Maternal Gestational Immune Response and Autism Spectrum Disorder Phenotypes at 7 Years of Age in the Seychelles Child Development Study
Findings from observational and experimental studies suggest that maternal inflammation during pregnancy is associated with autism spectrum disorder (ASD). We report the first study in humans to examine this association in a large prospective birth cohort. We studied 788 mother-child pairs from the Seychelles Child Development Study Nutrition Cohort 2. Thirteen inflammatory markers were measured in mothers’ serum at 28 weeks’ gestation, along with the sum of T-helper 1 (Th1) and 2 (Th2) cytokines. The Social Communication Questionnaire (SCQ) and Social Responsiveness Scale (SRS) were administered at age 7 years to obtain information on ASD phenotype. We evaluated associations between maternal inflammatory markers and ASD phenotype using multivariable linear regression. For the SCQ, increased MCP-1 (a chemokine that is upregulated in response to pro-inflammatory cytokines) was associated with fewer ASD symptoms (B = − 0.40; 95% CI = − 0.72, − 0.09). Increased IL-4 (a cytokine that is typically associated with an enhanced anti-inflammatory response) was associated with more ASD symptoms (B = 2.10; 95% CI = 0.78, 3.43). For the SRS, higher concentrations of the anti-inflammatory cytokine IL-10 were associated with fewer ASD symptoms (B = − 0.18; 95% CI = − 0.35, − 0.01), but only after removal of outliers. No associations were observed for other markers. These findings suggest that a shift in the maternal immune balance during pregnancy may be associated with ASD symptomatology. While the use of well-established measures that capture ASD phenotypic variability is a strength of the study, measurement of peripheral immune markers only once during gestation is a limitation. Our results should be confirmed using maternal immune markers measured throughout gestation.
KeywordsPregnancy Immune response Inflammation Autism Spectrum disorder Cytokines Chemokines
We acknowledge with thanks the contribution of the nursing and laboratory teams in Seychelles. The study sponsors had no role in the design, collection, analysis, or interpretation of the data; in the writing of the report; or in the decision to submit the article for publication.
This research was supported by grants R01-ES010219, P30-ES01247, R03-ES027514, T32-ES007271, and T32-ES007026 from the US National Institute of Environmental Health Sciences (National Institutes of Health) and in-kind by the Government of the Republic of Seychelles.
Compliance with ethical standards
The study was reviewed and approved by the Seychelles Ethics Board and the Research Subjects Review Board at the University of Rochester.
Conflict of interest
The authors declare that they have no conflict of interest.
- 1.American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders (5th ed). American Psychiatric Association, Arlington, VAGoogle Scholar
- 2.Baio J, Wiggins LD, Christensen DL, Maenner MJ, Daniels J, Warren Z, Kurzius-Spencer M, Zahorodny W et al (2018) Prevalence of autism spectrum disorder among children aged 8 years—autism and developmental disabilities monitoring network, 11 sites, United States, 2014. Morb Mortal Wkly Rep Surveill Summ 67:1–23. https://doi.org/10.15585/mmwr.ss6706a1 CrossRefGoogle Scholar
- 3.Lyall K, Croen L, Daniels J, Fallin MD, Ladd-Acosta C, Lee BK, Park BY, Snyder NW et al (2017) The changing epidemiology of autism spectrum disorders. Annu Rev Public Health 38:81–102. https://doi.org/10.1146/annurev-publhealth-031816-044318 CrossRefPubMedGoogle Scholar
- 7.Saito S, Sakai M, Sasaki Y, Tanebe K, Tsuda H, Michimata T (1999) Quantitative analysis of peripheral blood Th0, Th1, Th2 and the Th1:Th2 cell ratio during normal human pregnancy and preeclampsia. Clin Exp Immunol 117:550–555. https://doi.org/10.1046/j.1365-2249.1999.00997.x CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Zerbo O, Traglia M, Yoshida C, Heuer LS, Ashwood P, Delorenze GN, Hansen RL, Kharrazi M et al (2016) Maternal mid-pregnancy C-reactive protein and risk of autism spectrum disorders: the early markers for autism study. Transl Psychiatry 6:e783. https://doi.org/10.1038/tp.2016.46 CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Goines PE, Croen LA, Braunschweig D, Yoshida CK, Grether J, Hansen R, Kharrazi M, Ashwood P et al (2011) Increased midgestational IFN-γ, IL-4 and IL-5 in women bearing a child with autism: a case-control study. Mol Autism 2:13. https://doi.org/10.1186/2040-2392-2-13 CrossRefPubMedPubMedCentralGoogle Scholar
- 24.Jones KL, Croen LA, Yoshida CK, Heuer L, Hansen R, Zerbo O, DeLorenze GN, Kharrazi M et al (2017) Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation. Mol Psychiatry 22:273–279. https://doi.org/10.1038/mp.2016.77 CrossRefPubMedGoogle Scholar
- 25.Abdallah MW, Larsen N, Mortensen EL, Atladóttir HÓ, Nørgaard-Pedersen B, Bonefeld-Jørgensen EC, Grove J, Hougaard DM (2012) Neonatal levels of cytokines and risk of autism spectrum disorders: an exploratory register-based historic birth cohort study utilizing the Danish newborn screening biobank. J Neuroimmunol 252:75–82. https://doi.org/10.1016/j.jneuroim.2012.07.013 CrossRefPubMedGoogle Scholar
- 26.Abdallah MW, Larsen N, Grove J, Bonefeld-Jørgensen EC, Nørgaard-Pedersen B, Hougaard DM, Mortensen EL (2013) Neonatal chemokine levels and risk of autism spectrum disorders: findings from a Danish historic birth cohort follow-up study. Cytokine 61:370–376. https://doi.org/10.1016/j.cyto.2012.11.015 CrossRefPubMedGoogle Scholar
- 29.Zerbo O, Yoshida C, Grether JK, van de Water J, Ashwood P, Delorenze GN, Hansen RL, Kharrazi M et al (2014) Neonatal cytokines and chemokines and risk of autism spectrum disorder: the early markers for autism (EMA) study: a case-control study. J Neuroinflammation 11:1–9. https://doi.org/10.1186/1742-2094-11-113 CrossRefGoogle Scholar
- 30.Abdallah MW, Larsen N, Grove J, Nørgaard-Pedersen B, Thorsen P, Mortensen EL, Hougaard DM (2013) Amniotic fluid inflammatory cytokines: potential markers of immunologic dysfunction in autism spectrum disorders. World J Biol Psychiatry 14:528–538. https://doi.org/10.3109/15622975.2011.639803 CrossRefPubMedGoogle Scholar
- 31.Abdallah MW, Larsen N, Grove J, Nørgaard-Pedersen B, Thorsen P, Mortensen EL, Hougaard DM (2012) Amniotic fluid chemokines and autism spectrum disorders: an exploratory study utilizing a Danish historic birth cohort. Brain Behav Immun 26:170–176. https://doi.org/10.1016/j.bbi.2011.09.003 CrossRefPubMedGoogle Scholar
- 32.Strain JJ, Yeates AJ, van Wijngaarden E, Thurston SW, Mulhern MS, McSorley EM, Watson GE, Love TM et al (2015) Prenatal exposure to methyl mercury from fish consumption and polyunsaturated fatty acids: associations with child development at 20 mo of age in an observational study in the Republic of Seychelles. Am J Clin Nutr 101:530–537. https://doi.org/10.3945/ajcn.114.100503 CrossRefPubMedPubMedCentralGoogle Scholar
- 33.Constantino JN, Gruber CP (2005) Social responsiveness scale (SRS): manual. Western Psychological Services, Los Angeles, CAGoogle Scholar
- 34.Rutter M, Bailey A, Lord C (2003) Social Communication Questionnaire. Manual. Western Psychological Services, Los Angeles, CAGoogle Scholar
- 40.van Wijngaarden E, Thurston SW, Myers GJ, Strain JJ, Weiss B, Zarcone T, Watson GE, Zareba G et al (2013) Prenatal methyl mercury exposure in relation to neurodevelopment and behavior at 19 years of age in the Seychelles child development study. Neurotoxicol Teratol 39:19–25. https://doi.org/10.1016/j.ntt.2013.06.003 CrossRefPubMedGoogle Scholar
- 46.Lundström S, Chang Z, Råstam M, Gillberg C, Larsson H, Anckarsäter H, Lichtenstein P (2012) Autism spectrum disorders and autisticlike traits: Similar etiology in the extreme end and the normal variation. Arch Gen Psychiatry 69:46–52. https://doi.org/10.1001/archgenpsychiatry.2011.144 CrossRefPubMedGoogle Scholar
- 49.Moody EJ, Reyes N, Ledbetter C, Wiggins L, DiGuiseppi C, Alexander A, Jackson S, Lee LC et al (2017) Screening for autism with the SRS and SCQ: variations across demographic, developmental and behavioral factors in preschool children. J Autism Dev Disord 47:3550–3561. https://doi.org/10.1007/s10803-017-3255-5 CrossRefPubMedPubMedCentralGoogle Scholar