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.
PregnancyTwin-to-Twin Transfusion SyndromeFetoscopic TechniquesRCT Protocol
Open Access
Hsu JZ et al., 2025·Eur J Obstet Gynecol Reprod Biol
Endometriosis is a chronic gynaecological condition affecting reproductive-aged women. It has been associated with infertility and potential risks for adverse pregnancy outcomes, although population-level evidence remains limited. This retrospective cohort study, including 147,950 pregnant women aged 20-45 years, used nationwide population-based data to compare the outcomes between women with (n = 11,400) and without (n = 136,550) endometriosis between 2000 and 2021. Baseline characteristics, comorbidities and pregnancy outcomes were compared between the groups. Multivariable regression analyses were performed to calculate adjusted relative risks (aRR) and 95 % confidence intervals (CI) for various pregnancy outcomes, and subgroup analyses were conducted by maternal age and infertility status. Among 147,950 pregnancies, women with endometriosis [mean ± standard deviation (SD) age 32.38 ± 4.51 years] had higher socio-economic status, more comorbidities, and more surgical history compared with women without endometriosis (mean ± SD age 30.06 ± 4.96 years). Women with endometriosis had increased risk of miscarriage (aRR 1.13, 95 % CI 1.03-1.24), preterm birth (aRR 1.31, 95 % CI 1.26-1.37), premature rupture of membranes (aRR 1.11, 95 % CI 1.06-1.16), placenta previa (aRR 1.63, 95 % CI 1.45-1.84), urinary tract infection (aRR 1.44, 95 % CI 1.31-1.59), and caesarean section (aRR 1.13, 95 % CI 1.11-1.16). Subgroup analysis revealed that risk of miscarriage was only higher in women aged 35-45 years and women without infertility. Risks of preterm birth, placenta previa and caesarean section were elevated across all subgroups, suggesting that endometriosis contributes independently to adverse pregnancy outcomes. Endometriosis is an independent risk factor for several pregnancy complications, supporting the need for tailored prenatal care and closer monitoring of affected women to improve maternal outcomes.
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.
Redondo‐Delgado P et al., 2025·Acta Obstet Gynecol Scand
Physical activity is known to improve physical and psychological outcomes in pregnant women. While aerobic exercise is typically emphasized in physical activity guidelines for pregnant women, emerging research suggests that strength training may offer unique benefits beyond those provided by aerobic exercise alone. This systematic review aimed to systematically explore the effects and characteristics of strength training interventions on the health‐related quality of life of pregnant women, with the goal of informing more comprehensive and specific exercise guidelines. A systematic literature search was conducted across PubMed, Web of Science, and EBSCO Host databases without time restrictions, following PRISMA guidelines (Prospero Id: CRD42024511477). Nine randomized controlled trials met the inclusion criteria, involving a total of 1581 participants. The studies reviewed demonstrated that strength training during pregnancy can mitigate excessive weight gain, alleviate low back and sciatic pain, enhance mood, and improve various aspects of health‐related quality of life. These aspects include physical activity levels, muscular strength, flexibility, sleep quality, energy expenditure, and psychological well‐being. Despite these promising findings, this review highlights the need for standardized methodologies and detailed reporting in future research. Incorporating strength training into general exercise recommendations for pregnant women has the potential to optimize maternal health outcomes such as muscle strength, weight gain, physical activity levels, low back pain, pelvic pain, fatigue, anxiety, energy levels, vitality, sleep duration, and health status.
General OB/GYNChemical ExposuresEnvironmental Toxicants
Rovira J et al., 2025·Journal of Environmental Science and Health. Part A, Toxic/hazardous Substances & Environmental Engineering
Global textile production, driven by consumer demand, raises significant concerns about exposure to chemicals in clothing and related products. This review synthesizes evidence (2019-2025) on hazardous substances in textiles, including dyes, plasticizers, per- and polyfluoroalkyl substances (PFAS), and metals, and identifies and categorizes their associated human health risks. Emerging evidence highlights microfibers as critical vectors for chemical exposure via inhalation and dermal routes, necessitating updated risk assessments. Focusing on dermal absorption as the primary exposure route, risks to vulnerable populations (e.g., infants, pregnant women) and gaps in regulatory frameworks are highlighted. The current analysis reveals that chronic exposure to chemical mixtures in textiles remains poorly understood, with current safety assessments often neglecting synergistic effects. Key findings include elevated risks from phthalates in infant clothing, PFAS in water-repellent fabrics, and carcinogenic aromatic amines (AAs) from azo dyes. We underscore the urgency of harmonized global regulations, advanced biomonitoring, and sustainable alternatives (e.g., enzymatic dyes, biodegradable finishes). Public awareness initiatives and stricter enforcement of certifications like OEKO-TEX(®) or GOTS are critical to mitigating risks. Interdisciplinary collaboration among textile technologists, toxicologists, and public health experts is essential to develop safer textile alternatives and integrate health-centric approaches into sustainability agendas, safeguarding consumers, workers, and ecosystems.
PregnancyAir Pollution EpigeneticsAsthma and Allergy RiskDNA Methylation
Open Access
Prenatal exposure to air pollution is an important risk factor for child health outcomes, including asthma. Identification of DNA methylation changes associated with air pollutant exposure can provide new intervention targets to improve children's health. The aim of this study is to test the association between prenatal air pollutant exposure and DNA methylation in developmental and asthma-/allergy-relevant biospecimens (placenta, buccal, cord blood, nasal mucosa, and lavage). A subset of 2294 biospecimens collected from 1906 child participants enrolled in the Environmental Influences on Child Health Outcomes program with prenatal air pollutant and high-quality Illumina Asthma&Allergy DNA methylation array measures (n = 37 197 probes) were included. Prenatal ozone, nitrogen dioxide, and fine particulate matter were derived using residential history during pregnancy and spatiotemporal models. For each pollutant, biospecimen type, and prenatal exposure window, we estimated the effects of air pollution on gene DNA methylation levels. We compared results across pollutants, biospecimen types, and trimesters and tested for critical months of exposure using distributed lag models. DNA methylation levels at 154 out of 4746 tested genes were associated with air pollution; over 95% were exposure window, pollutant, and biospecimen-type specific. The fewest gene associations were detected in trimester 2, relative to other exposure windows. A variety of trends in methylation patterns were observed in response to lagged monthly pollution levels. Child DNA methylation changes at specific respiratoryand immune-relevant genes are associated with prenatal air pollutant exposures. Future studies should examine the relationship between these pollution-sensitive genes and child health.
General OB/GYNChildhood ObesityOffspring OutcomesLongitudinal Cohort
Open Access
Identifying atypical body mass index (BMI) trajectories in children and understanding associated, modifiable early-life factors may help prevent childhood obesity. To characterize multiphase BMI trajectories in children and identify associated modifiable early-life factors.Design, Setting, and ParticipantsThis cohort study included longitudinal data obtained from January 1997 to June 2024, from the Environmental influences on Child Health Outcomes (ECHO) cohort, which included children aged 1 to 9 years with 4 or more weight and height assessments. Analyses were conducted from January to June 2024. sPrenatal exposure to substances and stress (smoking, alcohol, depression, anxiety), maternal characteristics (prepregnancy BMI, gestational weight gain), child characteristics (preterm birth, birth weight, breastfeeding), and demographic covariates.Main Outcomes and MeasuresBMI (calculated as weight in kilograms divided by length in meters squared for children aged 1 and 2 years and as weight in kilograms divided by height in meters squared for children older than 2 years) obtained using medical records, staff measurements, caregiver reports, or remote study measures. The analysis was conducted using a multiphase latent growth mixture model. This study included 9483 children (4925 boys [51.9%]). Two distinct 2-phase typical and atypical. The typical group (n = 8477 [89.4%]) showed linear decreases in BMI (b2, −0.23 [95% CI, −0.24 to −0.22]), with the lowest BMI at age 6 years (95% CI, 5.94-6.11), followed by linear increases from 6 to 9 years (slope difference [b4 − b2], 0.81 [95% CI, 0.76-0.86]; mean BMI at 9 17.33). The atypical group (n = 1006 [10.6%]) showed a stable BMI from ages 1 to 3.5 years (b6, 0.06 [95% CI, −0.04 to 0.15]), followed by rapid linear increases from ages 3.5 to 9 years (slope difference [b8 − b6], 1.44 [95% CI, 1.34-1.55]). At age 9 years, this group reached a mean BMI (26.2) that exceeded the 99th percentile. Prenatal smoking, high prepregnancy BMI, high gestational weight gain, and high birth weight were key risk factors for the atypical trajectory. Conclusions and RelevanceIn this cohort study of children in the ECHO cohort, analyses identified children on the path to obesity as early as age 3.5 years. Modifiable factors could be targeted for early prevention and intervention programs aimed at reducing childhood obesity.
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.
PregnancyMaternal-Infant TransmissionGut Health DevelopmentECHO Microbiome
Open Access
There is growing interest in the use of microbial-seeding interventions to mitigate the impacts of prenatal antibiotics, C-section, and lack of breastfeeding on mother-child microbe sharing. However, the relative importance of maternal vaginal vs. fecal microbiota in this process is unclear. Analyzing 16S rRNA sequences from five US birth cohorts, we found that maternal vaginal and fecal microbiota became more similar as pregnancy progressed, and both niches influenced the child's fecal microbiota. The relative contribution of maternal vaginal microbiota increased when vaginal sampling occurred later in gestation. As children aged from birth to 5 years, their fecal microbiota increasingly resembled their mother's fecal microbiota as compared to vaginal microbiota. Patterns of sharing appeared to differ by prenatal antibiotic use, birth mode (C-section vs. vaginal), and breastfeeding. Our findings enhance understanding of niche-specific mother-child microbe sharing and may inform microbial-seeding interventions. Metagenomic studies are needed to identify specific shared strains.
Ectopic pregnancy occurs when a fertilized egg implants outside the uterine cavity, a condition that affects approximately 1% to 2% of pregnancies in the United States. Ectopic pregnancy is a potentially life-threatening condition and accounts for 2.7% of pregnancy-related deaths. Most ectopic pregnancies (approximately 97%) occur within the fallopian tube, commonly linked to underlying fallopian tube abnormalities. Such abnormalities may result from prior infections (eg, gonorrhea or chlamydia), tubal surgeries (including sterilization), prior ectopic pregnancies, or exposure to diethylstilbestrol in utero. Additional risk factors include conception while using intrauterine devices (IUDs) or progesterone-only contraceptives. Although rare, ectopic pregnancies can also occur outside the fallopian tube, such as in the cervix, ovary, abdomen, uterine cornua, or cesarean scars. These extratubal ectopic pregnancies are less likely to be associated with the typical risk factors or tubal pathology, making their diagnosis and management particularly challenging. Regardless of the location, early detection is critical for conservative treatment and improving outcomes. Ectopic pregnancy often causes lower abdominal pain, typically on one side, along with vaginal bleeding. Symptoms like dizziness, fainting, shoulder pain, or severe pelvic pain may indicate a ruptured ectopic pregnancy. However, these signs can mimic other conditions, eg, early normal intrauterine pregnancy, miscarriage, ovarian cyst rupture, or appendicitis. Therefore, differentiating ectopic pregnancy from conditions with similar clinical features can be difficult, making prompt medical evaluation crucial for accurate diagnosis and treatment. Management primarily aims to preserve fertility, improve diagnostic accuracy, and provide psychological support. Treatment varies, depending on clinical stability, ectopic location, beta-human chorionic gonadotropin (β-hCG) levels, and ultrasound findings ranging from expectant management to surgical interventions. In select cases, nonsurgical treatment with methotrexate may be effective, especially when pregnancies are diagnosed early and meet specific criteria. However, medical treatment is less likely to succeed in cases involving larger masses, high β-hCG levels, or visible embryos. Advanced or ruptured cases typically require urgent surgical intervention.
PregnancyNeurodevelopmental DisordersMaternal Diet and Child HealthMixtures Analysis
Open Access
Previous research on the role of maternal diet in relation to autism has focused on examining individual nutrient associations. Few studies have examined associations with multiple nutrients using mixtures approaches, which may better reflect true exposure scenarios. To examine associations of nutrient mixtures with children's autism diagnosis and traits scores within a large, diverse population. Participants were drawn from the US Environmental influences on Child Health Outcomes (ECHO) consortium. Maternal prenatal diet was reported via validated food frequency questionnaires. Children's autism-related traits were measured using the Social Responsiveness Scale (SRS) and autism diagnoses were from parent report of physician diagnosis. Bayesian kernel machine regression (BKMR) was used to examine the overall mixture effect and interactions between a set of 5 primary nutrients (folate, vitamin D, omega 3 and omega 6 fatty acids, and iron), adjusted for potential confounders, in relationship to child outcomes. Secondary analyses were conducted in a subset of cohorts with an expanded set of 14 nutrients. Traditional linear and logistic regression models were also run for comparison of results to mixture models. 2,614 participants drawn from 7 ECHO cohorts were included in primary analysis. Mixture analyses suggested that increasing the overall 5-nutrient mixture was associated with lower SRS scores. Individual U-shaped associations and bivariate interactions between folate and omega 3 fatty acids were suggested. In the subset included in the secondary analyses of the 14-nutrient mixture, a modest inverse trend remained, but individual nutrient associations were altered, with vitamin D demonstrating higher relative importance than other nutrients. Strong associations with autism diagnosis were not observed. In this large sample, we found evidence for combined nutrient effects with broader autism-related traits. Because results for individual nutrients were sensitive to mixture components, replication of combined associations between nutrients and autism-related outcomes is needed.
Prevalence of autism diagnosis has historically differed by demographic factors. Using data from 8224 participants drawn from the Environmental influences on Child Health Outcomes (ECHO) Program, we examined relationships between demographic factors and parent-reported autism-related traits as captured by the Social Responsiveness Scale (SRS; T score > 65) and compared these to relations with parent-reported clinician diagnosis of ASD, in generalized linear mixed effects regression analyses. Results suggested lower odds of autism diagnosis, but not of SRS T > 65, for non-Hispanic Black children (adjusted odds ratio [OR] = 0.76, 95% CI 0.55, 1.06) relative to non-Hispanic White children. Higher maternal education was associated with reduced odds of both outcomes (OR = 0.73, 95% CI 0.51, 1.05 for ASD autism diagnosis and 0.4, 95% CI 0.29, 0.55 for SRS score). In addition, results suggested a lower likelihood of autism diagnosis but a higher likelihood of an SRS score > 65 in Black girls. Findings suggest lower diagnostic recognition of autism in non-Hispanic Black children, despite a similar degree of SRS-assessed autism-related traits falling in the clinically elevated range. Further work is needed to address this disparity.
What are the roles of maternal preconception diabetes and related periconceptional hyperglycemia on the risk of major congenital malformations (MCMs) in offspring? Maternal periconceptional glycated hemoglobin (HbA1c) levels over 5.6% were associated with an increased risk of congenital heart defects (CHD) in the offspring, and maternal preconception diabetes was associated with an increased risk of CHD, including when HbA1c levels were within euglycemic ranges. Maternal preconception diabetes has been linked with MCMs in the offspring. However, evidence concerning associations with specific periconception serum measures of hyperglycemia, and susceptibility of different organ systems, is inconsistent. Moreover, limited evidence exists concerning the effectiveness of antidiabetic medications in mitigating diabetes-related teratogenic risks. STUDY DESIGN, SIZE, A large Israeli birth cohort of 46 534 children born in 2001-2020. PARTICIPANTS/MATERIALS, SETTING, Maternal HbA1c test results were obtained from 90 days before conception to mid-pregnancy. Maternal diabetes, other cardiometabolic conditions, and MCMs in newborns were ascertained based on clinical diagnoses, medication dispensing records, and laboratory test results using previously validated algorithms. Associations were modeled using generalized additive logistic regression models with thin plate penalized splines. MAIN Maternal periconceptional HbA1c value was associated with CHD in newborns, with the risk starting to increase at HbA1c values exceeding 5.6%. The association between HbA1c and CHD was stronger among mothers with type 2 diabetes mellitus (T2DM) compared to the other diabetes groups. Maternal pre-existing T2DM was associated with CHD even after accounting for HbA1C levels and other cardiometabolic comorbidities (odds ratio (OR)=1.89, 95% CI 1.18, 3.03); and the OR was materially unchanged when only mothers with pre-existing T2DM who had high adherence to antidiabetic medications and normal HbA1c levels were considered. LIMITATIONS, The rarity of some specific malformation groups limited the ability to conduct more granular analyses. The use of HbA1c as a time-aggregated measure of glycemic control may miss transient glycemic dysregulation that could be clinically meaningful for teratogenic risks. The observed association between pre-existing diabetes and the risk of malformations within HbA1c levels suggests underlying causal pathways that are partly independent of maternal glucose control. Therefore, treatments for hyperglycemia might not completely mitigate the teratogenic risk associated with maternal preconception diabetes. STUDY FUNDING/COMPETING INTEREST(S): The work was supported by NIH grants K99ES035433, R01HD097778, and P30ES000002. None of the authors reports competing interests. N/A.
Could the risk of subsequent pregnancy loss be predicted based on the risk factors of recurrent pregnancy loss (RPL) patients? A nomogram, constructed from independent risk factors identified through multivariate logistic regression, serves as a reliable tool for predicting the likelihood of subsequent pregnancy loss in RPL patients. Approximately 1-3% of fertile couples experience RPL, with over half lacking a clear etiological factor. Assessing the subsequent pregnancy loss rate in RPL patients and identifying high-risk groups for early intervention is essential for pregnancy counseling. Previous prediction models have mainly focused on unexplained RPL, incorporating baseline characteristics such as age and the number of previous pregnancy losses, with limited inclusion of laboratory and ultrasound indicators. STUDY DESIGN, SIZE, The retrospective study involved 3387 RPL patients who initially sought treatment at the Reproductive Immunology Clinic of Renji Hospital, Shanghai Jiao Tong University School of Medicine, between 1 January 2020 and 31 December 2022. Of these, 1153 RPL patients met the inclusion criteria and were included in the analysis. PARTICIPANTS/MATERIALS, SETTING, RPL was defined as two or more pregnancy losses (including biochemical pregnancy loss) with the same partner before 28 weeks of gestation. Data encompassing basic demographics, laboratory indicators (autoantibodies, peripheral immunity coagulation, and endocrine factors), uterine and endometrial ultrasound results, and subsequent pregnancy outcomes were collected from enrolled patients through initial questionnaires, post-pregnancy visits fortnightly, medical data retrieval, and telephone follow-up for lost patients. R software was utilized for data cleaning, dividing the data into a training cohort (n = 808) and a validation cohort (n = 345) in a 7:3 ratio according to pregnancy success and pregnancy loss. Independent predictors were identified through multivariate logistic regression. A nomogram was developed, evaluated by 10-fold cross-validation, and compared with the model incorporating solely age and the number of previous pregnancy losses. The constructed nomogram was evaluated using the AUC, calibration curve, decision curve analysis (DCA), and clinical impact curve analysis (CICA). Patients were then categorized into lowand high-risk subgroups. MAIN We included age, number of previous pregnancy losses, lupus anticoagulant, anticardiolipin IgM, anti-phosphatidylserine/prothrombin complex IgM, anti-double-stranded DNA antibody, arachidonic acid-induced platelet aggregation, thrombin time and the sum of bilateral uterine artery systolic/diastolic ratios in the nomogram. The AUCs of the nomogram were 0.808 (95% CI: 0.770-0.846) in the training cohort and 0.731 (95% CI: 0.660-0.802) in the validation cohort, respectively. The 10-fold cross-validated AUC ranged from 0.714 to 0.925, with a mean AUC of 0.795 (95% CI: 0.750-0.839). The AUC of the nomogram was superior compared to the model incorporating solely age and the number of previous pregnancy losses. Calibration curves, DCAs, and CICAs showed good concordance and clinical applicability. Significant differences in pregnancy loss rates were observed between the lowand high-risk groups (P < 0.001). LIMITATIONS, This study was retrospective and focused on patients from a single reproductive immunology clinic, lacking external validation data. The potential impact of embryonic chromosomal abnormalities on pregnancy loss could not be excluded, and the administration of medication to all cases impacted the investigation of risk factors for pregnancy loss and the model's predictive efficacy. This study signifies a pioneering effort in developing and validating a risk prediction nomogram for subsequent pregnancy loss in RPL patients to effectively stratify their risk. We have integrated the nomogram into an online web tool for clinical applications. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Natural Science Foundation of China (82071725). All authors have no competing interests to declare. 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.
NaProTECHNOLOGYHormonal SupplementationDHEA TreatmentFemale
Open Access
Hypoandrogenemia is not usually considered as a potential cause of recurrent miscarriage. We present the case of a 30-year-old female with 6 previous pregnancies resulting in one live birth and 5 pregnancy losses, including fetal demise at 24 weeks gestation. She had standard investigations after her 4th loss, at a specialized miscarriage clinic. Lupus anticoagulant, anticardiolipin antibodies, thyroid function, parental karyotypes were all normal. Fetal products confirmed triploidy for her 4th miscarriage at 16 weeks gestation. She was reassured and advised to conceive again but had fetal demise after 24 weeks gestation. This was her 5th pregnancy loss with no explanation. She attended our Restorative Reproductive Medicine (RRM) clinic in January 2022. In addition to poor follicle function, we found hypoandrogenemia for the first time. Treatment included follicle stimulation with clomiphene and DHEA 25 mg twice daily pre-conception with DHEA 20 mg once daily maintained throughout pregnancy. She delivered a healthy baby boy by cesarean section at 36 weeks gestation in November 2023. Hypoandrogenemia should be considered as a contributory factor for women with recurrent miscarriage or late pregnancy loss. Restoration of androgens to normal levels with oral DHEA is safe and can improve pregnancy outcome.
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.
Very little is known about the prevalence and risk factors of postpartum depression among women with vaginal births without major pregnancy complications. This study aimed to assess the prevalence of postpartum depression and identify its characteristics 2 months after singleton vaginal delivery at or near term. This was an ancillary cohort study of the TRanexamic Acid for Preventing Postpartum Hemorrhage After Vaginal Delivery randomized controlled trial, which was conducted in 15 French hospitals in 2015-2016 and enrolled women with singleton vaginal deliveries after 35 weeks of gestation. After randomization, the characteristics of labor, delivery, and the immediate postpartum experience, including the experience of childbirth, were prospectively collected. Medical records provided women's other characteristics, particularly any psychiatric history. Of note, 2 months after childbirth, provisional postpartum depression diagnosis was defined as a score of ≥13 on the Edinburgh Postnatal Depression Scale, a validated self-administered questionnaire. The corrected prevalence of postpartum depression was calculated with the inverse probability weighting method to take nonrespondents into account. Associations between potential risk factors and postpartum depression were analyzed by multivariate logistic regression. Moreover, an Edinburgh Postnatal Depression Scale cutoff value of ≥11 was selected to perform a sensitivity analysis. The questionnaire was returned by 2811 of 3891 women (72.2% response rate). The prevalence rates of the provisional diagnosis were 9.9% (95% confidence interval, 8.6%-11.3%) defined by an Edinburgh Postnatal Depression Scale score of ≥13 and 15.5% (95% confidence interval, 14.0%-17.1%) with a cutoff value of ≥11. The characteristics associated with higher risks of postpartum depression in multivariate analysis were mostly related to prepregnancy characteristics, specifically age of <25 years (adjusted odds ratio, 1.8; 95% confidence interval, 1.1-2.9) and advanced age (adjusted odds ratio, 1.8; 95% confidence interval, 1.2-2.6), migration from North Africa (adjusted odds ratio, 2.9; 95% confidence interval, 1.9-4.4), previous abortion (adjusted odds ratio, 1.4; 95% confidence interval, 1.0-2.0), and psychiatric history (adjusted odds ratio, 2.9; 95% confidence interval, 1.8-4.8). Some characteristics of labor and delivery, such as induced labor (adjusted odds ratio, 1.5; 95% confidence interval, 1.1-2.0) and operative vaginal delivery (adjusted odds ratio, 1.4; 95% confidence interval, 1.0-2.0), seemed to be associated with postpartum depression. In addition, bad memories of childbirth in the immediate postpartum were strongly associated with postpartum depression symptoms at 2 months after giving birth (adjusted odds ratio, 2.4; 95% confidence interval, 1.3-4.2). Approximately 10% of women with vaginal deliveries have postpartum depression symptoms, assessed by a score of ≥13 on the depression scale that was used at 2 months. Prepregnancy vulnerability factors; obstetrical characteristics, such as induced labor and operative vaginal delivery; and bad memories of childbirth 2 days after delivery were the main factors associated with this provisional diagnosis. A screening approach that targets risk factors may help to identify women at risk of postpartum depression who could benefit from early intervention.
Fetal Lower Urinary Tract Obstruction (LUTO) is associated with oligohydramnios and significant fetal morbidity, resulting in poor lung development and perinatal death. However, oligohydramnios may develop at different gestational periods, and the impact of timing on fetal outcomes remains unknown. Our objective was to characterize the impact onset of oligohydramnios had on prenatal outcomes. This study is a retrospective cohort study of all patients with a prenatal diagnosis of LUTO at our tertiary referral center from 2014 to 2023. All patients underwent detailed ultrasonography and interdisciplinary counseling and were subsequently delivered at our institution. Data were obtained from electronic medical records and complete extraction was required for final inclusion. During the study time period, 93 patients met inclusion criteria of which 68 (73.1%) developed oligohydramnios during their pregnancy. 63 (93%) of these pregnancies resulted in livebirths with 28 (41.1%) perinatal deaths. Onset of oligohydramnios was earlier in pregnancies with perinatal death (23 vs. 28 weeks, p = 0.004) and associated with pulmonary hypoplasia. Our data show the impact of oligohydramnios timing in pregnancy on pulmonary hypoplasia and ultimately perinatal death. This allows for detailed patient counseling on the impact oligohydramnios may have on pregnancies by the gestational age of onset.
PregnancyGrief Assessment ToolsReproductive GriefTool Development
Open Access
Women who have experienced reproductive loss (i.e., miscarriage, stillbirth, abortion) evaluated the usefulness of a novel screening tool, Reproductive Grief Screen (RGS), to identify patients struggling with ongoing, complicated grief. This mixed-methods study involved U.S. women who had experienced reproductive loss. Online data collection resulted in 27 interviews and 282 surveys completed. Perceptions of and preferences about RGS were thematically analyzed. Chi square analyses assessed relationships between demographics and tool preferences. RGS validated women's experiences with grief after reproductive loss. Women noted their providers may be unaware of their loss(es). Participants requested periodic screening using RGS beginning shortly after a loss (or during new patient intake) and occurring regularly (e.g., annually). Overall, women preferred completing RGS online before an appointment, though preferences varied by demographics (i.e., age, time since loss). Participants want providers to compassionately discuss RGS results with them and offer appropriate resources. The RGS can help identify largely ignored grief after reproductive loss. Findings from group and individual interviews and a survey of women who have coped with reproductive loss suggest that use of a brief RGS tool could reshape clinical practice to aid women who might be facing complicated grief. Moreover, women expressed clear preferences for how to implement use of the RGS in clinical contexts.
PregnancyIron and Vitamin D StatusAntenatal DepressionMicronutrient Assessment in Pregnancy
Open Access
The maternal status of multiple micronutrients during pregnancy and postpartum and their potential associations with maternal health outcomes are largely undescribed. This study aimed to examine associations between maternal iron and vitamin D status, individually and in combination, on depression symptoms in pregnant individuals. The Alberta Pregnancy Outcomes and Nutrition cohort study included pregnant participants and their children from Calgary and Edmonton, Canada. Iron biomarkers (serum ferritin [SF], soluble transferrin receptor, and hepcidin) were measured via immunoassays and vitamin D [25-hydroxyvitamin D3 (25(OH)D3) and 3-epi-25-hydoxyvitamin D3 (3-epi-25(OH)D3)] metabolites were quantifed using liquid chromatography with tandem mass spectroscopy. Four categories of maternal iron and vitamin D status during the second trimester were conceptualized using concentrations of SF and total 25-hydoxyvitamin D [25(OH)D], respectively. Maternal Edinburgh Postnatal Depression Scale (EPDS) scores during the third trimester (n = 1920) and 3 mo postpartum (n = 1822) were obtained. Concentrations of maternal 25(OH)D3, 3-epi-25(OH)D3, and the ratio of both metabolites were significantly higher during the second trimester compared with their status at 3 mo postpartum. Higher second trimester maternal concentrations of SF (β: -0.8; 95% confidence interval [CI]: -1.5, -0.01), hepcidin (β: -0.5; 95% CI: -0.9, -0.2), and 25(OH)D3 (β: -0.01; 95% CI: -0.02, -0.004) predicted lower maternal EPDS scores during the third trimester. Pregnant individuals with a low iron (SF <15 μg/L) and replete vitamin D (25(OH)D ≥75 nmol/L) (β: 1.1; 95% CI: 0.03, 2.1) or low iron (SF <15 μg/L) and vitamin D (25(OH)D <75 nmol/L) (β: 2.2; 95% CI: 0.3, 4.2) status during midpregnancy had higher third trimester EPDS scores compared with those that were replete in both micronutrients. A higher midpregnancy maternal iron and vitamin D status, independently or in combination, predicted fewer maternal depression symptoms in the third trimester. Concentrations of maternal 25(OH)D3 and 3-epi-25(OH)D3 may be lower in the postpartum period compared with midpregnancy.
PregnancyHypertensive DisordersProgesterone SupplementationSystematic Review and Meta-Analysis
Open Access
Treatment with vaginal progesterone reduces the risk of miscarriage and preterm birth in selected high-risk women. The hypothesis that vaginal progesterone can reduce the risk of hypertensive disorders of pregnancy (HDP) is unexplored. To summarise the evidence on the effectiveness of vaginal progesterone to reduce the risk of HDP.
We searched Embase (OVID), MEDLINE (OVID), PubMed, CENTRAL and clinicaltrials.gov from inception until 20 June 2023.
We included placebo-controlled randomised trials (RCTs) of vaginal progesterone for the prevention or treatment of any pregnancy complications.
We extracted absolute event numbers for HDP and pre-eclampsia in women receiving vaginal progesterone or placebo, and meta-analysed the data with a random effects model. We appraised the certainty of the evidence using GRADE methodology. The quantitative synthesis included 11 RCTs, of which three initiated vaginal progesterone in the first trimester, and eight in the second or third trimesters. Vaginal progesterone started in the first trimester of pregnancy lowered the risk of any HDP (risk ratio [RR] 0.71, 95% confidence interval [CI] 0.53-0.93, 2 RCTs, n = 4431 women, I(2) = 0%; moderate-certainty evidence) and pre-eclampsia (RR 0.61, 95% CI 0.41-0.92, 3 RCTs, n = 5267 women, I(2) = 0%; moderate-certainty evidence) when compared with placebo. Vaginal progesterone started in the second or third trimesters was not associated with a reduction in HDP (RR 1.19, 95% CI 0.67-2.12, 3 RCTs, n = 1602 women, I(2) = 9%; low-certainty evidence) or pre-eclampsia (RR 0.97, 95% CI 0.71-1.31, 5 RCTs, n = 4274 women, I(2) = 0%; low-certainty evidence). Our systematic review found first-trimester initiated vaginal micronised progesterone may reduce the risk of HDP and pre-eclampsia.
PregnancyMolar PregnancyPreterm BirthGestational Trophoblastic Disease
Open Access
Maternal b-HCG levels fell to undetectable levels one month after birth without treatment. She was doing well and a follow-up six months later revealed no evidence of retained tissue or recurrence.
Spontaneous preterm birth significantly increases the risk for a recurrent preterm birth. Only a few identifiable clinical risk factors can be referenced in counseling for recurrent preterm birth. Furthermore, treatment using progesterone supplementation has not consistently prevented preterm birth among high-risk patients, but it may be effective in a subset of those patients. Placental pathology from a previous pregnancy may be used to predict which patients will experience a recurrent preterm birth or to identify a subset of patients more likely to respond to treatment with antenatal progesterone. This study aimed to determine if histologic patterns are associated with recurrent preterm birth among patients with an index spontaneous preterm birth. A secondary objective was to determine if placental histologic types and/or progesterone receptor density in the decidua are associated with the response to progesterone supplementation with intramuscular 17-hydroxyprogesterone caproate. This was a retrospective cohort study at a single institution of women with singleton pregnancies with an index spontaneous preterm birth and a subsequent birth within the same hospital system between 2009 and 2019. Patients were included if placental pathology was available for the index spontaneous preterm birth. A logistic regression was used to determine if there were independent associations between 4 histologic types (acute inflammation, maternal vascular malperfusion, fetal vascular malperfusion, chronic inflammation) and recurrent preterm birth. For the secondary endpoint, 17-hydroxyprogesterone caproate response was defined as prolonging gestation by >3 weeks beyond the gestational age at delivery in the index pregnancy. Patients who delivered <3 weeks beyond the gestational age in the index pregnancy but at ≥39 weeks' gestation were excluded. A logistic regression was used to assess the independent association between placental histology and 17-hydroxyprogesterone caproate response. Sensitivity analyses were completed using only patients with an index birth <36 weeks' gestation, and then excluding those with medically indicated preterm birth in a subsequent pregnancy. A nested case-control immunohistochemical study was done among 20 patients with a subsequent term birth and 20 patients with a subsequent spontaneous preterm birth. The percentage of cells in the maternal decidua positive for progesterone receptors was correlated with the subsequent pregnancy outcome. A total of 352 patients were included. Acute inflammation was the most common histologic type seen among patients with spontaneous preterm birth (44.1%), followed by chronic inflammation (40.9%) and maternal vascular malperfusion (31.3%). No histologic type was independently associated with recurrent preterm birth. A total of 155 patients received 17-hydroxyprogesterone caproate in a second pregnancy. Low-grade acute inflammation was significantly associated with a decreased likelihood of 17-hydroxyprogesterone caproate response. Low-grade maternal vascular malperfusion among those with an index pregnancy delivered at <36 weeks' gestation was significantly associated with a more than 4 times increased likelihood of 17-hydroxyprogesterone caproate response when excluding those with a subsequent iatrogenic preterm birth. Progesterone receptor staining was not associated with recurrent preterm birth. Although acute inflammation was prevalent among spontaneous preterm births, more than half of the spontaneous preterm births were not associated with acute inflammation. Low-grade acute inflammation was associated with a significantly decreased response to 17-hydroxyprogesterone caproate supplementation. Low-grade maternal vascular malperfusion was associated with a 4-fold increased likelihood of 17-hydroxyprogesterone caproate response among those with index deliveries <36 weeks' gestation. Further work is needed to determine if placental pathologic examination can be used to target treatment in subsequent pregnancies to prevent recurrent preterm birth.
PregnancyFirst Trimester Anatomy UltrasoundFetal Anatomy Assessment in ObesityPrenatal Imaging
Second-trimester ultrasound is the standard technique for fetal anatomy evaluation in the United States despite international guidelines and literature that suggest that first-trimester timing may be superior in patients with obesity. First-trimester imaging performs well in cohorts of participants with obesity. Our aim was to compare the completion rate of a first-trimester fetal anatomy ultrasound scan with that of a second-trimester fetal anatomy ultrasound scan among pregnant people with a body mass index ≥35 kg/m(2). This randomized controlled trial enrolled participants with a body mass index ≥35 kg/m(2) with a singleton gestation and who presented before 14+0/7 weeks of gestation. Participants were randomized to receive an ultrasound assessment of anatomy at either 12+0/7 to 13+6/7 weeks or at 18+0/7 to 22+6/7 weeks. The primary outcome was completion rate (percentage of scans that optimally imaged all the required fetal structures). Secondary outcomes included the necessity of a transvaginal approach, completion rates for each individual view, number of anomalies identified and missed in each group, scan duration, and patient perspectives. A 1-year pilot sample was analyzed using Bayesian methods for the primary outcome with a neutral prior and frequentist analyses for the remaining outcomes. A total of 128 participants were enrolled, and 1 withdrew consent; 62 subjects underwent a first-trimester ultrasound scan and 62 underwent a second-trimester ultrasound scan. A total of 2 participants did not attend the research visits, and 1 sought termination of pregnancy. In the first-trimester group, 66% (41/62) of ultrasound scans were completed in comparison with 53% (33/62) in the second-trimester ultrasound group (Bayesian relative risk, 1.20; 95% credible interval, 0.91-1.73). When compared with a second-trimester scan plus a follow-up ultrasound, a first-trimester ultrasound plus a second-trimester ultrasound was equally successful in completing the anatomy views (76%). First-trimester anatomy ultrasound scans required a transvaginal approach in 63% (39/62) of cases and had a longer duration than a second-trimester ultrasound scan. No anomalies were missed in either group. First-trimester ultrasound participants who responded to a survey described that they were very satisfied with the technique. In pregnant subjects with a body mass index ≥35 kg/m(2), a single first-trimester anatomy ultrasound scan was more likely to obtain all the recommended anatomic views than a single second-trimester ultrasound scan. An evaluation of anatomy at 12+0/7 to 13+6/7 weeks' gestation plus an evaluation at 18+0/7 to 22+6/7 led to complete anatomic evaluation 4 weeks earlier than 2 second trimester scans. Assessment of ultrasound duration in a clinical setting is needed to ensure feasibility outside of a research setting.
General OB/GYNFetal Anatomy UltrasoundUltrasound ChallengesUltrasound Completion Rates
As maternal body mass index (BMI) increases, fetal anatomy ultrasound becomes more challenging, less sensitive, and less likely to be complete. We sought to report our experience of incomplete evaluation of anatomy in patients with BMI of 50 kg/m(2) or greater. This is a retrospective cohort of singleton gestations in mothers with BMI of 50 kg/m(2) or greater, undergoing anatomy evaluations between 2017 and 2021 at 9 maternal-fetal-medicine sites in Houston, TX. Patient variables and scan results were collected throughout pregnancy to provide a longitudinal assessment of the primary outcome, completion rate (percent of all scans which optimally captured 24 American Institute of Ultrasound in Medicine-recommended images). Secondary outcomes included the rate of optimal capture of each individual structure. In total, 293 patients with BMI ≥50 kg/m(2) were identified. Only 28% of initial scans were complete, but over the entire pregnancy, a complete anatomic evaluation was achieved in 76% of women, largely due to weekly ultrasounds done for antenatal testing later in pregnancy. Neither BMI, placental location, nor amniotic fluid volume affected completion rate. The most difficult views are the outflow tracts, 4-chamber view, and spine. One quarter of women with BMI of 50 kg/m(2) or greater will not have a complete fetal anatomic evaluation by the end of pregnancy, since even basic fetal anatomic views are technically challenging to complete. Solutions deserve further attention, and may include first trimester imaging, transvaginal imaging, and optimization of ultrasound machine settings.
Cesarean delivery is a major source of maternal morbidity, and repeat cesarean delivery accounts for 40% of cesarean delivery, but recent data on the trial of labor after cesarean and vaginal birth after cesarean are limited. This study aimed to report the national rates of trial of labor after cesarean and vaginal birth after cesarean by number of previous cesarean deliveries and examine the effect of demographic and clinical characteristics on these rates. This was a population-based cohort study using the US natality data files. The study sample was restricted to 4,135,247 nonanomalous singleton, cephalic deliveries between 37 and 42 weeks of gestation, with a history of previous cesarean delivery and delivered in a hospital between 2010 and 2019. Deliveries were grouped by number of previous cesarean deliveries (1, 2, or ≥3). The trial of labor after cesarean (deliveries with labor among deliveries with previous cesarean delivery) and vaginal birth after cesarean (vaginal deliveries among trial of labor after cesarean) rates were computed for each year. The rates were further subgrouped by history of previous vaginal delivery. Year of delivery, number of previous cesarean deliveries, history of previous cesarean delivery, age, race and ethnicity, maternal education, obesity, diabetes mellitus, hypertension, inadequate prenatal care, Medicaid payer, and gestational age were examined concerning the trial of labor after cesarean and vaginal birth after cesarean using multiple logistic regression. SAS software (version 9.4) was used for all analyses. The trial of labor after cesarean rates increased from 14.4% in 2010 to 19.6% in 2019 (P<.001). This trend was seen in all categories of number of previous cesarean deliveries. Moreover, vaginal birth after cesarean rates increased from 68.5% in 2010 to 74.3% in 2019. The trial of labor after cesarean and vaginal birth after cesarean rates were the highest for deliveries with a history of both 1 previous cesarean delivery and a vaginal delivery (28.9% and 79.7%, respectively) and the lowest for those with a history of ≥3 previous cesarean deliveries and no history of vaginal delivery (4.5% and 46.9%, respectively). Factors associated with the trial of labor after cesarean and vaginal birth after cesarean rates are similar, but several factors have different directions of effect, such as non-White race and ethnicity, which is associated with a higher likelihood of trial of labor after cesarean but a lower likelihood of successful vaginal birth after cesarean. More than 80% of patients with a history of previous cesarean delivery deliver by repeat scheduled cesarean delivery. With vaginal birth after cesarean rates increasing among those who attempt a trial of labor after cesarean, emphasis should be put on safely increasing the trial of labor after cesarean rates.
PregnancyMaternal Mental HealthDepression and Anxiety ScreeningPerinatal Depression
Perinatal depression and anxiety are major causes of maternal morbidity, and are more common in high-risk pregnancies compared to low-risk pregnancies. This study used validated screening tools to assess the prevalence of depression and anxiety symptoms in pregnant patients who transferred their obstetric care to a specialized fetal center for fetal anomaly. This is a prospective cohort of patients with a fetal anomaly prompting transfer of obstetric care to Texas Children's Hospital Fetal Center between January 2021 and February 2022. The primary outcome was a self-assessed Edinburgh Postnatal Depression Scale score of 13 or higher, either antepartum or postpartum ("ever-positive EPDS"). Secondary outcomes included self-assessed Perinatal Anxiety Screening Scale (PASS) scores of 21 or higher ("ever-positive PASS"), obstetric outcomes, and neonatal outcomes. A frequentist analysis was performed. Of 149 women who transferred to Texas Children's Hospital during the study period, 94 enrolled in this study. Twenty-six percent of women had an ever-positive EPDS; 20% of patients had an ever-positive PASS. Patients were more likely to have an ever-positive EPDS if they were single (46% compared to 20%, p = 0.025). Women who had an ever-positive EPDS were more likely to be referred to psychiatry (46% compared to 14%, p = 0.004) and psychotherapy (29% compared to 1%, p < 0.001). Surprisingly, patients were more likely to have an ever-positive PASS if they reported good social support (p = 0.03). Antepartum EPDS and PASS scores had no relationship with postpartum EPDS scores. Women who transfer care to a tertiary setting have positive EPDS scores at double the rate of the general population, but tend to experience this either antepartum or postpartum (not both). Fetal centers should be prepared to screen for mental health symptoms before and after delivery and provide appropriate referral or treatment.
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.
PregnancyEmbryo Transfer AttemptsEctopic Pregnancy ManagementEctopic Pregnancy Treatment
The objectives of this review are to identify and characterize attempts to transfer ectopic embryos to the uterus, and to understand arguments for and against the feasibility of such an intervention. An electronic literature search involved all English language articles published in MEDLINE (1948-), Web of Science (1899-), and Scopus (1960-) before July 1, 2022. Articles were included that identify or describe attempts to transfer the embryo from its ectopic location to the uterine cavity, or discuss the feasibility of such an intervention; there were no exclusion criteria (PROSPERO registration number CRD42022364913). The initial search yielded 3060 articles; 8 articles were included. Of these, two articles were case reports that described the successful transfer of the embryo from its ectopic location to the uterus, followed by term births; both cases involved laparotomy with salpingostomy, followed by transfer of the embryonic sac into the uterine cavity through an opening made in the uterine wall. The other six articles varied in type, and provided a number of arguments for and against the feasibility of such a procedure. The evidence and arguments identified in this review may help manage expectations for those interested in transferring an ectopically implanted embryo in the hope of continuing the pregnancy, but who are uncertain about the extent to which such a procedure has been attempted or may be possible. Isolated case reports, with no evidence of replication, should be interpreted with the utmost caution and do not constitute a procedure for clinical use.
Human embryogenesis is a complicated process by which a fertilized egg develops into an embryo. During the first eight weeks of development, the conceptus shifts from a single-celled zygote into a multi-layered, multi-dimensional fetus with primitively functioning organs. The continued growth and increased intra-embryonic complexity during the first eight weeks of development are highly dependent upon cell signaling, proliferation, and differentiation. Due to the intricacies involved, the development of the human embryo is divided into developmental events by week. Week 1 is a major part of the germinal stage of development, a period of time that continues from fertilization through uterine implantation. Important events that occur during the first week of human embryonic development include gamete approximation, contact and fusion of gametes, fertilization, mitotic cleavage of the blastomere, morula formation, blastocyst formation, and implantation of the blastocyst.
PregnancyDietary Risk FactorsMeta-AnalysisPericonceptual Diet and Outcomes
Open Access
The evidence on the association between diet and miscarriage risk is scant and conflicting. To summarize the evidence on the association between periconceptual diet and miscarriage risk in healthy women of reproductive age. Electronic databases were searched from inception to August 2022 without restriction of regions, publication types, or languages. Experimental or observational studies were considered for inclusion. The population was healthy women of reproductive age. Exposure was periconception diet. Study quality was assessed using the modified Newcastle-Ottawa Scale. Summary effect sizes (odds ratio [OR] with 95% confidence interval [CI]) were calculated for each food category. Miscarriage rate (as defined by primary studies). We included 20 studies (11 cohort and 9 case-control), of which 6 presented data suitable for meta-analysis (2 cohort and 4 case-control, n = 13,183 women). Our primary analyses suggest a reduction in miscarriage odds with high intake fruit (OR, 0.39; 95% CI, 0.33-0.46), vegetables (OR, 0.59; 95% CI, 0.46-0.76), fruit and vegetables (OR, 0.63; 95% CI, 0.50-0.81), seafood (OR, 0.81; 95% CI, 0.71-0.92), dairy products (OR, 0.63; 95% CI, 0.54-0.73), eggs (OR, 0.81; 95% CI, 0.72-0.90), and cereal (grains) (OR, 0.67; 95% CI, 0.52-0.87). The evidence was uncertain for meat, red meat, white meat, fat and oil, and sugar substitutes. We did not find evidence of an association between adherence to predefined dietary patterns and miscarriage risk. However, a whole diet containing healthy foods as perceived by the trialists, or with a high Dietary Antioxidant Index score (OR, 0.43; 95% CI, 0.20-0.91) may be associated with a reduction in miscarriage risk. In contrast, a diet rich in processed food was demonstrated to be associated with increased miscarriage risk (OR, 1.97; 95% CI, 1.36-3.34). A diet abundant in fruit, vegetables, seafood, dairy, eggs, and grain may be associated with lower miscarriage odds. Further interventional studies are required to accurately assess the effectiveness of periconception dietary modifications on miscarriage risk. CRD42020218133.
Selective fetal growth restriction (sFGR) complicates 10%-26% of monochorionic twins. Treatment options include cord coagulation, expectant management, and fetoscopic laser photocoagulation. This review compared laser to expectant management for situations when cord coagulation is not an option. The MEDLINE, EMBASE, and Cochrane databases were queried for studies that compared laser to expectant management for sFGR. GRADE was used to assess quality prior to meta-analysis. A random-effects model was used to generate relative risks. Six studies were included, encompassing 299 pregnancies. One study was randomized and the remainder were retrospective cohorts. Laser is associated with more fetal deaths of the FGR twin compared to expectant management (risk ratio [RR] 2.5, 95% confidence interval [CI] 1.43-4.37, p = 0.001, I2 = 48%). Neonatal deaths and gestational age at delivery did not differ. Laser was associated with decreased abnormal neuroimaging in the AGA twin (RR 0.25, 95% CI 0.07-0.97, p = 0.05). Neurodevelopmental outcomes did not differ, although these data are limited. Laser causes more fetal deaths of the FGR twin without altering gestational age at delivery or rates of neonatal death. The literature is heterogeneous and the level of bias is high. Randomized trials that address laser for type II sFGR are needed and should include long-term neurological outcomes.
Brennan PA et al., 2022·Res Child Adolesc Psychopathol
Prenatal antidepressant exposure has been associated with increased risk for neurodevelopmental disorders in childhood, including autism spectrum disorder (ASD). The current study utilized multi-cohort data from the Environmental influences on Child Health Outcomes (ECHO) program (N = 3129) to test for this association, and determine whether the association remained after adjusting for maternal prenatal depression and other potential confounders. Antidepressants and a subset of selective serotonin reuptake inhibitors (SSRIs) were examined in relation to binary (e.g., diagnostic) and continuous measures of ASD and ASD related traits (e.g., social difficulties, behavior problems) in children 1.5 to 12 years of age. Child sex was tested as an effect modifier. While prenatal antidepressant exposure was associated with ASD related traits in univariate analyses, these associations were statistically non-significant in models that adjusted for prenatal maternal depression and other maternal and child characteristics. Sex assigned at birth was not an effect modifier for the prenatal antidepressant and child ASD relationship. Overall, we found no association between prenatal antidepressant exposures and ASD diagnoses or traits. Discontinuation of antidepressants in pregnancy does not appear to be warranted on the basis of increased risk for offspring ASD.
To evaluate the effect of birth ball abdominal core training on fatigue, waist pain, and delivery outcomes in middle and late pregnancy. A prospective study of 209 primipara in total with 24–27 weeks of gestation were recruited and divided into the training group (109 cases) and the control group (100 cases). The control group received routine prenatal exercise. On the basis of routine prenatal exercise, pregnant women in the training group were given birth ball exercises based on abdominal core training. The difference in pregnancy fatigue, waist discomfort, and delivery outcomes between the two groups were compared. The waist pain and fatigue ratings of women were significantly lower and the vaginal delivery rate (74.3%) was significantly higher (62%) (P < 0.001) in the training group. There were no significant differences in the total stage of labor, postpartum hemorrhage, neonatal weight and 1‐min neonatal Apgar score between the two groups. The rate of episiotomy in the training group (14.7%) was significantly lower than that in the control group (25.0%) (P < 0.05). Birth ball exercises can relieve fatigue and waist pain in middle and late 2021 pregnancy, reduce the rate of episiotomy, and promote spontaneous vaginal delivery.
PregnancyPerinatal Palliative CarePrenatal Decision MakingFamily-Centered Care
Perinatal palliative care is an emerging concept in fetal medicine that offers quality-of-life options and anticipatory grief management for families of fetuses with complex conditions. Few perinatal palliative care outcomes are detailed in peer-reviewed literature. This study aimed to describe outcomes of perinatal palliative care at the Fetal Center of the University of Texas Health Science Center at Houston and Women's Center at Children's Memorial Hermann Hospital. This was a retrospective cohort of families receiving perinatal palliative care for life-limiting fetal diagnosis, such as trisomy 13 or 18 and some major structural anomalies between 2016 and 2020. The primary outcome was whether delivery events matched families' birth plans, including fetal/neonatal clinical course matching expectations described by consultant notes. Secondary outcomes included maternal safety outcomes, use of perinatal interventions, delivery outcomes, and resource utilization outcomes. Of 187 perinatal palliative care consults, delivery events matched families' plans and clinicians' expectations in 89% of cases (165/185); 39% (73/187) of families requested some perinatal interventions, 64% of whom planned postnatal comfort care even while choosing antenatal interventions. Demographics and median income were similar between families who chose some interventions and those who chose comfort care. Patients choosing any interventions had more mismatches between their plans and delivery events (19% vs 2%; P<.001), were more likely to change their plans (24% vs 6%; P=.001), and unsurprisingly used more healthcare resources. They were also more likely to have intraamniotic infection or postpartum hemorrhage (9% vs 22%; P=.02), but this was associated with mode of delivery and not choice of interventions. Most families' perinatal experiences matched birth plans and expectations in this perinatal palliative care program. Families who desired interventions used more healthcare resources, but often did so with plans for postnatal comfort care, demonstrating insight into neonatal prognosis but achieving value-consistent goals, such as meeting a live neonate. Perinatal palliative care was safe for maternal patients and equitable across racial, ethnic, and income groups. Perinatal palliative care and some perinatal interventions are options for care of the whole family in complex fetal medicine cases.
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.
To assess risk factors for anxiety and depression among pregnant women during the COVID-19 pandemic using Mind-COVID, a prospective cross-sectional study that compares outcomes in middle-income economies and high-income economies. A total of 7102 pregnant women from 12 high-income economies and nine middle-income economies were included. The web-based survey used two standardized instruments, General Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-9 (PHQ-9). Pregnant women in high-income economies reported higher PHQ-9 (0.18 standard deviation [SD], P < 0.001) and GAD-7 (0.08 SD, P = 0.005) scores than those living in middle-income economies. Multivariate regression analysis showed that increasing PHQ-9 and GAD-7 scales were associated with mental health problems during pregnancy and the need for psychiatric treatment before pregnancy. PHQ-9 was associated with a feeling of burden related to restrictions in social distancing, and access to leisure activities. GAD-7 scores were associated with a pregnancy-related complication, fear of adverse outcomes in children related to COVID-19, and feeling of burden related to finances. According to this study, the imposed public health measures and hospital restrictions have left pregnant women more vulnerable during these difficult times. Adequate partner and family support during pregnancy and childbirth can be one of the most important protective factors against anxiety and depression, regardless of national economic status.
Over the last 5 decades, the fulfillment of maternity wishes in solid organ transplanted women has become a reality. Despite pregnancy contraindication in transplanted women during the early post-transplant period, such a condition can be overcome after 12 months if patients show a good clinical evolution and do not present other general pre-conceptional findings. This article presents the case report of a young female liver transplanted patient that used symptothermal method as a reliable family planning method. After her gestational contraindication was lifted, observation of biological fertility indicators and fertility-guided sexual intercourse helped her fulfill her maternity wish and conceive and carry out a healthy offspring. Based on this case and on the available bibliographic evidence, this paper reviews the potential implications of the use of this kind of approach as a safe and effective alternative to assisted reproduction technology in the management of potential infertility problems in the young female transplanted population, a population which according to literature has higher rates of unsuccessful parenthood and might also be more vulnerable to iatrogenicity of ovarian hyperstimulation process and to multiple pregnancy.
Schliep KC et al., 2022·Paediatr Perinat Epidemiol
Women with endometriosis may have an increased risk of adverse pregnancy outcomes. Research has focused on infertility clinic populations limiting generalisability. Few studies report differences by endometriosis severity. We investigated the relationships between endometriosis diagnosis, staging and typology and pregnancy outcomes among an operative and population-based sample of women. Menstruating women ages 18-44 years enrolled in the ENDO Study (2007-2009), 316 gravid women undergoing laparoscopy/laparotomy at surgical centres in Utah and California; 76 gravid women from the surgical centres' geographic catchment areas. Pregnancy outcomes were ascertained by questionnaire and included all pregnancies prior to study enrolment. Endometriosis was diagnosed via surgical visualisation in the operative cohort and pelvic magnetic resonance imaging in the population cohort. Adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) were estimated using generalised linear mixed models for pregnancy outcomes, adjusting for women's age at study enrolment and at pregnancy, surgical site, body mass index and lifestyle factors. Women in the operative cohort with visualised endometriosis (n = 109, 34%) had a lower prevalence of live births, aPR 0.94 (95% CI 0.85, 1.03) and a higher prevalence of miscarriages, aPR 1.48 (95% CI 1.23, 1.77) compared with women without endometriosis. The direction and magnitude of estimates were similar in the population cohort. Women with deep endometriosis were 2.98-fold more likely (95% CI 1.12, 7.95) to report a miscarriage compared with women without endometriosis after adjusting for women's age at study enrolment and at pregnancy, surgical site and body mass index. No differences were seen between endometriosis staging and pregnancy outcomes. While there was no difference in number of pregnancies among women with and without endometriosis in a population-based sample, pregnancy loss was more common among women with endometriosis, notably among those with deep endometriosis.
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.
Preterm birth is the leading cause of neonatal morbidity and mortality. The recurrence rate of spontaneous preterm birth is high, and additional preventive measures are required. Our objective was to assess the effectiveness of low-dose aspirin compared to placebo in the prevention of preterm birth in women with a previous spontaneous preterm birth. We performed a parallel multicentre, randomised, double-blinded, placebo-controlled trial (the APRIL study). The study was performed in 8 tertiary and 26 secondary care hospitals in the Netherlands. We included women with a singleton pregnancy and a history of spontaneous preterm birth of a singleton between 22 and 37 weeks. Participants were randomly assigned to aspirin 80 mg daily or placebo initiated between 8 and 16 weeks of gestation and continued until 36 weeks or delivery. Randomisation was computer generated, with allocation concealment by using sequentially numbered medication containers. Participants, their healthcare providers, and researchers were blinded for treatment allocation. The primary outcome was preterm birth <37 weeks of gestation. Secondary outcomes included a composite of poor neonatal outcome (bronchopulmonary dysplasia, periventricular leukomalacia > grade 1, intraventricular hemorrhage > grade 2, necrotising enterocolitis > stage 1, retinopathy of prematurity, culture proven sepsis, or perinatal death). Analyses were performed by intention to treat. From May 31, 2016 to June 13, 2019, 406 women were randomised to aspirin (n = 204) or placebo (n = 202). A total of 387 women (81.1% of white ethnic origin, mean age 32.5 ± SD 3.8) were 194 women were allocated to aspirin and 193 to placebo. Preterm birth <37 weeks occurred in 41 (21.2%) women in the aspirin group and 49 (25.4%) in the placebo group (relative risk (RR) 0.83, 95% confidence interval (CI) 0.58 to 1.20, p = 0.32). In women with ≥80% medication adherence, preterm birth occurred in 24 (19.2%) versus 30 (24.8%) women (RR 0.77, 95% CI 0.48 to 1.25, p = 0.29). The rate of the composite of poor neonatal outcome was 4.6% (n = 9) versus 2.6% (n = 5) (RR 1.79, 95% CI 0.61 to 5.25, p = 0.29). Among all randomised women, serious adverse events occurred in 11 out of 204 (5.4%) women allocated to aspirin and 11 out of 202 (5.4%) women allocated to placebo. None of these serious adverse events was considered to be associated with treatment allocation. The main study limitation is the underpowered sample size due to the lower than expected preterm birth rates. In this study, we observed that low-dose aspirin did not significantly reduce the preterm birth rate in women with a previous spontaneous preterm birth. However, a modest reduction of preterm birth with aspirin cannot be ruled out. Further research is required to determine a possible beneficial effect of low-dose aspirin for women with a previous spontaneous preterm birth. Dutch Trial Register (NL5553, NTR5675) //www.trialregister.nl/trial/5553.
PregnancyPerinatal Palliative CareLife-Limiting Fetal DiagnosisPalliative Care Programs
Perinatal palliative care (PPC) is an option for patients who discover that their infant has a life-limiting fetal condition, which decreases the burden of the condition using a multidisciplinary approach. This review discusses the landmark literature in the past two decades, which have seen significant growth and development in the concept of PPC. The literature describes the background, quality, and benefits of offering PPC, as well as the ethical principles that support its being offered in every discussion of fetal life-limiting diagnoses. PPC shares a similar risk profile to other options after life-limiting diagnosis, including satisfaction with choice of continuation of pregnancy. The present clinical opinion closes by noting common barriers to establishing PPC programs and offers a response to overcome each one. · Perinatal palliative care serves patients who continue pregnancies with life-limiting fetal anomaly.. · Perinatal palliative care has a risk profile similar to other options such as termination.. · Health care providers can serve as champions to extend PPC to patients in their region..
SurgeryScar ComplicationsCesarean Scar PregnancyUterine Scar Assessment
Open Access
The definition of a cesarean scar pregnancy (CSP) is the localization of the gestational sac (GS) in the cicatrix tissue, which is created in the front wall of the uterus after a previous cesarean section (CS). The worldwide prevalence of CSP has been growing rapidly. However, there are no general recommendations regarding prophylaxis and treatment of the abnormalities of the anterior wall of the uterus discovered in a non-pregnant myometrium, or how to deal with existing cases of CSP. We present the latest knowledge, a holistic approach to the biology, histology, imaging, and management concerning post-CS scars based on our cases, which were treated in the Department of Pregnancy and Pathology of Pregnancy in the Medical University of Lublin, Poland. In our study, we present images of tissue samples of areas with a cicatrix in the uterus, and ultrasound and MRI images of CSP. We discuss the advances in the biology of the post-CS scar tissue, the prevention techniques used to repair the scar defect (niche) before the pregnancy, and the treatment of different complications of CSP, such as the rupture of the gravid uterus or the dehiscence of the myometrium.
General OB/GYNFetal SurgeryMinimally Invasive TechniquesEmerging Therapies
The field of fetal medicine has evolved significantly over the past several decades. Our ability to identify and treat the unborn patient has been shaped by advancements in imaging technology, genetic diagnosis, an improved understanding of fetal physiology, and the development and optimization of in utero surgical techniques. The future of the field will be shaped by medical innovators pushing for the continued refinement of minimally invasive surgical technique, the application of pioneering technologies such as robotic surgery and in utero stem cell and gene therapies, and the development of innovative ex utero fetal support systems.
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.
α-Lipoic acid (ALA) is a natural molecule that is inconsistently synthesized by the human body and must be provided from exogenous sources, such as food and dietary supplements. Once absorbed, the oxidized form of ALA is transformed into its reduced form, dihydrolipoic acid (DHLA). ALA/DHLA exert direct and indirect antioxidant, anti-inflammatory and fine immunomodulatory effects. ALA/DHLA reduce the levels of pro-inflammatory cytokines (IL-1β, IL-6, IL-8 and IL-17), while increasing the secretion of anti-inflammatory cytokines (IL-10). They also inhibit cyclooxygenase 2, thereby decreasing the secretion of prostaglandin E2 and nitrogen oxide, and reducing the risk of miscarriage in the first trimester of pregnancy. In patients at risk of abortion, administration of ALA from the first trimester has shown efficacy by accelerating subchorionic hematoma resorption, with a significant decrease in the accompanying abdominal pain. ALA has been proven to be efficient in maintaining the length of the cervix and keeping it closed following one episode of premature labor. Preeclampsia is a dysfunction caused by abnormal placentation and an excessive maternal inflammatory response, leading to extreme hypoxia in the placental bed and exaggerated oxidative stress, with release of oxygen free radicals. Oxidative stress plays a key role in the development of preeclampsia and intrauterine growth restriction. The hypothesis of antioxidant supplementation may play an essential part in disease prevention and fetal neuroprotection.
Buskmiller C et al., 2021·Ultrasound Obstet Gynecol
Preoperative short cervical length (CL) remains a major risk factor for preterm birth after laser surgery for twin-twin transfusion syndrome (TTTS), but the optimal intervention to prolong pregnancy remains elusive. The objective of this study was to compare secondary methods for the prevention of preterm birth in twin pregnancies with TTTS undergoing fetoscopic laser photocoagulation (FLP), in the setting of a short cervix at the time of FLP, in five North American Fetal Treatment Network (NAFTNet) centers. This was a secondary analysis of data collected prospectively at five NAFTNet centers, conducted from January 2013 to March 2020. Inclusion criteria were a monochorionic diamniotic twin pregnancy complicated by TTTS, undergoing FLP, with preoperative CL < 30 mm. Management options for a short cervix included expectant management, vaginal progesterone, pessary (Arabin, incontinence or Bioteque cup), cervical cerclage or a combination of two or more treatments. Patients were not included if the intervention was initiated solely on the basis of having a twin gestation rather than at the diagnosis of a short cervix. Demographics, ultrasound characteristics, operative data and outcomes were compared. The primary outcome was FLP-to-delivery interval. Propensity-score matching was performed, with each treatment group matched (1:1) to the expectant-management group for CL, in order to estimate the effect of each treatment on the FLP-to-delivery interval. A total of 255 women with a twin pregnancy complicated by TTTS and a short cervix undergoing FLP were included in the study. Of these, 151 (59%) were managed expectantly, 32 (13%) had vaginal progesterone only, 21 (8%) had pessary only, 21 (8%) had cervical cerclage only and 30 (12%) had a combination of treatments. A greater proportion of patients in the combined-treatment group had had a prior preterm birth compared with those in the expectant-management group (33% vs 9%; P = 0.01). Mean preoperative CL was shorter in the pessary, cervical-cerclage and combined-treatment groups (14-16 mm) than in the expectant-management and vaginal-progesterone groups (22 mm for both) (P < 0.001). There was no significant difference in FLP-to-delivery interval between the groups, nor in gestational age at delivery or the rate of live birth or neonatal survival. Vaginal progesterone was associated with a decrease in the risk of delivery before 28 weeks' gestation compared with cervical cerclage and combined treatment (P = 0.03). Using propensity-score matching for CL, cervical cerclage was associated with a reduction in FLP-to-delivery interval of 13 days, as compared with expectant management. A large proportion of pregnancies with TTTS and a short maternal cervix undergoing FLP were managed expectantly for a short cervix, establishing a high (62%) risk of delivery before 32 weeks in this condition. No treatment that significantly improved outcome was identified; however, there were significant differences in potential confounders and there were also likely to be unmeasured confounders. Cervical cerclage should not be offered as a secondary prevention for preterm birth in twin pregnancies with TTTS and a short cervix undergoing FLP. A large randomized controlled trial is urgently needed to determine the effects of treatments for the prevention of preterm birth in these pregnancies.
Pregnant women are potentially a high-risk population during infectious disease outbreaks such as COVID-19, because of physiologic immune suppression in pregnancy. However, data on the morbidity and mortality of COVID-19 among pregnant women, compared to nonpregnant women, are sparse and inconclusive. We sought to assess the impact of pregnancy on COVID-19 associated morbidity and mortality, with particular attention to the impact of pre-existing comorbidity. We used retrospective data from January through June 2020 on female patients aged 18-44 years old utilizing the Cerner COVID-19 de-identified cohort. We used mixed-effects logistic and exponential regression models to evaluate the risk of hospitalization, maximum hospital length of stay (LOS), moderate ventilation, invasive ventilation, and death for pregnant women while adjusting for age, race/ethnicity, insurance, Elixhauser AHRQ weighted Comorbidity Index, diabetes history, medication, and accounting for clustering of results in similar zip-code regions. Out of 22,493 female patients with associated COVID-19, 7.2% (n = 1609) were pregnant. Crude results indicate that pregnant women, compared to non-pregnant women, had higher rates of hospitalization (60.5% vs. 17.0%, P < 0.001), higher mean maximum LOS (0.15 day vs. 0.08 day, P < 0.001) among those who stayed < 1 day, lower mean maximum LOS (2.55 days vs. 3.32 days, P < 0.001) among those who stayed ≥1 day, and higher moderate ventilation use (1.7% vs. 0.7%, P < 0.001) but showed no significant differences in rates of invasive ventilation or death. After adjusting for potentially confounding variables, pregnant women, compared to non-pregnant women, saw higher odds in hospitalization (aOR: 12.26; 95% CI (10.69, 14.06)), moderate ventilation (aOR: 2.35; 95% CI (1.48, 3.74)), higher maximum LOS among those who stayed < 1 day, and lower maximum LOS among those who stayed ≥1 day. No significant associations were found with invasive ventilation or death. For moderate ventilation, differences were seen among age and race/ethnicity groups. Among women with COVID-19 disease, pregnancy confers substantial additional risk of morbidity, but no difference in mortality. Knowing these variabilities in the risk is essential to inform decision-makers and guide clinical recommendations for the management of COVID-19 in pregnant women.
PregnancyTwin-Twin Transfusion SyndromeFetal and Neonatal MortalityRecursive Partitioning
Donor demise after laser surgery for twin-twin transfusion syndrome (TTTS) is well-characterized, but recipient demise is not, nor is neonatal death. This study aims to characterize factors associated with recipient death, donor death, and dual twin death after laser, both before and after birth. This is a prospective cohort study of monochorionic twin pairs who underwent laser ablation for TTTS. Risk factors for fetal and neonatal death of both twins were identified using univariable analysis and recursive partitioning, a novel statistical method to quantify contributions of each factor to outcomes. In 413 twin pairs, death of both twins occurred in 9.2% (38/413), donor death in 12.1% (50/413), and recipient death in 2.4% (10/413). Recursive partitioning showed that gestational age at delivery predicts dual twin death (below 23.7 weeks, likely [p < 0.001], above 28.3 weeks, unlikely [p = 0.004]). Abnormal umbilical artery Doppler and weight discordance predict donor demise (p < 0.001 and p = 0.033, respectively). Cervical length under 16 mm predicts neonatal death of both twins (p < 0.001). Parents can gain individualized information about the survival of each fetus based on variables available from preoperative and delivery variables. Short cervix and premature delivery cause significant mortality in TTTS.
PregnancyHerbal MedicineNatural InterventionsIntegrative Review
Open Access
Childbearing women have been using various herbs to assist with pregnancy, labour and birth for centuries. One of the most common is raspberry leaf. The evidence base for the use of raspberry leaf is however under-developed. It is incumbent on midwives and other maternity care providers to provide women with evidence-based information so they can make informed choices. The aim of this study was to review the research literature to identify the evidence base on the biophysical effects, safety and efficacy of raspberry leaf in pregnancy. A systematic, integrative review was undertaken. Six databases were searched to identify empirical research papers published in peer reviewed journals including in vitro, in vivo, human and animal studies. The search included the databases CINAHL, MEDLINE, Cochrane Library, Scopus and Web of Science Core Collection and AMED. Identified studies were appraised independently by two reviewers using the MMAT appraisal instrument. An integrative approach was taken to analysis. Thirteen studies were included. Five were laboratory studies using animal and human tissue, two were experiments using animals, and six were human studies. Included studies were published between 1941 and 2016. Raspberry leaf has been shown to have biophysical effects on animal and human smooth muscle including the uterus. Toxity was demonstrated when high doses were administered intravenously or intaperitoneally in animal studies. Human studies have not shown any harm or benefit though one study demonstrated a clinically meaningful (though non-statistically significant) reduction in length of second stage and augmentation of labour in women taking raspberry leaf. Many women use raspberry leaf in pregnancy to facilitate labour and birth. The evidence base supporting the use of raspeberry leaf in pregnancy is weak and further research is needed to address the question of raspberry leaf’s effectiveness.
Incidence, risk factors, and perinatal morbidity and mortality rates related to amniotic fluid embolism remain a challenge to evaluate, given the presence of differing international diagnostic criteria, the lack of a gold standard diagnostic test, and a significant overlap with other causes of obstetric morbidity and mortality. The aims of this study were (1) to analyze the clinical features and outcomes of women using the largest United States-based contemporary international amniotic fluid embolism registry, and (2) to investigate differences in demographic and obstetric variables, clinical presentation, and outcomes between women with typical versus atypical amniotic fluid embolism, using previously published and validated criteria for the research reporting of amniotic fluid embolism. The AFE Registry is an international database established at Baylor College of Medicine (Houston, TX) in partnership with the Amniotic Fluid Embolism Foundation (Vista, CA) and the Perinatology Research Branch of the Division of Intramural Research of the NICHD/NIH/DHHS (Detroit, MI). Charts submitted to the registry between August 2013 and September 2017 were reviewed, and cases were categorized into typical, atypical, non-amniotic fluid embolism, and indeterminate, using the previously published and validated criteria for the research reporting of AFE. Demographic and clinical variables, as well as outcomes for patients with typical and atypical AFE, were recorded and compared. Student t tests, χ(2) tests, and analysis of variance tables were used to compare the groups, as appropriate, using SAS/STAT software, version 9.4. A total of 129 charts were available for review. Of these, 46% (59/129) represented typical amniotic fluid embolism and 12% (15/129) atypical amniotic fluid embolism, 21% (27/129) were non-amniotic fluid embolism cases with a clear alternative diagnosis, and 22% (28/129) had an uncertain diagnosis. Of the 27 women misclassified as an amniotic fluid embolism with an alternative diagnosis, the most common actual diagnosis was hypovolemic shock secondary to postpartum hemorrhage. Ten percent (6/59) of the women with typical amniotic fluid embolism had a pregnancy complicated by placenta previa, and 8% (5/61) had undergone in vitro fertilization to achieve pregnancy. In all, 66% (49/74) of the women with amniotic fluid embolism reported a history of atopy or latex, medication, or food allergy, compared to 34% of the obstetric population delivered at our hospital over the study period (P < .05). Our data represent a series of women with amniotic fluid embolism whose diagnosis has been validated by detailed chart review, using recently published and validated criteria for research reporting of amniotic fluid embolism. Although no definitive risk factors were identified, a high rate of placenta previa, reported allergy, and conceptions achieved through in vitro fertilization was observed.
Function of the lower extremities after prenatal myelomeningocele (MMC) repair is best assessed with ambulatory function at 30-36 months of age, but parents often ask about function before this milestone. Lower extremity movement can be assessed by ultrasound (US) and at the newborn exam (NE), but correlation between US, NE, and ambulation is not firmly established. This was a retrospective correlation study of fetuses that underwent open prenatal MMC repair at SSM Cardinal Glennon Fetal Care Institute, St. Louis, MO, between January 2011 and June 2017. Movement at the ankles, knees, and hips was assessed by US after open repair on postoperative days (PODs) 0-5 and at 32 weeks gestation. NE was performed by physical therapy or neurosurgery within the first month of life, and pediatric follow-up between 30 and 36 months of age was obtained to document ambulation. Forty-two fetuses were included. Joint movement it was present on POD 1 in 7% of fetuses and 62% by POD 5. Degree of ventriculomegaly, lesion level, and lesion length did not have a significant effect on US, NE, or ambulation. Knee movement on POD 3 correlated with knee movement at NE (k = 0.58, p < 0.01), but only later knee movement correlated with ambulation (k = 0.28-0.46, p = 0.01). Hip movement at 32 weeks was the only single joint assessment that correlated with NE and ambulation (k = 0.45 and 0.46, p = 0.03 and 0.01, respectively). Lower extremity movement increases between POD 1 and POD 5 in fetuses after open fetal MMC repair. Knee and hip movement on US at 32 weeks correlates with ambulation at 30-36 months. These data may inform counseling, and direct therapy and spark prospective investigations.
Despite the available research investigating uterine physiology during and immediately following pregnancy, including at the vascular and muscular levels, knowledge of the potential long-term timeline of such changes is limited. Thus, our study sought to investigate the potential long-term changes in uterine vasculature and horn length in the postpartum rat, following delivery and weaning. Female Long-Evans rats (n = 9-11 rats/group/timepoint) a pregnant group and an age-matched virgin control group. Rat weight, food consumption and vaginal impedance measurements were recorded throughout the experiment. Rats in the pregnant group were bred and pregnancy was confirmed using ultrasound imaging. The uterus and its vasculature were collected at various 3 (week of weaning), 8-9 and 13 weeks postpartum, and at age-equivalent timepoints in the virgin group, and the diameters of the main uterine artery and vein, and lengths of the mesometrial segmental vessels (MSV) and uterine horns were recorded. The results indicated a significant difference between the previously-pregnant and virgin rats in both internal and external arterial diameters (but not arterial wall thickness), as well as the uterine horn length, 3 weeks postpartum, but not 8-9 and 13 weeks postpartum. Significant differences were observed in both venous diameter and MSV length at all timepoints measured. Placental scars were also observed in previously-pregnant rats at all timepoints measured. Our study highlights the long-term impact of pregnancy on the uterine vasculature and the necessity for consideration of such changes on subsequent pregnancies, as well as pregnancy-related vascular pathologies.
This study aims to evaluate the effects of myo-inositol supplementation on gestational diabetes mellitus (GDM) rates and body water distribution in overweight non-obese women. 223 overweight non-obese women pregnant were randomly assigned to the treatment group (2 g of myo-inositol plus 200 µg of folic acid) or to the placebo one (200 µg of folic acid). The treatment lasted until three weeks after delivery. A tetrapolar impedance analyser was used to study body composition. The incidence of GDM was significantly reduced in the myo-inositol group compared with the placebo group. There was a significant increase in TBW, ECW and ICW values in the placebo group compared to the myo-inositol group. We have recorded a significant reduction in the overall incidence of pregnancy-induced hypertension in the myo-inositol group compared with the placebo group. Our results demonstrate the effectiveness of myo-inositol supplementation in preventing GDM in overweight non-obese pregnant women.
Breastfeeding has immediate and long-term benefits for both maternal and child health. This study examines the association between Baby-Friendly Hospital Initiative (BFHI) experiences and breastfeeding outcomes in the Mountain West region. A cross-sectional (retrospective secondary data analysis) was performed using the 2016 Pregnancy Risk Assessment Monitoring System (PRAMS) data. The participants were derived from a stratified random sample of 2,013 women living in Utah and Wyoming who recently had a live birth and who were surveyed on BFHI practices. The association between BFHI experiences and breastfeeding duration were assessed using crude and adjusted Poisson regression models, controlling for other BHFI experiences and maternal age, pre-pregnancy BMI, household income, smoking, alcohol, delivery method, and number of days spent in the hospital post delivery. 82.4% and 82.3% of women from Utah and Wyoming, respectively, reported breastfeeding for 2 months or longer. After controlling for other BFHI experiences and potential confounders, the one shared BFHI experience that was associated with breastfeeding for 2 months or longer vs less than 2 months was starting breastfeeding in the hospital (adjusted prevalence ratio [aPR]=1.49, 95% CI (1.12, 1.98) in Utah and aPR=2.03, 95% CI (1.13, 3.64) in Wyoming. Among women in Utah and Wyoming, only 5 of 7 BFHI steps were significant for breastfeeding duration in at least one state. There is substantial epidemiological support for health benefits to both mother and infant for exclusive breastfeeding to 6 months and prolonged breastfeeding until at least 1-year. Our findings suggest that women who initiate breastfeeding in the hospital may be more likely to breastfeed for a longer duration.
Interventions to prevent pregnancy complications have been largely unsuccessful. We suggest this is because the foundation for a healthy pregnancy is laid prior to the establishment of the pregnancy at the time of endometrial decidualization. Humans are one of only a few mammalian viviparous species in which decidualization begins during the latter half of each menstrual cycle and is therefore independent of the conceptus. Failure to adequately prepare (decidualize) the endometrium hormonally, biochemically, and immunologically in anticipation of the approaching blastocyst-including the downregulation of genes involved in the proinflammatory response and resisting tissue invasion along with the increased expression of genes that promote angiogenesis, foster immune tolerance, and facilitate tissue invasion-leads to abnormal implantation/placentation and ultimately to adverse pregnancy outcome. We hypothesize, therefore, that the primary driver of pregnancy health is the quality of the soil, not the seed.
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
Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone supplementation may reduce the risk of miscarriage in women with recurrent or threatened miscarriage. Cochrane Reviews summarized the evidence and found that the trials were small with substantial methodologic weaknesses. Since then, the effects of first-trimester use of vaginal micronized progesterone have been evaluated in 2 large, high-quality, multicenter placebo-controlled trials, one targeting women with unexplained recurrent miscarriages (the PROMISE [PROgesterone in recurrent MIScarriagE] trial) and the other targeting women with early pregnancy bleeding (the PRISM [PRogesterone In Spontaneous Miscarriage] trial). The PROMISE trial studied 836 women from 45 hospitals in the United Kingdom and the Netherlands and found a 3% greater live birth rate with progesterone but with substantial statistical uncertainty. The PRISM trial studied 4153 women from 48 hospitals in the United Kingdom and found a 3% greater live birth rate with progesterone, but with a P value of .08. A key finding, first observed in the PROMISE trial, and then replicated in the PRISM trial, was that treatment with vaginal micronized progesterone 400 mg twice daily was associated with increasing live birth rates according to the number of previous miscarriages. Prespecified PRISM trial subgroup analysis in women with the dual risk factors of previous miscarriage(s) and current pregnancy bleeding fulfilled all 11 conditions for credible subgroup analysis. For the subgroup of women with a history of 1 or more miscarriage(s) and current pregnancy bleeding, the live birth rate was 75% (689/914) with progesterone vs 70% (619/886) with placebo (rate difference 5%; risk ratio, 1.09, 95% confidence interval, 1.03-1.15; P=.003). The benefit was greater for the subgroup of women with 3 or more previous miscarriages and current pregnancy bleeding; live birth rate was 72% (98/137) with progesterone vs 57% (85/148) with placebo (rate difference 15%; risk ratio, 1.28, 95% confidence interval, 1.08-1.51; P=.004). No short-term safety concerns were identified from the PROMISE and PRISM trials. Therefore, women with a history of miscarriage who present with bleeding in early pregnancy may benefit from the use of vaginal micronized progesterone 400 mg twice daily. Women and their care providers should use the findings for shared decision-making.
Harville EW et al., 2019·Paediatr Perinat Epidemiol
Preconception health may have intergenerational influences. We have formed the PrePARED (Preconception Period Analysis of Risks and Exposures influencing health and Development) research consortium to address methodological, conceptual, and generalisability gaps in the literature. The consortium will investigate the effects (1) fertility and miscarriage; (2) pregnancy-related conditions; (3) perinatal and child health; and (4) adult health outcomes. A study is eligible if it has data measured for at least one preconception time point, has a minimum of selected core data, and is open to collaboration and data harmonisation. The included studies are a mix of studies following women or couples intending to conceive, general-health cohorts that cover the reproductive years, and pregnancy/child cohort studies that have been linked with preconception data. The majority of the participating studies are prospective cohorts, but a few are clinical trials or record linkages. Data analysis will begin with harmonisation of data collected across cohorts. Initial areas of interest include nutrition and obesity; tobacco, marijuana, and other substance use; and cardiovascular risk factors. Twenty-three cohorts with data on almost 200 000 women have combined to form this consortium, begun in 2018. Twelve studies are of women or couples actively planning pregnancy, and six are general-population cohorts that cover the reproductive years; the remainder have some other design. The primary focus for four was cardiovascular health, eight was fertility, one was environmental exposures, three was child health, and the remainder general women's health. Among other cohorts assessed for inclusion, the most common reason for ineligibility was lack of prospectively collected preconception data. The consortium will serve as a resource for research in many subject areas related to preconception health, with implications for science, practice, and policy.
PregnancyPreventionMyo-InositolMacrosomia and Preterm Birth
Open Access
D'Anna R et al., 2019·J Nutr Sci Vitaminol (Tokyo)
Gestational Diabetes Mellitus (GDM) is one of the most frequent complications of pregnancy and is characterized by a carbohydrate intolerance which is diagnosed with the oral glucose tolerance test. The prevalence of GDM in our population is about 12%, but risk factors like a previous GDM, ethnicity, a parent with diabetes mellitus type 2 and maternal overweight may increase its occurrence. Complications of GDM are a pre-term birth (before 37 wk gestation), macrosomia (birth weight ≥4 kg) and gestational hypertension. Actually, GDM is principally treated with diet and, if it is necessary, with insulin; but the challenge is the prevention of GDM. Among the measures used, changes in life-style (diet+exercise) failed to prevent GDM whereas metformin showed conflicting results. A promising supplement is myo-inositol (MI) which was given from first trimester until delivery to women at risk for GDM reporting a significant decrease in GDM occurrence by more than 60% comparing to the placebo group. Recently, a secondary analysis from 3 randomized controlled trials demonstrated that MI may also significantly reduce some of GDM complications such as pre-term birth and macrosomia with a favorable impact on mother and fetus well being.
InfertilityThyroid Autoimmunity TreatmentThyroid AntibodiesRandomized Controlled Trial
Open Access
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.
Birth by cesarean delivery is increasing globally, particularly cesarean deliveries without medical indication. Children born via cesarean delivery may have an increased risk of negative health outcomes, but the evidence for psychiatric disorders is incomplete. To evaluate the association between cesarean delivery and risk of neurodevelopmental and psychiatric disorders in the offspring. Ovid MEDLINE, Embase, Web of Science, and PsycINFO were searched from inception to December 19, 2018. Search terms included all main mental disorders in the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition). Two researchers independently selected observational studies that examined the association between cesarean delivery and neurodevelopmental and psychiatric disorders in the offspring. Two researchers independently extracted data according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines and assessed study quality using the Newcastle-Ottawa Scale. Random-effects meta-analyses were used to pool odds ratios (ORs) with 95% CIs for each outcome. Sensitivity and influence analyses tested the robustness of the results. The ORs for the offspring with any neurodevelopmental or psychiatric disorder who were born via cesarean delivery compared with those were born via vaginal delivery. A total of 6953 articles were identified, of which 61 studies comprising 67 independent samples were included, totaling 20 607 935 deliveries. Compared with offspring born by vaginal delivery, offspring born via cesarean delivery had increased odds of autism spectrum disorders (OR, 1.33; 95% CI, 1.25-1.41; I2 = 69.5%) and attention-deficit/hyperactivity disorder (OR, 1.17; 95% CI, 1.07-1.26; I2 = 79.2%). Estimates were less precise for intellectual disabilities (OR, 1.83; 95% CI, 0.90-3.70; I2 = 88.2%), obsessive-compulsive disorder (OR, 1.49; 95% CI, 0.87-2.56; I2 = 67.3%), tic disorders (OR, 1.31; 95% CI, 0.98-1.76; I2 = 75.6%), and eating disorders (OR, 1.18; 95% CI, 0.96-1.47; I2 = 92.7%). No significant associations were found with depression/affective psychoses or nonaffective psychoses. Estimates were comparable for emergency and elective cesarean delivery. Study quality was high for 82% of the cohort studies and 50% of the case-control studies. The findings suggest that cesarean delivery births are associated with an increased risk of autism spectrum disorder and attention-deficit/hyperactivity disorder, irrespective of cesarean delivery modality, compared with vaginal delivery. Future studies on the mechanisms behind these associations appear to be warranted.
Perinatal palliative care refers to a coordinated care strategy that comprises options for obstetric and newborn care that include a focus on maximizing quality of life and comfort for newborns with a variety of conditions considered to be life-limiting in early infancy. With a dual focus on ameliorating suffering and honoring patient values, perinatal palliative care can be provided concurrently with life-prolonging treatment. The focus of this document, however, involves the provision of exclusively palliative care without intent to prolong life in the context of a life-limiting condition, otherwise known as perinatal palliative comfort care. Once a life-limiting diagnosis is suspected antenatally, the tenets of informed consent require that the pregnant patient be given information of sufficient depth and breadth to make an informed, voluntary choice for her care. Health care providers are encouraged to model effective, compassionate communication that respects patient cultural beliefs and values and to promote shared decision making with patients. Perinatal palliative comfort care is one of several options along a spectrum of care, which includes pregnancy termination (abortion) and full neonatal resuscitation and treatment, that should be presented to pregnant patients faced with pregnancies complicated by life-limiting fetal conditions. If a patient opts to pursue perinatal palliative comfort care, a multidisciplinary team should be identified with the infrastructure and support to administer this care. The perinatal palliative care team should prepare families for the possibility that there may be differences of opinion between family members before and after the delivery of the infant, and that there may be differences between parents and the neonatal care providers about appropriate postnatal therapies, especially if the postnatal diagnosis and prognosis differ substantially from antenatal predictions. Procedures for resolving such differences should be discussed with families ahead of time.
Buskmiller C et al., 2019·Proc (Bayl Univ Med Cent)
Poor social support is associated with adverse obstetric outcomes. Maternity group homes (MGHs), residential programs for pregnant women, have been found to improve social support in small studies. The present study aimed to verify these previous studies, discover whether there is a group of women whom MGHs most benefit, identify what services offer that benefit, and identify how to predict who will most benefit from MGH admission. Forty-three US MGHs from 14 states were surveyed from August 2015 to February 2017. The primary outcome was self-reported social support before and during MGH admission. The secondary outcome was the perception that MGH admission would help current and future relationships. Among 95 respondents, 54% perceived better in-MGH support compared to pre-MGH support. Women with poor pre-MGH support reported improvement; the converse was true of high pre-MGH support (P < 0.001). A total of 77% to 82% of participants anticipated that MGH admission would help current and future relationships, including 91% to 92% of women with stable or increased in-MGH support (P = 0.07 current, P < 0.01 future). Participants with increased in-MGH support reported more services as helpful (P < 0.05). In summary, MGHs are associated with improved support and relationships for most residents. The support score may identify which women may benefit most from MGH admission.
Hospitals are in a unique position to promote, protect, and support breastfeeding. However, the association between in-hospital events and breastfeeding success within population-based samples has not been well studied. A stratified (by education and birth weight) systematic sample of 5,770 mothers taking part in the Utah Pregnancy Risk Assessment Monitoring System, 2012-2015, were included. Mothers, 2-4 months postpartum, completed the 82-item questionnaire, including if they had ever breastfed their new baby, and if so, current breastfeeding status. Relationships between in-hospital experiences and breastfeeding termination and duration were evaluated via Poisson and Cox proportional hazard regression models, respectively, adjusting for other in-hospital experiences, maternal age, race/ethnicity, maternal education, marital status, smoking, physical activity, delivery method, pregnancy complications, and length of hospital stay. Of all, 94.4% of mothers self-reported breastfeeding initiation, of whom 18.8% had breastfed <2 months, having breastfed on average 3.2 weeks (standard 0.07). In fully adjusted models, mothers who reported receiving a pacifier, receiving formula, or had staff help them learn how to breastfeed had a higher prevalence of terminating breastfeeding before 2 months (adjusted prevalence ratio [aPR] = 1.13, 95% confidence interval [CI]: 0.97-1.32; aPR = 1.20, 95% CI: 1.07-1.36; and aPR = 1.25, 95% CI: 1.08-1.34). Conversely, mothers who reported starting and feeding only breast milk in the hospital and receiving a phone number to call for help with breastfeeding had a lower prevalence of breastfeeding termination before 2 months (aPR = 0.72, 95% CI: 0.61-0.86; aPR = 0.57, 95% CI: 0.51-0.64; and aPR = 0.91, 95% CI: 0.80-1.03). Adjusted Cox models showed similar direction of associations. Encouraging mothers to exclusively breastfeed in the hospital, and reducing gift packs containing pacifiers and formula, may be key areas United States hospitals can focus on to increase breastfeeding success. Prospective assessment in other geographical regions is needed to corroborate these findings.
PregnancyPreconception Risk FactorsVitamin D and Reproduction
Open Access
Purdue‐Smithe A et al., 2019·Current Developments in Nutrition
The association between caffeine and pregnancy loss remains controversial due to limitations of prior studies such as relying on self-reported intake only, exposure measurement after clinical confirmation of pregnancy, and potential time-varying confounding by nausea/vomiting and lifestyle factors, which may be affected by prior caffeine exposure. Thus, our aim was to evaluate associations of preconception and early pregnancy serum caffeine, paraxanthine, and theobromine, self-reported intake of caffeinated beverages, and risk of pregnancy loss among 1228 reproductive-age women attempting pregnancy in the EAGeR trial during 2007–2011. We estimated HRs and 95% CIs for any pregnancy loss, hCG loss (prior to ultrasound confirmation), and clinical loss (after ultrasound confirmation) according to caffeinated beverage intake and caffeine biomarkers measured at preconception and the 8(th) week of gestation using weighted adjusted Cox proportional hazards models. At preconception, 67%, 28%, and 9% of women reported any intake of caffeinated sodas, coffee, and tea, respectively. Preconception total caffeinated beverage intake of ≥3 vs. 0 cups/day was associated with 85% (95% CI: 1.18, 2.94) higher risk of any pregnancy loss, driven primarily by associations for hCG loss (HR: 2.88 (95% CI: 1.20, 6.91)). Caffeinated soda intake was associated with hCG loss (≥2 vs. 0.2 vs. ≤0.2 ng/mL) at preconception was strongly associated with hCG loss (HR: 4.51 (95% CI: 1.36, 14.91)). Serum caffeine, paraxanthine, and theobromine measured at the 8th week of gestation were not associated with risk of loss. Collectively, these data suggest that caffeine intake prior to pregnancy may increase risk of pregnancy loss, particularly in early gestation. Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD.
Bleeding in early pregnancy is strongly associated with pregnancy loss. Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone therapy may improve pregnancy outcomes in women who have bleeding in early pregnancy. We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate progesterone, as compared with placebo, in women with vaginal bleeding in early pregnancy. Women were randomly assigned to receive vaginal suppositories containing either 400 mg of progesterone or matching placebo twice daily, from the time at which they presented with bleeding through 16 weeks of gestation. The primary outcome was the birth of a live-born baby after at least 34 weeks of gestation. The primary analysis was performed in all participants for whom data on the primary outcome were available. A sensitivity analysis of the primary outcome that included all the participants was performed with the use of multiple imputation to account for missing data. A total of 4153 women, recruited at 48 hospitals in the United Kingdom, were randomly assigned to receive progesterone (2079 women) or placebo (2074 women). The percentage of women with available data for the primary outcome was 97% (4038 of 4153 women). The incidence of live births after at least 34 weeks of gestation was 75% (1513 of 2025 women) in the progesterone group and 72% (1459 of 2013 women) in the placebo group (relative rate, 1.03; 95% confidence interval [CI], 1.00 to 1.07; P = 0.08). The sensitivity analysis, in which missing primary outcome data were imputed, resulted in a similar finding (relative rate, 1.03; 95% CI, 1.00 to 1.07; P = 0.08). The incidence of adverse events did not differ significantly between the groups. Among women with bleeding in early pregnancy, progesterone therapy administered during the first trimester did not result in a significantly higher incidence of live births than placebo. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment program; PRISM Current Controlled Trials number, ISRCTN14163439.).
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.
PregnancyImmunological CausesLymphocyte Function in PregnancyTherapeutic Approaches
Open Access
Fetal survival and development is supported by the maternal immune system. Questions regarding those mechanisms have risen from development of transplantation medicine and observation of graft rejection. Initial theories of anatomic division, fetal immune immaturity and maternal immune system inertia were found incorrect. Rejection of fetal "semi-allograft" by maternal immune system could result in pregnancy loss. Two pregnancy losses of any etiology are considered recurrent and effort should be made to name the probable cause. Immune causes of pregnancy loss are probably multifactorial, thus difficult to research and implement findings in clinical practice. Although a full understating of pregnancy loss is not established, new therapies are being developed. This review summarizes the role of lymphocytes in pregnancy development, presents data from studies on recurrent pregnancy loss patients, evidence of new therapies and ESHRE guidelines regarding immunologic investigations.
SurgeryCesarean Scar Defect RepairIsthmocele Diagnosis and ManagementLong-Term Scar Complications
Open Access
The aim of the present study was to perform a comprehensive review of the literature to provide a complete and clear picture of isthmocele-a hypoechoic area within the myometrium at the site of the uterine scar of a previous cesarean section-by exploring in depth every aspect of this condition. A comprehensive review of the literature was performed to identify the most relevant studies about this topic. Every aspect of isthmocele pathophysiology, clinical symptoms, classification, and diagnosis. Its treatment, both medical and surgical, has also been reported according to the actual literature data. Cesarean section is the most common surgical procedure performed worldwide, and one of the consequences of this technique is isthmocele. A single and systematic classification of isthmocele is needed to improve its diagnosis and management. Further studies should be performed to better understand its pathogenesis.
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.
PregnancyPrevention and TreatmentInositolRandomized Controlled Trial
Celentano C et al., 2018·J Matern Fetal Neonatal Med
To identify the effects of different dietary inositol stereoisomers on insulin resistance and the development of gestational diabetes mellitus (GDM) in women at high risk for this disorder.Design: A preliminary, prospective, randomized, placebo controlled clinical trial. Nonobese singleton pregnant women with an elevated fasting glucose in the first or early second trimester were studied throughout pregnancy. Supplementation with myo-inositol, d-chiro-inositol, combined myoand d-chiro-inositol or placebo.Main Development of GDM on a 75 grams oral glucose tolerance test at 24-28 weeks' gestation. Secondary outcome measures were increase in BMI, need for maternal insulin therapy, macrosomia, polyhydramnios, neonatal birthweight and hypoglycemia. The group of women allocated to receive myo-inositol alone had a lower incidence of abnormal oral glucose tolerance test (OGTT). Nine women in the control group (C), one of the myo-inositol (MI), five in d-chiro-inositol (DCI), three in the myo-inositol/D-chiro-inositol group (MI/DCI) required insulin (p = .134). Basal, 1-hour, and 2 hours glycemic controls were significantly lower in exposed groups (p < .001, .011, and .037, respectively). The relative risk reduction related to primary outcome was 0.083, 0.559, and 0.621 for MI, DCI, and MI/DCI groups. This study compared the different inositol stereoisomers in pregnancy to prevent GDM. Noninferiority analysis demonstrated the largest benefit in the myo-inositol group. The relevance of our findings is mainly related to the possibility of an effective approach in GDM. Our study confirmed the efficacy of inositol supplementation in pregnant women at risk for GDM.
PregnancyInterstitial and Cesarean Scar TypesEctopic Pregnancy ManagementNon-Tubal Ectopic Intervention
Catholic bioethicists have extensively addressed extrauterine tubal pregnancies, which represent the great majority of ectopic pregnancies. However, additional management options have been developed for the other 7-10 percent of ectopic pregnancies. Using two cases of interstitial pregnancy and two cases of cesarean scar pregnancy (CSP) seen at a Catholic tertiary care center, this article discusses options including expectant management, systemic methotrexate, intragestational methotrexate, intragestational potassium chloride, uterine artery embolization, dilation and curettage (D&C), vasopressin use, cornuostomy, cornual wedge resection, CSP evacuation, CSP scar excision, CSP salvage, and hysterectomy. Cornual wedge resection, vasopressin use, and CSP scar excision are morally acceptable; less clearly licit are aspiration of gestational sac contents, cornuostomy, gestational excision for CSPs, and methotrexate. Certainly illicit are any techniques leading to direct abortion such as D&Cs on live embryos or fetuses, double-balloon catheter placement, and use of potassium chloride.
An ectopic pregnancy is any pregnancy outside the uterus. These are dangerous because the pregnancy can burst out of its abnormal location and cause life-threatening internal bleeding. Most are in the part of the fallopian tube outside the uterus, but there are other types, including interstitial pregnancies (located in the part of the tube tunneling through the uterine wall) and cesarean scar pregnancies (buried in the uterine scar where the cut for a C-section was made). This article lists the ways that physicians prevent women from dying from interstitial and cesarean scar pregnancies and proposes which treatments are morally acceptable.
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.
PregnancyHair Dye and Birth WeightChemical Exposure InteractionEnvironmental Reproductive Risk
Open Access
Limited evidences were reported about the risk of pre-pregnancy hair dye use or irregular menstruation with abnormal birth weight during pregnancy, and their joint effects were also unknown. The aim of our study was to explore whether the pre-pregnancy exposure of hair dye and irregular menstruation were associated with the risk of abnormal birth weight. We conducted a nested case-control study from a prospective cohort of 6203 pregnant women. Low birth weight study included 315 mother-infant pairs (105 LBW cases and 210 matched controls), and macrosomia study included 381 mother-infant pairs (127 macrosomia cases and 254 matched controls). Meanwhile, lifestyle information including hair dying custom and menstrual history were collected by face-to-face questionnaires and birth outcomes were extracted from the medical records. The logistic regressions models were used to analyze the join effect of irregular menstruation and hair dye use. Pre-pregnancy hair dye use was associated with increased risk of LBW (adjusted OR = 1.71, 95% CI: 1.01-2.92, P = 0.048). Irregular menstruation had high risk of LBW (adjusted OR = 2.79, 95% CI: 1.53-5.09, P = 0.001) and macrosomia (adjusted OR = 1.93, 95% CI: 1.09-3.44, P = 0.023). Additionally, in the LBW study, women who used hair dye with pre-pregnancy BMI < 18.5 kg/m(2) had higher OR than those with only one risk factor (3.07 vs 2.53, P (trend) = 0.015), and women with both hair dye use and irregular menstruation also had higher risk than those with only one factor (4.53 vs 2.07, P (trend) = 0.05). Moreover, in macrosomia study, women with irregular menstruation and pre-pregnancy BMI ≥ 24 kg/m(2) had higher risk than those with one factor (13.31 vs 2.09, P (trend) = 0.001). Our study showed that either pre-pregnancy hair dye use or irregular menstruation was associated with abnormal birth weight, especially, their joint effects could furthermore increase the risk of low birth weight infants when these two factors existed simultaneously.
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.
Down syndrome (trisomy 21) is a well-known cause of mental retardation. It can be diagnosed in early pregnancy. Scientists have made great strides in outlining the pathophysiologic mechanisms of mental retardation in Down syndrome. Much less has been published on human therapy. To our knowledge, these are the first published cases of fetal therapy for Down syndrome. Reports of three cases. In all cases, treatment was both biochemical (e.g. nutritional) and educational. In all cases, treatment was both before and after birth. All children lacked the characteristic faces usually seen in the children with Down syndrome. This suggests a treatment effect before birth. All children had better than expected development. Enhancement of development is proposed as a new therapeutic principle. Developing neurons exchange neurotrophic factors during development when they give or receive stimulation from other neurons. Neurons which receive neurotrophic stimulation survive, and those, which do not, are lost to apoptosis. The developmental therapeutic principle seeks to optimize brain development. Biochemical inputs (neurotransmitters, drugs, hormones, nutrients) and functional stimulation are integrated to optimize the growth and survival of neurons individually; other cells; subcellular organelles; and the brain as a whole. Treatment may be before and after birth, both biochemical and functional. These principles may be applied to Down syndrome, other conditions, and normal fetuses or children. Baggot PJ and Baggot RM (2014). Fetal Report of three cases and review of the literature. J Am Phys Surg 19(1):20-24.
The US cesarean delivery rate remains 30%-32%. Increases in maternal age, obesity, and diabetes put upward pressure on this rate. Alternatives to cesarean delivery, vaginal birth after cesarean (VBAC), and operative vaginal delivery, are underutilized and there are substantial challenges to their resurgence. Practice guidelines offer promise, but demonstrate only minor reductions in cesarean delivery. We estimate that the overall rate in the US will remain 27%-30% for the immediate future. As more states move to recognize the independent practice of midwifery and more payers seek lower cost options for childbirth, we anticipate the overall rate will drop to 20% or 25%, but not for another 15 years or more.
An isthmocele appears as a fluid pouchlike defect in the anterior uterine wall at the site of a prior cesarean section and ranges in prevalence from 19% to 84%, a direct relation to the increase in cesarean sections performed worldwide. Many definitions have been suggested for the dehiscence resulting from cesarean sections, and we propose standardization with a single term for all cases-isthmocele. Patients are not always symptomatic, but symptoms typically include intermittent abnormal bleeding, pain, and infertility. Pregnancy complications that result from an isthmocele include ectopic pregnancy, low implantation, and uterine rupture. Magnetic resonance imaging and transvaginal ultrasound are the gold standard imaging techniques for diagnosis. Surgical treatment of an isthmocele is still a controversial issue but should be offered to symptomatic women or the asymptomatic patient who desires future pregnancy. When surgery is the treatment choice, laparoscopy guided by hysteroscopy, hysteroscopy alone, or vaginal repair are the best options depending on the isthmocele's characteristics and surgeon expertise.
PregnancyProbiotic Depression PreventionLactobacillus rhamnosus InterventionProbiotic Pregnancy Mental Health Trial
Open Access
Probiotics may help to prevent symptoms of anxiety and depression through several putative mechanisms. The aim of this study was to evaluate the effect of Lactobacillus rhamnosus HN001 (HN001) given in pregnancy and postpartum on symptoms of maternal depression and anxiety in the postpartum period. This was a secondary outcome, the primary outcome being eczema in the offspring at 12 months of age.
Design, Setting, A randomised, double-blind, placebo-controlled trial of the effect of HN001 on postnatal mood was conducted in 423 women in Auckland and Wellington, New Zealand. Women were recruited at 14–16 weeks gestation. Women were randomised to receive either placebo or HN001 daily from enrolment until 6 months postpartum if breastfeeding. Modified versions of the Edinburgh Postnatal Depression Scale and State Trait Anxiety Inventory were used to assess symptoms of depression and anxiety postpartum. Australia ACTRN12612000196842. 423 women were recruited between December 2012 and November 2014. 212 women were randomised to HN001 and 211 to placebo. 380 women (89.8%) completed the questionnaire on psychological outcomes, 193 (91.0%) in the treatment group and 187 (88.6%) in the placebo group. Mothers in the probiotic treatment group reported significantly lower depression scores (HN001 mean = 7·7 (SD = 5·4), placebo 9·0 (6·0); effect size -1·2, (95% CI -2·3, -0·1), p = 0·037) and anxiety scores (HN001 12·0 (4·0), placebo 13·0 (4·0); effect size -1·0 (-1·9, -0·2), p = 0·014) than those in the placebo group. Rates of clinically relevant anxiety on screening (score > 15) were significantly lower in the HN001 treated mothers (OR = 0·44 (0·26, 0·73), p = 0·002). Women who received HN001 had significantly lower depression and anxiety scores in the postpartum period. This probiotic may be useful for the prevention or treatment of symptoms of depression and anxiety postpartum.
InfertilityDietary Patterns and Fecundability ReviewSemen Quality and Dietary FactorsMediterranean Diet and Fertility
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.
PregnancyInositol Prevention StrategyInositol Supplementation in PregnancyGDM Prevention with Inositol
The aim of the present study was to demonstrate that the use of inositol and folic acid from the first trimester of pregnancy, counteracts the onset of gestational diabetes mellitus (GDM) in women at risk, preserving the infants from macrosomia, hypoglycemia and preterm delivery. The authors collected data from the pregnant women at the laboratory (Unit of Cytogenic and Molecular Genetics), from January 2014 to April 2016, all with first trimester fasting plasma glucose (FPG) >92 mg/dl. A total of 40 women were treated with 250 mg/day D-chiro-inositol, 1.75 g/day D-myo-inositol, 12.5 mg/day zinc, 10 mg/day methylsulfonylmethane, 400 µg/day 5-methyltetrahydrofolic acid. The other 43 women (control group) were treated with only 400 µg/day folic acid. The primary outcome measure was the incidence of maternal GDM. The secondary outcome measures were the incidence of fetal macrosomia, preterm delivery and neonatal hypoglycemia. At the 24th week of pregnancy, the incidence of maternal GDM was recorded in 18 women in the control group and in 5 women in the treated group [relative risk (RR)=3.35; 95% confidence interval (CI)=1.37-8.17; P=0.0028). A significant difference was observed between treated and control groups in terms of risk of macrosomia. A total of seven infants in the control group, and two in the treated group, weighed >4,000 g (RR=5,12; 95% CI=1.21-21.68; P=0.0099). No significant difference was identified between two groups, regarding the other two secondary outcomes, neonatal hypoglycemia (RR=4.650; 95% CI=0.57-38.11; P=0.1086) and preterm delivery (RR=1.74; 95% CI=0.83-3.66; P=0.1301). The current study demonstrated the potential benefit of supplementation with the association of D-chiro-inositol and D-myo-inositol in pregnant 'at risk' women, with first trimester FPG >92 mg/dl, in preventing the onset of maternal GDM and macrosomia in newborns.
Preterm preeclampsia is an important cause of maternal and perinatal death and complications. It is uncertain whether the intake of low-dose aspirin during pregnancy reduces the risk of preterm preeclampsia. In this multicenter, double-blind, placebo-controlled trial, we randomly assigned 1776 women with singleton pregnancies who were at high risk for preterm preeclampsia to receive aspirin, at a dose of 150 mg per day, or placebo from 11 to 14 weeks of gestation until 36 weeks of gestation. The primary outcome was delivery with preeclampsia before 37 weeks of gestation. The analysis was performed according to the intention-to-treat principle. A total of 152 women withdrew consent during the trial, and 4 were lost to follow up, which left 798 participants in the aspirin group and 822 in the placebo group. Preterm preeclampsia occurred in 13 participants (1.6%) in the aspirin group, as compared with 35 (4.3%) in the placebo group (odds ratio in the aspirin group, 0.38; 95% confidence interval, 0.20 to 0.74; P=0.004). Results were materially unchanged in a sensitivity analysis that took into account participants who had withdrawn or were lost to follow-up. Adherence was good, with a reported intake of 85% or more of the required number of tablets in 79.9% of the participants. There were no significant between-group differences in the incidence of neonatal adverse outcomes or other adverse events. Treatment with low-dose aspirin in women at high risk for preterm preeclampsia resulted in a lower incidence of this diagnosis than placebo. (Funded by the European Union Seventh Framework Program and the Fetal Medicine Foundation; EudraCT number, 2013-003778-29 ; Current Controlled Trials number, ISRCTN13633058 .).
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.
The Zika virus has spread rapidly in the Americas since its first identification in Brazil in early 2015. Prenatal Zika virus infection has been linked to adverse pregnancy and birth outcomes, most notably microcephaly and other serious brain anomalies. To determine whether Zika virus infection during pregnancy causes these adverse outcomes, we evaluated available data using criteria that have been proposed for the assessment of potential teratogens. On the basis of this review, we conclude that a causal relationship exists between prenatal Zika virus infection and microcephaly and other serious brain anomalies. Evidence that was used to support this causal relationship included Zika virus infection at times during prenatal development that were consistent with the defects observed; a specific, rare phenotype involving microcephaly and associated brain anomalies in fetuses or infants with presumed or confirmed congenital Zika virus infection; and data that strongly support biologic plausibility, including the identification of Zika virus in the brain tissue of affected fetuses and infants. Given the recognition of this causal relationship, we need to intensify our efforts toward the prevention of adverse outcomes caused by congenital Zika virus infection. However, many questions that are critical to our prevention efforts remain, including the spectrum of defects caused by prenatal Zika virus infection, the degree of relative and absolute risks of adverse outcomes among fetuses whose mothers were infected at different times during pregnancy, and factors that might affect a woman’s risk of adverse pregnancy or birth outcomes. Addressing these questions will improve our ability to reduce the burden of the effects of Zika virus infection during pregnancy.
Were spontaneous miscarriages more frequent in women with histologically proven endometriosis when compared with endometriosis-free controls? Endometriosis-affected women display a significantly higher rate of previous spontaneous miscarriages than endometriosis-free controls. The association between endometriosis and miscarriages has long been debated without reaching a consensus. STUDY DESIGN, SIZE, We conducted a retrospective cohort study comparing exposed women (endometriosis) and control (without endometriosis) regarding the incidence of miscarriages. All study participants underwent surgery for benign gynaecological conditions in a tertiary-care university hospital between January 2004 and March 2013. After thorough surgical examination of the abdominopelvic cavity, 870 women with histologically proven endometriosis were allocated to the endometriosis group and 981 unaffected women to the control group. Only previously pregnant women were finally included 284 women in the endometriosis group and 466 in the control group. PARTICIPANTS/MATERIALS, SETTING, Data were collected preoperatively using a structured questionnaire. Among women with at least one pregnancy before the surgery, the type and number of the different previous first trimester pregnancies outcomes were studied. Previous history of miscarriage was studied according to the existence of previous infertility history and the disease severity (revised American Fertility Society and surgical classification). MAIN Four hundred and seventy-eight pregnancies in endometriosis-affected women and 964 pregnancies in controls were analysed. The previous miscarriage rate was significantly higher in women with endometriosis compared with the controls (139/478 [29] versus 187/964 [19%], respectively; ITALIC! P < 0.001). After a subgroup analysis, the miscarriage rates of women with endometriosis and the controls were, 20 versus 12% ( ITALIC! P = 0.003) among women without a previous history of infertility and 53 versus 30% ( ITALIC! P < 0.001) for women with a previous history of infertility. After using a random-effects Poisson regression and adjusting for confounding factors, we found a significantly increased incidence rate ratio (IRR) for miscarriages in women with endometriosis (adjusted 1.70, 95% 1.34-2.16). LIMITATIONS, There is a possible selection bias due to the specificity of the study design which included only surgical patients. In the control group, certain of the surgical gynaecological conditions, such as fibroids, ovarian cysts or tubal pathologies, might be associated with higher spontaneous miscarriage rates. In the endometriosis group, asymptomatic women were less likely to be referred for surgery and might therefore be underrepresented. This study opens the doors to future, more mechanistic studies to establish the exact link between endometriosis and spontaneous miscarriage rates. No external funding was used for this study. The authors have no conflicts of interest to declare.
PregnancyProgesterone TreatmentRecurrent MiscarriagePregnancy Support
Vissenberg R et al., 2016·Eur J Obstet Gynecol Reprod Biol
Thyroid dysfunction has been described as a possible risk factor for having an abnormal fetal position at birth. In this study we aim to determine the association between thyroid function in early pregnancy and breech presentation at term. We used data from the Amsterdam Born Children and their Development (ABCD) cohort. 3347 pregnant women were included between January 2003 and March 2004 in Amsterdam, the Netherlands. Thyroid function tests were performed between 5 and 37 weeks gestational age (median 12.9 weeks). The main outcome measure was the association between thyroid function in early pregnancy and breech presentation at term. Univariate and multivariate analysis were performed to determine the association between thyroid function and breech presentation. Increased TSH in pregnancy, defined as thyroid stimulating hormone (TSH) >97.5th percentile (>3.53mIU/L), was associated with a higher risk for breech presentation at term (aOR 2.32, CI 1.1-4.8, p=0.02) compared to euthyroidism (TSH between 2.5th and 97.5th percentile). After exclusion of overt hypothyroidism and hyperthyroidism the aOR was 2.34 (CI 1.1-5.0, p=0.03). Trimester specific analysis showed a significant association of increased TSH levels (>3.68mIU/L) in the second trimester with breech presentation (aOR 3.7, CI 1.7-7.8, p=0.001). In the second trimester low free thyroxine (FT4) <2.5th percentile (<6.7pmol/L) was also associated with breech presentation (aOR 2.5, CI 1.0-6.3, p=0.04). Increased TSH and decreased FT4 in the second trimester of pregnancy are associated with an increased risk for breech presentation at term. The association of abnormal thyroid parameters in the first of third trimester is still unclear.
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
Progesterone support in pregnancy has been in use for over 60 years, having received its start in the 1940s. Its initial use was in patients who had habitual spontaneous abortion caused by luteal phase deficiency. More recently, the administration of progesterone later in pregnancy has been considered to be justified because of an observed decrease in circulating progesterone with the onset of labor, an association of premature labor with decreased progesterone concentrations, and the observation that progesterone has a tocolytic effect. A considerable boost to the use of progestational agents to reduce preterm delivery was received with the publication of two papers which showed a significant reduction in preterm delivery rates with the prophylactic administration of either progesterone or 17-a hydroxyprogesterone caproate. Recently it has been shown, however, that its use is not universal. This may be related to the significant late sequelae that were documented following the in utero exposure of the fetus to the potent steroid diethylstilbestrol (DES) and that this bad experience cast “a long shadow,” In spite of this, the use of progesterone, at least in early pregnancy, is widespread in the various artificial reproductive programs and is growing in its use as an agent to reduce prematurity. Over the years, there has been an extraordinary amount of confusion related to the use of progesterone support in pregnancy. The Food & Drug Administration (FDA) created some of this confusion. In various labeling of progesterone products by the FDA, one of the contraindications to the use of oral progesterone is listed as “known or suspected pregnancy.” And, yet, no such contraindication is identified for the use of progesterone gel. In fact, progesterone gel is indicated for progesterone supplementation or replacement as a part of an assisted reproductive technology (ART) treatment program for infertile women with a progesterone deficiency. To make this even more confusing, oral progesterone, while it was contraindicated in “known or suspected pregnancy,” its official labeling stated that it “should be used during pregnancy only if indicated (see contraindications).” Also, up until very recently, there was a dire “warning” contained in the labeling for USP progesterone injection in sesame seed oil regarding an increased possibility of birth defects. An analysis of the fetal safety of isomolecular progesterone (Pregn-4-ene-3,20-dione) administration during the course of 1,310 pregnancies over a 35-year period of time (1979-2014) was undertaken to address this confusion.
Santamaria A et al., 2015·J Matern Fetal Neonatal Med
To evaluate whether myo-inositol supplementation may reduce gestational diabetes mellitus (GDM) rate in overweight women. In an open-label, randomized trial, myo-inositol (2 g plus 200 μg folic acid twice a day) or placebo (200 μg folic acid twice a day) was administered from the first trimester to delivery in pregnant overweight non-obese women (pre-pregnancy body mass index ≥ 25 and < 30 kg/m(2)). The primary outcome was the incidence of GDM. From January 2012 to December 2014, 220 pregnant women were randomized at two Italian University hospitals, 110 to myo-inositol and 110 to placebo. The incidence of GDM was significantly lower in the myo-inositol group compared to the placebo group (11.6% versus 27.4%, respectively, p = 0.004). Myo-inositol treatment was associated with a 67% risk reduction of developing GDM (OR 0.33; 95% CI 0.15-0.70). Myo-inositol supplementation, administered since early pregnancy, reduces GDM incidence in overweight non-obese women.
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.).
Very few studies describe the obstetric and neonatal outcome of spontaneous pregnancies in women with irregular menstrual cycles. However, menstrual cycle irregularities are common and may be associated with increased risk, and women who develop pregnancy complications more frequently recollect irregular menstrual cycles before the time of conception in case-control studies. This retrospective cohort study compares obstetric and neonatal outcomes in spontaneous singleton pregnancies in 3440 primiparous Danish women stratified according to menstrual cycle regularity. All pregnancies delivered after 22 weeks of gestation and had a nuchal translucency examination at Copenhagen University Hospital Hvidovre between 1 January 2009 and 31 December 2010. Menstrual cycle irregularity was defined as more than 7 days' deviation between self-reported and ultrasound examination-based gestational age. Outcome measures were gestational diabetes, hypertension, preeclampsia, preterm premature rupture of membranes, preterm birth, prolonged pregnancy, birthweight, umbilical artery pH <7.1, APGAR <7 after 5 min, admission to neonatal intensive care unit and stillbirth. Women with more than 7 days' deviation between self-reported and ultrasound examination-based gestational age were compared with women with a deviation of 7 days or less. Irregular menstrual cycle before conception increases the risk of preeclampsia (7.9% vs. 5.2%, p < 0.05) and low birthweight (6.0% vs. 3.6%, p < 0.05) in spontaneous pregnancies, but reduces the risk of prolonged pregnancy (1.4% vs. 4.7%, p < 0.001). Irregular menstrual cycle before conception is associated with increased risk of adverse obstetric and neonatal outcome.
Over the past quarter century it has become clear that adult onset chronic diseases like heart disease and type 2 diabetes have their roots in early development. The report by David Barker and colleagues showing an inverse relationship between birthweight and mortality from ischemic heart disease was the first clear-cut demonstration of fetal programming. Because fetal growth depends upon the placental capacity to transport nutrients from maternal blood, it has been a suspected causative agent since the original Barker reports. Epidemiological studies have shown that placental size and shape have powerful associations with offspring disease. More recent studies have shown that maternal phenotypic characteristics, such as body mass index and height, interact with placental size and shape to predict disease with much more precision than does birthweight alone. For example, among people in the Helsinki Birth Cohort, who were born during 1924–1944, the risk for acquiring colorectal cancer increased as the placental surface became longer and more oval. Among people in whom the difference between the length and breadth of the surface exceeded 6 cm, the hazard ratio for the cancer was 2.3 (95% CI 1.2–4.7, p=0.003) compared with those in whom there was no difference. Among Finnish men, the hazard ratio for coronary heart disease was 1.07 (1.02–1.13, P =0.01) per 1% increase in the placental weight/birthweight ratio. Thus, it appears that the ratio of birthweight to placental weight, known as placental efficiency, predicts cardiovascular risk as well. Babies born with placentas at the extremes of efficiency are more vulnerable for adult onset chronic diseases. Recent evidence suggests that placental growth patterns are sex specific. Boys’ placentas are, in general, more efficient than those made by girls. Another recent discovery is that the size, shape and efficiencies of the placenta can change over years of time with very narrow confidence limits. This suggests that the growth of the placenta within a population of women is strongly affected by their nutritional environment. Even though it is known that an individual placenta can expand to improve its nutrient acquisition capacity in the first 2/3(rd) of gestation, the mechanisms by which placentas grow in response to a specific nutritional environment are not known. Discovering those mechanisms is the task of the current generation of scientists. While it may seem obvious that good nutrition is highly important for women who are pregnant because it supports optimal placentation and fetal development, more research is needed to determine the mechanisms by which maternal nutrition, placenta growth and fetal health are related.
Several lines of evidence suggest that male embryos may have greater vulnerability than female embryos to disordered inflammation; therefore, antiinflammatory drugs, such as low-dose aspirin (LDA), may alter the sex ratio. Here, we assessed the effect of LDA on male live birth and male offspring, incorporating pregnancy losses (n = 56) via genetic assessment, as part of a parallel-design, block-randomized, placebo-controlled trial of preconception LDA. Participants (615 treated with LDA, 613 treated with placebo) ranged in age from 18 to 40 years of age, with 1 to 2 prior pregnancy losses. We estimated the intention-to-treat (ITT) risk ratio (RR) and 95% CI and assessed interaction with baseline high-sensitivity C-reactive protein (hsCRP) serum concentration - a marker of systemic inflammation. Among the 1,078 women who completed follow-up (535 treated with LDA, 543 treated with placebo), the male live birth ITT RR equaled 1.31 (95% CI: 1.07-1.59). With increasing tertile of hsCRP, the proportion of males at birth decreased in the placebo group, and the effect of LDA on male live birth increased (first 48% male in LDA vs. 52% in placebo, ITT RR = 0.97, 95% CI: 0.70-1.35; 57% male in LDA vs. 43% in placebo, ITT RR = 1.36, 95% CI: 0.98-1.90; 53% male in LDA vs. 35% in placebo, ITT RR = 1.70, 95% CI: 1.13-2.57; P interaction = 0.03). Analysis of pregnancy with male offspring yielded similar results. Initiation of LDA prior to conception restored numbers of male live births and pregnancy with male offspring among women with 1 to 2 prior pregnancy losses. Moreover, our data suggest that LDA modulates inflammation that would otherwise reduce the conception or survival of male embryos. ClinicalTrials.gov NCT00467363. Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health.
To evaluate whether myo-inositol supplementation, an insulin sensitizer, reduces the rate of gestational diabetes mellitus (GDM) and lowers insulin resistance in obese pregnant women. In an open-label, randomized trial, myo-inositol (2 g plus 200 micrograms folic acid twice a day) or placebo (200 micrograms folic acid twice a day) was administered from the first trimester to delivery in pregnant obese women (prepregnancy body mass index 30 or greater. We calculated that 101 women in each arm would be required to demonstrate a 65% GDM reduction in the myo-inositol group with a statistical power of 80% (α=0.05). The primary outcomes were the incidence of GDM and the change in insulin resistance from enrollment until the diagnostic oral glucose tolerance test. From January 2011 to April 2014, 220 pregnant women at 12-13 weeks of gestation were randomized at two Italian university hospitals, 110 to myo-inositol and 110 to placebo. Most characteristics were similar between groups. The GDM rate was significantly reduced in the myo-inositol group compared with the control group, 14.0% compared with 33.6%, respectively (P=.001; odds ratio 0.34, 95% confidence interval 0.17-0.68). Furthermore, women treated with myo-inositol showed a significantly greater reduction in the homeostasis model assessment of insulin resistance compared with the control group, -1.0±3.1 compared with 0.1±1.8 (P=.048). Myo-inositol supplementation, started in the first trimester, in obese pregnant women seems to reduce the incidence in GDM through a reduction of insulin resistance. ClinicalTrials.gov, www.clinicaltrials.gov, NCT01047982.
PregnancyHerbal RemediesHerbal Medicine UseSupplement Disclosure
Open Access
The prevalence of the herbal medicines use is on the rise across the world, especially amongst pregnant women. The scenario in the Middle Eastern region was reviewed to explore the prevalence, usage pattern, motivation, and attitude towards use of herbal medicine by pregnant women. Literature published up to December 2012 showed the prevalence of herbal medicine use varied between 22.3-82.3%, implying a rising trend in the utilization of herbal medicine during pregnancy. The most common herbs used were peppermint, ginger, thyme, chamomile, sage, aniseed, fenugreek, and green tea. The most common reasons for use included the treatment of gastrointestinal disorders and cold and flu symptoms. The majority of women used these products during their first trimester, and did not reveal this information to their physician. Most women were advised by family and friends to use herbal medicines and believed they were more effective and had fewer side effects than modern medicine especially during pregnancy. In conclusion, the use of herbal medicine is prevalent among pregnant women in the Middle Eastern region and healthcare providers need to seek information pertaining to their use.
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.
John LJ et al., 2015·Complementary Therapies in Nursing and Midwifery
The prevalence of the herbal medicines use is on the rise across the world, especially amongst pregnant women. The scenario in the Middle Eastern region was reviewed to explore the prevalence, usage pattern, motivation, and attitude towards use of herbal medicine by pregnant women. Literature published up to December 2012 showed the prevalence of herbal medicine use varied between 22.3-82.3%, implying a rising trend in the utilization of herbal medicine during pregnancy. The most common herbs used were peppermint, ginger, thyme, chamomile, sage, aniseed, fenugreek, and green tea. The most common reasons for use included the treatment of gastrointestinal disorders and cold and flu symptoms. The majority of women used these products during their first trimester, and did not reveal this information to their physician. Most women were advised by family and friends to use herbal medicines and believed they were more effective and had fewer side effects than modern medicine especially during pregnancy. In conclusion, the use of herbal medicine is prevalent among pregnant women in the Middle Eastern region and healthcare providers need to seek information pertaining to their use.
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.
Background. Several studies have shown a possible involvement of Helicobacter pylori (H. pylori) infection in individuals with hyperemesis gravidarum (HG), but the relationship remains controversial. This meta-analysis was performed to validate and strengthen the association between HG and H. pylori infection. Methods. PubMed, Embase, and Web of Science databases up to March 20, 2014, were searched to select studies on the prevalence of H. pylori infection between pregnant women with HG and the normal pregnant control subjects. Results. Of the HG cases, 1289 (69.6%) were H. pylori-positive; however, 1045 (46.2%) were H. pylori-positive in control group. Compared to the non-HG normal pregnant controls, infection rate of H. pylori was significantly higher in pregnant women with HG (OR = 3.34, 95% CI: 2.32-4.81, P < 0.001). Subgroup analysis indicated that H. pylori infection was a risk factor of HG in Asia, Africa, and Oceania, especially in Africa (OR = 12.38, 95% CI: 7.12-21.54, P < 0.001). Conclusions. H. pylori should be considered one of the risk factors of HG, especially in the developing countries. H. pylori eradication could be considered to relieve the symptoms of HG in some intractable cases.
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.
PregnancyVitamin D SupplementationMicronutrient InterventionsRandomized Controlled Trial
Gestational diabetes mellitus (GDM) has been recognized as a significant risk factor for unfavorable pregnancy outcomes. Prevalence of vitamin D deficiency is highly prevalent among women with GDM. This study was designed to assess the effect of vitamin D supplementation on pregnancy outcomes of pregnant women with GDM who were not on oral hypoglycemic agents. This randomized controlled clinical trial was performed among 45 pregnant women diagnosed with GDM at 24-28 weeks' gestation. Subjects were randomly assigned to consume either vitamin D supplements (cholecalciferol) or placebo. Individuals in the vitamin D group (n=22) received 50 000 IU vitamin D3 pearl 2 at study baseline and day 21 of intervention and those in placebo group (n=23) received 2 placebos at the mentioned times. Fasting blood samples were taken at baseline to measure fasting plasma glucose. Participants underwent a 3-h oral glucose tolerance tests (OGTT) and the blood samples were collected at time 60, 120, and 180 min to measure plasma glucose levels. Newborn's weight, height, head circumference, Apgar score, and hyperbilirubinemia were determined. Taking vitamin D supplements, compared with placebo, resulted in improved pregnancy outcomes; such that those in the vitamin D group had no case of polyhydramnios, while 17.4% of subjects in placebo group had this condition (p=0.04). In addition, newborn's hyperbilirubinemia was significantly lower in vitamin D group than that in placebo group (27.3% vs. 60.9%, p=0.02). In conclusion, vitamin D supplementation for 6 weeks among pregnant women with GDM resulted in decreased maternal polyhydramnios and infant hyperbilirubinemia compared with placebo. Clinical trial registration number www.irct.ir:IRCT201305115623N7.
Novel findings in microbiology question the long-standing paradigm that a healthy pregnancy implies a sterile uterus. It now seems that the placenta is frequently colonized with bacteria, and a placental microbiome has been identified. Recent literature findings are summarized here, and an attempt is made to separate pathological bacterial presence from a naturally occurring microbiome.
Reproductive EndocrinologyInherited Coagulation DisordersThrombophilia and Thrombosis RiskFactor V Leiden and Prothrombin Mutation
Thrombophilia alters normal hemostasis, shifting the balance in favor of thrombus formation. Inherited conditions include factor V Leiden (FVL), prothrombin G20210A mutation, deficiencies in natural anticoagulants (antithrombin [AT], protein C, and protein S), hyperhomocysteinemia, and elevations in clotting factors (factors VIII and XI). Although FVL and prothrombin mutation are common disorders, deficiencies in the natural anticoagulants are rare. The risk of initial thrombosis conferred by inherited thrombophilia varies with the highest risk in those homozygous for either FVL or prothrombin mutation, or with AT deficiency. In the nonpregnant patient, the presence of a thrombophilia does not affect treatment of an acute event. Although vitamin B supplementation has been shown to decrease the levels of homocysteine, the treatment has failed to show a benefit in thrombus prevention and is therefore not recommended.
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.
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.
Nausea and vomiting during pregnancy are the most common conditions affecting pregnancy, occurring in about 80% of all pregnancies and always disappearing on the 16th to 18th weeks of gestation. This may be mild and it does not affect the general condition of the patient (the condition is called emesis gravidarum), or it may be severe enough to affect the patient physically and psychologically, causing intractable vomiting, electrolyte imbalance, weight loss >5%, impairment of liver and kidney functions and dehydration. Helicobacter pylori is one of the most common bacterium affecting humans. It is a gram-negative helix-shaped microaerophilic bacterium transmitted by the oro-oral or feco-oral route. It is more prevalent in developing countries and affects young children. Acute infection manifests as acute gastritis and stomach pain, whereas chronic infection causes chronic gastritis and peptic ulcer, 2% of which may develop into stomach cancer. The authors tried to investigate the association between H pylori infection and hyperemesis gravidarum. Fifty patients with hyperemesis gravidarum and 50 patients with normal pregnancy were included in the study. H pylori infection was determined using a 1-step H pylori test device (serum/plasma), which is a qualitative membrane-based immunoassay. Regarding maternal age, gestational age and socioeconomic status, there is no statistical difference between both groups. There is a marked statistical difference between both groups in terms of Helicobacter pylori seropositivity and frequency of vomiting. There is a powerful correlation between H pylori and hyperemesis gravidarum.
To present a series of cases demonstrating successful reversal of mifepristone effects in women who chose to reverse the medical abortion process. Four of 6 women who took mifepristone were able to carry their pregnancies to term after receiving intramuscular progesterone 200 mg. Mifepristone has been available in the US since 2000. By 2008, approximately 25% of abortions prior to 9 weeks were accomplished with mifepristone. Some women who take mifepristone wish to reverse the medical abortion process. Progesterone competes with mifepristone for the progesterone receptor and may reverse the effects of mifepristone. A PubMed literature search from 1996 to May 2012 did not reveal any trials or case studies evaluating the efficacy of progesterone use to reverse the effects of mifepristone. Health care professionals should be aware of the possible use of progesterone to reverse mifepristone in women who have begun the medical abortion process by taking mifepristone and then change their minds.
Use of metformin throughout pregnancy in women with polycystic ovary syndrome (PCOS) has shown to reduce the rates of early pregnancy loss, preterm labor, and prevention of fetal growth restriction. Metformin has been shown to have encouraging effects on several metabolic aspects of polycystic ovarian syndrome, such as insulin sensitivity, plasma glucose concentration and lipid profile and since women with PCOS are more likely than healthy women to suffer from pregnancy-related problems like early pregnancy loss, gestational diabetes mellitus and hypertensive states in pregnancy, the use of metformin therapy in these patients throughout pregnancy may have beneficial effects on early pregnancy loss and development of gestational diabetes.
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.
PregnancyObstetric HemorrhagePostpartum HemorrhageTransfusion in Hemorrhage
An obstetric hemorrhage may occur before or after delivery, but more than 80% of cases occur postpartum. Worldwide, a massive obstetric hemorrhage, resulting from the failure of normal obstetrical, surgical and/or systemic hemostasis, is responsible for 25% of the estimated 358,000 maternal deaths each year. Most women will not have identifiable risk factors. Nonetheless, primary prevention of a postpartum hemorrhage (PPH) begins with an assessment of identifiable risk factors. Women identified as being at high risk of a PPH should be delivered in a center with access to adequately trained staff and an onsite blood bank. A critical feature of a massive hemorrhage in obstetrics is the development of disseminated intravascular coagulation (DIC), which, in contrast to DIC that develops with hemorrhage from surgery or trauma, is frequently an early feature. Data from clinical trials to guide management of transfusion in PPH are lacking. There are likely to be similarities in the management of transfusion in severe PPH to that of major bleeding in other clinical situations, but the pathophysiological processes that contribute to a massive PPH may necessitate different transfusion strategies such as the ratio of red blood cells to plasma components, in particular fibrinogen. Caution should be exercised when considering the appropriate place for recombinant activated factor VII (rFVIIa) in the management of a major PPH. An early hysterectomy is recommended for severe bleeding as a result of placenta accreta or uterine rupture. However, in women with uterine atony who have ongoing bleeding in spite of an adequate transfusion, it may be reasonable to consider a trial of rFVIIa before a hysterectomy.
Amy Kuebelbeck was 25 weeks into her pregnancy when she received the terrible news. Her fetus had been diagnosed with an incurable heart defect. If she carried through with her pregnancy, her baby's life would be a brief one. Kuebelbeck did continue her pregnancy and gave birth to a boy. Her new
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.
PregnancyPostpartum Depression and Hormonal ContraceptionDMPA and Mood DisordersDepression Screening and Risk Factors
Depot medroxyprogesterone acetate (DMPA) is commonly prescribed to women immediately postpartum due to its efficacy, convenience and lack of estrogen. It is unclear whether administering a progestin injection can affect the course of postpartum depression (PPD), which some suspect to be influenced by hormonal changes. In this retrospective study, the objective was to determine whether DMPA administered immediately postpartum influences the development of PPD. A retrospective review of a total of 404 charts was conducted of clinic patients who were scheduled for 6-week postpartum visits at a major medical center, where all patients are routinely asked to complete the Edinburgh Postnatal Depression Scale (EPDS). The average scores on the EPDS at these visits were compared between patients who had received DMPA prior to postpartum discharge from the hospital and patients who had not received any hormonal contraception by using an unpaired t test. In addition, the proportions of women diagnosed with PPD via the scale were compared via contingency tables. Fifty-five women who had received immediate DMPA were compared with 192 women with no hormonal contraception after delivery. The groups were similar in parity, race, mode of delivery and weight, but women receiving DMPA were significantly younger (24.2 vs. 26.2 years, p=.03). Mean EPDS scores at 6 weeks postpartum were not statistically significant between the groups (5.02 vs. 6.17, p=.16). Six patients (10.9%) who received immediate DMPA were diagnosed with PPD based on EPDS scores greater than or equal to 13, while 27 (14.1%) in the comparison group had PPD (p=.88). Administration of DMPA in the immediate postpartum period does not appear to predispose women to PPD.
PregnancyThyroid Dysfunction and Pregnancy LossTSH Reference Ranges in PregnancyFirst Trimester TSH Thresholds
The definition of what constitutes a normal TSH during pregnancy is in flux. Recent studies suggested that the first trimester upper limit of normal for TSH should be 2.5 mIU/liter. The objective of the study was to evaluate the pregnancy loss and preterm delivery rate in first-trimester thyroid peroxidase antibody-negative women with TSH values between 2.5 and 5.0 mIU/liter. The present study is a component of a recently published large-scale prospective trial that evaluated the impact of levothyroxine treatment on maternal and neonatal complications in thyroid peroxidase-positive women with TSH levels above 2.5 mIU/liter. The present study evaluated 4123 thyroid peroxidase antibody-negative women with TSH levels at or below 5.0 mIU/liter. Women were divided into two groups group A, TSH level below 2.5 mIU/liter, excluding hyperthyroid women defined as an undetectable TSH with an elevated free T(4), and group B, TSH level between 2.5 and 5.0 mIU/liter. The study was conducted at two ambulatory clinics of community hospitals in southern Italy. A total of 4123 women were evaluated. There was no intervention. The incidence of pregnancy loss and preterm delivery in group A as compared with group B was measured. The rate of pregnancy loss was significantly higher in group B as compared with group A (6.1 vs. 3.6% respectively, P = 0.006). There was no difference in the rate of preterm delivery between the two groups. The increased incidence of pregnancy loss in pregnant women with TSH levels between 2.5 and 5.0 mIU/liter provides strong physiological evidence to support redefining the TSH upper limit of normal in the first trimester to 2.5 mIU/liter.
Oral contraceptives (OCs) are the most commonly used reversible contraceptive method among US women. Although the majority of previous studies have reported no association between OC use during pregnancy and birth defects, some studies have reported increased occurrence of neural tube defects, limb reduction defects, and urinary tract anomalies. We assessed OC use among mothers who participated in the multisite, case-control, National Birth Defects Prevention Study. Mothers of 9986 infants with 32 types of birth defects and 4000 infants without birth defects were included. Maternal OC use during the first 3 months of pregnancy was associated with an increased odds ratio for 2 of 32 hypoplastic left heart syndrome (adjusted odds ratio = 2.3 [95% confidence interval = 1.3-4.3) and gastroschisis (1.8 [1.3-2.7]). Previous reports of associations between OC use and specific types of anomalies were not corroborated. Given that associations were assessed for 32 types of birth defects, our findings of 2 increased associations between OC use and gastroschisis and hypoplastic left heart syndrome should be interpreted as hypotheses until they can be evaluated further. Overall, our findings are consistent with the majority of previous studies that found women who use OCs during early pregnancy have no increased risk for most types of major congenital malformations.
To study the relationship between suboptimal maternal thyroid function during gestation and breech presentation at term. Prospective follow-up study during three trimesters of gestation. A total of 1058 Dutch Caucasian healthy pregnant women were prospectively followed from 12 weeks gestation until term (>or=37 weeks) delivery. Maternal thyroid parameters [TSH, free T4 (FT4) and auto-antibodies to thyroid peroxidase] were assessed at 12, 24 and 36 weeks gestation as well as foetal presentation at term. At term, 58 women (5.5%) presented in breech. Compared with women with foetuses in the cephalic position, those women who presented in breech at term had significantly higher TSH concentrations, but only at 36 weeks gestation (P = 0.007). No between group differences were obtained for FT4 level at any assessment. The prevalence of breech presentation in the subgroup of women with TSH >or= 2.5 mIU/l (90th percentile) at 36 weeks gestation was 11%, compared with 4.8% in the women with TSH < 2.50 mIU/l (P = 0.006). Women with TSH below the 5th percentile had no breech presentations. Breech position was significantly and independently related to high maternal TSH concentration (>or=2.5 mIU/l) at 36 weeks gestation (O.R.: 2.23, 95% CI: 1.14-4.39), but not at 12 and 24 weeks gestation. Women with TSH levels above 2.5 mIU/l during end gestation are at risk for breech presentation, and as such for obstetric complications.
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.
Yeung PP Jr et al., 2008·J Matern Fetal Neonatal Med
This is the first known case of extended somatic support beyond viability for a pregnant woman with brain death resulting from metastatic malignant melanoma, resulting in a live birth.
We postulated that impaired endometrial differentiation in women with pelvic endometriosis predisposes for pre-eclampsia. A retrospective case-control study set at the University of Ghent IVF centre. The incidence of pre-eclampsia and pregnancy-induced hypertension (PIH) following the clinical and/or laparoscopic diagnosis of endometriosis-associated infertility (case group; n = 245 pregnancies) was compared with the incidence of these obstetric complications in pregnancies following treatment for male-factor infertility (control group; n = 274 pregnancies). Pregnancy data were obtained by searching electronic databases and postal questionnaires. The case and control groups were matched for age, parity and multiple pregnancies. The incidence of pre-eclampsia was significantly lower in the case group (0.8%) when compared with control group (5.8%) (P = 0.002; odds ratio (OR) = 7.5, 95% confidence interval (CI): 1.7-33.3). Analysis of obstetric outcome in the subgroup of patients with laparoscopic data confirmed the lower risk of pre-eclampsia in the case (1.2%) versus control (7.4%) groups (P = 0.032; OR = 6.6, 95% CI: 1.2-37). PIH occurred in 3.5% and 8.7% of case and control pregnancies, respectively (P = 0.018; OR = 2.6, 95% CI: 1.2-6.0). The odds of developing pre-eclampsia were 5.67 times higher in the control group than in pregnancies following endometriosis-associated infertility. In multiple pregnancies, the odds of developing pre-eclampsia increased 1.93 times per additional child, with or without endometriosis. We found no evidence that endometriosis predisposes for pre-eclampsia. Instead, the risk of hypertensive disorder in pregnancy is significantly reduced in women with endometriosis-associated infertility.
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.
Euthyroid women with autoimmune thyroid disease show impairment of thyroid function during gestation and seem to suffer from a higher rate of obstetrical complications. We sought to determine whether these women suffer from a higher rate of obstetrical complications and whether levothyroxine (LT(4)) treatment exerts beneficial effects. This was a prospective study. The study was conducted in the Department of Obstetrics and Gynecology. A total of 984 pregnant women were studied from November 2002 to October 2004; 11.7% were thyroid peroxidase antibody positive (TPOAb(+)). TPOAb(+) patients group A (n = 57) was treated with LT(4), and group B (n = 58) was not treated. The 869 TPOAb(-) patients (group C) served as a normal population control group. Rates of obstetrical complications in treated and untreated groups were measured. At baseline, TPOAb(+) had higher TSH compared with TPOAb(-); TSH remained higher in group B compared with groups A and C throughout gestation. Free T(4) values were lower in group B than groups A and C after 30 wk and after parturition. Groups A and C showed a similar miscarriage rate (3.5 and 2.4%, respectively), which was lower than group B (13.8%) [P < 0.05; relative risk (RR), 1.72; 95% confidence interval (CI), 1.13-2.25; and P < 0.01; RR = 4.95; 95% CI = 2.59-9.48, respectively]. Group B displayed a 22.4% rate of premature deliveries, which was higher than group A (7%) (P < 0.05; RR = 1.66; 95% CI = 1.18-2.34) and group C (8.2%) (P < 0.01; RR = 12.18; 95% CI = 7.93-18.7). Euthyroid pregnant women who are positive for TPOAb develop impaired thyroid function, which is associated with an increased risk of miscarriage and premature deliveries. Substitutive treatment with LT(4) is able to lower the chance of miscarriage and premature delivery.
PregnancySelenium and MicronutrientsPreeclampsia and ToxemiaChemical Stress
Furthermore, direct questioning and a scrutiny of records of these patients showed that before the full development of the signs of toxaemia—that is, oedema, hypertension, and albuminuria—most had earlier in the pregnancy experienced a symptomatic stage characterized by relatively minor afflictions—for example, lethargy 43%, headache 48%, visual aura 37%, vertigo 29%, nausea and vomiting 16%, irritability 14%, depression 9%, and backache 6%. In fact, only 7% disclosed freedom from these symptoms during a toxaemic pregnancy.
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.
The purpose of this study was to determine the incidence of neurologic morbidity in preterm monochorionic (MC) and dichorionic (DC) twins. We collected perinatal, neonatal, and infant follow-up data of 76 MC and 78 DC twins born between 24 and 34 weeks of gestation (295 infants). Risks of neuromorbidity in the surviving infants were evaluated in relation to chorionicity, discordant birth weight (>20%), twin-twin transfusion syndrome (TTTS), and cotwin death. The overall incidence of cerebral palsy and minor neurologic disabilities in surviving twins was 4% and 9%, respectively. MC infants had a higher incidence of cerebral palsy (8% vs 1%, P<.05) and neurologic morbidity (15% vs 3%, P<.05) than DC infants. The risk of impaired neurodevelopment was higher in MC infants with discordant birth weight (42%, P<.01), TTTS (37%, P<.01), and cotwin death (60%, P<.01) than those with concordant birth weight (8%). In MC pregnancies, the cerebral palsy risk was higher in infants with discordant birth weight than those with chronic TTTS (19% vs 4%, P<.05). Similarly, discordant DC infants had higher neuromorbidity than concordant group (5% vs 1%, P<.05). In both MC and DC discordant infants, neurologic morbidity was independent of growth restriction. Neurologic morbidity in the preterm MC infants was 7-fold higher than DC infants because of chronic TTTS, discordant birth weight, and cotwin death in utero.
PregnancyExtreme Prematurity OutcomesNeurodevelopmental Follow-upSurvival and Long-term Prognosis
Long-term outcome, including school-age function, has been infrequently reported in infants born at ages as young as 23-26 weeks' gestation. The objective of this study is to report outcome on a large cohort of these infants to understand better the risks and factors that affect survival and long-term prognosis. Records from 1036 infants who were born between January 1, 1986, and December 31, 2000, were analyzed retrospectively by logistic regression to correlate multiple factors with both survival and long-term outcome. A total of 675 surviving infants were analyzed at a mean age of 47.5 months for developmental outcome. A subset of 147 surviving infants who were born before 1991 were followed through school-age years using the University of Vermont Achenbach Child Behavioral Checklist and Teachers Report Form. Longitudinal follow-up was performed comparing 1-year outcome with school-age performance. Gestational age and recent year of birth correlated highly with survival. Maternal nonwhite race, female sex, inborn status, surfactant therapy, single gestation, and secondary sepsis also correlated positively with survival. Normal cranial ultrasound results, absence of chronic lung disease, female sex, cesarean delivery, and increased birth weight correlated favorably with long-term outcome. Infants who were born at 23 weeks were more likely to have severe impairments compared with those who were born at 24-26 weeks. Early follow-up identified most subsequent physical impairments but correlated poorly with school-age function. Survival continues to improve for infants who are born at extremely early gestational ages, but long-term developmental concerns continue to be prevalent. Early outcomes do not reliably predict school-age performance. Strategies that reduce severe intraventricular hemorrhage and chronic lung disease will likely yield the best chances to improve long-term outlook.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY
Preterm birth remains a leading cause of perinatal mortality, with rates in the United States rising significantly over the latter half of the twentieth century despite decades of awareness. NaProTechnology's integrated prevention approach, developed at the Pope Paul VI Institute, addresses this problem through systematic risk stratification, hormonal support, infection surveillance, and cervical monitoring across the full course of pregnancy.
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.
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.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY
Serial progesterone measurement timed to the luteal phase and early pregnancy using CrMS Peak Day-referenced protocols reveals luteal insufficiency and early placental progesterone inadequacy that are associated with miscarriage risk and preterm labor. Progesterone supplementation guided by these standardized assessments has been associated with reduced pregnancy loss in NaProTECHNOLOGY-managed pregnancies, and the chapter details the specific drawing protocols, reference ranges, and supplementation decision thresholds used in clinical practice.
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.
Preterm birth affects 12% of all births in the United States. Recent studies support the hypothesis that progesterone supplementation reduces preterm birth in a select group of women (ie, those with a prior spontaneous birth at <37 weeks of gestation). Despite the apparent benefits of progesterone in this high-risk population, the ideal progesterone formulation is unknown. The American College of Obstetricians and Gynecologists Committee on Obstetric Practice believes that further studies are needed to evaluate the use of progesterone in patients with other high-risk obstetric factors, such as multiple gestations, short cervical length, or positive test results for cervicovaginal fetal fibronectin. When progesterone is used, it is important to restrict its use to only women with a documented history of a previous spontaneous birth at less than 37 weeks of gestation because unresolved issues remain, such as optimal route of drug delivery and long-term safety of the drug.
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.
PregnancyIntrauterine Growth RestrictionNeonatal Mortality and MorbidityPopulation-Based Study
We examined the effect of intrauterine growth restriction on mortality and morbidity in the Israel cohort of very low birth weight premature infants. The study population included 2764 singleton very low birth weight infants without congenital malformations born from 24 to 31 weeks of gestation during 1995 to 1999. Four hundred six (15%) were born small for gestational age (SGA). The effect of SGA on death, bronchopulmonary dysplasia, and retinopathy of prematurity was assessed using multiple logistic regression analysis. After adjustment for perinatal risk factors, SGA infants had a 4.52-fold risk for death (95% CI, 3.24-6.33), a 3.42-fold risk for bronchopulmonary dysplasia (95% CI, 2.29-5.13), and a 2.06-fold risk for grade 3 to 4 retinopathy of prematurity (95% CI, 1.15-3.66). SGA premature infants had an increased risk for death, and major morbidity among survivors was increased.
To review the evidence of effectiveness of prenatal care for preventing low birth weight (LBW). We reviewed original research, systematic reviews, meta-analyses and commentaries for evidence of effectiveness of the three core components of prenatal care--risk assessment, health promotion and medical and psychosocial interventions--for preventing preterm birth and intrauterine growth restriction (IUGR). Clinical risk assessment will fail to identify the majority of pregnancies at risk for preterm delivery or IUGR. While biophysical and biochemical modalities appear promising, their cost-effectiveness has not been demonstrated, nor can their routine use be recommended in the absence of effective interventions. Smoking cessation programs appear to be modestly effective. There is insufficient evidence to conclude a benefit for nutrition interventions, work counseling or preterm birth education. Only antenatal corticosteroid therapy has demonstrated a clear benefit in the tertiary prevention of preterm delivery. Interventions for which there is insufficient evidence to conclude a benefit include bed rest, hydration, sedation, cerclage, progesterone supplementation, antibiotic treatment, tocolysis without concomitant use of corticosteroids, thyrotropin-releasing hormone, psychosocial support and home visitation. Additionally, there is a paucity of evidence supporting the effectiveness of prenatal interventions, such as low-dose aspirin, bed rest, maternal hyperoxygenation, plasma volume expansion and antenatal fetal assessment, in preventing IUGR or its associated morbidity and mortality. Neither preterm birth nor IUGR can be effectively prevented by prenatal care in its present form. Preventing LBW will require reconceptualization of prenatal care as part of a longitudinally and contextually integrated strategy to promote optimal development of women's reproductive health not only during pregnancy, but over the life course.
PregnancyNeurodevelopmental OutcomesMortality and MorbidityResuscitation Thresholds
To determine the outcome of infants with a gestational age (GA) <27 weeks, born in the mid-1990s. Regional, prospective study; part of the Leiden Follow-Up Project on Prematurity. Three health regions in The Netherlands. A total of 266 live born infants (1996/1997) with GA <32 weeks; 46 infants were <27 weeks. Neurologic examination (according to Hempel) and assessment of mental and psychomotor development using the Bayley Scales of Infant Development I, at the corrected age of 2 years. Mortality was 35% (16 of 46) <27 weeks, compared with 6% (14 of 220) in infants with GA 27 to 32 weeks; withdrawal of treatment in 60% and 43%, respectively. Below 27 weeks mortality was higher after extra-uterine transport and pregnancy induction. Neonatal morbidity was higher in infants <27 weeks compared with infants 27 to 32 weeks. Below 27 weeks postnatal use of dexamethasone and being hospitalized at term were associated with abnormal neurologic outcome; there was a higher incidence in (mild) mental developmental delay compared with the older infants. Adverse outcome (dead or abnormal neurologic, psychomotor, or mental development) in infants 23 to 24, 25, 26, and 27 to 32 weeks GA was, respectively, 92% (11 of 12), 64% (7 of 11), 35% (8 of 23), and 18% (40 of 220). Mortality and neonatal morbidity were higher in infants with GA <27 weeks compared with infants born between 27 and 32 weeks. The high adverse outcome of infants <25 weeks suggests that one should carefully weigh whether or not to aggressively resuscitate and treat these extremely premature infants.
PregnancyPrevention with Progesterone17-alpha Hydroxyprogesterone CaproateMulticenter Trial
Women who have had a spontaneous preterm delivery are at greatly increased risk for preterm delivery in subsequent pregnancies. The results of several small trials have suggested that 17 alpha-hydroxyprogesterone caproate (17P) may reduce the risk of preterm delivery. We conducted a double-blind, placebo-controlled trial involving pregnant women with a documented history of spontaneous preterm delivery. Women were enrolled at 19 clinical centers at 16 to 20 weeks of gestation and randomly assigned by a central data center, in a 2:1 ratio, to receive either weekly injections of 250 mg of 17P or weekly injections of an inert oil placebo; injections were continued until delivery or to 36 weeks of gestation. The primary outcome was preterm delivery before 37 weeks of gestation. Analysis was performed according to the intention-to-treat principle. Base-line characteristics of the 310 women in the progesterone group and the 153 women in the placebo group were similar. Treatment with 17P significantly reduced the risk of delivery at less than 37 weeks of gestation (incidence, 36.3 percent in the progesterone group vs. 54.9 percent in the placebo group; relative risk, 0.66 [95 percent confidence interval, 0.54 to 0.81]), delivery at less than 35 weeks of gestation (incidence, 20.6 percent vs. 30.7 percent; relative risk, 0.67 [95 percent confidence interval, 0.48 to 0.93]), and delivery at less than 32 weeks of gestation (11.4 percent vs. 19.6 percent; relative risk, 0.58 [95 percent confidence interval, 0.37 to 0.91]). Infants of women treated with 17P had significantly lower rates of necrotizing enterocolitis, intraventricular hemorrhage, and need for supplemental oxygen. Weekly injections of 17P resulted in a substantial reduction in the rate of recurrent preterm delivery among women who were at particularly high risk for preterm delivery and reduced the likelihood of several complications in their infants.
PregnancyPrevention with ProgesteroneRisk Factors and Screening
It has become almost a platitude to lament the complexity and intractability of the problem of preterm delivery, the poor predictive value of screening tests for its occurrence, its resistance to attempted interventions, and its increasing rate.1 Preterm delivery is more common among blacks, the poor, the unmarried, cigarette smokers, underweight women, women with multiple gestations, women with uterine anomalies, women with a history of previous preterm delivery, and women without prenatal care. Although the perinatal mortality rate due to prematurity has decreased dramatically during the past three decades, this reduction has resulted from improvements in perinatal and pediatric care . . .
This report presents 2001 data on U.S. births according to a wide variety of characteristics. Data are presented for maternal demographic characteristics including age, live-birth order, race, Hispanic origin, marital status, and educational attainment; maternal characteristics (medical risk factors, weight gain, tobacco, and alcohol use); medical care utilization by pregnant women (prenatal care, obstetric procedures, complications of labor and/or delivery, attendant at birth, and method of delivery); and infant characteristics (period of gestation, birthweight, Apgar score, abnormal conditions, congenital anomalies, and multiple births). Also presented are birth and fertility rates by age, live-birth order, race, Hispanic origin, and marital status. Selected data by mother's State of residence are shown, as well as data on month and day of birth, sex ratio, and age of father. Trends in fertility patterns and maternal and infant characteristics are described and interpreted. Descriptive tabulations of data reported on the birth certificates of the 4.026 million births that occurred in 2001 are presented. Denominators for population-based rates are derived from the 1990 U.S. census. As a result, rates are generally larger than would be the case if 2000-based estimates were used. The magnitude of the overestimate will vary by population subgroup; overestimates are likely greatest for those of Hispanic origin. The number of births, the birth rate, fertility rate, and total fertility rates all declined 1 percent in 2001. The teenage birth rate reached another historic low. Birth rates for women in their twenties declined slightly, whereas rates for women aged 30 to 44 years continued to rise. Births to unmarried women changed very little. Smoking by pregnant women was down again. Women were more likely to begin care in the first trimester of pregnancy (83.4 percent). The cesarean delivery rate rose for the fifth consecutive year to 24.4 percent; the primary cesarean rate was up 5 percent and the rate of vaginal births after a previous cesarean fell 20 percent. Preterm and low birthweight levels both rose for 2001. The twin birth rate continued to climb, and following 2 years of decline, the rate of triplet/+ births also increased.
The purpose of this study was to evaluate the effect of prophylactic vaginal progesterone in decreasing preterm birth rate in a high-risk population. A randomized, double-blind, placebo-controlled study included 142 high-risk singleton pregnancies. Progesterone (100 mg) or placebo was administered daily by vaginal suppository and all patients underwent uterine contraction monitoring with an external tocodynamometer once a week for 60 minutes, between 24 and 34 weeks of gestation. Progesterone (n = 72) and placebo (n = 70) groups were compared for epidemiologic characteristics, uterine contraction frequency, and incidence of preterm birth. Data were compared by chi(2) analysis and Fisher exact test. The preterm birth rate was 21.1% (30/142). Differences in uterine activity were found between the progesterone and placebo groups (23.6% vs 54.3%, respectively; P <.05) and in preterm birth between progesterone and placebo (13.8% vs 28.5%, respectively; P <.05). More women were delivered before 34 weeks in the placebo group (18.5%) than in the progesterone group (2.7%) (P <.05). Prophylactic vaginal progesterone reduced the frequency of uterine contractions and the rate of preterm delivery in women at high risk for prematurity.
Adrenomedullin (AM) gains its bioactivity by amidation at its C-terminal, forming "mature AM." The mature AM and the expression of AM receptor component mRNAs, receptor activity-modifying protein 2 and calcitonin receptor-like receptor, from feto-maternal tissues of normal pregnant women and women with histologic chorioamnionitis were examined to clarify the pathophysiological features of this intrauterine infection. Samples of the placenta and fetal membranes were obtained from 10 normal pregnant women and eight women with histologic chorioamnionitis under informed consent. Mature AM in the fetal membranes was significantly lower in patients with chorioamnionitis than in normal pregnant women. On the other hand, there were no differences in mature AM levels in the placenta between the two groups. The total AM levels as a sum of mature and immature AM were not significantly different between the two groups in either area. The ratio of mature AM/total AM was significantly decreased in the fetal membranes of the patients with chorioamnionitis compared with normal pregnancies, but not in the placenta. Also, levels of mature AM were negatively correlated with C-reactive protein concentrations. The present results thus suggested that mature AM may have some role in chorioamnionitis.
PregnancyEpidemiology and TrendsPreterm Delivery RiskBirth Outcome Statistics
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.
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.
The purpose of this study was to evaluate the efficacy of the Edinburgh Postnatal Depression Scale versus routine clinical evaluation to detect postpartum depression among a low-income inner-city population and to evaluate risk factors associated with a positive score on the Edinburgh Postnatal Depression Scale. On the basis of the day of the month, all English-speaking patients who were seen for their postpartum visit were assigned either to routine clinical evaluation for postpartum depression or routine clinical evaluation plus the use of the 10-question Edinburgh Postnatal Depression Scale. During the 7-week study period, 72 women 35 women in the routine evaluation group and 37 women in the Edinburgh Postnatal Depression Scale group. Women who completed the Edinburgh Postnatal Depression Scale were significantly more likely than those in the routine evaluation group to be identified as 11 of 37 women (30%) versus 0 of 35 women (P <.001). A failed attempt at breast-feeding was associated with an increased risk of a score of > or =10 on the Edinburgh Postnatal Depression Scale (relative risk, 3.78; 95% CI, 1.03-13.89). The Edinburgh Postnatal Depression Scale appears to be a valuable and efficient tool for the identification of patients who are at risk for postpartum depression.
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.
PostpartumPostpartum Depression TreatmentPharmacotherapy During Lactation
The first 3 postpartum months represent a high-risk period for psychiatric illnesses. This article reviews the prevalence and diagnostic criteria for postpartum illnesses, including the "maternal blues," postpartum depression, and postpartum psychosis. Pharmacologic treatment of these disorders is often complicated by a patient's desire to breast-feed, yet there are no controlled trials of antidepressant treatment during lactation. Infant exposure and limitations to monitoring infant sera are reviewed. Lastly, a model and guide for reducing fetal and infant exposures is presented.
Women who are positive for thyroid antibodies in early gestation are prone to post-partum depression, apparently independent of thyroid dysfunction, as measured by serum levels of free thyroxine, free triodothyroxine and thyroid-stimulating hormone. This finding may be due to infrequent monitoring of thyroid function, because hyperthyroidism, hypothyroidism and combinations of both may occur post-partum. To test the hypothesis that stabilising thyroid function post-partum by administering daily thyroxine reduces the rate of occurrence and severity of associated depression. In a randomised double-blind placebo-controlled trial, 100 microg of thyroxine or placebo was given daily to 446 thyroid-antibody-positive women (342 of whom were compliant) from 6 weeks to 6 months post-partum, assessing their psychiatric and thyroid status at 4-weekly intervals. There was no evidence that thyroxine had any effect on the occurrence of depression. The 6-month period prevalence of depression was similar to that reported previously. The excess of depression in thyroid-antibody-positive women in the post-partum period is not corrected by daily administration of thyroxine.
PregnancyUltrasound vs LMP DatingClassification and PrevalenceVariability in Ovulation Timing
Early ultrasound scanning estimation of gestational age is known to increase the reported preterm delivery rate (<37 completed weeks) compared with estimation by date of the last normal menstrual period, but it is unclear how this systematic difference arises. This study was a hospital-based study of 44,623 women who delivered a live-born or stillborn infant between January 1, 1978, and March 31, 1996, and who had both last normal menstrual period-based and early (usually at 16-18 weeks) ultrasound scan-based gestational age estimates. Cross-classification of the 2 estimates by completed weeks was used to examine the direction and magnitude of the differences between them and to compare the resulting classifications of preterm birth. The early ultrasound scan-based gestational age distribution was shifted uniformly to the left (ie, lower gestational age) relative to the last normal menstrual period gestational age distribution; the early ultrasound scan-based preterm delivery rate was 9.1%, which was 19.5% (n = 659 births) higher than the 7.6% rate by last normal menstrual period (P <.0001). The last normal menstrual period estimate exceeded the early ultrasound scan estimate far more often than the reverse, up to and including early ultrasound scan estimates of 40 weeks. No concentration of 4-week discrepancies was observed in either direction, as would be expected with random or systematic errors in recall of the last normal menstrual period. The absolute number of births at 37 to 39 weeks of gestation (by last normal menstrual period) that were reclassified as preterm (n = 1206 births) was much higher than the number of preterm births at 34 to 36 weeks of gestation that were reclassified as term (n = 581 births). The net increase of 625 preterm births (from 581 to 1206 births) that resulted from reclassification of births at 37 to 39 last normal menstrual period weeks accounted for 95% of the total 659-birth increase in early ultrasound scan-based preterm births at all last normal menstrual period gestational ages. Early ultrasound scanning reduces the gestational age estimate across the entire gestational age range; early ultrasound scan-based reclassification of gestational age results in a substantial increase in the prevalence of preterm births. Small downward reclassifications exceed upward reclassifications of similar magnitude, which is consistent with previous reports that delayed (>14 days) ovulation is more frequent than early (<14 days) ovulation.
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.
PCOSMetformin in PregnancyGestational Diabetes PreventionPCOS Management
To assess whether metformin safely reduced development of gestational diabetes in women with the polycystic ovary syndrome (PCOS). Prospective and retrospective study. Outpatient clinical research center. PATIENT(S): The prospective study included 33 nondiabetic women with PCOS who conceived while taking metformin and had live births; of these, 28 were taking metformin through delivery. The retrospective study included 39 nondiabetic women with PCOS who had live birth pregnancies without metformin therapy. INTERVENTION(S): Metformin, 2.55 g/d, throughout pregnancy in women with PCOS. MAIN OUTCOME MEASURE(S): Development of gestational diabetes in women with PCOS. RESULT(S): Before metformin therapy, after covariance adjustment for age, the two cohorts did not differ in height, weight, basal metabolic index, insulin, insulin resistance, or insulin secretion. Both cohorts had high fasting insulin, were insulin resistant, and had high insulin secretion. Among the 33 women who received metformin, gestational diabetes developed in 1 of 33 (3%) pregnancies versus 8 of 12 (67%) of their previous pregnancies without metformin. Among the 39 women who did not take metformin, gestational diabetes developed in 14 of 60 (23%) pregnancies. When all live births were combined, gestational diabetes occurred in 22 of 72 pregnancies (31%) in women who did not take metformin versus 1 of 33 pregnancies (3%) in those who took metformin. With gestational diabetes as the response variable and age at delivery and treatment group (metformin or no metformin) as explanatory variables, the odds ratio for gestational diabetes in women with metformin versus without metformin was 0.093 (95% CI: 0.011 to 0.795). With gestational diabetes in 93 pregnancies as the response variable and age at delivery and treatment group (metformin no metformin) as explanatory variables, the odds ratio of gestational diabetes in pregnancies in women taking metformin versus without metformin was 0.115 (95% CI: 0.014 to 0.938). CONCLUSION(S): In PCOS, use of metformin is associated with a 10-fold reduction in gestational diabetes (31% to 3%). It also reduces insulin resistance and insulin secretion, thus decreasing the secretory demands imposed on pancreatic beta-cells by insulin resistance and pregnancy.
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.
PostpartumPostpartum Depression Risk FactorsPredictors of Adverse OutcomesCase-Control Studies
To identify and test the predictive power of potential independent risk factors of postpartum depressive symptoms during pregnancy and the perinatal period. We conducted a case-control study where 132 women with postpartum depressive symptoms were selected as an index group and 264 women without depressive symptoms as a control group. Data related to sociodemographic status, medical, gynecologic, and obstetric history, pregnancy, and perinatal events were collected from standardized medical records. The strongest risk factors for postpartum depressive symptoms were sick leave during pregnancy and a high number of visits to the antenatal care clinic. Complications during pregnancy, such as hyperemesis, premature contractions, and psychiatric disorder were more common in the postpartum depressed group of women. No association was found between parity, sociodemographic data, or mode of delivery and postpartum depressive symptoms. Women at risk for postpartum depression can be identified during pregnancy. The strongest risk factors, sick leave during pregnancy and many visits to the antenatal care clinic, are not etiologic and might be of either behavioral or biologic origin. The possibilities of genetic vulnerability and hormonal changes warrant further investigation to reach a more thorough understanding.
PregnancyImplantation MechanismsMolecular PathwaysEarly Pregnancy Loss
The implantation of fertilized ova and the formation of the placenta are crucial steps in reproduction. This review summarizes current information about these steps, including some of the molecular mechanisms that mediate them and how they may go awry, with consequent loss of the pregnancy.
We examined the hypothesis that amniotic fluid (AF) infection and elevated cytokine concentrations may cause neonatal injury beyond that expected solely from prematurity. The effects of exposure to AF infection and elevated cytokine concentrations were measured in 151 infants born to afebrile women in preterm labor with intact membranes at less than or equal to 34 weeks' gestation. Amniotic fluid was collected by amniocentesis for culture and determination of tumor necrosis factor-alpha and interleukin-6. Cytokine concentrations, stratified by AF infection, were compared for three gestational age groups. We then examined the associations between a positive AF culture or elevated AF tumor necrosis factor-alpha concentration and adverse neonatal outcomes, adjusted for birth weight. Amniotic fluid from 45 (30%) of 151 pregnancies had microorganisms, an elevated tumor necrosis factor-alpha concentration, or both. Amniotic fluid cytokine concentrations were significantly higher among women in preterm labor at less than or equal to 30 weeks, compared with 31-34 weeks. Nine of 11 infants who died at less than or equal to 24 hours of age had AF infection or elevated AF tumor necrosis factor-alpha. For the 140 surviving infants, AF infection and/or an elevated AF tumor necrosis factor-alpha was associated with respiratory distress syndrome (adjusted odds ratio [OR] 1.7), grade 3-4 intraventricular hemorrhage (adjusted OR 2.2), necrotizing enterocolitis (adjusted OR 1.8), and multiple organ dysfunction (adjusted OR 3.0). Among infants born at less than or equal to 34 weeks to women who have intact membranes and are initially afebrile, those exposed to AF bacteria or cytokines have more adverse neonatal outcomes than unexposed infants of similar birth weight.
PregnancySpontaneous Abortion PreventionLuteal Function and PregnancyPrematurity and IUGR Prevention
To determine the influence of chorioamnionitis and neonatal sepsis on procalcitonin (PCT) levels in very-low-birth-weight (VLBW) infants within the first week of life. PCT serum levels were measured in cord blood 1 h after delivery and on day 3 and day 7 of life. Chorioamnionitis and neonatal sepsis within the first week were monitored. Chorioamnionitis was present in eight of 37 patients (21.6%). PCT on day 3 was increased in both the "No chorioamnionitis" (2.54 ng mL(-1), SEM 0.51) and "Chorioamnionitis" (6.96 ng mL(-1), SEM 2.93) groups of VLBW infants compared with the 1st hour values (0.45 and 0.58 ng mL(-1) SEM 0.07 and 0.11, respectively, P < 0.001) of the same patients. The postnatal gain was higher in the "Chorioamnionitis" group (P < 0.01). Neonatal sepsis was diagnosed (after exclusion) in 12 of 32 patients (37.5%). Mean values of maximum PCT in patients with and without sepsis were 8.41 ng mL(-1) (SEM 1.87) and 3.02 ng mL(-1) (SEM 1.38), respectively (P < 0.05). Sensitivity to sepsis of PCT, ratio of immature to total neutrophils (I : T), and C-reactive protein (CRP) were 75%, 50% and 25%, respectively. In the group of VLBW infants the PCT level within 72 h of delivery was markedly increased in patients with chorioamnionitis. T and CRP, PCT appears to be a more sensitive marker of neonatal sepsis.
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.
To review validation studies of the Edinburgh Postnatal Depression Scale (EPDS). A systematic search was performed in Medline and the Science Citation Index Expanded (ISI) from the period 1987-2000. For sensitivity and specificity of the EPDS presented in each study, 95% confidence intervals were estimated. Positive and negative predictive values were estimated assuming prevalences of postpartum depression ranging from 5% to 20%. Eighteen validation studies were identified. The study design varied between studies. The sensitivity and specificity 65-100% and 49-100%, respectively. The confidence intervals were estimated to be wide. Our estimates suggest a lower positive predictive value in a normal population than in the validation study samples. Most studies show a high sensitivity of the EPDS. Because of the differences in study design and large confidence intervals, uncertainty remains regarding the comparability between the sensitivity and specificity estimates of the different EPDS versions.
This review presents data to suggest that postnatal estradiol and progesterone replacement therapy may be beneficial in preterm infants. During pregnancy, maternal plasma levels of estradiol and progesterone increase up to 100-fold compared to the nonpregnant status. The fetus is also exposed to these increasing hormone levels. After delivery, estradiol and progesterone levels drop by a factor of 100 within 1 day. Whereas this is a physiological condition for an infant born at term, preterm delivery means withdrawal from the placental supply of these hormones at an earlier developmental stage. Seventy years ago, the idea was raised that preterm infants may benefit from the replacement of estrogens. Studies in which estrogen was injected subcutaneously showed only a slightly better bodyweight gain compared to placebo-treated controls and therefore routine use was not established. The effective treatment of postmenopausal osteoporosis with hormone replacement therapy led to a pilot study of estradiol and progesterone therapy to prevent osteopenia of prematurity. The highest median bone mineral accretion rate was found in the replacement group when the supplementation with calcium and phosphorus was also sufficient. None of the previous studies dealing with estrogen replacement controlled for achieved plasma levels of estradiol in the infants. In our controlled randomised pilot study with 30 preterm infants (15 in each group), we aimed to maintain intra-uterine plasma levels of estradiol and progesterone. Preterm infants with replacement of estradiol and progesterone for 6 weeks postnatally showed trends to higher bone mineral accumulation. In addition, a trend towards a lower incidence of chronic lung disease was found. Neurodevelopmental follow-up showed normal psychomotor development in infants given estradiol and progesterone, whereas the untreated infants (controls) showed a trend towards delayed development. Recent research emphasises that estradiol and progesterone may be important for brain development. Thus, while there is data indicating that postnatal estradiol and progesterone replacement therapy may be beneficial in preterm infants, experience with this new therapy is limited and extensive research is needed to address the potential benefits and to rule out adverse effects.
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.
Although shortened cervical length has been consistently associated with spontaneous preterm birth, it is not known when in gestation this risk factor becomes apparent. To determine whether sonographic cervical findings between 16 weeks' and 18 weeks 6 days' gestation predict spontaneous preterm birth and whether serial evaluations up to 23 weeks 6 days' gestation improve prediction in high-risk women. DESIGN, SETTING, Blinded observational study performed between March 1997 and November 1999 at 9 university-affiliated medical centers in the United States in 183 women with singleton gestations who previously had experienced a spontaneous birth before 32 weeks' gestation. Certified sonologists performed 590 endovaginal sonographic examinations at 2-week intervals. Cervical length was measured from the external os to the functional internal os along a closed endocervical canal. Funneling and dynamic cervical shortening were also recorded. Spontaneous preterm birth before 35 weeks' gestation, analyzed by selected cutoff values of cervical length. Forty-eight women (26%) experienced spontaneous preterm birth before 35 weeks' gestation. A cervical length of less than 25 mm at the initial sonographic examination was associated with a relative risk (RR) for spontaneous preterm birth of 3.3 (95% confidence interval [CI], 2.1-5.0; sensitivity = 19%; specificity = 98%; positive predictive value = 75%). After controlling for cervical length, neither funneling (P =.24) nor dynamic shortening (P =.054) were significant independent predictors of spontaneous preterm birth. However, using the shortest ever observed cervical length on serial evaluations, after any dynamic shortening, the RR of a cervical length of less than 25 mm for spontaneous preterm birth increased to 4.5 (95% CI, 2.7-7.6; sensitivity = 69%; specificity = 80%; positive predictive value = 55%). Compared with a single cervical measurement at 16 weeks' to 18 weeks 6 days' gestation, serial measurements at up to 23 weeks 6 days significantly improved the prediction of spontaneous preterm birth in a receiver operating characteristic curve analysis (P =.03). Cervical length assessed by endovaginal sonography between 16 weeks' and 18 weeks 6 days' gestation, augmented by serial evaluations, predicts spontaneous preterm birth before 35 weeks' gestation in high-risk women.
PostpartumPsychotropic Medication in LactationTreatment During BreastfeedingMedication Safety
A high prevalence of psychiatric illness has been noted in the postpartum period. Recent research looks to the potential effects of maternal illness during this period on child development. With the promotion of breast feeding for well-documented medical benefits, there has been increasing attention to the potential effects on the infant of exposure to medication via breast milk. This article reviews the current literature on the secretion of psychotropic medication into breast milk, and any known negative effects. The shortcomings of these studies are highlighted, and recommendations to the clinician are given within the limitations of the current state of knowledge. The World Health Organization (WHO) has estimated that depression will be 1 of the 2 major illness burdens confronting the world by 2020. The incidence of depression is 2-fold higher in women than in men, and the average age at onset is 25 years. These facts combined with the noted risk of a marked increase in psychiatric illness postpartum have serious implications. Depression occurring at this time can present with depressed mood, anxiety, and difficulties coping with the infant. Suicide, although not more common in depression, is at the severe end of the spectrum in those with puerperal psychosis and bipolar disorder. The morbidity associated with depression is not confined to women suffering from it; there are also potential negative effects of maternal depression on child development, on older children, and on the woman's partner. These effects include impaired bonding and cognitive and behavioral delays in the infant and difficulties in childhood. Moreover, the increased use of antidepressants in the Western world in combination with the strong promotion of breast feeding also has implications for the dependent infant. What do we know? And, what are the risks?
PregnancyPublic Health EpidemiologyPerinatal Outcomes
Mattison DR et al., 2001·Paediatr Perinat Epidemiol
And his daughter‐in‐law, the wife of Phinehas, was pregnant near to giving birth, and got to hear the report that the ark of the true God was captured and that her father‐in‐law and her husband had died. At that she bowed herself and began giving birth, because her pangs came unexpectedly upon her.
PregnancyNurse Home Visit InterventionPrevention StrategiesPrenatal Care Models
To examine prenatal, maternal, and infant outcomes and costs through 1 year after delivery using a model of prenatal care for women at high risk of delivering low-birth-weight infants in which half of the prenatal care was provided in women's homes by nurse specialists with master's degrees. Randomized clinical trial. A sample of 173 women (and 194 infants) with high-risk pregnancies (gestational or pregestational diabetes mellitus, chronic hypertension, preterm labor, or high risk of preterm labor) were randomly assigned to the intervention group (85 women and 94 infants) or the control group (88 women and 100 infants). Control women received usual prenatal care. Intervention women received half of their prenatal care in their homes, with teaching, counseling, telephone outreach, daily telephone availability, and a postpartum home visit by nurse specialists with physician backup. For the full sample, mean maternal age was 27 years; 85.5% of women were single mothers, 36.4% had less than a high school education, 93.6% were African American, and 93.6% had public health insurance, with no differences between groups on these variables. The intervention group had lower fetal/infant mortality vs the control group (2 vs 9), 11 fewer preterm infants, more twin pregnancies carried to term (77.7% vs 33.3%), fewer prenatal hospitalizations (41 vs 49), fewer infant rehospitalizations (18 vs 24), and a savings of more than 750 total hospital days and $2,496,145 [corrected]. This model of care provides a reasoned solution to improving pregnancy and infant outcomes while reducing healthcare costs.
PregnancyNeonatal Outcomes at Extreme PrematurityNICU Resource UtilizationExtremely Preterm Infant Survival
The objective of this study was to examine survival, morbidity, and resource use in a large cohort of extremely preterm infants. We examined all (n = 754) neonatal intensive care unit admissions born at < or =25 weeks' gestation and inborn deliveries (n = 949) between 22 and 25 weeks' gestation at 17 Canadian neonatal intensive care units. The overall survival rate was 63%, with a range from 14% at 22 weeks' gestation to 76% at 25 weeks' gestation. There was a high incidence of chronic lung disease (33%-51%), > or =grade 3 intraventricular hemorrhage (0%-16%), necrotizing enterocolitis (0%-14%), > or =stage 3 retinopathy of prematurity (27%-55%), nosocomial infection (25%-39%), and multiple gestation (18%-46%). Extremely preterm infants comprise 4% of neonatal intensive care unit admissions but account for 22% of deaths, 20%-60% of major morbidities, 11% of patient days, and 10%-35% of major procedures. Outborn infants had a higher incidence of chronic lung disease, severe retinopathy of prematurity, and intraventricular hemorrhage. Extremely preterm infants have a high incidence of mortality and morbidity and consume disproportionate amounts of neonatal intensive care unit resources.
PostpartumPostpartum Depression TreatmentEstradiol Deficiency and MoodPostpartum Depression Hormonal Therapy
The postpartum period is a time when women are vulnerable to depressive disorders, which can be severe and have long-lasting adverse sequelae. In spite of multiple contacts with health care providers, women with postpartum depression often remain unrecognized and untreated. To evaluate the association between estradiol and postpartum depression, we measured serum estradiol concentration and performed an open-label study of physiologic 17beta-estradiol. Twenty-three women fulfilling ICD-10 criteria for major depression with postpartum onset were consecutively recruited from a psychiatric emergency unit. Serum estradiol concentrations were measured at baseline and weekly during sublingual 17beta-estradiol treatment for 8 weeks. The treatment effect was assessed using a clinician-rated depression symptom scale, the Montgomery-Asberg Depression Rating Scale (MADRS). At baseline, all patients were severely depressed (mean MADRS total score = 40.7; range, 35-45) and had a low serum estradiol concentration (mean = 79.8 pmol/L; range, 23-140 pmol/L); in 16/23 patients, the concentration was even lower than the threshold value for gonadal failure. During the first week of estradiol treatment, depressive symptoms diminished significantly, resulting in a mean MADRS score of 11.0 (Z = -4.20, p < .001), and serum estradiol concentrations approached those of the follicular phase (mean +/- SD = 342 +/- 141 pmol/L). At the end of the second week of treatment, the MADRS scores were compatible with clinical recovery in 19/23 patients. This preliminary study shows that depression symptoms may be rapidly reduced in patients with postpartum depression who have documented estradiol deficiency by treatment with 17beta-estradiol and suggests that estradiol can have significance in the pathophysiology of this condition and may be an option in the treatment of women vulnerable to postpartum depression.
The role of human chorionic gonadatropin (hCG) in the maintenance of early pregnancy is well known. Recent data suggests that hCG may play a role in the maintenance of the later stages of pregnancy as well, by directly and indirectly promoting uterine quiescence. If hCG acts as an endogenous tocolytic in normal pregnancy, then it may be an ideal candidate for therapy of preterm labor as well. We present compelling in vitro as well as in vivo data, which support the role of hCG in the maintenance of normal uterine quiescence. Additionally, we will present in vivo and in vitro data that confirms the ability of hCG to directly promote relaxation of uterine contractions. This review provides a basis for future study of the use of hCG in clinical obstetrics. Given the limited effectiveness of tocolytic therapies available at the time, hCG may provide a promising pharmacological approach to the pervasive problem of preterm labor in human pregnancy. While further work is needed, initial data strongly support this novel use of hCG in clinical obstetrics.
To determine the association between indomethacin tocolysis and neonatal intraventricular hemorrhage. Fifty-six preterm neonates with intraventricular hemorrhage were matched by gestational age with neonates (n = 224) without this morbidity. Maternal and neonatal charts were reviewed to ascertain the type of tocolytic exposure experienced by the neonate. Other maternal and neonatal demographic and outcome data were also abstracted. Results were analyzed using the Student t test, chi(2) analysis, and multivariable logistic regression. The number of studied subjects provided 80% power to determine if antenatal exposure to indomethacin was twice as likely among infants with intraventricular hemorrhage. Univariate analysis revealed that there were no significant differences between the study and control groups with respect to maternal age, parity, or betamethasone exposure. Infants with intraventricular hemorrhage were significantly more likely to be born at an earlier gestational age, a lower birth weight, after maternal chorioamnionitis, after vaginal delivery, and after exposure to either indomethacin alone or a combination of indomethacin and magnesium. Additionally, their neonatal course was significantly more likely to be complicated by sepsis and respiratory distress syndrome. In a multivariable logistic model, only gestational age, chorioamnionitis, vaginal delivery, and respiratory distress syndrome continued to be significantly associated with intraventricular hemorrhage. Indomethacin exposure, either as single-agent (adjusted odds ratio 1.3, 95% confidence interval 0.5, 3.3) or combination tocolytic therapy (adjusted odds ratio 2.0, 95% confidence interval 0.8, 4.8), was not significantly associated with intraventricular hemorrhage. Indomethacin tocolysis is not associated with an increased risk of intraventricular hemorrhage.
PregnancyBirth Defect RiskCongenital AnomaliesPopulation-Based Cohort Study
To investigate the relationship between prematurity and birth defects. In a population-based cohort study, infants with birth defects were ascertained through the Metropolitan Atlanta Congenital Defects Program, a surveillance system with active methods of ascertainment. Gestational age data were obtained from birth certificates of liveborn, singleton infants with and without birth defects born in the 5-county metropolitan Atlanta area. Among 264,392 infants with known gestational ages born between 1989 and 1995, 7738 were identified as having birth defects (2.93%). Premature infants (<37 weeks' gestation) were more than two times as likely to have birth defects than term infants (37-41 weeks) (risk ratio = 2.43; 95% CI 2.30-2.56). This relationship was evident for several categories of birth defects. The rate of birth defects varied by gestational age categories, with the highest risk in the 29- to 32-week gestational age category (risk ratio = 3.37). The risk for birth defects is increased in premature infants. Awareness of this relationship is important for clinicians caring for premature infants. The morbidity and mortality associated with a particular defect may be significantly altered by the presence of prematurity. Further study of this association may provide insight into the etiology of these relatively common problems.
PregnancyInflammatory BiomarkersTNF-Alpha PredictionCytokine Levels in Pregnancy
To evaluate maternal serum tumor necrosis factor-alpha (TNF alpha) levels in patients with preterm labor without clinical signs of chorioamnionitis and to compare these with levels in nonlaboring controls. The study group consisted of 44 patients with a singleton pregnancy admitted to our department with the diagnosis of preterm labor between 26 and 36 weeks' gestation. The control group consisted of 25 healthy consecutive patients with a singleton pregnancy without preterm contractions who were seen for routine antenatal visits. Maternal serum TNF alpha was measured using a solid-phase, two-site chemiluminescent enzyme immunometric assay method, and levels were compared in patients with preterm labor and nonlaboring controls. The median maternal serum TNF alpha level for patients with preterm labor was 29.4 pg/mL (range, 12.3-173) as compared with 23 pg/mL (range, 11.9-62.7) in the control group (P = .031). Among 44 patients with preterm labor, 14 (32%) delivered within one week of admission. The median maternal serum TNF alpha level was significantly higher in patients who delivered within one week than in those who delivered after one week and controls (71.3 pg/mL [range, 28-173]) versus 22 pg/mL (range, 12.3-86) versus 23 pg/mL (range, 11.9-62.7) (P < .0001). TNF alpha was elevated in patients with preterm labor, suggesting a role for maternal serum TNF alpha in its initiation.
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.
Josefsson A et al., 2001·Acta Obstet Gynecol Scand
Postnatal depression refers to a non-psychotic depressive episode that begins in or extends into the postpartum period. The aims of this study were to examine the prevalence of depressive symptoms in a pregnant and later postnatal population, to determine the natural course of these symptoms and whether there is an association between antenatal and postnatal depressive symptomatology. A longitudinal study with a total population of 1,558 consecutively registered pregnant women in the southeast region of Sweden. Presence of depressive symptoms was measured with the Edinburgh Postnatal Depression Scale on four occasions namely in gestational week 35-36, in the maternity ward, 6-8 weeks and 6 months postpartum. The prevalence of depressive symptoms during late pregnancy was 17%; in the maternity ward 18%; 6-8 weeks postnatally 13%; and 6 months postnatally, 13%. A correlation between antenatal and postnatal depressive symptoms was found (r=0.50, p<0.0001). Detection of women at risk for developing postnatal depressive symptoms can be done during late pregnancy. Antenatal care clinics constitute a natural and useful environment for recognition of women with depressive symptoms.
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.
PCOSMetforminMiscarriage PreventionRecurrent Pregnancy Loss
To determine whether metformin would safely reduce the rate of first-trimester spontaneous abortion without teratogenicity in 19 women with the polycystic ovary syndrome (PCOS). Prospective pilot study. Outpatient. PATIENT(S): Twenty-two previously oligoamenorrheic, nondiabetic women with PCOS; 125 women with PCOS who were not currently pregnant and who had > or = 1 previous pregnancy while they were not receiving metformin. INTERVENTION(S): Metformin, 1.5-2.55 g/day, throughout pregnancy. MAIN OUTCOME MEASURE(S): Rates of first-trimester spontaneous abortion and teratogenicity. RESULT(S): Before metformin, 10 women had 22 previous pregnancies with 16 first-trimester spontaneous abortions (73%). While receiving metformin, these 10 women had 6 normal live births (60%), 1 spontaneous abortion (10%), and 3 normal ongoing pregnancies (30%) (all > or = 13 weeks; median gestation, 23 weeks). Among women receiving metformin, including those with live births and normal pregnancy for at least the first trimester, 1 of 10 (10%) had first-trimester spontaneous abortion compared with 73% in 22 previous pregnancies without metformin (P<.002). To date, the 19 women receiving metformin have had no adverse maternal side effects, and no birth defects have occurred; 9 (47%) had normal term live births, 2 (11%) had normal and appropriate for gestational age births (one at 33 and one at 35 weeks), 6 (32%) have ongoing normal pregnancies lasting longer than the first trimester, and 2 (10.5%) had first-trimester spontaneous abortions. Sonography showed normal fetal development without congenital defects in the 6 ongoing pregnancies (median gestation, 23 weeks). Among women who received metformin before conception, reductions in insulin and plasminogen activator inhibitor activity were correlated (r=0.65, P=.04). CONCLUSION(S): Metformin therapy throughout pregnancy in women with PCOS reduces the otherwise high rate of first-trimester spontaneous abortion seen among women not receiving metformin and does not appear to be teratogenic.
To relate serum allopregnanolone and progesterone levels postpartum to maternity "blues." Forty primiparous, healthy, married women (24-39 years of age; at least 13 years of education) who delivered healthy neonates in the Department of Obstetrics at the University of Pavia entered the present study. Blood samples were drawn at 8:30 AM on postpartum day 3 for measurements of serum allopregnanolone, progesterone, cortisol, prolactin, and estradiol. On the same day, every woman was interviewed using the Hamilton Rating Scale for Depression for psychometric testing and completed a self-administered version of the Stein Questionnaire for symptoms of the "blues." Eighteen of 40 women (45%) experienced maternity "blues" (12 who delivered vaginally and six who delivered by cesarean). Serum allopregnanolone levels were significantly lower in those women experiencing postpartum "blues" with respect to euthymic women (1.1 +/- 0.4 versus 2.3 +/- 1.0 nmol/L; P <.001), whereas progesterone levels did not differ significantly (11.6 +/- 5.6 versus 19.1 +/- 15.6 nmol/L; P >.058). Allopregnanolone and progesterone levels correlated significantly in euthymic women (r =.648; P =.001) but not in those with postpartum "blues" (r =.317; P =.199). There was a significant negative correlation between the Hamilton score and levels of serum allopregnanolone (r = -.62; P =.001) and progesterone (r = -.36; P =.024). Serum allopregnanolone levels were detectable postpartum and were significantly decreased in women with maternity "blues."
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.
PregnancyNational Birth StatisticsMaternal Child Health OutcomesPreterm Birth Epidemiology
The number of births, the crude birth rate (14.5 in 2001), and the fertility rate (67.2 in 2001) all declined slightly (by 1% or less) from 2000 to 2001. Fertility rates were highest for Hispanic women (107.4), followed by Native American (70.7), Asian or Pacific Islander (69.4), black (69.3), and non-Hispanic white women (58.0). During the early to mid 1990s, fertility declined for non-Hispanic white, black, and American Indian women. Rates for these population groups have changed relatively little since 1995; however, fertility has increased for Asian or Pacific Islander and Hispanic women. The birth rate for teen mothers continued to fall, dropping 5% from 2000 to 2001 to 45.9 births per 1000 females aged 15 to 19 years, another record low. The teen birth rate has fallen 26% since 1991; declines were more rapid (35%) for younger teens aged 15 to 17 years than for older teens aged 18 to 19 years (20%). The proportion of all births to unmarried women remained about the same at one-third. Smoking during pregnancy continued to decline; smoking rates were highest among teen mothers. The use of timely prenatal care increased slightly to 83.4% in 2001. From 1990 to 2001, the use of timely prenatal care increased by 6% (to 88.5%) for non-Hispanic white women, by 23% (to 74.5%) for black women, and by 26% (to 75.7%) for Hispanic women. The number and rate of twin births continued to rise, but the triplet/+ birth rate declined for the second year in a row. For the first year in almost a decade, the preterm birth rate declined (to 11.6%); however, the low birth weight rate was unchanged at 7.6%. The total cesarean delivery rate jumped 7% from 2000 to 2001 to 24.4% of all births, the highest level reported since these data became available on birth certificates (1989). The primary cesarean rate rose 5%, whereas the rate of vaginal birth after a previous cesarean delivery tumbled 20%. In 2001, the provisional infant mortality rate was 6.9 per 1000 live births, the same as in 2000. Racial differences in infant mortality remain a major public health concern, with the rate for infants of black mothers 2.5 times those for infants of non-Hispanic white or Hispanic mothers. In 2000, 66% of all infant deaths occurred among the 7.6% of infants born low birth weight. Among all states, Maine and Massachusetts had the lowest infant mortality rates. The United States continues to rank poorly in international comparisons of infant mortality. The provisional death rate in 2001 was 8.7 deaths per 1000 population, the same as the 2000 final rate. In 2000, unintentional injuries and homicide remained the leading and second-leading causes of death for children 1 to 19 years of age, although the death rate for homicide decreased by 10% from 1999 to 2000. Among unintentional injuries to children, two-thirds were motor vehicle-related; among homicides, two-thirds were firearm-related.
To evaluate serial measurements of salivary estriol (E3) to detect increased risk of spontaneous preterm labor and preterm birth. A masked, prospective, multicenter trial of 956 women with singleton pregnancies was completed at eight United States medical centers. Saliva was collected weekly, beginning at the 22nd week of gestation until birth, and tested for unconjugated E3 by enzyme-linked immunosorbent assay. Women were separated into high-risk and low-risk groups using the Creasy scoring system. A single, positive (at or above 2.1 ng/mL) salivary E3 test predicted an increased risk of spontaneous preterm labor and delivery in the total population (relative risk [RR] 4.0, P <.005), in the low-risk population (RR 4.0, P < or =.05), and in the high-risk population (RR 3.4, P =.05). Two consecutive positive tests significantly increased the RR in all study groups, with a dramatic improvement in test specificity and positive predictive value but only a modest decrease in sensitivity. In women who presented with symptomatic preterm labor, salivary E3 identified 61% of those who delivered within 2 weeks, using a threshold of 1.4 ng/mL. Elevated salivary E3 is associated with increased risk of preterm birth in asymptomatic women and symptomatic women who present for evaluation of preterm labor.
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.
To determine whether the degree of cervical lengthening after cerclage and whether serial follow-up measurements of cervical length after cerclage are predictive of pregnancy outcome. Eighty women whose primary physician determined that a prophylactic (n = 50) or urgent cerclage (n = 30) was indicated had transvaginal ultrasonographic evaluation before and after cerclage. Thereafter, most women had three additional transvaginal ultrasound examinations until 32 weeks' gestation. At each examination, the mean of three measurements was calculated. Statistical analyses were done by t test, analysis of variance, and logistic regression, with significance set at P <.05. The mean +/- standard deviation precerclage cervical length was 27.2 +/- 10.3 mm and after cerclage was 34.1 +/- 9.9 mm (n = 80, P <.001, paired t test). No significant association was found (r = -0.26) between the difference in cervical length (postcerclage - precerclage lengths) and pregnancy outcome. Patients with a prophylactic cerclage had a mean cervical length that was consistently longer in patients delivering at term compared with those who delivered preterm at 20 to 32 weeks' gestation. In the urgent cerclage group a significant difference in cervical length between those who delivered at term compared with preterm was evident only at 28 to 32 weeks. The increase in cervical length after cerclage is not predictive of term delivery. Serial cervical length measurements in the late second or early third trimester predict preterm birth but could provide earlier warning in patients with a prophylactic cerclage than in patients with urgent cerclage.
The World Health Organization defines preterm birth as birth at less than 37 completed gestational weeks, but most studies have focused on very preterm infants (birth at <32 weeks) because of their high risk of mortality and serious morbidity. However, infants born at 32 through 36 weeks are more common and their public health impact has not been well studied. To assess the quantitative contribution of mild (birth at 34-36 gestational weeks) and moderate (birth at 32-33 gestational weeks) preterm birth to infant mortality. DESIGN, SETTING, Population-based cohort study using linked singleton live birth-infant death cohort files for US birth cohorts for 1985 and 1995 and Canadian birth cohorts (excluding Ontario) for 1985-1987 and 1992-1994. Relative risks (RRs) and etiologic fractions (EFs) for overall and cause-specific early neonatal (age 0-6 days), late neonatal (age 7-27 days), postneonatal (age 28-364 days), and total infant death among mild and moderate preterm births vs term births (at >/=37 gestational weeks). Relative risks for infant death from all causes among singletons born at 32 through 33 gestational weeks were 6.6 (95% confidence interval [CI], 6.1-7.0) in the United States in 1995 and 15.2 (95% CI, 13.2-17.5) in Canada in 1992-1994; among singletons born at 34 through 36 gestational weeks, the RRs were 2.9 (95% CI, 2.8-3.0) and 4.5 (95% CI, 4.0-5.0), respectively. Corresponding EFs were 3.2% and 4.8%, respectively, at 32 through 33 gestational weeks and 6.3% and 8.0%, respectively, at 34 through 36 gestational weeks; the sum of the EFs for births at 32 through 33 and 34 through 36 gestational weeks exceeded those for births at 28 through 31 gestational weeks. Substantial RRs were observed overall for the neonatal (eg, for early neonatal deaths, 14.6 and 33.0 for US and Canadian infants, respectively, born at 32-33 gestational weeks; EFs, 3.6% and and 6. 2% for US and Canadian infants, respectively) and postneonatal (RRs, 2.1-3.8 and 3.0-7.0 for US and Canadian infants, respectively, born at 32-36 gestational weeks; EFs, 2.7%-5.8% and 3.0%-7.0% for the same groups, respectively) periods and for death due to asphyxia, infection, sudden infant death syndrome, and external causes. Except for a reduction in the RR and EF for neonatal mortality due to infection, the patterns have changed little since 1985 in either country. Mild- and moderate-preterm birth infants are at high RR for death during infancy and are responsible for an important fraction of infant deaths. JAMA. 2000;284:843-849
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.
To estimate the community prevalence in Olmsted County, Minnesota of elevated scores on the Edinburgh Postnatal Depression Scale, a self-report screening tool for postpartum depression. At the 6-week postpartum visit, the Edinburgh Postnatal Depression Scale was administered to women who gave birth in Olmsted County between July 28, 1997 and March 28, 1998. Study sites included all ambulatory clinics that provide pregnancy care in the county, and women who missed postpartum visits were contacted by mail. A threshold of 12 or more points on the scale was selected for clinical use; data for scores of ten and above were also examined. Of the 909 Olmsted County women studied (response rate 83.2%), 11.4% (n = 104) had scores of 12 or greater, with a 95% confidence interval (CI) of 9.4%, 13.5%. The percentage of women with a positive screen increased to 19.8% (n = 180; 95% CI 17.2%, 22.4%) when scores of 10 or higher were included, as has been recommended for screening in primary care settings. Forty-eight or 5.3% of the subjects (95% CI 3.8%, 6.7%) indicated experiencing suicidal ideation during the previous week. More than 11% of women had elevated scores on the Edinburgh Postnatal Depression Scale, indicating a high likelihood of postpartum depression and the need for further assessment. The screening process required little extra time and was acceptable to the subjects and clinicians. Screening for postpartum depression is appropriate and feasible for clinical practice and increases the identification of women suffering from this serious, common, and highly treatable disorder.
PregnancyLast Menstrual Period ReliabilityStillbirth and Preterm BirthPregnancy Dating Implications
To estimate the risk of adverse outcomes in women whose first day of the last menstrual period (LMP) was unreliable. Among 20,244 singleton pregnancies with measurements of biparietal diameter between 12 and 22 weeks' gestation, LMP was registered as unreliable in 3775 (18.6%) and reliable in 16,469 (81.4%). Adverse outcomes were defined as spontaneous or missed abortions after 12 weeks' gestation, stillbirth or postnatal death within 1 year, preterm birth, birth weight less than 2500 g, and low birth weight (LBW) for gestation (lower than 22% below sex-specific expected weight). Logistic regression analysis and Kaplan-Meier survival analysis were used to analyze the risk of adverse outcomes. The risk of death was doubled in pregnant women with unreliable LMPs compared with those with reliable LMPs (odds ratio [OR] 2.0; 95% confidence interval [CI] 1.5, 2.6). This risk was highest with respect to stillbirth (OR 2.7; 95% CI 1.7, 4.3). The risks of preterm birth, LBW, and LBW for gestation were also significantly increased (ORs 1.5, 1.4, and 1.2; 95% CIs 1.3, 1.7; 1.2, 1.6; and 1. 0, 1.4, respectively). An unreliable LMP is associated with increased risk of adverse outcomes, especially fetal death.
Previous studies have demonstrated that human myometrium contains receptors for human chorionic gonadotropin (hCG) and that hCG can inhibit myometrial contractions in vitro. To use for the first time hCG as a tocolytic agent in the treatment of preterm labor. The study group included 100 women with preterm labor; 50 were assigned to receive HCC and 50 placebo. Assignment was made with stratification according to four categories of gestational age between 20–35 weeks. One half of the surviving infants were followed-up at 18 months. The protocol of the dosage consisted of one single dose of hCG 5,000 IV and 10,000 units of hCG in 500 dextrose as a drip of 20 drops per minute. The mean length of time from randomization to delivery differs significantly 28.8 days for the hCG group and 15 days for the placebo treatment group (highly statistically significant, P <0.001). There was statistically significant difference (P <0.05) between the two groups regarding the induction of delivery before 37 weeks and the proportion of infants weighing less than 2,500 g. Human chorionic gonadotropin treatment was associated with an improvement score on the Bayley psychomotor development index. Human chorionic gonadotropin exhibits potent tocolysis with no fetal side effects. This preliminary study suggests that HCG may be a candidate for tocolytic therapy of preterm labor.
PregnancyBiomarkers and PredictionIntra-amniotic InfectionInterleukin-6
To evaluate the potential role of amniotic fluid (AF) interleukin (IL)-6 as a predictor of preterm delivery and to consider possible explanations for the proportion of women with elevated AF IL-6 who deliver preterm yet lack microbiologically detectable intra-amniotic infection. We searched the English language human literature in MEDLINE, 1966 through September 1999, using the keywords "labor/infant," "premature," "cytokines/interleukin-6," and "AF." We also examined abstracts from the 1999 meetings of the Society for Maternal-Fetal Medicine and the Society for Epidemiologic Research. We identified other studies by reviewing the reference lists of published articles. The MEDLINE search yielded 55 citations. We focused on studies that reported on the association between AF IL-6 and preterm delivery. TABULATION, INTEGRATION, There is consensus in the literature that elevated AF IL-6 is a stronger predictor of preterm delivery than intra-amniotic infection detected by either microbiologic culture or polymerase chain reaction (PCR). Among women with elevated AF IL-6, PCR could detect a higher proportion of intra-amniotic infection than culture. A number of women with elevated AF IL-6 (33-70%) deliver preterm and do not have evidence of intra-amniotic infection by either culture or PCR. Possible explanations for this observation are considered. Elevated AF IL-6 is strongly associated with preterm delivery and merits future consideration in clinical settings to predict preterm delivery and guide patient care. Development of improved polymerase chain reaction-based clinical methods to detect intra-amniotic infection is necessary to better understand the relationship between elevated AF IL-6, intra-amniotic infection, and preterm delivery.
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.
PregnancyIndicated vs Spontaneous Delivery OutcomesRespiratory MorbidityPreterm Indications
To assess maternal morbidity, and neonatal outcome and especially long term sequelae in infants born preterm due to maternal or fetal indications.
Analysis of retrospective cohort.
Oulu University Central Hospital, Finland. One hundred and three women, who were between the 24th and the 33rd week of pregnancy, delivered by caesarean delivery because of maternal or fetal indications. They were matched with 103 women who had spontaneous preterm delivery at corresponding gestational weeks between 1990-1997. Maternal morbidity, reasons for caesarean delivery, neonatal mortality and morbidity rates, and later development of the infants. Pre-eclampsia was diagnosed in 57% of the women in the indicated group and only in one woman in the control group. All infants in the indicated group and almost a third in the control group were born by caesarean birth; the main indication was threatening fetal asphyxia. There was a significant difference in neonatal mortality rates between the groups (175 vs 78 per thousand live births in the indicated vs control infants; RR 2.3, 95% CI 1.02, 4.9) and the main cause of death 64% in the indicated group and 22% in the controls; RR 2.9, 95% CI 0.8, 10. Respiratory distress syndrome occurred more often (73% vs 53%, RR 1.4, 95% CI 1.1, 1.7) and it was more severe and more complicated in infants in the indicated group, compared with those in the control group. Symptomatic chronic lung disease at one year of age was more common in infants in the indicated group than in the control group (15% vs 3%; RR 4.6, 95% CI 1.4, 15.9). Not only the risks of neonatal mortality and morbidity but also long term pulmonary consequences, appear to be greater in infants born preterm by indicated delivery than in preterm infants born spontaneously at corresponding weeks.
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.
PregnancyEpidemiology and PatternsSymptom Assessment ToolsSymptom Tracking
Our purpose was to provide a detailed description of patterns of nausea and vomiting of pregnancy. A prospective study was performed with 160 women who provided daily recordings of frequency, duration, and severity of nausea and vomiting. Seventy-four percent of women reported nausea lasting a mean of 34.6 days. "Morning sickness" occurred in only 1.8% of women, whereas 80% reported nausea lasting all day. Only 50% of women were relieved by 14 weeks' gestation; 90% had relief by week 22. Data based on the McGill Nausea Questionnaire indicate that the nausea experienced by pregnant women is similar in character and intensity to the nausea experienced by patients undergoing cancer chemotherapy. Traditional teachings about nausea and vomiting of pregnancy are contradicted by our findings. Standardized tools for measuring the distribution, duration, and intensity of nausea are applicable to the study of nausea and vomiting of pregnancy and could be used in clinical trials to assess palliative measures.
To compare the efficacy of intravaginal and intrarectal plus oral indomethacin for the treatment of preterm labor. Between December 1996 and November 1998, 46 eligible gravidas admitted with singleton pregnancies and idiopathic preterm labor before 33 gestational weeks were randomized to receive 200 mg of intravaginal or intrarectal plus oral indomethacin. Twenty-three subjects were allocated to each study group. The interval from initiation of treatment to delivery was significantly longer in the intravaginal indomethacin group (26.5 +/- 5.7 versus 12.6 +/- 3.7 days; P =.007). Delivery was delayed by more than 7 days in 18 of 23 subjects (78%) in the intravaginal indomethacin group compared with ten (43%) in the intrarectal plus oral indomethacin group (P =.03). Birth weights were significantly higher (2306 +/- 436 versus 1862 +/- 232 g; P =.002) and hospitalization in a neonatal intensive care unit (NICU) (3.1 +/- 0.8 versus 9.3 +/- 3. 7 days; P =.001) and mechanical ventilation (1.4 +/- 0.2 versus 5.3 +/- 1.6 days; P =.001) were significantly shorter in the intravaginal indomethacin group. Intravaginal indomethacin is more effective than intrarectal plus oral application in delaying preterm labor and is associated with higher birth weights, shorter NICU stays, and shorter intervals of mechanical ventilation.
We compared nifedipine and ritodrine for treatment of preterm labor with respect to neonatal outcome. We conducted an open randomized multicenter study of neonatal outcome in 185 women who received either oral nifedipine (n = 95) or intravenous (IV) ritodrine (n = 90) for treatment of preterm labor. Secondary outcome measures included neonatal mortality and morbidity, especially neonatal intensive care unit (NICU) admission, respiratory distress syndrome (RDS), and intracranial bleeding. There were no significant differences in umbilical artery pH values and Apgar scores between groups. Nifedipine was associated with lower admission rates to the NICU (49% versus 66%; odds ratio 0. 51, confidence interval 0.28, 0.93) compared with ritodrine, and lower incidences of RDS (21% versus 37%; 0.46, 0.24, 0.89), intracranial bleeding (18% versus 31%; 0.48, 0.24, 0.96), and neonatal jaundice (52% versus 67%; 0.53, 0.29, 0.97). Logistic regression analysis showed that even after correction for gestational age at birth, newborn risk of RDS, intracranial bleeding, or neonatal jaundice was significantly lower in the nifedipine group than the ritodrine group. Nifedipine for treatment of preterm labor was associated with a lower incidence of neonatal morbidity than ritodrine. That difference appeared to be partly because of the higher tocolytic efficacy of nifedipine and partly because of an intrinsic beneficial effect of nifedipine, or the lack of harmful effects when compared with ritodrine.
This is the second edition of this guideline; the first edition was published in 2011 under the same name. It supplements NICE guideline NG25 Preterm labour and birth. Cerclage remains one of the standard options for prophylactic intervention in the care of women at risk of preterm birth and second trimester fetal loss and is used by most obstetricians, despite difficulties in identifying the population of women who would most benefit. The procedure, a stitch inserted into the cervix, was first performed in 1902 in women with a history of second trimester loss or spontaneous preterm birth suggestive of cervical insufficiency, with the aim of preventing recurrent loss. Cervical insufficiency is an imprecise clinical diagnosis frequently applied to women with such a history, where it is assumed that the cervix is ‘weak’ and unable to remain closed during the pregnancy. Recent evidence suggests that, rather than being a dichotomous variable, cervical integrity is likely to be a continuum influenced by factors related not solely to the intrinsic structure of the cervix but also to processes driving premature effacement and dilatation. While cerclage may provide a degree of structural support to a ‘weak’ cervix, its role in maintaining the cervical length and the endocervical mucus plug as a mechanical barrier to ascending infection may be more important. There is lack of consensus on the optimal cerclage technique, timing of suture placement, the role of amniocentesis before emergency cerclage insertion and optimal care following insertion. Complications are not well documented and often difficult to separate from risks inherent to the underlying condition. The purpose of this guideline is to review the literature and provide evidence-based guidance on the use of cerclage in women at risk of preterm birth and second trimester loss. This guideline supplements NICE guideline [NG25] Preterm labour and birth.1 Within this document we use the terms woman and women’s health. However, it is important to acknowledge that it is not only people who identify as women for whom it is necessary to access women’s health and reproductive services in order to maintain their gynaecological health and reproductive wellbeing. Gynaecological and obstetric services and delivery of care must therefore be appropriate, inclusive and sensitive to the needs of those individuals whose gender identity does not align with the sex they were assigned at birth. This Royal College of Obstetricians and Gynaecologists (RCOG) guideline was developed in accordance with the standard methodology for producing RCOG Green-top Guidelines.2 The Cochrane Library (including the Cochrane Database of Systematic Reviews), DARE, EMBASE, TRIP, Medline and PubMed (electronic databases) were searched for relevant randomized control trials, systematic reviews and meta-analyses. The search was restricted to articles published between 2011 and April 2020. The databases were searched using the relevant MeSH terms, including all subheadings and this was combined with a keyword search. Search words included ‘cervical cerclage’, ‘cervical suture’, ‘cervical stitch’, ‘midtrimester miscarriage’, ‘McDonald cerclage’, ‘Shirodkar cerclage’, ‘infection and cerclage’, ‘tocolytics and cerclage’ and ‘inflammatory mediators and cerclage’; the search was limited to humans and the English language. The National Library for Health and National Guidelines Clearing House were also searched for relevant guidelines and reviews. The full search strategy is available to view online as supporting information (Appendices S1 and S2). Previous terminology (prophylactic, as a planned procedure, emergency, urgent, rescue) of cervical sutures/cerclage can be ambiguous. More appropriate nomenclature based on indication for cervical suture is recommended. The terms below are increasingly used in the scientific literature. History-indicated cerclage Insertion of a cerclage as a result of factors in a woman’s obstetric or gynaecological history, which increase the risk of spontaneous second trimester loss or preterm birth.3 A history-indicated suture is performed as a prophylactic measure in asymptomatic women and usually inserted as a planned procedure at 11–14 weeks of gestation. Preterm Birth Birth before to 37+0 weeks’ gestation. Ultrasound-indicated cerclage Insertion of a cerclage as a therapeutic measure in cases of cervical length shortening seen on transvaginal ultrasound.3 Ultrasound-indicated cerclage is performed on asymptomatic women who do not have exposed fetal membranes in the vagina. Sonographic assessment of the cervix is usually performed between 14 and 24 weeks of gestation by transvaginal scan and with an empty maternal bladder. Emergency cerclage (also known as physical exam-indicated or emergency cerclage) Insertion of cerclage as a salvage measure in the case of premature cervical dilatation with exposed fetal membranes in the vagina.3 This may be discovered by ultrasound examination of the cervix or as a result of a speculum/physical examination performed for symptoms such as vaginal discharge, bleeding or ‘sensation of pressure’. It can be considered up to 27+6 weeks gestation.1 Transvaginal cerclage (McDonald) A transvaginal purse-string suture placed at the cervical isthmus junction, without bladder mobilization.4 High transvaginal cerclage requiring bladder mobilization (including Shirodkar) A transvaginal purse-string suture placed following bladder mobilization, to allow insertion above the level of the cardinal ligaments.5 Transabdominal cerclage A suture performed via a laparotomy or laparoscopy, placing the suture at the cervicoisthmic junction.6 Occlusion cerclage Occlusion of the external os by placement of a continuous non-absorbable suture. The theory behind the potential benefit of occlusion cerclage is retention of the mucus plug.7 Routine surveillance of women at low risk is not currently recommended by the National Screening Committee. Ultrasound surveillance of cervical length is advocated in women at high and intermediate risk in Element 5 of the Saving Babies Lives Care Bundle,21 the timing of which is dependent on the women’s history. These women are recommended to be reviewed by a preterm prevention specialist by 12 weeks where possible, or with the dating scan whichever is sooner, and offered transvaginal cervix scanning as a secondary screening test every 2–4 weeks between 16 and 24 weeks. There is, however, uncertainty as to how to care for these women if a short cervix is identified in women who have had serial screening but do not have a history of a previous preterm birth; an ultrasound indicated cerclage may be considered. STOPPIT-2 is a randomised trial of the Arabin pessary to prevent preterm birth in twin pregnancies with a short cervix. Data collection is now complete and the results are currently being analysed.26 Carers should be aware of the potential psychological sequelae associated with fetal death and miscarriage, and women and their families supported by debriefing services and the offer of counselling. Families should also be signposted to the relevant patient support groups. There is no clear evidence that the gestation at which the cerclage is inserted affects the magnitude of prolongation of the pregnancy; however, consideration should be given to the fact that, in cases presenting before 20 weeks of gestation, insertion of a emergency cerclage is highly likely to result in a preterm birth before 28 weeks of gestation. Furthermore, emergency cerclage can rarely be justified beyond 24 weeks’ gestation due to the potential risk of iatrogenic membrane rupture and subsequent preterm birth. Prior to cerclage insertion, women should be given appropriate verbal and written information; patient information can be found on the RCOG website.50 The interval between presentation and suture insertion varies between studies. Any delay must balance the risk of inserting a suture in a cervix that is inevitably going to continue dilating against the increased risk of ascending infection. There are no studies evaluating the effect of sexual intercourse on the risk of second trimester loss or preterm birth in women with cervical cerclage. Although other tests are commercially available for the prediction of preterm birth, such as Partosure and Actim Partus no studies to date have evaluted their use following cervical cerclage insertion. Multiple studies have compared different agents (cerclage, progesterone and pessaries) for the prevention of preterm birth, however these often do not control for clinician preference and many of the studies are retrospective in nature. Conde-Agudelo et al.87 also compared the efficacy of vaginal progesterone and cerclage in preventing preterm birth and adverse perinatal outcomes in women with a singleton gestation, previous spontaneous preterm birth and short cervix undertaking a meta-analysis of RCTs comparing vaginal progesterone to placebo/no treatment or cerclage to no cerclage in women with a singleton gestation, previous spontaneous preterm birth and a sonographic cervical length less than 25 mm. Five trials comparing vaginal progesterone versus placebo and five comparing cerclage versus no cerclage were included. Both progesterone and cerclage were equally effective for preventing preterm birth and improving perinatal outcomes. However, cerclage and progesterone were not compared directly. A number of randomized controlled trials are planned comparing the efficacy of cerclage versus pessary versus progesterone.83, 88 There are no studies comparing elective removal of transvaginal cerclage with removal in labour. However, in the absence of preterm labour, elective removal at 36–37 weeks of gestation is advisable owing to the potential risk of cervical injury in labour and the minimal risk to a neonate born at this gestation. There are no studies regarding the use of anaesthesia in the removal of a cerclage inserted with bladder mobilization but, given that the technique involves burial of the suture, an anaesthetic is likely to be necessary for removal. Decisions regarding use of anaesthetic should be taken jointly with the woman. There are no published studies on long-term outcome comparing a policy of removing a transabdominal cerclage to it remaining in place. However, if further pregnancies are contemplated, it is reasonable to recommend leaving the cerclage in place. There have been anecdotal reports of suture ‘pulling through’ prior to labour, and a vaginal birth can occur safely if this is identified. The developers would like to acknowledge Miss Meekai To for their work as co-developer of the previous edition of this guideline. AHS has declared no conflicts of interest. LS has declared no conflicts of interest. Full disclosure of interests are available to view online as supporting information. All those involved in the development of the Green-top Guidelines, including the Guidelines Committee, Guidelines Committee co-chairs, guideline developers, peer reviewers and other reviewers, are unpaid volunteers and receive no direct funding for their work in producing the guideline. The exception to this are the RCOG staff involved who are salaried employees of the College and GC members who receive reimbursement for expenses for attending GC meetings. Please see more information on travel expense rules on the RCOG website. Appendix S1. Cervical cerclage literature search strategy. Appendix S2. Cervical cerclage search strategy top up. The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. This guideline was produced on behalf of the Royal College of Obstetricians Professor Andrew H Shennan FRCOG, London; Dr Lisa Story MRCOG, London. Miss A Gorry MRCOG, London; Dr G Kumar FRCOG, Wrexham; Mr D Fraser FRCOG, Norwich; Dr P Maouris FRCOG, Perth, Western Australia; Mr B Kumar FRCOG, Wrexham; Dr KC Dundas FRCOG, Edinburgh; Miss M To MRCOG, London; Professor JE Norman FRCOG, Bristol; RCOG Women’s Network; Imperial College Academic Health Science Centre. Dr A Macleod FRCOG,1 Edinburgh, Dr B Magowan FRCOG, Melrose2 and Mr A McKelvey MRCOG, Norfolk.3 1until December 2020; 2until May 2021; 3from December 2021. The chair of Dr MA Ledingham MRCOG, Glasgow; Dr B Magowan FRCOG, Melrose. All RCOG guidance developers are asked to declare any conflicts of interest. A statement summarising any conflicts //www.rcog.org.uk/en/guidelines-research-services/guidelines/gtg75. The final version is the responsibility of the Guidelines Committee of the RCOG. The guideline will be considered for update 3 years after publication, with an intermediate assessment of the need to update 2 years after publication. The Royal College of Obstetricians and Gynaecologists produces guidelines as an educational aid to good clinical practice. They present recognised methods and techniques of clinical practice, based on published evidence, for consideration by obstetricians and gynaecologists and other relevant health professionals. The ultimate judgement regarding a particular clinical procedure or treatment plan must be made by the doctor or other attendant in the light of clinical data presented by the patient and the diagnostic and treatment options available. This means that RCOG Guidelines are unlike protocols or guidelines issued by employers, as they are not intended to be prescriptive directions defining a single course of management. Departure from the local prescriptive protocols or guidelines should be fully documented in the patient’s case notes at the time the relevant decision is taken.
PregnancyRisk FactorsEffects of Prior AbortionAbortion Consequences
To examine whether induced abortion influences subsequent pregnancy duration. Women who had their first pregnancies during 1980, 1981, and 1982 were identified in three Danish national registries. A total of 15,727 women whose pregnancies were terminated by first-trimester induced abortions were compared with 46,026 whose pregnancies were not terminated by induced abortions. All subsequent pregnancies until 1994 were identified by register linkage. Preterm and post-term singleton live births were more frequent in women with one, two, or more previous induced abortions. After adjusting for potential confounders and stratifying by gravidity, the odds ratios of preterm singleton live births in women with one, two, or more previous induced abortions were 1.89 (95% confidence interval [CI] 1.70, 2.11), 2.66 (95% CI 2.09, 3.37), and 2.03 (95% CI 1.29, 3.19), respectively. Odds ratios of post-term singleton live births in women with one, two, or more previous induced abortions were 1.34 (95% CI 1.24, 1.44), 1.50 (95% CI 1.26, 1.78), and 1.58 (95% CI 1.09, 2.28), respectively. The study showed an increase in preterm and post-term pregnancies after induced abortions. The risk of post-term delivery was high regardless of the interpregnancy interval, whereas increased risk of preterm delivery was seen mainly when interpregnancy intervals were longer than 12 months.
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.
To examine the effectiveness of any tocolytic compared with a placebo or no tocolytic for preterm labor. We checked MEDLINE (1966-1998) and the Cochrane Controlled Trials Register for articles, using the search terms "randomized controlled trial" (RCT), "preterm labor," "tocolysis," "betamimetics," "ritodrine," "terbutaline," "hexaprenaline," "isoxuprine," "prostaglandin synthetase inhibitors," "indomethacin," "sulindac," "calcium channel blockers," "nifedipine," "oxytocin receptor blockers," "atosiban," "nitroglceride," and "magnesium sulfate." We included all RCTs that compared effect of a tocolytic with a placebo or no tocolytic in women in preterm labor, and reported perinatal, neonatal, or maternal outcomes. Studies were excluded if loss to follow-up exceeded 20% of those originally enrolled, or if data were not reported on a per-patient-treated basis. Eighteen of 76 articles retrieved met the inclusion criteria. TABULATION, INTEGRATION, Two authors independently reviewed the articles and abstracted the data. Discrepancies were resolved by consensus. Meta-analyses (odds ratio [OR] and 95% confidence interval [CI]) were done for each outcome for all trials and for specific types of tocolytic therapy when possible. Tocolytics decreased the risk of delivery within 7 days (OR 0.60, 95% CI 0.38, 0.95). Betamimetics, indomethacin, atosiban, and ethanol, but not magnesium sulfate, were associated with significant prolongations in pregnancy. Tocolytics were not associated with improved perinatal outcomes. Maternal side effects significantly associated with tocolytic use were palpitations, nausea, tremor, chorioamnionitis, hyperglycemia, hypokalemia, and need to discontinue treatment. Although tocolytics prolong pregnancy, they have not been shown to improve perinatal or neonatal outcomes and have adverse effects on women in preterm labor.
We sought to evaluate the effect of antepartum and intrapartum antibiotic use on antimicrobial-resistant neonatal sepsis. We analyzed perinatal outcomes for 8474 pregnancies (8593 live births) delivered at 6 hospitals. Data were collected regarding maternal antibiotic use and perinatal course, neonatal cultures, and outcomes. The diagnosis of confirmed neonatal sepsis required at least one positive blood or cerebrospinal fluid culture. Neonatal cultures were evaluated on the basis of the occurrence and timing of maternal antibiotic exposure. There were 96 neonates with confirmed sepsis (11.2/1000 live births). Sepsis was 19.3-fold more common after preterm birth (57 vs 3. 1/1000; P <.001), with 76% of septic infants being delivered preterm. Forty-five percent of pathogens were ampicillin resistant. Ampicillin resistance increased with preterm birth (50% vs 26%; P =. 04), antepartum antibiotics (57% vs 34%; P =.03), intrapartum antibiotics (55% vs 28%; P <.01), and any prenatal antibiotic exposure (52% vs 22%; P =.01). Infection with an organism resistant to at least one maternal antibiotic was more common with intrapartum antibiotic exposure than with antepartum exposure only (57% vs 17%; P =.01). Regarding early-onset sepsis (n = 55), ampicillin resistance was more common with intrapartum antibiotics (50% vs 16%; P <.01), and resistance to at least one maternally administered antibiotic was more frequent with intrapartum exposure (56.7% vs 0%; P <.01). Maternal antibiotic treatment is associated with neonatal sepsis by organisms resistant to ampicillin and to maternally administered antibiotics.
PregnancyPrediction and ScreeningCervical CerclageCervical Length Measurement
We sought to determine the predictive accuracy for preterm delivery of transvaginal ultrasonography of the cervix between 14 and 24 weeks' gestation in high-risk patients and to determine whether cerclage prevents preterm delivery in patients with ultrasonographic cervical changes. Patients with asymptomatic singleton pregnancies at high risk for preterm delivery were followed prospectively from 14 weeks' to 23 weeks 6 days' gestation with transvaginal ultrasonography of the cervix. The subgroup of patients with either a cervical length of <25 mm or funneling of >25% or both was offered McDonald salvage cerclage, which was performed at the discretion of the patient and the obstetrician. The 2 groups (with and without cerclage) were compared for the primary outcome of preterm delivery at <35 weeks' gestation. One hundred sixty-eight women were followed, including 97 (58%) with >/=1 prior 14- to 34-week preterm deliveries. Of 63 (37. 5%) patients identified as having cervical changes, 23 (37%) had preterm delivery; of 105 patients with no cervical changes, 8 (8%) had preterm delivery (relative risk, 4.8; 95% confidence interval, 2. 3-10.1). The sensitivity, specificity, and positive and negative predictive values of either a short cervix of <25 mm or funneling of >25% or both were 74%, 70%, 37%, and 92%, respectively. Of 63 pregnancies in which there were cervical changes, 39 underwent cerclage and 24 did not. These 2 groups were similar for demographic characteristics, risk factors, and transvaginal ultrasonographic cervical length and funneling but dissimilar for gestational age at identification of cervical changes (18.3 vs 21.2 weeks' gestation in the groups with and without cerclage, respectively; P <.001). Multivariate logistic regression analysis after adjustment for gestational age at cervical changes showed no difference in the rate of preterm delivery between the groups with and without cerclage (odds ratio, 1.1; 95% confidence interval, 0.3-4.6). Stratified analysis of patients identified between 18 and 24 weeks revealed 22 pregnancies with cerclage and 22 pregnancies without cerclage, which was similar for all characteristics studied. The incidence of preterm delivery remained similar (27% vs 23%, respectively; P =.7), as did days from cervical changes to delivery (111 vs 96, respectively; P =.2). Transvaginal ultrasonography of the cervix between 14 and 24 weeks' gestation is a good predictor of preterm delivery in high-risk pregnancies. Cerclage may not prevent preterm delivery in patients identified to be at high risk for this outcome by transvaginal ultrasonography.
PregnancyInfant MortalityHealth DisparitiesLinked Birth-Death Records
Infant mortality has decreased nationwide; however, our national rates still log behind those of other industrialized countries, especially the rates for minority groups. This study evaluates the effect of prenatal care and risk factors on infant mortality rates in Chicago. Using linked infant birth and death certificates of Chicago residents for 1989-1995, a total of 5838 deaths occurring during the first year of life were identified. Birth certificate variables, especially prenatal care, were reviewed. Variables were compared by stratified analysis. Pearson chi 2 analysis and odd ratios (ORs) were computed. Infant mortality rate (IMR) in Chicago decreased from 17 in 1989 to 12.6 in 1995 (P < .0001). Some factors prematurity (OR 17.43), no prenatal care (OR 4.07), inadequate weight gain (OR 2.95), African-American ethnicity (OR 2.55), and inadequate prenatal care (OR 2.03). Compared with no care, prenatal care was associated with lower IMR; however, early care was associated with higher IMR and ORs than later care. These results demonstrate prenatal care is associated with lower IMR; however, compared with late prenatal care, early care does not improve IMR. Further studies should evaluate whether improving the quality of care improves IMRs.
PregnancyAdolescent PregnancyPerinatal Morbidity and MortalityHigh-Risk Populations
The incidence of cardiovascular disease in women is negligible before natural or surgically-induced menopause, and increases after menopause. Epidemiological data suggest that estrogen replacement therapy reduces the occurrence of coronary artery, and possibly cerebrovascular, disease by 25 to 50% in treated women compared with non-users. These findings are supported by the evidence that estrogens have a beneficial effect on cholesterol metabolism and deposition, contributing to the inhibition of atherosclerotic plaque formation in arterial walls. Early reports suggested that up to 60% of the protective effect of estrogens on coronary artery disease was attributable to favourable changes in plasma lipids. Reanalysis of the data indicated that the lipid changes probably account for approximately 25% of the cardioprotective effect of estrogens and that other effects are, therefore, likely to be important. The influence of estrogens on carbohydrate metabolism, atheroma formation and cardiovascular haemodynamics may also play an integral role in the overall beneficial effect of the hormones. Animal and human studies have shown that the administration of estrogens leads to a restoration of endothelial function, an increase in cardiac output, an increase in arterial flow velocity, a decrease in vascular resistance, and a decrease in systolic and diastolic blood pressure. Recent studies on hormone replacement regimens have shown that estrogens may favourably affect fibrinolysis and reduce plasma fibrinogen to premenopausal levels. Despite these effects of estrogens the recent Heart and Estrogen/Progestin Replacement Study (HERS) failed to show a cardioprotective effect of hormone replacement therapy (HRT) in elderly women with coronary artery disease. However, the HERS study has several limitations and stands alone against the large body of evidence that suggest that HRT may reduce cardiovascular mortality and morbidity.
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.
To test the association between cytokine levels in the amniotic fluid and (i) the vascular invasion phase of intrauterine infection, (ii) the occurrence of periventricular leukomalacia; to assess the correlation between C-reactive protein levels, a recognised biological marker of inflammation in maternal serum and cytokine levels in the amniotic fluid. Prospective clinical study. Fetal medicine unit and neonatal intensive care unit, Antoine Beclere Hospital, Clamart, France. Thirty-one pregnancies complicated by chorioamnionitis leading to birth before 32 weeks of gestation. Interleukin 1-beta, Interleukin 6 and TNF-alpha prospectively measured in the amniotic fluid. Histological examination of the placenta. Ultrasound examination and magnetic resonance imaging of the brains of the newborn infants performed within the first week of life. The occurrence of periventricular leukomalacia was assessed by transfontanellar ultrasound and magnetic resonance imaging. There was a significant positive correlation between the occurrence of histological chorioamnionitis, vascular extension of infection of the membranes, maternal inflammatory syndrome and neonatal sepsis. A strong association was found between maternal serum C-reactive protein concentrations and cytokine levels in the amniotic fluid. Interleukin-1beta was the best predictor of vascular extension of chorioamnionitis, and TNF-alpha was the best predictor of the development of severe early neonatal infection. There was no association between the amniotic fluid levels of cytokines and the development of periventricular leukomalacia. These data suggest that IL-1beta, IL-6 and TNF-alpha are produced in relation to intrauterine inflammation and infection, but cannot be directly implicated in the development of fetal cerebral white matter lesions.
To determine the accuracy of amniotic fluid (AF) matrix metalloproteinase-9 measurements for diagnosing intra-amniotic infection in women with preterm labor. We performed amniocenteses in 44 women between 22 and 35 weeks' gestation who presented to our center with preterm labor and clinical suspicion of intra-amniotic infection. Each sample was analyzed by glucose measurement, Gram stain, and culture for aerobes, anaerobes, and mycoplasmas. We tested the AF for matrix metalloproteinase-9 using gelatin zymography and a commercial enzyme-linked immunosorbent assay (ELISA) system. We calculated accuracy and confidence intervals (CIs) for AF matrix metalloproteinase-9, glucose, and Gram stain for diagnosing intra-amniotic infection, using culture as the criterion standard. All patients who had matrix metalloproteinase-9 detectable by ELISA also demonstrated matrix metalloproteinase-9 by zymography. Six cases of intra-amniotic infection were confirmed by culture (prevalence 14%). The performance statistics of AF matrix metalloproteinase-9 for diagnosing sensitivity 83% (95% CI 53, 99), specificity 95% (95% CI 88, 99), positive predictive value 71% (95% CI 37, 99), and negative predictive value 97% (95% CI 92, 99). Two women had false-positive results; one had gram-negative rods on the AF Gram stain and developed clinical signs and symptoms of chorioamnionitis several hours after amniocentesis and the other had a purulent vaginal discharge and an AF glucose level less than 15 mg/dL. Both delivered within 24 hours of amniocentesis. Measuring matrix metalloproteinase-9 in the AF appeared to be reliable for diagnosing intra-amniotic infection. An elevated matrix metalloproteinase-9 concentration in the AF at a preterm gestational age may portend imminent delivery regardless of microbiologic confirmation of intra-amniotic infection.
PregnancyCerclagePreventionCervical Length Measurement
Open Access
To determine changes in length of incompetent cervices after cerclage, using transvaginal ultrasound. Patients were enrolled in a prospective, observational study under an Institutional Review Board-approved protocol. McDonald or Shirodkar sutures were placed according to physician preference. Pre- and postcerclage cervical lengths were measured within 72 hours of the procedure. At each examination, the first measurement was discarded, and a mean of the subsequent three measurements was calculated. Twenty-one Shirodkar and ten McDonald operations were done. The mean (+/- standard deviation) precerclage cervical length was 2.7+/-0.9 cm and the postcerclage cervical length was 3.6+/-0.9 cm (P<.001, paired t test). Prophylactic cerclage results in measurable increases in cervical length, which might contribute to the success of the procedure. Further study is needed to determine whether the degree of cervical lengthening after cerclage predicts term delivery.
PregnancyBiomarkersPremature Rupture of MembranesPeptide Markers
To determine whether adrenomedullin levels in amniotic fluid were associated with preterm labor. We measured immunoreactive adrenomedullin in amniotic fluid collected by amniocentesis from 36 women with clinical diagnosis of preterm labor or preterm premature rupture of membranes (PROM) and from 18 normal pregnant women. Amniotic fluid from cases of PROM and failure to respond to tocolysis were associated significantly with higher amniotic fluid adrenomedullin concentrations (177.0 +/- 22.5 pg/mL and 182.7 +/- 22.0 pg/mL, respectively, P < .01) than that from uncomplicated pregnancies (101.2 +/- 28.1 pg/mL) or preterm labor responsive to tocolysis (102.3 +/- 26.8 pg/mL). Amniotic fluid adrenomedullin is higher than normal in cases of PROM and preterm labor unresponsive to tocolysis, perhaps indicating enhanced synthesis from placenta or fetal membranes being stimulated by bacterial products.
To describe the anatomic and technical difficulties encountered with transvaginal ultrasound imaging of the cervix in a consecutive series of women at risk for preterm delivery. Three groups of women had cervical those with histories of preterm birth, those with incompetent cervices, and those admitted for preterm labor that did not progress. Standardized ultrasound examinations of the cervix involved measuring the length of the endocervical canal, funneling length, and internal os dilation with and without fundal pressure. Sixty consecutive women had transvaginal ultrasound examinations for assessment of the cervix. Forty-six had histories of preterm birth, five had incompetent cervices, and nine had arrested preterm labor. Six types of problems arose, which can be divided into anatomic or technical considerations, with an overall frequency of 27% (95% confidence interval 16%, 40%). Anatomic pitfalls that hampered identification of the internal os included an undeveloped lower uterine segment (n = 5), a focal myometrial contraction (n = 1), rapid and spontaneous cervical change (n = 1), and an endocervical polyp (n = 1). Technical pitfalls included incorrect interpretation of internal os dilation because of vaginal probe orientation (n = 7) and artificial lengthening of the endocervical canal because of distortion of the cervix by the transducer (n = 1). We caution those who perform cervical length examinations to be wary of falsely reassuring findings due to potential anatomic and technical pitfalls.
This article reviews the arguments for the use of multifetal pregnancy reduction (MFPR) for the prevention of preterm deliveries in triplet and higher order multiple pregnancies and evaluates its effectiveness based on data from published studies. The arguments in favour of pregnancy reduction are based on the substantial mortality and morbidity associated with these pregnancies. Triplets and higher order multiples have increased rates of preterm delivery and intrauterine growth retardation, both of which are independent risk factors for death and handicap. Even controlling for gestational age, rates of mortality and handicap are higher for multiples than for singletons. Moreover, the family's risk of losing a child or having a handicapped child is greater because there are more infants at risk. MFPR effectively lowers these risk by reducing the frequency of preterm delivery. However, its effectiveness may be limited. In some studies, the proportion of preterm deliveries in reduced pregnancies remains above levels found in spontaneous twin or singleton pregnancies and MFPR does not appear to reduce the prevalence of low birth weight. Furthermore, the procedure itself it increases the risk of miscarriage, premature rupture of the membranes and causes adverse psychological effects such as grief or depression for many patients. The authors note that a majority of the higher order multiple pregnancies result from a medical intervention in the first place, either through IVF techniques or the use of ovulation stimulation drugs. Although MFPR is an effective measure for reducing the substantial morbidity and mortality associated with higher order multiple pregnancies, preventive methods, such as limiting to 2 the number of embryos transferred for IVF and better control of the use of ovulation induction drugs, remain more effective and less intrusive.
Our goal was to study the effect of therapeutic McDonald cerclage on cervical length with the use of transvaginal ultrasonography. Cervical length was measured serially in singleton pregnancies in which there were doubts regarding cervical competence. When shortening of the cervix was substantial before 27 weeks' gestation a McDonald cerclage was applied. Wilcoxon signed rank test was used, and 1-tailed P <.05 was considered significant. In the 34 pregnancies studied, the mean cervical length measured at a mean gestational age of 14 weeks had decreased significantly (P <.0001) from 42 mm (95% confidence interval 38-47) to 21 mm (95% confidence interval 19-23) at a mean gestational age of 20 weeks 5 days, when a cerclage was applied. After the cerclage the mean cervical length increased significantly (P <.0001) to 34 mm (95% confidence interval 30-38) at a mean gestational age of 22 weeks 1 day (95% confidence interval 21 weeks 1 day-23 weeks 2 days). Therapeutic McDonald cerclage results in a longer cervical length as measured by transvaginal ultrasonography.
PregnancyRisk FactorsPreeclampsia and Preterm LaborMultivariate Logistic Regression
Martius JA et al., 1998·Eur J Obstet Gynecol Reprod Biol
The study was conducted to identify medical, obstetrical and social risk factors associated with early preterm births (<32+0 gestational weeks). The Statewide Perinatal Survey of Bavaria is a collection of perinatal data from all Bavarian maternity units using a uniform numbered questionnaire. Data on 106345 singleton births from the 1994 Survey were analysed using univariate and multivariate logistic regression analysis. In the multivariate analysis, early preterm birth was associated with premature rupture of the membranes (odds ratio (OR) 1.6, 95% confidence interval (CI) 1.37-1.86), treatment for infertility (OR 1.7, 95% CI 1.19-2.34), previous induced abortion (OR 1.8, 95% CI 1.57-2.13), maternal age >35 years (OR 1.8, 95% CI 1.47-2.16), premature cervical dilatation (OR 2.3, 95% CI 1.86-2.94), a history of stillbirth (OR 3.2, 95% CI 2.13-4.83), a history of preterm birth (OR 3.3, 95% CI 2.45-4.48), maternal age <18 years (OR 3.4, 95% CI 2.03-5.61), malpresentation (OR 3.9, 95% CI 3.10-4.93), preeclampsia (OR 4.0, 95% CI 3.20-4.94), uterine bleeding (OR 5.0, 95% CI 4.08-6.02), preterm labour (OR 7.0, 95% CI 5.94-8.22), and chorioamnionitis (OR 22.3, 95% CI 17.40-28.66). These data identify a subgroup of women at an increased risk for early preterm birth and may benefit from an intensified prenatal care. Risk factors related to the obstetrical history, genital infections, preeclampsia and maternal age are the most relevant for early preterm birth.
PregnancyPremature Rupture of MembranesC-Reactive Protein in PregnancyChorioamnionitis Detection
The purpose of our study was to analyze the efficacy of serum C-reactive protein (CRP), white blood cell count (WBC) and erythrocyte sedimentation rate (ESR) serial evaluations in the prediction of chorioamnionitis in cases of premature rupture of membranes (PROM). A group of 80 patients with PROM before 35 weeks' gestation were evaluated prospectively and managed expectantly. We applied the expectant management with the permanent use of tocolysis, antibiotics, steroids, amnioinfusions of artificial amniotic fluid and intravaginal chemotherapeutics. Patients were monitored with frequent vital signs, fetal heart rate evaluation and everyday CRP, WBC and ESR. All afterbirths were examined to establish the presence of histologic chorioamnionitis (gold standard of intrauterine infection). S: 59 (73.7%) patients had significant chorioamnionitis on histopathology and only 15 of them had clinical chorioamnionitis. Serum CRP serial determinations (definition 1) > 1.2 mg/dl; 2) > 2.0 mg/dl; 3) > 1.2 mg/dl and increasing in two consecutive days) were found the most reliable with a sensitivity 1) 91.5%; 2) 85%; 3) 88%, specificity 57%; 76%; 86%, positive predictive value 86%; 90%; 94.5%, negative predictive value 70.5%; 64%; 72% and accuracy 82.5%; 82.5%; 87.5% respectively. The efficacy of WBC (abnormal > 12500/mm3; > 15000/mm3; > 12500/mm3 and increasing in two consecutive days) and ESR (abnormal > 60 mm/h; > 60 mm/h and increasing in two consecutive days) serial evaluations was significantly lower. Moreover, in cases of chorioamnionitis CRP increased above the upper limit of normal 3 days earlier than WBC or ESR. S: CRP was found the most reliable indicator of histologic chorioamnionitis and indicated the presence of intrauterine infection earlier than WBC or ESR.
PregnancyTocolytic TherapyBeta-Mimetic AgentsOff-Label Use in Pregnancy
beta-mimetics have been prescribed by physicians to arrest or prevent premature labor for more than 20 years. Although not approved by the Food and Drug Administration (FDA) for tocolytic use, terbutaline sulfate has been the most widely prescribed beta-mimetic in the United States. Recently, the role of terbutaline in the treatment and prevention of preterm labor has been questioned by the FDA. Because the off-label use of drugs is a formally accepted practice in medicine when scientific studies support such use, we reviewed the currently available clinical literature on terbutaline use intravenous, oral, and subcutaneous via infusion pump. This review describes the clinical evidence that supports the safe and effective use of terbutaline as a tocolytic agent in certain patient populations. Practicing physicians should continue to have unrestricted use of terbutaline for tocolysis as one of the few remaining therapeutic options remaining in the fight against preterm birth.
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.
PregnancyGroup B Streptococcus ProphylaxisAntibiotic Resistance ConsequencesEarly-Onset Sepsis
Recommendations for the use of antenatal antibiotics in obstetrics have increased in the past few years, especially for prophylaxis against group B streptococci, for prolongation of the latency time in patients with preterm premature rupture of the membranes, and as an adjuvant treatment in preterm labor. Our objective was to determine whether the use of antenatal ampicillin affects the incidence of and resistance of early-onset neonatal sepsis with organisms other than group B streptococci. A prospective cohort study was performed between January 1, 1991, and December 31, 1996. Every case of blood culture-proven neonatal sepsis was prospectively surveyed. The type of bacteria isolated, drug resistance, antenatal antibiotic use and treatment indication, gestational age at delivery, and other antenatal and outcome variables were gathered. Early-onset neonatal sepsis was defined as disease onset within 7 days after birth. A total of 42 cases of early-onset neonatal sepsis among 29,897 neonates delivered were found during the 6-year period. Of these, 15 cases were due to group B streptococci and 27 were the result of non-group B streptococcal organisms (21 gram-negative rods and 6 gram-positive cocci). Among the 27 non-group B streptococcal cases, 15 mothers had received antenatal ampicillin and 13 of the 15 bacterial isolates from these neonates (87%) were resistant to ampicillin, versus only 2 ampicillin-resistant isolates (17%) among the 12 cases in which no antenatal antibiotics were administered (P = .0004). Of the 15 mothers who were treated with ampicillin, 13 received more than 1 dose. In evaluating each year of the study, the overall administration of antibiotics to pregnant women in the antenatal period increased from <10% in 1991 to 16.9% in 1996. The incidence of early-onset neonatal sepsis with group B streptococci decreased during this time, whereas the incidence of early-onset sepsis with non-group B streptococcal organisms, especially Escherichia coli, increased. The increased administration of antenatal ampicillin to pregnant women may be responsible for the increased incidence of early-onset neonatal sepsis with non-group B streptococcal organisms that are resistant to ampicillin. At this time penicillin G, rather than ampicillin, is therefore recommended for prophylaxis against group B streptococci. In addition, future studies are needed to determine whether alternate approaches, such as immunotherapy or vaginal washing, could be of benefit.
Preterm birth, which occurs in 11 percent of all pregnancies, is responsible for the majority of neonatal deaths and nearly one half of all cases of congenital neurologic disability, including cerebral palsy.1Although all births before 37 weeks of gestation are considered premature, births before 32 weeks' gestation (2 percent of all births) account for most neonatal deaths and disorders.2 State and national vital statistics indicate that the incidence of preterm birth has risen over the past 15 years (Figure 1), and it remains twice as high among black women as among white women.35 Preterm birth is commonly categorized . . .
PostpartumAnxiety and DepressionMood DisordersEdinburgh Postnatal Depression Scale
A community-based sample of 107 women completed the Beck Anxiety Inventory, Beck Depression Inventory, State-Trait Anxiety Inventory, and Edinburgh Postnatal Depression Scale at 14 weeks postpartum and at 30 weeks postpartum. The point prevalence of anxiety was 8.7% at 14 weeks and 16.8% at 30 weeks postpartum. The point prevalence of depression was 23.3% at 14 weeks and 18.7% at 30 weeks postpartum. The incidence of anxiety during this time period was 10.28%, and the incidence of depression was 7.48%, indicating high incidences of both postpartum anxiety and depression later in the postpartum period. The Edinburgh Postnatal Depression Scale was found to have a strong correlation with the State Anxiety Scale of the State-Trait Anxiety Inventory (r = .73 at 14 weeks, r = .82 at 30 weeks), suggesting that the Edinburgh Postnatal Depression Scale may be a good screening instrument for anxiety as well as depression.
PregnancyPrediction BiomarkersFetal FibronectinDiagnostic Test Accuracy
To assess the cervicovaginal fetal fibronectin test to predict preterm delivery. We searched MEDLINE, Current Contents, Index Medicus, and proceedings of meetings for studies published between 1991 and June 1997. Inclusion criteria were prospective cohort study; test performed between 20 and 36 weeks' gestation; fetal fibronectin measured by a previously described assay, with a cutoff level set at 50 ng/mL; test results not disclosed to women or physicians; and fewer than 20% of study participants excluded from the analysis. TABULATION, INTEGRATION, Twenty-nine relevant studies were stratified according to the prevalence of preterm delivery, the number of tests performed, and delivery before 34, 35, or 37 weeks. Sensitivities, specificities, and likelihood ratios were calculated in each study. The summary estimates of the likelihood ratio for tests yielding positive results or tests yielding negative results along with their 95% confidence intervals (CIs) were computed in each stratum according to a random-effects model. All summary likelihood ratios for a test yielding positive results indicated a significant association with preterm delivery. The strongest association was found between a single test with positive results and delivery before 37 weeks in a low-risk population (likelihood ratio 7.5; 95% CI 4.6, 12.3). This association also was found in high-risk women (likelihood ratio 3.5; 95% CI 2.6, 4.6). In high-risk women, a test yielding negative results was associated with a reduction in risk of preterm delivery (likelihood ratio 0.4; 95% CI 0.3, 0.5). Fetal fibronectin in cervicovaginal secretions is associated with preterm delivery in both high-risk and low-risk women.
To examine the occurrence of polycystic ovaries (PCO) in women with gestational diabetes mellitus (GDM). This was a retrospective comparative study of ultrasonographic findings of ovaries in 31 women with GDM and 30 healthy controls matched according to maternal age and body mass index (BMI). Women who presented evidence of impaired glucose tolerance during pregnancy were excluded from the control group. Transvaginal ultrasonographic examination was performed during the follicular phase of the menstrual cycle, after breast-feeding had been discontinued. Polycystic ovary was a more frequent finding among women 14 women with GDM (44%) and two controls exhibited PCO. No differences were found in BMI before pregnancy or in the weight gain during pregnancy between the groups. No difference was observed in the mean birth weight of the infants between the study groups. Polycystic ovaries were a common finding among women with GDM. The data suggest that women with PCO are at risk for developing GDM and should be screened accordingly.
PostpartumDepression Risk FactorsPostpartum Depression PredictionPredictive Scales for PPD
Depressed new mothers usually do not seek and therefore do not receive any psychiatric help. In order to assess predictive signs of postpartum depression (PPD), an unselected sample of 570 women were seen by midwives during their pregnancy, using a questionnaire elaborated by ourselves and Derogatis' Hopkins Symptom Checklist. Three months after delivery each new mother was examined again by the same midwife using Cox' Edinburgh Postnatal Depression Scale. The medical files were also examined. Of the new mothers, 58 (10.2%) suffered from PPD. Most significant factors were socio-professional difficulties, multiparity, deleterious life events, depressive mood prior to delivery, early mother-child separation and negative birth experience. The coping abilities of the depressed mother were decreased and her vulnerability to new stress factors increased. It is possible to detect women at risk for PPD already during pregnancy. We therefore elaborated a very simple, short predictive scale which is in the process of validation. Protective factors still have to be studied. Knowledge of these factors should help all caregivers to recognize, during pregnancy, women at risk for PPD, in order to initiate preventive and/or therapeutic measures.
PostpartumHormonal Etiology of DepressionPostpartum PeriodMood Disorders
The months following childbirth are a time of heightened vulnerability to depressive mood changes. Because of the abrupt and dramatic changes occurring in hormone levels after delivery, many studies have examined the role of hormonal factors in postpartum depression. The authors review the literature on potential hormonal etiologies in postpartum depression, in particular for progesterone, estrogen, prolactin, cortisol, oxytocin, thyroid, and vasopressin. While evidence for an etiologic role is lacking for most hormones, changes in certain hormonal axes may contribute to depressive mood changes in some women following childbirth.
PregnancyPrevention InterventionsNursing Support ProgramsMaternal Health
To test the effect of telephone calls from registered nurses to low-income pregnant women on the rates of low birth weight (LBW) and preterm births. A total of 1554 women receiving prenatal care in a public clinic who met study criteria and who consented were assigned randomly to intervention and control groups. Women in the intervention group received telephone calls from a registered nurse, one or two times weekly from 24 weeks' through 37 weeks' gestation. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated. Low birth weight rates were 10.9% in the intervention group and 14.0% in the control group (RR 0.75; 95% CI 0.55, 1.03; P = .072). For gestational age less than 37 weeks, rates were 9.7 in the intervention group and 11.0 in the control group (RR .87; 95% CI 0.62, 1.22; P = .415). In the subgroup of low-income black women 19 years of age and older, a statistically significant difference was found in preterm birth rates before 37 weeks (8.7% in the intervention group versus 15.4% in the controls [RR 0.56; 95% CI 0.38, 0.84; P = .004]). There was no difference in LBW or preterm births between intervention and control groups in the total sample. In a secondary analysis of black subjects 19 years of age and older, there was a significant difference in preterm birth rates.
PregnancyPsychiatric DisordersMood and Anxiety DisordersPsychotropic Drugs
Because the onset of mood and anxiety disorders often occurs during the childbearing years, many women may be taking psychotropic medications for these disorders when they conceive. These medications easily diffuse across the placenta, and their impact on the fetus is of concern. But discontinuation may lead to relapse, in which case psychiatric symptoms may affect the fetus. Thoughtful treatment planning presents a dilemma to the clinician. Limited data suggest heightened vulnerability to relapse of mood and anxiety disorders in women during the postpartum period. Pregnancy appears to exacerbate symptoms of obsessive-compulsive disorder, while panic disorder patients may remain well after discontinuing medication. Future studies should address the prevalence and relapse rates of mood and anxiety disorders, particularly after medication discontinuation, among pregnant women.
It is now accepted that gelatinase B (92 kd type IV collagenase) is involved in blastocyst implantation and trophoblast invasion. However, little is known about the regulation of this enzyme at the fetomaternal interface. Progesterone has been demonstrated to inhibit gelatinase B secretion from endometrial cells, myometrium, and cervical fibroblasts. Interestingly, the promotor of gelatinase B contains a progesterone-responsive element that may explain transcriptional activation of this metalloproteinase by progesterone. It may be hypothesized that progesterone secreted from trophoblast cells, representing the fetal part of the fetomaternal interface, may have a role in the regulation of gelatinase secretion and blastocyst implantation. To this end, use was made of first-trimester trophoblast cells obtained from first-trimester pregnancy terminations. The trophoblast cells were separated by trypsin degradation and fractionation on Percoll gradients. Metalloproteinase activity was measured by zymography, and the expression of the gelatinase B messenger ribonucleic acid was determined by the solution hybridization/ribonuclease protection assay. Primary cell cultures of trophoblasts from first trimesters of pregnancy constitutively elaborated two species of type IV collagenases (gelatinase A and B) as assessed on a gelatin matrix. Treatment with progesterone decreased the accumulation of a gelatinase B species in a dose-dependent fashion. Administration of a progesterone receptor antagonist onapristone (ZK-98.299) neutralized the progesterone inhibitory effect on the gelatinase B in a dose-dependent fashion, thus supporting the presumption that the progesterone effect is receptor mediated. Progesterone significantly attenuated the expression of gelatinase B by trophoblast cells, an effect that was neutralized by ZK-98.299. These observations provide strong indirect support for the participation of progesterone in the regulation of gelatinase B in trophoblast cells. It may be an important regulator of gelatinase production at the fetomaternal interface.
This study was undertaken to determine the relationship between fetal fibronectin, short cervix, bacterial vaginosis, other traditional risk factors, and spontaneous preterm birth. From 1992 through 1994, 2929 women were screened at the gestational age 22 to 24 weeks. The odds ratios for spontaneous preterm birth were highest for fetal fibronectin, followed by a short cervix and history of preterm birth. These factors, as well as bacterial vaginosis, were more strongly associated with early than with late spontaneous preterm birth. Bacterial vaginosis was more common--and a stronger predictor of spontaneous preterm birth--in Black women, while body mass index less than 19.8 was a stronger predictor in non-Black women. This analysis suggests a pathway leading from Black race through bacterial vaginosis and fetal fibronectin to spontaneous preterm birth. Prior preterm birth is associated with spontaneous preterm birth through a short cervix. Fetal fibronectin and a short cervix are stronger predictors of spontaneous preterm birth than traditional risk factors. Bacterial vaginosis was found more often in Black than in non-Black women and accounted for 40% of the attributable risk for spontaneous preterm birth at less than 32 weeks.
PregnancyhCG Structure and MetabolismhCG Measurement in Trophoblastic DiseaseGestational Trophoblastic Disease
To examine the structure and metabolism of human chorionic gonadotropin (hCG) and the effect of molecular heterogeneity on the immunodiagnosis and monitoring of gestational trophoblastic disease. A review of the current medical literature concerning measurement of hCG and hCG-related molecules. hCG molecules in gestational trophoblastic disease are more heterogeneous or degraded in serum and urine samples than in normal pregnancy. Appropriate measurement and monitoring of hCG levels in gestational trophoblastic disease require an understanding of hCG structure and metabolism.
PregnancyBiomarkersCytokine MeasurementPremature Rupture of Membranes
To determine whether serum interleukin-6 concentrations predict impending preterm delivery. Blood samples were collected from 130 gravidas at 22-34 weeks' gestation. The study group consisted of 89 women evaluated for preterm contractions or premature rupture of membranes, and these women were compared with 41 outpatient controls without evidence of labor or infection, chosen by clinicians at the time of routine prenatal visits. Serum interleukin-6 concentrations were measured using a specific enzyme-linked immunosorbent assay kit. Analyses were by the Mann-Whitney U and the Kruskal-Wallis tests. All 41 control subjects had serum interleukin-6 concentrations less than 8 pg/mL. Sixteen of the 89 study patients had serum interleukin-6 concentrations greater than or equal to 8 pg/mL and 73 had values less than 8 pg/mL. When the serum interleukin-6 concentration was at least 8 pg/mL, the median interval from collection to delivery was significantly shorter than that among study and control subjects with serum interleukin-6 less than 8 pg/mL (5.5 versus 240 and 1801 hours, respectively; P < .001). The median gestational age at delivery was significantly lower when the serum interleukin-6 concentration was at least 8 pg/mL, compared with study and control subjects with serum interleukin-6 concentrations less than 8 pg/mL (29.6 versus 33.4 and 39.0 weeks, respectively; P < .001). In patients with preterm contractions, the interval from collection to delivery was significantly shorter when the serum interleukin-6 concentration was at least 8 pg/mL than when it was less than 8 pg/mL (3 versus 600 hours, P < .001). Similarly, the median gestational age at delivery was significantly lower when serum interleukin-6 was at least 8 pg/mL (29.0 versus 36.1 weeks, P < .001). Maternal serum interleukin-6 concentrations appear to be elevated in women destined to deliver prematurely. Measurement of this cytokine may prove useful in treating patients at high risk for preterm delivery.
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.
PregnancyMonitoring and PreventionTwin PregnancyObstetric Interventions
Preterm birth is a major cause of perinatal morbidity and mortality. Whether the rate of preterm birth can be reduced by frequent contact between nurses and pregnant women or home monitoring of uterine activity is not known. We randomly assigned 2422 pregnant women with known risk factors for preterm labor (including 844 women who were pregnant with twins) to receive education and weekly contact with a nurse, daily contact with a nurse, or daily contact with a nurse and home monitoring of uterine activity. The nurses elicited the women's own assessments of their symptoms and signs of preterm labor. The primary end point was the incidence of birth at less than 35 weeks' gestation. Secondary end points included cervical status at the time preterm labor was diagnosed and birth weight. There were no significant differences among the groups in the incidence of birth at less than 35 weeks (14 percent in the weekly-contact group, 13 percent in the daily-contact group, and 14 percent in the home-monitoring group), in the mean amount of cervical dilatation at the time preterm labor was diagnosed (1.8 cm, 1.5 cm, and 1.4 cm, respectively), or in such neonatal outcomes as birth weights of less than 1500 g or less than 2500 g. However, daily contact with a nurse increased the mean number of unscheduled visits to obstetricians (1.2 in the weekly-contact group, 1.8 in the daily-contact group, and 2.3 in the home-monitoring group) and the proportion of women who received prophylactic tocolytic drugs (12 percent, 14 percent, and 19 percent, respectively). Women who have daily contact with a nurse, with or without home monitoring of uterine activity, have no better pregnancy outcomes than women who have weekly contact with a nurse.
This study explored a multifactorial model for the prediction of the intensity of depressive symptoms in postpartum women. Data were gathered from 213 pregnant women during the second trimester of pregnancy and at 6 months postpartum. Participants were assessed according to a number of psychosocial variables. A path analysis indicated that four variables had a direct effect on postpartum depressive lower occupational status, prenatal depression level, more distal stressors and a personal psychiatric history. Eight variables, which reflected past and present experiences, showed an indirect effect. The implications of these findings are discussed.
Preterm infants are at 8 times higher risk than term infants for pre- and perinatal brain damage, resulting in cerebral palsy. In this paper we have analysed the influence of prenatal and birth-related risk factors on cerebral palsy in preterm infants. In a register-based study, 175 preterm singleton infants with cerebral palsy, born in 1982-86, were compared with 687 controls matched by gestational age and year of birth. Statistically significant higher rates in cases were found in parity > or = 3 (22% vs. 16%, p < 0.05), Cesarean section (67% vs. 56%, p < 0.01), and low Apgar scores at 1 minute (45% vs. 36%, p < 0.05). By multivariate analyses, two variables remained parity > or = 3 (adjusted OR = 1.53 (95% CI 1.00-2.34), p < 0.05) and Cesarean section (adjusted OR = 1.57 (95% CI 1.07-2.32), p < 0.05). Pregnancy complications preceding preterm birth did not imply a higher risk of cerebral palsy. Delivery by Cesarean section was a prognostic factor for developing cerebral palsy, and the predictive value of Apgar scores was highly limited.
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.
PregnancyPostpartum Mood DisordersDepression and PsychosisPerinatal Mental Health
Mood disorders are common in women. A prepregnancy personal history of mood disorder (bipolar or major depression), premenstrual syndrome, or (possibly) postpartum blues places a woman at high risk for a postpartum exacerbation of symptoms. Untreated or unrecognized postpartum mood disorders can lead to serious psychologic and social consequences, in some cases even leading to suicide or infanticide. Women at risk for postpartum mood disorders need to be referred for psychiatric consultation before pregnancy and parturition. Informed, professional collaboration offers the best opportunities for prevention, as well as the earliest recognition and treatment of emergent symptoms.
PCOSGestational DiabetesPregnancy-Induced HypertensionMetabolic Disorders in PCOS
To evaluate the complications and outcome of pregnancy in women with polycystic ovary disease (PCOD). The course and outcome of 47 singleton pregnancies in women with well-documented PCOD were compared with those in 100 healthy controls. Women with PCOD had a significantly higher body mass index as compared to the control group (P < .05); however, the proportion of lean versus obese subjects in the two groups was similar. The incidence of an abnormal glucose challenge test, gestational diabetes mellitus and pregnancy-induced hypertension was significantly increased in pregnant women with PCOD (P < .05). When lean PCOD subjects were compared with lean control subjects, the difference in the incidence of the above complications was still significant (P < .05). The incidence of pregnancy complications was similar when obese PCOD subjects were compared with obese controls. Women with PCOD were at increased risk of gestational diabetes and pregnancy-induced hypertension, and this risk appeared to be independent of body mass index.
PregnancyIntergenerational RiskEpidemiology and Risk FactorsLinked Database Analysis
To examine the risk of preterm birth for mothers who themselves were born before term. Data were taken from a linked data base of birth certificates 1) a parental cohort of women born between 1947 and 1957 and 2) their offspring born between 1970 and 1992. "Preterm mothers" were women in the parental cohort who were born at less than 37 weeks' gestation. "Term mothers" were women in the parental cohort born at or after 38 weeks' gestation. Preterm mothers and term mothers were matched for birth year, county of birth, marital status, parity, and age. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for the risk of preterm delivery in preterm mothers. Multiple logistic regression was used to assess the interaction of concomitant variables with the risk of premature delivery. The risk of preterm birth was significantly higher in preterm mothers than in term mothers (OR 1.18; 95% CI 1.02, 1.37). The risk increased as the gestational age at the mothers' birth decreased (less than 30 weeks'; OR 2.38; 95% CI 1.37, 4.16). The interaction between maternal age and parity increased the risk of preterm delivery at less than 34 weeks in some age and parity strata. An increased risk of preterm delivery exists for women who themselves were born before 37 weeks' gestation. The risk is inversely correlated with the maternal gestational age at birth and is influenced by maternal age and parity.
PregnancyInfection and Inflammation BiomarkersInterleukin-6 and Neopterin in PregnancyImmunological Mechanisms
Oleszczuk J et al., 1997·Eur J Obstet Gynecol Reprod Biol
We estimated the levels of interleukin 6 (IL-6) and neopterin, in serum of twelve nonpregnant (group A) and 28 pregnant women between 28-36 weeks of pregnancy. Group B consisted of eight patients with uncomplicated pregnancy, group C consisted of thirteen pregnant women with clinical signs of preterm labour and without laboratory markers of infection and group D consisted of seven pregnant women with signs of preterm labour and with laboratory markers of infection. The levels of IL-6 and neopterin were significantly higher in group D compared to groups A, B and C (p < 0.05). Similarly, the level of C-reactive protein (CRP) and total white blood cell count (the laboratory markers of infection) were significantly higher in group D than in groups A, B and C. Total white blood cell count was significantly lower in group A than in group B and D (p < 0.05). There were no significant differences in values of IL-6, neopterin and CRP between groups A, B and C (p > 0.05). In all groups, significant correlations were found between IL-6 and neopterin as well as total white blood cell count and CRP. Our results suggest that IL-6 and neopterin may be the markers of preterm labour caused by infection. On the other hand, cell-mediated immune response may be involved in the mechanisms of preterm labour.
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 develop and evaluate a questionnaire used antepartum to screen for postpartum depression. Demographic and clinical data, based on previously identified variables, were obtained from 106 second-trimester gravidas (sample I) by interview, self-administered questionnaire and medical record review. The Beck Depression Inventory (BDI) was administered at 1, 6 and 12 weeks postpartum (PP). Statistical analysis, including stepwise linear regression with maximum r-squared improvement, identified a subset of the 24 most predictive variables. This antepartum questionnaire (APQ) was validated retrospectively in the original sample and prospectively in a second group of 99 women (sample II). In both sample populations the APQ had acceptable sensitivity (80-82%) and specificity (78-82%). The incidence of postpartum depressive symptoms (PPDS) rose from 10% to 17% by six weeks without an appreciable decline at 12 weeks (15%). The percentage of women showing more than mild depressive symptoms increased with PP time from 30% at 1 week to 47% at 12. The APQ is now available for screening and evaluating early therapeutic intervention in PPDS.
PregnancyPremature Rupture of MembranesInterleukin-8Chorioamnionitis
Interleukin-8 (IL-8), a 72 amino acid peptide secreted by cells of the immune system and of the amnion, chorion and decidua, was measured in women in late pregnancy. IL-8 was detected in the urine of 91 of 104 women with premature rupture of the fetal membranes, with values exceeding 1000 ng/L in cases of severe intra-amniotic infection. Women with urinary tract infections were excluded. The routine measurement of IL-8 in urine, together with C-reactive protein in serum, thus provides a low risk and technically simple approach to the assessment of intra-amniotic infection.
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.
EndometriosisMalignant TransformationOvarian Cancer in PregnancyOvarian Clear Cell Carcinoma
Sugiyama T et al., 1997·Eur J Obstet Gynecol Reprod Biol
We encountered a case of ovarian cancer in a 33-year-old, 8-week pregnant woman. Histological examination revealed both a transitive form of ovarian endometriosis with marked decidual changes due to pregnancy and clear cell carcinoma. Benign and borderline clear cell adenofibroma and benign and borderline endometrioid adenofibroma were also found. Parts of these adenofibromas showed transformation to clear cell carcinoma. This case suggests that clear cell carcinoma can arise from clear cell adenofibromas and/or ovarian endometriosis, even in young patients.
PostpartumPostpartum Depression PsychobiologyHPA and HPT Axis DysfunctionPerinatal Mood Disorders
Postpartum mood disorders are common. The clustering of mood-disorder episodes after birth compels a search for factors particularly potent during childbearing. In this article, the complex relationships between the dynamic postbirth physiological environment and mood disorder are discussed. Available studies show a lack of evidence that serum levels of gonadal hormones account for mood disturbance in women. However, substantial amounts of data demonstrate their ability to modulate other neuroendocrine systems. Alterations in hypothalamic-pituitary-adrenal (HPA) axis function attributable to childbearing show remarkable similarity to those observed in depressed women. Postpartum women are also at increased risk for hypothalamic-pituitary-thyroidal (HPT) axis dysfunction that may increase affective-disorder vulnerability. A decreased rate
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.
Epidemiologic studies demonstrate a twofold higher rate of depression in women than in men. The childbearing years are a time of increased risk for onset of depression in women. Pregnancy, miscarriage or pregnancy loss, infertility, and the postpartum period may challenge a woman's mental health. Virtually no life event rivals the neuroendocrine and psychosocial changes associated with pregnancy and childbirth. This paper provides a brief overview of depression during pregnancy and the postpartum period. Incidence, risk factors, and complications of depression during pregnancy and the puerperium are discussed to aid the clinician in early identification of at-risk patients. Treatment recommendations are also provided based on the available literature, clinical experience, and consideration of the possible special circumstances (i.e., breast-feeding) of this population of women.
PregnancyBiomarkersPremature Rupture of MembranesC-Reactive Protein
C-reactive protein (CRP) levels were evaluated during spontaneous labour, in imminent premature parturition (IPP) and after preterm rupture of oocyst membranes (PROM). Increasing CRP level during spontaneous labour was found in 16.6% parturients. Elevated CRP level in patients with IPP makes it impossible to predict premature labour. In parturients with PROM, increase in CRP level makes further infection predictable only in a few cases.
Despite the high prevalence of postpartum depressive disorders, many signs and symptoms of this illness are dismissed as normal physiologic changes associated with childbirth. Prompt recognition and treatment are imperative in order to limit the negative impact on both the mother and infant. Mood disturbances may have a minor functional impact that respond well to social support (eg. postpartum blues) or cause significant functional compromise requiring more aggressive therapy (eg. postpartum depression). The most extreme case of postpartum depressive disorder, postpartum psychosis, occurs when patients develop psychosis, mania, or thoughts of infanticide. Depression during pregnancy or the presence of risk factors suggests the need for careful follow-up. If postpartum depression develops, psychotherapy is the first-line treatment. Antidepressant treatment may be warranted for some patients, and the risks and benefits to both the mother and infant should be considered in the decision to institute pharmacotherapy.
PregnancyDepression ScreeningBeck Depression InventorySensitivity and Specificity
To determine the test characteristics of a self-report questionnaire, the Beck Depression Inventory, when used as a screening test for depression in a population of ambulatory pregnant women. One hundred five pregnant women completed the Beck Depression Inventory and underwent a structured interview using the National Institute of Mental Health Diagnostic Interview Schedule-version III. Current depression was diagnosed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders-III-R. A receiver operating characteristic curve was constructed for the Beck Depression Inventory score as a predictor of current depression. A table of sensitivities, specificities, predictive values, and likelihood ratios was created for various cutoff values. For the 105 women enrolled, the median Beck Depression Inventory score was 8.0. Twelve women (11%) were diagnosed with current depression and had a median Beck Depression Inventory score of 25.5, compared with those without current depression, who had a median score of 8.0 (P = .001). The area under the receiver operating characteristic curve was 0.9940. Using a cutoff range of greater than 16, the sensitivity of the Beck Depression Inventory to detect current depression was 0.83, the specificity was 0.89, the positive predictive value was 0.50, and the negative predictive value was 0.98. The Beck Depression Inventory can serve as a rapid screening test for depression during pregnancy. A higher cutoff value is required for pregnant women than is customarily used outside of pregnancy.
To compare the effectiveness of routine management of patients at high risk for preterm delivery to the effectiveness of routine management in combination with daily telephone nursing contact. The control group, 1 (n = 21), had education and frequent prenatal visits and cervical examinations. The study group, 2 (n = 21), had education, frequent prenatal visits and cervical examination, and daily telephone contact. Group 3 (n = 22) received education but refused to participate. There were no significant differences (SD) between groups in race, smoking, age, multiple gestation, visits, diagnosis of premature labor, mean days gained after diagnosis of premature labor, tocolytic use or bed rest. There was also no SD in preterm birth rate, mode of delivery, number of maternal or neonatal hospital days, mean neonatal weight or gestational age at delivery between groups. While not reducing the overall incidence of preterm birth, this management for all groups resulted in a more advanced gestational age at the time of delivery (mean change = 7.5 weeks, P < .0001) when compared to the patient's first preterm birth. This study indicated that daily contact, while providing reassurance and support, did not change the outcome when the study group was compared to women managed similarly but without daily contact.
Our purpose was to determine whether perioperative transvaginal ultrasonographic evaluation of the incompetent cervix treated with emergency cerclage is predictive of pregnancy outcome. Twenty-nine women who underwent emergency cerclage at 16 to 26 weeks of gestation had transvaginal ultrasonographic evaluation of the cervix within 48 hours before and after surgery and at least three times thereafter until 28 weeks of gestation. The following (1) funnel width, (2) funnel length, (3) endocervical canal length, (4) the distance between the internal and external os, (5) upper cervix (length of closed endocervical canal above the cervical cerclage), (6) lower cervix (endocervical canal length below suture), and (7) cervical index (1+ Funnel length/Endocervical canal length). Values are reported as the median in millimeters, and statistical analysis was performed by use of the Mann-Whitney U test, Wilcoxon signed-rank test, Spearman rank correlation, 2 x 2 contingency tables, and multiple regression analysis with significance set at p < 0.05. Cerclage procedures resulted in significant improvement in postoperative median measurements of funnel width (15 vs 4.0 mm, p < 0.0001), funnel length (29 vs 3 mm, p < 0.0001), and endocervical canal length (2 vs 27 mm, p < 0.0001). There was a significant relationship between preoperative funnel width (r = -0.51, p = 0.007), postoperative endocervical canal length (r = 0.39, p = 0.04), length of the lower cervix (r = 0.39, p = 0.038), and the cervical index (r = -0.39, p = 0.038). An upper cervical length < 10 mm was a good predictor of delivery before 36 weeks of gestation, sensitivity 85.7% (12/14), specificity 66.7% (10/15), positive predictive value 70.6% (12/17), negative predictive value 83% (10/12), and Fisher's exact p = 0.008. Postoperatively all patients had upper cervical lengths < 10 mm by 28 weeks of gestation. Preoperative digital assessments of cervical dilatation before surgery did not correlate with gestational age at birth (r = -0.031, p = 0.36). In cases of cervical incompetence treated with emergency cerclage, perioperative transvaginal ultrasonographic assessment of the cervix reveals that the procedure results in improved ultrasonographic status of the cervix and that the ultrasonographic cervical findings before and after surgery correlate with pregnancy outcome.
PregnancyScreening and PreventionCervical Length ScreeningOutpatient Tocolysis Management
To characterize the continuum between normal and preterm labor to prevent spontaneous preterm birth and low birth weight. Between August 1, 1992, and November 30, 1993, obstetric patients from a large managed care medical group were assigned in rotation to five private practice offices for pregnancy care. In the study office (374 births), a systematic approach of visit-by-visit screening, patient education, selective office evaluation of cervical change by transvaginal ultrasound examination, outpatient modification of activity, and graded oral or subcutaneous tocolysis was used; inpatient tocolysis was used only when outpatient management failed. In the comparison offices (1391 births), transvaginal ultrasound was not used and conventional methods were used at the discretion of the attending physicians. Birth weights below 1500 g (P = .008; odds ratio [OR] 0.08, 95% confidence interval [CI] 0.05-1.32), 2000 g (P = .21; OR 0.21, 95% CI 0.05-0.88), and 2500 g (P = .008; OR 0.44, 95% CI 0.23-0.83) occurred significantly less often in the study group than in the comparison group. The difference in spontaneous preterm births under 2500 g was also significant (P < .001; OR 0.08, 95% CI 0.01-0.58). By emphasizing transvaginal ultrasound and graded outpatient tocolysis, the diagnosis and management of preterm prelabor was associated with a reduction in the rate of spontaneous preterm birth and low birth weight infants.
The third trimester of human pregnancy is characterized by a hyperactive hypothalamic-pituitary-adrenal axis, possibly driven by progressively increasing circulating levels of placental CRH and gradually decreasing levels of CRH-binding protein. The postpartum period, on the other hand, is characterized by an increased vulnerability to psychiatric manifestations (postpartum "blues," depression, and psychosis), a phenomenon compatible with suppressed hypothalamic CRH secretion. To investigate the hypothesis that the postpartum period is associated with suppression of hypothalamic CRH secretion, we studied prospectively 17 healthy euthymic women (mean +/- SE age, 32.0 +/- 1.1 yr) with no prior history of depression, starting at the 20th week of gestation. Psychometric testing was performed monthly during pregnancy and postpartum on day 2 and weeks 2, 3, 6, 8, 12, 16, and 20, whereas serial ovine (o) CRH tests were performed postpartum at 3, 6, and 12 weeks. While pregnant, all 17 subjects remained euthymic; in the postpartum period, 7 women developed the "blues," and 1 developed depression. Overall, the mean plasma ACTH response to an iv bolus of 1 microgram/kg oCRH was markedly blunted at 3 and 6 weeks, but normal at 12 weeks postpartum, whereas the mean plasma cortisol response was at the upper limit of normal at all 3 times. These data are compatible with a suppressed hypothalamic CRH neuron that gradually returns to normal while hypertropic adrenal cortexes are progressively down-sizing. When the postpartum ACTH responses to oCRH were analyzed separately for the euthymic women and the women who had the "blues" or depression, the blunting of ACTH was significantly more severe and long lasting in the latter group; this was observed at all 3 times of testing. We conclude that there is central suppression of hypothalamic CRH secretion in the postpartum, which might explain the increased vulnerability to the affective disorders observed during this period. The suppressed ACTH response to oCRH might serve as a biochemical marker of the postpartum "blues" or depression.
To evaluate the presence of fetal fibronectin in the cervix and vagina as a screening test for spontaneous preterm birth. Two thousand nine hundred twenty-nine women at ten centers were routinely screened every 2 weeks from 22-24 to 30 weeks for cervical and vaginal fetal fibronectin. A positive test was defined as a value equal to or greater than 50 ng/mL. The relation between a positive test at four gestational ages and spontaneous preterm birth at various intervals after the test was determined. In each testing period, 3-4% of the fetal fibronectin tests were positive. The correlation between cervical and vaginal fetal fibronectin at the same visit was always approximately 0.7 (P < .001), and that between cervical or vaginal fetal fibronectin in consecutive visits was between 0.17 and 0.25 (P < .001). The sensitivity of fetal fibronectin at 22-24 weeks to predict spontaneous preterm birth at less than 28 weeks was 0.63, and the relative risk for a positive versus negative test was 59. The specificity was always 96-98%, whereas the positive predictive value rose from 13% to 36% as the upper limit of the definition of preterm birth was increased from less than 28 to less than 37 weeks. The relative risk for spontaneous preterm birth after a positive fetal fibronectin test compared with a negative fetal fibronectin test varied substantially by testing period and by the definition of spontaneous preterm birth, but always remained greater than 4 and statistically significant. A positive cervical or vaginal fetal fibronectin test at 22-24 weeks predicted more than half of the spontaneous preterm births at less than 28 weeks (sensitivity 0.63). As the definition of spontaneous preterm birth was extended to include later gestational ages or when the fetal fibronectin test was performed later in pregnancy, the level of association between a positive fetal fibronectin test and spontaneous preterm birth, while remaining highly significant, tended to decrease. Although fetal fibronectin is an excellent test for predicting spontaneous preterm birth, we present no evidence that the use of this test will result in a reduction in spontaneous preterm birth.
The role of the cervix in the pathogenesis of premature delivery is controversial. In a prospective, multicenter study of pregnant women, we used vaginal ultrasonography to measure the length of the cervix; we also documented the incidence of spontaneous delivery before 35 weeks' gestation. At 10 university-affiliated prenatal clinics, we performed vaginal ultrasonography at approximately 24 and 28 weeks of gestation in women with singleton pregnancies. We then assessed the relation between the length of the cervix and the risk of spontaneous preterm delivery. We examined 2915 women at approximately 24 weeks of gestation and 2531 of these women again at approximately 28 weeks. Spontaneous preterm delivery (at less than 35 weeks) occurred in 126 of the women (4.3 percent) examined at 24 weeks. The length of the cervix was normally distributed at 24 and 28 weeks (mean [+/- SD], 35.2 +/- 8.3 mm and 33.7 +/- 8.5 mm, respectively). The relative risk of preterm delivery increased as the length of the cervix decreased. When women with shorter cervixes at 24 weeks were compared with women with values above the 75th percentile, the relative risks of preterm delivery among the women with shorter 1.98 for cervical lengths at or below the 75th percentile (40 mm), 2.35 for lengths at or below the 50th percentile (35 mm), 3.79 for lengths at or below the 25th percentile (30 mm), 6.19 for lengths at or below the 10th percentile (26 mm), 9.49 for lengths at or below the 5th percentile (22 mm), and 13.99 for lengths at or below the 1st percentile (13 mm) (P < 0.001 for values at or below the 50th percentile; P = 0.008 for values at or below the 75th percentile). For the lengths measured at 28 weeks, the corresponding relative risks were 2.80, 3.52, 5.39, 9.57, 13.88, and 24.94 (P < 0.001 for values at or below the 50th percentile; P = 0.003 for values at the 75th percentile). The risk of spontaneous preterm delivery is increased in women who are found to have a short cervix by vaginal ultrasonography during pregnancy.
To compare the diagnostic and prognostic performance of maternal blood C-reactive protein, white blood cell count (WBC), and temperature with that of amniotic fluid (AF) WBC in preterm labor. One hundred two women with preterm labor and intact membranes were studied. Maternal blood was collected to measure C-reactive protein concentration and WBC, and maternal temperature was also measured. Amniotic fluid obtained by amniocentesis was cultured and WBC determined. Receiver operating characteristic curve, logistic regression, and survival techniques were used for analysis. Patients with acute histologic chorioamnionitis had significantly higher median C-reactive protein concentration, WBC, temperature, and AF WBC than patients without this lesion (P < .05). Receiver operating characteristic curve and survival analysis demonstrated that an elevated C-reactive protein, WBC, or AF WBC was strongly associated with the likelihood of histologic chorioamnionitis, shorter interval to delivery, clinical chorioamnionitis, and neonatal morbidity (P < .05 for each). Of all the tests, AF WBC was the best independent predictor of a positive AF culture (odds ratio [OR] 16.8), interval to delivery (hazard ratio 5.7), clinical chorioamnionitis (OR 15.2), neonatal sepsis (OR 16.8), and significant neonatal complications (OR 7.4), after other confounding variables were adjusted (P < .05 for each). An elevated C-reactive protein, WBC, or AF WBC identified patients with intrauterine infection and adverse perinatal outcomes. Amniotic fluid WBC was a better independent predictor of these outcomes than C-reactive protein, WBC, or temperature.
The aim of this study was to investigate the correlation between the cytokine levels in the amniotic fluid (AF) and the histological stage of chorioamnionitis (CAM) in premature labor. AF of 6 cases (7 samples of AF were obtained as one was a twin pregnancy) in whom CAM was diagnosed histologically, and 12 cases without CAM were included in this study. Amniotic fluid was obtained within 24 hours prior to delivery. Cytokine levels (IL-2, -4, -6, TNF-alpha, IFN-gamma) in AF were measured by an ELISA method. Levels of IL-2 and -6 in the CAM-positive group (mean +/-S.E., 52.9 +/- 83.9 pg/ml, and 20,537.9 +/- 8853.7 pg/ml, respectively) were higher than those in the CAM-negative group (i.e. undetectable, and 65.6 +/- 27.5, respectively) with a statistical significance of p < 0.05, p < 0.001, respectively. There was a positive linear relationship between IL-6 levels of AF and the placental histological inflammatory stages of Blanc in the CAM-positive group. From these results it would appear that the IL-6 level in AF is the most sensitive test in the detection of extraamniotic infection or intraamniotic infection in preterm labor with intact membranes and also indicates the severity infection.
Preterm birth complicates 8-10% of all pregnancies in the United States and is the leading cause of infant morbidity and mortality. Neonatal morbidity and mortality is concentrated among very low-birthweight and extremely premature infants, particularly those delivered prior to 30 weeks' gestational age. In addition to the contribution of preterm birth to neonatal morbidity and mortality, the economic costs associated with this pregnancy complication are staggering. Efforts to reduce the preterm birth rate have been largely focused on prevention and early intervention with treatment for preterm labor. Mixed results regarding the success of prematurity prevention programs have been reported, and controversy continues to surround the efficacy of tocolytic therapy in the treatment of preterm labor. Although neonatal survival for infants born at early gestational ages has steadily improved in recent years, survival of infants delivered prior to 24 weeks' gestation remains very poor. Additionally, despite this decline in neonatal mortality, the United States still lags behind most industrialized nations in infant mortality, and no change in the rate of low birthweight has occurred in recent decades. Multiple lines of evidence support a role for infection as an etiologic factor in preterm labor. Although this association has been well known for many years, a wealth of new data is emerging, linking subclinical genital tract infection with spontaneous preterm birth, particularly among pregnancies that result in birth prior to 30 weeks' gestational age as a result of spontaneous preterm labor or preterm, premature rupture of membranes. Conversely, preterm birth that occurs closer to term is less likely to be associated with genital tract infection. Improved understanding of the link between genital tract infection and preterm birth now provides an exciting potential for the development of sensitive new markers to identify women at risk and effective interventions to prevent preterm birth. A review and comment on this growing literature is provided.
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 describe the relationship between pregnancy complications and fetal outcome in first and second pregnancies, focusing on idiopathic and indicated preterm birth of singleton infants in either pregnancy. Included in the study were 13,967 women in Denmark who gave birth to their first singleton infant in 1982 and a second infant in 1982-1987. Information on pregnancy and birth was obtained by linking the National Medical Birth Register and the National Register of Hospital Discharges, based on personal identification numbers. The risk of a preterm second birth in women with idiopathic and indicated preterm first birth did not differ significantly (15.2 and 12.8%, respectively). However, women with idiopathic preterm birth in the first pregnancy tended to repeat idiopathic preterm birth twice as often as women with indicated preterm birth repeated indicated preterm birth (11.3 versus 6.4%). Adjustment by logistic regression analysis for other risk factors for preterm birth did not influence the relative risk (6.0 before 32 weeks and 4.8 for 32-36 weeks) of a second preterm birth after a first preterm birth. Women with idiopathic preterm delivery in their first and second pregnancies gave birth to infants with lower birth weight than in previous or subsequent pregnancies. Emergency cesarean delivery in a first term pregnancy was a risk factor for subsequent idiopathic preterm birth. Idiopathic preterm birth is associated with emergency cesarean delivery at term in previous pregnancies and infants with lower birth weight in previous and subsequent pregnancies.
To evaluate whether preterm-birth prevention educational programs are effective at reducing neonatal mortality, low birth weight (LBW), and preterm delivery. A MEDLINE literature search of English-language studies was performed, supplemented by a bibliography search of original research and review articles to locate studies assessing preterm-birth prevention programs. We identified 31 studies that reported results from trials evaluating preterm-birth prevention programs. From this group, only the six randomized controlled trials evaluating preterm-birth prevention education programs satisfied criteria of homogeneity to be included in a meta-analysis. One of these six studies was a subset of another study and was excluded except when reporting outcomes that were not included in the larger report. Two independent reviewers assessed LBW frequency, preterm birth frequency, neonatal survival, birth weight, gestational age at delivery, and preterm labor diagnosis rates. When data were combined using meta-analytic techniques, no significant benefits were found for preterm-birth education programs in preventing neonatal death (cumulative relative risk [RR] 1.00, 95% confidence interval [CI] 0.99-1.01), LBW rates (RR 0.99, 95% CI 0.88-1.11), or preterm delivery rates (RR 1.08, 95% CI 0.92-1.27). The only statistically significant effect of preterm birth education programs appears to be an increase in the frequency at which preterm labor is diagnosed (RR 1.71, 95% CI 1.41-2.08). Preterm-birth prevention educational programs appear to have little benefit in reducing preterm birth and may result in an increased rate of diagnosis of preterm labor.
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.
To compare ampicillin with and without sulbactam with respect to the effect on the latency period after preterm premature rupture of membranes (PROM). Patients with PROM at 25-35 weeks' gestation were offered participation in a randomized blinded trial comparing ampicillin-sulbactam with ampicillin. Evaluations for cervical pathogens were performed on admission and patients were followed-up with daily maternal and fetal evaluation. Maternal and neonatal outcomes were analyzed using indicated techniques. Fifty-three women were studied, with 25 receiving ampicillin-sulbactam and 28 receiving ampicillin. The ampicillin-sulbactam group had a significantly longer latency period (433 +/- 625 versus 143 +/- 165 hours, P = .03) and significantly fewer neonatal complications (five versus 20, P < .001). Although no neonatal infectious complications were observed in sulbactam-treated cases, there were four cases of neonatal sepsis and two of neonatal pneumonia in the ampicillin group. Also, significantly more neonates in the ampicillin group required prolonged oxygen and ventilatory support. There was no significant difference in maternal morbidity. In our population with preterm PROM, a broad-spectrum antibiotic that provides anaerobic coverage appears to extend latency and decrease neonatal morbidity without increasing adverse maternal outcome.
There is considerable evidence that the childbearing years represent a time when women are highly vulnerable to developing mood disorders. Prospective, cross-sectional, and retrospective studies have demonstrated that more than 10% of new adult mothers will experience a major depressive episode during the first postpartum year. Changes in the health care delivery system will result in increased pressure on the obstetrician/gynecologist to identify and treat women with postpartum-onset depression. Despite shortcomings in the available literature, prospective studies have identified risk factors for developing postpartum depression. Furthermore, the clear overlap between the normal sequelae of childbirth and the symptoms of major depression, including alterations in sleep, energy, libido, appetite, and body weight, underscores the need to develop guidelines for early identification. We furnish a brief overview of postpartum mood disorders with a primary focus on the antenatal and postnatal risk factors for developing postpartum depression. Based on the extent literature and our clinical experience, a set of recommendations for early identification and treatment is provided.
PregnancyUltrasound AssessmentFirst Trimester ViabilityGestational Sac and CRL Dynamics
To compile, for the first time, serial ultrasonographic findings during the first trimester of pregnancy in women with a history of primary recurrent spontaneous abortion so as to define the dynamics of early normal and abnormal gestations in this category of gravidas. Transvaginal ultrasonograms were obtained weekly from 5 to 12 weeks' gestational age in 40 women, 10 recurrent spontaneous aborters and primiparas (controls), with both successful and failed gestations. Embryonic heart motion was detected in 40-50% of successful pregnancies during the fifth week of gestation and in the balance by the sixth week, while heart motion was detected in no more than 50% of pregnancies that later failed. Of the failed pregnancies, all were evident by the eighth week of gestation, including those with previously documented viability. The gestational sac size and crown-rump length were smaller than expected in both failed groups, with the sac size difference evident as early as week 5 and the crown-rump length difference apparent by week 7. Appropriate timing of the initial ultrasonogram in recurrent aborters (i.e., 8 weeks' gestational age) can identify, by means of heart motion and gestational sac features, all pregnancies that will ultimately fail.
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 evaluate catalase activity as a rapid predictor of microbial invasion of amniotic fluid (AF). The study population consisted of 74 patients before 36 weeks' gestation with preterm labor or premature rupture of membranes (PROM). Subjects were excluded if there was evidence of clinical chorioamnionitis or fetal distress at admission. Amniocentesis was done within 24 hours of admission, and the AF was cultured for aerobic and anaerobic bacteria and for Mycoplasma species. All AF samples were Gram stained, and slides were examined by microbiology technologists. Amniotic fluid catalase activity was measured immediately after amniocentesis using a commercially available kit. The sensitivity of the Gram stain and catalase activity were compared using McNemar exact test. Amniotic fluid cultures were positive in 12 of 37 (32%) patients presenting with preterm labor and in 21 of 37 (56%) patients with PROM. Catalase activity was significantly more sensitive than Gram stain in detecting positive AF cultures in cases of PROM (P < .001) and preterm labor (P < .04). Catalase activity is a simple, rapid test that is useful in identifying subclinical intra-amniotic infection in patients with preterm labor or PROM.
In this study we evaluated different markers of infection and their relationship to preterm delivery. Forty-four consecutive women with singleton pregnancies in uncomplicated preterm labor were investigated. C-reactive protein (CRP) in peripheral maternal blood, amniotic fluid cytokines, amniotic fluid leukocyte count, and amniotic fluid culture were performed in all patients. Thirty-six patients responded to standard tocolytic therapy and delivered after 34 weeks' gestation. In eight patients treatment failed and they delivered before 34 weeks' gestation. Two of these eight patients had a positive amniotic fluid culture for Ureaplasma urealyticum. The positive culture was accompanied by an elevated neutrophil count in the amniotic fluid. Elevated amniotic fluid levels of tumor necrosis factor (TNF) (more than 23 pg/mL), interleukin-6 (IL-6) (more than 2292 pg/mL) and interleukin-8 (more than 164 pg/mL) correlated with early preterm delivery. CRP levels in serum had a low sensitivity (38%) but a high specificity (94%) in predicting preterm delivery. This study indicates that preterm labor can be initiated by infection. Markers of infection obtained by amniocentesis have a better sensitivity and positive predictive value than noninvasive markers. Elevated IL-6 (more than 2292 pg/mL) seems to be the best predictor for preterm delivery, with a sensitivity of 75% and a specificity of 97%.
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.
We report the existence of a 'placental clock', which is active from an early stage in human pregnancy and determines the length of gestation and the timing of parturition and delivery. Using a prospective, longitudinal cohort study of 485 pregnant women we have demonstrated that placental secretion of corticotropin-releasing hormone (CRH) is a marker of this process and that measurement of the maternal plasma CRH concentration as early as 16-20 weeks of gestation identifies groups of women who are destined to experience normal term, preterm or post-term delivery. Further, we report that the exponential rise in maternal plasma CRH concentrations with advancing pregnancy is associated with a concomitant fall in concentrations of the specific CRH binding protein in late pregnancy, leading to a rapid increase in circulating levels of bioavailable CRH at a time that coincides with the onset of parturition, suggesting that CRH may act directly as a trigger for parturition in humans.
We investigated the impact of pregestationally elevated insulin plasma levels on glycemic control in pregnant women with polycystic ovary disease (PCOD). Twelve patients with PCOD who became pregnant within six months following evaluation of their metabolic status were the study subjects. Four were obese and six (two obese) had a hyperinsulinemic response to the oral glucose tolerance test (OGTT). They were tested with the OGTT at 28-30 weeks of gestation. We also tested 12 normal patients and 10 consecutive patients with gestational diabetes; all were at the same gestational age. Plasma levels of insulin and glucose were determined in the samples collected for a period of four hours after glucose load (100 g). All PCOD patients significantly increased their insulin secretion in pregnancy. The hyperinsulinemic PCOD patients developed gestational diabetes (two patients) and impaired gestational glucose tolerance (three patients). The area under the insulin curve was greater in PCOD patients than in control and gestational diabetes patients (P < .01). In spite of their large increase in insulin secretion observed during pregnancy, patients with PCOD may develop a derangement of glycemic control, probably related to their pregestational insulinemic status.
The aim of this study was to investigate women who had first-episode psychosis within 1 year after parturition. The Danish Psychiatric Central Register and the Danish Medical Birth Register were linked to identify all women admitted for the first time to a psychiatric department in Arhus County with a psychotic episode. Fifty cases were found, giving a frequency of first-episode psychosis within 1 year after delivery of 1 per 1000. First-episode psychotic disease within the first month postpartum occurred in 1 case per 2000 deliveries. The age distribution corresponded to that of the background population, but the cases were primiparous more often than expected. The socioeconomic status was equal to that of a matched control group of obstetric patients. Birth complications did not occur more frequently than expected, but the probands had a higher risk of preterm delivery than the controls. The clinical picture of the index episode was that of manic-depressive psychosis in nearly half of the cases, but no cases of schizophrenia were found. Sixty percent of the patients had a picture of severe depression, and 20% suffered from manic disorder. The follow-up, 7 to 14 years later, was carried out by interviewing the general practitioners. Forty percent of the women had not preserved full working capacity due to mental disorder. Moreover, the follow-up pointed to schizophreniform symptoms at the index episode as a predictor of incapacity to work. Recurrences were very common (60%), especially of the nonpuerperal type, and half of the recurrences belonged to the manic-depressive disorders.(ABSTRACT TRUNCATED AT 250 WORDS)
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.
To determine if first-trimester exposure to sex hormones, and oral contraceptives (OCs) specifically, is associated with an increased risk of external fetal genital malformations. MEDLINE and Science Citation Index data bases were searched for the years 1966-1992 for relevant English-language articles on first-trimester sex-hormone exposure and fetal genital changes. One hundred eighty-six articles were identified initially. Inclusion criteria were cohort or case-control studies, first-trimester sex-hormone exposure, and live infants or full-term stillborn infants with external genital malformations. Exclusion criteria were diethylstilbestrol exposure, spontaneous abortions, and teratogen exposure. The Methods section of each study was reviewed independently by two authors and two outside reviewers, using the above criteria. Fourteen studies, seven cohort and seven case-control, involving 65,567 women, met the criteria for meta-analysis. Extracted data were entered into 2 x 2 tables. The overall summary odds ratio (OR) was 1.09 (95% confidence interval [CI] 0.90-1.32); subanalysis of OC exposure identified an OR of 0.98 (95% CI 0.24-3.94). There was no association between first-trimester exposure to sex hormones generally (or to OCs specifically) and external genital malformations. Thus, women exposed to sex hormones after conception may be assured there is no increased risk of fetal sexual malformation.
To determine whether long-term intravenous (IV) tocolysis using combined terbutaline and magnesium sulfate is safe and effective. One thousand consecutive women in preterm labor were treated with combination IV tocolytic therapy. Terbutaline was initiated with an infusion rate of 1.75 micrograms/minute and increased to a maximum of 80 micrograms/minute. Magnesium sulfate was infused at 2 g/hour without any bolus and increased to maintain a serum level of 6.5-7.5 mg/dL. Tocolysis was continued until fetal lung maturity was achieved or delivery occurred. Combination tocolytic therapy prolonged pregnancy by a mean (+/- standard deviation) of 61 +/- 23.6 days in 751 women with intact membranes and by 20.5 +/- 17.4 days in 249 with ruptured membranes. The longest durations of continuous IV tocolysis were 123 days in a patient with intact membranes and 77 days in one with ruptured membranes. The most common side effects were nausea and vomiting, followed by chest tightness and shortness of breath. Long-term IV tocolysis appeared to be safe and to have acceptable side effects, allowing patients to receive combined terbutaline and magnesium sulfate until delivery.
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.
PregnancyInfection ScreeningPuerperal EndometritisC-Reactive Protein in Pregnancy
Silent intrauterine infection as cause of preterm labour should be recognised early by measuring C-reactive protein (CRP) levels in the maternal serum. Ensuing antibiotic therapy may not only cause gestational prolongation, but also has a positive effect on pathology during the puerperal period. Consequently, we examined the rate of infectious puerperal complications of 181 patients who suffered from so-called idiopathic preterm labour. 84 patients showed normal CRP-levels at the onset of tocolysis (< 5 mg/l); an elevated level was found in 97 patients (> 5 mg/l). Patients with elevated CRP-levels and supplemented antibiotic therapy during pregnancy (n = 51) showed significantly fewer symptoms of postpartal endometritis than women with similarly elevated CRP-levels but without antibiotics (n = 46). This effect was not produced when preterm labour was associated with normal CRP-levels. Patients with premature contractions and elevated CRP-values at the onset of tocolysis seem to benefit from the antibiotic therapy during pregnancy because they show reduced infectious complications throughout the puerperal period.
The primary objective of this prospective study was to test whether preterm birth prevention education plus increased clinic visits and selected prophylactic interventions reduce preterm birth. Eight West Los Angeles prenatal county clinics, comparable with respect to selected demographics, were randomized to be either experimental or control clinics. High-risk patients in all clinics were identified with a risk scoring system derived from a similar population. High-risk patients (N = 1774) in experimental clinics were offered a program of education and more frequent visits and were randomized to receive various secondary intervention protocols in addition to the basic interventions of education and more frequent visits. Control clinic patients (N = 880) received standard county care. Preterm birth rates were 19% lower among the experimental high-risk patients (7.4% vs 9.1%), and differences were significant (p < 0.05) when preterm risk was taken into account. There was no evidence to suggest that the secondary interventions provided added benefit over the primary intervention protocol of preterm birth prevention education and increased visits. The 19% reduction in preterm birth rate observed in the experimental clinics suggest an overall program benefit from a protocol that offered education, more frequent visits, and greater attention given to patients while the selected interventions were applied.
Schöpf J et al., 1994·Eur Arch Psychiatry Clin Neurosci
A group of 119 patients suffering from a severe psychiatric postpartum disorder who were admitted for the first time in their life to a psychiatric hospital has been investigated. The onset of illness occurred within 3 months following delivery. The patients represented 92% of the total sample fulfilling the inclusion criteria. A follow-up investigation was performed after a mean of 21 years (range 2-35 years). Of the patients 66% had nonpuerperal psychotic episodes in later life. The diagnosis, taking into account the long-term course, was affective psychosis in 57%, schizoaffective psychosis in 18%, schizophreniform psychosis in 12%, brief reactive psychosis in 4% and schizophrenia in 9%. A bipolar psychosis was found in 31%. The relation of unipolar to bipolar psychoses corresponded to that in a control group of affectively ill women without puerperal onset. The frequency of a manic syndrome in bipolar psychoses at the index episode was the same as in nonpuerperal episodes, which does not suggest a mania-provoking pathoplastic effect of the puerperium. The comparison with female nonpuerperal controls matched for age and diagnosis revealed evidence of a better long-term course in the index patients. The risk of a puerperal relapse for further pregnancies was 35%. The global morbidity risk for functional psychoses in first-degree relatives was 11%, with affective psychoses representing the majority of secondary cases (6.8%). The index patients showed a nonsignificant lower morbidity risk in relatives than a control group of psychotically ill women without puerperal onset. The major aetiological factor found for postpartum psychoses is the relation of these disorders to functional psychoses. There is strong evidence that the postpartum period tends to provoke affective psychoses and other nonschizophrenic psychoses, but not, or only to a lesser degree, narrowly defined schizophrenias. The liability to puerperal decompensations suggests some common pathophysiological mechanism, the nature of which remains unknown.
General OB/GYNMeconium AspirationAmniotic Fluid Complications
To determine prospectively the incidence of several pulmonary diagnoses among infants born through clear or meconium-stained amniotic fluid (AF) managed by a selective approach to tracheal intubation. All live births greater than 36 weeks' gestation occurring between January 1990 and December 1992 were included. Diagnostic criteria for several respiratory disorders were determined prospectively and monitored. Infants with light meconium and vigorous infants with moderate to thick meconium were selectively not suctioned. A control group of infants with clear AF matched for gestational age and year of birth was randomly selected for comparison. The incidence and severity of respiratory disease were compared between the groups. Of 4938 live births, 799 (16%) had meconium-stained AF (light, 334; moderate to thick, 465). Compared to 211 infants with moderate to thick meconium selectively not suctioned, 196 suctioned infants had significantly greater rates of abnormal fetal heart rate (FHR) patterns, fetal acidosis, low Apgar scores at 5 minutes, need for resuscitation, and neonatal intensive care unit admission. Meconium aspiration syndrome was significantly more common in suctioned infants as compared to those selectively not suctioned, those with light meconium, and those with clear fluid (11 versus 3 versus 0 versus 0%; P < .01). The need for ventilator or oxygen support was similar between infants with clear fluid, lightly stained fluid, and moderate to thick fluid who were selectively not suctioned, but was significantly greater among suctioned infants (P < .01). We conclude that a selective approach to tracheal intubation and suction of infants with meconium-stained AF was not associated with increased pulmonary morbidity or mortality. Postnatal management of neonates at greatest risk of meconium aspiration syndrome does not necessarily prevent adverse pulmonary outcome.
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.
PregnancyCervical Length AssessmentTransvaginal Cervical MeasurementPrediction and Risk Stratification
To establish a nomogram for the length of the uterocervical canal and to determine whether this can be used to predict preterm delivery. Cervical length was measured by transvaginal ultrasonography in 32 women (21 primigravid, 11 multigravid) with threatened preterm delivery, and in 177 normal singleton pregnancies between 18-37 weeks' gestation. Regression analysis was used to create the nomogram. Student t test was used to compare the groups. A linear relationship was found between cervical length and gestational age (r = -0.4, P < .001). Comparison of cervical length on admission in the patients with threatened preterm delivery showed that 11 preterm deliveries occurred in women who had a mean cervical length of 23.2 mm (range 17-29), whereas 21 term deliveries occurred in women with a mean cervical length of 31.7 mm (range 21-42). The difference was significant (P < .001). A cervical length of less than 20 mm on admission had a positive predictive value of 100%. These patients had preterm delivery despite tocolytic therapy during hospitalization. The risk of preterm delivery is high in women whose cervical length on admission is less than 30 mm, and strict management is required for those with a cervical length of less than 20 mm.
Although low-dose aspirin has been reported to reduce the incidence of preeclampsia among women at high risk for this complication, its efficacy and safety in healthy, nulliparous pregnant women are not known. We studied 3135 normotensive nulliparous women who were 13 to 26 weeks pregnant to determine whether treatment with aspirin reduced the incidence of preeclampsia. Of this group, 1570 women received 60 mg of aspirin per day and 1565 received placebo for the remainder of their pregnancies. We also evaluated the effect of aspirin on maternal and neonatal morbidity. Of the original group of 3135 women, 2985 (95 percent) were followed throughout pregnancy and the immediate puerperium. The incidence of preeclampsia was lower in the aspirin group (69 of 1485 women [4.6 percent]) than in the placebo group (94 of 1500 women [6.3 percent]) (relative risk, 0.7; 95 percent confidence interval, 0.6 to 1.0; P = 0.05), whereas the incidence of gestational hypertension was 6.7 and 5.9 percent, respectively. There were no significant differences in the infants' birth weight or in the incidence of fetal growth retardation, postpartum hemorrhage, or neonatal bleeding problems between the two groups. Subgroup analysis showed that preeclampsia occurred primarily in women whose initial systolic blood pressure was 120 to 134 mm Hg (incidence among such women, 5.6 percent in the aspirin group vs. 11.9 percent in the placebo group; P = 0.01). The incidence of abruptio placentae was greater among the women who received aspirin (11 women, vs. 2 in the placebo group; P = 0.01). Low-dose aspirin decreases the incidence of preeclampsia among nulliparous women, primarily through its effect in those who have elevated systolic blood pressure initially. This treatment does not decrease perinatal morbidity but increases the risk of abruptio placentae.
The purpose of this study was to determine the relationship between C-reactive protein (CRP) levels and intraamniotic infection in 48 women presenting with preterm labor and intact membranes. Blood samples for CRP tests were obtained immediately before the performance of transabdominal amniocentesis. The prevalence of amniotic fluid cultures positive for organisms was 14.6%. In 16 women (33.3%) positive CRP levels were obtained. There were no significant differences in the prematurity rate or the prevalence of microbial invasion of the amniotic cavity between women with positive CRP levels and women with negative levels. The sensitivity, specificity, and positive and negative predictive values for the detection of amniotic infection were 71.5%, 73.2%, 31.3% and 93.8%, respectively. Based on these results, we suggest that in women with preterm labor and negative CRP levels, routine amniocentesis may not be essential to the initial workup.
PregnancyInflammatory BiomarkersInfection DiagnosisC-Reactive Protein in Pregnancy
To evaluate clinical, microbiologic, and histologic findings associated with elevated C-reactive protein levels among women in preterm labor or with preterm premature rupture of the membranes (PROM). Obstetric data, serum C-reactive protein levels, and amniotic fluid (AF) and chorioamniotic membrane cultures and histology were obtained on 203 women presenting between 22-34 weeks' gestation in preterm labor or with PROM. Women with C-reactive protein greater than 1.5 mg/dL were more likely to deliver within 7 days of enrollment (54 of 68, 79%) than were women with normal C-reactive protein levels (45 of 135, 33%) (P < .001). The median C-reactive protein levels and association with rapid delivery did not differ between women with intact versus ruptured membranes. Elevated C-reactive protein levels were associated with a positive AF culture among women in preterm labor with intact membranes. To control for confounding by a long interval to delivery, only the group delivering within 7 days was considered for evaluation of C-reactive protein levels and placental and infant outcome. Among women delivering within 7 days, elevated C-reactive protein was associated with the development of clinical chorioamnionitis and with infant death before hospital discharge, but not with a positive membrane culture or histologic chorioamnionitis. Elevated C-reactive protein appears to be associated with AF infection, delivery within 7 days of admission, and infant death among women delivering preterm, but not with membrane infection or inflammation. Elevated C-reactive protein may be helpful in determining the need for AF culture and in targeting studies of antibiotic therapy among women in preterm labor or with preterm PROM.
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.
MRC/RCOG Working Party on Cervical Cerclage, 1993·Br J Obstet Gynaecol
To assess whether cervical cerclage in women deemed to be at increased risk of cervical incompetence prolongs pregnancy and thereby improves fetal and neonatal outcome. Multicentre randomised controlled trial. Hospitals in the United Kingdom, France, Hungary, Norway, Italy, Belgium, Zimbabwe, South Africa, Iceland, Ireland, the Netherlands and Canada. One thousand two hundred and ninety-two pregnant women whose obstetricians were uncertain whether to recommend cervical cerclage, most of whom had a history of early delivery or cervical surgery. Cervical cerclage was compared with a policy of withholding the operation unless it was considered to be clearly indicated. Delivery before 33 completed weeks, preterm delivery (< 37 weeks), and vital status of the baby after completion of the pregnancy. The overall preterm delivery rate was 28%. There were fewer deliveries before 33 weeks in the cerclage group (83 (13%) compared with 110 (17%), P = 0.03) and this difference reflected deliveries characterised by features of cervical incompetence (painless cervical dilatation and prelabour rupture of the membranes). There was a corresponding difference in very low birthweight deliveries (63 (10%) compared with 86 (13%), P = 0.05). The difference in the overall rate of miscarriage, stillbirth or neonatal death (55 (9%) compared with 68 (11%)) was less marked and was not statistically significant. The use of cervical cerclage was associated with increased medical intervention and a doubling of the risk of puerperal pyrexia. These results suggest that the operation had an important beneficial effect in 1 in 25 cases in the trial (95% confidence interval (CI) 1 in 12 to 1 in 300 sutures). Its use is associated with increased medical intervention and puerperal pyrexia. Nevertheless, this trial suggests that, on balance, cervical cerclage should be offered to women at high risk, such as those with a history of three or more pregnancies ending before 37 weeks gestation.
To compare the effect of hCG therapy with placebo or bed rest in women with threatened abortion. Random assignment, double-blind. Community hospitals. Sixty-one women with viable pregnancies under 8 weeks' gestation on admission to hospital were randomly allocated to receive injections of hCG or placebo, or were advised to rest in bed. Abortion vs. continuation of pregnancy at 16 weeks' gestation. Thirty-one 6/20 on hCG, 10/21 on placebo, 15/20 on bed rest. hCG vs. bed rest, P < .01; placebo vs. bed rest, hCG vs. placebo--not significant. continuing pregnancy > abortion, P < .01; continued with hCG vs. aborted on placebo, P < .001; continued with hCG vs. aborted with bed rest, P < .001. No significant differences in pregnancy/birth complications or infants' birth weight. Female/male ratio was 2:1. hCG is significantly better than bed rest.
Serum progesterone (P) levels were determined at the time of routine prenatal registration (227 patients) or upon presentation for evaluation of vaginal bleeding and/or abdominopelvic cramping/pain (135 patients). P associated with a normal intrauterine gestation was 24.63 +/- 4.19 (SD) ng/mL as compared with 6.29 +/- 2.43 ng/mL and 6.02 +/- 2.39 ng/mL for spontaneous abortions and ectopic gestations, respectively. Further, P differed between asymptomatic (11.92 +/- 9.61 ng/mL) and symptomatic patients (4.81 +/- 3.92 ng/mL) who were subsequently shown to have an abnormal gestation. By establishing a P cutoff point of < or = 14.2 ng/mL and < or = 10.5 ng/mL in asymptomatic and symptomatic patients, respectively, 100% screening sensitivity was reached, and therefore no abnormal gestations would escape detection in our study population. P was either in the normal or abnormal range as early as four weeks' estimated gestational age and persisted as such through the luteal-to-placental shift and up to the time of pregnancy loss or 12 weeks' estimated gestational age. Although there was no significant correlation between P and chorionic gonadotropin levels and pregnancy outcome, the binding constant for native chorionic gonadotropin was 15-52 times lower in 12 of 41 cases of spontaneous abortion but not ectopic gestation, suggesting a possible molecular basis for suboptimal P production. P is therefore an excellent adjunctive marker for prediction of early pregnancy outcome, and in some cases qualitative abnormalities in chorionic gonadotropin may dictate its production.
Our aim was to determine the efficacy and safety of tocolytic agents currently used to treat premature labor. We carried out a comprehensive review of tocolytic agents in the treatment of premature labor. Three hundred twenty-eight studies published between 1933 and 1992 were analyzed. An analysis of randomized, placebo-controlled, clinical trials showed that magnesium sulfate is not better than placebo in the treatment of premature labor. beta-Adrenergic receptor agonists effectively stop premature labor for only 24 to 48 hours. Calcium channel blockers and oxytocin antagonists inhibit uterine contractions, but their role in stopping labor is undefined. Prostaglandin inhibitors appear to be effective in treating premature labor and have few adverse side effects. The only tocolytic drugs that might be effective are the prostaglandin inhibitors. Tocolytic agents should be used only between 24 and 32 completed weeks of gestation. Magnesium sulfate should not be used to treat premature labor. Oxytocin antagonists should be used only in experimental clinical trials. Calcium channel blockers and beta-adrenergic receptor agonists inhibit uterine contractions but do not prolong gestation for longer than 48 hours.
Preterm labor is defined as the onset of uterine contractions in a woman who has completed less than 37 weeks of pregnancy. It may be due to maternal, placental, fetal, or idiopathic causes, and it is associated with a number of risk factors. Nondrug measures such as bedrest and hydration have been used alone or in combination with drug therapy to treat the disorder. Pharmacologic (tocolytic) agents include ethanol, progesterone, indomethacin, nifedipine, beta-adrenergic agonists, and magnesium salts. The three most commonly used drugs are ritodrine, terbutaline, and magnesium.
PregnancyhCG TherapyhCG in Early PregnancyRecurrent Miscarriage
Harrison RF, 1992·Eur J Obstet Gynecol Reprod Biol
An international ten-centre double-blind trial comparing hCG with placebo in the management of habitual abortion was conducted. The dose regime for hCG used was 10,000 IU i.m. on first diagnosis of pregnancy, 5000 IU thence twice weekly to week 12, followed by once weekly up to week 16. Identical ampoulage of placebo was used. Seventy-five patients completed the trial. Thirty-six received hCG and thirty-nine placebo. 83% of the pregnancies on hCG were successful compared with 79% on placebo (P = 0.45). Of the 25 defined as having no cause for their habitual abortion history, 83% on hCG were successful, as were 85% on placebo (P = 0.73). No significant differences were found between the two therapies in terms of delivery weight, placental weight or neonatal Apgar score. This study fails to confirm previous promising placebo-controlled data advocating the use of hCG in habitual abortion.
To compare the tocolytic efficacy and side effects of parenteral and oral magnesium and terbutaline. Ninety-eight patients in labor between 23-35 weeks were prospectively entered into a controlled trial of intravenous and oral magnesium versus subcutaneous and oral terbutaline. Tocolytic effectiveness was judged by delay of delivery for 48 hours or 1 week, and to 37 weeks or more. The need to change therapy to the alternate drug was identified, as were side effects. Entrance characteristics of the population, initial pelvic examination, and concomitant infection or cervicovaginal isolates were noted. Outcomes included gestational age at delivery, birth weights, and Apgar scores. Outcome analysis was based on initial tocolytic therapy. Significantly more patients in the magnesium group delivered at 37 34 of 46 versus 27 of 52 (P < .05). No significant differences were found for delivery by 48 hours or 1 week. The interval between treatment and delivery 7.1 +/- 3.9 versus 5.0 +/- 3.2 weeks (P < .005). Failure to achieve 37 completed weeks was more often due to obstetric complications than to preterm labor itself. Tocolytic effectiveness was reduced if secondary therapy or re-treatment was required or if the patient had cervical dilatation of 3 cm or greater. Infectious complications were common but were not associated with tocolytic effectiveness. Side effects were more noticeable with oral magnesium and subcutaneous terbutaline. For short-term tocolysis, no significant difference was found between magnesium and terbutaline. Magnesium was associated with a higher term delivery rate. Idiopathic preterm labor accounted for only a small part of the overall prematurity in the study population.
The null hypothesis of this study is that maternal administration of indomethacin or terbutaline will not affect fetal breathing and body movements. Thirty patients with a low-risk pregnancy, gestational age 26 to 32 weeks, and no signs of preterm labor were randomly assigned to receive either terbutaline (5 mg), indomethacin (50 mg), or a placebo. Ultrasonographic evaluation of fetal breathing and body movements was performed for 1 hour before and 1 hour after treatment. The total amount of time of fetal breathing and body movements in each group was subject to statistical analysis that included analysis of variance and covariance and a multiple comparison procedure. Indomethacin increased fetal breathing from 20.8 +/- 13.1 minutes to 42.2 +/- 14.8 minutes (p < 0.01), whereas terbutaline increased fetal breathing movements from 19.8 +/- 9.0 minutes to 35.2 +/- 12.4 minutes (p < 0.01). No significant treatment effect was detected on fetal body movements. Between 26 and 32 weeks' gestation, a single dosage of indomethacin or terbutaline increases fetal breathing movements by 103% and 78%, respectively.
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.
PregnancyPuerperal PsychosisPostpartum Psychotic DisordersMood Disorders in Pregnancy
Thirty cases of post-partum psychotic disorders occurred between 1973 and 1987 and hospitalized at the Psychiatric Ward of Florence University were studied and followed up. A structured diagnostic interview was used, which explored DSM Ill-R diagnosis both for mood disorders and for psychotic features. The psychotic symptoms had started within 8 weeks of parturition in all cases. Only 36.7% of the patients showed no subsequent pathology after the puerperal symptoms. The diagnoses, both at the index episode and at the follow-up, revealed a great predominance of mood disorders and the absence of schizophrenia. The follow-up survey showed a greater proportion of bipolar disorders than it appeared at the puerperal onset of the disease. A high frequency of puerperal psychotic relapses has also occurred after subsequent deliveries during the follow-up period.
PostpartumPostpartum DepressionFolate and Maternal MoodRisk Factors for Depression
Hypofolatemia can cause psychiatric disturbances of a depressive nature. Pregnancy and delivery are often associated with hypofolatemia. This study was conducted to determine if hypofolatemia at day 3 post partum is a risk factor for baby blues or post partum depression. To study this hypothesis, 131 post partum women were followed prospectively for the 3 months immediately following delivery. 19% were found to have 'baby blues', as defined by a score greater than 20 on Pitt's scale (Pitt, 1968, J. Psychiatry 114, 1325-1335) and 12% had post partum depression as defined by a score greater than 7 on QD2A scale (Pichot et al., 1984, Rev. Psycholog. App. 34, 229-250, 323-340), within the three months post partum. No relationship was observed between the serum or erythrocyte folate levels on the third day following delivery and the maternal post partum depression scores. A statistically significant correlation between post partum depression and previous psychiatric disturbance was, however, observed.
The clinician is often held responsible for obstetric events that are suspected of being related to cerebral palsy. To review the incidence of cerebral palsy and to aid the clinician in this situation, a search of published studies was conducted. Composite rates of cerebral palsy in different birth weight infants and cerebral palsy with and without serious mental retardation were calculated. The cumulative incidence rate at the age of 5 to 7 years was 2.7 cases of cerebral palsy for 1000 birth cohorts. Approximately 36% of all cerebral palsy occurred in the infant less than 2500 gm. Serious mental retardation (intelligence quotient less than 50) accompanied cerebral palsy approximately 30% of the time for the term infant and 18% of the time when the infant was less than 2500 gm. On the basis of a past estimation that 70% of cerebral palsy is of antepartum or unknown origin, the term infant at risk for intrapartum-attributed cerebral palsy may be about 1 in 2000 term births.
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 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.
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).
PregnancyInfection-Related MechanismsChorioamnionitisGenital Tract Infections in Pregnancy
Premature birth causes high rates of neonatal morbidity and mortality. There are multiple causes of preterm birth. This article reviews the evidence linking subclinical infection and premature birth. Although maternal genital tract colonization with specific organisms has been inconsistently associated with preterm birth and/or premature rupture of membranes, some infections have been consistently associated with preterm delivery. The association of histologic chorioamnionitis with prematurity is a consistent finding, but the mechanisms require further study. The relationship between histologic chorioamnionitis infection and the chorioamnionitis of prematurity requires additional research. A varying number of patients in "idiopathic" preterm labor have positive amniotic fluid cultures (0% to 30%), but it is not clear whether infection preceded labor or occurred as a result of labor. Evidence of subclinical infection as a cause of preterm labor is raised by finding elevated maternal serum C-reactive protein and abnormal amniotic fluid organic acid levels in some patients in preterm labor. Biochemical mechanisms for preterm labor in the setting of infection are suggested by both in vitro and in vivo studies of prostaglandins and their metabolites, endotoxin and cytokines. Some, but by no means all, antibiotic trials conducted to date have reported decreases in prematurity. These results support the hypothesis that premature birth results in part from infection caused by genital tract bacteria. In the next few years, research efforts must be prioritized to determine the role of infection and the appropriate prevention of this cause of prematurity.
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.
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.
There are no absolute objective diagnostic criteria for cervical incompetence. Abdominal and endovaginal ultrasonographic assessment of endocervical length, both of which have been associated with technical problems, have been used to establish the diagnosis. Cervical cerclage may be useful in preventing silent cervical dilatation; however, no prospective trials with and without cerclage have been performed when endocervical shortening has been demonstrated by ultrasonography.
PregnancyPremature Rupture of MembranesC-Reactive Protein in PregnancyChorioamnionitis Prediction
Physicians compared clinical history, examination, and laboratory data on 10 pregnant women at various gestational ages with intact membranes till labor began (controls) with data on 25 pregnant women also at various gestational ages who experienced premature rupture of membranes (PROM) (cases) to determine the value of C-reactive protein (CRP) in maternal and cord blood as a predictor of chorioamnionitis in women with PROM. 32% of cases had clinical chorioamnionitis and 44% histopathological chorioamnionitis. The maternal serum level of CRP in cases with and without chorioamnionitis at delivery was statistically higher than that of the controls (45.82 CRP mg/L and 9.71 CRP mg/L vs. 6.6 CRP mg/l; P.05). Further the CRP level in cord blood of cases with chorioamnionitis also stood much higher than that of the controls (p.001). In addition, the total leukocytic count (TLC) for cases with chorioamnionitis at delivery was much higher than it was for the control group at delivery (12,510 TLC/cubic mm vs. 18,231 TLC/cubic mm; p.05). A significant difference also existed between the temperature of the cases with chorioamnionitis and that of the controls (37.11 degrees Celsius vs. 63.97 degrees Celsius; p.05). Sensitivity and specificity tests showed that CRP 24 mg/L was the most reliable predictor of chorioamnionitis (100% and 93.3% respectively) followed by TLC (77.8% and 92.8% respectively) then temperature (55.6% and 78.6% respectively). Thus CRP can be used to predict premature delivery and simultaneously reduces unnecessary premature delivery of many PROM cases which occur due to fear of developing infections in both the mother and the fetus.
Some randomized studies have suggested a significant beneficial effect of 17-hydroxyprogesterone caproate in the prevention of preterm labor [1, 2], The therapy in both studies was initiated at approximately 12-16 weeks and continued until labor.
We considered the possibility that a deficient proges terone effect during the first trimester may lead to a higher rate of preterm deliveries. A retrospective study was thus performed comparing the incidence of preterm versus full-term pregnancies in women with luteal phase defects who were either treated or not treated with proges terone supplementation during the first trimester.
Home uterine activity monitoring has been proposed as an effective technique for reducing the incidence of preterm birth by early recognition of incipient labor. Five randomized controlled trials evaluating this technique have been published in peer review journals. As judged by accepted criteria for such trials, all have serious methodologic deficiencies. Four of the five trials demonstrated no significant benefit from this monitoring. Two other trials not published in peer review journals support the hypothesis that home uterine activity monitoring is no more effective than daily nursing contact. Until the efficacy of this technology has been established, home uterine activity monitoring should not be used clinically.
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.
Fifty-one consecutive twin pregnancies studied prospectively were compared with 153 consecutive control twin gestations that were concurrently delivered, but chosen retrospectively. Study patients were managed by a protocol that used weekly ultrasound surveillance combined with clinical assessment. Control subjects were not managed by protocol or ultrasound surveillance. Seven of 51 study patients (13.7%) were diagnosed as having cervical incompetency before 30 weeks' gestation (range 18-28 weeks, mean 24). In comparison, 14 of 153 controls (9.2%) delivered before 30 weeks' gestation (range 18-29 weeks, mean 25). The mean cervical length, dilatation, and membrane herniation (funneling) at diagnosis were 1.9, 2.2, and 3.6 cm, respectively, for patients with cervical incompetency. There was a significant difference in perinatal mortality. All study twins survived, whereas nine control subjects delivered at a mean gestational age of 22.7 weeks, with a loss of 17 infants. Life table analysis demonstrated that a significantly greater proportion of controls delivered very low birth weight, premature twins. The use of ultrasound and clinical criteria to select patients for cerclage placement helped prevent birth of the youngest and smallest twins and significantly decreased perinatal mortality in the study group. Routine cerclage placement is not recommended for twin gestations, but multifetal gestations may benefit from ultrasound surveillance for cervical incompetency.
Home uterine activity monitoring has been described as an effective means of detecting uterine contractions, but controversy exists whether it is home uterine activity monitoring or increased nursing support in conjunction with it that contributes to earlier detection of preterm labor. In this study 377 women at risk for preterm labor from three centers were prospectively, randomly assigned to high-risk prenatal care alone (not monitored) or to the same care with twice-daily home uterine activity monitoring without increased nursing support (monitored). The two groups were medically and demographically similar at entry into the study. Routine visits, nonroutine visits, and gestational age at diagnosis of preterm labor were similar in both groups. Preterm labor occurred in 41 of 198 monitored and 39 of 179 not monitored patients. Mean cervical dilatation was 1.4 cm in 41 monitored compared with 2.5 cm for 37 not monitored (p = 0.0006); 73.1% of monitored and 27.5% of not monitored had preterm labor detected before 2 cm dilatation (p = 0.00009). Neonatal outcome of singleton pregnancies showed greater birth weight, fewer days in the neonatal intensive care unit, and fewer babies requiring oxygen therapy and mechanical ventilation in the monitored group. The better outcomes are probably due to the increased likelihood of diagnosis of preterm labor before advanced cervical dilatation with home uterine activity monitoring, thus providing the clinician with a better chance to initiate tocolytic therapy directed at improving pregnancy outcome.
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.
Noblot G et al., 1991·Eur J Obstet Gynecol Reprod Biol
The results of a study concerning the treatment of acute menace beta-mimetics were administered intravenously in all cases (44) and micronized progesterone or placebo was administered orally after classical double-blind randomization (22 cases in each group). The mean index of pregnancy prolongation was the same in both groups. However the mean duration of the intravenous perfusion and the mean quantity of beta-mimetics administered intravenously were significantly reduced in the progesterone group (P less than 0.01). The mean duration of hospital stay was also significantly reduced (P less than 0.05). Cost and risks are finally significantly lessened.
At an interdisciplinary workshop on home monitoring of uterine activity, participants reviewed the basis of this technology and its use in the identification of women at high risk of preterm delivery and in the prevention of preterm birth. Although the guard-ring devices in current use appear capable of detecting uterine activity, they do not clearly distinguish between Braxton Hicks contractions and the contractions of early labor. There was agreement that women destined for preterm delivery have more uterine activity on average than do other women of comparable gestational age but that there is substantial overlap between the two groups. Thus it is uncertain whether this difference can be used effectively for screening purposes. Conferees agreed that there is considerable evidence that twice-daily monitoring of very-high-risk women, in conjunction with daily nursing support and high-quality obstetric care, may prevent preterm births. Available evidence does not clearly distinguish the contribution of tocodynamometry from that of nursing support. A number of areas were identified in which further research is needed.
The relative contributions of home tokodynamometry and daily nursing telephone contact to the success of preterm birth prevention programs remains a subject of debate. Because investigators have obtained conflicting data, a reinterpretation of published results was undertaken by proposing a dynamic interface between the nurse and the machine. Experience gained from the technology and the development of nursing expertise with assessment of patient symptoms are presented as interdependent factors, both of which are critical to a therapeutic nurse-patient relationship. It is proposed that this combined interactive expertise increases sensitivity to the early recognition of preterm labor. The nurse's role in providing social support to high-risk pregnant women is then identified as a potential additional independent contributing factor to reported observed reductions in preterm births. Discussion focuses on future research, public policy issues, and the need for expanding nurse-patient interactions into the home.
Rabbit uterine cervical fibroblasts produced a large amount of matrix metalloproteinases (MMPs) such as collagenase (MMP-1) and stromelysin (MMP-3) and a small relatively amount of tissue inhibitor of metalloproteinases (TIMP). When cells were treated with progesterone or oestradiol-17 beta, both steroids concurrently decreased the level of procollagenase and prostromelysin in the culture media and the steady-state levels of the respective mRNAs. On the other hand, the level of TIMP in the culture media and the steady-state level of its mRNA were simultaneously increased by these steroids. Similarly, the suppression of production of MMPs and the augmentation of TIMP production by both steroids were observed with interleukin 1 (IL-1)-treated cells, but the action of progesterone was more effective than that of oestradiol-17 beta in the IL-1-untreated and -treated cells. These results suggest that collagenolysis in uterine cervical fibroblasts is negatively regulated by steroid hormones via the acceleration of TIMP production and the suppression of synthesis of MMPs at the pretranslational level.
A randomized prospective trial was performed to compare the efficacy and safety of ritodrine and indomethacin in the long-term treatment of preterm labor. Forty patients with intact membranes in preterm labor at 23 to 34 weeks' gestation were randomized to receive either intravenous ritodrine or oral indomethacin as the first-line tocolytic agent. Successful intravenous ritodrine therapy was followed by oral terbutaline therapy, and indomethacin-treated patients continued to receive oral indomethacin. Treatment failures were defined as progressive preterm labor or patient intolerance, and these patients were treated with intravenous magnesium sulfate. Ritodrine and indomethacin were equally successful in delaying preterm birth as defined by interval to delivery, gestational age at delivery, delivery delayed greater than 7 days, attainment of 35 weeks of gestation, percentage of patients who required magnesium sulfate therapy, percentage of patients who were readmitted with premature rupture of membranes, absence of recurrent preterm labor, and infant birth weight. More than 80% of mothers who received ritodrine voiced complaints of beta-sympathomimetic side effects, and one patient discontinued treatment as the result of intolerance. There were minimal patient complaints with indomethacin use. No statistically significant differences were noted in neonatal outcome as defined by Apgar scores, umbilical cord pH, intensive care days, ventilator days, or neonatal deaths. However, three cases of primary pulmonary hypertension were observed in the indomethacin group. We had not previously observed this problem with short-term (24 to 48 hours) indomethacin therapy.
A total of 394 patients were enrolled in a study to assess the effectiveness of an educational preterm delivery prevention program and to determine whether the addition of home uterine monitoring to the program improved results in patients at high risk of preterm labor. Both the educational program and home uterine monitoring were found to increase the percentage of women with preterm labor who sought care while still favorable for long-term suppression, resulting in a decreased incidence of preterm births and improved outcome when compared with similar high-risk patients who did not participate in these programs. In a randomized, prospective study, addition of home uterine monitoring to the educational program was found to significantly improve outcome in twin gestations but not in singleton gestations. However, the number of singleton pregnancies was too small to rule out possible benefit from home uterine monitoring in that group.
Maternal serum C-reactive protein (CRP) has been studied extensively as an adjunct in the diagnosis of subclinical infection among pregnant women with preterm labor or preterm rupture of membranes. However, before the utility of CRP can be studied in pregnancies with these complications, the effects of normal pregnancy and labor on maternal serum CRP levels must be established. We determined CRP levels serially from 22 weeks' gestation until delivery in healthy pregnant women without antepartum complications. Median CRP values for women not in labor ranged from 0.7-0.9 mg/dL, depending on gestational age; 95% of the values were 1.5 mg/dL or lower. No consistent change in CRP levels with gestational age was found among serially sampled women not in labor. The median CRP value for women in labor at term was 1.3 mg/dL, and 32% of values were over 1.5 mg/dL. Median CRP values in normal pregnancies appear to be higher than standardized values for nonpregnant individuals, and CRP values are further elevated in labor. Understanding the physiology and temporal course of the increase in CRP in normal pregnancy and labor may help to clarify the appropriate use of CRP in complicated pregnancies.
NaProTECHNOLOGYDating PregnancyOvulation-Based Dating
Functional psychosis in the puerperal period is a dramatic phenomenon that presents a unique set of diagnostic and therapeutic challenges. Despite its omission from modern classificatory systems such as DSM-III and DSM-III-R, the concept of puerperal psychosis continues to receive support from clinicians on the basis of the apparently distinctive clinical picture that characterizes psychoses occurring at this time. The range of possible nosological models is considered in light of relevant studies of puerperal illness, and the evidence for and against each model is presented. The question of the prognosis of puerperal psychosis is reviewed and guidelines for its estimation in the individual case proposed. The heuristic importance of puerperal psychosis in terms of basic research and preventive psychiatry is also stressed.
PregnancyDetection and MonitoringHome Uterine Activity MonitoringTocodynamometry
The relative contribution of uterine activity obtained by home monitoring with a guard ring tocodynamometer compared with seven specific signs and symptoms reported during patient/nurse contact as an aid in detecting preterm labor has not been studied. In this prospective, multicenter study, patients at risk for developing early labor who were randomized to receive home uterine activity monitoring and perinatal nursing support were assessed. The initiator of provider contact (uterine activity detected on routine transmission, patient-perceived signs and symptoms of preterm labor during perinatal nurse contact, or both) resulting in a diagnosis of preterm labor was recorded. Contraction data were then analyzed for an association with preterm labor. There was a strong association of increased uterine activity (four or more contractions per hour) on a repeat monitoring strip with preterm labor (P less than .001). Among patients diagnosed with preterm labor, 31% had increased uterine activity detected on a routine transmission without patient-reported signs and symptoms, compared with 24% who were diagnosed as the result of patient-reported symptoms without increased uterine activity. Daily objective uterine activity data alone have greater incremental value over and above other signs and symptoms as an aid to the physician in diagnosing preterm labor.
PregnancyPrevention ProgramsRisk Assessment and ScreeningPrenatal Interventions
A preterm birth prevention program consisting of risk scoring, intensive weekly observation including cervical examinations, and detailed education about preterm labor signs and symptoms was tested in a predominantly black, indigent population. One thousand high-risk women were randomized to treatment or control groups. Although more preterm labor was diagnosed and treated in the treatment group, there were no significant differences between the groups with respect to mean birth weight or gestational age, spontaneous preterm delivery rates, or low or very low birth weight rates. The rates of respiratory distress syndrome and fetal and neonatal mortality, although greater in the treatment group, were not statistically different. However, the treatment-group infants had significantly more intracranial hemorrhages and spent more days on ventilators. At this institution, the preterm birth prevention program was not effective.
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)
PregnancySigns and SymptomsPatient Education and AwarenessPreterm Labor Symptom Recognition
Patient and staff education concerning the subtle signs and symptoms that precede a clinical diagnosis of preterm labor have not been well established. Therefore we interviewed 100 patients for the presence or absence of various symptoms and signs during the 7 days preceding diagnosis of preterm labor. An additional 100 patients without preterm labor matched for gestation were chosen at random as control subjects. A history of increased uterine contractions, menstrual cramps, constant backache, constant pelvic pressure, increased amount and consistency and color change of vaginal discharge, and increased frequency of urination were present with a statistically significant higher frequency in patients with preterm labor compared with controls. Twenty-nine percent of patients did not report any uterine contractions and only half described them as painful. Fewer than 50% of the women reported contractions as frequently as every 10 minutes or more.
The early detection of preterm labor and the prevention of preterm birth require special attention to early subtle signs and symptoms of preterm labor. The concept of "Braxton Hicks contractions" may negate these early signs and symptoms by falsely reassuring patients, thus encouraging them not to seek medical care promptly.
PregnancyInfection DetectionC-Reactive Protein ChorioamnionitisChorioamnionitis Prediction
The purpose of this study was to critically review published studies regarding sensitivity, specificity, and positive and negative predictive values of antenatal tests to diagnose chorioamnionitis or fetal-neonatal sepsis in preterm premature rupture of the membranes. A Medline Data-Base computer program search from 1980 to 1988 identified 39 studies, 23 of which were accepted after independent review with preset criteria. An ideal test to predict chorioamnionitis or neonatal sepsis was not found. The low success rate for amniocentesis and the need for repeat taps preclude the acceptance of tests on the basis of amniotic fluid. Single, small studies, the precision of which has never been tested, show good indices for repeatedly increased serum levels of C-reactive protein (greater than 20 mg/L), a high level of C-reactive protein greater than 40 mg/L, or a day-to-day coefficient of variation for C-reactive protein of greater than 30% in the prediction of histologic or clinical chorioamnionitis. Ultrasonographic observation of fetal activity, if published study results are confirmed, may be of value to predict amniotic fluid bacterial colonization.
Two recently published meta-analyses of controlled trials of a wide variety of progestational agents, used in pregnancy (Daya 1989; Goldstein et al. 1989), prompted this third meta-analysis of placebo-controlled trials involving the prophylactic use of a single agent, 17 alpha-hydroxyprogesterone caproate. Of seven relevant published reports of controlled trials, six had involved women considered to be a high risk of miscarriage or preterm birth. This analysis provides no support for the view that 17 alpha-hydroxyprogesterone caproate protects against miscarriage, but suggests that it does reduce the occurrence of preterm birth. The latter effect was reflected in a reduced rate of low birthweight babies, but not in a statistically significant reduction in perinatal mortality and morbidity. The difference between this meta-analysis and the two earlier meta-analyses illustrates the problems both of selective sub-grouping and of comprehensive pooling of data from small trials.
The usefulness of maternal C-reactive protein (CRP) measurements in the diagnosis of chorioamnionitis and puerperal and neonatal infectious morbidity was studied among 147 patients with preterm rupture of the membranes (PROM). Thirty-three patients developed chorioamnionitis, 10 patients developed puerperal endometritis, and 21 newborn infants developed neonatal infections. There was no difference in the highest antepartum CRP between patients with or without chorioamnionitis. The overall test performance for CRP was poor suggesting that elevated antepartum CRP may be misleading in the diagnosis of chorioamnionitis. However, use of serial CRP measurements increases the test performance. The high negative predictive value suggests that CRP is useful in predicting the absence of chorioamnionitis.
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.
C-reactive protein (CRP) is an acute-phase protein synthesized by the liver during the course of a large number of diseases. During gestation and parturition, progressively increasing numbers of gravida develop elevated levels up to 32, 48 to 80 per cent, respectively). These elevations in pregnancy, the nonspecificity of the test, and the inability to function as a reliable marker of fetal and/or maternal infectious morbidity have obscured the pragmatic utility of CRP determinations in both obstetrics and gynecology. Because of its biophysical kinetics, C-reactive protein determinations are best used as a monitoring parameter after the documentation of infection rather than as a diagnostic indicator of infection. They can provide valuable end titration points for termination of parenteral antibiotic therapy.
General OB/GYNInflammatory MarkersC-Reactive ProteinInfectious Morbidity
We tested the hypothesis that disturbed follicular development and disturbed luteal progesterone (P4) secretion are associated with reduced gonadotropin secretion in the early follicular phase by measuring pulsatile LH and FSH secretion at that time in 53 normally menstruating women. Three groups of women were identified on the basis of serum sex steroid concentrations (measured daily throughout the cycle) and luteal phase length. Group A (n = 27) had normal ovarian hormone secretion with peak serum estradiol (E2) concentrations of 440 pmol/L or more, peak serum P4 concentrations of 19 nmol/L or more, and luteal phase length of 9 days or more. Group B (n = 16) had normal peak serum E2 values, but peak serum P4 values less than 19 nmol/L and/or luteal phase length less than 9 days. Group C (n = 10) had peak serum E2 values below 440 pmol/L. Risk factors for the disturbances found in groups B and C were exercise and/or intermittent dieting. Compared to group A, both groups B and C had reduced mean serum LH concentrations (3.1 +/- 1.5 vs. 2.3 +/- 1.4 and 2.0 +/- 1.0 IU/L; P less than 0.05) and reduced LH pulse frequencies (5.2 +/- 2.1 vs. 3.5 +/- 1.8 and 3.3 +/- 2.3 pulses/12 h; P less than 0.02). LH amplitude was similar in all 3 groups. Mean serum FSH concentrations were slightly but not significantly lower in group C. We conclude that reduced gonadotropin secretion during the follicular phase may indeed affect E2 and P4 secretion at later stages of the menstrual cycle. The patterns of alteration associated with disturbed E2 and P4 secretion in normally menstruating women are similar to those that occur in women with hypothalamic amenorrhea.
PregnancyInfection BiomarkersTocolysis OutcomesC-Reactive Protein in Pregnancy
Tocolytics were administered in 66 consecutive women in uncomplicated preterm labour with intact fetal membranes (53 singleton and 13 twin pregnancies). C-reactive protein (CRP), a marker of infection, was determined daily and used retrospectively to investigate the role of subclinical infection in preterm labour and to predict the efficacy of tocolysis and the development of a clinical perinatal infection. CRP was also determined in 66 women in uncomplicated labour at term (53 singleton and 13 twin pregnancies). The placenta was examined for histological evidence of infection in all patients who were delivered before 36 weeks (n = 21) and in all women in the control group (n = 66). Elevated CRP levels were more often found in patients who were refractory to tocolysis, suggesting an underlying infectious morbidity. Placental infection was found in 62% of the preterm delivery group and in 12% of the control group. There was an association between elevated CRP levels and histological evidence of placental infection. However, confounding factors such as urinary tract infections limit the usefulness of the CRP test. Because CRP cannot predict clinical perinatal infection accurately, its clinical relevance is very limited.
PregnancyExercise During PregnancyExercise-Associated AmenorrheaPhysical Activity and Reproduction
Two runners who were not aware they had conceived continued their intense running regimens during the first and second trimesters of pregnancy. Both women assumed that their amenorrhea was due to endurance training. When their pregnancies were diagnosed, both women markedly reduced their training mileage during the third trimester because they feared that intense exercise might harm the fetus. Retrospective data were collected on their antenatal and intrapartum courses. Both women delivered healthy infants of normal weight. Although these two cases suggest that strenuous anaerobic exercise during pregnancy is not harmful, more studies are needed to determine if these cases are isolated.
PregnancyMenstrual Dating AccuracyUltrasound vs Menstrual DatingPostterm Pregnancy Diagnosis
Despite recognition that estimation of gestational age (GA) based on maternal recollection of the last normal menstrual period (LNMP) is fraught with error, it is not generally appreciated that the magnitude and direction of this error vary as a function of the LNMP estimate. Early second-trimester (16 to 18 weeks) ultrasound determinations of the fetal biparietal diameter were used as the "gold standard" to test the validity of LNMP-based GA estimates in 11,045 women. The large majority of deliveries occurring at or near term showed LNMP estimates that were valid within plus or minus seven days of the ultrasound estimate. As the LNMP GA deviated progressively toward earlier or later GAs, however, the discrepancies became quite marked, especially for postterm dates. The positive predictive values of the LNMP GA estimates decreased dramatically from term (.949) to preterm (.775) to postterm (.119) deliveries. These systematic errors in menstrual GA estimates have profound implications for unnecessary induction, dysfunctional labor and cesarean section, and resultant neonatal and maternal morbidity.
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.
Nine patients in preterm labor requiring long-term tocolysis were managed with subcutaneous terbutaline administered via a portable infusion pump. All had failed oral tocolytic therapy and were therefore faced with prolonged hospitalization. In this feasibility study, the patients were treated at home and monitored with portable tocodynamometers and home nursing visits. Uterine activity data were transmitted via telephone to the study center and terbutaline pump infusion rates were adjusted accordingly. Terbutaline pump therapy consisted of a combination of low-dose continuous basal infusion supplemented with intermittent high-dose boluses. Total daily drug dosage remained exceptionally low (less than 3 mg/24 hours). The mean gestational age at initiation of therapy was 29.6 +/- 3.7 weeks, and pregnancy was prolonged an average of 9.2 +/- 4.3 weeks. The minimum gestational age at delivery was 37.3 weeks. Patient tolerance was excellent and, in a total 394 patient-days of therapy, there were no significant complications. We conclude that the portable subcutaneous terbutaline pump may be a promising new method for long-term outpatient tocolysis in patients who cannot be maintained on oral therapy.
The low-molecular-mass insulin-like growth factor-binding protein (IGF-BP) and placental protein 12 (PP12) are identical proteins that are present in human serum, amniotic fluid, secretory endometrium and decidua. IGF-BP/PP12 is believed to act as an autocrine or paracrine regulator of cell growth. A cDNA clone encompassing the entire protein coding region of this protein was isolated from a human decidual cDNA library. The authenticity of the cDNA was verified by in vitro transcription/translation experiments and by the identity of the 10 N-terminal amino acids deduced for the mature peptide with those obtained by direct protein sequencing. The amino acid sequence indicates that pre-IGF-BP/PP12 consists of 259 amino acid residues. The putative signal peptide is 25 residues long, and the mature protein thus contains 234 amino acids and has a molecular mass of 25293 Da. The sequence is very cysteine-rich at the N-terminus after which there are regions of clustered Pro, Glu, Ser and Thr residues (so-called PEST regions), which exist in proteins with short half-lives. The amino acid sequence also includes an Arg-Gly-Asp tripeptide that may function as a cell recognition signal. The IGF-BP/PP12 gene encodes a single 1.6 kb mRNA species that is expressed in decidua, secretory endometrium, liver and a human hepatoma cell line (HepG2). Southern blot analysis suggests that there is a single IGF-BP/PP12 gene in the human genome.
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.
To assess uterine activity before labor in patients delivering preterm, at term, and postterm, the maximum spontaneous contraction frequency per 10-minute window during the initial portion of antepartum fetal heart rate monitoring was analyzed. Patients with multiple gestation, third trimester bleeding, polyhydramnios, or premature rupture of membranes and those already diagnosed with preterm labor were eliminated from the study. Of the 2446 remaining patients (7247 antepartum fetal heart rate tests) who went into spontaneous labor, 237 did so before 37 completed weeks of gestation, 1077 entered labor at term (38 to 42 completed weeks), and 1132 did so after 42 weeks. There was a significant increase in maximum uterine activity per 10-minute window from 30 to 44 weeks of gestation (average 4.7% per week; r = 0.97, p less than 0.0001). When compared with patients delivering spontaneously at term, average maximum uterine activity per 10-minute window was greatest in the preterm labor group (p less than 0.05) and least in the postterm labor group (p less than 0.05). These differences were present for several weeks preceding the onset of spontaneous labor. All three groups showed a surge of uterine activity during the 3 days before the onset of spontaneous labor.
Cervical cerclage as a temporizing measure for the treatment of patients with placenta previa was evaluated in 25 patients admitted to the hospital for vaginal bleeding between 24-30 weeks' gestation and sonographic evidence of a placenta previa. The patients were randomly assigned to either cerclage (13) or conventional management (12). Cerclage patients had significantly better perinatal outcome, as indicated by more advanced gestational age at the time of delivery (34.9 +/- 3.0 versus 31.6 +/- 2.9 weeks; P = .02), larger birth weight (2709 +/- 511 versus 1812 +/- 506 g; P = .002), and fewer neonatal complications (two of 13 versus ten of 12 infants; P = .001). Maternal bleeding was more frequent and severe for patients in the control group. The total hospital cost was less for cerclage patients than for those receiving conventional expectant management ($9898 +/- 3943 versus $27,271 +/- 9901; P = .02). These results support the use of cervical cerclage for the treatment of patients with symptomatic placenta previa early in gestation.
General OB/GYNInfection MarkersC-Reactive ProteinDiagnosis and Management
This study was designed to derive the predictive value of C-reactive protein (CRP) in peripheral venous serum of patients admitted to hospital with suspected premature rupture of the membranes (PROM). CRP was assayed by each of 4 separate methods and the results have been compared for accuracy and practical value with respect to clinical outcome and the histopathology of the placenta. Of the 4 techniques used only the latex test had characteristics suitable for a diagnostic screen. While the results were only semiquantitative, when comparisons were made to other techniques no significant change in clinical diagnosis would have been made. The results have confirmed that chorioamnionitis and preterm labour are often associated, but in some instances the extent of inflammatory infiltration was greater than might have been expected from the short time interval between documented membrane rupture and delivery. Thus it may be speculated that some cases of PROM are secondary to, rather than causative of, infection. Finally it is suggested that a controlled therapeutic trial of active intervention in those cases of PROM with elevated CRP in the absence of other clinical parameters suggestive of intrauterine infection should be undertaken.
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)
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.
PregnancyPremature Rupture of MembranesChorioamnionitis PreventionAmnioinfusion
To determine the best method of preventing ascending infection in the management of premature rupture of membranes, antibiotics such as latamoxef sodium, cefoperazone sodium, and cefotaxime sodium were infused directly into the amniotic cavity in 64 patients undergoing induction of labor at term. A single infusion of 100 or 500 mg of each drug resulted in a concentration of 200 to 1000 micrograms/ml immediately after infusion, and the concentration remained above 10 micrograms/ml for about 24 hours without significant increase in fetal or maternal blood levels. Consequently, a daily single dose of 100 mg or more is probably effective prophylaxis in cases of premature rupture of membranes. When intrauterine infection is suspected, the dose can be increased to 500 mg or more, and transplacental administration may be added to achieve a higher concentration in fetal blood. The present study simulates well premature rupture of membranes, and an amnioinfusion of antibiotics will be reliable and effective in managing premature rupture of membranes.
PregnancyPremature Rupture of MembranesC-Reactive Protein ChorioamnionitisChorioamnionitis Screening
Chaaban M et al., 1988·J Gynecol Obstet Biol Reprod (Paris)
We have retrospectively studied the changes in the level of C-reactive protein (CRP) and of white blood cells in 82 patients who had premature rupture of the membranes between the 20th and the 36th week of pregnancy in order to estimate the possibility of prenatal screening for amnion infections in early rupture of the membranes. The level of CRP was shown to be quickly and significantly raised in cases of clinical or histological chorioamnionitis, whereas the change in maternal leucocytes alters little and later. The level of CRP can be worked out as an early biological marker which is sensitive and cheap in the clinical supervision of cases with early rupture of the membranes.
PregnancyPremature Rupture of MembranesC-Reactive ProteinChorioamnionitis
In a prospective blind study 380 daily serum samples from 55 women with preterm premature rupture of the membranes were analysed for C-reactive protein (CRP). Although the last CRP before delivery was higher in patients with histological chorioamnionitis (P = 0.007), considerable overlap between infected and non-infected pregnancies occurred, precluding the use of CRP as a diagnostic test if published normal levels were used. When upper limits were set at 30, 35, or 40 mg/l, the last CRP before delivery proved 90, 95 and 100% specific and 88, 92 and 100% positively predictive of infection in singleton pregnancies. Such high specificities are needed to prevent inappropriate intervention based on false positive results. We therefore propose upper limits for single estimations of 30, 35, or 40 mg/l depending on the relative risks of preterm delivery versus infection at various gestational ages. In addition, consecutive values greater than 20 mg/l appeared highly predictive of infection.
Two hundred eighty-five charts were reviewed from patients who underwent surgery for ectopic pregnancy. Excluded were patients with previous tubal reparative surgery, linear salpingotomy, or failed sterilization. The incidence of isthmic ectopic pregnancy in the remaining 255 cases was 15.3%. The association of salpingitis isthmica nodosa (SIN) and isthmic ectopic pregnancy was determined by review of resected tubal segments. SIN was noted in 17 of 37 cases (45.9%) of isthmic ectopic pregnancy. SIN places the patient at risk for recurrent ectopic pregnancy or infertility. Recommended conservative management of isthmic ectopic pregnancy is segmental resection with postoperative emphasis on documentation of SIN when present. Postoperative hysterosalpingography is recommended with an abnormal contralateral tube or when SIN is noted in the resected tubal segment. Management options after an isthmic ectopic pregnancy when future fertility is desired are presented.
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.
PregnancyPremature Rupture of MembranesInflammatory BiomarkersC-Reactive Protein in Pregnancy
The value of maternal C-reactive protein (CRP) levels as predictors of fetal and maternal infective morbidity and fetal mortality was assessed prospectively over a 6-month period in all cases of premature rupture of the fetal membranes or suspected premature labour. Statistical analysis of results showed that CRP at a level of 1.32 mg/dl is a sensitive marker of infective morbidity in mother and neonate. Furthermore, there was a significant association between raised CRP levels and low-birth-weight babies, suggesting that intra-uterine infection is a major cause of prematurity in the study population.
The development of a 10-item self-report scale (EPDS) to screen for Postnatal Depression in the community is described. After extensive pilot interviews a validation study was carried out on 84 mothers using the Research Diagnostic Criteria for depressive illness obtained from Goldberg's Standardised Psychiatric Interview. The EPDS was found to have satisfactory sensitivity and specificity, and was also sensitive to change in the severity of depression over time. The scale can be completed in about 5 minutes and has a simple method of scoring. The use of the EPDS in the secondary prevention of Postnatal Depression is discussed.
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).
Cervical incompetence is one of the main contributors to repeated pregnancy loss, accounting for approximately 25% of the cases. Typically it results in progressive cervical dilatation, leading to a painless second- or early-third-trimester abortion. In most instances cervical incompetence is the result of previous obstetric or gynecologic trauma; a congenital etiology is unusual. Despite the various reported diagnostic procedures, the obstetric history and frequent visual and digital examinations during pregnancy remain the most important factors in arriving at the correct diagnosis. In spite of the fact that numerous procedures have been advocated as treatment, the McDonald purse string closure technique is by far the most simple and effective corrective surgical technique, yielding an overwhelming number of successful pregnancies.
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.
C-reactive protein has been used to identify patients at high risk for infectious morbidity with preterm labor or preterm rupture of membranes. In this article we report on 104 patients with preterm labor symptoms (n = 45) or preterm rupture of the membranes (n = 59) and serial evaluations of C-reactive protein measured by latex agglutination and laser nephelometry. The simple, inexpensive latex method appears comparable to the laser method in predicting infectious morbidity and can be used clinically. Elevated C-reactive protein values before delivery predict infectious morbidity in only 8% to 29% of patients, and up to 18% of patients with serious infections may be misdiagnosed as having normal C-reactive protein values before delivery.
Gerhard I et al., 1987·Biol Res Pregnancy Perinatol
Between 1983 and 1984 a double-blind randomized study with progesterone substitution in threatened abortion was carried out. Fifty-six patients with vaginal bleeding during the first trimester of pregnancy, the internal cervical os being closed, were referred to the hospital. Twenty-five women (5th and 6th week of gestation) with positive serum concentrations of beta-hCG were admitted to the study without regard to sonogram results. In other 25 women (7th-10th week of pregnancy) and 6 women (greater than or equal to 11th week of pregnancy) fetal heart action and movement could be demonstrated by ultrasound. The patients were prescribed bed rest and vaginal suppositories twice daily, containing either 25 mg progesterone or only polyethylene glycol. The code was not broken until after completion of the study. Serial serum determinations of beta-hCG, estradiol-17 beta (E2), progesterone, and ultrasound were performed. Four patients had to be omitted from final analysis (two tubal pregnancies, one intrauterine infection, one sectio parva). Three of 26 patients progesterone (11%) and five of 26 patients with placebo (19%) had an abortion, which represented no significant difference. Frequency of abortion was increased in women more than 30 years old, in women with previous abortions and after ovulation induction. Progesterone treatment resulted in a significant elevation of serum progesterone concentrations (p less than 0.01), while beta-hCG and E2 were unchanged. The results of this study confirm that pregnancy outcome is favorable in women with bleeding and normal hormone concentrations without hormonal treatment and unfavorable in women with reduced beta-hCG and E2-concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
Examples of a combined approach using in vivo as well as in vitro methods for the assessment of prenatal toxicity are presented. The topics discussed include the analysis of the possible embryotoxic potential of valproic acid (VPA), female sex hormones, bis(tri-n-butyltin) oxide (TBTO), and acyclovir and the problem of supplementing in vitro systems with drug-metabolizing activity.
Effective tocolytic therapy depends on the ability to make an early diagnosis of preterm labor. This study was designed to assess whether daily ambulatory home monitoring of uterine activity could facilitate early diagnosis of preterm labor. Of 76 patients at high risk for preterm labor who used daily ambulatory tocodynamometry, approximately half developed preterm labor. Evaluation when the diagnosis of preterm labor was first established has shown that in 8% of the patients the cervix was dilated more than 2 cm, shortened to less than 0.5 cm in 23%, and the fetal membranes were intact in all subjects. The same evaluation in 76 nonrandom contemporary controls matched for risk factors, maternal age, and parity has shown that more than 50% had a cervix dilated more than 2 cm, 38% had a cervix shorter than 0.5 cm, and 24% had rupture of the fetal membranes. Ultimately, 88% of the monitored patients and 59% of controls delivered at term. Comparisons between these groups indicate that intermittent home tocodynamometry may indeed be useful in making the early diagnosis of preterm labor.
General OB/GYNElectronic Fetal MonitoringFetal Monitoring StrategiesProspective Comparative Studies
We investigated the effects of using intrapartum electronic fetal monitoring in all pregnancies, as compared with using it only in cases in which the fetus is judged to be at high risk. Predominant risk factors included oxytocin stimulation of labor, dysfunctional labor, abnormal fetal heart rate, or meconium-stained amniotic fluid. This prospective alternate-month clinical trial took place over a 36-month period during which 34,995 women gave birth. In alternate months, either 7 (for "selective monitoring") or 19 (for "universal monitoring") fetal monitors were made available in the labor and delivery unit. During the "selective" months, 6420 of 17,409 women (37 percent) were electronically monitored, as compared with 13,956 of 17,586 women (79 percent) during the "universal months." Universal monitoring was associated with a small but significant increase in the incidence of delivery by cesarean section because of fetal distress, but perinatal outcomes as assessed by intrapartum stillbirths, low Apgar scores, a need for assisted ventilation of the newborn, admission to the intensive care nursery, or neonatal seizures were not significantly different. We conclude that not all pregnancies, and particularly not those considered at low risk of perinatal complications, need continuous electronic fetal monitoring during labor.
Cervical examination between 26 and 30 weeks' gestation is described as a method for identifying women at risk for delivery before 34 weeks. Blinded cervical examinations were performed in 185 consecutive women, and 15 (8%) were found to have cervixes dilated 2 or 3 cm. The incidence of delivery before 34 weeks' gestation was 27% in such women compared with 2% in those whose cervixes were undilated or 1 cm. Other factors linked to cervical dilatation included parity and prior preterm delivery. However, parous women with cervical dilatation remained at increased risk for delivery before 34 weeks' gestation. We conclude that early third-trimester cervical examination may be an important adjunct in identifying women at risk for preterm delivery.
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.
PregnancyMonitoring and PreventionTocolysis ManagementAmbulatory Tocodynamometry
A study to evaluate whether ambulatory tocodynamometry at home could enhance the management of oral tocolysis was performed. On discharge from the hospital, after completing parenteral tocolysis, 60 patients received a lightweight tocodynamometer, designed for storage and transmission of uterine activity data. Sixty additional contemporary patients, who were matched for maternal age, parity, and risk factors, served as a control group. In addition to instructions regarding self-detection of recurrent preterm labor, monitored patients recorded uterine activity for greater than or equal to 200 min/day and then transmitted the data to the study center. Tocolytic dosage was adjusted to maintain mean uterine contraction frequency of less than 4/hr. Persistent uterine contractions of greater than or equal to 4/hr lead to in-hospital evaluation for recurrent preterm labor. The results indicate that the monitored group had a lower incidence of preterm births mostly because of a decrease in the proportion of patients with failed tocolysis. It is suggested that surveillance of uterine activity at home during oral treatment for preterm labor may be instrumental in improving perinatal outcome in high-risk patients.
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.
PregnancyCervical Incompetence DiagnosisCervical Length MeasurementPrevention of Preterm Delivery
To evaluate the feasibility of the use of serial ultrasound measurements of cervical length, membrane protrusion, and dilatation to discriminate between the competent and the incompetent cervix, 107 at-risk patients and 30 control subjects were examined prospectively. Patients were divided into five groups based on treatment and method of diagnosis. Epidemiologic, ultrasound, and outcome data were analyzed. Means and standard deviations for ultrasound measurements were established. Highly significant differences between all prediagnostic and postdiagnostic-pretreatment measurements were found (p less than 0.001). Highly significant differences were also found between all postdiagnostic-pretreatment and postdiagnostic-posttreatment measurements (p less than 0.001). No significant differences between prediagnostic and postdiagnostic-posttreatment measurements were noted. The incidence of preterm delivery was significantly higher among untreated diagnosed patients (p less than 0.01). By combined clinical and ultrasound criteria 51 patients (47.7%) were identified as not having cervical incompetency. Fifty-six patients (52.3%) were diagnosed.
The potential tocolytic effect of natural progesterone administration on premature labor was investigated in a double-blind study. An oral progesterone formulation was used because its ability to increase both plasma and myometrial concentration of progesterone in pregnant women had been previously demonstrated. Furthermore, no commercial intravenous or intramuscular natural progesterone formulation is currently available in France. Fifty-seven patients in two obstetric clinics, admitted because of the risk of premature delivery, were included in the study, and uterine contractility and fetal cardiac rhythm were monitored in all of them. At random and after 30 minutes' rest, 29 women absorbed four capsules of 100 mg of progesterone each and 28 women absorbed four capsules of a placebo. Plasma progesterone levels were evaluated in all cases after 30 minutes' rest and 1 hour after absorption of the capsules. The results showed that bed rest and placebo administration decrease uterine activity in 42% of the cases and oral progesterone decreases activity in 75% to 88% of cases, depending on the initial severity of the menace of premature delivery. The difference between the effects of progesterone and of placebo is significant. The tocolytic effect of oral progesterone is not as intense or as rapid as the effect of intravenous beta-mimetics but is sufficient in 80% of cases, on the average, to stop the premature labor without any detectable side effects. This tocolytic effect of oral progesterone is related not just to an increase in plasma progesterone levels but probably to an increase in myometrial progesterone concentration.
PregnancyCervical Ripening PredictionCervical AssessmentScreening and Prevention
A group of 8303 women was studied to determine the timing of cervical ripening. It was confirmed that these signs of cervical change can be observed several weeks before preterm births. The precocious signs of external ripening can be recognized during a vaginal examination and may be useful in predicting preterm labor.
General OB/GYNDiagnostic ImagingCervical AssessmentCervical Insufficiency
Artifacts interfering with sonographic imaging of the uterine cervix in pregnancy are described. Increasing the amount of fluid in the urinary bladder closes the cervix and alters the configuration of the lower uterine segment, while increased intra-uterine pressure results in reciprocal changes. Angulation of the transducer and manual pressure thereon distort sonographic findings. It is concluded that, contrary to recent reports in the literature, sonography cannot reliably demonstrate changes in cervical compliance during pregnancy. Vaginal examination remains the ultimate diagnostic modality for the diagnosis of the incompetent cervix, while sonography may be used as an adjunct only.
A single dose of MPA (Depo-Provera; Upjohn Co., Kalamazoo, Michigan) was administered intramuscularly to 12 time-mated pregnant cynomolgus monkeys on day 27 (+/- 2) of gestation at 25 mg/kg or at 100 mg/kg. Maternal blood samples were collected immediately prior to MPA injection and then at regular intervals until cesarean section at term (day 152 +/- 3). Infants in both dose groups had external genital abnormalities. Female infants in the low-dose groups had partial or complete labial fusion, prominent median raphe, and clitoral hypertrophy; at high doses (100 mg/kg), the female infants had complete labial fusion and a distinct penile urethra. MPA had an opposite effect on external genitalia of male infants. The penis was short and the scrotal swelling was absent or less conspicuous, and two males had hypospadias. The adrenal glands were significantly smaller (P less than 0.05) in infants of both sexes treated with 100 mg/kg. One of the infants treated with 25 mg/kg of MPA had a muscular ventricular septal defect. Serum concentrations of MPA were determined by radioimmunoassay in eight pregnant monkeys. In the 25 mg/kg group the patterns of MPA profiles in the serum were similar in all four animals. An initial peak occurred at 24-48 hr postinjection (2.7-9.6 ng/ml), followed by a slight decrease at 3 days postinjection (gestational day 30), and then a steady increase to maximum levels of 10-14 ng/ml occurring between gestational days 37 and 50. Serum levels gradually declined to concentrations below 5 ng/ml by midgestation in three of four monkeys. By comparison, both the patterns and magnitude of MPA concentration showed great interanimal variation in the 100 mg/kg group. MPA was present in cord blood at measurable concentrations in infants at both dose groups; the levels ranged from 0.6 to 8.3 ng/ml, corresponding to 40-72% of the maternal concentrations. These results demonstrate that a single injection of MPA during early pregnancy causes selective embryotoxicity in both male and female fetuses. Presence of high levels of MPA in maternal sera during the critical period of genital development can cause specific genital defects; however, the exact mechanism by which MPA causes these paradoxical genital abnormalities is unknown.
PregnancySubclinical InfectionTocolysis ResponseC-Reactive Protein in Pregnancy
The role of subclinical intrauterine infection in preterm labor was evaluated prospectively in 40 patients and appropriate control subjects. The 24 preterm labor patients (60%) with a negative C-reactive protein value responded to tocolysis 95.8% of the time, with a mean delay of delivery of 35.5 days and a mean gestational age of 36.9 weeks. The 16 patients (40%) with a positive C-reactive protein value responded to tocolysis only 37.5% of the time, with a mean delay of delivery of 14.4 days and a mean gestational age of 33.2 weeks. Pathologic evidence of chorioamnionitis was present in 32.9% of 310 preterm deliveries as compared to only 22.3% of 1631 term deliveries. The presence of subclinical infection must be considered in cases of preterm labor, especially among patients for whom tocolytic therapy is unsuccessful.
A single dose of MPA (Depo-Provera; Upjohn Co.; USA) was administered intramuscularly on day 27 (+/- 2) of gestation to three dosage groups of pregnant baboons. The dosage expressed as mg/kg corresponded to 1 (2.5 mg/kg), 10 (25 mg/kg) and 40 (100 mg/kg) times the human contraceptive dose equivalent (HDE) based on body weight. Injectable MPA was not teratogenic in baboons at 1x HDE. The teratogenicity was confined to the higher doses which included malformations of the external genitalia at 10x and 40x HDE and adrenal gland hypoplasia at 40x HDE. The maternal serum MPA concentrations were high during the critical period of adrenal and genital development. The pattern of MPA concentrations in maternal sera was similar between animals in the low dose group (10x HDE). In contrast, animals in the high dose group (40x HDE) showed interanimal variations in maternal serum concentrations of MPA. This study has demonstrated that injectable MPA is not teratogenic in baboons at human contraceptive dose equivalent and, even at higher doses, does not result in any nontarget organ malformations.
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.
The likelihood of repetition of preterm birth after spontaneous onset of labour has been studied in 6572 reproductive careers after excluding stillbirths, multiple births, all careers in which any labour had been induced, and all careers in which the gestation length in any pregnancy was not certain. The analysis was controlled not only for pregnancy number, but for the nature of the reproductive outcomes. In most reproductive sequences there was a weak correlation between the gestation in one pregnancy and subsequent ones. The risk of preterm birth was tripled after one previous preterm birth with or without a preceding abortion, and increased six-fold after two previous preterm births. However, the attributable risk was low, and most multiparae with preterm births did not have a previous history.
A system capable of ambulatory home monitoring of uterine activity and data transmission was evaluated in a group of pregnant patients. The evaluation 1) Is the information as reliable as that obtained by the current stationary monitors; 2) Does the information obtained by the tested system relate to that obtained by direct intrauterine pressure measurements; and 3) Is the system simple enough to be used by the unsupervised gravida at home? The results indicate that the tested system can provide reliable information about uterine activity in ambulatory patients. A good correlation between the intensity of contractions and the recording of uterine activity by this system could be demonstrated, particularly in the presence of mild to moderate contractions. The tested monitor proved to be simple to use even in the untrained gravida. Additional studies to determine the role of ambulatory home monitoring of uterine activity in patients with cervical cerclage, placenta previa, and preterm labor will need to be performed to establish its role in current obstetric practice.
The medical records of 330 patients treated with terbutaline infusion for the inhibition of preterm labor were reviewed over a five-year period. In patients with intact membranes the results were uniformly good, particularly when treatment was instituted before the 30th week. Half these patients had a prolonged labor of six weeks or more; in most cases of treatment failure complications already existed on admission. In only nine patients (2.7%) terbutaline treatment was predominantly maternal tachycardia or vomiting. Two patients had chest symptoms, but in no case was pulmonary edema diagnosed. The results suggested that a low incidence of severe side effects can be obtained if the following glucose is used as the infusion medium, instead of sodium chloride; concentrated solutions are given to avoid fluid overload; the patients are carefully controlled; and the infusion is immediately reduced or stopped if signs of severe side effects appear.
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.
Possible teratogenic effects of exogenous progestational agents given during early pregnancy were investigated by a controlled historic prospective study of 2754 infants born to mothers who had bled during the first trimester of pregnancy. The study group consisted of 1608 newborns whose mothers had been treated with progestogens (mostly medroxyprogesterone acetate) beginning in the first trimester. The control group comprised 1146 infants of untreated mothers. All newborns were subjected to thorough examination during the first days of life, with special attention to detection of various malformations classified according to the different anatomic systems. No significant difference was found between the treated and the control groups with respect to malformations in any of the systems examined. The overall rate of malformations was 120 per 1000 in the study group and 123.9 per 1000 in the control group. Major malformations occurred at rates of 63.4 and 71.5 per 1000, respectively. The study thus fails to demonstrate an increase in teratogenicity after administration of gestagens during the first trimester of pregnancy.
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.
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.
Comparison of a cohort of 988 offspring exposed in utero to exogenous progestins with a matched cohort of unexposed offspring did not result in detection of an association of congenital anomalies with exposure. The conclusions are based primarily on outcomes of pregnancy with exposure to progesterone and 17 alpha-hydroxyprogesterone caproate, and may not apply to androgenic progestins. Offspring exposed to combinations of progestins and estrogens were excluded from this study and may have a different distribution of anomalies.
Eighty pregnant women at high risk of giving birth prematurely were divided randomly into two groups. Treatment with either 17 alpha-hydroxyprogesterone caproate, 250 mg by intramuscular injection once a week, or a placebo was given in a double-blind fashion. Imminent premature labor occurred in 29.0% of the treated group and in 59.4% of the control group (p less than 0.025). The rate of premature deliveries was also significantly lower in the treated group (16.1%) than in the control group (37.82%) (p less than 0.05). There were no cases of perinatal death or fetal malformations in either group. The mean birth weight of all infants of the treated group was significantly higher than in those of the control group (3111.9 +/- 905 gm versus 2680 +/- 813.4 gm, p less than 0.05). The results support treatment with progesterone caproate for the prevention of premature labor.
The plasma concentrations of medroxyprogesterone acetate (MPA) in 14 women administered the progestagen for threatened abortion during the first 6 weeks of pregnancy were measured by specific radioimmunoassay. Treatment (52 nmol orally every 6 h) was continued to 18 weeks of gestation. The mean plasma concentration of MPA rose rapidly during day 1 of treatment to 14.1 +/- 1.84 nmol/l. It reached 21.5 +/- 2.3 nmol/l by 7 days and subsequently stabilized at around 26.8 +/- 5.0 nmol/l by the end of week 2. Urinary steroid profiles were determined by gas-liquid chromatography and mass spectrometry for six of the MPA-treated women and compared with those of six untreated women of similar gestational age. No differences were detected between the two groups of women, suggesting that the administration of MPA during pregnancy did not alter qualitatively or quantitatively the metabolism and excretion into urine of progesterone and oestrogens.
PregnancyEtiology and Risk FactorsGenital InfectionsPreterm Delivery Prevention
Although major advances have been made in both obstetric care of the high-risk patient and in neonatal care, prematurity and its consequences remain the major contributor to perinatal mortality. The identification of maternal or obstetric risk factors associated with preterm delivery has enhanced our ability to provide special obstetric care to gravidas at increased risk. The selective management of patients at increased risk for preterm delivery may ultimately reduce the incidence of preterm births. Maternal genital infections are also associated with preterm delivery. Further research is needed to explore the pathogenesis of preterm delivery associated with genital infections, since infections may represent a potentially preventable cause of prematurity.
The effect of cervical suture on pregnancy outcome was studied in 194 women with a high risk (approximately 30%) of having a late abortion or a preterm delivery. The women were randomly allocated either to have a cervical suture inserted (n = 96) or to be managed without a suture (n = 98). There was no evidence that cervical cerclage either prolonged gestation or improved survival. Patients allocated to receive cerclage spent significantly longer in hospital, even when the period of admission for insertion was excluded. The patients in the cerclage group were more likely to receive tocolytic drugs, and more of them experienced puerperal pyrexia, although these differences between the groups were not statistically significant.
Thirty-seven consecutive patients with singleton pregnancies in "uncomplicated" preterm labor with intact membranes suitable for tocolysis were evaluated for evidence of silent chorioamnionitis by means of maternal serum C-reactive protein and amniotic fluid white blood cell count, Gram stain, and cultures. Abnormalities in these markers of infection were found to be significantly more common in cases that were refractory to tocolysis. These cases also showed both pathologic evidence of chorioamnionitis and a significantly greater neonatal early infectious morbidity. We conclude that silent chorioamnionitis is a significant cause of "uncomplicated" preterm labor refractory to conventional methods of tocolysis.
A total of 506 women at moderate risk of preterm delivery were randomly allocated to either cervical cerclage or a control group. Significantly more women in the group allocated to cerclage were admitted to hospital for reasons other than the operation and more received oral tocolytic drugs. There were also more caesarean sections and more preterm deliveries in the women allocated to cerclage although the differences between the two groups were small and not statistically significant.
EndometriosisSpontaneous AbortionMedical and Surgical TherapyRecurrent Pregnancy Loss
There seems to be an association of first-trimester spontaneous abortion and untreated endometriosis. In this report, 52% of an untreated group of patients with endometriosis aborted. However, 12% of a second group of surgically treated patients and 7% of a third group of patients treated with danazol aborted. Therefore, either medical or surgical therapy for endometriosis lowers the abortion rate significantly.
We interviewed 128 women regularly during pregnancy and the first postnatal year. Psychiatric interviews identified eight 'cases' of psychiatric disorder (6 per cent) in early pregnancy and twenty 'cases' (16 per cent) at six weeks after birth. Postnatal affective disorder, which accounted for 15 of these cases, was significantly associated with dissatisfaction with the marital relationship and also with previous psychiatric history. The implications of the term 'postnatal depression' are considered in terms of the course of the disorder in the 29 women (23 per cent) who had episodes of affective disorder at some time during pregnancy and the postnatal year. We found that the majority of episodes of affective disorder could be understood in terms of previous psychiatric history and/or reaction to life-events, including the stress of childbirth itself.
PregnancyTocolysis OutcomesInfection BiomarkersC-Reactive Protein Pregnancy
Subclinical intrauterine infection is an important cause of preterm labor, specifically where tocolysis has failed. Fifty patients in preterm labor with singleton pregnancies were studied prospectively to determine whether the presence or absence of C-reactive protein, a nonspecific marker for infection, would correlate with success or failure of tocolysis. Of the 50 patients, tocolysis failed in 11 of 15 women with a positive C-reactive protein determination. Tocolysis succeeded in 33 of 35 cases where C-reactive protein was negative (P less than .0005). Urinary tract infection occurred in 40% of the study patients, but was not a confounding factor in the interpretation of C-reactive protein.
A single dose of micronized oral progesterone was administered to 15 pregnant women immediately prior to elective cesarean section. Levels of progesterone, 17 beta-estradiol, and estrone were measured in the plasma, in the placenta, and at different sites in myometrium obtained during the surgical procedure. Results were compared to those observed in a control group of women who did not receive progesterone. Progesterone levels demonstrated a marked increase in plasma and in the whole myometrium 150 minutes after administration. The levels then decreased rapidly to control values in 1 hour. The concentrations of progesterone in the placenta did not show any changes. No difference appeared in 17 beta-estradiol levels in the plasma or the myometrium, whereas an increase was observed in the placenta. Estrone levels did not change in the plasma, but they decreased in the myometrium and in the placenta.
The principal function of muscular tissue is contraction. This is also true for the uterus this function begins with sexual maturation. During pregnancy special conditions are brought about by the increasing distention of the uterine cavity. For clinical practice, external tocography is of importance for the recognition of uterine motility Data in the literature on the normal frequency of contractions during pregnancy vary greatly and caused us to study this topic. Moreover, most cases of prematurity independent of other causes suppose a prematurely increased uterine motility. In order to register this activity a portable recording apparatus was developed. We studied in particular the question for how long and how often uterine contractions should be recorded. A one hour daily recording was found to be sufficient. In order to gain information on the average number of contractions it suffices to record during one week. In 26 healthy primiparous and 28 multiparous women the number of contractions from the 25th to 41st gestation week was recorded. A notable finding was the frequency peak about the 32nd week. The number of pregnancy contractions as a sole parameter for the recognition of impending premature delivery is not sufficient. However, the information may be important when taking in conjunction with the previous history and the state of the cervix. We considered tocolysis indicated when as a weekly average there are more than two contractions per hour with beginning cervical dilation or more than three contractions per hour regardless of cervical findings.(ABSTRACT TRUNCATED AT 250 WORDS)
Fourteen women experiencing early pregnancy failure have been studied during the time of conception and at frequent intervals until spontaneous abortion occurred. Serial measurements of serum estradiol, progesterone, 17 alpha-hydroxyprogesterone, prolactin, human placental lactogen (hPL), and human chorionic gonadotropin (hCG) were determined; regular sonar scanning allowed the time of fetal death to be determined to within 7 days in six patients and a diagnosis of blighted ovum to be made in the remainder. In all patients serum progesterone and estradiol concentrations were within the normal range up to 7 weeks but appeared to decrease from about 8 weeks' gestation whether or not a living fetus was present. The placenta continued to produce hCG and hPL but, despite the continuing presence of hCG, the levels of 17 alpha-hydroxyprogesterone declined to concentrations below those associated with normal pregnancy. These data suggest that the placenta may require a particular stimulus to take over production of progesterone and estradiol.
PregnancyPremature Rupture of MembranesChorioamnionitis PredictionC-Reactive Protein in Pregnancy
A group of 52 patients with premature rupture of the membranes (PROM) before 34 weeks' gestation were evaluated prospectively and managed expectantly. Of 42 patients who were delivered of their infants, 26 (61.9%) had significant chorioamnionitis on histopathology, and 18 had positive microbial cultures at delivery. However, only seven patients (16.7%) developed clinical signs of chorioamnionitis. There were no maternal deaths or perinatal deaths attributable to sepsis. Only two infants (less than 5%) had positive blood cultures. All patients were assessed daily for the development of chorioamnionitis. Amniocenteses were not routinely performed. White blood cell counts, band neutrophil counts, and erythrocyte sedimentation rate determinations were found to be unreliable. C-reactive protein determinations were found most reliable with a high sensitivity and specificity. Elevated C-reactive protein levels correlated better with pathologic confirmation of chorioamnionitis than with the clinical febrile morbidity. Clinical implications for the management of PROM are discussed.
Swiss Webster female mice weighing 25-30 gm were injected subcutaneously on days 6-15 of gestation with the synthetic sex steroid Delalutin (17 alpha-hydroxyprogesterone caproate). Treatment was given daily in doses ranging from 42 to 833 mg/kg body weight, or 10, 100, and 200 times the human therapeutic dose. On day 18 fetuses were removed from the uterus and examined for malformations and other fetotoxic effects. Prenatal treatment with the two higher doses resulted in 8 and 13% maternal deaths, and all doses resulted in a slight increase (4-12% above control) in resorption frequency. Treatment with Delalutin did not significantly affect intrauterine growth, sex ratio, or malformation rate of the offspring. The results of the present study confirm other reports that Delalutin is not androgenic, and that it, like progesterone and certain other sex steroids, does not alter the development of nonreproductive organs.
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.
The results of combined ritodrine and indomethacine treatment (RI) in premature labor contractions were compared with ritodrine alone (R). One hundred and twenty patients with threatened premature labor in weeks 26-34 were studied. Sixty RI women received 100 mg ritodrine in infusion followed by 60 mg daily orally until 35 weeks and indomethacine 200 mg on the first day of treatment only. The R group included 60 women with identical tocolysis indices, age of pregnancy and anamnestic parameters who received ritodrine only. The mean prolongation index (PI) was 18.2 in the RI group, against 11.5 in the R patients (P less than 0.05). The mean prolongation of pregnancy was 5.6 weeks in the first and 3.6 in the control group (P less than 0.05). Birthweight and Apgar scores were similar in the two groups. In order to examine the possible early closure of the ductus arteriosus due to the indomethacin therapy, echocardiograms were done the pre-ejection period and right ventricular ejection time ratio was 0.19-0.26 after delivery and 0.17-0.22 1 month later, which excludes pulmonary diastolic hypertension due to premature closure of the duct. The combined RI treatment is more effective that R alone and does not give rise to any complications in the mother or the fetus.
From 1964 to 1976, a cohort study was performed in West Germany to study the possible influence of various factors on pregnancy and child development. Results of the evaluation of 13,643 pregnancies are given with respect to possible teratogenetic effects of antiemetic drugs and sex hormones administered in early pregnancy. There was no evidence of an increased risk of major malformations following the intake of certain antiemetic drugs and progesterone. Also, the use of a hormonal pregnancy test was not significantly associated with an increase of major malformations.
PregnancyCervical CerclageCongenital MalformationsCerclage for Uterine Anomalies
Fifteen women with diminished fertility as a result of congenital uterine anomalies were treated by cervical suture (cerclage) in the 11th-12th week of pregnancy without surgical correction of the uterine anomaly. None of these women had either clinical or radiological evidence of cervical incompetence. As a result of the treatment, 13 of the women delivered live full-term mature infants. None of the women aborted, only two women delivered prematurely, and both infants were alive and well. Comparison of these good results to the very poor outcome of previous pregnancies in these women points to a distinct advantage to be gained by cervical suture. As a result of this experience, we recommend cervical suture in cases of diminished fertility as a result of congenital uterine anomaly. We recommend that the suture be performed before considering surgical repair of the anomaly and irrespective of lack of evidence of cervical incompetence. Only in cases where cervical suture is unsuccessful, would we recommend surgical correction according to the accepted techniques.
A preliminary study of 'screened' women with two consecutive miscarriages revealed an incidence of abortion in 47.4% in a subsequent pregnancy whilst hCG therapy in a similar group of women where biochemical monitoring with plasma progesterone suggested a potentially jeopardized pregnancy resulted in a continuing pregnancy in 92.3% of treated women. An urgent need for a true randomized double-blind evaluation of this therapy has been established in order to re-examine the therapeutic nihilism which currently pervades the management of women with recurrent abortion.
Pregnant mice were treated with a single subcutaneous injection of either cyproterone acetate (CA) or medroxyprogesterone acetate (MPA). In the first experiment the animals received 5-900 mg/kg of the hormone before implantation (day 2 of pregnancy). CA treatment on day 2 caused a dose-dependent decrease in fetal weight and a significant dose-dependent increase in the rates of cleft palate and urinary tract abnormalities. Exencephaly and heart abnormalities were also significantly more frequent, but this increase was not dose-dependent. MPA treatment on day 2 was followed by sporadic increases in dead and resorbed fetuses, a decrease in fetal weight and an increase in the rates of cleft palate, and malformed or abnormally developed fetuses. None of these effects, however, was dose-dependent. In the second experiment the mice were given one single injection (30 mg/kg) of CA or MPA on any one of days 1-12 of gestation. Treatment with CA on one day between days 1 and 12 revealed that the specific sensitivity for abnormalities of the urinary tract was on days 5 and 6, for the respiratory tract on days 8 and 9, and for cleft palate on days 10 and 11. Treatment with MPA on one day between days 1 and 12 only revealed a high rate of respiratory and urinary tract abnormalities on day 9. After treatment with MPA cleft palate was again significantly more frequent in all treated groups, however, days of peak sensitivity were not detected. The long half-life of CA (60 hours) explains the teratogenic effect of high doses of this progestin after treatment on day 2 and also the pattern of abnormal development found after treatment with a single dose of CA on one of the days between day 1 and day 12.
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.
This study evaluates the effect of treatment with Proluton-Depot (hydroxyprogesterone hexanoate) in early pregnancy, and the final outcome of pregnancy and fetal status. One hundred and fifty patients received intramuscular injection of Proluton-Depot from 6 weeks to 8 weeks to 16 weeks to 18 weeks gestation. The outcome of this treated group was compared with a similar number of 150 patients with similar problems, but the second group received no hormonal treatment. There was no evidence to suggest that Proluton-Depot had any adverse effect on the infant or the final outcome of pregnancy.
PregnancyProgesterone Withdrawal MechanismsUterine FunctionMyometrial Gap Junctions
Rats which were subjected to ovariectomy on day 18 of pregnancy and were treated with 17 beta-estradiol underwent delivery prematurely at 0900 +/- 1.9 hours on the morning of day 18. All animals had in plasma and uterine tissue a precipitate and highly significant progesterone withdrawal and a corresponding significant increase in prostaglandin F and prostaglandin F metabolite. Progesterone replacement therapy given to a second group of castrated animals prevented progesterone withdrawal and premature labor, because the hormonal profile in plasma and uterine tissue of these animals was identical with that of the intact pregnant vehicle controls. Electron microscopy of longitudinal and circular myometrial layers showed a precipitate and highly significant increase in the number, size, and area of gap junctions in the uteri of the group undergoing premature delivery. In the uteri of the progesterone-treated and vehicle control groups (both intact pregnant), gap junctions were conspicuously scarce. Thus the extensive regulatory imbalance, provoked by progesterone withdrawal, induced a significant increase in myometrial gap junctions. This structural change established contacts between individual myometrial cell which could transform the multibillion cell community of the uterus into a syncytium, to generate low-resistance pathways to the flow of current and thus promote the propagation of trains of electrical discharge in support of labor.
SurgeryMetroplasty for Uterine AnomaliesReproductive OutcomesUterine Malformations
Heinonen PK et al., 1982·Acta Obstet Gynecol Scand
A total of 182 women with uterine anomalies were observed over a period of 18 years. In all, 126 women had 265 pregnancies, fetal survival rate was 66%, perinatal mortality 8% and premature labors occurred in 23%. When the uterine anomalies were grouped according to degree of failure of normal and uterine development, the complete septate uteri had the best fetal survival rate (86%), complete bicornuate uteri (50%) and unicornuate (40%) poorest. Cervical cerclage was applied most in the partial bicornuate uteri (17%), where fetal before operation, 53% and after, 100%. The frequency of breech presentation was 40-50% in all groups except complete septate uteri (25%) and complete bicornuate (0%). The highest cesarean section rate (82%) was in deliveries of patients with uterus didelphys. The frequency of cesarean section among total deliveries was 53%. Metroplasty was carried out on 19 patients. The obstetric outcome improved from 10% successful pregnancies before surgery to 88% postoperatively.
Fifty-eight psychoses beginning within two weeks of childbirth are compared with 52 episodes of nonpuerperal psychotic illness occurring in young women. A clinical approach based on the use of multiple information sources and integrated assessment was used. Statistically significant differences between the two groups of patients were found in 52 of 214 psychopathological variables. Postpartum patients had more manic symptoms and "confusion," while nonpuerperal patients had more schizophrenic symptoms. The Research Diagnostic Criteria (RDC) showed an excess of schizoaffective (manic) puerperal patients and schizoaffective (depressed) or schizophrenic nonpuerperal patients. Only five of 58 puerperal episodes met RDC for schizophrenia. The relative lack of schizophrenic symptoms in the puerperal group was confirmed by self-ratings. The results are interpreted as supporting a link between puerperal psychosis and manic-depressive disease.
General OB/GYNDiagnosis and Risk FactorsEctopic Pregnancy ManagementEctopic Pregnancy
The increasing importance of an ectopic pregnancy as a cause of maternal death presents a challenge that will be met when primary care physicians combine a high index of suspicion with the ability to recognize the patient most at risk. The major symptoms, abdominal pain, secondary amenorrhea and abnormal vaginal bleeding are well known, as are the major signs, abdominal tenderness, adnexal mass and tenderness on motion of the cervix. Less well known are factors in the clinical history which indicate the patient to be at high risk. These include primary or secondary infertility, previous abortion or ectopic pregnancy and previous tubal operation, either reconstructive or sterilizing. In addition, the use of an intrauterine contraceptive device or its recent removal because of abdominal pain or bleeding, or both, is highly significant. Of major importance is a history of recent uterine evacuation. Should the diagnosis of ectopic pregnancy be under consideration, procrastination by observation is no longer acceptable. An active effort must be made to confirm or deny the diagnosis, Culdocentesis should be performed in the emergency department or clinic. If positive, prompt laparotomy is indicated. Should the result of culdocentesis be unsatisfactory or negative, laparotomy should be undertaken with further delay.
A case-control study of the epidemiology of preterm delivery was undertaken at Yale-New Haven Hospital in Connecticut during 1977. The study population consisted of 175 mothers of singleton preterm infants and 313 mothers of singleton term infants. Significant risk factors of a preterm delivery included low socioeconomic status; low pregravid weight; inadequate weight gain during the pregnancy; a previous preterm delivery; a history of infertility problems; an induced abortion terminating the previous pregnancy; vaginal spotting or light bleeding during the pregnancy; antepartum hemorrhage and abnormal placental implantation; lack of leisure-time physical activities during the pregnancy; alcohol consumption prior to the third trimester of pregnancy; and negative attitudinal expression toward the pregnancy.
A review of the extensive literature on the subject indicates that sex hormones have been associated with a wide variety of adverse clinical conditions following usage during pregnancy. About 230 cases of female pseudohermaphroditism have been reported following use of hormones with androgenic potency, but masculinization observed with estrogens in a few females may represent only adrenal-stimulated pseudohermaphroditism. Feminization of males, mostly by progestogens in some 45 cases, is unproven at present. Realizing the limitations of the published studies when all present data are considered, there seems no justification for undue concern over the induction of nongenital congenital malformations through hormone use in pregnancy. The available data on the association to cardiac, limb, and CNS defects, and to several malformative syndromes, the effects appear to be remarkably nonspecific, the studies are contradicted by a large number of negative reports, and an increased incidence of defects with increased usage has not materialized. A possible exception are the CNS malformations associated with the use of the antifertility agent clomiphene, and careful surveillance is warranted at present. While a reasonable interpretation from this review would be that hormones present no major teratogenic hazard, elimination of hormonal exposure whenever possible during pregnancy is suggested.
PregnancyPremature Rupture of MembranesC-Reactive ProteinChorioamnionitis Prediction
The management of patients with premature rupture of membranes (PROM) poses one of the most serious dilemmas in obstetrics since PROM significantly increases the likelihood of prematurity and serious perinatal infection. Early infection is not reliably predicted nor detected by standard laboratory parameters. Serum C-reactive protein (CRP) levels were assayed along with white blood cell count, differential, and temperature course in patients with PROM and controls. Elevated CRP very accurately divided patients with evidence of infectious morbidity from those without such evidence (p < 0.001). In 109 patients there were 11 false negatives and no false positives. In 14 of 20 patients followed with serial comparisons who developed morbidity, CRP became elevated at least 12 hours prior to any other parameter measured. Changes in the other six patients were concurrent. The results suggest that CRP may be a reliable, early predictor of infectious morbidity and thus may be of benefit in the selective management of patients with PROM.
PregnancyTocolytic TherapyPreterm Birth PreventionProgesterone Supplementation in Pregnancy
A shift in progesterone-to-estradiol balance to estradiol dominance is assumed to be a prerequisite for regular uterine contractions. To antagonize this effect in premature labor 24 consecutive women were treated with intravenous cortisol for 3 days and with weekly intramuscular injections of 17 alpha-hydroxyprogesterone caproate (17 OHP-C). Twenty-four similar patients treated with ritodrine served as a reference group. The delivery was postponed by at least 1 week in 21 patients (87.5%) in the steroid treatment group and in 18 patients (75%) in the ritodrine group. The premature labor lasted for 5.1 +/- 0.4 hours (mean +/- SEM) with steroid therapy and for 2.2 +/- 0.3 hours with ritodrine. In singleton pregnancies the gestational length and birth weight of the newborn infants were greater in the steroid treatment group (N = 23, 39.1 +/- 0.3 weeks, 3,460 +/- 119 gm) than in the ritodrine group (N = 24, 37.7 +/- 0.4 weeks, 3,106 +/- 118 gm). Steroid treatment suppressed serum estradiol concentrations (maximally by 60%) and, to a lesser extent, testosterone, estriol, and progresterone levels (maximally by 30%).
Cytogenetic analysis of 1000 spontaneous abortions showed 463 to have an abnormal chromosome constitution. The proportion of chromosome abnormalities varied with the gestational age of the abortus and the type of tissue cultured but was not significantly different among the five racial groups represented in the study population. It was suggested that differences in the rate of chromosome abnormalities among cytogenetic studies of spontaneous abortions were the result of methodological differences in sample selection rather than real biological variation among study populations. The only factor found to be unequivocally associated with the aetiology of chromosome abnormalities in spontaneous abortions was increasing maternal age in trisomies.
PregnancyHormonal MonitoringProgesterone and hCG in Early PregnancyPredictive Hormone Markers
Progesterone and human chorionic gonadotrophin (HCG) in serum and pregnandiol in urine were measured in 64 patients admitted to hospital because of threatened abortion. Blood samples were taken and urine specimens collected at regular intervals during admission and after discharge during the rest of the pregnancy. A reference range was worked out for each hormone based on the hormone values obtained from the pregnancies proceeding to term. The predictive significance of values within and below the reference range was determined, for the initial sample and for serial samples. An association between hormone levels and outcome of pregnancy was observed but it is concluded that both single and serial determinations of progesterone and pregnandiol and serial determinations of HCG are unsatisfactory for the evaluation of threatened abortion. However, an initial progesterones value below the reference range and HCG values below 10,000 mIU/ml between the 8th and 15th week of pregnancy was in every case always followed by spontaneous abortion. A hormonal test of fetoplacental origin is recommended for monitoring threatened abortion.
The plasma concentrations of progesterone and 5-alpha-pregnane-3,20-dione (5-alpha-dihydroprogesterone) were measured from as early as 12 weeks through 41 weeks of gestation in primigravid women. Two groups of primigravid women were assessed, those with uncomplicated pregnancies and those who developed pregnancy-induced hypertension. Plasma levels of progesterone and 5-alpha-dihydroprogesterone rose progressively throughout gestation in both groups of women. The ratio of the level of progesterone to that of 5-alpha-dihydroprogesterone in individual plasma samples of women with uncomplicated pregnancies was 7.0 from 12 to 15 weeks' gestation while at 35 to 41 weeks' gestation the ratio had declined to 4.6. Similar results were obtained in plasma samples of women who ultimately developed pregnancy-induced hypertension. Since no differences in plasma levels of progesterone or 5-alpha-dihydroprogesterone were detected between primigravid women with uncomplicated pregnancies and those who developed pregnancy-induced hypertension, we conclude that neither progesterone nor 5-alpha-dihydroprogesterone concentrations in plasma are of value in identifying women at risk of developing pregnancy-induced hypertension.
Studies have been undertaken regarding the efficacy and modus operandi of 17 alpha-hydroxyprogesterone caproate (17 alpha-OHP-C) in preventing premature labor in high-risk patients. In a total of 70 patients, the treated patient population had a prematurity rate (12.8%) and a perinatal mortality rate (5%) which were significantly lower than those of the total placebo or untreated patient group (40.9 and 25%, respectively). In addition, sequential plasma steroid values were determined in 21 patients, 10 of whom delivered prematurely. The results indicate that low plasma progesterone (P) and 17 alpha-hydroxyprogesterone (17 alpha-OHP) levels precede the onset of preterm labor by weeks. Successful treatment with 17 alpha-OHP-C was characterized by elevated P levels. Plasma estradiol (E2) and cortisol (C) values did not vary with time of delivery or treatment. These findings support the progesterone block theory as an important mechanism affecting preterm delivery in this high-risk population.
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.
Lymphocyte reactivity was measured in human mixed lymphocyte (MLC) and mitogen-stimulated cultures in the presence of various steroids. When present during the entire culture period at concentrations between 1 and 20 µg/ml progesterone, estradiol, and testosterone blocked 3H-thymidine (3H-TdR) incorporation. Estriol and 16 α-hydroxy progesterone were without suppressive effects. The kinetics of steroid mediated suppression of thymidine incorporation and DNA synthesis was investigated at various times during lymphocyte activation. When progesterone was present only at the beginning of culture, subsequent DNA content, but not thymidine incorporation was suppressed. However, if added late during the activation process, progesterone reduced thymidine incorporation independent of cellular DNA content. If present during the entire culture period both were suppressed. Cortisol, but not progesterone irreversibly inhibited lymphocyte thymidine incorporation if added during the first 12 hr of culture. A reversible blockade of lymphocyte thymidine uptake could be observed with progesterone even during the final hours of mitogen or MLC cultures. Thus, effects of steroid hormones on cellular DNA synthesis and thymidine incorporation appear to be independent processes. Cell fractionation experiments demonstrated that progesterone blocked the uptake of 3H-TdR into the lymphocyte nucleoside pool thereby reducing its availability for incorporation into DNA. This study is consistent with the hypothesis that lymphocyte proliferation at the maternal fetal-interface during pregnancy may be under specific regulation by progesterone. The relatively high local concentrations of the hormone produced by trophoblast are immunosuppressive whereas the substantially lower peripheral steroid levels are entirely inadequate to suppress systemic immunity. We suggest that at least one important role of progesterone in maintaining pregnancy is its regulation of cellular immunity in the maternal-fetal bed.
HYPOSPADIAS is a common anomaly of the urogenital system. The prevalence rate reported by various birth-defect monitoring programs shows a rather wide variation, ranging from about five per 10,000 to about 30 per 10,000 births. During recent years increasing incidence has been reported from England and Wales1 and Norway.2 In the United States the Center for Disease Control, Atlanta, Georgia, has noted an annual increase in the reported incidence of 3 per cent per year from 1970 to 1975. Though relatively small, this increase was nevertheless statistically highly significant (P<0.0001).3 More frequent recognition and reporting of the condition may explain . . .
Reproductive EndocrinologyProgesteroneHormonal Changes Before LaborRIA vs CPB Methodology
Conflicting results have been published regarding changes in plasma progesterone during the last trimester of pregnancy. Some have demonstrated a fall in plasma progesterone before labor, and this has been taken as a possible explanation of the onset of labor. It has been suggested that the various results could be due to differences in methods for progesterone determination. In this study the progesterone levels were determined by both RIA and CPB. In 11 women the plasma progesterone, human placenta lactogen, and serum estriol were measured weekly during the last trimester of normal pregnancies and immediately after delivery. All samples were analysed radioimmunologically. In order to compare the radioimmunoassay and competitive protein binding techniques (RIA and CPB), the progesterone levels were determined by both methods. This was also done for 80 successive plasma progesterone routine samples drawn from women who were not pregnant or who were in the early stages of pregnancy. Both methods showed a significant rise in the plasma progesterone level during the last 6 weeks before spontaneous labor. However, the values obtained were lower when assayed by CPB than by RIA, presumably because of a higher specificity and a cross reaction in RIA. Serum estriol exhibited increasing values throughout pregnancy, but without a significant rise during the last few weeks. Plasma HPL settled at a constant level during the last few weeks before labor.
PregnancyRecurrent Second Trimester LossProgestagen SupplementationProgesterone-Estradiol Ratio
Patients with two or more previous spontaneous second trimester abortions and vaginal cytology indicating a poor progestational response in current pregnancies were selected for treatment with Provera (medroxyprogesterone acetate) and/or Delalutin (17 alpha-hydroxyprogesterone caproate). Serum was examined serially for progesterone (P) and estradiol (E) by radioimmunoassay. Serum from 174 untreated patients with no known complications ranging from 6--40 weeks gestation provided normal distribution data. Of 14 progestagen-treated patients, four aborted during the second trimester. These all had chronically low (greater than 50% of observations were less than 1 standard deviation of the normal population) or falling P/E ratios. The rest delivered normal full-term infants although five of the 10 had chronically low P, seven had chronically low P/E ratios, and in one other P/E was falling. Chronically high E contributed to the low P/E ratio in three cases. Thus, these selected cases with poor obstetrical histories demonstrated steroid patterns outside the +/- 1 standard deviation range, although the steroid levels were still within the normal range. Serum progesterone and estradiol analysis may eventually be useful in identifying patients who will best respond to progestagen treatment.
The development of two groups of children whose mothers had been given progesterone supplements during pregnancy to relieve symptoms of toxaemia was assessed, one group at 2 yr of age and the other at 16 yr of age. There was no evidence that progesterone supplements accelerated development in the 2-yr-old age group or enhanced intellectual and academic attainment in the 16-yr-old age group. In addition, the evidence regarding the reported beneficial effects on intellectual attainment of in utero exposure to excess sex steroids is discussed.
PregnancyHormone MonitoringSpontaneous AbortionProgesterone Levels in Pregnancy
Plasma progesterone, 17-hydroxyprogesterone, 20alpha hydroxypregn-4-en-3-one levels were determined twice weekly up to 16 weeks gestation, where possible, in a twin pregnancy, in two patients who aborted spontaneously and in three patients who were treated with 'progesterone supplements' because of abnormal vaginal cytology. There was no correlation between vaginal smears and the plasms hormone levels and there was no evidence to suggest that progesterone supplements influenced clinical outcome. Compared with normal mean values the only difference was a significantly rise in progesterone and 20alpha hydroxypregn-4-en-3-one levels in the twin pregnancy after the 12th week and a precipitate fall in all hormone levels just prior to abortion. Plasma hormone levels could not be used to predict outcome.
General OB/GYNObstetrical UltrasoundBladder Artifact EffectsPlacenta Previa Diagnosis
Observations of random obstetrical cases out of a large-volume practice are presented to demonstrate the often overlooked effects of filling the urinary bladder for obstetrical sonography. The effects, predominantly evident in the second trimester, perssure effects on the lower uterine segment, displacement of the cervix and/or corpus of the uterus, rotation, flexion, version, and tilting of the uterus. These events may affect the perception of placenta location and fetal position. This is especially important in the diagnosis of placenta previa in the second trimester. Many instances of placental "migration" may be due to this phenomenon. Implications for amniocentesis are briefly discussed.
PregnancyPregnancy-Induced HypertensionMetabolites and Vascular FunctionBlood Pressure Regulation
In gravid women who are destined to develop pregnancy-induced hypertension (PIH), normal pregnancy-associated refractoriness to the pressor effects of administered angiotensin II (A-II) is lost several weeks before the onset of hypertension. From a study of the determinants of A-II pressor responsiveness in normal gravid women, it appears likely that the loss of resistance to A-II is principally unrelated to plasma renin activity or to plasma A-II levels. However, it recently has been shown that the vascular refractoriness to A-II in normal women can be reduced significantly by the administration of the prostaglandin synthetase inhibitors, indomethacin or aspirin. In seven women who had developed PIH and who had lost their refractoriness to A-II, the infusion of 5alpha-pregnan-3,20-dione (5alpha-DHP) was associated with restoration of refractoriness to the pressor effects of A-II. Moreover, in five normotensive gravid women beyond 28 weeks' gestation in whom the refractoriness to A-II was reduced by the administration of indomethacin, the intravenous infusion of 5alpha-DPH was associated with restoration of refractoriness to the pressor effects of A-II. These observations are consistent with the view that a progesterone metabolite(s) may be important in the maintenance of normal blood pressure during human pregnancy.
17 beta-Estradiol (E2) and progesterone (P) concentrations in blood and in the myometrium of human pregnancy at term (n=33) and in a few samples (n=5) around midterm of pregnancy were determined. E2 concentration in the myometrium (per g wet wt) at midterm was lower than the concentration in the plasma (per ml) so that the myometrium to plasma (My:Pl) ratio was 0.7. Relative to plasma concentration, the myometrial E2 increased little from Pl was only 0.2 at term. Although P concentration in the myometrium was much greater than that in the plasma at midterm, My:Pl ratio being 2.2, it was lower than that Pl ratio was only 0.6. A fairly good correlation between plasma steroids and the myometrial steroids was observed at midterm but was distorted at term, probably due to saturation of the tissue-binding capacity. Steroid concentrations determined on the basis of protein showed a good correlation to the values expressed on the basis of wet weight. Whereas myometrial E2 concentration was significantly influenced by the distance from placenta, P concentration was not.
PregnancyFetal Growth RetardationHormone LevelsEstrogen and Progesterone in Pregnancy
Plasma levels of progesterone (P), oestradiol (OE2), unconjugated oestriol (OE3) and total OE3 were measured in blood samples taken from patients with fetal growth retardation, pre-eclampsia and other complications of pregnancy. The levels were compared with the 24-hour urinary excretion levels of total oestrogen (OE) in these patients, and with the plasma levels found in 31 normal pregnant patients from whom blood samples were taken serially from 21 weeks gestation onwards. There was good correlation between plasma unconjugated and total OE, levels, and urinary OE levels (r = 0.77). In 12 patients with fetal growth retardation and no other abnormality, levels of all hormones were significantly lower than normal; unconjugated OE3, total OE3, and urinary OE levels were significantly less than 1 SD below the normal mean. In 22 patients with mild or moderate pre-eclampsia who were delivered of normal birth weight infants none of the hormone levels were significantly different from normal. In 12 patients with mild or moderate pre-eclampsia in association with fetal growth retardation OE2, unconjugated OE3 and urinary OE levels were significantly lower than normal, and total OE3 levels were significantly less than 1 SD below the normal mean. In 12 patients with severe pre-eclampsia, OE2, levels were significantly less than 1 SD below the normal mean and unconjugated OE3, total OE3, and urinary OE levels were significantly less than 2 SD below the normal mean. In studies of diurnal and day-to-day variation the coefficients of variation for P were respectively 12.7 per cent and 14.2 per cent, for OE2, 11 per cent and 12.7 per cent, for unconjugated OE3, 15.6 per cent and 14.1 per cent, and for total OE3, 15 per cent and 15.8 per cent. It was concluded that measurements of plasma total OE, and urinary OE were probably of comparable value and that the plasma estimation had much to commend it.
Following Fraenkel's discovery, demonstrating that the rabbit corpora lutea are indispensable in pregnancy maintenance, Corner and Allen showed (1) in a series of now classic studies that luteectomy predictably terminates pregnancy, except when progesterone is provided as substitution therapy. Despite the clarity of these demonstrations and the accumulation of complementary data over 40 years (2, 3, 4), many investigators held the view that the studies in the rabbit model failed to establish a basic biological law of broad …
Intrauterine pressure was monitored in vivo in oestrogen-treated ovariectomized ewes before, during and after treatment with progesterone (50 mg s.c./day for 3 days). Progesterone reversibly reduced the frequency and amplitude of myometrial activity and abolished uterine reactivity to oxytocin (i.v.) and PGF-2alpha (intrauterine infusion). The rate of rise of intrauterine pressure during active pressure cycles was significantly reduced. These results confirm that the action of progesterone on the ovine myometrium is comparable to the classic progesterone 'block'. The intrauterine infusion of PGF-2alpha (10 microgram/min), which elicited a marked mechanical response in the control animals, failed to stimulate the progesterone-'blocked' uterus, suggesting that the inhibition produced by progesterone is due to a direct action of the hormone on the uterine muscle and not to an indirect mechanism operating through endometrial prostaglandin output.
Perforation of the sigmoid colon in a 28-year-old woman during the 37th week of pregnancy is reported. There was almost complete replacement of the bowel wall by endometriotic tissue showing extensive decidualization of its stroma. This appears to be a very rare complication of endometriosis and the effects of pregnancy upon endometriosis are briefly reviewed.
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.
Reproductive EndocrinologyPreterm LaborHormonal FactorsProgesterone and Estradiol in Pregnancy
A total of 30 to 50 per cent of premature labors occur without identifiable predisposing conditions. To evaluate the hormonal status of these pregnancies, serum progesterone (P) and estradiol (E2) were measured by radioimmunoassay singly in 60 premature labor patients and serially in 19 normal pregnancies. Premature labor patients as a group have significantly lower P and E2 levels than controls. Pregnancies complcated by idiopathic premature labor (IPL) (p less than 0.01), premature labor secondary to abruptio-marginal separation (A-MS) (p less than 0.05), and premature rupture of membranes (PROM) (p less than 0.05) have significantly lower P levels than controls. Patients with IPL and A-MS have significantly lower P levels (p less than 0.01) than PROM patients. No significant change in P or E2 occurs immediately prior to normal term labor. Conclusions are that (1) premature labor patients have significantly lower Pand E2 levels than controls, (2) the degree of P depression varies according to the type of premature labor and (3) IPL is characterized by premature labor with no identifiable predisposing factors.
Medroxyprogesterone acetate (MPA) was given once daily sc at 0.1-3,000 mg/kg/day for 3, 6, or 9 consecutive days during gestation days 7 to 15 to CD1 and A/J mice, and New Zealand (NZ) and Dutch Belted (DB) rabbits, and during days 8 to 16 to CD rats. Malformations attributable to MPA did not occur in fetuses of mice or rats exposed to the largest dosage tested. However, 1, 3, or 10 mg/kg on days 13 to 15 to NZ rabbits resulted in 6, 28, and 42% cleft palate, respectively. Comparable cleft palate frequencies were seen in DB offspring.
In a cohort of 50,282 pregnancies 19 children with cardiovascular defects were born to 1042 women who received female hormones during early pregnancy (18.2 per 1000). Among 49,240 children not exposed in utero to these agents there were 385 with cardiovascular malformations (7.8 per 1000). Six children with cardiovascular defects were born to a sub-group of 278 women who used oral contraceptives during early pregnancy (21.5 per 1000). After the data were controlled for a wide variety of potentially confounding factors by multivariate methods, the association between in utero exposure to female hormones and cardiovascular birth defects was statistically significant.
Reproductive EndocrinologyPrenatal Exposure OutcomesOffspring NeurodevelopmentChild Development Outcomes
Children whose mothers received prenatal progesterone have been shown to be advanced in development at one year and to have greater academic achievement at 9-10 years. This study compares the educational attainments at 17-20 years of 34 progesterone children with 37 normal and 12 toxaemic controls. More progesterone children continued schooling after 16 years compared with controls; a higher proportion left school with 'O' level and 'A' level passes, the average number of passes per child was greater at both levels and more obtained a university place. The best academic results were in those whose mothers had received over 5 grams of prenatal progesterone, and for whom administration commenced before the sixteenth week and treatment lasted longer than eight weeks.
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.
PregnancyPrior Pregnancy Loss EffectsPreterm Birth HistoryPregnancy Risk Assessment
Data from 25,958 consecutive UCLA deliveries were analyzed to determine the effect of prior abortions and premature births on current pregnancy outcome. Perinatal death rate, combining stillbirths and neonatal deaths, increased more than threefold among women with at least one prior premature in birth and at least one prior abortion and approached 18 per cent of current deliveries when there were three or more prior premature births. Abnormal live births, defined as infants with either birth weight under 2,501 grams, gestational age less than 37 weeks, or congenital anomalies, significantly increased as the number of prior abortions and premature births increased, each in a range of 0 through 3 or more. For example, among women with at least three prior premature births, there were greater than 50 per cent abnormal live births. The risk was mostly that of low birth weight and low gestational age, although there was a slight increase in congenital anomalies. The risk was reduced considerably when there were previous term births and was influenced variably by race, clinic classification, maternal illness, and prior pregnancy complications. This empirical data on pregnancy outcome should be useful in reproductive counseling among women with pregnancy losses and premature births.
Progesterone, at five times normal 24 h endogenous production rates, was administered daily to 37 rats over Days 2 to 10, 11 to 17 or 2 to 21 term is Day 23. Peanut oil, the vehicle, was administered alone to 18 control rats over Days 2 to 21. The effect of treatment on fetal, placental and corpus luteal weights was examined on Day 22 of gestation. The administration of progesterone had no apparent effect on the maternal weight gain with pregnancy, myometrial, fetal or placental weights. No external malformations or abnormalities of the internal genitalia were detected in any of the fetuses examined. The mean number of dead fetuses per litter, 0.72 ± 0.19 (SEM) in the control rats, was significantly increased to 1.57 ± 0.34 and 2.25 ± 0.54 in rats treated with progesterone over Days 11 to 17 and 2 to 21 respectively. Male fetuses were about 7.4 percent heavier than female fetuses in the control rats but this difference was significantly less in rats treated with progesterone over Days 11 to 17(3.4 percent). Progesterone treatment had no apparent effect on the mean corpus luteal weight per rat. Over all groups combined, the mean corpus luteal weight was negatively related to the number of corpora lutea per rat. This relationship was unlikely to have been due to local nutritional or overcrowding factors since there was no apparent relationship between corpus luteal weight and the number of corpora lutea in the one ovary.
Serum progesterone was measured by competitive protein-binding assay in 331 cases of normal pregnancy ranging from 6 to 42 weeks. Serial estimations of serum progesterone were performed in nine cases of severe hypertensive disorder of pregnancy, eight cases of twin pregnancy, three cases of twin pregnancy complicated by severe hypertensive disorder of pregnancy, three cases of triplet pregnancy, three cases of previous bad obstetric history, one case of anencephaly, and seven cases of intrauterine fetal death. Serum progesterone remained within normal range in severe hypertensive disorder of pregnancy and the levels were indistinguishable in cases of fetal growth retardation from those without growth retardation. In twin and triplet pregnancies, serum progesterone was within normal range or elevated and was usually higher than normal in twin pregnancies after weeks 33 to 34. Serum progesterone levels were normal in anencephalic pregnancy and in most cases of intrauterine fetal death. The findings are discussed with reference to placental hormonal activity. It is concluded that serum progesterone is a poor index of placental function.
Androstenedione, testosterone, progesterone and human chorionic gonadotrophin (HCG) in plasma and total oestrogens, luteinizing hormone (LH) and HCG in urine were measured in five women during conceptual cycles and in early pregnancy. There were increased levels in plasma and urine of all the hormones measured between 12 to 48 days after ovulation except progesterone. The concentration of this hormone in plasma decreased during this time. The possible sources of these hormones in early pregnancy are discussed.
Forty-eight uterine strips were excised from 24 New Zealand white rabbits and studied in vitro. Sixteen strips were examined when eight animals were 25 days pregnant, 24 strips when 12 animals were about 12 hours postpartum, and eight strips about 12 hours after four animals received a single dose of 5 mg. progesterone (P) at spontaneous delivery. When after repeated exposures to electric fields (60 cycles per second, alternating current, of optimum strength, four seconds' duration at intervals of 30 seconds) the approximately 0.5 Gm. strips developed approximately 40-50g wall tension (WT) in steady state, the field strength was reduced in graded steps from 12 v per 5 cm. to 10, 8, 6, 4 and 3 v per 5 cm. and WT recorded. By measuring the effect on WT of "decreasing electric field stimulation" (DEFS), myometrical excitably and threshold were characterized and quantitated. The technique is based on the relationship between the fraction of myometrial cells activated in the total cell population and WT. As the stimulus is decreased in graded steps from optimal to increasingly suboptimal, DEFS activates fewer and fewer cells reflected by the decrease in WT. Threshold is defined by the strength of the minimum electric field which provokes WT and subthreshold by the field strength which fails to excite. Thus fractional WT averages the excitability of cells in the tissue and thus DEFS characterizes this important parameter of uterine function and quantitates threshold under a variety of regulatory conditions. The comparative study of excised uteri in three different endocrine states showed that the regulatory conditions of normal pregnancy (P levels 9 ng. per milliliter) suppressed excitability and increased threshold (to 6 v per 5 cm.). Post partum (P levels 1 ng. per milliliter) excitability increased and threshold decreased (to 4 v per 5 cm.), unless P treatment prevented this characteristic change by suppressing excitability and increasing threshold (to 6 v per 5 cm.). Both regulatory agents, prostaglandin F2alpha (PGF2alpha) and its analogue ICI 81008, increased excitability and decreased threshold significantly in picogram per milliliter concentrations. However, this effect was observed only when the P levels were low. These compounds had little effect, even in manogram per milliliter concentrations, when the P levels were high. The studies also revealed a close relationship between threshold and spontaneous uterine activity. Low threshold promoted while high threshold suppressed spontaneous activity. In similar concentrations the oxytocic actions of PGF2alpha and ICI 81008 were similar but the effect of ICI 81008 was prolonged through strong binding at myometrical sites.
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.
We conducted a double-blind study to determine the efficacy of 17alpha-hydroxyprogesterone caproate in preventing premature delivery in 43 high-risk patients. Premature delivery did not occur in 18 patients receiving the progestational agent, whereas 41 per cent of the 22 receiving the palcebo had premature delivery (P less than 0.01). The mean duration of pregnancy and the mean birth weight in the former group (38.6 weeks +/- 1.6 S.D., and 2836 g +/- 412 S.D.) were both significantly greater (P less than 0.025) than that in the latter (35.2 weeks +/- 6.7 S.D.; 2361 g +/- 1085 S.D.). The perinatal mortality rate in the group given the progestational agent (O per cent) was significantly less than that observed in the placebo group (27 per cent) (P less than 0.05). Although there were no complications attributable to the progestational drug, the study population was too small for assessment of immediate or long term safety. However, the results indicate a possible obstetric use for this drug.
Reproductive EndocrinologyProgesterone MetabolitesAntibiotic Effects on HormonesUrinary and Fecal Steroids
Progesterone metabolites and estriol were determined in urine and faeces collected daily from three pregnant women (33–37 weeks) before and during ampicillin administration (2 g/day orally).
Two of the three subjects showed marked changes in their faecal steroid excretion during the faecal progesterone-metabolite pattern changed from containing 69–79% unconjugated metabolites and 19–26% glucuronides under control conditions, to high steroid sulphate content (28–44%); the faecal elimination of 3β-hydroxy-5α-pregnan-20-one and 5α-pregnane-3β,20α-diol glucuronide all but ceased; two 16α-hydroxylated progesterone metabolites were detected in significant amounts in faeces during ampicillin administration but not under normal conditions. Steroid sulphate hydrolysis, epimerization of 3α,5αto 3β,5α-steroids and 16α-dehydroxylation are all well known actions of intestinal bacteria on biliary steroids. It thus seems clear that the changes found in the faecal progesterone metabolite pattern are due to the reduction of the intestinal flora by ampicillin.
Under control conditions the bulk of the faecal estriol was unconjugated. During ampicillin administration this excretion remained unchanged but in addition large quantities of conjugated estriol appeared in the faeces, apparently as a result of inhibition of bacterial deconjugation.
Ampicillin administration also caused decreased urinary excretion of estriol and pregnanediol glucuronide. It seems likely that these well documented effects of ampicillin on urinary steroid excretion are caused by an interruption of the enterohepatic circulation of steroids which results from the inhibition of intestinal steroid metabolism described above.
PregnancyChromosomal AbnormalitiesKaryotype AnalysisRetrospective and Prospective
Epidemiologic studies, retrospective and prospective, were done on 1500 abortions collected from 1966-1972. No secular or seasonal variations were observed. From the analysis of the relative frequencies of the different types of chromsome anomalies it is estimated that 1 out of every 2 conceptions has a chromosome anomaly. Maternal-age influence was found only for the autosomal trisomy group, mainly D and G trisomies. No effect of oral contraceptives were discovered. An increased frequency of chromosome anomalies occurred after ovulation-inducing therapy and after occupational exposure of the father to irradiation. No variations in the fertility rate and in the frequency of congenital malformations in births following abortions was noted. The incidence of recurring abortion was mainly influenced by the reproductive history of the couple before the karyotyped abortion.
Reproductive EndocrinologyPlasma Levels in PregnancyProgesterone SecretionRadioimmunoassay
The plasma concentration of progesterone (P) has been measured by radioimmunoassay in maternal peripheral vein (M.P.V.) at early pregnancy and in M.P.V. umbilical artery (U.A.) and umbilical vein (U.V.) at term pregnancy. In early preganacy marked hour-to-hour fluctuation of plasma progesterone was noted. At term pregnancy plasma P levels of U.V. were higher than those of U.A. and the umbilical venous arterial differences of plasma P did not differ between male and femal fetuses. Administration of hydrocortisone and ACTH to patients scheduled to undergo cesarean section had no effect on M.P.V., U.A., and U.V. plasma P concentration. On the basis of the differences between U.V. and U.A. plasma P concentrations and reported umbilical flow it was estimated that the secretion rate of P into the fetal circulation is approximately 23 mg. per 24 hr. and would amount to approximately 10 per cent of the reported total daily production rate of P at term pregnancy. The fraction of P which is unbound to the plasma proteins was estimeated by equilibrium dialysis at 37 degrees C. The per cent unbound P in M.P.V. plasma of pregnant patients at term was not different from that of nonpregnant patients but was 40 per cent lower than that in umbilical cord plasma (P LESS THAN 0.01), and the ratio between the concentrations of unbound P and estradiol in M.P.V. increased as pregnancy progressed. Plasma P in re-eclamptic patients who subsequently sustained intrauterine fetal death had no value in assessing placental function.
5alpha-Pregnane-3,20-dione and progesterone were isolated from a pregnancy plasma pool and were identified by using a combination of chromatographic techniques and mass spectrometry. Antibodies to progesterone were obtained in rabbits by immunization with progesterone-1alpha-carboxyethyl-thioether-thyroglobulin. The raised antibodies were of high affinity and one of them cross-reacted (137%) with 5alpha-pregnane-3,20-dione. This property was used to develop radioimmunoassays for measuring circulating levels of both progesterone and 5alpha-pregnane-3,20-dione in pregnancy plasma. The levels of both progesterone and 5alpha-pregnane-3,20-dione increase throughout pregnancy, but a highly significant increase is observed only after the 32nd week of gestation.
PregnancyGestational Trophoblastic DiseaseProgesterone in Abnormal PregnancyProgesterone
Lindberg BS et al., 1974·Acta Obstet Gynecol Scand
Plasma progesterone levels were estimated by competitive protein binding in 815 samples from healthy pregnant women with uncomplicated pregnancies. This series includes 32 patients who were followed serially throughout pregnancy. The mean level increased from 47 ng/ml in week 22 to 148 ng/ml in week 41. The spread was large. Individual patients showed very large variations between two consecutive weeks.
Diurnal variations were examined in 7 patients and short-time variations during one hour in 5 patients. Large but non-systematic variations were found in most cases. The maximal difference between values observed over a 24-hour-period was 123 ng/ml and during one hour 150 ng/ml.
Plasma progesterone levels were studied in 87 cases of toxemia of pregnancy, 6 cases of hypertension, 54 cases of Rh-immunization, 37 cases of diabetes and 5 cases of fetal growth retardation of unknown origin. The results indicate that no constant changes occur in plasma progesterone levels in these groups or in cases of impending fetal death.
As the normal limits are very wide, the intraindividual variations large, and the progesterone values in high risk pregnancies are inconclusive, plasma progesterone estimates during the latter part of pregnancy seem to be of limited value.
During human pregnancy large amounts of progesterone are produced by the placenta (1, 14). The production rate during the third trimester lies between 200 and 300 mg/day (9). Part of the progesterone produced is metabolized to pregnanediol and excreted in the urine as the 3-glucuronidate (16). The percentage of conversion to pregnanediol seems to vary with the stage of gestation and is influenced by pathological alterations in risk pregnancies (2, 5).
Large day to day variations in the urinary pregnanediol levels have been found. It is thus hardly surprising that the clinical value of serial determinations of urinary pregnanediol in late pregnancy has been limited.
Recently useful methods for the assay of progesterone in plasma have been developed and applied to physiological and clinical studies. A number of reports dealing with the prognostic value of progesterone determinations in complicated pregnancies have been published (8, 12, 17). The number of cases investigated is, however, small and the results are, in many respects, inconclusive. The aim of the present investigation was to determine the normal limits during the latter half of uncomplicated pregnancies, circadian and short-time variations, and to evaluate the prognostic value of progesterone determinations in plasma in high risk pregnancies.
Progesterone levels in the human fetoplacental unit at term were determined by a competitive protein binding method. Progesterone levels in the umbilical vein were always higher than in the umbilical artery. The concentration of progesterone in the umbilical vein of male and female fetuses was identical. However, the umbilical venous-arterial difference in progesterone levels was significantly greater in female than in male fetuses. The fetal genotype therefore may affect the fate of progesterone available to the fetus.
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.
To describe normal relationships between the various plasma unconjugated estrogens and progesterone during the second half of human pregnancy, the plasma concentrations of progesterone, 17-hydroxyprogesterone (17-OHP), and unconjugated estrone (E1), estradiol (E2), and estriol (E3) were measured in 126-310 normal women. Progesterone and unconjugated E1, E2, and E3 increased gradually throughout later pregnancy; 17-OHP increased only after the thirty-third week. At term the mean value of progesterone was 9 times higher than that 17-OHP. Throughout pregnancy the mean value of E2 was higher than that of E1 or E3. During the second half of pregnancy the ratios of progesterone to estradiol and estriol and of estradiol to estriol remained unchanged, indicating no preferential increase of plasma concentration of maternal or fetal hormones.
Following the total removal of luteal tissue, circulating plasma progesterone, intrauterine pressure, oxytocin response, and clinical progress in abortion were determined sequentially in 12 first-trimester pregnant patients. 3 patients were ovariectomized for the removal of ovarian cysts and 9 were luteectomized during tubal ligation in an attempt to terminate pregnancy in spontaneous abortion. 7 patients had corpora lutea which averaged 21 plus or minus 1mm in diameter at operation when performed at Day 49 plus or minus 2 (mean S.E.) of pregnancy. These patients responded to ovariectomy or luteectomy by a continuing decrease in progesterone, evolution in intrauterine pressure, oxytocin response, progress in cervical dilitation and, abortion. Abortion occurred with a mean lapse time of 5 plus or minus 1 days after operation. In contrast, 5 patients whose corpora lutea averaged only 11 plus or minus 1mm in diameter when removed at Day 61 plus or minus 4 of pregnancy showed only transient decrease in progesterone after operation. This decrease was followed by an increase in progesterone; no progress in the evolution of intrauterine pressure, oxytocin response, cervical dilatation, and abortion. It appears that so long as the corpus luteum serves as the major source of progesterone, it is indispensable in the maintenance of pregnancy in human subjects as it is in the clinical model animal, the rabbit. However, with the shift of progesterone production from the corpus luteum to the placenta (the luteoplacental shift) the human corpus luteum becomes dispensable. These findings identify the corpus luteum and its secretory product, progesterone, as feasible targets of fertility control strategy.
PROSTAGLANDINS (PGs) are being used increasingly as abortifacients although their precise mechanism of action is uncertain. One of the compounds frequently used is PGF2α, which has been shown to stimulate the myometrium in vitro1 and in vivo2. Whether or not the direct action of this agent on the uterine muscle alone is responsible for the interruption of pregnancy is not clear, but the long interval between infusion and abortion3 suggests that other mechanisms might be involved; for example, a luteolytic effect4–6. The prompt increase in uterine activity after treatment with prostaglandin, however, argues that the direct effect plays some part in the abortifacient action. Little is known of the influence of other myometrial regulatory agents such as the ovarian steroids on the uterine response to PGs. Accordingly we examined the influence of progesterone on myometrial responses to prostaglandin F2α in the rabbit, a species in which progesterone is known to have a blocking action on the uterine muscle7.
PregnancyProgesterone LevelsPregnancy and LaborHormonal Changes
Plasma progesterone concentration was determined in the maternal peripheral vein, umbilical vein, uterine vein, and both ovarian veins at elective cesarean section in term pregnancy. In 10 cases plasma from both ovarian veins was analyzed. In all but one the ovarian vein draining blood from the corpus luteum contained greater concentrations of progesterone than did the blood from the side without the corpus luteum. It has been suggested for some time that the corpus luteum of pregnancy continues to function throughout pregnancy. Our data appear to support this concept.
PregnancyProgesterone LevelsGestational ProfilesCompetitive Protein Binding
Plasma levels of progesterone* were measured during normal human pregnancy by a sensitive and rapid competitive protein binding technique. During the first half of gestation 440 determinations in 321 women and in the second half of gestation, 209 determinations in 160 women were performed.
The average plasma level of progesterone in the 5th week of gestation was 24.8 ± 7.3 (s) ng/ml which is above the normal range of the luteal plateau of the menstrual cycle (10–20 ng/ml). Between the 5th and the 9th week of gestation the plasma concentration decreased significantly. From the 9th to the 32nd week of gestation the plasma level of progesterone increased from 16.7 ± 7.4 (s) to 125.2 ± 37.9 (s) ng/ml. During the last 8 weeks of gestation the plasma levels of progesterone did not show any significant rise. One woman was followed up from the day of ovulation to the 8th week of gestation. An increase in progesterone levels was observed about 10 days after ovulation. Morning samples of progesterone, which were taken before the 20th week of gestation, when the woman was still in bed, were found to be somewhat higher than levels found during the remainder of the day.
Progesterone concentrations in a few abnormal pregnancies are also reported.
A method to measure plasma progesterone by gas-liquid chromatography is presented. The procedure allows for the preparation of a plasma progesterone extract clean enough for accurate submicrogram quantification by gas-liquid chromatography. In a gas chromatograph equipped with a hydrogen flame detector, the instrument modifications and operating conditions as outlined make possible the measurement of 0.001 μg (1 ng.) of progesterone standard on a stable recorder base line. In biologic samples the sensitivity of the assay is in the order of 0.01 μg (10 ng.) of progesterone.
Reproductive EndocrinologyPregnancy LevelsHormonal Changes in LaborProgesterone Decline
One hundred and seventy-two plasma progesterone determinations were performed in normal pregnancy, labor, and the puerperium. One hundred and nineteen of the assays were done on isolated samples; 53 of the assays were done in 11 serial studies. While the concentration of progresterone in peripheral blood increased progressively with advancing pregnancy, no apparent decrease in the hormone level occurred at or near the onset of labor or during its progress. A significant decrease in plasma progesterone one hour after the delivery of the placenta continued to decline to menstrual cycle levels by 72 hours post partum.
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 …
Reproductive EndocrinologyFetal EffectsProgestins in PregnancyHormonal Teratogenicity
239 women received medroxyprogesterone during their pregnancies; they received no other hormone therapy. Of the 203 who went to term 172 were treated prior to the 12th week; the latter are discussed. Average daily dose varied from 5-50 mg or more orally with or without injectable supplements. Sex distribution of infants was 92 male to 82 female there were 2 sets of twins 1 stillborn and 1 newborn with congenital heart disease. The authors report a case of transient masculization of a female infant born with an enlarged clitoris which persisted until age 6 months. Masculization of the female fetus may occur if the fetus is subjected to some source of androgen prior to the 12th week of gestation after which the female generative tract is well differentiated and not likely to be affected. Other studies have reported up to 18% masculization using exogenous hormones with abnormalities as extreme as labial fusion and cloacal formation necessitating surgical correction.
InfertilityEpidemiologyRisk Factors and PrognosisReproductive History Analysis
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.
After many years of use and a large number of publications there is still no good evidence to indicate that progestogens have a valid role in the treatment of patients with a history of abortion. In many of the published series the amount of material administered has been inadequate in the light of current concepts of progesterone secretion in pregnancy (Zander, 1959) and inadequate control observations have invalidated much published data. To assess the salvage rate in treated pregnancies and then compare it with that found for previous untreated pregnancies in the same patients ignores the number of pregnancies that would have reached viability if no treatment had been given at all. Malpas (1938) produced a theoretical estimate that any woman with a history of three consecutive abortions. . .
A new progestational steroid, the acetophenone derivative of 16α,17α;- dihydroxyprogesterone, was compared with several progestogens for masculinizing effects on the offspring of rats treated during pregnancy. The results were similar to those obtained with progesterone and 17α-hydroxyprogesterone this new steroid female sex ratio and did not virilize the internal or external sex structures of the newborn. The present results confirm those of others in finding that 6α-methyl-17α-hydroxyprogesterone acetate, 17α-ethinyl-19-nortestosterone and 17aethinyl- 19-nortestosterone acetate increased the number of male and intersex offspring, as determined by ano-genital measurements and masculinization of internal and external sex organs.
PregnancyHormonal AssessmentPlacental Insufficiency MarkersPregnanediol and Estrogens
The content of progesterone was determined in the peripheral venous blood of pregnant women from the 11th week after the last menstrual period up to the day of birth. There was a steady increase in the blood level from the 11th to the 35th week, but thereafter the level rose more rapidly, and remained high during labour itself. The significance of this rise after the 35th week is not fully understood. It may reflect a decrease in the rate of progesterone metabolism which occurs at this time. The blood level in three cases of twin pregnancy tended to be higher than the corresponding levels for single pregnancies. After removal of the placenta during elective caesarean sections, it was found that the blood progesterone level rapidly fell below the limits of sensitivity of the method. It has been estimated that the half-life of progesterone in the circulating blood must be 5 min or less.
Normal Pregnancy. Eleven pregnant women were studied at weekly intervals for periods ranging from 24 to 32 weeks. Three hundred and ten estimations were done in this group. An additional 68 assays were made in 40 patients at various stages of pregnancy, a total of 378 estimations being done in 51 patients, 189 in primigravidae and an equal number in multigravidae. Two of the patients in the first group had been attending the sterility clinic before becoming pregnant. None of the patients were suffering from hypertension …
There are relatively few reports of female pseudohermaphrodism not associated with congenital adrenal hyperplasia. The writers report 21 cases of females born with partial masculinization of the external gcnitalia, consisting of an enlarged phallus, with or without varying degrees of fusion of the labioscrotal folds. The diagnosis was established by finding female chromatin patterns, low excretion of urinary 17-kctosteroids and absence of progressive virilization. Exploratory laparotomy revealed normal ovaries and a normal female genital tract, although in some cases the vagina and urethra opened into a common urogenital sinus. In 15 of the cases, the mother had been treated because of threatened or habitual abortion with an oral progestin, 17-cthinyltestosterone (anhydrohydroxyprogesterone or ethisterone), marketed undersuch trade names as Pranone, Progestoral and Lutocjlol. In 2 cases the mother had received intramuscular injections of progesterone. In 1 case both intramuscular progesterone and oral methyltcstosterone had been given. In 3 cases no steroids were administered during pregnancy. The progestinic medication was usually begun before the tenth week of gestation and in most instances between the fourth and sixth weeks. Reasons are discussed for believing that the oral and intramuscular administration of progestins induced the partial masculinization of the female fetus. It is believed that the female fetus is affected in only occasional mothers who receive these steroids, and that in such mothers there may be an abnormality of cither the metabolism of progestins or their transmission across the placenta. It is most important to diagnose the condition correctly at birth, and to rear the infant as a female. No treatment is required except surgical correction of the abnormalities of the external genitalia. Normal female development is certain.
While investigating the use of progesterone for the relief of premenstrual syndrome (Greene and Dalton, 1953) a high incidence of toxaemia of pregnancy (19.1 %) was recognized among sufferers from this syndrome. A further investigation, undertaken to ascertain the incidence of premenstrual syndrome in those who had previously suffered from toxemia of pregnancy, revealed that 86% of the 237 women thus affected at one time or another during the previous twelve years also suffered from premenstrual syndrome (Dalton, 1954). Furthermore, direct questioning and a scrutiny of records of these patients showed that before the full development of the signs of toxaemia–that is, oedema, hypertension, and albuminuria–most had earlier in the pregnancy experienced a symptomatic stage characterized by relatively minor afflictions–for example, lethargy 43 %, headache 48%, visual aura 37%, vertigo 29%, nausea and vomiting 16%, irritability 14%, depression 9%, and backache 6%. In fact, only 7% disclosed freedom from these symptoms during a toxaemic pregnancy. 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. Apart from the similarities of these minor symptoms in the two conditions, other points in common were noted. For example, day-to-day observations of sufferers of premenstrual syndrome had shown that, apart from minor symptoms, some developed oedema, hypertension, and albuminuria during the premenstruum, with spontaneous improvement during menstruation. This appeared to be analogous to the spontaneous resolution of oedema, hypertension, and albuminuria following delivery. Furthermore, if symptoms remain untreated either in premenstrual syndrome or in toxaemia both diseases may culminate in fits, epileptic in the one case, eclamptic in the other. In an earlier investigation one of the reasons for using progesterone in the treatment of premenstrual syndrome had been that some patients suffering from this condition were symptom-free during pregnancy. It was considered that the corpus luteum and placenta supplied enough progesterone during pregnancy to keep these patients symptom-free. Others were not only unrelieved of their premenstrual symptoms during pregnancy, but, as already indicated, developed symptoms closely resembling those of the premenstruum and culminating in toxaemia. It was therefore thought possible that the development of toxaemia might in such cases arise from failure of the corpus luteum and placenta to produce sufficient progesterone. 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 albuminuria in the premenstruum (Dalton, 1954, 1955), it was decided to carry out a trial, employing large doses of progesterone in patients disclosing early minor symptoms of toxaemia, in an attempt to arrest full development of that condition.
In 1899 Gustav Born advanced the theory that the corpus luteum of the ovary is a gland of internal secretion, its activity being a prerequisite for the implantation and early development of the fertilized ovum. Conclusive proof of the theory was provided by Fraenkel ('10) in demonstrating that cauterization of the corpora lutea in pregnant rabbits leads to the resorption of the fertilized ova, provided that the operation took place during the first 7 days of gestation. He extended the period of the indispensable role of the corpora lutea in the …