A GREB1-steroid receptor feedforward mechanism governs differential GREB1 action in endometrial function and endometriosis.

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.

Intrauterine Insemination After Human Chorionic Gonadotropin Trigger or Luteinizing Hormone Surge: A Meta-analysis.

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.

Inflammatory Activity After Diverse Fertility Treatments: A Multicenter Analysis in the Modern Multiple Sclerosis Treatment Era.

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.

Association of State Insurance Mandates for Fertility Treatment With Multiple Embryo Transfer After Preimplantation Genetic Testing for Aneuploidy.

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.

Neighborhood disadvantage is associated with decreased ovarian reserve in women with overweight and obesity.

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/m2. 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.

Diverse monogenic subforms of human spermatogenic failure.

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.

A multidisciplinary Prematurity Research Cohort Study.

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.

Association of the human semen DNA virome with successful in vitro fertilization.

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.

Sleep behavior and chronotype before and throughout pregnancy.

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.

State-Mandated Insurance Coverage and Preimplantation Genetic Testing in the United States.

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.

Maternal body mass index is not associated with increased rates of maternal embryonic aneuploidy.

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/m2), normal weight (BMI, 18.5-24.9 kg/m2), overweight (BMI, 25-29.9 kg/m2), and obese (BMI, ≥30 kg/m2). 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/m2 and 39.3% for BMI of <30 kg/m2. 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.

Dietary patterns are associated with improved ovarian reserve in overweight and obese women: a cross-sectional study of the Lifestyle and Ovarian Reserve (LORe) cohort.

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/m2) 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/m2 (ß = 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.

Reproductive urologic consultation in subfertile men: predictors of establishing care and patient perceptions after abnormal semen testing.

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.

Fertility preservation discussions, referral and follow-up in male-to-female and female-to-male adolescent transgender patients.

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.

Association of vaginal bacterial communities and reproductive outcomes with prophylactic antibiotic exposure in a subfertile population undergoing in vitro fertilization: a prospective exploratory study.

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.

Effect of an Active vs Expectant Management Strategy on Successful Resolution of Pregnancy Among Patients With a Persisting Pregnancy of Unknown Location: The ACT or NOT Randomized Clinical Trial.

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.

Association between arthritis treatments and ovarian reserve: a prospective study.

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 (T0 and T1) in 129 premenopausal women with arthritis. AMH at T0 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 T0 and T1 was 1.72 years. At time T0, 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.

Ovarian stimulation for fertility preservation in women with cancer: A systematic review and meta-analysis comparing random and conventional starts.

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 I2 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.