<p>Autism Spectrum Disorder (ASD) has witnessed a rise in global prevalence, yet the underlying etiological factors remain incompletely understood. While research over the past century has predominantly focused on neurobiological and genetic underpinnings, emerging evidence points to the importance of prenatal and perinatal influences, particularly those mediated through the placenta. In this context, we introduce the OPEN Autism framework—Obstetric, Placenta, Epigenetic, and Neurodevelopment—as a novel interdisciplinary approach aimed at elucidating how maternal, intrauterine, and placental factors influence early brain development and ASD risk. Drawing from preliminary observations in our clinical cohort and leveraging a robust placental database, we identify a distinct pattern of obstetric risk factors and placental anomalies in children later diagnosed with ASD. We hypothesize that epigenetic mechanisms, particularly those mediated via the placenta in response to maternal stressors or metabolic conditions, may contribute to altered neurodevelopmental trajectories. Our concept builds on global research efforts such as EARLI, MARBLE, and Eurosib, advocating for the creation of longitudinal, integrative cohorts that capture maternal, placental, and neurodevelopmental data. We propose that standardized placental examination, early developmental tracking, and harmonized, multicentric collaboration are essential to unravel the complex gene-environment interactions shaping ASD. By establishing this framework and addressing methodological, ethical, and infrastructural challenges, particularly within low- and middle-income settings, we aim to foster early identification, improve mechanistic understanding, and ultimately enhance intervention strategies for ASD.</p> Graphical Abstract <p></p>