Background: Oxidative stress (OS) is one of the underlying teratogenic mechanisms of medical drugs. Folate is indirectly involved in OS because of its role in the methylation steps in the detoxification of xenobiotics and in the repair of OS-induced DNA damage. Our study was to explore the associations of exposure to OS-inducing drugs in the first trimester of pregnancy and groups of birth defects. Additionally, drugs with folate antagonism (FAA) and folic acid supplementation in the periconceptional period (FOLIC) were investigated. Methods: A case control study was conducted, using the Eurocat NNL database (birth years 1997-2013). Cases were offspring with a group of birth defects, either isolated or with other defects, not associated with genetic disorders. Two control groups were controls 1 with other defects and controls 2 with genetic disorders. All drugs used in the first trimester were identified from the database, and were cross-referenced against previously compiled lists of drugs with reactive intermediates and drugs with FAA. Drugs with reactive intermediates, with systemic absorption and with a daily dose ≥50mg were considered OS-inducing drugs. When there was an association between OS-inducing drugs and a group of birth defects, we further investigated two different FAA exposure categories: concurrent exposure to both OS-inducing drugs and FAA drugs (OS+/FAA+) and exposure to OS-inducing drugs only (OS+/FAA-). When the number of subjects allowed (at least five cases/controls were exposed), we examined the role of FOLIC. Odds ratios (ORs) with 95% confidence intervals were adjusted for maternal smoking and alcohol use in the first trimester in controls 1 and additionally adjusted for maternal age in controls 2. Results: A total of nine groups of birth defects were investigated. Only nervous system defects were associated with OS-inducing drugs. Exposure rates were 65/464 (14.0%) for cases, 512/6033 (8.5%) for controls 1 and 130/1564 (8.3%) for controls 2 and adjusted ORs (95%CIs) were 1.71 (1.29-2.26) and 1.77 (1.27-2.46), respectively. This association was unchanged when we examined OS+/FAA+ and OS+/FAA- separately. The OS+/FAA+ category, however, had slightly higher OR values than the OS+/FAA- (2.41 vs. 1.61 for controls 1, and 2.55 vs. 1.67 for controls 2). Because of the low number of exposed subjects, we could only examine FOLIC in relation to OS+/FAA-. Using OS-/FAA-/FOLIC+ as reference, we found the highest risk with OS+/FAA-/FOLICand a lesser magnitude with OS+/FAA-/FOLIC+ (ORs being 2 and 1.6 times respectively for both controls). Conclusion: Our study suggests an increased risk of having a child with nervous system defects in mothers who were exposed to OS-inducing drugs during pregnancy, and a potential risk reduction with FOLIC.