Psychiatric Drugs, Pregnancy and Lactation: SSRIs and Neonatal Neurobehavior

March 15, 2004 from ObGynNews

By Lee S. Cohen, M.D.

With increasing recognition and treatment of depression in women during their childbearing years, more patients and their physicians are faced with the dilemma of whether to use antidepressants in pregnancy. The literature over the last decade has been relatively consistent regarding the absence of teratogenic effects associated with the use of selective serotonin reuptake inhibitors (SSRIs). The data have not been so straightforward regarding the potential risk for perinatal syndromes when these drugs are used during pregnancy.

An increasing number of studies have described syndromes occurring during the perinatal period in babies whose mothers used SSRIs. Symptoms ascribed to perinatal exposure to SSRIs have included tremulousness, increased motor activity, jitteriness, and heightened startle. One trial suggested that fluoxetine (Prozac, Sarafem) exposure during the latter part of pregnancy through labor and delivery was associated with higher rates of special care nursery admissions for what the authors called "poor neonatal adaption." But in another study, my colleagues and I found no evidence of neonatal toxicity in newborns exposed to fluoxetine at term that could be directly ascribed to exposure to this medicine.

Studies that have evaluated the effects of SSRIs on neonatal outcome have suffered from consistent methodologic limitations, the most notable being the failure to blind investigators evaluating the infants with regard to in utero drug exposure and the failure to take into account the potential impact of maternal mood disorder on acute neonatal outcome.

In a study published last month, 34 healthy, full birthweight newborns were evaluated in a prospective trial; 17 mothers took SSRIs during pregnancy and 17 were unexposed. The investigators noted that exposed newborns exhibited significantly more tremors, heightened levels of motor activity and tremulousness, and fewer changes in behavioral state during an hour-long observation period, compared with unexposed newborns (Pediatrics 113[2]:368-75, 2004).

While this is an important study, in which the evaluators were blinded, it is limited by its small sample size. Though both groups were matched for maternal use of cigarettes, alcohol, and marijuana during pregnancy, alcohol use was not insignificant, and four women on SSRIs used marijuana while pregnant.

Most notably, the study failed to include an assessment of maternal mood during pregnancy and did not control for the impact of maternal depression on the outcome variables measured.

The authors acknowledge the negative impact that maternal depression can have on neonatal outcome, though they do not acknowledge adequately how the failure to measure maternal depression in their study could have confounded it greatly. They note that maternal depression, "through its action as a stressor, may have an impact on fetal development through its effect on the hypothalamic-pituitary-adrenal axis, adrenocorticotropic hormones, and b-endorphins," and that infants of depressed mothers are at risk for physical anomalies and birth complications, delayed habituation of fetal heart rates, higher neonatal cortisol levels, higher levels of indeterminate sleep, and elevated norepinephrine levels."

They do cite an important study from the Motherisk program in Toronto indicating that postpartum mood is one of the strongest predictors of neurocognitive function in children assessed up to 6 years of age.

The authors suggest that milder forms of tremulousness in the extremities during the neonate's first week may reflect "CNS depression and/or stress/withdrawal from prenatal drug exposure," and that these findings "may be a harbinger of the persisting tremors found in SSRI-exposed infants at 6-40 months of age," as observed in a study last year (J. Pediatr. 142[4]:402-08, 2003). But that study was also limited by a small sample size and the failure to prospectively assess maternal mood during pregnancy.

We remain at a point where the literature fails to take into account one of the strongest predictors of newborn neurobehavior, namely maternal mood during pregnancy. Pending better controlled studies that do consider these factors, it would be unwise to use small confounded studies for making clinical decisions, and best to make treatment decisions based on individual clinical situations and patients' wishes.

Dr. Lee Cohen is a psychiatrist and director of the perinatal psychiatry program at Massachusetts General Hospital, Boston. He is a consultant for and has received research support from manufacturers of several SSRIs. He is also a consultant to Astra Zeneca, Lilly and Jannsen - manufacturers of atypical antipsychotics.

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Reviewed: 03/2006