Divergent Pontine and Cerebellar Pathology in Preterm Infants With Necrotizing Enterocolitis
- 1Children's National Hospital; The George Washington University School of Medicine and Health Sciences
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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BibTeX
@misc{sanidas2026divergent,
title = {{Divergent Pontine and Cerebellar Pathology in Preterm Infants With Necrotizing Enterocolitis}},
author = {G. Sanidas and H. Chen and G. Simonti and J. Ghaemmaghami and R. Cardenas and C. Byrd and C. Lowe and L. Kim and M. Triantafyllou and N. Wolff and R. Vidva and A. Sandler and B. L. Short and T. Siahanidou and C. Kanaka-Gantenbein and H. S. Pettersen and M. Said and K. Rais-Bahrami and V. Gallo and F. Northington and I. Koutroulis and P. Kratimenos},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.30.763262},
url = {https://www.biorxiv.org/content/10.64898/2026.10.30.763262v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Divergent Pontine and Cerebellar Pathology in Preterm Infants With Necrotizing Enterocolitis
AU - G. Sanidas
AU - H. Chen
AU - G. Simonti
AU - J. Ghaemmaghami
AU - R. Cardenas
AU - C. Byrd
AU - C. Lowe
AU - L. Kim
AU - M. Triantafyllou
AU - N. Wolff
AU - R. Vidva
AU - A. Sandler
AU - B. L. Short
AU - T. Siahanidou
AU - C. Kanaka-Gantenbein
AU - H. S. Pettersen
AU - M. Said
AU - K. Rais-Bahrami
AU - V. Gallo
AU - F. Northington
AU - I. Koutroulis
AU - P. Kratimenos
PY - 2026
DA - 2026/10/30
PB - bioRxiv
DO - 10.64898/2026.10.30.763262
UR - https://www.biorxiv.org/content/10.64898/2026.10.30.763262v1
AB - 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.
ER -