Autism Spectrum Disorder and Associated Risk Factors: A Matched Case-Control Study

Document Type: Original Article


1 Students Research Committee, Hamadan University of Medical Sciences, Hamadan, Iran/Department of Biostatistics, School of Public Health, Hamadan University of Medical Sciences, Hamadan, Iran

2 Students Research Committee, Hamadan University of Medical Sciences, Hamadan, Iran

3 Department of Epidemiology, School of Public Health, Hamadan University of Medical Sciences, Hamadan, Iran /Modeling of Noncommunicable Diseases Research Center, School of Public Health, Hamadan University of Medical Sciences, Hamadan, Iran


Background and aims: Despite substantial advances in the etiology of autism spectrum disorder (ASD),
the environmental risk factors have not yet been well understood. The present study investigated the
association between ASD, and maternal and perinatal risk factors.
Methods: This matched, case-control study was conducted in Hamadan, the west of Iran, from
November 2015 to May 2016. We enrolled 41 children with ASD aged 3-17 years. We selected four
controls per one case from the same hospital where patients were born. Controls were separately
matched with cases for sex, age, and birth year.
Results: We compared 41 ASD cases with 164 controls. After adjusting the odds ratio (95% CI),
ASD was significantly associated with third-degree relatives consanguinity [3.29 (1.39, 7.75)], short
birth length [4.99 (1.15, 21.60)], short head circumference [7.87 (1.48, 41.76), respiratory distress
syndrome at birth 3.97 (1.91, 8.22)], respiratory assistance at birth [2.92 (1.39, 6.10)], birth hypoxia
[2.85 (1.35, 5.99)], and low 1-minute Apgar score [3.65 (1.04, 12.75)].
Conclusions: Our findings suggest that ASD may be associated with multiple maternal and perinatal
risk factors. Evidence based on large prospective multicenter cohort studies is required to indicate the
impacts of maternal and perinatal exposures.


Main Subjects

1. American Psychiatric Association (APA). Diagnostic and
statistical manual of mental disorders. 5th ed. Arlington: APA;
2. Prevalence of autism spectrum disorder among children aged
8 years - autism and developmental disabilities monitoring
network, 11 sites, United States, 2010. MMWR Surveill
Summ. 2014;63(2):1-21.
3. Christensen DL, Baio J, Van Naarden Braun K, Bilder D,
Charles J, Constantino JN, et al. Prevalence and Characteristics
of Autism Spectrum Disorder Among Children Aged 8 Years--
Autism and Developmental Disabilities Monitoring Network,
11 Sites, United States, 2012. MMWR Surveill Summ.
2016;65(3):1-23. doi: 10.15585/mmwr.ss6503a1.
4. Fombonne E. Epidemiology of pervasive developmental
disorders. Pediatr Res. 2009;65(6):591-8. doi: 10.1203/
5. Chakrabarti S, Fombonne E. Pervasive developmental
disorders in preschool children. JAMA. 2001;285(24):3093-9.
6. Baird G, Simonoff E, Pickles A, Chandler S, Loucas T,
Meldrum D, et al. Prevalence of disorders of the autism
spectrum in a population cohort of children in South Thames:
the Special Needs and Autism Project (SNAP). Lancet.
2006;368(9531):210-5. doi: 10.1016/s0140-6736(06)69041-
7. Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen
B, Torigoe T, et al. Genetic heritability and shared
environmental factors among twin pairs with autism. Arch
Gen Psychiatry. 2011;68(11):1095-102. doi: 10.1001/
8. Muhle R, Trentacoste SV, Rapin I. The genetics of autism.
Pediatrics. 2004;113(5):e472-86.
9. Gardener H, Spiegelman D, Buka SL. Perinatal and neonatal
risk factors for autism: a comprehensive meta-analysis.
Pediatrics. 2011;128(2):344-55. doi: 10.1542/peds.2010-
10. Krakowiak P, Walker CK, Bremer AA, Baker AS, Ozonoff S,
Hansen RL, et al. Maternal metabolic conditions and risk for
autism and other neurodevelopmental disorders. Pediatrics.
2012;129(5):e1121-8. doi: 10.1542/peds.2011-2583.
11. Xiang AH, Wang X, Martinez MP, Walthall JC, Curry ES,
Page K, et al. Association of maternal diabetes with autism
in offspring. JAMA. 2015;313(14):1425-34. doi: 10.1001/
12. Reichenberg A, Gross R, Weiser M, Bresnahan M, Silverman
J, Harlap S, et al. Advancing paternal age and autism.
Arch Gen Psychiatry. 2006;63(9):1026-32. doi: 10.1001/
13. Croen LA, Najjar DV, Fireman B, Grether JK. Maternal and
paternal age and risk of autism spectrum disorders. Arch
Pediatr Adolesc Med. 2007;161(4):334-40. doi: 10.1001/
14. Grether JK, Anderson MC, Croen LA, Smith D, Windham
GC. Risk of autism and increasing maternal and paternal
age in a large north American population. Am J Epidemiol.
2009;170(9):1118-26. doi: 10.1093/aje/kwp247.
15. Sandin S, Hultman CM, Kolevzon A, Gross R, MacCabe JH,
Reichenberg A. Advancing maternal age is associated with
increasing risk for autism: a review and meta-analysis. J Am
Acad Child Adolesc Psychiatry. 2012;51(5):477-86.e1. doi:
16. Pinto-Martin JA, Levy SE, Feldman JF, Lorenz JM, Paneth
N, Whitaker AH. Prevalence of autism spectrum disorder
in adolescents born weighing <2000 grams. Pediatrics.
2011;128(5):883-91. doi: 10.1542/peds.2010-2846.
17. Gilliam JE. Gilliam Autism Rating Scale. 2nd ed. (GARS-2)
Pearson Education Limited; 2005.
18. Mosrati MA, Schrauwen I, Kamoun H, Charfeddine I, Fransen
E, Ghorbel A, et al. Genome wide analysis in a family with
sensorineural hearing loss, autism and mental retardation.
Gene. 2012;510(2):102-6. doi: 10.1016/j.gene.2012.09.006.
19. Mamidala MP, Kalikiri MK, Praveen Kumar PT, Rajesh N,
Vallamkonda OR, Rajesh V. Consanguinity in India and
its association with autism spectrum disorder. Autism Res.
2015;8(2):224-8. doi: 10.1002/aur.1431.
20. Al-Owain M, Kaya N, Al-Shamrani H, Al-Bakheet A, Qari
A, Al-Muaigl S, et al. Autism spectrum disorder in a child
with propionic acidemia. JIMD Rep. 2013;7:63-6. doi:
21. Hamade A, Salameh P, Medlej-Hashim M, Hajj-Moussa E,
Saadallah-Zeidan N, Rizk F. Autism in children and correlates
in Lebanon: a pilot case-control study. J Res Health Sci.
22. Meguid NA, Hashish AF, Anwar M, Sidhom G. Reduced
serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D
in Egyptian children with autism. J Altern Complement Med.
2010;16(6):641-5. doi: 10.1089/acm.2009.0349.
23. Maramara LA, He W, Ming X. Pre- and perinatal risk factors for
autism spectrum disorder in a New Jersey cohort. J Child Neurol.
2014;29(12):1645-51. doi: 10.1177/0883073813512899.
24. Burstyn I, Wang X, Yasui Y, Sithole F, Zwaigenbaum L. Autism
spectrum disorders and fetal hypoxia in a population-based
cohort: accounting for missing exposures via Estimation-
Maximization algorithm. BMC Med Res Methodol. 2011;11:2.
doi: 10.1186/1471-2288-11-2.
25. Kolevzon A, Gross R, Reichenberg A. Prenatal and perinatal
risk factors for autism: a review and integration of findings.
Arch Pediatr Adolesc Med. 2007;161(4):326-33. doi: 10.1001/
26. van Handel M, Swaab H, de Vries LS, Jongmans MJ. Long 

term cognitive and behavioral consequences of neonatal
encephalopathy following perinatal asphyxia: a review. Eur J
Pediatr. 2007;166(7):645-54. doi: 10.1007/s00431-007-0437-
27. Rei M, Ayres-de-Campos D, Bernardes J. Neurological
damage arising from intrapartum hypoxia/acidosis. Best Pract
Res Clin Obstet Gynaecol. 2016;30:79-86. doi: 10.1016/j.
28. Cengiz P, Uluc K, Kendigelen P, Akture E, Hutchinson E, Song
C, et al. Chronic neurological deficits in mice after perinatal
hypoxia and ischemia correlate with hemispheric tissue loss
and white matter injury detected by MRI. Dev Neurosci.
2011;33(3-4):270-9. doi: 10.1159/000328430.
29. Schieve LA, Clayton HB, Durkin MS, Wingate MS, Drews-
Botsch C. Comparison of Perinatal Risk Factors Associated
with Autism Spectrum Disorder (ASD), Intellectual Disability
(ID), and Co-occurring ASD and ID. J Autism Dev Disord.
2015;45(8):2361-72. doi: 10.1007/s10803-015-2402-0.
30. Polo-Kantola P, Lampi KM, Hinkka-Yli-Salomaki S, Gissler
M, Brown AS, Sourander A. Obstetric risk factors and autism
spectrum disorders in Finland. J Pediatr. 2014;164(2):358-65.
doi: 10.1016/j.jpeds.2013.09.044.
31. 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(6):618-27.
doi: 10.1001/archpsyc.61.6.618.