The use of aspirin and other NSAIDs during the first trimester of pregnancy is widespread, despite inconclusive evidence regarding the possible risks for the baby. We present an overview of the current evidence relating to the associations between aspirin or NSAID use during the first trimester of pregnancy and the risk of congenital malformations. We systematically searched Medline, Embase, the Cochrane Library and the reference lists of all relevant articles from 1966 to March 2008 that examined the association between aspirin and NSAID use during the first trimester of pregnancy and the risk of congenital malformations in humans. We analyzed 30 studies that met the predefined inclusion criteria: 22 case-control studies, seven cohort studies and one randomized, controlled trial. There are not enough human data available to assess the effect of high-dose aspirin and NSAIDs in pregnant women, such as those used in the treatment of rheumatoid arthritis, osteoarthritis and pain relief. This review suggests that the exposure to aspirin or NSAIDs during the first trimester of pregnancy is associated with an increased risk of gastroschisis (aspirin), cardiac malformations (NSAIDs) and orofacial malformations (naproxen).