STUDY QUESTION:Are preconception sleep characteristics associated with pregnancy loss and adverse pregnancy outcomes? SUMMARY ANSWER:Preconception sleep characteristics were not associated with pregnancy loss, but earlier sleep midpoints were associated with lower risk of adverse pregnancy outcomes, while social jetlag >1 h was associated with greater risk of a composite of adverse pregnancy outcomes. WHAT IS KNOWN ALREADY:Short sleep duration in mid-pregnancy has been associated with risk of second-trimester pregnancy loss, preterm birth (PTB), and hypertensive disorders of pregnancy (HDP). The relationships between preconception sleep and pregnancy loss, and adverse pregnancy outcomes have not been well characterized, despite plausible links. STUDY DESIGN, SIZE, DURATION:This was a secondary analysis of a randomized controlled trial conducted between 2006 and 2012 that prospectively followed 1228 women who were attempting to become pregnant after a history of pregnancy loss. Women were followed for ≤6 cycles while attempting pregnancy, and throughout pregnancy if they conceived. Over the follow-up, 140 women withdrew from the study. PARTICIPANTS/MATERIALS, SETTING, METHODS:This study evaluated baseline, self-reported preconception sleep duration, sleep latency, sleep midpoint, and social jetlag with risk of pregnancy loss and adverse pregnancy outcomes (e.g. PTB, HDP, and gestational diabetes (GDM)) among 1228 women with a history of pregnancy loss in the EAGeR trial. Pregnancy was documented by hCG tests; 797 women became pregnant over the follow-up. Pregnancy losses were defined as any loss after a positive hCG test; there were 188 pregnancy losses. PTB, HDP, and GDM cases were ascertained via medical record abstraction. PTB (n = 53), HDP (n = 62), and GDM (n = 22) were examined as a composite outcome (n = 118) and PTB and HDP were examined individually in exploratory analyses. GDM was not examined individually due to insufficient numbers. Log-Poisson models were used to estimate relative risks (RR) and 95% CIs for associations between preconception sleep characteristics, and pregnancy loss or adverse pregnancy outcomes with adjustment for age, BMI, lifestyle, and sociodemographic factors. Stabilized inverse probability weights were applied to address potential selection bias from loss to follow-up and from restricting to pregnancy. MAIN RESULTS AND THE ROLE OF CHANCE:Preconception sleep characteristics were not associated with risk of pregnancy loss. Preconception sleep duration and sleep latency were not associated with risk of the composite adverse pregnancy outcome. Early preconception sleep midpoints were associated with a lower risk of the composite adverse pregnancy outcome (first vs second tertile RR; 0.63, 95% CI: 0.40, 0.98) and preconception social jetlag was associated with a higher risk of the composite adverse pregnancy outcome (>1 vs ≤1 h RR; 1.65, 95% CI: 1.11, 2.44). LIMITATIONS, REASONS FOR CAUTION:Preconception sleep was restricted to baseline self-report, which may be non-differentially misclassified and may underestimate these associations. The EAGeR study did not measure sleep during pregnancy. There were few adverse pregnancy outcomes and thus limited power to evaluate individual outcomes; the findings could be due to chance. WIDER IMPLICATIONS OF THE FINDINGS:These findings suggest that preconception sleep is not associated with pregnancy loss, but preconception sleep timing may be relevant for risk of adverse pregnancy outcomes. Additional studies on preconception sleep and adverse pregnancy outcomes are needed given the potential impact of poor sleep on pregnancy outcomes. STUDY FUNDING/COMPETING INTEREST(S):Joshua R. Freeman and this work were supported by the Intramural Research Program Cancer Research Training Award, National Cancer Institute, National Institutes of Health (ZIA CP010197), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (Contract numbers: HHSN267200603423, HHSN267200603424, HHSN267200603426, HHSN275201300023I). Dr Silver received NIH funding through the listed contracts as site-PI for the original EAGeR trial at the University of Utah. Dr O'Brien reports receiving funding from the Star Legacy Foundation (paid to institution); an advisory board role at the Star Legacy Foundation; and receiving travel support from the Star Legacy Foundation. Dr Dunietz reports a role as Associate Editor at Human Reproduction and a role on the Journal Editorial Board of SLEEP. Dr Purdue-Smithe is an employee of Merck & Co. and has received stock compensation as an employee of Merck & Co. in the past 36 months. The work in this manuscript was completed before Dr Purdue-Smithe's employment at Merck & Co. and is unrelated to Dr Purdue-Smithe's work at the company. Dr Silver reports royalties or licenses from BJOG and UpToDate, Inc. in the past 36 months, receiving payment or honoraria for Grand Rounds in the past 36 months, and participating on a Data Safety Monitoring Board or Advisory Board for a National Institutes of Health-funded Apple Trial in the past 36 months. The other authors report there are no competing interests to declare. TRIAL REGISTRATION NUMBER:Clinicaltrials.gov NCT00467363.

BACKGROUND:Many environmental chemicals have been shown to cross the placental barrier, threatening the health of offspring. Additionally gestational diabetes mellitus (GDM) may affect the transplacental transfer ratios (TTRs) of environmental chemicals, but the rate of transfer of a wide variety of environmental chemicals have not been widely studied. OBJECTIVE:We examined the TTRs of per- and poly- fluoroalkyl substances (PFAS), phthalates, parabens, bisphenols, and benzophenones in pregnant women, and if GDM increases transplacental transfer of these chemicals. METHODS:We examined 576 mother-newborn pairs from the Growing up in Singapore Towards healthy Outcomes (GUSTO) birth cohort enrolled 2009-2010. Fetal cord plasma to maternal plasma ratios from samples around delivery (TTRs) were estimated for 10 PFAS, 6 phthalates, bisphenol-S (BPS), 2 parabens, and 2 benzophenones. GDM was defined as elevated fasting plasma glucose or 2 h plasma glucose from an oral glucose tolerance test at mid-gestation. We estimated covariate-adjusted associations of GDM with TTRs using multivariable regressions. RESULTS:Median TTRs ranged from 0.13 for benzophenone to 2.2 for mono-2-ethylhexyl phthalate. Overall, TTRs were highest for phthalates and short-chain PFAS and lowest for benzophenone and long-chain PFAS. GDM was significantly associated with higher TTRs for perfluorooctanoic, perfluorononanoic, and perfluoroheptanoic acids, BPS, monoethyl phthalate, and oxybenzone. Mothers with GDM had 15% (95% confidence intervals [CI]: 5%, 25%) and 123% (95% CI: 32%, 214%) higher TTRs for oxybenzone and BPS respectively as compared to mothers without GDM. CONCLUSIONS:We found high TTRs for multiple short half-life chemicals and more recently introduced short-chain PFAS. Importantly, GDM was associated with increased transplacental efficiency of several classes of environmental chemicals, particularly chemicals with shorter half-lives.

Journal Article Accepted manuscript Inverse Probability Weighting for Categorical Exposures Get access Ashley I Naimi, Ashley I Naimi Department of Epidemiology, Emory University Correspondence Address: Department of Epidemiology Rollins School of Public Health Emory University 1518 Clifton Road CNR 3023 Atlanta, GA 30322 [email protected] Search for other works by this author on: Oxford Academic PubMed Google Scholar Brian Whitcomb Brian Whitcomb Department of Epidemiology, University of Massachusetts at Amherst Search for other works by this author on: Oxford Academic PubMed Google Scholar American Journal of Epidemiology, kwaf050, https://doi.org/10.1093/aje/kwaf050 Published: 07 March 2025 Article history Received: 06 July 2024 Revision received: 23 October 2024 Accepted: 27 October 2024 Published: 07 March 2025

Few studies have evaluated sleep characteristics, including social jetlag, with ovulatory dysfunction, which may be an indicator of subfertility and poor metabolic health. Our objective was to evaluate whether sleep characteristics, including sleep duration, chronotype, social jetlag, sleep latency, nocturnal awakenings, and shift work, were associated with risk of anovulation among eumenorrheic women. Participants had a history of pregnancy loss and regular menstrual cycles, but no history of infertility. Typical sleep characteristics were self-reported at baseline. Participants were followed up to the cycle of conception or up to six menstrual cycles. Fertility monitor data and reproductive hormone concentrations were used to assess anovulation. We used generalized estimating equations with log-Poisson distributions to estimate relative risks (RR). The study is registered at clinicaltrials.gov (NCT00467363). Sleep duration, social jetlag, sleep latency, and nocturnal awakenings were not associated with anovulation. Later chronotype was associated with greater anovulation risk (3rd vs. 2nd tertile RR: 1.33, 95% CI: 1.05-1.68; per 1-hour increase RR: 1.05 95% CI 1.00-1.11). The RR for rotating work was 1.14 (95% CI: 0.90-1.46) and for night shift work was 1.22 (95% CI: 0.98-1.52). These results suggest that later chronotype and potentially shift work may be related to menstrual cycle dysfunction.

Statistical methods are fundamental to science. However, scientists routinely misinterpret P-values, confidence intervals, and other statistical metrics. This partly results from a lack of clar-ity around core concepts in statistical reasoning. These includeideas about the structure of scientific arguments, as well as the assumptions involved in constructing statistical measures.1For many fields, there is an important distinction betweenproblems that can be classified as "direct" or "inverse." Theseproblems relate to the foundations of statistical inference. Here,we explain the structure of direct and inverse problems, connectthem to inductive and deductive reasoning, and comment on how understanding these issues can bring clarity to the interpretationof statistical results

Objective: This study aimed to examine sexual orientation differences in natural menopause timing and symptoms between lesbian and bisexual women compared with heterosexual women. Methods: We used longitudinal questionnaire data (1989-2015) from 92,314 women (858 lesbian, 375 bisexual) in the Nurses' Health Study II cohort. Women were 24-44 yr old at baseline and biennially reported their menopause status, including reasons for cessation of menstrual periods. In 2009 and 2013, women reported on their experience of hot flashes and night sweats. Covariates included age, age at menarche, body mass index, smoking, and parity. Sexual orientation was reported in 1995 and 2009. Results: Age-adjusted Cox models and logistic regression models suggest that there were no statistically significant differences in menopause timing between lesbian or bisexual women when compared with heterosexual women. When examining menopause symptoms, lesbian women consistently had a statistically significantly (P < 0.05) higher odds of experiencing hot flashes or night sweats (odds ratio range: 1.17 to 1.72) and moderate/severe symptoms (OR range: 1.26 to 1.77) than heterosexual women, even after adjusting for covariates such as smoking and obesity. There were no statistically significant differences in menopause symptoms between bisexual and heterosexual women. Conclusions: Our findings suggest no meaningful difference in menopause timing between sexual minority and heterosexual women. Additionally, menopause symptoms were more likely among lesbian women and warrants additional study.

OBJECTIVE:To estimate the effect of platinum-based chemotherapy on live birth (LB) and infertility after cancer, in order to address a lack of treatment-specific fertility risks for female survivors of adolescent and young adult cancer, which limits counseling on fertility preservation decisions. DESIGN:Retrospective cohort study. SETTING:US administrative database. PATIENTS:We identified incident breast, colorectal, and ovarian cancer cases in females aged 15-39 years who received platinum-based chemotherapy or no chemotherapy and matched them to females without cancer. INTERVENTION:Platinum-based chemotherapy. MAIN OUTCOME MEASURES:We estimated the effect of chemotherapy on the incidence of LB and infertility after cancer, overall, and after accounting for competing events (recurrence, death, and sterilizing surgeries). RESULTS:There were 1,287 survivors in the chemotherapy group, 3,192 in the no chemotherapy group, and 34,147 women in the no cancer group, with a mean age of 33 years. Accounting for competing events, the overall 5-year LB incidence was lower in the chemotherapy group (3.9%) vs. the no chemotherapy group (6.4%). Adjusted relative risks vs. no chemotherapy and no cancer groups were 0.61 (95% confidence interval [CI] 0.42-0.82) and 0.70 (95% CI 0.51-0.93), respectively. The overall 5-year infertility incidence was similar in the chemotherapy group (21.8%) compared with the no chemotherapy group (20.7%). The adjusted relative risks vs. no chemotherapy and no cancer groups were 1.05 (95% CI 0.97-1.15) and 1.42 (95% CI 1.31-1.53), respectively. CONCLUSIONS:Cancer survivors treated with platinum-based chemotherapy experienced modestly increased adverse fertility outcomes. The estimated effects of platinum-based chemotherapy were affected by competing events, suggesting the importance of this analytic approach for interpretations that ultimately inform clinical fertility preservation decisions.

Objective: Adverse pregnancy outcomes (APOs) and early menopause are each associated with increased risk of cardiovascular disease (CVD); whether APOs are associated with age at menopause is unclear. We examined the association of gestational diabetes (GDM), hypertensive disorders of pregnancy (HDP), preterm birth, and multiple gestation with age at natural menopause.Study design: Observational, prospective study within the Nurses' Health Study II cohort (1989-2019). Main outcomes measures: Risk of early natural menopause, defined as occurring before the age of 45 years, and age at onset of natural menopause (hazard ratio (HR) >1 indicates younger age at menopause).Results: The mean [SD] baseline age of 69,880 parous participants was 34.5 [4.7] years. Compared with participants who had a term singleton first birth, those with a term multiple-gestation first birth had higher risk of early menopause (HR: 1.65, 95% CI: 1.05, 2.60) and younger age at natural menopause (HR: 1.46, 95% CI: 1.31, 1.63). Estimates for preterm multiple gestation were of similar magnitude. Menopause occurred at a younger age for those with a preterm birth with spontaneous labor (HR: 1.08, 95% CI: 1.03, 1.14) compared to those with a term birth with spontaneous labor. Conversely, estimates for GDM (HR: 0.95, 95% CI: 0.89, 1.02) and HDP (preeclampsia, HR: 0.93, 95% CI: 0.89, 0.97) suggested an association with older age at menopause.Conclusions: In this large cohort study, several statistically significant associations between APOs and age at natural menopause were observed. A deeper understanding of the relationships among APOs, menopause, and CVD is needed to help identify people at higher risk for early menopause and later CVD.

Objectives: To evaluate risks of preterm birth and severe maternal morbidity (SMM) in female adolescent and young adult cancer survivors; assess maternal comorbidity as a potential mechanism; determine whether associations differ by use of assisted reproductive technology (ART). Design: Retrospective cohort Setting: Privately insured females in the U.S. Sample: Female with live births from 2000 to 2019 within OptumLabs®, a U.S. administrative health claims dataset Methods: Log-binomial regression models estimated relative risks of preterm birth and SMM by cancer status and tested for effect modification. Causal mediation analysis based on a counterfactual approach evaluated the proportions explained by maternal comorbidity. Main Outcome Measures: SMM, preterm birth Results: Among 46,064 cancer survivors, 2,440 singleton births, 214 multiple births, and 2,590 linked newborns occurred after cancer. In singleton births, preterm birth incidence was 14.8% in cancer survivors versus 12.4% in females without cancer (aRR 1.19, 95%CI 1.06-1.34); SMM incidence was 3.9% in cancer survivors versus 2.4% in females without cancer (aRR 1.44, 95%CI 1.13-1.83). Cancer survivors had more maternal comorbidities before and during pregnancy; 26% of the association between cancer and preterm birth and 30% of the association between cancer and SMM was mediated by maternal comorbidities. Associations between cancer and outcomes did not differ between ART and non-ART births. Conclusion: Preterm birth and SMM risks were modestly increased after cancer. Significant proportions of elevated risks may be due to increased comorbidities. Prevention and treatment of comorbidities provides an opportunity to improve perinatal outcomes among cancer survivors.

Correlated data refers to a situation where the outcome of interest is clustered within a particular grouping, and they are very common in epidemiology and public health research.Here, we discuss situations that lead to, and complications that result from, correlated data.We demonstrate 2 simple strategies that can be used to analyze correlated data and still obtain valid inferences.Correlated data arise as the result of dependent sampling.Correlations among model covariates (i.e., independent variables) can result in collinearity problems, but we focus here on correlated outcomes.Examples scenarios include:

BACKGROUND:Women with abnormal glucose tolerance during pregnancy are at risk for cardiovascular disease (CVD), with higher rates among Hispanics. However, studies on the impact of lifestyle interventions on postpartum CVD profiles are sparse. METHODS:This is a secondary analysis of a controlled trial among a subsample of Hispanic women with abnormal glucose tolerance participating in Estudió PARTO (Project Aiming to Reduce Type twO diabetes; mean age = 28.2 y, SD: 5.8) who were randomized to a culturally modified Lifestyle intervention (n = 45) or a comparison Health and Wellness intervention (n = 55). Primary endpoints were biomarkers of cardiovascular risk (lipids, C-reactive protein, fetuin-A, and albumin-to-creatinine ratio) and insulin resistance (fasting insulin, glucose, HbA1c, homeostasis model assessment, leptin, tumor necrosis factor-alpha, and adiponectin) measured at baseline (6-wk postpartum) and 6 and 12 months. RESULTS:In intent-to-treat analyses, there were no significant differences in changes in biomarkers of CVD risk or insulin resistance over the postpartum year. In prespecified sensitivity analyses, women adherent with the Lifestyle Intervention had more favorable improvements in insulin (intervention effect = -4.87, SE: 1.93, P = .01) and HOMA-IR (intervention effect = -1.15, SE: 0.53, P = .03) compared with the Health and Wellness arm. In pooled analyses, regardless of intervention arm, women with higher postpartum sports/exercise had greater increase in HDL-cholesterol (intervention effect = 6.99, SE: 1.72, P = .0001). CONCLUSIONS:In this randomized controlled trial among Hispanic women with abnormal glucose tolerance, we did not observe a significant effect on postpartum biomarkers of CVD risk or insulin resistance. Women adherent to the intervention had more favorable changes in insulin and HOMA-IR.

OBJECTIVE:Nearly two-thirds of Black women in the US are obese. Studies have focused more on lifestyle and behavioral factors to explain racial disparities; less research has examined psychosocial factors such as psychological distress and social cohesion. While research suggests that social cohesion may confer benefits for health, no studies have assessed how social cohesion is related to both mental health and obesity, and potential racial differences. Our study examined associations between psychological distress, social cohesion, and obesity among Black and White adult women. DESIGN:Data are from the 2014-2018 National Health Interview Survey (n = 66,743). Participants self-reported psychological distress (Kessler K6 scale), obesity (body mass index≥30 kg/m2), and social cohesion. We fit logistic regression models of obesity with likelihood ratio tests for effect modification by social cohesion and by race. RESULTS:Psychological distress was associated with a 1.19 and 1.31 higher odds of obesity for Black (95% confidence interval: 1.05, 1.36) and White women (1.24, 1.39), respectively. Social cohesion was associated with a 0.75 lower odds of obesity among White (0.69, 0.81) but not Black women (odds ratio 0.94; 0.80, 1.10). Tests of interaction indicated no differences by social cohesion or race in the association between psychological distress and obesity. CONCLUSION:Findings highlight complex relationships between psychological distress, obesity, and social cohesion in Black and White women. Public health efforts should focus on understanding mechanisms relating social factors to health.

Adiposity has been associated with several health conditions as well as timing of menopause. Prior epidemiologic studies on the association of adiposity and anti-Mullerian hormone (AMH) have been inconsistent. We evaluated the relations of anthropometric measures with AMH at two time periods in a subset of premenopausal participants in the Nurses' Health Study II. This prospective study included 795 women who provided a premenopausal sample in 1996-1999 and in 2010-2012. Current weight and height, and weight at age 18 were assessed in 1989 and weight again in 1996-1999. Waist and hip circumference were measured and reported in 1993. In linear regression models adjusted for smoking, reproductive events, and other factors, AMH was inversely related to BMI at age 18 (P= .03) and in 1996-1999 (P < .0001). Higher waist circumference was related to lower AMH levels in 1996-1999 (p = .0009). BMI in 1996-1999 was inversely associated with AMH levels in 2010-2012 (P = .005). Weight gain between age 18 and 1996-1999 was strongly inversely associated with AMH levels in 1996-1999 (P < .0001) and in 2010-2012 (P < .0001). Our results indicate that adiposity and weight gain are associated with lower AMH levels, suggesting an adverse impact on ovarian function.

BACKGROUND:Currently, the precise mechanisms that underline male infertility are still unclear. Accumulating data implicate non-coding RNA cargo of seminal plasma extracellular vesicles due to their association with poor semen quality and higher expression levels relative to vesicle-free seminal plasma.METHOD:We assessed sperm-free seminal plasma extracellular vesicle non-coding RNA profiles from 91 semen samples collected from male participants of couples seeking infertility treatment. Men were classified into two groups (poor, n = 32; normal, n = 59) based on World Health Organization semen cutoffs. Small RNA sequencing reads were mapped to standard biotype-specific transcriptomes in the order micro RNA > transfer RNA > piwi-interacting RNA > ribosomal RNA  > ribosomal RNA > circular RNA > long non-coding RNA using STAR. Differential expression of normalized non-coding RNA read counts between the two groups was conducted by EdgeR (Fold change ≥1.5 and (false discovery rate [FDR] < 0.05).RESULT:Small RNA sequencing identified a wide variety of seminal plasma extracellular vesicle non-coding RNA biotypes including micro RNA, ribosomal RNAs, piwi-interacting RNAs, transfer RNA, long non-coding RNAs as well as circular RNAs, and fragments associated with pseudogenes, and nonsense-mediated decay. The expression levels of 57 seminal plasma extracellular vesicle non-coding RNAs (micro RNA: 6, piwi-interacting RNA: 4, ribosomal RNA: 6, circular RNA: 34, and long non-coding RNA: 7) were altered in men with poor semen quality relative to normal semen parameters, many (60%) of which were circular RNA species. Ontology analysis of differentially expressed micro RNAs and circular RNAs showed enrichment in functional terms related to cellular communication and early development.CONCLUSION:This is the first study to generate comprehensive seminal plasma extracellular vesicle non-coding RNA profiles in a clinical setting and to determine the differences between men with normal and abnormal semen parameters. Thus, our study suggests that seminal plasma extracellular vesicle non-coding RNAs may represent novel biomarkers of male reproductive phenotypes.