title: Prospective assessment of autism traits in children exposed to antiepileptic drugs during pregnancy.
abstract: OBJECTIVE
  The association between autism spectrum disorders (ASDs) and prenatal anticonvulsant exposure is increasingly investigated, but comprehensive, blinded assessment using a validated instrument for autism within a well-characterized prospective cohort has not been conducted. Thus, existing studies may represent an underestimate of the true risk. Herein we present a prospective cohort study in children exposed to anticonvulsants during pregnancy, with all assessments conducted by examiners who were blinded to drug-exposure status.
  
  
  METHODS
  Participants were 105 Australian children aged 6-8 years who were recruited via the Australian Pregnancy Register for Women on Antiepileptic Medication. Maternal epilepsy, pregnancy, and medical history data were obtained prospectively. Autism traits were assessed using the Childhood Autism Rating Scale (CARS).
  
  
  RESULTS
  Eleven children (10.5%) had elevated CARS scores. Two were exposed to valproate monotherapy (2/26; 7.7%), two to carbamazepine monotherapy (2/34; 5.9%), and seven to valproate in polytherapy (7/15; 46.7%). Linear regression analysis showed that the mean valproate dose during pregnancy was a significant predictor of CARS scores after controlling for polytherapy, mean carbamazepine dose, folic acid use, seizures during pregnancy, tobacco and marijuana use, maternal intelligence quotient (IQ), and socioeconomic status. First trimester folic acid supplementation and marijuana use were also significant predictors of CARS scores.
  
  
  CONCLUSIONS
  Using direct assessment of children in our prospective study, we found an elevated rate of autism traits across the sample. The most important determinant of association with autistic traits was higher doses of sodium valproate exposure. The use of valproate in women who may become pregnant is now generally avoided; however, there are insufficient data regarding the risk of ASD with low-dose valproate. If this risk is no greater than with other antiepileptic drugs (AED)s, it may enable women with genetic generalized epilepsy to retain optimal seizure control as well as minimize harm to their unborn child.
authors.affiliation: Clinical Sciences, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia.|Department of Medicine, Southern Clinical School, Monash University, Melbourne, Victoria, Australia.|School of Psychology, The University of Birmingham, Birmingham, United Kingdom.
authors.forename: Amanda G
authors.initials: AG
authors.lastname: Wood
authors.affiliation: Clinical Sciences, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia.|School of Psychology and Psychiatry, Monash University, Melbourne, Victoria, Australia.
authors.forename: Caroline
authors.initials: C
authors.lastname: Nadebaum
authors.affiliation: Clinical Sciences, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia.|Royal Children's Hospital, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Vicki
authors.initials: V
authors.lastname: Anderson
authors.affiliation: Centre for Advanced Imaging, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Reutens
authors.affiliation: Clinical Sciences, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia.|School of Psychology and Psychiatry, Monash University, Melbourne, Victoria, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Barton
authors.affiliation: Department of Medicine, The Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Terence J
authors.initials: TJ
authors.lastname: O'Brien
authors.affiliation: Department of Medicine, The Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia.|Australian Pregnancy Register for Women on Antiepileptic Medication, Melbourne, Victoria, Australia.
authors.forename: Frank
authors.initials: F
authors.lastname: Vajda
mesh_terms: D000927:Anticonvulsants / Q000009:adverse effects*; D001315:Australia / Q000453:epidemiology; D001321:Autistic Disorder / Q000139:chemically induced* / Q000175:diagnosis / Q000453:epidemiology; D002648:Child; D015331:Cohort Studies; D004827:Epilepsy / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology; D005260:Female; D006801:Humans; D008297:Male; D011247:Pregnancy; D011248:Pregnancy Complications / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000175:diagnosis / Q000453:epidemiology; D011446:Prospective Studies
chemical_list: D000927:Anticonvulsants
keywords: Anticonvulsant; Autism spectrum; Neurodevelopment; Prenatal; Valproate