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.

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.

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.

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.

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.

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.

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.

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.

Video Summary:http://links.lww.com/MENO/A860 .

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.

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.

The role of maternal preconception vitamin D status in human offspring sex ratio.

Evolutionary theory suggests that some animal species may experience shifts in their offspring sex ratio in response to maternal health and environmental conditions, and in some unfavorable conditions, females may be less likely to bear sons. Experimental data in both animals and humans indicate that maternal inflammation may disproportionately impact the viability of male conceptuses; however, it is unknown whether other factors associated with both pregnancy and inflammation, such as vitamin D status, are associated with the offspring sex ratio. Here, we show that among 1,228 women attempting pregnancy, preconception 25-hydroxyvitamin D concentrations are positively associated with the live birth of a male infant, with notably stronger associations among women with elevated high sensitivity C-reactive protein, a marker of systemic low-grade inflammation. Our findings suggest that vitamin D may mitigate maternal inflammation that would otherwise be detrimental to the implantation or survival of male conceptuses in utero.

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.

Association of Parity and Breastfeeding With Risk of Early Natural Menopause.

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.

The Joint Role of Thyroid Function and Iodine Status on Risk of Preterm Birth and Small for Gestational Age: A Population-Based Nested Case-Control Study of Finnish Women.

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 (2012-2013). 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 10-14 weeks' 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 = 1.02-1.40), but was not associated with SGA (adjusted OR = 1.01, 95% CI = 0.86-1.18). Tg was not associated with preterm birth (OR per 1 log-unit increase = 0.87, 95% CI = 0.73-1.05), but was inversely associated with SGA (OR per log-unit increase = 0.78, 95% CI = 0.65-0.94). 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.

A prospective study of inflammatory biomarker levels and risk of early menopause.

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 antimüllerian 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.

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.