestradiol and progesterone every three days until day 35, when a first ultrasound examination was carried out to confirm fetal vitality. Subsequently, pregnancies were monitored sonographically at regular intervals. In cases of miscarriage, dilatation and curettage was performed and histology analysed. A total of 120 pregnant 55 of them received hormone treatment and 65 patients were controls. Within the treatment group 48 (89%) clinically ongoing pregnancies were observed, five (9%) miscarriages occurred after the seventh week of gestation and one preclinical pregnancy was noted. In the control group, 38 (59%) ongoing pregnancies were observed, nine (14%) miscarriages occurred and 17 (27%) preclinical pregnancies were recorded. Two ectopic pregnancies, one in each group, were excluded from evaluation. A significantly higher percentage of pregnancies were intact at 7 weeks of gestation after treatment with PC/EV (p less than or equal to 0.01).
InfertilityAssociation with Pregnancy LossRisk FactorsObstetrical Outcomes
Women experiencing recurrent spontaneous abortion have a higher frequency of infertility than that expected in the general population. To further define the relationships between infertility and spontaneous abortion, the obstetrical histories of 43 women with unexplained secondary infertility were evaluated for the frequency of spontaneous abortion. Of the 88 pregnancies studied, 39 (44%) resulted in spontaneous abortion. Women with unexplained secondary infertility experienced a three-fold increase (P less than 0.0001) in the frequency of spontaneous abortions and half the number of live births (P less than 0.0001) compared with the general population. We conclude that the association between infertility and spontaneous abortion includes a higher frequency of spontaneous abortion among infertile couples as well as a higher prevalence of infertility among recurrent spontaneous aborters compared with the general population.
InfertilityMultiple Pregnancy OutcomesMultiple GestationNeonatal Morbidity and Mortality
To review the maternal morbidity and neonatal morbidity and mortality associated with in vitro fertilization (IVF) multiple pregnancies. Retrospective analysis of data collected from office and hospital records and from questionnaires sent to patients, their obstetricians, and pediatricians. Patients (all with private insurance carriers) enrolled in an academic IVF program (The Jones Institute for Reproductive Medicine). PATIENTS, All IVF pregnancies resulting in one or more gestational sacs on the initial ultrasound at 6 to 7 weeks were reviewed. The frequency and severity of obstetrical and neonatal complications and the perinatal mortality of IVF twins, triplets, and quadruplets were compared. These were also compared with non-IVF multiple pregnancies. From 1982 to 1990, 629 IVF pregnancies progressed beyond 20 weeks; 115 twins (18.3%), 15 triplets (2.4%), and 4 quadruplets (0.6%). There was a high incidence of antenatal complications such as abortions (30.3%, 42%, and 20%), premature labor (41.5%, 92.3%, and 75%), pregnancy-induced hypertension (17.0%, 38.6%, and 50%), and gestational diabetes mellitus (3.1%, 38.5%, and 25%) for twins, triplets, and quadruplets, respectively. The mean gestational age at delivery was 35.5 +/- 3.7, 31.8 +/- 2.7, and 31.0 +/- 1.7 weeks, respectively. There was also a proportionate progressive increase in neonatal complications. The mean weights were 2,473 +/- 745, 1,666 +/- 441 and 1,414 +/- 368 g, respectively. Twins (22.7%), 64.1% of triplets, and 75% of quadruplets needed admission to the neonatal intensive care unit and remained for an average of 12.0 +/- 2.3, 17.4 +/- 14.0, and 57.8 +/- 17.9 days, respectively. There was no difference in the mean Apgar scores or the incidence of congenital malformations in the three groups. The corrected perinatal mortality rates were 38.5, 0.0, and 0.0 per thousand live births, respectively. Triplet and quadruplet IVF pregnancies have increased obstetrical and neonatal complications compared with IVF twins. The perinatal mortality and the incidence of congenital malformations are, however, comparable in all three groups.
Eight patients with extensive adhesions and 10 undergoing myomectomy had Gore-Tex surgical membranes placed to prevent adhesion formation/reformation. At the time of second-look laparoscopy, the membranes were removed easily, and the extent of adhesion was minimal. Further studies are ongoing to validate these findings and to compare the Gore-Tex surgical membrane with antiadhesion agents.
PregnancyPreterm DeliveryIVF OutcomesSmall for Gestational Age
The Medical Research Council In-Vitro Fertilization (IVF) Register report on births resulting from assisted conception in Great Britain demonstrated a high incidence of preterm and low birthweight babies. This incidence remained high even when the analysis was restricted to singleton babies. The present paper investigates possible risk factors for prematurity, low birthweight and small-for-gestational-age (SGA) in singleton IVF births. Thirteen per cent of singleton IVF babies were preterm, 11% low birthweight and 17% small-for-gestational-age. Analysis by multiple regression indicated that hypertension during pregnancy was an independent risk for preterm delivery, low birthweight and SGA, bleeding during pregnancy for preterm delivery, and the number of embryos transferred and the type of infertility for low birthweight.
Cyclofenil is a triphenylethylene derivative, similar in structure to clomiphene citrate, which is used to induce ovulation in anovulatory women. The effects of cyclofenil on a group of 10 normal cyclic and 10 oligomenorrhoeic subjects were examined in a double blind controlled cross-over study. Both groups of women were administered either cyclofenil or, following a washout cycle, a placebo in two treatment cycles. Urinary oestrone and pregnanediol excretion were measured daily and ultrasound scans performed to assess follicular development. Frequent sampling of blood was performed on day 6 to study luteinizing hormone (LH) and follicle stimulating hormone (FSH) pulsatile release. Cervical mucus changes and sperm-cervical mucus interaction were studied after identification of the LH peak. There were no significant differences between cyclofenil and placebo ovulation rates, daily urinary oestrone and pregnanediol excretion, the number or size of developing follicles, LH pulsatility (parameters number of peaks, pulse interval, pulse amplitude, pulse area and mean nadir LH), mean FSH level on day 6, cervical mucus and sperm-cervical mucus interaction. In view of our inability to demonstrate an effect on any parameter of endocrine function in normal and oligomenorrhoeic women, these results throw doubt on the therapeutic value of cyclofenil in its present dosage and formulation.
To assess the deleterious effect of clomiphene citrate (CC) on the development of the endometrium and its improvement by the addition of ethinyl estradiol (E2). Infertility-treated patients, monitored for induction of ovulation or timing of insemination (control group). We studied four groups of women during an ovulatory cycle with various treatment schedules. Group 1: untreated patients; group 2: patients treated by CC; group 3: patients treated by CC + ethinyl E2; group 4: patients treated by human menopausal gonadotropin. Follow-up of the patients was done by vaginal ultrasonography and measurements of blood E2. In the group treated by CC, both endometrial thickness and uterine volume growth during the follicular phase were lower as compared with untreated controls and menotropin-treated patients. The addition of ethinyl E2 to these patients reversed this deleterious effect of CC without interfering with ovulation. Ethinyl E2 may reverse the deleterious effect of CC on endometrial development during the follicular phase.
In order to clarify the relationship between endometrial histology and progesterone (P4), plasma P4 and estradiol levels in the luteal phase were measured in 126 cases of unexplained infertility. Endometrial biopsies were performed in the midluteal period of menstrual cycles. Forty-three of the 126 cases showed retarded endometrium. Of these 43 cases, 23 exhibited three different types of abnormal P4 secretion. Type A showed low P4 levels throughout the luteal period. Type B showed low P4 levels only in the early luteal period. Type C showed normal P4 levels in the early luteal period followed by a prompt decline. These findings indicated that P4 determination during the early, mid- and late luteal phases is necessary to assess P4 secretion. However, 20 of the 43 cases had normal P4 levels through the entire luteal phase, demonstrating an insufficient response of the endometrium to P4. Consequently, histological examination of the endometrium is required to investigate the luteal phase defect.
Clomiphene citrate therapy has been found to improve the infertility rate in women suffering from polycystic ovarian disease (PCOD). However, there still exists a group of women with PCOD who fail to respond to clomiphene citrate or human menopausal gonadotropin/human chorionic gonadotropin or urofollitropin/chorionic gonadotropin treatment, an ovarian wedge resection by laparotomy approach which has been known for 50 years. Within the last decade, translaparoscopic electrocautery and laser drilling techniques have been utilized. In 1986, a translaparoscopic carbon dioxide laser ovarian wedge resection was introduced for resistant PCOD. This paper describes the surgical principle of a translaparoscopic carbon dioxide laser ovarian wedge resection. This type of treatment results in a 75% crude conception rate, with a 67% rate of healthy live birth. There was an 8% postsurgical adhesion rate among 12 cases that were incorporated into the study. This mode of therapy may prove to be very useful, safe, easy to perform, and cost effective as a second-line therapy for resistant PCOD in cases where medical inductions fail to achieve ovulation.
A study was initiated to evaluate the prevalence of the luteinized unruptured follicle (LUF) syndrome in a group of 355 women with infertility. The diagnosis was established by carefully observing daily sonograms along with measuring estradiol, progesterone, and luteinizing hormone (LH) levels. Two distinct types of mature follicle LUF, in which release of an ovum was not demonstrated after a follicle attained maturity (serum estradiol reached 200 pg/mL while serum progesterone remained less than 2.5 ng/mL), versus premature luteinization LUF, where the serum progesterone increased above 2.5 ng/mL before follicular maturation was attained. The use of either hCG alone or hCG in combination with hMG in a single injection at the time of follicular maturation successfully corrected mature follicle LUF in 21 of 46 patients (46%), whereas ovulation-inducing drugs plus hCG or hCG and hMG corrected LUF in 24 of 25 patients (96%). Clomiphene citrate proved inferior to hMG in that it corrected LUF in 3 of 25 patients (12%) versus 12 of 22 patients (95%) who had undergone hMG therapy. Thus, hMG-hCG therapy is the most efficacious for mature follicle LUF, but because release can occur spontaneously on occasion by an appropriately timed single gonadotropin injection, one could offer the less costly options first. For premature luteinization, speeding up follicular maturation with gonadotropin therapy is effective. Upon failure of this technique, the more costly endogenous gonadotropin suppression followed by hMG can be employed.
Excised tubal segments from 94 infertile women with tubal obstruction, with a mean infertility duration of 5.3 years, and 40 women with ectopic tubal pregnancy were studied histopathologically to evaluate the association with salpingitis isthmica nodosa (SIN). The mean age of the 94 infertile women with tubal obstruction was 24.5 years. Hysterosalpingographies and laparoscopy were performed on all of them. Only the women with ectopic pregnancies we performed salpingectomy on were included in the present study. The incidence of SIN in women with tubal obstruction was 7.4%, in women with ectopic tubal pregnancy 10%, and in the control group the incidence was 0.2%. In 60% of the cases, SIN was present in both of the tubes. Based on this study, we conclude that SIN is significantly associated with infertility and ectopic tubal pregnancy.
PregnancyAdvanced Maternal AgeHypertension and DiabetesMaternal Age
Infertility, spontaneous abortions and trisomic anomalies increase with maternal age, as do ectopic pregnancy, low birth weight, macrosomia, abruptio placentae and labor dysfunction. However, those phenomena are multifactorial in origin and cannot be ascribed solely to advancing age. Older pregnant women are also at increased risk for diabetes and hypertension. Whereas the older gravida is at increased risk for maternal mortality and morbidity and for fetal and infant mortality, those problems are explainable in large part by coexisting medical complications. The healthy older pregnant woman who receives appropriate prepregnancy counseling and up-to-date perinatal care can achieve results comparable to those achieved by younger ones.
We report an interesting case of above-normal serum estradiol concentration of unknown origin. A 30-year-old white woman was seen for infertility problems. Hormonal evaluation revealed the following results. Postovulatory progesterone concentrations and profile (a plot of hormone concentration vs time of cycle) were within the normal range for our laboratory (Table 1). However, the post-ovulatory estradiol concentrations were extremely high, although the curve appeared normal in profile (Table 1).
The incidence and fertility effects of postoperative adhesion formation after laparoscopic ovarian electrocautery or laser photocoagulation of polycystic ovaries has not been adequately analyzed. Short-interval second-look laparoscopy appears to be a useful method for addressing this issue. Employing short-interval second-look laparoscopy 3 to 4 weeks after the initial laparoscopic intervention, we were able to demonstrate adhesions in 6 of 7 patients (85%) treated with ovarian electrocautery and 8 of 10 patients (80%) submitted to laser therapy. The adhesions were amenable to laparoscopic lysis in 12 of 14 patients (85%). The subsequent conception rates within 6 months of second-look laparoscopy that were 57% and 40% in YAG laser groups, respectively, may in part be attributed to the restoration of normal pelvic anatomy during this procedure.
To determine possible etiologies of unsuccessful fluoroscopically guided tubal canalization, we studied the histology of tubal segments in cases of failed canalization for proximal tubal obstruction. Factors contributing to cases of unsuccessful fluoroscopically guided tubal canalization remain unclear. Prospective. Reproductive Endocrinology Clinic. Twenty-seven cornual and/or isthmic tubal segments from 15 patients who underwent proximal tubal surgery after fluoroscopically guided tubal canalization were studied. Specimens were prepared with hemotoxylin-eosin and Masson trichrome stains. Histologic examination of excised cornual and isthmic tubal segments revealed abnormalities in 93% of specimens. Obliterative fibrosis (61%), chronic salpingitis (57%), and salpingitis isthmica nodosa (42%) were the most commonly found histologic tubal abnormalities. One case of complete tubal occlusion and tubal schistosomiasis was also detected. These data suggest that cases of failed fluoroscopically guided tubal canalization may be secondary to severe intrinsic tubal disease and tubal occlusion and not to the technique. Fluoroscopically guided tubal canalization may provide a means of differentiating a functional obstruction amenable to conservative management from true occlusion requiring management by microsurgical techniques or in vitro fertilization.
InfertilityPregnancy ComplicationsLow Birth WeightCross-Sectional Study
We evaluated the association between subfertility and low birth weight infants. Women in this analysis participated in a cross-sectional investigation of maternal risk factors for adverse pregnancy outcomes. Medical and obstetric history and life style information were obtained from women who delivered at the Boston Hospital for Women, 1977 to 1980. PATIENTS, Our analysis was restricted to nondiabetic married women who planned their pregnancies and subsequently delivered viable singletons (3,622). The 644 "subfertile" women (no conception during a year of unprotected intercourse) were compared with 2,978 "fertile" women (conception within 1 year). MAIN OUTCOME MEASURE(S): The relative risk of low birth weight was estimated using the cumulative incidence risk ratio. After adjusting for confounding, the relative risk of delivering a low birth weight infant (less than 2,500 g) for subfertile women versus fertile women was 1.9 (95% confidence interval [CI], 1.3 to 2.8). The adjusted relative risk of delivering a term low birth weight (intrauterine growth retarded) infant was 2.3 (95% CI, 1.2 to 4.4). In these data, subfertility is a predictor for low birth weight. The association may result from endocrinological, immunological, cervical, or other factors that interfere with optimal fetal growth.
To test a sonoscopic technique developed for transvaginal catheterization and recanalization of the fallopian tube. In a feasibility study, catheterization was performed with the use of laparoscopic control. Patients with bilateral proximal tubal obstruction underwent fallopian tube recanalization under ultrasonic observation. This study represents patients evaluated for primary or secondary infertility at Humboldt University Hospital. PATIENTS, Proximal tubal obstruction had been diagnosed on previous hysterosalpingogram and with laparoscopy. None. Tubal patency was assessed by hydrotubation under ultrasonic observation. Transvaginal catheterization was successful in 31 (91.2%) of the 34 tubes. In 19 patients with proximal tubal obstruction, patency of both or at least one tube was achieved in 16 (84.2%) women. Five (31.6%) of 16 patients successfully recanalized were found to have an intrauterine pregnancy at a 6-month follow-up interval. This catheterization technique should be investigated for possible use in diagnostic schedule early in the evaluation of the infertile patient. Also, the transvaginal recanalization of proximally obstructed tubes calls into question the application of microsurgical treatment of a selected group of patients.
The role of natural killer (NK) cells in the decreased cellular immunity of women with endometriosis was investigated. DESIGN, SETTING, Thirty-four women were investigated prospectively before a CO2-laser laparoscopy for infertility and/or pain at the University Hospital Gasthuisberg. Endometriosis was scored blindly. The cytotoxicity, directed against the endometrium, was mediated by NK cells because this cytotoxicity could be removed by treating the effector cells with the NK-specific anti-Leu-11b monoclonal antibody. Consequently, we evaluated prospectively in those women the lymphocyte-mediated cytotoxicity toward NK sensitive (K562-assay) and autologous endometrial target cells. The NK activity (K562-assay) and the cytotoxicity against autologous endometrial cells were similarly decreased in women with endometriosis and correlated with the severity of the disease. Using heterologous effector cells, the decreased chromium release in women with endometriosis was less pronounced but still present. The decreased cytotoxicity to endometrial cells in women with endometriosis is mainly because of a defect in NK activity but is also partially because of a resistance of the endometrium to NK cytotoxicity.
Luteal phase abnormalities are known to complicate ovulation induction with gonadotropins. This study was performed to test the effect of a modified human chorionic gonadotropin (hCG) regimen on the luteal phase during gonadotropin treatment. Fifteen women from a private practice setting volunteered to be studied during each of two nonconception, gonadotropin-stimulated cycles. After ovarian stimulation with human menopausal gonadotropins (hMG), hCG was administered either as a single dose of 10,000 IU (single dose) or in two divided doses of 5,000 IU given 1 week apart (split dose). Early, midluteal, and late luteal estradiol (E2) and progesterone (P) levels and luteal phase lengths were measured, and their median values and intraquartile ranges (IQR) compared using nonparametric analysis. Early and midluteal E2 and P levels were similar regardless of which hCG regimen was administered. The median late luteal E2 level was 1,146.0 pg/mL (the IQR ranged from 633 to 1,650, IQR = 1,017) with the split-dose regimen and 240.0 pg/mL (the IQR ranged from 150 to 460, IQR = 310) with the single-dose regimen. The median late luteal P level was 108.0 ng/mL (the IQR ranged from 58.5 to 129, IQR = 70.5) with the split-dose regimen and 4.2 ng/mL (the IQR ranged from 1.9 to 11.7, IQR = 9.8) with the single-dose regimen. Median luteal phase lengths were 16 days (the IQR ranged from 15 to 17, IQR = 2) for the split-dose regimen and 11 days (the IQR ranged from 10 to 12, IQR = 2) for the single-dose regimen. In hMG-stimulated cycles, a second dose of hCG given during the midluteal phase significantly increases late luteal E2 and P levels and consistently lengthens the luteal phase.
The rate of adhesion formation after ovarian electrocauterization has been described in two selective and unselective groups of patients with PCOS. The rate of this complication in the selective group was 0 from 16 ovaries and in the unselective group (5/25). However, the rate of major adnexal adhesion in the unselective group was 1 from 25 ovaries.
Evaluation of selective salpingography for diagnosis and treatment of tubal injection failure during hysterosalpingography (HSG). Prospective study. Obstetrics and Gynecology Department, University of Genoa (Italy)--tertiary care. One hundred eighty infertile women with unilateral or bilateral proximal tubal injection failure during HSG were submitted to the procedure. Under fluoroscopy, a 4.5-F nylon catheter (3-F tip) was inserted into the ostium with or without the aid of a J-shaped, coaxial, angiographic guide wire, and 2 to 3 mL of contrast medium were injected. The procedure lasts 20 to 30 sec/tube. Of 155 tubal ostia, 145 (94.2%) were catheterized. Of the 146 catheterized tubes, 110 (75%) were rendered patent. Of the others, 21 (14.3%) presented hydrosalpinx or distal obstructions, and isthmic obstruction was present in 5 (3.4%). Patency of at least one tube was achieved in 82 (81.2%) of the 101 catheterized women; 8 conceived spontaneously and 11 after gamete intrafallopian transfer to the recanalized tube. During HSG, selective salpinography can be performed when proximal injection failure is observed to determine its cause or to restore patency.
James Parkinson, a general physician, was interested in all facets of medical care, and wrote two books for the lay public that contained comments on diverse things. He may have been one of the first physicians to publicly describe child abuse. Some of his advice to the public was of a neurologic nature, and included directions on the diagnosis and treatment of pseudoseizures, epilepsy, drowning, and stroke.
Data from previous studies suggest that infertility is a risk factor for endometrial cancer. We used data from the Cancer and Steroid Hormone Study to further characterize this relationship. The subject group comprised 399 women ages 20-54 with newly diagnosed epithelial endometrial cancer ascertained through six cancer registries. The control group comprised 3040 women in the same age range selected by random-digit telephone dialing from the same geographic areas where cancer patients resided. Compared with women who reported no fertility problem, women with physician-diagnosed infertility who had reported at least 2 years of infertility had an odds ratio for endometrial cancer, adjusted for age, of 1.7 (95% confidence interval 1.1-2.6). Women who reported infertility resulting from ovarian factors had an adjusted odds ratio of 4.2 (95% confidence interval 1.7-10.4). These results suggest that factors such as anovulation may explain much of the increased risk of endometrial cancer found among subgroups of infertile women.
Obstruction of the uterine (proximal) end of the fallopian tube is noted on up to 20% of hysterosalpingograms and has a variety of underlying causes. Definitive diagnosis and treatment in the past have required laparoscopy or laparotomy with tubal resection. Selective salpingography and fallopian tube recanalization with fluoroscopically guided catheters has emerged as an improved method both for diagnosis and treatment in these patients. Technical success rates for overcoming the obstruction and visualizing distal tubal anatomy range from 76% to 95%. Pregnancy rates after the procedure vary depending on the patient populations studied; however, early results indicate a greater than 50% intrauterine pregnancy rate by 1 year. The rate of ectopic pregnancy is approximately 10% and that of early tubal reocclusion is less than 30%. Selective salpingography and fallopian tube recanalization is recommended as the first intervention in patients with obstruction of the proximal fallopian tube.
Fifteen infertile women with inadequate luteal phase, histologically documented in at least two separate cycles, and normal midluteal plasma levels of progesterone (greater than or equal to 10 ng/mL), estradiol (70 to 300 pg/mL), and prolactin (less than 20 ng/mL) received "pure" follicle-stimulating hormone (pFSH), 150 IU intramuscularly, for 4 days (days 1 to 4 of the cycle). The endometrial defect was corrected in 7 of the 15 (46.7%) patients during the first treated cycle. Hormonal levels were similar in control and treatment cycles. Two of 5 patients with no additional infertility factors except luteal phase deficiency (LPD) became pregnant and carried to term singleton pregnancies. In 5 additional infertile patients with normal luteal function as assessed by endometrial histological study (2 cycles) and hormone measurements (first study cycle), a third biopsy was performed in a consecutive cycle under pFSH administration. In no case was the normal secretory pattern impaired. It is concluded that (1) some forms of LPD may be successfully treated by early follicular pFSH therapy and (2) pFSH does not alter the normal endometrial secretory pattern.
Transcervical fallopian tube catheterization (TFTC) was performed in 22 infertile patients with bilateral fallopian tube obstruction and a mean duration of infertility of 3.3 years. A high prevalence of previous ectopic pregnancy (n = 8, 36%), tubal ligation and/or reconstruction (n = 5, 23%), spontaneous or therapeutic abortion (n = 6, 27%), and previous intrauterine device use (n = 14, 64%) was noted. The authors successfully catheterized 40 (98%) of 41 tubes without serious complication and visualized the distal tube in 36 (88%) of 41 tubes. Free spill in at least one tube was seen in 17 (77%) of 22 patients. Nineteen patients had a history of previous laparoscopy or laparotomy for tubal disease, in 16 of whom laparoscopic results were available for review. Retrospectively, in 15 (94%) of 16 patients all clinically relevant abnormalities would have been detected by means of TFTC alone. Five patients conceived, three with intrauterine and two with ectopic pregnancies. Patients with intrauterine pregnancies had normal-appearing tubes after TFTC, while those with ectopic pregnancies had residual tubal abnormalities after recanalization. TFTC is a safe, accurate diagnostic procedure that provides more information than hysterosalpingography and, in most cases, as much or more information about the fallopian tubes than laparoscopy.
Mollicutes are frequently isolated from sperma of infertile men. The potential effect on the fertility of mollicute infection is controversial as is antibiotic therapy. In our andrological patients, the prevalence of mollicutes is approximately 10%. To evaluate the benefit of antibiotic therapy, we investigated group 1-patients with positive or negative mollicute cultures and normal spermiogram; morphological changes on spermatozoa were particularly evaluated (n = 40); group 2 - patients with positive mollicute cultures treated with doxycycline or erythromycin. Sperm parameters were analysed before and after treatment (n = 20). When infected and non-infected sperma from group 1 were compared, the only difference found was an alteration of the sperm tail (p less than 0.005). Light microscopy and electron microscopy (EM) often revealed coiled tails which were probably due to adhesion of mollicutes (EM). The most frequently observed pathology in group 2 was found in patients with teratoasthenozoospermia. Compared with the post-therapy spermiogram, a significant difference was only observed in spermatozoal morphology (p less than 0.005). Therefore, we conclude that mollicutes produce important alterations in the human spermatozoal morphology, especially in the tail which appears in a spiral form. Since teratozoospermia is considered to be an important factor of infertility in man, antibiotic therapy is recommended in cases of mollicute involvement.
Reproductive EndocrinologyCorpus Luteum DynamicsLaparoscopy and UltrasoundDiagnosis
In 20 fertile women one menstrual cycle was monitored by ovarian ultrasonography, laparoscopy, and estimation of 17 beta-estradiol (E2) and progesterone levels in serum and peritoneal fluid (PF). Three groups were studied, performing the laparoscopy within 1, 3, and 5 days after ovulation. The results indicate that the opening in the corpus luteum remains at least during the first 1.5 postovulatory days. The process of the closure starts thereafter and has been accomplished 4 to 5 days after ovulation. Progesterone and E2 levels in PF follow a similar pattern, showing high levels in the first, decreasing levels in the second, and low levels in the last laparoscopy groups. Therefore the significance of inspection of the ovaries and hormone level estimation in PF depend on the timing of the laparoscopy in relation to the moment of ovulation, especially in the first 5 postovulatory days.
A prospective, controlled study of ovarian function using ovarian ultrasound and daily plasma hormone estimations (estradiol, progesterone [P], follicle-stimulating hormone [FSH], luteinizing hormone [LH]) was carried out on 175 spontaneously cycling patients with unexplained infertility. Forty-one (23.4%) demonstrated luteal phase cyst formation. In 21 cycles the dominant follicle reduced in size after the LH peak (cystic corpus luteum cycles), and in 20 no shrinkage was seen (luteinized unruptured follicles). Progesterone concentrations in the early luteal phase were significantly reduced in the luteinized unruptured follicle cycles. Elevation in plasma FSH was seen in the early follicular and luteal phases of both cyst forming groups and may be due to disturbances in ovarian metabolism. Follicular rupture is important for efficient P release by the corpus luteum.
This series of 64 myomectomies describes the indications, technique, and efficacy of the procedure; the majority of operations were performed on large multinodular uteri. Indications included enlarging pelvic mass, menorrhagia, anemia, and pregnancy wastage in women who wished to preserve reproductive capability. Although infertility was not the primary indication in any case, 32 patients were nulligravid. Only 10 patients were parous and 14 had a history of spontaneous abortion or pregnancy wastage. The average age of the patients was 35.8 years (range, 27 to 47 years). There were no major complications and no patients received blood transfusions. Follow-up revealed three patients with recurrent tumors necessitating repeat procedures. Successful pregnancies have occurred in 40% of those attempting pregnancy. It is concluded that successful myomectomy can be performed in most patients regardless of uterine size, thereby preserving reproductive potential.
Ninety pregnancies conceived by infertile couples using assisted reproductive technologies and 86 pregnancies conceived by infertile couples with routine infertility treatment were analyzed to determine the outcome of and the complications experienced during the pregnancies. Pregnancies ending after 24 weeks' gestation were evaluated for pregnancy-induced hypertension, diabetes mellitus, preterm labor, premature rupture of membranes, placenta previa, and fetal growth retardation. A matched control group of normal fertile patients admitted to the obstetric service at Vanderbilt University Medical Center was used to compare the incidence of pregnancy complications among the groups. In the group treated by assisted reproduction, 81 pregnancies were singleton and nine were multiple gestations, whereas in the routine group, 84 were singleton and two were multiple gestations. In the group treated by assisted reproduction, 29 of 90 gestations (32%) ended before 24 weeks, compared with 18 of 86 (21%) in the routine group, a nonsignificant difference. Mean birth weight and gestational age were similar among the three groups for singleton gestations. Among multiple gestations, the mean (+/- standard error of the mean [SEM]) birth weights were 2513 +/- 115, 724 +/- 57, and 2282 +/- 132 g in the group treated by assisted reproduction, the group receiving routine methods, and the control group, respectively (P less than .001 when those treated by routine methods were compared with the other two groups). The mean (+/- SEM) gestational ages were 36 +/- 1.2, 26.5 +/- 2.0, and 35.5 +/- 1.2 weeks, respectively (P less than .01 comparing those treated by routine methods and the other two groups).(ABSTRACT TRUNCATED AT 250 WORDS)
InfertilityDiagnosis and TreatmentTransvaginal Catheter DilatationSelective Salpingography
Selective salpingography and transvaginal catheter dilatation were performed in 157 women with infertility to diagnose, localize, and classify obstructive diseases of the fallopian tubes and to correct obstruction of the proximal (uterine-end) tube. In 61 (39%) of the patients, the selective salpingograms showed patent tubes despite the fact that two previous hysterosalpingograms showed obstruction of the proximal (uterine-end) tube. Transvaginal catheter dilatation successfully recanalized the proximal portion of the tubes in 79 (82%) of 96 patients with obstructed tubes. In 18 of 25 with successful transvaginal catheter dilatation and 6-month follow-up salpingography, the tubes remained patent. Coexisting disease of the distal (ovarian-end) tubes was diagnosed in 29 (18%) of the patients. Pregnancy was achieved in 11 of the 157 patients (six in whom obstructions were corrected by transvaginal catheter dilatation and five in whom selective salpingograms showed patent tubes). There were no complications due to the procedure. The excellent diagnostic and therapeutic yield, lack of complications, and low cost justify the use of these percutaneous techniques to investigate female infertility and to treat obstruction of the uterine end of the fallopian tube.
It has been reported that the pregnancy rate after in vitro fertilization (IVF) after pituitary desensitization with luteinizing hormone-releasing hormone agonist (LH-RH-a) is twice as low if the luteal phase is not supported. We therefore tested the respective advantages of luteal support using human chorionic gonadotropin (hCG, 1,500 IU three times) and progesterone (P, micronized, oral administration, 400 mg/d) after 171 embryo transfers (ET) in which the cycle was stimulated with the LH-RH-a triptoreline. The type of luteal phase support was randomly selected except when the estradiol level exceeded 2,700 pg/mL. The clinical pregnancy rate and the ongoing pregnancy rate were significantly higher using hCG (after the transfer of 3 embryos, 45% and 43% with hCG versus 23% and 17% with P). The same results were noted for the embryo implantation rate per ET (19% of embryos are viable after 6 months of pregnancy after hCG versus 7.5% after P). Adequate luteal support, therefore, significantly improves the results of IVF when LH-RH-a are used. The poor results obtained with P in this study might be related to its poor bioavailability after oral administration.
Proximal tubal obstruction, either unilateral or bilateral, is a frequent finding on hysterosalpingogram (HSG). Approximately two-thirds of the fallopian tubes resected for proximal tubal obstruction reveal an absence of luminal occlusion. The distinction between true pathologic occlusion and either spasm or plugging is crucial in determining therapy. We combined hysteroscopic cannulation of the proximal fallopian tube with laparoscopy in 11 patients with proximal tubal obstruction diagnosed by HSG and confirmed at laparoscopy. Hysteroscopic cannulation was able to be performed in 72% of the fallopian tubes attempted, and there was a postcannulation patency rate by HSG of 73%. Six of the 11 patients became pregnant after tubal cannulation and adjunctive distal tubal surgery. Hysteroscopic cannulation of the fallopian tube is a safe diagnostic procedure that can be used to identify those patients with true proximal occlusion, and may also serve as a therapeutic procedure in some of these patients.
Perineal endometriosis was found unexpectedly in a 32-year-old woman with primary infertility. Since there had been no prior perineal trauma, the transport of endometrium through a venous or lymphatic route could have accounted for the location of the endometriosis.
Audebert A, 1990·J Gynecol Obstet Biol Reprod (Paris)
Luteinization of a follicle without its rupture and without the oocyte being expelled which is also called the LUF-syndrome by English speaking authors is one of a number of functional abnormalities that can occur to the follicle in the ovary and is diagnosed by ultrasound methods. It is one that has been known for quite a long time. Many publications have appeared since 1978 to describe this syndrome, which all the same is still very controversial. One has learnt how to diagnose it fairly well. One knows more about its physiopathogenesis and how often it occurs. This seems to be more often when there is pelvic endometriosis or so-called unexplained infertility. What is more difficult however is to find out how important it is as a cause of lowered fertility, and it is also it just happens occasionally or is a true syndrome? It is still not possible today to give a definite answer to this question because of reasons of methodology. Finally, as far as treatment goes, even if the facts about its pathogeneiity have been found out and should be able to help decide on a logical treatment there have been no controlled studies to find out whether the treatment works.
InfertilityOvarian Function EvaluationSalivary ProgesteroneLuteal Phase Insufficiency
Ovarian function was evaluated over a minimum of 3 consecutive menstrual cycles from each of 41 women with unexplained infertility. Follicular development and ovulation were monitored using real time ultrasonography and luteal function was evaluated by daily salivary progesterone measurement. In 129 spontaneous cycles, normal single ovulations were detected in 121 (93.8%). Luteal phase insufficiency was identified in 21 (17.4%) of these 121 cycles and this was a recurrent phenomenon in the cycles of 5 of the 41 women (12.2%). A successful pregnancy was seen only in association with consistently normal salivary progesterone profiles or where the empirical use of clomiphene citrate therapy had corrected previously diagnosed luteal phase insufficiency. Basal body temperature records or mid-luteal serum progesterone measurements were less satisfactory indices of luteal function than a salivary progesterone profile.
InfertilityEmotional CopingPsychological Support Services
Psychologic issues enter into all aspects of providing infertility services. At the onset the infertile are faced with decisions regarding treatment options. Treatment involves uncertainty and lack of control and exposes the couple to the possibility of failure. The introduction of in vitro fertilization and gamete intrafallopian transfer exposes a proportion of couples to successive experiences of failure. These treatments have implications for emotional processing; some factors can increase the likelihood of impaired coping. Specific ways of dealing with the psychologic needs of infertile couples at all stages of their treatment can be helpful.
Twenty-four women with luteal phase defects who were ovulatory on clomiphene therapy with or without human chorionic gonadotropin (hCG) at midcycle for three to eight cycles yet failed to produce a live birth were treated with a short course of menotropin (hMG-S), one to two ampules for five days in the early follicular phase followed or not followed by hCG at midcycle for three to eight cycles. The luteal phase defect was diagnosed with repeat endometrial biopsies with a lag time of three or more days prior to clomiphene therapy. A complete infertility workup revealed only eight patients (33%) with a purely endocrine factor (luteal phase defect). The rest (16 patients, or 67%) had one or two additional infertility factors. Two abortions occurred in this group during clomiphene therapy, while five pregnancies (four live births and one spontaneous abortion) occurred during hMG-S therapy. The ovulation rates were similar for hMG-S (89%) and clomiphene (91%) therapy, but the frequency of a normal ovulatory cycle was significantly greater (P = .026) for hMG-S therapy (71%) than for clomiphene therapy (57%). The midluteal mean serum progesterone level was lower and the mean luteal length shorter in the cycles with less than 130 ng/mL/d of total integrated luteal progesterone. The postcoital test results showed better cervical mucus, with increased mucus volume and better fluidity and spinnbarkeit, in hMG-S cycles than in clomiphene cycles. It appears that hMG-S treatment can improve ovarian function and achieve successful pregnancy in patients with luteal phase defects who fail to produce a live birth during clomiphene treatment.
Inadequate production of progesterone by the corpus luteum results in luteal phase deficiency, which is a frequent cause of recurrent spontaneous abortion. The diagnosis is made by assessment of endometrial biopsy specimens. Measurement of serum progesterone offers a less invasive alternative, but its utility as a diagnostic test is limited since there is no agreement on the level that will accurately differentiate between normal and luteal phase deficiency cycles. The purpose of this study was to determine whether there was an optimal time in the menstrual cycle when serum progesterone measurement could improve the diagnostic accuracy of the test. The results demonstrate that this time period is day 25 to day 26 and not the midluteal phase as has previously been suggested. The discriminatory level was found to be 21 nmol/L and provided a test with sensitivity of 81% and specificity of 73%.
Luteal phase deficiency (LPD) is a reproductive disorder associated with infertility and spontaneous abortion. This study was undertaken to determine whether LPD might be related to an abnormal pattern of gonadotropin secretion. We tested this hypothesis by evaluating the pattern of pulsatile LH secretion in both the follicular and luteal phases of the menstrual cycle in normal women (n = 21) and women with LPD (n = 20), which was diagnosed on the basis of two out of phase endometrial biopsies. In addition, we sought to determine whether changes in progesterone (P) pulse patterns could account for the decrease in average serum P levels in women with LPD. To this end, we examined the pulse patterns of P and compared these patterns between normal women and those with LPD. Frequent blood sampling was performed in both groups to determine their respective hormone secretion patterns. In the follicular phase, blood samples were obtained every 10 min for 12 h; in the luteal phase the samples were obtained every 10 min for 12 h; in the luteal LH, FSH, and P were assayed in each sample. Pulse detection was performed by an adaptive threshold method of pulse analysis. The LH pulse frequency was significantly higher in the women with LPD than in the normal women in the early follicular phase [P less than 0.05; LPD, 12.8 +/- 1.4 (+/- SE); normal, 8.2 +/- 0.7 pulses/12 h]. LH pulse frequency was similar in the early and late follicular phases in the women with LPD, whereas it was higher in the late follicular phase in normal women. Mean serum FSH levels were not different between groups in both the early and late follicular phases. In the luteal phase the P pulse amplitude and mean serum P level were significantly lower in the LPD group than in the normal women (P less than 0.01). We conclude that 1) a too rapid LH pulse pattern in the early follicular phase may lead to inadequate LH support of the corpus luteum and become manifest as LPD; 2) the mechanism for inadequate P secretion in LPD is decreased P pulse amplitude; 3) the finding of similar serum FSH levels in the two groups in both the early and late follicular phases did not support compromised folliculogenesis as an etiological factor for LPD.
Endovaginal and transabdominal sonography (EVS and TAS, respectively) are effective methods for monitoring ovarian follicular development. Our study evaluates both modalities by subjective comparisons and objective correlations with serum estradiol levels. In 21 of 41 studies, TVS showed more follicles over 1 cm than did TAS. The same number was seen by both in 17 studies and more by TAS in only 3 studies. Margins of the follicles were sharply defined in 37 of 41 EVS studies (90%) but only in 18 of 41 TAS studies (41%). In each of the 4 cases in which follicles were not sharply defined by EVS the ovaries were located high in the pelvis. In 29 sonographic studies, there were corresponding estradiol levels. The number and size of dominant follicles correlated well with estradiol levels (r = .9074) for EVS but less so (r = .3816) for TAS. EVS has several advantages when monitoring follicular development.
InfertilityClomiphene Citrate DosingPharmacological StimulationWHO Group II Treatment
One hundred fifty-six women with cycle disorders presenting as absence or infrequency of ovulation and with luteal phase deficiency (group II, according to the World Health Organization classification) received clomiphene citrate (CC) for ovulation induction. The administered dosage ranged from 50 to 250 mg/d. The follicular development in terms of numbers of small (less than 8 mm), intermediate (9 to 15 mm), and large (greater than 15 mm) follicles and their distribution in either one or both ovaries on the day of assumed ovulation was related to the dosage of CC. A statistically significant increase was found in the total number of follicles in relation to the dosage of CC (P less than 0.003). In view of the development of the mature follicles, the gradual increase in CC daily dosage was thought to be associated with additional mature follicles before ovulation. However, this increased follicular recruitment was not regarded as statistically significant. Treatment with low doses of CC resulted in follicular development in only one ovary, whereas increased follicular recruitment after high CC dosage was found in association with follicular development in both ovaries.
Selective fetal reduction was performed in the first trimester of pregnancy in 20 women with multifetal gestations after ovulation induction with human menopausal gonadotropin (hMG). In 10 women (group A) reduction was performed transabdominally, and in 10 women (group B) the transvaginal approach was used. The transvaginal technique achieved penetration of several gestational sacs without withdrawing the needle from the uterus. Fetal termination using either procedure occurred with intrafetal injection of potassium chloride. Six (60%, group A) and eight (80%, group B) patients delivered healthy newborns. One patient (group B) is at 30 weeks' gestation. Four (40%, group A) and one (10%, group B) aborted 1 day to 8 weeks after the procedure (1 septic abortion, each group). Our results suggest that transvaginal fetal reduction offers a better outcome, with minimal complications, to patients referred for selective continuation of pregnancy.
InfertilityDepression and Mood DisordersPsychiatric Symptoms in InfertilityInfertility Psychology
Women who undergo treatment for infertility frequently report depression, but it is crucial to distinguish between subjective distress, symptoms, and clinical depressive disorders. In the initial assessment of a prospective, longitudinal study, 59 women presenting for infertility treatment were compared with 35 women presenting for routine gynecological care. Infertility patients and controls were not significantly different on self-report measures of partner satisfaction, sexual functioning, or self-esteem. There was also no difference in psychiatric symptomatology, or in the percentage of subjects who were currently experiencing or had ever experienced a major depressive episode. However, the infertility patients perceived themselves to have been already quite affected by their inability to conceive. For instance, 49.2% reported changes in their sexual functioning and 74.6% reported changes in their mood.
The sonographic definition of the empty follicle syndrome is presented in a group of 89 consecutive, unmedicated menstrual cycles in women with primary or secondary infertility. The incidence of the empty follicle syndrome was found to be 50%. The incidence increased with age and was independent of gravidity or the type of follicular rupture (or lack of rupture). These data suggest that the empty follicle syndrome may represent a significant etiologic factor in infertility or other reproductive abnormalities.
INTERCEED(TC7) (Johnson & Johnson Patient Care Inc., New Brunswick, NJ) is an absorbable fabric specially designed to reduce postsurgical adhesions. The authors report on a prospective, randomized, multicenter, clinical trial that evaluated the efficacy of Interceed in reducing adhesions in humans. Infertility patients (n = 74) with bilateral pelvic sidewall adhesions were studied at treatment laparotomy and "second-look" laparoscopy to determine Interceed's effectiveness. After removal of adhesions at laparotomy, the deperitonealized area of one pelvic sidewall was covered with Interceed. The contralateral untreated sidewall served as the control. Pelvic sidewalls covered with Interceed had a 90% improvement over control sidewalls in preventing adhesion formation. Additionally, Interceed treatment was associated with a 57% reduction of the extent of adhesion formation over that obtained by microsurgical techniques alone. Interceed also provided a significant benefit in reducing the severity of those adhesions that did form, and significantly reduced the number of adhesions between the ovary and pelvic sidewall. In conclusion, Interceed significantly reduced the incidence, extent, and severity of postsurgical pelvic adhesions.
InfertilityClomiphene CitrateLuteal Phase AssessmentDiagnosis and Treatment
Eighty-seven patients who underwent a late secretory phase endometrial biopsy while taking clomiphene citrate (CC) for ovulation induction were studied. Of the endometrial biopsies, 21 (24%) showed an endometrium greater than 2 days out of phase (OOP) with respect to the subsequent menstrual cycle. All 87 patients were categorized by age, weight, CC dosage, and underlying disease entity. The patients then were evaluated by these categories in relation to the incidence of an OOP biopsy while taking CC. Patients with a diagnosis of hypothalamic amenorrhea were statistically more likely to have an OOP endometrium. No other subgroup showed an increased or decreased incidence of OOP biopsies. Conception and spontaneous abortion rates were similar among patients with in-phase biopsies and those with out-of-phase biopsies, which subsequently were corrected with further medical therapy. An aggressive approach to the diagnosis and treatment of luteal phase insufficiency in patients who receive CC for ovulation induction is recommended.
Borenstein R et al., 1989·Aust N Z J Obstet Gynaecol
Fourteen pregnancies were achieved with tamoxifen therapy in 12 women who failed to conceive with clomiphene citrate. There were no side-effects and fewer treatment cycles were required than with clomiphene citrate treatment. Ovulation and cervical score with tamoxifen therapy were significantly higher (p less than 0.005).
Ultrasound (US) has been demonstrated to be the method of choice for diagnosing luteinized unruptured follicle syndrome and to be a valuable adjuvant in the assessment of luteal phase defect. In this prospective study, the use of US with postcoital testing (PCT) is evaluated. Fifty control infertility patients were examined with serial US for follicle dynamics in conjunction with PCT. Standard curves for follicle dynamics versus cervical mucus quality (Insler score) were calculated. Eighteen patients referred for abnormal mucus underwent similar evaluation. Their follicle dynamics versus mucus quality were compared with those of the controls. (1) there is a predictable relationship between follicle size and mucus quality, (2) the majority of patients with abnormal mucus have normal follicular dynamics, and (3) a minority of patients with abnormal mucus have either a narrow mucus window or abnormal follicular dynamics. In addition, US was found to be cost-effective in the overall fertility evaluation.
InfertilityDiagnostic EvaluationLuteal Phase ProfilesLuteal Phase Dating
The authors have further analyzed women diagnosed as having luteal phase insufficiency in hope of determining the value of specific screening tests as well as determining the degree of heterogeneity of pathophysiologic mechanisms involved in the disorder. Twelve women with the disorder were identified, 6 with two consecutive midluteal serum progesterone (P) levels less than 10 ng/ml (group 1) and 6 with two consecutive late luteal phase endometrial biopsies out of phase (group 2); 4 infertile women with normal serum P and late luteal biopsies also were studied (group 3). All underwent serum sampling for P and luteinizing hormone (LH) at 20-minute intervals for 24 hours, beginning at 9:00 A.M. of day 7 post-LH surge. No significant differences were noted among the three groups for LH area under the curve, pulse frequency, or pulse amplitude. Furthermore, no differences were ascertained for P area under the curve. However, individuals were identified who had one or more hormonal abnormalities but no abnormal biopsy, as well as patients with normal hormonal profiles but having abnormal endometrial development. Receiver Operating Characteristic curves demonstrated that pooled morning serum P levels provided optimal predictive ability of biopsy results. The authors conclude that luteal phase insufficiency is a heterogeneous disorder, and that neither endometrial biopsy nor serum hormonal analysis obviates the need for the other.
InfertilityDiagnostic CriteriaAccuracy and ReproducibilityReference Standards
Five regularly menstruating women of proven fertility, with normal prolactin and thyroid function studies, underwent a total of 39 endometrial biopsies (EMBs). The slides were dated in blinded fashion, and the cycle date determined by considering the date of the next menstrual period as day 28 and counting backward. Using a 2-day or greater lag in endometrial maturity to define a luteal phase defect (LPD), the incidence of single and sequential out-of-phase EMBs was 51.4% and 26.7%, respectively. Using a 3-day or greater lag to define a LPD, the incidence of single and sequential out-of-phase EMBs was 31.4% and 6.6%, respectively. These incidences in normal, fertile women are as high as the rates quoted for infertile populations, and call into question the standard criteria for defining this condition and evaluating therapies to correct it.
Reproductive EndocrinologyNeuron Development and MigrationEmbryologyKallmann Syndrome
Neurons expressing luteinizing hormone-releasing hormone (LHRH), found in the septal-preoptic nuclei and hypothalamus, control the release of gonadotropic hormones from the anterior pituitary gland and facilitate reproductive behaviour. LHRH-expressing neurons are also found in the nervus terminalis, a cranial nerve that is a part of the accessory olfactory system and which projects directly from the nose to the septal-preoptic nuclei in the brain. During development, LHRH-immunoreactivity is detected in the peripheral parts of the nervus terminalis before it is found in the brain. Using a combination of LHRH immunocytochemistry and tritiated thymidine autoradiography in fetal mice, we show that LHRH neurons originate in the medial olfactory placode of the developing nose, migrate across the nasal septum and enter the forebrain with the nervus terminalis, arching into the septal-preoptic area and hypothalamus. Clinically, this migratory route for LHRH-expressing neurons could explain the deficiency of gonadotropins seen in 'Kallmann's syndrome' (hypogonadotropic hypogonadism with anosmia).
InfertilityClomiphene Citrate Side EffectsAnti-Estrogen EffectsEndometrial Thickness Monitoring
Fifteen ovulating women had serial ultrasound scans to measure follicular, endometrial, and uterine growth, as well as biochemical indices including estradiol (E2) and the free androgen index, throughout a natural and a clomiphene-citrate-induced cycle. Despite higher E2 levels in the 5 days preceding ovulation, the clomiphene cycles were characterized by absence of the normal increase in uterine volume and an inhibition of endometrial thickening. It is proposed that the anti-estrogen effect of clomiphene inhibits the normal cyclical growth of the uterus and endometrium.
Oral clomiphene citrate (CC) and vaginal progesterone suppositories (PS) are common treatment modalities in luteal phase dysfunction (LPD). Little is known regarding the relative efficacy of these agents. To study the use of CC and PS in the management of LPD, a retrospective cohort study of patients presenting with infertility was undertaken. Sixty-five patients in whom LPD was diagnosed and corrected, as judged by endometrial biopsies, were studied; 35 were treated with PS and 30 with CC. Using Student's t-tests and chi-square analyses, the two treatment groups were demographically comparable. Using life-table analysis, no one therapeutic approach proved superior. Clomiphene citrate and PS are comparable treatment modalities in the setting of LPD given correction of endometrial lag.
Sonographic visualization of the cumulus oophorus or of morphologic alterations in the wall of the dominant follicle have been reported to be reliable signs of imminent ovulation when conventional transabdominal sonography is used. To determine if transvaginal sonography could allow a more frequent and confident prediction of imminent ovulation, we prospectively monitored 22 ovulatory menstrual cycles in four women undergoing artificial insemination and in 13 normally menstruating volunteers. Scanning was done on alternate days in the periovulatory period; a 7.5-MHz transvaginal transducer was used. Despite the improved resolution obtained with transvaginal sonography, confident identification of the cumulus oophorus or of mural changes in the follicle was not possible in any of the cycles followed. No other consistent follicular characteristic predicted imminent ovulation. We conclude that confident prediction of imminent ovulation is not possible with sonographic analysis.
Traditional therapies for abnormal cervical mucus, other than timed intrauterine insemination, are noteworthy for being ineffectual. Patients (n = 27) with documented abnormal Insler scores in repetitive cycles and failure to conceive with traditional treatments were screened with conjugated equine estrogens (CEE) for estrogen responsiveness of the cervix. Only 5 patients were found unresponsive. Seventeen patients with CEE-responsive cervices then were treated with human gonadotropins (hMG), initially 1 ampule days 5 to 11. If the mucus failed to improve, the hMG was increased to standard doses. Eight patients responded to 1 ampule hMG with improved mucus and conception. The remainder required 2 ampules hMG. In patient cycles with corrected cervical mucus, the viable fecundibility (fv) was 0.35. This is significantly higher than predicted for this population (fv = 0.09; P less than 0.01). In all, 14 of 17 patients conceived viable pregnancies during hMG treatment. It is concluded that graduated hMG is efficacious in treating patients with abnormal cervical mucus responsive to CEE. It is preferable to either in vitro fertilization or gamete intrafallopian transfer, based on both cost and efficacy for most patients.
Endometrial biopsy specimens (n = 62) were evaluated by five pathologists to assess the effect of interobserver variation on histologic dating of the endometrium. The potential effect of this variation on the diagnosis of luteal phase defects (LPDs) and resulting clinical management was also determined. Mean (+/- standard error) interobserver variation was 0.96 +/- 0.08 days, comparable to results reported by other investigators. The magnitude of the variation was not affected by whether the biopsy specimen was obtained in the mid or late luteal phase, the degree of lag between the dating and subsequent menses, or the presence of an LPD. Redating of a specimen by another pathologist would have resulted in a change in the determination of "in" or "out" of phase in 22% of cases. The subsequent probability of changing patient management altered ranged from 22% to 39% depending on the clinical setting.
Reproductive EndocrinologyLuteinized Unruptured FollicleAnovulation MechanismsFollicle Rupture and Luteinization
DlJ. ring the last stage of puberty, the hypothalamic-pituitary-ovarian axis acquires the ability to respond to high levels of estradiol; this results in a sharp increase in the pituitary output of luteinizing hormone (LH). It is believed that within a mature follicle, the LH surge triggers a complex set of events that results in two apparently ovulation and luteinization. The term ovulation will imply rupture of the follicular wall and release of an oocyte, whereas luteinization will imply the morphologic and biochemical shift in the …
Pregnancy outcomes were evaluated retrospectively in 350 women to investigate the relationship between endometriosis and spontaneous abortions. The frequency of spontaneous abortions in women with endometriosis was significantly higher than in both a fertile nonendometriosis group and an infertile group with tubal disease. There was no correlation between the severity of the endometriosis and the frequency of spontaneous abortions. After treatment, the frequency of spontaneous abortions was significantly decreased in both the endometriosis and the tubal disease group, but these values were not significantly different from each other. We conclude that high spontaneous abortion rates are a characteristic of other subgroups of women with secondary infertility and not just in women with endometriosis, and that the majority of spontaneous abortions associated with endometriosis are not caused by the condition.
Medroxyprogesterone acetate (MPA; Provera) was given orally to 449 women from the 5th to 7th week of pregnancy until at least the 18th week. Data are recorded from two treatment groups (recurrent abortion and threatened abortion) and are compared to a matched series. A total of 1,016 pregnancies are included in the study, and all patients were recruited from a subfertile population conceiving from a range of infertility treatments. Early pregnancy wastage was high throughout the groups and was significantly elevated (43%; P less than .001) in those women who had vaginal bleeding in early pregnancy. The study focuses on the question of potential teratogenicity of progestagens administered in the first trimester. There were 15/366 (4.1%) infants with congenital abnormalities in the MPA-treated group and 15/428 in the untreated group (3.5%). The difference was not significant, and MPA is considered to have no embryopathic risk, nor is it likely to retain an abnormal fetus that might otherwise abort. It appears that MPA is a safe drug to use in pregnancy although the question of efficacy has not been addressed in this report. Considering other recent negative epidemiologic studies with regard to teratogenicity, we add to the conclusion that MPA cannot be demonstrated to have a measurable teratogenic risk and certainly does not present a risk for congenital heart disease and limb reduction defects.
Luteal phase deficiency is an ovulatory dysfunction problem that is subtle but real. It may be the most common ovulatory problem in women. Luteal phase deficiency has been clearly demonstrated in the research setting (1) in spontaneous cycles, (2) when follicular maturation has been impeded, and (3) when luteotrophic influences have been suppressed. The diagnosis of LPD in the clinical setting remains problematic and controversial primarily because there is no practical diagnostic method that has been validated. This article has reviewed the methods that have been used to diagnose LPD. BBT charts are insensitive; these charts reliably diagnose LPD only when there are persistent short luteal phases. There is disagreement whether ovarian follicular size, as determined by ultrasonography, is decreased in LPD; however, ultrasonographic diagnosis of LPD would require daily scans through ovulation, which makes this approach impractical. Mild hyperprolactinemia is a probable cause of LPD in a minority of patients; a physician should obtain a PRL level in LPD women with the realization that there is considerable sampling variability. Determination of serum gonadotropin levels (LH or FSH or both) is not practical for the clinical diagnosis of LPD. Random serum P levels, whether single or multiple, are not helpful in the diagnosis of LPD in individual patients. The secretory pattern of P results in such wide confidence limits that P samples from individuals cannot be compared to normal in a useful manner. Most of the controversy about the diagnosis of LPD has centered around the use of individual serum P levels. The timed endometrial biopsy relies on the endometrium as a bioassay of P over time. The endometrial biopsy has not been carefully validated in terms of its sensitivity or accuracy for the diagnosis of LPD. However, it remains the best current method for the diagnosis of LPD when the standard guidelines for its use are followed. As opposed to the other tests for LPD, awareness of the usefulness of the biopsy has increased as we have learned more about CL physiology. No current research method for the diagnosis of LPD appears to be a practical method that could be applied in the clinical setting. Specific secretory proteins from the endometrium and methods to measure hormone secretion that circumvent the secretory pattern hold promise for improved methods to diagnose LPD in the future.
Research MethodologyBiomaterial CompatibilityGamete Handling Materials
Several popular and well-characterized polymeric materials were evaluated for their biocompatibility toward the cells unique to reproduction. To accomplish these studies, several in vitro tests were developed that evaluated biocompatibility between the polymers and spermatozoa, ova, and embryos. The data indicated significant differences between the materials with respect to their biocompatibility toward sperm motility, the sperm's ability to penetrate zona-free hamster eggs, and the ability of two-cell mouse embryos to divide. Polytetrafluoroethylene (PTFE-Teflon; PTFE, Chemplast Inc., Wayne, NJ), polyethylene glycol (PEG), and polyhydroxyethyl methacrylate (PHEMA) appear to be the most inert of the materials studied. Polyvinyl chloride (PVC; Tygon-Norton, Akron, OH) was found to be the most detrimental material toward gametes and embryos, with gross physiologic and morphologic changes observed in the PVC-exposed cells.
SurgeryTubal and Uterine PathologyClassificationClassification and Staging
Pulsatile administration of gonadotrophin releasing hormone (GnRH) is a very effective treatment for induction of ovulation in hypothalamic amenorrhoea (HA). Thirty-seven women have been treated for a total of 117 cycles which resulted in 42 pregnancies--four treatment failures occurred. If these cycles are excluded, the 42 pregnancies were obtained within 2.3 cycles. One twin pregnancy occurred and no hyperstimulation was observed. The treatment was administered intravenously with a dosage schedule based on the grading of HA. We concluded that pulsatile GnRH was safe and very successful in induction of pregnancy in HA. Other indications (polycystic ovary syndrome and luteal phase defect) remain much less suitable for this treatment.
Ten years' experience of artificial insemination with cryopreserved donor semen for 1023 courses in 783 women resulting in 572 pregnancies is reported. A simple approach with multiple inseminations timed on the basis of cycle length, temperature charts, mucus symptoms and signs was used. The life table pregnancy rate was 61% after 12 cycles of treatment and 75% after 24 cycles. Women had a significantly higher rate of pregnancy in second and subsequent courses of treatment, and the pregnancy rate for treatment beyond 12 cycles was significantly less successful. Women over 35 years of age were significantly less successful.
Samples of semen and cervical mucus were provided by 18 couples. Cervical mucus was obtained for each day possible and stored at 4 degrees C until all the samples were collected. Flat capillary tubes were loaded with the mucous samples and spermatozoa from the husband's semen sample were allowed to migrate through the cervical mucus (3 cm column) into culture medium. The spermatozoa recovered after migration through cervical mucus were assayed in vitro with zona-free hamster oocytes. Control experiments were carried out using spermatozoa from the same semen sample but prepared by the swimming-up technique. Altogether, 557 eggs in the control group and 1236 eggs in the experimental group were analysed, and the results demonstrated that the % of sperm penetration, the mean number of sperm decondensations per penetrated egg and the mean number of spermatozoa adhering per egg all had higher values (P less than 0.05) for the control samples than for the experimental samples. We suggest that cervical mucus modifies human spermatozoa, as measured by their interaction with zona-free hamster oocytes.
The existence of luteal phase defect has been the focus of much debate, mainly because of inconsistencies in its diagnosis and management. This study was performed to compare progesterone profiles in women with luteal phase defect with those of women with normal cycles and to establish a discriminatory level of serum progesterone that may aid in the diagnosis of this condition. Compared with patients with luteal phase defect cycles, women with normal cycles produced significantly more progesterone in the luteal phase. The serum progesterone level (less than or equal to 21 nmol/L) was the optimal discriminatory level between luteal phase defect and normal cycles and provided a diagnostic test with 70% sensitivity and 71% specificity. In women with recurrent abortion, the incidence of luteal phase defect was 40%, but with treatment 81% of pregnancies were successful. The findings in this study support the existence of luteal phase defect as a clinically significant entity in recurrent first-trimester spontaneous abortion and one that can be treated successfully with the administration of progesterone. The histologic diagnosis of luteal phase defect may also be confirmed with serum progesterone.
Pregnancy following a period of infertility was considered to be an increased risk for the fetus. During a period of 3 years (1983-85), 748 couples were seen at this infertility clinic; 515 women (68.9%) conceived, and were followed up and studied prospectively. Fifteen of these women moved out of the area. We analysed the results of pregnancies for the remaining 500, (Group 1) and compared them with the outcome for the total obstetric population (Group 2) during the same period. Mean age at conception in the infertility group (Group 1) was 31.8 (+/- 2.7, 2 SD) years, as compared with 23.7 (+/- 2.9, 2 SD) in the total hospital obstetric population (Group 2) (p less than 0.05). The incidences of spontaneous abortion for the two groups (8 and 6.2%) did not differ (p greater than 0.05). However, the incidence of ectopic pregnancy was higher (3.0%) in Group 1 than in Group 2 (1.5%) (p less than 0.01). The incidence of pre-existing hypertensive vascular disease (7.7%) complicating pregnancy and multiple pregnancy (4.1%) was significantly higher in Group 1 than in Group 2 (1.5% and 1.4% respectively), (p less than 0.01). The incidences of induction of labor (29.5%) and elective operative delivery (10.6%) were higher in Group 1 (p less than 0.01). The incidences of infants with birth weight below the tenth centile (12.9%), of fetal distress in labor (14.6%) and a low Apgar score (0-5) (9.5%), were higher in Group 1, but there was no difference in the perinatal mortality rate between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)
A deficiency in follicle stimulating hormone (FSH) levels during the early follicular phase of the menstrual cycle has been shown to result in luteal phase defect (LPD). A short course of human urinary FSH (uFSH) (Metrodin, Serono Laboratories) was given for a maximum of six cycles to 18 women with endometrial-biopsy-proven (EBX-proven) LPD. Adjunctive therapy in the form of midcycle human chorionic gonadotropin was given after the third therapy cycle. The uFSH therapy reduced the mean EBX lag time (2.0 +/- 0.6 days with therapy vs. 4.1 +/- 0.4 pretherapy, P less than .01), normalized the follicular phase length (15 +/- 0.4 days vs. 17.2 +/- 0.8 pretherapy, P less than .25) and increased the luteal phase length (12.7 +/- 0.4 days vs. 10.8 +/- 0.2 pretherapy, P less than .001). Twelve of 46 cycles (26%) in which uFSH was given without adjunctive therapy were anovulatory. Seven patients conceived; the result was seven viable pregnancies, all delivered at term. The cumulative pregnancy rate approached 48% by the sixth therapy cycle. uFSH therapy is useful for the correction of LPD and yields an acceptable pregnancy rate.
Reproductive EndocrinologyDevelopmental ToxicologyProgesterone SafetyLuteal Phase Support
Progesterone, the naturally-occurring 21-carbon steroid produced by the corpus luteum of the ovary and by the placenta, plays an important role in re-production. It is not surprising, then, that it has been used extensively as a supplement in the treatment of disorders of fertility and pregnancy. For example, progesterone is necessary for maintenance of pregnancy in mammals, including humans, and has been given for threatened or habitual miscarriage. The relaxant effect of progesterone on smooth muscle, including that of the uterus, has led to administration of this agent for preterm labor. The effect of progesterone in preparing the endometrium for implantation of the blastocyst has given rise to use of this hormone after natural or induced ovulation to supplement the function of the corpus luteum. How well such treatments work has been argued for many years; however, the fact remains that large numbers of women of reproductive age have received this hormone. It is pertinent, then, to consider whether progesterone or similar agents exert adverse effects on embryo development.
InfertilityPharmacological AgentsNeuroendocrine ControlClomiphene Citrate and Gonadotropins
Attempts to induce ovulation have been made since the early 1920s, but the major breakthrough came in the early 1960s with the introduction of clomiphene citrate and the gonadotropins. Additional progress was made in the early 1970s with the introduction of bromocriptine and in the early 1980s with the introduction of pulsatile GnRH. At the present, 'pure' FSH and GnRH agonists are being evaluated as adjuncts to HMG for induction of ovulation. As more insight is gained in the neuroendocrine control of the ovulating cycle, we may soon be able to induce ovulation by direct manipulation of the central nervous system.
Kennedy JL et al., 1987·Obstet Gynecol Clin North Am
Methods to induce ovulation in anovulatory women have blossomed over the last three decades. The introduction of clomiphene citrate in 1960 allowed us for the first time to provoke follicle development in patients with normo or hyperestrogenic forms of anovulation. The development of human menopausal gonadotropins in the early 1960s gave us a much more powerful tool with which to influence ovulation in all forms of ovulatory disturbances. Elucidation of the pulsatile secretion of gonadotropin-releasing hormone together with its isolation and synthesis has allowed us to streamline our methods of inducing ovulation in hypothalamic amenorrheic patients by using endogenous control mechanisms to maximize both safety and effectiveness. However, there are problems yet to solve. Polycystic ovarian disease has long eluded our efforts to resolve its pathophysiology as well as to devise a consistently effective and safe means of treatment. Methods to restore ovulation in patients with polycystic ovarian disease refractory to clomiphene citrate is the quest of future investigations.
InfertilityCumulative Pregnancy RatesClomiphene Treatment OutcomesPrognosis and Outcomes
From our study of 234 cases of AID with fresh semen, (1) women who do not have other infertility problems, such as ovulatory dysfunction or evidence of tubal disease, have approximately a 90% chance of pregnancy if they stay in the program for up to 12 cycles; (2) with even greater persistence (i.e., greater than 12 cycles), it is predicted that virtually 100% of these women would conceive, but this conclusion is based on extrapolated data and therefore must be interpreted with caution; (3) women with ovulatory dysfunction who are treated with CC during their AID cycles ultimately achieve the same likelihood of pregnancy as women with normal ovulatory function, but at a slower rate; and (4) women with one patent tube (possibly a marker for generalized tubal damage) have a poorer outcome from AID than those with bilaterally patent tubes, from the standpoint of both the ultimate likelihood of pregnancy and the pregnancy rate per cycle.
AndrologyPenetration AssayDiagnostic TestingSperm Function Tests
The human sperm-hamster egg penetration assay (SPA) has been used to evaluate male fertility under in vivo conditions. The test is not only unstandardized, but agreement does not exist as to the lower limits of normal penetration rates. Therefore, it is not surprising that there is considerable doubt as to whether any correlation exists between SPA results and the behavior of sperm in an in vitro laboratory situation. We investigated this question by examining the SPA results and the subsequent fertilization and cleavage rates in the in vitro fertilization program at Pennsylvania Hospital. The sperm from men whose SPA results were 11% or more fertilized 86% of the morphologically normal and mature human oocytes to which they were exposed. Men whose SPA scores ranged from 1% through 10% fertilized 65% of human oocytes, and men whose sperm failed to penetrate hamster eggs still were able to fertilize 41% of the human oocytes. The differences between these groups are statistically significant. This information can be of practical prognostic value during in vitro fertilization cycles in which the number of mature oocytes seen ultrasonographically appears to be at a minimum.
An integrated luteal progesterone (ILPL) was calculated on the basis of a luteal progesterone (P) level with the assumption that the daily plasma P level in the luteal phase closely approximates a sine curve. The midluteal P-amplitude (K) was also obtained mathematically. Daily luteal P levels from five normal ovulatory cycles were assessed for the biologic variation of ILPL and K, then compiled to construct a normogram of the ILP during the luteal phase. The coefficient of variation of K and total ILPL in each cycle ranged from 9.7% to 24.3% and 3.5% to 13.2%, respectively. Fifty-two infertility patients were evaluated for their luteal function by the luteal P and estradiol (E2) level, K, ILPL, endometrial biopsy (EBX)-lag-day, as well as the lengths of follicular phase, luteal phase (L#), and cycle. Thirty-nine patients had EBX-lag day less than or equal to 2 days and were designated as infertile-normal (INF-NL) luteal phase, while the remaining 13 patients who had EBX-lag day greater than 2 days were considered as luteal phase defect (LPD). Significant (P less than 0.05) differences were observed luteal length (13.2 +/- 0.31 versus 11.0 +/- 0.58 days, respectively), and total ILPL (170 +/- 8.3 versus 113 +/- 8.5 ng/ml-day, respectively). No differences were seen in luteal P, E2 and K levels, nor in follicular and cycle length. Significant (P less than 0.05) correlations were observed between total ILPL and luteal P, E2, L#, and K; while a negative correlation was noted between follicular and luteal length.(ABSTRACT TRUNCATED AT 250 WORDS)
This prospective study was designed to investigate the effect of glucocorticoids, promethazine (Phenergan), hyskon, heparin, and Ringer's lactated solution in the prevention of pelvic adhesion formation after pelvic surgery. The patients The first consisted of 396 patients who had laparotomy for different types of pelvic surgery, and the second group consisted of 546 patients who had operative laparoscopy for different types of pelvic disease. Patients in these two major groups were divided prospectively into different subgroups with different modalities of adjuvant therapy to prevent postoperative pelvic adhesions. A second-look laparoscopy was performed for some of the patients who failed to conceive in each of these subgroups. Pregnancy rate and adhesion formation were compared between these subgroups with no statistical difference noted. It is concluded that glucocorticoids, promethazine, heparin, and hyskon have no therapeutic advantage over Ringer's lactated solution in the prevention of postoperative pelvic adhesion formation.
In order to evaluate the relationship between the urinary luteinizing hormone (LH) surge as detected by the OvuSTICK (Monoclonal Antibodies, Inc., Mountain View, CA) method and daily cervical mucus parameters, ten spontaneously ovulating women undergoing infertility evaluation were followed during their cycles with twice daily urinary LH testing as well as daily ultrasound, mucus evaluation, and hormonal assays of serum LH, progesterone (P), and estradiol (E2). Maximal cervical mucus scores, as determined using a modified Insler score, were noted to coincide consistently with the urinary LH surge as detected by twice daily testing and to precede ultrasound evidence of ovulation by 0 to 24 hours. Mucus scores rapidly declined in the 24-hour period following the urinary LH surge. Detection of the urinary LH surge may therefore help identify that period of time during which cervical mucus parameters are optimal and therefore facilitate the timing of artificial insemination, intercourse, or postcoital testing.
Thyroid disorders are often ubiquitous and insidious in their presentation. They have been implicated in a broad spectrum of reproductive disorders ranging from abnormal sexual development to menstrual irregularities and infertility. If pregnancy occurs in a patient with thyroid disease, the physician must ensure that therapeutic measures instituted to restore the health of the mother do not adversely affect the developing fetus. This review examines the role of thyroid disease in disorders confronting the obstetrician/gynecologist and provides a theoretical framework upon which to base practical management decisions.
From 1979 to 1985, 18 patients who were found to have proximal tubal obstruction by hysterosalpingography and laparoscopic chromopertubation underwent resection of the obstructed tubal segment and reimplantation or microanastomosis. Resected tubal segments were studied histologically, and in 11 of the 18 cases no tubal occlusion could be demonstrated. A variety of histologic abnormalities were noted, however, including six cases in which the tubal lumen contained an amorphous material of unknown etiology, often appearing to form a cast of the tube. Such "plugs," which the authors believe to be previously unreported, have no clearly established clinical significance at present. However, if they cause tubal occlusion, this would explain several previously published findings, and would also have implications for therapy.
Artificial insemination with donor sperm (AID) has been a major form of treatment among infertile couples with defects in sperm production. In this report, we review our experience from 1980-1985. A total of 108 patients underwent AID, with 75 resultant pregnancies. Of patients achieving pregnancy, 47% became pregnant after the third cycle and 92% by the twelfth cycle. A higher success rate and/or smaller number of AID cycles were positively associated with patient age of 35 or less and negatively associated with endometriosis. This information is useful in counseling couples interested in pursuing AID.
A technique of translaparoscopic salpingoscopy is utilized to evaluate the ampullary segment of the Fallopian tube in patients suffering from infertility. Comparison of this technique with hysterosalpingography in a series of 32 patients with hydrosalpinges demonstrates its superiority in the evaluation of the tubal mucosa. This new diagnostic approach allows a more accurate selection of patients for either microsurgical repair, in-vitro fertilization (IVF) or gamete intra-Fallopian transfer (GIFT).
The technique for reduction of the number of embryos was applied in a patient who conceived following IVF and transfer of six embryos. On the 10th week of gestation, the number of embryos was reduced from five to three by an U/S-guided intra-uterine procedure. Two healthy girls and a boy were delivered in the 36th week by cesarean section. No trace of the other two fetuses was found. The moral and technical aspects of partial preventive termination of multiple pregnancy are discussed.
Endometriosis has been associated with corpus luteum inadequacy and abnormalities of luteal phase progesterone (P) secretion. In this study, abnormal luteolysis, as a second factor of luteal dysfunction, was assessed in 13 women with endometriosis and 25 control patients by measurement of ovarian vein estradiol (E2) and P during the follicular phase. The results reveal that women with endometriosis have (1) significantly lower ovarian vein E2, (2) significantly higher both peripheral and ovarian vein P, and (3) threefold higher P/E2 ratios than controls during the follicular phase. These data support the concept of continued P production from an active corpus luteum well into the follicular phase of the following cycle in women with endometriosis. Failure of adequate luteolysis is a second aspect of luteal dysfunction in endometriosis and strongly supports the growing body of data confirming ovulatory asynchrony in the minimal; endometriosis infertility syndrome.
A study was designed to see if the use of prophylactic progesterone vaginal suppositories (PVS) reduced the risk of spontaneous abortions in women with a history of at least one spontaneous abortion. PVS was employed during the luteal phase to the end of the first trimester. The dosage was initially 50 mg/day, but was increased according to the endometrial biopsy and doubled as soon as pregnancy was established. Only 10 women (10%) aborted, and 8 of these 10 were successful in their next PVS-treated pregnancies. Overall there were 12 losses in 132 pregnancies (9%) in these PVS-treated patients. Forty-two percent of untreated controls aborted (10/24). The results suggest that PVS is effective in reducing the risk of spontaneous abortions in high-risk patients.
InfertilityPregnancy ComplicationsHypertension and Gestational DiabetesComparative Outcomes by Diagnosis
We studied 500 women who conceived after investigation and treatment for different infertility problems and compared the outcome of the 5 infertility groups (Group 1 to 5), the ovulatory dysfunction (Group 1), male infertility (Group 2), A.I.D. (Group 3), tubal surgery and IVF (Group 4) and no treatment (Group 5) with the outcome in the hospital group during a period of 3 years. The incidence of abortion in Group 3 is significantly higher (13.8%), the incidence of ectopic pregnancy is significantly higher in Group 4 (21.7%) as compared with the incidence in the hospital group (P less than 0.01). The rate of pre-existing hypertension and gestational diabetes is significantly higher in all the 5 infertility groups as compared with the incidence in the hospital group (P less than 0.05). The incidence of preterm labor in general is less in the infertility group as compared with the incidence in the hospital group (P greater than 0.05). The incidence of older women, multiple pregnancy, induction of labor, operative deliveries, fetal distress, low Apgar score, babies with birth weight below the tenth centile were higher in the infertility groups (P less than 0.05). But the perinatal mortality or major or minor fetal anomalies were not significantly different in the infertility groups as compared with the rate in the hospital groups (P greater than 0.05).
The nature and incidence of normal and abnormal spontaneous ovarian cycles, identified with ultrasound and endocrine tracking, were examined in 45 regularly cycling infertile women with no definitive cause and 15 women who were apparently normal and were receiving donor insemination because of clearly infertile partners. In 136 cycles, four apparently distinct abnormal patterns were detected. The total incidence in the infertile group was 58% compared with 23% in the donor insemination group (P less than 0.005). Twelve of 26 subjects who had at least three cycles tracked showed two different abnormalities, and 1 subject had three different abnormalities in five abnormal cycles. These results suggest that abnormal cycles are a significant factor in unexplained infertility and that diagnosis and treatment cannot be based on the study of a single cycle.
InfertilityLuteinized Unruptured Follicle SyndromeLimitations of Traditional MethodsLUF Syndrome
The luteinized unruptured follicle syndrome is a form of anovulation and a subtle cause of female infertility. The syndrome cannot be diagnosed by traditional progesterone-dependent ovulation detection methods. Without the use of invasive procedures or sophisticated equipment, the luteinized unruptured follicle syndrome may go unnoticed. The patient diagnosed as ovulatory, on the basis of traditional ovulation detection methods, who does not conceive may be experiencing the luteinized unruptured follicle syndrome, and thus infertility. The syndrome's incidence, detection, etiology, and treatment are described.
Controversy still exists as to the proper therapy of luteal phase defects. Some advocate using drugs to improve follicular dynamics, e.g., clomiphene citrate, while others treat luteal phase defects with progesterone. The possibility exists that in some cases the luteal phase defect is secondary to failure to produce a mature follicle, the better drug then being an ovulation-inducing drug, e.g., clomiphene. However, if the follicle is mature, then progesterone may be the best treatment. We defined mature follicle as one between 18 and 24 mm while the serum estradiol (E2) level is over 200 pg/mL. The efficacy of exclusive P therapy was evaluated in 50 women, all with a minimum of 1 1/2 years infertility and with no obvious fertility problems other than luteal phase defect. Seventy percent of the women conceived within 6 months. The abortion rate was 14.7%. The average period of infertility was 2.8 years in the 35 patients who conceived within 6 months. These data suggest that determining the degree of follicular maturation by serum E2 and pelvic sonography plus excluding the luteinized unruptured follicle syndrome by pelvic sonography helps determine the proper therapy for luteal phase defect.
We have previously shown that prophylactic supplementation of progesterone beginning in the luteal phase of patients treated with human menopausal gonadotropins (hMG) could reduce the risk of spontaneous abortions. The present study was initiated with 100 patients to evaluate the efficacy of a new progesterone therapeutic regime in patients requiring either hMG or clomiphene citrate. A significantly decreased risk of spontaneous abortion (6% vs. 28%) was seen in 50 patients prophylactically treated with progesterone as compared with 50 control patients. The progesterone regimen was then tried on 566 consecutive patients who were treated and conceived with hMG or clomiphene citrate, and approximately the same risk (6.2% by 20 weeks) was found. This incidence of spontaneous abortion is even less than the accepted risk for the general population.
EndometriosisPelvic Distribution by AgeDisease Progression PatternsEndometriosis and Fertility
In this series of patients, endometriosis does not involve more pelvic areas in older age groups. Exposure to pregnancy is associated with slightly less pelvic involvement, although this effect is inconstant when age groups are studied individually.
InfertilityCervical Mucus DeficiencyEstrogen Receptor AssessmentEndocervical Gland Function
Endocervical gland estrogen receptor (ER) deficiency has been proposed as a possible cause for the poor cervical mucus (CM) in some infertile women with cervical factor. Cytosol ERs were measured in endocervical tissue obtained by biopsy within 3 days of ovulation (determined by the endogenous luteinizing hormone [LH] surge) in five infertile women with persistent poor preovulatory CM (group 1) and in endocervical tissue obtained in the late follicular phase in eight ovulatory women with excellent CM (group 2). ER concentrations were measured in Fmol/mg protein by the dextran-coated charcoal separation method (New England Nuclear Kit, Boston, MA). CM score evaluation and measurement of serum estradiol (E2) and progesterone (P) levels were performed concomitantly. Serum E2 levels of 123.4 +/- 29.3 pg/ml (mean +/- standard error of the mean [SEM]) in group 1 were comparable to E2 levels of 123.3 +/- 15.0 pg/ml in group 2. Serum P concentrations of 0.9 +/- 0.27 ng/ml in group 1 were comparable to 0.79 +/- 0.29 in group 2. A CM score of 4.6 +/- 0.69 in group 1 was significantly lower than 11.6 +/- 0.53 in group 2 (P less than 0.01). The cytosol ER was negative in four of five women in group 1, whereas in group 2, ER was positive in six, borderline in one, and negative in one subject. This study suggests that cytosol ER may be deficient in some women with cervical factor.
Four patients who had no oocytes retrieved during an IVF cycle were studied in an attempt to identify predictors of such an occurrence and suggestions for its cause. All 30 follicles aspirated in five cycles in these four women yielded no oocytes. One patient had two cycles that produced no eggs. The empty follicle syndrome may represent a new syndrome and a cause of infertility.
InfertilityFollicular Development AbnormalitiesFollicular Growth AssessmentLH Surge Abnormalities
A prospective study of six unselected couples diagnosed as having unexplained infertility was done. In three of six patients, subtle abnormalities in follicular development were detected. In the first case poor follicular growth was observed. There was a premature small rise of luteinizing hormone (LH) with subsequent low levels of estradiol (E2) in the late follicular phase and unusual wide LH peak. This was followed by low progesterone levels in the luteal phase. In the second case follicular growth was abrupted by premature LH surge. This surge was triggered by early rise of E2 level while the follicle was still small in size. In the third case luteinized unruptured follicle syndrome was diagnosed, on ultrasound examination. All of the abnormalities were repetitive.
EndometriosisLUF SyndromeDanazol and Ovulation InductionEndometriosis Cases
The effectiveness of ovulation induction with clomiphene citrate or human menopausal gonadotropins was evaluated in 52 infertile women with stage I or stage II endometriosis anovulation or luteinized unruptured follicle (LUF) syndrome before (group I) and after (group II) danazol treatment. The incidence of anovulation and LUF in the endometriosis population was 9% and 34%, respectively. In group I, 10 of 36 patients (27.8%) conceived, with an average of 17.6 induction cycles per pregnancy. In group II, 21 of 30 patients (70%) conceived, with an average of 4.5 cycles per pregnancy (difference significant at P less than 0.001). There was no difference in the average number of ovulation induction cycles per patient between groups I and II (4.9 and 3.1, respectively). Of 14 patients who did not conceive in group I and crossed over to group II, 9 (64.3%) conceived (not different from group II). Spontaneous abortion rates were 20% in group I and 14% in group II. These results indicate that mild endometriosis may interfere with conception through mechanisms other than ovulatory dysfunction and that treatment with danazol appears to more than double the fertility rate.
Two hundred seventy-four infertile patients and 43 women with two or more previous first-trimester abortions underwent a luteal function evaluation by basal body temperature, plasma progesterone, estradiol and prolactin determination, and endometrial biopsy (repeated in a later cycle when the first was defective). An endometrial luteal phase deficiency was detected in 37 (13.5%) of the infertility cases and in 14 (32.5%) of the patients with recurrent miscarriage. However, the endometrial defect was associated with normal hormonal levels in the great majority of patients (86.3%).
Factors influencing the probability of conception after artificial insemination with donor semen were investigated in a series of 80 infertile couples. Overall, 46 pregnancies were achieved for a crude pregnancy rate of 58%. Life table analysis showed a cumulative probability of conception of 97.1% at the end of 12 cycles and an average fecundability of 15.1%. These results were achieved using a single insemination per cycle and individualizing the day of insemination based on the woman's basal body temperature. Women who had been pregnant previously had a significantly better fecundability than nulligravid women (P less than .05). The overall rates of conception in those women who required therapy for ovulatory dysfunction were the same as normal women although the fecundability was somewhat lower. Women who had abdominal pathology had an overall conception rate of 23%.
Data on 575 couples undergoing 1057 consecutive cycles of in vitro fertilization (IVF) were used to calculate cumulative pregnancy rates for repeated IVF cycles. Excluding preclinical abortions and couples in whom the male partner had poor semen parameters, calculated cumulative pregnancy rates for cycles 1 to 6 were 13.6%, 24.8%, 37.2%, 47.8%, 52.2%, and 59.6%, respectively. A parametric model used to fit these data yielded a strong correlation between observed and predicted pregnancy rates (r = 0.99, P less than 0.001). Predicted cumulative pregnancy rates after 9 and 12 cycles were 75% and 84%, respectively. Excluding preclinical abortions, the pregnancy rate per cycle was approximately constant, at approximately 15% over repeated cycles. As the cost of IVF declines and as treatment cycles become more easily tolerated, persistence in IVF can lead to successful pregnancy for a large proportion of couples.
Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, and Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina
Natural Family Planning (NFP) is defined by the World Health Organization (WHO) as "methods for planning or avoiding pregnancies by observation of the natural signs and symptoms of the fertile and infertile phase of the menstrual cycle. It is implicit in the definition of natural family planning, when used to avoid conception that drugs, devices and surgical procedures are not used, there is abstinence from sexual intercourse during the fertile phase of the menstrual cycle, and the act of intercourse, when it occurs, is complete."(1) The fertile period may be determined by using Rhythm, a calculation based on previous cycles, basal body temperature (BBT) charting alone, mucus secretion alone (Billings or Ovulation method), or symptothermal charting (Serena method), which includes observation of both mucus and BBT. The effectiveness of each method is discussed, and the social and psychological profile of couples who use NFP is reviewed. Nfp methods can be used not only to avoid pregnancy, but also to achieve pregnancy and thus are particularly useful in investigating and treating infertility. The function of the Family Life Clinic at St. Michael's Hospital in Toronto is described.
Women with a history of recurrent spontaneous abortions (repeaters) are compared with women who have had live births and no spontaneous abortions (multiparae) and women who have had live births and only one spontaneous abortion (sporadics) to identify characteristics of the women and their abortuses that might predict subsequent fetal loss. A number of risk factors for recurrent spontaneous the loss of a chromosomally normal conception, loss after the first trimester of pregnancy, a delay in conceiving prior to the study pregnancy, a diagnosis of cervical incompetence, and a history of very low birthweight deliveries. The odds ratios associated with being a repeater vary from 1.4 to 5.6 depending on the number of characteristics present.
The association between in vitro fertilization (IVF) and the zona-free hamster egg sperm penetration assay (SPA) was studied in 134 couples. The indications for IVF were tubal disease in 82 couples, unexplained infertility in 23, male infertility in 10, and combined mechanical and male factors in 19. In general, a positive SPA was a good predictor of subsequent IVF (91 of 107 couples). Specificity (number of couples with fertilization in vitro divided by the number of couples with a positive SPA times 100) was 94% for tubal infertility, 76% for unexplained infertility, and 46% for male infertility. A negative SPA predicted an overall fertilization failure of 78% (21 of 27 couples). Sensitivity of the test (number of couples with IVF failure divided by the number of couples with a negative SPA times 100) was 100% for tubal and unexplained infertility but only 63% for male infertility. The high predictive value of the SPA for subsequent IVF outcome in tubal infertility and unexplained infertility warrants its routine use for prescreening in IVF programs. Because of the lack of association between SPA and IVF in oligoasthenospermia, the bioassay should not be relied upon for predicting IVF outcome in male subfertility. The overall high association between the animal model and human IVF reinforces the use of the SPA for both basic research and clinical decision-making.
InfertilitySecondary vs Primary InfertilityOvulation DisordersInfertility Outcomes
To determine the reason for the higher pregnancy rate in couples with secondary infertility, the authors compared 237 infertile couples who had a previous pregnancy in the current partnership (secondary infertility) with 135 infertile couples in whom the woman had been pregnant only in a previous partnership and 925 couples with primary infertility. Couples with secondary infertility had the highest proportion of ovulation disorders (36%); these couples with secondary infertility and an ovulation disorder had the shortest duration of infertility (26 months). Cumulative pregnancy rates at 36 months were 56% in secondary fertility, 44% in primary infertility, and 42% in pregnancy in a previous partnership (P = 0.001). In this study, the better prognosis in secondary infertility may be related to the higher proportion of couples with ovulation disorders, who had a shorter duration of infertility. Abortion rates in the earlier pregnancies with current or previous partners were 37% and 30%, respectively; after the period of infertility, the abortion rates were 14% and 12%, respectively.
InfertilityDiagnosis and TreatmentEndometrial BiopsyLuteal Phase Support
Luteal phase deficiency, diagnosed by endometrial biopsy, was found in 1 out of 25 control fertile women and in 46 out of 355 infertile patients, a difference that was not significant. It was also found in 19 [corrected] out of 60 patients with early recurrent abortion which was significantly higher than in controls and in infertile patients. Pregnancy outcome was evaluated in treated and untreated groups of patients diagnosed as having luteal phase deficiency. Our data suggest that treatment improved the results of pregnancy in patients with recurrent abortion, but not in infertile patients.
Reproductive EndocrinologySafety in PregnancyFetal Anomaly RiskProgesterone Safety
The incidence of congenital anomalies in infants born to 382 women treated with P was noted. Only five anomalies occurred in the infants born to women who had taken P. This study supports the data of Rock et al. by demonstrating a similar low incidence of birth defects in a much larger series of patients who also took a much higher dosage of P. Similarly, because only 1 of 189 patients treated with both P and 17-OHP developed anomalies, the data supports the study by Katz et al., suggesting no increase in anomalies related to 17-OHP therapy.
Ovulation was induced with one-quarter tablet (12.5 mg) of clomiphene citrate given for five days to three oligoovulatory patients who had consistently formed functional ovarian cysts when given 50 and 25 mg of clomiphene citrate for five days. Two of the patients had polycystic ovary syndrome and the other had hypothalamic dysfunction associated with an eating disorder. On clomiphene citrate 12.5 mg for five days, one patient conceived, another produced inadequate cervical mucus but later conceived after in vitro fertilization and embryo transfer, and the third woman, who had concomitant fallopian tube disease, ovulated but has not conceived. Women oversensitive to clomiphene citrate can be effectively treated with very low doses of the drug. Perhaps other oligoovulatory patients may benefit from lower than currently recommended clomiphene citrate doses.
Research MethodologyFertility StudiesMethodologic ReviewBias Analysis
It has been demonstrated that PF contains some factor or factors that interfere with effective gamete interaction as determined by an in vitro animal assay. PF from patients with mild endometriosis has an increased activity of this substance and/or additional inhibitory factors. In endometriosis, this peritoneal fluid factor or factors appear to be filterable and to a significant degree heat-labile. This observation may be of importance in explaining subfertility associated with early stages of endometriosis.
DiagnosticsLuteal Phase AssessmentDiagnostic MethodsEndometrial Dating
We studied endometrial luteal phase in specimens from 660 biopsies done in 300 patients from our infertility clinic. A minimum of two (240 women) or three (60 women) endometrial biopsy specimens from separate cycles were taken regardless of the previous histologic findings in all patients. Statistical analysis of results by the McNemar and the Cochran Q tests for the significance of changes leads us to conclude that a minimum of two, and even three, endometrial biopsy specimens are needed for diagnosis of luteal phase deficiency.
The purpose of this study was to evaluate the effect of peritoneal fluid (PF) on in vitro cleavage of 2-cell mouse embryos. PF was aspirated from the posterior cul-de-sac at laparoscopy and centrifuged, and the cell-free supernatant was heat-inactivated at 56 degrees C for 30 minutes and filtered (0.22 micron). Five percent PF in Ham's F-10 media was prepared and eight to ten 2-cell mouse embryos cultured for 72 hours. There were two study groups, one consisting of 10 PF samples from infertile patients with no endometriosis (PF-NE) and 18 from infertile patients with endometriosis (PF-E). Each sample was assayed along with a control consisting of media only. At 72 hours, greater than 50% of the embryos in the control groups reached the blastocyst and hatching stages. Individual PF samples in both study groups were classified as toxic if less than 50% of the embryos reached the blastocyst and hatching stages at 72 hours. Eight of the 10 samples in the PF-NE group were nontoxic and 14 of the 18 samples in the PF-E group were toxic (P less than 0.01). For evaluation of the overall effect of PF, all results in the PF-E group were pooled (162 embryos) and compared by the Mann-Whitney U test to pooled results in the PF-NE group (100 embryos). The embryonic stages in the PF-NE group were significantly more advanced than those in the PF-E group (P less than 0.001) at 24, 48, and 72 hours.(ABSTRACT TRUNCATED AT 250 WORDS)
An examination was made of the possibility that 100 to 200 ml of intraperitoneal 32% dextran 70 and/or 0.5% hydrocortisone sodium succinate (randomized independently with similar volumes of Ringer's lactate solution) might help to lessen the postoperative formation of adhesions among patients undergoing surgical procedures for peritubal adhesions (n = 76), endometriosis (n = 27), or midtubal occlusion (n = 61). Patients in the first two groups who were given intraperitoneal corticosteroids were also given systemic steroids. Nonparametric comparison of median adhesion scores at operation and at subsequent laparoscopy showed that there was a poorer outcome with dextran than when dextran was not used in every subgroup except one (repeat salpingolysis after previous operation for adhesions), including first operations for adnexal adhesions (Mann-Whitney U = 200, m = 23, n = 26; p less than 0.05). The probability was small (p beta less than 0.002) that an important beneficial effect of dextran was overlooked. Systemic corticosteroids were associated with a consistent trend toward improved outcome, especially in patients who initially had few or no adhesions, such as those operated on for endometriosis (U = 2, m = 7, n = 4; p less than 0.025), but among patients with tubal resections and anastomoses with adnexal adhesions the use of intraperitoneal hydrocortisone alone was associated with a worse outcome (U = 15, m = 12, n = 8; p less than 0.02). Life-table analysis of the accumulating probability of pregnancy showed that no significant difference resulted from adjunct use in any group. The conclusion is that no empiric basis supports the use of intraperitoneal 32% dextran 70 or 0.5% hydrocortisone in the attempt to prevent peritoneal adhesions, but further investigations on the systemic administration of corticosteroids to decrease the formation of adhesions would be useful.
Harrison RF, 1985·Eur J Obstet Gynecol Reprod Biol
Human chorionic gonadotropin was administered intramuscularly in an open study of 32 women whose last three pregnancies had ended in spontaneous abortion. An initial dosage of 10 000 iu on earliest diagnosis of pregnancy was followed up by 5000 IU twice weekly up to wk 12, then once weekly up to wk 16. Only 2 of the 32 patients aborted (6.2%). Using the same regime a further 20 habitual aborters were randomly allocated double-blind to either hCG or placebo. All 10 women on active therapy continued (100%) compared with only 3 on placebo (30%) (P less than 0.01). These results suggest that hCG should be considered as treatment in women with habitual abortion where other specific causes have been ruled out and a potentially treatable hormonal imbalance surmised.
In a consecutive series of 167 patients reaching the stage of embryo transfer after in vitro fertilization and embryo transfer, 19 clinical pregnancies ensued. The serum progesterone (P) levels were significantly greater on the first and second (P less than 0.01) and third (P less than 0.05) postaspiration days for those who conceived. Higher circulating levels of P were achieved on days 1, 2, and 3 (P less than 0.05) by the daily injection of P, 50 mg in oil, given for 5 consecutive days, beginning immediately after follicle aspiration. Both pregnancy and nonpregnancy cycles demonstrated high circulating P levels, but the study implies that relatively higher levels are required for conception, and such levels can be achieved by the use of intramuscular P.
To examine the site of action of clomiphene citrate (CC), LH and FSH pulsatile amplitude, frequency, and responsiveness to GnRH (10 micrograms, iv) were studied in 11 women during the early follicular phase of the menstrual cycle. Six women received CC (150 mg/day) on cycle days 2, 3, and 4, while 5 women received placebo tablets. Blood samples were drawn at 10-min intervals for 8 h before and after the treatment regimen on cycle days 2 and 5, respectively. All women treated with CC had multiple follicular development, as determined by ultrasound. Peripheral levels of estradiol did not change after CC treatment, while progesterone levels decreased slightly. Mean levels of LH increased from 7.5 +/- 0.9 (+/- SEM) to 10.7 +/- 1.4 mIU/ml (P less than 0.05), and FSH increased from 6.7 +/- 0.9 to 10.1 +/- 0.9 mIU/ml (P less than 0.01). After exposure to CC, the pulse frequency of LH during an 8-h period increased significantly (3.3 +/- 0.7 on day 2 vs. 6.8 +/- 0.8 on day 5; P less than 0.01), while the pulse frequency of FSH increased from 3.8 +/- 0.6 to 5 +/- 1.4, as determined by computer pulse analyses. The pulse amplitude of LH and FSH was not significantly altered. In the placebo-treated group, neither pulse amplitude nor pulse frequency changed significantly between cycle days 2 and 5. Pituitary sensitivity to exogenous GnRH did not change after CC treatment. Since the pulsatile frequency of LH is governed by hypothalamic influences, these findings provide compelling evidence for a hypothalamic site of action for CC, probably by inducing an increase in the frequency of GnRH secretion.
Gonadal steroids are altered by the reproductive system's adaptation to conditioning exercise. Contraceptive options for the athletic woman include all measures appropriate for the sedentary woman. Barrier methods (always with spermicidal jelly) are the preferred choice. The cardiovascular risks, decreased aerobic performance, and shorter time to muscular exhaustion related to oral contraceptives make this a less desirable option. Potential complications from the steroid changes low oestrogen and progesterone with risk of loss of trabecular bone and early osteoporosis, and absent progesterone with low normal oestrogen levels associated with risk of endometrial or breast cancer. Therapeutic options for the amenorrhoeic or young athlete include supplemental oral calcium, cyclic oral progesterone, or possibly cyclic physiological oestrogen and progesterone. The anovulatory (usually older) athlete with regular menses needs cyclic progesterone. Medroxyprogesterone 10mg on days 16 to 25 of the cycle or for 10 days monthly can potentially prevent endometrial and breast cancer, give predictable cycles, improve trabecular bone balance and stimulate the return of ovulatory cycles. A practical approach to anovulatory infertility in the athlete includes a 10% reduction in exercise intensity and/or an increase in percentage body fat to 18 to 20%. Cyclic vaginal progesterone (25mg bid) can then treat short luteal phase cycles. With improved understanding of the hormonal adaptations to conditioning exercise, we will be better able to outline contraceptive and therapeutic options in the future.
This report presents the outcome of pregnancies of 93 women who conceived while taking progesterone (P) suppositories (n = 42) or P in oil intramuscularly (n = 51). The dosage and duration of treatment varied according to the indication. The total dose (in milligrams) increased with the duration of treatment and ranged from 75 to 13,500 mg. Two of 75 term pregnancies (2.6%) were noted to have congenital anomalies. Both women had been treated with P in oil. No patient treated with P suppositories gave birth to a malformed infant. An increased spontaneous abortion rate (28.6%) was noted among women treated with P suppositories. The authors recommend that a national registry be created to document fetal outcome after P therapy.
InfertilityOvulatory DysfunctionCombined Ultrasound and Hormonal MonitoringLuteinized Unruptured Follicle
We have examined for the presence of subtle hormonal abnormalities in women with long-standing unexplained infertility. For a full cycle serum LH, FSH, progesterone and oestradiol levels were measured about three times a week, and serial ultrasound scans of the ovaries made until the time of apparent ovulation. The results on 45 cycles in 35 women with unexplained infertility and in three normal volunteers are presented. Normal ovulatory cycles were defined by a length of 26-32 d, and progressive follicular maturation followed by disappearance or abrupt reduction in size of a follicle within 48 h of the recorded LH peak, followed by progressive and sustained rise in serum progesterone levels to more than 25 nmol/l and a luteal phase length of greater than or equal to 13 d. Thirty spontaneous cycles (28 women) were clearly normal while 15 spontaneous cycles (12 women) were abnormal. Abnormalities included luteinization of an unruptured follicle (eight cycles), absence of follicular development (two cycles), poor follicular development (two cycles), persistence of a large ovarian cyst from the preceeding cycle (two cycles) and one aluteal cycle. Six of the abnormal cycles were characterized hormonally by inappropriate elevation of serum LH levels throughout. If this study had been based only on serial ultrasound scans, all results on abnormal cycles might have been misinterpreted. If it had been conducted only with (multiple) progesterone determinations and the level of greater than 25 nmol/l had been taken as indicative of ovulation nine clearly abnormal cycles would have been considered as normal. We conclude that the combination of the hormonal and ultrasound assessment of ovulation increases our confidence for confirmation of normality and reveals various ovulatory disorders which are possibly due to an endocrinological defect or defects.
This study examined the characteristics and attitudes of 132 married couples who had received training in use of the symptothermal method of natural family planning (NFP). 61% of respondents were 20-30 years of age and over 2/3 had completed college; 59% were Catholic. The largest group of subjects (35%) became aware of NFP through friends, neighbors, and relatives. 71% said they were drawn to NFP because it represented a safe and healthy alternative to other methods of birth control; only 17% gave moral or religious reasons for learning about NFP. 42% of the sample were using NFP at the time of the survey, 32% had discontinued use, and 25% were using fertility awareness in conjunction with barrier methods (combination-continuers). There was a significant difference between these 3 48% of combination-continuers and 67% of continuers compared with 41% of discontinuers attended church once a week or more. The combination-continuer group had more Catholics (50%) than the discontinuer group (37%) but less than the continuers (76%). No significant differences were found between the 3 groups in terms of age, education, or regularity of menstrual cycle length. Over 3/4 of continuers had been married for less than 5 years compared with about 1/2 of those in the 2 other groups. 69% of continuers believed that NFP is extremely effective compared to 13% of discontinuers and 40% of combination-continuers. Spouses encouraged each other in the use of NFP in 88% of combination-continuer couples and 86% of continuer couples, but only about half of discontinuers received such encouragement. Although most NFP advocates emphasize a nonsexual form of abstinence during the fertile period, the vast majority of respondents in this study defined abstinence to include the possibility of orgasm. Combination-continuers, positioned between continuers and discontinuers or both dissatisfaction with other methods and with abstinence, warrant more attention in future NFP research.
InfertilityDiagnosis and AssessmentEndometrial Biopsy HistologyProgesterone Insufficiency
Endometrial biopsy specimens were obtained from 107 normally menstruating infertile women 2 to 3 days before the anticipated onset of menses and were day-dated according to histologic criteria. A simultaneous blood sample was obtained for measurement of progesterone (P) and beta-subunit of human chorionic gonadotropin. Of 98 biopsies which could be accurately dated, 56 were in-phase (IP) and 42 were out-of-phase (OOP). Mean serum P levels were significantly lower in women with OOP biopsies undertaken more than 4 days before the onset of menses. A sharp decline in serum P levels was observed in women with IP but not OOP biopsies, so that on the final premenstrual day serum P levels were significantly higher than normal in women with OOP biopsies. Pregnancy continued without interruption in two of six patients who underwent biopsy in the cycle of conception. One patient had an ectopic pregnancy; and the three remaining pregnant patients, all with subnormal P values, aborted. The study suggests that there is a high frequency of minor abnormalities in luteal function in normally menstruating, infertile women for whom tubal and male factors were normal. The frequency of subclinical pregnancy (2 of 107) was lower than anticipated from earlier studies.
A prospective longitudinal and standardized study is presented, dealing with ultrasonographic and hormonal characteristics of the luteinized unruptured follicle (LUF) syndrome. Among 600 cycles monitored in 270 infertility patients, 40 cycles in 27 patients showed no evidence of follicle rupture, in spite of signs of luteinization, as reflected by basal body temperature recordings and progesterone determinations. In this study, 20 LUF cycles in 20 infertile patients were compared with 45 ovulatory cycles in 45 control women. During the follicular phase, no substantial difference in follicle growth was found, but after the luteinizing hormone peak, LUF follicles, instead of rupturing, showed a typical accelerated growth pattern. Both mean luteinizing hormone peak levels and midluteal progesterone levels were significantly lower in LUF cycles than in the control cycles. However, the duration of the luteal phase was not affected. Both central and local factors can be held responsible for the lack of follicle rupture. Ultrasound offers new possibilities as a noninvasive method in diagnosing the LUF syndrome.
One case of extensive endometriosis with ascites in a young nulliparous woman is reported. The patient had been maintained on suppressive therapy with danazol for over two years, demonstrating the feasibility of conservative management in this extremely rare form of endometriosis. However, long-term efficacy and potential for fertility remain to be determined.
Fertility AwarenessMethod ComparisonUltrasound vs BiomarkersDonor Insemination Timing
Ninety-five menstrual cycles were studied in 20 women undergoing donor artificial insemination (AID). In 49 cycles basal body temperature (BBT) changes were charted daily and both daily cervical mucus scoring (modified Insler score) and daily realtime ultrasonography (USS) were performed from day 11 to ovulation. AID was performed only on the day of follicular rupture. A control group, not subjected to USS, were inseminated two to three times per cycle over 46 cycles in the periovulatory period. The Insler score was found to be a reliable indicator of follicular development and rupture. The BBT was found to be less reliable than the Insler score or USS. While USS may be used to confirm follicular development, the Insler score is reliable and less costly.
Sonographic criteria of endometrial tissue were obtained following serial observations in normally ovulating women, and a prospective identification of a specific phase was made in those with regular menstrual cycles. This may be the first report of endometrial tissue characterization. Clinical management of infertility and monitoring of follicular growth will thus be facilitated.
Excised tubal segments from 42 women with uterotubal junction obstruction were studied histologically to evaluate the pathologic spectrum of disease and correlate this with clinical data. The most frequent lesion encountered was obliterative fibrosis (38.1%), confirmed by connective tissue stains, which was not associated with cornual nodularity. Other pathologic entities included salpingitis isthmica nodosa (23.8%), intramucosal endometriosis (14.3%), and chronic tubal inflammation (21.4%). Intramucosal endometriosis was distinguishable from salpingitis isthmica nodosa by virtue of its unique stroma confirmed by connective tissue staining. Women with previous pregnancies were included in all the groups. In all instances, the obstruction was present in the transmural portion of the tube and extended a variable distance into the isthmic segment. These observations on uterotubal junction 1) There are multiple distinct histologic patterns, 2) Intraabdominal findings do not predict the histology of the uterotubal junction pathology, 3) Any histologic pattern can be associated with a previous intrauterine or ectopic pregnancy, and 4) The obstruction begins within the transmural portion of the oviduct, extends a variable distance into the isthmic segment, but does not obstruct the ampullary segment. These data suggest that the initiating process originates within the uterus and that fibrosis may represent a nonspecific response to chronic injury of the transmural and isthmic segments of the oviduct.
InfertilityCryosurgery TreatmentCryosurgeryIn Vitro Penetration Test
Eighteen women with cervical ectropion and 12 women with ectropion and vaginal discharge were treated by cryosurgery. Evaluation of the cervical mucus characteristics by cervical score and in vitro penetration test was performed before treatment and 2 months later. In the group with ectropion only (group A) the total cervical score was 5.7 +/- 0.4 and 11.9 +/- 0.06 (P less than 0.001) (mean +/- standard error) before treatment and 2 months later, respectively. In the group with ectropion and vaginal discharge (group B) the total cervical score before and after cryosurgery was 3.8 +/- 0.4 and 11.8 +/- 0.1 (P less than 0.001), respectively. In vitro penetration tests in group A before and after treatment were 0.72 +/- 0.1 and 2.9 +/- 0.08 (P less than 0.001), respectively. In group B, in vitro penetration tests before and after cryosurgery were 0.25 +/- 0.1 and 2.8 +/- 0.1 (P less than 0.001), respectively. It appears that cryosurgery improves the cervical mucus characteristics. It is recommended that infertile patients with hostile cervical mucus and ectropion will be treated by cryosurgery.
The intraperitoneal instillation of 32% dextran 70 (HyskonR, Pharmacia AB, Sweden) has previously been reported to prevent the formation of postoperative adhesions. Against this background, the present study was undertaken to evaluate the efficacy of HyskonR in counteracting peritoneal adhesions following tubal microsurgery. 105 infertile women were operated upon in a prospective, randomized, controlled, double-blind, multicenter study. The intra-abdominal adhesions present from the beginning were classified by means of a standardized scoring scale and the extent of adhesions was again evaluated at follow-up laparoscopy 4-10 weeks later. A reduction in the extent of the intra-abdominal adhesions (statistically highly significant) was revealed in both the Hyskon group and the saline control group. The extent of adhesions in the Hyskon group was not lesser than in the saline group, however. The pregnancy rates in the two groups were also similar.
More than 100 years after the first description of endometriosis, the pathophysiology of the disorder still remains an enigma. In addition to infertility, an increased frequency of clinically apparent spontaneous abortions (32% vs. 8-15% in the normal population and 19% in the infertile one) has been found in women with endometriosis and secondary infertility. Treatment of endometriosis with conservative surgery, danazol or both results in a frequency of spontaneous abortion within the range of the normal population's. Although the factors involved in the pathophysiology of endometriosis are probably multiple, abnormal corpus luteum function is a common mechanism that might explain both the infertility and the spontaneous abortions. Several studies suggested a relationship between endometriosis and corpus luteum function, which may be mediated by prostaglandins. However, not all the data have been supportive. We developed a hypothetical scheme (modified from Drake) that outlines possible mechanisms of endometriosis mediated by the adverse effects of increased prostaglandins. Further investigation of this scheme may provide new information about the pathophysiology of endometriosis.
Twenty-five infertile women conceived while taking tamoxifen (TMX). Daily serum profiles of 5 of the 25 TMX-induced conception cycles were elucidated and compared with those found in 5 normal cycles. In spite of lower levels of follicle-stimulating hormone and luteinizing hormone during the follicular phases, estradiol concentrations were higher in the TMX-induced conception cycles. It is suggested that this may be due to a direct ovarian effect of TMX as one of its major mechanisms in the course of folliculogenesis. On the other hand, progesterone concentrations on days 6 and 7 during the luteal phases were also higher in the TMX-induced conception cycles. It is suggested that this may be due to a luteotropic influence at the blastocyst stage.
Tamoxifen (Norvadex), synthesized by the Imperial Chemical Industries Ltd., is a triphenylethylene derivative having a clomiphene-like structure and displays anti-estrogenic activities. In this study we used tamoxifen for the treatment of anovulatory infertility and investigated the clinical results. Induction rate of ovulation recorded 100% in the patients with sporadic anovulatory cycle, 83.3% in those with persistent anovulatory cycle, 70% in those with the first grade amenorrhea type I and 66.7% in those with the first grade amenorrhea type II. However, tamoxifen was absolutely ineffective against the second grade amenorrhea. The patients with sporadic or persistent anovulatory cycle responded to 40 mg-daily tamoxifen-treatment, recording 100% of ovulatory induction rate. The patients with the first grade amenorrhea also responded to 60 mg-daily treatment, indicating 70% of ovulatory induction rate. The rate of pregnancy established in the women desiring pregnancy marked 15.4%, and 2 out of 4 women with successful pregnancy experienced spontaneous abortion. Out of 4 patients who did not respond to the previous clomiphene treatment, 3 women accomplished ovulatory induction with tamoxifen. The endocrinological dynamics in the tamoxifen treatment were similar to those in the clomiphene treatment.
InfertilityClomiphene Citrate Side EffectsHormonal InfluencesAnti-Estrogenic Effects
The antiestrogenic effect of clomiphene citrate (CC) on cervical mucus was evaluated in women receiving 150 mg CC daily for 5 days. Daily cervical mucus scores and serum estradiol (E2) concentrations were determined in control (n = 25) and CC (n = 24) cycles. E2 concentrations were significantly higher in the CC-treated women (mean +/- standard error of the mean, 1254 +/- 102 pg/ml versus 337 +/- 18 pg/ml, P less than 0.0001). Despite supraphysiologic E2 concentrations, however, cervical mucus scores were significantly reduced in the CC-treated group (P less than 0.01). These data indicate that CC exerts a direct suppressive effect on cervical mucus despite markedly increased E2 concentrations.
Fertility AwarenessCanalization PhenomenonFerning and Channel FormationMonitoring Methods
Cervical mucus forms channels when dried under a coverslip. The 1) to prove mucus canalization both in spontaneous ovulatory cycles and during ovulation induction with gonadotropins; 2) to prove the estrogen dependence of this phenomenon; 3) to check the importance of the proteidic and electrolytic concentration on chaneling; and 4) to use this phenomenon clinically, shortening the time in which it occurs. The number and arrangement of channels vary during the cycle. The phenomenon is estrogen-dependent. The comparison between estradiol values and the number of channels during spontaneous ovulatory cycles and treatment with gonadotropins showed a linear relationship. Treatment with estradiol 17 beta-valerate and ethinyl estradiol induced channel formation in women with primary amenorrhea. Canalization and ferning disappeared after dialysis or treatment with proteolytic enzymes. It follows that the two phenomena have similar characteristics. Canalization increases daily, as does estradiol, whereas ferning maintains the same grade for a longer period, and when a grade of + + + is reached, it provides no further indications. With the use of a thermostat, canalization occurred in only a few hours. Chaneling, a more precise index, could therefore substitute for ferning, particularly when monitoring the induction of ovulation.
Tamoxifen at a dose of 10 mg/day for 5 days was given to five infertile women in the luteal phase. Daily serum samples were obtained during the luteal phase for radioimmunoassay of progesterone (P), estradiol (E2), follicle-stimulating hormone, luteinizing hormone (LH), and prolactin levels. The integrated luteal phase concentrations of serum P and E2 before and after cycles of tamoxifen treatment increased from 87.8 +/- 16.2 ng/ml and 1120 +/- 164.4 pg/ml to 131.6 +/- 18.9 ng/ml and 1461 +/- 205.2 pg/ml, respectively (P less than 0.01 and P less than 0.05). No apparent increase in circulating LH levels was seen in one of the five cases, but this patient's serum P and E2 levels rose nonetheless. This suggests that the significant increase in circulating P and E2 induced by tamoxifen is not consistently associated with an increase in serum LH concentration.
InfertilityClomiphene CitrateAdjunctive DexamethasoneDHEA-S and Ovulation
Improved understanding of follicular dynamics has led to a reevaluation of suppression of adrenal androgens in ovulation induction. To test whether adrenal suppression during clomiphene citrate (CC) therapy would improve ovulation/pregnancy rates, 64 anovulatory patients who had not previously received CC were randomly assigned to receive either 50 mg CC on days 5 to 9 alone or with 0.5 mg dexamethasone (CC + DEX). Patients were then screened for dehydroepiandrosterone sulfate (DHEA-S) (normal range, 80 to 320 micrograms/dl), prolactin, testosterone, and semen analysis of the partner. Nine patients discontinued participation prior to completing the first treatment cycle, and ten patients were found to have either elevated prolactin (4), severe male factors (3), or tubal disease (3) and were discontinued. CC was increased 50 mg/day per cycle through 150 mg/day until ovulation occurred. Once the patient was ovulatory on therapy, a properly timed postcoital test and endometrial biopsy for luteal phase defect were performed. If anovulatory at 150 mg/day of CC or demonstrating abnormal postcoital test or endometrial biopsy at 150 mg/day of CC, patients were crossed to the other arm of the treatment protocol. The results revealed a significantly higher rate of ovulation (P less than 0.01) and conception (P less than 0.05) in the CC + DEX-treated group. When correlated with DHEA-S levels, this improvement occurred in patients with DHEA-S greater than 200 micrograms/dl (P less than 0.05).
InfertilityProgesterone TreatmentProgesterone SupplementationDiagnosis and Management
Diagnosis, choice of therapy, and pregnancy outcome were analyzed in 79 women evaluated for luteal phase inadequacy. Criteria for the diagnosis were established, and groups at risk for luteal inadequacy were identified. Treatment choices, tailored to the suspected cause, included progesterone suppositories in 54 women, with 23 pregnancies and 19 deliveries; clomiphene citrate in 6 women, with 2 pregnancies and deliveries; and combined treatment in 7 women, with 5 pregnancies and 4 deliveries. Eight women received no treatment, including three who underwent endometrial biopsy in the cycle of conception and who subsequently delivered. These data suggest that careful diagnosis and the proper choice of treatment are important, and that progesterone supplementation may result in improved pregnancy outcome for patients with infertility and pregnancy wastage who have luteal phase inadequacy.
Solutions of sodium carboxymethylcellulose (SCMC) were studied in rats to determine their longevity within the peritoneal cavity and their potential for prevention of postoperative intraperitoneal adhesions. In 18 rats, test solutions of SCMC and 10% dextran 40 were instilled at laparotomy. At 48 hours copious amounts of SCMC remained, whereas no 10% dextran 40 could be detected. In addition, standardized surgical injury was produced on the ceca of 100 rats at laparotomy. All control animals had significant adhesions at 2 weeks. Eighty-two percent of the 10% dextran 40 group had significant adhesions, while only 16% of the 0.9 wt% SCMC and 17% of the 1.0 wt% SCMC groups had significant adhesions. Solutions of SCMC were significantly more effective than 10% dextran 40 in the prevention of adhesions (P less than 0.001). Properties of SCMC and a possible mechanism for its striking effectiveness in adhesion prevention in this study are discussed.
Among 150 patients admitted for ovum aspiration, in vitro fertilization, and embryo transfer in Perth, Western Australia, 14 were found to have had at least one ovulated follicle at the time of laparoscopy. Based upon ultrasound estimation of follicle diameter 24 hours previously, ovulation occurred in 6 of 22 follicles less than 1.7 cm in mean diameter and in 16 of 19 follicles greater than 1.7 cm in mean diameter. When the ruptured follicles were flushed with heparinized fertilization medium, oocytes were collected in 13 of the 22 dispersed follicles. Twelve oocytes developed pronuclei 16 hours after the addition of spermatozoa, and 11 cleaved to the 4-cell stage within 44 hours of insemination. Oocytes were recovered from 6 of 11 patients stimulated with clomiphene alone and from all 3 patients stimulated with clomiphene supplemented with human menopausal gonadotropin. These observations suggest that oocyte release and follicle rupture are not necessarily synonymous events and that the incidence of retained oocytes in ovulated follicles following stimulation with clomiphene or clomiphene plus human menopausal gonadotropin could be on the order of 60%.
Luteal phase lengths and hormonal profiles (progesterone, oestradiol-17 beta, beta HCG and prolactin) have been documented in 77 cases derived from a series of patients undergoing IVF. Nineteen pregnancies were generated during this series and 12 healthy infants have already been delivered. Luteal phase lengths were 14.5 +/- 0.5 days with 14.3% demonstrating mid-luteal progesterone levels of less than 31 nmols/l, considered to be low for successful conception. A random study of luteal support regimens comparing HCG or medroxyprogesterone acetate (MPA) with nil therapy was studied in a series of 44 consecutive embryo transfers during which 10 pregnancies were achieved. No difference was noted in the pregnancy rates for the 3 groups but the pregnancy outcome was better in those who had HCG support and this was more apparent in the overall series of 19 pregnancies. A significant luteotrophic effect was noted with HCG support regimens whilst MPA appeared to have a luteal suppressant action. Six pregnancies which aborted with blighted ova were derived from cycles in which the luteal phase progesterone levels were low raising the possibility that a poor hormonal environment may predispose to blighted ova.
Postoperative pelvic adhesions represent a major challenge to the surgeon operating to correct or prevent infertility. Many approaches have been tried, but intraperitoneal treatment seems to be the most efficacious. Some major landmarks led to the development of the intraperitoneal substances currently used to prevent postoperative pelvic adhesions. On comparing the data on both animals and humans we see that high-molecular-weight dextran seems to be superior to other substances. Much work needs to be done to enhance this adjunctive therapy since excellent surgical technique alone seems insufficient. The future emphasis will probably be on these medications in conjunction with precise surgical techniques and adjunctive intraperitoneal therapy.
General OB/GYNGonorrhea and Chlamydia TreatmentSexually Transmitted InfectionsAntibiotic Comparison
We evaluated the effect of treatment of gonorrhea on simultaneous Chlamydia trachomatis infection by randomly assigning 293 heterosexual men and 246 heterosexual women with gonorrhea to receive one of the (1) 4.8 million units of aqueous procaine penicillin plus 1 g of probenecid, (2) nine tablets of trimethoprim-sulfamethoxazole daily for three days, or (3) 500 mg of tetracycline four times a day for five days. Among the men, gonococcal infection was cured in 99 per cent given penicillin plus probenecid, 96 per cent given trimethoprim-sulfamethoxazole, and 98 per cent given tetracycline. Among the women, only 90 per cent given tetracycline were cured, in contrast to 97 per cent given penicillin plus probenecid and 99 per cent given trimethoprim-sulfamethoxazole. Chlamydial infection, present in 15 per cent of the men and 26 per cent of the women, was cured in 30 of 32 patients given trimethoprim-sulfamethoxazole and 27 of 29 given tetracycline, but in only 10 of 23 given penicillin plus probenecid. Among chlamydia-positive patients, postgonococcal urethritis in men and cervicitis in women occurred more often in patients given penicillin plus probenecid. Salpingitis developed in 6 of 20 women given penicillin plus probenecid, but in only 1 of 26 given trimethoprim-sulfamethoxazole and in none of 24 given tetracycline. We conclude that the use of penicillin plus probenecid alone for gonorrhea in heterosexual patients carries an unacceptably high risk of postgonococcal chlamydial morbidity. Trimethoprim-sulfamethoxazole and tetracycline were highly effective against both pathogens and were well tolerated in men, but both drugs caused frequent side effects in women. The failure of tetracycline to cure gonorrhea in 10 per cent of women argues against its use alone; treatment with penicillin followed by tetracycline has been recommended for further trial.
SurgeryHigh Molecular Weight DextranAdhesion ReductionDouble-Blind Study
The use of intraperitoneal 32% high-molecular weight dextran 70 (Hyskon, Pharmacia Inc.) has been reported to reduce the incidence of surgical adhesions in several species. The present study was undertaken to determine the effect of 32% dextran 70 in human females who underwent major abdominal infertility operations. Adhesions were quantitated by means of standardized objective criteria in 44 women in a prospective, randomized, double-blind study, and reevaluated at second-look laparoscopy approximately 6 weeks later. The mean change in the adhesion score for all patients in the 32% dextran 70 group (n = 23) was -2.57 units (i.e., clinically "improved") versus +2.41 units (i.e., clinically "worsened") in the control group (n = 21), p = 0.016. For the subgroup of patients who underwent lysis of adhesions, the 32% dextran 70 group (n = 17) improved significantly, whereas the control group (n = 12) tended not to improve with careful technique alone (-4.2 units versus +0.3 unit, p less than 0.05). These data indicate that 32% dextran 70 not only significantly reduces the formation of adhesions overall in human infertility operations, but also is highly effective in reducing the reformation of adhesions after lysis.
InfertilityAntiestrogen TherapyPostcoital Test TreatmentClomiphene vs Tamoxifen
Twenty-two infertile women with repeated deficient results in the postcoital test received clomiphene citrate or tamoxifen. The patterns of luteinizing hormone, follicle-stimulating hormone, prolactin, 17 beta-estradiol (E2), and progesterone were examined during the follicular and periovulatory phases of the menstrual cycle, as were the cervical mucus characteristics. Under clomiphene treatment, an overproduction of E2 was observed (P less than 0.01), which did not result in an improvement of the cervical mucus characteristics. The pH of the endocervical mucus was lower (P less than 0.01). Under tamoxifen treatment, the serum E2 levels were higher (P less than 0.05) and normalized. Higher spermatozoa penetration meter scores were observed during the preovulatory and periovulatory periods, whereas the pH of the endocervical mucus was not lowered. These data support that tamoxifen may be preferential to clomiphene in treating this kind of infertile woman.
InfertilityUltrasound-Guided TherapyFollicular Development AssessmentProgesterone Supplementation
In some series the most appropriate therapy for luteal phase defects is supplemental progesterone in the luteal phase. Clomiphene's efficacy is more controversial since in one series only 8% achieved a successful pregnancy versus 45% in another study. Pelvic sonography was used to evaluate follicular development and release of the ovum in 50 infertile women with luteal phase defects. The results showed that only 40% had "pure" luteal phase defects whereas 52% had immature follicles and 8% had unruptured follicles. Sixty-two percent of the patients had previous therapy for a luteal phase defect and failed to conceive. Sixty-eight percent of this group did conceive when ultrasound was used to determine the appropriate therapy. Thus ultrasound can be employed to determine if the women with a luteal phase defect should be treated with a fertility drug, e.g., clomiphene or just with luteal phase progesterone support. Supplemental progesterone might still be needed with clomiphene based on repeat endometrial biopsy results.
In 121 women attending the infertility clinic between 1978 and 1982, 127 cycles with luteal phases of 10 days or more were investigated by a complete basal body temperature (BBT) chart, three plasma progesterone assays taken between 11 and 4 days before menses, and a dated endometrial biopsy (EB) taken at the time of the last blood sample. All parameters were normal in 78 women (64.4%) categorized as group I 'normal luteal phases (NLP)'. There were some discordances between the three parameters in the remaining 43 8 had normal BBT but low progesterone levels and delayed EB. They form group II 'inadequate luteal phases'. 29 women (23.9%) had delayed EB despite forming group III 'dysharmonic luteal phases (DLP)'. 6 women had advanced EB group IV. Apart from endometrial maturation, there was no difference between NLP and DLP, neither in clinical parameters (length of the follicular phase, date and duration of the thermal shift, length of the luteal phase), nor in progesterone levels. Fertilization occurred pregnancies went normally to term, giving birth to normal babies. Therefore, the DLP syndrome, characterized by normal midluteal progesterone levels and a delayed endometrial development, is not incompatible with normal nidation and gestation.
The important role of cervical mucus from a reproduction standpoint is the transport and selection of spermatozoa. The study of the fertilizing ability of human spermatozoa by the use of zona-free hamster oocytes has shown that morphologically abnormal sperm can fuse with the zona-free hamster oocyte. The high proportion of morphologically abnormal spermatozoa present in human semen is significantly reduced after sperm migration through cervical mucus. The mucus, while a favorable environment for sperm survival, does not seem to contribute to the occurrence of sperm capacitation and acrosome reaction.
A prospective study is presented in order to determine the frequency of the luteinized unruptured follicle (LUF) in a population of 66 regularly cycling women. They were monitored by daily ultrasound for a total of 183 cycles, and the LUF was detected in 9 cycles, giving an incidence of 4.9%. The results of daily changes of luteinizing hormone, estradiol, and progesterone provide support for the thesis that the LUF behaves steroidogenically as a corpus luteum and that the luteal phase duration is normal. Continued monitoring in 35 cycles revealed a recurrence in only one case during a fourth subsequent cycle. Thus, the findings indicate that the LUF is a sporadic and infrequent phenomenon. It is therefore an uncommon cause of infertile cycles in potentially fertile women and represents a biologic variable rather than a syndrome. Based on ultrasonic and endocrine observations, a mechanism is proposed for the resolution of the LUF.
It is generally accepted that laparoscopy should be performed if a woman's basic infertility evaluation reveals no abnormalities. Although it has been shown that a significant number of these patients have unsuspected pelvic pathology that can be detected by laparoscopy, there is concern about the real benefit of this procedure, ie, does the laparoscopic examination truly lead to more pregnancies than otherwise expected? Presented is a review of a series of 50 female patients whose basic infertility evaluation had failed to reveal any abnormalities. Laparoscopy revealed significant pelvic pathology in 28 cases; of the 16 who had appropriate therapy, eight became pregnant.
SurgeryDextran 70 Barrier AgentsTubal and Pelvic SurgerySurgical Interventions
Infertile women of reproductive age requiring an operation for distal tubal disease, endometriosis, or pelvic adhesions were recruited from nine study centers. Prior to closing the peritoneal cavity, 250 ml of 32% dextran 70 (n = 55) or saline (n = 47) was instilled into the dependent portion of the pelvis; 8 to 12 weeks later, laparoscopy was performed on those patients not pregnant. Patients with severe adnexal adhesions at the initial laparotomy had a greater reduction in adhesions if they received 32% dextran 70. Further, patients with a marked reduction in adhesion formation following the initial laparotomy were found to occur more frequently in the 32% dextran 70-treated group (26 of 51 for 32% dextran 70 versus 12 of 40 for saline; P less than 0.05). During second-look laparoscopy, adhesions were found to occur more frequently in control patients than in 32% dextran 70-treated patients at ovary (P less than 0.05); cul-de-sac (P = 0.017); pelvic side wall (P less than 0.001). Thus, in a prospective, randomized, blinded clinical trial, the intraperitoneal high-molecular-weight dextran was found to reduce postoperative adhesion formation effectively.
The concentrations of pregnanediol-3-glucuronide (PGD) and pregnanolone (PN) were measured in daily morning urine specimens from 66 infertile women (40 with varying degrees of endometriosis and 26 control subjects) and correlated with daily changes in basal body temperature (BBT) and with midluteal levels of serum progesterone (P). PN and BBT rose at midcycle in women with endometriosis, as expected, indicating secretion of some P at that time. However, PGD, the major endpoint of P metabolism, was delayed in its excretion. Endometrial biopsies were similarly delayed (out of phase) in women with endometriosis, and a significantly higher incidence of follicular luteinization was seen. It appears that while P secretion begins at midcycle, the bulk of P secretion is delayed, perhaps because of the process of follicular luteinization, and that a shortened functional luteal phase thus exists in women with endometriosis.
Basal body temperature (BBT) charts from three menstrual cycles of 20 normal women and 20 women with biopsy-proven luteal phase defect (LPD) were reviewed. Mean luteal phase length in the normal women was 13.4 days, and that of the women with LPD was 11.8 days (P less than 0.05). Six (30%) of the LPD patients had luteal phases of less than 11 days according to BBT, and five of these patients had severely out-of-phase endometrial biopsies. None of the normal patients had luteal phases of less than 11 days. There was no significant difference in the mean rate of postovulatory BBT rise between the two groups. It is suggested that the slope of postovulatory temperature shift is not helpful in the diagnosis of LPD but that evidence of a luteal phase of less than 11 days on BBT does indicate a high likelihood of LPD.
InfertilityClomiphene Citrate SafetyCongenital Malformations After Fertility TreatmentClomiphene Teratogenicity
The effect of clomiphene citrate (CC) on the incidence of congenital malformations in newborn infants was assessed from the outcome of 1034 pregnancies after CC-induced ovulation recorded at nine university hospitals in a 5-year period. Of these pregnancies, 14.2% ended in abortion, 0.5% in ectopic pregnancy, 0.1% in molar pregnancy, and 1.6% in stillbirth. In all, 935 infants were born, and 21 (2.3%) showed visible malformations. This incidence of malformations was not significantly different from that in 30,033 infants (1.7%) after spontaneous ovulation (spontaneous ovulation group), and the types of malformations after CC treatment were similar to e those in the spontaneous ovulation group. These data indicate that CC has no teratogenic effect.
Daily estimations of follicle-stimulating hormone, luteinizing hormone, prolactin, estradiol, and progesterone were made in the serum of eight infertile patients from day 1 through the follicular phase during menstrual cycles before and after tamoxifen therapy. Tamoxifen therapy was found to shorten the follicular phase from 15.4 +/- 0.8 days (mean +/- standard error of the mean) to 14.0 +/- 0.6 days (difference not significant) and to lengthen the luteal phase from 12.8 +/- 0.4 days to 14.1 +/- 0.8 days (P less than 0.05). The mean estradiol concentration in the eight patients during tamoxifen treatment cycles rose on day 8 (3 days after starting tamoxifen treatment) and increased significantly (P less than 0.05) from day 10 to midcycle. The integrated follicular phase estradiol concentration in the tamoxifen treatment cycle increased to 2450.1 +/- 208.1 pg/ml/cycle, and was significantly higher (P less than 0.025) than that in the nontreatment cycle. In contrast, the concentrations of follicle-stimulating hormone, luteinizing hormone, and prolactin during the follicular phase and at the midcycle peak of tamoxifen treatment cycles were not significantly different from those of the nontreatment cycle. These results suggest that the mechanism of tamoxifen in improving folliculogenesis may involve a direct action on the ovary without intervention of the hypothalamic-pituitary system.
During the five years ending on December 31, 1981, 159 anovulatory and oligomenorrheic patients were treated with clomiphene citrate for induction of ovulation. Overall, 86% of these patients ovulated, and 49% of the patients who ovulated conceived. Life table analysis was employed to investigate factors contributing to reduced conception rates, including abnormal semen analysis, pelvic or tubal abnormalities, and poor cervical mucus. Elevated serum testosterone levels did not affect conception rates. The most significant factor contributing to reduced overall pregnancy rates was patient discontinuation of therapy. Cumulative pregnancy rates corrected for discontinuation approach 100% after ten cycles of therapy. During this period, the monthly probability of pregnancy (monthly fecundability) remained constant. Optimal pregnancy rates are attained if other infertility factors are corrected and treatment is continued for ten to 12 ovulatory cycles.
Thirteen women with luteal phase defects (LPD) confirmed by endometrial biopsies and 14 with histologically normal endometria were studied for early follicular and midfollicular phase follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels and for midluteal phase progesterone, estrogen, testosterone, and prolactin levels. The results showed that the women with LPD had significantly lower FSH levels and FSH/LH ratios in the early and midfollicular phases. LH levels, however, were similar in the LPD and normal women. During the midluteal phase, the LPD women showed significantly lower levels of progesterone and estrogen and normal levels of testosterone and prolactin. These findings reaffirm the prevailing concept that events surrounding follicular growth and development can indeed influence the quality of that cycle's corpus luteum. Furthermore, LPD as a result of hyperprolactinemia appears to be a different entity from that due to inadequate follicular phase FSH.
A group of 22 women with anovulatory cycles was treated with tamoxifen in 46 cycles. We elucidated daily hormone profiles in 5 of the 33 tamoxifen-induced ovulatory cycles in order to make a comparison with those found in 5 normal cycles. Serum follicle-stimulating hormone and luteinizing hormone (LH) rose during or a few days after the tamoxifen therapy, and thereafter serum estradiol levels rose gradually over the normal ranges during the follicular phase and reached an extremely high preovulatory peak which triggered an LH surge. This increased estradiol production exerted its usual negative feedback on LH secretion. Following ovulation, serum progesterone rose and fell in a manner similar to that in the normal cycles, with occasional values that exceeded the normal range. The endocrine significance of these findings is discussed.
The cause of infertility has remained obscure in women with endometriosis in whom the tuboovarian relationship is unaltered. Abnormal corpus luteum function has been one mechanism implicated in the pathophysiology of endometriosis in infertilityl-3 and may also be a possible explanation for the high frequency of spontaneous abortions among women with untreated endometriosis.4 However, we have observed only an occasional occurrence of luteal phase deficiency in women with an ultimate diagnosis of endometriosis. In order to verify this observation, we examined the incidence of luteal phase defects (LPDs) in. our infertility population.
Inadequate levels of circulating progesterone (P) seen in clinical practice can be increased by P supplementation. When supplementation is via the vaginal route, its presentation may be in many different suppository bases. We have measured circulating P in the follicular phase to compare delivery from the vagina after P was presented in three different bases (glycerinated gelatin, cocoa butter, and polyethylene glycol). The mean peak level achieved and the area under the curve were highest after supplementation from polyethylene glycol-based suppositories. The duration of elevation above baseline was similar with all three suppositories. It is concluded that the suppository base is important in controlling the amount of this steroid absorbed from a given amount presented by this route.
Ultrasonographic measurement of follicle growth and estradiol concentrations have been shown to correlate well in spontaneous and Clomid-induced ovulatory cycles. However, little is known about these changes during human menopausal gonadotropin (hMG) therapy. Twenty-five women who did not ovulate when treated with clomiphene were treated with hMG during 70 treatment cycles. Eleven patients had withdrawal bleeding after progesterone administration (group 1) and 14 did not bleed (group 2). Follicle growth was monitored with intermittent serum estrogen determinations and daily ovarian ultrasound with an ADR Model 2140 real-time sector scanner. The mean dominant follicle size at the time of human chorionic gonadotropin (hCG) injection was 21.2 mm +/- 0.6 (SEM) and was not different between the two groups. Mean serum estrogen level at the time of hCG injection was 1,121 pg/ml and correlated with follicle volume. At the time of hCG injection in group 2, one dominant follicle was present in 65% and two were present in 35% of the patients. Among those in group 1, two or more dominant follicles were present during all cycles. Mean serum estrogen levels were significantly higher in group 1 patients than those in group 2. This "chemical hyperstimulation" was induced in order to delay ovulation until adequate follicular size had been achieved. All cycles were ovulatory. Five patients in group 1 and eight in group 2 conceived. The use of ultrasound enables the physician to evaluate follicular growth and development daily and thus to individualize treatment and to reduce the need for estrogen monitoring.
The incidence of luteal phase defects in 366 infertility patients was 12.7%. Life-table analysis was used for determination of the conception rate with clomiphene citrate therapy, and with this method, evidence was found for the presence of two subgroups with respect to response. The crude conception rate was 40.9%. In a group of patients with a luteal phase defect and no other infertility factors, those that conceived had a significantly larger mean biopsy delay than those who did not (6.28 days versus 4.32; P less than 0.02). In a group with a histologic delay of 5 days or more, the conception rate was 79%, while the rate was only 8.9% in those with a less severe deficit (P less than 0.001). Theoretic considerations for clomiphene citrate therapy are discussed.
PCOSOvulation InductionClomiphene ProtocolsDHEA-S and Testosterone
Twelve oligomenorrhic women with polycystic ovary syndrome (PCO) in whom clomiphene (250 mg daily for 5 days) and 10,000 IU human chorionic gonadotropin had failed to induce ovulation were treated with clomiphene and dexamethasone. Eight of the 12 women underwent complete hormonal assessment during treatment. Six of the 12 ovulated and 1 conceived. Serum total and unbound estradiol and testosterone (T), serum dehydroepiandrosterone sulfate (DHEA-S), sex hormone binding-globulin binding capacity (SHBG-BC), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and prolactin (PRL) were measured during clomiphene and dexamethasone therapy. SHBG-BC increased in response to clomiphene whether or not ovulation occurred. After treatment with clomiphene and dexamethasone there was a significant decrease in serum T, unbound T, and DHEA-S 2 weeks after dexamethasone administration, but there were no change in LH, FSH, or PRL. In patients who ovulated after clomiphene and dexamethasone, T and unbound T increased again after clomiphene was begun despite the continuation of dexamethasone. The women who ovulated after clomiphene and dexamethasone treatment had significantly higher pretreatment levels of DHEA-S than those who did not ovulate. Clomiphene and dexamethasone treatment may be beneficial to women who have elevated levels of DHEAS and who fail to ovulate with maximum doses of clomiphene.
A group of 17 patients with suspected luteal phase deficiency was treated with tamoxifen. Tamoxifen therapy was found to lengthen the luteal phase in all patients and resulted in pregnancy in 6 of 17 patients. The integrated luteal phase progesterone (P) concentration in the nontreatment cycle of seven patients was significantly lower (P less than 0.01) than that of five normal women. Therapy with tamoxifen increased the P concentration to 186.0 +/- 24.4 ng/ml/cycle (mean +/- standard error of the mean), i.e., twice that of the control cycle. The mean estradiol (E2) concentration at the midcycle peak was about twice that observed during the nontreatment cycle. The glycogen content of the endometrial tissue at the midluteal phase in the tamoxifen cycle was significantly higher (P less than 0.025) than that of endometrial tissue in the nontreatment cycle, indicating improvement of the endometrial function.
Reproductive EndocrinologyConception Cycle ProfilesConceiving vs Non-ConceivingProgesterone Markers
Hormonal profiles were obtained throughout 26 conception cycles and 27 non-conception control cycles. The pregnancies followed treatment (clomiphene or bromocriptine) in 12 women but were spontaneous in the remaining 14. No sustained significant difference between the various types of conception cycle was found for LH, FSH, oestradiol or progesterone concentrations. Prolactin concentrations varied widely, suggesting that mean cycle prolactin concentrations ranging from 45 to 760 mi.u./l are compatible with conception. Although there were no significant differences in progesterone secretion within the conception cycles, there were highly significant differences between the conception cycles and the non-pregnant control cycles. Mean progesterone concentrations in the conception group were higher (P less than 0.005) than those in the control women over Days 3-8 following the LH peak. This difference could only be partly accounted for by heterogeneity within the control group (15-20% of the control cycles had low progesterone concentrations and were probably subfertile. It is suggested that the higher conception cycle progesterone concentrations during the early part of the luteal phase may constitute a preimplantation component of the maternal recognition of pregnancy in women.
Sixty-nine infertile women with a midluteal serum progesterone level of 4 to 14 ng/ml were treated with a graduated dosage schedule of clomiphene citrate until the progesterone level on day 21 was greater than 20 ng/ml. Thirty-one pregnancies occurred, 58% during the first adequate treatment cycle and 19% during the second cycle. The abortion rate was 23%. After 6 adequate treatment cycles, laparoscopic evaluation was performed on 28 of 39 patients who did not conceive. Pathology was noted in 57%. Seven of 17 patients with intraperitoneal causes of infertility conceived after alternative therapy. The corrected pregnancy rate was 60%. Results of this study suggest that low luteal phase progesterone levels may compromise fertility and that clomiphene citrate enhances pregnancy rates.
Many studies have been published on luteal phase deficiency, and the emphasis in most of them is on progesterone deficiency. In this study 144 patients (455 cycles) with infertility were studied. The patients were divided into four groups. Group 1 consisted of patients with high estradiol and high progesterone levels in the midluteal phase. Group 2 consisted of patients with high estradiol and low progesterone levels. Group 3 consisted of patients with low estradiol and low progesterone levels. Group 4 consisted of patients with low estradiol and high progesterone levels. As expected, patients in groups 2 and 3 showed a low conception rate with outphased endometrial biopsy. However, group 4, in spite of the normal progesterone levels, had a low conception rate with an outphased endometrium. We conclude that estradiol deficiency during the luteal phase is a major factor in infertility, and replacement therapy with progesterone alone in these patients may not improve fertility.
InfertilityOvulatory DysfunctionFollicular MonitoringEstradiol and Progesterone
A significant portion of human infertility is presumably due to defective ovulation, including patients who fail to conceive despite medical induction of ovulation, those who fail despite repeated timely donor inseminations, and those with "infertility of unknown etiology". All point out the inadequacy of standard criteria for normal ovulation. This investigation correlates preovulatory serum estradiol and gonadotropin concentrations with dominant follicle growth measured ultrasonographically and serum progesterone levels. The data indicate a 35% incidence of cycles with significantly abnormal serum estradiol levels, decreased dominant follicle size, and abnormal progesterone levels despite biphasic basal body temperature curves and normal cycle length. If these cycles represent inadequate or abnormal ovulation, they can be distinguished from adequate cycles prior to follicle rupture and may benefit the treatment of human infertility.
Contraception/ComparisonReturn to FertilityPost-Contraceptive Delayed ConceptionRetrospective Cohort
Interview data from 3,214 married women having planned pregnancies and singleton deliveries who had no history of fertility treatment and who conceived more than two weeks after cessation of contraception were analyzed. The interval from cessation of contraception to conception was 13 months or greater for 24.8% of prior "pill" users vs 10.6% for former users of all other methods. As compared with former users of other methods, pill users had a notably lower monthly percentage of conceptions for the first three months and somewhat lower percentage from four to ten months. Results were not altered when potential confounding variables were controlled by logistic regression. At least 15 months of unsuccessful trials might be a more appropriate working definition of infertility for previous pill users rather than the 12-month interval generally accepted for this purpose.
The outcome of pregnancy was studied in all women conceiving after ovulation induction with clomiphene at the gynaecological endocrine clinics operating in 2 Tasmanian cities. In 156 pregnancies where details were available, abortion rate 10.3%; multiple pregnancy rate 4.1%; congenital abnormality rate 3.6%; and perinatal mortality rate 3.5%. The results are compared with other reported series.
InfertilityOvulation InductionClomiphene vs TamoxifenAnti-Estrogen Therapy
Messinis IE et al., 1982·Acta Obstet Gynecol Scand
The effectiveness of tamoxifen and clomiphene in inducing ovulation was compared in 46 women with anovulatory infertility. All the women were given both the drugs in an alternate way. If one cycle was treated by tamoxifen the next was treated by clomiphene and vice versa. Forty-one out of the 46 women (89.1%) ovulated at least once during the study. Similar ovulation rates were achieved by tamoxifen (56.2%) and clomiphene (62.9%). The lengths of the ovulatory cycles and their luteal phases and the mid-luteal phase serum progesterone levels did not differ significantly between the two compounds. Nor did the occurrence of luteal phase defects during the tamoxifen and clomiphene treatment cycles differ. Thirty-seven of the 46 women (80.4%) responded similarly to both drugs. Thus, tamoxifen is just as effective as clomiphene in inducing ovulation in women with anovulation.
Meier-Vismara E et al., 1982·Geburtshilfe Frauenheilkd
During the last decade, the World Health Organization has paid increasing attention to some reliable methods of birth control based on periodic abstinence. There are 2 main methods of natural family planning--the Sympto-Thermal method and the Billings Ovulation method. The latter is explained in this paper. Its scientific basis, use, effectiveness, and importance as a birth control method as well as for understanding certain types of infertility are discussed. (author's)
PCOSOvarian Wedge ResectionWedge Resection Fertility OutcomesPCOS Ovarian Surgery
Fertility following bilateral ovarian wedge resection (BOWR) was evaluated in a retrospective cohort study of 90 consecutive cases of the polycystic ovary syndrome. Post-BOWR follow-up was available for varying time spans of up to 10 years. BOWR resulted in the resumption of menstrual cyclicity in 91.1% (82/90) of the cases. However, within this ovulatory group, 26 patients were characterized by oligo-ovulation and a significantly reduced conception rate (29.2%), as compared with that of 56 normo-ovulatory counterparts (60.3%). Although the crude overall conception rate for this series was 47.8%, the overall cumulative probability of conception at the end of follow-up as determined by life table analysis was 73%. The likelihood of conception at any given point in time was estimated by a monthly fecundability rate of 1.34%. Our findings also indicate that the probability of post-BOWR conception was unaffected by age, race, ward status, or duration of infertility. In contrast, persistent post-BOWR oligo- or anovulation and the presence of concurrent tuboperitoneal disease were reaffirmed as the most important determinants of the likelihood of post-BOWR conception. A minimum incidence of 7.8% was documented for acquired post-BOWR pelvic disease.
Reproductive EndocrinologyCancer RiskLong-term Health OutcomesHormonal Risk Factors
In order to investigate the nature of the association of involuntarily delayed first birth and risk of breast cancer, 1083 white women who had been evaluated and treated for infertility from 1945-1965 were followed prospectively through April 1978 to ascertain their breast cancer incidence. These women were categorized as to the cause of infertility into two groups, those with endogenous progesterone deficiency (PD) and those with nonhormonal causes (NH). Women in the PD group had 5.4 times the risk of premenopausal breast cancer compared to women in the NH group. This excess risk could not be explained by differences between the two groups in ages at menarche or menopause, history of oral contraceptive use, history of benign breast disease or age at first birth. Women in the PD group also experienced a 10-fold increase in deaths from all malignant neoplasms compared to the NH group. The incidence of postmenopausal breast cancer did not differ significantly between the two groups.
Previously, we demonstrated that selective suppression of serum follicle-stimulating hormone (FSH) in monkeys treated with charcoal-extracted porcine follicular fluid (pFF) in the early follicular phase induced luteal defects resembling those which occur spontaneously in women and monkeys. Here, we assessed whether luteal phase defects arising in association with induced FSH deficiencies during the early follicular phase can be treated by early FSH therapy. Rhesus monkeys were treated with pFF and human menopausal gonadotropin (hMG) (FSH:luteinizing hormone [LH], 3:1) on cycle days 1 to 3 or day 4, respectively. Daily femoral blood samples were analyzed for LH, FSH, and estradiol by radioimmunoassay. In the monkeys treated with the pFF-hMG combination, a single ovulation was uniformly noted at laparoscopy, and initial luteal phase elevations in serum progesterone levels were nearer those of normal ovulatory cycles than after pFF alone. These results suggest that FSH/LH treatment in the early follicular phase compensated, in part, for the pFF-induced deficiency in endogenous FSH levels.
This study was intended to correlate different clinical and biologic parameters to better define luteal insufficiency (LI) and to contribute to a better understanding of its origin. Endometrial patterns were used as the basis for classification of clinical cases. Of 328 outpatients with menstrual disorders and/or infertility, 88 were considered to have LI. Their cycles were compared with 79 normal cycles. Two different principal endometrial pure LI, when the endometrium is more than 2 days out of phase; and LI with persistent estrogenic influence, when the histologic estrogenic stigmata are excessive during the luteal phase. Basal body temperature charts demonstrated either ovulation delay or a slow increase in temperature (longer than 2 days). Plasma steroid concentrations also demonstrated a perturbation progesterone levels were statistically significantly lower in LI than in normal cycles and this defect was worse when the estrogenic influence was persistent; the preovulatory estradiol peak was disturbed in all circumstances, as was the concentration of endometrial steroid receptors. These simultaneous abnormalities strongly suggest a central origin of LI.
EndometriosisConservative Surgery OutcomesPostoperative Pregnancy RatesStaging Systems and Fertility
A homogeneous group of 214 infertile women with endometriosis treated at the Johns Hopkins Hospital from 1960 to 1979 received conservative surgery as the sole therapeutic modality. Among this group, 115 patients (54%) conceived following surgery; of these conceptions, 109 resulted in a living child. Among 49 patients with secondary infertility, the spontaneous abortion rate was reduced from 49% to 20% after conservative surgery (P less than or equal to 0.01). Three contemporary classification systems were utilized to categorize patients according to the sites and amount of endometriosis at the time of conservative surgery. Those systems suggested by Buttram (Fertil Steril 30:240, 1978) and by Kistner and coauthors (Fertil Steril 28:108, 1977) revealed differences among fecundability rates among the different categories (P less than or equal to 0.01); however, the system suggested by The American Fertility Society (AFS) (Fertil Steril 32:633, 1979) revealed significant differences only if categories were combined (mild plus moderate versus severe plus extensive, P less than or equal to 0.05). Nevertheless, the AFS system revealed that pregnancy success was significantly reduced if an ovarian endometrioma was greater than 3 cm or had ruptured (P less than or equal to 0.01).
General OB/GYNTreatmentSexually Transmitted PathogensPID Prevention
The treatment of pelvic inflammatory disease depends upon the etiology of the condition. Pelvic infection (PI) after parturition and abortion, gynecologic surgery, and a variety of invasive procedures is commonly associated with the isolation of anaerobic and aerobic flora of the vagina. The factors which influence the choice of antimicrobial treatment and the role of Bacteroides fragilis and Escherichia coli are discussed. Sexually transmissible agents of importance are Neisseria gonorrhoeae and Chlamydia trachomatis. Pelvic infections associated with these pathogens require antibiotics which exert an optimum effect against them. Examination and treatment of the sexual partner(s) are important. The possible role of the anaerobic and aerobic vaginal flora as opportunistic secondary pathogens is discussed. Developments in the surgical treatment of the sequelae of PID are reviewed. The results of treatment of uncomplicated gonorrhea in 262 women are reported. C. trachomatis was isolated from 53% of women before treatment. After treatment, PI developed in 11 women who had been given penicillin and in one woman who had been given tetracycline (P = 0.0071). It is suggested that recognition and treatment of postgonococcal cervicitis in women treated for uncomplicated gonorrhea with penicillin might provide one form of preventive treatment for nongonococcal PI.
Two cases of ovum retention occurring in postovulatory follicles are described. The ova were recovered at laparoscopy by aspiration of decompressed ovulatory follicles, one during a natural cycle and the other following a programmed clomiphene/human chorionic gonadotropin cycle. Each patient had a normal luteal phase with an increased progesterone level indicative of ovulation. The implications of these findings and their relevance to human fertility studies are discussed.
Leyendecker G et al., 1980·J Clin Endocrinol Metab
In previous studies it could be demonstrated that in severe hypothalamic amenorrhea, which is associated with absent or deficient hypothalamic secretion of Gn-RH, ovarian function could be restored by chronic intermittent (pulsatile) administration of Gn-RH. In order to apply chronic intermittent administration of Gn-RH as a new mode of treatment of infertility in hypothalamic amenorrhea on an outpatient basis a portable device ("Zyklomat") was constructed consisting of a peristaltic pump, a computerized timing device and a Gn-RH containing bag, which delivers 50 microliters of a Gn-RH containing solution once every 90 minutes via an i.v. catheter into the circulation. It is the purpose of this communication to present this new method of treatment and the successful induction of the first two pregnancies with this method in two patients with severe hypothalamic amenorrhea.
The luteinized unruptured follicle syndrome is a frequent phenomenon, occurring in half of our women with regular cycles and infertility. Progesterone concentrations and 17 beta-oestradiol concentrations were assayed in peritoneal fluid of women during the luteal phase. Up to day 20 of the cycle, the concentrations were significantly higher in women with an ovulation stigma than in women without an ovulation stigma on their corpus luteum. The range of concentrations was sufficiently different in the early luteal phase to be used diagnostically, the only limitation being the presence of a cystic corpus luteum. We suggest that the assay of progesterone and 17 beta-oestradiol in peritoneal fluid should be done in all women with infertility and biphasic basal body temperature charts in order to diagnose the luteinized unruptured follicle syndrome.
InfertilityLuteal Phase DefectProgesterone MeasurementLuteal Phase Dating
Plasma progesterone concentrations drawn at the time of endometrial biopsy in 26 infertility patients with histologically documented luteal phase inadequacy were compared with those of 26 infertility patients with normal biopsies. Although as a group the former patients had lower progesterone values and shorter cycles, there was considerable overlap. Therefore, although plasma progesterone determinations and temperature charts are useful in the detection of ovulation and in the interpretation of the biopsy results, a properly obtained endometrial biopsy is essential for the diagnosis of luteal phase inadequacy.
Three hundred and ninety-six patients were evaluated for primary and secondary infertility between December 1976 and May 1979 at a large referral center. Timed late luteal endometrial biopsies were routinely obtained as part of the work-up and were repeated for confirmation if subsequent menses did not occur within 2 days of the expected date. If both biopsies were abnormal, a diagnosis of luteal phase defect (LPD) was made and patients were treated with vaginal progesterone suppositories for a minimum of 6 months. LPD was discovered in 32 of 396 patients (8.1%); among those patients whose infertility was not complicated by other abnormalities, 9 of 13 conceived (70%) and 7 of 13 carried to term (54%). These data suggest an incidence higher than generally recognized and a very encouraging response to replacement therapy.
Crowley WF Jr et al., 1980·J Clin Endocrinol Metab
The administration of small doses of LHRH at 2-hourly intervals over a 27 day period to a 24-year old patient with Kallman's syndrome resulted (1) a biphasic temperature response, (2) anatomical changes in the ovaries demonstrated by ultrasound, and (3) the pattern of circulating gonadotropin and gonadal steroid concentrations.
Fertility AwarenessSperm-Mucus InteractionHormonal Effects on CervixSemen Quality and Cervical Transport
Twenty-five women scheduled for hysterectomy for nonmalignant disease participated in the study. Sperm storage in endocervical crypts was examined nine women pretreated with estrogen and inseminated with normal semen, nine women pretreated with gestagen and inseminated with normal semen, and seven women pretreated with estrogen and inseminated with abnormal semen. The number of crypts containing spermatozoa (colonized crypts) and the sperm density per crypt were examined in serially sectioned cervices. In estrogen-pretreated cervices both the percentage of colonized crypts and the sperm density were significantly higher than in gestagen-pretreated cervices. Large and giant crypts proved to be the main storage facility for spermatozoa. The localization of crypts along the endocervical canal did not influence sperm storage. The quality of semen appeared to be of critical importance to sperm storage. The percentage of colonized crypts and sperm density were severly reduced in patients inseminated with abnormal semen.
One hundred and forty-nine patients presenting with infertility underwent two hundred and ten endometrial biopsies as part of a routine infertility evaluation. The initial biopsy was out of phase in 44 (29.5%), confirmed by subsequent biopsy to yield a total of 28 (19%) patients with luteal phase inadequacy. Of 44 patients taking clomiphene citrate, 13 (29.5%) had out-of-phase biopsies. Although hyperprolactinemia, recurrent miscarriages, extremes of reproductive life, and clomiphene citrate administration have been associated with an increased incidence of the defect, in this series a predisposing cause could not be detected in approximately one-half of the patients. The routinely obtained endometrial biopsy provides a safe, reproducible, and adequate means of providing histologic evidence for normal endometrial development for subsequent implantation.
Tubal abrasions were surgically induced in 25 rhesus monkeys following demonstration of tubal patency. Five monkeys received dexamethasone, promethazine, and ampicillin perioperatively, five received intraperitoneal 10% dextran 40, five received intraperitoneal 32% dextran 70, and 10 received no additional therapy. Fimbrial biopsies were obtained from two additional monkeys treated with 32% dextran 70 before and postoperatively on days 2, 5, and 7. Only those treated with 32% dextran 70 retained tubal patency and avoided development of adhesions, involving fimbria, omentum, ovary, uterus, and bladder. Histologic examination of fimbrial biopsies demonstrated sufficient epithelial repair to have occurred during the 5 days 32% dextran 70 remained in the pelvin cavity to prevent adhesion formation.
Fertility AwarenessCycle Day VariabilityTiming and PredictionOvulation Timing
It is commonplace for gynecologists to refer to "midcycle" ovulation of women. This concept has often led to the routine diagnosis of ovulatory status on day 14 of what is expected to be a 28-day menstrual cycle. For example, the postcoital test in an infertile patient, or intercourse to achieve pregnancy in a normally fertile patient, is often timed around day 14 under the assumption that ovulation is occurring then. Advocates of natural family planning (NFP) have criticized the concept of "midcycle" ovulation, because their clinical experience suggests that the natural irregularity of menstrual-cycle length militates against ovulation's occurring with any great frequency on day 14.
This report analyzes the relationship of day 14 and the actual midcycle of the menstrual cycle to each other and to indirect hormonal parameters that more directly estimate the time of ovulation.
Lack of standardization in analytic methods for assigning infertility data is attributed to inadequate classification of fertility problems, and a lack of consistent methodology in evaluating outcome of infertility therapy. A classification scheme ideally should consider types of fertility problems as well as clinical assessment of its severity. Until an adequate classification system is developed, researchers are encouraged to describe fully the nature of infertility problem examined, and present results for homogenous groups of patients. The life-table method of analysis is a useful technique for assessing infertility statistics. The starting point of this method should depend on the group examined and may be either the date of 1st visit to the clinic or the date that therapy is instituted. Approximate date of conception should be the endpoint. A mathematical model of infertility predicated on the assumption that there is a constant monthly probability of conception of fecundability can be used to derive equations with potential for clinical application.
Patients with different types of luteal phase defects were studied with the use of the radioimmunoassay for the beta subunit of human chorionic gonadotropin (hCG) to determine if unsuspected subclinical pregnancies were more common in a particular type of defect. A type I luteal phase defect is always characterized by a chronologic lag in endometrial development when repeatedly studied with timed endometrial biopsies. A type II luteal phase defect is always characterized by an in phase endometrium when repeatedly studied by timed endometrial biopsies but always has less than a 14 day luteal span. All blood samples were drawn at least 7 days after ovulation/conception. In 22 cycles in which patients had a type I luteal phase defect, no subclinical pregnancies were detected. In 18 cycles in which a type II luteal phase defect was present, 12 instances of unsuspected subclinical pregnancy were detected and all ended in spontaneous abortion. This study shows that unsuspected subclinical pregnancies ending in abortion do occur and are quite commonly associated with the type II luteal phase defect.
InfertilityClomiphene OutcomesDrug-Related Gestational RiskClomiphene vs Surgical
The experience of the gynecologic endocrinology and infertility clinic at The Johns Hopkins Hospital has been subjected to a nonconcurrent prospective analysis in an attempt to evaluate the gestational fate of clomiphene-related conceptions (study series, n = 86). This latter series was contrasted with a series of pregnancies following bilateral ovarian wedge resection (BOWR) (n = 51) in a comparative analysis of gestational outcome event rates. Post-therapy follow-up was available for varying time spans of up to 15 years. A 12.8% twinning rate constituted the single most important complication of clomiphene therapy, resulting in measurable increments in perinatal morbidity and mortality rates. The observation of a 26.5% spontaneous abortion rate would seem to suggest that clomiphene-related conceptions are at little or more risk for spontaneous abortion than would have been expected from the infertile population under discussion. A 3.1% incidence of post-clomiphene birth defects was not increased as compared with commonly quoted rates for the population at large. The corresponding incidence rates of twinning, spontaneous abortion, and birth defects for the BOWR series were 0%, 21.6%, and 0%, respectively.
Pelvic adhesion formation represents a major problem following fallopian tube surgery for infertility. Intraperitoneal dextran may prevent pelvic adhesions. Extensive personal clinical experience (W. H. U.) with intraperitoneal dextran organ-flotation on completion of tubal and ovarian surgery has appeared to limit adhesions. A specific study was designed to test the validity of this theory. Four randomized groups of rabbits were subjected to bilateral tubocornual division and microsurgical reanastomosis with total hemostasis and pelvic lavage. Routine peritoneal closure was performed on one group, but followed instillation of 30 to 50 ml of normal saline into the peritoneal cavities of the second group, and 30 to 50 ml of 6% dextran 70 into those of the third. Study of fourth group, which received 32% dextran 70 in the peritoneal cavity, was discontinued because of complications. A second laparotomy was performed 4 weeks later for precise assessment and photography of adhesion formation. Each animal was mated 4 weeks after the second operation in order to determine fertility rates. Reduced adhesion formation and increased fertility rates following the instillation of dextran are reported. A role for dextran 70 in infertility surgery is recommended.
Salpingostomy for hydrosalpinx was carried out using a microsurgical technique. The postoperative patency rate was over 90%. Among the 41 patients followed for more than 1 year, 29% have had one or more intrauterine pregnancies and 27% have had live births. The ectopic gestation rate was 12%. All of the tubal gestations occurred in the 1st postoperative year whereas 60% of the intrauterine pregnancies occurred after the 1st year, suggesting a degree of restoration in the mucosa and the musculature of the oviduct with the re-establishment of patency and the passage of time.
A clinical description of luteinized unruptured follicles is presented. This abnormality in ovulation is characterized by normal endocrinologic biphasic basal body temperature curves, secretory endometrium, and laboratory evidence of progesterone production by elevated urinary pregnanediol or plasma progesterone levels. In a group of 102 such infertile women, laparoscopy performed 3 to 5 days after apparent ovulation revealed the absence of a corpus hemorrhagicum in 30 women, and the absence of a sigma on a corpus hemorrhagicum in an additional 32 women. These findings were evidence that a follicle had not ruptured and an ovum had not escaped. Of 28 patients undergoing follicular stimulation with clomiphene citrate or human menopausal gonadotropin after this diagnosis, 15 conceived.
The cervical canal mucus is important to human fertility since conception can only occur if sperm pass through the contents of the cervical canal to reach the ovum. The biophysical properties of the cervical mucus and their relation to sperm migration are, therefore, curcial. A variety of laboratory experimentation methods have been used 1) sperm migration measurements; 2) reheological studies; 3) cell countings; 4) crystallization studies; 5) 6) EPR; and 7) photoelectron spectroscopy. Cervical mucus is the end result of complicated biosynthetic processes occurring in the epithelial cells of the cervical mucosa; this biosynthesis is regulated by many factors. Type E, characteristic for estrogenic stimuli on mucus biosynthesis, and type G, for gestagenic stimulation, are the 2 main types of cervical secretions. The 2 types always occur together, in differing proportions. For example, at normal ovulation there is a 97:3 ratio of type E to type G; at normal corpus luteum, the ratio is 10:90. The string variety of type E seems to aid in conveying sperm from the vagina while the loaf variety is inactive. The very low viscosity of the string variety intermicellar fluid permits very rapid sperm swimming. Not much is known regarding cervical mucus pathology or therapy.
Plasma levels of progesterone were measured during the luteal phase in 10 of 15 women with clinical histories of at least three spontaneous abortions in the last three gestations, and in 15 healthy nonpregnant women during the same phase of the ovarian cycle. Progesterone values found in the women with habitual abortion were lower (P less than 0.05-0.005) than in the nonpregnant group almost throughout the period of observation. The habitually aborting women who became pregnant again aborted between the seventh and 12th weeks. Their progesterone concentrations were less than 6 ng/ml, 48-72 hours before vaginal bleeding or abortion. These values were compared with those found during the first 12 weeks in normal pregnancy (P less than 0.001). The results suggest a useful method of evaluating the treatment of habitual abortion.
DiagnosticsProgesterone vs Endometrial BiopsyLuteal Phase EvaluationOvulation Assessment
An endometrial biopsy and a blood sample for progesterone determination obtained simultaneously in the midluteal phase of the cycles of 55 infertile women were compared for reliability for confirmation of presumptive ovulation and evaluation of luteal function. Progesterone levels of 3 ng/ml or greater were found in 90.5% of the cycles. Secretory endometrium was identified in 81% of the cycles. Thirty-three cycles yielded sufficient information to compare the two methods for evaluation of luteal function. Histology and progesterone levels were consistent with each other and the presumed time of ovulation in only 11 cycles. Histology was inconsistent with the presumed time of ovulation in 20 cycles, while progesterone was inconsistent in only two cycles. Additional samples for progesterone determinations were obtained during the biopsy cycles of 15 patients who presented adequate data for evaluation of luteal function. A single, well-timed progesterone determination appeared adequately to reflect the data obtained from serial samples in the same cycle. These results support the thesis that a single, well-timed serum progesterone determination is superior to a single endometrial biopsy as a screening method for confirmation of presumptive ovulation and for evaluation of luteal function.
Summary In 1968, a prospective study was started in collaboration with the Family Planning Association to try to provide a balanced view of the beneficial and harmful effects of different methods of contraception. This investigation is now in progress at seventeen clinics and over 17,000 women are under observation. At the time of recruitment, all these women were married white British subjects, aged 25–39 years, who voluntarily agreed to participate. Fifty-six per cent were using oral contraceptives, 25% were using a diaphragm and 19% were using an intrauterine device (IUD). During follow-up each woman is questioned at return visits to the clinic and a record of pregnancies and their outcome, hospital referrals (inpatient or outpatient), changes in contraceptive methods and the results of cervical smears, is accumulated. Women who default are sent a postal questionnaire and, if this is not returned, are telephoned or visited in their homes to collect the necessary information. So far, data obtained during 56,000 woman-years of observation are available for analysis. Follow-up has been maintained with an annual lapse rate of about 0.3%due to withdrawal of co-operation or loss of contact; adherence to the method of contraception in use at recruitment has been reasonably good, and the reporting of pregnancies and hospital admissions appears to have been both reliable and unbiased. The present data include only 24 deaths, so the mortality associated with different contraceptive methods cannot yet be estimated. With regard to morbidity, however, our preliminary results closely resemble those obtained in the prospective study carried out by the Royal College of General Practitioners (1974) and in the principal retrospective studies carried out in Britain and the United States. Women who used oral contraceptives at the start of the study experienced a deficiency of hospital referrals for cancer, benign lesions of the breast, menstrual disorders other than amenorrhoea, duodenal ulcer, and retention cysts of the ovary; they showed an excess of referrals for cerebrovascular disease, cervical erosion, skin disorders, self-poisoning, migraine, venous thrombosis and embolism, hayfever, gallbladder disease, amenorrhoea, and sterility. Women who used a diaphragm showed a deficiency of hospital referrals for carcinoma-in-situ and dysplastic lesions of the cervix uteri and accidental injury; and an excess of referrals for haemorrhoids and cystitis. Women who used an IUD experienced an excess of hospital referrals for anaemia, varicose veins and salpingitis. About half of these differences (12 out of 23) were predicted from other studies while some suggestive evidence already existed for a further five. Of the remaining six, some probably reflect the influence of selective factors or chance. Multiple pregnancies, stillbirths, malformations, the sex ratio and birthweight showed no consistent relationship to method of contraception. The outcome of unplanned pregnancies occurring in women using an IUD, however, was remarkably unfavourable both in terms of ectopic gestation and miscarriage. Clear evidence was found of impairment of fertility after discontinuation of oral contraceptives. Whether this is likely to lead to permanent sterility in some women is uncertain. The study has provided data on the efficacy of a wide variety of contraceptive methods. In general the failure rates are in keeping with those obtained in other large-scale studies, save that those for the diaphragm and the sheath are much lower than those usually quoted. The available evidence does not yet allow a final balance to be struck between the benefits and risks associated with the new methods of contraception that have become widely used during the last two decades. It seems clear, however, that there are no material risks associated with the use of the diaphragm apart from the risk of pregnancy and that there may be some unintended benefits.
Fifteen years have passed since our group first proposed the use of clomiphene citrate as an ovulation-inducing agent. Our 15-year experience with over 2,000 patients has not dampened our enthusiasm for this drug. The benefits have far outweighted the minor side effects or the possibility of multiple births. Serious birth defects were minimal and have been no greater than what one may expect in the general population. Clomiphene citrate has been a boon to womankind and deserves the confidence it is a drug with a record of utility and with but minor risks.
Reproductive EndocrinologyLuteal Phase DefectLuteal Phase InsufficiencyHistologic Dating
In summary, the luteal phase defect is a deficiency of corpus luteum progesterone steroidogenesis, either in amount or duration, or both. The clinical manifestations include either primary infertility or repeated first trimester abortions. The diagnosis can only be made clinically on the basis of a well-timed endometrial biopsy that is read histologically as 2 or more days out of phase with the next period in at least two cycles.
InfertilityClomiphene and GonadotropinsAnovulation TreatmentHMG-HCG Therapy
In an effort to diminish the incidence of multiple pregnancy, ovarian hyper-stimulation syndrome, and the excessive cost of human menopausal gonadotropin (HMG) administration, a sequence of Clomid-HMG-human chorionic gonadotropin (HCG) was used in 80 patients with infertility due to prolonged amenorrhea. Criteria for (1) normal seminal fluid analysis and postcoital test; (2) lack of withdrawal bleeding from progesterone following amenorrhea of more than 6 months' duration; (3) normal x-ray of the sella turcica and visual fields; (4) low serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels; (5) normal endoscopic examination; and (6) lack of response to clomiphene in excessive dose (200 mg daily for 5 days) or prolonged dose (100 mg daily for 10 days) with or without HCG, or apparent ovulatory response to the above sequence for five or six consecutive cycles without pregnancy. Clomiphene was administered in a dose of 100 mg daily for 7 days. HMG was then two ampules daily for 4 days, then one ampule daily for 2 days (75 IU of FSH and 75 IU of LH/ampule). After a 24-hour interval without treatment, 10,000 IU of HCG were given and 2000 IU of HCG 4 days later. Twenty-three pregnancies occurred in 80 patients. However, 15 of the first 25 patients became pregnant--in these patients the only abnormality noted was lack of ovulation. Six additional pregnancies occurred subsequent to one or more unsuccessful cycles. Multiple pregnancies occurred in only two patients (twins delivered at 32 weeks in one and an abortion of five fetuses at 20 weeks in another). However, multiple pregnancy did not occur in any patient whose urinary estrogen level was monitored and in whom the level was 100 mug or less when the HCG was given. The ovarian hyperstimulation syndrome did not occur in any patient.
Seven cases of polycystic ovarian disease were investigated by laparoscopy and endocrinologic tests after failure of ovarian resection to restore fertility. One case of bilateral and two cases of unilateral ovarian atrophy were recorded. In all seven patients the common features were extensive perivarian and peritubal adhesions. Four of the six patients amenable to cure were submitted to reconstructive surgery; three of them conceived and had normal deliveries. The present observations support the plea to relegate the surgical approach to a minor position in patients with Stein-Leventhal syndrome and stress the importance of meticulous surgical technique in the performance of ovarian surgery. Laparoscopic investigation is mandatory in all cases of unsuccessful ovarian resection.
Of 159 pregnancies conceived after clomiphene therapy, 141 ended in childbirth, including seven sets of twins. There was a probable increase in the number of infants born with major malformations. These were exclusively to women who had not previously borne a normal infant. The incidence of malformed infants compares well with that published after gonadotropin therapy. The possibly higher incidence of malformations seen after drug-induced ovulation would therefore seem to be due to the underlying subfertility state and thus not a direct drug effect.
Reproductive EndocrinologyOpioid EffectsDrug-Induced AmenorrheaSubstance Abuse Related
The ability of morphine to block ovulation in animals prompted investigation of the frequency and mechanisms of menstrual abnormalities in women addicted to narcotic analgesics. Menstrual histories obtained from 76 former heroin addicts receiving daily methadone maintenance revealed that more than one-half of these women had experienced menstrual abnormalities while taking heroin or methadone. In order to determine the specific physiologic effects of narcotic analgesics on reproductive function, detailed endocrinologic studies were carried out in seven of these patients who complained of amenorrhea or irregular menses while receiving methadone. Four of the seven women manifested abnormalities of the control of gonadotropin secretion. Three of these four failed to exhibit cyclic gonadotropin release, as evidenced by an absence of increased levels of follicular phase follicle-stimulating hormone, midcycle gonadotropin peaks or luteal phase progesterone increments. In the fourth patient a prolonged follicular phase (30 days) of the menstrual cycle was detected. One of these four patients also had low basal gonadotropin levels and failed to exhibit luteinizing hormone increments greater than control levels in response to ethinyl estradiol (positive feedback). The remaining three women exhibited normal patterns of gonadotropin secretion during the observation period. In these women, menstrual bleeding occurred in response to withdrawal from luteal phase (10 to 20 ng/ml) progesterone levels and to exogenous ethinyl estradiol, suggesting normal uterine responsivity to progesterone and estrogen. Although not documented, it is likely that oligo-ovulation was the cause of the irregular menses in these three patients. Amenorrhea is commonly associated with methadone ingestion or heroin addiction and appears to be related to an alteration of the hypothalamic mechanisms controlling gonadotropin secretion. Tolerance to these effects of methadone may develop after chronic ingestion.
To develop a practical yet statistically valid means of indicating ovulation and adequacy of corpus luteum function concentrations of plasma progesterone (P) were measured daily during the luteal phase of 30 normal and abnormal menstrual cycles. During a normal cycle any 3 P measurements taken from 11 days before the first day of the following menses (M) to Day M-4 gave a total equal to or greater than 15 ng/ml. An abnormal cycle was considered one in which the total P (for 3 measurements) was less than 15 ng. Individual levels were often at 3 ng/ml in normal cycle and above 3 ng/ml in abnormal cycles indicating that the single P measurement proposed by Israel et. al. would not always be valid.
The use of clomiphene in gradually increasing doses, in cases of infertility due to anovulation, oligo-ovulation and inadequate luteal phase, led to a high pregnancy rate, particularly in the initial stages of treatment. Although clomiphene is a relatively safe and inexpensive drug, there is a possibility that high doses in repeated cycles may adversely affect fertility by its anti-oestrogenic effect. It is therefore suggested that therapy be commenced with a lower dosage than that generally recommended.
Reproductive EndocrinologyLuteal Phase DeficiencyOligomenorrhea Hormonal ProfileHormonal Evaluation of Ovulatory Dysfunction
The irregular menses experienced by obese and/or hirsute women were studied by daily measurement of serum LH, FSH, estradiol (E2) and progesterone (P). During 8 cycles of 24 to 157 days, each episode of menstrual bleeding was preceded by hormonal evidence of follicular maturation and corpus luteum formation. The premenstrual fluctuations of LH and E2 were not different from those observed in normal cycles. Although the luteal phase was of more than 10 days' duration, progesterone secretion was subnormal during each cycle. Serum FSH was low throughout the time preceding the LH/FSH surge. These data suggest that inadequate corpus luteum progesterone secretion may be characteristic of the menstrual cycles in oligomenorrheic, obese infertile women.
Reproductive EndocrinologyExogenous Progesterone EffectsLuteal Phase Progesterone SupportLuteal Phase Dating
A group of infertility patients were evaluated by an endometrial biopsy, timed with a basal body temperature chart, serum luteinizing hormone radioimmunassay to pinpoint ovulation, and daily serum progesterone values during a control and a treatment cycle. Progesterone in the suppository or intramuscular form and 17-hydroxyprogesterone caproate* were administered during the luteal phase to a group of volunteer patients with normal corpus luteum function to determine if these compounds would depress serum progesterone levels as do certain progestational agents. There was no apparent inhibition of corpus luteum function as no decrease in progesterone production occurred. Despite the additive effect of progesterone administration demonstrated by elevated serum levels, endometrial biopsies remained in phase when dated from the estimated day of ovulation.
SurgeryCorticosteroid ProtocolsPostoperative OutcomesReproductive Surgery Outcomes
A combination of Decadreon (dexamethasone) and Phenergan (promethazine) was tested in this collaborative study of 240 infertility patients as a means of preventing postoperative adhesion formation after simple pelvic surgery. 24 patients were lost to follow-up. The overall pregnancy rate among the 240 patients was 51.7% (124): 49% with primary infertility and 58% with secondary infertility conceived after surgery. 90 full-term deliveries were recorded, 27 spontaneous abortions occurred, and 7 ectopic gestations were conceived. In all, 31 cases were reinspected for various reasons after the drug treatment postsurgery; 42% showed no adhesions, 23% showed minimal adhesions, and 35% had significant adhesions. Complications coincident with use of the combined medication were seen in 2.2% (11 of 240) patients. Though this study lacked controls, the authors feel thta the use of corticosteroids postoperatively after pelvic intervention may control the numbers of adhesions which form postoperatively.
Reproductive EndocrinologyGnRH DiscoveryFSH and LH RegulationGnRH Therapy
This article has been designed to review recent developments in the field of hypothalamic hormones involved in the control of reproductive functions. A brief resume of early physiologic and anatomic studies was presented initially to give a better understanding of the concept of hypothalamic regulation of the release of gonadotropic hormones from the pituitary gland. Recently, an advance was achieved with the isolation from porcine hypothalami of a decapeptide which has both FSH-releasing hormone (FSH-RH) activity and LH-releasing hormone (LH-RH) activity. Its amino acid sequence was determined to be (pyro) gluhis-trp-ser-tyr-gly-leu-arg-pro-gly-NH2. The decapeptide corresponding to this structure was synthesized and shown to stimulate the release of LH and of FSH in laboratory and domestic animals and human beings. Natural and synthetic FSH-RH/LH-RH also stimulated the synthesis of both gonadotropins in tissue cultures of rat pituitaries in vitro. It was postulated that this decapeptide represents the hypothalamic hormone which regulates the release of both LH and FSH from the anterior pituitary gland. Complex effects of sex steroids on the release of LH and FSH were reviewed briefly. It was suggested that the over-all control of secretion of FSH and LH is most likely mediated by the interaction of hypothalamic FSHand LH-releasing hormone with sex steroids. Clinical studies performed with natural and synthetic LH-RH/FSH-RH were reviewed. These studies, particularly induction of ovulation, suggest that LH-RH should find practical application in the treatment of sterility. Subsequent synthesis of LH-RH/FSH-RH by several laboratories and drug houses should provide enough material for large-scale clinical evaluation of this hormone. Some comments were made concerning probable clinical use of LH-RH. Finally, some speculations were offered about the possibility of developing new birth control methods based on LH-RH/FSH-RH, its analogues, or its derivatives.
Eighty-six women reached at least 20 weeks' pregnancy in 96 instances, after ovulation induced by clomiphene citrate. Although 37 of the women had 44 previous pregnancies, there had been a high pregnancy wastage (70.5%) producing only 13 live infants prior to the successful clomiphene therapy. After clomiphene therapy, pregnancies were normal except for a high incidence of toxemia (16.7%) and a possibly increased incidence of prediabetes. The pregnancies resulted in 88 single and 8 twin births. The total fetal and neonatal loss was 6.7%. The loss of single births (3.1%) included two stillbirth infants of prediabetic mothers. The twin loss of 25% was due to prematurity. The incidence of congenital malformations was within normal limits.
A study was undertaken to determine whether solitary progesterone as says performed on serum samples obtained in the midluteal phase would provide the clinician with a convenient indicator that ovulation had occurred in that cycle. After a normal luteal-phase range was establish ed, single luteal-phase serum progesterone sampling was performed in 51 infertile women with regular menses and 35 oligomenorrheic women undergoing clomiphene citrate therapy. In the follicular phase of the cycle, progesterone levels were consistently less than 2 ng/ml. Between 11 and 4 days prior to the onset of menses in presumptively ovulatory cycles, serum progesterone levels were always 3 ng/ml or greater. Progesterone values in this range were always accompanied by a secretory endometrium and can be considered presumptive evidence of ovulation. This rapid, easily performed technique enables 1 technician to assay 30 or more samples for progesterone in a single working day and the results are available within 24 hours. This assay technique is easier to perform and more reproducible than a urinary pregnanediol assay, and it is expected that clinical laboratories will soon perform serum progesterone assays as a routine procedure.
One hundred and thirty-five patients diagnosed as ovulatory failure have been treated in our clinic since 1966. One hundred and eighteen of these have been treated with clomiphene citrate, or more recently, its cisisomer, and 17 patients with long-standing secondary amenorrhea or primary amenorrhea have been treated with human menopausal gonadotropins, in combination with human chorionic gonadotropins. Of the latter group, 14 of the 17 were shown to be capable of response to exogenous gonadotropins and 12 of these ovulated and 7 (50 per cent) became pregnant. The over-all ovulatory rate with clomiphene citrate or its cisisomer was 78 per cent, with a pregnancy rate of 31 per cent. The results of our present investigation with clomiphene citrate in 10 and 20 mg. dosage are presented in detail, and compared with our previous experience with clomiphene. It appears that cisclomiphene 20 mg. is as effective as clomiphene citrate 100 mg., but has the decided advantage of fewer side effects associated with its use. With the human menopausal gonadotrophins, no major complications, such as ovarian overstimulation or multiple pregnancies, were encountered, and we feel this is attributed to careful selection of patients and daily tracking of total urinary estrogens.
From among a group of women with apparently normal menstrual cycles, 7 cycles with short luteal phases were identified. These cycles were characterized by grossly normal FSH and LH patterns although the FSH/LH ratio was below normal. Mean plasma progesterone increased to less than 2 ng/ml shortly after the LH peak; thus, the peak level was lower and the peak occurred earlier than in the normal cycle. Plasma 17-hydroxyprogesterone increased at the time of the LH peak although the mean peak level was only 60% that of normal cycles. There was no secondary increase of 17-hydroxyprogesterone during the luteal phase. These observations are consistent with the hypothesis that a relative deficiency of FSH during the follicular phase results in diminished follicular development and subsequent inadequate corpus luteum formation or function.
Clomiphene citrate, in selected patients, is an effective agent for the treatment of infertility due to anovulation. An adequate laboratory and physical evaluation of each individual patient is essential for proper use of the drug. The major adverse reactions encountered are ovarian enlargements and cysts; in most patients, these conditions regress spontaneously after withdrawal of the drug.
For years the gynecological endocrinologist has been seeking an effective gonadotrophin for the treatment of ovarian dysfunction and anovulation in the human. 7
Animal preparations have been self-limiting because of allergic reactions, antihormone formation, failure to obtain a uniform response from a standard dose, and the absence of data on animal specificity.
A breakthrough occurred in 1958 when Gemzell et al. reported a human pituitary gonadotropin which induced follicular growth and estrogen production in the ovaries of amenorrheic women. The human source does not permit widespread application of this material. A few years later, Pergonal (HMG ),* a human menopausal urine gonadotropin which had similar effects,16 was developed; but standardization of HMG has been difficult and the extraction process complicated and expensive.
A most important contribution was made in 1959 by Tyler et al., who were able to induce ovulation in 6 patients with severe anovulatory problems, and in 1960 by Kistner and Smith, who successfully induced ovulation in 4 patients with the Stein-Leventhal syndrome, by using the estrogen antagonist MER 25.t Related compounds were further investigated and clomiphene citrate (Clomidt) proved more effective and had fewer side effects. 5, 12
The exact mechanism of action of the drug is stilI in doubt. It is postulated that clomiphene acts either directly on the hypothalamic-pituitary axis, causing an increase in gonadotropin output,9, 12, 17 or sensitizes the ovary to respond more readily to endogenous gonadotropins. 6
Smith and Kistner believe that Clomid directly influences the enzyme systems involved in ovarian steroidogenesis, or merely acts as a potentiator of gonadotropins. Pildes believes that there is a change in the synthesis of estrogen in both the adrenals and ovaries at the pre-estradiol phase of steroid synthesis.
Dickey et al. postulate a direct anti-estrogen effect in the system involved in estrogen metabolism, with subsequent stimulation of the hypothalamic-pituitary axis due to a fall in estrogen levels. Probably more than one mechanism of action is responsible for the response to the drug.
We first used clomiphene in the treatment of infertile patients with impaired ovarian function in May 1962. Because of the frequent side effects such as large ovarian cysts, reported by the early investigators, its use was limited to women with major endocrine defects and in cases where all other treatments had failed. With more experience and smaller dosages, 50-200 mg. daily for a short period of time, 3-5 days of each cycle, the drug was effective and most of the side effects were eliminated.14 With a program of at least monthly checkups, the drug proved safe and we have extended its use to infertile patients with only minor problems of ovarian dysfunction.
All patients, prior to treatment, have a thorough infertility and endocrine evaluation. The patient who is a proper candidate for this drug should be one with a moderately intact pituitary-ovarian axis and norm~or low total urinary gonadotropin levels, although we have had several patients with mildly elevated total gonadotropin who have responded. The patient should have a fair endogenous estrogen production. Thyroid function is usually normal or mildly subnormal. The 17-ketosteroid concentration is usually normal, although 32.5% of our patients who conceived did show levels of 13.0 mg. 24 hr. or more. Several of these decreased to normal levels after treatment with clomiphene; Pildes has reported a similar finding. Of our patients who conceived, 35.5% showed a diabetic or a prediabetic glucose tolerance curve on initial evaluation.
Pituitary tumors should be ruled out. Patients with ovarian damage due to chronic infection are not likely to respond. Since clomiphene citrate is detoxified in the liver, one should be hesitant to prescribe the drug to a patient with chronic liver disease.
Visualization of the ovaries by culpotomy with ovarian biopsy or culdos-copy is helpful in establishing the diagnosis, especially in patients who fail to respond.
The concept that a cervix could be inadequate or incompetent for retaining a normal pregnancy was publicized by Lash and Lash in 1950. It did not catch the fancy of the majority of obstetricians to any extent until the introduction of the relatively simple corrective procedure advocated by Shirodkar in 1955 and publicized by Barter et al. Since then there has been a constantly increasing number of reports discussing this problem. Incompetent cervical os is estimated to represent only a small percentage of all causes of fetal wastage …
Clomiphene citrate [1-p(β-diethylaminoethoxy) phenyl-1,2-diphenyl-2-chloroethylene citrate], because of its ability to induce ovulation, was administered to 26 patients with excessive anovulatory uterine bleeding. Of the 129 menstrual cycles during which the drug was administered, 105 cycles (81.3%) were ovulatory and were followed by normal uterine bleeding. After clomiphene was discontinued, observations made in 52 cycles showed that only 20 (38.4%) were ovulatory
Study of 54 habitual aborters with low or normal pregnanediol excretion, in a double-blind trial, revealed the spontaneous-salvage rate and the possible benefit of therapy with medroxyprogesterone acetate. The salvage rate in the placebo group with the worst prognosis (never a term pregnancy, low pregnanediol in the current pregnancy) was ten of 13, and the salvage rate in the other placebo groups showed no statistically significant difference. In view of this high spontaneous salvage rate, the numbers required to demonstrate a therapeutic effect of progestin administration are prohibitively large. This indicates the need for new criteria to pinpoint cases with a poor prognosis, and it raises the question whether habitual abortion is a disease entity or a statistical coincidence.
SPONTANEOUS ABORTION is one of the most common and least understood pathological processes. Because it is so difficult to obtain reliable information about abortion, even the basic facts about its frequency, familial distribution, and relation to parity and parental age are largely unknown or disputable. Such information is needed to provide a basis for advising women with several abortions about their chances of successfully completing another pregnancy, to evaluate measures for the prevention of abortion, as well as to provide clues to the etiology of the condition. Reproductive histories taken by personal interview with a random series of women would probably be the best available data for estimating spontaneous abortion statistics. These would include very early terminations of pregnancy, recognized as spontaneous abortions by the women concerned but not receiving medical attention, which are under-represented in series of consecutive hospital admissions or in consecutive cases from private obstetrical practice. They would allow estimation of abortion risks in women with given numbers of previous abortions and at given ages. Some reservations must be held about the validity of self-diagnosis of early abortion, but this source of error should not affect comparisons within the sample.
Gonadotrophins were prepared from human postmenopausal urine with the kaolin-acetone method and purified by adsorption of impurities on diethylamine ethyl cellulose (DEAE-C).
The last step, namely chromatography on the column of permutit, resulted in a significantly improved specific activity.
The immunoelectrophoresis showed that the purified HMG is not homogeneous and that the constituents are glycoproteins which migrate into the region α1, α2and β globulins.
Induction of ovulation in the human has been of considerable research interest for several decades. Various hormonal regimens and other procedures have been tried in the past.1 • 2 In spite of all these trials, the problem of ovulatory failure remains a frustrating dilemma for the physician. Recently, the induction of ovulation with clomiphene citrate in about 70% of anovulatory women was reported by our group.3- 6 It was felt that an important breakthrough in this difficult field of endeavor was at hand. 7- 9 Our observations have been confirmed by other groups of investigators.10- 12 The present report embodies a detailed analysis of the results of administration of this agent to 200 women, of whom 179 were anovulatory. The results of our studies on the probable mode of action of this drug are also discussed.
IT APPEARS TO BE WELL ESTABLISHED that the synthetic nonsteroidal analogue of chlorotrianisene (Tace), which has been given the generic name of clomiphene citrate (MRL/41)*, is capable of stimulating ovarian secretory activity in women.1-4 Perhaps the most convincing evidence for this is found in the high incidence of cystic ovaries observed among treated patients, together with the associated microscopic ovarian and endometrial changes, indicating that the cystic structures produced are functional.2,3 The striking similarity between the histopathology of this response to clomiphene and the ovarian response to administered gonadotropins of both human and animal origin has been pointed out by Southam and Janovski.2 With both forms of treatment, the degree of ovarian response to a given dosage appears to be unpredictable and all patterns of atypical stimulation have been observed. In view of this analogy, it has been logical to assume that the ovarian response
A partially purified follicle-stimulating hormone preparation (human pituitary FSH) has been obtained from human pituitaries. The ovarian response to this preparation was studied in 7 amenorrheic women. The effect of human chorionic gonadotropin (HCG) was studied in addition. In 4 patients exhibiting no endometrial activity or only slight proliferation, HCG alone did not induce ovulation and had no effect on the size of the uterus, on the endometrium, or on the urinary excretion of estrogen and pregnanediol. In 2 patients showing endometrial proliferation, the administration of HCG alone was followed by ovulation, a secretory transformation of the endometrium, and a marked increase in urinary pregnanediol excretion. The administration of human pituitary FSH alone to 2 patients resulted in an increase in the size of the uterine cavity, in polycystic enlargement of the ovaries, and in a pronounced increase in urinary estrogen output. Treatment with human pituitary FSH followed by HCG produced in all patients polycystic enlargement of the ovaries, ovulation in 4 out of 5, and a secretory transformation of the endometrium in 3 out of these 5 patients. Ovulation was accompanied by a marked increase in the urinary excretion of both estrogen and pregnanediol.
Reproductive EndocrinologyEmbryo Development EffectsIn Vitro Embryo CultureIn Vitro Studies
SUMMARY 1. The action of progesterone on the development of the mouse ovum from the eight-celled stage to the blastula has been studied in vitro . 2. Concentrations of progesterone below 2 μg/ml. produced no observable effect, whereas some toxicity was observed at 4 μg/ml. and few ova survived higher concentrations. 3. Herniation of the zona pellucida by the developing blastula is described; this process was inhibited by 4 μg/ml., but not by 2 μg/ml. of progesterone. 4. Blastulae appear to be more sensitive to the action of progesterone than are earlier stages. 5. Oestrogens afforded no demonstrable protection against the toxic action of progesterone when added to the culture medium. 6. The possible physiological significance of these findings is discussed.
Accurate timing of ovulation is especially necessary (1) in artificial insemination in order to avoid wastage of donor semen; (2) in cases where the husband is relatively infertile and it is necessary to conserve his semen. While many physicians rely upon the basal body temperature curve for timing ovulation, the interpretation of such curves is varied. Some physicians believe ovulation occurs prior to the lowest point in the temperature cycle, while others believe that ovulation occurs either at the low point or following the thermal shift. We have been disappointed in our ability to interpret the basal body temperature curve for accurate timing of ovulation, and have placed greater reliance upon concurrent phenomena, such as changes in the quantity and viscosity of cervical mucus and the cyclic changes observed in the vaginal smear. Although the relationship between the occurrence of a profuse, thin cervical mucus discharge and the optimal time of fertility in the human has been recognized for the past century, in our opinion this relationship requires further evaluation.
In his excellent review, "Cervical Cyclic variations and their clinical significance," Shettles quotes Robin who, in 1848, noted the viscous nature of human cervical secretions; and Smith who, in 1865, concluded that conception is most likely when the mucus contents of the cervix are in the most fluid condition. J. Marion Sims, who invented a vaginal speculum and first described the postcoital examination in 1868, observed that the test is positive for motile spermatozoa when the cervical mucus becomes clear and translucent, and about the consistency of the white of egg. Although these observations on human cervical mucus have been well documented, they have been almost disregarded by gynecologists. The significance of the cyclical outpouring of cervical mucus has been rediscovered in the past few years and has aroused great interest in students of sterility.
The optimal time of fertility in domestic animals is the period of heat or estrus. In 1925, Woodman and Hammond showed that during estrus, bovine cervical mucus is fluid and capable of being drawn out into threads, whereas in diestrus the mucus is thick. Seguy and Vimeux, and Seguy and Simonnet called attention to the optimal conditions of longevity of human spermatozoa in the fluid, glairy mucus of the cervix at midcycle. They postulated that these changes in cervical mucus were associated with ovulation and could be compared to the period of estrus in subprimate mammals. They correlated these changes with visual evidence of ovulation at laparotomy. ively, many women observe an increased sticky, mucoid discharge which is typical at midcycle and which is present over a period of days. On occasion this discharge is blood-tinged and may be compared to the distinct bloody mucoid discharge present in the domestic animal "in heat."
This mucus can be seen exuding from the cervix at midcycle and it may be aspirated from the endocervix and actually weighed, as reported by Viergiver and Pommerenke. Clift demonstrated certain rheologic properties of cervical mucus, especially flow elasticity and Spinnbarkeit. Flow elasticity, or elastic recoil of mucus, is measured by an instrument described by Blair. The use of the Blair capillary viscometer is a cumbersome method which we discontinued. We have had no experience with the new modification of the viscometer described by Clift, Glover, and Blair. Spinnbarkeit is easily tested, and we have found it to be a very practical objective method for determining viscosity of cervical mucus. In performing this test (Fig. 1), a vaginal speculum is inserted, exposing the cervix. A glass cannula is inserted into the endocervix and by means of gentle suction, a quantity of endocervical mucus is obtained. This mucus is blown onto a glass slide and a cover slip is placed on it. The mucus adheres to both the slide and the cover slip, and by withdrawing the cover slip, a thread of mucus is formed which can be measured in centimeters (Fig. 2). Usually, the cover slip is withdrawn several times, and the average length of the thread is ascertained. It is our purpose to show the relationship of Spinnbarkeit to other cyclic phenomena occurring during the menstrual cycle, such as basal body temperatures, vaginal smears, quantity of cervical mucus, and longevity of spermatozoa (Fig. 3).
InfertilityTime to ConceptionFecundability EstimationConception Rates
More than twenty-five years ago Edward Reynolds gave an excellent description of the polycystic ovary, and expressed the opinion that ovarian surgery was the most important single feature in the treatment of sterility of the female. This view was not accepted by later workers in the field. Indeed, the tendency has been to consider retention cysts as items of small importance, unlikely to cause symptoms and rarely calling for treatment on their own account. It remained for Stein15- 18 and his followers to define a type of case where the presence of multiple cysts evidently interferes both with ovulation and with endocrine activity, and to show that surgery frequently succeeds in restoring normal function. I propose to discuss certain aspects of this clinical problem, and to report my own series of 65 operated cases.
The fundamental cause of retention cysts is probably, as Zondek believes, a phase of hypergonadotropism. Under normal conditions large numbers of primordial follicles start to mature but never complete the process. At some point along the way the ova die, whereupon the follicles regress and ultimately become insignificant corpora fibrosa. Under the influence of excessive pituitary stimulation, however, such follicles may continue to secrete liquor and to grow after the disappearance of their ova.
Some of them eliminate themselves by delayed resorption and atrophy or, less often, by rupturing through the tunica albuginea. Others remain as permanent cystic structures. These retention cysts are pathologic, whereas atretic follicles in various stages of regression represent nothing more than phases of the normal ovulatory cycle.
InfertilityDefinition and CriteriaHistorical PerspectivesDelayed Childbearing
A discussion of infertility would be incomplete without a comment on the changing concepts of the definition. For statistical purposes it may be necessary to retain the criterion of a three year barren marriage. However, for the most satisfactory therapeutic results it appears that investigations for infertility must be instituted before these three, possibly most valuable, years have been wasted. The validity of shortening the period is substantiated by work of Diddle1 and Guttmacher,2 who independently obtained a figure of six months as the average time for a normal couple to achieve pregnancy. Relative infertility may be considered to exist any time after a six month interval. As late marriages and prolonged use of contraceptives are an integral part of our present society (especially in the private practice group) the foregoing fact is extremely important. Patients who marry after the age of 28 are contending, after a three
PregnancyRecurrent Pregnancy LossProgesterone SupplementationHormonal Support in Pregnancy