Maternal Infection and Fever during Pregnancy and Risk of Autism Spectrum Disorder: Findings from the Study to Explore EARLY Development (SEED)

Background: Evidence from animal and human studies indicates that in utero exposure to maternal immune activation can adversely impact neurodevelopment. Maternal infection and fever during pregnancy have been implicated in the etiology of autism spectrum disorder (ASD) in several studies; however, studies have not been able to separate the effects of fever itself from the impact of a specific infectious organism on the developing brain.

Objectives: To investigate specific types of infection during pregnancy, the timing of exposure, and the impact of fever associated with those infections, and their association with ASD and other developmental disorders (DD) in the child.

Methods: The study population was drawn from the Study to Explore Early Development, a multi-site case-control study conducted in six sites across the United States among children born between 2003-2006. Three groups of children were enrolled at 2-5 years of age. For each enrolled child, final study group classification (ASD, DD, general population control (POP)) was determined by an in-person standardized developmental assessment. Infection and fever during pregnancy were ascertained via maternal interview conducted over the telephone shortly after study enrollment and review of maternal medical records. For each infection reported, the mother was asked to specify the timing during pregnancy, the types of medications taken, and whether fever was present. Infection was classified according to microorganism type (e.g. bacterial, viral, etc.) and organ system affected. For each exposure definition, separate unadjusted and adjusted logistic regression models were run to estimate the association with ASD (vs. POP) and DD (vs. POP) by trimester of exposure. Covariates included in adjusted analyses were maternal race/ethnicity, education, age at delivery, psychiatric condition history, and hypertension, household income during pregnancy, child’s sex, and study site.

Results: The final analytic sample included 606 with ASD, 856 with DD, and 796 POP. Approximately 60% of mothers in each study group experienced an infection during pregnancy. Bacterial infection was the most common maternal infection type during pregnancy, occurring in roughly a third of the population, and significantly more often in mothers of children with ASD than mothers of POP controls (36.3% vs. 31.3%, P=0.05). After adjustment for covariates, maternal infection anytime during pregnancy was not associated with ASD or DD. No significant associations with ASD or DD were observed for infections with specific organ systems or specific microorganism types in any time period. However, second trimester infection accompanied by fever was associated with approximately 2-fold increase in odds of ASD (adjusted odds ratio=2.19, 95% confidence interval 1.14-4.23). Neither infection with fever nor infection without fever during pregnancy increased risk for DD.

Conclusions: Our findings suggest that maternal infection with fever in the second trimester is associated with ASD. These findings suggest that perhaps the immune response rather than the infectious agent is etiologically relevant. Future studies with increased sample size could help provide more detailed analyses on type and timing of maternal exposure to infection and fever and specific developmental outcomes in the child to elucidate potential biologic mechanisms underlying the associations reported here.