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good evidence that minor anomalies, learning difficulties and other problems may also be
related to AED therapy. It has been found that the children of women with epilepsy, whether
or not they are taking AEDs, are at increased risk of minor anomalies140, and specific AED-
related fetal syndromes have been suggested for most of the older AEDs129,120,141. The types
of abnormalities found have included minor craniofacial and digital anomalies and growth
retardation. However, possibly except for valproate120,142, there is no real convincing evidence
that specific syndromes are associated with specific AEDs, hence the term ‘fetal-AED’
syndrome may be more appropriate. It is unclear what the influence of other variables is, such
as maternal epilepsy and hereditary factors. In any case such abnormalities, although
undesirable, have usually been felt in themselves to cause little disability. However, whether
or not they are markers for more diffuse problems, cognitive and behavioral upset is
increasingly being questioned in particular.

The effects of AEDs on long-term cognitive functioning of children exposed to AEDs in
utero have not been studied as extensively as major congenital malformations. An early
Cochrane review concluded that the majority of studies in this area are of limited quality and
that there is little evidence overall implicating one drug over another with respect to a
detrimental effect on development143. While previous studies have shown mean IQ to be
significantly lower in the children of women with epilepsy68,144,145 it is suggested that this is
independent of AED exposure. However, a growing number of retrospective and prospective
studies have found that developmental delay is more common in children born to mothers or
fathers with epilepsy. There is also an increasing body of evidence to suggest that these
effects vary by AED exposure, with valproate consistently being associated with poorer
outcomes, which are likely to persist long term. One study found that 16% of 224 children
who had been exposed to AEDs prenatally had additional educational needs compared with
11% of 176 exposed to no drugs (odds ratio 1.49; 95% CI 0.83–2.67%)146. A total of 30% of
those exposed to valproate, and 20% exposed to polytherapy containing valproate, had
additional educational needs. This compared with 3.2% and 6.5% exposed to carbamazepine
and other monotherapy regimes, respectively. In a more thorough investigation of partly the
same cohort of children the authors found that verbal IQ was significantly lower in children
exposed to valproate monotherapy (mean 83.6; 95% CI 78.2–89.0%; n = 41) than in
unexposed children (90.9; CI 87.2–94.6%; n = 80) or in children exposed to carbamazepine
(94.1; CI 89.6–98.5; n = 52) or phenytoin (98.5; CI 90.6–106.4; n = 21). Multiple regression
analysis revealed exposure to valproate, five or more tonic-clonic seizures in pregnancy and
low maternal IQ to be associated with lower verbal IQ after adjustment for confounding
factors. Doses of valproate above 800 mg/day were associated with lower verbal IQ than
lower doses. There was also a significant negative correlation between dysmorphic features
and verbal IQ in children exposed to valproate147. These results compare with those from
previous studies which have shown higher rates for developmental delay for infants exposed
prenatally to carbamazepine of between 8% and 20%143,148,149. In another study 24% of AED
exposed infants had a developmental disorder compared with 10.5% of non-exposed siblings.
Differences were noted between AEDs. However, infants exposed to carbamazepine,
phenytoin and valproate had significantly higher rates of developmental delay than infants
not exposed to AEDs150.

In a study from Finland the authors reported similar findings among a small number of
exposed infants where full scale IQ was low (<80) in four of 21 infants that had been exposed
to valproate (19%) and exceptionally low (<70) in two infants (10%). Of importance
however, the mothers of the valproate exposed group performed significantly worse on IQ
tests and also had significantly lower educational levels151.

A study from India recently addressed some of the above concerns. Using an Indian
adaptation of the Bayley Scale of Infant Development, motor and mental development were