Necrotizing enterocolitis (NEC) remains the most threatening gastrointestinal complication of prematurity leading to high mortality, morbidity and cost. Common complications of NEC include neurodevelopmental delay, failure to thrive, gastrointestinal problems including strictures and adhesions, cholestasis, short bowel syndrome with or without intestinal failure that can be difficult to manage. Infants who develop NEC benefit from close follow-up for early diagnosis and treatment of complications. Those who present with severe complications such as intestinal failure benefit from a multidisciplinary approach involving careful assessment and treatment. Studies done so far are limited in providing a long-term prognosis. Here we review some of these complications. More studies with a longer follow-up period are needed to better understand the later comorbidities that develop in babies with NEC.

NEC is a devastating disease that, once present, is very difficult to treat. In the absence of an etiologic treatment, preventive measures are required. Advances in decoding the pathophysiology of NEC are being made but a more comprehensive understanding is needed for the targeting of preventative strategies. A better definition of the disease as well as diagnostic criteria are needed to be able to specifically label a disease as NEC. Multiple environmental factors combined with host susceptibility appear to contribute to enhanced risks for developing this disease. Several different proximal pathways are involved, all leading to a common undesired outcome: Intestinal necrosis. The most common form of this disease appears to involve inflammatory pathways that are closely meshed with the intestinal microbiota, where a dysbiosis may result in dysregulated inflammation. The organisms present in the intestinal tract prior to the onset of NEC along with their diversity and functional capabilities are just beginning to be understood. Fulfillment of postulates that support causality for particular microorganisms is needed if bacteriotherapies are to be intelligently applied for the prevention of NEC. Identification of molecular effector pathways that propagate inflammation, understanding of, even incipient role of genetic predisposition and of miRNAs may help solve the puzzle of this disease and may bring the researchers closer to finding a treatment. Despite recent progress, multiple limitations of the current animal models, difficulties related to studies in humans, along with the lack of a “clear” definition will continue to make it a very challenging disease to decipher.

Antibiotic use in neonates can have detrimental effects on the developing gut microbiome, increasing the risk of morbidity. A majority of preterm neonates receive antibiotics after birth without clear evidence to guide this practice. Here microbiome, metabolomic, and immune marker results from the routine early antibiotic use in symptomatic preterm Neonates (REASON) study are presented. The REASON study is the first trial to randomize symptomatic preterm neonates to receive or not receive antibiotics in the first 48 h after birth. Using 16S rRNA sequencing of stool samples collected longitudinally for 91 neonates, the effect of such antibiotic use on microbiome diversity is assessed. The results illustrate that type of nutrition shapes the early infant gut microbiome. By integrating data for the gut microbiome, stool metabolites, stool immune markers, and inferred metabolic pathways, an association was discovered between Veillonella and the neurotransmitter gamma-aminobutyric acid (GABA). These results suggest early antibiotic use may impact the gut-brain axis with the potential for consequences in early life development, a finding that needs to be validated in a larger cohort.Trial Registration This project is registered at clinicaltrials.gov under the name “Antibiotic ‘Dysbiosis’ in Preterm Infants” with trial number NCT02784821.

on behalf of the PENUT Trial Consortium* Objective To evaluate whether extremely low gestational age neonates (ELGANs) randomized to erythropoietin have better or worse kidney-related outcomes during hospitalization and at 22-26 months of corrected gestational age (cGA) compared with those randomized to placebo. Study designWe performed an ancillary study to a multicenter double-blind, placebo-controlled randomized clinical trial of erythropoietin in ELGANs. ResultsThe prevalence of severe (stage 2 or 3) acute kidney injury (AKI) was 18.2%. We did not find a statistically significant difference between those randomized to erythropoietin vs placebo for in-hospital primary (severe AKI) or secondary outcomes (any AKI and serum creatinine/cystatin C values at days 0, 7, 9, and 14). At 22-26 months of cGA, 16% of the cohort had an estimated glomerular filtration rate (eGFR) <90 mL/min/1.73 m 2 , 35.8% had urine albumin/creatinine ratio >30 mg/g, 23% had a systolic blood pressure (SBP) >95th percentile for age, and 40% had a diastolic blood pressure (DBP) >95th percentile for age. SBP >90th percentile occurred less often among recipients of erythropoietin (P < .04). This association remained even after controlling for gestational age, site, and sibship (aOR 0.6; 95% CI 0.39-0.92). We did not find statistically significant differences between treatment groups in eGFR, albumin/creatinine ratio, rates of SBP >95th percentile, or DBP >90th or >95th percentiles at the 2 year follow-up visit.Conclusions ELGANs have high rates of in-hospital AKI and kidney-related problems at 22-26 months of cGA.Recombinant erythropoietin may protect ELGANs against long-term elevated SBP but does not appear to protect from AKI, low eGFR, albuminuria, or elevated DBP at 22-26 months of cGA.

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and for the PENUT Consortium BACKGROUND: Outcomes of extremely low gestational age neonates (ELGANs) may be adversely impacted by packed red blood cell (pRBC) transfusions. We investigated the impact of transfusions on neurodevelopmental outcome in the Preterm Erythropoietin (Epo) Neuroprotection (PENUT) Trial population. METHODS: This is a post hoc analysis of 936 infants 24-0/6 to 27-6/7 weeks' gestation enrolled in the PENUT Trial. Epo 1000 U/kg or placebo was given every 48 h × 6 doses, followed by 400 U/kg or sham injections 3 times a week through 32 weeks postmenstrual age. Six hundred and twenty-eight (315 placebo, 313 Epo) survived and were assessed at 2 years of age. We evaluated associations between BSID-III scores and the number and volume of pRBC transfusions. RESULTS: Each transfusion was associated with a decrease in mean cognitive score of 0.96 (95% CI of [−1.34, −0.57]), a decrease in mean motor score of 1.51 (−1.91, −1.12), and a decrease in mean language score of 1.10 (−1.54, −0.66). Significant negative associations between BSID-III score and transfusion volume and donor exposure were observed in the placebo group but not in the Epo group. CONCLUSIONS: Transfusions in ELGANs were associated with worse outcomes. We speculate that strategies to minimize the need for transfusions may improve outcomes.

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Within a randomized prospective pilot study of preterm infants born at less than 33 weeks’ gestation, weekly fecal samples from 19 infants were collected and metabolomic analysis was performed. The objective was to evaluate for differences in fecal metabolites in infants exposed to antibiotics vs. not exposed to antibiotics in the first 48 h after birth. Metabolomics analysis was performed on 123 stool samples. Significant differences were seen in the antibiotics vs. no antibiotics groups, including pathways related to vitamin biosynthesis, bile acids, amino acid metabolism, and neurotransmitters. Early antibiotic exposure in preterm infants may alter metabolites in the intestinal tract of preterm infants. Broader multi-omic studies that address mechanisms will guide more prudent antibiotic use in this population.