Key learning points from a CHD necrotising enterocolitis learning collaborative across high- and low-performing centres.

Neonatal Necrotizing Enterocolitis: Possible Role of Probiotic Supplementation

Introduction: The management of neonates with congenital heart disease (CHD) may be complicated by necrotizing enterocolitis (NEC), however, there is limited multicenter data describing the incidence and outcomes of NEC in the CHD population. Objective: We aimed to assess the incidence and risk factors for the development of NEC in neonates with major CHD and the impact on survival. Methods: A retrospective cohort study of neonates with CHD was performed for all index hospitalizations of neonates (<28 days) with major CHD between 2004 and 2014 using the Pediatric Health Information System database. The diagnosis of NEC was determined by the presence of ICD-9 code 777.5x. The incidence of NEC was determined as were risk factors for the development of NEC. Mortality was the primary outcome measure. Results: Of 38770 neonates with major CHD, 1448 (3.6%) were diagnosed with NEC. The rate of NEC varied between 0-8% by hospital and was not associated with hospital volume (p=0.4). Among neonates with a single, major CHD diagnosis, the rate of NEC was 6% in hypoplastic left heart syndrome (HLHS), 6% in truncus arteriosus (TA) , 4% in tetralogy of Fallot (TOF), 3% in aortic arch obstruction (AO), and 2% in transposition of the great arteries (TGA); these diagnoses accounted for 47% of all NEC. Prematurity and chromosomal anomalies were independently associated with the diagnosis of NEC (p≤0.01 for both). Unadjusted mortality among neonates with NEC was 24% compared to 12% in neonates without NEC (OR 2.4, 95%CI 2.1-2.7). When evaluating changes in adjusted mortality associated with NEC by CHD diagnosis, TOF mortality increased from 8% to 16% (p<.01), TGA increased from 5% to 21% (p<0.01), AO increased from 6% to 20% (p<0.01), HLHS increased from 22% to 28% (p=.07), and TA decreased from 13% to 12% (p=0.7). Median LOS was higher in neonates with NEC than without NEC (54d [IQR 31-93] vs. 18d [IQR 9-34], p<0.01) as was median hospital charge ($600k [IQR 310k-1.1m] vs. $220k [IQR 100k-430k], p<0.01). Conclusions: The incidence of NEC among neonates with major CHD is highest in HLHS and TA. NEC is associated with significantly higher hospital mortality, LOS, and charges. Determining modifiable factors associated with NEC may allow for interventions to reduce morbidity in this population.

A Large Scale Metagenomic Analysis of the Faecal Microbiota in Preterm Infants Developing Necrotising Enterocolitis

Objective To explore the clinical features and risk factors of poor prognosis in neonatal necrotizing enterocolitis(NEC). Methods A retrospective study was carried out in the infants with NEC admitted to 6 cooperative hospitals in Guangdong Province between January 2005 and December 2014.The clinical features and risk factors of poor prognosis in preterm and full-term infants diagnosed NEC, early onset and late onset NEC were analyzed. Results A total of 449 cases who met the criteria were admitted during the study time.The mortality was 23.6% (106/449 cases), of which the preterm group was 24.6% (58/238 cases) while the full-term group was 22.7% (48/211 cases), the early onset group was 22.1% (45/204 cases) while the late onset group was 24.3% (57/235 cases). The median number of NEC onset in preterm group was 11 d after birth while the number of the full-term group was 6 d. Full-term infants who diagnosed NEC were more likely to manifest themselves as abdominal distension(52.1% vs.42.0%, χ2=4.597, P=0.032), vomiting(36.5% vs.17.2%, χ2=21.428, P=0.000) and bloody stool(30.3% vs.21.4%, χ2=4.653, P=0.031); but in the onset of NEC, preterm infants more likely to have feeding intolerance(21.0% vs.12.8%, χ2=5.309, P=0.021). The early onset group of full-term NEC was much common in twins or multiplets(9.4% vs.1.1%, χ2=6.226, P=0.013), which rate of surgical therapy was much higher(41.0% vs.27.0%, P=0.036) and the breast-feeding rate before NEC was lower than the late onset group(14.5% vs.32.6%, χ2=9.500, P=0.002), the differences were statistically significant.The gestational age and birth weight were bigger in the early onset group of preterm NEC[(33.8±2.5) weeks vs.(32.2±2.8) weeks, t=4.261, P=0.000; (2.1±0.5) kg vs.(1.7±0.5) kg, t=4.735, P=0.000)], but length of stay was shorter than the late onset group(18.0 d vs.26.5 d, P=0.000). Logistic regression analysis showed that the risk factors of poor prognosis of full-term NEC were shock, peritonitis and sepsis; while risk factors of poor prognosis of preterm NEC were small for gestational age infant, pulmonary hemorrhage, shock, intestinal perforation and sepsis; the risk factors of poor prognosis of the early onset group of full-term NEC was shock; while those of the late onset group were shock and peritonitis; the risk factors of poor prognosis in the early onset group of preterm NEC were shock and sepsis, while those in the late onset group were pulmonary hemorrhage, shock, intestinal perforation and sepsis. Conclusions Compared to the preterm NEC, the onset time of full-term NEC was earlier and the clinical manifestations were more typical.Early identification and management of shock, peritonitis, intestinal perforation, sepsis and pulmonary hemorrhage can reduce the risk of poor prognosis of neonate NEC. Key words: Necrotizing enterocolitis; Infant, newborn; Clinical features; Prognosis; Risk factor

BackgroundBetter measures are needed to identify infants at risk for developing necrotizing enterocolitis (NEC) and facilitate communication about risk across transitions. Although NEC is multi-factorial, quantification of composite risk for NEC in an individual infant is not clearly defined.ObjectiveThis study’s objective was to describe the derivation, validation and calibration testing of a novel clinical NEC risk index, GutCheckNEC. Individual risk factors were weighted to assess composite odds of developing NEC. GutCheckNEC is designed to improve communication about NEC risk and coordination of care among clinicians across an infant’s clinical course.MethodsBased on a synthesis of research evidence about NEC risk and an e-Delphi study including 35 neonatal experts, we identified NEC risk factors believed by the experts to be most relevant for a NEC risk index then applied a logistic model building process to derive and validate GutCheckNEC. De-identified data from the Pediatrix BabySteps Clinical Data Warehouse (discharge date 2007-2011) were split into three samples for derivation, validation and calibration. By comparing infants with medical NEC, surgical NEC, and those who died to infants without NEC, we derived the logistic model using the un-matched derivation set. Discrimination was then tested in a case-control matched validation set and an un-matched calibration set using ROC curves.ResultsSampled from a cohort of 58 820 infants, the randomly selected derivation set (n= 35 013) revealed 9 independent risk factors (gestational age, history of packed red blood cell transfusion, unit NEC rate, late onset sepsis, multiple infections, hypotension treated with inotropic medications, Black or Hispanic race, outborn status, and metabolic acidosis) and 2 risk reducers (human milk feeding on both days 7 and 14 of life, and probiotics). Unit NEC rate carried the most weight in the summed score. Validation using a 2: 1 matched case-control sample (n=360) demonstrated fair to good discrimination. In the calibration set (n= 23 447), GutCheckNEC scores (range 0-58) discriminated those infants who developed surgical NEC (AUC=0.84, 95% CI 0.82-0.84) and NEC leading to death (AUC=0.83, 95% CI 0.81-0.85), more accurately than medical NEC (AUC= 0.72, 95% CI 0.70-0.74).ConclusionGutCheckNEC represents weighted composite risk for NEC and discriminated infants who developed NEC from those who did not with very good accuracy. We speculate that targeting modifiable NEC risk factors could reduce national NEC prevalence.

Objective: The purpose of this study is to report our experience with an exclusive human milk–based diet (EHM) versus diets of mother’s milk supplemented with banked human milk (DHM) or formula (PTF) plus bovine fortifier. Second, we evaluated the cost-effectiveness of using EHM. Design/Methods: This is a retrospective study of infants ≤1500 g birth weight (VLBW) admitted to the NICU from January 1, 2007, to December 31, 2011. Primary outcomes were rates of Bell stage 2 to 3 necrotizing enterocolitis (NEC) and NEC plus significant gastrointestinal bleeding (GIB). There were 3 groups for analysis according to diet: PTF, DHM, and EHM. Binary outcomes were analyzed using a multivariate logistic regression. Linear analysis of covariance was used to analyze continuous outcomes. Cost analysis used costs from a previous study for stage 2 and 3 NEC and from a matched control analysis for infants in our study for stage 1 NEC. Results: Infants who received EHM (n = 44) had higher rates of risk factors for NEC compared with DHM (n = 224) and PTF (n = 93). Rates of NEC were decreased for EHM versus PTF (odds ratio [OR] = 0.060; confidence interval [CI] = 0.003-0.445; P = .019) and NEC plus GIB were decreased for EHM versus DHM (OR = 0.070; CI = 0.004-0.369; P = .012) and EHM versus PTF (OR = 0.062; CI = 0.003-0.366; P = .011). A cost saving was shown when using EHM for VLBW infants with several risk factors for NEC but not all VLBW infants. Conclusions: EHM lowered the incidence of NEC compared with PTF and NEC plus GIB compared with DHM and PTF. Using EHM in VLBW infants at higher risk of NEC appears to be cost-effective.

Background: Infants with congenital heart disease are at high risk of developing necrotizing enterocolitis (NEC), with increased morbidity and mortality compared to infants without heart disease who develop NEC. Shunted single ventricle patients are at even higher risk. The hybrid stage 1 palliation (HS1P) is an alternative to the Norwood procedure for high-risk single ventricle patients or as initial palliation for patients with future two ventricle repair, as bridge to transplant, or as destination therapy. Few small studies have shown similar or slightly higher rates of NEC after HS1P compared to after Norwood. Aims: To evaluate the incidence, risk factors, and outcomes of NEC in HS1P versus Norwood patients. Methods: This is a single-center retrospective cohort study of all neonates who underwent HS1P or Norwood procedure from 2011-2022. Demographic data and episodes of NEC (defined using modified Bell’s criteria) were collected. NEC incidences and risk factors were compared between HS1P and Norwood patients using Chi-square test. For HS1P patients, more extensive data were collected including planned and final physiologic outcomes (single ventricle palliation, biventricular repair, transplant, and destination) and primary patient risk factors that led to HS1P. Risk factors and clinical outcomes of HS1P patients with and without NEC were compared using standard univariate tests. Results: The cumulative incidence of NEC in the HS1P group was 53% versus 37% in the Norwood group (p=0.01) and HS1P patients had more NEC episodes than the Norwood group (median 2 vs 1, p=0.03). Suspected NEC (stage 1A/1B) accounted for 70-75% of NEC cases in both groups. Only two infants, both in the HS1P group, had surgical (stage 3B) NEC. We found no differences in baseline demographics between patients with and without NEC in both HS1P and Norwood groups. In the HS1P group, NEC was associated with longer hospital length of stay (LOS), (median 49 days vs 23 days, p<0.0001) and greater need for tube feeds at 1 year (32% of the NEC group exclusively orally fed versus 43% of the non-NEC group, p=0.03). Final physiologic outcome was not associated with development of NEC in the HS1P group (p=0.38). Conclusions: While the exact risk factors or predictors are not clear, NEC is more common after HS1P compared to Norwoods and is associated with longer hospital LOS and late feeding difficulty. Further studies to better understand the physiologic causes of NEC in the HS1P population are needed.

Antenatal magnesium sulfate (MgSO4) treatment is widely used for fetal neuroprotection in women at risk of preterm delivery. However, some studies have recently suggested that in utero MgSO4 exposure is associated with an increased risk of necrotizing enterocolitis (NEC). This study aimed to investigate the association between antenatal MgSO4 treatment and risk of NEC. This retrospective cohort study included 756 infants born at 24–31 weeks’ gestation. Subjects were classified into three groups: period 1, when MgSO4 treatment protocol for fetal neuroprotection was not adopted (n = 267); period 2, when the protocol was adopted (n = 261); and period 3, when the protocol was withdrawn because of concern of risk of NEC (n = 228). Rates of NEC (≥ stage 2b) were analyzed according to time period and exposure to antenatal MgSO4. Significant difference in the rate of NEC was not found across the three time periods (2.6% vs. 6.5% vs. 4.8% in periods 1, 2 and 3, respectively, p = 0.103). The rate of NEC was comparable between the infants unexposed and exposed to antenatal MgSO4 (5.1% vs. 3.6%, p = 0.369). These results showed that antenatal MgSO4 treatment was not associated with risk of NEC in our study population.

Background: Necrotizing enterocolitis (NEC) is a rare comorbidity in infants with heart disease, specifically those with shunt-dependent congenital heart disease (SDCHD). We aimed to describe NEC incidence and cofactors in our center’s SDCHD population and diagnostic practice changes. Methods: A retrospective case-control study in patients who underwent first staged palliation for SDCHD between 1/1/2013 and 6/30/2022. Palliation procedures included stage one Norwood with a BTTS or RV to PA conduit, hybrid, BTTS only or PDA stent. Demographics, clinical factors, and diagnostics including abdominal ultrasound (AUS) were abstracted for subjects for 21 days after palliation. NEC was defined with Bell’s criteria from databases and AUS was assessed by chart review. Hierarchical logistic regression models assessed surgical era rates into three cohorts 2013-2016, 2017-2019, and 2020-2022. Groups were compared with Chi-square, Fisher’s exact test, Wilcoxon rank-sum tests, and trends over time with logistical regression. Results: Of 531 patients included, 77 (14.5%) had NEC. There was no association of NEC diagnosis with sex, race, and ethnicity, presence of genetic syndromes or extracardiac abnormalities. The primary and majority SDCHD diagnosis was hypoplastic left heart syndrome and variants (61%). On univariate analysis, risks significantly associated with NEC include younger gestational age, delayed sternal closure, catheter reintervention, ECMO, cardiac arrest, seizures, >/= moderate ventricular dysfunction, increased pre- and post-procedural VIS scores, and postoperative anemia. Logistic regression found a significant increase in NEC by year, with a 23% increase in odds for each increasing year across the time range (OR 1.23, 95% CI 1.12-1.36, p<0.001) and odds of AUS use significantly increased by year (OR 1.14, 95% CI 1.05-1.24, p=0.003). When controlling for gestational age, procedure type, presence of a genetic syndrome and chromosomal abnormality the odds of having a NEC diagnosis increased by 1.24 on average with each change in era. Conclusions: Rates of NEC diagnoses at our institution have increased over time with ultrasound as a diagnostic indicator. Clinical risks factors suggesting higher acuity of illness were associated with higher rates of NEC. Further studies are needed to assess AUS sensitivity and its contribution to NEC rates, as well as a multicenter analysis to collate risk factors for this fragile patient population.

Necrotizing Enterocolitis: Updates on Morbidity and Mortality Outcomes

Background: Necrotizing enterocolitis (NEC) is the leading cause of gastrointestinal morbidity in preterm infants, and prevention and treatment strategies have remained largely unchanged over the past several decades. As understanding of the microbiome has increased, probiotics have been hypothesized as a possible strategy for decreasing rates of NEC, and several studies have noted significant decreases in rates of NEC after initiation of probiotics in preterm infants. However, a recent AAP report cited caution on the use of probiotic use in part because studies of probiotic use in ELBW infants are lacking. As our unit began routine use of probiotics for all infants <33 weeks in 2015 and we are a leading institution for intact survival of ELBW infants, we attempted to answer if probiotic use can impact the rate of NEC in VLBW and ELBW infants.Methods: We conducted a single-center retrospective chart review of infants with modified Bell's stage ≥2a NEC for the 4 years prior to and 5 years after initiation of a protocol involving routine supplementation of a multispecies probiotic to premature infants at the University of Iowa, Stead Family Children's Hospital. The primary outcome measures were rates of modified Bell's stage ≥2a NEC and all-cause pre-discharge mortality at our institution before and after initiation of routine probiotic supplementation in 2015.Results: In our institution, neither the rates of modified Bell's stage ≥2a NEC, nor the rates of all-cause mortality were significantly altered in very low birth weight (VLBW) infants by the initiation of routine probiotic use (NEC rates pre-probiotic 2.1% vs. post-probiotic 1.5%; all-cause mortality rates pre-probiotic 8.4% vs. post-probiotic 7.4%). Characteristics of our two cohorts were overall similar except for a significantly lower 5-minute APGAR score in infants in the post-probiotic epoch (pre-probiotic 8 vs. post-probiotic 6 p = 0.0316), and significantly more infants in the post-probiotic epoch received probiotics (pre-probiotics 0% vs. post-probiotics 65%; p < 0.0001). Similarly, probiotic use had no impact on the incidence of NEC when we restricted our data to only extremely low birth weight (ELBW) infants (pre-probiotics 1.6% vs post-probiotics 4.1%). When we restricted our analysis to only inborn infants, probiotics still had no impact on NEC rates in VLBW infants (1.5% pre- and 1.1% post-probiotic, p = 0.61) or ELBW infants (2% pre- and 2.1% post-probiotic, p = 0.99)Conclusions: Contrary to other studies, we found no significant difference in rates of modified Bell's stage ≥2a NEC or all-cause pre-discharge mortality in VLBW infants following routine administration of a multispecies probiotic supplement.

To determine if infants with very low birth weight who receive packed red blood cell (PRBC) transfusions have increased odds of developing necrotizing enterocolitis (NEC), to determine the rate of NEC after PRBC transfusion, and to characterize the blood transfused preceding the onset of NEC. A retrospective cohort design was used. The study population included infants with a birth weight of <1500 g who were from a single center. NEC after transfusion was defined as NEC that occurred in the 48 hours after initiation of PRBC transfusion. Statistical analysis included unadjusted and multivariable analyses. The study sample included 2311 infants. A total of 122 infants (5.3%) developed NEC, and 33 (27%) of 122 NEC cases occurred after transfusion. NEC occurred after 33 (0.5%) of 6484 [corrected] transfusions. Infants who received a transfusion had increased adjusted odds (odds ratio: 2.3 [95% confidence interval: 1.2-4.2]) of developing NEC compared with infants who did not receive a transfusion. PRBCs transfused before NEC were predominantly (83%) from male donors and were a median of 5 days old. In our study sample, PRBC transfusion was associated with increased odds of NEC. The rate of NEC after transfusion was 1.4%. From our data we could not determine if PRBC transfusions were part of the causal pathway for NEC or were indicative of other factors that may be causal for NEC.

Necrotizing enterocolitis: The road to zero

To reduce the incidence of necrotizing enterocolitis (NEC) among very low birth weight (VLBW) infants admitted to 8 intensive care nurseries from a 2010 baseline of 8.0% to <4.0% by 2012 and sustain for 6 months using quality improvement (QI) methodology. A multidisciplinary NEC QI team used the Vermont Oxford Network definition of NEC and the Institute for Healthcare Improvement model. The specific aims were evidenced based and included (1) standardized early human milk feedings, (2) conservative feeding guidelines during blood transfusions and indomethacin treatment, and (3) restriction of ranitidine use in VLBW infants. Inclusion criteria included VLBW infants admitted within the study period without NEC. Exclusion criteria included established NEC or spontaneous intestinal perforation unrelated to NEC. The incidence of NEC and NEC-related surgery were tracked using statistical process control methodology. The baseline NEC rate in 2010 was 8% (27 NEC cases in 335 VLBW infants). After initiation of early human-milk feeding and conservative feeds during blood transfusions guidelines in November 2011, only 3.1% (19 of 606 VLBW infants) had developed NEC through December 2013 (P = .001). Special cause variation was noted in June 2012 establishing a new centerline at 3.1%. NEC-related mortality decreased from a 2010 baseline mean of 2.7% to a new baseline mean of 0.9% from January 2011 to December 2013. Implementation of QI initiatives decreased the NEC rate from 8.0% to <4.0%. Early human milk feedings and conservative feeding during blood transfusion policies appear to have significant impact on NEC reduction.

Necrotizing enterocolitis (NEC) and postnatal growth restriction are significant clinical dilemmas that contribute to short- and long-term morbidities for the most premature infants. After a rise in NEC rates in a regional neonatal intensive care unit (NICU), improvement practices were implemented by an interdisciplinary quality improvement (QI) work group whose focus was initially on nutrition and growth. QI work was refocused to address both NEC and growth concurrently. Through various QI initiatives and with evolving understanding of NEC and nutrition, the work group identified and implemented multiple practices changes over 2-decade time span. A standardized tool was used to review each case of NEC and outcomes were continually tracked to guide QI initiatives. Focused QI work contributed to a significant reduction in NEC rates from 16.2% in 2007 to 0% in 2018 for inborn infants. Exclusive human milk diet was a critical part of the success. Postnatal growth outcomes initially declined after initial NEC improvement work. Improvement work that focused jointly on NEC and nutrition resulted in improved growth outcomes without impacting NEC. Use of historical perspective along with evolving scientific understanding can guide local improvement initiatives. Work must continue to optimize lactation during NICU hospitalization. More research is needed to determine impact of care practices on gastrointestinal inflammation including medication osmolality, probiotics, and noninvasive respiratory support.