OBJECTIVES:To determine whether antidepressants as a group, as well as each individual drug, increases the incidence of major malformations above the baseline of 1-3%. METHODS:At The Motherisk Program, we analyzed pregnancy outcomes of 1243 women from prospectively collected cases in our database, who were exposed to antidepressants during pregnancy. We then compared them to a matched comparison group of 1243 women who were not exposed (non-teratogen group) and the two groups were compared for the incidence of major malformations. RESULTS: A total of 928 women who fit the criteria for inclusion, who were exposed in the 1st trimester of pregnancy, were matched to 928 women in the comparison group. Antidepressants in the analysis included: bupropion (113) citalopram (184), escitalopram (21), fluvoxamine (52), fluoxetine (61), mirtazepine (68), nefazodone (49), paroxetine (148), sertraline (61) trazodone (17), venlafaxine (154). There were 24 (2.5%) major malformations in the antidepressant group and 25 (2.6%) in the comparison group: (RR=0.96, CI95%:0.55-1.67). CONCLUSIONS: First trimester exposure to antidepressants as a group was not associated with an increased incidence of major malformations above baseline. In addition, no individual antidepressant was associated with an increased risk of a specific malformation. The results of this study will add to the current literature in this field, as there has been conflicting data. Pregnant women requiring antidepressants in pregnancy and their health care providers, will find this information reassuring.