Critical relationship between sodium valproate dose and human teratogenicity: results of the Australian register of anti-epileptic drugs in pregnancy.
To compare the incidence of foetal malformations (FMs) in pregnant women with epilepsy treated with different anti-epileptic drugs (AED) and doses, and the influence of seizures, family and personal history, and environmental factors. A prospective, observational, community-based cohort study.


METHODS
A voluntary, Australia-wide, telephone-interview-based register prospectively enrolling three groups of pregnant women: taking AEDs for epilepsy; with epilepsy not taking AEDs; taking AEDs for a non-epileptic indication. Four hundred and fifty eligible women were enrolled over 40 months. Three hundred and ninety six pregnancies had been completed, with 7 sets of twins, for a total of 403 pregnancy outcomes.


RESULTS
354 (87.8%) pregnancy outcomes resulted in a healthy live birth, 26 (6.5%) had a FM, 4 (1%) a death in utero, 1 (0.2%) a premature labour with stillbirth, 14 (3.5%) a spontaneous abortion and 4 lost to follow-up. The FM rate was greater in pregnancies exposed to sodium valproate (VPA) in the first trimester (16.0%) compared with those exposed to all other AEDs (16.0% vs. 2.4%, P < 0.01) or no AEDs (16.0% vs. 3.1%, [Formula: see text] ). The mean daily dose of VPA taken in pregnancy with FMs was significantly greater than in those without (1,975 vs. 1,128 mg, P < 0.01). The incidence of FM with VPA doses >or= 1,100 mg was 30.2% vs. 3.2% with doses <1,100 mg (P <0.01).


CONCLUSIONS
There is a dose-effect relationship for FM and exposure to VPA during the first trimester of pregnancy, with higher doses of VPA associated with a significantly greater risk than with lower doses or with other AEDs. These results highlight the need to limit, where possible, the dose of VPA in pregnancy.
Vajda
Frank J
FJ
Department of Medicine, The Australian Centre For Neuropharmacology, Raoul Wallenberg Centre, St. Vincent's Hospital, Fitzroy, 3065 Melbourne, Vic., Australia. vajdafj@svhm.org.au
O'brien
Terence J
TJ
Hitchcock
Alison
A
Graham
Janet
J
Cook
Mark
M
Lander
Cecilie
C
Eadie
Mervyn J
MJ
D000014:Abnormalities, Drug-Induced / Q000453:epidemiology / Q000209:etiology*; D000927:Anticonvulsants / Q000009:adverse effects*; D001315:Australia / Q000453:epidemiology; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000188:drug therapy; D005260:Female; D005315:Fetal Diseases / Q000139:chemically induced* / Q000453:epidemiology; D006801:Humans; D011247:Pregnancy; D011248:Pregnancy Complications / Q000139:chemically induced* / Q000453:epidemiology; D012042:Registries; D014635:Valproic Acid / Q000009:adverse effects*
D000927:Anticonvulsants; D014635:Valproic Acid