Case-crossover and case-time-control designs in birth defects epidemiology.

The case-crossover and the case-time-control designs can be used to evaluate the effect of intermittent exposures on the risk of acute events. To explore how birth defects epidemiology could benefit from these approaches, the authors compared them with a traditional case-control study design that evaluated the association between use of folic acid antagonists during the second and third pregnancy months and the risk of cardiovascular defects. Among 3,870 cases and 8,387 control infants in the Slone Epidemiology Center Birth Defects Study (1976-1998), the odds ratio was 2.3 (95% confidence interval (CI): 1.4, 3.9). The case-crossover approach compared folic acid antagonist use between the 2-month embryologically sensitive period (case window) and the 2 months preceding the last menstrual period (control window) among mothers of case infants (odds ratio = 1.0, 95% CI: 0.5, 2.0). Although it controls between-person confounding and avoids issues of control selection, this design may be biased by time trends of exposure prevalence during pregnancy. The case-time-control design, which adjusts for exposure time trends under certain assumptions, yielded an odds ratio of 2.9 (95% CI: 1.2, 7.2), but it requires controls. In the presence of gestational time trends of exposure, the new designs do not offer clear advantages over the case-control design.