Degree of Uncertainty in Reporting Imaging Findings for Necrotizing Enterocolitis: A Secondary Analysis from a Pilot Randomized Diagnostic Trial.

Diagnosis of necrotizing enterocolitis (NEC) relies heavily on imaging, but uncertainty in the language used in imaging reports can result in ambiguity, miscommunication, and potential diagnostic errors. To determine the degree of uncertainty in reporting imaging findings for NEC, we conducted a secondary analysis of the data from a previously completed pilot diagnostic randomized controlled trial (2019-2020). The study population comprised sixteen preterm infants with suspected NEC randomized to abdominal radiographs (AXRs) or AXR + bowel ultrasound (BUS). The level of uncertainty was determined using a four-point Likert scale. Overall, we reviewed radiology reports of 113 AXR and 24 BUS from sixteen preterm infants with NEC concern. The BUS reports showed less uncertainty for reporting pneumatosis, portal venous gas, and free air compared to AXR reports (pneumatosis: 1 [1-1.75) vs. 3 [2-3], p < 0.0001; portal venous gas: 1 [1-1] vs. 1 [1-1], p = 0.02; free air: 1 [1-1] vs. 2 [1-3], p < 0.0001). In conclusion, we found that BUS reports have a lower degree of uncertainty in reporting imaging findings of NEC compared to AXR reports. Whether the lower degree of uncertainty of BUS reports positively impacts clinical decision making in infants with possible NEC remains unknown.

Current Patterns of Probiotic Use in U.S. Neonatal Intensive Care Units: A Multi-Institution Survey.

OBJECTIVE: Probiotic supplementation is associated with health benefits in preterm infants. The 2021 American Academy of Pediatrics (AAP) statement on probiotic use advised caution, citing heterogeneity and absence of federal regulation. We assessed the impact of the AAP statement and current institution-wide patterns of probiotic use across neonatal intensive care units (NICU) across the United States. STUDY DESIGN: A cross-sectional web-based institutional survey using REDCap was emailed to 430 Children's Hospital Neonatal Consortium (CHNC) and Pediatrix Medical Group institutions. The survey captured data on probiotic formulations, supplementation, initiation and cessation criteria, reasons for discontinuation, interest in initiating, and AAP statement's impact. RESULTS: Ninety-five (22.1%) hospitals, including 42/46 (91%) CHNC and 53/384 (14%) Pediatrix institutions, completed the survey. Thirty-seven (39%) currently use probiotics. Fourteen different probiotic formulations were reported. The common criteria for initiation were birth weight <1,500 g and gestational age <32 weeks. Parental consent or assent was obtained at only 30% of institutions. Five hospitals (11%) with prior probiotic use discontinued solely due to the AAP statement. Overall, 23 (24%) of hospitals indicated that the AAP statement significantly influenced their decision regarding probiotic use. Nineteen of 51 nonusers (37%) are considering initiation. CONCLUSION: Probiotic use in preterm infants is likely increasing in NICUs across the United States, but significant variability exists. The 2021 AAP statement had variable impact on NICUs' decision regarding probiotic use. The growing interest in adopting probiotics and the significant interhospital variability highlight the need for better regulation and consensus guidelines to ensure standardized use. KEY POINTS: · Probiotic use in preterm infants is likely increasing in U.S. NICUs, but clinical variability exists.. · The AAP statement on probiotic use in preterm infants had a modest impact on current practices.. · There's a need for better product regulation and consensus guidelines to ensure standardized use..

The Detrimental Effects of Peripartum Antibiotics on Gut Proliferation and Formula Feeding Injury in Neonatal Mice Are Alleviated with Lactobacillus rhamnosus GG.

Peripartum antibiotics can negatively impact the developing gut microbiome and are associated with necrotizing enterocolitis (NEC). The mechanisms by which peripartum antibiotics increase the risk of NEC and strategies that can help mitigate this risk remain poorly understood. In this study, we determined mechanisms by which peripartum antibiotics increase neonatal gut injury and evaluated whether probiotics protect against gut injury potentiated by peripartum antibiotics. To accomplish this objective, we administered broad-spectrum antibiotics or sterile water to pregnant C57BL6 mice and induced neonatal gut injury to their pups with formula feeding. We found that pups exposed to antibiotics had reduced villus height, crypt depth, and intestinal olfactomedin 4 and proliferating cell nuclear antigen compared to the controls, indicating that peripartum antibiotics impaired intestinal proliferation. When formula feeding was used to induce NEC-like injury, more severe intestinal injury and apoptosis were observed in the pups exposed to antibiotics compared to the controls. Supplementation with the probiotic Lactobacillus rhamnosus GG (LGG) reduced the severity of formula-induced gut injury potentiated by antibiotics. Increased intestinal proliferating cell nuclear antigen and activation of the Gpr81-Wnt pathway were noted in the pups supplemented with LGG, suggesting partial restoration of intestinal proliferation by probiotics. We conclude that peripartum antibiotics potentiate neonatal gut injury by inhibiting intestinal proliferation. LGG supplementation decreases gut injury by activating the Gpr81-Wnt pathway and restoring intestinal proliferation impaired by peripartum antibiotics. Our results suggest that postnatal probiotics may be effective in mitigating the increased risk of NEC associated with peripartum antibiotic exposure in preterm infants.

Early antibiotics and risk for necrotizing enterocolitis in premature infants: A narrative review.

While prompt initiation of antibiotics at birth due to concerns for early onset sepsis is common, it often leads to many preterm infants being exposed to treatment despite negative blood cultures. Such exposure to early antibiotics can impact the developing gut microbiome putting infants at increased risk of several diseases. Necrotizing enterocolitis (NEC), a devastating inflammatory bowel disease that affects preterm infants, is among the most widely studied neonatal disease that has been linked to early antibiotics. While some studies have demonstrated an increased risk of NEC, other studies have demonstrated seemingly contrary findings of decreased NEC with early antibiotics. Studies using animal models have also yielded differing findings of benefit vs. harm of early antibiotic exposure on subsequent NEC susceptibility. We thus sought to conduct this narrative review to help clarify the relationship between early antibiotics exposure and future risk of NEC in preterm infants. Our objectives are to: (1) summarize findings from human and animal studies that investigated the relationship between early antibiotics and NEC, (2) highlight important limitations of these studies, (3) explore potential mechanisms that can explain why early antibiotics may increase or decrease NEC risk, and (4) identify future directions for research.

Necrotizing enterocolitis in premature infants-A defect in the brakes? Evidence from clinical and animal studies.

A key aspect of postnatal intestinal adaptation is the establishment of symbiotic relationships with co-evolved gut microbiota. Necrotizing enterocolitis (NEC) is the most severe disease arising from failure in postnatal gut adaptation in premature infants. Although pathological activation of intestinal Toll-like receptors (TLRs) is believed to underpin NEC pathogenesis, the mechanisms are incompletely understood. We postulate that unregulated aberrant TLR activation in NEC arises from a failure in intestinal-specific mechanisms that tamponade TLR signaling (the brakes). In this review, we discussed the human and animal studies that elucidate the developmental mechanisms inhibiting TLR signaling in the postnatal intestine (establishing the brakes). We then evaluate evidence from preclinical models and human studies that point to a defect in the inhibition of TLR signaling underlying NEC. Finally, we provided a framework for the assessment of NEC risk by screening for signatures of TLR signaling and for NEC prevention by TLR-targeted therapy in premature infants.

Effect of Various Preterm Infant Milk Formulas on NEC-Like Gut Injury in Mice.

Formula feeding is an important risk factor for the development of necrotizing enterocolitis in preterm infants. The potential harmful effects of different preterm formulas on the developing intestinal tract remain incompletely understood. Here we demonstrate that feeding newborn mouse pups with various preterm formulas resulted in differing effects on intestinal inflammation, apoptosis, and activation of the pro-inflammatory transcription factor NFκB. 16S rRNA sequencing revealed that each preterm formula resulted in significant gut microbial alterations that were different from dam-fed controls. Formula feeding with EleCare and Similac Special Care caused greater intestinal injury compared to NeoSure. Pre-treatment with Lactobacillus rhamnosus GG ameliorated severity of intestinal injury from EleCare and Similac Special Care. Our findings indicate that not all preterm formulas are the same, and different formulations can have varying effects on intestinal inflammation, apoptosis, and microbiome composition.

Feasibility and acceptability of a diagnostic randomized clinical trial of bowel ultrasound in infants with suspected necrotizing enterocolitis.

We conducted a pilot diagnostic randomized clinical trial (RCT) to examine the feasibility, acceptability, and preliminary outcomes of adding bowel ultrasound (BUS) to the diagnostic evaluation for necrotizing enterocolitis (NEC). Infants ≤ 32 weeks' gestational age with NEC concern were randomized to undergo abdominal X-ray (AXR) or AXR + BUS. The primary outcome was study feasibility. Secondary outcomes included rates of NEC diagnosis and duration of treatment with bowel rest and antibiotics. A total of 56 infants were enrolled; 16 developed NEC concern and were randomized. Rates of recruitment (56/82 = 68%), retention (16/16 = 100%), and protocol compliance (126/127 = 99%) met pre-specified thresholds for feasibility. No significant differences in rates of NEC diagnosis were found between the two groups. Durations of bowel rest and antibiotic treatment were also similar.   Conclusion: Our study supports the feasibility of conducting a definitive diagnostic RCT to establish safety and efficacy of BUS for NEC.   Clinical trial registration: The study was registered at https://clinicaltrials.gov (NCT03963011). What is Known: • Bowel ultrasound (BUS) is increasingly being utilized as an adjunct to abdominal radiographs in evaluating for necrotizing enterocolitis (NEC). • The impact of BUS on patient outcomes is unknown. What is New: • A diagnostic randomized controlled trial study design to determine safety and effectiveness of adding BUS to NEC evaluation is feasible and acceptable.

Chronic lung disease in full-term infants: Characteristics and neonatal intensive care outcomes in infants referred to children's hospitals.

OBJECTIVE: To describe characteristics, outcomes, and risk factors for death or tracheostomy with home mechanical ventilation in full-term infants with chronic lung disease (CLD) admitted to regional neonatal intensive care units. STUDY DESIGN: This was a multicenter, retrospective cohort study of infants born ≥37 weeks of gestation in the Children's Hospitals Neonatal Consortium. RESULTS: Out of 67,367 full-term infants admitted in 2010-2016, 4886 (7%) had CLD based on receiving respiratory support at either 28 days of life or discharge. 3286 (67%) were still hospitalized at 28 days receiving respiratory support, with higher mortality risk than those without CLD (10% vs. 2%, p < 0.001). A higher proportion received tracheostomy (13% vs. 0.3% vs. 0.4%, p < 0.001) and gastrostomy (30% vs. 1.7% vs. 3.7%, p < 0.001) compared to infants with CLD discharged home before 28 days and infants without CLD, respectively. The diagnoses and surgical procedures differed significantly between the two CLD subgroups. Small for gestational age, congenital pulmonary, airway, and cardiac anomalies and bloodstream infections were more common among infants with CLD who died or required tracheostomy with home ventilation (p < 0.001). Invasive ventilation at 28 days was independently associated with death or tracheostomy and home mechanical ventilation (odds ratio 7.6, 95% confidence interval 5.9-9.6, p < 0.0001). CONCLUSION: Full-term infants with CLD are at increased risk for morbidity and mortality. We propose a severity-based classification for CLD in full-term infants. Future work to validate this classification and its association with early childhood outcomes is necessary.

Corticosteroid response predicts bronchopulmonary dysplasia status at 36 weeks in preterm infants treated with dexamethasone: A pilot study.

IMPORTANCE: A major barrier to therapeutic development in neonates is a lack of standardized drug response measures that can be used as clinical trial endpoints. The ability to quantify treatment response in a way that aligns with relevant downstream outcomes may be useful as a surrogate marker for new therapies, such as those for bronchopulmonary dysplasia (BPD). OBJECTIVE: To construct a measure of clinical response to dexamethasone that was well aligned with the incidence of severe BPD or death at 36 weeks' postmenstrual age. DESIGN: Retrospective cohort study. SETTING: Level IV Neonatal Intensive Care Unit. PARTICIPANTS: Infants treated with dexamethasone for developing BPD between 2010 and 2020. MAIN OUTCOME(S) AND MEASURE(S): Two models were built based on demographics, changes in ventilatory support, and partial pressure of carbon dioxide (pCO2 ) after dexamethasone administration. An ordinal logistic regression and regularized binary logistic model for the composite outcome were used to associate response level to BPD outcomes defined by both the 2017 BPD Collaborative and 2018 Neonatal Research Network definitions. RESULTS: Ninety-five infants were treated with dexamethasone before 36 weeks. Compared to the baseline support and demographic data at the time of treatment, changes in ventilatory support improved ordinal model sensitivity and specificity. For the binary classification, BPD incidence was well aligned with risk levels, increasing from 16% to 59%. CONCLUSIONS AND RELEVANCE: Incorporation of response variables as measured by changes in ventilatory parameters and pCO2 following dexamethasone administration were associated with downstream outcomes. Incorporating drug response phenotype into a BPD model may enable more rapid development of future therapeutics.

Imaging for Diagnosis and Assessment of Necrotizing Enterocolitis.

Necrotizing enterocolitis (NEC) is inflammatory bowel necrosis of preterm and critically ill infants. The disease is seen in 6-10% of preterm infants who weigh less than 1500 g at birth and carries considerable morbidity, mortality, and healthcare cost burden. Efforts focused on timely mitigation remain restricted due to challenges in early diagnosis as clinical features, and available laboratory tests remain nonspecific until late in the disease. There is renewed interest in the radiological and sonographic assessment of intestinal diseases due to technological advances making them safe, cost-efficient, and supporting Web-based transmission of images, thereby reducing time to diagnosis by disease experts. Most of our experience has been with plain abdominal radiography, which shows characteristic features such as pneumatosis intestinalis in up to 50-60% of patients. Many patients with advanced disease may also show features such as portal venous gas and pneumoperitoneum. Unfortunately, these features are not seen consistently in patients with early, treatable conditions, and hence, there has been an unfulfilled need for additional imaging modalities. In recent years, abdominal ultrasound (AUS) has emerged as a readily available, noninvasive imaging tool that may be a valuable adjunct to plain radiographs for evaluating NEC. AUS can allow real-time assessment of vascular perfusion, bowel wall thickness, with higher sensitivity in detecting pneumatosis, altered peristalsis, and characteristics of the peritoneal fluid. Several other modalities, such as contrast-enhanced ultrasound (CEUS), magnetic resonance imaging (MRI), and near-infrared spectroscopy (NIRS), are also emerging. In this article, we have reviewed the available imaging options for NEC evaluation.

A comparison of newer classifications of bronchopulmonary dysplasia: findings from the Children's Hospitals Neonatal Consortium Severe BPD Group.

OBJECTIVE: To compare three bronchopulmonary dysplasia (BPD) definitions against hospital outcomes in a referral-based population. STUDY DESIGN: Data from the Children's Hospitals Neonatal Consortium were classified by 2018 NICHD, 2019 NRN, and Canadian Neonatal Network (CNN) BPD definitions. Multivariable models evaluated the associations between BPD severity and death, tracheostomy, or length of stay, relative to No BPD references. RESULTS: Mortality was highest in 2019 NRN Grade 3 infants (aOR 225), followed by 2018 NICHD Grade 3 (aOR 145). Infants with lower BPD grades rarely died (<1%), but Grade 2 infants had aOR 7-21-fold higher for death and 23-56-fold higher for tracheostomy. CONCLUSIONS: Definitions with 3 BPD grades had better discrimination and Grade 3 2019 NRN had the strongest association with outcomes. No/Grade 1 infants rarely had severe outcomes, but Grade 2 infants were at risk. These data may be useful for counseling families and determining therapies for infants with BPD.

Association of time of first corticosteroid treatment with bronchopulmonary dysplasia in preterm infants.

OBJECTIVE: To evaluate the association between the time of first systemic corticosteroid initiation and bronchopulmonary dysplasia (BPD) in preterm infants. STUDY DESIGN: A multi-center retrospective cohort study from January 2010 to December 2016 using the Children's Hospitals Neonatal Database and Pediatric Health Information System database was conducted. The study population included preterm infants <32 weeks' gestation treated with systemic corticosteroids after 7 days of age and before 34 weeks' postmenstrual age. Stepwise multivariable logistic regression was used to assess the association between timing of corticosteroid initiation and the development of Grade 2 or 3 BPD as defined by the 2019 Neonatal Research Network criteria. RESULTS: We identified 598 corticosteroid-treated infants (median gestational age 25 weeks, median birth weight 760 g). Of these, 47% (280 of 598) were first treated at 8-21 days, 25% (148 of 598) were first treated at 22-35 days, 14% (86 of 598) were first treated at 36-49 days, and 14% (84 of 598) were first treated at >50 days. Infants first treated at 36-49 days (aOR 2.0, 95% CI 1.1-3.7) and >50 days (aOR 1.9, 95% CI 1.04-3.3) had higher independent odds of developing Grade 2 or 3 BPD when compared to infants treated at 8-21 days after adjusting for birth characteristics, admission characteristics, center, and co-morbidities. CONCLUSIONS: Among preterm infants treated with systemic corticosteroids in routine clinical practice, later initiation of treatment was associated with a higher likelihood to develop Grade 2 or 3 BPD when compared to earlier treatment.

Effectiveness and safety of repeat dexamethasone for bronchopulmonary dysplasia.

OBJECTIVE: To describe effectiveness of repeat dexamethasone for bronchopulmonary dysplasia (BPD) and to evaluate adverse effects on growth. STUDY DESIGN: Retrospective study of infants treated with 1 or 2 courses of dexamethasone for BPD. Effectiveness was defined as successful step-down in respiratory support by end of treatment. Adverse effects on growth were analyzed and compared to untreated controls. RESULTS: A total of 132 dexamethasone-treated infants were identified. In total, 52% (69/132) of infants treated with initial dexamethasone achieved step-down in respiratory support compared to 38% (20/52) of infants with repeat dexamethasone. Growth trajectory did not significantly differ among infants treated with 1 or 2 courses of dexamethasone compared with controls (weight: P = 0.23, length: P = 0.68, and head circumference: P = 0.77). CONCLUSIONS: Repeat dexamethasone for BPD was less effective in weaning respiratory support compared to initial course. Changes in growth parameters to discharge were comparable between controls and infants treated with 1 or 2 dexamethasone courses.

Racial Disparities in Necrotizing Enterocolitis.

Necrotizing enterocolitis (NEC) is a serious disease of the intestinal tract affecting 5-10% of pre-term infants with up to 50% mortality in those that require surgery. There is wide variation in the rates and outcomes of NEC by race and ethnicity, and the reasons for this disparity are poorly understood. In this article, we review the epidemiology and discuss possible explanations for racial and ethnic differences in NEC. Most of the current evidence investigating the role of race in NEC comes from North America and suggests that Hispanic ethnicity and non-Hispanic Black race are associated with higher risk of NEC compared to non-Hispanic White populations. Differences in pre-term births, breastfeeding rates, and various sociodemographic factors does not fully account for the observed disparities in NEC incidence and outcomes. While genetic studies are beginning to identify candidate genes that may increase or decrease risk for NEC among racial populations, current data remain limited by small sample sizes and lack of validation. Complex interactions between social and biological determinants likely underly the differences in NEC outcomes among racial groups. Larger datasets with detailed social, phenotypic, and genotypic information, coupled with advanced bioinformatics techniques are needed to comprehensively understand racial disparities in NEC.

Dynamics of the preterm gut microbiome in health and disease.

Advances in metagenomics have allowed a detailed study of the gut microbiome, and its role in human health and disease. Infants born prematurely possess a fragile gut microbial ecosystem that is vulnerable to perturbation. Alterations in the developing gut microbiome in preterm infants are linked to life-threatening diseases such as necrotizing enterocolitis (NEC) and late-onset sepsis; and may impact future risk of asthma, atopy, obesity, and psychosocial disease. In this mini-review, we summarize recent literature on the origins and patterns of development of the preterm gut microbiome in the perinatal period. The host-microbiome-environmental factors that portend development of dysbiotic intestinal microbial patterns associated with NEC and sepsis are reviewed. Strategies to manipulate the microbiome and mitigate dysbiosis, including the use of probiotics and prebiotics will also be discussed. Finally, we explore the challenges and future directions of gut microbiome research in preterm infants.

Implementation of bowel ultrasound practice for the diagnosis and management of necrotising enterocolitis.

Necrotising enterocolitis (NEC) is a serious inflammatory bowel disease of prematurity with potentially devastating complications and remains a leading cause of morbidity and mortality among premature infants. In recent years, there has been accumulating data regarding benefits of using bowel ultrasound (BUS) in the diagnosis and management of NEC. Despite this, adoption of robust BUS programmes into clinical practice has been slow. As BUS is a relatively new technique, many barriers to implementation exist, namely lack of education and training for sonographers and radiologists, low case volume and unfamiliarity by clinicians regarding how to use the information provided. The aim of this manuscript is to provide a framework and a roadmap for units to implement BUS in day-to-day practice for NEC diagnosis and management.

Using quality improvement to implement consensus guidelines for postnatal steroid treatment of preterm infants with developing bronchopulmonary dysplasia.

OBJECTIVE: Achieve over 90% adherence to consensus guidelines on use of postnatal steroids (PNS) in preterm infants for bronchopulmonary dysplasia (BPD) within 6 months. METHODS: A multidisciplinary team formulated and implemented consensus guidelines using the Plan-Do-Study-Act method of quality improvement. Outcome measure was rate of compliance to guidelines, process measure was age of starting PNS treatment, and balancing measure was rate of repeat steroid courses. RESULTS: Retrospective application of guidelines to preceding 10 months showed mean baseline compliance rate of 71% (n = 42). After implementation, compliance escalated to a mean rate of 96% within 6 months. Rate of PNS treatment ≤ 30 days of life increased from 50 to 80%, while rate of repeat PNS was unchanged. CONCLUSIONS: Compliance with new guidelines for PNS treatment of BPD was quickly attained using simple quality improvement interventions. Further study is needed to evaluate effects of these guidelines on clinical outcomes.

NEC-like intestinal injury is ameliorated by Lactobacillus rhamnosus GG in parallel with SIGIRR and A20 induction in neonatal mice.

BACKGROUND: Exaggerated Toll-like receptor (TLR) signaling and intestinal dysbiosis are key contributors to necrotizing enterocolitis (NEC). Lactobacillus rhamnosus GG (LGG) decreases NEC in preterm infants, but underlying mechanisms of protection remain poorly understood. We hypothesized that LGG alleviates dysbiosis and upregulates TLR inhibitors to protect against TLR-mediated gut injury. METHODS: Effects of LGG (low- and high-dose) on intestinal pro-inflammatory TLR signaling and injury in neonatal mice subjected to formula feeding (FF) and NEC were determined. 16S sequencing of stool and expression of anti-TLR mediators SIGIRR (single immunoglobulin interleukin-1-related receptor) and A20 were analyzed. RESULTS: FF induced mild intestinal injury with increased expression of interleukin-1ß (IL-1ß) and Kupffer cell (KC) (mouse homolog of IL-8) compared to controls. LGG decreased IL-1ß and KC in association with attenuated TLR signaling and increased SIGIRR and A20 expression in a dose-dependent manner. Low- and high-dose LGG had varying effects on gut microbiome despite both doses providing gut protection. Subsequent experiments of LGG on NEC revealed that pro-inflammatory TLR signaling and intestinal injury were also decreased, and SIGIRR and A20 expression increased, in a dose-dependent manner with LGG pre-treatment. CONCLUSIONS: LGG protects against intestinal TLR-mediated injury by upregulating TLR inhibitors without major changes in gut microbiome composition.

Impact of tracheostomy on language and cognitive development in infants with severe bronchopulmonary dysplasia.

OBJECTIVE: The impact of tracheostomy on language and cognitive development in infants with severe bronchopulmonary dysplasia (BPD) is not known. We hypothesize that tracheostomy has an independent negative impact on language and cognitive development in infants with severe BPD. STUDY DESIGN: This is a retrospective cohort study of de-identified data of infants with severe BPD who received tracheostomy at <2 years of age, compared with infants with severe BPD without tracheostomy. The primary outcomes measured were total language and cognitive scores at 2-3 years of age as determined by Bayley Scales of Infant and Toddler Development, 3rd Edition. RESULTS: A total of 26 patients with tracheostomies and 28 patients without tracheostomies were analyzed. There was no significant difference in total language development or cognitive development between patients with tracheostomies and those without. Insurance status had an effect on language and cognition while controlling for trach status. CONCLUSIONS: Tracheostomy does not independently impact the language and cognitive development of infants with severe BPD.