title: Valproic acid monotherapy in pregnancy and major congenital malformations.
abstract: BACKGROUND
  The use of valproic acid in the first trimester of pregnancy is associated with an increased risk of spina bifida, but data on the risks of other congenital malformations are limited.
  
  
  METHODS
  We first combined data from eight published cohort studies (1565 pregnancies in which the women were exposed to valproic acid, among which 118 major malformations were observed) and identified 14 malformations that were significantly more common among the offspring of women who had received valproic acid during the first trimester. We then assessed the associations between use of valproic acid during the first trimester and these 14 malformations by performing a case-control study with the use of the European Surveillance of Congenital Anomalies (EUROCAT) antiepileptic-study database, which is derived from population-based congenital-anomaly registries. Registrations (i.e., pregnancy outcomes with malformations included in EUROCAT) with any of these 14 malformations were compared with two control groups, one consisting of infants with malformations not previously linked to valproic acid use (control group 1), and one consisting of infants with chromosomal abnormalities (control group 2). The data set included 98,075 live births, stillbirths, or terminations with malformations among 3.8 million births in 14 European countries from 1995 through 2005.
  
  
  RESULTS
  Exposure to valproic acid monotherapy was recorded for a total of 180 registrations, with 122 registrations in the case group, 45 in control group 1, and 13 in control group 2. As compared with no use of an antiepileptic drug during the first trimester (control group 1), use of valproic acid monotherapy was associated with significantly increased risks for 6 of the 14 malformations under consideration; the adjusted odds ratios were as follows: spina bifida, 12.7 (95% confidence interval [CI], 7.7 to 20.7); atrial septal defect, 2.5 (95% CI, 1.4 to 4.4); cleft palate, 5.2 (95% CI, 2.8 to 9.9); hypospadias, 4.8 (95% CI, 2.9 to 8.1); polydactyly, 2.2 (95% CI, 1.0 to 4.5); and craniosynostosis, 6.8 (95% CI, 1.8 to 18.8). Results for exposure to valproic acid were similar to results for exposure to other antiepileptic drugs.
  
  
  CONCLUSIONS
  The use of valproic acid monotherapy in the first trimester was associated with significantly increased risks of several congenital malformations, as compared with no use of antiepileptic drugs or with use of other antiepileptic drugs.
authors.affiliation: Department of Pharmacoepidemiology and Pharmacoeconomics, Division of Pharmacy, University of Groningen, Groningen, the Netherlands.
authors.forename: Janneke
authors.initials: J
authors.lastname: Jentink
authors.forename: Maria A
authors.initials: MA
authors.lastname: Loane
authors.forename: Helen
authors.initials: H
authors.lastname: Dolk
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Barisic
authors.forename: Ester
authors.initials: E
authors.lastname: Garne
authors.forename: Joan K
authors.initials: JK
authors.lastname: Morris
authors.forename: Lolkje T W
authors.initials: LT
authors.lastname: de Jong-van den Berg
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000453:epidemiology* / Q000209:etiology; D000927:Anticonvulsants / Q000009:adverse effects* / Q000627:therapeutic use; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D011247:Pregnancy; D011248:Pregnancy Complications / Q000188:drug therapy*; D011261:Pregnancy Trimester, First; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000453:epidemiology*; D015995:Prevalence; D012307:Risk Factors; D014635:Valproic Acid / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D000927:Anticonvulsants; D014635:Valproic Acid