Search

Summary Objective Obesity has become a major, worldwide public health issue and is associated with a greater risk of adverse pregnancy outcomes. Leptin, a hormone produced by adipocytes, is elevated in individuals with obesity and may mediate the association between obesity and pregnancy outcomes. Though leptin levels during pregnancy have been associated with pregnancy outcomes, less is understood regarding preconception levels. Therefore, the objective of this study was to evaluate associations between preconception leptin levels and adverse pregnancy outcomes. Methods This was a prospective cohort study nested within a large randomized controlled trial conducted at four medical centres in the United States. A total of 1078 women completed the parent study; this analysis involved women who became pregnant during that study (n = 776). Patients were healthy women, ages 18 to 40, attempting to conceive, with 1 to 2 prior pregnancy losses. Participants were followed for less than or equal to 6 cycles while trying to conceive and throughout pregnancy if they conceived. Preconception leptin concentrations were measured in serum collected at baseline then categorized by tertiles (using the lowest as reference group). Weighted log‐binomial regression estimated risk ratios (RR) and 95% confidence intervals (CIs) for pregnancy loss, preterm delivery (PTD), gestational diabetes (GDM), and hypertensive disorders in pregnancy, adjusting for age, waist‐to‐hip ratio (WHR), and body mass index (BMI). Results The mean (SD) BMI in this cohort was 25.4 ± 6.0. GDM (RR 18.37; 95% CI, 2.39‐141.55) and hypertensive disorders of pregnancy (RR 2.35; 95% CI, 1.20‐4.61) risks were higher among women in the high tertile after adjusting for age and WHR. The associated risk persisted when adjusting for BMI for GDM but was attenuated for hypertensive disorders in pregnancy. Leptin levels were not associated with risk of pregnancy loss or PTD. Conclusions Women with higher baseline preconception leptin levels had a higher likelihood of experiencing some adverse pregnancy outcomes including GDM and hypertensive disorders of pregnancy. These findings warrant further evaluation, especially in light of the association between leptin and obesity.

STUDY QUESTION How do the calciotropic hormones (25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and intact parathyroid hormone (iPTH)) vary across the menstrual cycle and do cyclic patterns of reproductive hormones (estradiol, progesterone, LH, FSH) differ by vitamin D status? SUMMARY ANSWER Calciotropic hormones vary minimally across the menstrual cycle; however, women with 25-hydroxyvitamin D below 30 ng/ml have lower mean estradiol across the menstrual cycle. WHAT IS KNOWN ALREADY Prior human studies suggest that vitamin D status is associated with fecundability, but the mechanism is unknown. Exogenous estrogens and prolonged changes in endogenous estradiol (pregnancy or menopause) influence concentrations of 25-hydroxyvitamin D. In vitro, treatment with 1,25-dihydroxyvitamin D increases steroidogenesis in ovarian granulosa cells. There are little data about changes in calciotropic hormones across the menstrual cycle or cyclic patterns of reproductive hormones by categories of vitamin D status. STUDY DESIGN, SIZE, DURATION A prospective cohort study of 89 self-identified white women aged 18–44, across two menstrual cycles. Participants were a subset of the BioCycle Study, a community-based study conducted at the University of Buffalo, 2005–2007. PARTICIPANTS/MATERIALS, SETTING, METHODS Eligible participants had self-reported regular menstrual cycles between 21 and 35 days and were not using hormonal contraception or vitamins. Early morning fasting blood samples were drawn at up to eight study visits per cycle. Visits were timed to capture information in all cycle phases. Serum samples for 89 women (N = 163 menstrual cycles) were analyzed for estradiol, progesterone, LH, FSH and 25-hydroxyvitamin D (25(OH)D). Variability in calciotropic hormones within and across menstrual cycles was assessed using intraclass correlation coefficients and non-linear mixed models. Given the relative stability of the calciotropic hormones across the menstrual cycle, non-linear mixed models were used to examine differences in the cyclic patterns of estradiol, progesterone, LH and FSH by categories of each calciotropic hormone (split at the median). These models were conducted for all ovulatory cycles (N = 142 ovulatory menstrual cycles) and were adjusted for age, BMI (measured in clinic) and self-reported physical activity. MAIN RESULTS AND THE ROLE OF CHANCE Median 25(OH)D concentration was 29.5 ng/ml (SD 8.4), and only 6% of women had vitamin D deficiency ( LIMITATIONS, REASONS FOR CAUTION Women included in this study had self-reported ‘regular’ menstrual cycles and very few were found to have 25(OH)D deficiency. This limits our ability to examine cycle characteristics, anovulation and the effects of concentrations of the calciotropic hormones found in deficient individuals. Additionally, the results may not be generalizable to women with irregular cycles, other races, or populations with a higher prevalence of vitamin D deficiency. WIDER IMPLICATIONS OF THE FINDINGS These findings support current clinical practice that does not time testing for vitamin D deficiency to the menstrual cycle phase. We find that women with lower vitamin D status (lower 25(OH)D or higher iPTH) have lower mean concentrations of estradiol across the menstrual cycle. Although this study cannot identify a mechanism of action, further in vitro work or clinical trials may help elucidate the biologic mechanisms linking calciotropic and reproductive hormones. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contract numbers: HHSN275200403394C, HHSN275201100002I and Task 1 HHSN27500001) and the National Institute of Environmental Health Sciences. There are no competing interests.

Systematic reviews and meta-analyses are essential for drawing conclusions regarding etiologic associations between exposures or interventions and health outcomes. Observational studies comprise a substantive source of the evidence base. One major threat to their validity is residual confounding, which may occur when component studies adjust for different sets of confounders, fail to control for important confounders, or have classification errors resulting in only partial control of measured confounders. We present the confounder matrix-an approach for defining and summarizing adequate confounding control in systematic reviews of observational studies and incorporating this assessment into meta-analyses. First, an expert group reaches consensus regarding the core confounders that should be controlled and the best available method for their measurement. Second, a matrix graphically depicts how each component study accounted for each confounder. Third, the assessment of control adequacy informs quantitative synthesis. We illustrate the approach with studies of the association between short interpregnancy intervals and preterm birth. Our findings suggest that uncontrolled confounding, notably by reproductive history and sociodemographics, resulted in exaggerated estimates. Moreover, no studies adequately controlled for all core confounders, so we suspect residual confounding is present, even among studies with better control. The confounder matrix serves as an extension of previously published methodological guidance for observational research synthesis, enabling transparent reporting of confounding control and directly informing meta-analysis so that conclusions are drawn from the best available evidence. Widespread application could raise awareness about gaps across a body of work and allow for more valid inference with respect to confounder control.

Salivary steroid immunoassays are widely used in psychoneuroendocrinological studies of menstrual cycle phase, puberty, and menopause. Though manufacturers advertise their assays as suitable, they have not been rigorously validated for these purposes. We collated data from eight menstrual cycle studies across >1,200 women and >9,500 time points. Seven studies collected saliva and one collected serum. All assayed estradiol and progesterone and had an independent measure of cycle phase (LH-surge, menstrual onset). In serum, cycle phase measures strongly predicted steroid concentrations. In saliva, cycle phase poorly predicted estradiol values, which showed an upward bias compared to expectations from serum. For salivary progesterone, predictability from cycle phase was mixed. Widely used enzyme-linked assays performed poorly, while LC-MS/MS performed better. Imputing the population-average serum steroid changes from cycle phase may yield more valid values of hormonal changes for an independent person than directly assessing their hormone levels using salivary immunoassays.

Despite research indicating that sleep disorders influence reproductive health, the effects of sleep on reproductive hormone concentrations are poorly characterized. We prospectively followed 259 regularly menstruating women across one to two menstrual cycles (the BioCycle Study, 2005–2007), measuring fasting serum hormone concentrations up to eight times per cycle. Women provided information about daily sleep in diaries and chronotype and night/shift work on a baseline questionnaire. We evaluated percent differences in mean hormone concentrations, the magnitude of shifts in the timing and amplitude of hormone peaks, and the risk for sporadic anovulation associated with self-reported sleep patterns and night/shift work. We estimated chronotype scores – categorizing women below and above the interquartile range (IQR) as “morning” and “evening” chronotypes, respectively. For every hour increase in daily sleep duration, mean estradiol concentrations increased by 3.9% (95% confidence interval [CI] 2.0, 5.9%) and luteal phase progesterone by 9.4% (CI 4.0, 15.2%). Receiving less than 7 hours of sleep per day was associated with slightly earlier rises in peak levels for several hormones. Women reporting night/shift work (n = 77) had lower testosterone relative to women employed without night/shift work (percent difference: −9.9%, CI −18.4, −0.4%). Women with morning chronotypes (n = 47) had earlier rises in estradiol during their cycles and potentially an earlier rise in luteinizing hormone. Compared to those who had intermediate chronotypes, women with evening chronotypes (n = 42) had a later luteinizing hormone peak of borderline statistical significance. A reduced risk for sporadic anovulation was suggested, but imprecise, for increasing hours of daily sleep leading up to ovulation (risk ratio 0.79, CI 0.59, 1.06), while an imprecise increased risk was observed for women with morning chronotypes (risk ratio 2.50, CI 0.93, 6.77). Sleep-related hormonal changes may not greatly alter ovarian function in healthy women, but have the potential to influence gynecologic health.

Background Although fatty acids are involved in critical reproductive processes, the relationship between specific fatty acids and fertility is uncertain. We investigated the relationship between preconception plasma fatty acids and pregnancy outcomes. Methods We included 1,228 women attempting pregnancy with one to two previous pregnancy losses from the EAGeR trial (2007-2011). Plasma fatty acids were measured at baseline. We used log-binomial regression to assess associations between fatty acids and pregnancy, pregnancy loss, and live birth, adjusting for age, race, smoking, BMI, physical activity, income, parity, treatment arm, and cholesterol. Results Although total saturated fatty acids (SFAs) were not associated with pregnancy outcomes, 14:0 (myristic acid; relative risk [RR] = 1.10, 95% confidence interval [CI] = 1.02, 1.19, per 0.1% increase) and 20:0 (arachidic acid; RR = 1.05, 95% CI = 1.01, 1.08, per 0.1% increase) were positively associated with live birth. Findings suggested a positive association between total monounsaturated fatty acids (MUFAs) and pregnancy and live birth and an inverse association with loss. Total polyunsaturated fatty acids (PUFAs) were associated with lower probability of pregnancy (RR = 0.97, 95% CI = 0.95, 1.00) and live birth (RR = 0.96, 95% CI = 0.94, 0.99), and increased risk of loss (RR = 1.10, 95% CI = 1.00, 1.20), per 1% increase. Trans fatty acids and n-3 fatty acids were not associated with pregnancy outcomes. Conclusions Preconception total plasma MUFAs were positively associated with pregnancy and live birth. PUFAs were inversely associated with pregnancy outcomes. Specific SFAs were associated with a higher probability of live birth. Our results suggest that fatty acids may influence pregnancy outcomes.

Background Women who experience pregnancy loss are especially prone to high stress, though the effects of stress on reproductive outcomes in this vulnerable population are unknown. We assessed relationships between perceived stress and hormones, anovulation, and fecundability among women with prior loss. Methods One thousand two hundred fourteen women with 1-2 prior losses were followed for ≤6 cycles while attempting pregnancy and completed end-of-cycle stress assessments. For cycles 1 and 2, women also collected daily urine and completed daily perceived stress assessments. We assessed anovulation via. an algorithm based on human chorionic gonadotropin (hCG), pregnanediol-3-glucuronide (PdG), luteinizing hormone (LH), and fertility monitor readings. Pregnancy was determined via. hCG. Adjusted weighted linear mixed models estimated the effect of prospective phase-varying (menses, follicular, periovulatory, and luteal) perceived stress quartiles on estrone-1-glucuronide (E1G), PdG, and LH concentrations. Marginal structural models accounted for time-varying confounding by hormones and lifestyle factors affected by prior stress. Poisson and Cox regression estimated risk ratios and fecundability odds ratios of cycle-varying stress quartiles on anovulation and fecundability. Models were adjusted for age, race, body mass index (BMI), parity, and time-varying caffeine, alcohol, smoking, intercourse, and pelvic pain. Results Women in the highest versus lowest stress quartile had lower E1G and PdG concentrations, a marginally higher risk of anovulation [1.28; 95% confidence interval (CI) = 1.00, 1.63], and lower fecundability (0.71; 95% CI = 0.55, 0.90). Conclusion Preconception perceived stress appears to adversely affect sex steroid synthesis and time to pregnancy. Mechanisms likely include the effects of stress on ovulatory function, but additional mechanisms, potentially during implantation, may also exist.

STUDY QUESTION: Is sperm epigenetic aging (SEA) associated with probability of pregnancy among couples in the general population? SUMMARY ANSWER: We observed a 17% lower cumulative probability at 12 months for couples with male partners in the older compared to the younger SEA categories. WHAT IS KNOWN ALREADY: The strong relation between chronological age and DNA methylation profiles has enabled the estimation of biological age as epigenetic ‘clock’ metrics in most somatic tissue. Such clocks in male germ cells are less developed and lack clinical relevance in terms of their utility to predict reproductive outcomes. STUDY DESIGN, SIZE, DURATION: This was a population-based prospective cohort study of couples discontinuing contraception to become pregnant recruited from 16 US counties from 2005 to 2009 and followed for up to 12 months. PARTICIPANTS/MATERIALS, SETTING, METHODS: Sperm DNA methylation from 379 semen samples was assessed via a beadchip array. A state-of-the-art ensemble machine learning algorithm was employed to predict age from the sperm DNA methylation data. SEA was estimated from clocks derived from individual CpGs (SEA(CpG)) and differentially methylated regions (SEA(DMR)). Probability of pregnancy within 1 year was compared by SEA, and discrete-time proportional hazards models were used to evaluate the relations with time-to-pregnancy (TTP) with adjustment for covariates. MAIN RESULTS AND THE ROLE OF CHANCE: Our SEA(CpG) clock had the highest predictive performance with correlation between chronological and predicted age (r = 0.91). In adjusted discrete Cox models, SEA(CpG) was negatively associated with TTP (fecundability odds ratios (FORs)=0.83; 95% CI: 0.76, 0.90; P = 1.2×10(−5)), indicating a longer TTP with advanced SEA(CpG). For subsequent birth outcomes, advanced SEA(CpG) was associated with shorter gestational age (n = 192; −2.13 days; 95% CI: −3.67, −0.59; P = 0.007). Current smokers also displayed advanced SEA(CpG) (P

Background: Maternal prenatal stress is associated with physiologic and adverse mental health outcomes in the offspring, but the underlying biologic mechanisms are unknown. We examined the associations of maternal perceived stress, including preconception exposure, with DNA methylation (DNAm) alterations in the cord blood buffy coats of 358 singleton infants. Methods: Maternal perceived stress was measured prior to and throughout pregnancy in a cohort of women enrolled in Effects of Aspirin in Gestation and Reproduction Trial (EAGeR) trial. Perceived stress assessments based on a standardized Likert-scale were obtained in periconception (~2 months preconception and 2-8 weeks of gestation) and pregnancy (8-36 weeks of gestation). Cumulative perceived stress was estimated by calculating the predicted area under the curve of stress reported prior to and during pregnancy. DNAm was measured by the Infinium MethylationEPIC BeadChip. Multivariable robust linear regression was used to assess associations of perceived stress with individual CpG probes. Results: Based on a 0 to 3 scale, average reported preconception and early pregnancy stress were 0.76 (0.60) and 0.67 (0.50), respectively. Average mid- to late-pregnancy stress, based on a 0 to 10 scale, was 4.9 (1.6). Neither periconception nor pregnancy perceived stress were associated with individual CpG sites in neonatal cord blood (all false discovery rate [FDR] >5%). Conclusion: No effects of maternal perceived stress exposure on array-wide cord blood neonatal methylation differences were found.

OBJECTIVE Ultraprocessed foods (UPFs) have been linked with obesity and cardiometabolic diseases in the general population but are understudied in pregnancy. We examined associations of UPF intake with gestational weight gain (GWG), glycemic, and blood pressure outcomes in pregnancy. RESEARCH DESIGN AND METHODS Pregnant women (n = 1,948) in a prospective U.S. cohort self-reported the past 3-month diet using a food frequency questionnaire (FFQ) at 8–13 weeks of gestation. The intake quantity (g/day) of foods and beverages identified as UPFs was ranked into quartiles. Associations of UPFs were evaluated, after adjusting for confounders, with 2nd and 3rd trimester Institute of Medicine (IOM) GWG categories, gestational diabetes mellitus (GDM), and hypertensive disorders of pregnancy (GHTN). Secondary outcomes included GWG rate, glucose challenge test 1-h glucose, and blood pressure trajectories from linear mixed models. RESULTS A total of 492 (25.2%) and 699 women (35.9%) had 2nd and 3rd trimester excessive GWG, respectively, and 85 women (4.4%) had GDM and 63 (3.2%) had severe hypertension or preeclampsia. UPF intake was not associated with higher odds of excessive GWG (quartile 4 vs. 1: adjusted odds ratio 0.68 [95% CI 0.44, 1.05], P-trend = 0.10 for 2nd trimester) or GDM risk (quartile 4 vs. 1: adjusted risk ratio 0.99 [95% CI 0.46, 2.11], P-trend = 0.85). Although UPF intake was positively associated with minor differences blood pressure trajectories, associations with GHTN were null. CONCLUSIONS The expected unfavorable association of higher UPF intake with excessive GWG, GDM, and GHTN was not observed in our cohort of low-risk pregnant women. These results are based on a limited sample size and require replication.

Key Points Question Is caffeine intake associated with major cardiometabolic complications during pregnancy (ie, gestational diabetes [GDM], preeclampsia, gestational hypertension)? Findings In this cohort study of 2802 pregnant women, low and moderate caffeinated beverage intake early in second trimester within current guidelines of less than 200 mg per day were associated with a lower risk for GDM, lower glucose levels at GDM screening, and more favorable cardiometabolic profile compared with no consumption. Caffeine was not associated with gestational hypertension or preeclampsia. Meaning The findings of this study may be reassuring for pregnant women with moderate caffeine intake and should be considered in the context of published data on associations with offspring health., This cohort study examines whether caffeinated-beverage intake and plasma caffeine and paraxanthine are associated with cardiometabolic complications in pregnancy., Importance Women are recommended to limit caffeine consumption to less than 200 mg per day based on risks to fetal health. Impacts of caffeine on maternal health remain unclear. Objective To determine whether caffeinated-beverage intake and plasma caffeine and paraxanthine are associated with cardiometabolic complications in pregnancy (ie, gestational diabetes [GDM], preeclampsia, and gestational hypertension [GH]). Design, Setting, and Participants This cohort study used data from a longitudinal pregnancy cohort study from the National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-Singletons (2009-2013). This post hoc secondary analysis of 2802 pregnant women without major chronic conditions enrolled at 12 US clinical sites was completed in 2021. The final sample for caffeinated beverage analyses included 2583 women. After excluding women who did not consent to have their biospecimens stored for future research (n = 54), plasma caffeine analyses included 2529 women. Analyses of caffeine consumption and fasting cardiometabolic profiles included 319 women. Exposures Daily total caffeine intake was estimated at 10 to 13 gestational weeks and 16 to 22 gestational weeks based on self-reported past week intake of caffeinated coffee, tea, soda, and energy drinks. Plasma caffeine and paraxanthine were measured in specimens collected at 10 to 13 weeks. Main Outcomes and Measures Clinical diagnoses of GDM, preeclampsia, GH, glucose concentrations from GDM screening, and blood pressure were extracted from medical records. Results Participants had a mean (SD) age of 28.1 (5.5) years and 422 participants (16.3%) were Asian/Pacific Islander women, 741 (28.9%) were Hispanic women, 717 (27.8%) were non-Hispanic Black women, and 703 (27.2%) were non-Hispanic White women. At 10 to 13 weeks, 1073 women (41.5%) reported consuming no caffeinated beverages, 1317 (51.0%) reported consuming 1 mg/d to 100 mg/d, 173 (6.7%) reported consuming 101 mg/d to 200 mg/d, and 20 (0.8%) reported consuming more than 200 mg/d. At 16 to 22 weeks, 599 women (23.6%) reported consuming no caffeinated beverages, 1734 (68.3%) reported consuming 1 mg/d to 100 mg/d, 186 (7.3%) reported consuming 101 mg/d to 200 mg/d, and 20 (0.8%) reported consuming more than 200 mg/d caffeinated beverages. Intake at 16 to 22 weeks was associated with lower GDM risk and lower glucose concentrations (1 mg/d to 100 mg/d vs none: relative risk, 0.53 [95% CI, 0.35 to 0.80]; β, –2.7 mg/dL [95% CI, –5.4 mg/dL to 0 mg/dL]) and lower C-reactive protein and C-peptide concentrations and favorable lipid profiles. Total plasma caffeine and paraxanthine at 10 to 13 weeks was inversely associated with glucose (quartile 4 vs quartile 1: β = –3.8 mg/dL [95% CI, –7.0 mg/dL to –0.5 mg/dL]; trend of P = .01). No associations were observed with preeclampsia or GH. Conclusions and Relevance In this cohort study, second trimester caffeinated beverage intake within current recommendations was associated with lower GDM risk, but not preeclampsia or GH. These findings may be reassuring for women with moderate caffeine intake.

Pregnancy loss is a common reproductive complication, but its association with long-term mortality and whether this varies by maternal race/ethnicity is not well understood. Data from a racially diverse cohort of pregnant women enrolled in the Collaborative Perinatal Project (CPP) from 1959 to 1966 were used for this study. CPP records were linked to the National Death Index and the Social Security Death Master File to identify deaths and underlying cause (until 2016). Pregnancy loss comprised self-reported losses, including abortions, stillbirths, and ectopic pregnancies. Among 48,188 women (46.0% White, 45.8% Black, 8.2% other race/ethnicity), 25.6% reported at least 1 pregnancy loss and 39% died. Pregnancy loss was associated with a higher absolute risk of all-cause mortality (risk difference, 4.0 per 100 women, 95% confidence interval: 1.4, 6.5) and cardiovascular mortality (risk difference, 2.2 per 100 women, 95% confidence interval: 0.8, 3.5). Stratified by race/ethnicity, a higher risk of mortality persisted in White, but not Black, women. Women with recurrent losses are at increased risk of death, both overall and across all race/ethnicity groups. Pregnancy loss is associated with death; however, it does not confer an excess risk above the observed baseline risk in Black women. These findings support the need to assess reproductive history as part of routine screening in women.

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.

To examine the relationship of preconception hemoglobin A1c, a marker of cumulative exposure to glucose over the preceding 2-3 months, with time to pregnancy, pregnancy loss, and live birth among fecund women without diagnosed diabetes or other medical diseases.A secondary analysis of a prospective cohort of women participating in the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial.Four US academic medical centers.A total of 1,194 healthy women aged 18-40 years with a history of one or two pregnancy losses attempting spontaneous conception were observed for up to six cycles while attempting pregnancy and throughout pregnancy if they conceived.Not applicable.Time to pregnancy, human chorionic gonadotropin pregnancy, clinical pregnancy, pregnancy loss, and live birth.Although increasing preconception A1c level was associated with reduced fecundability (fecundability odds ratio [FOR] per unit increase in A1c 0.74; 95% confidence interval [CI] 0.57, 0.96) in unadjusted models and models adjusted for age, race, smoking and treatment arm (FOR 0.79; 95% CI 0.60, 1.04), results were attenuated after further adjustment for body mass index (FOR 0.91; 95% CI 0.68, 1.21). Preconception A1c levels among women without diagnosed diabetes were not associated with live birth or pregnancy loss.Among healthy women without diagnosed diabetes, we observed no association of A1c with live birth or pregnancy loss. The association between A1c and fecundability was influenced by body mass index, a strong risk factor for both diabetes and infertility. These data support current recommendations that preconception A1c screening should be reserved for patients with risk factors for diabetes.ClinicalTrials.gov: 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.

Background: Preconception health may have intergenerational influences. We have formed the PrePARED (Preconception Period Analysis of Risks and Exposures influencing health and Development) research consortium to address methodological, conceptual, and generalisability gaps in the literature. Objectives: The consortium will investigate the effects of preconception exposures on four sets of outcomes: (1) fertility and miscarriage; (2) pregnancy-related conditions; (3) perinatal and child health; and (4) adult health outcomes. Population: A study is eligible if it has data measured for at least one preconception time point, has a minimum of selected core data, and is open to collaboration and data harmonisation. Design: The included studies are a mix of studies following women or couples intending to conceive, general-health cohorts that cover the reproductive years, and pregnancy/child cohort studies that have been linked with preconception data. The majority of the participating studies are prospective cohorts, but a few are clinical trials or record linkages. Methods: Data analysis will begin with harmonisation of data collected across cohorts. Initial areas of interest include nutrition and obesity; tobacco, marijuana, and other substance use; and cardiovascular risk factors. Preliminary results: Twenty-three cohorts with data on almost 200 000 women have combined to form this consortium, begun in 2018. Twelve studies are of women or couples actively planning pregnancy, and six are general-population cohorts that cover the reproductive years; the remainder have some other design. The primary focus for four was cardiovascular health, eight was fertility, one was environmental exposures, three was child health, and the remainder general women's health. Among other cohorts assessed for inclusion, the most common reason for ineligibility was lack of prospectively collected preconception data. Conclusions: The consortium will serve as a resource for research in many subject areas related to preconception health, with implications for science, practice, and policy.

Background Inflammation and elevated blood lipids are associated with infertility. Aspirin and statin therapy may improve infertility treatment outcomes among overweight and obese women with systemic inflammation, but little is known about the short-term effects of statins in this population. We conducted a pilot study of aspirin, pravastatin, or combined treatment among a group of overweight and obese, reproductive-aged women. Our goal was to characterize short-term changes in inflammatory and lipid biomarkers during and after treatment. Methods In this open-label trial, women aged 18–40 years with a body mass index ≥25 kg/m2 were randomized to receive either 162 mg aspirin, 40 mg pravastatin, or both. The study medication was taken daily for 2 weeks, and participants were then followed for a two-week washout period. Participants provided blood samples at baseline, after the intervention period, and after the washout period. The outcomes were changes in biomarkers of inflammation and lipids measured in blood components at each timepoint. Results Nine, 8, and 8 women were randomized to the aspirin, pravastatin, and combined arms, respectively. Analyses were conducted among 8, 7, and 7 women in the aspirin, pravastatin, and combined arms for whom biomarker data was available at baseline. High-sensitivity C-reactive protein (hsCRP) levels were lower after treatment in all arms and continued to decrease after washout in the pravastatin and combined arms. Results were consistent between the whole sample and women with baseline hsCRP between 2 and 10 mg/L. Low-density lipoprotein (LDL) cholesterol was lower after treatment in the pravastatin and combined arms and rose slightly after washout. Conclusions Our results provide preliminary evidence that short-term aspirin and pravastatin therapy reduces hsCRP and LDL cholesterol among overweight and obese women of reproductive age, including those with low-grade inflammation. Because of these short-term effects, these drugs may improve infertility treatment outcomes in this population, which we will assess in a future randomized trial.

Context With the increase of obesity, it is imperative to understand the neuroendocrine mechanisms, including the neuroendocrine hormone leptin, by which obese or overweight women are at increased risk for subfertility and infertility. Objective The objective was to examine associations between preconception serum leptin concentrations, fecundability, pregnancy, and live birth. Design Secondary analysis of a prospective cohort among women with prior pregnancy losses. Setting The study was conducted at four US medical centers (2006 to 2012). Intervention Not available. Materials and Methods Preconception serum leptin concentrations were measured at baseline, and women were followed for up to six menstrual cycles, and throughout pregnancy if they conceived. Discrete Cox proportional hazard regression models were used to assess fecundability odds ratios (FORs) and log-binomial regression to estimate risk ratios (RRs) for pregnancy and live birth. Models were adjusted for age, physical activity, treatment arm, and adiposity, either by measured waist-to-hip ratio or body mass index (BMI). Results High leptin concentrations were associated with decreased fecundability (FOR 0.72, 95% CI 0.58, 0.90), reduced risk of pregnancy (RR 0.87, 95% CI 0.78, 0.96) and live birth (RR 0.76, 95% CI 0.65, 0.89) comparing the upper to the lower tertile. However, adjustment for BMI in lieu of waist-to-hip ratio nullified observed associations. Conclusions In women with a history of pregnancy loss, relations between higher preconception leptin and fecundability were attenuated after adjustment for BMI, although not after adjustment for other markers of adiposity. Leptin may serve as a complementary marker of adiposity for assessment of obesity and reproductive outcomes.

Background Tampons are used by up to 86% of US women and are a rarely considered potential source of pesticide and metal exposure. Tampons may be of particular concern given the likely higher absorption that occurs in the vagina. Our objective was to examine the potential associations between tampon use and metal concentrations, and biomarkers of inflammation and oxidative stress among healthy women. Methods We used information from a prospective cohort of 259 regularly menstruating women, aged 18–44, followed for two menstrual cycles. Tampon use was assessed using information provided in participant study diaries. Metal concentrations were measured from a blood sample collected at enrollment. Oxidative stress and inflammation biomarker concentrations were determined from blood samples collected at up to 8 clinic visits for each cycle. Linear regression models were used to estimate associations of tampon use with metal exposure, and linear mixed models to estimate associations of tampon use with inflammation and oxidative stress biomarkers at different times during the menstrual cycle. Results We observed non-significantly higher mean levels of mercury for tampon users compared to non-tampon users (exp(β) = 1.25, 95% CI = 0.93, 1.68). We found no evidence of an association between tampon use and inflammation biomarkers. We observed consistently higher isoprostane levels, an oxidative stress biomarker, among tampon users compared to non-tampon users (e.g. exp.(β) = 1.05, 95%CI = 0.96, 1.16, for the average isoprostane during the menstruating week); however, these results were not statistically significant. Conclusions While our results are not statistically significant, we observed suggestive associations between tampon use and elevated levels of mercury and oxidative stress biomarkers. Although our finding should be interpreted in light of our limitations, they indicate that tampons may be a source of exposure to metals and chemicals that have been largely ignored, and any related health effects are an important public health concern. Electronic supplementary material The online version of this article (10.1186/s12940-019-0452-z) contains supplementary material, which is available to authorized users.

Aim: We examined maternal prepregnancy anthropometry and cord blood DNA methylation. Methods: Associations between maternal measures (i.e., weight, height, waist circumference, hip circumference, skinfolds, leptin) and methylation β-values at each CpG (measured by the Infinium MethylationEPIC BeadChip) were estimated among 391 singletons. Results: Total of 18% of mothers were obese (body mass index ≥ 30) and 27% centrally obese (waist-to-hip ratio ≥ 0.85). One Bonferroni significant CpG with respect to obesity (cg02975187) and two with central obesity (cg12053563, cg12549355) were identified (p -8). A suggestive association (p -6) was observed at SFRS8 with increasing body mass index. SFRS8 was previously identified with propensity for weight gain in adults. Conclusion: While associations identified with multiple measures related to maternal adiposity suggest different pathways, methylation differences were small in magnitude.

Background Little is known about the associations of bisphenol A, chlorophenols, benzophenones, and parabens with reproductive hormone levels in women. Our goal was to evaluate the associations between repeated measures of these chemicals and their mixtures with reproductive hormones in women. Methods Longitudinal urine samples from healthy, premenopausal women (n = 143 with 3–5 urine samples each) were measured for bisphenol A, five chlorophenols (2,4-dichlorophenol (2,4-DCP), 2,5-dichlorophenol, 2,4,5-trichlorophenol, 2,4,6-trichlorophenol, triclosan), two ultraviolet (UV) filters (benzophenone-1, benzophenone-3), and eight parabens and their metabolites (benzyl, butyl, ethyl, heptyl, methyl, propyl, 4-hydroxybenzoic acid (4-HB), 3,4-dihydroxybenzoic acid (3,4-DHB)) over two menstrual cycles. Estradiol, progesterone, luteinizing hormone (LH), and follicle stimulating hormone (FSH) were measured in blood up to 8 times each menstrual cycle. Linear mixed models were used for both single and multi-chemical exposures estimated using principal component analysis. Four factors were identified including: paraben; paraben metabolites and BPA, phenols, and UV filters. Models were adjusted for creatinine, age, race, and body mass index and weighted with inverse probability of exposure weights to account for time varying confounding. Results In single-chemical models, 3,4-DHB was associated with estradiol (0.06 (95% confidence interval (CI): 0.001, 0.12)), 2-4-DCP with increased progesterone 0.14 (0.06, 0.21) and decreased FSH −0.08 (−0.11, −0.04), and 4-HB was associated with increased FSH 0.07 (0.01, 0.13). In multi-chemical models, all factors were associated with increased progesterone (beta coefficient range: 0.15 for UV filter factor to 0.32 for paraben factor). The paraben factor and the paraben metabolite and BPA factor were associated with increased estradiol [0.21 (0.15, 0.28); 0.12 (0.07, 0.18)]. The phenol and UV filter factors were associated with decreased estradiol, FSH, and LH. The UV filter factor showed the strongest inverse association with estradiol −0.16 (−0.22, −0.10), FSH −0.12 (−0.17, −0.07), and LH −0.17 (−0.23, −0.10). Conclusion Mixtures of phenols were associated with changes in reproductive hormones. Such changes could contribute to adverse health in women but additional research is necessary.

Background Research has established that maternal diet influences fetal growth and preterm birth, but most studies only evaluate single nutrients. Relations between dietary patterns and neonatal outcomes are understudied. Objective We evaluated associations of neonatal outcomes with maternal diet patterns derived using 3 a priori diet scores [Alternative Healthy Eating Index-2010 (AHEI-2010), alternate Mediterranean diet score (aMed), and Dietary Approaches to Stop Hypertension (DASH)] as well as principal components analysis (PCA). Methods We studied 1948 women from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singletons, a racially diverse multisite cohort of pregnant women in the USA (2009-2013). Diet in the past 3 mo was assessed using a self-administered FFQ at 8-13 weeks of gestation. Birthweight was abstracted from medical records and neonatal anthropometry measured postdelivery using standardized protocols. Results All 3 a priori scores were significantly associated with increased birthweight, and aMed was also associated with reduced odds of low birthweight [quartile 4 versus 1: ORadj = 0.42; 95% CI: 0.18, 1.00 (P-trend = 0.02)]. Greater aMed and DASH scores were significantly associated with increased length [aMed: quartile 4 versus 1: 0.54 cm; 95% CI: 0.10, 0.99 (P-trend = 0.006); DASH: quartile 4 versus 1: 0.62 cm; 95% CI: 0.25, 0.99 (P-trend = 0.006)] and upper arm length. Neither diet pattern derived from PCA was significantly associated with birthweight. Conclusion Among mostly low-risk pregnant women, pre- and early pregnancy healthful diet quality indices, particularly the aMed score, were associated with larger neonatal size across the entire birthweight distribution. In the absence of generally accepted pregnancy-specific diet quality scores, these results provide evidence for an association between maternal diet patterns and neonatal outcomes.

Background A previous large randomized trial indicated that preconception-initiated low-dose aspirin (LDA) therapy did not have a positive effect on pregnancy outcomes. However, this trial was subject to nonadherence, which was not taken into account by the intention-to-treat approach. Objective To estimate per protocol effects of preconception-initiated LDA on pregnancy loss and live birth. Design The EAGeR (Effects of Aspirin on Gestation and Reproduction) trial was used to construct a prospective cohort for a post hoc analysis. (ClinicalTrials.gov: NCT00467363). Setting 4 university medical centers in the United States. Participants 1227 women between the ages of 18 and 40 years who had 1 or 2 previous pregnancy losses and were attempting pregnancy. Measurements Adherence to LDA or placebo, assessed by measuring pill bottle weights at regular intervals during follow-up. Primary outcomes were human chorionic gonadotropin (hCG)-detected pregnancies, pregnancy losses, and live births, determined by pregnancy tests and medical records. Results Relative to placebo, adhering to LDA for 5 of 7 days per week led to 8 more hCG-detected pregnancies (95% CI, 4.64 to 10.96 pregnancies), 15 more live births (CI, 7.65 to 21.15 births), and 6 fewer pregnancy losses (CI, -12.00 to -0.20 losses) for every 100 women in the trial. In addition, compared with placebo, postconception initiation of LDA therapy led to a reduction in the estimated effects. Furthermore, effects were obtained in a minimum of 4 of 7 days per week. Limitation The EAGeR trial data for this study were analyzed as observational data, thus are subject to the limitations of prospective observational studies. Conclusion Per protocol results suggest that preconception use of LDA at least 4 days per week may improve reproductive outcomes for women who have had 1 or 2 pregnancy losses. Increasing adherence to daily LDA seems to be key to improving effectiveness. Primary funding source National Institutes of Health.

Objective This study aimed to examine whether prenatal low-dose aspirin (LDA) therapy affects risk of cesarean versus vaginal delivery. Study design This study is a secondary analysis of the randomized clinical effects of aspirin in gestation and reproduction (EAGeR) trial. Women received 81-mg daily aspirin or placebo from preconception to 36 weeks of gestation. Mode of delivery and obstetric complications were abstracted from records. Log-binomial regression models estimated relative risk (RR) of cesarean versus vaginal delivery. Data were analyzed among the total preconception cohort, as well as restricted to women who had a live birth. Results Among 1,228 women, 597 had a live birth. In the intent-to-treat analysis, preconception-initiated LDA was not associated with risk of cesarean (RR = 1.02; 95% confidence interval [CI]: 0.98-1.07) compared with placebo. Findings were similar in just women with a live birth and when accounting prior cesarean delivery and parity. Conclusion Preconception-initiated daily LDA was not associated with mode of delivery among women with one to two prior losses. Key points · Aspirin was not associated with risk of cesarean section.. · Aspirin was not associated with mode of delivery.. · No increased risk of bleeding with use of aspirin..

OBJECTIVE: To prospectively investigate the association of selective serotonin reuptake inhibitors (SSRI) exposure through critical windows of pregnancy establishment with fecundability and pregnancy loss. DESIGN: Prospective cohort study utilized longitudinal urine measurements of common SSRIs while women were actively trying to conceive. SETTING: Four U.S. clinical sites. PATIENTS: 1228 women without uncontrolled depression/anxiety, attempting natural conception while participating in a randomized trial of preconception-initiated low-dose aspirin. INTERVENTIONS: not applicable. MAIN OUTCOME MEASURES: Urinary SSRIs (fluoxetine, sertraline, escitalopram/citalopram) were measured while trying to conceive and, for women who became pregnant, at weeks 0, 4, and 8 of pregnancy. Fecundability odds ratios (FOR) and incidence of pregnancy loss and live birth were estimated. RESULTS: 172 women (14%) were exposed to SSRIs while trying to conceive. SSRI exposure was associated with 24% reduced fecundability (FOR 0.76; 95% CI: 0.60, 0.96), and accordingly, a non-significant 9% lower live birth incidence (relative risk [RR] 0.91; 95% CI: 0.76, 1.08), with significantly lower live birth in fluoxetine-exposed women (RR 0.71; 95% CI: 0.53, 0.96). SSRI exposure was not associated with subsequent pregnancy loss whether exposure was prior to conception (RR 1.04; 95% CI: 0.74, 1.47) or at zero (RR 1.08; 95% CI: 0.77, 1.53), four (RR 1.11; 95% CI: 0.75, 1.66), or eight (RR 0.84; 95% CI: 0.44, 1.63) weeks of gestation, though estimates varied by specific SSRI drug. CONCLUSION: Women using SSRIs may have more difficulty becoming pregnant and although SSRI exposure overall was not associated with pregnancy loss, fluoxetine deserves caution and future study.

To estimate the prevalence of ovulatory cycles in eumenorrheic subfertile women and compare the diagnostic accuracy of a single ultrasound with serum midluteal progesterone measurement in detecting ovulatory cycles.Prospective diagnostic accuracy study.University-level hospital.A total of 208 subfertile eumenorrheic women.None.To estimate the prevalence of ovulatory cycles in eumenorrheic women and compare the diagnostic accuracy of a single, well-timed ultrasound scan (index test) with serum progesterone measurement (reference test) by calculating the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and positive likelihood ratio (LR+) and negative likelihood ratio (LR-).The prevalence of ovulatory cycles among subfertile eumenorrheic women was 92.9% and 99.5% when midluteal serum progesterone level and ultrasound scanning were used as the reference test, respectively. The sensitivity, specificity, PPV, and NPV of ultrasound in identifying ovulatory cycles were 100%, 7.1%, 93.4%, and 100%, respectively. The LR+ and LR- were 1.1 and 0, respectively. The agreement between the ultrasound and serum progesterone was almost perfect (prevalence and bias-adjusted kappa = 0.81.The prevalence of ovulatory cycles in eumenorrheic subfertile women appears to be high. A single well-timed ultrasound can be performed to identify ovulatory cycles during the infertility workup in eumenorrheic women.

OBJECTIVE To characterize variation in circulating vascular endothelial growth factor (VEGF) and its receptor, soluble fms-like tyrosine kinase-1 (sFLT-1), across the menstrual cycle in normal ovulating women in relation to reproductive hormones to identify the utility of VEGF and sFLT-1 as peripheral biomarkers of endometrial remodeling. METHODS Ninety-six healthy, regularly menstruating ovulatory women, aged 18-44 years, enrolled in the BioCycle Study, a prospective cohort study at a U.S. academic research center. Vascular endothelial growth factor and sFLT-1 were measured in concurrently collected plasma, serum, and urine up to eight times across a single cycle. Reproductive hormones were measured in serum. Mean concentrations of VEGF and sFLT-1 were compared across phases of the cycle, and correlations between specimen types were calculated. Harmonic models estimated associations between VEGF and sFLT-1 and characteristics of hormonal patterns. RESULTS No variation in VEGF or sFLT-1 levels were detected over the menstrual cycle. Median (25th percentile, 75th percentile) concentrations of VEGF during the menstrual cycle were 31.2 pg/mL (24.1, 56.9) in plasma, 194.1 pg/mL (125.4, 350.2) in serum, and 101.7 pg/mL (64.2, 165.8) in urine. Plasma and serum measures were consistently correlated, whereas urinary measures were not. Vascular endothelial growth factor was not consistently associated with reproductive hormone concentrations, although sFLT-1 was associated with higher mean and amplitude of estradiol. CONCLUSION Circulating VEGF and sFLT-1 did not vary across the menstrual cycle and therefore are unlikely to be useful peripheral biomarkers of endometrial changes across the menstrual cycle. For studies measuring circulating VEGF for other reasons, plasma may be the preferred medium and timing to menstrual cycle phase need not be considered for reproductive-age women.

Background Obesity, a body mass index (BMI) ≥30 kg/m2 , is linked to infertility, potentially through a greater risk of anovulation due to elevated androgens. Yet, previous studies have not directly assessed the impact of adiposity, or body fat, on anovulation in the absence of clinical infertility. Objective To characterise the associations between adiposity and anovulation among women menstruating on a regular basis. Methods Women from the EAGeR trial (n = 1200), a randomised controlled trial of low-dose aspirin and pregnancy loss among women trying to conceive, were used to estimate associations between adiposity and incident anovulation. Participants completed baseline questionnaires and anthropometry, and provided blood specimens. Women used fertility monitors for up to six consecutive menstrual cycles, with collection of daily first morning voids for hormone analysis in the first two menstrual cycles for prospective assessment of anovulation. Anovulation was assessed by urine pregnanediol glucuronide or luteinising hormone concentration or the fertility monitor. Weighted mixed-effects log-binomial regression was used to estimate associations between measures of adiposity and incident anovulation, adjusted for free (bioavailable) testosterone, anti-Mullerian hormone (AMH), serum lipids, and demographic and life style factors. Results 343 (28.3%) women experienced at least one anovulatory cycle. Anovulation risk was higher per kg/m2 greater BMI (relative risk [RR] 1.03, 95% confidence interval (CI) 1.01, 1.04), cm waist circumference (RR 1.01, 95% CI 1.00, 1.02), mm subscapular skinfold (RR 1.02, 95% CI 1.01, 1.03), and mm middle upper arm circumference (RR 1.04, 95% CI 1.01, 1.06) adjusted for serum free testosterone, AMH, lipids, and other factors. Conclusions Adiposity may be associated with anovulation through pathways other than testosterone among regularly menstruating women. This may account in part for reported associations between greater adiposity and infertility among women having menstrual cycles regularly. Understanding the association between adiposity and anovulation might lead to targeted interventions for preventing infertility.

Prescription opioid use is common among men and women of reproductive age, including during assisted-reproduction procedures. Opioid use disorder and chronic use are associated with harms to fertility and pregnancy outcomes, but it is unclear whether these associations extend to common short-term patterns of prescription opioid use. We conducted a literature review using PubMed, Embase, Web of Science, and Scopus to identify studies of nonchronic, nondependent opioid use and reproductive endpoints including fertility, pregnancy loss, and pregnancy complications (i.e., preterm birth, birth weight, gestational diabetes, and hypertensive disorders of pregnancy). Seventeen studies were included. Although results of the studies suggest possible harms of short-term opioid use on fertility and pregnancy loss, methodologic limitations and the small number of studies make the literature inconclusive. This review highlights important data gaps that must be addressed to make conclusions about potential reproductive effects of short-term opioid use. These include the need for additional data on opioid use before clinically recognized pregnancy; accurate measurement of opioid exposure by multiple means with detailed information on the types and quantity of opioids used; assessment of important confounders, including opioid use indication, comorbidities, and use of other medications and substances; and studies of paternal opioid use, fertility, and pregnancy outcomes. A primary limitation of this review targeting studies of nonchronic opioid exposure is the possibility that selected studies included populations with unspecified chronic or dependent opioid use. Efforts to understand the impact of the prescription opioid epidemic should address potential reproductive harms of these medications among people of reproductive age.

Background Studies linking large pregnancy cohorts with mortality data can address critical questions about long-term implications of gravid health, yet relevant US data are scant. We examined the feasibility of linking the Collaborative Perinatal Project, a large multiracial U.S. cohort study of pregnant women (n = 48,197; 1959-1966), to death records. Methods We abstracted essential National Death Index (NDI) (1979-2016) (n = 46,428). We performed a linkage to the Social Security Administration Death Master File through 2016 (n = 46,450). Genealogists manually searched vital status in 2016 for a random sample of women (n = 1,249). We conducted agreement analyses for women with abstracted data among the three sources. As proof of concept, we calculated adjusted associations between mortality and smoking and other sociodemographic factors using Cox proportional hazards regression. Results We successfully abstracted identifying information for most of the cohort (97%). National Death Index identified the greatest proportion of participants deceased (35%), followed by genealogists (31%) and Death Master File (23%). Estimates of agreement (κ [95% confidence interval]) between National Death Index and Death Master File were lower (0.52 [0.51, 0.53]) than for National Death Index and genealogist (0.66 [0.61, 0.70]). As expected, compared with nonsmokers, smoking ≥1 pack per day was associated with elevated mortality for all vital sources and was strongest for National Death Index. Conclusions Linking this historic cohort with mortality records was feasible and agreed reasonably on vital status when compared with other data sources. Such linkage enables future examination of pregnancy conditions in relation to mortality in a diverse U.S. cohort.

Objective To estimate the effect of daily 81 mg low-dose aspirin (LDA) on menstrual cycle length and hormone profiles. Design Secondary analysis of a trial evaluating the effect of daily LDA or placebo on live birth among women with one or two previous pregnancy losses. Setting University medical centers. Patient(s) A total of 915 regularly menstruating women who had at least one menstrual cycle (3,190 total cycles) in which pregnancy did not occur. Intervention(s) Randomized allocation to LDA versus placebo. Main Outcome Measure(s) Menstrual cycle length and follicular and luteal phases were measured. Urinary pregnanediol glucuronide, follicle-stimulating hormone, luteinizing hormone, and estrone-3-glucuronide were assessed up to six times during the first two cycles. Generalized estimating equations estimated relative risk of short ( 75th percentile: ≥32 days) versus normal cycle length. Linear mixed models estimated mean hormone level differences with weights used to account for multiple cycles contributed per participant. Result(s) There were no significant differences in total menstrual cycle, follicular phase, or luteal phase length between LDA and placebo groups. LDA posed no greater risk of having a short versus normal-length or long versus normal-length follicular phase, or having a short versus normal-length or long versus normal-length luteal phase. There were no significant differences in hormone levels across the menstrual cycle between the LDA and placebo groups. Conclusion(s) Daily LDA use did not result in any changes to menstrual cycle, follicular phase, or luteal phase length or hormone levels across the menstrual cycle compared with placebo. Clinical Trial Registration Number NCT00467363

In 575 women with 1–2 prior pregnancy losses; total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) were evaluated preconception and throughout pregnancy to evaluate whether previously observed associations between third trimester maternal lipid profile and birthweight outcomes are driven by preconception lipids or lipid changes during pregnancy. Lipid trajectories were compared by pre-pregnancy body mass index (BMI) 2; logistic regression models evaluated preconception lipid concentration and change from preconception to 28 weeks with adjusted odds of large- or small-for-gestational age (LGA or SGA) neonate by BMI group. Preconception lipid concentrations and gestational lipid trajectories varied by BMI group (P

Several autoimmune conditions have adverse effects on reproductive outcomes, but the relationship between family history of autoimmune disease in women without these conditions and pregnancy is uncertain. The objective of this study was to determine if there is an association between a family history of an autoimmune condition and time-to-pregnancy (TTP), pregnancy loss, and live birth. This was a prospective cohort study from a RCT of 1228 adult women ages 18–40, who were healthy, had no history of infertility, were actively attempting to conceive, and had one or two prior pregnancy losses. Of these, 1172 women had data available regarding family history of autoimmune conditions. Women with an affected first-degree relative had similar TTP when compared to those without a FHx (fecundability odds ratio 0.90, 95% confidence interval [CI] 0.70, 1.15). Women with an affected first-degree relative had a lower likelihood of live birth (relative risk [RR] 0.83, 95% CI 0.69, 0.99). Among women who achieved pregnancy, FHx of autoimmune disease was associated with a higher likelihood of pregnancy loss (RR 1.49, 95% CI 1.10, 2.03). Women who had a first-degree relative with an autoimmune disease had a similar TTP as unaffected women but a lower likelihood of live birth and higher risk of pregnancy loss. This information may encourage clinicians to evaluate women with a family history of autoimmune conditions prior to pregnancy and highlights the need for further studies to ascertain the effects of autoimmunity and pregnancy., Highlights • Some autoimmune conditions may negatively impact reproductive health. • Autoimmune disease can cluster in families highlighting relevance of family history. • Women with family history of autoimmunity had higher risk of pregnancy loss. • Results suggest possible shared mechanism of miscarriage and predisposition to autoimmunity. • Family history may be important for understanding risk factors for pregnancy loss.

Objective To assess the reproductive and neonatal outcomes of cycles in which donor oocyte embryos were transferred to gestational carriers compared to intended parent recipients. Design Retrospective cohort study. Setting Not applicable. Patient(s) Intended parent recipients and gestational carriers receiving donor oocyte embryos in 2014 in the United States. Interventions(s) None. Main Outcomes Measure(s) Clinical pregnancy, live birth, miscarriage, plurality, prematurity, and birth weight from pregnancies conceived with donor oocyte embryos transferred to either a gestational carrier or an intended parent recipient. Result(s) The mean ages of intended parent recipients (N=18,317) and gestational carriers (N=1,927) were 41.6 and 31.6 years, respectively. Compared to an intended parent recipient, patients using a gestational carrier had significantly higher odds of a clinical pregnancy (65.2% vs. 56.3%, adjusted odds ratio (aOR) 1.33, 95% confidence interval (CI) 1.17–1.51) and live birth (57.1% vs. 46.4%, aOR 1.37, 95% CI 1.21–1.55) using fresh or frozen donor-oocyte embryos. Of the singletons born (n=716 using a gestational carrier and n=5,632 in intended parent recipients), the incidence of prematurity was significantly lower in gestational carriers compared to intended parent recipients (17.5% vs. 25.4%, aOR 0.78, 95% CI 0.61–0.99). The incidence of low birthweight among singletons was significantly reduced in gestational carrier cycles (6.4% vs. 12.1%, aOR 0.62, 95% CI 0.44–0.89). Conclusion Intended parent recipients had decreased pregnancy rates and poorer neonatal outcomes compared to a gestational carrier. This suggests that a history of infertility adversely affects the uterine microenvironment, independent of the oocyte.

BACKGROUND: Preconception nutrition sets the stage for a healthy pregnancy. Maternal fatty acids (FAs) are related to beneficial neonatal outcomes with DNA methylation proposed as a mechanism; however, few studies have investigated this association and none with preconception FAs. OBJECTIVES: We examined the relations of maternal plasma FA concentrations at preconception (n = 346) and 8 weeks of gestation (n = 374) with newborn DNA methylation. METHODS: The Effects of Aspirin in Gestation and Reproduction Trial (2006–2012) randomly assigned women with previous pregnancy loss to low dose aspirin or placebo prior to conception. We measured maternal plasma phospholipid FA concentration at preconception (on average 4 mo before pregnancy) and 8 weeks of gestation. Cord blood DNA from singletons was measured using the MethylationEPIC BeadChip. We used robust linear regression to test the associations of FA concentration with methylation β-values of each CpG site, adjusting for estimated cell count using a cord blood reference, sample plate, maternal sociodemographic characteristics, cholesterol, infant sex, and epigenetic-derived ancestry. False discovery rate correction was used for multiple testing. RESULTS: Mean ± SD concentrations of preconception marine (20:5n–3+22:6n–3+22:5n–3) and ω-6 PUFAs, SFAs, MUFAs, and trans FAs were 4.7 ± 1.2, 38.0 ± 2.0, 39.4 ± 1.8, 11.6 ± 1.1, and 1.0 ± 0.4 % of total FA, respectively; concentrations at 8 weeks of gestation were similar. Preconception marine PUFA concentration was associated with higher methylation at GRAMD2 (P = 1.1 × 10(−8)), LOXL1 (P = 5.5 × 10(−8)), SIK3 (P = 1.6 × 10(−7)), HTR1B (P = 1.9 × 10(−7)), and MCC (P = 2.1 × 10(−7)) genes. Preconception SFA concentration was associated with higher methylation at KIF25-AS1 and lower methylation at SLC39A14; other associations exhibited sensitivity to outliers. The trans FA concentration was related to lower methylation at 3 sites and higher methylation at 1 site. FAs at 8 weeks of gestation were largely unrelated to DNA methylation. CONCLUSIONS: Maternal preconception FAs are related to newborn DNA methylation of specific CpG sites, highlighting the importance of examining nutritional exposures preconceptionally. This trial was registered at clinicaltrials.gov as NCT00467363.

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.

STUDY QUESTIONIs cannabis use assessed via urinary metabolites and self-report during preconception associated with fecundability, live birth and pregnancy loss?SUMMARY ANSWERPreconception cannabis use was associated with reduced fecundability among women with a history of pregnancy loss attempting pregnancy despite an increased frequency of intercourse.WHAT IS KNOWN ALREADYCannabis use continues to rise despite limited evidence of safety during critical windows of pregnancy establishment. While existing studies suggest that self-reported cannabis use is not associated with fecundability, self-report may not be reliable.STUDY DESIGN, SIZE, DURATIONA prospective cohort study was carried out including 1228 women followed for up to six cycles while attempting pregnancy (2006 to 2012), and throughout pregnancy if they conceived.PARTICIPANTS/MATERIALS, SETTING, METHODSWomen aged 18–40 years with a history of pregnancy loss (n = 1228) were recruited from four clinical centers. Women self-reported preconception cannabis use at baseline and urinary tetrahydrocannabinol metabolites were measured throughout preconception and early pregnancy (up to four times during the study: at baseline, after 6 months of follow-up or at the beginning of the conception cycle, and weeks 4 and 8 of pregnancy). Time to hCG-detected pregnancy, and incidence of live birth and pregnancy loss were prospectively assessed. Fecundability odds ratios (FOR) and 95% CI were estimated using discrete time Cox proportional hazards models, and risk ratios (RRs) and 95% CI using log-binomial regression adjusting for age, race, BMI, education level, baseline urine cotinine, alcohol use and antidepressant use.MAIN RESULTS AND THE ROLE OF CHANCEPreconception cannabis use was 5% (62/1228), based on combined urinary metabolite measurements and self-report, and 1.3% (11/789) used cannabis during the first 8 weeks of gestation based on urinary metabolites only. Women with preconception cannabis use had reduced fecundability (FOR 0.59; 95% CI 0.38, 0.92). Preconception cannabis use was also associated with increased frequency of intercourse per cycle (9.4 ± 7 versus 7.5 ± 7 days; P = 0.02) and higher LH (percentage change 64%, 95% CI 3, 161) and higher LH:FSH ratio (percentage change 39%, 95% CI 7, 81). There were also suggestive, though imprecise, associations with anovulation (RR 1.92, 95% CI 0.88, 4.18), and live birth (42% (19/45) cannabis users versus 55% (578/1043) nonusers; RR 0.80, 95% CI 0.57, 1.12). No associations were observed between preconception cannabis use and pregnancy loss (RR 0.81, 95% CI 0.46, 1.42). Similar results were observed after additional adjustment for parity, income, employment status and stress. We were unable to estimate associations between cannabis use during early pregnancy and pregnancy loss due to limited sample size.LIMITATIONS, REASONS FOR CAUTIONOwing to the relatively few cannabis users in our study, we had limited ability to make conclusions regarding live birth and pregnancy loss, and were unable to account for male partner use. While results were similar after excluding smokers, alcohol use and any drug use in the past year, some residual confounding may persist due to these potential co-exposures.WIDER IMPLICATIONS OF THE FINDINGSThese findings highlight potential risks on fecundability among women attempting pregnancy with a history of pregnancy loss and the need for expanded evidence regarding the reproductive health effects of cannabis use in the current climate of increasing legalization.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 numbers: HHSN267200603423, HHSN267200603424, HHSN267200603426, HHSN275201300023I). Jeannie G. Radoc has been funded by the National Institutes of Health Medical Research Scholars Program, a public–private partnership supported jointly by the National Institutes of Health and generous contributions to the Foundation for the National Institutes of Health from the Doris Duke Charitable Foundation (DDCF Grant # 2014194), Genentech, Elsevier, and other private donors. The authors report no conflict of interest in this work and have nothing to disclose.TRIAL REGISTRATION NUMBERClinicaltrials.gov NCT00467363

Biomarker assay measurement often consists of a two-stage process where laboratory equipment yields a relative measure which is subsequently transformed to the unit of interest using a calibration curve. The calibration curve establishes the relation between the measured relative units and sample biomarker concentrations using stepped samples of known biomarker concentrations. Samples from epidemiologic studies are often measured in multiple batches or plates, each with independent calibration experiments. Collapsing calibration information across batches before statistical analysis has been shown to reduce measurement error and improves estimation. Additionally, collapsing in practice can also create an additional layer of quality control (QC) and optimization in a part of the laboratory measurement process that is often highly automated. Principled recalibration is demonstrated via. a three-step process of identifying batches where recalibration might be beneficial, forming a collapsed calibration curve and recalibrating identified batches, and using QC data to assess the appropriateness of recalibration. Here, we use inhibin B measured in biospecimens from the BioCycle study using 50 enzyme-linked immunosorbent assay (ELISA) batches (3875 samples) to motivate and display the benefits of collapsing calibration experiments, such as detecting and overcoming faulty calibration experiments, and thus improving assay coefficients of variation from reducing unwanted measurement error variability. Differences in the analysis of inhibin B by testosterone quartile are also demonstrated before and after recalibration. These simple and practical procedures are minor adjustments implemented by study personnel without altering laboratory protocols which could have positive estimation and cost-saving implications especially for population-based studies.

OBJECTIVE: Hormonal contributions to the sex-dependent development of both obsessive-compulsive disorder (OCD) and obesity have been described, but the underlying mechanisms are incompletely understood. A-kinase anchoring protein 13 (AKAP13) significantly augments ligand-dependent activation of estrogen receptors alpha and beta. The hypothalamus and pituitary gland are implicated in the development and exacerbation of OCD and obesity and have strong AKAP13 expression. The AKAP13 localization pattern observed in these key brain regions together with its effects on sex steroid action suggest a potential role for AKAP13 in compulsive-like behaviors. Here we tested the role of AKAP13 in compulsive-like behavior and body weight using an Akap13 haploinsufficient murine model. MATERIALS AND METHODS: Targeted deletion of the Akap13 gene generated haploinsufficient (Akap13+/−) mice in a C57BL6/J genetic background. Established behavioral assays were conducted, video recorded, and scored blindly to assess compulsive-like behavior based on genotype and gender. Tests included: marble-burying, grooming, open-field and elevated plus-maze. Brain and body weights were also obtained. Mean levels of test outcomes were compared using multi-way ANOVA to test for genotype, sex, genotype*sex, and genotype*sex*age interaction effects with Bonferroni adjustment for multiple comparisons, to further explain any significant interactions. RESULTS: The marble-burying and grooming assays revealed significant sex-dependent increases in perseverative, compulsive-like behaviors in female Akap13 haploinsufficient mice compared to female wild type (WT) mice by demonstrating increased marble-burying activity (p=0.0025) and a trend towards increased grooming behavior (p=0.06). Male Akap13 haploinsufficient mice exhibited no behavioral changes (p>0.05). Elevated plus-maze and open-field test results showed no overt anxiety-like behavior in Akap13 haploinsufficient mice irrespective of sex (p>0.05, both). No differences in brain weight were found in Akap13 haploinsufficient mice compared to WT mice (p>0.05). However, female Akap13 haploinsufficient mice weighed more than female WT mice in the 4 to 0.05) at any age range examined. CONCLUSION: Akap13 haploinsufficiency led to sex-dependent, compulsive-like behavioral changes in a murine model. Interestingly, Akap13 haploinsufficiency also led to a sex-dependent increase in body weight. These results revealed a requirement for AKAP13 in murine behavior, particularly in female mice, and is the first report of AKAP13 involvement in murine behavior. Future studies may show AKAP13 involvement in the pathophysiology of OCD in female humans and may contribute to a better understanding of the role of AKAP13 and sex hormones in the development and exacerbation of OCD.