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Background Cadmium is an endocrine disrupting chemical that affects the hypothalamic-pituitary-gonadal axis. Though evidence suggests its potential role in altering androgen synthesis and metabolic pathways that are characteristic of polycystic ovary syndrome (PCOS), its relation in healthy women of reproductive age is largely unknown. As women with mild sub-clinical features of PCOS who do not meet the diagnostic criteria of PCOS may still experience reduced fecundability, investigating associations between cadmium and PCOS-phenotypes among healthy women may provide unique insight into the reproductive implications for many on the PCOS spectrum. Therefore, the objective of this study was to evaluate associations between cadmium and androgens, anti-Müllerian hormone (AMH), and metabolic markers in women of reproductive age. Methods This was a prospective cohort study of 251 healthy premenopausal women without self-reported PCOS (mean age 27.3 years and BMI 24.1 kg/m2). Cadmium was measured in blood collected at baseline. Reproductive hormones and metabolic markers were measured in fasting serum 8 times per menstrual cycle for 2 cycles. Linear mixed models and Poisson regression with a robust error variance were used to examine associations between cadmium and reproductive hormones and metabolic markers and anovulation, respectively. Results Median (interquartile range) blood cadmium concentrations at baseline were 0.30 (0.19–0.43) µg/L. Higher levels of testosterone (2.2 %, 95 % confidence interval [CI] 0.4, 4.1), sex hormone-binding globulin (2.9 %, 95 % CI 0.5, 5.5), and AMH (7.7 %, 95 % CI 1.1, 14.9) were observed per 0.1 µg/L increase in cadmium concentrations. An 18 % higher probability of a mild PCOS-phenotype (95 % CI 1.06, 1.31), defined by a menstrual cycle being in the highest quartile of cycle-averaged testosterone and AMH levels, was also found per 0.1 µg/L increase in cadmium levels. No associations were observed for insulin and glucose. These findings were consistent even after analyses were restricted to non-smokers or further adjusted for dietary factors to account for potential sources of exposure. Conclusions Overall, among healthy reproductive-aged women, cadmium was associated with endocrine features central to PCOS, but not with metabolic markers. These suggest its potential role in the hormonal milieu associated with PCOS even at low levels of exposure.

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

The annual meeting of the Society for Epidemiologic Research (SER) is a major forum for sharing new research and promoting the career development of participants. Because of this, evaluating representation in key presentation formats is critical. For the 3,257 presentations identified at the 2015–2017 SER annual meetings, we evaluated presenter characteristics, including gender, affiliation, subject area, and h-index, and representation in 3 highlighted presentation formats: platform talks (n = 382), invited symposium talks (n = 273), and chairing a concurrent contributed session or symposium (n = 188). Data were abstracted from SER records, abstract booklets, and programs. Gender was assessed using GenderChecker software, and h-index was determined using the Scopus application programming interface. Log-binomial models were adjusted for participant characteristics and conference year. In adjusted models, women were less likely than men to present an invited symposium talk (relative risk = 0.60, 95% confidence interval: 0.45, 0.81) compared with all participants with accepted abstracts. Researchers from US public universities, US government institutions, and international institutions were less likely to present a symposium talk or to chair a concurrent contributed session or symposium than were researchers from US private institutions. The research areas that were most represented in platform talks were epidemiologic methods, social epidemiology, and cardiovascular epidemiology. Our findings suggest differences in representation by gender, affiliation, and subject area after accounting for h-index.

Background Opioids are commonly prescribed to women of reproductive age, including after delivery and miscarriage. However, to our knowledge, opioid use has not been frequently studied in relation to the common reproductive complications of impaired fecundability and pregnancy. We examined the association of opioid use during the critical window of pregnancy establishment with fecundability and pregnancy loss. Methods We measured opioid use by urine screening and self-report at multiple time points during preconception and early pregnancy in a prospective cohort of women attempting conception (n=1228). The main outcomes included time to hCG-detected pregnancy and incidence of live birth and pregnancy loss. We estimated fecundability odds ratios (FOR) and risk ratios (RR) with 95% confidence intervals (CI) adjusting for sociodemographic characteristics, reproductive characteristics, and use of antidepressants, tobacco, alcohol, and marijuana. Results Prevalence of preconception opioid use was 18% (n=226 of 1228), and in early pregnancy was 5% (n=33 of 685). Opioid use while attempting pregnancy was associated with reduced fecundability (FOR: 0.71; 95% CI: 0.50, 1.0). Risk of pregnancy loss increased as opioid exposure was detected later in gestation, from the beginning of the cycle of conception (RR: 1.5; 95% CI 0.85, 2.6), to week 4 of pregnancy (RR: 2.1; 95% CI: 1.1, 4.1), and to week 4 and 8 of pregnancy (RR: 2.5; 95% CI: 1.3, 5.0). Conclusions Our results are consistent with the hypothesis that opioid exposure while trying to conceive may be harmful, even among healthy, non-opioid-dependent women. Possible risks to fecundability and pregnancy viability are relevant to patients and providers when evaluating pain management approaches.ClinicalTrials.gov registration number: #NCT00467363.

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.

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.

Using web-based survey data collected June – August 2018 from the Society for Epidemiologic Research (SER) members, we characterized numerous dimensions of social identity and lived experience, and assessed relationships between these characteristics and perceptions of inclusion and society participation. We quantified associations between characteristics, feeling very welcomed, high (top 25th percentile) self-initiated participation, and any (top 10th percentile) society-initiated participation. Racial/ethnic and religious minority categories were blinded to preserve anonymity and we accounted for missing data. Most 2018 SER members (n = 1631) were white (62%) or female (66%). Females with racial/ethnic non-response were least likely, while white males were most likely to report feeling very welcomed. Members who did not report race, identified with a specific racial/ethnic minority, or were politically conservative/right-leaning were less likely than white or liberal/left-leaning members to have high self-initiated participation. Women and individuals of a specific racial/ethnic minority or minority religious affiliations were less likely to participate in events initiated by the society. These data represent a baseline for assessing trends and the impact of future initiatives aimed at improving diversity, inclusion, representation and participation within SER.

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: 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

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

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

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

OBJECTIVES: The association between caffeine and pregnancy loss remains controversial due to limitations of prior studies such as relying on self-reported intake only, exposure measurement after clinical confirmation of pregnancy, and potential time-varying confounding by nausea/vomiting and lifestyle factors, which may be affected by prior caffeine exposure. Thus, our aim was to evaluate associations of preconception and early pregnancy serum caffeine, paraxanthine, and theobromine, self-reported intake of caffeinated beverages, and risk of pregnancy loss among 1228 reproductive-age women attempting pregnancy in the EAGeR trial during 2007–2011. METHODS: We estimated HRs and 95% CIs for any pregnancy loss, hCG loss (prior to ultrasound confirmation), and clinical loss (after ultrasound confirmation) according to caffeinated beverage intake and caffeine biomarkers measured at preconception and the 8(th) week of gestation using weighted adjusted Cox proportional hazards models. RESULTS: At preconception, 67%, 28%, and 9% of women reported any intake of caffeinated sodas, coffee, and tea, respectively. Preconception total caffeinated beverage intake of ≥3 vs. 0 cups/day was associated with 85% (95% CI: 1.18, 2.94) higher risk of any pregnancy loss, driven primarily by associations for hCG loss (HR: 2.88 (95% CI: 1.20, 6.91)). Caffeinated soda intake was associated with hCG loss (≥2 vs. 0.2 vs. ≤0.2 ng/mL) at preconception was strongly associated with hCG loss (HR: 4.51 (95% CI: 1.36, 14.91)). Serum caffeine, paraxanthine, and theobromine measured at the 8th week of gestation were not associated with risk of loss. CONCLUSIONS: Collectively, these data suggest that caffeine intake prior to pregnancy may increase risk of pregnancy loss, particularly in early gestation. FUNDING SOURCES: Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD.

OBJECTIVES: Experimental data indicate that maternal exposure to factors known to alter inflammatory milieu may be specifically harmful to the conception or survival of male fetuses. Indeed, in a recent clinical trial, preconception administration of low dose aspirin versus placebo restored the skewed sex ratio at birth among women with elevated inflammation, providing direct evidence of this phenomenon in humans. However, it is unknown whether other factors associated with inflammation, such as vitamin D status, are associated with offspring sex ratio at birth. Our objective was thus to evaluate the association of preconception serum 25-hydroxyvitamin D levels [25(OH)D] and male live birth among 1228 reproductive-age women with a history of 1–2 prior losses who were enrolled in the Effects of Aspirin in Gestation and Reproduction trial between 2007–2011. METHODS: We estimated RRs and 95% CIs for male live birth according to 25(OH)D sufficiency (≥75 vs. 1.95 ng/mL: RR: 1.41; 95% CI: 0.99, 2.00 versus ≤1.95 ng/mL RR: 1.11; 95% CI: 0.88, 1.41), a marker of systemic low-grade inflammation. CONCLUSIONS: Preconception vitamin D status was associated with male live birth, particularly among women with low-grade inflammation. These data suggest that maternal vitamin D sufficiency may mitigate maternal inflammation that would otherwise be detrimental to male fetal survival. FUNDING SOURCES: Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD.

OBJECTIVES: Vitamin D levels have been associated with premenstrual syndrome (PMS) and symptom severity, but data are mixed. Our aim was to assess the relationship between serum vitamin D and PMS in women with regular menstrual cycles. METHODS: We looked at vitamin D and PMS using two cohorts of healthy women with regular cycles. BioCycle followed 76 women, for up to 2 menstrual cycles prospectively and EAGeR followed 1191 women with 1–2 prior pregnancy losses. 25(OH)D was measured in serum at baseline in both cohorts, with PMS assessed via questionnaire evaluating the presence and severity of 14 psychological and physical menstrual symptoms the week before and after menses. EAGeR assessed symptoms over the past year, and BioCycle assessed symptoms prospectively over the next cycle. We used status and PMS associations adjusting for age, BMI, race, smoking, income, physical activity, and season of blood draw. RESULTS: 54% and 47% of women had sufficient 25(OH)D (≥30 ng/mL) and 33% and 40% exhibited PMS in BioCycle and EAGeR, respectively. Vitamin D status was not associated with risk of PMS in either cohort (BioCycle: D insufficiency was associated with risk of breast fullness/tenderness (RR 1.27, 95% CI 1.03, 1.55) and generalized aches and pains (RR 1.33, 95% CI 1.01, 1.78), compared to women with vitamin D sufficiency. Similar associations were observed in BioCycle though confidence intervals were wide. No associations were observed between vitamin D status and psychological symptoms. CONCLUSIONS: Among women with regular menses, 25(OH)D was not associated with PMS, though it may be associated with individual symptoms. Additional studies are needed to understand these relationships in women with irregular menstrual. FUNDING SOURCES: Intramural Research Program, Division of Population Health Research, NICHD. NIH Medical Research Scholars Program. Doris Duke Charitable Foundation.