Lipidomic Transitions and Neurodevelopmental Implications in Preterm Neonates Born Before 32 Weeks Gestational Age: A Prospective, Single-Center Study Integrated with Brain MRI Data

Abstract Background: Prematurity is a major cause of neonatal morbidity and mortality, with infants born before 32 weeks of gestation at high risk for neurological and metabolic complications. Lipids play a fundamental role in neonatal development, particularly in brain maturation, pulmonary function, and energy metabolism, yet lipidomic alterations in preterm neonates remain largely unexplored. Objectives: This study aimed to characterize lipidomic transitions in preterm neonates (<32 weeks gestation) and investigate their associations with key clinical outcomes, including brain injury and mechanical ventilation. We hypothesized that specific lipidomic profiles could serve as potential biomarkers for neonatal complications and neurodevelopmental trajectories. Methods: A prospective, single-center study was conducted at IRCCS Giannina Gaslini Hospital, enrolling preterm neonates (24+0 to 31+6 weeks gestation). Lipidomic profiling was performed at five time points from birth to term-equivalent age (TEA), integrating liquid chromatography-mass spectrometry (LC-MS) and Weighted Gene Co-expression Network Analysis (WGCNA) to identify lipid clusters associated with neonatal morbidities. Pathway enrichment analysis was conducted using MetaboAnalyst. Results: After quality control, 81 out of 103 neonates were included in the analysis. Key findings showed that diacylglycerols (DG), phosphatidylcholines, lysophosphatidylcholines, sphingomyelins, and triglycerides were enriched in neonates with germinal matrix-intraventricular hemorrhage (GMH-IVH) (r = 0.22, p = 0.001). DG levels had a weak but significant negative correlation with mechanical ventilation (r = -0.21, p = 0.001). A metabolic trajectory was observed from birth (T0) to term-equivalent age (TEA), shifting from an oxidative state at birth to a more regulated, neuroprotective environment at TEA. The increase in oligodendrocyte differentiation pathways from 32 weeks of gestation onward highlights accelerated myelination within the central nervous system. Conclusion: This study highlights lipidomic changes in preterm neonates, particularly regarding brain injury and mechanical ventilation, suggesting metabolic adaptations tied to vascular stability, neuroinflammation, and pulmonary function. The lipid profile shift from placental dependence to endogenous regulation emphasizes the roles of beta-oxidation, sphingolipid metabolism, and myelination. Optimizing nutrition, including lipid supplementation and metabolic support, may improve neurodevelopmental outcomes. Integrating lipidomics into neonatal care could enhance biomarker discovery and targeted interventions, ultimately improving long-term outcomes for preterm infants.