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Second-generation antipsychotics (SGAs) are increasingly used for a variety of mental illnesses; however, the data regarding the safety of these medications during pregnancy are inconclusive and contradictory. We examined the risk of adverse pregnancy outcomes associated with in utero exposure to SGAs by conducting a systematic review and meta-analysis. We searched the databases EMBASE and MEDLINE from January 1990 to December 2014. Eligible studies had to report pregnant women who took SGAs during pregnancy (first trimester exposure if analyzing congenital malformations), follow a healthy comparison group in a similar manner, and report data on pregnancy outcomes. There was no restriction on language, sample size, or publication date. The primary outcome analyzed was major congenital malformations, and secondary outcomes included miscarriages, stillbirths, preterm births, small or large for gestational age neonates, and differences in gestational ages and birth weights. A total of 12 studies met our inclusion criteria, totalling 1782 cases and 1,322,749 controls. The use of SGA during the first trimester of pregnancy was associated with a significant increased risk for major congenital malformations (odds ratio, 2.03; 95% confidence interval, 1.41–2.93); however, no specific pattern of malformations was found. An increased risk was also found for preterm births (odds ratio, 1.85; 95% CI, 1.20–2.86). The use of SGA during pregnancy was not found to be associated with an increased risk for secondary outcomes analyzed. The absence of a specific pattern of malformations makes it difficult to identify an explicit risk posed by SGAs, and therefore, further studies sufficiently controlling for confounding factors are needed to validate these findings.