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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.

Background and ObjectiveMigraine is a highly prevalent neurovascular disorder among reproductive-aged women. Whether migraine history and migraine phenotype might serve as clinically useful markers of obstetric risk is not clear. The primary objective of this study was to examine associations of prepregnancy migraine and migraine phenotype with risks of adverse pregnancy outcomes.MethodsWe estimated associations of self-reported physician-diagnosed migraine and migraine phenotype with adverse pregnancy outcomes in the prospective Nurses' Health Study II (1989–2009). Log-binomial and log-Poisson models with generalized estimating equations were used to estimate relative risks (RRs) and 95% CIs for gestational diabetes mellitus (GDM), preeclampsia, gestational hypertension, preterm delivery, and low birthweight.ResultsThe analysis included 30,555 incident pregnancies after cohort enrollment among 19,694 participants without a history of cardiovascular disease, diabetes, or cancer. After adjusting for age, adiposity, and other health and behavioral factors, prepregnancy migraine (11%) was associated with higher risks of preterm delivery (RR = 1.17; 95% CI = 1.05–1.30), gestational hypertension (RR = 1.28; 95% CI = 1.11–1.48), and preeclampsia (RR = 1.40; 95% CI = 1.19–1.65) compared with no migraine. Migraine was not associated with low birthweight (RR = 0.99; 95% CI = 0.85–1.16) or GDM (RR = 1.05; 95% CI = 0.91–1.22). Risk of preeclampsia was somewhat higher among participants with migraine with aura (RR vs no migraine = 1.51; 95% CI = 1.22–1.88) than migraine without aura (RR vs no migraine = 1.30; 95% CI = 1.04–1.61;p-heterogeneity = 0.32), whereas other outcomes were similar by migraine phenotype. Participants with migraine who reported regular prepregnancy aspirin use had lower risks of preterm delivery (p-interaction < 0.01) and preeclampsia (p-interaction = 0.39); however, power for these stratified analyses was limited.DiscussionMigraine history, and to a lesser extent migraine phenotype, appear to be important considerations in obstetric risk assessment and management. Future research should determine whether aspirin prophylaxis may be beneficial for preventing adverse pregnancy outcomes among pregnant individuals with a history of migraine.

Background Epigenetic mechanisms may underlie associations between maternal caffeine consumption and adverse childhood metabolic outcomes. However, limited studies have examined neonate DNA methylation (DNAm) patterns in the context of preconception or prenatal exposure to caffeine metabolites. Objective We examined preconception and pregnancy caffeine exposure with DNAm alterations in neonate cord blood (n = 378). Design In a secondary analysis of the Effects of Aspirin in Gestation and Reproduction Trial (EAGeR), we measured maternal caffeine, paraxanthine, and theobromine concentrations from stored serum collected preconception (on average 2 months before pregnancy) and at 8 weeks of gestation. In parallel, self-reported caffeinated beverage intake was captured via administration of questionnaires and daily diaries. We profiled DNAm from the cord blood buffy coat of singletons using the MethylationEPIC BeadChip. We assessed associations of maternal caffeine exposure and methylation β-values using multivariable robust linear regression. A false discovery rate (FDR) correction was applied using the Benjamini-Hochberg method. Results In preconception the majority of women reported consuming one or fewer servings/day on average and caffeine and paraxanthine metabolite levels were 88 and 36 µmol/L, respectively. Preconception serum caffeine metabolites were not associated with individual CpG sites (FDR > 5%), though pregnancy theobromine was associated with DNAm at cg09460369 near RAB2A (β = 0.028; SE = 0.005; FDR P = 0.012). Preconception self-reported caffeinated beverage intake compared to no intake was associated with DNAm at cg09002832 near GLIS3 (β = -0.013; SE = 0.002; FDR P = 0.036). No associations with self-reported intake during pregnancy were found. Conclusions Few effects of maternal caffeine exposure on neonate methylation differences in leukocytes were identified in this relatively low caffeine consumption population.Clinical Trial Registry: #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.

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.

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.

We evaluated relationships between preconception adiposity and human offspring sex and sex ratio. Using data from a prospective preconception cohort nested within a randomized controlled trial based at 4 US clinical sites (2006–2012), we used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for male:female sex ratio, and log-identity regression to estimate risk differences (RDs) and 95% CIs for male and female livebirth according to preconception adiposity measures. Inverse-probability weights accounted for potential selection bias. Among 603 women attempting pregnancy, there were meaningful reductions in sex ratio for the highest category of each adiposity measure. The lowest sex ratios were observed for obesity (body mass index of ≥30, calculated as weight (kg)/height (m)2, OR = 0.48, 95% CI: 0.26, 0.88) relative to normal body mass index, and the top tertiles (tertile 3) of serum leptin (OR = 0.50, 95% CI: 0.32, 0.80) and skinfold measurements (OR = 0.50, 95% CI: 0.32, 0.79) relative to the lowest tertiles. Reductions were driven by 11–15 fewer male livebirths per 100 women (for obesity, RD = −15, 95% CI: −23, −6.7; for leptin tertile 3, RD = −11, 95% CI: −20, −3.2; and for skinfolds tertile 3, RD = −11, 95% CI: −19, −3.3). We found that relationships between preconception adiposity measures and reduced sex ratio were driven by a reduction in male births.

Preeclampsia, a pregnancy disorder that includes hypertension and proteinuria, is a major cause of maternal and fetal morbidity and mortality. Some studies, but not all, have found that women with preeclampsia have significantly lower iodine levels than healthy pregnant women. Resolving this issue is important because iodine deficiency in pregnancy is common in the USA and parts of Europe including Finland. We conducted a nested case-control study to determine whether the risk for preeclampsia is associated with iodine status. We measured serum iodine, thyroglobulin (Tg), and thyroid stimulating hormone (TSH) at 10-14 weeks gestational age in 204 women with preeclampsia and 246 unaffected controls selected from all births in Finland. We found no significant difference in iodine (case mean = 26.04 ng/mL, control mean = 27.88 ng/mL, p = 0.995), Tg (case mean = 31.11 ng/mL, control mean = 29.61 ng/mL, p = 0.996), and TSH (case mean = 1.30 mIU/L, control mean = 1.24 mIU/L, p = 0.896) levels between cases and controls. There was no significant relationship between preeclampsia risk and iodine, Tg, or TSH after adjustment for known risk factors. These results are reassuring given the high prevalence of iodine deficiency in pregnancy.

Diet, lifestyle, and psychosocial factors might influence fertility for men and women, although evidence is mixed, and couple-based approaches are needed for assessing associations with reproductive outcomes. The Impact of Diet, Exercise, and Lifestyle (IDEAL) on Fertility Study is a prospective cohort with contemporaneous detailed follow-up of female partners of men enrolled in the Folic Acid and Zinc Supplementation Trial studying couples seeking infertility treatment (2016–2019). Follow-up of men continued for 6 months, while female partners were followed for 9 months while attempting pregnancy and throughout any resulting pregnancy (up to 18 months). Longitudinal data on diet, physical activity (including measurement via wearable device), sleep, and stress were captured at multiple study visits during this follow-up. A subset of women (IDEALplus) also completed daily journals and a body fat assessment via dual-energy x-ray absorptiometry. IDEAL enrolled 920 women, and IDEALPlus enrolled 218. We demonstrated the ability to enroll women in a prospective cohort study contemporaneous to a partner-enrolled randomized trial. In combination with data collected on male partners, IDEAL data facilitates a couple-based approach to understanding associations between lifestyle factors and infertility treatment outcomes. We describe in detail the study design, recruitment, data collection, lessons learned, and baseline characteristics.

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.

BACKGROUND: Caffeine is the most frequently used psychoactive substance in the United States and >90% of reproductive-age women report some amount of intake daily. Despite biological plausibility, previous studies on caffeine and fecundability report conflicting results. Importantly, prior studies measured caffeine exposure exclusively by self-report, which is subject to measurement error and does not account for factors that influence caffeine metabolism. OBJECTIVES: Our objective was to examine associations between preconception serum caffeine metabolites, caffeinated beverage intake, and fecundability. METHODS: Participants included 1228 women aged 18–40 y with a history of 1–2 pregnancy losses in the EAGeR (Effects of Aspirin in Gestation and Reproduction) trial. We prospectively evaluated associations of preconception caffeine metabolites (i.e., caffeine, paraxanthine, and theobromine) measured from 1191 serum samples untimed to a specific time of day, self-reported usual caffeinated beverage intakes at baseline, and time-varying cycle-average caffeinated beverage intake, with fecundability. Using Cox proportional hazards models, we estimated fecundability odds ratios (FORs) and 95% CIs according to each metabolite. Follow-up was complete for 89% (n = 1088) of participants. RESULTS: At baseline, 85%, 73%, and 91% of women had detectable serum caffeine, paraxanthine, and theobromine, respectively. A total of 797 women became pregnant during ≤6 cycles of preconception follow-up. After adjusting for potential confounders, neither serum caffeine [tertile (T)3 compared with T1 FOR: 0.87; 95% CI: 0.71, 1.08], paraxanthine (T3 compared with T1 FOR: 0.92; 95% CI: 0.75, 1.14), nor theobromine (T3 compared with T1 FOR: 1.15; 95% CI: 0.95, 1.40) were associated with fecundability. Baseline intake of total caffeinated beverages was not associated with fecundability (>3 compared with 0 servings/d adjusted FOR: 0.99; 95% CI: 0.74, 1.34), nor was caffeinated coffee (>2 compared with 0 servings/d adjusted FOR: 0.93; 95% CI: 0.45, 1.92) or caffeinated soda (>2 servings/d adjusted FOR: 0.92; 95% CI: 0.71, 1.20). CONCLUSIONS: Our findings are reassuring that caffeine exposure from usual low to moderate caffeinated beverage intake likely does not influence fecundability. This trial was registered at clinicaltrials.gov as NCT00467363.

OBJECTIVES: Prior research has suggested that epigenetic mechanisms may underly associations between maternal caffeine intake and adverse childhood metabolic outcomes. We examined preconception and early pregnancy maternal caffeine exposure with DNA methylation (DNAm) patterns in the cord blood of 378 neonates. METHODS: DNAm was profiled by the Infinium MethylationEPIC BeadChip in women enrolled in the EAGeR Trial. Maternal serum was collected 1–2 cycles preconception and at 8 weeks gestation as was self-reported caffeinated beverage intake through standardized questionnaires or daily diaries. Serum caffeine, paraxanthine, and theobromine were measured by liquid chromatography mass spectrometry. We performed multivariable robust linear regression to assess associations between maternal caffeine and methylation β-values and Ingenuity Pathway Analysis to evaluate biologic implications. RESULTS: Preconceptionally, 65%, 21% and 7% reported any soda, coffee or tea intake, respectively with the majority consuming on average ≤ 1 serving/day. Preconception self-reported intake compared to no intake was associated with DNAm at cg09002832 near GLIS3 (false discovery rate [FDR] p = 0.036). No associations with self-reported intake were found during pregnancy. Preconception serum markers were not associated with individual CpG sites (FDR > 5%), though pregnancy theobromine (tertile 2 vs 1) was associated with DNAm at cg09460369 near RAB2A (FDR p = 0.012). Overlapping pathways for the top 100 CpG sites identified in the preconception intake and pregnancy theobromine analyses elucidated cell cycle and lipid metabolism processes. CONCLUSIONS: Few differences in DNAm were identified in association with maternal caffeine intake in this low consumption population. DNAm changes from preconception caffeine or pregnancy theobromine exposure may be linked to signaling networks involving lipid metabolism, but further research among women with higher caffeine and theobromine exposure is warranted. FUNDING SOURCES: Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.

Suboptimal pregnancy conditions may affect ovarian development in the fetus and be associated with early natural menopause (ENM) for offspring. A total of 106,633 premenopausal participants in Nurses’ Health Study II who provided data on their own prenatal characteristics, including diethylstilbestrol (DES) exposure, maternal cigarette smoking exposure, multiplicity, prematurity, and birth weight, were followed from 1989 to 2017. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of in utero exposures with ENM. During 1.6 million person-years of follow-up, 2,579 participants experienced ENM. In multivariable models, women with prenatal DES exposure had higher risk of ENM compared with those without it (HR = 1.33, 95% CI: 1.06, 1.67). Increased risk of ENM was observed for those with low (

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

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.

Earlier age at menopause is associated with increased long-term health risks. Moderate alcohol intake has been suggested to delay menopause onset, but it is unknown whether alcohol subtypes are associated with early menopause onset at age 45 years. Therefore, we aimed to evaluate risk of early natural menopause among 107,817 members of the Nurses’ Health Study II who were followed from 1989 to 2011. Alcohol consumption overall and by subtypes, including beer, red wine, white wine, and liquor, was assessed throughout follow-up. We estimated hazard ratios in multivariable models that were adjusted for age, body mass index, parity, smoking, and other potential confounders. Women who reported moderate current alcohol consumption had lower risks of early menopause than did nondrinkers. Those who reported consuming 10.0–14.9 g/day had a lower risk of early menopause than did nondrinkers (hazard ratio = 0.81, 95% confidence interval: 0.68, 0.97). Among specific beverages, evidence of lower early menopause risk was confined to consumption of white wine and potentially red wine and liquor, but not to beer. Data from this large prospective study suggest a weak association of moderate alcohol intake with lower risk of early menopause, which was most pronounced for consumption of white and red wine and liquor. High consumption was not related to lower risk of early menopause.

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

Context Phytoestrogens may influence fecundability, although biological mechanisms remain elusive. Since it is hypothesized that phytoestrogens may act through influencing hormone levels, we investigated associations between phytoestrogens and menstrual cycle length, a proxy for the hormonal milieu, in healthy women attempting pregnancy. Design A population-based prospective cohort of 326 women ages 18 to 40 with self-reported cycles of 21 to 42 days were followed until pregnancy or for 12 months of attempting pregnancy. Methods Urinary genistein, daidzein, O-desmethylangolensin, equol, enterodiol, and enterolactone were measured upon enrollment. Cycle length was determined from fertility monitors and daily journals. Linear mixed models assessed associations with continuous cycle length and were weighted by the inverse number of observed cycles. Logistic regression models assessed menstrual regularity (standard deviation > 75th vs ≤ 75th percentile). Models were adjusted for age, body mass index, race, creatinine, exercise, supplements, lipids, lead, cadmium, cotinine, parity, alcohol, and other phytoestrogens. Results Individual phytoestrogens were not associated with cycle length, although total phytoestrogens were associated with shorter cycles (−0.042 days; 95% confidence interval [CI], −0.080 to −0.003, per 10% increase). Each 1 nmol/L increase in enterolactone (odds ratio [OR] 0.88; 95% CI, 0.79-0.97) and total lignans (OR 0.85; 95% CI, 0.76-0.95) was associated with reduced irregularity, and each 1 nmol/L increase in genistein with irregularity (OR 1.19; 95% CI, 1.02-1.38). Conclusion Phytoestrogens were not meaningfully associated with cycle length but may be associated with menstrual regularity, among women with self-reported regular cycles. These results highlight differences between isoflavones and lignans and are reassuring for women attempting pregnancy.

Normal maternal thyroid function during pregnancy is essential for fetal development and depends upon an adequate supply of iodine. Little is known about how iodine status is associated with preterm birth and small for gestational age (SGA) in mildly iodine insufficient populations. Our objective was to evaluate associations of early pregnancy serum iodine, thyroglobulin (Tg), and thyroid-stimulating hormone (TSH) with odds of preterm birth and SGA in a prospective, population-based, nested case-control study from all births in Finland (2012&ndash, 2013). Cases of preterm birth (n = 208) and SGA (n = 209) were randomly chosen from among all singleton births. Controls were randomly chosen from among singleton births that were not preterm (n = 242) or SGA (n = 241) infants during the same time period. Women provided blood samples at 10&ndash, 14 weeks&rsquo, gestation for serum iodide, Tg and TSH measurement. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for preterm birth and SGA. Each log-unit increase in serum iodide was associated with higher odds of preterm birth (adjusted OR = 1.19, 95% CI = 1.02&ndash, 1.40), but was not associated with SGA (adjusted OR = 1.01, 95% CI = 0.86&ndash, 1.18). Tg was not associated with preterm birth (OR per 1 log-unit increase = 0.87, 95% CI = 0.73&ndash, 1.05), but was inversely associated with SGA (OR per log-unit increase = 0.78, 95% CI = 0.65&ndash, 0.94). Neither high nor low TSH (versus normal) were associated with either outcome. These findings suggest that among Finnish women, iodine status is not related to SGA, but higher serum iodide may be positively associated with preterm birth.

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.

Early menopause, which is the cessation of ovarian function before age 45 years, affects 5%–10% of Western women and is associated with an increased risk of adverse health outcomes. Literature suggests that high levels of vegetable protein intake may prolong female reproductive function. We evaluated the association of long-term intake of vegetable protein, animal protein, and specific protein-rich foods with incidence of early natural menopause in the Nurses’ Health Study II cohort. Women included in analyses (n = 85,682) were premenopausal at baseline (1991) and followed until 2011 for onset of natural menopause. Protein intake was assessed via food frequency questionnaire. In Cox proportional hazard models that were adjusted for age, smoking, body mass index, and other factors, women in the highest quintile of cumulatively averaged vegetable protein intake (median, 6.5% of calories) had a significant 16% lower risk of early menopause compared with women in the lowest quintile (3.9% of calories; 95% confidence interval: 0.73, 0.98; P for trend = 0.02). Intake of specific foods, including pasta, dark bread, and cold cereal, was also associated with lower risk (P < 0.05). Conversely, animal protein intake was unrelated to risk. High consumption of vegetable protein, equivalent to 3–4 servings per day of protein-rich foods, is associated with lower incidence of early menopause in US women.

Background: Early menopause, defined as the cessation of ovarian function before the age of 45 y, affects ∼10% of women and is associated with higher risk of cardiovascular disease, osteoporosis, and other conditions. Few modifiable risk factors for early menopause have been identified, but emerging data suggest that high vitamin D intake may reduce risk.Objective: We evaluated how intakes of vitamin D and calcium are associated with the incidence of early menopause in the prospective Nurses' Health Study II (NHS2).Design: Intakes of vitamin D and calcium from foods and supplements were measured every 4 y with the use of a food-frequency questionnaire. Cases of incident early menopause were identified from all participants who were premenopausal at baseline in 1991; over 1.13 million person-years, 2041 women reported having natural menopause before the age of 45 y. We used Cox proportional hazards regression to evaluate relations between intakes of vitamin D and calcium and incident early menopause while accounting for potential confounding factors.Results: After adjustment for age, smoking, and other factors, women with the highest intake of dietary vitamin D (quintile median: 528 IU/d) had a significant 17% lower risk of early menopause than women with the lowest intake [quintile median: 148 IU/d; HR: 0.83 (95% CI: 0.72, 0.95); P-trend = 0.03]. Dietary calcium intake in the highest quintile (median: 1246 mg/d) compared with the lowest (median: 556 mg/d) was associated with a borderline significantly lower risk of early menopause (HR: 0.87; 95% CI: 0.76, 1.00; P-trend = 0.03). Associations were stronger for vitamin D and calcium from dairy sources than from nondairy dietary sources, whereas high supplement use was not associated with lower risk.Conclusions: Findings suggest that high intakes of dietary vitamin D and calcium may be modestly associated with a lower risk of early menopause. Further studies evaluating 25-hydroxyvitamin D concentrations, other dairy constituents, and early menopause are warranted.

OBJECTIVES: Marijuana is the most widely used and fastest growing drug in the United States, with legislation currently broadening legalization for both medical and recreational use. However, there are limited data evaluating associations with fecundity and adverse pregnancy outcomes. A few studies evaluating self-reported use suggest marijuana may not be harmful for pregnancy, yet there is a concern for underreporting due to stigma as marijuana is not universally legalized. Our aim was to examine the association between preconception marijuana use, using both self-reported and urinary levels of tetrahydrocannabinol (THC), and fecundability, live birth, and pregnancy loss. METHODS: Women aged 18–40 years old (n = 1212) enrolled in the EAGeR trial were screened for urinary THC at up to 2 time points during preconception using a homogenous enzyme immunoassay from Randox Laboratories, and asked at baseline to report any marijuana use during the past year. Women were followed for up to 6 months while attempting pregnancy. Cox proportional hazard regression was used to calculate fecundability odds ratios (FOR), and log-binomial regression to estimate risk ratios (RR) for live birth and pregnancy loss adjusting for age, race, BMI, education, smoking, alcohol, and detectable levels of opioids. RESULTS: 33 (2.7%) women screened positive for THC during the preconception period, of which 14 also self-reported use during the past year. 62 women (5.1%) either screened positive or self-reported use. Women who screened positive for preconception THC had reduced fecundability (FOR 0.50; 95% CI 0.25, 1.00), as well as women who self-reported marijuana use (FOR 0.54; 95% CI 0.31, 0.94), or who were positive using either urinary or self-report (FOR 0.53, 95% CI 0.33, 0.86). No associations were observed between marijuana use and live birth (RR 0.71; 95% CI 0.41, 1.22) and pregnancy loss (RR 0.78; 95% CI 0.28, 2.18). CONCLUSIONS: Women who screened positive for THC during preconception, or self-reported use during the past year had reduced fecundability, though no associations were observed with live birth or pregnancy loss. Further investigations are needed to determine what duration and dose of marijuana may negatively impact fecundability. FUNDING SOURCES: Intramural Research Program, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development.

OBJECTIVES: Exposure to toxic metals mostly occurs via contaminated food intake. Though toxic metals adversely affect reproductive health, common food sources among reproductive aged women are less understood. We addressed this gap among healthy premenopausal women, residing in western New York, 2005–2007. METHODS: Women enrolled in the BioCycle Study (n = 249, mean age 27.4 years and body mass index [BMI] 24.1 kg/m(2)) completed a baseline food frequency questionnaire and provided blood samples to measure levels of mercury (Hg), lead (Pb), and cadmium (Cd). We used linear regression to examine associations between food intake and log-transformed toxic metals, adjusted for age, BMI, race, smoking, physical activity, and intakes of total energy, protein, fat, and fiber. Models were adjusted for false discovery rate. RESULTS: Total fish intake ≥ 1 serving per day was associated with 54.7% (95% confidence interval [CI] 36.1, 75.9) higher Hg levels, compared to 0 versus no intake). Compared to no intake, green pepper (11.8%) and cauliflower (9.9%) were positively associated with Pb, whereas apples were inversely associated with Pb (−14.6%). No associations were found between food intakes and Cd in our data. CONCLUSIONS: We found that intakes of certain foods are related to a higher blood level of toxic metals among reproductive aged women with metals level typical of the US population. Given the nutritional values of these food items, further research on food preparations (e.g., washing, packing) to reduce toxic metals exposure is needed. FUNDING SOURCES: Intramural Research Program, DIPHR, NICHD.

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.

Background: Clinically significant premenstrual syndrome (PMS) affects 15–20% of premenopausal women, substantially reducing quality of life. Women with PMS often are counseled to minimize caffeine intake, although only limited evidence supports this recommendation. Objective: We evaluated the association between total caffeine, coffee, and tea intake and the development of PMS in a case-control study nested within the prospective Nurses’ Health Study II. Design: All participants were free from PMS at baseline (1991). PMS cases reported a new clinician-made diagnosis of PMS on biennial questionnaires between 1993 and 2005, and then confirmed symptom timing and moderate-to-severe impact and severity of symptoms with the use of a retrospective questionnaire (n = 1234). Controls did not report PMS and confirmed experiencing no symptoms or few mild symptoms with limited personal impact (n = 2426). Caffeine, coffee, and tea intake was measured by food-frequency questionnaires every 4 y, and data on smoking, body weight, and other factors were updated every 2–4 y. Logistic regression was used to evaluate the associations of total caffeine intake and frequency of coffee and tea consumption with PMS. Results: After adjustment for age, smoking, and other factors, total caffeine intake was not associated with PMS. The OR comparing women with the highest (quintile median = 543 mg/d) to the lowest (quintile median = 18 mg/d) caffeine intake was 0.79 (95% CI: 0.61, 1.04; P-trend = 0.31). High caffeinated coffee intake also was not associated with risk of PMS or specific symptoms, including breast tenderness (OR for ≥4 cups/d compared with

Early natural menopause, the cessation of ovarian function prior to age 45 years, affects approximately 10% of women and increases risk of cardiovascular disease and other adverse conditions. Laboratory evidence suggests a potential role of dairy foods in the ovarian aging process; however, no prior epidemiologic studies have evaluated how dairy-food intake is associated with risk of early menopause. We therefore evaluated how intakes of total, low-fat, high-fat, and individual dairy foods were associated with early menopause in Nurses' Health Study II. Women who were premenopausal at the start of follow-up in 1991 were followed until 2011 for early menopause. Food frequency questionnaires were used to assess dietary intake. In Cox proportional hazards models adjusting for age, smoking, and other factors, total baseline dairy-food intake of ≥4 servings/day versus

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.

CONTEXT: Early natural menopause (i.e., before age 45 years) is associated with increased risk of adverse outcomes. Associations of earlier menopause with younger age at menarche and short and/or regular cycle length are suggested, but study findings are inconsistent and few address early menopause risk. OBJECTIVE: To evaluate the relationship between menstrual cycle characteristics in early life with incident early natural menopause. DESIGN: The prospective Nurses’ Health Study 2 (1989 to 2011). SETTING AND PARTICIPANTS: Women ages 25 to 42 years and premenopausal in 1989 (N = 108,811). MAIN OUTCOME MEASURE(S): Risk of early natural menopause not due to surgery, radiation, or chemotherapy (n = 2794) was evaluated with Cox proportional hazards models. Anti-Müllerian hormone (AMH) levels were considered in a nested case-control sample (n = 820). RESULTS: In adjusted models, risk was associated with earlier age at menarche (P for trend = 0.05), shorter (P for trend < 0.0001), and more-regular cycles (P for < 0.0001). The hazard ratio (HR) for women with age at menarche ≤9 (vs. 12) years was 1.28 (95% CI, 0.99 to 1.67). Women reporting usual menstrual cycle lengths

BACKGROUND: Early natural menopause, the cessation of ovarian function before age 45 y, is positively associated with cardiovascular disease and other conditions. Dietary vitamin D intake has been inversely associated with early menopause; however, no previous studies have evaluated risk with regard to plasma 25-hydroxyvitamin D [25(OH)D] concentrations. OBJECTIVE: We prospectively evaluated associations of total and free 25(OH)D and vitamin D–binding protein (VDBP) concentrations and the risk of early menopause in a case-control study nested within the Nurses’ Health Study II (NHS2). We also considered associations of 25(OH)D and VDBP with anti-Müllerian hormone (AMH) concentrations. METHODS: The NHS2 is a prospective study in 116,430 nurses, aged 25–42 y at baseline (1989). Premenopausal plasma blood samples were collected between 1996 and 1999, from which total 25(OH)D and VDBP concentrations were measured and free 25(OH)D concentrations were calculated. Cases experienced menopause between blood collection and age 45 y (n = 328) and were matched 1:1 by age and other factors to controls who experienced menopause after age 48 y (n = 328). Conditional logistic regression models were used to estimate ORs and 95% CIs for early menopause according to each biomarker. Generalized linear models were used to estimate AMH geometric means according to each biomarker. RESULTS: After adjusting for smoking and other factors, total and free 25(OH)D were not associated with early menopause. Quartile 4 compared with quartile 1 ORs were 1.04 (95% CI: 0.60, 1.81) for total 25(OH)D and 0.70 (95% CI: 0.41, 1.20) for free 25(OH)D. 25(OH)D was unrelated to AMH concentrations. VDBP was positively associated with early menopause; the OR comparing the highest with the lowest quartile of VDBP was 1.80 (95% CI: 1.09, 2.98). CONCLUSIONS: Our findings suggest that total and free 25(OH)D are not importantly related to the risk of early menopause. VDBP may be associated with increased risk, but replication is warranted.