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..

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.

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.

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.

Usefulness of an Online Risk Estimator for Bronchopulmonary Dysplasia in Predicting Corticosteroid Treatment in Infants Born Preterm.

OBJECTIVE: To assess the usefulness of a bronchopulmonary dysplasia (BPD) outcome estimator developed by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) in identifying high-risk preterm infants treated with steroids. STUDY DESIGN: This was a single-center retrospective study of infants born ≤30 weeks of gestational age. The NICHD BPD outcome estimator was used to retrospectively calculate BPD risk at various postnatal ages. The best combination of risk estimates for identifying steroid treatment was identified using stepwise model selection. A cut-off value with the best combination of sensitivity and specificity was identified using receiver operating characteristic analysis. RESULTS: A total of 165 infants born preterm (mean gestational age 26 ± 1.6 weeks, mean birth weight 837 ± 171 g) were included. Of these, 61 were treated with steroids for BPD and 104 were not. Risk estimates for BPD or death were significantly greater in infants treated with steroids compared with controls. Both combined risk for severe BPD or death and single risk of no BPD were identified as factors with the best predictive power for identifying treatment with steroids, with accurate prediction possible as early as the second week of life. A greater than 37% risk for severe BPD or death or a less than 3% risk of no BPD on day of life 14 had 84%-92% sensitivity and 77%-80% specificity for predicting steroid treatment. CONCLUSION: The NICHD BPD outcome estimator can be a useful objective tool for identifying infants at high risk for BPD who may benefit from postnatal steroids.

Single-Immunoglobulin Interleukin-1-Related Receptor regulates vulnerability to TLR4-mediated necrotizing enterocolitis in a mouse model.

BackgroundThe mechanisms underlying aberrant activation of intestinal Toll-like receptor 4 (TLR4) signaling in necrotizing enterocolitis (NEC) remain unclear. In this study, we examined the role of single-immunoglobulin interleukin-1 receptor-related molecule (SIGIRR), an inhibitor of TLR signaling, in modulating experimental NEC vulnerability in mice.MethodsExperimental NEC was induced in neonatal wild-type and SIGIRR-/- mice using hypoxia, formula-feeding, and lipopolysaccharide administration. Intestinal TLR canonical signaling, inflammation, apoptosis, and severity of experimental NEC were examined at baseline and after NEC induction in mice.ResultsSIGIRR is developmentally regulated in the neonatal intestine with a restricted expression after birth and a gradual increase by day 8. At baseline, breast-fed SIGIRR-/- mouse pups exhibited low-grade inflammation and TLR pathway activation compared with SIGIRR+/+ pups. With experimental NEC, SIGIRR-/- mice had significantly more intestinal interleukin (IL)-1ß, KC (mouse homolog to IL-8), intercellular adhesion molecule-1 (ICAM-1), and interferon-beta (IFN-ß) expression in association with the amplified TLR pathway activation. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining, cleaved caspase 3, and severity of intestinal injury with NEC were worse in SIGIRR-/- mice in comparison with SIGIRR+/+ mice.ConclusionSIGIRR is a negative regulator of TLR4 signaling in the developing intestine, and its insufficiency results in native intestinal TLR hyper-responsiveness conducive to the development of severe experimental NEC in mice.

Bowel ultrasound for predicting surgical management of necrotizing enterocolitis: a systematic review and meta-analysis.

BACKGROUND: Necrotizing enterocolitis (NEC) is a devastating inflammatory disease of the intestinal tract that represents a significant source of morbidity and mortality in preterm infants. Imaging of the abdomen is valuable for timely diagnosis and close monitoring of disease progression in NEC. Bowel ultrasound (US) is increasingly being recognized as an important imaging tool for evaluating NEC that provides additional detail than plain abdominal radiographs. OBJECTIVE: To identify bowel US findings associated with surgical management or death in infants with NEC. MATERIALS AND METHODS: We searched Embase, PubMed, and the Cumulative Index to Nursing and Allied Health Literature for studies investigating the association between bowel US findings and surgical management or death in NEC. Selected articles were evaluated for quality of study methodology using the Newcastle-Ottawa Scale, and aggregate statistics for odds ratio (OR) and 95% confidence interval were calculated. RESULTS: Of 521 articles reviewed, 11 articles comprising 748 infants were evaluated for quality. Nine of the studies were retrospective and from single-center experiences. Pooled analysis showed that focal fluid collections (OR 17.9, 3.1-103.3), complex ascites (OR 11.3, 4.2-30.0), absent peristalsis (OR 10.7, 1.7-69.0), pneumoperitoneum (OR 9.6, 1.7-56.3), bowel wall echogenicity (OR 8.6, 3.4-21.5), bowel wall thinning (OR 7.11.6-32.3), absent perfusion (OR 7.0, 2.1-23.8), bowel wall thickening (OR 3.9, 2.4-6.1) and dilated bowel (OR 3.5, 1.8-6.8) were associated with surgery or death in NEC. In contrast, portal venous gas (OR 3.0, 0.8-10.6), pneumatosis intestinalis (OR 2.1, 0.9-5.1), increased bowel perfusion (OR 2.6, 0.6-11.1) and simple ascites (OR 0.54, 0.1-2.5) were not associated with surgery or death. CONCLUSION: This meta-analysis identified several bowel US findings that are associated and not associated with surgery or death in NEC. Bowel US may be useful for early identification of high-risk infants with NEC who may benefit from more aggressive treatment, including surgery. Future studies are needed to determine whether the addition of bowel US in NEC evaluation would improve outcomes.

Quality Improvement Project to Reduce Delayed Vaccinations in Preterm Infants.

BACKGROUND: Preterm infants are especially vulnerable to infectious diseases. Although vaccinations are a safe and effective measure to protect preterm infants from vaccine-preventable diseases, delays in vaccinations are not uncommon. PURPOSE: The goal of this quality improvement project was to improve on time vaccinations of preterm infants hospitalized in the neonatal intensive care unit. METHODS: The Plan-Do-Study-Act model of quality improvement was adopted to develop, test, and implement interventions aimed at improving timely vaccination of preterm infants. The primary outcome measure of interest was the rate of on time vaccination, which was defined as the proportion of medically eligible preterm infants who received vaccinations within 2 weeks of the recommended schedule. RESULTS: Baseline on time vaccination rate was only 36%. Following several Plan-Do-Study-Act cycles, a steady increase in on time vaccinations of eligible infants was observed, and a new baseline on time vaccination rate of 82% was achieved. IMPLICATIONS FOR PRACTICE: Simple interventions implemented within the context of Plan-Do-Study-Act cycles are effective in improving timely vaccinations among preterm infants. IMPLICATIONS FOR RESEARCH: Future research that focuses on vaccinations in preterm infants is needed to further reinforce the safety and efficacy of vaccines. Effective methods on how to disseminate and apply this knowledge to practice should also be studied.Video Abstract available at http://links.lww.com/ANC/A27.

Regulation of alveolar septation by microRNA-489.

MicroRNAs (miRs) are small conserved RNA that regulate gene expression. Bioinformatic analysis of miRNA profiles during mouse lung development indicated a role for multiple miRNA, including miRNA-489. miR-489 increased on completion of alveolar septation [postnatal day 42 (P42)], associated with decreases in its conserved target genes insulin-like growth factor-1 (Igf1) and tenascin C (Tnc). We hypothesized that dysregulation of miR-489 and its target genes Igf1 and Tnc contribute to hyperoxia-induced abnormal lung development. C57BL/6 mice were exposed to normoxia (21%) or hyperoxia (85% O2) from P4 to P14, in combination with intranasal locked nucleic acid against miR-489 to inhibit miR-489, cytomegalovirus promoter (pCMV)-miR-489 to overexpress miR-489, or empty vector. Hyperoxia reduced miR-489 and increased Igf1 and Tnc. Locked nucleic acid against miR-489 improved lung development during hyperoxia and did not alter it during normoxia, whereas miR-489 overexpression inhibited lung development during normoxia. The 3' untranslated region in vitro reporter studies confirmed Igf1 and Tnc as targets of miR-489. While miR-489 was of epithelial origin and present in exosomes, its targets Igf1 and Tnc were produced by fibroblasts. Infants with bronchopulmonary dysplasia (BPD) had reduced lung miR-489 and increased Igf1 and Tnc compared with normal preterm or term infants. These results suggest increased miR-489 is an inhibitor of alveolar septation. During hyperoxia or BPD, reduced miR-489 and increased Igf1 and Tnc may be inadequate attempts at compensation. Further inhibition of miR-489 may permit alveolar septation to proceed. The use of specific miRNA antagonists or agonists may be a therapeutic strategy for inhibited alveolarization, such as in BPD.

Alterations in gene expression and DNA methylation during murine and human lung alveolar septation.

DNA methylation, a major epigenetic mechanism, may regulate coordinated expression of multiple genes at specific time points during alveolar septation in lung development. The objective of this study was to identify genes regulated by methylation during normal septation in mice and during disordered septation in bronchopulmonary dysplasia. In mice, newborn lungs (preseptation) and adult lungs (postseptation) were evaluated by microarray analysis of gene expression and immunoprecipitation of methylated DNA followed by sequencing (MeDIP-Seq). In humans, microarray gene expression data were integrated with genome-wide DNA methylation data from bronchopulmonary dysplasia versus preterm and term lung. Genes with reciprocal changes in expression and methylation, suggesting regulation by DNA methylation, were identified. In mice, 95 genes with inverse correlation between expression and methylation during normal septation were identified. In addition to genes known to be important in lung development (Wnt signaling, Angpt2, Sox9, etc.) and its extracellular matrix (Tnc, Eln, etc.), genes involved with immune and antioxidant defense (Stat4, Sod3, Prdx6, etc.) were also observed. In humans, 23 genes were differentially methylated with reciprocal changes in expression in bronchopulmonary dysplasia compared with preterm or term lung. Genes of interest included those involved with detoxifying enzymes (Gstm3) and transforming growth factor-ß signaling (bone morphogenetic protein 7 [Bmp7]). In terms of overlap, 20 genes and three pathways methylated during mouse lung development also demonstrated changes in methylation between preterm and term human lung. Changes in methylation correspond to altered expression of a number of genes associated with lung development, suggesting that DNA methylation of these genes may regulate normal and abnormal alveolar septation.

Integrated genomic analyses in bronchopulmonary dysplasia.

OBJECTIVE: To identify single-nucleotide polymorphisms (SNPs) and pathways associated with bronchopulmonary dysplasia (BPD) because O2 requirement at 36 weeks' postmenstrual age risk is strongly influenced by heritable factors. STUDY DESIGN: A genome-wide scan was conducted on 1.2 million genotyped SNPs, and an additional 7 million imputed SNPs, using a DNA repository of extremely low birth weight infants. Genome-wide association and gene set analysis was performed for BPD or death, severe BPD or death, and severe BPD in survivors. Specific targets were validated via the use of gene expression in BPD lung tissue and in mouse models. RESULTS: Of 751 infants analyzed, 428 developed BPD or died. No SNPs achieved genome-wide significance (P < 10(-8)), although multiple SNPs in adenosine deaminase, CD44, and other genes were just below P < 10(-6). Of approximately 8000 pathways, 75 were significant at false discovery rate (FDR) <0.1 and P < .001 for BPD/death, 95 for severe BPD/death, and 90 for severe BPD in survivors. The pathway with lowest FDR was miR-219 targets (P = 1.41E-08, FDR 9.5E-05) for BPD/death and phosphorous oxygen lyase activity (includes adenylate and guanylate cyclases) for both severe BPD/death (P = 5.68E-08, FDR 0.00019) and severe BPD in survivors (P = 3.91E-08, FDR 0.00013). Gene expression analysis confirmed significantly increased miR-219 and CD44 in BPD. CONCLUSIONS: Pathway analyses confirmed involvement of known pathways of lung development and repair (CD44, phosphorus oxygen lyase activity) and indicated novel molecules and pathways (adenosine deaminase, targets of miR-219) involved in genetic predisposition to BPD.

B-type natriuretic peptide and mortality in extremely low birth weight infants with pulmonary hypertension: a retrospective cohort analysis.

BACKGROUND: B-type natriuretic peptide (BNP) is a strong predictor of mortality in adult patients with various forms of pulmonary hypertension (PH) and may be a strong prognostic marker in extremely low birth weight (ELBW) infants with bronchopulmonary dysplasia (BPD) associated PH as well. We sought to assess the relationship between BNP levels and all-cause mortality in a cohort of ELBW infants with BPD and PH. METHODS: We retrospectively identified ELBW infants with BPD and PH who had serum BNP levels measured as part of routine clinical care in the neonatal intensive care unit. Peak serum BNP levels were correlated with survival to discharge or death. RESULTS: Thirty-six ELBW infants (mean gestational age 26.0 ± 1.9 weeks and mean birth weight 740 ± 290 grams) with BPD and PH had available survival data and had serum BNP levels measured. Peak BNP level was significantly lower among infants who survived than among those who died (128 pg/ml, [IQR 23 to 463] vs. 997 pg/ml, [IQR 278 to 1770], P < 0.004). On multivariate Cox proportional hazard analysis, BNP predicted survival independent of age, gender, and BPD severity. Area under receiver operator characteristic analysis identified a BNP value of 220 pg/ml to have 90% sensitivity and 65% specificity in predicting mortality. CONCLUSION: BNP estimation may be useful as a prognostic marker of all-cause mortality in ELBW infants with BPD associated PH.

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.

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.

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.

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.

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.