Depression: Perspective - Reevaluating the Risk for PPHN

January 15, 2012

January 2012, Clinical Psychiatry News, Lee S. Cohen

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.

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]).

Although a study of such a large group of women is a welcome addition to the literature, I do not believe these results affect the FDA’s recent conclusions – or how we should approach the management of major depression during pregnancy. Like most of the previous studies, the data presented in the most recent study are from a large administrative database, where documentation of actual ingestion of medication, the existence or severity of the psychiatric diagnosis for which the medication is prescribed, and rigorous confirmation of the outcome – PPHN – is challenging.

The authors noted that while the absolute risk for PPHN among infants exposed to SSRIs was as low as 3 cases per 1,000 infants exposed (risk in unexposed newborns is 1-2 per 1,000), the risk appeared to be doubled and they recommended “caution when treating pregnant women with SSRIs.” They added that it was “essential to plan the treatment and to weigh” the risks of PPHN when treating women in late pregnancy “with those of relapse of depression and neonatal abstinence syndrome if therapy is interrupted.” Clinicians definitely need to weigh these relative risks, but the risks are strikingly different. Even the recent Nordic report supports the very low absolute risk of PPHN with SSRI exposure, compared with risk of relapse of depression during pregnancy noted with antidepressant discontinuation, which is high.

One has to wonder about the wisdom of implying that an antidepressant should be discontinued close to delivery given that the risk of relapse of depression close to term is one of the strongest predictors of postpartum depression, which can have a profound impact on women and their families. As the amount of data on the reproductive safety of SSRIs continues to grow, clinicians are put in a bind as to how to interpret data that has tended to be variable with respect to both results and implications for clinical care. There may be no perfect decision, and no decision is risk free. But suffice it to say, the most recent FDA communication appears to be balanced in its conclusion that some of the earlier concerns regarding extent of elevation of risk have now been modulated or diminished given the data that have emerged over the last 5 years. This modest risk may factor into decisions women make with their doctors about SSRI use during pregnancy; but for many, the accumulated data are now reassuring and may provide some license to use these medications during pregnancy to treat major depression and its attendant morbidity.

This column, Drugs, Pregnancy, and Lactation, appears regularly in Ob.Gyn. News, a publication of Elsevier. Dr. Cohen directs the perinatal psychiatry program at Massachusetts General Hospital, Boston, which provides information about pregnancy and mental health at He has been a consultant to manufacturers of SSRIs. To comment, e-mail him at