Teratogenicity of antiepileptic dual therapy: Dose-dependent, drug-specific, or both?

To determine the relative risk (RR) of major congenital malformations (MCMs) in infants with antenatal exposure to antiepileptic drug (AED) dual therapy and to explore the influence of specific AEDs vs dose.

All completed pregnancies prospectively enrolled in the Kerala Registry of Epilepsy and Pregnancy from 1998 until December 2013 on AED dual therapy exposure during the first trimester were analyzed for the outcome, MCMs. Dose was expressed as ratio of prescribed to daily defined dose (PDD/DDD), and the RR for malformation was referenced to lamotrigine monotherapy.

Of 1,688 completed pregnancies, 368 women were on dual therapy. The risk of MCM with dual therapy was 1.6 times more than with monotherapy (p = 0.0015). The frequency of renal, alimentary, and skeletal malformations was higher with dual therapy, while cardiac malformations were more common with monotherapy. The risk of MCM was highest with topiramate dual therapy (14.82, 95% confidence interval [CI] 1.88-113.83). No MCMs were seen with levetiracetam or lamotrigine dual therapy. There was a marked reduction in the risk of MCM when dual therapies involving topiramate or valproate were excluded (RR 1.78, 95% CI 1.00-3.15). The risk of MCM with dual therapy was higher even at lower doses (8.2%, PDD/DDD 0.5-1), and the subsequent dose-dependent increment was less profound than with monotherapy.

Our data indicate that the excess risk of dual therapy over monotherapy is contributed largely by topiramate or valproate. The complex pharmacokinetic and pharmacodynamic effects of dual therapy adversely influence MCM risk.