Depression, Anxiety, and Risk of Metabolic Syndrome in Women With Polycystic Ovary Syndrome: A Longitudinal Study.

CONTEXT: Patients with PCOS are at high risk of depression, anxiety, and metabolic syndrome (MetSyn), a key predictor of cardiovascular disease. The impact of depression and/or anxiety on MetSyn is unknown in this population. OBJECTIVE: To compare the risk of developing MetSyn in patients with PCOS with and without a history of depression and/or anxiety. DESIGN: Retrospective longitudinal cohort study (2008-2022) with median follow-up of 7 years. SETTING: Tertiary care ambulatory practice. PATIENTS OR OTHER PARTICIPANTS: Patients with hyperandrogenic PCOS and at least 2 evaluations for MetSyn ≥3 years apart (n=321). INTERVENTION(S): N/A. MAIN OUTCOME MEASURE(S): The primary outcome was risk of developing MetSyn. We hypothesized that this risk would be higher with a history of depression and/or anxiety. RESULTS: At the first visit, 33.0% had a history of depression and/or anxiety, with a third prescribed antidepressants or anxiolytics. Depression and/or anxiety increased risk of developing MetSyn during the study period (adjusted hazard ratio [aHR] 1.45, 95% CI 1.02-2.06, p=0.04) with an incidence of MetSyn of 75.3 compared to 47.6 cases per 100 person-years among those without (p=0.002). This was primarily driven by depression (aHR 1.56, 95% CI 1.10-2.20, p=0.01). CONCLUSIONS: Patients with PCOS and depression and/or anxiety have a high risk of developing MetSyn, with a stronger association between depression and MetSyn. Our findings highlight the urgent need for guideline-directed screening for depression and anxiety at time of diagnosis of PCOS as well as screening at subsequent visits to facilitate risk stratification for metabolic monitoring and early intervention in this high-risk group.

Neuroactive steroid hormone trajectories across the menstrual cycle in premenstrual dysphoric disorder (PMDD): the PHASE study.

It is presently not known whether endogenous neuroactive steroid hormone trajectories across the menstrual cycle are distinguishable in women with premenstrual dysphoric disorder (PMDD). To improve the rigor in this area of research, we implemented a validated study methodology, involving blood sample collection at 8 key menstrual cycle timepoints, following which the study data is realigned so that all women are compared at the same biological window (i.e., menstrual cycle subphase). Using liquid chromatography-mass spectrometry (LC-MS), we analyzed serum levels of nine steroid hormones previously implicated in the etiology of PMDD, including allopregnanolone. Other than progesterone (p ≤ 0.001), none of the steroid hormones displayed significant changes across menstrual cycle subphases when comparing participants with PMDD to the healthy controls. A thorough investigation of the progesterone trajectory showed that its left shift in the luteal phase (e.g., earlier rise in progesterone) exposes women with PMDD to a higher periovulatory progesterone and a more acute withdrawal in the late luteal subphase. Results of the present study indicate that the largely overlooked brief periovulatory subphase should be thoroughly examined in PMDD and agree with prior conclusions that rapid progesterone withdrawal associates with the development of negative affect.

Oxytocin and women's health in midlife.

Menopause marks the cessation of fertility and the transition to post-reproductive years. Nearly 1M US women experience menopause annually, but despite the significant impact it has on their physical and mental health, menopause has been insufficiently studied. Oxytocin is a neurohormone that regulates emotionality, social behaviors, and fundamental physiological systems. Localization of oxytocin receptors in the brain, reproductive tissues, bone, and heart support their role in mental health and potentially sleep, along with reproductive and cardiovascular functions. While experimental data linking oxytocin to behavior and physiology in animals are largely consistent, human data are correlative and inconclusive. As women transition into menopause, oxytocin levels decrease while their susceptibility to mood disorders, poor sleep, osteoporosis, and cardiovascular diseases increases. These concurrent changes highlight oxytocin as a potential influence on the health and mood of women along their reproductive lifespan. Here we summarize experimental rodent studies that link oxytocin to reproductive aging and metabolic health and highlight the inconclusive findings in studies of women. Most human studies relied on a single oxytocin assessment in plasma or on intranasal oxytocin administration. The pulsatile release and short half-life of plasma oxytocin limits the validity of these methods. We discuss the need for oxytocin assessments in stable bio-samples, such as urine, and to use valid assays for assessment of associations between changing oxytocin levels and well-being across the reproductive lifespan. This work has the potential to guide therapeutic strategies that will one day alleviate adverse health outcomes for many women.

Multiplexed Serum Biomarkers to Discriminate Nonviable and Ectopic Pregnancy.

OBJECTIVE: The use of multiplexed biomarkers may improve the diagnosis of normal and abnormal early pregnancies. In this study we assessed 24 markers with multiple machine learning-based methodologies to evaluate combinations of top candidates to develop a multiplexed prediction model for identification of 1) viability and 2) location of an early pregnancy. DESIGN: A nested case-control design evaluating the predictive ability and discrimination of biomarkers in patients at risk of early pregnancy failure in the first trimester to classify viability and location SUBJECTS: 218 individuals with a symptomatic (pain and/or bleeding) early pregnancy: 75 with an ongoing intrauterine gestation, 68 ectopic pregnancies, and 75 miscarriages. INTERVENTIONS: Serum values of 24 biomarkers were assessed in the same patients. Multiple machine learning-based methodologies to evaluate combinations of these top candidates to develop a multiplexed prediction model for identification of 1) a nonviable pregnancy (ongoing intrauterine pregnancy vs miscarriage or ectopic pregnancy) and 2) an ectopic pregnancy (ectopic pregnancy vs ongoing intrauterine pregnancy or miscarriage). MAIN OUTCOME MEASURES: The predicted classification by each model was compared to actual diagnosis and sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), conclusive classification, and accuracy were calculated. RESULTS: Models using classification regression tree analysis using three markers (PSG3, CG-Alpha and PAPPA) were able to predict a maximum sensitivity 93.3%, a maximum specificity 98.6%. The model with the highest accuracy was 97.4% (with 70.2% receiving classification). Models using an overlapping group of three markers (sFLT, PSG3 and TFP12) achieved a maximum sensitivity of 98.5%. and a maximum specificity of 95.3%. The model with the highest accuracy was 94.4% (with 65.6% receiving classification). When the models were used simultaneously the conclusive classification increased to 72.7% with an accuracy 95.9%. The predictive ability of the biomarkers random forest produced similar test characteristics when using 11 predictive markers. CONCLUSION: We have demonstrated a pool of biomarkers from divergent biological pathways that can be used to classify individuals with potential early pregnancy loss. The biomarkers CG-Alpha, PAPPA and PSG3 can be used to predict viability and sFLT, TPFI2 and PSG3 can be used to predict pregnancy location.

Does embryo biopsy, independent of vitrification, impact perinatal outcomes? An analysis of perinatal outcomes following preimplantation genetic testing biopsy in fresh and frozen embryo transfer cycles.

Objective: To compare neonatal outcomes in pregnancies resulting from embryos that have undergone preimplantation genetic testing (PGT) biopsy compared with no biopsy in both fresh and frozen embryo transfers (ETs) and determine whether findings are mediated by multiple births. Design: Retrospective cohort study. Setting: Society of Assisted Reproductive Technologies-Clinical Outcomes Reporting System data, 2014-2015. Patients: Autologous in vitro fertilization treatment cycles using fresh or frozen blastocyst ET, with or without PGT biopsy. Interventions: Not applicable. Main Outcome Measures: Large for gestational age (LGA), small for gestational age, and preterm delivery. Secondary outcomes included high birthweight, low birthweight, and clinical pregnancy measures. Outcomes were evaluated using log-binomial regression models with repeated measures. Models were used to estimate the controlled direct effects of biopsy on birth outcomes that were not mediated by multiple gestations. Results: In fresh ET, biopsy was associated with an increase in LGA (relative risk [RR] 1.45, confidence interval [CI] 1.04-2.02) that persisted in the model mediated for multiple gestation (RR 1.36, 95% CI 1.01-1.83) but was not present in an analysis restricted to elective single ET (RR 0.99, 95% CI 0.91-1.09). In frozen ET, there were no differences in any of the primary outcomes after accounting for multiple gestations. Conclusions: In a large multicenter database, there were no differences in neonatal outcomes after PGT biopsy in frozen ET cycles, and an increase in LGA was noted in fresh transfers that persisted even after accounting for multiple gestations but was not present in analysis restricted to elective single ET.

Frozen autologous and donor oocytes are associated with differences in clinical and neonatal outcomes compared with fresh oocytes: a Society for Assisted Reproductive Technology Clinic Outcome Reporting System Analysis.

Objective: To study the clinical and neonatal outcomes of embryos derived from frozen oocytes relative to fresh oocytes in both autologous and donor oocyte cycles after fresh embryo transfer (ET). Design: This is a retrospective cohort study using the Society for Assisted Reproductive Technology Clinic Outcome Reporting System database between 2014 and 2015. Setting: The Society for Assisted Reproductive Technology Clinic Outcome Reporting System database was used to identify autologous and donor oocyte cycles that resulted in a fresh ET during 2014 and 2015. Patients: There were 154,706 total cycles identified that used embryos derived from fresh or frozen oocytes and resulted in a fresh ET, including 139,734 autologous oocyte cycles and 14,972 donor oocyte cycles. Interventions: Generalized linear regression models were used to compare the clinical and neonatal outcomes of frozen oocytes relative to fresh oocytes. Models were adjusted for maternal age, body mass index, smoking status, parity, infertility diagnosis, number of embryos transferred, and preimplantation genetic testing. An additional sensitivity analysis was performed to examine singleton pregnancies separately. Main Outcome Measures: The live birth (LB) rate was the primary outcome. Secondary outcomes include pregnancy and birthweight outcomes. Results: Differences in clinical and neonatal outcomes between fresh and frozen-thawed oocytes after fresh ET were observed. Specifically, our study found a higher incidence of high-birthweight infants after the use of frozen oocytes relative to fresh oocytes in both autologous oocytes (12.5% [frozen] vs. 4.5% [fresh], adjusted risk ratio [aRR] 2.67, 95% confidence interval [CI] 1.65-4.3) and donor oocyte cycles (6.2% [frozen] vs. 4.6% [fresh], aRR 1.42, 95% CI 1.1-1.83). This finding remained true when the analysis was restricted to singleton gestations only for both groups: autologous (17.3% [frozen] vs. 7.1% [fresh], aRR 2.77, 95% CI 1.74-4.42) and donor oocytes (9.4% [frozen] vs. 7.8% [fresh], aRR 1.38, 95% CI 1.07-1.77). Additionally, we observed a decrease in LB (aRR 0.81, 95% CI 0.77-0.85); clinical pregnancy (aRR 0.83, 95% CI 0.8-0.87); and an increase in biochemical pregnancy loss (aRR 1.22, 95% CI 1.05-1.43) after the use of frozen oocytes in donors, but not autologous cycles. Conclusions: Our findings of an increased incidence of high-birthweight infants after the transfer of embryos derived from frozen oocytes in both autologous and donor oocyte cycles raise questions about oocyte vitrification and deserve further study. Additionally, the finding of a decreased likelihood of LB with frozen-donor oocytes compared with fresh donor oocytes is an important finding, especially because more patients are seeking to use frozen oocytes in their donor egg cycles. Future research should be directed toward these findings to optimize the use of frozen oocytes in clinical practice.

Patterns of Sleep Duration and Metabolic Biomarkers Across the Menstrual Cycle.

CONTEXT: Along the menstrual cycle, associations between inconsistent sleep duration and levels of metabolic biomarkers are uncertain and could involve fluctuations in estrogen concentrations. OBJECTIVE: To examine associations between patterns of sleep duration and metabolic biomarkers across two menstrual cycles within a cohort of premenopausal women. METHODS: The BioCycle Study was conducted in New York between 2005-2007, enrolling 259 premenopausal women over two menstrual cycles. This micro-longitudinal cohort study involved intensive data collection including daily sleep diaries and biomarker assessments of leptin, insulin, and glucose at 16 key points timed to menstrual cycle phases. We considered dynamic sleep duration, as hours slept one night or as mean hours slept during the two nights prior to each biomarker assessment. Variability in habitual sleep duration, i.e., reported daily sleep duration, summarized across both menstrual cycles. Variation in habitual sleep duration was computed using L-moments, a robust version of dispersion, skewness, and kurtosis. To examine associations between patterns of sleep duration and metabolic biomarkers, we fitted a series of linear mixed models with random intercepts and inverse probability weighting. These models were adjusted for potential demographic, lifestyle, health confounders, and menstrual cycle phase. RESULTS: Sleep duration one night or two nights prior to clinic visits were not associated with metabolic biomarker measures we assessed. However, overall variability (dispersion) in habitual sleep duration was associated with lower mean insulin HOMA-IR levels, but not glucose. Moreover, extreme short or long bouts of sleep duration was associated with higher mean levels of leptin, insulin, and HOMA-IR. CONCLUSIONS: These data suggest that variation in habitual sleep duration along the menstrual cycle may be associated with metabolic function.

Similar pregnancy outcomes from fresh and frozen donor oocytes transferred to gestational carriers: a SART database analysis isolating the effects of oocyte vitrification.

PURPOSE: This work aimed to study clinical and neonatal outcomes of embryos derived from frozen compared to fresh donor oocytes in gestational carrier cycles. METHODS: This is a retrospective cohort study using the Society for Assisted Reproductive Technology Clinic Outcome Reporting System database between 2014 and 2015, comprising of 1284 fresh transfer cycles to gestational carrier recipients of embryos resulting from fresh (n = 1119) and vitrified/thawed (n = 165) donor oocytes. Models were adjusted for gestational carrier age, preimplantation genetic testing (PGT-A), number of embryos transferred, multiple gestation, and fetal heart reduction. As our models were part of a larger analysis, intended parent BMI, smoking status, and parity were also adjusted for, but did not influence outcomes in this analysis. RESULTS: There was no significant difference in probability of live birth rates when comparing embryos derived from fresh and frozen donor oocytes in gestational carrier cycles. There were also no significant differences in biochemical pregnancy losses or clinical miscarriage. There were no significant differences noted in low birthweight or high birthweight infants derived from fresh versus frozen donor oocyte after transfer into a gestational carrier. CONCLUSIONS: The analysis of fresh and frozen donor oocytes in gestational carrier cycles provides the opportunity to assess for a possible effect of vitrification on the oocyte by controlling for differences in the uterine environment. We observed no significant differences in live birth, pregnancy loss, low birthweight or high birthweight infants when comparing fresh and frozen donor oocytes in gestational carrier cycles.

Nutritional Intake in Dichorionic Twin Pregnancies: A Descriptive Analysis of a Multisite United States Cohort.

INTRODUCTION: Twin gestations have greater nutritional demands than singleton gestations, yet dietary intakes of women with twin gestations have not been well described. METHODS: In a prospective, multi-site US study of 148 women with dichorionic twin gestations (2012-2013), we examined longitudinal changes in diet across pregnancy. Women completed a food frequency questionnaire during each trimester of pregnancy. We examined changes in means of total energy and energy-adjusted dietary components using linear mixed effects models. RESULTS: Mean energy intake (95% CI) across the three trimesters was 2010 kcal/day (1846, 2175), 2177 kcal/day (2005, 2349), 2253 kcal/day (2056, 2450), respectively (P = 0.01), whereas the Healthy Eating Index-2010 was 63.9 (62.1, 65.6), 64.5 (62.6, 66.3), 63.2 (61.1, 65.3), respectively (P = 0.53). DISCUSSION: Women with twin gestations moderately increased total energy as pregnancy progressed, though dietary composition and quality remained unchanged. These findings highlight aspects of nutritional intake that may need to be improved among women carrying twins.

The association between preconception cannabis use and gestational diabetes mellitus: The Preconception Period Analysis of Risks and Exposures Influencing health and Development (PrePARED) consortium.

BACKGROUND: The metabolic changes that ultimately lead to gestational diabetes mellitus (GDM) likely begin before pregnancy. Cannabis use might increase the risk of GDM by increasing appetite or promoting fat deposition and adipogenesis. OBJECTIVES: We aimed to assess the association between preconception cannabis use and GDM incidence. METHODS: We analysed individual-level data from eight prospective cohort studies. We identified the first, or index, pregnancy (lasting ≥20 weeks of gestation with GDM status) after cannabis use. In analyses of pooled individual-level data, we used logistic regression to estimate study-type-specific odds ratios (OR) and 95% confidence intervals (CI), adjusting for potential confounders using random effect meta-analysis to combine study-type-specific ORs and 95% CIs. Stratified analyses assessed potential effect modification by preconception tobacco use and pre-pregnancy body mass index (BMI). RESULTS: Of 17,880 participants with an index pregnancy, 1198 (6.7%) were diagnosed with GDM. Before the index pregnancy, 12.5% of participants used cannabis in the past year. Overall, there was no association between preconception cannabis use in the past year and GDM (OR 0.97, 95% CI 0.79, 1.18). Among participants who never used tobacco, however, those who used cannabis more than weekly had a higher risk of developing GDM than those who did not use cannabis in the past year (OR 2.65, 95% CI 1.15, 6.09). This association was not present among former or current tobacco users. Results were similar across all preconception BMI groups. CONCLUSIONS: In this pooled analysis of preconception cohort studies, preconception cannabis use was associated with a higher risk of developing GDM among individuals who never used tobacco but not among individuals who formerly or currently used tobacco. Future studies with more detailed measurements are needed to investigate the influence of preconception cannabis use on pregnancy complications.

History of multifetal gestation and long-term maternal mortality.

BACKGROUND: Multifetal gestation could be associated with higher long-term maternal mortality because it increases the risk of pregnancy complications such as preeclampsia and preterm birth, which are in turn linked to postpartum cardiovascular risk. OBJECTIVES: We examined whether spontaneously conceived multifetal versus singleton gestation was associated with long-term maternal mortality in a racially diverse U.S. METHODS: We ascertained vital status as of 2016 via linkage to the National Death Index and Social Security Death Master File of 44,174 mothers from the Collaborative Perinatal Project (CPP; 1959-1966). Cox proportional hazards models with maternal age as the time scale assessed associations between history of spontaneous multifetal gestation (in the last CPP observed pregnancy or prior pregnancy) and all-cause and cardiovascular mortality, adjusted for demographics, smoking status, and preexisting medical conditions. We calculated hazard ratios (HR) for all-cause and cause-specific mortality over the study period and until age 50, 60, and 70 years (premature mortality). RESULTS: Of eligible participants, 1672 (3.8%) had a history of multifetal gestation. Participants with versus without a history of multifetal gestation were older, more likely to have a preexisting condition, and more likely to smoke. By 2016, 51% of participants with and 38% of participants without a history of multifetal gestation had died (unadjusted all-cause HR 1.14, 95% confidence interval [CI] 1.07, 1.23). After adjustment for smoking and preexisting conditions, a history of multifetal gestation was not associated with all-cause (adjusted HR 1.00, 95% CI 0.93, 1.08) or cardiovascular mortality (adjusted HR 0.99, 95% CI 0.87, 1.11) over the study period. However, history of multifetal gestation was associated with an 11% lower risk of premature all-cause mortality (adjusted HR 0.89, 95% CI 0.82, 0.96). CONCLUSIONS: In a cohort with over 50 years of follow-up, history of multifetal gestation was not associated with all-cause mortality, but may be associated with a lower risk of premature mortality.

The association between parental age differences and perinatal outcomes.

STUDY QUESTION: Are there significant associations existing between parental age differences and adverse perinatal outcomes? SUMMARY ANSWER: Large differences in parental age are associated with adverse perinatal outcomes, particularly with older mothers paired with younger fathers. WHAT IS KNOWN ALREADY: The association between advanced maternal age and perinatal outcomes is well-documented with women over 35 years showing an increased risk of several adverse outcomes. Other studies have identified potential associations between advanced paternal age and adverse perinatal outcomes. STUDY DESIGN, SIZE, DURATION: A historical (retrospective) cohort analysis was performed utilizing a multivariable logistic regression model to evaluate the association between varying differences in parental age and adverse perinatal outcomes while controlling for demographic and health-related covariates. Data were compiled from the National Vital Statistics System for 20 613 704 births between 2012 and 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Parental age differences, categorized into eleven 4-year intervals, were stratified by seven maternal age categories and evaluated for their associations with adverse perinatal outcomes. Main outcome measures included low birth weight, very low birth weight, preterm birth, very preterm birth, small size for gestational age, low 5-min appearance, pulse, grimace, activity, and respiration score, congenital defects, and chromosomal anomalies. MAIN RESULTS AND THE ROLE OF CHANCE: Increased parental age differences, in either direction, were associated with significant risks for all adverse outcomes, aside from congenital defects, even when controlling for maternal age. Restricting maternal age to the reference range of 25-29 years, infants born to fathers aged 9-12 years younger (n = 3773) had 27% (odds ratio (OR) 1.27, 95% CI, 1.17-1.37) higher odds of having any adverse perinatal outcome. Infants born to fathers aged >16 years older (n = 98 555) had 14% (OR 1.14, 95% CI, 1.12-1.16) higher odds of having any adverse perinatal outcome. LIMITATIONS, REASONS FOR CAUTION: Data extracted from US birth certificates may be compromised by errors in reporting or documentation. Information regarding the mother's socioeconomic status was estimated using proxy variables and may be susceptible to uncontrolled factors. Use of a pre-compiled dataset may potentially exclude additional maternal comorbidities that could impact perinatal outcomes. WIDER IMPLICATIONS OF FINDINGS: Older mothers paired with younger fathers demonstrated the highest risk, even when maternal age was below the threshold of 35 years. For the clinical setting, parental age differences should be considered alongside maternal and paternal age when assessing risks of adverse perinatal outcomes for potential parents. This is particularly relevant for older women with younger male partners as this may exacerbate the impact of advanced maternal age. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the NIH Research Fellowship T35 Training Grant. There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Food, nutrition, and fertility: from soil to fork.

Food and nutrition-related factors, including foods and nutrients consumed, dietary patterns, use of dietary supplements, adiposity, and exposure to food-related environmental contaminants, have the potential to impact semen quality and male and female fertility; obstetric, fetal, and birth outcomes; and the health of future generations, but gaps in evidence remain. On 9 November 2022, Tufts University's Friedman School of Nutrition Science and Policy and the school's Food and Nutrition Innovation Institute hosted a 1-d meeting to explore the evidence and evidence gaps regarding the relationships between food, nutrition, and fertility. Topics addressed included male fertility, female fertility and gestation, and intergenerational effects. This meeting report summarizes the presentations and deliberations from the meeting. Regarding male fertility, a positive association exists with a healthy dietary pattern, with high-quality evidence for semen quality and lower quality evidence for clinical outcomes. Folic acid and zinc supplementation have been found to not impact male fertility. In females, body weight status and other nutrition-related factors are linked to nearly half of all ovulation disorders, a leading cause of female infertility. Females with obesity have worse fertility treatment, pregnancy-related, and birth outcomes. Environmental contaminants found in food, water, or its packaging, including lead, perfluorinated alkyl substances, phthalates, and phenols, adversely impact female reproductive outcomes. Epigenetic research has found that maternal and paternal dietary-related factors can impact outcomes for future generations. Priority evidence gaps identified by meeting participants relate to the effects of nutrition and dietary patterns on fertility, gaps in communication regarding fertility optimization through changes in nutritional and environmental exposures, and interventions impacting germ cell mechanisms through dietary effects. Participants developed research proposals to address the priority evidence gaps. The workshop findings serve as a foundation for future prioritization of scientific research to address evidence gaps related to food, nutrition, and fertility.

Preconception Phthalate Exposure and Women's Reproductive Health: Pregnancy, Pregnancy Loss, and Underlying Mechanisms.

BACKGROUND: Phthalates are endocrine-disrupting chemicals linked to adverse pregnancy outcomes. Despite the sensitivity of female reproductive processes to oxidation-reduction reaction stress and endocrine disruption, evidence for the impact of women's phthalate exposure on the ability to establish and maintain pregnancy has been inconclusive. OBJECTIVES: We aimed to determine the relationship of preconception phthalate metabolite exposure with a) fecundability and pregnancy loss and b) markers of potential biological mechanisms, including reproductive hormones, inflammation, and oxidative stress. METHODS: Data were collected from the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial, a preconception study following 1,228 women who were attempting pregnancy, for up to six menstrual cycles and throughout pregnancy if they became pregnant. Twenty phthalate metabolites were measured in a consecutive 3-d pooled urine sample at enrollment. Pregnancy was determined through urinary human chorionic gonadotropin (hCG) at the expected date of menses during each cycle and pregnancy loss as an observed loss following positive hCG. Highly sensitive C-reactive protein (hsCRP) and isoprostanes were measured at enrollment, and reproductive hormones were measured during the follicular phase, ovulation, and luteal phase. Discrete-time Cox proportional hazards models evaluated the relationship of phthalate metabolites with fecundability and weighted Poisson models with robust variance evaluated the risk of pregnancy loss. RESULTS: An interquartile range (IQR) higher mono-(2-ethylhexyl) phthalate [fecundability odds ratio (FOR)=0.88; 95% confidence interval (CI): 0.78, 1.00], mono-butyl phthalate (FOR=0.82; 95% CI: 0.70, 0.96), and mono-benzyl phthalate (FOR=0.85; 95% CI: 0.74, 0.98) was associated with lower fecundability. No consistent associations were observed with pregnancy loss. Preconception phthalates were consistently associated with higher hsCRP and isoprostanes, as well as lower estradiol and higher follicle-stimulating hormone across the menstrual cycle. DISCUSSION: Women's preconception exposure to phthalates was associated with lower fecundability, changes in reproductive hormones, and increased inflammation and oxidative stress. The pre- and periconception periods may represent sensitive windows for intervening to limit the reproductive toxicity of phthalate exposure. https://doi.org/10.1289/EHP12287.

Maternal educational attainment in pregnancy and epigenome-wide DNA methylation changes in the offspring from birth until adolescence.

Maternal educational attainment (MEA) shapes offspring health through multiple potential pathways. Differential DNA methylation may provide a mechanistic understanding of these long-term associations. We aimed to quantify the associations of MEA with offspring DNA methylation levels at birth, in childhood and in adolescence. Using 37 studies from high-income countries, we performed meta-analysis of epigenome-wide association studies (EWAS) to quantify the associations of completed years of MEA at the time of pregnancy with offspring DNA methylation levels at birth (n = 9 881), in childhood (n = 2 017), and adolescence (n = 2 740), adjusting for relevant covariates. MEA was found to be associated with DNA methylation at 473 cytosine-phosphate-guanine sites at birth, one in childhood, and four in adolescence. We observed enrichment for findings from previous EWAS on maternal folate, vitamin-B12 concentrations, maternal smoking, and pre-pregnancy BMI. The associations were directionally consistent with MEA being inversely associated with behaviours including smoking and BMI. Our findings form a bridge between socio-economic factors and biology and highlight potential pathways underlying effects of maternal education. The results broaden our understanding of bio-social associations linked to differential DNA methylation in multiple early stages of life. The data generated also offers an important resource to help a more precise understanding of the social determinants of health.

Examination of newborn DNA methylation among women with polycystic ovary syndrome/hirsutism.

Research suggests that polycystic ovary syndrome (PCOS) traits (e.g., hyperandrogenism) may create a suboptimal intrauterine environment and induce epigenetic modifications. Therefore, we assessed the associations of PCOS traits with neonatal DNA methylation (DNAm) using two independent cohorts. DNAm was measured in both cohorts using the Infinium MethylationEPIC array. Multivariable robust linear regression was used to determine associations of maternal PCOS exposure or preconception testosterone with methylation ß-values at each CpG probe and corrected for multiple testing by false-discovery rate (FDR). In the birth cohort, 12% (102/849) had a PCOS diagnosis (8.1% PCOS without hirsutism; 3.9% PCOS with hirsutism). Infants exposed to maternal PCOS with hirsutism compared to no PCOS had differential DNAm at cg02372539 [ß(SE): -0.080 (0.010); FDR p = 0.009], cg08471713 [ß(SE):0.077 (0.014); FDR p = 0.016] and cg17897916 [ß(SE):0.050 (0.009); FDR p = 0.009] with adjustment for maternal characteristics including pre-pregnancy BMI. PCOS with hirsutism was also associated with 8 differentially methylated regions (DMRs). PCOS without hirsutism was not associated with individual CpGs. In an independent preconception cohort, total testosterone concentrations were associated with 3 DMRs but not with individual CpGs, though the top quartile of testosterone compared to the lowest was marginally associated with increased DNAm at cg21472377 near an uncharacterized locus (FDR p = 0.09). Examination of these probes and DMRs indicate they may be under foetal genetic control. Overall, we found several associations among newborns exposed to PCOS, specifically when hirsutism was reported, and among newborns of women with relatively higher testosterone around conception.

Gestational weight change in a diverse pregnancy cohort and mortality over 50 years: a prospective observational cohort study.

BACKGROUND: High weight gain in pregnancy is associated with greater postpartum weight retention, yet long-term implications remain unknown. We aimed to assess whether gestational weight change was associated with mortality more than 50 years later. METHODS: The Collaborative Perinatal Project (CPP) was a prospective US pregnancy cohort (1959-65). The CPP Mortality Linkage Study linked CPP participants to the National Death Index and Social Security Death Master File for vital status to 2016. Adjusted hazard ratios (HRs) with 95% CIs estimated associations between gestational weight gain and loss according to the 2009 National Academy of Medicine recommendations and mortality by pre-pregnancy BMI. The primary endpoint was all-cause mortality. Secondary endpoints included cardiovascular and diabetes underlying causes of mortality. FINDINGS: Among 46 042 participants, 20 839 (45·3%) self-identified as Black and 21 287 (46·2%) as White. Median follow-up time was 52 years (IQR 45-54) and 17 901 (38·9%) participants died. For those who were underweight before pregnancy (BMI <18·5 kg/m2; 3809 [9·4%] of 40 689 before imputation for missing data]), weight change above recommendations was associated with increased cardiovascular mortality (HR 1·84 [95% CI 1·08-3·12]) but not all-cause mortality (1·14 [0·86-1·51]) or diabetes-related mortality (0·90 [0·13-6·35]). For those with a normal pre-pregnancy weight (BMI 18·5-24·9 kg/m2; 27 921 [68·6%]), weight change above recommendations was associated with increased all-cause (HR 1·09 [1·01-1·18]) and cardiovascular (1·20 [1·04-1·37]) mortality, but not diabetes-related mortality (0·95 [0·61-1·47]). For those who were overweight pre-pregnancy (BMI 25·0-29·9 kg/m2; 6251 [15·4%]), weight change above recommendations was associated with elevated all-cause (1·12 [1·01-1·24]) and diabetes-related (1·77 [1·23-2·54]) mortality, but not cardiovascular (1·12 [0·94-1·33]) mortality. For those with pre-pregnancy obesity (≥30·0 kg/m2; 2708 [6·7%]), all associations between gestational weight change and mortality had wide CIs and no meaningful relationships could be drawn. Weight change below recommended levels was associated only with a reduced diabetes-related mortality (0·62 [0·48-0·79]) in people with normal pre-pregnancy weight. INTERPRETATION: This study's novel findings support the importance of achieving healthy gestational weight gain within recommendations, adding that the implications might extend beyond the pregnancy window to long-term health, including cardiovascular and diabetes-related mortality. FUNDING: National Institutes of Health.

Tissue-specific DNA methylation variability and its potential clinical value.

Complex diseases have multifactorial etiologies making actionable diagnostic biomarkers difficult to identify. Diagnostic research must expand beyond single or a handful of genetic or epigenetic targets for complex disease and explore a broader system of biological pathways. With the objective to develop a diagnostic tool designed to analyze a comprehensive network of epigenetic profiles in complex diseases, we used publicly available DNA methylation data from over 2,400 samples representing 20 cell types and various diseases. This tool, rather than detecting differentially methylated regions at specific genes, measures the intra-individual methylation variability within gene promoters to identify global shifts away from healthy regulatory states. To assess this new approach, we explored three distinct questions: 1) Are profiles of epigenetic variability tissue-specific? 2) Do diseased tissues exhibit altered epigenetic variability compared to normal tissue? 3) Can epigenetic variability be detected in complex disease? Unsupervised clustering established that global epigenetic variability in promoter regions is tissue-specific and promoter regions that are the most epigenetically stable in a specific tissue are associated with genes known to be essential for its function. Furthermore, analysis of epigenetic variability in these most stable regions distinguishes between diseased and normal tissue in multiple complex diseases. Finally, we demonstrate the clinical utility of this new tool in the assessment of a multifactorial condition, male infertility. We show that epigenetic variability in purified sperm is correlated with live birth outcomes in couples undergoing intrauterine insemination (IUI), a common fertility procedure. Men with the least epigenetically variable promoters were almost twice as likely to father a child than men with the greatest number of epigenetically variable promoters. Interestingly, no such difference was identified in men undergoing in vitro fertilization (IVF), another common fertility procedure, suggesting this as a treatment to overcome higher levels of epigenetic variability when trying to conceive.

Large-Scale Data Harmonization Across Prospective Studies.

The Preconception Period Analysis of Risks and Exposures Influencing Health and Development (PrePARED) Consortium creates a novel resource for addressing preconception health by merging data from numerous cohort studies. In this paper, we describe our data harmonization methods and results. Individual-level data from 12 prospective studies were pooled. The crosswalk-cataloging-harmonization procedure was used. The index pregnancy was defined as the first postbaseline pregnancy lasting more than 20 weeks. We assessed heterogeneity across studies by comparing preconception characteristics in different types of studies. The pooled data set included 114,762 women, and 25,531 (22%) reported at least 1 pregnancy of more than 20 weeks' gestation during the study period. Babies from the index pregnancies were delivered between 1976 and 2021 (median, 2008), at a mean maternal age of 29.7 (standard deviation, 4.6) years. Before the index pregnancy, 60% of women were nulligravid, 58% had a college degree or more, and 37% were overweight or obese. Other harmonized variables included race/ethnicity, household income, substance use, chronic conditions, and perinatal outcomes. Participants from pregnancy-planning studies had more education and were healthier. The prevalence of preexisting medical conditions did not vary substantially based on whether studies relied on self-reported data. Use of harmonized data presents opportunities to study uncommon preconception risk factors and pregnancy-related events. This harmonization effort laid the groundwork for future analyses and additional data harmonization.

Feasibility and acceptability of virtual group contraceptive counseling prior to abortion care.

OBJECTIVES: This study aimed to evaluate the feasibility and acceptability of virtual group contraceptive counseling in the abortion care setting. STUDY DESIGN: Patients seeking abortion care at an urban university hospital were invited to participate in this cohort study. Prior to their clinical appointments, groups of two to six patients participated in 45-minute virtual contraceptive counseling visits facilitated by study staff. Contraceptive method use, effectiveness, and side effects were reviewed according to group interest. Participant satisfaction scores were collected immediately following the sessions. After their appointments, providers estimated the time spent on contraceptive counseling during the clinical visit. RESULTS: Of 195 patients approached, 86 (44%) were enrolled. Fifty-seven (66%) enrolled patients completed a session. The most common reason for declining enrollment was concern about the time commitment. Most (93%) participants reported being "satisfied" or "very satisfied" overall, and 96% would recommend group contraceptive counseling to a friend. Providers reported that compared to typical counseling, participants required a shorter amount of time during the clinical visit than nonparticipants (time spent <5 minutes: 74% vs 54%). CONCLUSIONS: Virtual group contraceptive counseling for patients seeking abortion was feasible and acceptable in this study. Group virtual visits may reduce provider time burden, add value when virtual care delivery is desired or required, and deserve further study. IMPLICATIONS: Family planning clinics can consider incorporating virtual group counseling as a person-centered and efficient approach to contraceptive counseling at the time of abortion care.