Enrique Schisterman

Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health | NICHD · Epidemiology Branch

Children born via cesarean delivery have a higher risk of metabolic, immunological, and neurodevelopmental disorders compared to those born via vaginal delivery, although mechanisms remain unclear. We conducted a meta-analysis of epigenome-wide association studies to examine the associations between delivery mode and blood DNA methylation at birth...

( Am J Obstet Gynecol. 2024;230:440.e1–440.e13. doi: 10.1016/j.ajog.2023.12.038) Maternal health concerns in the United States have intensified due to rising maternal mortality rates (MMR). However, there is skepticism about the accuracy of these estimates. Maternal mortality is often underreported, even in countries with reliable vital registratio...

Background Reports of high and rising maternal mortality ratios (MMR) in the United States have caused serious concern. We examined spatiotemporal patterns in cause-specific MMRs, in order to obtain insights into the cause for the increase. Methods The study included all maternal deaths recorded by the Centers for Disease Control and Prevention fr...

(Abstracted from Am J Obstet Gynecol 2024;230:440.e1–440.e13) High reported maternal death rates in the United States have garnered attention and skepticism, especially with reports indicating a near doubling of maternal mortality between 2018 and 2021. Some attribute this increase to changes in reporting criteria for maternal mortality developed i...

Context Dyslipidemia is common, and resultant endothelial dysfunction may impact reproductive outcomes. No prospective study has examined the effect of preconception lipid parameters in both female and male partners or their interaction on live birth. Objective To determine whether live birth is associated with preconception lipids in both partner...

Background: Accumulating evidence shows that peri-conceptional and in-utero exposures have lifetime health impacts for mothers and their offspring. Objectives: We conducted a Follow-Up Study of the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial with two objectives. First, we determined if women who enrolled at the Utah site (N =...

Worldwide trends to delay childbearing have increased parental ages at birth. Older parental age may harm offspring health, but mechanisms remain unclear. Alterations in offspring DNA methylation (DNAm) patterns could play a role as aging has been associated with methylation changes in gametes of older individuals. We meta‐analyzed epigenome‐wide a...

(Abstracted from Lancet 2023;402:1857–1865 Weight gain during pregnancy that exceeds the recommendations updated by the National Academy of Medicine (NAM) in 2009 has been associated with greater postpartum weight retention. One systematic review of 9 studies found an association between excessive weight gain during pregnancy and postpartum weight...

It is presently not known whether endogenous neuroactive steroid hormone trajectories across the menstrual cycle are distinguishable in women with premenstrual dysphoric disorder (PMDD). To improve the rigor in this area of research, we implemented a validated study methodology, involving blood sample collection at 8 key menstrual cycle timepoints,...

Menopause marks the cessation of fertility and the transition to post-reproductive years. Nearly 1M US women experience menopause annually, but despite the significant impact it has on their physical and mental health, menopause has been insufficiently studied. Oxytocin is a neurohormone that regulates emotionality, social behaviors, and fundamenta...

Context Along the menstrual cycle, associations between inconsistent sleep duration and levels of metabolic biomarkers are uncertain and could involve fluctuations in estrogen concentrations. Objective To examine associations between patterns of sleep duration and metabolic biomarkers across 2 menstrual cycles within a cohort of premenopausal wome...

Background: Phthalates are endocrine-disrupting chemicals linked to adverse pregnancy outcomes. Despite the sensitivity of female reproductive processes to oxidation-reduction reaction stress and endocrine disruption, evidence for the impact of women's phthalate exposure on the ability to establish and maintain pregnancy has been inconclusive. Ob...

Maternal educational attainment (MEA) shapes offspring health through multiple potential pathways. Differential DNA methylation may provide a mechanistic understanding of these long-term associations. We aimed to quantify the associations of MEA with offspring DNA methylation levels at birth, in childhood and in adolescence. Using 37 studies from h...

Research suggests that polycystic ovary syndrome (PCOS) traits (e.g., hyperandrogenism) may create a suboptimal intrauterine environment and induce epigenetic modifications. Therefore, we assessed the associations of PCOS traits with neonatal DNA methylation (DNAm) using two independent cohorts. DNAm was measured in both cohorts using the Infinium...

Background Multifetal gestation could be associated with higher long‐term maternal mortality because it increases the risk of pregnancy complications such as preeclampsia and preterm birth, which are in turn linked to postpartum cardiovascular risk. Objectives We examined whether spontaneously conceived multifetal versus singleton gestation was as...

Background The metabolic changes that ultimately lead to gestational diabetes mellitus (GDM) likely begin before pregnancy. Cannabis use might increase the risk of GDM by increasing appetite or promoting fat deposition and adipogenesis. Objectives We aimed to assess the association between preconception cannabis use and GDM incidence. Methods We...

Background: Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear. Methods: We carried...

Complex diseases have multifactorial etiologies making actionable diagnostic biomarkers difficult to identify. Diagnostic research must expand beyond single or a handful of genetic or epigenetic targets for complex disease and explore a broader system of biological pathways. With the objective to develop a diagnostic tool designed to analyze a comp...

Background: The PrePARED consortium creates a novel resource for addressing preconception health by merging cohorts. We describe our data harmonization methods and results. Methods: Individual-level data from 12 prospective studies were pooled. The crosswalk-cataloging-harmonization procedure was used. The index pregnancy was defined as the firs...

Importance: Premenstrual symptoms, including food cravings, are often a regular complaint among menstruating women. However, existing evidence regarding the biological mechanisms by which these food cravings occur remains unclear. Inflammation may play an essential role in the occurrence of these food cravings before menstruation. Objective: The...

Background: While redox stress likely plays an important role in reproductive health, the utility of peripheral biomarkers of oxidative stress, such as isoprostanes, during the periconception period remains underexplored. We evaluated the relationship between isoprostanes during preconception and gestational week 4 and women's reproductive health...

Variability in sleep duration and cardiovascular health have been infrequently investigated, particularly among reproductive-age women. We examined these associations across the menstrual cycle among a cohort of 250 healthy premenopausal women, aged 18-44y. The BioCycle study had collected cardiovascular biomarkers (serum high- and low-density lipo...

Background: Pregnancy complications are associated with increased risk of development of cardiometabolic diseases and earlier mortality. However, much of the previous research has been limited to White pregnant women. We aimed to investigate pregnancy complications in association with total and cause-specific mortality in a racially diverse cohort...

Background Premenstrual symptoms, including food cravings, are often a regular complaint among menstruating women. However, existing evidence regarding the biological mechanisms by which these food cravings occur remains unclear. Inflammation may play an essential role in the occurence of these food cravings before menstruation. Purpose The purpos...

Background: Maternal adaptations may vary by foetal sex. Whether male infants influence long-term mortality in mothers remains uncertain. Objective: The objective of the study was to examine whether male infants increase the risk of maternal mortality. Methods: This study included pregnant women enrolled at 12 US sites from 1959 to 1966 in the Coll...

Objective: Determine relations between preconception adiposity and human offspring sex and sex ratio. Methods: Within a prospective preconception cohort nested within a randomized controlled trial based at 4 U.S. clinical sites, logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) for male:female sex ratio and log-i...

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 female participants and >9,500 t...

Objective: To evaluate the associations between preconception sleep characteristics and shift work with fecundability and live birth. Design: Secondary analysis of the Effects of Aspirin in Gestation and Reproduction study, a preconception cohort. Setting: Four US academic medical centers. Patient(s): Women aged 18-40 with a history of 1-2 p...

Objective: To examine whether semen parameters are associated with live birth among couples seeking infertility treatment after accounting for semen parameter variability. Design: Folic Acid and Zinc Supplementation Trial (FAZST) prospective cohort. Setting: Four US reproductive endocrinology and infertility care study centers, 2013-2017. Pat...

Inverse probability weighting (IPW) and g-computation are commonly used in time-varying analyses. To inform decisions on which to use, we compared these methods using a plasmode simulation, based on the Effects of Aspirin in Gestation and Reproduction trial. In our main analysis, we simulated 1226 individuals, followed for up to 10 weeks. The expos...

Introduction We have recently shown that sperm epigenetic age (SEA), a surrogate measure of biological aging in sperm, is associated with couples’ time-to-pregnancy (TTP). Advanced SEA was also observed among smokers, suggesting its susceptibility to environmental exposures. Therefore, we assessed the association between urinary phthalate metabolit...

There are important challenges to the estimation and identification of average causal effects in longitudinal data with time-varying exposures. Here, we discuss the difficulty in meeting the positivity condition. Our motivating example is the per-protocol analysis of the Effects of Aspirin in Gestation and Reproduction trial. We estimated the avera...

Objectives High pregnancy weight gain is associated with greater postpartum weight retention; yet the long-term implications remain unknown. We examined associations of pregnancy weight change with mortality after ∼50 years of follow-up. Methods The Collaborative Perinatal Project (CPP) Mortality Linkage Study linked maternal participants in the C...

Background Preconception pregnancy risk profiles—characterizing the likelihood that a pregnancy attempt results in a full-term birth, preterm birth, clinical pregnancy loss, or failure to conceive—can provide critical information during the early stages of a pregnancy attempt, when obstetricians are best positioned to intervene to improve the chanc...

Introduction Irregular sleep duration may disrupt circadian rhythms necessary for optimal cardiovascular function. Yet, few studies have examined irregular sleep duration in relation to cardiovascular health, particularly among diverse cohorts of reproductive-age women. This study examined associations between sleep duration irregularities across t...

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 chro...

Limited data are available about the potential health effects of infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on pregnant women and their developing offspring. We developed the International Registry of Coronavirus Exposure in Pregnancy (IRCEP) to provide data on the risk of major adverse obstetric and neonatal ou...

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 singleto...

Background Complex diseases have multifactorial etiologies making clinically actionable diagnostic markers difficult to identify. Novel tools with higher diagnostic yield and utility in driving personalized care are needed. Methods We utilized Illumina methylation array data from 2612 samples to assess DNA methylation patterns in 19 distinct cell...

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. A racially diverse cohort of pregnant women enrolled in the Collaborative Perinatal Project (CPP) from 1959-1966 was used for this study. CPP records were linked to the National...

Objective 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 (TTP), pregnancy loss, and live birth among fecund women without diagnosed diabetes or other medical diseases. Design A secondary analysis of a prospective cohort of women participa...

Background: Caffeine is the most frequently used psychoactive substance in the U.S. and more than 90% of reproductive-age women report some level of intake daily. Despite biological plausibility, previous studies on caffeine and fecundability report conflicting results. Importantly, prior studies measured caffeine exposure exclusively by self-repo...

Background: Epigenetic mechanisms may underlie associations between maternal caffeine consumption and adverse childhood metabolic outcomes. However, limited studies have examined neonate DNA methylation (DNAm) patterns in the context of preconception or prenatal exposure to caffeine metabolites. Objective: We examined preconception and pregnancy...

The average causal effect compares counterfactual outcomes if everyone had been exposed versus if everyone had been unexposed, which can be an unrealistic contrast. Alternatively, we can target effects that compare counterfactual outcomes against the factual outcomes observed in the sample, i.e., we can compare against the natural course. Here, we...

Objective To determine if 6-month folic acid (5 mg) and zinc (30 mg) supplementation impacts sperm DNA methylation patterns. Design A multicenter, double-blind, block randomized, placebo-controlled trial titled “The Folic Acid and Zinc Supplementation Trial (FAZST).” Setting Infertility care centers. Patient(s) Male partners (18 years and older)...

Study question: Is preconception leukocyte telomere length associated with fecundability, pregnancy loss and live birth among women attempting natural conception with a history of 1-2 prior pregnancy losses? Summary answer: Preconception leukocyte telomere length is not associated with fecundability, pregnancy loss or live birth. What is known...

( Obstet Gynecol . 2021;137:763–771) Despite what reputable publications have lead health physicians and experts to believe, reports from the National Center for Health Statistics show United States maternal mortality rates have not increased, rather the surveillance of maternal deaths has improved.

Effect measure modification is often evaluated using parametric models. These models, though efficient when correctly specified, make strong parametric assumptions. While nonparametric models avoid important functional form assumptions, they often requirelarger samples to achieve a given accuracy. We conducted a simulation study to evaluate perform...

Objectives Maternal diet prior to and during pregnancy has been related to child health across the lifespan; however, mechanisms remain unclear. Gestational age acceleration (GAA), a measure of epigenetic aging relative to clinically estimated gestational age (GA), has emerged as a potential biomarker predictive of childhood BMI and atopic diseases...

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 Infi...

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 wit...

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 imp...

The Society for Epidemiologic Research’s (SER) annual meeting is a major forum for sharing new research and promoting participants’ career development. As such, 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, inclu...

Rigorous studies carried out by the National Center for Health Statistics show that previously reported increases in maternal mortality rates in the United States were an artifact of changes in surveillance. The pregnancy checkbox, introduced in the revised 2003 death certificate and implemented by the states in a staggered manner, resulted in incr...

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 preconceptio...

Study question: Is cannabis use assessed via urinary metabolites and self-report during preconception associated with fecundability, live birth and pregnancy loss? Summary answer: Preconception cannabis use was associated with reduced fecundability among women with a history of pregnancy loss attempting pregnancy despite an increased frequency o...

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. Method...

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...

Study question: Do sperm mitochondrial DNA measures predict probability of pregnancy among couples in the general population? Summary answer: Those with high sperm mitochondrial DNA copy number (mtDNAcn) had as much as 50% lower odds of cycle-specific pregnancy, and 18% lower probability of pregnancy within 12 months. What is known already: Se...

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 week...

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...

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 b...

Background: Attaining pregnancy is conditional upon a series of complex processes, including adequately timed intercourse, ovulation, fertilisation, and implantation. Anovulation is a first-line treatment target for couples with difficulty conceiving and is frequently examined in studies of fecundability. Objectives: To identify whether sporadic...

Anti-müllerian hormone (AMH) is an established marker of ovarian reserve that decreases with age. Though the pool of ovarian follicles is established during fetal development, impacts of in utero exposures on AMH are uncertain. Thus, we sought to evaluate associations of in utero exposures with AMH of adult daughters with a prospective cohort study...

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 regula...

In trials with noncompliance to assigned treatment, researchers might be interested in estimating a per-protocol effect-a comparison of two counterfactual outcomes defined by treatment assignment and (often time-varying) compliance with a well-defined treatment protocol. Here, we provide a general counterfactual definition of a per-protocol effect...