Prenatal Stress, Maternal Immune Dysregulation, and Their Association With Autism Spectrum Disorders

Abstract

Purpose of review: While genetic factors are a major etiological contributor to autism spectrum disorder (ASD), evidence also supports a role for environmental factors. Herein, we will discuss two such factors that have been associated with a significant proportion of ASD risk: prenatal stress exposure and maternal immune dysregulation, and how sex and gender relate to these factors.

Recent findings: Recent evidence suggests that maternal stress susceptibility interacts with prenatal stress exposure to affect offspring neurodevelopment. Additionally, understanding of the impact of maternal immune dysfunction on ASD has recently been advanced by recognition of specific fetal brain proteins targeted by maternal autoantibodies, and identification of unique mid-gestational maternal immune profiles. Animal models have been developed to explore pathophysiology targeting both of these factors, with limited sex-specific effects observed. While prenatal stress and maternal immune dysregulation are associated with ASD, most cases of these prenatal exposures do not result in ASD, suggesting interaction with multiple other risks. We are beginning to understand the behavioral, pharmacopathological, and epigenetic effects related to these interactions, as well as potential mitigating factors. Sex differences of these risks have been understudied but are crucial for understanding the higher prevalence of ASD in boys. Continued growth in understanding of these mechanisms may ultimately allow for the identification of multiple potential points for prevention or intervention, and for a personalized medicine approach for this subset of environmental-associated ASD cases.

Keywords: Antibodies; Autism spectrum disorder; Gene × environment; Immunity; Prenatal; Stress.

Fig. 1

Examples of some environmental factors known to interact with genetics, augmenting the relative risk in selected cases beyond the modest relative risk of the environmental factors in isolation

Fig. 2

Proposed etiological pathway illustrating how elevated midgestational maternal cytokines and chemokines may lead to increased risk of ASD with intellectual disability. Genetic and environmental risk factors, either individually or in combination, can alter the production of circulating levels of inflammatory T cell and innate immune cell cytokines and chemokines in women. As these immune analytes are normally downregulated during mid-gestation, persistent elevation of these inflammatory maternal cytokines and chemokines throughout pregnancy lead to an altered gestational immune environment. This can lead to changes in the neurodevelopmental trajectory of the developing child, as there is a fine balance of immune signaling molecules needed to participate in healthy neurodevelopment. In turn, these alterations to neurodevelopment can manifest in neurodevelopmental disorders such as ASD with intellectual disability (ASD+ID)