Maternal infection during pregnancy and the likelihood of autism and intellectual disability in children in Sweden: a negative control and sibling comparison cohort study
Background
Maternal infections during pregnancy are associated with intellectual disability and autism in vulnerable children. Whether these associations are causal, and therefore should be targets for prevention strategies, remains unknown. We aimed to investigate these associations, to determine whether there is a causal role of maternal infection during pregnancy for children’s risk of autism and intellectual disability, taking into account unmeasured family factors.
Methods
We used a registry-based cohort study design and included children born 1987–2010 from Stockholm County, Sweden. We excluded children who were not born in Sweden, adopted children and children with unknown biological mothers or fathers. Maternal infections during pregnancy, defined by ICD-8, ICD-9, and ICD-10 codes, were identified in the National Patient Registry and Medical Birth Registry. Children were followed up from birth until an outcome or a censoring event (death, migration from Stockholm, age 18 or 31 Dec 2016, whichever occurred first). The primary outcomes were diagnosis of autism or diagnosis of intellectual disability. We performed a survival analysis to examine the association between inpatient and outpatient care for infections during pregnancy and the likelihood of autism or intellectual disability in the child. To address potential residual confounding, we also estimated the association of maternal infection in the year before pregnancy as a negative control exposure and conducted a matched sibling analysis of sibling pairs discordant for autism or intellectual disability.
Bargain
647,947 children living in Stockholm County were identified and after excluding 97,980 children, we included 549,967 in the study (267,995 [48·7%] were women and 281,972
[51·3%] were male; mean age at censoring 13·5 years [SD 5·0; range <1 to 18]; 142,597
[25·9%] had a mother who was not born in Sweden). 445 (1.3%) of 34,013 children exposed to maternal infection during pregnancy were diagnosed with intellectual disability and 1123 (3.3%) with autism. 5087 (1.0%) of 515,954 unexposed children were diagnosed with intellectual disability and 13,035 (2.5%) with autism. Maternal infection during pregnancy was associated with autism (hazard ratio [HR] 1·16, 95% CI 1·09–1·23) and intellectual disability (1·37, 1·23–1·51) in exposed children compared to unexposed children. Maternal infection in the year before pregnancy (negative control exposure) was also associated with autism (HR 1·25, 95% CI 1·14–1·36), but was not associated with intellectual disability (1·09, 0·94) – 1·27). In sibling comparisons, associations with maternal infection during pregnancy were attenuated for autism (HR 0·94, 95% CI 0·82–1·08; n=21,864), but not to the same extent for intellectual disability (1·15, 0·95 -1.40; n=9275).
Interpretation
Although infections in pregnant women are associated with both autism and intellectual disability in their children, the association with autism does not appear to reflect a causal relationship, but is more likely to be explained by factors shared between family members such as genetic variation or aspects of the shared environment. Thus, prevention of infections is not expected to reduce the incidence of autism. For intellectual disability, unmeasured family factors may not fully explain the observed associations, and a causal role of maternal infections cannot be ruled out. Causal effects of specific but rare infections or infections that do not require healthcare contact cannot be excluded in either autism or intellectual disability.
Financing
The Swedish Research Council, Stanley Medical Research Institute and Autism Speaks.
Translation
For the Swedish translation of the summary, see the section Supplementary material.