Reproductive Epidemiology Group
Environmental Toxins & Human Reproduction
Allen J. Wilcox, M.D., Ph.D.
Environmental toxins produce infertility, fetal loss and malformations in laboratory animals. These effects have been less well studied in humans and the Reproductive Epidemiology Group has worked to extend the study of environmental exposures to the area of human reproduction. Allen J. Wilcox, M.D., Ph.D., heads the Reproductive Epidemiology Group, and has a secondary appointment in the NIEHS Reproductive & Developmental Biology Laboratory. His research falls into 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.
NIEHS scientist Allen Wilcox, M.D., Ph.D., provides helpful tips on how to have a healthy pregnancy and how NIEHS research played a role in those discoveries.
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.
("/Rhythmyx/assembler/render?sys_contentid=35374&sys_revision=1&sys_variantid=639&sys_context=0&sys_authtype=0&sys_siteid=&sys_folderid=" sys_dependentvariantid="639" sys_dependentid="35374" inlinetype="rxhyperlink" rxinlineslot="103" sys_dependentid="35374" sys_siteid="" sys_folderid="")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
("/Rhythmyx/assembler/render?sys_contentid=35427&sys_revision=2&sys_variantid=639&sys_context=0&sys_authtype=0&sys_siteid=&sys_folderid=" sys_dependentvariantid="639" sys_dependentid="35427" inlinetype="rxhyperlink" rxinlineslot="103" sys_dependentid="35427" sys_siteid="" sys_folderid="")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)
("/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="")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.
- Wilcox AJ, Weinberg CR, O'Connor JF, Baird DD, Schlatterer JP, Canfield RE, Armstrong EG, Nisula BC: Incidence of early loss of pregnancy. New Engl J Med 319:189-94, 1988.[Abstract]
- Lie RT, Wilcox AJ, Skjærven R. A population–based study of risk of recurrence of birth defects. New Engl J Med 331:1-4, 1994.
- Wilcox AJ, Weinberg CR, Baird DD: Timing of sexual intercourse in relation to ovulation: Effects on the probability of conception, survival of the pregnancy and sex of the baby. New Engl J Med 333: 1517-21, 1995.[Abstract]
- Wilcox AJ, Baird DD, Weinberg CR, Hornsby PP, Herbst AL. Fertility in men exposed prenatally to diethylstilbestrol. New Engl J Med 332:1411-16; 1995.[Abstract]
- Wilcox AJ, Baird DD, Weinberg CR: Time of implantation of the conceptus and loss of pregnancy. New Engl J Med 340:1796-9, 1999.[Abstract]
- Skjærven R, Wilcox AJ, Lie RT. A population–based study of survival and childbearing in women with birth defects, and risk of recurrence in offspring. New Engl J Med 340: 1057-62, 1999.
- Wilcox AJ, Taylor JA, Sharp RR, London SJ. Genetic determinism and the over-protection of human subjects. Nature Genet 21: 362, 1999.
- Wilcox AJ, Dunson D, Baird DD: The timing of the fertile window in the menstrual cycle: day-specific estimates from a prospective study. Brit Med J 321:1259-62; 2000.[Abstract][Full Text]
- Wilcox AJ, Baird DD, Dunson D, McChesney R, Weinberg CR. Natural limits of pregnancy testing in relation to the expected menstrual period. JAMA 286:1759-61, 2001.[Abstract][Full Text][Download PDF]
- Wilcox AJ. On the importance – and the unimportance – of birth weight. Int J Epidemiol 30:1233-41, 2001.[Abstract][Full Text][PDF]
- Lie RT, Wilcox AJ, Skjaerven R. Survival and reproduction in males with birth defects. JAMA 285:755-60, 2001.
- Skjaerven R, Wilcox AJ, Lie RT. The interval between pregnancies and the risk of preeclampsia. New Engl J Med 346:33-8, 2002.[Abstract]
- Wilcox AJ, Baird DD, Dunson DB, McConnaughey DR, Kesner JS, Weinberg CR. On the frequency of intercourse around ovulation: evidence for biological influences. Hum Reprod 19:1539-43; 2004.[Abstract][Full Text][download the PDF]
- Sallmén M, Weinberg CR, Baird DD, Lindbohm M–L, Wilcox AJ. Has fertility declined over time? Why we may never know. Epidemiology 16:494-9, 2005.[Abstract]
- Basso O, Wilcox AJ and Weinberg CR. Extreme fetal growth restriction and mortality: A hypothesis. Am J Epidemiol 164:303-11, 2006.
- Wilcox AJ. The perils of birth weight -- a lesson from directed acyclic graphs. American journal of epidemiology 164(11):1121-1123, 2006.[Abstract]
- Wilcox AJ, Lie RT, Solvoll K, Taylor JA, McConnaughey DR, Åbyholm F, Vindenes H, Vollset SE, Drevon CA. Folic acid supplements and the risk of facial clefts: A national population-based case-control study. Brit Med J 334(7591):464-9, 2007. [Abstract]
- Wilcox AJ, Skaerven R, Lie RT. Familial patterns of preterm delivery: maternal and fetal contributions. American journal of epidemiology 167(4):474-479, 2008.[Abstract]
- Sivertsen A, Wilcox AJ, Skjaerven R, Vindenes HA, Aabyholm F, Harville E, Lie RT. Familial risk of oral clefts by morphological type and severity: Population based cohort study of first-degree relatives. British medical journal 336:432-434, 2008.[Abstract]
- DeRoo LA, Wilcox AJ, Drevon CA, Lie RT. First trimester maternal alcohol consumption and the risk of infant oral clefts in Norway: a population-based case-control study. American journal of epidemiology 168(6):638-646, 2008.[Abstract]
- Rahimov F, Marazita ML, Visel A, Cooper ME, Hitchler MJ, Rubin M, Domann FE, Govil M, Christensen K, Bille C, Melbye M, Jugessur A, Lie RT, Wilcox AJ , Fitzpatrick DR, Green ED, Mossey PA, Little J, Steegers-Theunissen RP, Pennacchio LA , Schutte BC, Murray JC. Disruption of an AP-2alpha binding site in an IRF6 enhancer is associated with cleft lip. Nature genetics 40(11):1341-1347, 2008.[Abstract]
- Basso O, Wilcox AJ. Intersecting birth-weight-specific mortality curves: solving the riddle. American journal of epidemiology 169(7):787-797, 2009.[Abstract]
- Wilcox AJ. Fertility and Pregnancy: An Epidemiologic Perspective. Oxford University Press, 2010.
- Beaty TH, Murray JC, Marazita ML, Munger RG, Ruczinski I, Hetmanski JB, Liang KY, Wu T, Murray T, Fallin MD, Redett RA, Raymond G, Schwender H, Jin SC, Cooper ME, Dunnwald M, Mansilla MA, Leslie E, Bullard S, Lidral AC, Moreno LM, Menezes R, Vieira AR, Petrin A, Wilcox AJ, Lie RT, Jabs EW, Wu-Chou YH, Chen PK, Wang H, Ye X, Huang S, Yeow V, Chong SS, Jee SH, Shi B, Christensen K, Melbye M, Doheny KF, Pugh EW, Ling H, Castilla EE, Czeizel AE, Ma L, Field LL, Brody L, Pangilinan F, Mills JL, Molloy AM, Kirke PN, Scott JM, Arcos-Burgos M, Scott AF. A genome wide search for genes influencing risk to oral clefts using case-parent trios of European and Asian ancestry identifies both recognized and novel candidate genes. Nature Genetics 42(6):525-529, 2010.[Abstract]
- Basso O, Wilcox AJ. Mortality risk among preterm babies: Immaturity versus underlying pathology. Epidemiology (Cambridge, Mass.) 21(4):521-527, 2010.[Abstract]
- Moster D, Wilcox AJ, Vollset SE, Markestad T, Lie RT. Cerebral palsy among term and postterm births. JAMA 304(9):976-982, 2010.[Abstract]
- Wacholder S, Chen BE, Wilcox AJ, Macones G, Gonzalez P, Befano B, Hildesheim A, Rodríguez AC, Solomon D, Herrero R, Schiffman M for the CVT group. Risk of miscarriage in two randomized controlled trials of a bivalent vaccine against human papillomavirus types 16 and 18. Brit Med J 340:c712, 2010.
- Basso O, Wilcox AJ. Might rare factors account for most of the mortality of preterm babies? Epidemiology (Cambridge, Mass.) 22(3):320-327, 2011.[Abstract]
- Wilcox AJ, Weinberg CR, Basso O. On the Pitfalls of Adjusting for Gestational Age at Birth. American journal of epidemiology 174(9):1062-1068; 2011.[Abstract]
- Håberg SE, Trogstad L, Gunnes N, Wilcox AJ, Gjessing HK, Samuelsen SO, Skrondal A, Cappelen I, Engeland A, Aavitsland P, Madsen S, Buajordet I, Furu K, Nafstad P, Vollset SE, Feiring B, Nøkleby H, Magnus P, Stoltenberg C. Risk of fetal death after pandemic influenza virus infection or vaccination. The New England journal of medicine 368(4):333-40, 2013.[Abstract]
- Jukic AMZ, Baird DD, Weinberg CR, McConnaughey DR, Wilcox AJ. Length of human pregnancy and contributors to its natural variation. Human reproduction (Oxford, England) 28(10):2848-2855, 2013.[Abstract]
- Ananth CV, Wilcox AJ, Gyamfi-Bannerman C. Obstetrical interventions for term first deliveries in the US. Paediatric and perinatal epidemiology 27(5):442-51, 2013.[Abstract]
- Trønnes H, Wilcox AJ, Lie RT, Markestad T, Moster D. The association of preterm birth with severe asthma and atopic dermatitis: a national cohort study. Pediatric allergy and immunology: official publication of the European Society of Pediatric Allergy and Immunology 2013 24(8):782-787.[Abstract]
- Markunas CA, Xu Z, Harlid S, Wade PA, Lie RT, Taylor JA, Wilcox AJ. Identification of DNA methylation changes in newborns related to maternal smoking during pregnancy. Environmental health perspectives 2014 122(10):1147-1153.[Abstract]
- Tollånes MC , Wilcox AJ , Lie RT , Moster D. Familial risk of cerebral palsy: population based cohort study. British Medical Jorunal (BMJ) 2014 349():g4294-.[Abstract]
- Trønnes H, Wilcox AJ, Lie RT, Markestad T, Moster D. Risk of cerebral palsy in relation to pregnancy disorders and preterm birth: a national cohort study. Developmental medicine and child neurology 2014 56(8):779-785.[Abstract]