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Purpose: Weight thresholds have historically determined timing of enterostomy closure (EC) in premature neonates. Recent evidence suggests that neonates less than 2 kg (L2K) can safely undergo EC. We evaluate our single-center experience with performing EC in preterm neonates at L2K versus greater than 2 kg (G2K) at time of EC. Methods: A retrospective review of neonates who underwent EC from January 2018 to 2020 was performed. Neonates who were greater than 90 days at initial operation were excluded. Demographics, clinical characteristics including gestational age (GA) and birth weight (BW), operative reports, and outcomes were reviewed. We compared 30-day complications between neonates who underwent EC at L2K and G2K. We also compared time to full feeds (FF) and postoperative length of stay (LOS). Results: Twenty-four neonates were included: 11 L2K and 13 G2K. The median GA and BW was 25.9 weeks (IQR 2.89) and 805 g (IQR 327), respectively. The most common intraoperative diagnosis during index operation was spontaneous perforation (70%), followed by necrotizing enterocolitis (8.69%). There were no significant differences in GA, BW, or diagnosis, between the L2K versus G2K cohort. We found no difference in complication rates, time to FF (12 days versus 10 days, P =.89), or postoperative LOS (31 days versus 36.5 days, P =.76) between patients who underwent EC at L2K versus G2K, respectively. Conclusion: Although weight gain may be an important indicator of perioperative nutrition status, this study shows that weight alone should not preclude otherwise appropriate patients from undergoing EC. [ABSTRACT FROM AUTHOR]

Purpose: The primary objective was to evaluate the impact of necrotising enterocolitis (NEC) and spontaneous intestinal perforation (SIP) on mortality and neurodevelopmental outcomes at 2 years' corrected age (CA) in infants born before 32 weeks' gestation (WG). Methods: We studied neurodevelopment at 2 years' CA of infants with NEC or SIP who were born before 32 WG from the EPIPAGE-2 cohort study. The primary outcome was death or the presence of moderate-to-severe motor or sensory disability defined by moderate-to-severe cerebral palsy or hearing or visual disability. The secondary outcome was developmental delay defined by a score < 2 SDs below the mean for any of the five domains of the Ages and Stages Questionnaire. Results: At 2 years' CA, 46% of infants with SIP, 34% of infants with NEC, and 14% of control infants died or had a moderate-to-severe sensorimotor disability (p < 0.01). This difference was mainly due to an increase in in-hospital mortality in the infants with SIP or NEC. Developmental delay at 2 years' CA was more frequent for infants with SIP than controls (70.8% vs 44.0%, p = 0.02) but was similar for infants with NEC and controls (49.3% vs 44.0%, p = 0.5). On multivariate analysis, the likelihood of developmental delay was associated with SIP (adjusted odds ratio = 3.0, 95% CI 1.0–9.1) but not NEC as compared with controls. Conclusion: NEC and SIP significantly increased the risk of death or sensorimotor disability at 2 years' CA. SIP was also associated with risk of developmental delay at 2 years' CA. [ABSTRACT FROM AUTHOR]

Objective: We aimed to determine the incidence of growth failure in infants with necrotizing enterocolitis (NEC) or spontaneous intestinal perforation (SIP) and whether initial laparotomy versus peritoneal drainage (PD) impacted the likelihood of growth failure. Summary Background Data: Infants with surgical NEC and SIP have high mortality, and most have neurodevelopmental impairment and poor growth. Existing literature on growth outcomes for these infants is limited. Methods: This is a preplanned secondary study of the Necrotizing Enterocolitis Surgery Trial dataset. The primary outcome was growth failure (Z-score for weight < -2.0) at 18 to 22 months. We used logistic regression, including diagnosis and treatment, as covariates. Secondary outcomes were analyzed using the Fisher exact or Pearson χ² test for categorical variables and the Wilcoxon rank sum test or one-way ANOVA for continuous variables. Results: Among 217 survivors, 207 infants (95%) had primary outcome data. Growth failure at 18 to 22 months occurred in 24/50 (48%) of NEC infants versus 65/157 (42%) SIP (P=0.4). The mean weight-for-age Z-score at 18 to 22 months in NEC infants was -2.05±0.99 versus -1.84±1.09 SIP (P= 0.2), and the predicted mean weight-for-age Z-score SIP (Beta -0.27; 95% CI: -0.53, -0.01; P=0.041). Median declines in weight-for-age Z-score between birth and 18 to 22 months were significant in all infants but most severe (>2) in NEC infants (P=0.2). Conclusions: This first ever prospective study of growth outcomes in infants with surgical NEC or SIP demonstrates that growth failure is very common, especially in infants with NEC, and persists at 18-22 months. [ABSTRACT FROM AUTHOR]

Necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) affect 6–8% of extremely low birth weight (ELBW) infants. SIP has lower mortality than NEC, but with similar short-term morbidity in length of stay, growth failure, and supplemental oxygen requirements. Comparative long-term neurodevelopmental outcomes have not been clarified. Data were prospectively collected from 59 North American neonatal units, regarding ELBW infants (401–1000 g or 22–27 weeks gestational age) born between 2011 and 2018 and evaluated again at 16–26 months corrected age. Outcomes were collected from infants with laparotomy-confirmed NEC, laparotomy-confirmed SIP, and those without NEC or SIP. The primary outcome was severe neurodevelopmental disability. Secondary outcomes were weight <10th percentile, medical readmission, post-discharge surgery and medical support at home. Adjusted risk ratios (ARR) were calculated. Of 13,673 ELBW infants, 6391 (47%) were followed including 93 of 232 (40%) with NEC and 100 of 235 (42%) with SIP. There were no statistically significant differences in adjusted risk of any outcomes when directly comparing NEC to SIP (ARR 2.35; 95% CI 0.89, 6.26). However, infants with NEC had greater risk of severe neurodevelopmental disability (ARR 1.43; 1.09–1.86), rehospitalization (ARR 1.46; 1.17–1.82), and post-discharge surgery (ARR 1.82; 1.48–2.23) compared to infants without NEC or SIP. Infants with SIP only had greater risk of post-discharge surgery (ARR 1.64; 1.34–2.00) compared to infants without NEC or SIP. ELBW infants with NEC had significantly increased risk of severe neurodevelopmental disability and post-discharge healthcare needs, consistent with prior literature. We now know infants with SIP also have increased healthcare needs. Level II. • What is currently known about this topic? SIP has decreased risk of mortality compared to NEC, with similar short-term morbidity. NEC has increased risk of long-term morbidity. Limited data exists in SIP. • What new information is contained in this article? ELBW NEC infants had increased risk of neurodevelopmental disability and post-discharge healthcare needs. SIP infants also have increased healthcare needs. [ABSTRACT FROM AUTHOR]

AbstractBackgroundMethodsResultsConclusionNecrotizing enterocolitis (NEC) is an inflammatory and necrotizing intestinal emergency that occurs in preterm infants and low birth weight newborns; however, no specific serum biomarkers for the diagnosis of NEC has been identified so far.Serum samples were collected from healthy neonatal controls and patients with NEC newly admitted to the Children’s Hospital of Chongqing Medical University. ELISA was used to measure serum PK2 levels, and ROC curve analysis was sued to evaluate the diagnostic efficacy of PK2 and other clinical biomarkers.Serum PK2 levels in the NEC group (n = 53) were significantly lower than those in the control group (n = 18), but increased to near-normal levels after the postoperative recovery period. The NLR value of NEC group was higher than that of control group (P < 0.05). There was no significant difference in WBC and PLT count between NEC group and control group (P > 0.05). Serum CRP and PCT levels in NEC group were significantly higher than those in control group (P < 0.001 for CRP and P < 0.05 for PCT, respectively). After surgery, serum CRP, NLR and PCT levels were lower than before surgery, while serum PK2 levels were higher than before surgery (P < 0.05). The areas under the ROC curve (AUC) of PK2, PCT and CRP for the diagnosis of NEC were 0.837, 0.662 and 0.552, respectively. The AUC of PK2 combined with PCT, PK2 combined with CRP, and PK2 combined with PCT and CRP were 0.908, 0.854 and 0.981, respectively. PK2 exhibited the highest diagnostic efficacy for NEC.PK2 has higher diagnostic efficacy than PCT and CRP in the diagnosis of NEC; the combination of PK2 and PCT or CRP can significantly improve its diagnostic efficiency, especially when the three are combined at the same time. [ABSTRACT FROM AUTHOR]

Background: Necrotizing enterocolitis (NEC) is a complex disease characterized by gastrointestinal inflammation and is one of the most common gastrointestinal emergencies in neonates. Mild to moderate cases of NEC require medical treatment, whereas severe cases necessitate surgical intervention. However, evidence for surgical indications is limited and largely dependent on the surgeon's experience, leading to variability in outcomes. The primary aim of this study is to identify the risk factors for surgical intervention in neonatal NEC, which will aid in predicting the optimal timing for surgical intervention. Methods: A literature search was conducted in PubMed, Embase, and Web of Science databases for case-control studies exploring risk factors for NEC requiring surgical intervention. The search was completed on June 16, 2024, and data analysis was performed using R Studio 4.3.2. Results: 18 studies were included, comprising 1,104 cases in the surgery group and 1,686 in the medical treatment group. The meta-analysis indicated that high C-reactive protein (CRP) levels [OR = 1.42, 95% CI (1.01, 1.99)], lower gestational age [OR = 0.52, 95% CI (0.3, 0.91)], sepsis [OR = 2.94, 95% CI (1.87, 4.60)], coagulation disorder [OR = 3.45, 95% CI (1.81, 6.58)], lack of enteral feeding [OR = 3.18, 95% CI (1.37, 7.35)], and hyponatremia [OR = 1.22, 95% CI (1.07, 1.39)] are significant risk factors for surgical treatment in neonatal NEC. Conclusions: High CRP levels, coagulation disorders, sepsis, lower gestational age, lack of enteral feeding, and hyponatremia are significant risk factors for surgical intervention in neonatal NEC. These findings have potential clinical significance for predicting surgical risk. [ABSTRACT FROM AUTHOR]

Introduction: Optimal oxygen saturation targets remain unknown for extremely preterm infants. Methods: Cohort analysis of eligible preterm infants born <29 weeks’ gestation admitted between 2011 and 2018 to centers submitting data to the Canadian Neonatal Network (CNN) database. Site questionnaires to determine saturation targets, alarm settings, and date of change, allowed assignation of centers to intermediate (88–93%) or high (90–95%) saturation targets. A 6-month washout period was applied to sites which switched targets during the study period. Our primary outcome was survival free of major morbidity. Secondary outcomes were death, necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD), treated retinopathy of prematurity, and evidence of brain injury during admission. Generalized estimating equations were applied to compensate for demographic differences and site practices. Results: There were 2,739 infants in the high (mean gestational age [GA] 26 ± 1.6 weeks) and 6,813 infants in the intermediate (mean GA 26.2 ± 1.6 weeks) saturation target group. Survival without morbidity was higher in the intermediate target group (adjusted odds ratio [aOR] 1.59; 95% CI: 1.04, 2.45). There was no difference in mortality between groups (aOR 0.81; 95% CI: 0.59, 1.11), in NEC, treated retinopathy, or brain injury. On subgroup analysis, restricting data to sites which switched targets during the study, intermediate saturation targets were associated with lower rates of BPD (aOR 0.45; 95% CI: 0.28, 0.72). Conclusion: For neonates <29 weeks’ gestation, intermediate saturation target was associated with higher odds of survival without major morbidity compared to higher oxygen saturation target. [ABSTRACT FROM AUTHOR]

Necrotizing enterocolitis (NEC) is one of the most devasting diseases affecting preterm neonates. However, despite a lot of research, NEC's pathogenesis remains unclear. It is known that the pathogenesis is a multifactorial process, including (1) a pathological microbiome with abnormal bacterial colonization, (2) an immature immune system, (3) enteral feeding, (3) an impairment of microcirculation, and (4) possibly ischemia-reperfusion damage to the intestine. Overall, the immaturity of the mucosal barrier and the increased expression of Toll-like receptor 4 (TLR4) within the intestinal epithelium result in an intestinal hyperinflammation reaction. Concurrently, a deficiency in counter-regulatory mediators can be seen. The sum of these processes can ultimately result in intestinal necrosis leading to very high mortality rates of the affected neonates. In the last decade no substantial advances in the treatment of NEC have been made. Thus, NEC animal models as well as in vitro models have been employed to better understand NEC's pathogenesis on a cellular and molecular level. This review will highlight the different models currently in use to study immunological aspects of NEC. [ABSTRACT FROM AUTHOR]

We describe cases of three infants who developed acquired colonic atresia presumed secondary to significant systemic cardiovascular compromise and in the absence of necrotizing enterocolitis. An acquired colonic atresia may present as feed intolerance and should be investigated with a lower gastrointestinal contrast study. We would also recommend routine lower gastrointestinal contrast study prior to stoma closure in an infant with history of significant cardiovascular compromise, even in the absence of significant widespread colonic inflammation such as necrotizing enterocolitis. [ABSTRACT FROM AUTHOR]

Introduction: Necrotizing enterocolitis (NEC) is a severe gastrointestinal problem that predominantly affects premature babies. The aim of this retrospective study was to evaluate patients who underwent surgical treatment for NEC and newborns who initially recovered with medical treatment but later developed a stricture and required surgery. Materials and Methods: We analyzed patients diagnosed with NEC between January 2009 and December 2021. Our study included patients who developed strictures after initially receiving medical treatment for NEC and subsequently underwent surgery. Demographic findings, mother's age, gestational weeks, birth weight, type of birth, postnatal age at NEC diagnosis, pH, first C-reactive protein (CRP) after onset of symptoms, leukocytes, hemoglobin and thrombocytes at the onset of NEC, echocardiography results, age at surgery, blood values before surgery, surgery technique, and outcomes were retrospectively analyzed. Results: Out of 40 patients who underwent primary surgery for NEC during the newborn period, 6 patients underwent surgery after initially receiving medical treatment. The female-to-male ratio was 15/31, and the median gestational age was 29 weeks. The median mother's age was 30 years, and the median birth weight was 1097g. The median postnatal age at NEC onset was 6 days (range 2-39). Echocardiography was performed in 43 patients, with 6 showing normal results and 28 having congenital cardiac anomalies. The median surgery day for patients who underwent primary surgery for NEC was 19 days (range 2-90). Ileostomy was performed in 26 patients, colostomy in 8 patients, and ileostomy plus colostomy in 1 patient. Surgery was conducted in 6 out of 392 patients who developed post- NEC strictures after initial medical treatment. Comparison between post-NEC stricture patients and those who underwent surgery for NEC revealed significant differences only in the age at surgery (p=0.024). Conclusion: Patients who clinically experience NEC should be considered for the development of strictures, especially in cases of prolonged feeding intolerance, distention, gastric residual, and rectal bleeding. Therefore, close follow-up and multidisciplinary approaches are crucial, and contrast barium radiography should be the initial diagnostic step. [ABSTRACT FROM AUTHOR]

Congenital heart disease (CHD) and patent ductus arteriosus (PDA) are risk factors of necrotizing enterocolitis (NEC) in infants. However, it is unclear whether the prognosis of NEC is different between very preterm infants (VPIs) with and without heart diseases. This was an observational cohort study that enrolled VPIs (born between 24+0 and 31+6 weeks) admitted to 79 tertiary neonatal intensive care units (NICU) in the Chinese Neonatal Network (CHNN) between 2019 and 2021. The exposure was CHD or isolated PDA, and VPIs with NEC were divided into three groups: complicated with CHD, with isolated PDA, and without heart diseases. The primary outcomes were NEC-related adverse outcomes (death or extrauterine growth restriction (EUGR)). Logistic regression models were used to adjust potential confounders and calculate the odds ratios (ORs) and 95% confidential intervals (CIs) for each outcome. A total of 1335 VPIs with NEC were enrolled in this study, including 65 VPIs with CHD and 406 VPIs with isolated PDA. The VPIs with heart diseases had smaller gestational ages and lower body weights at birth, more antenatal steroids use, and requiring inotrope prior to the onset of NEC. While suffering from NEC, there was no significant increased risks in NEC-related death in VPIs with either CHD (adjusted OR [aOR]: 1.10; 95% CI: 0.41–2.50) or isolated PDA (aOR: 1.25; 95% CI 0.82–1.87), and increased risks in EUGR were identified in either survival VPIs with CHD (aOR: 2.35; 95% CI: 1.31–4.20) or isolated PDA (aOR: 1.53; 95% CI: 1.16–2.01) in survivors. The composite outcome (death or EUGR) was also more often observed in VPIs with either CHD (aOR: 2.07; 95% confidence interval [CI]: 1.20–3.60) or isolated PDA (aOR: 1.51; 95% CI: 1.17–1.94) than that without heart diseases. VPIs with either CHD or isolated PDA were associated with significantly prolonged duration of fasting, extended time to achieve full enteral feeding, and longer ventilation duration and hospitalization duration. Similar characteristics were also seen in VPIs with isolated PDA, with the exception that VPIs with CHD are more likely to undergo surgical intervention and maintain a prolonged fast after NEC. Conclusion: In VPIs with NEC, CHD and isolated PDA are associated with an increased risk in worse outcomes. We recommend that VPIs with cardiac NEC be managed with aggressive treatment and nutrition strategies to prevent EUGR. What is Known: • CHD and PDA are risk factors for NEC in infants, which can lead to adverse outcomes such as death and EUGR. • NEC in infants with heart disease differs clinically from that in infants without heart disease and should be recognized as a separate disease process. What is New: • CHD and isolated PDA are associated with increased risks of EUGR in VPIs with NEC. • Risk factors associated with VPIs with cardiac NEC suggested these patients should be managed with aggressive treatment and nutrition strategies to adverse outcomes. [ABSTRACT FROM AUTHOR]

While neonatal necrotising enterocolitis (NEC) is associated with high mortality rates in newborns, survivors can face long-term sequelae. However, the relationship between NEC and neurodevelopmental impairment (NDI) in preterm infants remains unclear. To explore the relationship between neonatal NEC and neurodevelopmental outcomes in preterm infants, we searched PubMed, EMBASE, and the Cochrane Library from their inception to February 2024 for relevant studies. Studies included were cohort or case–control studies reporting neurodevelopmental outcomes of NEC in preterm infants. Two independent investigators extracted data regarding brain damage and neurodevelopmental outcomes in these infants at a corrected age exceeding 12 months. Odds ratios (ORs) were pooled using a random effects model. We included 15 cohort studies and 18 case–control studies, encompassing 60,346 infants. Meta-analysis of unadjusted and adjusted ORs demonstrated a significant association between NEC and increased odds of NDI (OR 2.15, 95% CI 1.9–2.44; aOR 1.89, 95% CI 1.46–2.46). Regarding brain injury, pooled crude ORs indicated an association of NEC with severe intraventricular haemorrhage (IVH) (OR 1.42, 95% CI 1.06–1.92) and periventricular leucomalacia (PVL) (OR 2.55, 95% CI 1.76–3.69). When compared with conservatively treated NEC, surgical NEC potentially carries a higher risk of NDI (OR 1.78, 95% CI 1.09–2.93) and severe IVH (OR 1.57, 95% CI 1.20–2.06). However, the risk of PVL did not show a significant difference (OR 1.60, 95% CI 0.47–5.40). Conclusions: Our meta-analysis provides evidence suggesting an association between NEC and NDI. Additionally, the severity of intestinal lesions appears to correlate with a higher risk of NDI. Further high-quality studies with comprehensive adjustments for potential confounding factors are required to definitively establish whether the association with NDI is causal. What is Known: • NEC is a serious intestinal disease in the neonatal period with a high mortality rate, and surviving children may have digestive system sequelae. • Compared with non-NEC preterm infants, the reported incidences of brain injury and neurodevelopmental disorders in NEC preterm infants are not the same. What is New: • The risk of neonatal brain injury and neurodevelopmental disorders in preterm infants with NEC is higher than that in non-NEC infants, and the risk of NDI in surgical NEC infants is higher than that in the conservative treatment group. • NEC may increase the risk of motor, cognitive, language development delays, and attention deficits in children. [ABSTRACT FROM AUTHOR]

Reduction–oxidation (redox) chemistry plays a vital role in human homeostasis. These reactions play critical roles in energy generation, as part of innate immunity, and in the generation of secondary messengers with various functions such as cell cycle progression or the release of neurotransmitters. Despite this cornerstone role, if left unchecked, the body can overproduce reactive oxygen species (ROS) or reactive nitrogen species (RNS). When these overwhelm endogenous antioxidant systems, oxidative stress (OS) occurs. In neonates, OS has been associated with retinopathy of prematurity (ROP), leukomalacia, and bronchopulmonary dysplasia (BPD). Given its broad spectrum of effects, research has started to examine whether OS plays a role in necrotizing enterocolitis (NEC). In this paper, we will discuss the basics of redox chemistry and how the human body keeps these in check. We will then discuss what happens when these go awry, focusing mostly on NEC in neonates. [ABSTRACT FROM AUTHOR]

Objective Necrotizing enterocolitis (NEC) primarily affects preterm, especially small for gestational age (SGA), infants. This study was designed to (1) describe frequency and timing of NEC in SGA versus non-SGA infants and (2) assess whether NEC is independently associated with the severity of intrauterine growth failure. Study Design Retrospective cohort study of infants without severe congenital malformations born <33 weeks' gestational age (GA) carried out from 2009 to 2021. The frequency and time of NEC were compared between SGA and non-SGA infants. Multivariate logistic regression was used to assess whether NEC was independently associated with intrauterine growth restriction. Severe growth restriction was defined as birth weight Z -score < −2. Results Among 2,940 infants, the frequency of NEC was higher in SGA than in non-SGA infants (25/268 [9.3%] vs. 110/2,672 [4.1%], respectively, p < 0.001). NEC developed 2 weeks later in SGA than non-SGA infants. In multivariate analysis, the adjusted odds of NEC increased with extreme prematurity (<28 weeks' GA) and with severe but not moderate growth restriction. The adjusted odds of NEC increased with urinary tract infection or sepsis within a week prior to NEC, were lower in infants fed their mother's own milk until discharge, and did not change over five epochs. NEC was independently associated with antenatal steroid (ANS) exposure in infants with birth weight (BW) Z -score < 0. Conclusion NEC was more frequent in SGA than in non-SGA infants and developed 2 weeks later in SGA infants. NEC was independently associated with severe intrauterine growth failure and with ANS exposure in infants with BW Z -score < 0. Key Points We studied 2,940 infants <33 weeks' GA. We assessed NEC. NEC was more frequent in SGA infants. NEC occurred 2 weeks later in SGA infants. NEC was associated with severe growth restriction. [ABSTRACT FROM AUTHOR]

\nIntroduction: Providing adequate nutrition in the management of preterm infants has been challenging. The objective of this secondary analysis of data from the randomized trial comparing “less invasive surfactant therapy (LISA) with InSurE method of surfactant administration” is to demonstrate the feasibility of early total enteral feeding (ETEF) in hemodynamically stable preterm neonates on respiratory support and to examine the factors associated with failure of ETEF. Methods: Secondary analysis of a randomized controlled trial comparing “LISA versus InSurE among preterm infants between 26 and 34 weeks of gestation” enrolled 150 infants with 117 being hemodynamically stable. ETEF without any parenteral supplementation was started on day 1 of life using the mother’s own milk (MoM) or donor human milk (<32 weeks of GA) and MoM or preterm formula (33–34 weeks of GA). The data were analyzed to assess the proportion of babies developing feed intolerance and/or necrotizing enterocolitis (NEC) and factors associated with failure of ETEF. All Infants were assessed for the day of attainment of full enteral feeding defined as receiving and tolerating 150 mL/kg of enteral feeds per day. Results: Out of these 117 babies, 102 tolerated ETEF, and 15 had one or more episodes of FI requiring total parenteral nutrition, but none developed NEC till discharge or death. On the assessment of possible factors associated with ETEF failure, there were no differences in baseline characteristics but statistically significantly increased incidence of culture-positive sepsis as well as the requirement of antibiotic therapy for possible sepsis (early as well as late-onset sepsis) in babies with failure of ETEF. The babies who tolerated ETEF achieved full enteral feeding (150 mL/kg/day) significantly earlier (5.48 ± 1.1 days) compared to those with ETEF failure (7 ± 3.4 days) (p 0.001). The time to regain birth weight was earlier in the ETEF group without significant differences in growth parameters. There was also a reduction in the duration of hospital stay in babies who tolerated ETEF, but both these results were not statistically significant. Conclusion: ETEF is feasible in preterm neonates with respiratory distress syndrome who are on respiratory support. It resulted in earlier attainment of full enteral feeds and decreased the incidence of sepsis with reduced antibiotic usage. The objective of this secondary analysis of data from the randomized trial comparing less invasive surfactant therapy (LISA) with InSurE method of surfactant administration among preterm infants with respiratory distress syndrome (RDS) is to demonstrate the feasibility of ETEF in hemodynamically stable preterm neonates on respiratory support.In this randomized control trial comparing LISA versus InSurE among preterm infants with RDS between 26 and 34 weeks of gestation, 150 infants were enrolled with 117 being hemodynamically stable. In 33 patients, early total enteral feeding could not be started due to various reasons – 7 babies had absence/reversal of end-diastolic flow (A/REDF) on antenatal Doppler, 15 babies had shock and required inotropic support on day 1 of life, 8 babies had higher ventilatory settings at the time of admission, and in the 3 babies, the abdomen was not soft to start total enteral feeding. Full-volume enteral feeding without any parenteral supplementation was started on day 1 of life using the mother’s own milk (MoM) or donor human milk (≤32 weeks of GA) and MoM or preterm formula (33–34 weeks of GA). The data were analyzed to assess the proportion of babies developing feed intolerance and/or NEC and factors associated with failure of ETEF. Out of these 117 babies, 102 tolerated ETEF, and 15 had one or more episodes of FI requiring parenteral supplementation, but none developed NEC. There was a statistically significantly increased incidence of culture-positive sepsis as well as the requirement of antibiotic therapy for possible sepsis in babies with failure of ETEF. There was no difference in the morbidities noted such as intraventricular hemorrhage grade 2 or more, patent ductus arteriosus requiring medical or surgical management, retinopathy of prematurity requiring treatment, and NEC stage II or more. Our study suggests that hemodynamically stable preterm infants with RDS on respiratory support can be successfully fed with exclusive enteral feeds started immediately post-birth. ETEF results in early attainment of full feeding and reduces the incidence of sepsis and the duration of hospital stay without increasing the risk of NEC. [ABSTRACT FROM AUTHOR]

Background: Necrotizing enterocolitis (NEC) is a life-threatening disease that affects premature infants. However, the role of inflammatory biomarkers in identifying surgical/death NEC without pneumoperitoneum remains elusive. Purpose: We aimed to verify the value of platelet-to-lymphocyte ratio (PLR) and the combination of white blood cell (WBC), absolute neutrophil count (ANC), absolute lymphocyte count (ALC), neutrophil lymphocyte ratio (NLR), PLR, C reactive protein (CRP) and procalcitonin (PCT) in predicting the severity of NEC, and to construct a model to differ surgically NEC from non-surgically NEC. Methods: A retrospective analysis was performed on 191 premature infants with NEC. Based on the inclusion and exclusion criteria, 90 infants with Stage II and IIIA NEC were enrolled in this study, including surgical/death NEC (n = 38) and medical NEC (n = 52). The values of inflammatory biomarkers were collected within 24 h of onset. Results: The univariate analysis revealed that the values of WBC (p = 0.040), ANC (p = 0.048), PLR (p = 0.009), CRP (p = 0.016) and PCT (p < 0.01) in surgical/death NEC cohort were significantly higher than medical NEC cohort. Binary multivariate logistic regression analysis indicates that ANC, PLR, CRP, and PCT are capable of distinguishing infants with surgical/death NEC, and the AUC of the regression equation was 0.79 (95% CI 0.64–0.89; sensitivity 0.63; specificity 0.88), suggesting the equation has a good discrimination. Implications for practice and research: Elevated PLR is associated with severe inflammation in surgical/death NEC patients. The prediction modelling of combination of ANC, PLR, CRP and PCT can differentiate surgical/death NEC from infants with medical NEC, which may improve risk awareness and facilitate effective communication between nurses and clinicians. However, multicentre research is needed to verify these findings for better clinical management of NEC. [ABSTRACT FROM AUTHOR]

Objective The aim of the study is to determine clinical correlates of moderate to severe bronchopulmonary dysplasia (BPD) in preterm infants following surgical necrotizing enterocolitis (NEC). Study Design This is a retrospective, single-center cohort study comparing patients with moderate to severe BPD to patients with non/mild BPD among surgical NEC infants. BPD was defined by NIH 2001 consensus definition. Results Of 92 consecutive neonates with surgical NEC, 77% (71/92) had moderate/severe BPD and 22% (21/92) had non/mild BPD. The patent ductus arteriosus (PDA) was significantly higher in those developing moderate/severe BPD (67.6% [48/71]) than non/mild BPD (28.6% [6/21]; p = 0.001). Postoperatively, infants with moderate/severe BPD had more severe acute kidney injury (AKI; 67.6 [48/71] vs. 28.6% [6/21]; p = 0.001), were intubated longer (40.5 [interquartile (IQR): 12, 59] vs. 6 days [IQR: 2, 13]; p <0.001), received more parenteral nutrition (109 [IQR: 77, 147] vs. 55 days [IQR: 19, 70]; p <0.001), developed higher surgical morbidity (46.5 [33/71] vs. 14.3% [3/21]; p = 0.008), had more intestinal failure (62.5 vs. 13.3%; p <0.001), required a longer hospital stay (161 [IQR: 112, 186] vs. 64 days [IQR: 20, 91]; p <0.001), and were more likely to need home oxygen. In a multivariable analysis, lower birth weight (OR = 0.3, [95% confidence interval (CI): 0.1–0.5]; p = 0.001), PDA (OR = 10.3, [95% CI: 1.6–65.4]; p = 0.014), and longer parenteral nutritional days (OR = 8.8; [95% CI: 2.0–43.0]; p = 0.005) were significantly and independently associated with higher odds of moderate/severe versus non-/mild BPD. Conclusion Development of moderate/severe BPD occurred in the majority of preterm infants with surgical NEC in this consecutive series. Preterm infants with moderate/severe BPD were more likely to have a PDA before NEC. Development of moderate/severe BPD was associated with significantly greater burden and duration of postoperative morbidity following surgical NEC. Identifying surgical NEC infants at increased risk of moderate/severe BPD and developing lung protection strategies may improve surgical NEC outcomes. Key Points Three-fourths of preterm infants experienced severe lung injury following surgical NEC. The infants with severe moderate/severe BPD were most likely associated with greater duration of postoperative morbidity. There is need to understand and develop lung protective strategies in infants with surgical NEC. [ABSTRACT FROM AUTHOR]

Intestinal dysbiosis is believed to play a role in the development of necrotizing enterocolitis (NEC). The efficacy of JNK‐inhibitory peptide (CPJIP) in treating NEC was assessed. Treatment with CPJIP led to a notable reduction in p‐JNK expression in IEC‐6 cells and NEC mice. Following LPS stimulation, the expression of RNA and protein of claudin‐1, claudin‐3, claudin‐4 and occludin was significantly decreased, with this decrease being reversed by CPJIP administration, except for claudin‐3, which remained consistent in NEC mice. Moreover, the expression levels of the inflammatory factors TNF‐α, IL‐1β and IL‐6 were markedly elevated, a phenomenon that was effectively mitigated by the addition of CPJIP in both IEC‐6 cells and NEC mice. CPJIP administration resulted in improved survival rates, ameliorated microscopic intestinal mucosal injury, and increased the total length of the intestines and colon in NEC mice. Additionally, CPJIP treatment led to a reduction in serum concentrations of FD‐4, D‐lactate and DAO. Furthermore, our results revealed that CPJIP effectively inhibited intestinal cell apoptosis and promoted cell proliferation in the intestine. This study represents the first documentation of CPJIP's ability to enhance the expression of tight junction components, suppress inflammatory responses, and rescue intestinal cell fate by inhibiting JNK activation, ultimately mitigating intestinal severity. These findings suggest that CPJIP has the potential to serve as a promising candidate for the treatment of NEC. [ABSTRACT FROM AUTHOR]

Neonatal sepsis is a devastating inflammatory condition that remains a leading cause of morbidity and mortality. Milk fat globule-EGF-factor VIII (MFG-E8) is a glycoprotein that reduces inflammation, whereas extracellular cold-inducible RNA binding protein (eCIRP) worsens inflammation. This study aimed to determine the therapeutic potential of a novel MFG-E8-derived oligopeptide 3 (MOP3) designed to clear eCIRP and protect against inflammation, organ injury, and mortality in neonatal sepsis. C57BL6 mouse pups were injected intraperitoneally with cecal slurry (CS) and treated with MOP3 (20 μg/g) or vehicle. 10 h after injection, blood, lungs, and intestines were collected for analyses, and in a 7-day experiment, pups were monitored for differences in mortality. MOP3 treatment protected septic pups from inflammation by reducing eCIRP, IL-6, TNFα, and LDH. MOP3 reduced lung and intestinal inflammation and injury as assessed by reductions in tissue mRNA levels of inflammatory markers, histopathologic injury, and apoptosis in lung and intestines. MOP3 also significantly improved 7-day overall survival for CS-septic mouse pups compared to vehicle (75% vs. 46%, respectively). Deriving from MFG-E8 and designed to clear eCIRP, MOP3 protects against sepsis-induced inflammation, organ injury, and mortality in a preclinical model of neonatal sepsis, implicating it as an exciting potential new therapeutic. Level 1. [ABSTRACT FROM AUTHOR]

We sought to evaluate postoperative antibiotic practices in a large population of patients with necrotizing enterocolitis (NEC) and determine whether any regimens were associated with better outcomes. The Pediatric Health Information Systems (PHIS) database was queried to identify patients who underwent an intestinal resection for acute NEC between July, 2016 and June, 2021. Data regarding post-resection antibiotic therapy, cutaneous or intraabdominal infection, and fungal or antibiotic-resistant infection were collected. 130 infants at 38 children's hospitals met inclusion criteria. Postoperative antibiotics were administered for a median of 13 days. The most frequently used antibiotics were vancomycin and piperacillin/tazobactam. Antibiotic duration greater than five days was not associated with a lower incidence of infection. No antibiotic was associated with a lower incidence of any of the complications assessed, although ampicillin was associated with more infections, overall. The incidence of fungal infection and treatment with a parenteral anti-fungal medication was greater with vancomycin. No antibiotic combination was used enough to be assessed. Administration of antibiotics for more than five days after resection for NEC was not associated with better infectious outcomes and no single antibiotic demonstrated superior efficacy. Consistent with prior studies, fungal infections were more frequent with vancomycin. Retrospective database study, level 3B. II. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate whether age at introduction of solid foods in preterm infants influences growth in the first year of life. This was a prospective observational study in very low birth weight infants stratified to an early (<17 weeks corrected age) or a late (≥17 weeks corrected age) feeding group according to the individual timing of weaning. In total, 115 infants were assigned to the early group, and 82 were assigned to the late group. Mean birth weight and gestational age were comparable between groups (early: 926 g, 26 + 6 weeks; late: 881 g, 26 + 5 weeks). Mean age at weaning was 13.2 weeks corrected age in the early group and 20.4 weeks corrected age in the late group. At 12 months corrected age, anthropometric parameters showed no significant differences between groups (early vs. late, mean length 75.0 vs. 74.1 cm, weight 9.2 vs. 8.9 kg, head circumference 45.5 vs. 45.0 cm). A machine learning model showed no effect of age at weaning on length and length z-scores at 12 months corrected age. Infants with comorbidities had significantly lower anthropometric z-scores compared to infants without comorbidities. Therefore, regardless of growth considerations, we recommend weaning preterm infants according to their neurological abilities. [ABSTRACT FROM AUTHOR]

Abstract Background Necrotizing enterocolitis (NEC) is a complex disease characterized by gastrointestinal inflammation and is one of the most common gastrointestinal emergencies in neonates. Mild to moderate cases of NEC require medical treatment, whereas severe cases necessitate surgical intervention. However, evidence for surgical indications is limited and largely dependent on the surgeon’s experience, leading to variability in outcomes. The primary aim of this study is to identify the risk factors for surgical intervention in neonatal NEC, which will aid in predicting the optimal timing for surgical intervention. Methods A literature search was conducted in PubMed, Embase, and Web of Science databases for case-control studies exploring risk factors for NEC requiring surgical intervention. The search was completed on June 16, 2024, and data analysis was performed using R Studio 4.3.2. Results 18 studies were included, comprising 1,104 cases in the surgery group and 1,686 in the medical treatment group. The meta-analysis indicated that high C-reactive protein (CRP) levels [OR = 1.42, 95% CI (1.01, 1.99)], lower gestational age [OR = 0.52, 95% CI (0.3, 0.91)], sepsis [OR = 2.94, 95% CI (1.87, 4.60)], coagulation disorder [OR = 3.45, 95% CI (1.81, 6.58)], lack of enteral feeding [OR = 3.18, 95% CI (1.37, 7.35)], and hyponatremia [OR = 1.22, 95% CI (1.07, 1.39)] are significant risk factors for surgical treatment in neonatal NEC. Conclusions High CRP levels, coagulation disorders, sepsis, lower gestational age, lack of enteral feeding, and hyponatremia are significant risk factors for surgical intervention in neonatal NEC. These findings have potential clinical significance for predicting surgical risk.

BACKGROUND: Bowel ultrasound (US) is one of the methods used to enhance diagnostic accuracy of necrotizing enterocolitis (NEC) and its associated complications in premature newborns. AIM: To explore the diagnostic accuracy of bowel US in extremely low birth weight (ELBW) infants with NEC. METHODS: A single-center retrospective case-control study included 84 extremely low birth weight (ELBW) infants. The infants were divided into three groups: Group 1 –infants with NEC (n = 26); Group 2 –infants with feeding problems (n = 28); Group 3 –control group (n = 30). RESULTS: The specific bowel US findings in premature newborns with NEC (stage 3) included bowel wall thinning, complex (echogenic) ascites, and pneumoperitoneum, p < 0.05. The diagnostic effectiveness of these sonographic signs was 96.8% (sensitivity 75.0% and specificity 97.6%), p < 0.05. These findings with high specificity were associated with the need for surgical intervention, poor outcomes, or increased mortality. Stage 2 NEC which did not require surgery showed impaired differentiation of the bowel wall layers, absent or decreased bowel peristalsis, pneumatosis intestinalis, portal venous gas, or simple ascites, with a diagnostic accuracy of 82.9% (sensitivity 55.6%, specificity 91.4%, p < 0.05). CONCLUSIONS: Bowel US can be used as an adjunct to abdominal radiography to aid in the diagnosis of infants with suspected NEC by providing more detailed evaluation of the intestine. [ABSTRACT FROM AUTHOR]

Enteral feeds are often withheld from neonates with ductal dependent cardiac lesions who are receiving prostaglandins. This is despite positive benefits of enteral feeding. We describe a multicenter cohort of these neonates who were fed pre-operatively. We also give a granular description of vital sign measurements and other risk factors prior to feeding. A retrospective chart review was performed at seven centers. Inclusion criteria were full-term neonates under one month of age with ductal dependent lesions receiving prostaglandins. These neonates were fed for at least 24 h during the pre-operative period. Premature neonates were excluded. Using the inclusion criteria, 127 neonates were identified. While being fed, 20.5% of the neonates were intubated, 10.2% were on inotropes, and 55.9% had an umbilical arterial catheter in place. Median oxygen saturations in the six hours prior to feeding were 92.5% in patients with cyanotic lesions, median diastolic blood pressure was 38 mmHg and median somatic NIRS were 66.5%. The median peak daily feeding volume reached was 29 ml/kg/day (IQ range 15.5–96.8 ml/kg/day). One patient developed suspected necrotizing enterocolitis (NEC) in this cohort. Only one adverse event occurred, which was an aspiration thought to be related to feeding, but did not result in intubation or cessation of feeds. NEC was rare among neonates with ductal dependent lesions while receiving enteral nutrition pre-operatively. Umbilical arterial catheters were in place in the majority of these patients. Hemodynamic measures demonstrated a high median oxygen saturation prior to initiation of feeds. [ABSTRACT FROM AUTHOR]

Background: Necrotizing enterocolitis (NEC) is common in preterm infants, especially infants less than 32 weeks gestation. Mortality from NEC is 7% and occurs in 1 out of 1000 preterm infants. Studies have shown the efficacy of an exclusive milk from mother diet in decreasing rates of NEC and associated mortality. Purpose: To evaluate the effectiveness of an existing exclusive human milk diet (EHMD) protocol on the incidence of NEC in extremely premature infants. EHMD, for the purposes of this project is defined as breast milk of mother, with or without human milk-based fortifier. Methods: A single-center retrospective quasi-experimental study. The sample included 201 infants born less than 32 weeks gestation, weighing less than 1250 grams, small for gestational age (SGA) and with low Apgar scores. Outcomes measured included incidences of NEC, mortality, and co-morbidities in infants pre- and postinitiation of an EHMD protocol. Results: Just 4.8% of the EHMD group had a NEC diagnosis compared to 10.5% of the bovine-based (BOV) group. There was a 1% mortality rate of the EHMD group as compared to 6% in the BOV group. The EHMD group had a statistically significant greater weight gain during hospitalization as compared to infants fed BOV (P = < .05). Implications for Practice and Research: Neonatal intensive care units should consider EHMDs for use in this infant population. Future research is needed to support dissemination of the use of EHMD as standard of practice. [ABSTRACT FROM AUTHOR]

Yunhan Zhang,1,&ast; Yuyun Chen,2,&ast; Jilin Lv,1 Xiao Xiang,1 Peiyao Wang,1 Wei Feng,1 Zhenhua Guo1 1Department of Neonatal Surgery, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development, Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, People’s Republic of China; 2Fujian Children’s Hospital, Fujian Branch of Shanghai Children’s Medical Center, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, People’s Republic of China&ast;These authors have contributed equally to this workCorrespondence: Zhenhua Guo, Department of neonatal surgery, Children’s Hospital of Chongqing Medical University, 20 Jinyu Road, Yubei District, Chongqing, 400025, People’s Republic of China, Tel +86-23-68370286, Email zhguo@cqmu.edu.cnBackground: This study aims to investigate the potential significance of mean platelet volume (MPV) and platelet distribution width (PDW) in predicting surgical neonatal necrotizing enterocolitis (NEC) and establish the correlation between MPV/PDW levels and the severity/prognosis of NEC.Methods: A retrospective study was conducted on a cohort of 372 patients diagnosed with NEC. The patients were categorized into two groups based on whether they underwent surgical therapy. Univariate /multivariate analysis were employed to compare the MPV and PDW between the two groups. Moreover, patients in surgical group were categorized into multiple subgroups based on intraoperative findings and postoperative prognosis, and the levels of MPV and PDW were compared among these subgroups.Results: Of the 372 patients, the operative group exhibited significantly higher levels of MPV and PDW than the nonoperative group (P < 0.05). Logistic regression analysis revealed that MPV (OR = 4.895, P < 0.001) and PDW (OR = 1.476, P < 0.001) independently associated with surgical NEC. The analysis of the receiver operating characteristic (ROC) curve revealed that the area under the curve (AUC) was 0.706 for MPV alone, with a cut-off value of 11.8 fL. Similarly, the AUC was 0.728 for PDW alone, with a cut-off value of 16%. However, when MPV and PDW were combined, the AUC increased to 0.906 for predicting surgical NEC. In accordance with the intraoperative findings, the levels of MPV and PDW were found to be higher in the large area necrosis group than in the partial or mild necrosis group (P < 0.01). Furthermore, the MPV and PDW values in the death group were significantly greater than those in the survival group (P =0.040, P =0.008).Conclusion: MPV and PDW may serve as potentially valuable indicators for determining the need for surgical intervention and predicting the prognosis of patients with NEC.Keywords: mean platelet volume, platelet distribution width, necrotizing enterocolitis, neonatal

Abstract Background Necrotizing enterocolitis (NEC) and intracranial hemorrhage are severe emergencies in the neonatal period. The two do not appear to be correlated. However, our report suggests that parenchymal brain hemorrhage in full-term newborns may put patients at risk for NEC by altering intestinal function through the brain-gut axis. Case presentation We present a case of spontaneous parenchymal cerebral hemorrhage in a full-term newborn who developed early-stage NEC on Day 15. Conclusions It is possible to consider brain parenchymal hemorrhage as a risk factor for the appearance of NEC. Clinicians should be highly cautious about NEC in infants who have experienced parenchymal hemorrhage. This article is the first to discuss the relationship between parenchymal hemorrhage and NEC in full-term newborns.

A severe condition of sepsis can be a complication of necrotizing enterocolitis (NEC), which can occur in premature infants and becomes a medical challenge in the neonatal intensive care unit (NICU). It is a multifactorial intestinal disease (can affect both the small and large intestine) that can lead to ischemia of the intestinal tissues that evolves into acute organ necrosis. One of these factors is that different types of nutrition can influence the onset or the progression of the disease. Cow-milk-based infant formulas have been shown to cause it in premature infants more frequently than human milk. Recently, nutrition has been shown to be beneficial after surgery. Several issues still under study, such as the pathogenesis and the insufficient and often difficult therapeutic approach, as well as the lack of a common and effective prevention strategy, make this disease an enigma in daily clinical practice. Recent studies outlined the emerging role of the host immune system and resident gut microbiota, showing their close connection in NEC pathophysiology. In its initial stages, broad-spectrum antibiotics, bowel rest, and breastfeeding are currently used, as well as probiotics to help the development of the intestinal microbiota and its eubiosis. This paper aims to present the current knowledge and potential fields of research in NEC pathophysiology and therapeutic assessment.

Abstract Background Investigating the trend of changes in the occurrence of necrotizing enterocolitis (NEC) in preterm infants during 9 years and analyzing the risk factors of NEC with the purpose of providing reference for clinical diagnosis and treatment of NEC. Methods Clinical data of NEC in preterm infants with Bell’s stage ≥ II from January 2013 to December 2021 in the Neonatology Department of the Third Affiliated Hospital of Zunyi Medical University was retrospectively analyzed. Trends in the occurrence of NEC in preterm infants were analyzed by the trend chi-square test. Subsequently, the general data (sex, gestational age, singleton or multiple births, birth weight, serum albumin, alkaline phosphatase, sepsis, blood transfusion, mechanical ventilation, RDS, arterial catheterization) and perinatal data (intrauterine distress, turbid amniotic fluid, premature rupture of membranes, mode of delivery, fetal heart abnormalities, diabetes mellitus) were collected; then, the risk factors for NEC were analyzed by univariate and multivariate logistic-regression analysis. Results In the past 9 years, 77 cases of NEC occurred, with the incidence rate of 1.95%, and the incidence of NEC in preterm infants has been increasing year by year (P

Abstract The practice of routine gastric residual aspiration in preterm infants remains controversial, with conflicting evidence regarding its impact on necrotizing enterocolitis (NEC). As front-line caregivers, nurses play a vital role in gastric aspiration procedures and must be informed by evidence. This quasi-experimental nursing study aimed to assess whether gastric aspiration is clinically relevant in reducing the risk of NEC in preterm infants. A total of 250 preterm infants from two NICUs in Egypt were allocated to the gastric aspiration (n = 125) and non-aspiration (n = 125) groups. Feeding practices, gastric residuals, and incidence/severity of NEC were compared between groups according to modified Bell’s criteria. Risk factors were analyzed using multivariate regression. There were no significant baseline differences between the groups. The gastric residual attributes and feeding outcomes did not differ substantially from aspiration. The overall incidence of NEC was 14–15%, with no significant differences in the odds of onset or progression of NEC by stage between the groups. Lower gestational age and birth weight emerged as stronger predictors of NEC. Routine gastric aspiration does not appear to directly prevent or reduce the severity of NEC in this population. Although gastric residuals retain clinical importance, study findings question assumptions that aspiration protects against NEC and informs nursing practice. Evidence-based feeding protocols must continually evolve through ongoing research on modifiable risk factors for this devastating intestinal disease in preterm infants.

Abstract 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