individuals from the cohort will no longer be available for follow-up of the pregnancy outcome. Postmarketing surveillance by the pharmaceutical industry can be viewed as a type of cohort study, although an unexposed cohort is often not studied concurrently.

The case-control study is the most common design used in assessing the association between exposure and pregnancy outcome. In this type of study, the pregnancy outcome is identified (usually congenital anomalies in live-born infants), and a retrospective evaluation is then conducted to determine the exposure pattern. In case-control studies, the number of developmental end points that can be assessed is small, but several exposures can be investigated. The case-control study is the most efficient study design for capturing rare events, such as congenital anomalies. Accurate ascertainment of exposure can be problematic for case-control studies. Recall bias can occur among women who deliver abnormal infants (i.e., exposures are recalled more extensively by women with abnormal infants than by those with normal infants). Selection of an appropriate control group, which ideally is identical to the case group except for the outcome of interest, can also be difficult.

There is no formula whereby a causal relationship can be established between an exposure and an adverse pregnancy outcome. Results from epidemiological studies should be interpreted with caution because associations found can be due to the following:

  • Unmeasured confounding, particularly confounding by indication.

  • Exposure misclassification (inability to pinpoint relevant dose and timing).

  • Outcome misclassification (related to the heterogeneity of birth defects).

  • Biological interactions (subgroups with differing genetic susceptibilities or presence of additional exposures).

  • Differential prenatal survival (in studies evaluating live-born infants, spontaneous abortion or elective termination of abnormal fetuses should be taken into account).

Evidence from a number of sources, including human and experimental animal data, must be collectively considered to determine the strength of the association (Rothman 1986; Khoury et al. 1992).

There are many problems in identifying associations between exposures and adverse pregnancy outcomes using conventional epidemiological approaches. Weak or moderate associations (relative risks or odds ratios ranging from 1 to 3) are typically found between environmental exposures and pregnancy outcomes (Khoury et al. 1992). For example, maternal smoking is weakly associated with oral clefts (odds ratios between 1 and 2) (Khoury et al. 1989). Insulin-dependent diabetes is associated somewhat more strongly with major malformations (a relative risk of 7) (Becerra et al. 1990), and potent developmental toxicants, such as isotretinoin and thalidomide, are very strongly associated with major malforma-



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