Antidepressants and the Risk of Birth Defects

New research suggests use during pregnancy does not increase risk

A decade ago, studies started reporting that rare heart birth defects were associated with antidepressant use during pregnancy, causing concern among women taking these medications and their doctors. But a new study, published in the New England Journal of Medicine, has found that, although there was a small increase in heart defect risk associated with antidepressants, the risk was probably due to depression, factors related to the condition, and other illnesses.

The new study involved nearly 950,000 American women covered by Medicaid who were pregnant between 2000 and 2007 – large enough to examine other reasons for heart defects.

The researchers looked at the prescriptions that the women received in the first trimester when the baby's developing heart is most vulnerable to malformation. They considered prescriptions for antidepressants including SSRIs (paroxetine, sertraline, fluoxetine), SNRIs (citalopram, venlafaxine), buproprion, TCAs including clomipramine, and others such as mirtazapine and selegiline. They also considered prescriptions for diabetes medications, blood pressure medications, and other psychiatric drugs. 

The researchers found that the risk of having a baby with a heart defect was low for all women in the study. Among the women who took an antidepressant during the first trimester, 9 out of 1,000 babies were diagnosed with a cardiac malformation within three months of birth, compared to about 7 out of 1,000 babies born to women who did not take an antidepressant. In other words, exposure to an antidepressant was associated with 25 percent higher risk.

Other factors increased risk
However, the current study involved an additional analysis: The researchers compared the rate of heart defects among just the women who were diagnosed with depression to see how the illness itself affected risk. Depressed women who took an antidepressant in the first trimester faced only about 12 percent higher risk of having a baby with a heart defect compared to depressed women who had not received antidepressant treatment.

It is unclear how having depression during pregnancy could increase the risk of heart defects. One possibility is that the illness on its own could be responsible. In addition, depression is associated with smoking, alcohol use, poor diet, and other factors that could increase the risk of birth defects.

The researchers also found that having diabetes and taking other medications (such as anticonvulsants) during pregnancy also increased risk. And when the researchers looked at women who had these factors in addition to depression, they found that taking an antidepressant during pregnancy did not pose more risk of giving birth to a baby with a cardiac malformation.

The risk of depression during pregnancy
"Depression during pregnancy is really toxic because it increases the risk of postpartum depression and risks to the baby, including low birth weight,” says Lee S. Cohen, MD, author of the current study, director of the Center for Women's Mental Health at Massachusetts General Hospital, and Seleni advisory board member. From this work, it also seems that "depression is a risk factor for cardiac malformations," says Cohen.

Making the choice about taking an antidepressant
In 2005, the U.S. Food and Drug Administration issued a warning about paroxetine (Paxil) in response to a pair of studies that reported an association between taking paroxetine during pregnancy and specific defects that caused holes in the walls of the heart. The defects ranged from mild to serious (requiring surgery). Since that warning, additional studies have found associations between sertraline, citalopram, and fluoxetine and similar heart defects.

In the current study, Cohen and his collaborators did not find an association between paroxetine, sertraline, and fluoxetine and any heart defects after they took into account the effect of depression itself. Similarly, although there was an association between taking an SSRI during pregnancy, or an SNRI or antidepressant such as mirtazapine and selegiline, and an increased risk of heart defect, the risk went away after the researchers adjusted for the effect of depression, other illnesses (such as diabetes), and other medications (namely anticonvulsants). The researchers did not find any risk associated with other types of antidepressants, such as buproprion.

"One of the messages from our paper is that no antidepressant is absolutely contraindicated during pregnancy if the advantage to be gained is that the woman stays emotionally well during pregnancy," Cohen says. Although a woman should not arbitrarily take an antidepressant if she does not need one, the priority should be to keep women mentally healthy, he emphasizes.

Sura Alwan, PhD, a postdoctoral researcher at the University of British Columbia, published one of the first studies linking paroxetine to heart defects. She notes that it is excellent that the current study was large enough to examine the role of depression in heart defect risk.

Even though the current study could relieve some concern over the risk of heart defects, "there has recently been a lot of research on antidepressants and later onset cognitive and developmental disorders, such as autism, and women must also think about that," cautions Alwan.

Several large studies have looked at whether SSRI use during pregnancy increases the likelihood of having a child with autism, and although the findings vary, it generally appears that SSRI use is associated with either no or small increases in autism risk. There is also preliminary evidence in these studies suggesting that the increased risk may be due to depression rather than the medication.

Alwan says that the unresolved questions about the risk of antidepressants during pregnancy mean women and their doctors should consider alternative treatments, such as therapy, when possible. However, she believes that "if a woman has moderate or severe depression or a family history of depression, it is probably a good idea to stay on the medication."

Cohen agrees that for a woman who needs an antidepressant, the benefits of taking the medication are clear. The current study, he says, could help women and doctors "refine the estimate of risk and make a more informed risk-benefit decision."

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