During pregnancy, infection, chronic inflammatory disorders, or toxic exposures that cause maternal immune activation (MIA), can result in lasting health impacts on the developing fetus. In addition, MIA has also been associated with an increased risk of neurodevelopmental disorders, such as autism spectrum disorder (ASD), in offspring. Maternal allergic asthma (MAA), which is a form of MIA, is also identified to be a potential risk factor for the onset of neurodevelopmental disorders. An analysis in Neural Regeneration Research evaluates previous studies that assess the possible relationship between MAA and ASD.
Although there is a knowledge gap in terms of the mechanisms of the relationship, multiple population-based studies indicate a relationship between MAA and the development of ASD in the infant. Additionally, animal models have also built onto this evidence by providing mechanistic insights, which can serve as tools in future and ongoing mechanistic studies.
Meta-analyses of biomarker studies also show that investigations of plasma and sera cytokine levels had demonstrated an increase in pro-inflammatory cytokines—such as interleukin (IL)-6, IL-8, IL-1β, and IL-12—in those with ASD, whereas the regulatory cytokine transforming growth factor β1 decreased. Further, cytokine dysregulation was also present in postmortem brain studies that evaluated individuals with ASD, and included elevations in IL-6 levels. Although the current authors note that these studies are not direct links to maternal asthma or MIA, they still highlight the immune involvement associated with ASD, and that potential immune dysregulation while the brain is developing can alter one’s neurodevelopmental trajectories and result in different behavioral outcomes.
In addition, epidemiological studies linked MAA to an increased risk of ASD in offspring. When adjusted for familial factors, a 2019 study found an increased risk of ASD in the children born to mothers with asthma. Similarly, a 2018 study found that mothers with history of asthma or allergies who had children with ASD had an increase in social impairments compared with children with ASD who were born to mothers without asthma or allergies. A follow-up to this study conducted in 2020 found that children with ASD born to mothers with asthma, allergies, eczema, autoimmune diseases, or inflammatory bowel disease during pregnancy had worsened behavioral and emotional symptoms compared to mothers who did not have these conditions. The current authors acknowledge that although there are different variables (eg, differing conditions), an association between MAA and ASD is still present, and the mechanism or causation are still undetermined.
Key Takeaways
- Maternal Immune Activation and ASD Risk: Maternal immune activation (MIA) during pregnancy, triggered by infections, chronic inflammatory disorders, or toxic exposures, is linked to an increased risk of neurodevelopmental disorders like autism spectrum disorder (ASD) in offspring. Maternal allergic asthma (MAA), a form of MIA, is identified as a potential risk factor for the onset of ASD.
- Cytokine Dysregulation and Neurodevelopment: Population-based and animal studies indicate a relationship between MAA and ASD, with increased pro-inflammatory cytokines (e.g., IL-6, IL-8, anad IL-1β) in individuals with ASD. These cytokine dysregulations highlight the immune involvement in ASD, suggesting that immune dysregulation during brain development can alter neurodevelopmental trajectories and result in different behavioral outcomes.
- Sex-Dependent Behavioral Impacts: Animal models show that MAA can lead to neuroinflammatory mechanisms and altered microglia, impacting synaptic pruning and resulting in decreased social behavior and increased repetitive behaviors in offspring. Male offspring are more behaviorally affected, showing more severe impacts compared to females. These models demonstrate that maternal asthma can influence neurodevelopment and behavior through immune-related changes in the brain.
Finally, several animal models have also demonstrated that neuroinflammatory mechanisms and altered or activated microglia may be influenced by MAA, potentially causing effects later on that impact synaptic pruning. One study that utilized an ovalbumin-induced MAA mouse model found that offspring presented decreased social behavior, increased repetitive behaviors, and an increased weight and length compared with controls. In addition, the mice also demonstrated increased serotonin transporter protein in the cortex, indicating a possible association between peripheral immune response and altered neurodevelopment during signaling disruption. TH2 immune profile with elevations in IL-4, IL-5, IL-6, and IL-13 was also present, which is typical of asthma.
Further, male offspring were shown to be more affected behaviorally in MIA-based models, with males experiencing increased behavioral impacts compared to females. Another study also found that sex-dependent, region-specific changes in dendritic spine patterns in the brain impacted social and cognitive behaviors of the offspring. Additionally, in offspring born to mothers with MAA, epigenomic changes associated with ASD-risk genes were identified within microglia cells along with differences in genes that are involved in microglia proliferation. The current authors note that differences in exposure timelines, such as how many days a pregnant mouse is exposed to allergens, may contribute to the differences that can occur in chronic asthma compared to short-term allergic offenses.
Overall, the analysis demonstrated that, based on population and ASD patient studies, there may be an increased prevalence of ASD among children born to mothers with asthma. Additionally, the findings indicated immune dysregulation in those with ASD, with mouse models showing an association between maternal asthma and altered behavior and brain function. The investigators note that any current or future research featuring rodent models should investigate glial cells, neuronal function, synapse formation, and epigenetic changes that are present in the offspring brains.
Reference
Osman, H, Ashwood, P. Evidence supporting the relationship between maternal asthma and risk for autism spectrum disorders. Neural Regeneration Research 20(4):1101-1102. doi:10.4103/nrr.nrr-d-24-00252
