Krista F. Huybrechts, Ph.D., Kristin Palmsten, Sc.D., Jerry Avorn, M.D., Lee S. Cohen, M.D., Lewis B. Holmes, M.D., Jessica M. Franklin, Ph.D., Helen Mogun, M.S., Raisa Levin, M.S., Mary Kowal, B.A., Soko Setoguchi, M.D., Dr.P.H., and Sonia Hernández-Díaz, M.D., Dr.P.H.

N Engl J Med 2014; 370:2397-2407June 19, 2014DOI: 10.1056/NEJMoa1312828


Whether the use of selective serotonin-reuptake inhibitors (SSRIs) and other antidepressants during pregnancy is associated with an increased risk of congenital cardiac defects is uncertain. In particular, there are concerns about a possible association between paroxetine use and right ventricular outflow tract obstruction and between sertraline use and ventricular septal defects.


We performed a cohort study nested in the nationwide Medicaid Analytic eXtract for the period 2000 through 2007. The study included 949,504 pregnant women who were enrolled in Medicaid during the period from 3 months before the last menstrual period through 1 month after delivery and their liveborn infants. We compared the risk of major cardiac defects among infants born to women who took antidepressants during the first trimester with the risk among infants born to women who did not use antidepressants, with an unadjusted analysis and analyses that restricted the cohort to women with depression and that used propensity-score adjustment to control for depression severity and other potential confounders.


A total of 64,389 women (6.8%) used antidepressants during the first trimester. Overall, 6403 infants who were not exposed to antidepressants were born with a cardiac defect (72.3 infants with a cardiac defect per 10,000 infants), as compared with 580 infants with exposure (90.1 per 10,000 infants). Associations between antidepressant use and cardiac defects were attenuated with increasing levels of adjustment for confounding. The relative risks of any cardiac defect with the use of SSRIs were 1.25 (95% confidence interval [CI], 1.13 to 1.38) in the unadjusted analysis, 1.12 (95% CI, 1.00 to 1.26) in the analysis restricted to women with depression, and 1.06 (95% CI, 0.93 to 1.22) in the fully adjusted analysis restricted to women with depression. We found no significant association between the use of paroxetine and right ventricular outflow tract obstruction (relative risk, 1.07; 95% CI, 0.59 to 1.93) or between the use of sertraline and ventricular septal defects (relative risk, 1.04; 95% CI, 0.76 to 1.41).


The results of this large, population-based cohort study suggested no substantial increase in the risk of cardiac malformations attributable to antidepressant use during the first trimester. (Funded by the Agency for Healthcare Research and Quality and the National Institutes of Health.)

Supported by an award from the Agency for Healthcare Research and Quality (R01 HSO18533), a career development grant from the National Institute of Mental Health of the National Institutes of Health (NIH) (K01MH099141, to Dr. Huybrechts), and a training grant in reproductive, perinatal, and pediatric epidemiology from the National Institute of Child Health and Human Development of the NIH (T32HD060454, to Dr. Palmsten).

Disclosure forms provided by the authors are available with the full text of this article at

We thank Robert J. Glynn, Sc.D., Ph.D., for helpful comments on an earlier version of the manuscript.

Source Information

From the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School (K.F.H., J.A., J.M.F., H.M., R.L., M.K., S.S.), the Department of Epidemiology, Harvard School of Public Health (K.P., S.H.-D.), the Center for Women’s Mental Health, Massachusetts General Hospital (L.S.C.), and the Medical Genetics Unit, MassGeneral Hospital for Children (L.B.H.) — all in Boston; and Duke University School of Medicine, Durham, NC (S.S.).

Address reprint requests to Dr. Huybrechts at the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, 1620 Tremont St., Suite 3030, Boston, MA 02120, or at .

Meg Marshall