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consistently reported that women who take polytherapy are more at risk than those who take
monotherapy102-104. Again this could be argued as simply being a reflection of the severity of
the epilepsy. Finally, animal studies have demonstrated teratogenicity with all of the older
AEDs105.

Overall based on current information, it is generally accepted that women with epilepsy who
are taking an AED in monotherapy have at least a 23 times increased risk over the
background population of having an infant with a major congenital malformations. This is
equivalent to a 49% chance of a major congenital malformation for each pregnancy
occurring to a woman taking an AED101, 102, 106, 107.

With regard to the safety of AEDs taken in monotherapy, there is now well established
evidence from multiple sources of differences between AEDs, with the greatest risks
consistently being found for valproate. There is now also data available for the newer AEDs,
with the greatest number of outcomes being reported to date for lamotrigine108.

Barbiturates (phenobarbital, primidone) and phenytoin have been associated with congenital
heart defects and facial clefts109-111. A few studies have found a positive dose-response
relationship for barbiturates. Phenytoin has also been implicated as causing urogenital
defects, and dysmorphic facial and other features such as distal phalangeal hypoplasia112. The
North American AED Pregnancy Registry has published data on 199 women who had used
phenobarbital as monotherapy during the first trimester of pregnancy. The incidence of major
birth defects was 5.5% (95% CI 2.8%9.7%). Compared with the background risk of 1.1%,
this was significantly increased (relative risk 5.1; 95% CI 1.814.9%)113.

An early case-control study found the rate of major congenital malformations for 210 infants
exposed to carbamazepine was approximately twice that in the control group (relative risk
2.24; 95% CI 1.1–4.56)114. Such an increase was not found by the UK Epilepsy and Pregnancy
Register, where the major malformation rate for carbamazepine monotherapy exposures
among 1657 prospectively collected pregnancies was 2.6%, with no significant increase in
risk from the control group115. Carbamazepine has been reported to be associated with major
malformations, including neural tube defects, at a rate of anything between 0.2% and 1% of
exposed pregnancies116, heart defects, inguinal hernia, hypospadias and hip dislocations.
There have also been reports of reduced head circumference, weight and length at birth. In a
recent systematic review and case control study the EUROCAT Antiepileptic Study Working
Group reported that for carbamazepine teratogenicity appeared to be relatively specific to
spina bifida117.

Valproate has been shown to increase the risk of major congenital malformations in both
preclinical studies and in human pregnancies. Results from the North American Pregnancy
Registry described 30 major malformations among 323 valproate-exposed women (9.3%;
95% CI 6.4–13.0%). Compared to the background prevalence of 1.1% for major
malformations, they calculated a relative risk for major malformations in valproate-exposed
pregnancies of 9.0 (95% CI 3.4–23.3%)113. That pregnancies exposed to valproate alone have
the highest risk for a major congenital malformation was also shown by the UK Epilepsy and
Pregnancy Register and the EURAP Epilepsy and Pregnancy Registry. In the UK Epilepsy
and Pregnancy Register, of 1220 pregnancies exposed to valproate alone, 6.7% had a major
malformation115. In EURAP, of 1010 pregnancies exposed to valproate alone, 98 had a major
malformation (9.7%)61. There is also growing data to suggest that total daily dose of valproate
is an important determinant for risk of major malformations. Data from all three of the main
epilepsy and pregnancy registries has shown a dose-related increase in rates of major
congenital malformations with higher valproate doses61,113,115.