Skip to main content Accessibility help

Prenatal risk factors for autism: comprehensive meta-analysis

  • Hannah Gardener (a1), Donna Spiegelman (a2) and Stephen L. Buka (a3)



The aetiology of autism is unknown, although prenatal exposures have been the focus of epidemiological research for over 40 years.


To provide the first quantitative review and meta-analysis of the association between maternal pregnancy complications and pregnancy-related factors and risk of autism.


PubMed, Embase and PsycINFO databases were searched for epidemiological studies that examined the association between pregnancy-related factors and autism. Forty studies were eligible for inclusion in the meta-analysis. Summary effect estimates were calculated for factors examined in multiple studies.


Over 50 prenatal factors have been examined. The factors associated with autism risk in the meta-analysis were advanced parental age at birth, maternal prenatal medication use, bleeding, gestational diabetes, being first born v. third or later, and having a mother born abroad. The factors with the strongest evidence against a role in autism risk included previous fetal loss and maternal hypertension, proteinuria, pre-eclampsia and swelling.


There is insufficient evidence to implicate any one prenatal factor in autism aetiology, although there is some evidence to suggest that exposure to pregnancy complications may increase the risk.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Prenatal risk factors for autism: comprehensive meta-analysis
      Available formats

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Prenatal risk factors for autism: comprehensive meta-analysis
      Available formats

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Prenatal risk factors for autism: comprehensive meta-analysis
      Available formats


Corresponding author

Hannah Gardener, Department of Neurology, University of Miami Miller School of Medicine, Post Office Box 016960 (M712), Miami, FL 33101, USA. Email:


Hide All

H.G. received a National Research Service Award grant from the Training Program in Psychiatric Epidemiology and Biostatistics (T32 MH17119). Partial funding was provided by the Stanley Medical Research Institute.

Declaration of interest




Hide All
1 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (4th edn, text revision) (DSM–IV–TR). APA, 2000.
2 Ozonoff, S, Goodlin-Jones, BL, Solomon, M. Evidence-based assessment of autism spectrum disorders in children and adolescents. J Clin Child Adolesc Psychol 2005; 34: 523–40.
3 Fombonne, E. The changing epidemiology of autism. J Appl Res Intellect Disabil 2005; 18: 281–94.
4 Klauck, SM. Genetics of autism spectrum disorder. Eur J Hum Genet 2006; 14: 714–20.
5 Bailey, A, Le Couteur, A, Gottesman, I, Bolton, P, Simonoff, E, Yuzda, E, et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 1995; 25: 6377.
6 Newschaffer, CJ, Fallin, D, Lee, NL. Heritable and noninheritable risk factors for autism spectrum disorders. Epidemiol Rev 2002; 24: 137–53.
7 Santangelo, SL, Tsatsanis, K. What is known about autism: genes, brain, and behavior. Am J Pharmacogenomics 2005; 5: 7192.
8 DiCicco-Bloom, E, Lord, C, Zwaigenbaum, L, Courchesne, E, Dager, SR, Schmitz, C, et al. The developmental neurobiology of autism spectrum disorder. J Neurosci 2006; 26: 6897–906.
9 Kolevson, A, Gross, R, Reichenberg, A. Prenatal and perinatal risk factors for autism: a review and integration of findings. Arch Pediatr Adolesc Med 2007; 161: 326–33.
10 Akçakin, M, Polat, S. A comparison of demographic and birth-related characteristics of autistic and intellectually handicapped children. Türk Psikiyatri Dergisi 1993; 4: 3946.
11 Badawi, N, Dixon, G, Felix, JF, Keogh, JM, Petterson, B, Stanley, FJ, et al. Autism following a history of newborn encephalopathy: more than a coincidence? Dev Med Child Neurol 2006; 48: 85–9.
12 Barak, Y, Ring, A, Sulkes, J, Gabbay, U, Elizur, A. Season of birth and autistic disorder in Israel. Am J Psychiatry 1995; 152: 798800.
13 Bolton, P, Pickles, A, Harrington, R, Macdonald, H, Rutter, M. Season of birth: issues, approaches and findings for autism. J Child Psychol Psychiatry 1992; 33: 509–30.
14 Brimacombe, M, Ming, X, Lamendola, M. Prenatal and birth complications in autism. Matern Child Health J 2007; 11: 73–9.
15 Burd, L, Severud, R, Kerbeshian, J, Klug, MG. Prenatal and perinatal risk factors for autism. J Perinat Med 1999; 27: 441–50.
16 Croen, L, Grether, J, Selvin, S. Descriptive epidemiology of autism in a California population: who is at risk? J Autism Dev Disord 2002; 32: 217–24.
17 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: 151–7.
18 Croen, LA, Yoshida, CK, Odouli, R, Newman, TB. Neonatal hyperbilirubinemia and risk of autism spectrum disorders. Pediatrics 2005; 115: e1358.
19 Cryan, E, Byrne, M, O'Donovan, A, O'Callaghan, E. Brief report: a case–control study of obstetric complications and later autistic disorder. J Autism Dev Disord 1996; 26: 453–60.
20 Deykin, EY MacMahon, B. Viral exposure and autism. Am J Epidemiol 1979; 109: 628–38.
21 Deykin, EY MacMahon, B. Pregnancy, delivery, and neonatal complications among autistic children. Am J Dis Child 1980; 134: 860–4.
22 Eaton, WW, Mortensen, PB, Thomsen, PH, Frydenberg, M. Obstetric complications and risk for severe psychopathology in childhood. J Autism Dev Disord 2001; 31: 279–85.
23 Finegan, J, Quarrington, B. Pre-, peri-, and neonatal factors and infantile autism. J Child Psychol Psychiatry 1979; 20: 119–28.
24 Gillberg, C Maternal age and infantile autism. J Autism Dev Disord 1980; 10: 293–7.
25 Gillberg, C. Do children with autism have March birthdays? Acta Psychiatr Scand 1990; 82: 152–6.
26 Glasson, EJ, Bower, C, Petterson, B, de Klerk, N, Chaney, G, Hallmayer, JC. Perinatal factors and the development of autism. Arch Gen Psychiatry 2004; 61: 618–27.
27 Guillem, P, Cans, C, Guinchat, V, Ratel, M, Jouk, P. Trends, perinatal characteristics, and medical conditions in pervasive developmental disorders. Dev Med Child Neurol 2006; 48: 896900.
28 Hultman, CM, Sparen, P, Cnattingius, S. Perinatal risk factors for infantile autism. Epidemiology 2002; 13: 417–23.
29 Juul-Dam, N, Townsend, J, Courchesne, E. Prenatal, perinatal, and neonatal factors in autism, pervasive developmental disorder-not otherwise specified, and the general population. Pediatrics 2001; 107: 63–8.
30 Klug, MG, Burd, L, Kerbeshian, J, Benz, B, Martsolf, JT. A comparison of the effects of parental risk markers on pre- and perinatal variables in multiple patient cohorts with fetal alcohol syndrome, autism, Tourette syndrome, and sudden infant death syndrome: an enviromic analysis. Neurotoxicol Teratol 2003; 25: 707–17.
31 Knobloch, H, Pasamanick, B. Some etiologic and prognostic factors in early infantile autism and psychosis. Pediatrics 1975; 55: 182–91.
32 Kocijan-Hercigonja, D, Remeta, D, Orehovac, M, Brkljacic, D. Prenatal, perinatal and neonatal factors in infantile autism. Acta Med Croatica 1991; 45: 357–62.
33 Larsson, HJ, Eaton, WW, Madsen, KM, Vestergaard, M, Olesen, AV, Agerbo, E, et al. Risk factors for autism: Perinatal factors, parental psychiatric history, and socioeconomic status. Am J Epidemiol 2005; 161: 916–25.
34 Lauritsen, MB, Pedersen, CB, Mortensen, PB. Effects of familial risk factors and place of birth on the risk of autism: a nationwide register-based study. J Child Psychol Psychiatry 2005; 46: 963–71.
35 Laxer, G, Rey, M, Ritvo, ER. A comparison of potentially pathologic factors in European children with autism, Down Syndrome, and multiple physical handicaps. J Autism Dev Disord 1988; 18: 308–14.
36 Levy, S, Zoltak, B, Saelens, T. A comparison of obstetrical records of autistic and nonautistic referrals for psychoeducational evaluations. J Autism Dev Disord 1988; 18: 573–81.
37 Lobascher, ME, Kingerlee, PE, Gubbay, SS. Childhood autism: an investigation of aetiological factors in twenty-five cases. Br J Psychiatry 1970; 117: 525–9.
38 Maimburg, RD, Vaeth, M. Perinatal risk factors and infantile autism. Acta Psychiatr Scand 2006; 114: 257–64.
39 Mason-Brothers, A, Ritvo, ER, Pingree, C, Petersen, PB, Jenson, WR, McMahon, WM, et al. The UCLA-University of Utah epidemiologic survey of autism: prenatal, perinatal, and postnatal factors. Pediatrics 1990; 86: 514–9.
40 Matsuishi, T, Yamashita, Y, Ohtani, Y, Ornitz, E, Kuriya, N, Murakami, Y, et al. Brief report: incidence of and risk factors for autistic disorder in neonatal intensive care unit survivors. J Autism Dev Disord 1999; 29: 161–6.
41 Piven, J, Simon, J, Chase, GA, Wzorek, M, Landa, R, Gayle, J, et al. The etiology of autism: pre-, peri-, and neonatal factors. J Am Acad Child Adolesc Psychiatry 1993; 32: 1256–63.
42 Reichenberg, A, Bresnahan, M, Rabinowitz, J, Lubin, G, Davidson, M. Advancing paternal age and autism. Arch Gen Psychiatry 2006; 63: 1026–32.
43 Soldin, OP, Lai, S, Lamm, SH, Mosee, S. Lack of a relation between human neonatal thyroxine and pediatric neurobehavioral disorders. Thyroid 2003; 13: 193–8.
44 Stein, D, Weizman, A, Ring, A, Barak, Y. Obstetric complications in individuals diagnosed with autism and in healthy controls. Compr Psychiatry 2006; 47: 6975.
45 Sugie, Y, Sugie, H, Fukuda, T, Ito, M. Neonatal factors in infants with Autistic Disorder and typically developing infants. Autism 2005; 9: 487–94.
46 Tanoue, Y, Oda, S, Asano, F, Kawashima, K. Epidemiology of infantile autism in Southern Ibaraki, Japan: differences in prevalence in birth cohorts. J Autism Dev Disord 1988; 18: 155–66.
47 Ward, AJ. A comparison and analysis of the presence of family problems during pregnancy of mothers of ‘autistic’ children and mothers of normal children. Child Psychiatry Hum Dev 1990; 20: 279–88.
48 Wier, ML, Yoshida, CK, Odouli, R, Grether, JK, Croen, LA. Congenital anomalies associated with autism spectrum disorders. Dev Med Child Neurol 2006; 48: 500–7.
49 Williams, G, Oliver, JM, Allard, A, Sears, L. Autism and associated medical and familial factors: a case control study. J Dev Phys Disabil 2003; 15: 335–49.
50 Atladottir, HO, Parner, ET, Schendel, D, Dalsgaard, S, Thomsen, PH, Thorsen, P. Variation in incidence of neurodevelopmental disorders with season of birth. Epidemiology 2007; 18: 240–5.
51 Beversdorf, DQ, Manning, SE, Hillier, A, Anderson, SL, Nordgren, RE, Walters, SE, et al. Timing of prenatal stressors and autism. J Autism Dev Disord 2005; 35: 471–8.
52 Bolton, PF, Murphy, M, Macdonald, H, Whitlock, B, Pickles, A, Rutter, M. Obstetric complications in autism: consequences or causes of the condition? J Am Acad Child Adolesc Psychiatry 1997; 36: 272–81.
53 Bryson, SE, Smith, IM, Eastwood, D. Obstetrical suboptimality in autistic children. J Am Acad Child Adolesc Psychiatry 1988; 27: 418–22.
54 Deb, S, Prasad, KBG, Seth, H, Eagles, JM. A comparison of obstetric and neonatal complications between children with autistic disorder and their siblings. J Intellect Disabil Res 1997; 41: 81–6.
55 Gillberg, C, Gillberg, IC. Infantile autism: a total population study of reduced optimality in the pre-, peri-, and neonatal period. J Autism Dev Disord 1983; 13: 153–66.
56 Harper, J, Williams, S. Early environmental stress and infantile autism. Med J Aus 1974; 1: 341–6.
57 Hazlett, HC, Poe, M, Gerig, G, Smith, RG, Provenzale, J, Ross, A, et al. Magnetic resonance imaging and head circumference study of brain size in autism: birth through age 2 years. Arch Gen Psychiatry 2005; 62: 1366–76.
58 Konstantareas, MM, Hauser, P, Lennox, C, Homatidis, S. Season of birth in infantile autism. Child Psychiatry Hum Dev 1986; 17: 5365.
59 Li, S, Yang, X, Jia, M. A study of perinatal risk factors in patients with autism. Chin J Psychiatry 1998; 31: 178–80.
60 Links, PS, Stockwell, M, Abichandani, F, Simeon, J. Minor physical anomalies in childhood autism. Part I. Their relationship to pre-and perinatal complications. J Autism Dev Disord 1980; 10: 273–85.
61 Lord, C, Mulloy, C, Wendelboe, M, Schopler, E. Pre- and perinatal factors in high-functioning females and males with autism. J Autism Dev Disord 1991; 21: 197209.
62 Mouridsen, SE, Nielsen, S, Rich, B, Isager, T. Season of birth in infantile autism and other types of childhood psychoses. Child Psychiatry Hum Dev 1994; 25: 3143.
63 Mouridsen, SE, Rich, B, Isager, T. Brief report: parental age in infantile autism, autistic-like conditions, and borderline childhood psychosis. J Autism Dev Disord 1993; 23: 387–96.
64 Park, RJ, Bolton, PF. Pervasive developmental disorder and obstetric complications in children and adolescents with tuberous sclerosis. Autism 2001; 5: 237–48.
65 Steffenberg, S, Gillberg, C, Hellgren, L, Andersson, L, Gillberg, IC, Jakobsson, G, et al. A twin study of autism in Denmark, Finland, Iceland, Norway, and Sweden. J Child Psychol Psychiatry 1989; 30: 405–16.
66 Stevens, MC, Fein, DH, Waterhouse, LH. Season of birth effects in autism. J Clin Exp Neuropsychol 2000; 22: 399407.
67 Torrey, EF, Dhavale, D, Lawlor, JP, Yolken, RH. Autism and head circumference in the first year of life. Biol Psychiatry 2004; 56: 892–4.
68 Torrey, EF, Hersh, SP, McCabe, KD. Early childhood psychosis and bleeding during pregnancy. A prospective study of gravid women and their offspring. J Autism Child Schizophr 1975; 5: 287–97.
69 Tsai, LY, Stewart, MA. Etiological implications of maternal age and birth order in infantile autism. J Autism Dev Disord 1983; 13: 5765.
70 Wilkerson, DS, Volpe, AG, Dean, RS, Titus, JB. Perinatal complications as predictors of infantile autism. Int J Neurosci 2002; 112: 1085–98.
71 Yeates-Frederikx, MH, Nijman, H, Logher, E, Merckelbach, HL. Birth patterns in mentally retarded autistic patients. J Autism Dev Disord 2000; 30: 257–62.
72 Zambrino, CA, Balottin, U, Bettaglio, E, Gerardo, A, Lanzi, G. Obstetrical suboptimality in autistic children: An Italian sample. J Autism Dev Disord 1997; 27: 493–4.
73 Zwaigenbaum, L, Szatmari, P, Jones, MB, Bryson, SE, MacLean, JE, Mahoney, WJ. Pregnancy and birth complications in autism and liability to the broader autism phenotype. J Am Acad Child Adolesc Psychiatry 2002; 41: 572–9.
74 DerSimonian, R, Laird, N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 177–88.
75 Takkouche, B, Cadarso-Suarez, C, Spiegelman, D. Evaluation of old and new tests of heterogeneity in epidemiologic meta-analysis. Am J Epidemiol 1999; 150: 206–15.
76 Greenland, S, Longnecker, MP. Methods for trend estimation from summarized dose-response data, with applications to meta-analysis. Am J Epidemiol 1992; 135: 1301–9.
77 Sterne, JAC, Bradburn, MJ, Egger, M. Meta-analysis in stata. In Systematic Reviews in Health Care: Meta-analysis in Context (eds Egger, M, Smith, GD, Altman, DG): 8695. BMJ Publishing Group, 2006.
78 Higgins, JP, Thompson, SG, Deeks, JJ, Altman, DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327: 557–60.
79 Sharp, S. Meta-analysis regression. Stata Technical Bulletin 1998; 42: 1624.
80 Stram, DO. Meta-analysis of published data using a linear mixed-effects model. Biometrics 1996; 52: 536–44.
81 Khoshdel, A, Attia, J, Carney, SL. Basic concepts in meta-analysis. A primer for clinicians. Int J Clin Pract 2006; 60: 1287–94.
82 Begg, CB, Mazumdar, M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994; 50: 1088–101.
83 Egger, M, Smith, GD, Schneider, M, Minder, C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315: 629–34.
84 Sterne, JAC, Gavaghan, D, Egger, M. Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol 2000; 53: 1119–29.
85 Rosenthal, AN, Paterson-Brown, S. Is there an incremental rise in the risk of obstetric intervention with increasing maternal age? Br J Obstet Gynaecol 1998; 105: 1064–9.
86 Ezra, Y, McParland, P, Farine, D. High delivery intervention rates in nulliparous women over age 35. Eur J Obstet Gynecol Reprod Biol 1995; 62: 203–7.
87 Kazmaura, MR, Lie, RT. Down's syndrome and paternal age in Norway. Paedaitr Perinat Epidemiol 2002; 16: 314–9.
88 Tang, C, Wu, M, Liu, J, Lin, H, Hsu, C. Delayed parenthood and the risk of Cesarean delivery – is paternal age an independent risk factor? Birth 2006; 33: 1826.
89 Jones, MB, Szatmari, P. Stoppage rules and genetic studies of autism. J Autism Dev Disord 1988; 18: 3140.
90 Gillberg, C, Schaumann, H, Gillberg, IC. Autism in immigrants: children born to in Sweden to mothers born in Uganda. J Intellect Disabil Res 1995; 39; 141–4.
91 Previc, FH. Prenatal influences on brain dopamine and their relevance to the rising incidence of autism. Med Hypotheses 2007; 68: 4660.
92 Ben-Haroush, A, Yogev, Y, Hod, M. Epidemiology of gestational diabetes mellitus and its association with type 2 diabetes. Diabet Med 2004; 21: 103–13.
93 Catalano, PM, Kirwan, JP, Haugel-de Mouzon, S, King, J. Gestational diabetes and insulin resistance: Role in short- and long-term implications for mother and fetus. J Nutr 2003; 133: s167483.
94 Eidelman, AI, Samueloff, A. The pathophysiology of the fetus of the diabetic mother. Semin Perinatol 2002; 26: 232–6.
95 Biri, A, Onan, A, Devrim, E, Babacan, F, Kavutcu, M, Durak, I. Oxidant status in maternal and cord plasma and placental tissue in gestational diabetes. Placenta 2006; 27: 327–32.
96 Martin, JA, Hamilton, BE, Ventura, SJ, Menacker, F, Park, MM. Births: final data for 2000. Natl Vital Stat Rep 2002; 50: 1101.
97 Stroup, DF, Berlin, JA, Morton, SC, Olkin, I, Williamson, GD, Rennie, D, et al. Meta-analysis of observational studies for epidemiology: a proposal for reporting. JAMA 2000; 283: 2008–12.

Related content

Powered by UNSILO
Type Description Title
Supplementary materials

Gardener et al. supplementary material
Supplementary Table S1

 PDF (40 KB)
40 KB

Prenatal risk factors for autism: comprehensive meta-analysis

  • Hannah Gardener (a1), Donna Spiegelman (a2) and Stephen L. Buka (a3)


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed.

Prenatal risk factors for autism: comprehensive meta-analysis

  • Hannah Gardener (a1), Donna Spiegelman (a2) and Stephen L. Buka (a3)
Submit a response


No eLetters have been published for this article.


Reply to: Submit a response

Your details

Conflicting interests

Do you have any conflicting interests? *