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Women who use selective serotonin reuptake inhibitors (SSRIs) during pregnancy may be placing their unborn children at risk for persistent pulmonary hypertension of the newborn, a large cohort study showed.

In a study of more than 1.6 million births, SSRI exposure in the second half of pregnancy was associated with a doubling of the odds of persistent pulmonary hypertension of the newborn (OR 2.1, 95% CI 1.5 to 3.0), according to Helle Kieler, MD, PhD, of the Karolinska Institute in Stockholm, and colleagues.

That equates to an increase in absolute risk from 1.2 to 3 cases per 1,000 live-born infants, the researchers reported online in BMJ.

Although an observational study cannot prove causality, Kieler and colleagues recommended caution when using SSRIs for pregnant women.

"It is essential to plan the treatment and to weigh the risks of persistent pulmonary hypertension of the newborn when treating women in late pregnancy with those of relapse of depression and neonatal abstinence syndrome if therapy is interrupted," they wrote.

Persistent pulmonary hypertension in the newborn occurs when the pulmonary vascular resistance fails to decrease after birth and the ductus arteriosus remains open to ensure circulation. Mortality ranges from 5% to 10%.

Some previous studies have identified SSRI use late in pregnancy as a risk factor for the condition, although others have not.

To further explore the issue, Kieler and colleagues performed a cohort study using national health registries from Denmark, Finland, Iceland, Norway, and Sweden. The analysis included 1,618,255 singletons born after 33 weeks of gestation from 1996 to 2007.

Overall, about 30,000 women filled a prescription for an SSRI during pregnancy, including 17,053 (1.1%) before eight weeks of gestation and 11,014 (0.7%) after 20 weeks of gestation.

Filling a prescription for an SSRI late in pregnancy was associated with increased odds of persistent pulmonary hypertension in the newborn after adjustment for maternal age, dispensed nonsteroidal anti-inflammatory drugs and diabetes medications, preeclampsia, chronic illnesses during pregnancy, country of birth, birth year, level of delivery hospital, and birth order.

The odds ratio increased slightly after excluding newborns with meconium aspiration, the most common cause of the condition.

The relationship remained consistent across different types of SSRI.

Also associated with a greater likelihood of having persistent pulmonary hypertension in the newborn were filling a prescription for an SSRI early in pregnancy (OR 1.4, 95% CI 1.o to 2.0) and a previous maternal admission for a psychiatric disorder (OR 1.3, 95% CI 1.o to 1.6). Both findings require further investigation, according to the researchers.

A possible mechanism underlying the relationship between prenatal exposure to an SSRI and the newborn condition could involve the accumulation of SSRIs in the lungs combined with the ability of serotonin to cause vasoconstriction and to mediate pulmonary arterial smooth muscle cell proliferation, the authors noted.

The findings that other antidepressants that affect serotonin or norepinephrine activity were also associated with persistent pulmonary hypertension in the newborn support a possible causal role of serotonin, they said.

In an accompanying editorial, Gideon Koren, MD, of the Hospital for Sick Children in Toronto, and Hedvig Nordeng, PhD, of the University of Oslo, noted that a review of criteria for establishing the causation of teratogenic effects of drugs in humans suggests the relationship is causal, but said more work is needed.

They criticized the researchers for failing to control for other causes of the condition other than meconium aspiration.

"By not controlling for these confounding or modifying conditions, the authors have missed an opportunity to calculate the attributable risk of SSRIs in causing pulmonary hypertension in the newborn," they wrote.

Kieler and colleagues acknowledged some additional limitations of the study, including the inability to determine whether filled prescriptions were used and the lack of an assessment of the possible exposure to more than one antidepressant.

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