Are newer antiepileptic drugs associated with improved safety in pregnancy compared to older antiepileptic drugs?

Commentary As a group, antiepileptic drugs (AEDs) are associated with an increased risk of major congenital malformations (MCMs) (1). Older AEDs are the best studied. Valproate (VPA) is consistently associated with an increased risk of MCMs including an increased risk of spina bifida (2). Phenobarbital (PB) exposure increases the risk of MCMs, including oral clefts (3). Although not consistent among published studies, some have found an increased risk of neural tube defects in association with carba-mazepine (CBZ) therapy (4, 5). Less is known about the risk of MCMs in association with newer AEDs (6). Better understanding of these agents' impact on the developing fetus is critical, as AEDs such as lamotrigine (LTG), levetiracetam (LEV), and topiramate (TPM) are being used in increasing numbers. Internationally, the epilepsy community has established different registries to address this issue. The North American Registry was established in 1997 (7). Women using AEDs for any indication are enrolled early in pregnancy. Gathering information on AEDs used for any indication is important , as many AEDs are used for multiple indications including headaches, pain, and mood disorders. Hopefully, with increasing enrollment, there will be enough numbers to do analyses that compare outcomes among the different indications. Hernández-Díaz and colleagues (7) presented updated analyses from the North American Pregnancy Registry. The outcomes of interest were MCMs diagnosed before 12 completed weeks after birth. It is important to note that different registries have variable periods of follow-up. For example, the EURAP register collects information through 12 months of age (8). Excluded were 1) minor anomalies, birthmarks, deformities , and anatomic findings by ultrasound not identified by examining pediatrician, 2) complications of prematurity, 3) genetic disorders, and 4) chromosomal abnormalities. The investigators identified multiple reference groups: 1) the primary reference group was women exposed to LTG; 2) an internal reference group of pregnant women without epilepsy, not taking an AED who have been recruited among friends and family of AED exposed subjects; and 3) an external reference group of 206,224 infants born at Brigham and Women's Hospital in Boston, MA. Using the LTG group as an internal comparison provides advantages, including offering a direct comparison among AEDs and minimizing confounding. The investigators used a multivariate logistic regression analysis. Risk ratios (RRs) and 95% confidence intervals (CIs) were estimated. Multiple confounders were controlled for, OBJECTIVE: To assess the safety of the newer antiepileptic drugs (AEDs) during pregnancy. METHODS: The study population …