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measured in 395 infants born to women with epilepsy152. In addition to paediatricians being
blinded to AED exposure, multiple confounders were taken into account. Unfortunately these
did not include maternal IQ. Valproate was associated with significantly lower mental and
motor developmental scores, compared with carbamazepine, but not with other AEDs used
in monotherapy. While maternal educational status was significantly correlated with motor
development in infants, mental development was not. The importance of including all
confounding variables was shown in a prior study from the same group where low maternal
IQ and maternal education as well as AED exposure were found to be associated with
significant impairment of intellectual and language functions in children of mothers with
epilepsy153.

The situation for the newer AEDs is even less clear, with very limited data being available
on their influence on cognitive functioning and other aspects of development. With regard to
lamotrigine data to date suggests less of an effect than for valproate. The Neurodevelopmental
Effects of Antiepileptic drugs (NEAD) study assessed IQ and multiple other cognitive
domains in children at six years of age. Mean IQ in the valproate group was reduced by 11
points compared with the lamotrigine group, 11 points compared with the phenytoin group
and 8 points compared with the carbamazepine group62. The association between valproate
use and IQ was dose dependent. Fetal valproate exposure was also significantly associated
with a wide range of cognitive deficits, including reduced measures of verbal ability, non-
verbal ability, memory and executive function that were also dose-related. Children’s IQs
were significantly related to maternal IQs among children exposed to carbamazepine,
lamotrigine and phenytoin but not among those exposed to valproate. That valproate is
associated with worse cognitive outcomes compared with lamotrigine and carbamazepine, in
particular with regard to language skills, has also recently been reported by other authors154-
157. A Cochrane review published in 2014 included 22 prospective cohort studies and six
registry-based studies. It concluded that the IQ of children exposed to valproate during
pregnancy was lower than in children born to women without epilepsy or with untreated
epilepsy. IQ for children exposed to valproate was on average 8.69 points lower than those
exposed to carbamazepine, 10.8 points lower than those exposed to lamotrigine and 9.25
points lower compared to phenytoin, with a dose effect being reported in six studies. The
magnitude of these results was felt to be sufficient to affect educational and occupational
outcomes later in life. No significant association was found between carbamazepine exposure
and development quotient or IQ158.

Recent data published by the Liverpool and Manchester Neurodevelopment Group suggests
that there may also an association between AED use during pregnancy and other
neurodevelopmental disorders such as Aspergers, ADHD, autistic spectrum disorders (ASD)
and dyspraxia. Neurodevelopmental disorders were more frequently seen in the children of
women with epilepsy (15 of 201, 7.46%) compared to control women (four of 214, 1.87%).
Although the numbers in each group were small, a differential effect of AED exposure was
seen, with valproate exposure being associated with an odds ratio for neurodevelopmental
disorders of 6.05 compared to the control group (P = 0.007). Lamotrigine was also associated
with a higher incidence of neurodevelopmental disorders than the control group (6.67%, odds
ratio 4.06), but this was not statistically significant (P = 0.1)159.

Similar results were described in a recent population-based study from Denmark, which also
found a higher incidence of ASD and childhood autism in children exposed to valproate
during pregnancy. In this study, from all children born alive in Denmark from 1996 to 2006
(total 665,615) 5437 children were identified with ASD, including 2067 with childhood
autism. In this population, 2644 were exposed to AEDs during pregnancy and 508 were
exposed to valproate. In women with epilepsy, the use of valproate during pregnancy was
associated with an increased absolute risk for ASD (4.15%; 95% CI 2.20–7.81%) and