While data accumulated over the last 30 years suggest that certain antidepressants may be used with relative safety during pregnancy, our knowledge regarding the risks of prenatal exposure to psychotropic medications is incomplete. Because neuronal migration and differentiation occur throughout pregnancy and into the early years of life, development of the central nervous system (CNS) remains particularly vulnerable throughout pregnancy.

Several studies have systematically investigated the impact of prenatal exposure to antidepressants on development and behavior in humans. The first of these studies followed a cohort of 135 children exposed to either tricyclic antidepressants or fluoxetine (Prozac) during pregnancy (most commonly during the first trimester) and compared these subjects to a cohort of non-exposed, non-depressed controls. No significant differences in IQ, temperament, behavior, reactivity, mood, distractibility, or activity level were observed between exposed and non-exposed children followed up to 7 years of age.

Another study from the same group followed a cohort of children exposed to fluoxetine (n=40) or tricyclic antidepressants (n=47) for the entire duration of the pregnancy and yielded similar results.

A new study from Nulman and colleagues at the Motherisk Program inTorontocontributes information on the impact of exposure to venlafaxine (Effexor) during pregnancy.  What distinguishes this study from the previous two is that this study also attempts to distinguish the effects of maternal depression from the effects of exposure to antidepressant.

In this study, participants were women who contacted the Motherisk program seeking information regarding the reproductive safety of medications, including antidepressants. Three groups of women with depression were selected: those who took venlafaxine during pregnancy (n=62, group 1), those who took selective serotonin reuptake inhibitors (SSRIs) during pregnancy (n=63, group 2), and those who discontinued pharmacotherapy before conception (n=54, group 3).  Group 4 (n=62) consisted of healthy pregnant women with no psychiatric history who called Motherisk to inquire about non-teratogens (e.g., acetaminophen).

Excluded were mothers exposed to polytherapy for depression or known teratogens (e.g., antiepileptic drugs), mothers with substance abuse (e.g., alcohol use disorders), mothers with other psychiatric conditions (e.g., schizophrenia), premature children (before 37 weeks of gestation), and mothers and/or children with medical conditions unrelated to in utero exposure that may affect cognitive outcomes (e.g., postnatal head trauma, encephalitis).

Data were collected prospectively.  At the time of first contact with Motherisk during pregnancy, information about maternal medical, genetic, and obstetric histories was collected. Information about pregnancy course, medication changes, perinatal outcomes, and breast-feeding was ascertained through a follow-up telephone call at 6 to 9 months after delivery. Information was also obtained regarding the severity, course, and treatment of depression at the time of the child’s assessment in order to identify potential confounding or predictive variables.  Depressive episodes were defined according to DSM-IV criteria and were diagnosed by the woman’s psychiatrist.

The children were assessed between 3 and 7 years of age.  A rater blinded to the mother’s group affiliation tested all children using a battery of age-appropriate standardized tests. The Wechsler Preschool and Primary Scale of Intelligence evaluated the children’s IQ.  Behavioral profiles were assessed by using the Child Behavior Checklist and Conners’ Parent Rating Scale, both completed by the mother.

Children from the four groups did not differ in gestational age or birth weight. Among the children exposed to antidepressants, 11.3% received a diagnosis of poor neonatal adaptation signs (i.e., jitteriness, poor tone, respiratory distress, weak or absent cry).

Children exposed to venlafaxine, SSRIs, and maternal depression during pregnancy had similar full-scale IQs (105, 105, and 108, respectively). The IQs of the venlafaxine and SSRI groups were lower than the IQs of the children of non-depressed mothers (112).

Groups 1, 2, and 3 had consistently, but non-significantly, higher rates of problematic behaviors than the children of non-depressed mothers.  The severity of maternal depressive symptoms during pregnancy and at the time of testing predicted child behavioral problems.  Maternal IQ and child sex predicted child IQ. Antidepressant dose and duration during pregnancy did not predict any cognitive or behavioral outcomes.

Although this study is relatively small in size, it is meticulously done, with prospective data gathered by blinded raters.  Most important is that this study included a group of women with histories of depression who had discontinued antidepressants prior to conception.  On all outcomes assessed, the children exposed to antidepressants did not differ significantly from the children who were born to mothers with histories of depression but who did not take antidepressants (group 3).  On all outcomes assessed, the children of non-depressed mothers did better than the children born to mothers with histories of depression, whether exposed to antidepressants or not.

This study failed to find an effect of antidepressant medication on children’s intellectual or behavioral outcomes. However, it did demonstrate that exposure to untreated maternal depression in utero and during early childhood is associated with worse cognitive and behavioral outcomes.

Ruta Nonacs, MD PhD

Nulman I, Koren G, Rovet J, et al.  Neurodevelopment of Children Following Prenatal Exposure to Venlafaxine, Selective Serotonin Reuptake Inhibitors, or Untreated Maternal Depression.  Am J Psychiatry 2012; 169: 1165–1174.