Biomarkers for Early Detection and Therapeutic Monitoring of Abnormal Brain Development in Mild Fetal Growth Restriction

Fetal growth restriction (FGR), driven by intrauterine hypoperfusion, delays brain development and heightens the risk of neurodevelopmental disorders. Nonetheless, current diagnostic strategies rarely capture the subtle neuropathology that emerges in mild FGR. To overcome this limitation, we employed an innovative rodent model that replicates mild FGR through gradual and chronic intrauterine hypoperfusion, mirroring clinical conditions overlooked by conventional severe or acute FGR models. Global proteomics of cerebrospinal fluid identified Alpha-2-Macroglobulin, Neuroserpin, CD200, and Polyubiquitin-B as biomarkers correlated with birth weight and persisting postnatally. Their expression reflected changes in brain tissue and serum, was linked to behavioral deficits, and partially recovered under mesenchymal stem/stromal cell treatment—indicating potential for therapeutic monitoring. Notably, Neuroserpin, brain-specific, emerged as a robust indicator of FGR-related neurodevelopmental impairment. This study is the first to propose low-invasive serum biomarkers for early postnatal detection of mild FGR-induced brain abnormalities, enabling neonatal screening, targeted interventions, and improved long-term outcomes.