SSRIs and PPHN Revisited

March 15, 2009

March 2009, ObGyn News, Lee S. Cohen, MD

The risks associated with selective serotonin reuptake inhibitor use in pregnancy have been addressed in previous columns because of the accumulating data suggesting that depression during pregnancy is common and that many pregnant women use SSRIs. A recent study indicated that as many as 8% of pregnant women are treated with SSRIs, so clearly delineating the spectrum of associated risks is of critical clinical importance.

Although an increasing amount of data suggests that the teratogenic risks associated with fetal exposure to SSRIs are small and the potential for problems with neonatal adaptation symptoms are common (about 30%) but typically self-limit­ed, several recent studies have evaluated the risk for persistent pulmonary hypertension of the newborn (PPHN) associated with late trimester exposure to SSRIs.

I have reviewed several studies suggesting a spectrum of risk, dating back to the case-control study using data from a birth defects database, which ascribed about a sixfold increase in risk for PPHN to late trimester exposure to SSRIs (N. Engl. J. Med. 2006;354:579-87). This was followed by a case-control study published last year from the Swedish Medical Birth Register, which found approximately a twofold increased risk of PPHN associated with SSRI exposure late in pregnancy (Pharmacoepidemiol. Drug Saf. 2008;17:801-6).

Recently, another study using an administrative database from four health plans in an ongoing HMO research network study of birth outcomes provided yet another estimate. The investigators retrospectively identified 1,104 full-term infants whose mothers were dispensed an antidepressant in the third trimester and 1,104 full-term infants whose mothers did not receive an antidepressant in the third trimester (Pharmacoepidemiol. Drug Saf. 2009 January 15).

Possible cases of PPHN were identified using different diagnosis and procedure codes and confirmed with reviews of hospital records. There was no difference in risk for PPHN between exposed and unexposed children: The prevalence of PPHN was 2.14 per 1,000 among infants exposed to an SSRI during the third trimester and 2.72 per 1,000 among the infants not exposed to SSRIs. Only a small number of cases of possible PPHN were confirmed-two among SSRI-exposed infants and three among those not exposed-and some cases may have been missed, hence one of the limitations of the study.

The conflicting data are not terribly surprising because these studies are not prospective and they use various databases; each has its own respective limitations. It is noteworthy, however, that in the most recent study, the frequency of PPHN was similar to rates reported in the literature and the general population, suggesting that the methods used were comprehensive and that the results may reflect what we see in the real world. Also noteworthy is that maternal diabetes and asthma, two known risk factors for PPHN, were common in the exposed group, compared with the unexposed group, but other risk factors known to drive PPHN-increased body mass index, alcohol and cigarette smoking, or African American ethnicity-were not ascertained in this study.

Hence, we are faced once again with studies addressing critical questions for patients that have provided different results, which certainly makes it challenging for clinicians to attempt to navigate a thoughtful clinical course for their patients.

When counseling patients, one concern is how these data cumulatively inform the care of patients with histories of recurrent major depression treated with SSRIs during pregnancy. Given the warnings in the SSRI labels regarding PPHN, many patients-in collaboration with their doctors-may elect to discontinue antidepressants just before delivery because of concern over PPHN, an extremely serious outcome. Given the study with the sixfold increased risk, the Swedish registry data indicating a twofold increased risk, and these new data, which suggest the absence of risk, the answer regarding the true risk for PPHN may fall somewhere in the middle, with perhaps some modest increase in risk.

Even if we assume a modest increase in the risk for PPHN in this scenario, the absolute risk is extremely small and it may not justify discontinuing antidepressants close to delivery because this clearly puts patients at risk for depressive relapse and at a very high risk for worsening of mood in the postpartum period, with its attendant morbidity and adverse sequelae for both the mother and child.

Clinicians and patients together will make decisions based on the available information, and those decisions will vary from patient to patient, based on patients’ wishes and individual clinical situations. We make the best clinical decisions possible on a case by case basis, and we welcome more of these analyses from rich datasets so we can continue to refine risk estimates-particularly for rare but serious outcomes such as PPHN.

Dr. Cohen directs the perinatal psychiatry program at Massachusetts General Hospital, Boston, which provides information about pregnancy and mental health at He also is a consultant to manufacturers of SSRIs.