Persistent pulmonary hypertension of the newborn (PPHN) is a rare but often fatal condition in which the fetal circulation persists after birth, leading to hypoxemia and respiratory failure. Results of a previous cohort study suggested a possible link between PPHN and maternal selective serotonin reuptake inhibitor (SSRI) use in late pregnancy. Chambers and colleagues conducted a case-control study involving women whose infants developed PPHN to determine whether SSRI use after 20 weeks’ gestation was associated with a higher risk of this condition.
Potential participants were identified from medical record reviews, telephone calls, and referrals at 97 institutions in Boston, Mass.; Philadelphia, Penn.; San Diego, Calif.; and Toronto, Canada. Criteria for PPHN were (1) severe respiratory failure shortly after birth at greater than 34 weeks’ gestation, and (2) evidence of pulmonary hypertension on echocardiography or a difference of more than 5 percent between preductal and post-ductal oxygen saturation. The control group consisted of mothers who delivered healthy newborns at the same hospitals; control participants were matched to patients by delivery dates in a 2:1 ratio.
About seven out of 10 mothers in each group who were invited to participate in the study agreed, making a total of 377 study participants and 836 matched control participants. Mothers who delivered infants with PPHN were more likely than those in the control group to be black (adjusted odds ratio [OR], 2.3; 95% confidence interval [CI], 1.4 to 3.8) or Asian (adjusted OR, 2.2; 95% CI, 1.2 to 3.9) and to have had a pre-pregnancy body mass index greater than 27 kg per m2 (adjusted OR, 2.6; 95% CI, 1.6 to 4.0).
All mothers were interviewed over the telephone within six months after delivery. The interviews were conducted by trained nurses who did not know the study hypothesis and included elicitation of a medication history with specific questions about antidepressant use during pregnancy. To aid recall of medication use, calendars were provided highlighting the dates of the last menstrual period and delivery. Late pregnancy exposure to SSRIs was defined as any use that occurred more than 20 calendar weeks after the first day of the last menstrual period.
Fourteen mothers who delivered infants with PPHN and six control mothers reported using SSRIs after 20 weeks’ gestation. When adjustments were made for potential confounders, multivariate regression analysis demonstrated that mothers who reported using SSRIs in late pregnancy were approximately six times more likely to deliver infants with PPHN than mothers who reported no such use (adjusted OR, 6.1; 95% CI, 2.2 to 16.8). In contrast, no increased risk for PPHN was found with maternal SSRI use before 20 weeks’ gestation or with use of other classes of antidepressants at any time during pregnancy. The results did not change significantly when the analysis was restricted to infants born at 37 weeks’ gestation or later.
The authors conclude that maternal SSRI use after 20 weeks’ gestation is associated with a significantly increased risk of delivering an infant with PPHN. They speculate that higher circulating serotonin levels may predispose newborns to PPHN by stimulating smooth-muscle cell proliferation in the fetal lung and inhibiting nitric oxide synthesis.
Ten to 15 percent of women of reproductive age develop a major depressive disorder. Because the absolute increase in risk for PPHN observed in this study was small (i.e., six to 12 cases per 1,000 births), the authors recommend that physicians incorporate these findings into discussions about the benefits and risks of antidepressant treatment with patients who are pregnant.