In 2006, Chambers and colleagues published an article linking SSRI use during late pregnancy to an increased risk of persistent pulmonary hypertension in the newborn (PPHN). Since that time, several other reports have been published which have examined the association between SSRI antidepressants and PPHN.  Here is a summary of the findings to date:

Chambers et al (2006): Using a case-control design to evaluate risk factors for PPHN, the authors identified 377 infants with PPHN. Diagnosis of PPHN was confirmed by review of the medical records by a neonatologist blinded to the mother’s medication status. A matched control group of 836 women and their infants was also identified.  The use of an SSRI antidepressant after the 20th week of gestation was significantly associated with PPHN (adjusted odds ratio 6.1).  Based on the results of this analysis, the authors estimated the risk of PPHN to be about 1% in infants exposed to SSRIs late in pregnancy (after 20 weeks).  Exposure to an SSRI before the 20th week or the use of a non-SSRI antidepressant did not increase risk for PPHN.

Wichman et al (2007): Researchers at the Mayo Clinic in Rochester, Minnesota reviewed the medical records of 25,214 deliveries, including 745 mothers who had been treated with SSRIs during pregnancy. They found no association between SSRI use during pregnancy and the occurrence of PPHN. Of the 16 infants diagnosed with persistent pulmonary hypertension in this cohort, none had been exposed to SSRIs.

Kallen et al (2008): In this case-control study, data was collected by midwives during the first antenatal visit, which usually occurred prior to week 12 of gestation. Information on maternal drug use was obtained at the first antenatal visit.  (Information on drug exposure late in pregnancy was not available, unless the drug was prescribed by the antenatal clinic itself.)  Infants with PPHN were identified using neonatal discharge diagnoses noted in the medical record.  The study included a total of 831,324 infants born between the years of 1997 and 2005. A total of 506 infants were identified with a discharge diagnosis of PPHN.  When all cases were analyzed, an increased risk for PPHN was observed among the SSRI-exposed infants (risk ratio 2.01) and it was marginally statistically significant.  The authors calculated that prenatal exposure to an SSRI was associated with a 0.15% (1.5 per 1000) risk of PPHN.

Andrade et al (2009): In this retrospective study, an administrative HMO database was used to identify women who had delivered an infant in a hospital between 1996 and 2000.  Hospitalization data were used to identify diagnoses or procedure codes indicative of PPHN.  The researchers found no association between SSRI use during pregnancy and the occurrence of PPHN.  Only five cases of possible PPHN were confirmed: two among SSRI-exposed infants and three among those not exposed.  Among the 1104 infants whose mothers were exposed to SSRIs in the third trimester, the prevalence of PPHN was 2.14 per 1000.  The prevalence of PPHN among a matched group of 1104 infants whose mothers were not exposed to SSRIs was 2.72 per 1000.

It is of interest that both of the studies which relied upon chart review failed to demonstrate an association between SSRI exposure and PPHN.  Only the case-control studies have identified an association, although the magnitude of risk varies considerably.  Chamber and colleagues estimated that the risk of PPHN to be about 1% in infants exposed to SSRIs late in pregnancy.  In contrast, Kallen and colleagues calculated the risk to be 0.15% (1.5 per 1000).

In general, it is felt that while case control studies may be helpful in detecting an association between exposure and a particular outcome, they may overestimate the magnitude of the risk.  These studies may also have certain limitations; for example, they are vulnerable to recall bias if drug use is self-reported (as in the Chambers study).  Risks may be overestimated if mothers of children with poor outcomes are more likely to recall or report drug exposures than women who gave birth to healthy infants.

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 associations but may less reliable in quantifying the relative risk.

When caring for women with histories of mood and anxiety disorders, these data cumulatively inform decisions regarding the use of SSRI antidepressants during pregnancy.  Given the warnings included in the SSRI packaging labels regarding PPHN, many patients, in collaboration with their doctors, may elect to avoid or discontinue antidepressants near the time of delivery because of concern over PPHN, an extremely serious decision which may significantly affect risk for relapse.

It is important to note that 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 avoiding or discontinuing antidepressants proximate to delivery.  In women with histories of recurrent or severe depression, avoiding antidepressants near the time of delivery increases the risk of postpartum depression and thus may not be the safest option.

Ruta Nonacs, MD PhD

Andrade SE, McPhillips H, Loren D, Raebel MA, Lane K, Livingston J, Boudreau DM, Smith DH, Davis RL, Willy ME, Platt R. Antidepressant medication use and risk of persistent pulmonary hypertension of the newborn. Pharmacoepidemiol Drug Saf. 2009 Mar;18(3):246-52.

Chambers CD, Hernandez-Diaz S, Van Marter LJ, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. New Engl J Med 2006; 354(6):579-87.

Källén B, Olausson PO. Maternal use of selective serotonin re-uptake inhibitors and persistent pulmonary hypertension of the newborn. Pharmacoepidemiology and drug safety 2008; 17: 801-806.

Wichman C, Moore K, Lang T, et al. Congenital Heart Disease Associated With Selective Serotonin Reuptake Inhibitor Use During Pregnancy. Mayo Clin Proc. 2009 January; 84(1): 23–27.

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