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Reproductive Epidemiology Group

Environmental Toxins & Human Reproduction

Allen J. Wilcox, M.D., Ph.D.
Allen J. Wilcox, M.D., Ph.D.
Principal Investigator

Tel (919) 541-4660
Fax (919) 541-2511

Curriculum Vitae (  Download Adobe Reader (130 KB)
P.O. Box 12233
Mail Drop A3-05
Research Triangle Park, North Carolina 27709
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Research Summary

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 his research falls into the following three areas:

  • fertility, conception and early pregnancy
  • low birth weight
  • environmental teratogens

Fertility, Conception and Early Pregnancy
In the 1980s Wilcox and his research established that one–quarter of human pregnancies end in loss before the woman is aware she is pregnant. These methods for measuring early pregnancy loss have been widely adapted by environmental researchers searching for subtle effects of reproductive toxins. His has also identified the timing of a woman´s fertile days in relation to ovulation – an average of six fertile days in each menstrual cycle, ending at ovulation.

In an extension of this work, the proved that intercourse is more frequent during fertile days, suggesting that unrecognized biological mechanisms are influencing intercourse frequency during the menstrual cycle. In addition the demonstrated the difficulty of determining whether environmental factors have reduced human fertility in recent decades. While this is an important question, it is fundamentally intractable owing to the confounding effects of changes in the availability of contraception and abortion, changes in desired family size and other social factors.

Low Birth Weight
Low birth weight is a convenient endpoint in studies involving environmental toxins. However, low birth weight is apparently not on the causal pathway to perinatal risk, as has been generally assumed. Wilcox has developed his critique of low birth weight as an inappropriate endpoint in health research through a series of analytic papers. As an alternative, he has suggested that research and public health efforts should be directed at preterm delivery, an endpoint presumably more subject to intervention. His arguments are summarized in the review paper, "On the importance–and unimportance–of birth weight," and have contributed to a shift in World Health Organization (WHO) policy that suggests that low birth weight is a measure of infant well-being.

Environmental Teratogens
Wilcox and colleagues completed a population–based case–control study of babies born with facial clefts in Norway with the purpose of investigating environmental teratogens and their role in genetic susceptibility. In this study, they integrated data on environmental risk factors with genetic data to firmly establish the role of candidate teratogens such as low dietary folate, cigarette smoking, passive exposure to tobacco smoke and others in the causation of clefts.

Wilcox heads the Reproductive Epidemiology Group and is editor-in-chief of the journal, Epidemiology (;jsessionid=GKyQLp2KF2tLQZ5YTD60GybHHQRtHSysvcQqB1hp9ZnFM375v3sM!741375937!-949856145!8091!-1) Exit NIEHS. He is also a past president of both the American College of Epidemiology and the Society for Epidemiologic Research. Wilcox serves as Adjunct Professor of Epidemiology at the University of North Carolina at Chapel Hill. He earned an M.D. in medicine from the University of Michigan, an M.P.H. in Maternal and Child Health and a Ph.D. in epidemiology from the School of Public Health at the University of North Carolina at Chapel Hill. Wilcox came to NIEHS in 1979, served twenty years in the U.S. Public Health Service, and 10 years as Epidemiology Branch Chief.


  • Analysis of Birth Weight and Infant Mortality ( Exit NIEHS
    Birth weight is one of the most commonly studied variables in epidemiology. It is associated with health risks ranging from infant mortality to cardiovascular disease. The usual approach assumes that birth weight is on the causal pathway to whatever health endpoint is of interest. The alternative, discussed here, is that birth weight is not causally related to health, at least on a population level.
  • 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.
  • Norway Facial Clefts Study (
    This population–based, case–control, parent–triad study explores the environmental and genetic causes of cleft lip and palate.
  • Norwegian Mother & Child Cohort Study (MoBa) (
    The Norwegian Mother & Child study (MoBa) is an ongoing long–term prospective cohort study of 100,000 pregnant women and their babies. In collaboration with the Norwegian National Public Health Institute, NIEHS is supporting the collection of additional biologic specimens from the pregnant women.


Selected Publications

  1. Bonde JP, Wilcox A. Ratio of boys to girls at birth. BMJ (Clinical research ed.) 2007 334(7592):486-487. [Abstract] ( Exit NIEHS
  2. Lie RT, Wilcox AJ, Taylor J, Gjessing HK, Saugstad OD, Aabyjholm F, Vindenes H. Maternal smoking and oral clefts: The role of detoxification pathway genes. Epidemiology (Cambridge, Mass.) 2008 19(4):606-615. [Abstract] ( Exit NIEHS
  3. 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] ( Exit NIEHS
  4. 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.
  5. 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] (,%20survival%20of%20the%20pregnancy%20and%20sex%20of%20the%20baby) Exit NIEHS
  6. 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] ( Exit NIEHS
  7. 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] ( Exit NIEHS
  8. 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.
  9. Wilcox AJ, Taylor JA, Sharp RR, London SJ. Genetic determinism and the over-protection of human subjects. Nature Genet 21: 362, 1999.
  10. 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] ( Exit NIEHS  [Full Text] ( Exit NIEHS [download the PDF] (  Download Adobe ReaderExit NIEHS
  11. 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] ( Exit NIEHS  [Full Text] ( Exit NIEHS  [download the PDF] (  Download Adobe ReaderExit NIEHS
  12. Wilcox AJ. On the importance – and the unimportance – of birth weight. Int J Epidemiol 30:1233-41, 2001.  [Abstract] ( Exit NIEHS  [Full Text] ( Exit NIEHS [download the PDF] (  Download Adobe ReaderExit NIEHS
  13. Lie RT, Wilcox AJ, Skjaerven R. Survival and reproduction in males with birth defects. JAMA 285:755-60, 2001.
  14. Skjaerven R, Wilcox AJ, Lie RT. The interval between pregnancies and the risk of preeclampsia. New Engl J Med 346:33-8, 2002.  [Abstract] ( Exit NIEHS
  15. 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] ( Exit NIEHS  [Full Text] ( Exit NIEHS [download the PDF] (  Download Adobe ReaderExit NIEHS
  16. 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] ( Exit NIEHS
  17. Lie RT, Wilcox AJ, Skjaerven R. Maternal and paternal influences on gestational age. Obstet Gynecol 107:880-85, 2006.
  18. Basso O, Wilcox AJ and Weinberg CR. Extreme fetal growth restriction and mortality: A hypothesis. Am J Epidemiol 164:303-11, 2006.
  19. Wilcox AJ. The perils of birth weight -- a lesson from directed acyclic graphs. American journal of epidemiology 2006 164(11):1121-1123. [Abstract] ( Exit NIEHS
  20. 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] ( Exit NIEHS
  21. Wilcox AJ. The analysis of recurrence risk as an epidemiologic tool. Paediatric and perinatal epidemiology 2007 21(supp 1):4-7. [Abstract] ( Exit NIEHS
  22. Wilcox AJ, Skaerven R, Lie RT. Familial patterns of preterm delivery: maternal and fetal contributions. American journal of epidemiology 2008 167(4):474-479. [Abstract] ( Exit NIEHS
  23. Johansen AMW, Lie RT, Wilcox AJ, Andersen LF, Drevon CA. Maternal dietary intake of vitamin A and risk of orofacial clefts; a population based case-control study in Norway. American journal of epidemiology 2008 167(10):1164-1170. [Abstract] ( Exit NIEHS
  24. Sivertsen A, Lie RT, Wilcox AJ, Abyholm F, Vindenes H, Haukanes BI, Houge G. Prevalence of deletions and duplications of the 22q11 DiGeorge syndrome region in a population-based sample of infants with cleft palate. Am J Med Genet A.143:129-134, 2007. [Abstract] ( Exit NIEHS
  25. 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] ( Exit NIEHS
  26. Jugessur A, Rahimov F, Lie RT, Wilcox AJ, Gjessing HK, Nilsen RM, Trung TN, Murray JC. Genetic variants in IRF6 and facial clefts: Exploring a case-control, infant-parent triad design in a large population-based sample from Norway. Genetic epidemiology 32(5):413-424, 2008. [Abstract] ( Exit NIEHS
  27. Jukic AMZ, Weinberg CR, Baird DD, Hornsby PP, Wilcox AJ. Measuring menstrual discomfort: a comparison of interview and diary data. Epidemiology (Cambridge, Mass.) 19(6):872-875, 2008 . [Abstract] ( Exit NIEHS

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