Fetal Antiepileptic Drug Exposure and Cognitive Outcomes at Age 6 Years (NEAD Study): A Prospective Observational Study
03/2013
Journal Article
Authors:
Meador, K.J.;
Baker, G.A.;
Browning, N.;
Cohen, M.J.;
Bromley, R.L.;
Clayton-Smith, J.;
Kalayjian, L.A.;
Kanner, A.;
Liporace, J.D.;
Pennell, P.B.;
Privitera, M.;
Loring, D.W.;
Group, N.E.A.D.Study
Secondary:
Lancet Neurol
Volume:
12
Pagination:
244-252
URL:
http://www.ncbi.nlm.nih.gov/pubmed/23352199
Keywords:
Anticonvulsants; Anticonvulsants/adverse effects; Child Development/drug effects; Cognition/drug effects; Epilepsy/drug therapy; Phenytoin; Phenytoin/adverse effects; Pregnancy; Triazines; Triazines/adverse effects; Triazines/therapeutic use
Abstract:
{BACKGROUND: Many women of childbearing potential take antiepileptic drugs, but the cognitive effects of fetal exposure are uncertain. We aimed to assess effects of commonly used antiepileptic drugs on cognitive outcomes in children up to 6 years of age. METHODS: In this prospective, observational, assessor-masked, multicentre study, we enrolled pregnant women with epilepsy on antiepileptic drug monotherapy (carbamazepine, lamotrigine, phenytoin, or valproate) between October, 1999, and February, 2004, at 25 epilepsy centres in the UK and the USA. Our primary outcome was intelligence quotient (IQ) at 6 years of age (age-6 IQ) in all children, assessed with linear regression adjusted for maternal IQ, antiepileptic drug type, standardised dose, gestational birth age, and use of periconceptional folate. We also assessed multiple cognitive domains and compared findings with outcomes at younger ages. This study is registered with ClinicalTrials.gov, number NCT00021866. FINDINGS: We included 305 mothers and 311 children (six twin pairs) in the primary analysis. 224 children completed 6 years of follow-up (6-year-completer sample). Multivariate analysis of all children showed that age-6 IQ was lower after exposure to valproate (mean 97, 95% CI 94-101) than to carbamazepine (105, 102-108; p=0·0015), lamotrigine (108, 105-110; p=0·0003), or phenytoin (108, 104-112; p=0·0006). Children exposed to valproate did poorly on measures of verbal and memory abilities compared with those exposed to the other antiepileptic drugs and on non-verbal and executive functions compared with lamotrigine (but not carbamazepine or phenytoin). High doses of valproate were negatively associated with IQ (r=-0·56, p<0·0001), verbal ability (r=-0·40
