Studies Find No Link Between SSRIs and Congenital Heart Disease

BOSTON, June 27 -- Use of selective serotonin-reuptake inhibitors (SSRIs) during the first trimester of pregnancy did not significantly increase the risk of congenital heart defects overall, despite FDA and drug maker warnings to the contrary.

A pair of studies reported in the June 28 issue of the New England Journal of Medicine did find significant statistical increases in some specific, rare defects among babies born to women who used the popular antidepressants, but in both studies the absolute risks were small and, in the case of the first study, were tied to one or another specific agent.

Carol Louik, Sc.D., of Boston University, and colleagues from the Slone Epidemiology Center Birth Defects Study reported a significant association between sertraline (Zoloft) and omphalocele (odds ratio 5.7; 95% CI, 1.6 to 20.7, three exposed patients). Sertraline was also associated with an increased risk of septal defects (OR 2.0, 95% CI, 1.2-4.0; 13 exposed patients).

Likewise in their study of 9,849 infants with birth defects and 5,860 without birth defects there was a significant association between use of paroxetine (Paxil) and right ventricular flow tract obstruction defects (OR 3.3; 95% CI, 1.3 to 8.8, six exposed patients).

Sura Alwan, M.Sc. of the University of British Columbia in Vancouver, and colleagues said data from the National Birth Defects Prevention Study found that maternal SSRI use was associated with anencephaly (OR 2.4, 95 CI 1.1 to 5.1), craniosynostosis (OR 2.5, 95% CI 1.5 to 4.0) and omphalocele (OR 2.8, 95% CI 1.3 to 5.7).

But Alwan et al found no significant associations between maternal use of SSRIs overall during early pregnancy and congenital heart defects in the data from 9,622 infants with birth defects and 4,092 controls.

These studies combined with previously published data "makes it clear that neither SSRIs as a group nor individual SSRIs are major teratogens on the order of thalidomide or isotrentinoin," wrote Michael F. Greene, M.D., of Massachusetts General Hospital in an accompanying editorial.

The Sloane Birth Defects Study began in 1976 and enrolled infants at centers in Philadelphia, Toronto, San Diego, and part of New York State. In 1998, participants from Massachusetts were also included.

The National Birth Defects Study included infants born from 1997 through 2002 in Arkansas, California, Georgia, Iowa, Massachusetts, New Jersey, New York, and Texas.

Concern about the possible teratogenicity of SSRIs began in 2005 when GlaxoSmithKline disclosed that infants exposed to paroxetine during the first trimester were more than twice as likely to have congenital heart defects than non-exposed infants.

Following that disclosure the FDA posted a warning on its website and, eventually, GlaxoSmithKline agreed to add a category D warning to the paroxetine label stating, "studies in pregnant women [controlled or observational] have demonstrated a risk to the fetus."

Authors of both studies point out that there is a possibility that the significant associations reported are in fact chance associations generated by the multiple comparisons performed in each study.

Moreover, Alwan et al caution that they were unable to separate the effect of SSRI use from underlying depression. And Dr. Louik wrote that her team "included results based on small numbers of exposed subjects in order to allow other researcher to compare their observations with ours, but we caution that these observations should not be interpreted as strong evidence of increased risks."

Editorialist Dr. Greene wrote that although both patients and physicians would like simpler more exact answers to questions about risks, that's not possible with SSRIs. But the two new studies "together with other information, do suggest that any increased risk of these malformations in association with the use of SSRIs are likely to be small in terms of absolute risks."