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Is maternal infection linked to autism in offspring?

Many studies have suggested that maternal infection during pregnancy can cause autism in the baby.[1] The recent study, “Maternal infection during pregnancy and likelihood of autism and intellectual disability in children in Sweden: a negative control and sibling comparison cohort study,[2]” is murky on this notion. They demonstrated that children born to mothers with any infection in pregnancy appear to have more autism; however, pre-pregnancy infection gave similar results, and by comparing sibling outcomes, they conclude the results are more likely the result of genetic contributions. They followed 549 967 children “(267 995 [48·7%] were female and 281 972 [51·3%] were male; mean age at censoring 13·5 years.” This is a large, retrospective, epidemiologic study with data spanning over a decade. In the group exposed to infection (based on ICD codes) 3.3% were diagnosed with autism, versus 2.5% in the unexposed group. “Maternal infection during pregnancy was associated with autism (hazard ratio [HR] 1·16, 95% CI 1·09–1·23),” reaching statistical significance. Maternal infection in the year prior to pregnancy also showed a small but statistically significant increase. There were other statistical differences between the groups such as more twins in the autism group, as well as more foreign-born parents which could confound the results. Although this is a well-thought-out study, the main weakness is its reliance on ICD codes for maternal infection. This would only apply to women who sought treatment for infections and therefore would miss many minor or subclinical infections. For the main outcomes, the codes include any infection including viral, bacterial, and in any body site (lung, kidney, GI, bladder, vagina…). The researchers subdivided results by infections of viral, bacterial, inpatient, and trimester of pregnancy, none of which yielded any difference in the two groups. They did not look at specific viruses (i.e., influenza, RSV, norovirus…), bacteria (i.e., E. coli, Salmonella…), or type of infection (i.e., diarrhea, urinary, respiratory…); hence, which infections were most represented in this study is not clear. Bacterial vaginosis and urinary tract infections are quite common in pregnancy, but neither is largely implicated in causing autism. There is a Swedish study showing an increase in autism in children of mothers who had urinary tract infections;[2] however, in terms of maternal infections, those most often implicated as a cause of autism are viral infections, including rubella, cytomegalovirus (CMV), many herpes family viruses (HSV1, HSV2, EBV, HHV6), influenza, and polyomaviruses.[1,4] These are not so common in pregnancy and their presence in this study is likely drowned out by other more common infections. They also can cause infections quite mild such that women may not seek medical care, and therefore might not be included in the study at all. In conclusion, the recent article “Maternal infection during pregnancy and likelihood of autism and intellectual disability in children in Sweden: a negative control and sibling comparison cohort study [2]” does not definitively answer the question of whether maternal infections cause autism. There is still overwhelming data that infections are linked to autism, but which and to what extent are not clear.

1. 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.

2. Brynge M, Sjöqvist H, Gardner RM, Lee BK, Dalman C, Karlsson H. Maternal infection during pregnancy and likelihood of autism and intellectual disability in children in Sweden: a negative control and sibling comparison cohort study. Lancet Psychiatry. 2022 Oct;9(10):782-791. doi: 10.1016/S2215-0366(22)00264-4. Epub 2022 Sep 7. PMID: 36087610.

3. Al-Haddad BJS, Jacobsson B, Chabra S, Modzelewska D, Olson EM, Bernier R, Enquobahrie DA, Hagberg H, Östling S, Rajagopal L, Adams Waldorf KM, Sengpiel V. Long-term Risk of Neuropsychiatric Disease After Exposure to Infection In Utero. JAMA Psychiatry. 2019 Jun 1;76(6):594-602. doi: 10.1001/jamapsychiatry.2019.0029. PMID: 30840048; PMCID: PMC6551852.

4. Hutton J. Overlapped Pathways of Autism Genes and Cancer Genes are Targeted by Viruses. Vaccines Vacccin 2021, 6(1): 000148.

5. Hutton J. ‘Hit and Run’ Teratogenesis, with Specific Regards to Autism. Vaccines Vacccin 2017, 2(1): 000105.

6. Hughes HK, R J Moreno, Ashwood P. Innate immune dysfunction and neuroinflammation in autism spectrum disorder (ASD). Brain Behav Immun. 2022 Dec 6;108:245-254. doi: 10.1016/j.bbi.2022.12.001. Epub ahead of print. PMID: 36494048.

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