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Reported data on the other new AEDs are sparse. The North American AED Pregnancy
Registry has reported four major malformations of 182 first trimester exposures to
oxcarbazepine (2.2%)113. These are similar to figures published by EURAP, reporting six
malformations of 184 pregnancies (3.3%) exposed to oxcarbazepine61. Another report of 55
exposures to oxcarbazepine (35 monotherapy and 20 polytherapy) noted only one major
malformation130. Six malformations from the outcomes of the 248 monotherapy exposures to
oxcarbazepine (2.4%), either reported in the literature or held by the Novartis Germany
database, have also been reported131. In a post-marketing surveillance study of gabapentin as
add-on therapy for 3100 patients in England no congenital abnormalities were seen in the 11
infants born to women who used gabapentin in the first trimester of pregnancy132. In the
tiagabine clinical trials 22 patients who received the drug became pregnant, of whom nine
carried to term. In one of these a hip displacement was noted, though this was a breech
delivery133. Preliminary data for topiramate appears concerning. In a small study of five
women who received topiramate during pregnancy and lactation all women had uneventful
deliveries and gave birth to healthy children, although one had a premature delivery at 36
weeks’ gestation134. The UK Epilepsy and Pregnancy Register reported on 203 pregnancies
exposed to topiramate. Of the 70 cases that had just received topiramate, three (4.8%) had a
major congenital malformation, of which two were clefting abnormalities and one a case of
hypospadias135. Results from the North American AED Pregnancy Registry (15 from 359
pregnancies, 4.2%)113 and EURAP (five from 73 pregnancies, 6.8%)61 were similarly
concerning, and in 2011 topiramate was reclassified as a category D drug by the FDA to
reflect these results. Earlier results published by the North American AED Pregnancy
Registry in abstract form were in keeping with results from the UK Epilepsy and Pregnancy
Register, with two of eight major congenital malformations from 197 exposures to topiramate
being cleft lip deformities136. More recent population-based studies from Norway98 and
Denmark99 have also suggested an association between topiramate exposure in pregnancy
and fetal growth restriction, infants being born small for gestational age and microcephaly.
Increasing data is now available for levetiracetam. The UK Epilepsy and Pregnancy Register
reported a 0.7% risk of major malformations from 304 pregnancies exposed to levetiracetam
in monotherapy137. Similarly reassuring results have also been published by the North
American AED Pregnancy Registry (11 from 450 pregnancies, 2.4%)113 and EURAP (two
from 126 pregnancies, 1.6%)61. Collation of many more pregnancies would clearly be
beneficial to clarify the safety of these AEDs in pregnancy.

For zonisamide data for exposed pregnancies is limited. Animal and early human studies
previously raised concerns regarding use of zonisamide during pregnancy. However, data
recently published by the North American AED Pregnancy Registry is less concerning, with
no malformations observed among 90 monotherapy-exposed pregnancies (95 % CI 0–3.3)113.
Study of much larger numbers of pregnancies is required to confirm the validity of these
findings.

For all the newer AEDs, preclinical models are therefore of interest. In these studies
topiramate was teratogenic in mice, rats and rabbits at high doses, with limb and digital
malformations, including right-sided ectrodactyly being observed in rats and rib and vertebral
malformations in rabbits. Vigabatrin was also shown to be teratogenic in rabbits, inducing
cleft defects138. Gabapentin was associated with skeletal malformations, including delayed
ossification of the calcaneus and hindlimb digits in mice, and incomplete fusion of skull bones
and sternabrae in rats. However, the type and incidence of these abnormalities were not felt
to be indicative of developmental toxicity139. Tiagabine, oxcarbazepine and levetiracetam
have not been shown to be teratogenic.

When considering the effect of AEDs on embryonic and fetal development, most of the
emphasis to date has been on the risk of major congenital malformations. However, there is