Over the last several years, accumulating data on the reproductive safety of selective serotonin reuptake inhibitors (SSRIs) have included multiple reports evaluating the risks of teratogenicity, poor neonatal adaptation ("neonatal abstinence syndrome"), and persistent pulmonary hypertension of the newborn (PPHN) associated with prenatal exposure to this class of drugs.

The medical literature consistently supports a small risk, if any, of major congenital malformations associated with first trimester SSRI exposure, compared with the background risk for major congenital malformations. The consensus is that about 25%-30% of babies exposed to an SSRI in late pregnancy experience poor neonatal adaptation, which is typically characterized by transient jitteriness, but the absence of enduring sequelae.

Dr. Lee Cohen

The data on risk for PPHN have been less consistent, creating some confusion among patients and clinicians. An early study published in February 2006 reported a sixfold greater risk of PPHN among newborns whose mothers took an SSRI after 20 weeks’ gestation, compared with newborns whose mothers did not take an SSRI (N. Engl. J. Med. 2006;354:579-87). In response to this striking finding, the Food and Drug Administration issued a public health advisory in July 2006 and SSRI labels were subsequently changed to include information about what the FDA referred to as the "potential risk" for PPHN. Previously, PPHN, a serious and life-threatening condition, had been noted to be associated with increased maternal body mass index, cesarean section, meconium aspiration, and other risk factors (Pediatrics 2007:120;e272-e282).

But since 2006, there have been five other studies with conflicting results, although even the positive studies have not found an increased risk as high as the initial study. A major limitation of these studies is that they have been derived largely from administrative databases, so it is difficult to corroborate exposure to a particular medicine and other possible confounding factors.

After reviewing these studies, the FDA recently issued a drug safety communication stating that "it is premature to reach any conclusion about a possible link between SSRI use in pregnancy and PPHN." In the Dec. 14 statement, the FDA refers to two studies, including the 2006 study, that have found a statistically significant association between SSRI use and PPHN, and three others that found no increase in risk. Because the agency’s review did not find "sufficient evidence to conclude that SSRI use in pregnancy causes PPHN," the FDA recommended that "health care providers treat depression during pregnancy as clinically appropriate."

Perhaps creating some confusion, in January – a month after the FDA communication was issued – a study conducted in all five Nordic countries was published online reporting a twofold increased risk of PPHN associated with SSRI exposure in late pregnancy. The study compared the risk of PPHN among infants exposed to SSRIs with unexposed infants in a sample of 1.6 million infants born between 1996 and 2007 in these countries; the increased risk was found across all SSRIs (BMJ 2011;344:d8012 [doi:10.1136/bmj.d8012]).

01/23/12