CRITICAL DOSE-EFFECT RELATIONSHIP BETWEEN SODIUM VALPROATE AND TERATOGENICITY IN PREGNANY
Abstract number :
F.03
Submission category :
Year :
2003
Submission ID :
3596
Source :
www.aesnet.org
Presentation date :
12/6/2003 12:00:00 AM
Published date :
Dec 1, 2003, 06:00 AM
Authors :
Frank J. Vajda, Terence J. O[apos]Brien, Mark J. Cook, Alison Hithcock, Janet Graham, Cecile Lander, Mervyn J. Eadie 1Australian Centre for Neuropharmacology, Raoul Wallenberg Centre, St. Vincent[apos]s Hospital, Fitzroy, Victoria, Australia; The Departme
Retrospective studies have demonstrated an increased risk of having a child with a foetal malformation (FM) in women with epilepsy taking AEDs. This study evaluated prospectively the incidence of FMs in women exposed to AEDs; to determine whether certain AEDs, doses or combination of drugs are associated with greater risk; and to examine other factors possibly related to outcome.
A national, voluntary telephone-interview based register prospectively enrolled three groups of women: those taking AEDs for epilepsy; those with epilepsy not taking AEDs; or others taking AEDs for a non-epileptic indication. Pregnancy outcomes were evaluated by interviews and reference to records.
Over the first 40 months of the study (to October 2002) 450 eligible women were enrolled. Three hundred and ninety six pregnancies had been completed, with 7 sets of twins, for a final total of 403 outcomes. 354 (87.8%) resulted in a healthy live birth, and 21 (5.2%) a live birth with a birth defect. There were five (1.2%) induced abortions because of a malformation detected on ultrasound, four (1%) deaths in utero, one (0.2%) premature labour with a stillbirth and 14 (3.5%) spontaneous abortions. Four (1%) were lost to follow up. The incidence of FMs was significantly higher in women taking to valproate (VPA) than those taking no AEDs (19/119, 16% vs. 1/32, 3.1%, p[lt]0.01). There was a significant difference in the mean daily doses of VPA taken by women who had infants with a FM compared to those who did not (2027 mg vs. 1168 mg, p[lt]0.0001, Student t-test). The rate of FM in women taking [gt]1100 mg/day of VPA was 16/53 (30%) compared with 2/66 (3%) in those taking doses [lt]1100 mg/day. The rate of FM in VPA exposed women was not affected by the number of other AEDs being taken nor by folate supplementation. There were no significant differences in the rates of FM nor dose effects found for any of the other AEDs.
Women taking VPA in pregnancy, either in monotherapy or in combination with other drugs, are at a significantly greater risk of having a child with a FM. This risk appears particularly high when the dose of VPA exceeds 1100 mg per day.
[Supported by: The study received financial support in the way of grants from The Epilepsy Foundation of Victoria, The Epilepsy Society of Australia, Pfizer Pharmaceuticals, Aventis Pharma, Sanofi-Synthelabo, Novartis Pharmaceuticals, Janssen-Cilag, Galaxo Smith Kline and UCB (Belgium).]