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

Autor: T. Tomson, D. Battino, E. Bonizzoni, J. Craig, D. Lindhout, A. Sabers, E. Perucca, F. Vajda, E. U. R. . A. P. study group, TINUPER, PAOLO, BISULLI, FRANCESCA
Přispěvatelé: T. Tomson, D. Battino, E. Bonizzoni, J. Craig, D. Lindhout, A. Saber, E. Perucca, F. Vajda, P. Tinuper, F. Bisulli, E. U. R . A. P. study group
Rok vydání: 2011
Předmět:
Male
Pediatrics
administration /&/ dosage/adverse effects/therapeutic use
Valproic Acid
Epilepsy
Pregnancy
Prevalence
Medicine
Prospective Studies
Registries
Prospective cohort study
Valproic Acid
administration /&/ dosage/adverse effects/therapeutic use
Triazines
administration /&/ dosage/adverse effects/therapeutic use
Pregnancy
Prenatal Exposure Delayed Effects
Prevalence
Prospective Studies
Registries
Triazine
Abnormalities
Drug-Induced
Carbamazepine
Phenobarbital
Prenatal Exposure Delayed Effects
Anesthesia
Anticonvulsants
Female
Abnormalities
Drug
medicine.drug
administration /&/ dosage/adverse effects/therapeutic use
Carbamazepine
medicine.medical_specialty
Drug
Abnormalitie
administration /&/ dosage/adverse effects/therapeutic use
Epilepsy
Lamotrigine
Dose-Response Relationship
drug therapy
Female
Humans
Infant
Infant
Newborn
Male
Phenobarbital
Humans
Dose-Response Relationship
Drug
Relationship
business.industry
Infant
Infant
Newborn
Odds ratio
Newborn
medicine.disease
epidemiology
Anticonvulsant
Drug-Induced
Neurology (clinical)
business
Zdroj: The Lancet Neurology. 10:609-617
ISSN: 1474-4422
DOI: 10.1016/s1474-4422(11)70107-7
Popis: 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.
Databáze: OpenAIRE
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