Lifetime history of gestational diabetes and cognitive function in parous women in midlife.

AIMS/HYPOTHESIS: We aimed to determine whether a history of gestational diabetes mellitus (GDM) is associated with cognitive function in midlife. METHODS: We conducted a secondary data analysis of the prospective Nurses' Health Study II. From 1989 to 2001, and then in 2009, participants reported their history of GDM. A subset participated in a cognition sub-study in 2014-2019 (wave 1) or 2018-2022 (wave 2). We included 15,906 parous participants (≥1 birth at ≥18 years) who completed a cognitive assessment and were free of CVD, cancer and diabetes before their first birth. The primary exposure was a history of GDM. Additionally, we studied exposure to GDM and subsequent type 2 diabetes mellitus (neither GDM nor type 2 diabetes, GDM only, type 2 diabetes only or GDM followed by type 2 diabetes) and conducted mediation analysis by type 2 diabetes. The outcomes were composite z scores measuring psychomotor speed/attention, learning/working memory and global cognition obtained with the Cogstate brief battery. Mean differences (ß and 95% CI) in cognitive function by GDM were estimated using linear regression. RESULTS: The 15,906 participants were a mean of 62.0 years (SD 4.9) at cognitive assessment, and 4.7% (n=749) had a history of GDM. In models adjusted for age at cognitive assessment, race and ethnicity, education, wave of enrolment in the cognition sub-study, socioeconomic status and pre-pregnancy characteristics, women with a history of GDM had lower performance in psychomotor speed/attention (ß -0.08; 95% CI -0.14, -0.01) and global cognition (ß -0.06; 95% CI -0.11, -0.01) than those without a history of GDM. The lower cognitive performance in women with GDM was only partially explained by the development of type 2 diabetes. CONCLUSIONS/INTERPRETATION: Women with a history of GDM had poorer cognition than those without GDM. If replicated, our findings support future research on early risk modification strategies for women with a history of GDM as a potential avenue to decrease their risk of cognitive impairment.

The Role of Maternal Preconception Adiposity in Human Offspring Sex and Sex Ratio.

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.

Association of In Utero Exposures With Risk of Early Natural Menopause.

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 (<5.5 pounds (<2.5 kg)) versus normal (7.0-8.4 pounds (3.2-3.8 kg)) birth weight (HR = 1.21, 95% CI: 1.01, 1.45). Decreasing risk was observed per 1-pound (0.45-kg) increase in birth weight (HR = 0.93, 95% CI: 0.90, 0.97). Prenatal smoking exposure, being part of a multiple birth, and prematurity were not associated with ENM. In this large cohort study, lower birth weight and prenatal DES exposure were associated with higher risk of ENM. Our results support a need for future research to examine in utero exposures that may affect offspring reproductive health.

Iodine and thyroid status during pregnancy and risk of stillbirth: A population-based nested case-control study.

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.

Is Alcohol Consumption Associated With Risk of Early Menopause?

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.

Preconception leukocyte telomere length and pregnancy outcomes among women with demonstrated fecundity.

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.

A Prospective Cohort Study to Evaluate the Impact of Diet, Exercise, and Lifestyle on Fertility: Design and Baseline Characteristics.

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.

Platelet activation and placenta-mediated adverse pregnancy outcomes: an ancillary study to the Effects of Aspirin in Gestation and Reproduction trial.

BACKGROUND: Platelet activation may play a role in the pathophysiology of placenta-mediated obstetrical complications, as evidenced by the efficacy of aspirin in preventing preeclampsia, but published data regarding the relationship between biomarkers for platelet activation and adverse obstetrical outcomes are sparse. In particular, it is unknown whether prepregnancy biomarkers of platelet activation are associated with adverse pregnancy outcomes. OBJECTIVE: This study aimed to determine the following: (1) whether maternal plasma concentrations of platelet factor 4 are associated with risk of placenta-mediated adverse obstetrical outcomes, and (2) whether these associations are modified by low-dose aspirin. STUDY DESIGN: This ancillary study included measurement of platelet factor 4 among 1185 of 1228 women of reproductive age enrolled in the Effects of Aspirin in Gestation and Reproduction 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 prepregnancy study visit (before randomization to low-dose aspirin or placebo), 12 weeks' gestation, and 28 weeks' gestation. The primary outcome was a composite of hypertensive disorders of pregnancy, placental abruption, and small-for-gestational-age infant. We estimated the relative risks (RRs) and 95% confidence intervals (CIs) 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, body mass index, education, income, and smoking. To evaluate the potential effect modification of aspirin, we stratified the analyses by aspirin treatment assignment. RESULTS: During follow-up, 95 women experienced the composite adverse obstetrical outcome, with 57 cases of hypertensive disorders of pregnancy, 35 of small for gestational age, and 6 of placental abruption. Overall, prepregnancy platelet factor 4 was positively associated with the composite outcome (third tertile vs first tertile; relative risk, 2.36; 95% confidence interval, 1.38-4.03) and with hypertensive disorders of pregnancy (third tertile vs first tertile; relative risk, 2.14; 95% confidence interval, 1.08-4.23). In analyses stratified by treatment group, associations were stronger in the placebo group (third tertile vs first tertile; relative risk, 3.36; 95% confidence interval, 1.42-7.93) than in the aspirin group (third tertile vs first tertile; relative risk, 1.78; 95% confidence interval, 0.90-3.50). CONCLUSION: High concentrations of platelet factor 4 before 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 nonresponders may require higher doses of aspirin or alternate therapies to achieve obstetrical risk reduction.

A Prospective Study of Dairy-Food Intake and Early Menopause.

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 <4 servings/week was associated with 23% lower risk of early menopause (hazard ratio = 0.77, 95% confidence interval: 0.64, 0.93; P for trend = 0.08). Associations appeared to be limited to low-fat dairy foods (for ≥2 servings/day vs. <3 servings/month, hazard ratio = 0.83, 95% confidence interval: 0.68, 1.01; P for trend = 0.02), whereas high-fat dairy-food intake was not associated with early menopause. Low-fat dairy foods may represent a modifiable risk factor for reducing risk of early menopause among premenopausal women.

Cigarette Smoking and Risk of Early Natural Menopause.

Menopause before 45 years of age affects roughly 5%-10% of women and is associated with a higher risk of adverse health conditions. Although smoking may increase the risk of early menopause, evidence is inconsistent, and data regarding smoking amount, duration, cessation, associated risks, and patterns over time are scant. We analyzed data of 116,429 nurses from the Nurses' Health Study II from 1989 through 2011 and used Cox proportional hazards models to estimate hazard ratios adjusted for confounders. Compared with never-smokers, current smokers (hazard ratio (HR) = 1.90, 95% confidence interval (CI): 1.71, 2.11) and former smokers (HR = 1.10, 95% CI: 1.00, 1.21) showed an increased risk of early menopause. Increased risks were observed among women who reported current smoking for 11-15 pack-years (HR = 1.72, 95% CI: 1.36, 2.18), 16-20 pack-years (HR = 1.72, 95% CI: 1.38, 2.14), and more than 20 pack-years (HR = 2.42, 95% CI: 2.11, 2.77). Elevated risk was observed in former smokers who reported 11-15 pack-years (HR = 1.29, 95% CI: 1.07, 1.55), 16-20 pack-years (HR = 1.42, 95% CI: 1.13, 1.79), or more than 20 pack-years (HR = 1.54, 95% CI: 1.23, 1.93). Women who smoked 10 or fewer cigarettes/day but quit by age 25 had comparable risk to never-smokers (HR = 1.03, 95% CI: 0.91, 1.17). A dose-response relationship between smoking and early natural menopause risk, as well as reduced risk among quitters, may provide insights into the mechanisms of cigarette smoking in reproductive health.

Anti-Müllerian hormone levels and incidence of early natural menopause in a prospective study.

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.

Physical activity is not related to risk of early menopause in a large prospective study.

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 <3 MET h/week, the hazard ratio for women in the highest category (≥42 MET h/week) of cumulatively-averaged total physical activity was 0.89 (95% confidence interval: 0.76-1.04; P-trend: 0.26). Neither moderate nor strenuous activity in adolescence and young adulthood were related to risk. The relation of physical activity and early menopause did not vary across strata of body mass index or smoking status. LIMITATIONS, REASONS FOR CAUTION: Physical activity and menopausal status were self-reported, but repeated assessment of physical activity and prospective report of menopause status likely reduce the potential for non-differential misclassification. While the majority of our study participants were white, it is unlikely that the physiological relation of activity and early menopause varies by ethnicity. WIDER IMPLICATIONS OF THE FINDINGS: Findings from our large prospective study do not support an important association between physical activity and early menopause. STUDY FUNDING/COMPETING INTEREST(S): This project was supported by UM1CA176726 and R01HD078517 from the National Institutes of Health, Department of Health and Human Services. No competing interests are declared. TRIAL REGISTRATION NUMBER: N/A.

Vitamin D Status Is Not Associated with Risk of Early Menopause.

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.

Intake of Energy Drinks Before and During Pregnancy and Adverse Pregnancy Outcomes.

Importance: Consumption of energy drinks has increased drastically in recent years, particularly among young people. It is unknown whether intake of energy drinks is associated with health during pregnancy. Objective: To examine associations of energy drink intake before and during pregnancy with risk of adverse pregnancy outcomes (APOs). Design, Setting, and Participants: This prospective cohort study included data from women enrolled in the Nurses' Health Study 3 (NHS3) between June 1, 2010, and September 27, 2021, and the Growing Up Today Study (GUTS) who reported 1 or more singleton pregnancy from January 1, 2011, to June 1, 2019. Data were analyzed from October 1, 2021, to September 28, 2023. Exposure: Intake of energy drinks, assessed by food frequency questionnaire. Main Outcomes and Measures: The main outcomes were self-reported APOs, including pregnancy loss, gestational diabetes, gestational hypertension, preeclampsia, or preterm birth, and a composite APO, defined as development of any of the APOs. Risk of APOs was compared between consumers and nonconsumers of energy drinks. Results: This study included 7304 pregnancies in 4736 participants with information on prepregnancy energy drink intake and 4559 pregnancies in 4559 participants with information on energy drink intake during pregnancy. There were 1691 GUTS participants (mean [SD] age, 25.7 [2.9] years) and 3045 NHS3 participants (mean [SD] age, 30.2 [4.1] years). At baseline, 230 GUTS participants (14%) and 283 NHS3 participants (9%) reported any intake of energy drinks. While no associations were found for pregnancy loss (odds ratio [OR], 0.89; 95% CI, 0.71-1.11), preterm birth (OR, 1.07; 95% CI, 0.71-1.61), gestational diabetes (OR, 0.89; 95% CI, 0.58-1.35), preeclampsia (OR, 0.73; 95% CI, 0.41-1.30), or the composite APO (OR, 1.05; 95% CI, 0.87-1.26), prepregnancy energy drink use was associated with a higher risk of gestational hypertension (OR, 1.60; 95% CI, 1.12-2.29). A significant interaction was found between age and energy drink intake in relation to hypertensive disorders (P = .02 for interaction for gestational hypertension; P = .04 for interaction for any hypertensive disorders), with stronger associations for participants above the median age. No associations of energy drink intake during pregnancy with any of the APOs were found in NHS3 (eg, any APO: OR, 0.86; 95% CI, 0.41-1.79). Conclusions and Relevance: In this study, energy drink intake before pregnancy was associated with an elevated risk of gestational hypertension. Given the low prevalence of energy drink intake and low consumption levels among users, the results should be interpreted cautiously.

Prepregnancy Migraine, Migraine Phenotype, and Risk of Adverse Pregnancy Outcomes.

BACKGROUND AND OBJECTIVE: Migraine 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. METHODS: We 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. RESULTS: The 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 (<2×/week RR = 1.24; 95% CI = 1.11-1.38; ≥2×/week RR = 0.55; 95% CI = 0.35-0.86; p-interaction < 0.01) and preeclampsia (<2×/week RR = 1.48; 95% CI = 1.25-1.75; ≥2×/week RR = 1.10; 95% CI = 0.62-1.96; p-interaction = 0.39); however, power for these stratified analyses was limited. DISCUSSION: Migraine 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.

Association of adverse pregnancy outcomes and multiple gestation with natural menopause: A population-based cohort study.

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

Preconception sleep duration, sleep timing, and shift work in association with fecundability and live birth among women with a history of pregnancy loss.

OBJECTIVE: To evaluate the associations between preconception sleep characteristics and shift work with fecundability and live birth. DESIGN: Secondary analysis of the Effects of Aspirin in Gestation and Reproduction study, a preconception cohort. SETTING: Four US academic medical centers. PATIENT(S): Women aged 18-40 with a history of 1-2 pregnancy losses who were attempting to conceive again. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURES(S): 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. RESULT(S): Sleep duration ≥9 vs. 7 to <8 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 to <8 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. CONCLUSION(S): 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. CLINICAL TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT00467363.

Preconception caffeine metabolites, caffeinated beverage intake, and fecundability.

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.

Association of oral contraceptives and tubal ligation with antimüllerian hormone.

OBJECTIVE: Oral contraceptives (OCs) and tubal ligation are commonly used methods of contraception that may impact ovarian function. Few studies have examined the association of these factors with antimüllerian hormone (AMH), a marker of ovarian aging. METHODS: We examined the association of OC 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 OC use and tubal ligation were reported in 1989 and updated every 2 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 OCs 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 OC use and mean AMH levels (P for trend = 0.036). 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 < 0.01). AMH levels were not associated with age at first use of OCs or age at tubal ligation. CONCLUSIONS: Our analysis found an association between duration of OC use and certain types of tubal ligation with mean AMH levels. Further research is warranted to confirm the long-term association of these widely used contraceptive methods with AMH.

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