Over the last decade information has accumulated regarding the safety of antidepressants taken during pregnancy. While much research has addressed the effect of antidepressant drugs on risk for congenital malformation, less research has focused on the long-term effects of prenatal antidepressant exposure.

In a landmark study from Irena Nulman and her colleagues at the Mortherisk program in Toronto, a cohort of children exposed either to tricyclic antidepressants (n=80) or to fluoxetine (n=55) during pregnancy was followed prospectively for up to seven years. Outcomes in these children were compared to outcomes in a group of 84 non-exposed controls. At birth there were no differences between the two groups in terms of weight, height, head circumference, rates of perinatal complications, or incidence of major malformations. The children were examined between 16 and 86 months of age using specialized rating instruments; no significant differences between exposed and non-exposed children were observed across a number of variables, including IQ, language, temperament, behavior, reactivity, mood, distractibility, and activity level.

A subsequent study from the same group followed a group of children exposed to fluoxetine (n=40) or tricyclic antidepressants (n=47) for the entire duration of the pregnancy. In the first study, many of the children were exposed to antidepressants only during the first trimester. As in the first study, no differences were observed between exposed and non-exposed children examined between 15 and 71 months of age. Of note, children exposed to longer or more frequent episodes of maternal depression after delivery had lower scores on measurements of IQ and language, indicating that exposure to maternal depression may be more deleterious than prenatal exposure to medications.

A new study from Dr. Shaila Misri and her colleagues at the University of British Columbia has prospectively examined the relationship between prenatal antidepressant exposure and behavior in a group of 4-year-old children. In this study, outcomes were compared between children with prenatal exposure to SSRIs (n=22) and children of healthy, non-depressed mothers with no medication exposure (n=14); both groups were initially enrolled during pregnancy and were evaluated again when their children were four years old. The mothers were treated for depression and/or anxiety and took the following SSRIs: fluoxetine (n=5), paroxetine (n=14), and sertraline (n=3). Nine of the women also took clonazepam in conjunction with the SSRI. Standardized parent and caregiver questionnaires including the Child Behavior Checklist and a clinical measure of mother-child interactions (scored by a blinded rater) were used to assess levels of internalizing behaviors, i.e. depression, anxiety, withdrawal. Maternal mood and anxiety levels were assessed using the Hamilton Rating Scales for Anxiety and Depression.

Levels of internalizing behaviors, as reported by parents and other caregivers and as rated by a clinician, did not differ significantly between 4-year-old children with and without prenatal SSRI exposure. Although the study was small in size, the results are encouraging. Like the two previous studies from the Motherisk program, these findings support the hypothesis that in utero exposure to SSRI antidepressants has no long-term negative effects on the child. While these studies are reassuring, these data are preliminary. Furthermore, it should be noted that effects of antidepressant exposure may appear later in a child’s life. Clearly further investigation into the long-term neurobehavioral effects of prenatal exposure to antidepressants as well as other psychotropic medications is warranted.

While medication exposure was not associated with increased levels of internalizing behaviors in the current study, the authors observed a relationship between maternal mood and anxiety and internalizing behaviors in their children. Mothers with higher levels of depression and anxiety at the time of evaluation reported more internalizing behaviors in their children than mothers who did not have symptoms of depression or anxiety. These findings are consistent with a large number of previous reports in the medical literature documenting the negative impact of maternal depression on children. It is noteworthy that in this study all of the 22 mothers who used antidepressants during pregnancy continued to take them four years later and that despite treatment over half of the women had clinically significant symptoms of depression or anxiety at the time of evaluation. This suggests that for many women who decide to use antidepressants during pregnancy depression is a recurrent or chronic illness. Moreover these findings indicate that exposure to relapsing or chronic maternal depression or anxiety may have a more significant impact on child well-being than exposure to antidepressants in utero. Other studies have also suggested that depression itself may produce certain physiologic changes during pregnancy that may have long-term consequences for the child (Bonari 2004).

Ruta Nonacs, MD PhD

Position Statement of the Canadian Pediatric Society, Maternal Depression and Child Development, Paediatrics & Child Health 2004; 9(8): 575-583

Nulman I, Rovet J, Stewart DE, Wolpin J, Gardner HA, Theis JGW, Kulin N, Koren G: Neurodevelopment of children exposed in utero to antidepressant drugs. N Engl J Med 1997; 336:258-262

Nulman I, Rovet J, Stewart DE, Wolpin J, Pace-Asciak P, Shuhaiber S, Koren G: Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: a prospective, controlled study. Am J Psychiatry 2002; 159:1889-1895

Misri S, Reebye P, Kendrick K, Carter D, Ryan D, Grunau RE, Oberlander TF. Internalizing behaviors in 4-year-old children exposed in utero to psychotropic medications. Am J Psychiatry. 2006 Jun;163(6):1026-32