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.
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.
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).
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.
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