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Antidepressant use during the first trimester of pregnancy was not associated with a greater risk of cardiac malformations in the offspring, a large cohort study showed.

The rate of cardiac malformations was 72.3 per 10,000 babies who were not exposed to antidepressants early in pregnancy and 90.1 per 10,000 babies whose mothers did take antidepressants, although the difference was not statistically significant in a propensity-matched analysis confined to women with diagnosed depression (RR 1.06, 95% CI 0.93-1.22), according to , of Brigham and Women's Hospital and Harvard Medical School in Boston, and colleagues.

The findings were consistent for selective serotonin reuptake inhibitors (SSRIs) -- the most commonly prescribed agents -- and other antidepressants, the researchers reported in the June 19 issue of the .

In an interview, Huybrechts indicated that the study can help inform the decision made by women and their physicians about the relative risks and benefits of using antidepressants during pregnancy, which can involve numerous factors.

"What this study indicates is that concerns about a potential increased risk of cardiac malformations should not factor into that decision," she said. "The accumulated evidence suggests that the absolute risk is low, and our study indicates that there is no substantial increased risk of cardiac malformations associated with first trimester use of selective serotonin reuptake inhibitors or other antidepressants during pregnancy."

Previous studies have shown that 8% to 13% of pregnant women in the U.S. use antidepressants, with the rate increasing over time, and that there are possible relationships between prenatal exposure to the drugs and heart defects in the offspring. Results are mixed, however, and "it has remained unclear ... whether these associations are causal or due to systematic error or chance."

To explore the issue, Huybrechts and colleagues examined data from the nationwide Medicaid Analytic eXtract covering 2000 through 2007. The analysis included 949,504 adolescents and women ages 12 to 55 who were enrolled in Medicaid from 3 months before the last menstrual period through 1 month after delivery of a live-born baby.

Overall, 6.8% of the women used antidepressants during the first trimester (with some exposed to more than one such medication) -- an SSRI was used by 4.9%, a tricyclic antidepressant by 0.6%, a serotonin-norepinephrine reuptake inhibitor (SNRI) by 0.7%, bupropion by 0.9%, and "other" agents by 0.7%. The most common SSRIs were sertraline, paroxetine, and fluoxetine.

When comparing babies born to women who used antidepressants in the first trimester with those born to mothers who did not, there were greater risks of cardiac defects associated with the use of SSRIs, SNRIs, and "other" antidepressants in unadjusted analyses.

Those risks were attenuated when the analyses were restricted to women with diagnosed depression and were rendered nonsignificant in fully adjusted analyses that used propensity-score matching among women with depression.

Prior studies have raised particular concerns surrounding the use of paroxetine and sertraline, but the researchers found no significant relationship between paroxetine and right ventricular outflow tract obstruction (RR 1.07, 95% CI 0.59-1.93) or between sertraline and ventricular septal defects (RR 1.04, 95% CI 0.76-1.41).

"Our results do not support earlier findings of an association between antidepressant use and cardiac anomalies, in particular findings with respect to the use of paroxetine and sertraline," the authors wrote.

They noted that the current analysis differed from the previous studies in that it was restricted to women with diagnosed depression "to mitigate potential confounding by the underlying psychiatric illness and associated conditions and behaviors, factors that might increase the risk of structural cardiac malformations by means of several mechanisms."

"Smoking, alcohol and drug use, poor maternal diet, obesity, and chronic conditions such as diabetes and hypertension are all more common in patients with depression than in those without depression, and are potential risk factors for congenital cardiac anomalies," they wrote.

Also, they wrote, women with depression and anxiety are more likely to have cardiac defects detected in their offspring because they tend to use more healthcare resources -- including ultrasonography, amniocentesis, and echocardiography of the infant -- during pregnancy compared with other women.

The researchers acknowledged some limitations, however, including the restriction to women who had live births (which resulted in missing cardiac malformations that caused fetal death or resulted in termination of the pregnancy) and the potential for misclassification or residual confounding from incomplete or missing factors.

Although the data came only from a Medicaid population, Huybrechts said that she thinks the findings are applicable to the broader group of pregnant women. Medicaid cohorts tend to be younger and more racially diverse than the general population, she said, but neither age nor race/ethnicity had significant interactions with the results.

"Therefore, unless there are other factors distinguishing our study cohort from other populations of pregnant women that affect the biologic relations under study, our results should be generalizable to other populations," she and her colleagues wrote.

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