Page 437 - ILAE_Lectures_2015

Studies have indicated that exposure to valproate during early pregnancy is associated with a
significant incidence (12%) of spina bifida aperta52,109, with the greatest risk for those
exposed to doses of greater than 1000 mg per day53. It has also been reported that there is a
greater risk of cardiovascular and urogenital malformations, skeletal defects (including radial
ray aplasia and rib and vertebral anomalies118), and a combination of facial dysmorphic
patterns119, which is possibly distinct from that seen with other AEDs such as phenytoin.
However, the dysmorphic features, such as epicanthal folds, long philtrum, flat nasal bridge,
and hypertelorism, occur with other AEDs and their significance for long-term development
is unknown. There is evidence of a pharmacogenetic susceptibility to the teratogenic effects
of valproate both, from human reports120,121and preclinical studies122. There is also a
suggestion from preclinical studies that for valproate, at least, high peak plasma
concentrations are associated with an increased risk of malformations123. This finding was
replicated in the Australian study were the mean daily dose of valproate was higher in those
with a major malformation124. Thus, it has been suggested that a sustained-release preparation
may be preferable, with the total daily dose being divided into two or three administrations
per day. This approach, however, failed to show any benefit in a retrospective analysis by the
UK Epilepsy and Pregnancy Register, which showed similar rates of major congenital
malformations in women taking standard valproate once daily compared to those taking
prolonged-release valproate or standard-release valproate in multiple daily administrations
(relative risk 1.1; 95% CI 0.7–1.8)125. In January 2015 the MHRA published new warnings
regarding valproate exposure during pregnancy, advising that, in view of the risk of major
congenital malformations and neurodevelopmental delay associated with the drug, it should
not be used unless other alternatives are ineffective or not tolerated. It was also advised that
valproate should be started and supervised by a clinician with experience in treating epilepsy
and that the risks and benefits of treatment should be considered both on commencing
valproate and frequently at subsequent reviews, especially when a girl reaches puberty and
when pregnancy is being planned126.

Considering the newer AEDs, most human data are available for lamotrigine. The
International Lamotrigine Pregnancy Registry has recently reported the outcomes of 1558
first trimester lamotrigine-exposed pregnancies108. The percentage of outcomes exposed to
lamotrigine monotherapy with major birth defects was 2.2% (95% CI 1.6–3.1%). For
polytherapy outcomes containing lamotrigine the occurrence of birth defects varied according
to whether sodium valproate was included in the polytherapy regimen. For combinations
containing sodium valproate in addition to lamotrigine (n = 150) the rate of major birth
defects was 10.7% (95% CI 6.4–17.0%). This compared with a rate of 2.8% (95% CI 1.5–
5.0%) for polytherapy combinations which included lamotrigine but not sodium valproate (n
= 430). No distinctive pattern of malformations was reported in this study. Data from the
pregnancy register revealed a similar malformation rate for pregnancies exposed to
lamotrigine alone, with 49 of 2098 (2.3%) infants having a major congenital malformation.
In contrast to earlier results, only a small dose-response was seen, with 3.4% of pregnancies
exposed to more than 400 mg a day of lamotrigine having a major congenital malformation,
compared to 2.1% of those exposed to less than 200 mg daily115. This did not reach statistical
significance. A positive dose-response has not been reported by some other registers
including the International Lamotrigine Registry108. The North American Pregnancy Register
reported a total of 31 (2.0%) of 1562 infants exposed to lamotrigine to have a major
congenital malformation. No dose response was found but a 10.4-fold (95% C.I. 4.3–24.9)
increase in the rate of clefting abnormalities was noted127. In contrast the UK Epilepsy and
Pregnancy Register115,128 and the European Surveillance of Congenital Anomalies found no
evidence of increased isolated oro-facial clefts relative to other major congenital
malformations for lamotrigine129.