New-generation antiepileptic drugs during pregnancy and the risk of attention-deficit hyperactivity disorder: A scoping review

The use of maternal antiepileptic drug (AED) during pregnancy is associated with an increased risk of cognitive adverse effects among the offspring. As new-generation AEDs continue to enter the market, evidence on their safety during pregnancy is limited yet necessary. To date, there are no published reviews summarizing the evidence of new-generation AED exposure in utero and the development of attention deficit-hyperactivity disorder (ADHD) in the offspring. The objective of this scoping review is to summarize the available evidence on the risk of ADHD after maternal exposure to new-generation AEDs during pregnancy. We searched EMBASE and MEDLINE for articles published from January 1988 to April 2020. New-generation AEDs were considered if marketed after 1988. ADHD was defined as attention-deficit hyperactivity disorder, hyperkinetic disorder, hyperkinesis, or conduct disorder. Of the total articles screened (n = 805), eight publications were finally included (seven cohort studies and one systematic review). Across the studies, the sample size of pregnant women exposed to AEDs ranged from 1 to 1383. Monotherapy was examined in six studies (mostly lamotrigine), while only two studies examined polytherapy. The included studies reported a range of adjusted relative risks, from 0.84 [0.59-1.19] to 1.63 [0.41-6.06]. Lamotrigine monotherapy holds the largest body of evidence, concluding that no significant risk of ADHD exists among the offspring. However, the available evidence is considered scarce and has several methodological limitations. Disentangling the effect of AEDs from epilepsy itself and examining polytherapies are challenges that merit additional investigations. Further comparative safety studies with longer follow-up periods and large sample sizes are needed to accurately quantify the true impact of new-generation AED exposure during pregnancy and ADHD in children.