New Analysis of Antidepressants in Pregnancy Finds Little Added Risk of Newborn Pulmonary Hypertension

July 29, 2015

An overview of the largest study to examine persistent pulmonary hypertension in newborns (PPHN) exposed to antidepressants late in pregnancy.

[[{"type":"media","view_mode":"media_crop","fid":"31085","attributes":{"alt":"","class":"media-image media-image-right","height":"117","id":"media_crop_9113127569853","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"4024","media_crop_rotate":"0","media_crop_scale_h":"150","media_crop_scale_w":"176","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":" ","typeof":"foaf:Image","width":"138"}}]]The largest study to examine persistent pulmonary hypertension in newborns (PPHN) exposed to antidepressants late in pregnancy found little association with either SSRI or non-SSRI antidepressants, and the potential risk with SSRIs to be smaller than previous studies have suggested. The study, published in The Journal of the American Medical Association, included almost 4 million pregnant women. Approximately 129,000 of the women had used an antidepressant during the 90 days before delivery.1

Lead author Krista Huybrechts, MS, PhD, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, stated in an audio presentation linked to the JAMA publication, “although we cannot entirely exclude the possibility that there might be a small increase in the risk of PPHN with SSRI use late in pregnancy, what our study has shown is that the absolute risk is small, and any potential increase in risk, if present, is much more modest than some of the previous studies have indicated.”

Speaking with Psychiatric Times, Dr Huybrechts said, “Our findings should therefore be reassuring for women who suffer from severe depression that doesn’t respond to non-pharmacological treatments, requiring them to stay on treatment during pregnancy.” She cautioned, however, “Our study should not be interpreted as evidence that antidepressants are safe during pregnancy, since our study addresses only one of the potential adverse pregnancy outcomes.”

The question about risk of PPHN with SSRIs has remained, since conflicting studies prompted an FDA warning in 2006 to be withdrawn in 2011. The FDA advisory explained the reversal, “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.”2

“We decided to conduct this study to try and shed some light on this ongoing controversy,” explained Dr Huybrechts. While the initial FDA advisory was based on one study, which found a 6-fold increase in risk associated with the use of SSRIs after the 20th week of pregnancy, 3 of 5 subsequent studies did not find an increased risk. “The negative studies tended to be small, raising the possibility that they had insufficient power to detect an increased risk.”

Refining risk assessment

The absolute number of neonates with PPHN in the current study before controlling for confounding factors appears to reflect an increased risk with medication: there were 21 neonates with PPHN in 10,000 births in women without antidepressant exposure compared with 32 neonates who had been exposed to an SSRI and 29 who had been exposed to a non-SSRI antidepressant. The corresponding odds ratio (OR) calculation in the study-was 1.51 for SSRIs and 1.4 for non-SSRIs.

Delving further into the Medicaid Analytic eXtract (MAX) data base, the investigators distinguished women with depression from those with other illnesses and associated treatments, and controlled for conditions with a propensity to contribute to PPHN, such as diabetes, obesity, and cesarean delivery. In the initial stratification that limited the diagnoses to depression, the calculated risk for PPHN was attenuated to 1.36 for SSRIs and remained approximately the same at 1.38 for non-SSRIs. After applying “high-dimensional” propensity score stratification, the SSRI exposure OR was 1.1 (95% CI, 0.94, 1.29); the non-SSRIs exposure OR was 1.02 (95% CI, 0.77, 1.35).

Considering possible differences between the categories of antidepressants, Dr Huybrechts explained, “Given the width of the 95% confidence intervals, I believe we have to be careful drawing different conclusions from our study for SSRI and non-SSRI antidepressants.” With 2.7% of pregnancies in the current study exposed to an SSRI compared with 0.7% exposed to a non-SSRI, Dr Huybrechts noted, “Non-SSRIs are used much less frequently and their safety in pregnancy has been studied far less than SSRIs. There is, therefore, less known about other potential risks during pregnancy.”

The investigators concluded their published report by advising clinicians and patients to balance the potential small increase in the risk of PPHN associated with SSRI antidepressants, along with other risks that have been attributed to use during pregnancy, “with the benefits attributable to these drugs in improving maternal health and well-being.”


1. Huybrechts KF, Bateman BT, Palmsten K, et al. Antidepressant use late in pregnancy and risk of persistent pulmonary hypertension of the newborn. JAMA. 2015;313:2142-2151.

2. Food and Drug Administration. FDA Drug Safety Communication: Selective serotonin reuptake inhibitor (SSRI) antidepressant use during pregnancy and reports of a rare heart and lung condition in newborn babies. January 9, 2012. Accessed June 12, 2015.