title: Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism.
abstract: OBJECTIVE
  Valproate is used for the treatment of epilepsy and other neuropsychological disorders and may be the only treatment option for women of childbearing potential. However, prenatal exposure to valproate may increase the risk of autism.
  
  
  OBJECTIVE
  To determine whether prenatal exposure to valproate is associated with an increased risk of autism in offspring.
  
  
  METHODS
  Population-based study of all children born alive in Denmark from 1996 to 2006. National registers were used to identify children exposed to valproate during pregnancy and diagnosed with autism spectrum disorders (childhood autism [autistic disorder], Asperger syndrome, atypical autism, and other or unspecified pervasive developmental disorders). We analyzed the risks associated with all autism spectrum disorders as well as childhood autism. Data were analyzed by Cox regression adjusting for potential confounders (maternal age at conception, paternal age at conception, parental psychiatric history, gestational age, birth weight, sex, congenital malformations, and parity). Children were followed up from birth until the day of autism spectrum disorder diagnosis, death, emigration, or December 31, 2010, whichever came first.
  
  
  METHODS
  Absolute risk (cumulative incidence) and the hazard ratio (HR) of autism spectrum disorder and childhood autism in children after exposure to valproate in pregnancy.
  
  
  RESULTS
  Of 655,615 children born from 1996 through 2006, 5437 were identified with autism spectrum disorder, including 2067 with childhood autism. The mean age of the children at end of follow-up was 8.84 years (range, 4-14; median, 8.85). The estimated absolute risk after 14 years of follow-up was 1.53% (95% CI, 1.47%-1.58%) for autism spectrum disorder and 0.48% (95% CI, 0.46%-0.51%) for childhood autism. Overall, the 508 children exposed to valproate had an absolute risk of 4.42% (95% CI, 2.59%-7.46%) for autism spectrum disorder (adjusted HR, 2.9 [95% CI, 1.7-4.9]) and an absolute risk of 2.50% (95% CI, 1.30%-4.81%) for childhood autism (adjusted HR, 5.2 [95% CI, 2.7-10.0]). When restricting the cohort to the 6584 children born to women with epilepsy, the absolute risk of autism spectrum disorder among 432 children exposed to valproate was 4.15% (95% CI, 2.20%-7.81%) (adjusted HR, 1.7 [95% CI, 0.9-3.2]), and the absolute risk of childhood autism was 2.95% (95% CI, 1.42%-6.11%) (adjusted HR, 2.9 [95% CI, 1.4-6.0]) vs 2.44% (95% CI, 1.88%-3.16%) for autism spectrum disorder and 1.02% (95% CI, 0.70%-1.49%) for childhood autism among 6152 children not exposed to valproate.
  
  
  CONCLUSIONS
  Maternal use of valproate during pregnancy was associated with a significantly increased risk of autism spectrum disorder and childhood autism in the offspring, even after adjusting for maternal epilepsy. For women of childbearing potential who use antiepileptic medications, these findings must be balanced against the treatment benefits for women who require valproate for epilepsy control.
authors.affiliation: Department of Neurology, Aarhus University Hospital, Norrebrogade 44, DK-8000 Aarhus C, Denmark. jakob@farm.au.dk
authors.forename: Jakob
authors.initials: J
authors.lastname: Christensen
authors.forename: Therese Koops
authors.initials: TK
authors.lastname: Grønborg
authors.forename: Merete Juul
authors.initials: MJ
authors.lastname: Sørensen
authors.forename: Diana
authors.initials: D
authors.lastname: Schendel
authors.forename: Erik Thorlund
authors.initials: ET
authors.lastname: Parner
authors.forename: Lars Henning
authors.initials: LH
authors.lastname: Pedersen
authors.forename: Mogens
authors.initials: M
authors.lastname: Vestergaard
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects* / Q000627:therapeutic use; D001321:Autistic Disorder / Q000453:epidemiology*; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000453:epidemiology*; D002675:Child, Preschool; D003718:Denmark / Q000453:epidemiology; D004827:Epilepsy / Q000188:drug therapy*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D008297:Male; D008423:Maternal Age; D001523:Mental Disorders / Q000453:epidemiology; D011247:Pregnancy; D011248:Pregnancy Complications / Q000188:drug therapy*; D011297:Prenatal Exposure Delayed Effects; D012042:Registries / Q000706:statistics & numerical data; D012306:Risk; D014635:Valproic Acid / Q000009:adverse effects* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D014635:Valproic Acid