Search

Objective: To determine whether chronodisruption is associated with achieving pregnancy., Design: Pilot prospective cohort study., Setting: Academic Medical Center., Patient(s): One hundred eighty-three women desiring pregnancy were recruited from the local community of an academic medical center located in the Midwest and provided sleep information between February 1, 2015, and November 30, 2017., Intervention: Sleep and activity data were obtained via actigraphy watches worn continuously for 2 weeks to assess measures of chronodisruption, including sleep period onset, offset, midtime, and duration; as well as variability in each of these measures., Main Outcome Measures: Time to becoming pregnant over 1-year of follow-up., Results: Of the 183 eligible women, 82 became pregnant over a median of 2.8 months of follow-up. Greater interdaily variability in time of sleep onset and variability in sleep duration were associated with a longer time to achieving pregnancy after adjusting for age, body mass index, race, education, income, and smoking status (adjusted hazard ratio [aHR], 0.60; 95% confidence interval [CI], 0.36-0.999 comparing participants with a standard deviation of >1.8 hours to <1.8 hours in daily time of sleep onset; and aHR, 0.58; 95% CI, 0.36-0.98 comparing participants with a standard deviation of >2.3 hours to <2.3 hours in daily sleep duration). In adjusted analyses, no statistically significant associations were observed for average time of sleep onset and offset, midsleep time, and sleep duration, or for variability in time of sleep offset and midtime., Conclusions: Higher day-to-day variability in time of sleep onset and sleep duration-two measures of chronodisruption-were associated with a longer time to achieving pregnancy over 1 year of follow-up in women desiring pregnancy. If replicated in additional studies, these findings could point to lifestyle interventions to help women achieve a desired pregnancy., Competing Interests: Declaration of Interest P.Z. has nothing to disclose. E.S.J. reports funding from March of Dimes for the submitted work; funding from NIH RO1HD100318, NIH R01HD100341 subaward, NIH RO1HD105267 subaward, NIH RO1HD110448 subaward outside the submitted work. B.S.B. reports travel support SREI Resident Award for Excellence in REI. L.W. has nothing to disclose. P.T.J. has nothing to disclose. R.McC. has nothing to disclose. J.C. has nothing to disclose. J.C.F. reports funding from March of Dimes: Prematurity Research Center at Washington University in St. Louis for the submitted work; funding from National Institute of General Medical Sciences; travel support from American Society for Biochemistry and Molecular Biology Hotel and Vienna Population Genetics Group Seminar, Vienna, Austria. outside the submitted work. E.D.H. has nothing to disclose. S. S. reports honoraria from Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction; advisory board Alvin J. Siteman Cancer Center outside the submitted work. S.K.E. reports funding from March of Dimes for the submitted work; funding from March of Dimes, National Institutes of Health, and Chan Zuckerberg Foundation; honoraria from University of Pennsylvania, University of Michigan, RSDP Retreat - Chicago, UCSD, Baylor College of Medicine, Mass General, Yale University, Vanderbilt University, and University of Pittsburgh; travel support from NIEHS, Campion Fund meeting; ASRM Research Institute Advisory Committee, SRI Council outside the submitted work., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Cellular responses to the steroid hormones, estrogen (E2), and progesterone (P4) are governed by their cognate receptor's transcriptional output. However, the feed-forward mechanisms that shape cell-type-specific transcriptional fulcrums for steroid receptors are unidentified. Herein, we found that a common feed-forward mechanism between GREB1 and steroid receptors regulates the differential effect of GREB1 on steroid hormones in a physiological or pathological context. In physiological (receptive) endometrium, GREB1 controls P4-responses in uterine stroma, affecting endometrial receptivity and decidualization, while not affecting E2-mediated epithelial proliferation. Of mechanism, progesterone-induced GREB1 physically interacts with the progesterone receptor, acting as a cofactor in a positive feedback mechanism to regulate P4-responsive genes. Conversely, in endometrial pathology (endometriosis), E2-induced GREB1 modulates E2-dependent gene expression to promote the growth of endometriotic lesions in mice. This differential action of GREB1 exerted by a common feed-forward mechanism with steroid receptors advances our understanding of mechanisms that underlie cell- and tissue-specific steroid hormone actions., (© 2024. The Author(s).)

The number of patients seeking transgender healthcare is growing, and there is a potential impact of gender-affirming therapies on fertility. The use of fertility preservation (FP), particularly among transgender adolescents, has been limited. We aimed to examine differences in FP counselling, referral and utilisation between male-to-female (MtF) and female-to-male (FtM) transgender adolescents. A retrospective review of the medical records of patients ages 12-17 seen at an academic medical centre between 2012 and 2017 with a diagnosis of gender dysphoria was conducted. A total of 22 MtF and 45 FtM adolescents were included. The counselling on the potential fertility impact of gender-affirming therapy was documented in 55%, and of those counselled, 73% were counselled before receiving medication. There was no significant difference between the timing of counselling for MtF versus FtM adolescents. Of patients with documented reproductive wishes, 77% reported either desire for adopted children or no desire for biological children. Among patients offered FP referral, 2 (22.2%) MtF and 3 (12.5%) FtM patients accepted; both MtF patients cryopreserved sperm. While most adolescents were counselled on the fertility impact of gender-affirming therapy, there is room for improvement as 45% of patients had no documented counselling. The rate of transgender adolescents pursuing FP consultation and gamete cryopreservation was low, consistent with prior studies in this population.

Objective: To assess the odds of pregnancy after intrauterine insemination (IUI) timed by ultrasound monitoring and human chorionic gonadotropin (hCG) administration compared with monitoring luteinizing hormone (LH) levels., Data Sources: We searched PubMed (MEDLINE), EMBASE (Elsevier), Scopus (Elsevier), Web of Science (Clarivate Analytics), ClinicalTrials.gov (National Institutes of Health), and the Cochrane Library (Wiley) from the inception until October 1, 2022. No language limitations were applied., Methods of Study Selection: After deduplication, 3,607 unique citations were subjected to blinded independent review by three investigators. Thirteen studies (five retrospective cohort, four cross-sectional, two randomized controlled trials, and two randomized crossover studies) that enrolled women undergoing natural cycle, oral medication (clomid or letrozole), or both for IUI were included in the final random-effects model meta-analysis. Methodologic quality of included studies was assessed with the Downs and Black checklist., Tabulation, Integration, and Results: Data extraction was compiled by two authors, including publication information, hCG and LH monitoring guidelines, and pregnancy outcomes. No significant difference in odds of pregnancy between hCG administration and endogenous LH monitoring was observed (odds ratio [OR] 0.92, 95% CI 0.69-1.22, P =.53). Subgroup analysis of the five studies that included natural cycle IUI outcomes also showed no significant difference in odds of pregnancy between the two methods (OR 0.88, 95% CI 0.46-1.69, P =.61). Finally, a subgroup analysis of 10 studies that included women who underwent ovarian stimulation with oral medications (clomid or letrozole) did not demonstrate a difference in odds of pregnancy between ultrasonography with hCG trigger and LH-timed IUI (OR 0.88, 95% CI 0.66-1.16, P =.32). Statistically significant heterogeneity was noted between studies., Conclusion: This meta-analysis showed no difference between pregnancy outcomes between at-home LH monitoring and timed IUI., Systematic Review Registration: PROSPERO, CRD42021230520., Competing Interests: Financial Disclosure The authors did not report any potential conflicts of interest., (Copyright © 2023 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Objective(s): To evaluate the association between neighborhood disadvantage and ovarian reserve stratified by body mass index (BMI)., Design: Cross-sectional cohort study., Setting: Single academic medical center., Patient(s): A total of 193 healthy reproductive-age women with regular menstrual cycles in the St. Louis, Missouri metropolitan area., Intervention(s): Residence in a disadvantaged neighborhood., Main Outcome Measure(s): Ovarian reserve as assessed by ovarian antral follicle count (AFC) and serum anti-Müllerian hormone (AMH) concentration., Result(s): Women (n = 193) ranged from 20 to 44 years. The majority had overweight or obesity (59%, n = 117) with mean BMI of 28±7 kg/m 2 . Forty-eight women lived in the most disadvantaged neighborhood quartile, of which 75% had overweight or obesity, compared with 54% of the 145 women living in the 3 less disadvantaged neighborhood quartiles. When controlling for age, race, and smoking status, women with overweight or obesity living in the most disadvantaged neighborhoods had significantly lower AMH compared with those living in the less disadvantaged neighborhoods. Antral follicle count did not differ among women with overweight or obesity by neighborhood of residence. Neighborhood disadvantage was not associated with ovarian reserve by AFC or AMH in women with normal weight or underweight status., Conclusion(s): Living in a socioeconomically deprived area is associated with lower markers of ovarian reserve among women with an elevated BMI., (Copyright © 2022 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Patients with multiple sclerosis (MS) may seek fertility treatment (FT)-including in vitro fertilization (IVF). Variable relapse risk after IVF has been reported in small historical cohorts, with more recent studies suggesting no change in annualized relapse rate (ARR). The objective of this study was to evaluate ARR 12 months pre-FT and 3 months post-FT in a multicenter cohort and identify factors associated with an increased risk of relapse., Methods: Patients with clinically isolated syndrome (CIS) or MS aged 18-45 years with at least 1 FT from January 1, 2010, to October 14, 2021, were retrospectively identified at 4 large academic MS centers. The exposed period of 3 months after FT was compared with the unexposed period of 12 months before FT. FTs included controlled ovarian stimulation followed by fresh embryo transfer (COS-ET), COS alone, embryo transfer (ET) alone, and oral ovulation induction (OI). The Wilcoxon signed rank test and mixed Poisson regression models with random effects were used to compare ARR pre-FT vs post-FT, with the incidence rate ratio (IRR) and 95% CI reported., Results: One hundred twenty-four FT cycles among 65 patients with MS (n = 56) or CIS (n = 9) were included: 61 COS-ET, 19 COS alone, 30 ET alone, and 14 OI. The mean age at FT was 36.5 ± 3.8 years, and the mean disease duration was 8.2 ± 5.0 years. Across 80 cycles with COS, only 5 relapses occurred among 4 unique patients within 3 months of treatment. The mean ARR after COS and before was not different (0.26 vs 0.25, p = 0.37), and the IRR was 0.95 (95% CI: 0.52-1.76, p = 0.88). No cycles with therapeutic disease-modifying therapies (DMTs) during COS had 3 months relapse (ARR 0 post-COS vs 0.18 pre-COS, p = 0.02, n = 34). Relapse rates did not vary by COS protocol. Among COS-ET cycles that achieved pregnancy (n = 43), ARR decreased from 0.26 to 0.09 ( p = 0.04) within the first trimester of pregnancy. There were no relapses 3 months after ET alone and 1 relapse after OI., Discussion: In this modern multicenter cohort of patients with MS undergoing diverse FTs, which included 43% on DMTs, we did not observe an elevated relapse risk after FT., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Importance: Multiple gestation is one of the biggest risks after in vitro fertilization (IVF), largely due to multiple embryo transfer (MET). Single embryo transfer (SET) uptake has increased over time and has been attributed to various factors, such as mandated insurance coverage for IVF and preimplantation genetic testing for aneuploidy (PGT-A)., Objective: To investigate whether mandates for IVF insurance coverage are associated with decreased use of MET after PGT-A., Design, Setting, and Participants: This cohort study was conducted using data on embryo transfers reported to the Society for Assisted Reproductive Technology between 2014 and 2016. Data were analyzed from January to October 2021., Exposures: State-mandated coverage for fertility treatment and type of cycle transfer performed (PGT-A, untested fresh, and untested frozen)., Main Outcomes and Measures: Use of MET compared with SET, live birth, and live birth of multiples., Results: There were 110 843 embryo transfers (mean [SD] patient age, 34.0 [4.5] years; 5520 individuals identified as African American [5.0%], 10 035 as Asian [9.0%], 5425 as Hispanic [4.9%], 45 561 as White [41.1%], and 44 302 as other or unknown race or ethnicity [40.0%]); 17 650 transfers used embryos that underwent PGT-A. Overall, among transferred embryos that had PGT-A, there were 9712 live births (55.0%). The odds of live birth were 70% higher with MET vs SET after frozen embryo transfer with PGT-A (OR, 1.70; 95% CI, 1.61-1.78), but the risk of multiples was 5 times higher (OR, 5.33; 95% CI, 5.22-5.44). The odds of MET in cycles with PGT-A in states with insurance mandates were 24% lower than in states without mandates (OR, 0.76; 95% CI, 0.68-0.85)., Conclusions and Relevance: This study found that despite the promise of using SET with PGT-A, MET after PGT-A was not uncommon. This practice was more common in states without insurance mandates and was associated with a high risk of multiples.

Non-obstructive azoospermia (NOA) is the most severe form of male infertility and typically incurable. Defining the genetic basis of NOA has proven challenging, and the most advanced classification of NOA subforms is not based on genetics, but simple description of testis histology. In this study, we exome-sequenced over 1000 clinically diagnosed NOA cases and identified a plausible recessive Mendelian cause in 20%. We find further support for 21 genes in a 2-stage burden test with 2072 cases and 11,587 fertile controls. The disrupted genes are primarily on the autosomes, enriched for undescribed human "knockouts", and, for the most part, have yet to be linked to a Mendelian trait. Integration with single-cell RNA sequencing data shows that azoospermia genes can be grouped into molecular subforms with synchronized expression patterns, and analogs of these subforms exist in mice. This analysis framework identifies groups of genes with known roles in spermatogenesis but also reveals unrecognized subforms, such as a set of genes expressed across mitotic divisions of differentiating spermatogonia. Our findings highlight NOA as an understudied Mendelian disorder and provide a conceptual structure for organizing the complex genetics of male infertility, which may provide a rational basis for disease classification., (© 2022. The Author(s).)

Background: Worldwide, 10% of babies are born preterm, defined as a live birth before 37 weeks of gestation. Preterm birth is the leading cause of neonatal death, and survivors face lifelong risks of adverse outcomes. New approaches with large sample sizes are needed to identify strategies to predict and prevent preterm birth. The primary aims of the Washington University Prematurity Research Cohort Study were to conduct three prospective projects addressing possible causes of preterm birth and provide data and samples for future research., Study Design: Pregnant patients were recruited into the cohort between January 2017 and January 2020. Consenting patients were enrolled into the study before 20 weeks' gestation and followed through delivery. Participants completed demographic and lifestyle surveys; provided maternal blood, placenta samples, and cord blood; and participated in up to three projects focused on underlying physiology of preterm birth: cervical imaging (Project 1), circadian rhythms (Project 2), and uterine magnetic resonance imaging and electromyometrial imaging (Project 3)., Results: A total of 1260 participants were enrolled and delivered during the study period. Of the participants, 706 (56%) were Black/African American, 494 (39%) were nulliparous, and 185 (15%) had a previous preterm birth. Of the 1260 participants, 1220 (97%) delivered a live infant. Of the 1220 with a live birth, 163 (14.1%) had preterm birth, of which 74 (6.1%) were spontaneous preterm birth. Of the 1220 participants with a live birth, 841 participated in cervical imaging, 1047 contributed data and/or samples on circadian rhythms, and 39 underwent uterine magnetic resonance imaging. Of the 39, 25 underwent electromyometrial imaging., Conclusion: We demonstrate feasibility of recruiting and retaining a diverse cohort in a complex prospective, longitudinal study throughout pregnancy. The extensive clinical, imaging, survey, and biologic data obtained will be used to explore cervical, uterine, and endocrine physiology of preterm birth and can be used to develop novel approaches to predict and prevent preterm birth., Competing Interests: The authors have declared that no competing interests exist.

Study Objective: To compare sleep behavior before and during pregnancy., Methods: In this prospective cohort study, healthy women were followed from pre-pregnancy until delivery. At pre-pregnancy and each trimester, participants completed validated questionnaires of chronotype and sleep quality and timing, including the Munich ChronoType Questionnaire, Epworth Sleepiness Scale, and Pittsburgh Sleep Quality Index. The primary outcomes were sleep period start and end times, sleep duration, sleep midpoint, and social jetlag, compared between pre-pregnancy and each trimester. Wrist actigraphy was used to measure the same outcomes in a subset of participants., Results: Eighty-six women were included in analysis of questionnaires. Of these, 37 provided complete actigraphy data. Questionnaire and actigraphy data indicate that participants had less social jetlag during pregnancy than before pregnancy. Sleep period start times were earlier on both work and free days in the first and second trimesters than pre-pregnancy, and returned to pre-pregnancy times by the third trimester. Actigraphy data revealed that, compared to pre-pregnancy, participants had longer sleep periods in all trimesters on work days and in the first trimester on free days. Sleep surveys revealed that participants had poorer sleep quality in the first and third trimesters and more sleepiness in the first trimester than pre-pregnancy., Conclusion: The first trimester of pregnancy is characterized by earlier sleep period start time, longer sleep duration, and poorer sleep quality than pre-pregnancy. Sleep quality temporarily improves in the second trimester, and sleep period start time returns to pre-pregnancy time by the third trimester., Study Rationale: Multiple parameters of sleep have been studied in the context of pregnancy and pregnancy outcomes, but rarely in comparison to pre-pregnancy or longitudinally through pregnancy., Study Impact: Actigraphy and questionnaire data reveal sleep timing and quality change throughout pregnancy. These data on sleep changes in healthy pregnancy can be used as a baseline to identify sleep-related risk factors throughout pregnancy., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: To examine the association between state-mandated insurance coverage for infertility treatment in the United States and the utilization of and indication for preimplantation genetic testing., Methods: This was a retrospective cohort study of 301,465 in vitro fertilization (IVF) cycles reported to the Society for Assisted Reproductive Technology between 2014 and 2016. Binomial logistic regression was performed to examine associations between state-mandated insurance coverage and preimplantation genetic testing use. The neonate's sex from each patient's first successful cycle was used to calculate sex ratios. Sex ratios then were compared by state mandates and preimplantation genetic testing indication for elective sex selection., Results: The proportion of IVF cycles using preimplantation genetic testing increased from 17% in 2014 to 34% in 2016. This increase was driven largely by preimplantation genetic testing for aneuploidy testing. Preimplantation genetic testing was less likely to be performed in states with mandates for insurance coverage than in those without mandates (risk ratio [RR] 0.69, 95% CI 0.67-0.71, P<.001). Preimplantation genetic testing use for elective sex selection was also less likely to be performed in states with mandates (RR 0.44, 95% CI 0.36-0.53, P<.001). Among liveborn neonates, the male/female sex ratio was higher for IVF cycles with preimplantation genetic testing for any indication (115) than for those without preimplantation genetic testing (105) (P<.001), and the use of preimplantation genetic testing specifically for elective sex selection had a substantially higher (164) male/female sex ratio than preimplantation genetic testing for other indications (112) (P<.001)., Conclusion: The proportion of IVF cycles using preimplantation genetic testing in the United States is increasing and is highest in states where IVF is largely self-funded. Preimplantation genetic testing for nonmedical sex selection is also more common in states where IVF is self-funded and is more likely to result in male offspring. Continued surveillance of these trends is important, because these practices are controversial and could have implications for future population demographics., Competing Interests: Financial Disclosure The authors did not report any potential conflicts of interest., (Copyright © 2022 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To evaluate the relationship between maternal body mass index (BMI) and embryonic aneuploidy of maternal origin., Design: Retrospective cohort analysis., Setting: University hospital-based reproductive center., Patients: Maternal origin of aneuploidy was available for 453 cycles and 1,717 embryos., Interventions: Data regarding BMI were collected before egg retrieval. Comparison groups included underweight (BMI, <18.5 kg/m 2 ), normal weight (BMI, 18.5-24.9 kg/m 2 ), overweight (BMI, 25-29.9 kg/m 2 ), and obese (BMI, ≥30 kg/m 2 ). Overall embryonic aneuploidy and maternal aneuploidy rates were compared. The aneuploidy rate was the number of embryos with either maternal or mixed (maternal and paternal) aneuploidy divided by the total number of embryos tested., Main Outcome Measures: Overall embryonic aneuploidy and maternal aneuploidy rates., Results: Maternal aneuploidy rate was 51.5% for BMI of ≥30 kg/m 2 and 39.3% for BMI of <30 kg/m 2 . Female age as well as several in vitro fertilization characteristics were significantly different across groups and were included in the adjusted model. Both the overall embryonic aneuploidy rate (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.11-1.59) and the maternal aneuploidy rate (OR, 1.64; 95% CI, 1.25-2.16) increased with increasing maternal BMI. However, after controlling for significant confounders, BMI did not significantly predict the rate of maternal aneuploidy (OR, 1.16; 95% CI, 0.85-1.59)., Conclusions: Maternal BMI did not correlate with embryonic aneuploidy of maternal origin after adjusting for confounders., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the predictors of establishing care with a reproductive urologist (RU) among men with abnormal semen analyses (SAs) ordered by nonurologists and examine patient perceptions of abnormal SAs in the absence of RU consultation., Design: Retrospective cohort study with cross-sectional survey., Setting: Large, integrated academic healthcare system during 2002-2019., Patient(s): We identified adult men undergoing initial SAs with nonurologists who had abnormalities. Patients with index SAs during 2002-2018 were included for the analysis of RU consultation. Men tested in 2019 were recruited for cross-sectional survey., Intervention(s): Cross-sectional survey., Main Outcome Measure(s): RU consultation and accurate perception of abnormal SAs., Result(s): A total of 2,283 men had abnormal SAs ordered by nonurologists, among whom 20.5% underwent RU consultation. Mixed-effect logistic regression modeling identified oligospermia as the strongest predictor of RU care (odds ratio, 3.08; 95% confidence interval, 2.43-3.90) with a significant provider-level random intercept. We observed substantial provider-level heterogeneity among nonurologists with provider-specific rates of RU evaluation ranging from 3.7% to 35.8%. We contacted 310 men who did not undergo RU consultation with a 27.2% survey response rate. Of respondents, 6.7% reported receiving an RU referral. Among men with abnormal SAs not evaluated by RU, 22.7% appropriately perceived an abnormal SA., Conclusion(s): In men with abnormal SAs diagnosed by nonurologists, the rate of RU consultation was low and associated with substantial provider-level variation among ordering providers. Patients without RU consultation reported inaccurate perceptions of their SA. Multidisciplinary efforts are needed to ensure that subfertile men receive appropriate RU evaluation., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Growing evidence suggests that adherence to certain dietary patterns is associated with improved fecundity and reproductive outcomes in the general population and infertile couples assisted reproductive treatments. The objective of this study was to assess if dietary patterns are associated with ovarian reserve in reproductive age women without a history of infertility., Methods: This was a cross-sectional study of 185 women in the Lifestyle and Ovarian Reserve (LORe) cohort. Women aged 18-44 without a history of infertility were recruited from the local community at an academic medical center. Subjects completed validated food frequency and physical activity questionnaires to assess patterns over the year prior to presentation. Dietary patterns including a Western (including meat, refined carbohydrates, high-calorie drinks), prudent (including fruits, vegetables, olive oil and nuts), fertility (lower intake of trans fat with higher intake of monounsaturated fatty acids, increased intake of plant based protein, high-fat dairy, lower glycemic load carbohydrates and supplemental iron) and profertility diet (PFD) (characterize by whole grains, soy and seafood, low pesticide residue produce, supplemental folic acid, B12 and vitamin D) were identified through principal component analysis. Main outcome measures were serum antimullerian hormone concentration (AMH) (ng/mL) and antral follicle count (AFC) obtained by transvaginal ultrasound., Results: After stratifying by BMI, adjusting for age, smoking and physical activity, dietary patterns were not associated with ovarian reserve in normal weight women. Increased adherence to a profertility diet in overweight and obese women (BMI ≥ 25 kg/m 2 ) was associated with a significantly higher AMH. Women in the third and fourth quartiles of PFD adherence had a mean AMH concentration of 1.45 ng/mL (95%CI 0.33-2.56, p = 0.01) and 1.67 ng/mL (95%CI 0.60-2.74, p = 0.003) higher than women in the lowest quartile respectively. The highest adherence to PFD was also associated with a higher AFC in women with a BMI ≥ 25 kg/m 2 (β = 7.8, 95%CI 0.003-15.34, p < 0.05). Other common dietary patterns were not significantly associated with ovarian reserve., Conclusions: Increased adherence to a profertility diet is associated with improved markers of ovarian reserve in overweight and obese women. These findings provide novel insight on potential modifiable lifestyle factors associated with ovarian reserve., (© 2022. The Author(s).)

Objective: To comprehensively characterize the DNA virome in semen samples collected for in vitro fertilization (IVF)., Design: A descriptive clinical study., Setting: Single academic fertility center., Patient(s): Twenty-four male partners from couples undergoing IVF., Intervention(s): Couples were randomized to receive 1 g of azithromycin (standard of care) or no azithromycin at the time of baseline IVF assessment. Semen samples were collected at the time of the female partners' egg retrieval, and 100 μL of the sample was used for the virome analysis., Main Outcome Measure(s): Detection of viruses by ViroCap enrichment of viral nucleic acid and sequencing. Association between the virome, semen parameters, and pregnancy outcomes., Result(s): We detected viruses in 58% of the participants. Viruses included polyomaviruses, papillomaviruses, herpesviruses, and anelloviruses. Viromes detected in semen had little overlap with the viromes detected in vaginal samples from their female partners collected at the time of embryo transfer, which were analyzed in a previous study. A lower viral diversity in semen samples was positively associated with pregnancy (Hodges-Lehmann estimate of difference, 1; 95% confidence interval, 2-0.00003). There was no association between viral diversity and sperm concentration, motility, or fertilization rates., Conclusion(s): This comprehensive characterization of the DNA virome in semen reveals an association between virome diversity and pregnancy in couples undergoing IVF. However, no association was found with specific semen parameters or fertilization rates, suggesting that viral exposure may negatively affect pregnancy after fertilization. Future studies should be undertaken to evaluate the associations between the semen virome with IVF outcomes in larger cohorts., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: In female cancer patients anticipating chemotherapy or radiation, oocyte retrieval for fertility should be performed as efficiently as possible to avoid postponing cancer treatments. Our objective was to compare clinical outcomes among female cancer patients who underwent a conventional early follicular phase-start ovarian stimulation cycle and those who underwent a random-start ovarian stimulation cycle., Evidence Review: A systematic review of the literature was performed in accordance with PRISMA guidelines. Medline, Embase.com, Scopus, Cochrane Library, and Clinicaltrials.gov databases were searched to identify all original research published in English through July 2020 on the topic of female cancer patients undergoing ovarian stimulation with a random or conventional start. Studies lacking a comparison group or including women who had already undergone chemotherapy at the time of ovarian stimulation were excluded. The primary author assessed all identified article titles and abstracts, and two independent reviewers assessed full-text articles and extracted data. A meta-analysis with a random-effects model was used to calculate weighted mean differences (WMDs) for outcomes of interest. The primary outcome was the number of mature (meiosis II) oocytes retrieved. Secondary outcomes included duration of stimulation, total dose of gonadotropins, total number of oocytes retrieved, fertilization rate, and number of embryos or zygotes cryopreserved., Results: A total of 446 articles were screened, and 9 full-text articles (all retrospective cohort or prospective observational) were included for review. Additionally, pooled primary retrospective data from two institutions were included. In total, data from 10 studies including 1653 women were reviewed. Five studies reported the number of embryos cryopreserved, and four reported fertilization rates. Random-start cycles were slightly longer (WMD 0.57 days, 95 % confidence interval [CI] 0.0-1.14 days) and used more total gonadotropins (WMD 248.8 international units, 95 % CI 57.24-440.40) than conventional-start cycles. However, there were no differences in number of mature oocytes retrieved (WMD 0.41 oocytes, 95 % CI -0.84-1.66), number of total oocytes retrieved (WMD 0.90 oocytes, 95 % CI -0.21-2.02), fertilization rates (WMD -0.12, 95 % CI -1.22-0.98), or number of embryos cryopreserved (WMD 0.12 embryos, 95 %CI -0.98-1.22) between random-start and conventional-start cycles. All outcomes except for the parameter "total oocytes retrieved" yielded an I 2 of over 50 %, indicating substantial heterogeneity between studies., Conclusion(s): Although random-start cycles may entail a longer duration of stimulation and use more total gonadotropins than conventional-start cycles, the absolute differences are small and likely do not significantly affect treatment costs. The similar numbers of mature oocytes retrieved, fertilization rates, and number of embryos cryopreserved in the two start-types suggest that they do not differ in any clinically important ways. Given that random-start cycles can be initiated quickly, they may help facilitate fertility preservation for cancer patients., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Importance: Women with an early nonviable pregnancy of unknown location are at high risk of ectopic pregnancy and its inherent morbidity and mortality. Successful and timely resolution of the gestation, while minimizing unscheduled interventions, are important priorities., Objective: To determine if active management is more effective in achieving pregnancy resolution than expectant management and whether the use of empirical methotrexate is noninferior to uterine evacuation followed by methotrexate if needed., Design, Setting, and Participants: This multicenter randomized clinical trial recruited 255 hemodynamically stable women with a diagnosed persisting pregnancy of unknown location between July 25, 2014, and June 4, 2019, in 12 medical centers in the United States (final follow up, August 19, 2019)., Interventions: Eligible patients were randomized in a 1:1:1 ratio to expectant management (n = 86), active management with uterine evacuation followed by methotrexate if needed (n = 87), or active management with empirical methotrexate using a 2-dose protocol (n = 82)., Main Outcomes and Measures: The primary outcome was successful resolution of the pregnancy without change from initial strategy. The primary hypothesis tested for superiority of the active groups combined vs expectant management, and a secondary hypothesis tested for noninferiority of empirical methotrexate compared with uterine evacuation with methotrexate as needed using a noninferiority margin of -12%., Results: Among 255 patients who were randomized (median age, 31 years; interquartile range, 27-36 years), 253 (99.2%) completed the trial. Ninety-nine patients (39%) declined their randomized allocation (26.7% declined expectant management, 48.3% declined uterine evacuation, and 41.5% declined empirical methotrexate) and crossed over to a different group. Compared with patients randomized to receive expectant management (n = 86), women randomized to receive active management (n = 169) were significantly more likely to experience successful pregnancy resolution without change in their initial management strategy (51.5% vs 36.0%; difference, 15.4% [95% CI, 2.8% to 28.1%]; rate ratio, 1.43 [95% CI, 1.04 to 1.96]). Among active management strategies, empirical methotrexate was noninferior to uterine evacuation followed by methotrexate if needed with regard to successful pregnancy resolution without change in management strategy (54.9% vs 48.3%; difference, 6.6% [1-sided 97.5% CI, -8.4% to ∞]). The most common adverse event was vaginal bleeding for all of the 3 management groups (44.2%-52.9%)., Conclusions and Relevance: Among patients with a persisting pregnancy of unknown location, patients randomized to receive active management, compared with those randomized to receive expectant management, more frequently achieved successful pregnancy resolution without change from the initial management strategy. The substantial crossover between groups should be considered when interpreting the results., Trial Registration: ClinicalTrials.gov Identifier: NCT02152696.

Research Question: How do anti-Müllerian hormone (AMH) concentrations in women with and without arthritis compare? Is there an association between AMH and arthritis drug regimen?, Design: In this prospective cohort study, AMH was measured at two time points (T 0 and T 1 ) in 129 premenopausal women with arthritis. AMH at T 0 was compared with that from a bank of serum samples from 198 premenopausal women without arthritis. Primary outcomes were: (i) diminished ovarian reserve (DOR) (AMH <1.1 ng/ml) and (ii) annual rate of AMH decrease. Univariate, multivariable and Firth logistic regression identified variables associated with annual AMH decrease in excess of the 75th percentile., Results: Median time between T 0 and T 1 was 1.72 years. At time T 0 , median age-adjusted AMH in women with arthritis was significantly lower than that of women without arthritis (median 2.21 ng/ml versus 2.78 ng/ml; P = 0.009). Women with arthritis at highest risk for DOR had a history of tubal sterilization or were over the age of 35. Those with highest odds of having an annual AMH decrease in excess of the 75th percentile (over 28% decrease per year) were those: over the age of 35 or who sought care for infertility. Women with arthritis taking methotrexate alone (OR 0.08, 95% CI 0.01-0.67) or methotrexate plus tumour necrosis factor-alpha antagonists (OR 0.13, 95% CI 0.02-0.89) were less likely to be in the highest quartile of annual AMH decrease than women with arthritis not taking medication., Conclusions: Women with arthritis had lower AMH than healthy controls. Long-term methotrexate use was not associated with an annual AMH decrease., (Copyright © 2021 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Objective: To measure human sperm intracellular pH (pH i ) and develop a machine-learning algorithm to predict successful conventional in vitro fertilization (IVF) in normospermic patients., Design: Spermatozoa from 76 IVF patients were capacitated in vitro. Flow cytometry was used to measure sperm pH i , and computer-assisted semen analysis was used to measure hyperactivated motility. A gradient-boosted machine-learning algorithm was trained on clinical data and sperm pH i and membrane potential from 58 patients to predict successful conventional IVF, defined as a fertilization ratio (number of fertilized oocytes [2 pronuclei]/number of mature oocytes) greater than 0.66. The algorithm was validated on an independent set of data from 18 patients., Setting: Academic medical center., Patient(s): Normospermic men undergoing IVF. Patients were excluded if they used frozen sperm, had known male factor infertility, or used intracytoplasmic sperm injection only., Intervention(s): None., Main Outcome Measure(s): Successful conventional IVF., Result(s): Sperm pH i positively correlated with hyperactivated motility and with conventional IVF ratio (n = 76) but not with intracytoplasmic sperm injection fertilization ratio (n = 38). In receiver operating curve analysis of data from the test set (n = 58), the machine-learning algorithm predicted successful conventional IVF with a mean accuracy of 0.72 (n = 18), a mean area under the curve of 0.81, a mean sensitivity of 0.65, and a mean specificity of 0.80., Conclusion(s): Sperm pH i correlates with conventional fertilization outcomes in normospermic patients undergoing IVF. A machine-learning algorithm can use clinical parameters and markers of capacitation to accurately predict successful fertilization in normospermic men undergoing conventional IVF., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To determine whether prophylactic azithromycin is associated with the vaginal bacterial microbiome and clinical outcomes in subfertile women undergoing in vitro fertilization (IVF)., Design: Prospective exploratory cohort study., Setting: Single academic fertility center., Patients: Subfertile women aged 18-43 years undergoing their first IVF cycle and fresh embryo transfer., Intervention: Primary exposure to prophylactic azithromycin (1 g orally) once at baseline., Main Outcome Measures: The primary outcome was the effect of azithromycin on the vaginal microbiome compared with a no-azithromycin group at 3 time points throughout the IVF cycle (baseline, retrieval, and embryo transfer). The secondary outcomes were associations of vaginal bacterial communities with clinical outcomes., Results: A planned a priori exploratory cohort of 27 subjects (12 in the azithromycin treatment group and 15 in the no-azithromycin group) contributed 79 vaginal swabs for the analysis as part of an ongoing randomized, controlled noninferiority trial. No specific taxa were associated with azithromycin or pregnancy at any time point. Azithromycin did not affect alpha diversity or community stability. Although there were trends of a lower bacterial load and higher percentage of Lactobacillus species in the azithromycin group at the time of transfer, these were not statistically significant. In women who did not become pregnant, the percentage of Lactobacillus species was lower ( P = .048; Hodges-Lehmann estimate of difference, 0.41; 95% confidence interval, 0.08-0.65) and the change in community composition over time was higher. The percentage of Lactobacillus species at baseline was not predictive of the percentage of Lactobacillus species at the time of embryo transfer., Conclusions: Prophylactic azithromycin at baseline is not associated with changes in vaginal bacterial communities. Bacterial community features at the time of embryo transfer are associated with pregnancy. Bacterial community structures at baseline are not predictive of those at the time of embryo transfer., Clinical Trial Registration Number: NCT03386227.

Background: Polycystic ovary syndrome (PCOS) is a common yet underdiagnosed endocrinopathy with potentially serious sequelae. A screening questionnaire for PCOS can improve early identification and diagnosis. Objective: The purpose of this study was to test the utility of a self-administered questionnaire to help identify women at risk for PCOS. Study Design: We recruited women ages 18-50 with and without PCOS as defined by modified Rotterdam criteria to complete a self-administered survey of common PCOS signs and symptoms. The survey included questions regarding menstrual cycle characteristics and hyperandrogenism as measured by images from the Ferriman-Gallwey (FG) scoring system, and by report of depilatory practices. Results: Fifty-one women with PCOS and 50 women without PCOS participated in this study. Many study participants were current users of hormonal contraceptives making it difficult to discern menstrual cycle characteristics. Hirsutism, defined by a modification of the FG score of ≥3 from the upper lip and abdomen based on self-assessments, provided a sensitivity of 76% and specificity of 70%, whereas report of any depilatory practices provided a sensitivity of 71% and specificity of 74%. The combined sensitivity of these measures was 93% with a specificity of 52%. In multivariate logistic regression, women who used depilatory techniques had an adjusted odds ratio (aOR) of PCOS of 6.6 (95% confidence interval [CI] 2.5-17.3, p  = 0.0002). Those with obesity had similar aOR of PCOS (aOR 6.7, 95% CI 2.5-17.9, p  = 0.0001). Addition of other variables did not improve model fit and the net sensitivity and specificity of these two variables did not improve those of depilatory practices and hirsutism. Conclusions: Self-report of depilatory practices or hirsutism is sensitive for identifying women with PCOS. Given the prevalence of PCOS in reproductive-age women and the potentially serious health sequelae, it would be worthwhile to include questions about terminal hair growth and depilatory practices when providing general medical care to reproductive-age women to determine if further testing and screening for PCOS are indicated. This tool may also be helpful in populations where complete diagnostic evaluation may not be feasible., Competing Interests: No competing financial interests exist., (© Bronwyn S. Bedrick et al., 2020; Published by Mary Ann Liebert, Inc.)

Purpose: To assess longitudinal trends in in vitro fertilization (IVF) patients' choices for disposing of cryopreserved embryos., Methods: This is a retrospective cohort study of embryo disposition forms submitted between January 2000 and February 2020 at a university-based fertility clinic. Primary outcome was disposition decision. Binary and multivariable logistic regression were performed to determine odds ratios (OR) for decisions according to female age, education, race, religion, state of residence, area deprivation index based on zip code, and IVF pregnancy history. We also assessed disposition year, storage duration, and number of stored embryos., Results: Forms were reviewed from 615 patients; 50.6% chose to discard embryos, 45.4% donated to research, and 4.1% chose reproductive donation. In the regression model, two factors were significantly associated with donation to research: female listing "no preference" or declining to list religious preference (OR 2.56, 95%CI 1.44-4.54) and live birth of multiples after IVF (OR 1.58, 95%CI 1.05-2.36). Before 2012, females younger than age 30 at storage were equally likely to choose to donate embryos to research as discard them. However, between 2013 and 2020, females younger than 30 were significantly more likely to discard than donate embryos for research (OR 2.87, 95%CI 1.13-7.28)., Conclusion: Since 2013, the majority of patients younger than 30 at storage have chosen to discard cryopreserved embryos. Before then, patients were more likely to donate embryos for research. To ensure sufficient embryos are available for research, young patients, who are most likely to have cryopreserved embryos, should be counseled about options for donation.

Objective: To characterize dietary patterns and physical activity in a diverse cohort of Midwestern reproductive-age women and to determine associations between these lifestyle factors, socioeconomic factors, and obesity., Methods: In this cross-sectional study, 185 women completed validated food frequency and physical activity questionnaires. Dietary patterns were identified through principal component analysis. Sociodemographic characteristics associated with dietary pattern adherence and physical activity participation were identified through linear regression. Associations between lifestyle factors and obesity were assessed through logistic regression., Results: Two dietary patterns were identified: a "Prudent" pattern characterized by consumption of fruits, vegetables, olive oil, and nuts and a "Western" pattern including meat, refined carbohydrates, and high-calorie drinks. African-American women and women without a college degree were more likely to adhere to the Western dietary pattern than other women. Women in areas with higher socioeconomic deprivation had lower levels of physical activity, especially leisure-time exercise. Women who completed college participated in more leisure-time exercise and had less physically demanding occupations. Obesity was associated with increasing adherence to the Western dietary pattern in a dose-dependent fashion (aOR range 2.68-4.33, 95% CI range 0.69-16.61) but was not associated with adherence to the Prudent pattern (aOR range 0.46-1.06, 95% CI range 0.13-3.41). Increased physical activity was associated with reduced odds of obesity (aOR range 0.28-0.30, 95% CI range 0.10-0.93)., Conclusions for Practice: This study highlights dietary and physical activity patterns associated with obesity in reproductive-age women. Lifestyle interventions focused on minimizing consumption of the Western diet and increasing physical activity may provide an opportunity to reduce obesity among reproductive-age women.

Objective: To estimate the association between subchorionic hematoma (SCH) on ultrasound and pregnancy outcomes in in vitro fertilization (IVF) pregnancies., Design: Institutional Review Board-approved, retrospective cohort study., Setting: Tertiary care university-based facility., Patients: In this study, 1,004 patients who underwent IVF with a viable singleton pregnancy from January 1, 2009 through December 31, 2017., Interventions: Subchorionic hematoma versus no hematoma diagnosed on first-trimester ultrasound., Main Outcome Measures: Live birth, preterm birth, and spontaneous abortion., Results: We found that 1,004 women met the criteria and 187 (18.6%) had an SCH. In bivariate and multivariate regression models, there were no associations between SCH and the outcomes of live birth, preterm birth, or birth weight., Conclusions: Subchorionic hematoma detected on first-trimester ultrasound after IVF is not associated with probability of live birth, probability of preterm birth, or infant birth weight in this patient population., (© 2020 The Authors.)

Up to 30% of women experience early miscarriage due to impaired decidualization. For implantation to occur, the uterine endometrial stromal fibroblast-like cells must differentiate into decidual cells, but the genes required for decidualization have not been fully defined. Here, we show that Malignant Brain Tumor Domain-containing Protein 1 (MBTD1), a member of the polycomb group protein family, is critical for human endometrial stromal cell (HESC) decidualization. MBTD1 predominantly localized to HESCs during the secretory phase and the levels were significantly elevated during in vitro decidualization of both immortalized and primary HESCs. Importantly, siRNA-mediated MBTD1 knockdown significantly impaired in vitro decidualization of both immortalized and primary HESCs, as evidenced by reduced expression of the decidualization markers PRL and IGFBP1 . Further, knockdown of MBTD1 reduced cell proliferation and resulted in G2/M cell cycle arrest in decidualizing HESCs. Although progesterone signaling is required for decidualization, MBTD1 expression was not affected by progesterone signaling; however, MBTD1 knockdown significantly reduced expression of the progesterone target genes WNT4 , FOXOA1 , and GREB1 . Collectively, our data suggest that MBTD1 contributes to in vitro decidualization of HESCs by sustaining progesterone signaling. This work could have implications for designing diagnostic and therapeutic tools for recurrent pregnancy loss., (Copyright © 2020 Chadchan, Maurya, Krekeler, Jungheim and Kommagani.)

Successful establishment of pregnancy depends on steroid hormone-driven cellular changes in the uterus during the peri-implantation period. To become receptive to embryo implantation, uterine endometrial stromal cells (ESCs) must transdifferentiate into decidual cells that secrete factors necessary for embryo survival and trophoblast invasion. Autophagy is a key homeostatic process vital for cellular homeostasis. Although the uterus undergoes major cellular changes during early pregnancy, the precise role of autophagy in uterine function is unknown. Here, we report that conditional knockout of the autophagy protein FIP200 in the reproductive tract of female mice results in reduced fecundity due to an implantation defect. In the absence of FIP200, aberrant progesterone signaling results in sustained uterine epithelial proliferation and failure of stromal cells to decidualize. Additionally, loss of FIP200 impairs decidualization of human ESCs. We conclude that the autophagy protein FIP200 plays a crucial role in uterine receptivity, decidualization, and fertility. These data establish autophagy as a major cellular pathway required for uterine receptivity and decidualization in both mice and human ESCs., (© The Author(s) 2020. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Since 1992 ART clinics have been required to report outcome data. Our objective was to assess practitioners' opinions of the impact of public reporting of assisted reproductive technology (ART) outcomes on treatment strategies, medical decision-making, and fellow training., Methods: Survey study performed in an academic medical center. Members of the Society of Reproductive Endocrinology and Infertility and the Society of Reproductive Surgery were recruited to participate in an online survey in April 2012. : Categorical survey responses were expressed as percentages. Written responses were categorized according to common themes regarding effects of reporting on participants' medical management of patients. The study was primarily qualitative and was not powered to make statistical conclusions., Results: Of 1019 surveys sent, 323 participants (31.7%) responded from around the United States, and 275 provided complete data. Nearly all (273 of 282; 96.8%) participants responded that public reporting sometimes or always affected other providers' practices, and 264 of 281 (93.9%) responded that other practitioners were motivated to deny care to poor-prognosis patients to improve reported success rates. However, only 121 of 282 (42.9%) indicated that public reporting influenced their own medical management. The majority of respondents agreed that public reporting may hinder adoption of single embryo transfer practices (194 of 299; 64.9%) and contribute to the persistent rate of twinning in in vitro fertilization (187 of 279; 67%). A small majority (153 of 279; 54.8%) felt that public reporting did not benefit fellow training, and 58 (61.7%) of the 94 participants who trained fellows believed that having fellows perform embryo transfers reduced pregnancy rates. A small majority (163 of 277; 58.8%) of respondents reported their ART success rates on clinical websites. However, the majority (200 of 275; 72.7%) of respondents compared their success rates with those of other clinics. Finally, most respondents (211 of 277; 76%) believed that most centers that advertised their success rates did so in ways that were misleading to patients., Conclusions: Public reporting of ART clinical outcomes is intended to drive improvement, promote trust between patients and providers, and inform consumers and payers. However, providers reported that they modified their practices, felt others denied care to poor-prognosis patients, and limited participation of trainees in procedures in response to public reporting of ART outcomes., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Infertility affects 10 to 15% of couples worldwide, with a male factor contributing up to 50% of these cases. The primary tool for diagnosing male infertility is traditional semen analysis, which reveals sperm concentration, morphology, and motility. However, 25% of infertile men are diagnosed as normozoospermic, meaning that, in many cases, normal-appearing sperm fail to fertilize an egg. Thus, new information regarding the mechanisms by which sperm acquire fertilizing ability is needed to develop a clinically feasible test that can predict sperm function failure. An important feature of sperm fertilization capability in many species is plasma membrane hyperpolarization (membrane potential becoming more negative inside) in response to signals from the egg or female genital tract. In mice, this hyperpolarization is necessary for sperm to undergo the changes in motility (hyperactivation) and acrosomal exocytosis required to fertilize an egg. Human sperm also hyperpolarize during capacitation, but the physiological relevance of this event has not been determined. Here, we used flow cytometry combined with a voltage-sensitive fluorescent probe to measure absolute values of human sperm membrane potential. We found that hyperpolarization of human sperm plasma membrane correlated positively with fertilizing ability. Hyperpolarized human sperm had higher in vitro fertilization (IVF) ratios and higher percentages of acrosomal exocytosis and hyperactivated motility than depolarized sperm. We propose that measurements of human sperm membrane potential could be used to diagnose men with idiopathic infertility and predict IVF success in normozoospermic infertile patients. Patients with depolarized values could be guided toward intracytoplasmic sperm injection, preventing unnecessary cycles of intrauterine insemination or IVF. Conversely, patients with hyperpolarized values of sperm membrane potential could undergo only conventional IVF, avoiding the risks and costs associated with intracytoplasmic sperm injection., (Copyright © 2020 Puga Molina, Gunderson, Riley, Lybaert, Borrego-Alvarez, Jungheim and Santi.)

Uterine receptivity is critical for establishing and maintaining pregnancy. For the endometrium to become receptive, stromal cells must differentiate into decidual cells capable of secreting factors necessary for embryo survival and placental development. Although there are multiple reports of autophagy induction correlated with endometrial stromal cell (ESC) decidualization, the role of autophagy in decidualization has remained elusive. To determine the role of autophagy in decidualization, we utilized 2 genetic models carrying mutations to the autophagy gene Atg16L1. Although the hypomorphic Atg16L1 mouse was fertile and displayed proper decidualization, conditional knockout in the reproductive tract of female mice reduced fertility by decreasing the implantation rate. In the absence of Atg16L1, ESCs failed to properly decidualize and fewer blastocysts were able to implant. Additionally, small interfering RNA knock down of Atg16L1 was detrimental to the decidualization response of human ESCs. We conclude that Atg16L1 is necessary for decidualization, implantation, and overall fertility in mice. Furthermore, considering its requirement for human endometrial decidualization, these data suggest Atg16L1 may be a potential mediator of implantation success in women., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: The objective of this study was to use high-throughput sequencing to describe the vaginal eukaryotic DNA virome in patients undergoing in vitro fertilisation (IVF) to examine associations between the vaginal virome, antibiotic exposure and IVF outcomes., Design: Prospective exploratory study., Setting: Single academic fertility centre., Population: Subfertile women age 18-43 years undergoing their first IVF cycle with a fresh embryo transfer., Methods: The primary exposure was prophylactic azithromycin or no azithromycin before IVF. A mid-vaginal swab was obtained at the time of embryo transfer for virome analysis., Main Outcome Measures: The primary outcomes compared between exposure groups were characteristics of vaginal virome and clinical pregnancy rates. Secondary outcomes were virome associations with number of oocytes retrieved, number of blastocysts and implantation rate., Results: Twenty-six women contributed a vaginal swab before embryo transfer. There were no significant differences in IVF outcomes between azithromycin groups. There was no association between viral diversity and clinical pregnancy overall. A higher diversity of herpesviruses and α-papillomaviruses was observed in samples from the azithromycin-treated group compared with the no azithromycin group (P = 0.04). In women that received azithromycin, viral diversity was higher in the group that did not achieve clinical pregnancy compared with those who did (P = 0.06)., Conclusions: We demonstrate that the vaginal eukaryotic virome in women undergoing IVF is associated with antibiotic exposure. Additionally, we demonstrate an inverse trend between viral diversity and pregnancy, with a higher number of viruses detected associated with failure to achieve clinical pregnancy in the azithromycin group., Tweetable Abstract: Higher viral diversity is associated with prophylactic antibiotic exposure in subfertile women undergoing IVF., (© 2019 Royal College of Obstetricians and Gynaecologists.)

Pregnancy is influenced by the circadian ("circa" or approximately; diēm or day) system, which coordinates physiology and behavior with predictable daily changes in the environment such as light/dark cycles. For example, most species deliver around a particular time of day. In mammals, circadian rhythms are controlled by the master circadian pacemaker, the suprachiasmatic nucleus. One key way that the suprachiasmatic nucleus coordinates circadian rhythms throughout the body is by regulating production of the sleep-promoting hormone melatonin. Serum melatonin concentration, which peaks at night and is suppressed during the day, is one of the best biological indicators of circadian timing. Circadian misalignment causes maternal disturbances in the temporal organization of many physiological processes including melatonin synthesis, and these disturbances of the circadian system have been linked to an increased risk for pregnancy complications. Here, we review evidence that melatonin helps regulate the maternal and fetal circadian systems and the timing of birth. Finally, we discuss the potential for melatonin-based therapeutic strategies to alleviate poor pregnancy outcomes such as preeclampsia and preterm birth., (Copyright © 2019 McCarthy, Jungheim, Fay, Bates, Herzog and England.)

Objective: To investigate factors associated with early IVF treatment discontinuation., Design: Retrospective cohort study., Setting: Academic medical center., Patient(s): Six hundred sixty-nine first-attempt IVF patients who did not have a live birth., Intervention(s): None., Main Outcome Measure(s): Treatment discontinuation and time to return for a second IVF cycle., Result(s): Women without IVF insurance coverage were more likely to discontinue treatment than women with insurance coverage (adjusted odds ratio [aOR] = 3.12; 95% confidence interval [CI], 2.22-4.40). African-American women were more likely to discontinue treatment (aOR = 2.95; 95% CI, 1.54-5.66) and returned for treatment more slowly (adjusted hazard ratio [aHR] = 0.44; 95% CI, 0.28-0.71) than non-Hispanic white women, regardless of IVF insurance coverage or income. Women with a poor prognosis were more likely to discontinue treatment than women with a good prognosis. Older women with IVF insurance coverage or a good prognosis had a shorter time to return for a second IVF cycle than older women without IVF insurance coverage or with a poor prognosis. Estimated income, distance to clinic, fertility diagnosis, number of oocytes retrieved, and history of previous live birth were not associated with treatment discontinuation or time to return for a second IVF cycle after adjustment for covariates., Conclusion(s): IVF insurance coverage, race, age, and future treatment prognosis are associated with IVF treatment discontinuation and time to return., (Copyright © 2019 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Daily rhythms generated by endogenous circadian mechanisms and synchronized to the light-dark cycle have been implicated in the timing of birth in a wide variety of species. Although chronodisruption (e.g., shift work or clock gene mutations) is associated with poor reproductive outcomes, little is known about circadian timing during pregnancy. This study tested whether daily rhythms change during full-term pregnancies in mice and women. We compared running wheel activity continuously in both nonpregnant ( n = 14) and pregnant ( n = 13) 12- to 24-week-old C57BL/6NJ mice. We also monitored wrist actigraphy in women ( N = 39) for 2 weeks before conception and then throughout pregnancy and measured daily times of sleep onset. We found that on the third day of pregnancy, mice shift their activity to an earlier time compared with nonpregnant dams. Their time of daily activity onset was maximally advanced by almost 4 h around day 7 of pregnancy and then shifted back to the nonpregnant state approximately 1 week before delivery. Mice also showed reduced levels of locomotor activity during their last week of pregnancy. Similarly, in women, the timing of sleep onset was earlier during the first and second trimesters (gestational weeks 4-13 and 14-27) than before pregnancy and returned to the prepregnant state during the third trimester (weeks 28 until delivery). Women also showed reduced levels of locomotor activity throughout pregnancy. These results indicate that pregnancy induces changes in daily rhythms, altering both time of onset and amount of activity. These changes are conserved between mice and women.

Research Question: What concentration of anti-Müllerian hormone (AMH) corresponds to an antral follicle count (AFC) >15 for determination of ovarian reserve?, Design: A prospective study conducted at 13 US fertility clinics in women aged 21-44 years who presented for AFC evaluation by transvaginal ultrasound. Serum samples were collected at the time of AFC evaluation (menstrual cycle day 2-4). AMH concentrations were measured by the Elecsys ® AMH immunoassay; oestradiol and follicle-stimulating hormone (FSH) concentrations were also measured. The serum AMH cut-off able to detect AFC >15 with high sensitivity was determined (derivation cohort). Clinical performance of the AMH assay at the derived cut-off was evaluated (validation cohort). Receiver operating characteristic (ROC) analyses were also performed., Results: In the derivation cohort (n = 306), an optimal serum AMH cut-off value of 1.77 ng/ml was determined to correspond to AFC >15 with 89.63% sensitivity and 69.01% specificity, using the Elecsys AMH assay. In the validation cohort (n = 856), this 1.77 ng/ml cut-off could identify women with an AFC >15 with a sensitivity of 88.34% and a specificity of 68.29%; corresponding positive predictive and negative predictive values were 75.19% and 84.34%, respectively. ROC analyses demonstrated that AMH performed better than oestradiol or FSH in predicting AFC, with area under the curves of 85.7%, 57.1% and 69.7%, respectively, in the validation cohort., Conclusion: The Elecsys AMH immunoassay provides a robust and fully automated method to measure serum AMH levels. Women with AMH values below the cut-off of 1.77 ng/ml are unlikely to have AFC >15., (Copyright © 2019 Roche Diagnostics Ltd. Published by Elsevier Ltd.. All rights reserved.)

Objective: To estimate the clinical effectiveness, as determined by positive pregnancy test, of letrozole compared with clomiphene citrate for ovarian stimulation in patients with unexplained infertility., Data Sources: We conducted a systematic review and meta-analysis of data from electronic databases including Ovid-MEDLINE, EMBASE, Scopus, Cochrane Database of Systematic Reviews, Cochrane Register of Controlled Trials, Database of Abstracts of Reviews of Effects, and ClinicalTrials.gov., Methods: We searched for concepts of unexplained infertility, letrozole, clomiphene citrate, and clinical outcomes including pregnancy and live birth. Studies were included if they were randomized controlled trials (RCTs) comparing clomiphene citrate with letrozole in patients with unexplained infertility. Eight RCTs including 2,647 patients with unexplained infertility were included. Primary outcome was positive pregnancy test per patient. Secondary outcomes included positive pregnancy test per cycle, clinical pregnancy, live birth, spontaneous miscarriage, twin gestation, mean serum estradiol (E2), endometrial thickness, and number of dominant follicles. The Cochrane Q test and Higgin's I were used to assess heterogeneity. Random effects models were used to obtain pooled relative risks (RR) and 95% CIs., Tabulation, Integration, and Results: In analysis per patient, there was no significant difference in positive pregnancy test between patients treated with letrozole compared with clomiphene citrate (24% vs 23%, pooled RR 1.08, 95% CI 0.85-1.36). Significant heterogeneity was noted between studies (I=60.8%). There were no significant differences in clinical pregnancy (pooled RR 1.15, 95% CI 0.71-1.85), live birth (pooled RR 0.94, 95% CI 0.83-1.08), spontaneous miscarriage (pooled RR 0.92, 95% CI 0.61-1.38), or twin gestation (pooled RR 0.81, 95% CI 0.39-1.68). Mean serum E2 was significantly lower in the letrozole group than in the clomiphene citrate group., Conclusion: Although limited by heterogeneity, studies of ovarian stimulation in women with unexplained infertility show no difference in clinical outcomes between letrozole and clomiphene citrate.

Purpose: Implantation failure is a major limiting factor of successful in vitro fertilization (IVF). The objective of this study was to determine if endometrial mechanical stimulation (EMS) by endometrial biopsy in the luteal phase of the cycle prior to embryo transfer (ET) improves clinical outcomes in an unselected subfertile population., Methods: Double-blind, randomized controlled trial of EMS versus sham biopsy and odds of clinical pregnancy after IVF and embryo transfer. Secondary outcomes included spontaneous miscarriage and live birth., Results: One hundred women enrolled and were randomized from 2013 to 2017. Enrollment was terminated after futility analysis showed no difference in clinical pregnancy between EMS versus control, 47.2% vs 61.7% (OR 0.55, 95% CI 0.25-1.23, p = 0.15). There were no significant differences between women who underwent EMS and those who did not in terms of positive pregnancy test 54.7% vs 63.8% (OR 0.69, 95% CI 0.31-1.53, p = 0.36), miscarriage 7.5% vs 2.1% (OR 3.76 95% CI 0.41-34.85, p = 0.22), or live birth 43.4% vs 61.7% (OR 0.48 95% CI 0.21-1.06, p = 0.07)., Conclusions: EMS in the luteal phase of the cycle preceding embryo transfer does not improve clinical outcomes in an unselected subfertile population and may result in a lower live birth rate. We caution the routine use of EMS in an unselected population.

Preterm birth affects approximately 1 out of every 10 births in the United States, leading to high rates of mortality and long-term negative health consequences. To investigate the mechanisms leading to preterm birth so as to develop prevention strategies, researchers have developed numerous mouse models of preterm birth. However, the lack of standard definitions for preterm birth in mice limits our field's ability to compare models and make inferences about preterm birth in humans. In this review, we discuss numerous mouse preterm birth models, propose guidelines for experiments and reporting, and suggest markers that can be used to assess whether pups are premature or mature. We argue that adoption of these recommendations will enhance the utility of mice as models for preterm birth.

Circadian rhythms, endogenous and entrainable adaptations to 24-hour cycles of light and dark, influence almost all physiologic functions. Emerging evidence suggests that the disruption of normal circadian rhythms, termed chronodisruption, could affect a wide range of disease-related processes. In this review, we describe the molecular generation of circadian rhythms, the effects of chronodisruption on human health, the circadian timing of birth in multiple species, the possible effects of chronodisruption on preterm birth, and some of the open questions in this field., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The differentiation of human endometrial stromal cells (HESC) from fibroblast-like appearance into secretory decidua is a transformation required for embryo implantation into the uterine lining of the maternal womb. Improper decidualization has been established as a root cause for implantation failure and subsequent early embryo miscarriage. Therefore, understanding the molecular mechanisms underlying decidualization is advantageous to improving the rate of successful births. In vivo based studies of artificial decidualization are often limiting due to ethical dilemmas associated with human research, as well as translational complications within animal models. As a result, in vitro assays through primary cell culture are often utilized to explore the modulation of decidualization via hormones. This study provides a detailed protocol for the isolation of HESC and subsequent artificial decidualization via the supplementation of hormones to the culturing medium. Further, this study provides a well-designed method to knockdown any gene of interest by utilizing lipid-based siRNA transfections. This protocol permits the optimization of culture purity as well as product yield, thereby maximizing the ability to utilize this model as a reliable method to understand the molecular mechanisms underlying decidualization, and the subsequent quantification of secreted agents by decidualized endometrial stromal cells.

Methods of in vitro fertilization (IVF) have advanced dramatically since the first IVF baby was born in 1978. Originally yielding single-digit success rates, IVF is now successful in nearly 50% of cases in which the woman is younger than 35 years. Here, we describe the improvements in laboratory techniques and advances in our abilities to manipulate reproductive physiology that have facilitated this improvement. Additionally, we describe efforts to ensure safety standards in this competitive field.

This symposium includes twelve personal, heartfelt narratives about joys, challenges, and, in some cases, trauma associated with labor and delivery experiences. This issue also includes three commentaries on these narratives by 1.) Raymond De Vries, PhD, 2.) Anne Lyerly, MD, MA, 3.) Jason Wasserman, PhD and Nicole Wasserman, MPH. This issue can provide information for clinicians and support staff on ways to facilitate patient and family engagement during this emotionally-laden time for parents. Supporting birth experiences, connecting with patients, involving them in decisions, and recognizing the disappointment and distress that can arise when complications abound may play a part in reducing postpartum mood disorders and improving maternal and infant health outcomes.

A 2013 ASRM committee opinion titled "Optimizing natural fertility" stated that "there is little evidence that dietary variations such as vegetarian diets, low-fat diets, vitamin-enriched diets, antioxidants, or herbal remedies improve fertility …." However, there are emerging epidemiologic data demonstrating that certain components of the diet may influence reproductive health outcomes. Furthermore, translational work with human specimens and animal models lends biologic plausibility to the epidemiologic data, particularly in the context of female reproductive diseases associated with inflammation, including polycystic ovary syndrome (PCOS) and obesity. How to best apply these data clinically for improved reproductive outcomes remains to be determined. In this review, we outline a role for chronic inflammation in the reproductive sequelae of PCOS and obesity and we summarize epidemiologic and translational work demonstrating a potential role for diet in the regulation of inflammatory processes associated with these disorders. These studies identify areas for future research and potential clinical intervention in women affected by the reproductive sequelae of PCOS and obesity., (Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)