The Safety of Low-Dose Aspirin on the Mode of Delivery: Secondary Analysis of the Effect of Aspirin in Gestation and Reproduction Randomized Controlled Trial.

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..

A Data-Based Approach to Evaluating Representation by Gender and Affiliation in Key Presentation Formats at the Annual Meeting of the Society for Epidemiologic Research.

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.

Associations between blood cadmium and endocrine features related to PCOS-phenotypes in healthy women of reproductive age: a prospective cohort study.

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.

Assessing Representation and Perceived Inclusion among Members in the Society for Epidemiologic Research.

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.

Is opioid use safe in women trying to conceive?

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.

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

BACKGROUND: Platelet activation may play a role in the pathophysiology of placenta-mediated obstetrical complications, as evidenced by the efficacy of aspirin in preventing preeclampsia, but published data regarding the relationship between biomarkers for platelet activation and adverse obstetrical outcomes are sparse. In particular, it is unknown whether prepregnancy biomarkers of platelet activation are associated with adverse pregnancy outcomes. OBJECTIVE: This study aimed to determine the following: (1) whether maternal plasma concentrations of platelet factor 4 are associated with risk of placenta-mediated adverse obstetrical outcomes, and (2) whether these associations are modified by low-dose aspirin. STUDY DESIGN: This ancillary study included measurement of platelet factor 4 among 1185 of 1228 women of reproductive age enrolled in the Effects of Aspirin in Gestation and Reproduction trial with available plasma samples, with relevant outcomes assessed among 584 women with pregnancies lasting at least 20 weeks' gestation. We measured platelet factor 4 in plasma samples obtained at the prepregnancy study visit (before randomization to low-dose aspirin or placebo), 12 weeks' gestation, and 28 weeks' gestation. The primary outcome was a composite of hypertensive disorders of pregnancy, placental abruption, and small-for-gestational-age infant. We estimated the relative risks (RRs) and 95% confidence intervals (CIs) for the association between platelet factor 4 and the composite and individual outcomes at each time point using log-binomial regression that was weighted to account for potential selection bias and adjusted for age, body mass index, education, income, and smoking. To evaluate the potential effect modification of aspirin, we stratified the analyses by aspirin treatment assignment. RESULTS: During follow-up, 95 women experienced the composite adverse obstetrical outcome, with 57 cases of hypertensive disorders of pregnancy, 35 of small for gestational age, and 6 of placental abruption. Overall, prepregnancy platelet factor 4 was positively associated with the composite outcome (third tertile vs first tertile; relative risk, 2.36; 95% confidence interval, 1.38-4.03) and with hypertensive disorders of pregnancy (third tertile vs first tertile; relative risk, 2.14; 95% confidence interval, 1.08-4.23). In analyses stratified by treatment group, associations were stronger in the placebo group (third tertile vs first tertile; relative risk, 3.36; 95% confidence interval, 1.42-7.93) than in the aspirin group (third tertile vs first tertile; relative risk, 1.78; 95% confidence interval, 0.90-3.50). CONCLUSION: High concentrations of platelet factor 4 before pregnancy are associated with increased risk of placenta-mediated adverse pregnancy outcomes, particularly for hypertensive disorders of pregnancy. Aspirin may mitigate the increased risk of these outcomes among women with higher plasma concentrations of preconception platelet factor 4, but low-dose aspirin nonresponders may require higher doses of aspirin or alternate therapies to achieve obstetrical risk reduction.

Pilot randomized trial of short-term changes in inflammation and lipid levels during and after aspirin and pravastatin therapy.

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.

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

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

Circulating Vascular Endothelial Growth Factor and Soluble fms-Like Tyrosine Kinase-1 as Biomarkers for Endometrial Remodeling Across the Menstrual Cycle.

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.

Urinary selective serotonin reuptake inhibitors across critical windows of pregnancy establishment: a prospective cohort study of fecundability and pregnancy loss.

OBJECTIVE: To prospectively investigate the association of selective serotonin reuptake inhibitor (SSRI) exposure through critical windows of pregnancy establishment with fecundability and pregnancy loss. DESIGN: Prospective cohort study using longitudinal urine measurements of common SSRIs while women are actively trying to conceive. SETTING: Four clinical sites. PATIENT(S): A total of 1,228 women without uncontrolled depression/anxiety, attempting natural conception while participating in a randomized trial of preconception-initiated low-dose aspirin. INTERVENTIONS(S): Not applicable. MAIN OUTCOME MEASURE(S): 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 and incidence of pregnancy loss and live birth were estimated. RESULT(S): A total of 172 women (14%) were exposed to SSRIs while trying to conceive. SSRI exposure was associated with 24% reduced fecundability, and accordingly, a nonsignificant 9% lower live birth incidence, with significantly lower live birth in fluoxetine-exposed women. SSRI exposure was not associated with subsequent pregnancy loss, whether exposure was before conception or at 0, 4, or 8 weeks of gestation, although estimates varied by specific SSRI drug. CONCLUSION(S): 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. CLINICAL TRIAL REGISTRATION NUMBER: NCT00467363.

Urinary Phytoestrogens and Relationship to Menstrual Cycle Length and Variability Among Healthy, Eumenorrheic Women.

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.

Maternal fatty acid concentrations and newborn DNA methylation.

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 ß-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.

Preconception Leptin and Fecundability, Pregnancy, and Live Birth Among Women With a History of Pregnancy Loss.

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.