Over the past 15 years, multiple studies have addressed the reproductive safety of various antidepressants. Data on the overall teratogenicity of SSRIs has come from relatively small prospective observational studies, larger international birth registries, managed health care databases, and case series; these data have cumulatively supported the reproductive safety of fluoxetine and certain other SSRIs. In a recent meta-analysis including 1774 antidepressant-exposed infants, first trimester exposure to SSRIs was not associated with an increased risk of major malformations above the baseline of 2%-3% seen in the general population (Einarson & Einarson, 2005). The bulk of the data thus far has suggested that SSRIs are not major teratogens; however, concerns about the potential teratogenicity of SSRIs were first raised in 2005 when several preliminary studies suggested that paroxetine may be associated with a small increase in risk of congenital abnormalities.

More recently several other reports have raised concerns regarding the use of SSRIs during pregnancy. Using a retrospective case-control design to evaluate the risks of early exposure to SSRIs, Alwan and colleagues analyzed data from the National Birth Defects Prevention study, comparing 9622 infants with selected major birth defects to 4092 controls without defects. Their mothers were interviewed regarding exposures during pregnancy and other possible risk factors for major malformations. The investigators found an association between exposure to SSRI during the first trimester and increased risk of omphalocele (odds ratio, 2.8). The strongest effect was observed with paroxetine, which accounted for 36% of all SSRI exposures and was associated with an 8.1-fold increase in risk for omphalocele. For women who used SSRIs during the first trimester, the risk of giving birth to an infant with craniosynostosis was 2.5 times higher. The risk of anencephaly among SSRI-exposed infants was 2.4 times higher than in controls.

Using a similar study design, researchers from the Slone Epidemiology Center at Boston University, analyzed 9849 infants with identified birth defects and 5860 infants without such defects. In contrast to the previous study, they found that overall use of SSRIs was not associated with significantly increased risks of craniosynostosis, omphalocele, or heart defects. However, when they looked for associations between use of specific SSRIs and specific defects, they observed significant associations between first trimester exposure to sertraline and omphalocele (odds ratio, 5.7) and septal defects (odds ratio, 2.0) and between exposure to paroxetine and right ventricular outflow tract obstruction defects (odds ratio, 3.3).

This volley of conflicting reports has left many clinicians confused and uncertain about how to counsel their patients regarding the safety of SSRIs during pregnancy. For example, while several earlier studies suggested a link between paroxetine and septal defects, the two most recent studies show no such link. While one of these studies suggests that paroxetine may increase the risk of omphalocele, the other does not and instead indicates a link between sertraline and this defect. The differences in the results from the available studies and the diversity in the types of abnormalities reported make it difficult to definitively draw a causal link between SSRI exposure and any particular congenital abnormality.

The earliest data on the potential teratogenicity of SSRIs derived from smaller cohort studies and larger pregnancy registries. These studies, when data regarding drug exposure can be ascertained prospectively before the birth outcome is known, can yield reliable data regarding teratogenic risk; however, these studies are usually limited by their small size. It is estimated that at least 500 to 600 exposures must be collected to demonstrate a two-fold increase in risk for the most common malformations, and even more exposures are required to generate adequate statistical power to detect an increase in a rarer outcome. Case-control studies, on the other hand, rely upon much larger sample sizes and have greater statistical power to detect small differences in teratogenic risk, but these studies also have limitations; for example, they are vulnerable to recall bias if drug use is self-reported. Risks may be overestimated if mothers of children with defects are more likely to recall or report drug exposures than women who gave birth to children without defects. Furthermore, one must understand that the word “association” does not necessarily mean “causation.” Antidepressant exposure may be associated with other characteristics or behaviors, such as smoking or being overweight, that also modulate risk. Given these limitations, case-control studies may be more useful in identifying potential teratogens but may less reliable in quantifying the relative risk.

While there is clearly a need for more thorough analysis of the existing data, these reports, taken together, may signal an increase in risk of malformations in children exposed to SSRIs. However, it is important to put this risk in perspective. Even if we assume the associations from these case-control studies to be true, the overall risk of malformations remains low. For example, an 8.1-fold increase in risk for omphalocele translates into an absolute risk of only 0.2% (approximately 2 out of every 1,000 births). Absolute risk is of far greater clinical value than relative risk and should be taken into consideration before patients are arbitrarily counseled to discontinue antidepressants during pregnancy.

In an editorial accompanying these two studies, Michael F. Greene, MD, of the Division of Maternal and Fetal medicine at Massachusetts General Hospital in Boston, noted that these newer-and often conflicting-studies clearly have made it more difficult to make decisions regarding the treatment of depression during pregnancy. He noted further that “patients and physicians alike would prefer it if there were clear lines separating risk and no risk and if all studies gave consistent results pointing in the same direction.” While these more recent reports have raised concerns, the data, taken as a whole, are reassuring and indicate that the risks associated with SSRI exposure during pregnancy are low.

Ruta Nonacs, MD PhD

Alwan S, Reefhuis J, Rasmussen SA, et al. Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med. 2007;356: 2684-2692.

Einarson TR, Einarson A. Newer antidepressants in pregnancy and rates of major malformations: a meta-analysis of prospective comparative studies. Pharmacoepidemiol Drug Saf. 2005;14:823-827.

Greene MF. Teratogenicity of SSRIs–serious concern or much ado about little? N Engl J Med. 2007;356: 2732-2733.

Louik C, Lin AE, Werler MM, et al. First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. N Engl J Med. 2007;356:2675-2683.

*This post was originally published as an article in our March 2008 newsletter.

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