Adverse Pregnancy Outcomes Associated With Gestational Exposure to Antiepileptic Drugs

Major congenital malformation risks in association with gestational exposure to antiepileptic drugs (AEDs) have been extensively studied. Less information is available on other adverse outcomes associated with the use of these drugs during pregnancy. This article critically examines the risk of fetal loss, intrauterine growth retardation (IUGR), and preterm birth following gestational exposure to 14 AEDs, based on information obtained from a recent network meta-analysis of mostly nonrandomized, observational studies. The AEDs studied were carbamazepine, clobazam, clonazepam, ethosuximide, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbitone, phenytoin, primidone, topiramate, valproate, and vigabatrin. The results show that very few AEDs are significantly associated with each adverse outcome and that the implicated AEDs are different for different outcomes. Furthermore, when one discounts findings obtained in small sample analyses, almost no significant associations remain. Next, even these associations become questionable when one considers that they could have been due to confounding by indication. Finally, the few significant associations may have been false-positive findings because they were identified after performing a very large number of statistical tests. These caveats notwithstanding, guidance should err on the side of caution. Therefore, a conservative conclusion is that whereas analyses based on exposures in 2,000-4,000 pregnancies suggest that lamotrigine and carbamazepine are not associated with an increased risk of fetal loss, IUGR, and preterm birth, there is insufficient evidence to either firmly indict or firmly exonerate the other AEDs with regard to these outcomes.