Surgical necrotizing enterocolitis but not spontaneous intestinal perforation is associated with adverse neurological outcome at school age

Abstract

the German neonatal network (Gnn) † Gastrointestinal complications during the neonatal period, i.e. necrotizing enterocolitis (nec) and spontaneous intestinal perforation (Sip), are associated with adverse short-term outcome in very-lowbirthweight infants (VLBWi, <1500 g birth weight). However, little is known about the neurological outcome of survivors at school age. We analysed data of 2241 infants followed-up at the age of 6 years. To determine the effect of NEC and SIP on cognitive outcome in consideration of other important confounding factors, we used multivariable logistic regression models. in addition, infants with surgical diagnosis of nec (n = 43) or SIP (n = 41) were compared to NEC (n = 43) or SIP (n = 41) negative controls using Mahalanobis distance matching. infants with a history for nec had a three times increased risk (RR 3.0 [1.8-4.2], p < 0.001) to develop IQ scores <85 while history of surgical SIP did not increase the relative risk for lower IQs at school age (RR 1.0 [0.4-2.1], p = 1.000). In a matched-cohort analysis, we confirmed that infants with surgical NEC had lower mean IQ results than unaffected controls (±SD) (85±17 vs. 94±14, p = 0.023) while no differences were found for history of SIP. Our results reflect that the different aetiology and inflammatory extent of NEC and SIP may lead to disparate neurodevelopment trajectories. Hence, our data suggest a potential role of early gut-brain axis distortion in infants with nec which needs to be further explored. Necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) are typical gastrointestinal complications in very-low-birthweight infants (VLBWI) and have a remarkable impact on mortality and long-term morbidity in this vulnerable group 1-4. In VLBWI, NEC mainly occurs during day 14-28 of life 5 and seems to have multifactorial facets including genetic predisposition, intestinal immaturity, inflammation, oxidative stress, ischemia, nutritional aspects and gut dysbiosis 2,6,7. SIP usually occurs in the first 14 days of life 8 and is mainly associated with extreme prematurity, use of non-steroidal and steroidal anti-inflammatory drugs and prolonged evacuation of meconium 9,10. Recently, we noted an increased SIP risk in infants <25 weeks of gestation who were primarily managed with less invasive respiratory care 3. Epidemiological data of infants with NEC or SIP show delayed neurodevelopment in early childhood 2,9,11 , but little is known about outcome at school age. Roze et al. found an increased rate of reduced intelligence quotient (IQ) and motor testing scores among children at school age who suffered from NEC or SIP 11 compared to controls without these complications. However, the authors did not adjust for confounding variables such as gestational age or maternal education level and did not differentiate between NEC and SIP.

Preterm birth and sustained inflammation: consequences for the neonate

“…The complex gut-CNS interplay via neural, endocrine, metabolic, and immune factors is referred to as the "gut-brain axis," but the pathways remain to be fully elucidated. However, several diseases of the gastrointestinal tract with inflammatory characteristics impact neurodevelopment and behavioral outcome [23,135]. In preterm infants, NEC is a good example for the potential clinical relevance of a "gut-brain axis."…”

“…A multifactorial pathogenesis with immune response to non-physiologic intestinal microbiota ("dysbiosis"), immature intestinal anatomy, and increased expression of pro-inflammatory mediators is involved in the pathogenesis. Several studies have shown significant higher incidences of neurodevelopmental dysfunction [23,[136][137][138][139][140], and brain injury in magnetic resonance imaging [141], especially when infants were longer exposed to the inflammatory process [139,140]. Given the major instability of the microbiome in the first months of life (Fig.…”

“…Longitudinal studies could therefore pioneer the investigation of entities in adulthood that are mediated by prolonged inflammation (e.g., chronic lung disease, coronary heart disease, neurodegenerative disease, metabolic syndrome) [18]. It is an overarching hypothesis of this narrative review that SI contributes to long-term complications of several organ systems including central nervous system (CNS) (e.g., cerebral palsy, neurobehavioral impairment), lung (chronic pulmonary insufficiency of prematurity, CPIP) [19,20], and gut [21][22][23][24] (Fig. 2).…”

Blockage of NLRP3 inflammasome activation ameliorates acute inflammatory injury and long-term cognitive impairment induced by necrotizing enterocolitis in mice

“…Parenteral nutrition usually increases the risk of metabolic abnormalities and liver injury, while prolonged exposure to antibiotics will lead to microbiota imbalance, drug resistance, and secondary infection [ 18 , 19 ]. Although surgical intervention in NEC could control enteric content spillage and remove necrotic intestine, severe complications like intestinal stenosis and short bowel syndrome commonly develop [ 20 ]. More importantly, neurodevelopmental delay occurs in a considerable proportion of NEC survivors, especially in infants that underwent surgical intervention [ 21 ]; meanwhile, no targeted treatment for neurological impairment has been recommended currently.…”

Breastfeeding for 3 Months or Longer but Not Probiotics Is Associated with Reduced Risk for Inattention/Hyperactivity and Conduct Problems in Very-Low-Birth-Weight Children at Early Primary School Age

“…Endogenous factors such as brain immaturity and dysregulated immune responses leading to inflammation-mediated morbidity play a crucial role [3]. Environmental factors such as intensive care, stress, maternal separation, nutritional deficits, circadian rhythm disruption, antibiotics and steroids have also been associated with altered brain development and may therefore contribute to the risk profile of VLBW children [2][3][4][5][6][7]. All these factors have an impact on fragile immune-microbiome co-establishment in preterm children, which occurs in timely association with central nervous system (CNS) development.…”