ROLE OF PARENTAL FACTORS, INCLUDING INFLAMMATION AND INFECTION IN AUTISM DEVELOPMENT

Autism is a congenital heterogeneous disorder with hereditary risks existing approximately evenly across both the paternal and maternal lines[1] [2] [3] [4], and advanced age of both parents at the time of conception could further increase the risk for both autism and de novo mutations[5] [6] [7] [8] [9] [10] [11] [12] [13]. Maternal diseases and pathological states, accompanied with inflammation, during pregnancy such as obesity, diabetes type 1 and 2, other autoimmune disorders, stress, prenatal hormonal stress, depression, pre-eclampsia, gestational diabetes, and infection during pregnancy have been linked to an increased risk of brain damage and ASD in offspring[14] [15] [16] [17] [18] [19]  [20] [21] [22] [23] [24] [25] [26] [27] [28] [29]. It is also believed that activation of the maternal immune system, caused by any maternal inflammatory state, leads to changes in the fetal brain which alter neurodevelopment[30] [31] [32] of offspring.

​

 Also, maternal hormonal interventions, especially the use of birth control pills, could pose a potential risk of autism in offspring[33] [34] [35] [36] [37] [38] due to a possibility of altering the immune system's responses leading to inflammation[39] [40] [41] and blocking the receptors responsible for reducing oxidative stress[42] [43] [44] [45]. 

Maternal infections and inflammation are the most reliable factors of making offspring more susceptible to developing ASD [46] [47]. The critical publication in 2019 in the journal JAMA Psychiatry showed the results of a multi-year study that of about 1.8 million children of Swedish origin from birth to 41 years. It was shown that maternal infection requiring hospitalization has increased the risk of autism and depression over the course of a child's lifetime. In another large Swedish study [48] of more than 2 million people born 1984 and 2007, with 24,414 cases of ASD showed that the chance of developing autism increased by about 30% in children born to mothers with an infection at any time in pregnancy.  The Danish study of medical histories of babies born between 1980 and 2005, showed that maternal viral infection in the first trimester and bacterial infection in the second trimester, significantly increased the risk of autism in the offspring[49].  Two meta-analyses of 36[50] and 15[51] published studies, found a significant correlation between maternal infection in the prenatal period and the risk of autism in the offspring.

In the cases of maternal infection, microorganisms present in the mother's bloodstream can infect and break the placenta, infiltrate the fetus's circulation, and spread throughout the fetal organism[52].

 

 

[1] Sandin S, Lichtenstein P, Kuja-Halkola R, Hultman C, Larsson H, Reichenberg A (2017): The heritability of autism spectrum disorder. Jama. 318:1182–1184.

[2] Yip BHK, Bai D, Mahjani B, Klei L, Pawitan Y, Hultman CM, et al. (2017): Heritable Variation, With Little or No Maternal Effect, Accounts for Recurrence Risk to Autism Spectrum Disorder in Sweden. Biol Psychiatry.

[3] Bai D, Marrus N, Yip BHK, Reichenberg A, Constantino JN, Sandin S. Inherited Risk for Autism Through Maternal and Paternal Lineage. Biol Psychiatry. 2020 Sep 15; 88(6):480-487. doi: 10.1016/j.biopsych.2020.03.013. Epub 2020 Apr 2. PMID: 32430199; PMCID: PMC7483301.

[4] Lu J, Wang Z, Liang Y, Yao P. Rethinking autism: the impact of maternal risk factors on autism development. Am J Transl Res. 2022 Feb 15; 14(2):1136-1145. PMID: 35273718; PMCID: PMC8902545.

[5] Croen LA, Najjar DV, Fireman B, Grether JK. Maternal and paternal age and risk of autism spectrum disorders. Arch Pediatr Adolesc Med. 2007 Apr; 161(4):334-40. doi: 10.1001/archpedi.161.4.334. PMID: 17404129.

[6] Reichenberg A, Gross R, Weiser M, Bresnahan M, Silverman J, Harlap S, Rabinowitz J, Shulman C, Malaspina D, Lubin G, Knobler HY, Davidson M, Susser E. Advancing paternal age and autism. Arch Gen Psychiatry. 2006 Sep; 63(9):1026-32. doi: 10.1001/archpsyc.63.9.1026. PMID: 16953005.

[7]Crow JF. The origins, patterns and implications of human spontaneous mutation. Nat Rev Genet. 2000 Oct; 1(1):40-7. doi: 10.1038/35049558. PMID: 11262873.

[8] Chandley AC. On the parental origin of de novo mutation in man. J Med Genet. 1991 Apr; 28(4):217-23. doi: 10.1136/jmg.28.4.217. PMID: 1677423; PMCID: PMC1016821.

[9] Sandin, S., Schendel, D., Magnusson, P. et al. Autism risk associated with parental age and with increasing difference in age between the parents. Mol Psychiatry 21, 693–700 (2016). https://doi.org/10.1038/mp.2015.70

[10] Goriely A, Wilkie AO. Paternal age effect mutations and selfish spermatogonial selection: causes and consequences for human disease. Am J Hum Genet. 2012 Feb 10; 90(2):175-200. doi: 10.1016/j.ajhg.2011.12.017. PMID: 22325359; PMCID: PMC3276674

[11] Hurles M. Older males beget more mutations. Nat Genet. 2012 Nov; 44(11):1174-6. doi: 10.1038/ng.2448. PMID: 23104062

[12] Singh NP, Muller CH, Berger RE. Effects of age on DNA double-strand breaks and apoptosis in human sperm. Fertil Steril. 2003 Dec; 80(6):1420-30. doi: 10.1016/j.fertnstert.2003.04.002. PMID: 14667878.

[13] Hassold T, Hunt P. Maternal age and chromosomally abnormal pregnancies: what we know and what we wish we knew. Curr Opin Pediatr. 2009 Dec; 21(6):703-8. doi: 10.1097/MOP.0b013e328332c6ab. PMID: 19881348; PMCID: PMC2894811.).

[14] Han V, Patel S, Jones H, Nielsen T, Mohammad S, Hofer M, Gold W, Brilot F, Lain S, Nassar N, Dale R (2021)

Maternal acute and chronic inflammation in pregnancy is associated with common neurodevelopmental disorders: a systematic review. Translational Psychiatry 11 (1). https://doi.org/10.1038/s41398-021-01198-w

[15]Wilson H, Creighton C, Scharfman H, Choleris E, MacLusky N (2021) Endocrine Insights into the Pathophysiology of Autism Spectrum Disorder. Neuroscientist 27 (6): 650‑667. https://doi.org/10.1177/1073858420952046

[16] Xiang AH, Wang X, Martinez MP, Page K, Buchanan TA, Feldman RK. Maternal Type 1 Diabetes and Risk of Autism in Offspring. JAMA. 2018 Jul 3; 320(1):89-91. doi: 10.1001/jama.2018.7614. PMID: 29936530; PMCID: PMC6134431.

[17] Rossignol, D. A., & Frye, R. E. (2011). A review of research trends in physiological abnormalities in autism spectrum disorders: immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures. Molecular Psychiatry, 17(4), 389–401. doi:10.1038/mp.2011.165

[18] Garcia, C., Feve, B., Ferré, P., Halimi, S., Baizri, H., Bordier, L. (2010). Diabetes and inflammation: Fundamental aspects and clinical implications. Diabetes & Metabolism, 36(5):327–338

[19]Shi G, Zhang J, Zhang Z, Zhang X. Systemic Autoimmune Diseases. Clin Dev Immunol. 2013;2013:728574. doi: 10.1155/2013/728574. Epub 2013 Dec 1. PMCID: PMC3864070.

[20] Abell SK, De Courten B, Boyle JA, Teede HJ. Inflammatory and Other Biomarkers: Role in Pathophysiology and Prediction of Gestational Diabetes Mellitus. Int J Mol Sci. 2015 Jun 11; 16(6):13442-73. doi: 10.3390/ijms160613442. PMID: 26110385; PMCID: PMC4490503.

[21]Ellulu MS, Patimah I, Khaza'ai H, Rahmat A, Abed Y. Obesity and inflammation: the linking mechanism and the complications. Arch Med Sci. 2017 Jun; 13(4):851-863. doi: 10.5114/aoms.2016.58928. Epub 2016 Mar 31. PMID: 28721154; PMCID: PMC5507106.

[22] Liu YZ, Wang YX, Jiang CL. Inflammation: The Common Pathway of Stress-Related Diseases. Front Hum Neurosci. 2017 Jun 20;11:316. doi: 10.3389/fnhum.2017.00316. PMID: 28676747; PMCID: PMC5476783.

[23] Harmon AC, Cornelius DC, Amaral LM, Faulkner JL, Cunningham MW Jr, Wallace K, LaMarca B. The role of inflammation in the pathology of preeclampsia. Clin Sci (Lond). 2016 Mar; 130(6):409-19. doi: 10.1042/CS20150702. PMID: 26846579; PMCID: PMC5484393.

[24]Wilson H, Creighton C, Scharfman H, Choleris E, MacLusky N (2021) Endocrine Insights into the Pathophysiology of Autism Spectrum Disorder. Neuroscientist 27 (6): 650‑667. https://doi.org/10.1177/1073858420952046

[25] Xiang AH, Wang X, Martinez MP, Page K, Buchanan TA, Feldman RK. Maternal Type 1 Diabetes and Risk of Autism in Offspring. JAMA. 2018 Jul 3; 320(1):89-91. doi: 10.1001/jama.2018.7614. PMID: 29936530; PMCID: PMC6134431.

[26] Braunschweig D, Ashwood P, Krakowiak P, et al. Autism: maternally derived antibodies specific for fetal brain proteins. Neurotoxicology 2008; 29:226– 231.

[27]Zimmerman AW, Connors SL, Matteson KJ, et al. Maternal antibrain antibodies in autism. Brain Behav Immun 2007; 21:351–357

[28]Singer HS, Morris CM, Gause CD, et al. Antibodies against fetal brain in sera of mothers with autistic children. J Neuroimmunol 2008; 194:165–172

[29] Braunschweig D, Duncanson P, Boyce R, et al. Behavioral Correlates of Maternal Antibody Status Among Children with Autism. Published online 2016:20.

[30]Jonakait GM (2007) The effects of maternal inflammation on neuronal development: possible mechanisms. Int J Dev Neurosci 25:415–425

[31] Meyer U, Nyffeler M, Yee BK, Knuesel I, Feldon J (2008) Adult brain and behavioral pathological markers of prenatal immune challenge during early/middle and late fetal development in mice. Brain Behav Immun 22:469–486 28.

[32] Hsiao EY, Patterson PH (2011) Activation of the maternal immune system induces endocrine changes in the placenta via IL-6. Brain Behav Immun 25(4):604–615 27.

[33] Whitaker-Azmitia PM, Lobel M, Moyer A. Low maternal progesterone may contribute to both obstetrical complications and autism. Med Hypotheses. (2014) 82:313–8. doi: 10.1016/j.mehy.2013.12.018

[34] Mamidala MP, Polinedi A, Kumar PT, Rajesh N, Vallamkonda OR, Udani V, et al. Maternal hormonal interventions as a risk factor for Autism Spectrum Disorder: an epidemiological assessment from India. J Biosci. (2013) 38:887–92. doi: 10.1007/s12038-013-9376-x

[35]Windham GC, Lyall K, Anderson M, Kharrazi M. Autism Spectrum disorder risk in relation to maternal mid-pregnancy serum hormone and protein markers from prenatal screening in California. J Autism Dev Disord. (2016) 46:478–88. doi: 10.1007/s10803-015-2587-2

[36]Strifert K. The link between oral contraceptive use and prevalence in autism spectrum disorder. Med Hypotheses. (2014) 83:718–25. doi: 10.1016/j.mehy.2014.09.026

[37] Li L, Li M, Lu J, Ge X, Xie W, Wang Z, Li X, Li C, Wang X, Han Y, Wang Y, Zhong L, Xiang W, Huang X, Chen H, Yao P. Prenatal Progestin Exposure Is Associated with Autism Spectrum Disorders. Front Psychiatry. 2018 Nov 19;9:611. doi: 10.3389/fpsyt.2018.00611. PMID: 30510526; PMCID: PMC6252360.

[38] Strifert K. An epigenetic basis for autism spectrum disorder risk and oral contraceptive use. Med Hypotheses. (2015) 85:1006–11. doi: 10.1016/j.mehy.2015.09.001

[39] Khalili H. Risk of inflammatory bowel disease with oral contraceptives and menopausal hormone therapy: current evidence and future directions. Drug Saf. 2016; 39(3):193-197.

[40] Dreon DM et al. Oral contraceptive use and increased plasma concentration of C-reactive protein. Life Sci. 2003; 73(10):1245-1252.

[41]Divani AA, Luo X, Datta YH, Flaherty JD, Panoskaltsis-Mortari A. Effect of oral and vaginal hormonal contraceptives on inflammatory blood biomarkers. Mediators Inflamm. 2015;2015:379501. doi: 10.1155/2015/379501. Epub 2015 Mar 16. PMID: 25861161; PMCID: PMC4378601.

[42][42] Aguirre C, Jayaraman A, Pike C, Baudry M. Progesterone inhibits estrogen-mediated neuroprotection against excitotoxicity by down-regulating estrogen receptor-beta. J Neurochem. (2010) 115:1277–87. doi: 10.1111/j.1471-4159.2010.07038.x

[43] Jayaraman A, Pike CJ. Progesterone attenuates oestrogen neuroprotection via downregulation of oestrogen receptor expression in cultured neurones. J Neuroendocrinol. (2009) 21:77–81. doi: 10.1111/j.1365-2826.2008.01801.x

[44] Willing J, Wagner CK. Exposure to the synthetic progestin, 17alpha-hydroxyprogesterone caproate during development impairs cognitive flexibility in adulthood. Endocrinology (2016) 157:77–82. doi: 10.1210/en.2015-1775

[45] Zou Y, Lu Q, Zheng D, Chu Z, Liu Z, Chen H, et al. Prenatal levonorgestrel exposure induces autism-like behavior in offspring through ERbeta suppression in the amygdala. Mol Autism. (2017) 8:46. doi: 10.1186/s13229-017-0159-

[46]Shuid AN, Jayusman PA, Shuid N, Ismail J, Kamal Nor N, Mohamed IN. Association between Viral Infections and Risk of Autistic Disorder: An Overview. Int J Environ Res Public Health. 2021 Mar 10; 18(6):2817. doi: 10.3390/ijerph18062817. PMID: 33802042; PMCID: PMC7999368.

[47] Rossignol, D. A., & Frye, R. E. (2011). A review of research trends in physiological abnormalities in autism spectrum disorders: immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures. Molecular Psychiatry, 17(4), 389–401. doi:10.1038/mp.2011.165

[48] Lee B, Magnusson C, Gardner R, Blomström Å, Newschaffer C, Burstyn I, Karlsson H, Dalman C (2015) Maternal hospitalization with infection during pregnancy and risk of autism spectrum disorders. Brain, Behavior, and Immunity 44: 100‑105.https://doi.org/10.1016/j.bbi.2014.09.001

[49]Atladóttir H, Thorsen P, Østergaard L, Schendel D, Lemcke S, Abdallah M, et al. Maternal Infection Requiring Hospitalization During Pregnancy and Autism Spectrum Disorders. Journal Of Autism and Developmental Disorders. 2010; 40(12):1423–1430 A

[50] Tioleco N, Silberman AE, Stratigos K, Marisa SB, Agnes NS, Turner JB (2021) Prenatal maternal infection and risk for autism in offspring: A meta-analysis. Autism Research 14 (6): 1296‑1316. https://doi.org/10.1002/aur.2499

[51] Jiang Hy, Xu Ll, Shao L, Xia Rm, Yu Zh, Ling Zx, Yang F, Deng M, Ruan B (2016) Maternal infection during pregnancy and risk of autism spectrum disorders: A systematic review and meta-analysis. Brain, Behavior, and Immunity 58: 165‑172. https://doi.org/10.1016/j.bbi.2016.06.005

[52] Zeichner SL, Plotkin SA. Mechanisms and pathways of congenital infections. Clin Perinatol. 1988 Jun; 15(2):163-88. PMID: 3288420.