Summary: Researchers at Karolinska Institutet examined whether infections in pregnant women directly cause autism or intellectual disability in their children. Their large Swedish cohort study suggests the link between maternal infection and autism is unlikely to be causal; instead, shared familial factors such as genetics or aspects of the shared environment probably explain the association. The relationship with intellectual disability is less clear and may still involve causal elements.
Source: Karolinska Institute
Infections during pregnancy have been associated with higher rates of neurodevelopmental outcomes, including autism spectrum disorder (ASD) and intellectual disability. A new register-based study from Karolinska Institutet, published in The Lancet Psychiatry, investigates whether those associations reflect a direct causal effect of maternal infection or whether shared familial factors can explain the observed risks.
“These findings can provide reassurance to expectant parents: infections that required specialised healthcare during pregnancy do not appear to be a direct cause of autism in children,” says Håkan Karlsson, researcher at the Department of Neuroscience at Karolinska Institutet and the study’s senior author.
The study analyzed healthcare and birth registry data for more than 500,000 children born in Stockholm County between 1987 and 2010. Maternal infections were defined using diagnostic codes (ICD-8, ICD-9, ICD-10) recorded in national patient and birth registers and included infections severe enough to result in outpatient or inpatient specialist care.
As in earlier research, the initial comparison across unrelated children showed that maternal infections during pregnancy were associated with an increased risk of both autism and intellectual disability in offspring. However, to test whether the infection itself was likely the cause, the research team used two additional approaches: (1) a negative-control analysis examining maternal infections in the year before pregnancy, and (2) matched sibling comparisons in families where mothers had an infection during one pregnancy but not another.
When siblings were compared, the association between maternal infection during pregnancy and autism disappeared. Specifically, in sibling pairs discordant for maternal infection exposure, no increased autism risk was observed for the child exposed during gestation. For intellectual disability, the association weakened in sibling comparisons but did not disappear to the same extent, leaving open the possibility of a causal contribution for that outcome.
In the negative-control analysis, infections recorded in the year before pregnancy were associated with autism to a similar degree as infections during pregnancy, but they were not associated with intellectual disability. This pattern supports the interpretation that unmeasured familial factors—shared genetics or environmental influences common within families—are likely driving the association with autism rather than a direct effect of infection in utero.
“Our results indicate that the observed increased risk of autism linked to maternal infection is more plausibly explained by family-shared factors, such as genetic variation or elements of the shared environment,” explains Martin Brynge, Ph.D. student at the Department of Global Public Health at Karolinska Institutet and a first author on the study.
The investigators emphasize that their analysis considered infections in general as recorded in specialist healthcare settings. The study does not contradict known, specific causal relationships between certain rare infections in pregnancy—such as rubella or congenital cytomegalovirus—and serious developmental disorders. Likewise, infections that do not lead to healthcare encounters or newly emerged infections such as SARS-CoV-2 were not part of this dataset.
Recommendations for pregnant women remain unchanged: follow clinical advice from healthcare providers about infection prevention and management during pregnancy.
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Author: Press Office
Source: Karolinska Institute
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Original Research: Open access.
“Maternal infection during pregnancy and likelihood of autism and intellectual disability in children in Sweden: a negative control and sibling comparison cohort study” by Håkan Karlsson et al. Lancet Psychiatry
Abstract
Maternal infection during pregnancy and likelihood of autism and intellectual disability in children in Sweden: a negative control and sibling comparison cohort study
Background
Maternal infections during pregnancy have been linked to increased risks of autism and intellectual disability in exposed children. It remains unclear whether these associations are causal and therefore amenable to prevention. This study aimed to determine whether maternal infection during pregnancy has an independent causal effect on offspring risk of autism and intellectual disability, accounting for unmeasured familial confounders.
Methods
The investigators used a register-based cohort comprising children born and living in Stockholm County between 1987 and 2010. After exclusions (children not born in Sweden, adoptees, and those with unknown biological parents), maternal infections were identified through ICD codes in national patient and birth registers. Children were followed from birth until diagnosis, death, migration, age 18, or Dec 31, 2016. Primary outcomes were clinical diagnoses of autism and intellectual disability. Analyses included survival models comparing exposed and unexposed children, negative-control analyses using infections in the year before pregnancy, and matched sibling comparisons among families with discordant exposure.
Findings
Out of 647,947 children identified, 549,967 met inclusion criteria (48.7% female, mean age at censoring 13.5 years). Among 34,013 children exposed to maternal infection during pregnancy, 445 (1.3%) were diagnosed with intellectual disability and 1,123 (3.3%) with autism. Among 515,954 unexposed children, 5,087 (1.0%) had intellectual disability and 13,035 (2.5%) had autism. Maternal infection during pregnancy was associated with increased hazards for autism (HR 1.16, 95% CI 1.09–1.23) and intellectual disability (HR 1.37, 95% CI 1.23–1.51) in conventional analyses.
In the negative-control analysis, maternal infection in the year before pregnancy was associated with autism (HR 1.25, 95% CI 1.14–1.36) but not with intellectual disability (HR 1.09, 95% CI 0.94–1.27). In sibling comparisons, the association with autism was attenuated (HR 0.94, 95% CI 0.82–1.08), while the attenuation was smaller for intellectual disability (HR 1.15, 95% CI 0.95–1.40).
Interpretation
While maternal infections recorded in specialist care are associated with both autism and intellectual disability in offspring, the evidence suggests the association with autism is unlikely to be causal and is better explained by familial confounding such as shared genetics or environment. Therefore, general infection prevention during pregnancy is not expected to substantially reduce autism incidence. For intellectual disability, the data do not fully exclude a causal role for maternal infection. The study also does not rule out causal effects from rare, specific infections or from infections that do not result in healthcare contacts.
Funding
Swedish Research Council, Stanley Medical Research Institute, and Autism Speaks.
Translation
For the Swedish translation of the abstract see Supplementary Materials section.