We analyzed data from case groups of 538 children with autism spectrum disorders (ASD) and 163 with developmental delays (DD), and from 421 typically developing controls to assess associations with maternal influenza or fever during pregnancy. Exposure information was obtained by telephone interviews, and outcomes were clinically confirmed. Though neither ASD nor DD was associated with influenza, both were associated with maternal fever during pregnancy: OR’s (odds ratios) were 2.12 (95 % CI 1.17, 3.84) and 2.50 (95 % CI 1.20, 5.20) respectively. However, the fever-associated ASD risk was attenuated among mothers who reported taking antipyretic medications (OR = 1.30, 95 % CI 0.59, 2.84), but remained elevated for those who did not (OR = 2.55, 95 % CI 1.30, 4.99).
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Abdallah, M. W., Larsen, N., Grove, J., Norgaard-Pedersen, B., Thorsen, P., Mortensen, E. L., et al. (2011). Amniotic fluid inflammatory cytokines: Potential markers of immunologic dysfunction in autism spectrum disorders. World Journal of Biology Psychiatry. doi:10.3109/15622975.2011.639803
Abdallah, M. W., Larsen, N., Grove, J., Norgaard-Pedersen, B., Thorsen, P., Mortensen, E. L., et al. (2012). Amniotic fluid chemokines and autism spectrum disorders: An exploratory study utilizing a Danish Historic Birth Cohort. Brain, Behavior, and Immunity, 26(1), 170–176.
Ashdown, H., Dumont, Y., Ng, M., Poole, S., Boksa, P., & Luheshi, G. N. (2006). The role of cytokines in mediating effects of prenatal infection on the fetus: Implications for schizophrenia. Molecular Psychiatry, 11(1), 47–55.
Atladottir, H. O., Thorsen, P., Ostergaard, L., Schendel, D. E., Lemcke, S., Abdallah, M., et al. (2010). Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders. Journal of Autism and Developmental Disorders, 40(12), 1423–1430.
Brown, A. S., Begg, M. D., Gravenstein, S., Schaefer, C. A., Wyatt, R. J., Bresnahan, M., et al. (2004a). Serologic evidence of prenatal influenza in the etiology of schizophrenia. Archives of General Psychiatry, 61(8), 774–780.
Brown, A. S., Hooton, J., Schaefer, C. A., Zhang, H., Petkova, E., Babulas, V., et al. (2004b). Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring. American Journal of Psychiatry, 161(5), 889–895.
CDC. http://www.cdc.gov/flu/about/season/flu-season.htm. From CDC.
Chess, S. (1971). Autism in children with congenital rubella. Journal of autism and childhood schizophrenia, 1(1), 33–47.
Conti, B., Tabarean, I., Andrei, C., & Bartfai, T. (2004). Cytokines and fever. Frontiers in Bioscience, 9, 1433–1449.
Dassa, D., Takei, N., Sham, P. C., & Murray, R. M. (1995). No association between prenatal exposure to influenza and autism. Acta Psychiatrica Scandinavica, 92(2), 145–149.
Deykin, E. Y., & MacMahon, B. (1979). Viral exposure and autism. American Journal of Epidemiology, 109(6), 628–638.
Edwards, M. J. (2006). Review: Hyperthermia and fever during pregnancy. Birth Defects Research. Part A, Clinical and Molecular Teratology, 76(7), 507–516.
Gilmore, J. H., Fredrik Jarskog, L., Vadlamudi, S., & Lauder, J. M. (2004). Prenatal infection and risk for schizophrenia: IL-1beta, IL-6, and TNFalpha inhibit cortical neuron dendrite development. Neuropsychopharmacology, 29(7), 1221–1229.
Goetzl, L., Evans, T., Rivers, J., Suresh, M. S., & Lieberman, E. (2002). Elevated maternal and fetal serum interleukin-6 levels are associated with epidural fever. American Journal of Obstetrics and Gynecology, 187(4), 834–838.
Goines, P. E., Croen, L. A., Braunschweig, D., Yoshida, C. K., Grether, J., Hansen, R., et al. (2011). Increased mid-gestational IFN-gamma, IL-4, and IL-5 in women giving birth to a child with autism: A case-control study. Molecular Autism, 2(1), 13.
Grether, J. K., Croen, L. A., Anderson, M. C., Nelson, K. B., & Yolken, R. H. (2010). Neonatally measured immunoglobulins and risk of autism. Autism Research, 3(6), 323–332.
Grether, J. K., & Nelson, K. B. (1997). Maternal infection and cerebral palsy in infants of normal birth weight. JAMA, 278(3), 207–211.
Hertz-Picciotto, I., Croen, L. A., Hansen, R., Jones, C. R., van de Water, J., & Pessah, I. N. (2006). The CHARGE study: An epidemiologic investigation of genetic and environmental factors contributing to autism. Environmental Health Perspectives, 114(7), 1119–1125.
Le Couteur, A., Rutter, M., Lord, C., Rios, P., Robertson, S., Holdgrafer, M., et al. (1989). Autism Diagnostic Interview: A standardized investigator-based instrument. Journal of Autism and Developmental Disorders, 19(3), 363–387.
Libbey, J. E., Sweeten, T. L., McMahon, W. M., & Fujinami, R. S. (2005). Autistic disorder and viral infections. Journal for Neurovirology, 11(1), 1–10.
Lieberman, E., Eichenwald, E., Mathur, G., Richardson, D., Heffner, L., & Cohen, A. (2000). Intrapartum fever and unexplained seizures in term infants. Pediatrics, 106(5), 983–988.
Lord, C., Risi, S., Lambrecht, L., Cook, E. H., Jr, Leventhal, B. L., DiLavore, P. C., et al. (2000). The Autism Diagnostic Observation Schedule-Generic: A standard measure of social and communication deficits associated with the spectrum of autism. Journal of Autism and Developmental Disorders, 30(3), 205–223.
Louie, J. K., Acosta, M., Jamieson, D. J., & Honein, M. A. (2009). Severe 2009 H1N1 influenza in pregnant and postpartum women in California. New England Journal of Medicine, 362(1), 27–35.
Maimburg, R. D., & Vaeth, M. (2006). Perinatal risk factors and infantile autism. Acta Psychiatrica Scandinavica, 114(4), 257–264.
Martin, L. A., Ashwood, P., Braunschweig, D., Cabanlit, M., Van de Water, J., & Amaral, D. G. (2008). Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism. Brain, Behavior, and Immunity, 22(6), 806–816.
Meyer, U., Schwendener, S., Feldon, J., & Yee, B. K. (2006). Prenatal and postnatal maternal contributions in the infection model of schizophrenia. Experimental Brain Research, 173(2), 243–257.
Moretti, M. E., Bar-Oz, B., Fried, S., & Koren, G. (2005). Maternal hyperthermia and the risk for neural tube defects in offspring: Systematic review and meta-analysis. Epidemiology, 16(2), 216–219.
Mullen, E. M. (1995). Mullen Scales of Early Learning. Circle Pines MN: American Guidance Services Inc.
Netea, M. G., Kullberg, B. J., & Van der Meer, J. W. (2000). Circulating cytokines as mediators of fever. Clinical Infectious Diseases, 31(Suppl 5), S178–S184.
O'Callaghan, M. E., MacLennan, A. H., Gibson, C. S., McMichael, G. L., Haan, E. A., Broadbent, J. L., et al. (2011). Epidemiologic associations with cerebral palsy. Obstet Gynecol, 118(3), 576–582.
Patterson, P. H. (2002). Maternal infection and immune involvement in autism. Trends in Molecular Medicine, 17(7), 384–389.
Patterson, P. H. (2011). Maternal infection and immune involvement in autism. Trends Molecular Medicine.
Ponzio, N. M., Servatius, R., Beck, K., Marzouk, A., & Kreider, T. (2007). Cytokine levels during pregnancy influence immunological profiles and neurobehavioral patterns of the offspring. Annals of the New York Academy of Sciences, 1107, 118–128.
SAS. (2002). SAS (Statistical Analysis Software). 9.1.3 ed. Cary, NC; Statistical Analysis Software Institute.
Shi, L., Fatemi, S. H., Sidwell, R. W., & Patterson, P. H. (2003). Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. Journal of Neuroscience, 23(1), 297–302.
Smith, S. E., Li, J., Garbett, K., Mirnics, K., & Patterson, P. H. (2007). Maternal immune activation alters fetal brain development through interleukin-6. Journal of Neuroscience, 27(40), 10695–10702.
Sparrow, S. S., Balla, D. A., & Cicchetti, D. V. (1984). Vineland Adaptive Behavior Scales Interview Edition Expanded Form Manual. Circle Pines: American Guidance Services Inc.
Torres, A. R. (2003). Is fever suppression involved in the etiology of autism and neurodevelopmental disorders? BMC Pediatrics, 3, 9.
Wilkerson, D. S., Volpe, A. G., Dean, R. S., & Titus, J. B. (2002). Perinatal complications as predictors of infantile autism. International Journal of Neuroscience, 112(9), 1085–1098.
Yamashita, Y., Fujimoto, C., Nakajima, E., Isagai, T., & Matsuishi, T. (2003). Possible association between congenital cytomegalovirus infection and autistic disorder. Journal of Autism and Developmental Disorders, 33(4), 455–459.
Zaretsky, M. V., Alexander, J. M., Byrd, W., & Bawdon, R. E. (2004). Transfer of inflammatory cytokines across the placenta. Obstetrics and Gynecology, 103(3), 546–550.
Zhang, X., Lv, C.C., Tian, J., Miao, R. J., Xi, W., Hertz-Picciotto, I., et al. (2010). Prenatal and perinatal risk factors for autism in China. Journal of Autism and Developmental Disorders, 40(11), 1311–1321.
The authors would like to thank Paula Krakowiak and Lora Delwiche both from the Department of Public Health Sciences at the University of California Davis for their great data management skills, Dr. Daniel Tancredi, PhD from the Department of Pediatrics at the University of California Davis for his statistical analysis advice.
The present work was supported by grants R01-ES015359 and P01-ES11269 from the National Institute of Environmental Health Sciences; # R-829388 & R-833292 from the U.S. Environmental Protection Agency’s STAR program; and the UC Davis MIND Institute.
Conflict of interest
The authors declare that they have no conflict of interest.
Electronic supplementary material
Below is the link to the electronic supplementary material.
About this article
Cite this article
Zerbo, O., Iosif, AM., Walker, C. et al. Is Maternal Influenza or Fever During Pregnancy Associated with Autism or Developmental Delays? Results from the CHARGE (CHildhood Autism Risks from Genetics and Environment) Study. J Autism Dev Disord 43, 25–33 (2013). https://doi.org/10.1007/s10803-012-1540-x
- Maternal influenza
- Anti-fever medication