Common Antidepressants Increase Risk of Infant Respiratory Disorder

February 14, 2006

Pharmaceutical Executive

Pharmaceutical Executive, Pharmaceutical Executive-02-14-2006, Volume 0, Issue 0

One percent of mothers taking SSRI’s during the second half of pregnancy gave birth to babies with pulmonary hypertension, a recent study found. But the mechanisms that connect increased serotonin with this disorder are unknown.

Women who take selective serotonin reuptake inhibitors late in pregnancy may have a small but significant risk of giving birth to a child with persistent pulmonary hypertension of the newborn (PPHN), according to a in the Feb. 9 issue of the New England Journal of Medicine.

    This severe respiratory disorder occurs when the newborn has difficulty beginning to breathe with it’s own lungs, or dies when it cannot live without receiving oxygen from the mother’s blood supply, explained Christina Chambers, lead author and professor of pediatrics, and family and preventive medicine at the University of California, San Diego. This can happen as a result of certain rare birth defects. But it can also be brought on by other, incompletely understood causes. Some risk factors include a mother who smokes and a non-head first presentation of the baby, Chambers said.

    The new study may add SSRIs to the list of risks factors for PPHN. Chambers emphasized, however, that the disorder was present in the babies of only 1 percent of women who took Paxil (paroxetine), Prozac (fluoxetine), or Zoloft (sertraline) in the second half of pregnancy.

    But Sheldon Preskorn, professor and chair of the Department of Psychiatry and Behavioral Sciences at the University of Kansas in Wichita, cautioned that this study’s results could indicate that depression, not SSRIs, is the increased risk factor for PPHN. He noted that the some of the women in the control group were taking tri-cyclic antidepressants, which are prescribed for conditions other than depression. If enough of these mothers were taking tri-cyclic antidepressants for other reasons, the results might not sufficiently eliminate depression itself as the risk factor.

    In addition, Preskorn noted that women taking Effexor (venlafaxine) were included in the control group. But since this drug also works on serotonin receptors, he would have liked to see an additional data analysis with mothers taking Effexor included in the SSRI group.

    “Even if it is the drugs, why does it affect so few infants since all of them would be exposed?” Preskorn asked. “There must be other factors at play, because it’s a minority who develop it.”

The Possible Mechanism

The study’s results do not give any clues about to how SSRI’s could work to increase the risk of PPHN. But the authors speculate that it could be related to serotonin’s known ability to constrict the blood vessels in the lung, making it difficult for the heart to pump blood into the lungs. This happens when serotonin binds to certain serotonin receptors in the pulmonary system, explained Yuichiro Suzuki, professor of pharmacology at Georgetown University. Suzuki was not one of the study’s authors.

    Serotonin could be present in higher-than-usual concentrations if the mother is taking a drug that prevents the neurotransmitter from being taken into the cell. As a result, its effect on the pulmonary system could be exaggerated.

    Serotonin is also known to stimulate smooth muscle growth in the pulmonary system by entering the cells through the serotonin transporter. This action, if exaggerated, could potentially cause a thickening of the blood vessels in the lungs, which, in turn, increases resistance to pumping blood into the lungs, Suzuki said.

    “Serotonin plays a key role in the control of pulmonary vascular tone,” Saadia Eddahibi, member of the physiology faculty at Henri Mondor hospital in Créteil, France, said via email.

    The NEJM paper’s authors also hypothesized that serotonin could be acting to inhibit an enzyme that produces nitric oxide, which is known to dilate blood vessels in the lungs. In a different study, Prozac was demonstrated to inhibit nitric oxide production in a joint cell culture. But it is unknown whether this action would carry over to lung tissue.

The Clinical Impact

Because the mechanisms underlying the risk of PPHN are not well understood, it is difficult to assess how the few of mothers who birth babies with this condition differs from the many who do not. Because the risk suggested by this study is low, doctors and mothers should weigh whether or not to discontinue SSRI use on a case-by-case basis, Chambers said.

    This is especially significant in light of another study published in the Feb. 1 issue of the Journal of the American Medical Association. This paper showed that women who stop taking antidepressants during pregnancy are five times more likely to relapse into depressionthan women who keep taking the drugs.

    The next step, Chambers said, is to use existing databases to confirm or refute the risk associating SSRIs and PPHN. If the findings are corroborated, researchers must try to understand why the SSRIs act differently in the one percent of mothers who give birth to babies with PPHN.

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