Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study

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, p=0·0045), non-verbal ability (r=-0·42, p=0·0028), memory (r=-0·30, p=0·0434), and executive function (r=-0·42, p=0·0004), but other antiepileptic drugs were not. Age-6 IQ correlated with IQs at younger ages, and IQ improved with age for infants exposed to any antiepileptic drug. Compared with a normative sample (173 [93%] of 187 children), right-handedness was less frequent in children in our study overall (185 [86%] of 215; p=0·0404) and in the lamotrigine (59 [83%] of 71; p=0·0287) and valproate (38 [79%] of 40; p=0·0089) groups. Verbal abilities were worse than non-verbal abilities in children in our study overall and in the lamotrigine and valproate groups. Mean IQs were higher in children exposed to periconceptional folate (108, 95% CI 106-111) than they were in unexposed children (101, 98-104; p=0·0009).

Interpretation: Fetal valproate exposure has dose-dependent associations with reduced cognitive abilities across a range of domains at 6 years of age. Reduced right-handedness and verbal (vs non-verbal) abilities might be attributable to changes in cerebral lateralisation induced by exposure to antiepileptic drugs. The positive association of periconceptional folate with IQ is consistent with other recent studies.

Figure 1. Relation between age-6 IQ and standardised dose of every antiepileptic drug during pregnancy

Therapeutic dosages (mg per day) vary between antiepileptic drugs, so doses were standardised to allow comparisons; ranges within each antiepileptic drug and total-enrolled group were used in following calculation: 100 × (observed dose-mini mum dose) ÷ range of doses (ie, maximum-mini mum). Note that this calculation is based on the total-enrolled sample, but scatter plots here depict only the subjects tested at 6 years of age. Correlations are parametric Pearson correlations; non-parametric rank correlations were much the same. Age-6 IQ=IQ score at 6 years of age. IQ=intelligence quotient.

Figure 2. Relation between age-6 IQ and maternal IQ for every antiepileptic drug during pregnancy

Correlations are parametric Pearson correlations; non-parametric rank correlations were much the same. Age-6 IQ=IQ scores at 6 years of age. IQ=intelligence quotient.

Figure 3. Child IQ at 6 years, by exposure to maternal antiepileptic drug use and periconceptional folate

Mean (95% CIs) are shown for folate (solid lines) and no folate (dashed lines). For carbamazepine, 56 children were exposed to periconceptional folate (mean IQ 106, 95% CI 102–110) and 38 children were not (103, 98–107); for lamotrigine 60 children were exposed to periconceptional folate (111, 108–115) and 40 children were not (103, 98–107); for phenytoin, 23 children were exposed to periconceptional folate (112, 107–118) and 32 children were not (103, 98–108); for valproate, 40 children were exposed to periconceptional folate (98, 94–103) and 22 children were not (96, 91–102); for all antiepileptic drugs combined, 179 children were exposed to periconceptional folate (107, 105–109) and 132 children were not (102, 99–105). Appendix p 7 shows means and analyses for dose effects. IQ=intelligence quotient.