Divergent Pontine and Cerebellar Pathology in Preterm Infants With Necrotizing Enterocolitis

Sanidas, G.; Chen, H.; Simonti, G.; Ghaemmaghami, J.; Cardenas, R.; Byrd, C.; Lowe, C.; Kim, L.; Triantafyllou, M.; Wolff, N.; Vidva, R.; Sandler, A.; Short, B. L.; Siahanidou, T.; Kanaka-Gantenbein, C.; Pettersen, H. S.; Said, M.; Rais-Bahrami, K.; Gallo, V.; Northington, F.; Koutroulis, I.; Kratimenos, P.

doi:10.64898/2026.10.30.763262

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bioRxiv · 10.64898/2026.10.30.763262

Divergent Pontine and Cerebellar Pathology in Preterm Infants With Necrotizing Enterocolitis

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Abstract

Importance: Preterm survivors of necrotizing enterocolitis (NEC) face substantial neurodevelopmental impairment, but the regional biology and timing of associated brain abnormalities remain poorly defined. Objective: To define the regional, cellular, molecular, and temporal features of NEC-associated brain pathology. Design: Prospective multimodal clinical cohort study (2012-2024), complemented by postmortem tissue analyses. Setting: Level IV neonatal intensive care unit at Children's National Hospital, Washington, DC. Participants: Of 400 infants screened, 253 preterm infants born before 37 weeks' gestation (128 with NEC and 125 without NEC) were included across neuroimaging, plasma metabolomic, and postmortem cohorts. Exposures: Medical or surgical NEC (modified Bell stage [≥]II). Main Outcomes and Measures: Primary outcomes were term-equivalent magnetic resonance imaging (MRI) abnormalities and serial ultrasound hindbrain growth; secondary outcomes were postmortem histopathology, brain and intestinal transcriptomics, and plasma metabolomics. Results: Among 179 infants with term-equivalent MRI (89 NEC, 90 controls; 102 [57.0%] male; mean [SD] gestational age, 26.3 [2.2] weeks), NEC was associated with a higher prevalence of pontine abnormalities (12.4% vs 1.1%; adjusted prevalence ratio, 9.14; 95% CI, 1.16-71.92), alongside white matter, callosal, and cerebellar abnormalities. In postmortem tissue (n = 27), white matter pathology qualitatively resembled that of prematurity, whereas the hindbrain showed distinct regional phenotypes. The cerebellum exhibited external granular layer contraction (42% reduction; P = .04), while the pons showed neuronal injury with increased morphological apoptotic burden (P [≤] .05). Brain and intestinal transcriptomics (n = 14), complemented by plasma metabolomics (n = 29), revealed divergent inflammatory and metabolic signatures. The pons showed increased neuroinflammatory and reduced mitochondrial programs, whereas the cerebellum showed reduced metabolic and cell-cycle programs alongside circulating lysophospholipid depletion. Serial ultrasonography (n = 159), anchored to the cohort mean NEC onset age of 29 weeks' postmenstrual age, identified earlier cerebellar dimensional deficits (P = .015) and later pontine growth deceleration (P < .001). Conclusions and Relevance: In this cohort study, NEC-associated hindbrain pathology showed asynchronous growth patterns accompanied by distinct cellular and molecular phenotypes. These findings support investigation of regional vulnerability and stage-specific neuroprotection; individual injury timing and causal mechanisms remain unresolved.

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Sanidas, G., Chen, H., Simonti, G., Ghaemmaghami, J., Cardenas, R., Byrd, C., Lowe, C., Kim, L., Triantafyllou, M., Wolff, N., Vidva, R., Sandler, A., Short, B. L., Siahanidou, T., Kanaka-Gantenbein, C., Pettersen, H. S., Said, M., Rais-Bahrami, K., Gallo, V., Northington, F., Koutroulis, I., Kratimenos, P.. 2026-11-02. Divergent Pontine and Cerebellar Pathology in Preterm Infants With Necrotizing Enterocolitis. https://doi.org/10.64898/2026.10.30.763262

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