title: Extremely low gestational age and very low birthweight for gestational age are risk factors for autism spectrum disorder in a large cohort study of 10-year-old children born at 23-27 weeks' gestation.
abstract: BACKGROUND
  No prospective cohort study of high-risk children has used rigorous exposure assessment and optimal diagnostic procedures to examine the perinatal antecedents of autism spectrum disorder separately among those with and without cognitive impairment.
  
  
  OBJECTIVE
  We sought to identify perinatal factors associated with increased risk for autism spectrum disorder with and without intellectual disability (intelligence quotient <70) in children born extremely preterm.
  
  
  METHODS
  This prospective multicenter (14 institutions in 5 states) birth cohort study included children born at 23-27 weeks' gestation in 2002 through 2004 who were evaluated for autism spectrum disorder and intellectual disability at age 10 years. Pregnancy information was obtained from medical records and by structured maternal interview. Cervical-vaginal "infection" refers to maternal report of bacterial infection (n = 4), bacterial vaginosis (n = 30), yeast infection (n = 62), mixed infection (n = 4), or other/unspecified infection (n = 43; eg, chlamydia, trichomonas, or herpes). We do not know the extent to which infection per se was confirmed by microbial colonization. We use the terms "fetal growth restriction" and "small for gestational age" interchangeably in light of the ongoing challenge to discern pathologically from constitutionally small newborns. Severe fetal growth restriction was defined as a birthweight Z-score for gestational age at delivery <-2 (ie, ≥2 SD below the median birthweight in a referent sample that excluded pregnancies delivered for preeclampsia or fetal indications). Participants were classified into 4 groups based on whether or not they met rigorous diagnostic criteria for autism spectrum disorder and intellectual disability (autism spectrum disorder+/intellectual disability-, autism spectrum disorder+/intellectual disability+, autism spectrum disorder-/intellectual disability+, and autism spectrum disorder-/intellectual disability-). Temporally ordered multinomial logistic regression models were used to examine the information conveyed by perinatal factors about increased risk for autism spectrum disorder and/or intellectual disability (autism spectrum disorder+/intellectual disability-, autism spectrum disorder+/intellectual disability+, and autism spectrum disorder-/intellectual disability+).
  
  
  RESULTS
  In all, 889 of 966 (92%) children recruited were assessed at age 10 years, of whom 857 (96%) were assessed for autism spectrum disorder; of these, 840 (98%) children were assessed for intellectual disability. Autism spectrum disorder+/intellectual disability- was diagnosed in 3.2% (27/840), autism spectrum disorder+/intellectual disability+ in 3.8% (32/840), and autism spectrum disorder-/intellectual disability+ in 8.5% (71/840). Maternal report of presumed cervical-vaginal infection during pregnancy was associated with increased risk of autism spectrum disorder+/intellectual disability+ (odds ratio, 2.7; 95% confidence interval, 1.2-6.4). The lowest gestational age category (23-24 weeks) was associated with increased risk of autism spectrum disorder+/intellectual disability+ (odds ratio, 2.9; 95% confidence interval, 1.3-6.6) and autism spectrum disorder+/intellectual disability- (odds ratio, 4.4; 95% confidence interval, 1.7-11). Severe fetal growth restriction was strongly associated with increased risk for autism spectrum disorder+/intellectual disability- (odds ratio, 9.9; 95% confidence interval, 3.3-30), whereas peripartum maternal fever was uniquely associated with increased risk of autism spectrum disorder-/intellectual disability+ (odds ratio, 2.9; 95% confidence interval, 1.2-6.7).
  
  
  CONCLUSIONS
  Our study confirms that low gestational age is associated with increased risk for autism spectrum disorder irrespective of intellectual ability, whereas severe fetal growth restriction is strongly associated with autism spectrum disorder without intellectual disability. Maternal report of cervical-vaginal infection is associated with increased risk of autism spectrum disorder with intellectual disability, and peripartum maternal fever is associated with increased risk for intellectual disability without autism spectrum disorder.
authors.affiliation: Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Joseph
authors.affiliation: Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA.|Department of Epidemiology & Biostatistics, Michigan State University, East Lansing, MI, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Korzeniewski
authors.affiliation: Boston Children's Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: Elizabeth N
authors.initials: EN
authors.lastname: Allred
authors.affiliation: Department of Pediatrics, University of North Carolina, Chapel Hill NC, USA.
authors.forename: T Michael
authors.initials: TM
authors.lastname: O'Shea
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Heeren
authors.affiliation: University of Massachusetts Memorial Health Care and University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Jean A
authors.initials: JA
authors.lastname: Frazier
authors.affiliation: Boston Children's Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: Janice
authors.initials: J
authors.lastname: Ware
authors.affiliation: Department of Pediatrics, Boston Medical Center, Boston, MA, USA.|The University of Vermont Medical Center, Burlington, VT, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Hirtz
authors.affiliation: Boston Children's Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Leviton
authors.affiliation: Department of Pediatrics, Boston Medical Center, Boston, MA, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Kuban
mesh_terms: D000067877:Autism Spectrum Disorder / Q000150:complications / Q000453:epidemiology*; D002648:Child; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age; D019102:Infant, Very Low Birth Weight; D008607:Intellectual Disability / Q000150:complications / Q000453:epidemiology*; D008297:Male; D011247:Pregnancy; D011446:Prospective Studies; D012307:Risk Factors
keywords: autism; cervical-vaginal infection; extremely preterm delivery; fetal growth restriction; intellectual disability