Evaluation of the Association Between Autism Spectrum Disorder and Attention-deficit/hyperactivity Disorder in the Offspring and Autoimmune and Autoinflammatory Disorders in Parents: A Systematic Review and Meta-analysis.

Document Type : Review Article


Department of Psychology, Shahab Danesh University, Qom, Iran


Background and aim: Neurodevelopmental disorders (NDs) are types of mental disorders that affect the way the brain functions and alter neural development, causing problems in social, cognitive, and emotional functioning. Autoimmune and autoinflammatory disorders-causing factors may be involved in NDs. The present study evaluated the association between autism spectrum disorder and attention-deficit/hyperactivity disorder in the offspring and autoimmune and autoinflammatory disorders in parents.
Material and methods: All international databases (PubMed, Scopus, Science Direct, ISI, Web of Knowledge, and Embase) were searched from 2010 to May 2023 with keywords based on the objectives of the study. Data analysis using STATA/MP. v17 software was done in 95% confidence intervals.
Results: Five cohort studies and five cross-sectional studies were selected. The odds ratio of autism spectrum disorder and attention-deficit/hyperactivity disorder in the offspring between the experimental group (autoimmune and autoinflammatory disorders in the parent) and control group (healthy parents) was (OR, 0.16 95% CI 0.10, 0.22; p<0.05) and (OR, 1.28 95% CI 0.91, 1.65; p<0.05), respectively. The odds ratio of attention-deficit/hyperactivity disorder in children whose mothers had type 1 diabetes was 1.28 (OR, 1.28 95% CI 0.91, 1.65; p<0.05). The odds ratio of autism spectrum disorder in children whose fathers had type 1 diabetes was 1.09 (OR, 1.09 95% CI 0.48, 1.70; p<0.05).
Conclusions: Based on the findings of the present study, there is a positive and direct relationship between autoimmune and autoinflammatory disorders in mothers and fathers with increased risk of autism spectrum disorder and attention-deficit/hyperactivity disorder in children.


Main Subjects

[1] von Gontard A, Hussong J, Yang SS, Chase J, Franco I, Wright A. Neurodevelopmental disorders and incontinence in children and adolescents: Attention‐deficit/hyperactivity disorder, autism spectrum disorder, and intellectual disability—A consensus document of the International Children's Continence Society. Neurourology and Urodynamics. 2022;41(1):102-14. https://doi.org/10.1002/nau.24798.
[2] Francés L, Caules J, Ruiz A, Soler CV, Hervás A, Fernández A, et al. An approach for prevention planning based on the prevalence and comorbidity of neurodevelopmental disorders in 6-year-old children receiving primary care consultations on the island of Menorca. BMC pediatrics. 2023;23(1):32. https://doi.org/10.1186/s12887-023-03844-2.
[3] van Galen M, Huskens B, von Gontard A, Didden R. Standard urotherapy for children with neurodevelopmental disabilities: A systematic review. Advances in Neurodevelopmental Disorders. 2023;7(1):1-3. https://doi.org/10.1007/s41252-022-00270-w.
[4] Roy M, Strate P. Autism Spectrum Disorders in Adulthood—Symptoms, Diagnosis, and Treatment. Deutsches Ärzteblatt International. 2023;120(6):87-93. https://doi.org/10.3238/arztebl.m2022.0379.
[5] Zeidan J, Fombonne E, Scorah J, Ibrahim A, Durkin MS, Saxena S, et al. Global prevalence of autism: A systematic review update. Autism research. 2022;15(5):778-90. https://doi.org/10.1002/aur.2696.
[6] Boshomane TT. Testing deficits in behavioural planning, set-shifting/cognitive flexibility and working memory in children with high levels of Attention Deficit/Hyperactivity Disorder symptoms (Doctoral dissertation).2022.
[7] Lichtenstein P, Carlström E, Råstam M, Gillberg C, Anckarsäter H. The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood. American Journal of Psychiatry. 2010;167(11):1357-63. https://doi.org/10.1176/appi.ajp.2010.10020223.
[8] Thapar A, Cooper M, Rutter M. Neurodevelopmental disorders. The Lancet Psychiatry. 2017;4(4):339-46. https://doi.org/10.1016/S2215-0366(16)30376-5.
[9] Lord C, Brugha TS, Charman T, Cusack J, Dumas G, Frazier T, et al. Autism spectrum disorder. Nature reviews Disease primers. 2020;6(1):1-23. https://doi.org/10.1038/s41572-019-0138-4.
[10] Stein DJ, Costa DL, Lochner C, Miguel EC, Reddy YJ, Shavitt RG, et al. Obsessive–compulsive disorder. Nature reviews Disease primers. 2019;5(1):52. https://doi.org/10.1038/s41572-019-0102-3.
[11] Gustavson K, Ask H, Ystrom E, Stoltenberg C, Lipkin WI, Surén P, et al. Maternal fever during pregnancy and offspring attention deficit hyperactivity disorder. Scientific reports. 2019;9(1):9519. https://doi.org/10.1038/s41598-019-45920-7.
[12] Croen LA, Qian Y, Ashwood P, Zerbo O, Schendel D, Pinto‐Martin J, et al. Infection and fever in pregnancy and autism spectrum disorders: findings from the study to explore early development. Autism Research. 2019;12(10):1551-61. https://doi.org/10.1002/aur.2175.
[13] Wu WL, Hsiao EY, Yan Z, Mazmanian SK, Patterson PH. The placental interleukin-6 signaling controls fetal brain development and behavior. Brain, behavior, and immunity. 2017;62:11-23. https://doi.org/10.1016/j.bbi.2016.11.007.
[14] Wang L, Wang FS, Gershwin ME. Human autoimmune diseases: a comprehensive update. Journal of internal medicine. 2015;278(4):369-95. https://doi.org/10.1111/joim.12395.
[15] Dendrou CA, Petersen J, Rossjohn J, Fugger L. HLA variation and disease. Nature Reviews Immunology. 2018;18(5):325-39. https://doi.org/10.1038/nri.2017.143.
[16] Chen SW, Zhong XS, Jiang LN, Zheng XY, Xiong YQ, Ma SJ, et al. Maternal autoimmune diseases and the risk of autism spectrum disorders in offspring: a systematic review and meta-analysis. Behavioural brain research. 2016;296:61-9. https://doi.org/10.1016/j.bbr.2015.08.035.
[17] Tugwell P, Tovey D. PRISMA 2020. Journal of Clinical Epidemiology. 2021;134:A5-6. https://doi.org/10.1016/j.jclinepi.2021.04.008.
[18] Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. European journal of epidemiology. 2010;25:603-5. https://doi.org/10.1007/s10654-010-9491-z.
[19] Hsu TW, Chen MH, Bai YM, Chang WH, Cheng CM, Su TP, et al. Family coaggregation of type 1 diabetes mellitus, major depressive disorder, attention-deficiency hyperactivity disorder and autism spectrum disorder in affected families: A nationwide study. Acta Diabetologica. 2023;60(4):517-25. https://doi.org/10.1007/s00592-022-02025-4.
[20] Lee H, Hsu JW, Tsai SJ, Huang KL, Bai YM, Su TP, et al. Risk of attention deficit hyperactivity and autism spectrum disorders among the children of parents with autoimmune diseases: a nationwide birth cohort study. European Child & Adolescent Psychiatry. 2023;32(2):283-91. https://doi.org/10.1007/s00787-021-01860-0.
[21] Li DJ, Tsai CS, Hsiao RC, Chen YL, Yen CF. Associations between allergic and autoimmune diseases with autism spectrum disorder and attention-deficit/hyperactivity disorder within families: a Population-Based Cohort Study. International Journal of Environmental Research and Public Health. 2022;19(8):4503. https://doi.org/10.3390/ijerph19084503.
[22] Hegvik TA, Chen Q, Kuja-Halkola R, Klungsøyr K, Butwicka A, Lichtenstein P, et al. Familial co-aggregation of attention-deficit/hyperactivity disorder and autoimmune diseases: a cohort study based on Swedish population-wide registers. International Journal of Epidemiology. 2022;51(3):898-909. https://doi.org/10.1093/ije/dyab151.
[23] Spann MN, Timonen-Soivio L, Suominen A, Cheslack-Postava K, McKeague IW, Sourander A, et al. Proband and familial autoimmune diseases are associated with proband diagnosis of autism spectrum disorders. Journal of the American Academy of Child & Adolescent Psychiatry. 2019;58(5):496-505. https://doi.org/10.1016/j.jaac.2018.09.444.
[24] Croen LA, Qian Y, Ashwood P, Daniels JL, Fallin D, Schendel D, et al. Family history of immune conditions and autism spectrum and developmental disorders: Findings from the study to explore early development. Autism Research. 2019;12(1):123-35. https://doi.org/10.1002/aur.1979.
[25] Rom AL, Wu CS, Olsen J, Jawaheer D, Hetland ML, Mørch LS. Parental rheumatoid arthritis and autism spectrum disorders in offspring: a Danish nationwide cohort study. Journal of the American Academy of Child & Adolescent Psychiatry. 2018;57(1):28-32. https://doi.org/10.1016/j.jaac.2017.10.002.
[26] Nielsen PR, Benros ME, Dalsgaard S. Associations between autoimmune diseases and attention-deficit/hyperactivity disorder: a nationwide study. Journal of the American Academy of Child & Adolescent Psychiatry. 2017;56(3):234-40. https://doi.org/10.1016/j.jaac.2016.12.010.
[27] Andersen AB, Ehrenstein V, Erichsen R, Frøslev T, Sørensen HT. autism spectrum disorders in children of parents with inflammatory bowel disease–a nationwide cohort study in Denmark. Clinical and Experimental Gastroenterology. 2014;7:105-10.
[28] Keil A, Daniels JL, Forssen U, Hultman C, Cnattingius S, Söderberg KC, et al. Parental autoimmune diseases associated with autism spectrum disorders in offspring. Epidemiology (Cambridge, Mass.). 2010;21(6):805. https://doi.org/10.1097/EDE.0b013e3181f26e3f.
[29] Zeng Y, Tang Y, Yue Y, Li W, Qiu X, Hu P, et al. Cumulative evidence for association of parental diabetes mellitus and attention-deficit/hyperactivity disorder. Neuroscience & Biobehavioral Reviews. 2020;117:129-39. https://doi.org/10.1016/j.neubiorev.2019.11.003.
[30] Pavlinkova G, Salbaum JM, Kappen C. Maternal diabetes alters transcriptional programs in the developing embryo. BMC genomics. 2009;10:1-12. https://doi.org/10.1186/1471-2164-10-274.
[31] Xiang AH, Wang X, Martinez MP, Getahun D, Page KA, Buchanan TA, et al. Maternal gestational diabetes mellitus, type 1 diabetes, and type 2 diabetes during pregnancy and risk of ADHD in offspring. Diabetes Care. 2018;41(12):2502-8. https://doi.org/10.2337/dc18-0733.
[32] Wan H, Zhang C, Li H, Luan S, Liu C. Association of maternal diabetes with autism spectrum disorders in offspring: a systemic review and meta-analysis. Medicine. 2018;97(2):e9438. https://doi.org/10.1097/MD.0000000000009438.
[33] Qu HQ, Qu J, Bradfield J, Marchand L, Glessner J, Chang X, et al. Genetic architecture of type 1 diabetes with low genetic risk score informed by 41 unreported loci. Communications Biology. 2021;4(1):908. https://doi.org/10.1038/s42003-021-02368-8.
[34] Khan MF, Wang H. Environmental exposures and autoimmune diseases: contribution of gut microbiome. Frontiers in immunology. 2020;10:3094. https://doi.org/10.3389/fimmu.2019.03094.
[35] Von Ehrenstein OS, Ling C, Cui X, Cockburn M, Park AS, Yu F, et al. Prenatal and infant exposure to ambient pesticides and autism spectrum disorder in children: population based case-control study. bmj. 2019;364. https://doi.org/10.1136/bmj.l962.
[36] Kim B, Ha M, Kim YS, Koh YJ, Dong S, Kwon HJ, et al. Prenatal exposure to paternal smoking and likelihood for autism spectrum disorder. Autism. 2021;25(7):1946-59. https://doi.org/10.1177/13623613211007319.
[37] Altink ME, Slaats-Willemse DI, Rommelse NN, Buschgens CJ, Fliers EA, Arias-Vásquez A, et al. Effects of maternal and paternal smoking on attentional control in children with and without ADHD. European Child & Adolescent Psychiatry. 2009;18:465-75. https://doi.org/10.1007/s00787-009-0001-3.
[38] Li X, Sjöstedt C, Sundquist J, Zöller B, Sundquist K. Familial association of attention-deficit hyperactivity disorder with autoimmune diseases in the population of Sweden. Psychiatric Genetics. 2019;29(2):37-43. https://doi.org/10.1097/YPG.0000000000000212.
[39] Leppert B, Havdahl A, Riglin L, Jones HJ, Zheng J, Smith GD, et al. Association of maternal neurodevelopmental risk alleles with early-life exposures. JAMA psychiatry. 2019;76(8):834-42. https://doi.org/10.1001/jamapsychiatry.2019.0774.
[40] Faraone SV, Ghirardi L, Kuja-Halkola R, Lichtenstein P, Larsson H. The familial co-aggregation of attention-deficit/hyperactivity disorder and intellectual disability: a register-based family study. Journal of the American Academy of Child & Adolescent Psychiatry. 2017;56(2):167-74. https://doi.org/10.1016/j.jaac.2016.11.011.
[41] Tsai PT, Greene-Colozzi E, Goto J, Anderl S, Kwiatkowski DJ, Sahin M. Prenatal rapamycin results in early and late behavioral abnormalities in wildtype C57BL/6 mice. Behavior genetics. 2013;43:51-9. https://doi.org/10.1007/s10519-012-9571-9.
[42] Coscia LA, Constantinescu S, Davison JM, Moritz MJ, Armenti VT. Immunosuppressive drugs and fetal outcome. Best practice & research Clinical obstetrics & gynaecology. 2014;28(8):1174-87. https://doi.org/10.1016/j.bpobgyn.2014.07.020.