Antidepressant Use in Pregnancy and the Risk for Cardiac Defects

Abstract

The use of antidepressants during pregnancy has increased, with prevalences of 8% to 13% in the United States. Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants during pregnancy. Because varied associations between drug use and fetal congenital cardiac malformations have been reported, this cohort study was performed to assess the risk for congenital cardiac defects after parturient use of antidepressants. The study cohort was drawn from the Medicaid Analytic eXtract for 2000 to 2007. This data set contains individual-level demographic and Medicaid enrollment information as well as data on all filled outpatient medication prescriptions. The exposure period extended from the date of the last menstrual period through day 90 of pregnancy (first trimester). Exposure categories were any SSRI, paroxetine, sertraline, fluoxetine, tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), bupropion, and other antidepressants. The reference group comprised parturients without antidepressant use during the first trimester. Congenital cardiac malformations included any cardiac malformation, right ventricular outflow tract obstruction, ventricular septal defect, and other cardiac malformations. Covariates included sociodemographic information; known or suspected risk factors of congenital cardiac malformations; use of teratogenic, other psychotropic, antidiabetic, and antihypertensive medications; and number of distinct prescription drugs used. Logistic regression analysis was used to estimate odds ratios for cardiac malformations. Because the odds ratio is an excellent approximation of the risk ratio in the case of rare outcomes, results are reported as relative risks (RRs). Of 949,504 eligible pregnancies, during the first trimester, 64,389 women (6.8%) used an antidepressant, 46,144 women (4.9%) were exposed to an SSRI, 5954 (0.6%) were exposed to a TCA, 6904 (0.7%) were exposed to an SNRI, 8856 (0.9%) were exposed to bupropion, and 7055 (0.7%) were exposed to other antidepressants. Sertraline was used by 14,040 women; paroxetine, by 11,126; and fluoxetine, by 11,048. Cardiac malformations were diagnosed in 6403 infants who were not exposed to an antidepressant during the first trimester (72.3 cardiac malformations per 10,000 infants) compared with 580 infants who were exposed (90.1 cardiac malformations per 10,000 infants). This higher unadjusted risk among exposed infants was observed for each specific type of malformation examined. In unadjusted analyses, the RR of any cardiac malformation was 1.25 with SSRIs (95% CI, 1.13–1.38), 0.98 with TCAs (95% CI, 0.72–1.32), 1.51 with SNRIs (95% CI, 1.20–1.90), 1.19 with bupropion (95% CI, 0.95–1.49), and 1.46 with other antidepressants (95% CI, 1.16–1.83). The propensity-score–adjusted RR of any cardiac malformation was 1.06 among women exposed to SSRIs (95% CI, 0.93–1.22), 0.77 for exposure to TCAs (95% CI, 0.52–1.14), 1.20 for exposure to SNRIs (95% CI, 0.91–1.57), 0.92 for exposure to bupropion (95% CI, 0.69–1.22), and 1.21 for exposure to other antidepressants (95% CI, 0.91–1.60). No significant associations were found between paroxetine and right ventricular outflow obstruction (1.07; 95% CI, 0.59–1.93) or between sertraline and ventricular septal defect (1.04; 95% CI, 0.76–1.41). The RR of cardiac malformations associated with SSRI use was 1.04 for those on antidepressant monotherapy (95% CI, 0.90–1.21) and 1.17 for polytherapy (95% CI, 0.90–1.53). Relative risks for associations between cardiac malformations and maternal diabetes, use of an anticonvulsant agent, and multifetal pregnancy were 3.7, 1.6, and 2.9, respectively (95% CI, 3.4–4.0; 95% CI, 1.3–1.8; and 95% CI, 2.8–3.1, respectively). After adjustment for depression and other confounding factors, these results fail to support previous findings of an association between antidepressant use and cardiac anomalies. Evidence implies low absolute risks and argues against important cardiac teratogenic effects associated with the most commonly used antidepressants.