State of the Fertility Sector 2023/2024

State of the Fertility Sector 2023/2024

Abstract:
# State of the fertility sector 2023/24
Annual publication on HFEA licensed clinics
(1st April 2023 – 31st March 2024)
Published: 1st October 2024
[Download the underlying dataset as .xlsx](https://www.hfea.gov.uk/media/cjwjns5j/state-of-the-fertility-sector-2023-2024-underlying-dataset.xlsx "State of the fertility sector 2023-2024 - underlying dataset")
## Table of contents
- [How we regulate](https://www.hfea.gov.uk/about-us/publications/research-and-data/state-of-the-fertility-sector-2023-2024/#how-we-regulate)
- [1\. Inspections in 2023/24](https://www.hfea.gov.uk/about-us/publications/research-and-data/state-of-the-fertility-sector-2023-2024/#section-1)
- [2\. There were 226 non-compliances identified at inspection in 2023/24](https://www.hfea.gov.uk/about-us/publications/research-and-data/state-of-the-fertility-sector-2023-2024/#section-2)
- [3\. In 2023/24, 135 clinics were licensed by the HFEA to provide fertility treatment, storage and/or research](https://www.hfea.gov.uk/about-us/publications/research-and-data/state-of-the-fertility-sector-2023-2024/#section-3)
- [4\. Total incidents reduced by 8% compared to the previous financial year](https://www.hfea.gov.uk/about-us/publications/research-and-data/state-of-the-fertility-sector-2023-2024/#section-4)
- [5\. Fewer Ovarian hyperstimulation syndrome (OHSS) incidents were reported in 2023/24](https://www.hfea.gov.uk/about-us/publications/research-and-data/state-of-the-fertility-sector-2023-2024/#section-5)
- [6\. Patient complaints in 2023/24 were consistent with the previous financial year](https://www.hfea.gov.uk/about-us/publications/research-and-data/state-of-the-fertility-sector-2023-2024/#section-6)
- [About our data](https://www.hfea.gov.uk/about-us/publications/research-and-data/state-of-the-fertility-sector-2023-2024/#about-our-data)
## How we regulate
The Human Fertilisation and Embryology Authority (HFEA) is the independent regulator of fertility treatment and human embryo research in the United Ki...


Increased Incidence of Endometriosis Coexisting with Polycystic Ovary Syndrome in Infertile Patients


Prospective 1-year assessment of within-woman variability of follicular and luteal phase lengths in healthy women prescreened to have normal menstrual cycle and luteal phase lengths

Sonia Shirin

University of British Columbia, Vancouver, BC, Canada

Sarah Henry

UBC Centre for Menstrual Cycle and Ovulation Research , Vancouver, BC,

Jerilynn C Prior

Vancouver Hospital and Health Sciences Centre

Abstract:
Study Question: What is the relative length variance of the luteal phase compared to the follicular phase within healthy, non-smoking, normal-weight, proven normally ovulatory, premenopausal women with normal-length menstrual cycles?

Summary Answer: Prospective 1-year data from 53 premenopausal women with two proven normal-length (21-36 days) and normally ovulatory (≥10 days luteal) menstrual cycles upon enrollment showed that, despite 29% of all cycles having incident ovulatory disturbances, within-woman follicular phase length variances were significantly greater than luteal phase length variances.

What Is Known Already: Many studies report menstrual cycle variability, yet few describe variability in follicular and luteal phase lengths. Luteal lengths are assumed 'fixed' at 13-14 days. Most studies have described follicular and luteal phase variability between-women.

STUDY DESIGN, SIZE, Duration: This study was a prospective, 1-year, observational cohort study of relative follicular and luteal phase variability both between and within community-dwelling women with two documented normal-length (21-36 days) and normally ovulatory (≥10 days luteal phase) menstrual cycles prior to enrollment. Eighty-one women enrolled in the study and 66 women completed the 1-year study. This study analyzed data from 53 women with complete data for ≥8 cycles (mean 13). PARTICIPANTS/MATERIALS, SETTING,

Methods: Participants were healthy, non-smoking, of normal BMI, ages 21-41 with two documented normal-length (21-36 days) and normally ovulatory (≥10 days luteal phase) menstrual cycles prior to enrollment. Participants recorded first morning temperature, exercise durations, and menstrual cycle/life experiences daily in the Menstrual Cycle Diary. We analyzed 694 cycles utilizing a twice-validated least-squares Quantitative Basal Temperature method to determine follicular and luteal phase lengths. Statistical analysis compared relative follicular and luteal phase variance in ovulatory cycles both between-women and within-woman. Normal-length cycles with short luteal phases or anovulation were considered to have subclinical ovulatory disturbances (SOD).

Main Results and the Role of Chance: The 1-year overall 53-woman, 676 ovulatory cycle variances for menstrual cycle, follicular, and luteal phase lengths were 10.3, 11.2, and 4.3 days, respectively. Median variances within-woman for cycle, follicular, and luteal lengths were 3.1, 5.2, and 3.0 days, respectively. Menstrual cycles were largely of normal lengths (98%) with an important prevalence of Sod: 55% of women experienced >1 short luteal phase (<10 days) and 17% experienced at least one anovulatory cycle. Within-woman follicular phase length variances were greater than luteal phase length variances (P < 0.001). However, follicular (P = 0.008) and luteal phase length (P = 0.001) variances, without differences in cycle lengths, were greater in women experiencing any anovulatory cycles (n = 8) than in women with entirely normally ovulatory cycles (n = 6).

LIMITATIONS, Reasons for Caution: Limitations of this study include the relatively small cohort, that most women were White, initially had a normal BMI, and the original cohort required two normal-length and normally ovulatory menstrual cycles before enrollment. Thus, this cohort's data underestimated population menstrual cycle phase variances and the prevalence of SOD. WIDER IMPLICATIONS OF THE FINDINGS: Our results reinforce previous findings that the follicular phase is more variable than the luteal phase in premenopausal women with normal-length and ovulatory menstrual cycles. However, our study adds to the growing body of evidence that the luteal phase is not predictably 13-14 days long. STUDY FUNDING/COMPETING INTEREST(S): This medical education project of the University of British Columbia was funded by donations to the Centre for Menstrual Cycle and Ovulation Research. The authors do not have any conflicts of interest to disclose.

Trial Registration Number: N/A.


Nonlinear correlation between serum vitamin D levels and the incidence of  endometrial polyps in infertile women

Zhenghong Zhu

Guangdong Province Women and Children Hospital

Abstract:
STUDY Question: Are serum vitamin D levels associated with the incidence of endometrial polyps (EPs) in infertile patients?

SUMMARY ANSWER: Serum 25(OH)D levels were nonlinearly correlated with the incidence of EPs in infertile women.

WHAT IS KNOWN ALREADY: EPs are a common condition that may affect the receptivity of the endometrium in women of reproductive age. Vitamin D regulates cell proliferation and differentiation, apoptosis, angiogenesis, anti-inflammation, and immunomodulation, in addition to its well-known functions in balancing calcium and phosphorus. Previous studies have shown that vitamin D concentrations are associated with reproductive outcomes, and that low vitamin D levels are associated with the incidence of colorectal polyps and nasal polyps. There is little evidence regarding the relationship between EPs and serum vitamin D levels.

STUDY DESIGN, SIZE, DURATION: We conducted a cross-sectional study using data from Guangdong Women and Children Hospital from January 2019 to October 2023, enrolling 3107 patients.

PARTICIPANTS/MATERIALS, SETTING, Methods: A total of 3107 infertile patients who underwent hysteroscopy were included in this study; 642 patients had endometrial polyps and 2465 had a normal uterine cavity. Hysteroscopy findings included risk of EPs, polyp size, percentage of multiple polyps, and incidence of chronic endometritis (CE). Serum vitamin D were assessed by measuring total 25(OH)D using chemiluminescence. According to international guideline recommendations for vitamin D deficiency, patients were divided into two groups: the <50 nmol/l group and the ≥50 nmol/l group. Univariable and multivariable logistic regression models, stratified analyses, and smooth curve fitting were used to examine the relationship between serum 25(OH)D levels and risk of EPs.

MAIN RESULTS AND THE ROLE OF CHANCE: Of all patients, 23.8% (740/3107) were vitamin D deficient (<50 nmol/l). The incidence of EPs was significantly higher in the 25(OH)D < 50 nmol/l group than in the ≥50 nmol/l group (24.9% vs 19.3%; P = 0.001). However, there were no differences in polyp size, proportion of multiple polyps, and presence of CE between the two groups. After controlling for confounders, 25(OH)D ≥ 50 nmol/l (compared with <50 nmol/l) was negatively associated with risk of EPs (adjusted OR, 0.733; 95% CI, 0.598-0.898). Other variables that had an impact on polyp incidence included BMI, type of infertility, CA125, and CD138-positive plasma cells. In addition, a linear regression model between age and serum 25(OH)D levels showed a positive linear association. Subgroup analyses were performed for different age groups, and the risk of EPs was significantly higher in the 25(OH)D < 50 nmol/l group than in the ≥50 nmol/l group, both in the younger subgroup (23.8% vs 19.1%) and in the older subgroup (28.0% vs 19.9%). The smooth curve fitting model showed a nonlinear correlation between 25(OH)D levels and risk of EPs (nonlinear P-value = 0.020), with an optimal threshold of 51.8 nmol/l for 25(OH)D levels. Moreover, subgroup smooth curve fitting models showed a nonlinear correlation between 25(OH)D levels and polyp risk in patients aged <35 years (nonlinear P-value = 0.010), whereas a linear correlation between 25(OH)D levels and polyp risk was found in patients aged ≥35 years (nonlinear P-value = 0.682).

LIMITATIONS, REASONS FOR CAUTION: Caution should be exercised in interpreting our findings as this is a correlational study and causality cannot be inferred from our results. In addition, because of strict inclusion and exclusion criteria, our results may not be generalizable to unselected populations, including premenopausal women or women of other races.

WIDER IMPLICATIONS OF THE Findings: This study demonstrated for the first time that vitamin D deficiency is an independent risk factor for the incidence of EPs in infertile patients. Identifying modifiable risk factors (e.g. vitamin D deficiency) can help in the development of new strategies for treating polyps or to protect against polyp development. Further clinical intervention trials and laboratory studies are needed to evaluate the effect of vitamin D on the development of EPs and to elucidate the mechanisms. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the National Natural Science Foundation of China (82101718) and Natural Science Foundation of Guangdong Province, China (2022A1515010776). No competing interest was involved in this study.

TRIAL REGISTRATION NUMBER: N/A.


Maternal periconception hyperglycemia, preconception diabetes, and risk of major  congenital malformations in offspring

Sonia Hernández-Diaz

Department of Epidemiology, Harvard T.H. Chan School of Public Health , Boston, MA,

Marc G Weisskopf

Department of Environmental Health, Harvard T.H. Chan School of Public Health , Boston, MA,

Abstract:
STUDY Question: What are the roles of maternal preconception diabetes and related periconceptional hyperglycemia on the risk of major congenital malformations (MCMs) in offspring?

SUMMARY ANSWER: 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.

WHAT IS KNOWN ALREADY: 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, DURATION: A large Israeli birth cohort of 46 534 children born in 2001-2020.

PARTICIPANTS/MATERIALS, SETTING, Methods: 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 RESULTS AND THE ROLE OF CHANCE: 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, REASONS FOR CAUTION: 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.

WIDER IMPLICATIONS OF THE Findings: 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.

TRIAL REGISTRATION NUMBER: N/A.


Endometriosis and pregnancy outcomes - another piece to a complex puzzle

Leslie V Farland

Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona; Department of Obstetrics and Gynecology, College of Medicine -...


HFEA Code of Practice (9th edition, version 9.4)

Human Fertilisation and Embryology Authority

Abstract: The HFEA Code of Practice gives guidance to clinics about the proper conduct of activities licensed under the Human Fertilisation and Embryology Act 1990 (as amended). The 9th edition (effective 26 October 2023) was further amended for version 9.4 (effective 1 October 2024). The Code consolidates statutory regulations, license conditions, and HFEA guidance covering: clinic governance, staff training and qualifications, identity checks and consent, gamete and embryo storage, donor recruitment and screening, donation arrangements, treatment licensing, pre-implantation genetic testing, multiple births policy, surrogacy, witnessing procedures, traceability, adverse incidents reporting, complaints, research licensing, and information disclosure. Compliance with the Code is a statutory requirement for all UK clinics licensed by the HFEA. Version 9.4 includes updated guidance on donor compensation (effective October 2024) and known donation for people with undetectable HIV (effective November 2024).


The fate of hazardous textile pollutants in an upcycling process for post-consumer garments


Association of mixed exposure to microplastics with sperm dysfunction: a multi-site study in China

Jiong Zhou

Second Affiliated Hospital of Zhejiang University

Xiyao Liu

First Affiliated Hospital of Chongqing Medical University

Hefeng Huang

International Peace Maternity & Child Health Hospital

Abstract:
BACKGROUND: Microplastics are environmental pollutants detected in various human organs and tissues. These particles originate from multiple sources including the degradation of larger plastic items and the intentional inclusion in consumer goods. Potential risks for human health resulting from microplastics exposure have also been reported. However, the distribution in the male reproductive system and its effect remains largely unknown. This study aims to investigate the presence of multiple microplastics in human semen and urine and their association with sperm quality in a multi-site study across China.

METHODS: We conducted a cross-sectional study involving 113 male participants from three regions in China. Semen and urine samples were collected and analysed using Raman microscopy to detect eight types of microplastics: polystyrene (PS), polypropylene (PP), polycarbonate (PC), polyethylene (PE), polyvinyl chloride (PVC), polytetrafluoroethylene (PTFE), polyethylene terephthalate (PET), and acrylonitrile butadiene styrene (ABS). Semen quality parameters, including total sperm count, concentration, motility, and morphology, were assessed. Statistical analyses, including single and multi-variable models, were used to evaluate the relationship between microplastic exposure and semen quality, with a focus on PTFE, after adjusting confounding factors of age, body mass index (BMI), smoking, alcohol drinking, and sites.

FINDINGS: Microplastics were detected in all semen and urine samples, with participants typically exposed to 3-5 different types. The detection rates of PS, PP and PE were the highest. Notably, PTFE exposure was significantly associated with decreased semen quality. Participants exposed to PTFE showed reductions in total sperm count [188.90 ± 163.71 vs. 207.67 ± 132.36 million, p = 0.091], sperm concentration [52.13 ± 47.47 vs. 58.32 ± 37.26 million/mL, p = 0.041], and progressive motility [40.29% ± 19.06 vs. 34.11% ± 17.02, p = 0.083]. The multi-linear regression analysis indicated that each additional type of microplastic exposure was associated with a significant decrease in total sperm number [β = -15.4 (95% CI: -25.6, -5.2)], sperm concentration [β = -7.2 (95% CI: -12.4, -2.0)], and progressive motility [β = -8.3 (95% CI: -13.5, -3.1)]. Latent category analysis further refined these groups by types of microplastic exposure, highlighting specific types more strongly associated with decreased semen quality (OR = 3.5, 95% CI: 1.8, 6.9, p < 0.001). The nomogram can be used to assess the risk of sperm damage by combining the type of microplastic exposure in urine with age and BMI.

INTERPRETATION: Our findings highlight the potential reproductive health risks posed by microplastic contamination, particularly PTFE, a non-stick pan coating material, and raise concerns about the potential of urine testing as an indicator of male reproductive microplastic exposure. Future research is warranted to further elucidate the mechanisms underlying the adverse effects of microplastics on male fertility and cross-generational effects.

FUNDING: This study was funded by the Clinical Research Project of Shanghai Municipal Commission of Health and Family planning (20224Y0085), Open Fund Project of Guangdong Academy of Medical Sciences (YKY-KF202202), CAMS Innovation Fund for Medical Sciences (2019-I2M-5-064), Shanghai Clinical Research Center for Gynecological Diseases (22MC1940200), Shanghai Urogenital System Diseases Research Centre (2022ZZ01012), Key Discipline Construction Project (2023-2025) of Three-Year Initiative Plan for Strengthening Public Health System Construction in Shanghai (GWVI-11.1-35, GWVI-11.2-YQ29) and Shanghai Frontiers Science Research Base of Reproduction and Development.


The Long-term Rate of Repeat Surgery After Optimal Excision Surgery of Endometriosis at a Single Tertiary Referral Center

Abstract: The primary purpose of this prospective cohort study was to determine if treating endometriosis with optimal excision surgery leads to lower rates of repeat surgery as compared to historical rates of repeat surgery by ablation. A secondary outcome was to examine whether the use of hormonal suppression differed before surgery, depending on the stage of endometriosis found at surgery. Optimal excision was defined as completely excising all areas of abnormal peritoneum, wherever found in the pelvis, having looked systematically with near contact laparoscopy. All surgeries were performed by a single surgeon specializing in optimal excision at a tertiary referral center. The rate of repeat surgery after optimal excision surgery for endometriosis was remarkably low (2.5%, 15/620) as compared to historical rates of repeat surgery by ablation. Additionally, the lack of significant evidence between hormonal suppression use and progression of stage of endometriosis provides implicit evidence that hormonal suppression does not prevent progression of the disease. Further controlled studies are needed to verify these findings.


Supplementation with Folic Acid or 5-Methyltetrahydrofolate and Prevention of Neural Tube Defects: An Evidence-Based Narrative Review

Abstract: Background: Folic acid (FA), which in its chemical form is pteroylglutamic acid, is the fully oxidised, water-soluble, monoglutamic form of vitamin B9. This compound is part of the folate group but with higher bioavailability, and it is found in vitamin supplements and fortified foods and drugs. Folate metabolism is complex and associated with various metabolic pathways, all of which confer protection on the cell and allow its survival. Methods: We conducted a non-systematic search of articles published in English and Spanish including controlled trials, cohort studies, systematic re-views, and meta-analyses were included, as well as key studies in animal models related to pharmacokinetic studies. Search terms encompassed: "folic acid", "folates", "5-metyltetrahydrofolate", "5-MTHF", "neural tube defects", "supplementation", "fortification", AND "homocysteine" Results: A crucial role demonstrated for FA is to help prevent neural tube defects (NTDs). However, more studies are definitely still needed to establish 5-MTHF as a safe and effective therapeutic approach comparable with FA. Moreover, there is a lack of clinical studies that evaluate the efficacy of 5-MTHF supplementation in the prevention of NTDs. The present evidence-based narrative review discusses differences between FA and 5-MTHF in terms of structure, metabolism, bioavailability, clinical efficacy, and safety. Conclusions: Despite the potential value of 5-MTHF as an alternative to FA, clinical studies would be urgently needed to support the efficacy, dosage, timing, and/or safety of its use as a supplement.


Neuroactive hormones and personal growth: associations in Chilean adolescents  (ages 12-25) with ovulatory dysfunction

Pilar Vigil

Pontificia Universidad Católica de Chile

Valeska Tapia

Reproductive Health Research Institute, Santiago, Chile.

Abstract:
Introduction: Hormones produced by the hypothalamic-pituitary-adrenal-gonadal (HPAG) axis are crucial for modulating central nervous system (CNS) function and development throughout a person's life. Disruptions in HPAG function can impact psychological development, particularly during adolescence-a period marked by psychological growth and the maturation of the HPAG axis. An early indicator of HPAG alterations is ovulatory dysfunction (OD), a common condition among adolescents.

Methods: This study explored the associations between neuroactive hormones and personal growth in adolescents with OD. Female participants aged 12-25 years with OD were recruited, and assessments were conducted to profile their basic hormonal levels and various dimensions of individual development, including self-concept clarity, sense of coherence, self-esteem, perfectionism, self-control, and mood states.

Results: Adolescents with OD (n = 117) had lower self-concept clarity and self-esteem compared to reference data. A significant portion of the sample displayed elevated levels of tension (71.25%), confusion (62.5%), fatigue (58.22%), and depression (52.6%). Self-esteem scores were negatively correlated with DHEAS (r = -0.224; p = 0.026) and glucose (r = -0.249; p = 0.010). Higher levels of free testosterone were associated with increased depression scores (coef = 0.2398; p = 0.002), whereas higher estradiol levels were linked to lower aggressiveness scores (coef = -0.0648; p = 0.001).

DISCUSSION: These findings indicate that hormonal imbalances in adolescents with OD could affect personal growth. Further research is needed to establish causal relationships between the variables considered.


Health risks from exposure to chemicals in clothing - Non-regulated halogenated aromatic compounds

Abstract: The objective of the present study was to investigate some commonly detected halogenated textile pollutants for their bioavailability and hazardous properties. Release into artificial sweat and skin absorption in vitro were examined as well as mutagenic effects by Ames test, and skin-sensitizing properties from a peptide reactivity assay combined with a cell test. All investigated compounds were shown to migrate from the textile into sweat and be absorbed by the skin, although to a different extent. The experimental values for migration were found to be up to 390 times higher compared to literature values. Two of the studied compounds, 2,5-dinitrochlorobenzene and 3,5-dinitrobromobenzene, both exhibited mutagenic effects in the Ames test, while both 2,5-dinitrochlorobenzene and 2,6-dichlorobenzene-1,4-diamine were classified as skin sensitizers. The allergenic reactivity of the latter was found to be due to an oxidized transformation product. Risks for the induction of skin allergy and other non-carcinogenic effects from dermal exposure to the individual compounds were found low, even when considering clothing with the highest reported levels. However, the complex mixtures of chemicals often present in garments may still constitute a health risk, especially when considering the many hours of daily exposure. It is important to further study the toxicity of other frequently occurring chemicals as well as the synergistic effects of chemicals that co-occur in clothing.


Associations of Early Prolonged Secondary Amenorrhea in Women With and Without HIV

Hélène C F Côté

Women's Health Research Institute, H214-4500 Oak St, Vancouver, British Columbia V6H 3N1, Canada; Department of Pathology & Laboratory Medicine, University of British Columbia, Rm. G227 - 2211 Wesb...

Amber R Campbell

Women's Health Research Institute  Vancouver British Columbia Canada

Melanie C M Murray

Oak Tree Clinic, BC Women's Hospital and Health Centre, 4500 Oak St, Vancouver, British Columbia V5Z 0A7, Canada; Women's Health Research Institute, H214-4500 Oak St, Vancouver, British Columbia V6...

Jerilynn C Prior

Vancouver Hospital and Health Sciences Centre

Abstract:
Background: The menstrual cycle is a critical indicator of women's health. Early prolonged secondary amenorrhea increases risks for morbidity and mortality. Menstrual cycle research in women with HIV is inconsistent and often lacks an adequate comparison sample. We aimed to determine whether women with HIV have a higher lifetime prevalence of amenorrhea and whether this is independently associated with HIV and/or other biopsychosocial variables.

Methods: With data from 2 established HIV cohorts, participants assigned female at birth were eligible if aged ≥16 years, not pregnant/lactating, and without anorexia/bulimia nervosa history. Amenorrhea was defined by self-reported history of (1) no menstrual flow for ≥12 months postmenarche not due to pregnancy/lactation, medications, or surgery or (2) early menopause or premature ovarian insufficiency. Multivariable logistic regression models explored biopsychosocial covariates of amenorrhea.

Results: Overall, 317 women with HIV (median age, 47.5 years [IQR, 39.2-56.4]) and 420 women without HIV (46.2 [32.6-57.2]) were included. Lifetime amenorrhea was significantly more prevalent among women with HIV than women without HIV (24.0% vs 13.3%). In the multivariable analysis, independent covariates of amenorrhea included HIV (adjusted odds ratio, 1.70 [95% CI, 1.10-2.64]), older age (1.01 [1.00-1.04]), White ethnicity (1.92 [1.24-3.03]), substance use history (6.41 [3.75-11.1]), and current food insecurity (2.03 [1.13-3.61]).

Conclusions: Nearly one-quarter of women with HIV have experienced amenorrhea, and this is associated with modifiable risk factors, including substance use and food insecurity. Care providers should regularly assess women's menstrual health and advocate for actionable sociostructural change to mitigate risks.


Prenatal Cannabis Use and Maternal Pregnancy Outcomes

Abstract:
IMPORTANCE: Many studies have evaluated whether in utero cannabis exposure is associated with fetal and neonatal outcomes, yet little is known about whether prenatal cannabis use is associated with maternal health outcomes during pregnancy.

OBJECTIVE: To evaluate whether prenatal cannabis use is associated with maternal health outcomes during pregnancy.

DESIGN, SETTING, AND PARTICIPANTS: This population-based retrospective cohort study included pregnancies in Northern California from January 2011 to December 2019 that lasted 20 weeks or longer and were screened for prenatal cannabis use.

EXPOSURES: Prenatal cannabis use was defined as any self-reported use during early pregnancy or a positive toxicology test result based on universal screening at entrance to prenatal care (approximately 8-10 weeks' gestation). Self-reported frequency of use (daily, weekly, monthly or less, never, unknown), use defined only by self-report, and use defined only by toxicology test results were examined.

MAIN OUTCOMES AND MEASURES: Electronic health record data were used to define the following outcomes: gestational hypertension, preeclampsia, eclampsia, gestational diabetes, gestational weight gain greater and less than guidelines, placenta previa, placental abruption, placenta accreta, and severe maternal morbidity. Adjusted risk ratios (aRRs) were calculated using a modified Poisson regression.

RESULTS: The sample (n = 316 722 pregnancies; 250 221 unique individuals) included 84 039 (26.5%) Asian/Pacific Islander, 20 053 (6.3%) Black, 83 145 (26.3%) Hispanic, and 118 333 (37.4%) White individuals; the mean (SD) age was 30.6 (5.4) years. Overall, 20 053 (6.3%) screened positive for prenatal cannabis use; 2.9% were positive by self-report, 5.3% by toxicology testing, and 1.8% by both. The frequency of cannabis use was 1930 (0.6%) daily, 2345 (0.7%) weekly, 4892 (1.5%) monthly or less, and 10 886 (3.4%) unknown. Prenatal cannabis use was associated with greater risk of gestational hypertension (aRR, 1.17; 95% CI, 1.13-1.21), preeclampsia (aRR, 1.08; 95% CI, 1.01-1.15), weight gain less than (aRR, 1.05; 95% CI, 1.01-1.08) and greater than (aRR, 1.09; 95% CI, 1.08-1.10) guidelines, and placental abruption (aRR, 1.19; 95% CI, 1.05-1.36). The pattern of results was similar when defining prenatal cannabis use only by self-report or only by toxicology testing, and associations between the frequency of prenatal cannabis use and outcomes varied with outcome.

CONCLUSIONS AND RELEVANCE: The results of this cohort study suggest that prenatal cannabis use was associated with several adverse maternal health outcomes during pregnancy. Continued research is needed to understand whether characteristics of prenatal cannabis use (eg, dose, mode, and timing) moderate these associations.


A nomogram and risk stratification to predict subsequent pregnancy loss in  patients with recurrent pregnancy loss

Ruiqiong Zhou

Guangdong Province Women and Children Hospital

Abstract:
STUDY Question: Could the risk of subsequent pregnancy loss be predicted based on the risk factors of recurrent pregnancy loss (RPL) patients?

SUMMARY ANSWER: 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.

WHAT IS KNOWN ALREADY: 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, DURATION: 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, Methods: 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 RESULTS AND THE ROLE OF CHANCE: 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, REASONS FOR CAUTION: 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.

WIDER IMPLICATIONS OF THE Findings: 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.

TRIAL REGISTRATION NUMBER: N/A.


Endometriosis Typology and Ovarian Cancer Risk

Barnard ME, Farland LV, Yan B, Wang J, Trabert B, Doherty JA, Meeks HD, Madsen M, Guinto E, Collin LJ, Maurer KA, Page JM, Kiser AC, Varner MW, Allen-Brady K, Pollack AZ, Peterson KR, Peterson CM, Schliep KC

Abstract:
Importance: Endometriosis has been associated with an increased risk of ovarian cancer; however, the associations between endometriosis subtypes and ovarian cancer histotypes have not been well-described.

Objective: To evaluate the associations of endometriosis subtypes with incidence of ovarian cancer, both overall and by histotype. DESIGN, SETTING, And

Participants: Population-based cohort study using data from the Utah Population Database. The cohort was assembled by matching 78 893 women with endometriosis in a 1:5 ratio to women without endometriosis.

Exposures: Endometriosis cases were identified via electronic health records and categorized as superficial endometriosis, ovarian endometriomas, deep infiltrating endometriosis, or other.

Main Outcomes and Measures: Estimated adjusted hazard ratios (aHRs), adjusted risk differences (aRDs) per 10 000 women, and 95% CIs for overall ovarian cancer, type I ovarian cancer, and type II ovarian cancer comparing women with each type of endometriosis with women without endometriosis. Models accounted for sociodemographic factors, reproductive history, and past gynecologic operations.

Results: In this Utah-based cohort, the mean (SD) age at first endometriosis diagnosis was 36 (10) years. There were 597 women with ovarian cancer. Ovarian cancer risk was higher among women with endometriosis compared with women without endometriosis (aHR, 4.20 [95% CI, 3.59-4.91]; aRD, 9.90 [95% CI, 7.22-12.57]), and risk of type I ovarian cancer was especially high (aHR, 7.48 [95% CI, 5.80-9.65]; aRD, 7.53 [95% CI, 5.46-9.61]). Ovarian cancer risk was highest in women with deep infiltrating endometriosis and/or ovarian endometriomas for all ovarian cancers (aHR, 9.66 [95% CI, 7.77-12.00]; aRD, 26.71 [95% CI, 20.01-33.41]), type I ovarian cancer (aHR, 18.96 [95% CI, 13.78-26.08]; aRD, 19.57 [95% CI, 13.80-25.35]), and type II ovarian cancer (aHR, 3.72 [95% CI, 2.31-5.98]; aRD, 2.42 [95% CI, -0.01 to 4.85]).

Conclusions and Relevance: Ovarian cancer risk was markedly increased among women with ovarian endometriomas and/or deep infiltrating endometriosis. This population may benefit from counseling regarding ovarian cancer risk and prevention and could be an important population for targeted screening and prevention studies.


The association between the use of fertility indicators and fecundability in a  Danish preconception cohort

Elizabeth E Hatch

Department of Epidemiology Boston University School of Public Health Boston MA USA

Anne Sofie Dam Laursen

Department of Clinical Epidemiology, Aarhus University Hospital Aarhus University  Aarhus N Denmark

Ellen M Mikkelsen

Department of Clinical Epidemiology Aarhus University Hospital Aarhus Denmark

Kenneth J Rothman

Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA

Lauren A Wise

Slone Epidemiology Center at Boston University, Boston, Massachusetts and 2Lombardi Comprehensive Cancer Center at Georgetown University Medical Center, Washington, District of Columbia

Abstract:
Background: The use of fertility indicators to predict ovulation has largely been studied for contraceptive purposes, while less so as fertility-promoting tools.

Objective: To investigate the association between fertility indicators and fecundability in Danish women trying to conceive.

Methods: Web-based preconception cohort study. We analysed data from 11,328 females aged 18-49 years trying to conceive without fertility treatment for ≤6 menstrual cycles, from the Danish SnartGravid.dk and SnartForældre.dk cohorts (2007-2023). Participants reported the use of fertility indicators (counting days since the last menstrual period, cervical fluid monitoring, urinary ovulation testing, feeling ovulation, using a smartphone fertility app and measuring basal body temperature [BBT]). Time to pregnancy was measured in menstrual cycles ascertained by self-reported pregnancy status. We estimated fecundability ratios (FR) and 95% confidence intervals (CI) using proportional probabilities regression models adjusted for age, socio-economic position, health indicators, reproductive history and gynaecological factors.

Results: Fertility indicators were used by 63.3% of participants at study entry. Counting days was the most common (46.9%), while measuring BBT was the least (3.0%). Other indicators ranged from 17.0% to 23.6%, with 69.7% using more than one indicator. Compared with non-use, use of any fertility indicator was associated with greater fecundability (adjusted FR 1.14, 95% CI 1.08, 1.19). Cervical fluid monitoring showed the strongest association (aFR 1.46, 95% CI 1.03, 2.07), followed by urinary ovulation testing (aFR 1.35, 95% CI 1.16, 1.58) and counting days (aFR 1.18, 95% CI 1.09, 1.29). Feeling ovulation and fertility apps were modestly associated with fecundability, while measuring BBT was not associated. Sensitivity analysis restricting to ≤2 cycles of attempt time and two cycles of follow-up showed an aFR for any indicator use of 1.21 (95% CI 1.13, 1.31).

Conclusion: In this Danish preconception cohort, use of fertility indicators was associated with a higher fecundability, varying by type of indicator.


Evaluating Pregnancy Rates in Fertility Awareness-Based Methods for Family  Planning: Simulated Comparison of Correct Use to Avoid, Method-Related, and Total  Pregnancy Rates

Abstract:
Fertility awareness-based methods (FABMs), also known as natural family planning (NFP), enable couples to identify the days of the menstrual cycle when intercourse may result in pregnancy ("fertile days"), and to avoid intercourse on fertile days if they wish to avoid pregnancy. Thus, these methods are fully dependent on user behavior for effectiveness to avoid pregnancy. For couples and clinicians considering the use of an FABM, one important metric to consider is the highest expected effectiveness (lowest possible pregnancy rate) during the correct use of the method to avoid pregnancy. To assess this, most studies of FABMs have reported a method-related pregnancy rate (a cumulative proportion), which is calculated based on all cycles (or months) in the study. In contrast, the correct use to avoid pregnancy rate (also a cumulative proportion) has the denominator of cycles with the correct use of the FABM to avoid pregnancy. The relationship between these measures has not been evaluated quantitatively. We conducted a series of simulations demonstrating that the method-related pregnancy rate is artificially decreased in direct proportion to the proportion of cycles with intermediate use (any use other than correct use to avoid or targeted use to conceive), which also increases the total pregnancy rate. Thus, as the total pregnancy rate rises (related to intermediate use), the method-related pregnancy rate falls artificially while the correct use pregnancy rate remains constant. For practical application, we propose the core elements needed to assess correct use cycles in FABM studies.
Summary: Fertility awareness-based methods (FABMs) can be used by couples to avoid pregnancy, by avoiding intercourse on fertile days. Users want to know what the highest effectiveness (lowest pregnancy rate) would be if they use an FABM correctly and consistently to avoid pregnancy. In this simulation study, we compare two different measures: (1) the method-related pregnancy rate; and (2) the correct use pregnancy rate. We show that the method-related pregnancy rate is biased too low if some users in the study are not using the method consistently to avoid pregnancy, while the correct use pregnancy rate obtains an accurate estimate. SHORT Summary: In FABM studies, the method-related pregnancy rate is biased too low, but the correct use pregnancy rate is unbiased.


Menstrual Cramps in Anovulatory versus Normally Ovulatory Cycles - SARS-COV-2 Pandemic Daily Data Plus a Meta-Analysis of Cramps and Anovulation

Sonia Shirin

University of British Columbia, Vancouver, BC, Canada

Abstract:
Purpose: It is asserted that primary dysmenorrhea/menstrual cramps only occur in ovulatory menstrual cycles. Our first objective was to present detailed menstrual cramps information in normally ovulatory versus anovulatory cycles from a single-cycle cohort study during the SARS-CoV-2 Pandemic. Secondly, we reviewed the literature for cohort studies documenting both menstrual cramps and ovulation. Participants and

Methods: The Menstruation and Ovulation Study 2 recruited 108 women ages 19-35 years to a prospective, observational single-cycle study, recording cramps daily (0-4 scale) in the Menstrual Cycle Diary© and assessing normal ovulation (luteal length ≥10 days) by the validated Quantitative Basal Temperature© (Mean Temperature Method). We searched databases for « primary dysmenorrhea » / » menstrual cramps »; « menstrual cycles »; « anovulation », finding four valid publications.

Results: In 75 women/cycles during the Pandemic, mean age was 28.5, body mass index 23.5, and higher education (16 years); 40 normally ovulatory and 35 anovulatory cycles had similar lengths (29.5-30.0 days), respectively (P=0.571). However, anovulatory cycles recorded significantly worse menstrual cramps versus normally ovulatory cycles; anovulatory median intensity was 1.9 versus 1.6, and Cramp Score was 8 versus 6 in normally ovulatory cycles (P=0.017). Four publications in 273 women (991 cycles) showed cramps in both anovulatory and ovulatory cycles; three were in adolescent/young adult women, one of which documented a significantly greater percentage of cramps in ovulatory cycles. The 694 cycles in premenopausal women (20-41 years) showed similar percentages of symptomatic cramps in cycles of both ovulatory types. Meta-analysis documented significantly higher cramp prevalence in ovulatory cycles (OR 2.10; 95% CI 1.31, 3.37; P=0.002).

Conclusion: This is the first documentation of more intense and frequent cramps in anovulatory cycles. However, meta-analysis showing the presence of symptomatic cramps in both ovulatory and anovulatory cycles documented they were twice as prevalent in ovulatory menstrual cycles. “Worse Menstrual Cramps in Anovulatory Cycles”. Medicine has long believed that menstrual cramps only occur in ovulatory menstrual cycles that release an egg and have high progesterone levels that decrease before the next period. The notion was that dropping progesterone levels triggered release of prostaglandins that cause the pain and uterus muscle contractions of menstrual cramps. This research studied 75 community women aged 19–35 years for a single cycle during COVID-19. Forty women had normally ovulatory cycles and 35 had anovulatory cycles with a similar mean cycle length of 29.7 days. Women in both groups were similar in age, weight, education and other reproductive characteristics. Women recorded Menstrual Cycle Diary© daily experiences for cramp presence and intensity (scored 0–4). Ovulation was documented by daily first morning temperatures analyzed by the valid Quantitative Basal Temperature© method. Results showed menstrual cramps occurred in both normally ovulatory and anovulatory cycles. Surprisingly, anovulatory compared with ovulatory cycles had cramps that lasted longer (4 rather than 3 days), were more intense (1.9 versus 1.6) and with significantly higher Cramp Scores (of 8 versus 6). We also found four other published studies showing cramps occurred in both anovulatory and ovulatory cycles. A meta-analysis of these, however, showed that cramps were twice as frequent in ovulatory cycles. These results matter because they stimulate the search for more accurate understandings of why menstrual cramps occur. They will likely stimulate more effective therapies for the rare, intense menstrual cramps that currently are not effectively treated by anti-inflammatory medicines such as ibuprofen.


Gut microbiota dysbiosis contributes to depression-like behaviors via hippocampal NLRP3-mediated neuroinflammation in a postpartum depression mouse model

Lei Sun

Eunice Kennedy Shriver National Institute of Child Health and Human Development

Liangzhen Xie

First Affiliated Hospital of Heilongjiang University of Chinese Medicine

Abstract: Postpartum depression (PPD) is a severe mental disorder that affects approximately 10---20% of women after childbirth. The precise mechanism underlying PPD pathogenesis remains elusive, thus limiting the development of therapeutics. Gut microbiota dysbiosis is considered to contribute to major depressive disorder. However, the associations between gut microbiota and PPD remain unanswered. Here, we established a mouse PPD model by sudden ovarian steroid withdrawal after hormone-simulated pseudopregnancy-human (HSP-H) in ovariectomy (OVX) mouse. Ovarian hormone withdrawal induced depression-like and anxiety-like behaviors and an altered gut microbiota composition. Fecal microbiota transplantation (FMT) from PPD mice to antibiotic cocktail-treated mice induced depression-like and anxiety-like behaviors and neuropathological changes in the hippocampus of the recipient mice. FMT from healthy mice to PPD mice attenuated the depression-like and anxiety-like behaviors as well as the inflammation mediated by the NOD-like receptor protein (NLRP)-3/caspase-1 signaling pathway both in the gut and the hippocampus, increased fecal short-chain fatty acids (SCFAs) levels and alleviated gut dysbiosis with increased SCFA-producing bacteria and reduced Akkermansia in the PPD mice. Also, downregulation of NLRP3 in the hippocampus mitigated depression-like behaviors in PPD mice and overexpression of NLRP3 in the hippocampal dentate gyrus induced depression-like behaviors in naïve female mice. Intriguingly, FMT from healthy mice failed to alleviate depression-like behaviors in PPD mice with NLRP3 overexpression in the hippocampus. Our results highlighted the NLRP3 inflammasome as a key component within the microbiota-gut-brain axis, suggesting that targeting the gut microbiota may be a therapeutic strategy for PPD.


Overview of indigo biosynthesis by Flavin-containing Monooxygenases: History, industrialization challenges, and strategies

Danni Zheng

Third Affiliated Hospital of Guangzhou Medical University

Ruiting Zhang

Women's Hospital, School of Medicine, Zhejiang University

Abstract: Indigo is a natural dye extensively used in the global textile industry. However, the conventional synthesis of indigo using toxic compounds like aniline, formaldehyde, and hydrogen cyanide has led to environmental pollution and health risks for workers. This method also faces growing economic, sustainability, and environmental challenges. To address these issues, the concept of bio-indigo or indigo biosynthesis has been proposed as an alternative to aniline-based indigo synthesis. Among various enzymes, Flavin-containing Monooxygenases (FMOs) have shown promise in achieving a high yield of bio-indigo. However, the industrialization of indigo biosynthesis still encounters several challenges. This review focuses on the historical development of indigo biosynthesis mediated by FMOs. It highlights several factors that have hindered industrialization, including the use of unsuitable chassis (Escherichia coli), the toxicity of indole, the high cost of the substrate L-tryptophan, the water-insolubility of the product indigo, the requirement of reducing reagents such as sodium dithionite, and the relatively low yield and high cost compared to chemical synthesis. Additionally, this paper summarizes various strategies to enhance the yield of indigo synthesized by FMOs, including redundant sequence deletion, semi-rational design, cheap precursor research, NADPH regeneration, large-scale fermentation, and enhancement of water solubility of indigo.


Hydroxychloroquine in recurrent pregnancy loss: data from a French prospective  multicenter registry

Jonathan Cohen

Service d'Obstétrique et de Fertilité, Clinique Saint Thérèse, Paris, France.

Amandine Dernoncourt

Centre Hospitalier Universitaire Amiens-Picardie

Emmanuelle Mathieu d'Argent

Service de Gynécologie Obstétrique et Médecine de la Reproduction, Centre de Fertilité Tenon, Hôpital Tenon, Sorbonne Université AP-HP, Paris, France.

Abstract:
STUDY Question: 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?

SUMMARY ANSWER: 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.

WHAT IS KNOWN ALREADY: 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, DURATION: 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, Methods: 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 RESULTS AND THE ROLE OF CHANCE: 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, REASONS FOR CAUTION: 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.

WIDER IMPLICATIONS OF THE Findings: 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.

TRIAL REGISTRATION NUMBER: clinicaltrial.gov NCT05557201.


Comparison of laparoscopic and hysteroscopic surgical treatments for isthmocele: A prospective cohort

Abstract:
OBJECTIVE: To evaluate the clinical outcomes of laparoscopic and hysteroscopic surgical approaches for treating symptomatic isthmocele and identify their associated factors.

MATERIALS AND METHODS: Forty-six patients with symptomatic isthmocele diagnosed using transvaginal saline infusion sonohysterography were enrolled in this prospective cohort study. Patients underwent either laparoscopic or hysteroscopic isthmoplasty based on their residual myometrial thicknesses and fertility desires and were subsequently followed by clinical and ultrasonographic examinations.

RESULTS: Twenty-two patients underwent laparoscopy and 24 underwent hysteroscopic surgery. At baseline, there was no significant difference in the mean age and years since the last cesarean section between the two groups. However, the hysteroscopy group had a higher mean parity and previous cesarean sections (p=0.00, 0.03). The most common symptoms were abnormal uterine bleeding, infertility, and dysmenorrhea. The mean baseline residual myometrial thickness was significantly higher in the laparoscopy group (p=0.00), and only laparoscopic surgery led to a significant increase in residual myometrial thickness in patients (p=0.00). Both procedures significantly reduced abnormal uterine bleeding (p=0.00), but only laparoscopy reduced infertility (p=0.00) and hysteroscopy reduced dysmenorrhea (p=0.03). Hysteroscopy showed better symptom resolution in younger patients (p=0.01), whereas age did not affect laparoscopy outcomes.

CONCLUSION: Both approaches showed similar effectiveness in resolving abnormal uterine bleeding, with laparoscopy excelling in infertility resolution and hysteroscopy excelling in dysmenorrhea resolution.

AMAÇ: Bu çalışmanın amacı semptomatik istmosel tedavisinde laparoskopik ve histeroskopik cerrahi yaklaşımların klinik sonuçlarını değerlendirmek ve ilişkili faktörleri belirlemektir.

GEREÇ VE YÖNTEMLER: Bu prospektif kohort çalışmasına transvajinal salin infüzyon sonohisterografi kullanılarak semptomatik istmosel tanısı konan 46 hasta dahil edildi. Hastalara rezidüel miyometrial kalınlık ve doğurganlık isteklerine göre laparoskopik veya histeroskopik istmoplasti uygulandı ve ardından hastalar klinik ve ultrasonografik muayenelerle takip edildi.

BULGULAR: Yirmi iki hastaya laparoskopi, yirmi dört hastaya ise histeroskopik cerrahi uygulandı. Başlangıçta, iki grup arasında ortalama yaş ve son sezaryenden bu yana geçen yıllar açısından anlamlı bir fark yoktu. Ancak histeroskopi grubunda ortalama parite ve önceki sezaryenlerin sayısı daha yüksekti (p=0,00, 0,03). En sık görülen semptomlar anormal uterin kanama, kısırlık ve dismenore idi. Başlangıçtaki ortalama rezidüel miyometrial kalınlık laparoskopi grubunda anlamlı derecede yüksekti (p=0,00) ve yalnızca laparoskopik cerrahi hastalarda anlamlı rezidüel miyometrial kalınlık artışına yol açtı (p=0,00). Her iki prosedür de anormal uterin kanamayı önemli ölçüde azalttı (p=0,00), ancak yalnızca laparoskopi kısırlığı azalttı (p=0,00) ve histeroskopi dismenoreyi azalttı (p=0,03). Histeroskopi genç hastalarda semptomlarda daha fazla düzelme sağladı (p=0,01), yaş ise laparoskopi sonuçlarını etkilemedi.

SONUÇ: Her iki yaklaşım da anormal uterin kanamanın çözümünde benzer etkinlik göstermiştir; laparoskopi kısırlığın çözümünde ve histeroskopi dismenorenin çözümünde üstündür.

Turkish journal of obstetrics and gynecology


Fertility Treatment 2022: Preliminary Trends and Figures

Human Fertilisation and Embryology Authority

Abstract:
# Fertility treatment 2022: preliminary trends and figures
Preliminary UK statistics for IVF and DI treatment, storage, and donation
Published: July 2024
[Download the underlying dataset as .xlsx](https://www.hfea.gov.uk/media/5jfpm1cw/fertility-treatment-2022-preliminary-trends-and-figures-underlying-dataset.xlsx "Fertility treatment 2022: preliminary trends and figures - underlying dataset")
## Table of contents
- [Main points](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2022-preliminary-trends-and-figures/#main-points)
- [Note on preliminary data](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2022-preliminary-trends-and-figures/#note-on-preliminary-data)
- [Section 1: Average IVF pregnancy rate using fresh embryo transfers increased](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2022-preliminary-trends-and-figures/#section-1)
- [Section 2: Average IVF pregnancy and birth rates using frozen embryo transfers similar to previous years](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2022-preliminary-trends-and-figures/#section-2)
- [Section 3: Average age at first IVF treatment increased above 35 years of age for first time](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2022-preliminary-trends-and-figures/#section-3)
- [Section 4: New egg and sperm donors increased by 21% from 2019 to 2022](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2022-preliminary-trends-and-figures/#section-4)
- [Section 5: Egg storage fastest growing treatment, but accounted for 5% of all cycles in 2022](https://www.hfea.gov.uk/about-us/publications/research-and-data/fertility-treatment-2022-preliminary-trends-and-figures/#section-5)
- [Section 6: Multiple births from IVF at lowest UK average yet of 4%](https://www.hfea.gov.uk/about-us/publications/research-and-data/fe...


The definition of unexplained infertility: A systematic review

Abstract:
BACKGROUND: There is no consensus on tests required to either diagnose unexplained infertility or use for research inclusion criteria. This leads to heterogeneity and bias affecting meta-analysis and best practice advice.

OBJECTIVES: This systematic review analyses the variability of inclusion criteria applied to couples with unexplained infertility. We propose standardised criteria for use both in future research studies and clinical diagnosis.

SEARCH STRATEGY: CINAHL and MEDLINE online databases were searched up to November 2022 for all published studies recruiting couples with unexplained infertility, available in full text in the English language.

DATA COLLECTION AND ANALYSIS: Data were collected in an Excel spreadsheet. Results were analysed per category and methodology or reference range.

MAIN RESULTS: Of 375 relevant studies, only 258 defined their inclusion criteria. The most commonly applied inclusion criteria were semen analysis, tubal patency and assessment of ovulation in 220 (85%), 232 (90%), 205 (79.5%) respectively. Only 87/220 (39.5%) studies reporting semen analysis used the World Health Organization (WHO) limits. Tubal patency was accepted if bilateral in 145/232 (62.5%) and if unilateral in 24/232 (10.3%). Ovulation was assessed using mid-luteal serum progesterone in 115/205 (56.1%) and by a history of regular cycles in 87/205 (42.4%). Other criteria, including uterine cavity assessment and hormone profile, were applied in less than 50% of included studies.

CONCLUSIONS: This review highlights the heterogeneity among studied populations with unexplained infertility. Development and application of internationally accepted criteria will improve the quality of research and future clinical care.

BJOG : an international journal of obstetrics and gynaecology


Phthalate esters in clothing: A review

Phthalate esters in clothing: A review

Abstract: Phthalate esters (PAEs) are widely used as plasticizers to enhance the flexibility and durability of different consumer products, including clothing. However, concerns have been raised about the potential adverse health effects associated with the presence of phthalates in textiles, such as endocrine disruption, reproductive toxicity and potential carcinogenicity. Based on examination of more than 120 published articles, this paper presents a comprehensive review of studies concerning the phthalate content in clothing and other textile products, with special emphasis on those conducted in the last decade (2014-2023). The types and role of PAEs as plasticizers, the relevant legislation in different countries (emphasizing the importance of monitoring PAE levels in clothing to protect consumer health) and the analytical methods used for PAE determination are critically evaluated. The review also discusses the models used to evaluate exposure to PAEs and the associated health risks. Finally, the study limitations and challenges related to determining the phthalate contents of textile products are considered.

Environmental Toxicology and Pharmacology


Navigating uterine niche 360 degree: a narrative review

Abstract:
Background
The increasing prevalence of cesarean section (CS) deliveries globally has sparked apprehension regarding potential long-term complications, notably the emergence of uterine niches. CS results in a scar that in certain patients, inadequate healing of that scar results in the development of a uterine niche. While most small niches show no symptoms, large cesarean scar niches in nonpregnant women can give rise to cesarean scar disorder syndrome. This syndrome is characterized by abnormal uterine bleeding, dysmenorrhea, and secondary infertility. In pregnant women, the presence of substantial niches may be linked to potentially life-threatening complications, including cesarean scar dehiscence, uterine rupture, placenta accreta spectrum disorders, placenta previa, and cesarean scar ectopic pregnancy.
Main body
Given the potential dangers associated with uterine niche occurrence, numerous studies in recent years have delved into the concept of cesarean scar niche, exploring its risk factors, diagnostic approaches, and treatment options. Various diagnostic modalities, such as twoor three-dimensional transvaginal ultrasonography, twoand three-dimensional sono-hysterography, hysterosalpingography, hysteroscopy, or magnetic resonance imaging, can be employed to detect uterine niches. However, none of these diagnostic methods is universally accepted as the “gold standard,” and there remains a lack of unequivocal guidelines on certain aspects related to the diagnosis of cesarean scar niche. These niches, characterized by hypoechoic regions within the myometrium at the site of a previous CS scar, pose diagnostic complexities and provoke inquiries into their prevalence, factors influencing their development, clinical presentations, and appropriate therapeutic approaches.
Conclusion
As CS rates rise, this review aims to understand and address uterine niches and mitigate their impact on maternal health and reproductive outcomes.


Fertility Awareness-Based Methods for Family Planning and Women's Health: Impact  of an Online Elective

Abstract:
BACKGROUND AND Objectives: Fertility awareness-based methods (FABMs) are evidence-based means of tracking observable biomarkers of a woman's fertility for the purpose of reproductive health monitoring and family planning. However, medical education regarding FABMs is limited. The purpose of this study was to examine the effect of a 4-week, two-part online elective on students' knowledge of FABMs, confidence in explaining and offering them to patients, and anticipated behaviors in future practice.

Methods: The online elective, "FABMs for Family Planning and Women's Health," was delivered from August 2020 to May 2023. Students completed preand postknowledge surveys. Paired t tests and the Wilcoxon signed rank test were used for analysis of the data.

Results: A total of 571 students completed the elective, and 462 students completed both preand posttest surveys (response rate=81%). Students' knowledge of FABMs increased significantly. Posttest scores increased by a mean of 9.02 for Part A and 5.95 for Part B. We identified a significant increase in students' confidence discussing FABMs to avoid pregnancy, achieve pregnancy, monitor reproductive health, and address reproductive health concerns. At the completion of the elective, students were significantly more likely to offer FABMs as an option for most or all women.

Conclusions: This online elective addresses the knowledge gap in FABMs and was effective in improving students' knowledge of FABMs and their confidence and willingness to offer these methods to patients for family planning and management of common women's health conditions.


Gastrointestinal Myoelectrical Activity (GIMA) Biomarker for Noninvasive  Diagnosis of Endometriosis

Ajit Kolatkar

Specialty Business Center, Integrative Ayurveda Gastroenterology and Nutrition Initiative, 202, Balewadi, Pune 411045, Maharashtra, India

John Mathias

Woman's Hospital of Texas, 7600 Fannin Street, Houston, TX 77054, USA.

Mark Noar

Endometriosis and Neuroenterology Research Institute, 53 Loveton Circle, Sparks Glencoe, MD 21152, USA

Abstract:
Background/Objectives: Endometriosis represents substantial direct and indirect healthcare costs impacted by an absence of uniformly accurate, non-invasive diagnostic tools. We endeavored to demonstrate gastrointestinal myoelectrical activity (GIMA) biomarkers, unique to endometriosis, will allow non-invasive, uniformly accurate diagnosis or exclusion of endometriosis.

Methods: Prospective open-label comparative study of 154 patients, age ≥ 18, with or without diagnosed endometriosis. Population included 62 non-endometriosis controls (Cohort 1), 43 subjects with surgically/histologically confirmed endometriosis (Cohort 2), and 49 subjects with abdominal pain and negative imaging (Cohort 3). Non-invasive electroviscerography (EVG) recorded GIMA biomarkers from three abdominal electrodes before and 30 min post water load protocol. Cohort 2 had postoperative EVG and Cohort 3 had preoperative EVG. Calculated specificity, sensitivity, negative predictive value (NPV), positive predictive value (PPV), and predictive probability or C-statistic used univariate, multivariate, linear, and logistical regression analyses of the area under the curve (AUC) at all frequency and time points, including age and pain covariants.

Results: The non-endometriosis cohort differed significantly from the endometriosis cohorts (p < 0.001) for median (IQR) and AUC percent frequency distribution of power at baseline, 10 min, 20 min, and 30 min post water load at all frequency ranges: 15-20 cpm, 30-40 cpm, and 40-50 cpm. The endometriosis cohorts were statistically similar (p > 0.05). GIMA biomarker threshold scoring demonstrated 95%/91% sensitivity and PPV, 96%/95% specificity and NPV, and a C-statistic of >99%/98%, respectively, for age subsets. GIMA biomarkers in Cohort 3 predicted 47/49 subjects positive and 2/49 negative for endometriosis, confirmed surgically. Hormonal therapy, surgical stage, nor pain score affected diagnostic accuracy.

Conclusions: EVG with GIMA biomarker detection distinguished participants with and without endometriosis based upon endometriosis-specific GIMA biomarkers threshold scoring.


Association of heavy menstrual bleeding with cardiovascular disease in US female hospitalizations

Abstract:
BACKGROUND: Heavy menstrual bleeding (HMB) is a common menstrual disorder associated with multiple risk factors of cardiovascular disease (CVD) in women. In addition, HMB is often present with irregular menstruation (IM) which is a risk factor for CVD outcomes. However, the relationship between HMB and CVD outcomes is unexplored in the presence or absence of IM. We determined the association of HMB with multiple CVD outcomes using a nationally representative sample of female hospitalizations in the US.

METHODS: All hospitalizations of females with HMB diagnosis and normal menstrual cycles from ages of 18 to 70 years were extracted from the National Inpatient Sample Database, 2017. The HMB was defined using the International Classification of Diseases (ICD)-10 for excessive and frequent menstruation bleeding and included any current or history of HMB diagnosis. Outcomes including major adverse cardiovascular events (MACE), coronary heart disease (CHD), stroke, heart failure (HF), atrial fibrillation (AF) or arrhythmia, myocardial infarction (MI), and diabetes (DM) were defined using ICD-10 codes. Adjusted logistic regression and prosperity scores-matched logistic regression analyses were conducted to summarize adjusted associations with an odds ratio (OR) and a 95% confidence interval (CI).

RESULTS: Among 2,430,851 hospitalizations, HMB was observed in 7762 (0.68%) females with age ≤ 40 years and 11,164 (0.86%) females with age > 40 years. Among hospitalizations with age ≤ 40 years, HMB was significantly associated with increased odds of CVD outcomes including MACE (OR = 1.61; 95% CI: 1.25, 2.08), CHD (OR = 1.72; 95% CI: 1.10, 2.71), stroke (OR = 1.95; 95% CI: 1.12, 3.40), HF (OR = 1.53; 95% CI: 1.15, 2.03), and AF/arrhythmia (OR = 1.84; 95% CI: 1.34, 2.54). These associations were confirmed in multiple sensitivity analyses. In contrast, HMB was not robustly associated with CVD events among hospitalizations of women with age > 40 years. HMB without IM was strongly associated with DM, HF, AF, and MACE outcomes while HMB with IM was strongly associated with CHD and AF outcomes in hospitalizations of young women.

CONCLUSIONS: HMB is associated with CVD events among US hospitalizations of young women. A routine investigation and screening of menstrual disorders, especially HMB, is useful for CVD risk stratification and management in young women.


Characterization of Chemical Additives in Daily Clothing Regarding Human Exposure and Environmental Emissions

Xiyao Liu

First Affiliated Hospital of Chongqing Medical University

Environmental Science & Technology Letters


Analysis of factors affecting pregnancy rate after laparoscopic surgery for  infertility associated with endometriosis

Abstract:
Objective: To analyze the factors that might influence the pregnancy rate in patients with infertility related to endometriosis (EMs) after undergoing laparoscopic surgery, providing guidance for our clinical diagnostic and therapeutic decision-making.

Methods: A retrospective analysis was conducted on clinical records and 1-year postoperative pregnancy outcomes of 335 patients diagnosed with endometriosis-related infertility via laparoscopic surgery, admitted to our department from January 2018 to December 2020.

Results: The overall pregnancy rate for patients with endometriosis (EMs) related infertility 1-year post-surgery was 57.3 %, with the highest pregnancy rate observed between 3 to 6 months after surgery. Factors such as Body Mass Index (BMI) (P = 0.515), presence of dysmenorrhea (P = 0.515), previous pelvic surgery (P = 0.247), type of EMs pathology (P = 0.893), and preoperative result of serum carbohydrate antigen 125 (CA125)（P = 0.615）had no statistically significant effect on postoperative pregnancy rates. The duration of infertility (P = 0.029), coexistence of adenomyosis (P = 0.042), surgery duration (P = 0.015), intraoperative blood loss (P = 0.050), preoperative result of serum anti-Müllerian hormone (AMH) (P = 0.002) and age greater than 35 (P = 0.000) significantly impacted postoperative pregnancy rates. The post-surgery pregnancy rate in patients with mild (Stage I-II) EMs was notably higher than those with moderate to severe (Stage III-IV) EMs (P = 0.009). Age (P = 0.002), EMs stage (P = 0.018), intraoperative blood loss (P = 0.010) and adenomyosis (P = 0.022) were the factors that affected the postoperative live birth rate.

Conclusion: For patients with EMs-related infertility undergoing laparoscopic surgery, factors such as age > 35 years, infertility duration > 3 years, concurrent adenomyosis, severe EMs, surgery duration ≥ 2 h, intraoperative blood loss ≥ 50 ml, and low AMH before surgery are detrimental for the pregnancy rate within the first postoperative year. However, BMI, dysmenorrhea, past history of pelvic surgery, EMs pathology types (ovarian, peritoneal, deep infiltrating),and preoperative result of serum CA125 barely show any statistical difference in their effect on postoperative pregnancy rates. In terms of postoperative live birth rate, age > 35 years, severe EMs, intraoperative blood loss ≥ 50 ml, and adenomyosis were adverse factors.

European Journal of Obstetrics, Gynecology, and Reproductive Biology


Advancing menopausal care: the importance of evidence on hormone therapy use and outcomes in women age 65 and older


Infertility treatment is associated with increased risk of postpartum hospitalization due to heart disease

Abstract:
BACKGROUND: Cardiovascular disease is a major cause of maternal mortality, but the extent to which infertility treatment is implicated in heart disease remains unclear.

OBJECTIVE: To evaluate the association between infertility treatment and postpartum heart disease.

METHODS: We designed a retrospective cohort study of patients who delivered in the United States between 2010 and 2018. The primary outcome was hospitalization within 12-month post-delivery due to heart disease (including ischemic heart disease, atherosclerotic heart disease, cardiomyopathy, hypertensive disease, heart failure, and cardiac dysrhythmias). We estimated the rate difference (RD) of hospitalizations among patients who conceived with infertility treatment and those who conceived spontaneously. Associations were expressed as hazard ratios (HRs) and 95% confidence intervals (CIs), derived from Cox proportional hazards regression after adjustment for potential confounders.

RESULTS: Infertility treatment was recorded in 0.9% (n = 287,813) of 31,339,991 deliveries. Rates of heart disease hospitalizations with infertility treatment and with spontaneous conception were 550 and 355 per 100,000, respectively (RD 195, 95% CI: 143-247; adjusted HR 1.99, 95% CI: 1.80-2.20). The most important increase in risk was observed for hypertensive disease (adjusted HR 2.16, 95% CI: 1.92-2.42). This increased risk was apparent as early as 30-day post-delivery (HR 1.61, 95% CI: 1.39-1.86), with progressively increasing risk up to a year.

CONCLUSIONS: Although the absolute risk of postpartum heart disease hospitalization is low, infertility treatment is associated with an increased risk, especially for hypertensive disease. These findings highlight the importance of timely postpartum follow-ups in patients who received infertility treatment.


Use of menopausal hormone therapy beyond age 65 years and its effects on women's health outcomes by types, routes, and doses

Abstract:
OBJECTIVES: The study aims to assess the use of menopausal hormone therapy beyond age 65 years and its health implications by types of estrogen/progestogen, routes of administration, and dose strengths.

METHODS: Using prescription drug and encounter records of 10 million senior Medicare women from 2007-2020 and Cox regression analyses adjusted for time-varying characteristics of the women, we examined the effects of different preparations of menopausal hormone therapy on all-cause mortality, five cancers, six cardiovascular diseases, and dementia.

RESULTS: Compared with never use or discontinuation of menopausal hormone therapy after age 65 years, the use of estrogen monotherapy beyond age 65 years was associated with significant risk reductions in mortality (19% or adjusted hazards ratio, 0.81; 95% CI, 0.79-0.82), breast cancer (16%), lung cancer (13%), colorectal cancer (12%), congestive heart failure (CHF) (5%), venous thromboembolism (3%), atrial fibrillation (4%), acute myocardial infarction (11%), and dementia (2%). For the use of estrogen and progestogen combo-therapy, both E+ progestin and E+ progesterone were associated with increased risk of breast cancer by 10%-19%, but such risk can be mitigated using low dose of transdermal or vaginal E+ progestin. Moreover, E+ progestin exhibited significant risk reductions in endometrial cancer (45% or adjusted hazards ratio, 0.55; 95% CI, 0.50-0.60), ovarian cancer (21%), ischemic heart disease (5%), CHF (5%), and venous thromboembolism (5%), whereas E+ progesterone exhibited risk reduction only in CHF (4%).

CONCLUSIONS: Among senior Medicare women, the implications of menopausal hormone therapy use beyond age 65 years vary by types, routes, and strengths. In general, risk reductions appear to be greater with low rather than medium or high doses, vaginal or transdermal rather than oral preparations, and with E2 rather than conjugated estrogen.


Isthmocele and Infertility

Isthmocele and Infertility

Antonio Malvasi

Obstetrics and Gynecology Unit, Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy

Abstract: Isthmocele is a gynecological condition characterized by a disruption in the uterine scar, often associated with prior cesarean sections. This anatomical anomaly can be attributed to inadequate or insufficient healing of the uterine wall following a cesarean incision. It appears that isthmocele may impact a woman's quality of life as well as her reproductive capacity. The incidence of isthmocele can range from 20% to 70% in women who have undergone a cesarean section. This review aims to sum up the current knowledge about the effect of isthmocele on fertility and the possible therapeutic strategies to achieve pregnancy. However, currently, there is not sufficiently robust evidence to indicate the need for surgical correction in all asymptomatic patients seeking fertility. In cases where surgical correction of isthmocele is deemed necessary, it is advisable to evaluate residual myometrial thickness (RMT). For patients with RMT >2.5-3 mm, hysteroscopy appears to be the technique of choice. In cases where the residual tissue is lower, recourse to laparotomic, laparoscopic, or vaginal approaches is warranted.


Hues of risk: investigating genotoxicity and environmental impacts of azo textile dyes

Abstract: The textile industry, with its extensive use of dyes and chemicals, stands out as a significant source of water pollution. Exposure to certain textile dyes, such as azo dyes and their breakdown products like aromatic amines, has been associated with health concerns like skin sensitization, allergic reactions, and even cancer in humans. Annually, the worldwide production of synthetic dyes approximates 7 × 107 tons, of which the textile industry accounts for over 10,000 tons. Inefficient dyeing procedures result in the discharge of 15-50% of azo dyes, which do not adequately bind to fibers, into wastewater. This review delves into the genotoxic impact of azo dyes, prevalent in the textile industry, on aquatic ecosystems and human health. Examining different families of textile dye which contain azo group in their structure such as Sudan I and Sudan III Sudan IV, Basic Red 51, Basic Violet 14, Disperse Yellow 7, Congo Red, Acid Red 26, and Acid Blue 113 reveals their carcinogenic potential, which may affect both industrial workers and aquatic life. Genotoxic and carcinogenic characteristics, chromosomal abnormalities, induced physiological and neurobehavioral changes, and disruptions to spermatogenesis are evident, underscoring the harmful effects of these dyes. The review calls for comprehensive investigations into the toxic profile of azo dyes, providing essential insights to safeguard the aquatic ecosystem and human well-being. The importance of effective effluent treatment systems is underscored to mitigate adverse impacts on agricultural lands, water resources, and the environment, particularly in regions heavily reliant on wastewater irrigation for food production.

Environmental Science and Pollution Research


The role of placental insufficiency in spontaneous preterm birth: A literature review

Abstract: Preterm Birth (delivery before 37 weeks of gestation) is the leading cause of childhood mortality and is also associated with significant morbidity both in the neonatal period and beyond. The aetiology of spontaneous preterm birth is unclear and likely multifactorial incorporating factors such as infection/inflammation and cervical injury. Placental insufficiency is emerging as an additional contributor to spontaneous preterm delivery; however, the mechanisms by which this occurs are not fully understood. Serum biomarkers and imaging techniques have been investigated as potential predictors of placental insufficiency, however none have yet been found to have a sufficient predictive value. This review examines the evidence for the role of the placenta in preterm birth, preterm prelabour rupture of the membranes and abruption as well as highlighting areas where further research is required.

European journal of obstetrics, gynecology, and reproductive biology


Hypertension, Cardiovascular Risk Factors, and Uterine Fibroid Diagnosis in Midlife

Lauren A Wise

Slone Epidemiology Center at Boston University, Boston, Massachusetts and 2Lombardi Comprehensive Cancer Center at Georgetown University Medical Center, Washington, District of Columbia

Abstract:
IMPORTANCE: Fibroids are benign neoplasms associated with severe gynecologic morbidity. There are no strategies to prevent fibroid development.

OBJECTIVE: To examine associations of hypertension, antihypertensive treatment, anthropometry, and blood biomarkers with incidence of reported fibroid diagnosis in midlife.

DESIGN, SETTING, AND PARTICIPANTS: The Study of Women's Health Across the Nation is a prospective, multisite cohort study in the US. Participants were followed-up from enrollment (1996-1997) through 13 semiannual visits (1998-2013). Participants had a menstrual period in the last 3 months, were not pregnant or lactating, were aged 42 to 52 years, were not using hormones, and had a uterus and at least 1 ovary. Participants with prior fibroid diagnoses were excluded. Data analysis was performed from November 2022 to February 2024.

EXPOSURES: Blood pressure, anthropometry, biomarkers (cholesterol, triglycerides, and C-reactive protein), and self-reported antihypertensive treatment at baseline and follow-up visits were measured. Hypertension status (new-onset, preexisting, or never [reference]) and hypertension treatment (untreated, treated, or no hypertension [reference]) were categorized.

MAIN OUTCOMES AND MEASURES: Participants reported fibroid diagnosis at each visit. Discrete-time survival models estimated hazard ratios (HRs) and 95% CIs for associations of time-varying hypertension status, antihypertensive treatment, anthropometry, and biomarkers with incident reported fibroid diagnoses.

RESULTS: Among 2570 participants without a history of diagnosed fibroids (median [IQR] age at screening, 45 [43-48] years; 1079 [42.1%] college educated), 526 (20%) reported a new fibroid diagnosis during follow-up. Risk varied by category of hypertension treatment: compared with those with no hypertension, participants with untreated hypertension had a 19% greater risk of newly diagnosed fibroids (HR, 1.19; 95% CI, 0.91-1.57), whereas those with treated hypertension had a 20% lower risk (HR, 0.80; 95% CI, 0.56-1.15). Among eligible participants with hypertension, those taking antihypertensive treatment had a 37% lower risk of newly diagnosed fibroids (HR, 0.63; 95% CI, 0.38-1.05). Risk also varied by hypertension status: compared with never-hypertensive participants, participants with new-onset hypertension had 45% greater risk of newly diagnosed fibroids (HR, 1.45; 95% CI, 0.96-2.20). Anthropometric factors and blood biomarkers were not associated with fibroid risk.

CONCLUSIONS AND RELEVANCE: Participants with untreated and new-onset hypertension had increased risk of newly diagnosed fibroids, whereas those taking antihypertensive treatment had lower risk, suggesting that blood pressure control may provide new strategies for fibroid prevention.


Planned oocyte cryopreservation to preserve future reproductive potential: an Ethics Committee opinion

Ethics Committee of the American Society for Reproductive Medicine. Electronic address: asrm@asrm.org

Abstract: Planned oocyte cryopreservation is an ethically permissible procedure that may help individuals avoid future infertility. Because planned oocyte cryopreservation is new and evolving, it is essential that those considering using it be informed about the uncertainties regarding its efficacy and long-term effects. This replaces the document of the same name, last published in 2017.


Tobacco or marijuana use and infertility: a committee opinion

Practice Committee of the American Society for Reproductive Medicine

Abstract: In the United States, approximately 21% of adults report some form of tobacco use, although 18% report marijuana use. Although the negative impact of tobacco use in pregnancy is well documented, the impact of tobacco and marijuana on fertility and reproduction is less clear. This committee opinion reviews the potential deleterious effects of tobacco, nicotine, and marijuana use on conception, ovarian follicular dynamics, sperm parameters, gamete mutations, early pregnancy, and assisted reproductive technology outcomes. It also reviews the current status of tobacco smoking cessation strategies. This document replaces the 2018 American Society for Reproductive Medicine Practice Committee document entitled Smoking and Infertility: a committee opinion (Fertil Steril 2018).


Minerals and the Menstrual Cycle: Impacts on Ovulation and Endometrial Health

Abstract: The role of minerals in female fertility, particularly in relation to the menstrual cycle, presents a complex area of study that underscores the interplay between nutrition and reproductive health. This narrative review aims to elucidate the impacts of minerals on key aspects of the reproductive system: hormonal regulation, ovarian function and ovulation, endometrial health, and oxidative stress. Despite the attention given to specific micronutrients in relation to reproductive disorders, there is a noticeable absence of a comprehensive review focusing on the impact of minerals throughout the menstrual cycle on female fertility. This narrative review aims to address this gap by examining the influence of minerals on reproductive health. Each mineral's contribution is explored in detail to provide a clearer picture of its importance in supporting female fertility. This comprehensive analysis not only enhances our knowledge of reproductive health but also offers clinicians valuable insights into potential therapeutic strategies and the recommended intake of minerals to promote female reproductive well-being, considering the menstrual cycle. This review stands as the first to offer such a detailed examination of minerals in the context of the menstrual cycle, aiming to elevate the understanding of their critical role in female fertility and reproductive health.


Low-Dose Naltrexone as an Adjuvant in Combined Anticancer Therapy

Abstract: Naltrexone (NTX) is a non-selective antagonist of opioid receptors, primarily used in the therapy of opioid and alcohol dependence. Low-dose naltrexone (LDN) exhibits antagonistic action against the opioid growth factor receptor (OGFr), whose signaling is associated with the survival, proliferation, and invasion of cancer cells. The mechanism of action of LDN depends on the dose and duration of the OGFr blockade, leading to a compensatory increase in the synthesis of the opioid growth factor (OGF), which has an inhibitory effect on carcinogenesis. Numerous studies on in vitro and in vivo models provide evidence of LDN's positive impact on inhibiting the OGF-OGFr axis in cancers. LDN's unique mechanism of action on cancer cells, lack of direct cytotoxic effect, and immunomodulating action form the basis for its use as an adjuvant in chemotherapy and immunotherapy of cancerous lesions.


Puberty Blocker and Aging Impact on Testicular Cell States and Function

Abstract: Spermatogonial stem cell (SSC) acquisition of meiotogenetic state during puberty to produce genetically diverse gametes is blocked by drugs collectively referred as 'puberty blocker' (PB). Investigating the impact of PB on juvenile SSC state and function is challenging due to limited tissue access and clinical data. Herein, we report largest clinically annotated juvenile testicular biorepository with all children with gender dysphoria on chronic PB treatment highlighting shift in pediatric patient demography in US. At the tissue level, we report mild-to-severe sex gland atrophy in PB treated children. We developed most extensive integrated single-cell RNA dataset to date (>100K single cells; 25 patients), merging both public and novel (52 month PB-treated) datasets, alongside innovative computational approach tailed for germ cells and evaluated the impact of PB and aging on SSC. We report novel constitutional ranges for each testicular cell type across the entire age spectrum, distinct effects of treatments on prepubertal vs adult SSC, presence of spermatogenic epithelial cells exhibiting post-meiotic-state, irrespective of age, puberty status, or PB treatment. Further, we defined distinct effects of PB and aging on testicular cell lineage composition, and SSC meiotogenetic state and function. Using single cell data from prepubertal and young adult, we were able to accurately predict sexual maturity based both on overall cell type proportions, as well as on gene expression patterns within each major cell type. Applying these models to a PB-treated patient that they appeared pre-pubertal across the entire tissue. This combined with the noted gland atrophy and abnormalities from the histology data raise a potential concern regarding the complete 'reversibility' and reproductive fitness of SSC. The biorepository, data, and research approach presented in this study provide unique opportunity to explore the impact of PB on testicular reproductive health.

bioRxiv : the preprint server for biology


Use of progestogens and the risk of intracranial meningioma: national case-control study

Abstract:
OBJECTIVE: To assess the risk of intracranial meningioma associated with the use of selected progestogens.

DESIGN: National case-control study.

SETTING: French National Health Data System (ie, Système National des Données de Santé).

PARTICIPANTS: Of 108 366 women overall, 18 061 women living in France who had intracranial surgery for meningioma between 1 January 2009 and 31 December 2018 (restricted inclusion periods for intrauterine systems) were deemed to be in the case group. Each case was matched to five controls for year of birth and area of residence (90 305 controls).

MAIN OUTCOME MEASURES: Selected progestogens were used: progesterone, hydroxyprogesterone, dydrogesterone, medrogestone, medroxyprogesterone acetate, promegestone, dienogest, and intrauterine levonorgestrel. For each progestogen, use was defined by at least one dispensation within the year before the index date (within three years for 13.5 mg levonorgestrel intrauterine systems and five years for 52 mg). Conditional logistic regression was used to calculate odds ratio for each progestogen meningioma association.

RESULTS: Mean age was 57.6 years (standard deviation 12.8). Analyses showed excess risk of meningioma with use of medrogestone (42 exposed cases/18 061 cases (0.2%) v 79 exposed controls/90 305 controls (0.1%), odds ratio 3.49 (95% confidence interval 2.38 to 5.10)), medroxyprogesterone acetate (injectable, 9/18 061 (0.05%) v 11/90 305 (0.01%), 5.55 (2.27 to 13.56)), and promegestone (83/18 061 (0.5%) v 225/90 305 (0.2 %), 2.39 (1.85 to 3.09)). This excess risk was driven by prolonged use (≥one year). Results showed no excess risk of intracranial meningioma for progesterone, dydrogesterone, or levonorgestrel intrauterine systems. No conclusions could be drawn concerning dienogest or hydroxyprogesterone because of the small number of individuals who received these drugs. A highly increased risk of meningioma was observed for cyproterone acetate (891/18 061 (4.9%) v 256/90 305 (0.3%), odds ratio 19.21 (95% confidence interval 16.61 to 22.22)), nomegestrol acetate (925/18 061 (5.1%) v 1121/90 305 (1.2%), 4.93 (4.50 to 5.41)), and chlormadinone acetate (628/18 061 (3.5%) v 946/90 305 (1.0%), 3.87 (3.48 to 4.30)), which were used as positive controls for use.

CONCLUSIONS: Prolonged use of medrogestone, medroxyprogesterone acetate, and promegestone was found to increase the risk of intracranial meningioma. The increased risk associated with the use of injectable medroxyprogesterone acetate, a widely used contraceptive, and the safety of levonorgestrel intrauterine systems are important new findings.