Elsevier

The Lancet Neurology

Volume 10, Issue 7, July 2011, Pages 609-617
The Lancet Neurology

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Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry

https://doi.org/10.1016/S1474-4422(11)70107-7Get rights and content

Summary

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.

Introduction

Between 0·3% and 0·7% of all pregnancies are in women with epilepsy.1 Most of these women need to continue use of antiepileptic drugs during pregnancy because uncontrolled seizures might harm the mother and fetus. This continuation is of concern to physicians, because antiepileptic drugs as a class might cause major congenital malformations2, 3 and adverse effects on cognitive development after prenatal exposure.4

In the past decade, the teratogenicity of antiepileptic drugs has been compared through large prospective registries.5 A recent systematic review3 concluded that “it is highly probable that intrauterine first-trimester exposure to valproic acid has a higher risk of major congenital malformations compared with carbamazepine, and possibly compared with phenytoin or lamotrigine”. Subsequent case-control studies have confirmed that, compared with other antiepileptic drugs, treatment with valproic acid has a greater risk of spina bifida, atrial septal defects, cleft palate, and craniosynostosis,6 and carbamazepine a greater risk of spina bifida.7 However, the associations reported in these observational studies could be influenced by confounders such as type or severity of epilepsy, socioeconomic status, and family history of birth defects. The findings of several studies also suggest an association between dose and risk of malformations, at least for valproic acid.8, 9, 10, 11, 12, 13 However, none of the previous studies had sufficient statistical power to compare risks associated with different doses of the most common drugs or to assess the influence of potential confounders. In this study, we aimed to assess data collected prospectively over 11 years by the International Registry of Antiepileptic Drugs and Pregnancy (EURAP)14 to establish the risks of major congenital malformations after monotherapy exposure to four major antiepileptic drugs at different doses.

Section snippets

Participants

The EURAP registry was established in 1999 and at present involves 42 countries with more than 700 collaborators. The eligibility criteria for prospective assessment in EURAP were treatment with antiepileptic drugs for any indication at conception, enrolment within gestation week 16, and enrolment before fetal outcome is known. Information is obtained in early pregnancy on demographics, type of epilepsy, seizure frequency, comorbidities, family history of major congenital malformations, drug

Results

For our present analysis, a cutoff date of June 9, 2010, was arbitrarily established, at which point 14 461 pregnancies had been registered. Of these pregnancies, we prospectively identified 5366 in which the women were exposed to antiepileptic monotherapy and had completed the 12-month follow-up (figure). 826 pregnancies were subsequently excluded (demographics listed webappendix pp 7–8), whereas 4540, representing 20 different antiepileptic drugs, fulfilled the eligibility criteria. These

Discussion

Our findings show that the risk of major congenital malformations increases dose-dependently with all assessed antiepileptic drugs. We recorded particularly high malformation rates for 1500 mg per day or greater doses of valproic acid. Doses of valproic acid of less than 700 mg per day were associated with a malformation rate in a similar range to that of carbamazepine doses of 400 mg per day to less than 1000 mg per day, phenobarbital of less than 150 mg per day, and lamotrigine of 300 mg per

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