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July 15 2001 • Volume 31 • Number 14

Rx

Drugs, Pregnancy, and Lactation
Antidepressants and Neurodevelopment

Gideon Koren, M.D.

DR. GIDEON KOREN is professor of pediatrics, pharmacology, pharmacy, medicine, and medical genetics at the University of Toronto. He is also the director of the Motherisk Program at the Hospital for Sick Children in Toronto, which conducts research and provides information and counseling to women and health care providers on drug therapy during pregnancy. More information is available at www.motherisk.org or by calling 416-813-6780.

There is no evidence that selective serotonin reuptake inhibitors increase the risk of malformations in babies exposed to these drugs in utero. In 1993 we published a study that did not find an excess of birth defects in the babies of women who took the SSRI fluoxetine (Prozac) or tricyclic antidepressants during pregnancy.

Since that time, there have been other studies, including some meta-analyses, that have not produced evidence that these drugs, or the newer SSRIs increase the risk of fatal malformations.

But women are also concerned about how these drugs affect their baby's brain and the neurodevelopment of their children.

We first addressed this issue in a study that compared neurodevelopmental measures in the preschool children of 80 women who had taken a tricyclic antidepressant during pregnancy, 55 women who had taken fluoxetine, and 84 women who had not taken any drug known to have adverse fetal effects. First-trimester exposure to tricylic antidepressants or fluoxetine had no impact on global IQ, cognitive abilities, or language development in the children, who were assessed between 16 and 86 months. There were also no differences in behavior problems, temperament, mood, activity level, distractibility, or arousability (N. Engl. J. Med. 336:258-62, 1997).

Most of these women had stopped taking the antidepressant after the first trimester, so the study did not address the issue of women who continue treatment throughout pregnancy. Unlike the limbs and heart, the brain develops throughout pregnancy, so drugs can theoretically affect brain development later in pregnancy as well.

To complete the picture, we did a prospective blinded study of 46 children whose mothers had taken tricyclics and 40 children whose mothers had taken fluoxetine throughout pregnancy and compared them with 36 unexposed controls. This was the first study to follow the neurodevelopment of children exposed to these drugs throughout pregnancy. Children were followed until they were preschool or early school age.

There were no differences in IQ, language development, or temperament between groups after adjusting for factors such as maternal IQ and socioeconomic class, smoking, alcohol use, and the duration and severity of the mother's depression.

There were also no differences in the same measures in the children whose mothers continued taking the medication while breast-feeding. Relatively small amounts of SSRIs and tricyclics get into breast milk.

What we did find, however, was that maternal depression had an adverse effect on some of these measures. There was a significant negative association between a child's IQ and the duration of maternal depression.

There also was a negative association between language development and the number of episodes of depression a mother had after delivery. It is therefore clear that untreated depression during and after pregnancy can have an adverse effect on the neurodevelopment of children. We recently presented these results at several meetings and have submitted the data for publication. The lead author was Dr. John Nulman, associate director of the Motherisk program.

This information can empower many women and their physicians to continue treatment with antidepressants during pregnancy if indicated. Those who wish to discontinue these drugs should not stop taking them cold turkey, which can be harmful.

Up to 20% of women have clinical depression during their lives, and in many women, depression does not improve during pregnancy. Pregnant women whose depression is not adequately treated may make decisions that can harm the baby, such as not eating well or using alcohol. We have documented some of the sequelae of abruptly stopping an antidepressant during pregnancy, which include suicidal ideology and increased alcohol use.

Similar studies will need to be done with the other SSRIs and other types of antidepressants. We have started a study to look at the malformation rate in babies exposed to bupropion (Wellbutrin) in utero and have completed another study, which found that in utero exposure to venlafaxine (Effexor) was not associated with an excess of malformations. Studies on the neurodevelopment of children exposed to these newer antidepressants have not been done yet.