Human Teratogens, Prenatal Mortality, and Selection Bias

Etiologic inferences on human teratogens are usually derived from case-control studies conducted either at birth or in spontaneous abortion series. Because both teratogens and defects may be associated with an increased risk of prenatal mortality, the possibility exists that selection bias may affect etiologic inferences. The authors derive relations between the true odds ratio (OR) relating a teratogen and a defect at the time of the occurrence of the defect and the apparent odds ratios observed in spontaneous abortion series and at birth, as functions of prenatal mortality. Depending on the pattern of interaction between the teratogen and the defect in affecting the rate of prenatal mortality, selection bias may lead to overestimation or underestimation of the true odds ratio. With increasing multiplicative effects on prenatal mortality, changes in selection bias tend to increase the observed odds ratio in spontaneous abortion series but to decrease the observed odds ratio at birth. For a range of rates of prenatal mortality, weak associations between exposures and defects (OR = 0.3-3) may well be due to selection bias; conversely, weak teratogens (OR less than 3) may be missed in case-control studies of defects conducted at birth. Selection bias due to prenatal mortality must be considered in the interpretation of etiologic studies of birth defects.