Journal of Autism and Developmental Disorders

, Volume 41, Issue 11, pp 1455–1463

Is Neonatal Jaundice Associated with Autism Spectrum Disorders: A Systematic Review

Original paper


Using guidelines of the Meta-analysis of Observational Studies in Epidemiology Group, we systematically reviewed the literature on neonatal jaundice (unconjugated hyperbilirubinemia) and Autism Spectrum Disorder (ASD) in term and preterm infants. Thirteen studies were included in a meta-analysis. Most used retrospective matched case–control designs. There was significant heterogeneity (Q = 31, p = 0.002) and no evidence of publication bias (p = 0.12). Overall, jaundice, assessed by total serum bilirubin (TSB), was associated with ASD (OR, 1.43, 95% CI 1.22–1.67, random effect model). This association was not found in preterms (OR 0.7, 95% CI 0.38–1.02) but deserves further investigation since other measures of bilirubin such as unbound unconjugated bilirubin may be better predictors of neurotoxicity than TSB in preterms.


Unconjugated hyperbilirubinemia Free bilirubin Premature infants Meta-analysis 


  1. Ahdab-Barmada, M., & Moossy, J. (1984). The neuropathology of kernicterus in the premature neonate: Diagnostic problems. Journal of Neuropathology and Experimental Neurology, 43(1), 45–56.PubMedCrossRefGoogle Scholar
  2. Ahlfors, C. E. (2001). Bilirubin–albumin binding and free bilirubin. Journal of Perinatology, 21(Suppl. 1), S40–42; discussion S59–62.Google Scholar
  3. Ahlfors, C. E., Amin, S. B., & Parker, A. E. (2009). Unbound bilirubin predicts abnormal automated auditory brainstem response in a diverse newborn population. Journal of Perinatology, 29(4), 305–309.PubMedCrossRefGoogle Scholar
  4. Ahlfors, C. E., & Parker, A. E. (2008). Unbound bilirubin concentration is associated with abnormal automated auditory brainstem response for jaundiced newborns. Pediatrics, 121(5), 976–978.PubMedCrossRefGoogle Scholar
  5. Amin, S. B. (2004). Clinical assessment of bilirubin-induced neurotoxicity in premature infants. Seminars in Perinatology, 28(5), 340–347.PubMedCrossRefGoogle Scholar
  6. Amin, S. B., Ahlfors, C., Orlando, M. S., Dalzell, L. E., Merle, K. S., & Guillet, R. (2001). Bilirubin and serial auditory brainstem responses in premature infants. Pediatrics, 107(4), 664–670.PubMedCrossRefGoogle Scholar
  7. Amin, S. B., Charafeddine, L., & Guillet, R. (2005). Transient bilirubin encephalopathy and apnea of prematurity in 28 to 32 weeks gestational age infants. Journal of Perinatology, 25(6), 386–390.PubMedCrossRefGoogle Scholar
  8. Amin, S. B., Prinzing, D., & Myers, G. (2009). Hyperbilirubinemia and language delay in premature infants. Pediatrics, 123(1), 327–331.PubMedCrossRefGoogle Scholar
  9. Bauman, M. L., & Kemper, T. L. (2005). Neuroanatomic observations of the brain in autism: A review and future directions. International Journal of Developmental Neuroscience, 23(2–3), 183–187.PubMedCrossRefGoogle Scholar
  10. Bertrand, J., Mars, A., Boyle, C., Bove, F., Yeargin-Allsopp, M., & Decoufle, P. (2001). Prevalence of autism in a United States population: The Brick Township, New Jersey, investigation. Pediatrics, 108(5), 1155–1161.PubMedCrossRefGoogle Scholar
  11. Bower, J. M. (1997). Is the cerebellum sensory for motor’s sake, or motor for sensory’s sake: The view from the whiskers of a rat? Progress in Brain Research, 114, 463–496.PubMedCrossRefGoogle Scholar
  12. Bryson, S. E., Smith, I. M., & Eastwood, D. (1988). Obstetrical suboptimality in autistic children. Journal of the American Academy of Child and Adolescent Psychiatry, 27(4), 418–422.PubMedCrossRefGoogle Scholar
  13. Buchmayer, S., Johansson, S., Johansson, A., Hultman, C. M., Sparen, P., & Cnattingius, S. (2009). Can association between preterm birth and autism be explained by maternal or neonatal morbidity? Pediatrics, 124(5), e817–e825.PubMedCrossRefGoogle Scholar
  14. Burd, L., Severud, R., Kerbeshian, J., & Klug, M. G. (1999). Prenatal and perinatal risk factors for autism. Journal of Perinatal Medicine, 27(6), 441–450.PubMedCrossRefGoogle Scholar
  15. Cashore, W. J., & Oh, W. (1982). Unbound bilirubin and kernicterus in low-birth-weight infants. Pediatrics, 69(4), 481–485.PubMedGoogle Scholar
  16. Chakrabarti, S., & Fombonne, E. (2001). Pervasive developmental disorders in preschool children. Jama, 285(24), 3093–3099.PubMedCrossRefGoogle Scholar
  17. Courchesne, E. (1991). Neuroanatomic imaging in autism. Pediatrics, 87(5 Pt 2), 781–790.PubMedGoogle Scholar
  18. Courchesne, E. (1995). New evidence of cerebellar and brainstem hypoplasia in autistic infants, children and adolescents: The MR imaging study by Hashimoto and colleagues. Journal of Austism and Developmental Disorders, 25(1), 19–22.CrossRefGoogle Scholar
  19. Courchesne, E., Yeung-Courchesne, R., Press, G. A., Hesselink, J. R., & Jernigan, T. L. (1988). Hypoplasia of cerebellar vermal lobules VI and VII in autism. The New England Journal of Medicine, 318(21), 1349–1354.PubMedCrossRefGoogle Scholar
  20. Croen, L. A., Yoshida, C. K., Odouli, R., & Newman, T. B. (2005). Neonatal hyperbilirubinemia and risk of autism spectrum disorders. Pediatrics, 115(2), e135–e138.PubMedCrossRefGoogle Scholar
  21. Deb, S., Prasad, K. B., Seth, H., & Eagles, J. M. (1997). A comparison of obstetric and neonatal complications between children with autistic disorder and their siblings. Journal of Intellectual Disablity Research, 41(Pt 1), 81–86.Google Scholar
  22. Deykin, E. Y., & MacMahon, B. (1980). Pregnancy, delivery, and neonatal complications among autistic children. American Journal of Diseases of Children, 134(9), 860–864.PubMedGoogle Scholar
  23. Eaton, W. W., Mortensen, P. B., Thomsen, P. H., & Frydenberg, M. (2001). Obstetric complications and risk for severe psychopathology in childhood. Journal of Austism and Developmental Disorders, 31(3), 279–285.CrossRefGoogle Scholar
  24. Finegan, J. A., & Quarrington, B. (1979). Pre-, peri-, and neonatal factors and infantile autism. Journal of Child Psychology and Psychiatry, 20(2), 119–128.PubMedCrossRefGoogle Scholar
  25. Funato, M., Tamai, H., Shimada, S., & Nakamura, H. (1994). Vigintiphobia, unbound bilirubin, and auditory brainstem responses. Pediatrics, 93(1), 50–53.PubMedGoogle Scholar
  26. Funato, M., Teraoka, S., Tamai, H., & Shimida, S. (1996). Follow-up study of auditory brainstem responses in hyperbilirubinemic newborns treated with exchange transfusion. Acta Paediatrica Japonica, 38(1), 17–21.PubMedGoogle Scholar
  27. Ganz, M. L. (2007). The lifetime distribution of the incremental societal costs of autism. Archives of Pediatrics and Adolescent Medicine, 161(4), 343–349.PubMedCrossRefGoogle Scholar
  28. Gartner, L. M., Snyder, R. N., Chabon, R. S., & Bernstein, J. (1970). Kernicterus: High incidence in premature infants with low serum bilirubin concentrations. Pediatrics, 45(6), 906–917.PubMedGoogle Scholar
  29. Gillberg, C., & Gillberg, I. C. (1983). Infantile autism: A total population study of reduced optimality in the pre-, peri-, and neonatal period. Journal of Austism and Developmental Disorders, 13(2), 153–166.CrossRefGoogle Scholar
  30. Jangaard, K. A., Fell, D. B., Dodds, L., & Allen, A. C. (2008). Outcomes in a population of healthy term and near-term infants with serum bilirubin levels of > or = 325 micromol/L (> or = 19 mg/dL) who were born in Nova Scotia, Canada, between 1994 and 2000. Pediatrics, 122(1), 119–124.PubMedCrossRefGoogle Scholar
  31. Johnson, S., Hollis, C., Kochhar, P., Hennessy, E., Wolke, D., & Marlow, N. (2010). Autism Spectrum disorders in extremely preterm children. Journal of Pediatrics, 156, 525–31.e2.Google Scholar
  32. Juul-Dam, N., Townsend, J., & Courchesne, E. (2001). Prenatal, perinatal, and neonatal factors in autism, pervasive developmental disorder-not otherwise specified, and the general population. Pediatrics, 107(4), E63.PubMedCrossRefGoogle Scholar
  33. Kemper, T. L., & Bauman, M. L. (1993). The contribution of neuropathologic studies to the understanding of autism. Neurology Clinic, 11(1), 175–187.Google Scholar
  34. Kern, J. K. (2002). The possible role of the cerebellum in autism/PDD: Disruption of a multisensory feedback loop. Medical Hypotheses, 59(3), 255–260.PubMedCrossRefGoogle Scholar
  35. Kern, J. K. (2003). Purkinje cell vulnerability and autism: A possible etiological connection. Brain and Development, 25(6), 377–382.PubMedCrossRefGoogle Scholar
  36. Kuehn, B. M. (2007). CDC: Autism spectrum disorders common. Jama, 297(9), 940.PubMedCrossRefGoogle Scholar
  37. Larsson, H. J., Eaton, W. W., Madsen, K. M., Vestergaard, M., Olesen, A. V., Agerbo, E., et al. (2005). Risk factors for autism: Perinatal factors, parental psychiatric history, and socioeconomic status. American Journal of Epidemiology, 161(10), 916–925; discussion 926–918.Google Scholar
  38. Leslie, D. L., & Martin, A. (2007). Health care expenditures associated with autism spectrum disorders. Archives of Pediatrics and Adolescent Medicine, 161(4), 350–355.PubMedCrossRefGoogle Scholar
  39. Levy, S., Zoltak, B., & Saelens, T. (1988). A comparison of obstetrical records of autistic and nonautistic referrals for psychoeducational evaluations. Journal of Austism and Developmental Disorders, 18(4), 573–581.CrossRefGoogle Scholar
  40. Limperopoulos, C. (2009). Autism spectrum disorders in survivors of extreme prematurity. Clinical Perinatology, 36(4), 791–805, vi.Google Scholar
  41. Limperopoulos, C., Bassan, H., Gauvreau, K., Robertson, R. L, Jr., Sullivan, N. R., Benson, C. B., et al. (2007). Does cerebellar injury in premature infants contribute to the high prevalence of long-term cognitive, learning, and behavioral disability in survivors? Pediatrics, 120(3), 584–593.PubMedCrossRefGoogle Scholar
  42. Lord, C., Mulloy, C., Wendelboe, M., & Schopler, E. (1991). Pre- and perinatal factors in high-functioning females and males with autism. Journal of Austism and Developmental Disorders, 21(2), 197–209.CrossRefGoogle Scholar
  43. Maimburg, R. D., & Vaeth, M. (2006). Perinatal risk factors and infantile autism. Acta Psychiatrica Scandinavica, 114(4), 257–264.PubMedCrossRefGoogle Scholar
  44. Maimburg, R. D., Vaeth, M., Schendel, D. E., Bech, B. H., Olsen, J., & Thorsen, P. (2008). Neonatal jaundice: A risk factor for infantile autism? Paediatric and Perinatal Epidemiology, 22(6), 562–568.PubMedCrossRefGoogle Scholar
  45. Mason-Brothers, A., Ritvo, E. R., Pingree, C., Petersen, P. B., Jenson, W. R., McMahon, W. M., et al. (1990). The UCLA-University of Utah epidemiologic survey of autism: Prenatal, perinatal, and postnatal factors. Pediatrics, 86(4), 514–519.PubMedGoogle Scholar
  46. Matsuishi, T., Yamashita, Y., Ohtani, Y., Ornitz, E., Kuriya, N., Murakami, Y., et al. (1999). Brief report: Incidence of and risk factors for autistic disorder in neonatal intensive care unit survivors. Journal of Austism and Developmental Disorders, 29(2), 161–166.CrossRefGoogle Scholar
  47. Moster, D., Lie, R. T., & Markestad, T. (2008). Long-term medical and social consequences of preterm birth. The New England Journal of Medicine, 359(3), 262–273.PubMedCrossRefGoogle Scholar
  48. Nakamura, H., Takada, S., Shimabuku, R., Matsuo, M., Matsuo, T., & Negishi, H. (1985). Auditory nerve and brainstem responses in newborn infants with hyperbilirubinemia. Pediatrics, 75(4), 703–708.PubMedGoogle Scholar
  49. Nakamura, H., Yonetani, M., Uetani, Y., Funato, M., & Lee, Y. (1992). Determination of serum unbound bilirubin for prediction of kernicterus in low birthweight infants. Acta Paediatrica Japonica, 34(6), 642–647.PubMedGoogle Scholar
  50. Palmen, S. J., van Engeland, H., Hof, P. R., & Schmitz, C. (2004). Neuropathological findings in autism. Brain, 127(Pt 12), 2572–2583.PubMedCrossRefGoogle Scholar
  51. Perlstein, M. (1960). The late clinical syndrome of posticteric encephalopathy. Pediatric Clinics of North America, 7, 665–687.Google Scholar
  52. Petitti, D. B. (2000). Statistical methods in meta-analysis. In D. B. Petitti (Ed.), Meta-analysis, decision analysis, and cost-effectiveness analysis: Methods for qunatitative synthesis in medicine (2nd ed., pp. 94–116). New York: Oxford University Press.Google Scholar
  53. Pierce, K., & Courchesne, E. (2001). Evidence for a cerebellar role in reduced exploration and stereotyped behavior in autism. Biological Psychiatry, 49(8), 655–664.PubMedCrossRefGoogle Scholar
  54. Piven, J., Simon, J., Chase, G. A., Wzorek, M., Landa, R., Gayle, J., et al. (1993). The etiology of autism: Pre-, peri- and neonatal factors. Journal of the American Academy of Child and Adolescent Psychiatry, 32(6), 1256–1263.PubMedCrossRefGoogle Scholar
  55. Ritter, D. A., Kenny, J. D., Norton, H. J., & Rudolph, A. J. (1982). A prospective study of free bilirubin and other risk factors in the development of kernicterus in premature infants. Pediatrics, 69(3), 260–266.PubMedGoogle Scholar
  56. Ritvo, E. R., Freeman, B. J., Scheibel, A. B., Duong, T., Robinson, H., Guthrie, D., et al. (1986). Lower Purkinje cell counts in the cerebella of four autistic subjects: Initial findings of the UCLA-NSAC Autopsy Research Report. American Journal of Psychiatry, 143(7), 862–866.PubMedGoogle Scholar
  57. Rosenhall, U., Nordin, V., Brantberg, K., & Gillberg, C. (2003). Autism and auditory brain stem responses. Ear and Hearing, 24(3), 206–214.PubMedCrossRefGoogle Scholar
  58. Russo, N. M., Skoe, E., Trommer, B., Nicol, T., Zecker, S., Bradlow, A., et al. (2008). Deficient brainstem encoding of pitch in children with Autism Spectrum Disorders. Clinical Neurophysiology, 119(8), 1720–1731.PubMedCrossRefGoogle Scholar
  59. Shaked, M., & Yirmiya, N. (2004). Matching procedures in autism research: Evidence from meta-analytic studies. Journal of Austism and Developmental Disorders, 34(1), 35–40.CrossRefGoogle Scholar
  60. Shea, B. J., Grimshaw, J. M., Wells, G. A., Boers, M., Andersson, N., Hamel, C., et al. (2007). Development of AMSTAR: A measurement tool to assess the methodological quality of systematic reviews. BMC Medical Research Methodology, 7, 10.PubMedCrossRefGoogle Scholar
  61. Stephens, B. E., & Vohr, B. R. (2009). Neurodevelopmental outcome of the premature infant. Pediatric Clinics of North America, 56(3), 631–646, Table of Contents.Google Scholar
  62. Stroup, D. F., Berlin, J. A., Morton, S. C., Olkin, I., Williamson, G. D., Rennie, D., et al. (2000). Meta-analysis of observational studies in epidemiology: A proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) group. Jama, 283(15), 2008–2012.PubMedCrossRefGoogle Scholar
  63. Sugie, Y., & Sugie, H. (2009). Perinatal and neonatal risk factors for autism spectrum disorders. Seishin Shinkeigaku Zasshi, 111(11), 1397–1403.PubMedGoogle Scholar
  64. Sugie, Y., Sugie, H., Fukuda, T., & Ito, M. (2005). Neonatal factors in infants with Autistic Disorder and typically developing infants. Autism, 9(5), 487–494.PubMedCrossRefGoogle Scholar
  65. Thivierge, J., Bedard, C., Cote, R., & Maziade, M. (1990). Brainstem auditory evoked response and subcortical abnormalities in autism. Amican Journal of Psychiatry, 147(12), 1609–1613.Google Scholar
  66. Valaes, T., Petmezaki, S., Henschke, C., Drummond, G. S., & Kappas, A. (1994). Control of jaundice in preterm newborns by an inhibitor of bilirubin production: Studies with tin-mesoporphyrin. Pediatrics, 93(1), 1–11.PubMedGoogle Scholar
  67. Watchko, J. F., & Maisels, M. J. (2010). Enduring controversies in the management of hyperbilirubinemia in preterm neonates. Seminars in Fetal and Neonatal Medicine, 15(3), 136–140.PubMedCrossRefGoogle Scholar
  68. Wennberg, R. P., Ahlfors, C. E., Bhutani, V. K., Johnson, L. H., & Shapiro, S. M. (2006). Toward understanding kernicterus: A challenge to improve the management of jaundiced newborns. Pediatrics, 117(2), 474–485.PubMedCrossRefGoogle Scholar
  69. Whitehouse, A. J., & Bishop, D. V. (2008). Do children with autism switch off to speech sounds? An investigation using event-related potentials. Developmental Science, 11(4), 516–524.PubMedCrossRefGoogle Scholar
  70. Wong, V., & Wong, S. N. (1991). Brainstem auditory evoked potential study in children with autistic disorder. Journal of Austism and Developmental Disorders, 21(3), 329–340.CrossRefGoogle Scholar
  71. Yeargin-Allsopp, M., Rice, C., Karapurkar, T., Doernberg, N., Boyle, C., & Murphy, C. (2003). Prevalence of autism in a US metropolitan area. Jama, 289(1), 49–55.PubMedCrossRefGoogle Scholar
  72. Yip, J., Soghomonian, J. J., & Blatt, G. J. (2007). Decreased GAD67 mRNA levels in cerebellar Purkinje cells in autism: Pathophysiological implications. Acta Neuropathologica, 113(5), 559–568.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Division of Neonatology, Department of PediatricsThe University of Rochester School of Medicine and DentistryRochesterUSA
  2. 2.Division of Developmental Pediatrics, Department of PediatricsThe University of Rochester School of Medicine and DentistryRochesterUSA
  3. 3.Department of BiostatisticsThe University of Rochester School of Medicine and DentistryRochesterUSA

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