Gestational hyperglycemia and autism spectrum disorder: Mechanistic pathways and emerging preventive strategies

Autism spectrum disorder is a neurodevelopmental disorder characterised by deficits in social communication, restricted interests, and repetitive behaviours. The severity and presentation of symptoms vary greatly among autistic individuals. The etiology of autism is multifactorial, including metabolic, environmental, and genetic factors. Emerging evidence suggests that the maternal metabolic environment, especially gestational diabetes mellitus, has a major impact on fetal neurodevelopment and the subsequent risk of autism spectrum disorder. Epidemiological studies have found that children born to mothers with gestational diabetes mellitus are much more likely to be diagnosed with autism, especially if GDM is identified before 26 weeks of pregnancy. The mechanistic pathways that link maternal hyperglycemia to autism are explored in this review. These include epigenetic suppression of SOD2, impaired neuronal migration through disrupted reelin signalling, elevated oxidative stress from advanced glycation end products, gut dysbiosis and many more, caused by GDM. The cumulative effect of the above factors involves disturbances in the intrauterine environment, which results in abnormal synaptic formation, neuroinflammation, and mitochondrial dysfunction in the developing fetal brain. This review also examines the new therapeutic strategies that can target these pathways, such as RORα agonist, SGLT-2 and DPP4 inhibitors, antioxidants and gut microbiota modification through various dietary interventions and supplementation to support the growth of beneficial microbiota. Thus, early detection and treatment of maternal metabolic disorders during pregnancy may be a promising way to lower the risk of autism in infants and enhance the neurodevelopmental outcomes.