Enrique F. Schisterman, Ph.D., M.A.
Reproductive EpidemiologyPerinatal EpidemiologyPediatric EpidemiologyMethodologic Research in Epidemiology
Branch Chief: Enrique F. Schisterman, Ph.D., M.A.
The Epidemiology Branch's mission is threefold: 1) to plan and conduct investigator-initiated original epidemiologic research focusing on reproductive, perinatal, and pediatric health endpoints to identify etiologic mechanisms, at risk subgroups, and interventions aimed at maximizing health and preventing, diagnosing, and/or treating disease; 2) to provide service to the Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Department of Health and Human Services, and the profession via consultation, collaboration, and assistance to advance the scientific discipline of epidemiology and the goals of the Institute; and 3) to recruit highly qualified students and trainees at various stages of their professional careers to provide them with training in reproductive, perinatal, and/or pediatric epidemiologic research. The Branch is organized around key areas of research, including reproductive, perinatal, pediatric, and methodologic epidemiologic research. Regardless of title, Branch members work collaboratively to forward the Division and Institute's mission. The Branch conducts team science and is committed to using trans-disciplinary, cutting-edge science to address critical data gaps throughout the life course.
Reproductive Epidemiology specifically investigates the various factors that affect both male and female reproductive health, and the processes that affect conception, reproduction, and infertility. The Epidemiology Branch has several key studies in this area: the BioCycle Study, the Effect of Aspirin in Gestation and Reproduction (EAGeR) Study, and the Folic Acid and Zinc Supplementation Trial (FAZST) Trial. A brief description of each study and its key components follows.
Principal Investigator: Enrique F. Schisterman, Ph.D.
Detectable oxidative stress in women may be affected by variations in hormone levels that occur as a part of normal menstrual function. Failure to address this underlying biological variability may impair study inference; however, this issue has received little attention. We designed the BioCycle Study with the primary goal to better understand the intricate relation between levels of sex hormones (e.g., estrogen) and oxidative stress during the menstrual cycle. Specifically, we were interested in: 1) the relation between hormone levels and oxidative stress biomarkers during the menstrual cycle in pre-menopausal women; 2) the intra-cycle variation of biomarkers of oxidative stress; and 3) the influence of external factors such as cigarette smoking, alcohol consumption, and exercise on oxidative stress and hormone levels.
The BioCycle Study was a prospective longitudinal cohort study comprising 251 women aged 18 to 40 years (98% follow-up rate). Participants were followed for two menstrual cycles. Blood and urine samples were obtained for key days of each menstrual cycle based on hormone levels approximated by fertility monitors. Serum samples were evaluated for levels of the oxidative stress markers F2 isoprostanes and conjugate dianes, as well as fasting glucose, total cholesterol and serum antioxidant vitamins. At each of the 16 clinic visits, we prospectively collected data on diet, physical activity and other environmental exposures.
Since completion of the study much progress has been made in the analysis of the BioCycle Study data. With regards to the main question under study, we found a significant positive association between F2-Isoprostanes (a marker of oxidative stress) and estrogen which calls into question the hypothesis of estrogen serving as an antioxidant. We have also shown that metabolic markers such as oxidative stress, lipoprotein cholesterol, inflammation, glucose metabolism, and uric acid vary significantly across the menstrual cycle among healthy regularly cycling women. While absolute changes were generally modest, we observed that women passed between clinically relevant risk categories depending on which phase of the menstrual cycle biomarkers were measured. The hypothesized cardioprotective effects of estrogen in premenopausal women may actually be partially explained by hormonal variability. While the best time to measure biomarkers during a woman's cycle has yet to be established, measurements should be made during the same cycle phase for consistent comparisons. Further, biomarker variability was observed among healthy women, and it is possible that other populations have even greater variability. These findings have implications for clinical practice (i.e., doctor visits should be timed to menstrual cycle phase) and for study designs among women of reproductive age.
Sunni L. Mumford , Ph.D., M.S.
Principal Investigator: Enrique F. Schisterman, Ph.D., M.A.Division Collaborators:
The EAGeR Trial is a multi-site prospective double-blind trial designed to assess the effects of low-dose aspirin on implantation and pregnancy outcome. In this trial, 1,228 regularly menstruating women age 18-40 years with up to two recent miscarriages and who planned to become pregnant again were randomized to either the treatment group (daily aspirin (81mg) plus folic acid (0.4 mg)) or the placebo group with folic acid only. Treatment/placebo administration began prior to conception and continued during pregnancy. Fertility monitors were used to assist with timing of intercourse; home digital pregnancy testing kits were used to indicate pregnancy; and, daily urine samples were collected to monitor very early pregnancy and pregnancy loss.
Women were followed by the clinic through regular visits as well as phone interviews. During follow-up, women were in what was referred to as active follow-up for two menstrual cycles. In this phase, women kept daily diaries and visited the clinic four times, where they filled out questionnaires and provided blood samples, in addition to daily urine samples. After this, they entered passive follow-up for an additional four cycles, visiting the clinic at the end of each cycle. At the end of passive follow-up if no pregnancy was confirmed, women were considered to have completed the study. However, if a woman became pregnant at any time during this stage, she switched to pregnancy follow-up. Women in pregnancy follow-up were followed actively for four weeks post-conception and passively through parturition. Pregnancy loss, pregnancy complications, and perinatal outcomes were monitored throughout pregnancy.Trial recruitment began June 15, 2007, and ended in July 2011, with the last screening done on July 14, 2011, and the last randomization on July 15, 2011. Follow-up has been completed as of September 2012 and results of the trial are pending.
Perinatal epidemiologic research focuses on parturient women and their pregnancy outcomes. There are several studies in the Epidemiology Branch that fall into the category of perinatal epidemiology, such as the: 1) Consortium on Safe Labor; 2) Diabetes and Women's Health (DWH) Study; 3) Gestational Diabetes Mellitus: Epidemiology, Etiology and Health Consequences; and the 4) NICHD Fetal Growth Studies. A brief description of each study follows.
S. Katherine Laughon, M.D., M.S.
Jagteshwar (Una) Grewal, Ph.D., M.P.H.
Pauline Mendola, Ph.D., M.S.
The Consortium on Safe Labor (CSL) was a multicenter retrospective observational study of 228,562 deliveries at 12 clinical centers across the U.S. The CSL team identified several key findings regarding contemporary clinical obstetrical management. These include: 1) identification of factors contributing to the high 33% U.S. cesarean delivery rate (viz., a high percentage of intrapartum cesarean deliveries being performed too soon or before women achieved active labor and that a prior history of a cesarean delivery accounted for most repeat cesarean sections); 2) labor patterns are longer now than approximately 50 years ago; and 3) 7% of neonates delivered late preterm or at 34 – 36 weeks of gestation were either elective or delivered based on clinical judgment instead of "hard" indications. The implications of these findings are that preventing cesarean delivery is especially important in the first pregnancy. Since providers are using definitions of abnormal labor developed in a population of women different from the contemporary obstetrical population, the CSL findings suggest that routine interventions such as the use of oxytocin and timing of cesarean delivery as well as modern-day labor process management warrant reconsideration. Collectively, this body of research is providing data to develop clinical guidance regarding the management of contemporary parturient women based upon empirically supported guidance.
In addition to multiple studies being published in high impact journals, few studies have been the focus of two NICHD Research Perspectives monthly podcast series hosted by the NICHD Director.
Principal Investigator: Cuilin Zhang M.D., Ph.D, M.P.H.
Cuilin Zhang M.D., Ph.D, M.P.H.
The DWH Study, based on a retrospective cohort design, aims to understand and discover novel pathways and determinants underlying the progression from gestational diabetes (GDM) to type 2 diabetes (T2DM) and complications.
GDM is a common pregnancy complication. Women who develop impaired glucose tolerance in pregnancy and/or GDM are at substantially increased risk for T2DM and metabolic disorders in the years following pregnancy. Determinants underlying the transition from GDM to T2DM and co-morbidities are not well understood. There is limited information about the genetic and environmental factors that impact this transition. The overall goal of this study is to investigate genetic factors and their interactions with risk factors amenable to clinical or public health intervention in relation to the development of T2DM and co-morbidities among the women at high risk and of understanding the underlying molecular mechanisms. A secondary goal of this study is to collect baseline information of children born from the pregnancies complicated by glucose intolerance.
Data collection for this study is built upon two large existing cohorts: the Nurses' Health Study II (NHS-II) and the Danish National Birth Cohort (DNBC). In the present study, we are enrolling approximately 4,000 women with a history of GDM who were members of either the NHS II or DNBC. After enrollment, participants are followed for additional years to collect updated information on major clinical and environmental factors including, but not limited to diet, physical activity and anthropometric information that may predict T2DM risk. Biospecimen collection is to measure genetic and biochemical markers (both pathway specific and non-targeted) believed relevant for glucose metabolism. Key medical and environmental factors and covariates have been collected using standardized questionnaires for both cohorts. Data collection is expected to be completed by September 2015.
Principal Investigator: Cuilin Zhang M.D., Ph.D.
Gestational diabetes mellitus (GDM), one of the most common complications of pregnancy, is related to substantial short-term and long-term adverse health outcomes for both women and their offspring. Understanding the epidemiology and etiology of GDM is critical for the development of effective and targeted intervention strategies to prevent GDM and to interrupt the vicious cycle across generations involving maternal GDM, childhood obesity and impaired glucose metabolism, and adulthood onset diabetes. Along this line of research, we are conducting research to address the following topics:
Principal Investigator: Germaine M. Buck Louis, Ph.D., M.S.
Germaine M. Buck Louis, Ph.D., M.S.
Determining optimal fetal growth remains a key research priority, as alterations in growth are associated with various pregnancy disorders and also infant/child morbidity and mortality. Moreover, the early origins of health and disease hypothesis posits that decrements in fetal size may be associated with various chronic diseases such as heart disease later in life. Thus, delineating optimal fetal growth has implications for clinical care and population health. The NICHD Fetal Growth Study is an ambitious observational epidemiologic study that is recruiting 2,400 low risk pregnant women from 12 clinical sites in the United States (Fetal Growth Studies). Study participants undergo longitudinal 2D- and 3D- ultrasounds at a priori defined gestational ages during pregnancy. The overarching goal of the Study is to determine the optimal fetal growth for four race/ethnic groups of women, and to develop methods for the accurate clinical estimation of birth size with the eventual goal of predicting the optimal timing of delivery. A second pregnancy cohort comprises approximately 150 pregnant women carrying dichorionic twins with the goal of establishing growth trajectory for contemporary twin populations. A third pregnancy cohort comprised 450 obese pregnant women. Follow-up of women in all cohorts will be completed in 2013.
Pediatric epidemiology focuses on the factors that affect the growth, development and health of children from infancy through adulthood. The Epidemiology Branch has three research projects, including the Birth Defects Research Group, Genetic factors in Birth Defects and the Upstate Kids Study. A brief summary of each of the studies follows.
James L. Mills, M.D., M.S.
Principal Investigator: James L. Mills, M.D., M.S.
The Birth Defects Research Group is a multi-center multi-disciplinary group led by NICHD to investigate the causes of birth defects. A primary focus is the effect of dietary factors on birth defect risks. These factors include folate, vitamin B12, and other B vitamins and their metabolites. The collaborating institutions are the NICHD and National Human Genome Research Institute, The Health Research Board of Ireland, and the Department of Biochemistry, Trinity College, Dublin.
Research continues to explore genetic factors related to folate and vitamin B12 status to identify additional risk genes for neural tube defects. Neural tube defects are known to have both a genetic and an environmental (dietary) component. The group has conducted extensive investigations into the role of folate enzyme genes and neural tube defects. Recently, Branch investigators published a paper focusing on 82 candidate genes associated with folate and related compound metabolism. This is the largest neural tube defect genetic association study to date. Ten genes were nominally associated with neural tube defects; but findings should be considered preliminary given the large sample size.
Ongoing research involves examining quantitative traits in a genome wide association study given the genetic analysis is complete. Collected samples have been stored for further analysis of genetic factors as is the case with von Willebrand factor (in press). Additional analyses are ongoing.
Principal Investigator: James L. Mills, M.D.
The Genetic Factors in Birth Defects Study is a multi-center multi-disciplinary study led by NICHD to identify genetic risk factors for a wide range of major birth defects. The collaborating institutions are the NICHD and National Human Genome Research Institute, the New York State Department of Health, and the University of Iowa. The New York State Congenital Malformations Registry has identified approximately 13,000 children who have major birth defects and suitable unaffected controls from among all New York births. This information has been linked to blood spots retained after neonatal testing. DNA has been extracted from anonymous blood spots and used to test for genetic variants associated with these birth defects.
A variety of defects has been selected and analyzed using a candidate gene approach. To date, genetic variants (single nucleotide polymorphisms) have been identified and the reported results include:
Because of the very large number of affected children included in this study, it has been possible to examine relatively rare conditions such as non-syndromic omphalocele. Folic acid-containing vitamins taken during the periconception period and the consumption of food fortified with folic acid have both been reported to reduce omphalocele rates. We found that a gene involved in vitamin B12 transport was strongly associated with omphalocele, suggesting that both folate and B12 status may influence omphalocele risk.
Our investigation of genetic factors associated with abnormal limb development identified a variant in the gene FGF 10 that was strongly associated with abnormal limb development. This gene plays a role in the embryonic development of bones (formation of the apical epidermal ridge). Our finding suggests that this variant could be an important factor in abnormal development of many bones.
We investigated the role of genes involved in neuronal migration in Hirschsprung's disease, since it is known that abnormal innervation is critical in this disorder. Our research showed that there are more variants in a key gene, RET, than had been previously appreciated involved in Hirschsprung's disease, and that the risk associated with RET may vary by ethnic background.
Because we are one of the few groups with sufficient cases to study the disorder, we investigated genetic factors at regulatory sites as possible risk factors for anorectal atresia in an exploratory study. This study demonstrated that several factors related to transcription factor binding, splicing, and DNA methylation were associated with anorectal atresia. However, the findings await confirmation.
The large number of cases has also enabled the group to make substantial contributions to consortia performing genome wide association studies. The group is currently collaborating in one such study examining craniosynostosis. This investigation has identified two new gene risk factors for craniosynostosis that are related to skeletal development. The group is interested in exploring collaborations with investigators conducting such studies.
Edwina Yeung, Ph.D.
The Upstate KIDS Study was designed in response to growing albeit equivocal evidence suggesting that pregnancies conceived with assisted reproductive technologies (ART) were at increased risk for pregnancy complications, perinatal and infant mortality, and decrements in gestation and birth size in both singletons and twins (Upstate Kids Study). This provocative body of evidence underscores the early origin of human development, including during sensitive windows or early childhood. However, much of the available evidence stems from cross-sectional data, serving as the impetus for the prospective Upstate KIDS Study with longitudinal data collection. The Upstate KIDS's Study overarching goal is to determine if fecundity and various infertility treatments adversely affect the growth, motor and social development of children from birth through age three years. A matched-exposure cohort design was used to establish a primary cohort of infants conceived with and without infertility treatment who resided in the 57 counties comprising Upstate New York State (exclusive of New York City) using the "infertility check box" on the birth certificate for cohort selection. Parents and their infants were recruited at approximately 3-5 months of age. The primary matched cohort designed comprises nearly 1,297 "exposed" infants (1,011 singletons and 286 twins) with reported infertility treatment and 3,692 "unexposed" infants (2,894 singletons and 789 twins) without reported treatment who were then matched for selection on maternal residence and plurality of birth irrespective of race/ethnicity. All co-twins of study participants and higher order multiples were enrolled in a secondary cohort.
Parental participation includes completion of: 1) a baseline questionnaire on reproductive and medical history, environmental exposures and infant characteristics; 2) parental developmental rating instruments (i.e., Ages & Stages at 4, 8, 12, 18, 24, 30, 36 months of age and the Modified Checklist for Autism in Toddlersat 18 and 24 months) and 3) children's longitudinal growth and medical history as recorded in journals. All infants or children who screen positive for developmental delays are referred to their primary health provider or for clinical assessment. The Upstate KIDS Cohort has been linked with the Society for Assisted Reproductive Technologies' database for the capture of ART treatment. The 24-, 30- and 36-month follow-ups of the cohort are in progress. With parental consent obtained at the 8-month screening, residual dried blood samples (punches) from Guthrie cards were harvested and analyzed for 5 panels of inflammatory and environmental chemical biomarkers. Such exposures are associated with alterations in child growth and development.
The Epidemiology Branch conducts methodologic research motivated by the many unique aspects of human reproduction and development across the lifespan. The specific methodologic areas that the Epidemiology Branch is conducting research on include the Modeling of Menstrual Cycle Function, Gene Environment Interactions and Pooling of Biological Specimens. A brief description of each research area follows.
The menstrual cycle is a complex process involving multiple hormones, which are regulated by intricate feedback mechanisms. Hormones such as luteinizing hormone, follicle stimulating hormone, estrogen, and progesterone follow a cyclical pattern, which is coordinated by the hypothalamic-pituitary-ovarian axis. Considerable cycle variability exists within and across women. Hormone levels and cycle characteristics have been associated with various reproductive outcomes, such as fertility and spontaneous abortion, and later onset disease. To better describe factors associated with menstrual cycle function and inform women's health research, statistical models are needed which appropriately account for the intricacies of the menstrual cycle biology. Our methodologic research is aimed at developing various approaches for modeling menstrual cycle function data to answer critical data gaps such as:
Current topics of interest include the application of harmonic models to model menstrual cycle function, as well as the use of joint-models to model the four reproductive hormones simultaneously.
Principal Investigator: Enrique F. Schisterman, Ph.D., M.A.
Genes and environment are important for complex disease such as gestational diabetes, birth defects and miscarriages. One important implication of unmasking gene-environment interactions is to identify highly susceptible populations, such that modifiable exposures associated with disease can be prevented or minimized. However, genetically susceptible individuals cannot be identified without a better understanding of gene-environment interactions.
One complication in studying gene-environment interactions is the high cost due to genotyping the large number of people necessary to have sufficient power to detect an interaction. Additional considerations include insufficient volume of biospecimens for genotyping, or restrictions on genotyping for privacy and confidentiality reasons. Division researchers are examining a new study design to increase statistical power by strategically pooling biospecimens. Pooling can reduce overall costs, while requiring less biospecimen volume from each individual. Therefore by using a pooling strategy, previously underpowered or abandoned gene-environment hypotheses can be explored.
These issues have been the motivation for numerous papers as well as a collaborative effort funded by the American Chemistry Council with the goal of providing the methodological tools necessary to assess and address issues related to gene-environment interactions.
Biomarkers of exposure and disease status play a critical role in epidemiological research, but fiscal limitations and the high cost of assays often require that investigators choose a subset of potential markers. Less often but equally of concern, samples may physically lack the volume necessary to perform a particular assay. Such issues may impact the ability to design the work or carry it through.
Pooling biospecimens is a technique in which samples from different individuals are physically combined and measured. This approach reduces the amount of each sample necessary for the assay and makes each assay more informative, thus reducing the number of tests required and overall cost. Division researchers have shown that a wide variety of statistical analyses (hypothesis testing, regression, ROC curves, semi and fully parametric methods) can be applied to pooled data, often with only minor adjustments to standard practice. Additional benefits of pooling have been demonstrated, such as increasing efficiency while limiting the impact of the limit of detection. A hybrid pooled-unpooled design also was developed by Division researchers and offers considerable cost savings when pooling, with the added ability to assess and address measurement error without the need for replicate assays.
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