Abstract
Background
We explored the association of 29 previously reported neonatal, perinatal, and prenatal conditions, and exposures with later diagnosis of autism spectrum disorder (ASD) in a large sample of children followed over multiple years.
Methods
A retrospective case–cohort study was formed using the Military Health System database. Cases were identified by International Classification of Diseases, Ninth Revision codes for ASD between 2000 and 2013, and were matched 3:1 with controls on sex, date of birth, and enrollment time frame. Exposures included 29 conditions previously associated with ASD; 17 prenatal conditions and their pharmaceutical treatment, 5 perinatal conditions, and 6 neonatal conditions.
Results
A total of 8,760 children diagnosed with ASD between the ages of 2 and 18 years were matched with 26,280 controls. ASD is associated with maternal mental illness, epilepsy, obesity, hypertension, diabetes, polycystic ovary syndrome, infection, asthma, assisted fertility, hyperemesis, younger maternal age, labor complications, low birth weight, infant infection, epilepsy, birth asphyxia, and newborn complications. The greatest increased risk was associated with infant epilepsy (odds ratio (OR) 7.57 (5.68–10.07)), maternal mental health (OR 1.80 (1.65–1.96)), and epilepsy (OR 1.60 (1.02–2.50)) medications.
Conclusion
ASD is associated with a range of prenatal, perinatal, and neonatal factors, with the highest magnitude associations with maternal medication use and neonatal seizure.
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References
Prevention, C.f.D.C.aAutism Spectrum Disorder. Data & Statistics 2016 March 31, 2016 [cited 2016 May 19, 2016]; Available at http://www.cdc.gov/ncbddd/autism/data.html.
Leonard H, de Klerk N, Bourke J, Bower C. Maternal health in pregnancy and intellectual disability in the offspring: a population-based study. Ann Epidemiol 2006;16:448–454.
Davis E, Fennoy I, Laraque D, Kanem N, Brown G, Mitchell J. Autism and developmental abnormalities in children with perinatal cocaine exposure. J Natl Med Assoc 1992;84:315–319.
Zhang X, Lv CC, Tian J et al. Prenatal and perinatal risk factors for autism in China. J Autism Dev Disord 2010;40:1311–1321.
Sorensen MJ, Grønborg TK, Christensen J et al. Antidepressant exposure in pregnancy and risk of autism spectrum disorders. Clin Epidemiol 2013;5:449–459.
Dodds L, Fell DB, Shea S, Armson BA, Allen AC, Bryson S. The role of prenatal, obstetric and neonatal factors in the development of autism. J Autism Dev Disord 2011;41:891–902.
Larsson HJ, Eaton WW, Madsen KM et al. Risk factors for autism: perinatal factors, parental psychiatric history, and socioeconomic status. Am J Epidemiol 2005;161:916–925 discussion 926–928.
Duan G, Yao M, Ma Y, Zhang W. Perinatal and background risk factors for childhood autism in central China. Psychiatry Res 2014;220:410–417.
Wood AG, Nadebaum C, Anderson V et al. Prospective assessment of autism traits in children exposed to antiepileptic drugs during pregnancy. Epilepsia 2015;56:1047–1055.
Eriksson MA, Westerlund J, Anderlid BM, Gillberg C, Fernell E. First-degree relatives of young children with autism spectrum disorders: some gender aspects. Res Dev Disabil 2012;33:1642–1648.
Gidaya NB, Lee BK, Burstyn I, Yudell M, Mortensen EL, Newschaffer CJ. In utero exposure to selective serotonin reuptake inhibitors and risk for autism spectrum disorder. J Autism Dev Disord 2014;44:2558–2567.
Gardner RM, Lee BK, Magnusson C et al. Maternal body mass index during early pregnancy, gestational weight gain, and risk of autism spectrum disorders: results from a Swedish total population and discordant sibling study. Int J Epidemiol 2015;44:870–883.
Gardener H, Spiegelman D, Buka SL. Prenatal risk factors for autism: comprehensive meta-analysis. Br J Psychiatry 2009;195:7–14.
Guinchat V, Thorsen P, Laurent C, Cans C, Bodeau N, Cohen D. Pre-, peri- and neonatal risk factors for autism. Acta Obstet Gynecol Scand 2012;91:287–300.
Atladottir HO, Pedersen MG, Thorsen P et al. Association of family history of autoimmune diseases and autism spectrum disorders. Pediatrics 2009;124:687–694.
Mamidala MP, Polinedi A, PK PTV et al. Prenatal, perinatal and neonatal risk factors of Autism Spectrum Disorder: a comprehensive epidemiological assessment from India. Res Dev Disabil 2013;34:3004–3013.
Burstyn I, Sithole F, Zwaigenbaum L. Autism spectrum disorders, maternal characteristics and obstetric complications among singletons born in Alberta, Canada. Chronic Dis Can 2010;30:125–134.
Kosidou K, Dalman C, Widman L et al. Maternal polycystic ovary syndrome and the risk of autism spectrum disorders in the offspring: a population-based nationwide study in Sweden. Mol Psychiatry 2015;21:1441–1448.
Atladottir HO, Henriksen TB, Schendel DE, Parner ET. Autism after infection, febrile episodes, and antibiotic use during pregnancy: an exploratory study. Pediatrics 2012;130:e1447–e1454.
Li M, Fallin MD, Riley A et al. The association of maternal obesity and diabetes with autism and other developmental disabilities. Pediatrics 2016;137:e20152206.
Brown AS, Surcel HM, Hinkka-Yli-Salomäki S, Cheslack-Postava K, Bao Y, Sourander A. Maternal thyroid autoantibody and elevated risk of autism in a national birth cohort. Prog Neuropsychopharmacol Biol Psychiatry 2015;57:86–92.
Croen LA, Grether JK, Yoshida CK, Odouli R, Van de Water J. Maternal autoimmune diseases, asthma and allergies, and childhood autism spectrum disorders: a case–control study. Arch Pediatr Adolesc Med 2005;159:151–157.
Gidaya NB, Lee BK, Burstyn I, Michael Y, Newschaffer CJ, Mortensen EL. In utero exposure to beta-2-adrenergic receptor agonist drugs and risk for autism spectrum disorders. Pediatrics 2016;137:e20151316.
Mamidala MP, Polinedi A, Kumar PT et al. Maternal hormonal interventions as a risk factor for Autism Spectrum Disorder: an epidemiological assessment from India. J Biosci 2013;38:887–892.
Froehlich-Santino W, Londono Tobon A, Cleveland S et al. Prenatal and perinatal risk factors in a twin study of autism spectrm disorders. J Psychiatric Res 2014;54:100–108.
Bilder D, Pinborough-Zimmerman J, Miller J, McMahon W. Prenatal, perinatal, and neonatal factors associated with autism spectrum disorders. Pediatrics 2009;123:1293–1300.
Maimburg RD, Vaeth M. Perinatal risk factors and infantile autism. Acta Psychiatr Scand 2006;114:257–264.
Gardener H, Spiegelman D, Buka SL. Perinatal and neonatal risk factors for autism: a comprehensive meta-analysis. Pediatrics 2011;128:344–355.
Glasson EJ, Bower C, Petterson B, de Klerk N, Chaney G, Hallmayer JF. Perinatal factors and the development of autism: a population study. Arch Gen Psychiatry 2004;61:618–627.
Sugie Y, Sugie H, Fukuda T, Ito M. Neonatal factors in infants with Autistic Disorder and typically developing infants. Autism 2005;9:487–494.
Polo-Kantola P, Lampi KM, Hinkka-Yli-Salomäki S, Gissler M, Brown AS, Sourander A. Obstetric risk factors and autism spectrum disorders in Finland. J Pediatr 2014;164:358–365.
International, I.2014 Demographics Profile of the Military Community, O.o.t.D.A.S.o. Defense, Editor. 2014, Department of Defense. p 200.
Atladottir HO, Schendel DE, Parner ET, Henriksen TB. A descriptive study on the neonatal morbidity profile of autism spectrum disorders, including a comparison with other neurodevelopmental disorders. J Autism Dev Disord 2015;45:2429–2442.
Andersen SL, Laurberg P, Wu CS, Olsen J. Attention deficit hyperactivity disorder and autism spectrum disorder in children born to mothers with thyroid dysfunction: a Danish nationwide cohort study. BJOG 2014;121:1365–1374.
Coleman KJ, Lutsky MA, Yau V et al. Validation of autism spectrum disorder diagnoses in large healthcare systems with electronic medical records. J Autism Dev Disord 2015;45:1989–1996.
Zu G, Jing J, Bowers K, Liu B, Bao W. Maternal diabetes and the risk of autism spectrum disorders in the offspring: a systematic review and meta-analysis. J Autism Dev Disord 2014;44:766–775.
Meldrum SJ, Strunk T, Currie A, Prescott SL, Simmer K, Whitehouse AJ. Autism spectrum disorder in children born preterm-role of exposure to perinatal inflammation. Front Neurosci 2013;7:123.
Roman GC, Ghassabian A, Bongers-Schokking JJ et al. Association of gestational maternal hypothyroxinemia and increased autism risk. Ann Neurol 2013;74:733–742.
Maimburg RD, Vaeth M. Do children born after assisted conception have less risk of developing infantile autism? Hum Reprod 2007;22:1841–1843.
Wu YW, Kuzniewicz MW, Croen L, Walsh EM, McCulloch CE, Newman TB. Risk of autism associated with hyperbilirubinemia and phototherapy. Pediatrics 2016;138:e20161813.
Acknowledgments
This study was conducted with support from the Congressional Directed Medical Research Program, Autism Research Award: W81XWH-12-2-0066 to C.M.N..
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The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the United States Departments of the Navy, Air Force, Defense, or the US Government. Some authors are a military service member or a US Government employee. This work was prepared as part of their official duties. Title 17 USC 105 provides that “Copyright protection under this title is not available for any work of the United States Government.” Title 17 USC 101 defines a United States Government work as a work prepared by a military service member or employee of the United States Government as part of that person’s official duties.
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Hisle-Gorman, E., Susi, A., Stokes, T. et al. Prenatal, perinatal, and neonatal risk factors of autism spectrum disorder. Pediatr Res 84, 190–198 (2018). https://doi.org/10.1038/pr.2018.23
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DOI: https://doi.org/10.1038/pr.2018.23
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