Taking selective serotonin re-uptake inhibitor (SSRI) antidepressants during pregnancy does not substantially increase the risk of congenital heart defects or most other types of birth defect, two new US studies have found.

While far from definitive, the results published in the June 28 issue of the New England Journal of Medicine will bring some comfort to manufacturers of SSRIs, which have been plagued by associations with psychiatric and other adverse effects in children, adolescents and adults.

GlaxoSmithKline, which part-funded one of the studies and whose SSRI paroxetine (Paxil/Seroxat) already carries a warning on its US labelling about increased risks of major congenital abnormalities, is facing product liability and personal injury lawsuits in the US from mothers who took the drug during pregnancy and gave birth to babies with persistent pulmonary hypertension or severe heart defects.

Paroxetine risks

Unlike a German study presented last June, the NEJM papers did not claim to exonerate Paxil of any link with birth defects. Indeed, they found a significantly increased risk of right ventricular outflow tract obstruction and other birth defects with paroxetine. Even in these cases, though, the absolute risks of defects were low.

The new studies will also bring some reassurance to pregnant and depressed mothers for whom withdrawal from therapy could result in a downward spiral of behaviour more damaging to both the unborn and newborn child.

In one of the studies, conducted by researchers from the University of British Columbia in Canada and the US Centers for Disease Control and Prevention, data were obtained from the US National Birth Defects Prevention Study on 9,622 infants with major birth defects and 4,092 control infants born in 1997-2002. The children’s mothers were then interviewed about exposure to potential risk factors, including four SSRIs (paroxetine, citalopram, fluoxetine and sertraline), from one month before to three months after conception.

No significant links

The researchers found no significant links between maternal use of SSRIs overall during early pregnancy and congenital heart defects or most other (sub-)categories of birth defects. Maternal SSRI use was associated with anencephaly (where the baby’s brain fails to develop), craniosynostosis (premature fusion of cranial sutures) and omphalocele (in which the intestines or other abdominal organs protrude through the naval), but the absolute risks were small.

The other study, conducted by researchers from Boston University, Massachusetts General Hospital for Children and Harvard School of Public Health in the US, looked at associations between first-trimester maternal use of SSRIs and the risk of birth defects among 9,849 infants with birth defects and 5,860 controls participating in the Slone Epidemiology Center Birth Defects Study.

In analyses of defects previously linked to SSRI treatment, overall use of SSRIs was not found to be associated with significantly increased risks of craniosynostosis, omphalocele or heart defects overall. Analyses of associations between individual SSRIs and specific birth defects revealed significant links between sertraline (Zoloft, Pfizer) and omphalocele as well as septal defects, and between paroxetine and right ventricular outflow tract obstruction defects.

The risks were not appreciably or significantly increased for other defects or for other SSRIs or non-SSRI antidepressants. At the same time, the researchers noted, the specific defects implicated with paroxetine and sertraline were rare and the absolute risks were slight.

Generally reassuring

As Jennita Reefhuis, one of the authors of CDC/University of British Columbia study, pointed out, every pregnancy has a 3% risk of a major birth defect, regardless of exposures, and a woman’s lifetime risk of major depression is 10-25%, with the highest prevalence during childbearing years.

As a point of comparison, the US studies indicated that the absolute risk of right ventricular outflow tract lesions associated with maternal use of paroxetine during pregnancy was less than 1%.

“Overall, our results are generally reassuring with respect to the use of antidepressants during pregnancy,” Reefhuis commented. “We know that both the mother and baby benefit when a pregnant woman with a serious depressive illness is able to stay on some sort of treatment…It’s important that women talk with their doctor about the risks and benefits of taking SSRIs during pregnancy.”

Writing in Journal Watch Psychiatry, Dr Peter Roy-Byrne, vice-chairman and professor in the Department of Psychiatry and Behavioral Sciences at the University of Washington, Seattle, took a more sceptical view.

While large and carefully performed, the two studies were limited because “the rates of SSRI exposure and individual birth defects were so low, because self-reported SSRI use was not confirmed by pharmacy records, and because this research method does not address whether the medication or the depression itself is responsible for these birth defects,” he said.