Probiotic supplementation and risk of necrotizing enterocolitis and mortality among extremely preterm infants-the Probiotics in Extreme Prematurity in Scandinavia (PEPS) trial: study protocol for a multicenter, double-blinded, placebo-controlled, and registry-based randomized controlled trial.

BACKGROUND: Extremely preterm infants, defined as those born before 28 weeks' gestational age, are a very vulnerable patient group at high risk for adverse outcomes, such as necrotizing enterocolitis and death. Necrotizing enterocolitis is an inflammatory gastrointestinal disease with high incidence in this cohort and has severe implications on morbidity and mortality. Previous randomized controlled trials have shown reduced incidence of necrotizing enterocolitis among older preterm infants following probiotic supplementation. However, these trials were underpowered for extremely preterm infants, rendering evidence for probiotic supplementation in this population insufficient to date. METHODS: The Probiotics in Extreme Prematurity in Scandinavia (PEPS) trial is a multicenter, double-blinded, placebo-controlled and registry-based randomized controlled trial conducted among extremely preterm infants (n = 1620) born at six tertiary neonatal units in Sweden and four units in Denmark. Enrolled infants will be allocated to receive either probiotic supplementation with ProPrems® (Bifidobacterium infantis, Bifidobacterium lactis, and Streptococcus thermophilus) diluted in 3 mL breastmilk or placebo (0.5 g maltodextrin powder) diluted in 3 mL breastmilk per day until gestational week 34. The primary composite outcome is incidence of necrotizing enterocolitis and/or mortality. Secondary outcomes include incidence of late-onset sepsis, length of hospitalization, use of antibiotics, feeding tolerance, growth, and body composition at age of full-term and 3 months corrected age after hospital discharge. DISCUSSION: Current recommendations for probiotic supplementation in Sweden and Denmark do not include extremely preterm infants due to lack of evidence in this population. However, this young subgroup is notably the most at risk for experiencing adverse outcomes. This trial aims to investigate the effects of probiotic supplementation on necrotizing enterocolitis, death, and other relevant outcomes to provide sufficiently powered, high-quality evidence to inform probiotic supplementation guidelines in this population. The results could have implications for clinical practice both in Sweden and Denmark and worldwide. TRIAL REGISTRATION: ( Clinicaltrials.gov ): NCT05604846.

Experimental necrotizing enterocolitis using oral lipopolysaccharide and protective role of breastmilk. / Enterocolitis necrotizante experimental con lipopolisacárido oral y función protectora de la leche materna.

INTRODUCTION: Necrotizing enterocolitis (NEC) is a life-threatening condition that afflicts neonates. Breastfeeding has demonstrated to play a protective role against it. By administering lipopolysaccharides (LPS) orally in newborn rats (NBR), we have developed an experimental model to induce NEC-like gut damage. Our aim was to assess the macroscopic and microscopic appearance of the gut, to evaluate the presence of NEC and study the role of breast milk (BM). MATERIALS AND METHODS: NBR were divided into 3 groups: Group A (control, n= 10) remained with the mother, group B (LPS, n= 25) was isolated after birth, gavage-fed with special rat formula and oral LPS, then submitted to stress (hypoxia after gavage) and group c (BM, n= 12) was breastfed once after birth, then isolated, and submitted to stress like group B. On day 4, NBR were sacrificed, and intestine was harvested and assessed. RESULTS: In the control group NEC was not present either macroscopically or histologically. Both groups submitted to stress (B and C) presented a global incidence of NEC of 73%. Most of group B developed histologic signs of NEC (85%) and group C showed a statistically lower incidence of NEC (50%, p= 0.04), playing the BM a protective role against NEC (OR= 0.19; 95% CI: 0.40-0.904). CONCLUSION: Our model showed a significant incidence of NEC in NBR (73%) with the same protective role of BM as in newborn humans, achieving a reliable and reproducible experimental NEC model. This will allow us to investigate new potential therapeutic targets for a devastating disease that currently lacks treatment.

INTRODUCCION: La enterocolitis necrotizante (ECN) es una enfermedad potencialmente mortal que afecta a los neonatos, y frente a la que la leche materna ha demostrado tener un papel protector. Administrando lipopolisacáridos (LPS) por vía oral en ratas recién nacidas (RRN), hemos desarrollado un modelo experimental para inducir un daño intestinal similar al que provoca la ECN con objeto de evaluar el aspecto macroscópico y microscópico del intestino, y de ese modo, analizar la presencia de ECN y estudiar el papel que desempeña la leche materna (LM). MATERIAL Y METODOS: Las RRN se dividieron en tres grupos: el grupo A (control, n= 10) permaneció con su madre; el grupo B (LPS, n= 25) fue aislado tras el nacimiento, alimentado por sonda con una fórmula especial para ratas y LPS oral, y sometido a estrés (hipoxia tras sonda); y el grupo C (LM, n= 12) fue alimentado con leche materna tras el nacimiento y posteriormente aislado y sometido a estrés al igual que el grupo B. El día 4 se sacrificó a las RRN y se recuperaron sus intestinos para su posterior evaluación. RESULTADOS: En el grupo de control, no se observó ECN ni macroscópica ni histológicamente, mientras que los dos grupos sometidos a estrés (B y C) presentaron una incidencia global de la ECN del 73%. La mayoría de los sujetos del grupo B desarrollaron signos histológicos de ECN (85%), y los del grupo C registraron una incidencia de la ECN estadísticamente menor (50%, p= 0,04), lo que significa que la LM desempeña una función protectora frente a la ECN (OR= 0,19; IC 95%: 0,40-0,904). CONCLUSION: Nuestro modelo reveló una incidencia significativa de la ECN en RRN (73%), desempeñando la LM la misma función protectora que en el caso de los humanos recién nacidos, lo que significa que este modelo experimental de ECN es fiable y reproducible. Gracias a dicho logro, podremos investigar nuevos y potenciales objetivos terapéuticos para una peligrosa enfermedad que, a día de hoy, carece de tratamiento.

Neurodevelopmental Outcomes of Extremely Preterm Infants Fed Donor Milk or Preterm Infant Formula: A Randomized Clinical Trial.

Importance: Maternal milk feeding of extremely preterm infants during the birth hospitalization has been associated with better neurodevelopmental outcomes compared with preterm formula. For infants receiving no or minimal maternal milk, it is unknown whether donor human milk conveys similar neurodevelopmental advantages vs preterm formula. Objective: To determine if nutrient-fortified, pasteurized donor human milk improves neurodevelopmental outcomes at 22 to 26 months' corrected age compared with preterm infant formula among extremely preterm infants who received minimal maternal milk. Design, Setting, and Participants: Double-blind, randomized clinical trial conducted at 15 US academic medical centers within the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Infants younger than 29 weeks 0 days' gestation or with a birth weight of less than 1000 g were enrolled between September 2012 and March 2019. Intervention: Preterm formula or donor human milk feeding from randomization to 120 days of age, death, or hospital discharge. Main Outcomes and Measures: The primary outcome was the Bayley Scales of Infant and Toddler Development (BSID) cognitive score measured at 22 to 26 months' corrected age; a score of 54 (score range, 54-155; a score of ≥85 indicates no neurodevelopmental delay) was assigned to infants who died between randomization and 22 to 26 months' corrected age. The 24 secondary outcomes included BSID language and motor scores, in-hospital growth, necrotizing enterocolitis, and death. Results: Of 1965 eligible infants, 483 were randomized (239 in the donor milk group and 244 in the preterm formula group); the median gestational age was 26 weeks (IQR, 25-27 weeks), the median birth weight was 840 g (IQR, 676-986 g), and 52% were female. The birthing parent's race was self-reported as Black for 52% (247/478), White for 43% (206/478), and other for 5% (25/478). There were 54 infants who died prior to follow-up; 88% (376/429) of survivors were assessed at 22 to 26 months' corrected age. The adjusted mean BSID cognitive score was 80.7 (SD, 17.4) for the donor milk group vs 81.1 (SD, 16.7) for the preterm formula group (adjusted mean difference, -0.77 [95% CI, -3.93 to 2.39], which was not significant); the adjusted mean BSID language and motor scores also did not differ. Mortality (death prior to follow-up) was 13% (29/231) in the donor milk group vs 11% (25/233) in the preterm formula group (adjusted risk difference, -1% [95% CI, -4% to 2%]). Necrotizing enterocolitis occurred in 4.2% of infants (10/239) in the donor milk group vs 9.0% of infants (22/244) in the preterm formula group (adjusted risk difference, -5% [95% CI, -9% to -2%]). Weight gain was slower in the donor milk group (22.3 g/kg/d [95% CI, 21.3 to 23.3 g/kg/d]) compared with the preterm formula group (24.6 g/kg/d [95% CI, 23.6 to 25.6 g/kg/d]). Conclusions and Relevance: Among extremely preterm neonates fed minimal maternal milk, neurodevelopmental outcomes at 22 to 26 months' corrected age did not differ between infants fed donor milk or preterm formula. Trial Registration: ClinicalTrials.gov Identifier: NCT01534481.

Risk factors of necrotizing enterocolitis in twin preterm infants.

PURPOSE: This study was aimed to investigate the risk factors of necrotizing enterocolitis (NEC) in twin preterm infants. METHODS: The clinical data of 67 pairs of twin preterm infants admitted to the neonatal department of our hospital from January 2010 to December 2021 were retrospectively collected. One of the twins had NEC (Bell II and above) and the other twin without NEC. They were divided into NEC group and control group according to whether NEC occurred or not. RESULTS: Univariate analysis showed that NEC was associated with congenital heart disease, small for gestational age, mild asphyxia at birth and feeding intolerance (P < 0.05). CONCLUSION: Occurrence of NEC was associated with congenital heart disease, small for gestational age, and asphyxia at birth. For twin preterm infants with congenital heart disease, small for gestational age, or asphyxia at birth, special attention should be paid to the occurrence of NEC to minimize and avoid the occurrence of NEC.

The role of nutrition in analysis of risk factors and short-term outcomes for late-onset necrotizing enterocolitis among very preterm infants: a nationwide, multicenter study in China.

BACKGROUND: Necrotizing enterocolitis (NEC) is a serious gastrointestinal disease, primarily affects preterm newborns and occurs after 7 days of life (late-onset NEC, LO-NEC). Unfortunately, over the past several decades, not much progress has been made in its treatment or prevention. This study aimed to analyze the risk factors for LO-NEC, and the impact of LO-NEC on short-term outcomes in very preterm infants (VPIs) with a focus on nutrition and different onset times. METHOD: Clinical data of VPIs were retrospectively collected from 28 hospitals in seven different regions of China from September 2019 to December 2020. A total of 2509 enrolled VPIs were divided into 2 groups: the LO-NEC group and non-LO-NEC group. The LO-NEC group was divided into 2 subgroups based on the onset time: LO-NEC occurring between 8 ~ 14d group and LO-NEC occurring after 14d group. Clinical characteristics, nutritional status, and the short-term clinical outcomes were analyzed and compared among these groups. RESULTS: Compared with the non-LO-NEC group, the LO-NEC group had a higher proportion of anemia, blood transfusion, and invasive mechanical ventilation (IMV) treatments before NEC; the LO-NEC group infants had a longer fasting time, required longer duration to achieve the target total caloric intake (110 kcal/kg) and regain birthweight, and showed slower weight growth velocity; the cumulative dose of the medium-chain and long-chain triglyceride (MCT/LCT) emulsion intake in the first week after birth was higher and breastfeeding rate was lower. Additionally, similar results including a higher proportion of IMV, lower breastfeeding rate, more MCT/LCT emulsion intake, slower growth velocity were also found in the LO-NEC group occurring between 8 ~ 14d when compared to the LO-NEC group occurring after 14 d (all (P < 0.05). After adjustment for the confounding factors, high proportion of breastfeeding were identified as protective factors and long fasting time before NEC were identified as risk factors for LO-NEC; early feeding were identified as protective factors and low gestational age, grade III ~ IV neonatal respiratory distress syndrome (NRDS), high accumulation of the MCT/LCT emulsion in the first week were identified as risk factors for LO-NEC occurring between 8 ~ 14d. Logistic regression analysis showed that LO-NEC was a risk factor for late-onset sepsis, parenteral nutrition-associated cholestasis, metabolic bone disease of prematurity, and extrauterine growth retardation. CONCLUSION: Actively preventing premature birth, standardizing the treatment of grade III ~ IV NRDS, and optimizing enteral and parenteral nutrition strategies may help reduce the risk of LO-NEC, especially those occurring between 8 ~ 14d, which may further ameliorate the short-term clinical outcome of VPIs. TRIAL REGISTRATION: ChiCTR1900023418 (26/05/2019).

Effect of oropharyngeal colostrum therapy on neonatal sepsis in preterm neonates: A systematic review and meta-analysis.

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.

Factors influencing necrotizing enterocolitis in premature infants in China: a systematic review and meta-analysis.

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.

Identifying Risk Factors for Surgical Site Infection After Stoma Closure in Infants for Targeted Implementation of Surgical Site Infection Reduction Bundle.

Background: To determine risk factors for surgical site infection (SSI) in infants after stoma closure, to identify at-risk patients, plan timing of surgery, and implement SSI-reduction strategies. Patients and Methods: A single center retrospective comparison study of all children less than one year of age who underwent enterostomy closure (2018-2020) with SSI diagnosed through a prospective surveillance program, using criteria from Public Health England (PHE). Demographics and risk factors, types of SSI, systemic sepsis, mortality and length of stay were compared between SSI and non-SSI. Significant factors associated with SSI were analyzed in a multivariate binomial logistic regression model. Results: Eighty-nine stoma closures were performed, most commonly for necrotizing enterocolitis (NEC) and anorectal malformation. Fourteen had SSI (16%): 12 superficial and two deep; three developed systemic sepsis, but no 30-day mortality. Surgical site infection was associated with NEC (12/14 vs. 32/75; p = 0.003), younger age (median 76 vs. 89 days; p = 0.014), lower corrected gestation (cutoff: 39 weeks gestation; 11/14 vs. 27/75; p = 0.004) and lower weight (cutoff: 2.2 kg; 7/14 vs. 16/75; p = 0.032), compared with non-SSI. After correcting for age, gestation, and weight, logistic regression showed NEC was an independent predictor for SSI (odds ratio [OR], 12; 95% confidence interval [CI],1.2-125). The at-risk cohort (n = 56; 63%) had seven-fold increased risk of SSI and four-fold longer hospital stay, which may be the target for SSI-reduction strategies. Conclusions: Necrotizing enterocolitis-related stoma closure is at increased risk for SSI. Considerations for delaying stoma closure until achieving 39 weeks gestation or 2.2 kg in weight may further reduce SSI. Targeting SSI-reduction strategies using these criteria may improve resource-rationalization.

Risk factors for postoperative complications in preterm infants with surgical necrotizing enterocolitis and associated outcomes.

BACKGROUND: We aim to determine clinical risk factors for postoperative complications in preterm infants with surgical necrotizing enterocolitis (NEC) or spontaneous intestinal perforation (SIP). METHODS: A retrospective cohort study of preterm infants with surgical NEC or SIP to compare clinical factors between those with and without postoperative complications. RESULTS: 78/109 (71.5%) infants had any complication following surgical NEC. Adhesions (20/35, 57.1%) and wound infection (6/35, 17.1%) were the most common single surgical complications. Patients with a single surgical complication (35/66, 53%) were significantly less likely to be exposed to antenatal steroids, more frequently had a jejunostomy, needed a central line longer, and had a longer length of stay than those without any surgical complication. Infants with > 1 surgical complication (43/71, 60.5%) included mainly females, and had AKI more frequently at NEC onset, lower weight z-scores and lower weight for length z- scores at 36 weeks PMA than those without any complications.On multinomial logistic regression, antenatal steroids exposure (OR 0.23 [CI 0.06, 0.84]; p = 0.027) was independently associated with lower risk and jejunostomy 4.81 (1.29, 17.9) was independently associated with higher risk of developing a single complication. AKI following disease onset (OR 5.33 (1.38, 20.6), P = 0.015) was independently associated with > 1 complication in surgical NEC/SIP infants. CONCLUSION: Infants with postoperative complications following surgical NEC were more likely to be female, have additional morbidities, and demonstrate growth failure at 36 weeks PMA than those without surgical complications. There was no difference in mortality between those with and without surgical complications.

Time to Attain Full Enteral Feeds Among Preterm Fetal Growth Restricted Neonates With Absent/Reversed End-Diastolic Flow.

OBJECTIVES: To determine the difference in time to attainment of full enteral feeds between fetal growth restricted (FGR) preterm neonates with and without absent/reversed end-diastolic flow (AREDF). Secondary objectives were to compare the short-term outcomes including the incidence of necrotizing enterocolitis (NEC) and feed intolerance between the two groups and to determine the factors affecting the time to attainment of full enteral feeds (FEF) among preterm FGR neonates. METHODS: A prospective cohort study was conducted among consecutive preterm FGR neonates delivered at 28-36 weeks gestation admitted in level III NICU. An umbilical artery doppler ultrasound was performed antenatally for all participants to detect AREDF. FGR neonates with AREDF were taken as the study group and those without AREDF were taken as the comparison group. Time to attain FEF was defined as time taken to establish enteral feeds of 150 ml/kg/day and tolerating it for the next 3 consecutive days. Delayed attainment of FEF was taken as ≥10 days needed to attain FEF. RESULTS: The median (IQR) time to attainment of full feeds was longer among neonates with AREDF compared to those without AREDF [12 (8, 16.5) vs 8 (5, 10) days; P < 0.001]. Neonates with AREDF had more feed intolerance [RR, 95% CI = 1.51 (1.13 - 2.02); P = 0.004], higher mortality [RR, 95% CI = 2.5 (1.02 - 6.2); P = 0.036], prolonged time to regain birth weight [15 (11.5, 19) days, P = 0.035], longer NICU stay [10 (7, 15), P < 0.001] and longer hospital stay [33 (23, 49), P < 0.001]. Also, neonates with AREDF had more hypoglycemia [RR, 95% CI=2.15 (1.2-3.7); P = 0.004], hypoxic ischemic encephalopathy [RR, 95% CI 5.05 (1.13 - 22.4); P = 0.016], hypothyroidism [RR, 95% CI= 8.08 (1.02 - 63.4), P = 0.016], cholestasis (P = 0.007), prolonged parenteral nutrition requirement [10 (7, 15) days, P < 0.001] and oxygen requirement [4.5 (2, 8) days, P < 0.001]. Multivariable logistic regression showed, AREDF [aOR 95% CI 2.91 (1.49 - 5.68), P = 0.002], lower gestational age [aOR 95% CI 0.724 (0.604 - 0.867), P < 0.001] and thrombocytopenia at birth [aOR 95% CI 2.625 (1.342 - 5.136), P = 0.005] are significant predictors of delayed attainment of full feeds among preterm FGR neonates. CONCLUSION: Preterm FGR neonates with AREDF are slower to attain FEF, have more feed intolerance, higher mortality, need longer time to regain birth weight, prolonged NICU stay and hospital stay. AREDF, lower gestation, sepsis and thrombocytopenia at birth are significant predictors of delayed full feed attainment among preterm FGR neonates. It is essential to devise strategies to reduce morbidity and mortality among this group of preterm neonates.

Using a new human milk fortifier to optimize human milk feeding among very preterm and/or very low birth weight infants: a multicenter study in China.

BACKGROUND: Human milk fortifier (HMF) composition has been optimized recently. But clinical evidence of its safety and efficacy is limited in Chinese population. The aim of this study was to evaluate effects of a new HMF in growth, nutritional status, feeding intolerance, and major morbidities among very preterm (VPT) or very low birth weight (VLBW) infants in China. METHODS: VPT/VLBW infants admitted from March 2020 to April 2021 were prospectively included in the experimental (new HMF, nHMF) group, who received a new powdered HMF as a breast milk feeding supplement during hospitalization. Infants in the control group (cHMF) admitted from January 2018 to December 2019, were retrospective included, and matched with nHMF group infants for gestational age and birth weight. They received other kinds of commercially available HMFs. Weight gain velocity, concentrations of nutritional biomarkers, incidence of major morbidities, and measures of feeding intolerance were compared between the two groups. RESULTS: Demographic and clinical characteristics of infants in nHMF and cHMF groups were comparable. Weight gain velocity had no significant difference between the nHMF (14.0 ± 3.5 g/kg/d) and the cHMF group (14.2 ± 3.8 g/kg/d; P = 0.46). Incidence of morbidities, including necrotizing enterocolitis, bronchopulmonary dysplasia, retinopathy of prematurity, culture-confirmed sepsis, and feeding intolerance during hospitalization between nHMF and cHMF, were similar (all P-values > 0.05). The time to achieve full enteral feeding [13.5 (10, 21) days] in the nHMF group was significantly shorter than that in the cHMF group [17 (12, 23) days, HR = 0.67, 95%CI: 0.49, 0.92; P = 0.01]. Compared with cHMF group, the decrease of blood urea nitrogen level over time in nHMF group was smaller (ß = 0.6, 95%CI:0.1, 1.0; P = 0.01). CONCLUSIONS: The new HMF can promote growth of preterm infants effectively without increasing the incidence of major morbidity and feeding intolerance. It can be used feasible in Chinese VPT/VLBW infants. TRIAL REGISTRATION: This study was registered on ClinicalTrials.gov (NCT04283799).

Neurodevelopmental impairment following surgical necrotizing enterocolitis with gestational age ≥ 28 weeks: who is at risk?

PURPOSE: Surgical necrotizing enterocolitis (NEC) is a severe medical condition that, even after surgery, a portion of the survival infants may still have neurological sequelae. The objective of this study was to identify the risk factors associated with the development of permanent neurodevelopmental impairment (NDI) in neonates with surgical NEC. METHODS: Between January 2016 and June 2022, a retrospective data collection was conducted on 98 individuals who experienced surgical NEC with gestational age ≥ 28 weeks. Among these patients, 27 patients were diagnosed with NDI, while the remaining 71 patients did not have NDI. Based on this division, the patients were categorized into the NDI group and the Non-NDI group. Demographics, comorbidities, and admission lab results were analyzed using univariate and logistic regression analyses. RESULTS: Of the 98 neonates following surgical NEC, 27(27.6%) developed permanent neurodevelopmental impairment (NDI). Predictors of NDI were identified through the final multivariable logistic regression analysis, which revealed that gestational age ≤ 32 weeks (p = 0.032; odds ratio [OR], 5.673), assisted mechanical ventilation after NEC onset (p = 0.047; OR, 5.299), postoperative acute kidney injury (p = 0.040; OR, 5.106), CRP day 3 after NEC onset (p = 0.049; OR, 1.037), time from presentation to surgery (p = 0.003; OR, 1.047) were significant risk factors. CONCLUSIONS: Our study identified gestational age ≤ 32 weeks, assisted mechanical ventilation after NEC onset, postoperative acute kidney injury, CRP day 3 after NEC onset, and time from presentation to surgery as significant risk factors for NDI in neonates with surgical NEC. These factors would be helpful to refine treatment modalities for better disease outcomes. We also determined the cut-off values of CRP day 3 after NEC onset and time from presentation to surgery, allowing for the individualized evaluation of NDI risk and the implementation of earlier targeted laparotomy.

Maternal body mass index and necrotizing enterocolitis: A case-control study.

INTRODUCTION: Our aim was to determine if maternal body mass index (BMI) is associated with necrotizing enterocolitis (NEC) in a large urban delivery center. METHODS: This single center retrospective case-control study included 291 infants under gestational age of 33 weeks admitted to the neonatal intensive care unit (NICU) during a 10-year period. Cases of stage 2 and 3 NEC were matched at a ratio of 2 controls (n = 194) to 1 case (n = 97). Maternal BMI was categorized as normal (≤24.9), overweight (25-29.9) and obese (≥30). Chi-square and stepwise logistic regression were used for analysis. A power analysis was performed to determine if sample size was sufficient to detect an association. RESULTS: Stepwise logistic regression demonstrated no association between NEC and maternal obesity. Maternal hypertension, pre-eclampsia, premature rupture of membranes, maternal exposure to antibiotics, placental abruption and gestational diabetes were not associated with NEC. Power analysis showed the sample size was sufficient to detect an association of NEC with maternal BMI in three groups analyzed. In this case-control study, there was an association between NEC and maternal overweight but not obesity at delivery. DISCUSSION: Our results did not show a significant association of NEC with maternal obesity. The percent of overweight and obese mothers prior to pregnancy and at delivery was significantly higher in our population than the national average and may be responsible for the limited ability to reveal any association between maternal obesity and NEC.

Economic and Clinical Impact of Using Human Milk-Derived Fortifier in Very Low Birth Weight Infants.

Background: Implementation of exclusive human milk (EHM) feeding defined as mother's own milk or donor human milk fortified with human milk-derived fortifiers can place an economic burden on institutions. Methods: Retrospective study of very low birth weight (VLBW) infants before and after the implementation of EHM feedings. Neonatal demographics and clinical outcomes including necrotizing enterocolitis, severe retinopathy of prematurity, bronchopulmonary dysplasia, late-onset sepsis, days on parenteral nutrition (PN), and length-of-stay were collected. The net cost to the institution was estimated using published data. Results: Sixty-four infants in the pre-EHM period and 57 infants in the post-EHM period were enrolled. Net product acquisition cost in 2020 and 2021 was $884,823. The EHM feeding guideline led to a reduction in the mean length of stay and mean days of PN use by 6.3 and 6.8 days per infant, respectively. This led to a cost saving of $1,813,444 ($31,815 per infant). No significant difference in incidence of short-term morbidities was observed. Combining the cost avoidance from clinical outcomes, the estimated financial impact over 2 years excluding insurance reimbursement was an estimated $ 913,840 ($16,032 per infant). Conclusion: Implementation of EHM-based feeding in VLBW infants is a cost-effective option for neonatal intensive care units that can result in reduced length of stay and days on PN without adversely impacting short-term morbidities.

Neonatal Diet Type and Associations With Adverse Feeding Outcomes in Neonates With Critical Congenital Heart Defects.

BACKGROUND: Neonates with critical congenital heart defects (CCHD neonates) experience high rates of feeding intolerance, necrotizing enterocolitis (NEC), and malnutrition. The benefits of human milk and direct chest/breastfeeding are well known, but research is limited in CCHD neonates. Therefore, the purpose of this study is to examine the impact of neonatal diet and feeding modality on the incidence of feeding intolerance, NEC, and malnutrition among a cohort of CCHD neonates. METHODS: A single-center retrospective study was conducted using electronic health record data of CCHD neonates admitted to a cardiac intensive care unit between April 2016 and April 2020. Regression models were fit to analyze associations between neonatal diet, feed modality, and adverse feeding outcomes. RESULTS: Seventy-four CCHD neonates were included. Increased days of direct chest/breastfeeding were associated with fewer signs of gastrointestinal distress ( P = .047) and bloody stools ( P = .021). Enteral feeding days of "all human milk" were associated with higher growth trajectory ( P < .001). CONCLUSIONS: Human milk and direct chest/breastfeeding may be protective against some adverse feeding outcomes for CCHD neonates. Larger, multicenter cohort studies are needed to continue investigating the effects of neonatal diet type and feeding modality on the development of adverse feeding outcomes in this unique population.

[Analysis of clinical characteristics and risk factors of postoperative complications in infants with early-onset necrotizing enterocolitis after enterostomy].

Objective: To investigate the clinical characteristics of children with early-onset necrotizing enterocolitis (NEC) undergoing enterostomy and analyze the risk factors for postoperative complications. Methods: Retrospective analysis was conducted on the clinical data (perinatal conditions, clinical characteristics, clinical outcomes, etc.) of NEC patients who underwent enterostomy at Beijing Children's Hospital from May 2016 to May 2023. The patients were divided into two groups based on the age of onset: an early-onset enterostomy group (<14 days) and a late-onset enterostomy group (≥14 days). Furthermore, the children with NEC were categorized into complication group and non-complication group based on whether there were complications after enterostomy. The differences in clinical data between these groups were analyzed, and the clinical characteristics of children with early-onset NEC and enterostomy were summarized. Multivariate logistic regression model was employed to analyze the risk factors for postoperative complications in NEC children with enterostomy. Results: A total of 68 cases were enrolled, including 43 cases in the early-onset enterostomy group [26 males and 17 females, aged (6.5±3.0) days] and 25 cases in the late-onset enterostomy group [15 males and 10 females, aged (21.0±3.0) days]. There were 28 cases (17 males and 11 females), age [M (Q1, Q3)] 9 (5, 14) days in the complication group and 33 cases (22 males and 11 females), aged of 14 (6, 21) days in the non-complication group. Compared to the late-onset enterostomy group, the early-onset enterostomy group had significantly higher rates of intraventricular hemorrhage [30.2% (13/43) vs 8.0% (2/25)], hemodynamically significant patent ductus arteriosus [37.2% (16/43) vs 12.0% (3/25)], mechanical ventilation≥72 hours after birth [39.5% (17/43) vs 16.0% (4/25)], stage Ⅲ NEC [(69.8% (30/43) vs 40.0% (10/25)], extensive NEC [27.9% (12/43) vs 8.0% (2/25)], and short-term postoperative complications [56.8% (21/37) vs 29.2% (7/24)] (all P<0.05).Multivariate logistic regression model analysis revealed that residual length of proximal small intestine was a protective factor for postoperative complications after enterostomy in NEC infants (OR=0.764, 95%CI: 0.648-0.901, P=0.001), but stage Ⅲ NEC was a risk factor (OR=1.042, 95%CI: 1.004-5.585, P=0.017). Conclusions: The incidence of postoperative complications is high, and the prognosis is poor in children with early-onset NEC enterostomy. The residual length of proximal enterostomy is a protective factor for postoperative complications of NEC enterostomy, but stage Ⅲ NEC is a risk factor.

Primary Anastomosis Versus Stoma for Surgical Necrotizing Enterocolitis in US Children's Hospitals.

INTRODUCTION: Multiple studies have documented the safety of intestinal anastomosis after resection for necrotizing enterocolitis (NEC). We sought to evaluate a large population of infants with surgical NEC and assess outcomes after primary anastomosis versus enterostomy. METHODS: The Pediatric Health Information System database was used to identify infants with Bell Stage 3 NEC who underwent an intestinal resection for acute disease between 2016 and 2021. Demographics and preoperative physiology were assessed, and nutritional, infectious, and surgical outcomes were analyzed. RESULTS: Two hundred twenty-two infants at 38 children's hospitals were included. Thirty-five (15.8%) were managed with a primary anastomosis. Among infants who underwent a resection within 10 d of their first operative intervention and survived for at least 3 d, a primary anastomosis was used in 26 (13.7%). These patients were older but had similar weight and physiological status at the time of resection as those managed with an enterostomy. The incidence of wound and infectious complications, duration of parenteral nutrition and length of stay were similar after anastomosis or enterostomy. CONCLUSIONS: In a large, geographically heterogenous population of infants with NEC, only 15.8% were managed with a primary anastomosis after intestinal resection. Survivors who underwent resection within 10 d were demographically and physiologically comparable to those who underwent enterostomy and had similar surgical outcomes. While there are clearly indications for enterostomy in some infants with NEC, these data confirm the conclusions of smaller, single-center studies that a primary anastomosis should be considered more frequently.

Early versus Late Caffeine Therapy Administration in Preterm Neonates: An Updated Systematic Review and Meta-Analysis.

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). CONCLUSION: 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.

Surgical Necrotizing Enterocolitis - Can We Predict the Need for Gastrostomy Tube Placement?

INTRODUCTION: Necrotizing enterocolitis (NEC) is a significant cause of morbidity and mortality among extremely premature infants. Approximately 50% of cases progress to surgery, frequently resulting in resection of necrotic bowel and ostomy creation. Premature neonates are at risk for bronchopulmonary dysplasia and feeding failure; surgery in these patients is higher risk. We evaluated the incidence of gastrostomy tube (GT) placement after ostomy reversal in surgical NEC to define a subset of patients who would benefit from concurrent ostomy reversal and GT placement. METHODS: A single-center retrospective study of infants with surgical NEC requiring ostomy creation between 2007 and 2021 was performed. RESULTS: Eighty patients met inclusion criteria. A GT was placed in 45/80 (56.3%), of which 3/45 (6.7%) were placed before, 20/45 (44.4%) concurrently with, and 22/45 (48.9%) after ostomy reversal. Between those who did and did not require GT placement, there were no significant differences in gestational age (27 versus 27 wk, P = 0.94) or birth weight (830 g versus 1055 g, P = 0.36). Hospital length of stay was longer in the GT group (128.2 versus 70.9 d, P < 0.0001). Time from ostomy reversal to hospital discharge was shorter when performed concurrently with GT (56 versus 77 d, P = 0.02). There were no differences in short-term or long-term GT related complications based on timing of GT placement. CONCLUSIONS: GT placement occurred in approximately 50% of patients with surgical NEC and GT may be accomplished safely at the time of ostomy reversal thus reducing the need for an additional procedure.

High risk of necrotising enterocolitis in term-born neonates with CHD delivered by caesarean section: a case-control study.

OBJECTIVE: Necrotising enterocolitis is linked with altered intestinal microbiota, and caesarean birth is associated with imbalance of newborn intestinal microbiome. We aimed to investigate the role of delivery mode (vaginal or caesarean) and gestational age in the development of necrotising enterocolitis among term-born neonates (≥ 37 weeks) with CHD. METHODS: Case-control study. We studied all newborns with CHD who underwent cardiac surgery during the neonatal (≤ 28 days of age) period, between 2007 and 2017. Totally, 60 cases of necrotising enterocolitis were matched (by year of birth and type of congenital heart lesion) with 180 controls (1:3 ratio). Multivariable conditional logistic regression was used to assess the study question. RESULTS: The overall prevalence of necrotising enterocolitis was 6.3% in term-born newborns with CHD. Neonates with a left-ventricular outflow tract lesion or single ventricle lesion accounted for 55% (n = 33) of cases. 62% (n = 37) cases were in the modified Bell's stage 2 or more for necrotising enterocolitis classification. In multivariable modelling, gestational age at birth was not associated with the development of necrotising enterocolitis [adjusted odds ratio per week increase, 95% confidence interval: 1.20 (0.90-1.60)]. Birth by caesarean delivery (compared to vaginal) was strongly associated with development of necrotising enterocolitis [adjusted odds ratio (95% confidence interval): 2.64 (1.31-5.29)]. We failed to identify an association between preoperative enteral nutrition and necrotising enterocolitis. CONCLUSION: This study showed a high risk of necrotising enterocolitis in newborns with critical CHD born via caesarean. This information is important given the high prevalence of planned birth by caesarean in newborns with CHD.