title: Valproate and the risk for congenital malformations: Is formulation and dosage regime important?
abstract: BACKGROUND
  Use of valproate in pregnancy, especially in doses over 1000mg a day, is known to be associated with a higher risk for major congenital malformations compared with other antiepileptic drugs. We sought to investigate whether the increased risk could be minimised by using controlled release or divided daily doses of valproate.
  
  
  METHODS
  The UK Epilepsy and Pregnancy Register is a prospective, observational and follow up study set up to determine the risks of major congenital malformations for infants exposed to antiepileptic drugs in utero. In this study we have extracted data for those pregnancies exposed to valproate in monotherapy. We have calculated malformation rates and relative risks as a function of valproate exposure.
  
  
  RESULTS
  Outcome data were available for 1109 pregnancies exposed to valproate in monotherapy. Exposure to 1000mg a day or more of valproate was associated with almost double the risk of major congenital malformation compared with daily valproate doses below 1000mg daily (8.86% vs 4.88%, RR: 1.7; 95% CI: 1.1-2.9). There were no differences in the risks for malformations between standard release valproate and controlled release valproate preparations (RR: 1.11; 95% CI: 0.67-1.83) or for those exposed to single or multiple daily administrations (RR: 0.99, 95% CI: 0.58-1.70).
  
  
  CONCLUSIONS
  Prescribing controlled release valproate or multiple daily administrations in pregnancy did not reduce the risk for malformations. Higher malformation rates observed with in utero exposure to valproate are more likely related to total daily dose, rather than peak serum levels.
authors.affiliation: Department of Neurology, Belfast Health and Social Care Trust, Grosvenor Road, Belfast BT12 6BA, United Kingdom.
authors.forename: E
authors.initials: E
authors.lastname: Mawhinney
authors.forename: J
authors.initials: J
authors.lastname: Campbell
authors.forename: J
authors.initials: J
authors.lastname: Craig
authors.forename: A
authors.initials: A
authors.lastname: Russell
authors.forename: W
authors.initials: W
authors.lastname: Smithson
authors.forename: L
authors.initials: L
authors.lastname: Parsons
authors.forename: I
authors.initials: I
authors.lastname: Robertson
authors.forename: B
authors.initials: B
authors.lastname: Irwin
authors.forename: P
authors.initials: P
authors.lastname: Morrison
authors.forename: B
authors.initials: B
authors.lastname: Liggan
authors.forename: N
authors.initials: N
authors.lastname: Delanty
authors.forename: S
authors.initials: S
authors.lastname: Hunt
authors.forename: J
authors.initials: J
authors.lastname: Morrow
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000453:epidemiology*; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects*; D004827:Epilepsy / Q000188:drug therapy*; D005260:Female; D006801:Humans; D011247:Pregnancy; D011248:Pregnancy Complications / Q000188:drug therapy*; D011297:Prenatal Exposure Delayed Effects / Q000453:epidemiology; D012307:Risk Factors; D014635:Valproic Acid / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D000927:Anticonvulsants; D014635:Valproic Acid