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Prior pregnancy outcome may be an important factor to consider during preconceptual
counselling. There is some evidence that women who have previously had a child with a
major malformation are at higher risk of future children also having major malformations if
the same AED is taken in subsequent pregnancies. Small studies of infants with fetal
anticonvulsant syndromes quoted this risk as between 39% and 55%, but more recent studies
have estimated the recurrence risk of major malformations as between 15.8% and 35.7%. In
studies by the UK Epilepsy and Pregnancy Register48 and the Australian Register of
Antiepileptic Drugs in Pregnancy49 the recurrence risk for congenital malformations was
higher for women taking valproate (21.9% and 57.2%) than for those on other AEDs. Women
attending for preconceptual counselling who have had a previous child with a major
malformation, particularly on valproate, should be informed that they may have a higher risk
of major malformations in subsequent pregnancies if the AED is not changed. The magnitude
of this increase in risk remains to be clarified.

The genetics of the seizure disorder may also need to be taken into consideration. For
example, for autosomal dominant conditions such as tuberous sclerosis there is a 1:2 risk of
a child inheriting the condition. Most of the inheritable syndromes which include epilepsy in
their phenotype are autosomal recessive and there is therefore a low risk of children
developing the condition. The risk of a child developing epilepsy is dependent on the type of
seizure disorder and the number of affected relatives. For primary generalised seizure
disorders there is up to a 10% chance of offspring developing epilepsy, but this is increased
if both parents have epilepsy or if the child’s siblings develop epilepsy. The risk seems to be
lower if only the father has epilepsy compared with if only the mother has epilepsy50.

Folic acid
The prescription of folic acid before conception and at least until the end of the first trimester
is recommended in patients taking antiepileptic medication, as it is for all women. This
followed the recognition that there is an increased risk of neural tube defect in children born
to mothers taking AEDs, in particular sodium valproate and carbamazepine51-53. Large
community-based studies have demonstrated a reduction in the rate of neural tube defects in
women taking folic acid preconceptually54-56. It has been inferred from this that folic acid will
protect women with epilepsy who are also at increased risk of this complication. The optimum
dosage of folic acid remains undetermined. Community-based studies have used dosages
ranging from 0.54.0 mg daily, the higher dosage being suggested for women considered at
higher risk. It is the higher dosage that is generally recommended in the UK for women with
epilepsy (5 mg daily).

Some concerns have been raised that folic acid may exacerbate seizures but these fears have
generally been felt to be unfounded. There is as yet no direct evidence that folic acid will
protect against the neural tube defects or other malformations seen in association with AEDs.
There is some evidence that the neural tube defects which occur in association with sodium
valproate are somewhat different from those seen in the general population. They tend to be
low lumbar or sacral in site57. Other abnormalities are less common and the defect may be
the result of altered canalisation rather than folding of the developing neural crest. It remains
uncertain as to whether folic acid will protect against this form of neural tube defect58, or
other defects associated with AEDs59. The potential effect of folate supplementation was
reported for 4680 cases from the UK Epilepsy and Pregnancy Register60. Those patients who
received preconceptual folic acid, approximately three-quarters of whom received 5 mg each
day, appeared more likely to have a child with a major congenital malformation than those
who did not (3.9% vs 2.2%; odds ratio 1.8; 95% CI 1.2–2.5). However, periconceptual folic
acid was associated with a reduction in the incidence of valproate-associated neural tube
defects (0.8% vs 1.6%). The EURAP pregnancy registry has reported similar findings, with