Maternal obesity and offspring neurodevelopment: Mechanisms, risks, and prevention opportunities

The prevalence of maternal obesity is continuously increasing worldwide, making maternal overweight and obesity one of the most important early life risk factors that can affect the neurodevelopment of offspring. Data from large epidemiological studies indicate that higher prepregnancy BMI, as well as excessive weight gain during pregnancy, are associated with an increased risk of autism spectrum disorder, attention deficit/hyperactivity disorder, internalizing symptoms, cognitive impairment, cerebral palsy, and other neurodevelopmental outcomes. Preclinical studies have also provided a clearer understanding of the biological mechanisms, suggesting that maternal obesity can induce oxidative stress, metabolic inflammation, and placental dysfunction, which impair nutrient and oxygen delivery during critical periods of brain development. Other proposed pathways include activation of microglia and astroglia, dysbiosis of the gut microbiota with alterations in microbial metabolites, epigenetic rearrangements of DNA and histones, and disruption of serotonergic and dopaminergic signaling. Collectively, these biological alterations affect processes such as synaptogenesis, neuroimmune maturation, and neuroplasticity, and sex-specific and even multigenerational effects have been reported in animal studies. Although the presence of familial factors and socioeconomic conditions makes it difficult to draw causal conclusions in human studies, the body of evidence supports the existence of a real biological vulnerability. Various interventions, including improved maternal nutrition, n-3 fatty acid intake, antioxidant strategies, and prenatal physical activity, have shown promising potential to improve metabolic and inflammatory status during pregnancy. Understanding these intertwined mechanisms highlights the importance of early prevention and implementation of targeted maternal health strategies to achieve the best neurodevelopmental outcomes in offspring.