CARDIOVASCULAR BIRTH-DEFECTS AND PRENATAL EXPOSURE TO FEMALE SEX-HORMONES - A REEVALUATION OF DATA REANALYSIS FROM A LARGE PROSPECTIVE-STUDY

In data of the U.S. Collaborative Preinatal Study (CPS), the Drug Epidemiology Unit (DEU) reported a relative risk of about 2.3 between maternal female sex hormone exposure during months 1 to 4 of pregnancy and cardiovascular malformation in infants (Heinonen et al., '77a N. Engl. J. Med., 296:67-70). Wiseman and Dodds-Smith ('84) reexamined the original CPS data and found the DEU had made errors in classification of exposure and disease of some cases. Also they challenged the classification of cases as "exposed" in those born to mothers who received the compounds outside the day 19 to 50 window of cardiovascular embryogenesis. Wiseman and Dodds-Smith stated that their reanalysis "clearly showed that there was [in the data used by the DEU] no statistically significant association between exposure in the critical organogenic period of pregnancy and cardiac malformation in offspring." They did not undertake any statistical analysis, but their reanalysis resulted in a widespread nonacceptance of the association reported by the DEU. The study reported here reclassified the cases of the original DEU study in accord with the implications of the Wiseman and Dodds-Smith reanalysis of exposure and disease. After this reclassification, an effect magnitude measure of association, the relative risk rose from 2.33 to 2.48 and remained nominally significant statistically at the .05 level. Thus, if anything, the quantitative consequences of the Wiseman and Dodds-Smith review of the data, when applied in an unbiased manner, result in an increase in the measure of effect. The increase is consistent with the theoretical epidemiological expectation that correction of random errors in a database and of other non-differential misclassification, will tend to raise the estimate of an underlying association in the population studied. While these results reestablish the reported association, they do not, of course, prove that the positive association represents causal induction of defects in conceptuses by female sex hormones.