The impact of pregestational stress on neurodevelopment: Implications for autism spectrum disorder and...

Emerging evidence indicates that stress experienced by parents before conception can influence offspring neurodevelopment through enduring neuroendocrine and epigenetic mechanisms. This review addresses the central question of how pregestational stress (PGS) might alter developmental trajectories and increase vulnerability to autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). We examined human and animal studies investigating the effects of PGS on germline epigenetic regulation, GABAergic signalling maturation and hypothalamic-pituitary-adrenal axis programming. We synthesized key findings using a narrative review approach, integrating mechanistic data, developmental neurobiology and evidence for transgenerational inheritance, and we summarized the converging results in a conceptual figure and comprehensive table. The findings indicate that PGS can disrupt germline DNA methylation patterns, alter early GABA system development and shift hypothalamic-pituitary-adrenal axis responsivity, thereby influencing fetal brain maturation and increasing the risk for ASD- and ADHD-related phenotypes. Additional evidence highlights that PGS might exert effects comparable to prenatal stress exposure, suggesting an overlooked but physiologically meaningful window of vulnerability. The conclusions emphasize that PGS represents a novel and under-recognized factor contributing to neurodevelopmental risk and that its mechanistic pathways offer new insight into how early-life vulnerability might begin even prior to pregnancy. The take-home message is that parental stress reduction and preconception health optimization might serve as promising strategies to mitigate intergenerational neurodevelopmental risk. The wider context underscores the broader physiological significance of PGS and raises important questions regarding the reversibility of epigenetic alterations, the timing and type of stressors most critical, and potential interventions to enhance resilience across generations.