Critical relationship between sodium valproate dose and human teratogenicity: results of the Australian register of anti-epileptic drugs in pregnancy

J Clin Neurosci. 2004 Nov;11(8):854-8. doi: 10.1016/j.jocn.2004.05.003.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Drug-Induced / epidemiology
  • Abnormalities, Drug-Induced / etiology*
  • Anticonvulsants / adverse effects*
  • Australia / epidemiology
  • Dose-Response Relationship, Drug
  • Epilepsy / drug therapy
  • Female
  • Fetal Diseases / chemically induced*
  • Fetal Diseases / epidemiology
  • Humans
  • Pregnancy Complications / chemically induced*
  • Pregnancy Complications / epidemiology
  • Pregnancy*
  • Registries
  • Valproic Acid / adverse effects*


  • Anticonvulsants
  • Valproic Acid