More information is available on the teratogenicity of psychiatric medications than perhaps any other class of medications women use during pregnancy, with the most data available for antidepressants. To date, many would argue that no signals for significant teratogenicity across psychiatric medications have been identified – with a few important exceptions such as sodium valproate and lithium carbonate. While data from smaller prospective studies and large administrative databases fail to demonstrate a teratogenic risk of typical antipsychotics, less information is available on the risk associated with newer atypical antipsychotics, such as olanzapine and aripiprazole.

Data also are certainly sparse regarding the potential for long-term neurobehavioral adverse effects of fetal exposure to older and newer antipsychotics, as is the case for most psychiatric medicines. Risk for longer-term neurobehavioral sequelae of fetal exposure to psychiatric medications remains a research frontier, which when mapped, will inform clinical decisions regarding use of these agents during pregnancy.

A prospective study recently published online in the Archives of General Psychiatry has addressed the critical question of long-term neurobehavioral sequelae of fetal exposure to antipsychotic medications. Other than some very preliminary studies dating back several decades, this is one of the first studies to evaluate the longer-term effects of prenatal exposure to antipsychotics.

The study compared neurobehavioral outcomes among 309 mothers with different psychiatric diagnoses and their infants at 6 months post partum: 22 infants had been exposed to antipsychotics, 202 had been exposed to antidepressants, and 85 had not been exposed to any psychotropic medications. Diagnoses among the women in all three groups included depression, bipolar disorder, anxiety disorder, and psychotic disorder. After confounding factors were controlled for, scores on a standardized neuromotor exam looking at parameters of posture, tone, reflexes, and motor skills at 6 months were significantly lower among infants exposed to antipsychotics than in infants in the other two groups (Arch. Gen. Psychiatry 2012 April [doi: 10.1001/archgenpsychiatry.2012.160]).

However, scores also were affected by maternal psychiatric history, including depression, psychosis, or chronicity and severity of maternal psychiatric illness. The authors noted that they could not completely adjust for confounders, and that "disentangling" the effects of medication from the effects of maternal illness remained a challenge. In addition, with a sample of only 12 infants exposed to multiple atypical antipsychotics (aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone), 9 exposed to the typical antipsychotic haloperidol, and 1 exposed to both haloperidol and ziprasidone, the results are not conclusive and must be interpreted cautiously.

Nonetheless, these investigators should be credited with addressing, even in a preliminary fashion, such an important area with such great clinical implications. Their findings complement the growing amount of existing information on the risk for organ malformations and perinatal sequelae associated with exposure to psychiatric medications during pregnancy.

What then can the clinician take away from this study, and does it inform the care of psychiatrically ill women during pregnancy?

I would argue that even if the authors were able to adjust for the confounders and they identified an even clearer signal suggesting risk, one must consider that this is a population of women who are treated with these medications to stay well during pregnancy and are at an increased risk for postpartum illness if they fail to sustain emotional well-being during pregnancy.

In the literature, depression during pregnancy has been identified as the strongest predictor of postpartum depression, and postpartum affective illness is one of the strongest predictors of long-term cognitive development in the child. This is particularly true for women with bipolar disorder.

Antipsychotic medications are used to treat women with bipolar disorder, psychotic illness, and severe depression, frequently in combination with other psychiatric medications, to sustain emotional well-being during pregnancy. Hence, even if the potential adverse effects of the medicine are equally balanced against the importance of keeping women well, when making a risk-benefit decision, perhaps the scale tilts further because of the extent to which maternal emotional well-being during pregnancy predicts the risk for postpartum psychiatric illness.

The results of the Archives study open the door for future studies that will delineate the long-term effects of prenatal exposure to antipsychotics, and will parse out the effects of other potential confounders like maternal psychiatric illness. Learning more about the effects of fetal exposure to atypical antipsychotics is particularly critical because of the increasing number of psychiatric disorders for which this class of medicine is being used, including bipolar disorder, major depression, and various anxiety disorders.

With growing numbers of women taking atypical antipsychotics, and with half of pregnancies remaining unplanned in this country, we established the National Pregnancy Registry for Atypical Antipsychotics at Massachusetts General Hospital, Boston. While registries such as this one will provide information regarding teratogenic potential, subjects who use these medicines during pregnancy also will give birth to a cohort of children who can be studied to more clearly delineate the long-term effects, if any, of in utero exposure to these medicines. But for clinicians today taking care of women with psychiatric disorders requiring this class of compounds, the message is that nothing can trump the importance of maternal euthymia; failure to sustain euthymia is the strongest predictor of postpartum illness and tips the scale from one of equipoise, to one where treatment becomes that much more imperative.

Dr. Cohen directs the perinatal psychiatry program at Massachusetts General Hospital, which provides information about pregnancy and mental health at www.womensmentalhealth.org. The National Pregnancy Registry for Atypical Antipsychotics is supported in part by manufacturers of these medicines.

Assessing Behavioral Effects of Fetal Exposure to Atypical Antipsychotics