SSRIs in Pregnancy Linked to Lung Hypertension in Newborns

Fran Lowry

January 13, 2012

January 13, 2012 — Pregnant women who take selective serotonin reuptake inhibitors (SSRIs) may be putting their babies at heightened risk of developing persistent pulmonary hypertension, a life-threatening condition that occurs in up to 2 per 1000 liveborn infants, according to new research.

Infants born to women treated with SSRIs in late pregnancy had a 2-fold increased risk for persistent pulmonary hypertension compared with infants born to women who did not use SSRIs, lead author Helle Kieler, MD, PhD, from the Karolinska Institutet, Stockholm, Sweden, and colleagues report.

"The absolute risk was 3 infants per 1,000 exposed, and the increased risk seemed to be a class effect of SSRIs, as risks for the specific SSRIs — sertraline, citalopram, paroxetine, and fluoxetine — were of similar magnitude," Dr. Kieler told Medscape Medical News.

The study is published online January 12 in the British Medical Journal.

Mechanism Unclear

An earlier study by Christina D. Chambers, MD, and colleagues, published in the New England Journal of Medicine in 2006, showed a 6-fold increased risk, but that study did not address specific substances because the study sample was limited, with too few infants exposed to the antidepressants, she said.

Prompted to study the issue further, Dr. Kieler and her team analyzed national birth registers in Denmark, Finland, Iceland, Norway, and Sweden. Their analysis included 1,618,255 singleton births born after gestational week 33 from 1996 to 2007.

They identified women exposed to SSRIs by linking with the drug registers on filled prescriptions. They found that 11,014 (0.7%) of the mothers had filled a prescription for an SSRI during late pregnancy, and 17,053 (1.1%) of the mothers had filled a prescription for an SSRI in early pregnancy only.

Mothers who filled a prescription were generally older and also smoked.

Another 54,184 mothers were found to have had a previous psychiatric diagnosis but were not on any medication during their pregnancy.

The study showed that 33 of the 11,014 infants exposed to an SSRI in late pregnancy had a diagnosis of persistent pulmonary hypertension.

Of the 17,053 infants exposed only in early pregnancy, 32 had persistent pulmonary hypertension of the newborn. Among the mothers who had a previous psychiatric diagnosis, 114 infants had a diagnosis of persistent pulmonary hypertension of the newborn.

The adjusted odds ratio (AOR) of risk after exposure to an SSRI in late pregnancy was 2.1 (95% confidence interval [CI], 1.5 - 3.0).

Additionally, there was a 40% risk for infants of women who filled a prescription with an SSRI in early pregnancy (before gestational week 8; AOR, 1.4; 95% CI, 1.0 - 2.0).

Small gestational age and Cesarean delivery did not influence the likelihood of having a newborn with persistent pulmonary hypertension.

The mechanism of how SSRIs would cause or promote persistent pulmonary hypertension in a newborn is unknown, Dr. Kieler said.

"SSRIs accumulate in the lungs," she suggested. "Also, considering our results suggesting a class effect for SSRIs and increased risks with other antidepressants with selectivity for serotonin and norepinephrine, one might suspect a serotonin effect. Serotonin can induce vasoconstriction and mediate pulmonary arterial smooth muscle cell proliferation."

For now, doctors should tell their patients about the increased risk but also about the rarity of the disease, Dr. Kieler said.

"We recommend caution when treating pregnant women with SSRIs and to consider nonmedical treatment for depression during pregnancy whenever possible."

Causation Difficult to Prove

Writing in an accompanying editorial, Gideon Koren, MD, director of the Motherisk Program at the Hospital for Sick Children, University of Toronto, Toronto, Canada, and Hedvig Nordeng, MSc, PharmD, from the University of Oslo, Oslo, Norway, note that pharmacoepidemiological studies can show an association but cannot prove causation.

They also point out that a major challenge in studies that rely on prescription database information is to prove that the prescriptions were in fact taken.

"A recent study showed that many women with depression did not take their prescribed antidepressants during pregnancy. In Kieler and colleagues’ study the timing of exposure was based on the pharmacies’ date of dispensing and defined daily dosages (which may differ from the prescribed doses), but they did not mention the uncertainty around the timing of exposure and how it was calculated," the editorialists observe.

They also ask whether the associations found in the current study can be explained by the underlying depression of the mother rather than use of SSRIs.

"Future studies, or additional analyses of Kieler and colleagues’ large cohort, may be able to quantify this risk, or the lack of one," Dr. Koren and Dr. Nordeng conclude.

The study was funded by the Swedish Pharmacy Company. Dr. Kieler, Dr. Koren, and Dr. Nordeng report no relevant financial relationships.

BMJ. Published online January 12, 2012. Article

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