OBJECTIVE: To describe the long-term health outcomes of neonates affected by necrotizing enterocolitis (NEC) and its implications for quality of life.
METHODS: This is an integrative review, conducted by searching the literature in the following databases: Virtual Health Library (BVS), Latin American and Caribbean Health Sciences Literature (LILACS), Medical Literature Analysis and Retrieval System Online (MEDLINE), and PubMed, using Health Sciences Descriptors (DeCS): \"necrotizing enterocolitis,\" \"quality of life,\" and \"prognosis\" combined with the Boolean operators AND and OR: \"quality of life\" OR \"prognosis.\" Inclusion criteria were: publication period between 2012 and 2022.
RESULTS: A total of 1,010 studies were located, of which ten were selected to comprise the bibliographic sample of this review. Children with NEC are prone to exhibit cognitive neurological impairment, especially those who undergo surgical procedures due to more severe conditions. Motor development was considered below average when compared to healthy children, with more noticeable delays in fine and gross motor function development. The search for the relationship between NEC and quality of life revealed that this condition has a negative impact on the well-being of affected individuals.
CONCLUSIONS: NEC has proven to be a serious condition contributing to high rates of morbidity and mortality in newborns, potentially leading to a reduction in the quality of life of affected patients.

Inflammation, oxidative injury, and gut dysbiosis play an important role in the pathogenesis of necrotising enterocolitis (NEC). Plant-derived substances have historically been used as therapeutic agents due to their anti-inflammatory, antioxidant, and antimicrobial properties. We aimed to review pre-clinical evidence for plant-derived substances in the prevention and treatment of NEC. A systematic review was conducted using the following databases: PubMed, EMBASE, EMCARE, MEDLINE and Cochrane Library (PROSPERO CRD42022365477). Randomized controlled trials (RCTs) and quasi-RCTs that evaluated a plant-derived substance as an intervention for NEC in an animal model of the illness and compared pre-stated outcomes (e.g., clinical severity, severity of intestinal injury, mortality, laboratory markers of inflammation and oxidative injury) were included. Sixteen studies (n = 610) were included in the systematic review. Ten of the sixteen included RCTs (Preterm rat pups: 15, Mice: 1) reported mortality and all reported NEC-related histology. Meta-analysis showed decreased mortality [12/134 vs. 27/135; RR: 0.48 (95% CI: 0.26 to 0.87); p = 0.02, 10 RCTs] and decreased NEC in the experimental group [24/126 vs. 55/79; RR: 0.34 (95% CI: 0.22 to 0.52); p < 0.001, 6 RCTs]. Markers of inflammation (n = 11) and oxidative stress (n = 13) improved in all the studies that have reported this outcome. There was no significant publication bias for the outcome of mortality. Plant-derived substances have the potential to reduce the incidence and severity of histologically diagnosed NEC and mortality in rodent models. These findings are helpful in guiding further pre-clinical studies towards developing a food supplement for the prevention of NEC in preterm infants.

Surgically treated necrotising enterocolitis (sNEC) is associated with significantly worse neurodevelopmental outcomes than that seen in premature infants without NEC. We aim to review the association between factors involved in the surgical treatment of NEC and subsequent neurodevelopmental outcomes to identify potential areas for improvement. The PubMed and Embase databases were interrogated for articles reporting neurodevelopmental outcomes in babies treated surgically for NEC using key terms including: \"Infant\", \"Necrotising enterocolitis\", \"Surgical\", \"Neurodevelopmental\" and \"Outcomes\". The search strategy yielded 1170 articles and after applying inclusion and exclusion criteria 22 studies remained and formed the review. A diverse range of neurodevelopmental outcomes were reported. Extreme prematurity and lower birth weight were associated with worse neurodevelopmental outcomes. The use of peritoneal drains and enterostomies were associated with worse outcomes. Modifications to surgical strategies in NEC may improve neurodevelopmental outcomes but the effect of confounding factors remains unclear. Further large scale studies are required to define the optimum strategies for treating NEC surgically and to develop a core outcome set for research into NEC.

BACKGROUND: Necrotizing enterocolitis (NEC) is a multifactorial gastrointestinal disease with high morbidity and mortality among premature infants. However, studies with large samples on the factors of NEC in China have not been reported. This meta-analysis aims to systematically review the literature to explore the influencing factors of necrotizing enterocolitis in premature infants in China and provide a reference for the prevention of NEC.
METHODS: PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), China Biomedical Literature Database (CBM), Wanfang and VIP databases were systematically searched from inception to February 2023. We used Stata14.0 software to perform the systematic review and meta-analysis. We used fixed or random effects models with combined odds ratios (ORs) and 95% confidence intervals (CIs), and quality was evaluated using the Newcastle‒Ottawa Scale (NOS).
RESULTS: The total sample was 8616 cases, including 2456 cases in the intervention group and 6160 cases in the control group. It was found that 16 risk factors and 3 protective factors were related to necrotizing enterocolitis in premature infants. Septicemia (OR = 3.91), blood transfusion (OR = 2.41), neonatal asphyxia (OR = 2.46), pneumonia (OR = 6.17), infection (OR = 5.99), congenital heart disease (OR = 4.80), intrahepatic cholestasis of pregnancy (ICP) (OR = 2.71), mechanical ventilation (OR = 1.44), gestational diabetes mellitus (GDM) (OR = 3.08), respiratory distress syndrome (RDS) (OR = 3.28), hypoalbuminemia (OR = 2.80), patent ductus arteriosus (PDA) (OR = 3.10), respiratory failure (OR = 7.51), severe anemia (OR = 2.86), history of antibiotic use (OR = 2.12), and meconium-stained amniotic fluid (MSAF) (OR = 3.14) were risk factors for NEC in preterm infants in China. Breastfeeding (OR = 0.31), oral probiotics (OR = 0.36), and prenatal use of glucocorticoids (OR = 0.38) were protective factors for NEC in preterm infants.
CONCLUSIONS: Septicemia, blood transfusion, neonatal asphyxia, pneumonia, infection, congenital heart disease, ICP, GDM, RDS, hypoproteinemia, PDA, respiratory failure, severe anemia, history of antibiotic use and MSAF will increase the risk of NEC in premature infants, whereas breastfeeding, oral probiotics and prenatal use of glucocorticoids reduce the risk. Due to the quantity and quality of the included literature, the above findings need to be further validated by more high-quality studies.

Various studies have shown that oropharyngeal colostrum application (OPCA) is beneficial to preterm neonates. We performed a systematic review and meta-analysis to assess whether OPCA reduces the incidence of culture-proven neonatal sepsis in preterm neonates. Randomized controlled trials comparing OPCA with placebo or standard care in preterm neonates were included. Medline, Embase, Web of Science, Cumulated Index to Nursing and Allied Health Literature, Scopus, and CENTRAL were searched for studies published up to June 15, 2023. We used the Cochrane Risk of Bias tool, version 2, for risk of bias assessment, the random-effects model (RevMan 5.4) for meta-analysis, and Gradepro software for assessing the certainty of evidence. Twenty-one studies involving 2393 participants were included in this meta-analysis. Four studies had a low risk of bias, whereas seven had a high risk. Oropharyngeal colostrum significantly reduced the incidence of culture-proven sepsis (18 studies, 1990 neonates, risk ratio [RR]: 0.78, 95% confidence interval [95% CI]: 0.65, 0.94), mortality (18 studies, 2117 neonates, RR: 0.73, 95% CI: 0.59, 0.90), necrotizing enterocolitis (NEC) (17 studies, 1692 neonates, RR: 0.59, 95% CI: 0.43, 0.82), feeding intolerance episodes (four studies, 445 neonates, RR: 0.59, 95% CI: 0.38, 0.92), and the time to full enteral feeding (19 studies, 2142 neonates, mean difference: -2 to 21 days, 95% CI: -3.44, -0.99 days). There was no reduction in intraventricular hemorrhage, retinopathy of prematurity, bronchopulmonary dysplasia, ventilator-associated pneumonia, neurodevelopmental abnormalities, hospital stay duration, time to full oral feeding, weight at discharge, pneumonia, and duration of antibiotic therapy. The certainty of the evidence was high for the outcomes of culture-positive sepsis and mortality, moderate for NEC, low for time to full enteral feeding, and very low for feeding intolerance. OPCA reduces culture-positive sepsis and mortality (high certainty), NEC (moderate certainty), and time to full enteral feeding (low certainty) in preterm neonates. However, scarcity of data from extremely premature infants limits the generalizability of these results to this population.

OBJECTIVE: The aim of this study was to assess outcomes of peritoneal drainage and laparotomy in the management of intestinal perforation secondary to necrotizing enterocolitis (NEC) and spontaneous intestinal perforation.
METHODS: A retrospective review of all preterm infants (birthweight ≤1500 g) who underwent surgical intervention (peritoneal drainage and/or laparotomy) for intestinal perforation between March 2010 and March 2020.
RESULTS: A total of 43 infants who underwent surgical intervention for intestinal perforation were included [19 (44%) with NEC and 24 (56%) with spontaneous intestinal perforation]. Peritoneal drainage was more commonly placed as the initial surgical procedure for management of spontaneous intestinal perforation compared with surgical NEC [23 (96%) vs. 11 (58%), p = 0.003]. Mortality was greater for infants who were initially managed with peritoneal drainage [11 (32%)] compared with those who underwent primary laparotomy [2 (22%), p = 0.5].
CONCLUSIONS: Initial surgical management of intestinal perforation is more often according to underlying pathology. Our data support primary laparotomy for infants with perforated NEC.

BACKGROUND: Caffeine is commonly used as therapy for apnea of prematurity and has shown potential in preventing other conditions in preterm neonates. However, the optimal timing for caffeine therapy remains uncertain.
OBJECTIVE: This study aimed to compare the outcomes of early versus late administration of caffeine in preterm neonates.
METHODS: PubMed, Embase, and Cochrane Library were searched for studies comparing 0-2 days to ≥3 days caffeine introduction in preterm neonates. Outcomes included were mortality, bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), patent ductus arteriosus (PDA), late-onset sepsis, length of hospital stay, and the composite of BPD or death. RevMan 5.4.1 was used for statistical analysis.
RESULTS: A total of 122,579 patients from 11 studies were included, 2 were randomized controlled trials (RCTs), and 63.9% of the neonates received early caffeine administration. The rates of BPD (OR: 0.70; 95% CI: [0.60-0.81]; p < 0.0001), IVH (OR: 0.86; 95% CI: [0.82-0.90]; p < 0.0001), ROP (OR: 0.80; 95% CI: [0.74-0.86]; p < 0.0001), late-onset sepsis (OR: 0.84; 95% CI: [0.79-0.89]; p < 0.00001), and PDA (OR: 0.60; 95% CI: [0.47-0.78]; p < 0.0001) were significantly reduced in the early caffeine group. The composite outcome of BPD or death was also lower in the early caffeine group (OR: 0.76; 95% CI: [0.66-0.88]; p < 0.0003). Mortality rate was higher in the early caffeine group (OR: 1.20; 95% CI: 1.12-1.29; p < 0.001).
CONCLUSIONS: As compared with late caffeine administration, early caffeine is associated with a reduction in BPD, IVH, ROP, late-onset sepsis, and PDA in preterm neonates, albeit increased mortality. Additional RCTs are warranted to confirm these findings and evaluate whether the effect on mortality may be related to survival bias in observational studies favoring the late treatment group.

The network meta-analysis (NMA) investigated the efficacy of six food supplements, namely glutamine, arginine, lactoferrin, prebiotics, synbiotics, and probiotics, in preventing necrotizing enterocolitis in premature infants.
MEDLINE, Embase, and Cochrane Library were searched. Randomized controlled trials comparing different food supplements for premature infants were included.
Probiotics (OR, 0.47; 95% CrI, 0.33-0.63), arginine (OR, 0.38; 95% CrI, 0.14-0.98), glutamine (OR, 0.30; 95% CrI, 0.079-0.90), and synbiotics (OR, 0.13; 95% CrI, 0.037-0.37). were associated with a decreased incidence of NEC. Only probiotics (OR, 0.81; 95% CrI, 0.69-0.95) and lactoferrin (OR, 0.74; 95% CrI, 0.54-0.92) achieved lower risk of sepsis. Probiotics (OR, 0.58; 95% CrI, 0.40-0.79), prebiotics (OR, 0.23; 95% CrI, 0.043-0.86), and synbiotics (OR, 0.15; 95% CrI, 0.035-0.50) were associated with lower odds of mortality. Probiotics (MD, -2.3; 95% CrI: -3.7- -0.63) appeared to have earlier age of attainment of full feeding.
Based on this NMA, probiotics and synbiotics had the potential to be the top two preferable food supplements.

Modulation of intestinal microbiome by administering probiotics, prebiotics, or both may prevent morbidity and mortality in premature infants.
To assess the comparative effectiveness of alternative prophylactic strategies through a network meta-analysis (NMA) of randomized clinical trials.
MEDLINE, EMBASE, Science Citation Index Expanded, CINAHL, Scopus, Cochrane CENTRAL, and Google Scholar from inception until May 10, 2023.
Eligible trials tested probiotics, prebiotics, lactoferrin, and combination products for prevention of morbidity or mortality in preterm infants.
A frequentist random-effects model was used for the NMA, and the certainty of evidence and inferences regarding relative effectiveness were assessed using the GRADE approach.
All-cause mortality, severe necrotizing enterocolitis, culture-proven sepsis, feeding intolerance, time to reach full enteral feeding, and duration of hospitalization.
A total of 106 trials involving 25 840 preterm infants were included. Only multiple-strain probiotics were associated with reduced all-cause mortality compared with placebo (risk ratio [RR], 0.69; 95% CI, 0.56 to 0.86; risk difference [RD], -1.7%; 95% CI, -2.4% to -0.8%). Multiple-strain probiotics alone (vs placebo: RR, 0.38; 95% CI, 0.30 to 0.50; RD, -3.7%; 95% CI, -4.1% to -2.9%) or in combination with oligosaccharides (vs placebo: RR, 0.13; 95% CI, 0.05 to 0.37; RD, -5.1%; 95% CI, -5.6% to -3.7%) were among the most effective interventions reducing severe necrotizing enterocolitis. Single-strain probiotics in combination with lactoferrin (vs placebo RR, 0.33; 95% CI, 0.14 to 0.78; RD, -10.7%; 95% CI, -13.7% to -3.5%) were the most effective intervention for reducing sepsis. Multiple-strain probiotics alone (RR, 0.61; 95% CI, 0.46 to 0.80; RD, -10.0%; 95% CI, -13.9% to -5.1%) or in combination with oligosaccharides (RR, 0.45; 95% CI, 0.29 to 0.67; RD, -14.1%; 95% CI, -18.3% to -8.5%) and single-strain probiotics (RR, 0.61; 95% CI, 0.51 to 0.72; RD, -10.0%; 95% CI, -12.6% to -7.2%) proved of best effectiveness in reduction of feeding intolerance vs placebo. Single-strain probiotics (MD, -1.94 days; 95% CI, -2.96 to -0.92) and multistrain probiotics (MD, -2.03 days; 95% CI, -3.04 to -1.02) proved the most effective in reducing the time to reach full enteral feeding compared with placebo. Only single-strain and multistrain probiotics were associated with greater effectiveness compared with placebo in reducing duration of hospitalization (MD, -3.31 days; 95% CI, -5.05 to -1.58; and MD, -2.20 days; 95% CI, -4.08 to -0.31, respectively).
In this systematic review and NMA, moderate- to high-certainty evidence demonstrated an association between multistrain probiotics and reduction in all-cause mortality; these interventions were also associated with the best effectiveness for other key outcomes. Combination products, including single- and multiple-strain probiotics combined with prebiotics or lactoferrin, were associated with the largest reduction in morbidity and mortality.

Our previous strain-specific systematic review (SR) showed that Lactobacillus reuteri (LR) DSM 17938 reduces necrotizing enterocolitis (NEC), late-onset sepsis (LOS), and time to full feeds (TFF) in preterm infants. Considering progress in the field over the past 6 years, we aimed to update our SR.
SR of randomized controlled trials (RCTs) and non-RCTs was conducted. MEDLINE, Embase, Emcare, Cochrane CENTRAL, and gray literature were searched in June 2023. Primary outcomes were TFF, NEC stage ≥II, LOS, and all-cause mortality. Meta-analysis was performed using random-effects model. Certainty of evidence (CoE) was summarized using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) guidelines. Trial sequential analysis (TSA) was applied for outcome of NEC in RCTs.
Twelve RCTs (n = 2284) and four non-RCTs (n = 1616) were included. Six RCTs and three non-RCTs were new. Meta-analysis of RCTs showed LR significantly reduced TFF (mean difference, -2.70 [95% CI, -4.90 to -1.31] days; P = 0.0001), NEC stage ≥II (risk ratio [RR], 0.57 [95% CI, 0.37-0.87]; P = 0.009; eight RCTs), and LOS (RR, 0.72 [95% CI, 0.54-0.97]; P = 0.03); but not mortality (RR, 0.76 [95% CI, 0.54-1.06]; P = 0.10). TSA showed diversity-adjusted required information size (DARIS) as 3624 for NEC. Overall CoE was \"very low.\" Meta-analysis of non-RCTs showed LR reduced NEC (odds ratio, 0.34 [95% CI, 0.15-0.77]; P = 0.01) but not LOS. LR had no adverse effects.
Very low CoE suggests that LR DSM 17938 may reduce NEC and LOS and shorten TFF in preterm infants. Additional RCTs are required to confirm our findings.