Dose-dependent risk of malformations with antiepileptic drugs

An analysis of data from the EURAP epilepsy and pregnancy registry

Torbjörn Tomson, Dina Battino, Erminio Bonizzoni, John Craig, Dick Lindhout, Anne Sabers, Emilio Perucca, Frank Vajda

Research output: Contribution to journalArticle

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Abstract

Background: Prenatal exposure to antiepileptic drugs is associated with a greater risk of major congenital malformations, but there is inadequate information on the comparative teratogenicity of individual antiepileptic drugs and the association with dose. We aimed to establish the risks of major congenital malformations after monotherapy exposure to four major antiepileptic drugs at different doses. Methods: The EURAP epilepsy and pregnancy registry is an observational cohort study representing a collaboration of physicians from 42 countries. We prospectively monitored pregnancies exposed to monotherapy with different doses of four common drugs: carbamazepine, lamotrigine, valproic acid, or phenobarbital. Our primary endpoint was the rate of major congenital malformations detected up to 12 months after birth. We assessed pregnancy outcomes according to dose at the time of conception irrespective of subsequent dose changes. Findings: After excluding pregnancies that ended in spontaneous abortions or chromosomal or genetic abnormalities, those in which the women had treatment changes in the first trimester, and those involving other diseases or treatments that could affect fetal outcome, we assessed rates of major congenital malformations in 1402 pregnancies exposed to carbamazepine, 1280 on lamotrigine, 1010 on valproic acid, and 217 on phenobarbital. An increase in malformation rates with increasing dose at the time of conception was recorded for all drugs. Multivariable analysis including ten covariates in addition to treatment with antiepileptic drugs showed that the risk of malformations was greater with a parental history of major congenital malformations (odds ratio 4·4, 95% CI 2·06-9·23). We noted the lowest rates of malformation with less than 300 mg per day lamotrigine (2·0% [17 events], 95% CI 1·19-3·24) and less than 400 mg per day carbamazepine (3·4% [5 events], 95% CI 1·11-7·71). Compared with lamotrigine monotherapy at doses less than 300 mg per day, risks of malformation were significantly higher with valproic acid and phenobarbital at all investigated doses, and with carbamazepine at doses greater than 400 mg per day. Interpretation: The risk of major congenital malformations is influenced not only by type of antiepileptic drug, but also by dose and other variables, which should be taken into account in the management of epilepsy in women of childbearing potential. Funding: Eisai, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Sanofi-Aventis, UCB, Netherlands Epilepsy Foundation, Stockholm County Council, and ALF.

Original languageEnglish
Pages (from-to)609-617
Number of pages9
JournalThe Lancet Neurology
Volume10
Issue number7
DOIs
Publication statusPublished - Jul 2011

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Anticonvulsants
Carbamazepine
Registries
Epilepsy
Valproic Acid
Pregnancy
Phenobarbital
Spontaneous Abortion
First Pregnancy Trimester
Pregnancy Outcome
Pharmaceutical Preparations
Netherlands
Observational Studies
Cohort Studies
Therapeutics
Odds Ratio
Parturition
Physicians
lamotrigine

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Dose-dependent risk of malformations with antiepileptic drugs : An analysis of data from the EURAP epilepsy and pregnancy registry. / Tomson, Torbjörn; Battino, Dina; Bonizzoni, Erminio; Craig, John; Lindhout, Dick; Sabers, Anne; Perucca, Emilio; Vajda, Frank.

In: The Lancet Neurology, Vol. 10, No. 7, 07.2011, p. 609-617.

Research output: Contribution to journalArticle

Tomson, Torbjörn ; Battino, Dina ; Bonizzoni, Erminio ; Craig, John ; Lindhout, Dick ; Sabers, Anne ; Perucca, Emilio ; Vajda, Frank. / Dose-dependent risk of malformations with antiepileptic drugs : An analysis of data from the EURAP epilepsy and pregnancy registry. In: The Lancet Neurology. 2011 ; Vol. 10, No. 7. pp. 609-617.
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