Elsevier

The Lancet Neurology

Volume 12, Issue 3, March 2013, Pages 244-252
The Lancet Neurology

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

https://doi.org/10.1016/S1474-4422(12)70323-XGet rights and content

Summary

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.

Funding

US National Institutes of Health, UK Epilepsy Research Foundation.

Introduction

Antiepileptic drugs are among the most common teratogens prescribed to women of childbearing potential.1 Knowledge of antiepileptic drug teratogenicity has increased in the past decade, including a concern that valproate is associated with impaired cognitive outcomes.2, 3 Based largely on our previously published analysis3 of outcomes at 3 years of age, the US Food and Drug Administration issued a warning that fetal valproate exposure is associated with impaired cognitive outcomes.4 In this study, our primary aim was to determine how fetal exposure to different antiepileptic drugs affect intelligence quotient (IQ) at 6 years of age (age-6 IQ). Compared with measurements done at younger ages, age-6 IQ is a more stable measure, more strongly related to adult IQ, and more predictive of school performance.5 Thus, understanding whether differences at 3 years of age persist to 6 years is important. In addition, we present a more comprehensive assessment of other cognitive domains than can be assessed at younger ages, and test the hypothesis that antiepileptic drugs can change cerebral lateralisation.

Section snippets

Study design and participants

The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study was a prospective observational investigation with masked cognitive assessment. We enrolled pregnant women with epilepsy who were receiving antiepileptic drug monotherapy (ie, carbamazepine, lamotrigine, phenytoin, or valproate) between October, 1999, and February, 2004, from 25 epilepsy centres in the UK and the USA. No other antiepileptic drugs were used in adequate numbers to include in the assessments. We excluded women

Results

We included 305 mothers and 311 livebirths (six twin pairs) in the primary analysis. Table 1 shows baseline maternal characteristics for the total-enrolled sample and appendix p 5 shows maternal characteristics for the age-6-completer sample. We interviewed all mothers about compliance, reviewed all diaries, and assessed antiepileptic drug levels for 229 (75%) mothers. We noted significant associations between antiepileptic drug group and maternal IQ, maternal education, dose, epilepsy type,

Discussion

Similar to our findings in children aged 3 years and 4·5 years,3, 16 children with fetal exposure to valproate had reduced IQ (7–10 points) at 6 years compared with other commonly used antiepileptic drugs (ie, carbamazepine, lamotrigine, and phenytoin). Valproate exposure was also associated with worse verbal and memory abilities compared with the other antiepileptic drugs, and worsened non-verbal and executive functions compared with lamotrigine. Teratogens act in a dose-dependent manner and

References (30)

  • N Bayley

    Bayley scales of infant development

    (1993)
  • MJ Cohen

    The children's memory scale

    (1997)
  • GA Gioa et al.

    Behavior rating inventory of executive function

    (2000)
  • M Korkman et al.

    NEPSY: a developmental neuropsychological assessment

    (1998)
  • R Brownell

    Expressive one-word picture vocabulary test

    (2000)
  • Cited by (0)

    Members listed in appendix

    View full text