BACKGROUND: Pregnancy exposure registries are valuable for studying the teratogenicity of drugs used in the post-marketing setting. However, their limited sample size and potential for selection bias can make data interpretation challenging. While enrolling an internal comparison group is ideal, this is often not feasible. To ease these limitations, pregnancy registries commonly use a population-based background rate as the primary comparison group. OBJECTIVES: The objectives of this research are to evaluate appropriate population-based birth defect surveillance systems, cohorts, and other studies from a variety of geographic areas and to systematically assess their utility as a comparison group for global pregnancy exposure registries. RESULTS:  Among the 14 studies evaluated, study designs include observational cohort studies, case control studies, population-based surveillance registries, and population-based active surveillance systems. Catchment areas are somewhat diverse geographically and range in scope from a metropolitan city, single state/province, or individual country, to multi-national/multi-continental networks of organizations contributing to a single data source. All identified studies have been ongoing for at least a decade. Studies range in size from several thousand participants in total to more than 1 million participants enrolled annually. Data reporters vary and include patients, physicians, and other healthcare personnel. Some studies ascertain infant outcome and birth defect status at the time of birth only, while others involve pediatricians and include follow-up for one to several years. CONCLUSIONS: There are many potential sources of comparison data for overall birth defect rates; however, the sources vary greatly in design, data collection methods, birth defect coding systems, clinical review procedures, and equation for calculating birth defect prevalence rate. Utilizing a population-based background rate can be useful, but care should be taken in selecting an appropriate comparison group. The differences between the individual pregnancy registry and the population-based comparator should be evaluated and recognized.