While much data focuses on the risk of prenatal exposure to antiepileptic drugs (AEDs) and the risk of congenital malformations, there is a growing body of literature to indicate that that exposure to certain antiepileptic drugs, most notably valproic acid (VPA, Depakote) during critical periods of development may be associated with long-lasting neurodevelopmental deficits across multiple domains. In contrast, other studies suggest that prenatal exposure to the newer AEDs (e.g., lamotrigine, leviceteram) appear to pose little risk in terms of neurodevelopmental outcomes.
Launched in 2012, the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is a prospective, observational investigation of neurodevelopmental outcomes in the children of mothers with epilepsy. In this study, pregnant women were recruited from 20 US epilepsy centers, and their children have been followed prospectively from birth to six years of age. A recent report details the assessments of children at two years of age.
The Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) was used to assess neurodevelopmental outcomes. The analysis included BSID-III assessments from 292 children of women with epilepsy and 90 children of healthy women. Among women with epilepsy most received monotherapy with either lamotrigine (n=97 ) or levetiracetam (n=70). Twenty-five of 55 using polytherapy used lamotrigine plus levetiracetam.
The researchers found no differences between the two groups across the five BSID-III domains (language, motor, cognitive, social-emotional, and general adaptive). Maternal anxiety, depression, and perceived stress were all associated with worse outcomes for the cognitive, social-emotional, and general adaptive domains. In a secondary analysis where they looked at the association between third trimester antiepileptic drug (AED) blood levels and BSID-III scores, they did observe that higher AED levels were associated with lower scores of motor and general adaptive functioning.
These findings are encouraging and suggest that the newer AEDs, specifically lamotrigine and levetiracetam, are not associated with worse neurodevelopmental outcomes, although there may be some shifts in motor and general adaptive functioning in children exposed to higher doses of these medications. The authors do point out that these findings, while reassuring, must be interpreted cautiously, with the understanding that neuropsychological assessments conducted at two years of age are not as strongly associated with adolescent and adult functioning as assessments performed in older children.
Even with those limitations, we can clearly see that lamotrigine is a much safer alternative than valproic acid (Depakote) which has been associated with adverse neurodevelopmental sequelae, including lower IQ, developmental delays and increased risk of autism spectrum disorders, autistic traits and/or attentional problems in exposed children.
Ruta Nonacs, MD PhD
Meador KJ, Cohen MJ, Loring DW, May RC, Brown C, Robalino CP, Matthews AG, Kalayjian LA, Gerard EE, Gedzelman ER, Penovich PE, Cavitt J, Hwang S, Sam M, Pack AM, French J, Tsai JJ, Pennell PB; Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs Investigator Group. Two-Year-Old Cognitive Outcomes in Children of Pregnant Women With Epilepsy in the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs Study. JAMA Neurol. 2021 Aug 1;78(8):927-936.