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Am J Perinatol 2023; 40(08): 858-866
DOI: 10.1055/s-0041-1731648
Original Article

The Effect of Neonatal Sepsis on Risk of Autism Diagnosis

Darios Getahun
1   Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California
2   Department of Health Systems Science, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, California
,
Michael J. Fassett
3   Department of Obstetrics and Gynecology, Kaiser Permanente West Los Angeles Medical Center, Los Angeles, California
4   Department of Clinical Sciences, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, California
,
Anny H. Xiang
1   Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California
,
Vicki Y. Chiu
1   Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California
,
Harpreet S. Takhar
1   Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California
,
Sally F. Shaw
1   Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California
,
Morgan R. Peltier
5   Department of Foundations of Medicine, NYU-Long Island School of Medicine, Mineola, New York
› Author Affiliations Funding This study was supported in part by Kaiser Permanente Direct Community Benefit Funds.
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Abstract

Objective The study aimed to examine the association between neonatal sepsis and autism risk among children and whether the risk varied with the timing of exposure, child's sex, and race/ethnicity.

Study Design We conducted a retrospective cohort study using electronic health records (EHR) extracted from Kaiser Permanente Southern California Health Care System. Mother–child dyads were constructed by linking records of children born to member mothers and continuing to receive care through the system during the follow-up period with those of their biological mothers (n = 469,789). Clinical health records were used to define neonatal sepsis. Diagnosis of autism was made by medical specialists. Potential confounders included maternal sociodemographic factors, obstetrical history, child's age, sex, race/ethnicity, and maternal and child medical history. Incident rates and adjusted hazard ratios (aHR) were used to estimate the associations.

Results Compared with children without the diagnosis of autism, children with the condition were more likely to be from Asian/Pacific Islander descent and male sex. Exposed children showed higher rates of autism as compared with unexposed children (3.43 vs. 1.73 per 1,000 person-years, aHR: 1.67–95% confidence interval [CI]: 1.39–2.00). Both preterm (aHR: 1.47; 95% CI: 1.09–1.98) and term (aHR: 1.63; 95% CI: 1.29–2.06) births were associated with increased risk for autism. Although the magnitude of the HRs and incidence ratios for neonatal sepsis to increase autism risk varied between race ethnicities, neonatal sepsis was associated with significantly increased likelihood of autism diagnosis for all race-ethic groups except for Asian/Pacific Islanders. Although neonatal sepsis was associated with significantly increased autism risk for both boys and girls, incident rates and HR point estimates suggested that the effect may be stronger in girls.

Conclusion Neonatal sepsis is associated with increased risk of autism diagnosis in preterm- and term-born children. The association was significant for both girls and boys and all race ethnicities except for Asian-Pacific Islanders.

Key Points

  • Neonatal sepsis is associated with increased risk of autism diagnosis.

  • The association was significant in preterm- and term-born children.

  • The association was significant for all race/ethnicities except for Asian-Pacific Islanders.

Keywords

neonatal sepsis - autism - autism spectrum disorder - race - ethnicity - race/ethnicity

Note

The opinions expressed are solely the responsibility of the authors and do not necessarily reflect the official views of the Kaiser Permanente Community Benefit Funds.


Authors' Contributions

D.G. obtained funding, conceptualized and designed the study, acquired data, analyzed and interpreted data, drafted the initial manuscript, and reviewed and revised the manuscript for important intellectual content. M.J.F., A.H.X., S.F.S., M.R.P., and H.S.T. conceptualized and designed the study and critically reviewed the manuscript for important intellectual content. V.Y.C. designed the study, acquired data, performed analyses, and reviewed and revised the manuscript.


Supplementary Material



Publication History

Received: 01 February 2021

Accepted: 12 May 2021

Article published online:
05 July 2021

© 2021. Thieme. All rights reserved.

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  • References

  • 1 Center for Disease Control and Prevention, Autism Spectrum Disorder (ASD). Data and Statistics on Autism Spectrum Disorder. Accessed December 27, 2020 at: https://www.cdc.gov/ncbddd/autism/data.html
    PubMedGoogle Scholar
  • 2 Newschaffer CJ, Croen LA, Daniels J. et al. The epidemiology of autism spectrum disorders. Annu Rev Public Health 2007; 28: 235-258
    CrossrefPubMedGoogle Scholar
  • 3 Biao J. Autism and Developmental Disabilities Monitoring Network Surveillance Year 2008 Principal Investigators, Centers for Disease Control and Prevention. Prevalence of autism spectrum disorders--autism and developmental disabilities monitoring network, 14 sites, United States, 2008. MMWR Surveill Summ 2012; 61 (03) 1-19
    PubMedGoogle Scholar
  • 4 Leigh JP, Du J. Brief report: forecasting the economic burden of autism in 2015 and 2025 in the United States. J Autism Dev Disord 2015; 45 (12) 4135-4139
    CrossrefPubMedGoogle Scholar
  • 5 Hallmayer J, Cleveland S, Torres A. et al. Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry 2011; 68 (11) 1095-1102
    CrossrefPubMedGoogle Scholar
  • 6 Bailey A, Le Couteur A, Gottesman I. et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 1995; 25 (01) 63-77
    CrossrefPubMedGoogle Scholar
  • 7 Xie F, Peltier M, Getahun D. Is the risk of autism in younger siblings of affected children moderated by sex, race/ethnicity, or gestational age?. J Dev Behav Pediatr 2016; 37 (08) 603-609
    CrossrefPubMedGoogle Scholar
  • 8 Fombonne E. Epidemiology of autistic disorder and other pervasive developmental disorders. J Clin Psychiatry 2005; 66 (Suppl. 10) 3-8
    PubMedGoogle Scholar
  • 9 Burd L, Severud R, Kerbeshian J, Klug MG. Prenatal and perinatal risk factors for autism. J Perinat Med 1999; 27 (06) 441-450
    CrossrefPubMedGoogle Scholar
  • 10 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 (10) 916-925 , discussion 926–928
    CrossrefPubMedGoogle Scholar
  • 11 Croen LA, Grether JK, Selvin S. Descriptive epidemiology of autism in a California population: who is at risk?. J Autism Dev Disord 2002; 32 (03) 217-224
    CrossrefPubMedGoogle Scholar
  • 12 Xiang AH, Wang X, Martinez MP. et al. Association of maternal diabetes with autism in offspring. JAMA 2015; 313 (14) 1425-1434
    CrossrefPubMedGoogle Scholar
  • 13 Xiang AH, Chow T, Martinez MP. et al. Hemoglobin A1c levels during pregnancy and risk of autism spectrum disorders in offspring. JAMA 2019; 322 (05) 460-461
    CrossrefPubMedGoogle Scholar
  • 14 Getahun D, Jacobsen SJ, Fassett MJ. et al. Association between maternal hypothyroidism and autism spectrum disorders in children. Pediatr Res 2018; 83 (03) 580-588
    CrossrefPubMedGoogle Scholar
  • 15 Getahun D, Fassett MJ, Jacobsen SJ. et al. Autism spectrum disorders in children exposed in utero to hyperemesis gravidarum. Am J Perinatol 2019
    PubMedGoogle Scholar
  • 16 Getahun D, Fassett MJ, Peltier MR. et al. Association of perinatal risk factors with autism spectrum disorder. Am J Perinatol 2017; 34 (03) 295-304
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Centers for Disease Control and Prevention. Prevention of perinatal group B streptococcal disease: a public health perspective. MMWR Recomm Rep 1996; 45 (RR-7): 1-24
    PubMedGoogle Scholar
  • 18 Committee on Obstetric Practice. American College of Obstetrics and Gynecologists. ACOG committee opinion. Prevention of early-onset group B streptococcal disease in newborns. Number 173--June 1996. Int J Gynaecol Obstet 1996; 54 (02) 197-205
    CrossrefPubMedGoogle Scholar
  • 19 American Academy of Pediatrics Committee on Infectious Diseases and Committee on Fetus and Newborn. Revised guidelines for prevention of early-onset group B streptococcal (GBS) infection. Pediatrics 1997; 99 (03) 489-496
    CrossrefPubMedGoogle Scholar
  • 20 Van Dyke MK, Phares CR, Lynfield R. et al. Evaluation of universal antenatal screening for group B streptococcus. N Engl J Med 2009; 360 (25) 2626-2636
    CrossrefPubMedGoogle Scholar
  • 21 Weston EJ, Pondo T, Lewis MM. et al. The burden of invasive early-onset neonatal sepsis in the United States, 2005-2008. Pediatr Infect Dis J 2011; 30 (11) 937-941
    CrossrefPubMedGoogle Scholar
  • 22 Bizzarro MJ, Raskind C, Baltimore RS, Gallagher PG. Seventy-five years of neonatal sepsis at Yale: 1928-2003. Pediatrics 2005; 116 (03) 595-602
    CrossrefPubMedGoogle Scholar
  • 23 Singh L, Das S, Bhat VB, Plakkal N. Early neurodevelopmental outcome of very low birth weight neonates with culture-positive blood stream infection: a prospective cohort study. Cureus 2018; 10 (10) e3492
    PubMedGoogle Scholar
  • 24 Bolisetty S, Tiwari M, Sutton L, Schindler T, Bajuk B, Lui K. New South Wales and the Australian Capital Territory Neonatal Intensive Care Units' Data Registry. Neurodevelopmental outcomes of extremely preterm infants in New South Wales and the Australian Capital Territory. J Paediatr Child Health 2019; 55 (08) 956-961
    CrossrefPubMedGoogle Scholar
  • 25 Cardoso FL, Herz J, Fernandes A. et al. Systemic inflammation in early neonatal mice induces transient and lasting neurodegenerative effects. J Neuroinflammation 2015; 12: 82
    CrossrefPubMedGoogle Scholar
  • 26 Smilga AS, Garfinkle J, Ng P. et al. Neonatal infection in children with cerebral palsy: a registry-based cohort study. Pediatr Neurol 2018; 80: 77-83
    CrossrefPubMedGoogle Scholar
  • 27 Deykin EY, MacMahon B. Pregnancy, delivery, and neonatal complications among autistic children. Am J Dis Child 1980; 134 (09) 860-864
    PubMedGoogle Scholar
  • 28 Getahun D, Rhoads GG, Fassett MJ. et al. Accuracy of reporting maternal and infant perinatal service system coding and clinical utilization coding. J Med Stat Inform 2013; 1: 1-3
    CrossrefPubMedGoogle Scholar
  • 29 Andrade SE, Scott PE, Davis RL. et al. Validity of health plan and birth certificate data for pregnancy research. Pharmacoepidemiol Drug Saf 2013; 22 (01) 7-15
    CrossrefPubMedGoogle Scholar
  • 30 Koebnick C, Langer-Gould AM, Gould MK. et al. Sociodemographic characteristics of members of a large, integrated health care system: comparison with US Census Bureau data. Perm J 2012; 16 (03) 37-41
    CrossrefPubMedGoogle Scholar
  • 31 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th Edition. Text Revision (DSM-IV-TR). Washington, DC: American Psychiatric Publishing; 2000
    Google Scholar
  • 32 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 (07) 1989-1996
    CrossrefPubMedGoogle Scholar
  • 33 Clinical Practice Guideline. Kaiser Permanente Southern California Preventive Services for Children and Adlolescents. Available at: First Issued: 6–1994, Last Reviewed/Revised: 4–2013. PMCID. Accessed June 20, 2019 at: http://cl.kp.org/pkc/scal/cpg/cpg/html/PrevSvcsChild.html
    PubMedGoogle Scholar
  • 34 Robins DL, Fein D, Barton ML, Green JA. The Modified Checklist for Autism in Toddlers: an initial study investigating the early detection of autism and pervasive developmental disorders. J Autism Dev Disord 2001; 31 (02) 131-144
    CrossrefPubMedGoogle Scholar
  • 35 VanderWeele TJ, Ding P. Sensitivity analysis in observational research: introducing the E-value. Ann Intern Med 2017; 167 (04) 268-274
    CrossrefPubMedGoogle Scholar
  • 36 Raymond SL, Stortz JA, Mira JC, Larson SD, Wynn JL, Moldawer LL. Immunological defects in neonatal sepsis and potential therapeutic approaches. Front Pediatr 2017; 5: 14
    CrossrefPubMedGoogle Scholar
  • 37 Elahi S, Ertelt JM, Kinder JM. et al. Immunosuppressive CD71+ erythroid cells compromise neonatal host defence against infection. Nature 2013; 504 (7478): 158-162
    CrossrefPubMedGoogle Scholar
  • 38 Atladóttir HÓ, 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 (08) 2429-2442
    CrossrefPubMedGoogle Scholar
  • 39 Polin RA. Systemic infection and brain injury in the preterm infant. J Pediatr (Rio J) 2008; 84 (03) 188-191
    CrossrefPubMedGoogle Scholar
  • 40 Shah DK, Doyle LW, Anderson PJ. et al. Adverse neurodevelopment in preterm infants with postnatal sepsis or necrotizing enterocolitis is mediated by white matter abnormalities on magnetic resonance imaging at term. J Pediatr 2008; 153 (02) 170-175 , 175.e171
    CrossrefPubMedGoogle Scholar
  • 41 Verboon-Maciolek MA, Groenendaal F, Cowan F, Govaert P, van Loon AM, de Vries LS. White matter damage in neonatal enterovirus meningoencephalitis. Neurology 2006; 66 (08) 1267-1269
    CrossrefPubMedGoogle Scholar
  • 42 Han Q, Lin Q, Huang P. et al. Microglia-derived IL-1β contributes to axon development disorders and synaptic deficit through p38-MAPK signal pathway in septic neonatal rats. J Neuroinflammation 2017; 14 (01) 52
    CrossrefPubMedGoogle Scholar
  • 43 Simonsen KA, Anderson-Berry AL, Delair SF, Davies HD. Early-onset neonatal sepsis. Clin Microbiol Rev 2014; 27 (01) 21-47
    CrossrefPubMedGoogle Scholar
  • 44 Petit-Pedrol M, Sell J, Planagumà J. et al. LGI1 antibodies alter Kv1.1 and AMPA receptors changing synaptic excitability, plasticity and memory. Brain 2018; 141 (11) 3144-3159
    PubMedGoogle Scholar
  • 45 Saunders-Pullman R, Gordon-Elliott J, Parides M, Fahn S, Saunders HR, Bressman S. The effect of estrogen replacement on early Parkinson's disease. Neurology 1999; 52 (07) 1417-1421
    CrossrefPubMedGoogle Scholar
  • 46 Rocca WA, Bower JH, Maraganore DM. et al. Increased risk of parkinsonism in women who underwent oophorectomy before menopause. Neurology 2008; 70 (03) 200-209
    CrossrefPubMedGoogle Scholar
  • 47 Tang MX, Jacobs D, Stern Y. et al. Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease. Lancet 1996; 348 (9025): 429-432
    CrossrefPubMedGoogle Scholar
  • 48 Barron AM, Pike CJ. Sex hormones, aging, and Alzheimer's disease. Front Biosci (Elite Ed) 2012; 4: 976-997
    PubMedGoogle Scholar
  • 49 Singh GK, Kogan MD. Persistent socioeconomic disparities in infant, neonatal, and postneonatal mortality rates in the United States, 1969-2001. Pediatrics 2007; 119 (04) e928-e939
    CrossrefPubMedGoogle Scholar
  • 50 Schrag SJ, Zywicki S, Farley MM. et al. Group B streptococcal disease in the era of intrapartum antibiotic prophylaxis. N Engl J Med 2000; 342 (01) 15-20
    CrossrefPubMedGoogle Scholar
  • 51 Mustarim M, Yanwirasti Y, Jamsari J, Rukmono R, Nindrea RD. Association of Gene Polymorphism of Bactericidal Permeability Increasing Protein Rs4358188, Cluster of Differentiation 14 Rs2569190, Interleukin 1β Rs1143643 and Matrix Metalloproteinase-16 Rs2664349 with Neonatal Sepsis. Open Access Maced J Med Sci 2019; 7 (17) 2728-2733
    CrossrefPubMedGoogle Scholar
  • 52 Hultman CM, Sparén P, Cnattingius S. Perinatal risk factors for infantile autism. Epidemiology 2002; 13 (04) 417-423
    CrossrefPubMedGoogle Scholar
  • 53 Buka SL, Shenassa ED, Niaura R. Elevated risk of tobacco dependence among offspring of mothers who smoked during pregnancy: a 30-year prospective study. Am J Psychiatry 2003; 160 (11) 1978-1984
    CrossrefPubMedGoogle Scholar