Early-life gastrointestinal inflammation and the developing brain: Unravelling the pathways to long-term cognitive dysfunction

Table 3 Summary of findings: Preterm Infants and necrotizing enterocolitis survivors

Ref.	Study type/follow-up age	Primary finding on NDI	Key associated deficits/brain pathology
Wang et al[133], 2024	Systematic review and meta-analysis (corrected age > 12 months)	Significant association between NEC and increased odds of NDI (adjusted odds ratio: 1.89).	Increased risk of severe brain injury: IVH and PVL. Severity matters: Surgical NEC carries a higher NDI risk than medical NEC
Matei et al[132], 2020	Systematic review and meta-analysis (n = 2403 NEC infants)	High NDI incidence: 40% (median interquartile range 28%-64%). Severity correlates: NDI incidence is higher in surgical NEC (43%) vs medical NEC (27%)	Most common NDI: Cerebral palsy (18%). NEC is associated with increased incidence of IVH and PVL compared to preterm controls
Mondal et al[134], 2021	Retrospective cohort (average follow-up: 11.2 years)	High burden: 61% of survivors had neurological impairment	Cognitive impairment was the most common deficit (56%), followed by motor (33%). High rates of special education needs and learning difficulties
Roze et al[136], 2011	Case-control cohort (mean age 9 years)	Borderline or abnormal functional scores: Mean total intelligence quotient was lower (86 vs 97 in controls)	Specific deficits in attention and visual perception. Children requiring surgery were at the highest risk for adverse outcomes
Shin et al[137], 2021	Retrospective cohort (preterm infants with surgical NEC vs SIP)	NEC group had more prevalent abnormal findings at 36 months in motor (gross and fine), cognitive, and social domains compared to SIP survivors	Slower head growth in surgical NEC group compared to SIP group
Arnold et al[135], 2010	Retrospective cohort (long-term follow-up: 39 months)	49% of long-term survivors had significant neurodevelopmental delay	The 20% had severe neurological deficits, including auditory and visual impairment. Highlights the ongoing morbidity risk
Hansen et al[138], 2019	Historic cohort study (school age)	Increased rates of abnormal behavioral scores and cerebral palsy observed, but differences were statistically insignificant after adjustment for confounders	Provides a counterpoint to the consensus, suggesting the long-term effects on behavioral and NDI scores may be moderate and of limited clinical importance

It summarizes the clinical evidence from systematic reviews and longitudinal cohort studies quantifying the enduring neurodevelopmental burden in survivors of necrotizing enterocolitis (NEC). The findings consistently demonstrate that NEC, particularly severe (surgically managed) NEC, significantly increases the risk for long-term neurodevelopmental impairment, cognitive deficits, and major structural brain lesions (intraventricular hemorrhage, periventricular leukomalacia), indicating that severe gut inflammation in the neonatal period critically compromises central nervous system development. IVH: Intraventricular hemorrhage; NDI: Neurodevelopmental impairment; NEC: Necrotizing enterocolitis; PVL: Periventricular leukomalacia; SIP: Spontaneous intestinal perforation.