Clinical and Research News
Birth-Defect Data Show SSRI Risks Are Minimal
Psychiatric News
Volume 42 Number 14 page 1-30

Two studies appearing in the June 28 New England Journal of Medicine suggest that a woman's taking selective serotonin reuptake inhibitors (SSRIs) during the first trimester of pregnancy may raise the risk of certain birth defects. Researchers emphasized, however, that the overall risk is small and that untreated depression can also be deleterious to the fetus.

Certain findings were replicated in both studies, such as the association between paroxetine use and an increased risk of a certain type of heart defect in newborns. Other findings were contradictory.

"I think the results of the study are fairly reassuring, overall," said a lead author of one of the studies, Carol Louik, Sc.D., in an interview with Psychiatric News. Louik is an assistant professor of epidemiology at Sloane Epidemiology Center at Boston University.

Louik and colleagues analyzed data from 9,849 infants with birth defects and 5,860 without birth defects born between 1993 and 2005 at five study sites in the United States and Canada.

The infants with birth defects were identified from admission and discharge lists and statewide birth-defect registries; the normal infants were identified by reviewing hospital records and through random samples of newborns in some areas.

Mothers of the infants completed interviews in person or by telephone and answered questions pertaining to demographic, reproductive, and medical factors and tobacco and alcohol use.

Researchers also determined whether the mothers took any type of antidepressant during the first trimester of pregnancy.


Louik found that of 127 infants born with omphalacele, three had been exposed to sertraline. She estimated that mothers who took the drug during their first trimester had a 5.7 higher odds of having an infant with omphalacele, but noted that the confidence interval (CI) for this finding ranged from 1.6 to 20.7.

Though the authors noted that they found "no appreciable or significantly increased risk" of congenital heart defects in relation to the use of SSRIs as a group, they found that mothers who took sertraline in the first trimester of pregnancy had twice the odds of having a baby with a septal heart defect as women who didn't take the drug. [CI: 1.2 to 4.0], a calculation based on 13 exposed infants.

Mothers who took paroxetine during the first trimester of pregnancy had three times higher odds of giving birth to an infant with right ventricular outflow tract obstruction defects [CI: 1.3 to 8.8], a calculation based on six exposed infants.

Right ventricular outflow tract obstruction impedes the flow of blood from the heart to the lungs and typically occurs in about 5 in 10,000 live births, according to Louik.

There were no significant risks for birth defects associated with non-SSRI antidepressants, according to the report. Although the analysis did not take into account depression levels as a confounding factor that may have affected birth outcomes, Louik said that if depression was a factor, "we'd expect to find the same risks no matter what antidepressant the mothers were taking."


In the second study, researchers at the University of British Columbia in Vancouver and the U.S. Centers for Disease Control and Prevention (CDC), linked SSRIs to an increased risk of certain types of birth defects, some fatal. However, absolute risks of these birth defects were small, according to the report.

Researchers with the National Birth Defects Prevention Study—an ongoing, multisite study to evaluate environmental and genetic risk factors for more than 30 categories of major birth defects—gathered data from more than 13,000 infants born between October 1997 and December 2002.

Data on infants with birth defects (9,622) came from population-based, birth-defects sur veillance systems at eight study sites throughout the United States, and data on control infants without birth defects (4,092) came from randomly selected hospital or birth records from the same geographic areas.

Researchers queried mothers by telephone to gather demographic information, including level of income and education, and whether they had used the SSRIs fluoxetine, sertraline, or paroxetine before or during pregnancy.

The fetuses were considered to be exposed to the medications if mothers used one of the SSRIs from one month before to three months after conception. Researchers found that 230 mothers of infants with birth defects and 86 mothers of infants without birth defects used one of the SSRIs in the specified period.

Researchers found that three types of birth defects were statistically significantly associated with any SSRI use: anencephaly (214 infants, with nine exposed to SSRIs), craniosynostosis (432 infants, with 24 exposed to SSRIs), and omphalocele (181 infants, with 11 exposed to SSRIs).

According to the report, these defects have not previously been associated with maternal SSRI use in pregnancy.


In addition, when the researchers analyzed the findings by body mass index (BMI) of mothers, they found that maternal obesity, defined as a BMI of 30 or greater, was associated with an increase in risk for newborns.

For instance, compared with nonobese mothers on SSRIs, obese mothers on SSRIs had 3.5 times higher odds of giving birth to an infant with conotruncal heart defects, 2.8 higher odds of giving birth to an infant with septal heart defects, and 5.9 percent higher odds of giving birth to an infant with craniosynostosis.

Jennita Reefhuis, Ph.D., one of the study investigators, told Psychiatric News that more research needs to be done on why a person's body fat may mediate the impact of medications on the developing fetus. "SSRIs tend to be lipophilic drugs," she said. Because they dissolve in fat with relative ease, obesity may intensify some effects of the medications in some cases.

Reefhuis is an epidemiologist with the CDC in Atlanta.

When the risk of birth defects was analyzed for each SSRI, Reefhuis found some significant associations for certain birth defects, although she noted that the statistical power was limited by the small number of exposed cases for each drug category.

She found that mothers who took sertraline had 3.2 higher odds of giving birth to infants with anencephaly, and mothers who took fluoxetine had 2.8 higher odds of giving birth to infants with craniosynostosis.

In addition, Reefhuis found a number of statistically significant risks related to the use of paroxetine: mothers had five times higher odds of giving birth to a baby with anencephaly, [CI: 1.7 to 15.3], a calculation based on five exposed infants; 2.5 higher odds of giving birth to a baby with right ventricular outflow tract obstruction [CI: 1.0 to 6.0], a calculation based on seven exposed infants; eight times higher odds of giving birth to a baby with omphalacele [CI: 3.1 to 20.8], a calculation based on six exposed infants; and about three times the odds of giving birth to a baby with gastroschisis [CI: 1.0 to 8.4], a calculation based on five exposed infants.

One major limitation for each study was the fact that findings did not include specific dosages of antidepressants taken, the authors acknowledged.

Both authors endorsed conducting additional research with a greater number of infants. "Because we are able to look at individual defects," Reefhuis said, "our numbers tend to be somewhat small. Hopefully we can look at additional data down the road and say with more certainty whether these findings are consistent."


In an editorial accompanying the two reports, Michael Greene, M.D., of the Division of Maternal and Fetal Medicine at Massachusetts General Hospital in Boston, noted that these additional data don't lend themselves to snap decisions about the treatment of depression in pregnant women.

"Patients and physicians alike would prefer it if there were clear lines separating risk and no risk and if all studies gave consistent results pointing in the same direction," he wrote. However, he concluded," [t]he two reports,.. .together with other available information, do suggest that any increased risks of these malformations in association with the use of SSRIs are likely to be small in terms of absolute risks."

According to A PA President-elect Nada Stotland, M.D., M.P.H., an expert on reproductive issues, small but significant statistical risks should be shared with depressed pregnant women considering their options, but that information is not very helpful to patients or physicians making clinical decisions.

"The facts remain: untreated depression poses risks to mother and fetus; treatment decisions have to be made on an individual basis, taking into account frequency, number, and severity of depressive episodes and responses to past or ongoing treatments, if any; and, unless the depression is severe, consider trying psychotherapy before prescribing antidepressants," Stotland said.

An abstract of "First-Trimester Use of Selective Serotonin-Reuptake Inhibitors and the Risk of Birth Defects" is posted at<content.nejm.org/cgi/content/abstract/356/26/2675>; and an abstract of "Use of Selective Serotonin-Reuptake Inhibitors in Pregnancy and the Risk of Birth Defects" is posted at<content.nejm.org/cgi/content/abstract/356/26/2684>.

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