Use of Antipsychotics During Pregnancy: Pregnant Women Get Sick-Sick Women Get Pregnant.

The blunt subtitle focuses attention on the pregnant woman as “the last true therapeutic orphan.”1(p227) Because of ethical,medicolegal, and fetal safety concerns, theyhavebeenexcluded from treatment studies. Pregnantwomen constitute a disadvantagedpopulation thathasbeen“protected” fromparticipation in research, only to carry the burden, with their prescribers, of apaucityof information to inform treatment decisionmaking. Through the TRxeating For Two initiative, the Centers for Disease Control and Prevention has promoted a conceptual shift from the dogma that medications during pregnancy must be avoided to their use to “improve the health of women and babies by working to identify the safest treatment options for themanagement of common conditions before and during pregnancy” (http://www.cdc.gov/pregnancy/meds/treatingfortwo /facts.html). Medication use by pregnant women is increasing across timeandnowisnearlyuniversal. Theaveragenumberofdrugs (over the counter or prescribed, excluding vitamins andminerals) used any time in pregnancy increased from 2.5 in 1976 to 1978 to4.2 in 2006 to2008. In 2008, nearly 94%ofwomen took at least 1 medication during pregnancy; in the first trimester, 82.3% used at least 1 and 27.6% reported taking 4 or more medications.2 These staggering statistics highlight the public health importance of research to inform pharmacotherapy for pregnant women. Forwomenwithschizophreniaandbipolardisorder,medications are themainstay of treatment, and the recurrence risk following discontinuation is high.3 In this issue of JAMA Psychiatry, Huybrechts et al4 present results from theMedicaid database (n = 1 341 715) to provide critical new information on the risk for overall birth defects and specifically cardiacmalformations in infantsborn topregnantwomen treated with antipsychotics (APs). The sophisticatedpharmacoepidemiologicmethodologycomprehensively tackles themajorchallenge in observational studies, that is, confounding byunderlying disease factors that are (like the APs) potentially associated with pregnancy outcomes. The task is to separate the effect of 2 exposures (APs and psychiatric disease) on the reproductive outcomes. The authors use propensity score stratification,whichallowswomenwithsimilar risk factors (eg, obesity, other drug use, smoking), butwhodiffer onAP exposure, to be compared. This strategy also addresses the differences inwomenwithpsychiatricdisorderswhochoose to continueAPtreatmentcomparedwith thosewhodonotonabroad range of potential confounders. The richness of theMedicaid database allowed for adjustment for potential confounders through the creationof 50equal-sized strata basedon thedistribution among the treated women of more than 250 variables in high-dimensional analyses. The authors found that associations between AP exposureandbirthdefectswereattenuatedafteradjustment forconfounding, which implies that these variables, rather than AP exposure, account for much of the effect on congenital malformations.Unadjusted analyses suggested a significantly increased risk for malformations overall for atypical AP exposure (relative risk [RR], 1.36; 95% CI, 1.24-1.50) but not for typical AP exposure (RR, 1.17; 95%CI, 0.81-1.68). After adjustment for confounding (which accounted for proxies of the severityof theunderlying illness, associatedbehaviors, andother potential confounding variables), the RRwas near the null at 1.05 (95%CI,0.96-1.16) for atypicalAPexposureand0.90 (95% CI, 0.62-1.31) for typical AP exposure. The results for cardiac malformations were similar. This landmark report, with the largest population of women exposed to APs published to date to our knowledge, demonstrates that exposure to APs (other than risperidone) does not significantly increase the risk for birth defects, which has been a major source of concern for women and prescribers. Several methodologic aspects of this study are important to highlight. The definition of exposure was filling Related article page 938 Editorial Opinion