Research Summary

Environmental toxins produce infertility, fetal loss and malformations in laboratory animals. These effects have been less well studied in humans. Allen J. Wilcox, M.D., Ph.D., formerly led the Reproductive Epidemiology Group which worked to extend the study of environmental exposures to the area of human reproduction. As Scientist Emeritus, Wilcox continues to carry out research in three areas:

• fertility, conception and early pregnancy
• birth weight and preterm delivery
• fetal development and childhood health

Fertility, Conception and Early Pregnancy
Fertility and early pregnancy are vulnerable to environmental toxicants. Wilcox and his colleagues have developed many of the current methods for studying fertility and early pregnancy. In the 1980s he carried out a landmark study of early pregnancy that identified the earliest detectable pregnancy loss – that which occurs between implantation and clinical recognition. This study established that one-quarter of human pregnancies are lost before women are even aware they are pregnant. The study has provided a benchmark for subsequent studies of toxicant effects on early pregnancy loss.

The Early Pregnancy Study has shed light on other basic aspects of human reproduction. For example, the study established that women are fertile for an average of six days in each menstrual cycle, ending on the day of at ovulation.  It also showed that intercourse is most frequent during the six fertile days of the cycle – even among couples who are not trying to become pregnant. These data suggest as-yet-unspecified biological mechanisms that influence intercourse frequency across the menstrual cycle.

Wilcox and his group have also developed some of the basic methods for assessing time to pregnancy (fecundability) as an epidemiologic endpoint, as well as showing the methodological pitfalls involved in such studies.

Birth Weight and Preterm Delivery
Low birth weight and early delivery are among the strongest predictors of infant survival, and are also easy endpoints to measure. These features have led both of these endpoints to be extensively used in studies of environmental toxicants.

In a series of papers, Wilcox has developed a critique of low birth weight and preterm delivery as endpoints in perinatal research. Reduced birth weights can be a sensitive marker of fetal growth restriction but not necessarily an indicator of poor health. Similarly, preterm delivery is useful as an endpoint in itself, but not as a predictable marker of subsequent outcome. Moreover, routine adjustment for gestational age in studies of perinatal outcomes (an adjustment that has been widely practiced) can cause considerable bias.

Fetal Development and Childhood Health
Wilcox and his colleagues carried out a population-based case–control study of babies born with facial clefts in Norway for the purpose of uncovering the causes of clefts. This study, has integrated data on environmental risk factors with genetic data to establish the role of candidate teratogens such as low folates, cigarette smoking, heavy alcohol consumption, and other factors as causes of facial clefts. This study is the major component of an international consortium to pursue genetic variants linked to facial clefts.

Currently Wilcox is conducting the MOBAND Study of Cerebral Palsy, with a focus on prenatal causes. The study is being conducted within the two 100,000-baby birth cohorts established in Norway and Denmark. This is the largest study of cerebral palsy to include prospectively collected information on maternal exposures, as well as biological samples collected during pregnancy.

Wilcox came to NIEHS in 1979, where he served from 1991 to 2001 as Chief of the Epidemiology Branch. Since 2001, he has been the Editor-in-Chief of the journal Epidemiology . He is past president of the American Epidemiological Society (AES), the Society for Pediatric and Perinatal Epidemiologic Research (SPER), and the Society for Epidemiologic Research (SER). He holds adjunct faculty appointments at the University of North Carolina and Harvard University. He has an M.D. from the University of Michigan, and an M.P.H. in maternal and child health and Ph.D. in epidemiology from the University of North Carolina. In 2008, he was awarded an honorary Ph.D. by the University of Bergen (Norway). He is the author of the book, Fertility and Pregnancy: An Epidemiologic Perspective, published in 2010 by Oxford University Press.

Studies

• DES Study
  The DES Study was a follow–up of men and women born during a clinical trial of DES (diethystilbestrol) in the early 1950's. This follow–up study explores adult health effects of prenatal DES exposure.

• Early Pregnancy Study
  The Early Pregnancy Study provides a detailed look at ovulation, conception and early pregnancy for a of 221 women who provided daily diary and urine specimens before and during early pregnancy.

• MOBAND Study of Cerebral Palsy (MOthers and BAbies in Norway and Denmark)
  MOBAND is a collaboration between the two large birth cohorts of Norway and Denmark for the study of prenatal causes of cerebral palsy.

• Norway Facial Clefts Study
  ("/Rhythmyx/assembler/render?sys_contentid=36031&sys_revision=1&sys_variantid=639&sys_context=0&sys_authtype=0&sys_siteid=&sys_folderid=" sys_dependentvariantid="639" sys_dependentid="36031" inlinetype="rxhyperlink" rxinlineslot="103" sys_dependentid="36031" sys_siteid="" sys_folderid="")This population–based, case–control, parent–triad study explores the environmental and genetic causes of cleft lip and palate.