title: Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Eisai, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Sanofi-Aventis, UCB, Netherlands Epilepsy Foundation, Stockholm County Council, and ALF.
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
authors.forename: Torbjörn
authors.initials: T
authors.lastname: Tomson
authors.forename: Dina
authors.initials: D
authors.lastname: Battino
authors.forename: Erminio
authors.initials: E
authors.lastname: Bonizzoni
authors.forename: John
authors.initials: J
authors.lastname: Craig
authors.forename: Dick
authors.initials: D
authors.lastname: Lindhout
authors.forename: Anne
authors.initials: A
authors.lastname: Sabers
authors.forename: Emilio
authors.initials: E
authors.lastname: Perucca
authors.forename: Frank
authors.initials: F
authors.lastname: Vajda
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000453:epidemiology*; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D002220:Carbamazepine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D000077213:Lamotrigine; D008297:Male; D010634:Phenobarbital / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D015995:Prevalence; D011446:Prospective Studies; D012042:Registries; D014227:Triazines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D014635:Valproic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: D000927:Anticonvulsants; D014227:Triazines; D002220:Carbamazepine; D014635:Valproic Acid; D000077213:Lamotrigine; D010634:Phenobarbital