Use of Case Reports in Assessing Adverse Outcomes of Human Prenatal Drug Exposures: An Approach
The use of case reports for assessing the developmental consequences of prenatal drug exposure is limited by the inability to determine the incidence of adverse outcomes and by the high likelihood for bias. Yet, because it is impossible to conduct clinical trials for the assessment of drug safety in pregnancy, post-marketing case reports are important and often the only means to detect untoward developmental events associated with maternal drug use. Presented here is an approach for utilizing case reports to identify adverse outcomes resulting from drug use in pregnancy. Each outcome is evaluated on the basis of several factors that allow assessing its relationship to the drug exposure. The evaluation includes the following steps: 1. Determination of the frequency of reporting for each adverse outcome; 2. Assessing the amount of evidence supporting a causal relationship of each outcome to drug exposure, according to uniform criteria (temporality, dose-effect, reversibility, specificity, biologic plausibility); 3. Ranking outcomes according to the frequency of reporting and evidence for a causal relationship; 4. Integrating the two rank orders and ranking outcomes according to the following categories: (a) frequently or (b) infrequently reported with high evidence for a causal relationship; (c) frequently or (d) infrequently reported with low evidence for a causal relationship. Highest priority with regard to likelihood that a given outcome results from the drug exposure is assigned to those effects that fall into the first category, while those in the last category are considered least likely to be related to the drug under study. Application of this approach is being explored for several drugs using cases reported to FDA through the Adverse Events Reporting System (AERS).