Estimates of the lifetime risk of major depression in women range from 10% to 25%, peaking during the reproductive years. Today, selective serotonin-reuptake inhibitors (SSRIs) are the most commonly used type of antidepressant medication. Recent studies suggest that taking these drugs while pregnant may be associated with birth defects in general and with congenital heart defects in particular. The investigators have analyzed data from 9622 case infants having major birth defects and 4092 control infants who were born in the years 1997 to 2002 and enrolled in the National Birth Defects Prevention Study. Both cases and controls were chosen through birth defects surveillance systems in 8 states. The mothers took part in a standardized phone interview dealing with exposure to potential risk factors, including medications, before and during pregnancy. Exposure was defined as taking any SSRI from 1 month before to 3 months after conception. Combining cases and control subjects, 3% of study participants reported having used a SSRI at some time before or during pregnancy, and 2.3% during the designated 4-month interval. No significant association was found between the maternal use of SSRIs during early pregnancy and congenital heart defects. There were, however, 3 conditions associated with maternal use of SSRIs. They included anencephaly (adjusted odds ratio [OR], 2.4; 95% confidence interval [CI], 1.1–5.1); craniosynostosis (OR, 2.5; 95% CI, 1.5–4.0); and omphalocele (OR, 2.8; 95% CI, 1.3–5.7). None of the mothers of case infants having defects associated with SSRI use were found to have been exposed at the same time to medications known to have teratogenic effects. This study failed to establish any association between the maternal use of SSRIs during early pregnancy and an elevated risk of congenital heart defects—or of several other classes of birth defects. Three associations were observed, but the absolute risks were small in view of the baseline risk of birth defects inherent in all pregnancies. At the same time, maternal stress and depression during pregnancy have been implicated in adverse reproductive outcomes, and discontinuing antidepressant therapy in pregnant women who are seriously depressed may negatively affect both the mother and infant.