The long-term neurodevelopmental effects of intrauterine antiepiletic drug exposure in children born to women with epilepsy
Epilepsy is the most common neurological disease with a prevalence of 5.25 per 1000 for
treated epilepsy. One third of this population are women of reproductive age.
Approximately 1 in 200 women that attend antenatal clinics in the United Kingdom are
receiving antiepileptic medication. At present it is difficult to provide pre-conceptual
advice regarding the safest antiepileptic medication to take during pregnancy.
Previous research has reported a 2-3 fold increase in major malformations in children
born to women with epilepsy, compared to the general population. A growing number
of both retrospective and prospective studies have documented the psychomotor and
cognitive functioning in children exposed to AEDs in utero, with conflicting results
reported. Some studies report a high prevalence of developmental delay and cognitive
dysfunction associated with AED exposure, others report a transient impairment, and
some studies report no deficit. Due to the wide variation of tests that have been applied
and the failure of a standardised approach it has been difficult to draw any meaningful
conclusions regarding the neurodevelopmental outcomes and the degree of risk
associated with intrauterine AED exposure especially for specific drug regimes.
The aim of this research was to investigate the long-term differential drug effects on
cognitive functioning in children born to women with epilepsy. This was the first large
scale study to use an adequate sized group and to provide a neuropsychological profile
for the differential drug effects in children aged between 6 months and 16 years, using
standardised tests and controlling for confounding factors. This was achieved by
assessing 356 children aged 6 months to 16 years born to women with epilepsy. Each
child received a medical examination that documented any malformations and
dysmorphic features associated with exposure to AEDs. The neurop~chological
assessment included the Wechsler Intelligence Scale for Children (WISC-III ), to assess
intellectual functioning, The Schedule of Growing Skills II (SGS II), to assess
development, the Rivermead Behavioural Memory Test for Children (RBMT -C), to
assess everyday memory functioning and in order to assess each child's behaviour each
parent was interviewed using the Vineland Adaptive Behaviour Scale (VABS) and stress
in the parent-child relationship was measured using the Parenting Stress Index (PSI).
The results for this study indicate that intrauterine exposure to valproate monotherapy
and valproate as part of polytherapy is associated with an increase risk of: malformations,
dysmorphic features, developmental delay, impaired verbal intelligence, impaired
memory functioning, special educational needs, behavioural problems and stress in the
parent-child relationship. In light of these findings it is essential that more adequately
controlled prospective studies are conducted in order to assess the teratogenic risks
associated with the established and newer AEDs so that pre-conceptual counselling can
be provided regarding the teratogenic risks to the unborn child.