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folic acid use three months prior to conception and in the first trimester carrying an odds ratio
of 1.4 (95% CI 1.02–1.82, P = 0.035) of major congenital malformations over those not
adhering to this regimen61. While the above results clearly do not mean that we should stop
prescribing folate periconceptually to women with epilepsy they do question the validity of
this approach for reducing the risk of major malformations.

Recent data from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study
group has suggested that periconceptual folic acid may have a positive effect on mean IQ in
infants exposed to AEDs in utero62. In this study of 225 children, periconceptual folic acid
was associated with higher child IQ at age six (mean IQ 108 vs 101, P = 0.0002). This effect
was seen across all AEDs studied (carbamazepine, lamotrigine, valproate and phenytoin).
Together with results from studies in the general population showing reduced risk of severe
language delay with folic acid supplementation in early pregnancy63, and improved measures
of verbal communication with preconceptual folic acid at high dose (5 mg daily)64, these data
would suggest that it may be of benefit to continue high dose folic acid supplementation
throughout pregnancy.

The effects of epilepsy and AEDs on pregnancy

Data on whether women with epilepsy are at increased risk of obstetric complications are
unclear. Complications that have been reported as being increased compared with control
mothers are vaginal bleeding, spontaneous abortion, pre-eclampsia, and premature or
prolonged labour65. Higher frequencies of labour induction and artificial labour have also
been reported66, but whether this is due to a greater frequency of medical indications or is due
to increased concern on the part of obstetricians or mothers-to-be is uncertain67. The adverse
outcomes most consistently reported are increased stillbirths and neonatal deaths68,69,
although there is some evidence that the latter has been improving70. Data on whether women
with epilepsy are at increased risk of early pregnancy loss are conflicting. A recent
population-based study from the Danish Medical Birth Registry identified a 13 % increase in
risk of spontaneous abortion in women taking AEDs during pregnancy. However, no increase
in risk was seen when this analysis was limited to women with epilepsy, suggesting this effect
may be due to confounding factors rather than seizures or AED consumption71. Clearly
research into early pregnancy loss is difficult and the authors highlight that this study was
designed to look only at clinically recognised pregnancies and that if AED consumption
caused an increase in very early spontaneous abortion, this would not have been identified.

Since 1958 over 40 cases of neonatal bleeding associated with maternal AED treatment have
been reported72. It is felt that this is due to reduced clotting factors, consequent to alterations
in vitamin K metabolism, in infants exposed to enzyme-inducing AEDs, such as phenytoin,
phenobarbitone and carbamazepine. There is evidence that newborn infants that have been
exposed to enzyme-inducing AEDs in utero may show increased levels of PIVKA II (protein
induced by vitamin K absence of factor II), an indirect marker of vitamin K deficiency73,74.
While there is no evidence directly linking this biochemical marker to a clinically increased
risk of bleeding in the neonate, its suppression with vitamin K1 supplementation given as 10
mg orally each day from the 36th week of gestation75 has resulted in most guidelines for best
practice advocating maternal supplementation with vitamin K1, with all infants also being
given 1 mg vitamin K1 intramuscularly at birth76,77. However, the results from a recent case-
control study did not show that there was an increased risk for bleeding in infants exposed in
utero to enzyme-inducing AEDs (mainly carbamazepine and phenytoin)78, although it was
felt that supplementation might be necessary in selected cases, such as when prematurity is
anticipated. Nevertheless, although the risk of haemorrhagic disease of the newborn is small,
early UK and other best practice guidelines recommended the prescription of 1020 mg/day
of vitamin K given orally to women with epilepsy in the last month of pregnancy76,77,