Necrotising enterocolitis in a middle-income country: Early onset and risk factors for mortality.

AIM: There is limited literature available about necrotising enterocolitis (NEC) in low- and middle-income countries. This study sought to determine the proportion, pattern and risk factors for mortality among very low birth weight (VLBW) neonates with NEC in a middle-income setting. METHODS: A retrospective observational cohort study was conducted on all infants with birth weights less than 1501 g admitted from 2018 to 2020 at Groote Schuur Hospital, Cape Town, South Africa. Data were obtained from the Vermont Oxford Network and hospital folders. RESULTS: A total of 104/1582 (6.6%) neonates were diagnosed with NEC with a median onset of 8 days of life. The mortality rate was 39.0%, compared to the all-cause mortality rate of 18.7% for VLBW neonates. Thirty-two (32.0%) neonates with NEC were transferred for surgery of whom 10 (31.3%) died. Small for gestational age (p = 0.13), NEC stage 2B or above (p = 0,002), a positive blood culture (p = 0.018), a raised C-reactive protein (p = 0.013), hyponatraemia (p = 0.004), anaemia requiring blood transfusion (p = 0.003) and thrombocytopenia requiring platelet transfusion (p = 0.033) were associated with mortality. A positive blood culture was found in 37.0% with a predominance of Klebsiella pneumoniae isolates. CONCLUSION: NEC has an early onset and a high mortality rate in our setting.

Intestinal Oxygenation and Survival After Surgery for Necrotizing Enterocolitis: An Observational Cohort Study.

OBJECTIVE: To assess whether regional intestinal oxygen saturation (rintSO2) and regional cerebral oxygen saturation (rcSO2) measurements aid in estimating survival of preterm infants after surgery for NEC. SUMMARY OF BACKGROUND DATA: Predicting survival after surgery for NEC is difficult yet of the utmost importance for counseling parents. METHODS: We retrospectively studied prospectively collected data of preterm infants with surgical NEC who had available rintSO2 and rcSO2 values measured via near-infrared spectroscopy 0-24 hours preoperatively. We calculated mean rintSO2 and rcSO2 for 60-120 minutes for each infant. We analyzed whether preoperative rintSO2 and rcSO2 differed between survivors and non-survivors, determined cut-off points, and assessed the added value to clinical variables. RESULTS: We included 22 infants, median gestational age 26.9 weeks [interquartile range (IQR): 26.3-28.4], median birth weight 1088 g [IQR: 730-1178]. Eleven infants died postoperatively. Preoperative rintSO2, but not rcSO2, was higher in survivors than in non-survivors [median: 63% (IQR: 42-68) vs 29% (IQR: 21-43), P < 0.01), with odds ratio for survival 4.1 (95% confidence interval, 1.2-13.9, P = 0.02) per 10% higher rintSO2. All infants with rintSO2 values of >53% survived, whereas all infants with rintSO2 <35% died. Median C-reactive protein [138 mg/L (IQR: 83-179) vs 73 mg/L (IQR: 12-98), P < 0.01), lactate [1.1 mmol/L (IQR: 1.0-1.6) vs 4.6 mmol/L (IQR: 2.8-8.0), P < 0.01], and fraction of inspired oxygen [25% (IQR: 21-31) vs 42% (IQR: 30-80), P < 0.01] differed between survivors and non-survivors. Only rintSO2 remained significant in the multiple regression model. CONCLUSIONS: Measuring rintSO2, but not rcSO2, seems of added value to clinical variables in estimating survival of preterm infants after surgery for NEC. This may help clinicians in deciding whether surgery is feasible and to better counsel parents about their infants' chances of survival.

Initial Laparotomy Versus Peritoneal Drainage in Extremely Low Birthweight Infants With Surgical Necrotizing Enterocolitis or Isolated Intestinal Perforation: A Multicenter Randomized Clinical Trial.

OBJECTIVE: The aim of this study was to determine which initial surgical treatment results in the lowest rate of death or neurodevelopmental impairment (NDI) in premature infants with necrotizing enterocolitis (NEC) or isolated intestinal perforation (IP). SUMMARY BACKGROUND DATA: The impact of initial laparotomy versus peritoneal drainage for NEC or IP on the rate of death or NDI in extremely low birth weight infants is unknown. METHODS: We conducted the largest feasible randomized trial in 20 US centers, comparing initial laparotomy versus peritoneal drainage. The primary outcome was a composite of death or NDI at 18 to 22 months corrected age, analyzed using prespecified frequentist and Bayesian approaches. RESULTS: Of 992 eligible infants, 310 were randomized and 96% had primary outcome assessed. Death or NDI occurred in 69% of infants in the laparotomy group versus 70% with drainage [adjusted relative risk (aRR) 1.0; 95% confidence interval (CI): 0.87-1.14]. A preplanned analysis identified an interaction between preoperative diagnosis and treatment group (P = 0.03). With a preoperative diagnosis of NEC, death or NDI occurred in 69% after laparotomy versus 85% with drainage (aRR 0.81; 95% CI: 0.64-1.04). The Bayesian posterior probability that laparotomy was beneficial (risk difference <0) for a preoperative diagnosis of NEC was 97%. For preoperative diagnosis of IP, death or NDI occurred in 69% after laparotomy versus 63% with drainage (aRR, 1.11; 95% CI: 0.95-1.31); Bayesian probability of benefit with laparotomy = 18%. CONCLUSIONS: There was no overall difference in death or NDI rates at 18 to 22 months corrected age between initial laparotomy versus drainage. However, the preoperative diagnosis of NEC or IP modified the impact of initial treatment.

Severe acute kidney injury in neonates with necrotizing enterocolitis: risk factors and outcomes.

BACKGROUND: To study the risk factors and outcomes of severe acute kidney injury (AKI) in neonates with necrotizing enterocolitis. METHODS: Retrospective chart review of 202 neonates with necrotizing enterocolitis (NEC) (Bell stage >IIa) from 2013 to 2018. AKI was defined as per-modified neonatal Kidney Disease: Improving Global Outcomes criteria. Demographic, clinical, and outcome data were compared between neonates without severe AKI (stage 0 and 1 AKI) and those with severe AKI (stage 2 and 3 AKI). RESULTS: Severe AKI occurred in 66/202 (32.6%) of neonates after NEC diagnosis and after 61/104 (58.7%) of surgical NEC diagnoses. On adjusted model, surgical NEC [adjusted odds ratio (aOR) = 30.6; 95% confidence interval (CI) = 8.9, 130.6], outborn [aOR = 3.9; 95% CI = 1.54, 11.0], exposure to antenatal steroids [aOR = 3.0; 95% CI = 1.1, 8.9], and positive blood culture sepsis [aOR = 3.5; 95% CI = 1.3, 10.0] had increased odds for severe AKI. Those with severe AKI required longer hospitalization [124 days (interquartile range (IQR) 88-187) vs. 82 days (IQR 42-126), p < 0.001]. CONCLUSIONS: Severe AKI is common in neonates with NEC who require surgical intervention, are outborn, have positive blood culture sepsis, and receive antenatal steroids. Severe AKI is associated with a significantly longer length of hospitalization. IMPACT: Neonates with NEC, who are transferred from outside hospitals, require surgical NEC management, and/or have a positive blood culture at NEC onset are at the highest odds for severe (stages 2 and 3) AKI. Assessment of urine output is important for patients with NEC. Without it, 11% of those with severe AKI would have been misdiagnosed using serum creatinine alone. Kidney-protective strategies in the pre-, peri-, and postoperative period may improve the morbidity and mortality associated with severe AKI in neonates with NEC.

Incomplete resection of necrotic bowel may increase mortality in infants with necrotizing enterocolitis.

BACKGROUND: Infants with advanced necrotizing enterocolitis (NEC) often need surgical resection of necrotic bowel. We hypothesized that incomplete resection of NEC lesions, signified by the detection of necrotic patches in margins of resected bowel loops, results in inferior clinical outcomes. METHODS: We reviewed the medical records of infants with surgical NEC in the past 15 years for demographic, clinical, and histopathological data. We also developed statistical models to predict mortality and hospital stay. RESULTS: Ninety infants with surgical NEC had a mean (±standard error) gestational age of 27.3 ± 0.4 weeks, birth weight 1008 ± 48 g, NEC onset at 25.2 ± 2.4 days, and resected bowel length of 29.2 ± 3.2 cm. Seventeen (18.9%) infants who had complete resection of the necrosed bowel had fewer (4; 23.5%) deaths and shorter lengths of hospital stay. In contrast, a group of 73 infants with some necrosis within the margins of resected bowel had significantly more (34; 46.6%) deaths and longer hospital stay. The combination of clinical and histopathological data gave better regression models for mortality and hospital stay. CONCLUSION: In surgical NEC, incomplete resection of necrotic bowel increased mortality and the duration of hospitalization. Regression models combining clinical and histopathological data were more accurate for mortality and the length of hospital stay. IMPACT: In infants with surgical NEC, complete resection of necrotic bowel reduced mortality and hospital stay. Regression models combining clinical and histopathological information were superior at predicting mortality and hospital stay than simpler models focusing on either of these two sets of data alone. Prediction of mortality improved with the combination of antenatal steroids, chorioamnionitis, and duration of post-operative ileus, with severity of inflammation and hemorrhages in resected intestine. Length of hospital stay was shorter in infants with higher gestational ages, but longer in those with greater depth of necrosis or needing prolonged parenteral nutrition or supervised feedings.

Association of High-Mobility Group Box 1 (HMGB1) Gene Polymorphisms with Susceptibility and Better Survival Prognosis in Chinese Han Neonatal Necrotizing Enterocolitis.

BACKGROUND High-mobility group box 1 (HMGB1) plays a crucial role in a variety of diseases, including neonatal necrotizing enterocolitis (NEC). The purpose of this study was to investigate the association of HMGB1 gene single-nucleotide polymorphisms (SNPs) with susceptibility and survival prognosis in Chinese Han neonates with NEC. MATERIAL AND METHODS The HMGB1 gene rs1360485, rs1045411, and rs2249825 site SNPs were genotyped in all participants. The mRNA expression of serum HMGB1 was examined using quantitative reverse transcription-polymerase chain reaction. The correlation of the HMGB1 rs1360485 SNP with NEC neonatal survival prognosis was evaluated by univariate analysis and logistic multivariate regression analysis. RESULTS The TC and CC genotype and C allele distribution frequencies of the rs1360485 SNP were lower in the NEC group, and the differences were statistically significant (all P<0.05). Individuals carrying the TC and CC genotype or C allele had a low risk of being affected by NEC. However, the genotype and allele distributions of rs1045411 and rs2249825 were not significantly different between the patient and control groups (P>0.05). NEC neonates with HMGB1 gene rs1360485 site mutations had lower mRNA levels of serum HMGB1 than those with rs1360485 site wild-type, and the rs1360485 genotypes TC and CC could independently predict better survival outcomes in NEC neonates. CONCLUSIONS This study demonstrated that the rs1360485 SNP of the HMGB1 gene is associated with susceptibility of NEC in neonates, and the rs1360485 genotypes TC and CC may affect HMGB1 expression and are associated with the survival prognosis of neonates with NEC.

Mortality and Morbidities according to Time of Birth in Extremely Low Birth Weight Infants.

BACKGROUND: Although the overall quality of high-risk neonatal care has improved recently, there is still concern about a difference in the quality of care when comparing off-hour births and regular-hour births. Moreover, there are no data in Korea regarding the impact of time of birth on mortality and morbidities in preterm infants. METHODS: A total of 3,220 infants weighing < 1,000 g and born at 23-34 weeks in 2013-2017 were analyzed based on the Korean Neonatal Network data. Mortality and major morbidities were analyzed using logistic regression according to time of birth during off-hours (nighttime, weekend, and holiday) and regular hours. The institutes were sub-grouped into hospital group I and hospital group II based on the neonatal intensive care unit (NICU) care level defined by the mortality rates of < 50% and ≥ 50%, respectively, in infants born at 23-24 weeks' gestation. RESULTS: The number of births during regular hours and off-hours was similar. In the total population and hospital group I, off-hour births were not associated with increased neonatal mortality and morbidities. However, in hospital group II, increased early mortality was found in the off-hour births when compared to regular-hour births. CONCLUSION: Efforts to improve the overall quality of NICU are required to lower the early mortality rate in off-hour births. Also, other sensitive indexes for the evaluation of quality of NICU care should be further studied.

Quality Improvement Efforts Reduce Incidence of Surgical Necrotizing Enterocolitis and Related Deaths.

OBJECTIVE: The aim of this study was to determine whether a regional quality improvement (QI) initiative decreased incidence and severity of surgical necrotizing enterocolitis (NEC) in very low birth weight (VLBW) infants. STUDY DESIGN: A retrospective review of all VLBW infants who received care at one of the three hospitals involved in a NEC QI initiative from 2011 to 2016. Primary outcome was the number of surgical NEC cases per year. Secondary outcomes included associated outcomes and mortality. RESULTS: Sixty-three infants with either a diagnosis of Stage III NEC (n = 40) or spontaneous intestinal perforation (SIP) (n = 23) were included. The incidence of medical and surgical NEC and the mortality rate of infants with surgical NEC decreased over time. Incidence and mortality of SIP did not significantly change. CONCLUSION: A regional QI bundle to reduce the overall incidence of NEC also significantly decreased the incidence of surgical NEC and all-cause mortality of infants diagnosed with surgical NEC. KEY POINTS: · QI reduces surgical necrotizing enterocolitis.. · Reduction in NEC rate improves mortality.. · Human milk does not change SIP incidence..

Neonatal surgical outcomes: a prospective observational study at a Tertiary Academic Hospital in Johannesburg, South Africa.

PURPOSE: The neonatal period is the most vulnerable period for a child. There is a paucity of data on the burden of neonatal surgical disease in our setting. The aim of this study was to describe the frequency with which index neonatal surgical conditions are seen within our setting and to document the 30-day outcome of these patients. METHODS: This was a single-centre prospective observational study in which all neonates with paediatric surgical pathology referred to the paediatric surgical unit with a corrected gestational age of 28 days were included. RESULTS: Necrotising enterocolitis was the most frequent reason for referral to the paediatric surgical unit (n = 68, 34.34%). Gastroschisis was the most frequent congenital anomaly referred (n = 20, 10.10%). The overall morbidity was 57.58%. Surgical complications contributed to 18.51% of morbidities. The development of gram negative nosocomial sepsis was the most frequent cause of morbidity (n = 98, 50.78%). Mortality at 30 days was 21.74% (n = 40). Sepsis contributed to mortality in 35 patients (87.5%), 16 of which had gram negative sepsis. CONCLUSION: Gram-negative sepsis was a major contributing factor in the development of morbidity and mortality in our cohort. Prevention and improvement in infection control are imperative if we are to improve outcomes in our surgical neonates.

C-reactive protein/albumin ratio is a prognostic indicator for predicting surgical intervention and mortality in neonates with necrotizing enterocolitis.

PURPOSE: The role of hypoalbuminemia and raised C-reactive protein (CRP) levels in predicting critical prognosis has been described extensively in adult literature. However, there are limited studies in pediatrics, particularly neonates. The CRP/albumin (CRP/ALB) ratio is often associated with higher mortality, organ failure and prolonged hospital stay. We hypothesized that the serum CRP/ALB ratio has a prognostic value in predicting surgery and mortality in neonates with necrotizing enterocolitis (NEC). METHODS: Retrospective review of all neonates with clinical and radiological evidence of non-perforated NEC that were treated in a tertiary-level referral hospital between 2009 and 2018. General patient demographics, laboratory parameters and outcomes were recorded. Receiver operating characteristics analysis was performed to evaluated optimal cut-offs and area under the curve (AUC) with 95% confidence intervals (CI). RESULTS: A total of 191 neonates were identified. Of these, 103 (53.9%) were born at ≤ 28 weeks of gestation and 101 (52.9%) had a birth weight of ≤ 1000 g. Eighty-four (44.0%) patients underwent surgical intervention for NEC. The overall survival rate was 161/191 (84.3%). A CRP/ALB ratio of ≥ 3 on day 2 of NEC diagnosis was associated with a statistically significant higher likelihood for surgery [AUC 0.71 (95% CI 0.63-0.79); p < 0.0001] and mortality [AUC 0.66 (95% CI 0.54-0.77); p = 0.0150], respectively. CONCLUSIONS: A CRP/ALB ratio of ≥ 3 on day 2 is indicative of a critical pathway in neonates with radiologically confirmed, non-perforated NEC. This could be used as an additional criterion to guide parental counselling in NEC for surgical intervention and mortality.

The effect of daily probiotics on the incidence and severity of necrotizing enterocolitis in infants with very low birth weight.

BACKGROUND: Necrotizing enterocolitis remains a leading cause of morbidity and mortality in premature infants. The role of prophylactic probiotics in its prevention is unclear. This study evaluates the effect of routine probiotics on the incidence and severity of necrotizing enterocolitis in infants with very low birth weight in the neonatal intensive care unit. METHODS: This retrospective cohort study compared infants cared for at a single institution before and after implementation of routine probiotic administration (2014- 2018). Babies born after July 2016 received probiotics containing Bifidobacterium and Lactobacillus daily until 35 weeks corrected gestational age. Baseline characteristics, necrotizing enterocolitis incidence and severity, infections, mortality, and length of stay were compared between groups. RESULTS: Of the 665 infants included in the study, 310 received probiotics and 355 did not. The 2 groups did not differ with regard to gestational age, birth anthropometrics, mode of delivery, comorbidities, and type of enteral feed. The incidence of necrotizing enterocolitis (Bell's stage 2 of 3) was similar between groups (4% v. 5%, p = 0.35), as was its severity (p = 0.10). In addition, there were no significant differences in mortality and length of stay between the groups. Significantly fewer infants receiving probiotics developed infections (27% v. 34%, p = 0.046), with the rate of urinary tract infections having the largest reduction. CONCLUSION: The routine use of Bifidobacterium and Lactobacillus probiotics in infants with very low birth weight did not significantly affect the incidence and severity of necrotizing enterocolitis. However, the use of probiotics was associated with fewer overall infections.

Contemporary Outcomes for Infants with Necrotizing Enterocolitis-A Systematic Review.

OBJECTIVE: To develop an accurate understanding of outcomes for necrotizing enterocolitis (NEC) to inform parental counseling, clinical care, and research agendas. STUDY DESIGN: A systematic review of recent (January 2010-January 2018) large cohort studies reporting outcomes of infants who developed NEC. Only studies reporting national, regional, or multicenter outcomes of NEC in high income countries were included. Outcomes assessed were mortality, neurodevelopmental outcome, and intestinal failure. Meta-analyses were used to generate summary statistics for these outcomes. RESULTS: Of 1375 abstracts, 38 articles were included. Overall mortality was 23.5% in all neonates with confirmed NEC (Bell stage 2a+) (95% CI 18.5%-28.8%), 34.5% (30.1%-39.2%) for neonates that underwent surgery for NEC, 40.5% (37.2%-43.8%) for extremely low birthweight infants (<1000 g), and 50.9% (38.1%-63.5%) for extremely low birthweight infants with surgical NEC. Studies examining causes of neonatal mortality showed NEC is responsible for around 1 in 10 of all neonatal deaths. Neurodevelopmental disability was reported in 4 studies at between 24.8% and 61.1% (1209 total NEC cases). Three studies reported intestinal failure with an incidence of 15.2%-35.0% (n = 1370). The main limitation of this review is the lack of an agreed definition for diagnosing NEC and the differences in the way that outcomes are reported. CONCLUSIONS: Mortality following NEC remains high. These contemporary data inform clinical care and justify ongoing research efforts. All infants with NEC should have long-term neurodevelopmental assessment. Data on the long-term risk of intestinal failure are limited. TRIAL REGISTRATION: CRD42018094791.

Trends in Perinatal Practices and Neonatal Outcomes of Very Low Birth Weight Infants during a 16-year Period at NEOCOSUR Centers.

OBJECTIVE: To describe trends in mortality, major morbidity, and perinatal care practices of very low birth weight infants born at NEOCOSUR Neonatal Network centers from January 1, 2001, through December 31, 2016. STUDY DESIGN: A retrospective analysis of prospectively collected data from all inborn infants with a birthweight of 500-1500 g and 23-35 weeks of gestation. RESULTS: We examined data for 13 987 very low birth weight infants with a mean birth weight of 1081 ± 281 g and a gestational age of 28.8 ± 2.9 weeks. Overall mortality was 26.8% without significant changes throughout the study period. Decreases in early onset sepsis from 6.3% to 2.8% (P <.001), late onset sepsis from 21.1% to 19.5% (P = .002), retinopathy of prematurity from 21.3% to 13.8% (P <.001), and hydrocephalus from 3.8% to 2.4% (P <.001), were observed. The incidence for bronchopulmonary dysplasia decreased from 17.3% to 16% (P = .043), incidence of severe intraventricular hemorrhage was 10.4%, necrotizing enterocolitis 11.1%, and periventricular leukomalacia 3.8%, and did not change over the study period. Administration of antenatal corticosteroids increased from 70.2% to 82.3% and cesarean delivery from 65.9% to 75.4% (P <.001). The use of conventional mechanical ventilation decreased from 67.7% to 63.9% (P <.001) and continuous positive airway pressure use increased from 41.3% to 64.3% (P <.001). Survival without major morbidity increased from 37.4% to 44.5% over the study period (P <.001). CONCLUSIONS: Progress in perinatal and neonatal care at network centers was associated with an improvement in survival without major morbidity of very low birth weight infants during a 16-year period. However, overall mortality remained unchanged.

Mixed probiotics decrease the incidence of stage II-III necrotizing enterocolitis and death: A systematic review and meta-analysis.

BACKGROUND: Necrotizing enterocolitis (NEC) is a major cause of morbidity and mortality in premature infants. In order to evaluate the efficacy of probiotics in the prevention of stage II-III NEC, we performed a meta-analysis of clinical studies. METHODS: We searched in PubMed, Medline and Embase from 1 January 1990 to 16 January 2018. Heterogeneity was examined by Q-test. Publication bias was evaluated by funnel plot and Egger's regression test. RESULTS: 30 articles were identified meeting the inclusion criteria. Data showed that probiotics supplement could significantly reduce the risk of stage II-III NEC (RR = 0.51, 95% CI, 0.38 to 0.67, P < 0.001) and death rate (RR = 0.69, 95% CI, 0.55 to 0.87, P = 0.002). The mixed probiotics and lactobacillus could reduce the risk of stage II-III NEC (for mixed probiotics, RR = 0.39, 95% CI, 0.26 to 0.57; for lactobacillus, RR = 0.53, 95% CI, 0.36 to 0.78), while bifidobacterium or saccharomyces did not have such effect. The results also indicated that only the mixed probiotics could reduce the risk of deaths (RR = 0.52, 95%CI, 0.34 to 0.80). Subgroup analysis for mortality revealed that probiotics had significant effect in Asian region (RR = 0.54, 95% CI, 0.37 to 0.80, P = 0.002) but not in non-Asian region (RR = 0.84, 95% CI, 0.66 to 1.08, P = 0.179). CONCLUSIONS: Probiotics could significantly decrease the risk of stage II-III NEC and death. Compared to using single probiotics species, the application of combining different probiotics has a better efficacy in the prevention of stage II-III NEC and death, especially in the Asian population.

ELBW infants receive inadvertent sodium load above the recommended intake.

BACKGROUND: To determine total sodium load, including inadvertent load, during the first 2 postnatal weeks, and its influence on serum sodium, morbidity, and mortality in extremely low birth weight (ELBW, birth weight <1000 g) infants and to calculate sodium replacement models. METHODS: Retrospective data analysis on ELBW infants with a gestational age <28 + 0/7 weeks. RESULTS: Ninety patients with a median birth weight of 718 g and a median gestational age of 24 + 6/7 weeks were included. Median sodium intake during the first 2 postnatal weeks was 10.2 mmol/kg/day, which was significantly higher than recommended (2-5 mmol/kg/day). Sodium intake did not affect the risk for hypernatremia. Each mmol of sodium intake during the first postnatal week was associated with an increased risk of bronchopulmonary dysplasia (45%) and higher-grade intraventricular hemorrhage (31%), during the second postnatal week for necrotizing enterocolitis (19%), and during both postnatal weeks of mortality (13%). Calculations of two sodium replacement models resulted in a decrease in sodium intake during the first postnatal week of 3.2 and 4.0 mmol/kg/day, respectively. CONCLUSIONS: Sodium load during the first 2 postnatal weeks of ELBW infants was significantly higher than recommended owing to inadvertent sodium intake and was associated with a higher risk of subsequent morbidity and mortality, although the study design does not allow conclusions on causality. Replacement of 0.9% saline with alternative carrier solutions might reduce sodium intake. IMPACT: Sodium intake in ELBW infants during the first 2 postnatal weeks was twofold to threefold higher than recommended; this was mainly caused by inadvertent sodium components. High sodium intake is not related to severe hypernatremia but might be associated with a higher morbidity in terms of BPD, IVH, and NEC. Inadvertent sodium load can be reduced by replacing high sodium-containing carrier solutions with high levels of sodium with alternative hypotonic and/or balanced fluids, model based.

Nutritional interventions to reduce rates of infection, necrotizing enterocolitis and mortality in very preterm infants.

Observational studies demonstrating reduced rates of infections, necrotizing enterocolitis (NEC), and mortality in preterm infants fed their own mother's milk, as opposed to formula, have prompted endeavors to achieve similar effects with the right choice of food and food additives. In a systematic review of meta-analyses and randomized controlled trials (RCTs), we considered nutritional interventions aimed at reducing the rates of infections, NEC, or mortality in very preterm infants. The overall effects of particular interventions were presented as risk ratios with 95% confidence intervals. In RCTs, pasteurized human donor milk, as opposed to formula, reduced NEC but not infections or mortality. No differences emerged between infants receiving human or bovine milk-based fortifiers. Pooled data of small trials and a recent large RCT suggested that bovine lactoferrin reduced rates of fungal sepsis without impact on other infections, NEC, or mortality. Pooled data of RCTs assessing the use of prebiotic oligosaccharides found reduced infection but not mortality. Enteral L-glutamine (six RCTs) lowered infection rates, and enteral L-arginine (three RCTs) reduced NEC. A meta-analysis sensitivity approach found multiple-strain (but not single-strain) probiotics to be highly effective in reducing NEC and mortality. Thus, selected food components may help to improve outcomes in preterm infants.

Probiotics to prevent necrotising enterocolitis in very preterm or very low birth weight infants.

BACKGROUND: Intestinal dysbiosis may contribute to the pathogenesis of necrotising enterocolitis (NEC) in very preterm or very low birth weight infants. Dietary supplementation with probiotics to modulate the intestinal microbiome has been proposed as a strategy to reduce the risk of NEC and associated mortality and morbidity.  OBJECTIVES: To determine the effect of supplemental probiotics on the risk of NEC and mortality and morbidity in very preterm or very low birth weight infants. SEARCH METHODS: We searched Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 2) in the Cochrane Library; MEDLINE Ovid (1946 to 17 Feb 2020), Embase Ovid (1974 to 17 Feb 2020), Maternity & Infant Care Database Ovid (1971 to 17 Feb 2020), the Cumulative Index to Nursing and Allied Health Literature (1982 to 18 Feb 2020). We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-RCTs. SELECTION CRITERIA: We included RCTs and quasi-RCTs comparing probiotic supplementation with placebo or no probiotics in very preterm or very low birth weight infants. DATA COLLECTION AND ANALYSIS: We used the standard methods of Cochrane Neonatal. Two review authors separately evaluated trial quality, extracted data, and synthesised effect estimates using risk ratio (RR), risk difference (RD), and mean difference. We used the GRADE approach to assess the certainty of evidence for effects on NEC, all-cause mortality, late-onset infection, and severe neurodevelopmental impairment. MAIN RESULTS: We included 56 trials in which 10,812 infants participated. Most trials were small (median sample size 149). Lack of clarity on methods to conceal allocation and mask caregivers or investigators were the main potential sources of bias in about half of the trials. Trials varied by the formulation of the probiotics. The most commonly used preparations contained Bifidobacterium spp., Lactobacillus spp., Saccharomyces spp., and Streptococcus spp. alone or in combinations. Meta-analysis showed that probiotics may reduce the risk of NEC: RR 0.54, 95% CI 0.45 to 0.65 (54 trials, 10,604 infants; I² = 17%); RD -0.03, 95% CI -0.04 to -0.02; number needed to treat for an additional beneficial outcome (NNTB) 33, 95% CI 25 to 50. Evidence was assessed as low certainty because of the limitations in trials design, and the presence of funnel plot asymmetry consistent with publication bias. Sensitivity meta-analysis of trials at low risk of bias showed a reduced risk of NEC: RR 0.70, 95% CI 0.55 to 0.89 (16 trials, 4597 infants; I² = 25%); RD -0.02, 95% CI -0.03 to -0.01; NNTB 50, 95% CI 33 to 100. Meta-analyses showed that probiotics probably reduce mortality (RR 0.76, 95% CI 0.65 to 0.89; (51 trials, 10,170 infants; I² = 0%); RD -0.02, 95% CI -0.02 to -0.01; NNTB 50, 95% CI 50 to 100), and late-onset invasive infection (RR 0.89, 95% CI 0.82 to 0.97; (47 trials, 9762 infants; I² = 19%); RD -0.02, 95% CI -0.03 to -0.01; NNTB 50, 95% CI 33 to 100). Evidence was assessed as moderate certainty for both these outcomes because of the limitations in trials design. Sensitivity meta-analyses of 16 trials (4597 infants) at low risk of bias did not show an effect on mortality or infection. Meta-analysis showed that probiotics may have little or no effect on severe neurodevelopmental impairment (RR 1.03, 95% CI 0.84 to 1.26 (five trials, 1518 infants; I² = 0%). The certainty on this evidence is low because of limitations in trials design and serious imprecision of effect estimate. Few data (from seven of the trials) were available for extremely preterm or extremely low birth weight infants. Meta-analyses did not show effects on NEC, death, or infection (low-certainty evidence). AUTHORS' CONCLUSIONS: Given the low to moderate level of certainty about the effects of probiotic supplements on the risk of NEC and associated morbidity and mortality for very preterm or very low birth weight infants, and particularly for extremely preterm or extremely low birth weight infants, further, large, high-quality trials are needed to provide evidence of sufficient quality and applicability to inform policy and practice.

Necrotizing Enterocolitis and Associated Mortality in Neonates With Congenital Heart Disease: A Multi-Institutional Study.

OBJECTIVE: There are scarce data about the prevalence and mortality of necrotizing enterocolitis in neonates with congenital heart disease. The purpose of this study is to provide a multi-institutional description and comparison of the overall prevalence and mortality of necrotizing enterocolitis in neonates with congenital heart disease. DESIGN: Retrospective multi-institutional study. SETTING: The Pediatric Health Information System database. PATIENTS: Neonates with congenital heart disease between 2004 and 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary study measure is the prevalence of necrotizing enterocolitis. Secondary measures include in-hospital mortality, hospital charges, ICU length of stay, hospital length of stay, and 30-day readmission. The prevalence of necrotizing enterocolitis was 3.7% (1,448/38,770) and varied significantly among different congenital heart disease diagnoses. The lowest prevalence of necrotizing enterocolitis was in transposition of the great arteries (n = 104, 2.1%). Compared with transposition of the great arteries, necrotizing enterocolitis occurred more frequently in neonates with hypoplastic left heart syndrome (odds ratio, 2.7; 95% CI, 2.1-3.3), truncus arteriosus (odds ratio, 2.6; 95% CI, 1.9-3.5), common ventricle (odds ratio, 2.1; 95% CI, 1.5-2.8), and aortic arch obstruction (odds ratio, 1.4; 95% CI, 1.1-1.7). Prematurity is a significant risk factor for necrotizing enterocolitis and for mortality in neonates with necrotizing enterocolitis, conferring varying risk by cardiac diagnosis. Unadjusted mortality associated with necrotizing enterocolitis was 24.4% (vs 11.8% in neonates without necrotizing enterocolitis; p < 0.001), and necrotizing enterocolitis increased the adjusted mortality in neonates with transposition of the great arteries (odds ratio, 2.5; 95% CI, 1.5-4.4), aortic arch obstruction (odds ratio, 1.8; 95% CI, 1.3-2.6), and tetralogy of Fallot (odds ratio, 1.6; 95% CI, 1.1-2.4). Necrotizing enterocolitis was associated with increased hospital charges (p < 0.0001), ICU length of stay (p = 0.001), and length of stay (p = 0.001). CONCLUSIONS: The prevalence of necrotizing enterocolitis among neonates with congenital heart disease is 3.7% and is associated with increased in-hospital mortality, length of stay, and hospital charges. The prevalence and associated mortality of necrotizing enterocolitis in congenital heart disease vary among different heart defects.

Antibiotic Treatments and Patient Outcomes in Necrotizing Enterocolitis.

OBJECTIVE: This study aimed to examine the impact of different antibiotic treatments on necrotizing enterocolitis (NEC) outcomes. STUDY DESIGN: Patient outcomes, including total parenteral nutrition and hospitalization durations, abdominal surgeries, intestinal strictures, and mortality data, were analyzed and compared by various antibiotic groups and treatment durations for 160 NEC patients managed at the Women and Children's Hospital of Buffalo between 2008 and 2016. RESULTS: Fourteen different antibiotics were used for NEC, most commonly ampicillin, gentamicin, and metronidazole (AGM). Medical (vs. surgical) NEC patients more likely received AGM (37 vs. 6%, p < 0.001). Surgical (vs. medical) NEC patients more likely received vancomycin (80 vs. 30%, p < 0.001) and antipseudomonal agents (69 vs. 15%, p < 0.001). For medical NEC there were no outcome differences between patients receiving only AGM versus those receiving other treatments; in patients receiving AGM, there were no outcome differences in durations of ≤10 days versus longer courses. CONCLUSION: Antibiotic use for NEC varies substantially without definite outcome differences. Particularly with medical NEC, AGM for ≤10 days had comparable outcomes to other treatments. In light of growing concern for short and longer term adverse effects with early-life antibiotic exposure, narrow-spectrum and shorter course NEC treatment may be preferred.

Platelet transfusions and mortality in necrotizing enterocolitis.

BACKGROUND: Prior studies have suggested an association between platelet transfusions (PTXs) and worse outcomes among infants with necrotizing enterocolitis (NEC), potentially mediated by proinflammatory factors released by platelets. However, the effects of storage on platelet proinflammatory factor release and the confounding role of illness severity on NEC outcomes have not been determined. STUDY DESIGN AND METHODS: First, neuropeptide Y (a potent splanchnic vasoconstrictor released by platelets) was measured by enzyme-linked immunosorbent assay in fresh frozen plasma and in the supernatant of leukoreduced apheresis-derived platelets at different times during storage. Next, we evaluated the relationship between PTX rates and death in a multicenter cohort of very-low-birth-weight infants with NEC, adjusting for illness severity. RESULTS: Neuropeptide Y levels increased over time in the supernatant of leukoreduced apheresis-derived platelets and were 4.4-fold and 8.9-fold higher than in fresh frozen plasma on Days 2 and 3 of storage, respectively (p < 0.001). Among 598 very-low-birth-weight infants, 44 developed NEC. In unadjusted analysis, PTX rate was 30.3 (95% confidence interval [CI], 11.5-80.1) per 100 infant-days among infants who died, compared to 6.0 (95% CI, 3.2-11.2) among survivors (incidence rate ratio, 5.1; 95% CI, 1.6-16.2; p = 0.006). In multivariable analysis, there was no association between PTX rate and mortality (incidence rate ratio, 3.0; 95% CI, 0.6-15.0; p = 0.18), although estimation was imprecise. CONCLUSION: Proinflammatory mediators accumulate in platelet suspensions during storage. Although PTX rates were not associated with increased mortality among infants with NEC in our study, our estimates suggest the potential for such an association that needs evaluation in larger studies.