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To evaluate the associations between preconception sleep characteristics and shift work with fecundability and live birth.Secondary analysis of the Effects of Aspirin in Gestation and Reproduction study, a preconception cohort.Four US academic medical centers.Women aged 18-40 with a history of 1-2 pregnancy losses who were attempting to conceive again.Not applicable.We evaluated baseline, self-reported sleep duration, sleep midpoint, social jetlag, and shift work among 1,228 women who were observed for ≤6 cycles of pregnancy attempts to ascertain fecundability. We ascertained live birth at the end of follow up via chart abstraction. We estimated fecundability odds ratios (FORs) using discrete, Cox proportional hazards models and risk ratios (RRs) for live birth using log-Poisson models.Sleep duration ≥9 vs. 7 to8 hours (FOR: 0.81, 95% confidence interval [CI], 0.61; 1.08), later sleep midpoints (3rd tertile vs. 2nd tertile: FOR: 0.85; 95% CI, 0.69, 1.04) and social jetlag (continuous per hour; FOR: 0.93, 95% CI: 0.86, 1.00) were not associated with reduced fecundability. In sensitivity analyses, excluding shift workers, sleep duration ≥9 vs. 7 to8 hours (FOR: 0.62; 95% CI, 0.42; 0.93) was associated with low fecundability. Night shift work was not associated with fecundability (vs. non-night shift work FOR: 1.17, 95% CI, 0.96; 1.42). Preconception sleep was not associated with live birth.Overall, there does not appear to be a strong association between sleep characteristics, fecundability, and live birth. Although these findings may suggest weak and imprecise associations with some sleep characteristics, our findings should be evaluated in larger cohorts of women with extremes of sleep characteristics.Clinicaltrials.gov NCT00467363.

OBJECTIVE: To evaluate the association between parity and breastfeeding and anti-Müllerian hormone levels (AMH) and change in AMH levels over time. Furthermore, we examined whether AMH levels mediate the relation of parity and breastfeeding with age at menopause. STUDY DESIGN: Observational, prospective cohort study. MAIN OUTCOME MEASURES: AMH levels were assessed in a subset of premenopausal participants in the Nurses’ Health Study II, including 1619 women who provided a blood sample in 1996–1999 and an additional 800 women who provided a second premenopausal sample in 2010–2012. RESULTS: In multivariable linear regression models adjusted for parity, body mass index, smoking, and other factors, mean log AMH levels in 1996–99 were 39% higher in women reporting ≥25 months of total breastfeeding vs.

OBJECTIVE: Oral contraceptives and tubal ligation are commonly used methods of contraception that may impact ovarian function. Few studies have examined the association of these factors with anti-Müllerian hormone (AMH), a marker of ovarian aging. METHODS: We examined the association of oral contraceptive use and tubal ligation with AMH in the Nurses’ Health Study II prospective cohort among a subset of 1,420 premenopausal participants who provided a blood sample in 1996–1999. History of oral contraceptive use and tubal ligation were reported in 1989 and updated every two years until blood collection. We utilized generalized linear models to assess whether mean AMH levels varied by duration of and age at first use of oral contraceptives and history, age, and type of tubal ligation. RESULTS: In multivariable models adjusted for smoking, reproductive events, and other lifestyle factors, we observed a significant, inverse association between duration of oral contraceptive use and mean AMH levels (P for trend=.036). Compared to women without a tubal ligation, AMH levels were significantly lower when the procedure included a clip, ring, or band (1.04 ng/ml vs. 1.72 ng/ml, p

STUDY QUESTION Is preconception leukocyte telomere length associated with fecundability, pregnancy loss and live birth among women attempting natural conception with a history of 1–2 prior pregnancy losses? SUMMARY ANSWER Preconception leukocyte telomere length is not associated with fecundability, pregnancy loss or live birth. WHAT IS KNOWN ALREADY As women increasingly delay childbearing, accessible preconception biomarkers to predict pregnancy outcomes among women seeking natural conception could improve preconception counseling. Findings of small case–control or cross-sectional studies suggest that telomere attrition is associated with adverse pregnancy outcomes among women undergoing fertility treatment, but prospective studies in non-clinical populations are lacking. STUDY DESIGN, SIZE, DURATION Participants included 1228 women aged 18–40 years with a history of 1–2 prior pregnancy losses who were recruited at four university medical centers (2006–2012). PARTICIPANTS/MATERIALS, SETTING, METHODS Preconception leukocyte telomere length was measured at baseline using PCR and reported as a ratio (T/S) in relation to population-specific standard reference DNA. Women were followed for up to six cycles while attempting to conceive. Associations of telomere length with fecundability, live birth and pregnancy loss were estimated using discrete Cox proportional hazards models and log-binomial models. MAIN RESULTS AND THE ROLE OF CHANCE After adjustment for age, BMI, smoking and other factors, preconception telomere length was not associated with fecundability (Q4 vs Q1 FOR = 1.00; 95% CI = 0.79, 1.27), live birth (Q4 vs Q1 RR = 1.00; 95% CI = 0.85, 1.19), or pregnancy loss (Q4 vs Q1 RR = 1.12; 95% CI = 0.78, 1.62). LIMITATIONS, REASONS FOR CAUTION Telomere length was measured in leukocytes, which is an accessible tissue in women attempting natural conception but may not reflect telomere length in oocytes. Most women were younger than 35 years, limiting our ability to evaluate associations among older women. Participants had a history of 1–2 prior pregnancy losses; therefore, our findings may not be widely generalizable. WIDER IMPLICATIONS OF THE FINDINGS Despite prior research suggesting that telomere length may be associated with pregnancy outcomes among women seeking fertility treatment, our findings suggest that leukocyte telomere length is not a suitable biomarker of pregnancy establishment or maintenance among women attempting natural conception. STUDY FUNDING/COMPETING INTEREST(S) This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (National Institutes of Health, Bethesda, MD, USA; contract numbers HHSN267200603423, HHSN267200603424 and HHSN267200603426). The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER The trial was registered with ClinicalTrials.gov, number NCT00467363.

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.Observational, prospective study within the Nurses' Health Study II cohort (1989-2019).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).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.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.

STUDY QUESTION Are insufficient 25-hydroxyvitamin D (25(OH)D) concentrations, and other markers of vitamin D metabolism, associated with premenstrual symptoms in healthy women with regular menstrual cycles? SUMMARY ANSWER 25(OH)D insufficiency was associated with specific physical premenstrual symptoms, while no associations were observed with psychological symptoms or with other markers of vitamin D metabolism. WHAT IS KNOWN ALREADY Prior studies evaluating vitamin D and premenstrual symptoms have yielded mixed results, and it is unknown whether 25(OH)D insufficiency and other markers of vitamin D metabolism are associated with premenstrual symptoms. STUDY DESIGN, SIZE, DURATION We used two cohorts of women with regular menstrual cycles; 1191 women aged 18–40 years in EAGeR (cross-sectional analysis of a prospective cohort within a randomized trial) and 76 women aged 18–44 years in BioCycle (prospective cohort). In EAGeR, premenstrual symptoms over the previous year were assessed at baseline, whereas in BioCycle, symptoms were assessed prospectively at multiple points over two menstrual cycles with symptoms queried over the previous week. In both cohorts, symptomatology was assessed via questionnaire regarding presence and severity of 14 physical and psychological symptoms the week before and after menses. Both studies measured 25(OH)D in serum. We also evaluated the association of additional markers of vitamin D metabolism and calcium homeostasis, including intact parathyroid hormone (iPTH), calcium (Ca), fibroblast growth factor 23 (FGF23), and 1,25 dihydroxyvitamin D (1,25(OH)2D) with premenstrual symptoms in the BioCycle cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS One cohort of women actively seeking pregnancy (Effects of Aspirin in Gestation and Reproduction (EAGeR)) and one cohort not seeking pregnancy (BioCycle) were evaluated. Log-binomial regression was used to estimate risk ratios (RR) and 95% CIs for associations between insufficient 25(OH)D ( MAIN RESULTS AND THE ROLE OF CHANCE 25(OH)D insufficiency was associated with increased risk of breast fullness/tenderness (EAGeR RR 1.27, 95% CI 1.03, 1.55; BioCycle RR 1.37, 95% CI 0.56, 3.32) and generalized aches and pains (EAGeR RR 1.33, 95% CI 1.01, 1.78; BioCycle 1.36, 95% CI 0.41, 4.45), though results were imprecise in the BioCycle study. No associations were observed between insufficient 25(OH)D and psychological symptoms in either cohort. In BioCycle, iPTH, Ca, FGF23, and 1,25(OH) 2D were not associated with any premenstrual symptoms. LIMITATIONS, REASONS FOR CAUTION Results from the EAGeR study were limited by the study design, which assessed both 25(OH)D at baseline and individual premenstrual symptoms over the past year at the baseline. As such, reverse causality is a potential concern. Though premenstrual symptoms were assessed prospectively in the BioCycle cohort, the power was limited due to small sample size. However, results were fairly consistent across both studies. WIDER IMPLICATIONS OF THE FINDINGS Serum 25(OH)D may be associated with risk and severity of specific physical premenstrual symptoms. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (Contract nos. HHSN267200603423, HHSN267200603424, and HHSN267200603426). JG.R. and D.L.K. have been funded by the NIH Medical Research Scholars Program, a public–private partnership jointly supported by the NIH and generous contributions to the Foundation for the NIH by the Doris Duke Charitable Foundation (Grant #2014194), the American Association for Dental Research, the Colgate Palmolive Company, Genentech, and other private donors. For a complete list, visit the foundation website at http://www.fnih.org. The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER Clinicaltrials.gov NCT00467363.

Prior research suggests that severe iodine deficiency in pregnancy may be associated with stillbirth. However, the relationship between mild to moderate iodine insufficiency, which is prevalent even in developed countries, and risk of stillbirth is unclear. We thus examined associations of iodine status and risk of stillbirth in a prospective population‐based nested case–control study in Finland, a mild to moderately iodine insufficient population. Stillbirth cases (n = 199) and unaffected controls (n = 249) were randomly selected from among all singleton births in Finland from 2012 to 2013. Serum samples were collected between 10 and 14 weeks gestation and analysed for iodide, thyroglobulin (Tg) and thyroid‐stimulating hormone (TSH). Odds ratios (ORs) and 95% confidence intervals (CIs) for stillbirth were estimated using logistic regression. After adjusting for maternal age, prepregnancy body mass index, socio‐economic status and other factors, neither high nor low serum iodide was associated with risk of stillbirth (Q1 vs. Q2–Q3 OR = 0.92, 95% CI = 0.78–1.09; Q4 vs. Q2–Q3 OR = 0.78; 95% CI = 0.45–1.33). Tg and TSH were also not associated with risk of stillbirth in adjusted models. Maternal iodine status was not associated with stillbirth risk in this mildly to moderately iodine‐deficient population. Tg and TSH, which reflect functional iodine status, were also not associated with stillbirth risk. The lack of associations observed between serum iodide, TSH and Tg and risk of stillbirth is reassuring, given that iodine deficiency in pregnancy is prevalent in developed countries.

Objective Early menopause, the cessation of ovarian function before age 45, has consequences for fertility and cardiovascular health. Evidence from studies of women with autoimmune conditions and genetic studies supports a role for inflammation in early menopause, but the association of inflammatory markers and risk has not been directly evaluated. Methods We assessed the relation of the soluble fraction of tumor necrosis factor alpha receptor 2 (sTNFR2), C-reactive protein, interleukin-6 (IL6) levels with incident early menopause among Nurses' Health Study II participants who provided a premenopausal blood sample in 1996 to 1999. Cases (n = 328) were women reporting natural menopause between blood collection and age 45.Controls (n = 492) included (1) 328 women with menopause after age 47, matched 1:1 with cases on age at blood collection and other factors; and (2) 164 additional women with menopause after age 45. Results In multivariable models comparing cases and n = 492 controls, we observed a significant association of sTNFR2 levels and risk of early menopause (P = 0.002). Compared with women with the lowest sTNFR2 levels, odds ratios (95% CIs) for quartiles 2 to 4 were 0.60 (0.38-0.95), 0.93 (0.61-1.43), and 1.40 (0.93-2.11). Results further adjusting for antimullerian hormone levels were similar in magnitude, as were results from sensitivity analyses of matched cases and controls (n = 328 pairs), nonsmokers, and leaner women. C-reactive protein and IL6 levels were unrelated to risk. Conclusions The observation of lower risk of early menopause among women with moderate sTNFR2 levels compared with women with lower and higher levels warrants further prospective study.

STUDY QUESTION What is the association of oral contraceptives (OCs) and tubal ligation (TL) with early natural menopause? SUMMARY ANSWER We did not observe an association of OC use with risk of early natural menopause; however, TL was associated with a modestly higher risk. WHAT IS KNOWN ALREADY OCs manipulate hormone levels, prevent ovulation, and may modify the rate of follicular atresia, while TL may disrupt the blood supply to the ovaries. These mechanisms may be associated with risk of early menopause, a condition associated with increased risk of cardiovascular disease and other adverse health outcomes. STUDY DESIGN, SIZE, DURATION We examined the association of OC use and TL with natural menopause before the age of 45 years in a population-based study within the prospective Nurses’ Health Study II (NHSII) cohort. Participants were followed from 1989 to 2017 and response rates were 85-90% for each cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS Participants included 106 633 NHSII members who were premenopausal and aged 25-42 years at baseline. Use, duration and type of OC, and TL were measured at baseline and every 2 years. Menopause status and age were assessed every 2 years. Follow-up continued until early menopause, age 45 years, hysterectomy, oophorectomy, death, cancer diagnosis, or loss to follow-up. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CIs adjusted for lifestyle, dietary, and reproductive factors. MAIN RESULTS AND THE ROLE OF CHANCE Over 1.6 million person-years, 2579 members of the analytic cohort experienced early natural menopause. In multivariable models, the duration, timing, and type of OC use were not associated with risk of early menopause. For example, compared with women who never used OCs, those reporting 120+ months of OC use had an HR for early menopause of 1.01 (95% CI, 0.87-1.17; P for trend=0.71). TL was associated with increased risk of early menopause (HR = 1.17, 95% CI, 1.06-1.28). LIMITATIONS, REASONS FOR CAUTION Our study population is homogenous with respect to race and ethnicity. Additional evaluation of these relations in more diverse populations is important. WIDER IMPLICATIONS OF THE FINDINGS To our knowledge, this is the largest study examining the association of OC use and TL with early natural menopause to date. While TL was associated with a modest higher risk of early menopause, our findings do not support any material hazard or benefit for the use of OCs. STUDY FUNDING/COMPETING INTEREST(S) The study was sponsored by UO1CA176726 and R01HD078517 from the National Institutes of Health and Department of Health and Human Services. The work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors have no competing interests to report. TRIAL REGISTRATION NUMBER N/A

Key Points Question What is the association of parity and breastfeeding with early natural menopause? Findings In this cohort study that included 108 887 premenopausal women, parity and breastfeeding were each associated with a significantly lower risk of early natural menopause. Findings for breastfeeding suggest that some of the lower risk attributed to parity could be attributable to breastfeeding. Meaning The findings suggest that breastfeeding at levels consistent with current recommendations may confer an additional benefit of lower risk of early menopause., This cohort study examines the association of parity and breastfeeding with the risk of early natural menopause among women in the Nurses’ Health Study II cohort., Importance Pregnancy and breastfeeding prevent ovulation and may slow the depletion of the ovarian follicle pool. These factors may lower the risk of early menopause, a condition associated with increased risk of cardiovascular disease and other adverse health outcomes. Objective To examine the association of parity and breastfeeding with the risk of early menopause. Design, Setting, and Participants This population-based cohort study within the Nurses’ Health Study II cohort (1989-2015) included premenopausal participants who were aged 25 to 42 years at baseline. Response rates were 85% to 90% for each cycle, and follow-up continued until menopause, age 45 years, hysterectomy, oophorectomy, death, cancer diagnosis, loss to follow-up, or end of follow-up in May 2015. Hypotheses were formulated after data collection. Data analysis took place from February to July 2019. Exposures Parity (ie, number of pregnancies lasting ≥6 months) was measured at baseline and every 2 years. History and duration of total and exclusive breastfeeding were assessed 3 times during follow-up. Menopause status and age were assessed every 2 years. Main Outcomes and Measures Risk of natural menopause before age 45 years. Results At baseline, 108 887 premenopausal women aged 25 to 42 years (mean [SD] age, 34.1 [4.6] years; 102 246 [93.9%] non-Hispanic white) were included in the study. In multivariable models, higher parity was associated with lower risk of early menopause. Hazard ratios were attenuated with adjustment for breastfeeding but remained significant. Compared with nulliparous women, those reporting 1, 2, 3, and 4 or more pregnancies lasting at least 6 months had hazard ratios for early menopause of 0.92 (95% CI, 0.79-1.06), 0.84 (95% CI, 0.73-0.96), 0.78 (95% CI, 0.67-0.92), and 0.81 (95% CI, 0.66-1.01), respectively (P for trend = .006). In multivariable models also adjusted for parity, hazard ratios for duration of exclusive breastfeeding of 1 to 6, 7 to 12, 13 to 18, and 19 or more months were 0.95 (95% CI, 0.85-1.07), 0.72 (95% CI, 0.62-0.83), 0.80 (95% CI, 0.66-0.97), and 0.89 (95% CI, 0.69-1.16), respectively, compared with less than 1 month of exclusive breastfeeding (P for trend = .001). Despite the significant test for trend, estimates were not observed to be lower as duration of exclusive breastfeeding increased. In a stratified analysis of parous women, risk of early menopause was lowest among those reporting exclusive breastfeeding for 7 to 12 months in each level of parity (women with 2 pregnancies and 7-12 months of breastfeeding: HR, 0.79; 95% CI, 0.66-0.96; ≥3 pregnancies and 7-12 months of breastfeeding: HR, 0.68; 95% CI, 0.52-0.88; 2 pregnancies and ≥13 months of breastfeeding: HR, 0.87; 95% CI, 0.66-1.15; ≥3 pregnancies and 13-18 months of breastfeeding: HR, 0.86; 95% CI, 0.66-1.13; and ≥3 pregnancies and ≥19 months of breastfeeding: HR, 0.98; 95% CI, 0.72-1.32). Conclusions and Relevance In this study, an inverse association of parity with risk of early menopause was observed. Breastfeeding was associated with significantly lower risk, even after accounting for parity. Breastfeeding at levels consistent with current recommendations may confer an additional benefit of lower risk of early menopause.

STUDY QUESTION: Is physical activity associated with incident early menopause? SUMMARY ANSWER: Physical activity is not associated with incident early menopause. WHAT IS KNOWN ALREADY: Lifestyle factors such as physical activity may influence menopause timing, but results from prior research are inconsistent. STUDY DESIGN, SIZE, DURATION: We evaluated the association between physical activity and the occurrence of early natural menopause in a prospective cohort study, the Nurses’ Health Study II. Women were followed prospectively from 1989 to 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS: Our analysis included 107 275 women who were premenopausal at baseline. Menopause status was self-reported biennially. Time per week participating in specific activities was reported approximately every 4 years and used to calculate metabolic task hours per week (MET h/week). We used Cox proportional hazards model to evaluate the association between physical activity and incidence of natural menopause before age 45 years while controlling for potential confounding factors. MAIN RESULTS AND THE ROLE OF CHANCE: There were 2 786 study members who experienced menopause before the age of 45. After adjustment for age, smoking and other factors, we observed no association between adulthood physical activity and early menopause. For example, compared to women reporting

Concerns remain about the health of children conceived by infertility treatment. Studies to date have predominantly not identified substantial long-term health effects after accounting for plurality, which is reassuring given the increasing numbers of children conceived by infertility treatment worldwide. However, as technological advances in treatment arise, ongoing studies remain critical for monitoring health effects. To study whether the techniques used in infertility treatment cause health differences, however, remains challenging due to identification of an appropriate comparison group, heterogeneous treatment, and confounding by the underlying causes of infertility. In fact, the factors that are associated with underlying infertility, including parental obesity and other specific male and female factors, may be important independent factors to consider. This review will summarize key methodological considerations in studying children conceived by infertility treatment including the evidence of associations between underlying infertility factors and child health.

STUDY QUESTION: Are anti-Müllerian hormone (AMH) levels assessed in women aged 32–44 associated with risk of incident early natural menopause? SUMMARY ANSWER: We observed strong, significant associations between lower AMH levels and higher risk of early menopause. WHAT IS KNOWN ALREADY: The ability to predict risk early menopause, defined as menopause before age 45, prior to fertility decline would improve options for family planning and cardiovascular disease prevention. Though AMH is an established marker of menopause timing in older reproductive-aged women, whether AMH is associated with risk of early menopause has not been evaluated. STUDY DESIGN, SIZE, DURATION: We assessed these relations in a nested case–control study within the prospective Nurses’ Health Study II cohort. Premenopausal blood samples were collected in 1996–1999. Participants were followed until 2011 for early natural menopause, with follow-up rates >94%. PARTICIPANTS/MATERIALS, SETTING, METHODS: Early menopause cases (n = 327) were women reporting natural menopause between blood collection and age 45. Controls (n = 491) experienced menopause after age 45 and included 327 cases matched to controls on the basis of age at blood draw (±4 months) and other factors. AMH levels up to 12 years before early menopause were assayed in 2016. MAIN RESULTS AND THE ROLE OF CHANCE: In multivariable conditional logistic regression models adjusting for matching factors, body mass index, smoking, parity, oral contraceptive use, and other factors, each 0.10 ng/ml decrease in AMH was associated with a 14% higher risk of early menopause (95% confidence interval (CI) 1.10 to 1.18; P < 0.001). In polynomial regression models including linear and quadratic terms for AMH, odds ratios for early menopause for women with AMH levels of 1.5, 1.0 and 0.5 ng/ml compared to 2.0 ng/ml were 2.6, 7.5 and 23 (all P < 0.001). Significant associations were observed irrespective of smoking status, adiposity, infertility history and menstrual cycle characteristics. Furthermore, models assessing the predictive ability of AMH showed high concordance, and C-statistics were high, ranging from 0.68 (age ≤35) to 0.93 (age 42). LIMITATIONS, REASONS FOR CAUTION: Our population was relatively homogenous with respect to race/ethnicity. Further work in more ethnically diverse populations is needed. WIDE IMPLICATION OF THE FINDINGS: To our knowledge, this is the first prospective study to evaluate whether AMH levels are associated with early menopause. These findings support the utility of AMH as a clinical marker of early menopause in otherwise healthy women. STUDY FUNDING/COMPETING INTEREST(S): This project was supported by UM1CA176726, R01CA67262, and R01HD078517 from the U.S. Department of Health and Human Services, National Institutes of Health. No competing interests declared.

STUDY QUESTION Is adult adiposity associated with early menopause? SUMMARY ANSWER Overall and abdominal adiposity were non-linearly associated with odds for early natural menopause with elevated odds observed among women who were underweight in early or mid-adulthood compared to lean-normal weight women. WHAT IS KNOWN ALREADY High and low adiposity have been associated with reproductive function and may potentially impact timing of menopause. It is unclear whether various aspects of adiposity are associated with risk of early menopause. STUDY DESIGN, SIZE, DURATION Prospective cohort study that examined data from 78 759 premenopausal women from the Nurses' Health Study II who were followed from 1989 to 2011 for incidence of early natural menopause. PARTICIPANTS/MATERIALS, SETTING, METHODS Participants were aged 25-42 years and premenopausal at baseline in 1989, when information on menopausal status, height and weight was reported via questionnaire. Information on menopausal status, type of menopause (natural, surgical, radiation/chemotherapy), hormone therapy use and weight was updated every two years along with information on smoking, physical activity and other behavioral and health-related factors. Multivariable logistic regression was used to estimate odds ratios for early menopause, defined as natural menopause before age 45 years, by aspects of adiposity. MAIN RESULTS AND THE ROLE OF CHANCE Early natural menopause was reported by 2804 participants. Body mass index (BMI) was non-linearly associated with risk for early menopause. Compared to women with BMI = 18.5-22.4 kg/m2, those with BMI < 18.5 kg/m2 had a significant 30% higher odds of early menopause (95% confidence interval (CI) = 1.08, 1.57), while women with BMIs between 25.0-29.9 kg/m2 had significant 21-30% lower odds. Odds were not higher in women with BMI ≥ 35.0 kg/m2 in fully adjusted analysis. Non-linear associations with higher odds in underweight women were also observed for age 18 and age 35 BMI, though lower odds for overweight women was only observed for age 35 BMI. Odds were highest among women with age 18 BMI < 18.5 kg/m2 reporting severe weight cycling. LIMITATIONS, REASONS FOR CAUTION Though weight and early menopause status were self-reported, validation studies conducted among Nurses' Health Study participants suggest that self-reported weight is highly correlated with directly measured weight, and prospective self-reported menopausal status is highly reproducible. It is possible that underweight women may have been misclassified with an earlier age at menopause if being underweight led to amenorrhea. WIDER IMPLICATIONS OF THE FINDINGS In one of the few studies to prospectively examine a variety of adiposity measures and risk for early menopause, our findings that women who were underweight in early or mid-adulthood had elevated risk for early menopause can assist in efforts to better understand the etiology of early menopause. Additional prospective research is needed to understand how low adiposity may physiologically impact timing of menopause. STUDY FUNDING/COMPETING INTEREST(S) This study was conducted with funding from NIH UM1CA176726 and R01HD078517. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER Not applicable.

Background Platelet activation may play a role in the pathophysiology of placenta-mediated obstetric complications, as evidenced by the efficacy of aspirin for preventing preeclampsia, but published data regarding the relationship between biomarkers for platelet activation and adverse obstetric outcomes are sparse. Specifically, it is unknown whether pre-pregnancy biomarkers of platelet activation are associated with adverse pregnancy outcomes. Objectives To determine: 1) whether maternal plasma concentrations of platelet factor 4 are associated with risk of placenta-mediated adverse obstetric outcomes, and 2) whether these associations are modified by low-dose aspirin. Study Design This ancillary study included measurement of platelet factor 4 among 1,185 of the 1,228 reproductive-age women enrolled in the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial with available plasma samples, with relevant outcomes assessed among 584 women with pregnancies lasting at least 20 weeks’ gestation. We measured platelet factor 4 in plasma samples obtained at the pre-pregnancy study visit (prior to randomization to low-dose aspirin or placebo), 12 weeks of gestation, and 28 weeks of gestation. The primary outcome was a composite of hypertensive disorders of pregnancy, placental abruption, and small-for-gestational age neonate. We estimated relative risks and 95% confidence intervals for the association between platelet factor 4 and the composite and individual outcomes at each time point using log-binomial regression that was weighted to account for potential selection bias and adjusted for age, BMI, education, income, and smoking. To evaluate potential effect modification by aspirin, we stratified analyses by aspirin treatment assignment. Results During follow-up, 95 women experienced the composite adverse obstetric outcome, with 57 cases of hypertensive disorders of pregnancy, 35 of small-for-gestational age (SGA), and 6 of placental abruption. Overall, pre-pregnancy platelet factor 4 was positively associated with the composite outcome (tertile 3 vs. tertile 1 RR 2.36, 95% CI 1.38, 4.03) and with hypertensive disorders of pregnancy (tertile 3 vs. tertile 1 RR 2.14, 95% CI 1.08, 4.23). In analyses stratified by treatment group, associations were stronger in the placebo (tertile 3 vs. tertile 1 RR 3.36, 95% CI 1.42, 7.93) versus the aspirin group (tertile 3 vs. tertile 1 RR 1.78, 95% CI 0.90, 3.50). Conclusions High concentrations of platelet factor 4 prior to pregnancy are associated with increased risk of placenta-mediated adverse pregnancy outcomes, particularly for hypertensive disorders of pregnancy. Aspirin may mitigate the increased risk of these outcomes among women with higher plasma concentrations of preconception platelet factor 4, but low-dose aspirin non-responders may require higher doses of aspirin or alternate therapies to achieve obstetric risk reduction.

OBJECTIVE: To study associations between dietary factors and circulating anti-Mullerian hormone (AMH) concentrations among late premenopausal women. DESIGN: AMH concentrations were measured in serum samples collected at enrollment from 296 women (aged 35–45 years) in the Sister Study cohort. Usual dietary intakes in the past 12 months were assessed using a validated food frequency questionnaire. Dietary exposures of interest included macronutrients, dietary fat subtypes, fiber, and glycemic index. Multivariable linear regression was used to evaluate associations between dietary variables and serum AMH concentrations. We also used nutrient density models to examine isocaloric replacement of macronutrients. SETTING: N/A PATIENTS/ANIMALS: Women aged 35–45 years INTERVENTIONS: N/A MAIN OUTCOME MEASURES: Serum AMH concentrations (ng/ml) RESULTS: AMH concentrations were positively associated with percentage of energy from carbohydrates (β per 5% calories=0.141 [95% CI: 0.023, 0.259]; p-trend=0.019), and inversely associated with percentage of energy from fat (β per 5% calories=−0.152 [95% CI: −0.299, −0.004]; p-trend=0.044). In analyses of dietary fat subtypes, AMH decreased with increasing monounsaturated fatty acids (p-trend=0.082) and polyunsaturated fatty acids (p-trend=0.043), particularly ω−6 fatty acids (p-trend=0.044), while no strong trend was observed for saturated fatty acids. Protein and alcohol intake were not strongly associated with AMH. CONCLUSIONS: Our cross-sectional analyses in a sample of late premenopausal women suggest that dietary fat intake may be inversely associated with circulating AMH concentrations. Further research in prospective studies is warranted to evaluate dietary factors as potential modifiers of ovarian reserve.