In 2006, Chambers and colleagues published an article in the New England Journal of Medicine linking SSRI use during late pregnancy to an increased risk of persistent pulmonary hypertension in the newborn (PPHN) Based on these findings, the “Usage in Pregnancy” section on the labels for SRRI antidepressants was updated to include the following warning: “Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN).”

Since that time, other reports have been published which have examined the association between SSRI antidepressants and PPHN.  Thurs far, there have been a total of six studies evaluating the association between PPHN and SSRI exposure.  Three of these studies showed no association between SSRI exposure and PPHN.  Three other studies showed an increased risk of PPHN in SSRI-exposed infants, with an estimated odds ratio ranging from 2.4 to 6.1.   (It should be noted, however, that two of these studies relied upon the same patient database.)

Based on these studies, the FDA issued a revision of the warning for SSRIs:

“FDA has reviewed the additional new study results and has concluded that, given the conflicting results from different studies, it is premature to reach any conclusion about a possible link between SSRI use in pregnancy and PPHN. FDA will update the SSRI drug labels to reflect the new data and the conflicting results.”

So what do we tell our patients regarding this risk? 

In a thorough and thoughtful review of the subject form Occhiogrosso and colleagues, the authors review many of the limitations of the studies to date:

  • Case-control studies (such as the positive studies from Chambers and Kallen) tend to overestimate risk
  • Prospective studies are smaller and are usually underpowered to detect an association between exposure and a relatively uncommon events such as PPHN

The authors also point out that many factors associated with depression (rather than exposure to antidepressant) may account for the association, and there has been no systematic examination of the role these factors may play.

  • Obesity and smoking, established risk factors for PPHN, are more common in depressed women.
  • Risk of PPHN is increased fourfold in babies born at 34–36 weeks’ gestation.  Untreated depression and treatment with SSRIs during pregnancy have been linked to reduced length of gestation.
  • Cesarean section, a known risk factor for PPHN, is more common among women with depression.

Taking all of these studies into consideration, the data supporting an association between SSRI exposure and PPHN is weak.  Cumulatively there were a total of 50 infants with PPHN among an estimated 25,000 infants exposed to SSRIs during pregnancy.  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 increases the risk of antenatal and 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 newbornPharmacoepidemiol Drug Saf 2009;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 newbornNew 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.

Occhiogrosso MOmran SSAltemus M. Persistent Pulmonary Hypertension of the Newborn and Selective Serotonin Reuptake Inhibitors: Lessons From Clinical and Translational StudiesAm J Psychiatry2011; Nov 8. [Epub ahead of print].

Reis M, Källén B. Delivery outcome after maternal use of antidepressant drugs in pregnancy: an update using Swedish data.  Psychol Med 2010; 40: 1723–1733.

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.

Wilson KL, Zelig CM, Harvey JP, Cunningham BS, Dolinsky BM, Napolitano PG.  Persistent pulmonary hypertension of the newborn is associated with mode of delivery and not with maternal use of selective serotonin reuptake inhibitors. Am J Perinatol 2011; 28:19–24.

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