Objective: Determine if differential long-term neurodevelopmental effects exist across commonly used antiepileptic drugs (AEDs). Background The primary outcome (age 6 year IQ) of the NEAD study and other cognitive findings at this age are reported here. Preliminary findings at age 3 were previously reported (Meador et al. NEJM 2009). Design/Methods: Pregnant women with epilepsy on AED monotherapy (carbamazepine, lamotrigine, phenytoin, or valproate) were enrolled in a prospective observational multicenter study in the USA and UK from 1999-2004. Multivariate analyses were conducted on intent-to-treat (n=310) and completer samples (n=224) with appropriate follow up analyses and secondary analyses of other cognitive measures. Results: Children exposed to valproate (adjusted mean IQ = 99) had significantly lower IQ scores than children in each of the other AED groups (carbamazepine = 105, lamotrigine = 108, phenytoin = 106). Children in the valproate group also performed more poorly vs. each of the other three AEDs on measures of verbal abilities and memory, and more poorly vs. lamotrigine on measures of non-verbal and executive functions. Valproate dose was negatively associated with IQ, verbal, non-verbal, memory, and executive functions, but the other AEDs did not demonstrate a dose relationship. Age 6 IQ correlated positively with IQ at earlier ages, and IQ scores improved with age across all AEDs. Verbal abilities were impaired compared to non-verbal abilities for all AEDs combined and for each individual AED except phenytoin. Children exposed to peirconception folate exhibited higher IQ (108 vs. 102 for those not receiving folate). Conclusions: Fetal valproate exposure is associated with lower IQ and reduced cognitive abilities across a range of cognitive domains at age 6 years. Verbal abilities may be impaired by several commonly used AEDs. Periconceptional folate may have positive effects on cognitive outcomes. Many unanswered questions remain, and additional research is needed. Supported by: NIH [NS038455 and NS050659] and UK Epilepsy Research Foundation [RB219738]. Disclosure: Dr. Meador has received research support from Cyberonics, Neuropace, Pfizer, and UCB Pharma. Dr. Baker has received personal compensation for activities with UCB as a speaker. Dr. Baker has received research support from UCB and Sanofi Aventis. Dr. Browning has nothing to disclose. Dr. Cohen has received personal compensation for activities with the Children9s Memory Scale. Dr. Brombley has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals, Inc. Dr. Brombley has received research support from Sanofi-Aventis Pharmaceuticals, Inc. Dr. Clayton-Smith has received personal compensation in an editorial capacity for Clinical Dysmophology. Dr. Kalayjian has received personal compensation for activites with GlaxoSmithKline as a speaker. Dr. Kanner has received research support from Pfizer Inc. Dr. Liporace has received personal compensation for activities with UCB Pharmaceuticals as a speaker. Dr. Pennell has nothing to disclose. Dr. Privitera has received personal compensation for activities with UCB Pharmaceuticals and GSK as a consultant and speaker.Dr. Privitera has received research support from UCB Pharmaceuticals and Eisai. Dr. Loring received personal compensation from NeuroPace as a consultant.

Objective: To examine outcomes at age 4.5 years and compare to earlier ages in children with fetal antiepileptic drug (AED) exposure. Methods: The NEAD Study is an ongoing prospective observational multicenter study, which enrolled pregnant women with epilepsy on AED monotherapy (1999–2004) to determine if differential long-term neurodevelopmental effects exist across 4 commonly used AEDs (carbamazepine, lamotrigine, phenytoin, or valproate). The primary outcome is IQ at 6 years of age. Planned analyses were conducted using Bayley Scales of Infant Development (BSID at age 2) and Differential Ability Scale (IQ at ages 3 and 4.5). Results: Multivariate intent-to-treat (n = 310) and completer (n = 209) analyses of age 4.5 IQ revealed significant effects for AED group. IQ for children exposed to valproate was lower than each other AED. Adjusted means (95% confidence intervals) were carbamazepine 106 (102–109), lamotrigine 106 (102–109), phenytoin 105 (102–109), valproate 96 (91–100). IQ was negatively associated with valproate dose, but not other AEDs. Maternal IQ correlated with child IQ for children exposed to the other AEDs, but not valproate. Age 4.5 IQ correlated with age 2 BSID and age 3 IQ. Frequency of marked intellectual impairment diminished with age except for valproate (10% with IQ <70 at 4.5 years). Verbal abilities were impaired for all 4 AED groups compared to nonverbal skills. Conclusions: Adverse cognitive effects of fetal valproate exposure persist to 4.5 years and are related to performances at earlier ages. Verbal abilities may be impaired by commonly used AEDs. Additional research is needed.

Offspring of women with epilepsy (WWE) on AEDs are at increased risks for major congenital malformations and reduced cognition. They may be at risk for other adverse neonatal outcomes. Women with epilepsy on carbamazepine (CBZ), lamotrigine (LTG), phenytoin (PHT), or valproate (VPA) monotherapy were enrolled in a prospective, observational, multicenter study of the neurodevelopmental effects of AEDs. The odds ratio for small for gestational age (SGA) was higher for VPA vs. PHT, VPA vs. LTG, and CBZ vs. PHT. Microcephaly rates were elevated to 12% for all newborns and at 12 months old, but normalized by age 24 months. Reduced Apgar scores occurred more frequently in the VPA and PHT groups at 1 min, but scores were near normal in all groups at 5 min. This study demonstrates increased risks for being born SGA in the VPA and CBZ groups, and transiently reduced Apgar scores in the VPA and PHT groups. Differential risks among the AEDs can help inform decisions about AED selection for women during childbearing years.

Background:Breastfeeding is known to have beneficial effects, but there is concern that breastfeeding during antiepileptic drug (AED) therapy may be harmful to cognitive development. Animal and human studies have demonstrated that some AEDs can adversely affect the immature brain. However, no investigation has examined effects of breastfeeding during AED therapy on subsequent cognitive abilities in children.Methods:The Neurodevelopmental Effects of Antiepileptic Drugs Study is an ongoing prospective multicenter observational investigation of long-term effects of in utero AED exposure on cognition. Between 1999 and 2004, we enrolled pregnant women with epilepsy who were taking a single AED (carbamazepine, lamotrigine, phenytoin, or valproate). We recently reported on differential AED effects on age 3 year cognitive outcomes. In this report, we focus on the effects of breastfeeding during AED therapy on age 3 cognitive outcomes in 199 children.Results:A total of 42% of children were breastfed. IQs for breastfed children did not differ from nonbreastfed children for all AEDs combined and for each of the 4 individual AED groups. Mean adjusted IQ scores (95% confidence intervals) across all AEDs were breastfed = 99 (96–103) and nonbreastfed = 98 (95–101). Power was 95% to detect a half SD IQ effect in the combined AED analysis, but was inadequate within groups.Conclusions:This preliminary analysis fails to demonstrate deleterious effects of breastfeeding during AED therapy on cognitive outcomes in children previously exposed in utero. However, caution is advised due to study limitations. Additional research is needed to confirm this observation and extend investigations to other AEDs and polytherapy.