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.

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.

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.

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.

Bowel Ultrasound for the Diagnosis of Necrotizing Enterocolitis: A Meta-analysis.

Radiographic evaluation for necrotizing enterocolitis (NEC) often yields nonspecific findings. Bowel ultrasound (BUS) provides additional information beyond that of abdominal radiographs and may be helpful in the diagnosis of NEC in neonates. We systematically reviewed and aggregated existing literature to get a better estimate of diagnostic accuracy of BUS in the diagnosis of NEC. A literature search was performed using PubMed, Embase, and Cumulative Index to Nursing and Allied Health Literature to identify studies in which infants with clinically suspected NEC were evaluated using BUS. Studies that used modified Bell staging criteria as the reference standard were included. Study quality was assessed, and pooled sensitivity and specificity of various BUS findings for diagnosing NEC were determined. Six articles with a total of 462 patients met eligibility and inclusion criteria. There was heterogeneity in BUS findings evaluated across studies. Ultrasound detection of classic signs of NEC (portal venous gas, pneumatosis, and free air) had pooled sensitivities ranging from 0.27 to 0.48 and pooled specificities ranging from 0.91 to 0.99. Bowel wall thinning and absent peristalsis had overall low sensitivity (0.22 and 0.30) but high specificity (0.96 and 0.96) for NEC. Assessment of abdominal fluid, which included ascites and focal fluid collection, also had overall low sensitivity and high specificity (simple ascites: 0.45 and 0.92; focal fluid collection: 0.19 and 0.98). In summary, individual BUS findings have low sensitivity and high specificity for diagnosis of NEC. Bowel ultrasound may be a useful adjunct to plain abdominal radiographs in the evaluation of infants with clinical suspicion of NEC.