Necrotizing Enterocolitis: Clinical Features, Histopathological Characteristics,
and Genetic Associations

Akhil      Maheshwari; Terri   M.   Traub; Parvesh   M.   Garg; Yahya      Ethawi; Giuseppe      Buonocore
Abstract

Necrotizing enterocolitis (NEC) is an inflammatory bowel necrosis seen in premature infants. Although the etiopathogenesis of NEC is unclear, genetic factors may alter a patient's susceptibility, clinical course, and outcomes. This review draws from existing studies focused on individual genes and others based on microarray-based high-throughput discovery techniques. We have included evidence from our own studies and from an extensive literature search in the databases PubMed, EMBASE, and Scopus. To avoid bias in the identification of studies, keywords were short-listed a priori from anecdotal experience and PubMed’s Medical Subject Heading (MeSH) thesaurus.
Keywords: Necrotizing enterocolitis, clinical, histopathology, genetic, genomic, microarray, necrosis.
« Previous Next »
[1] 
Gephart SM, Gordon PV, Penn AH, et al. Changing the paradigm of defining, detecting, and diagnosing NEC: Perspectives on Bell’s stages and biomarkers for NEC. Semin Pediatr Surg  2018; 27(1): 3-10.
[http://dx.doi.org/10.1053/j.sempedsurg.2017.11.002] [PMID:  29275814] 
[2] 
Stoll BJ, Hansen NI, Bell EF, et al. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal research network. Pediatrics  2010; 126(3): 443-56.
[http://dx.doi.org/10.1542/peds.2009-2959] [PMID:  20732945] 
[3] 
MohanKumar K. Namachivayam K, Ho TT, Torres BA, Ohls RK, Maheshwari A. Cytokines and growth factors in the developing intestine and during necrotizing enterocolitis. Semin Perinatol  2017; 41(1): 52-60.
[http://dx.doi.org/10.1053/j.semperi.2016.09.018] [PMID:  27832931] 
[4] 
Been JV, Lievense S, Zimmermann LJ, Kramer BW, Wolfs TG. Chorioamnionitis as a risk factor for necrotizing enterocolitis: A systematic review and meta-analysis. J Pediatr  2013; 162(2): 236-42.e2.
[http://dx.doi.org/10.1016/j.jpeds.2012.07.012] [PMID:  22920508] 
[5] 
Hällström M, Koivisto AM, Janas M, Tammela O. Frequency of and risk factors for necrotizing enterocolitis in infants born before 33 weeks of gestation. Acta Paediatr  2003; 92(1): 111-3.
[http://dx.doi.org/10.1111/j.1651-2227.2003.tb00479.x] [PMID:  12650310] 
[6] 
Gellen B, Kovacs J, Nemeth L, et al. Vascular changes play a role in the pathogenesis of necrotizing enterocolitis in asphyxiated newborn pigs. Pediatr Surg Int  2003; 19(5): 380-4.
[http://dx.doi.org/10.1007/s00383-003-1015-4] [PMID:  12756598] 
[7] 
Goldberg RN, Thomas DW, Sinatra FR. Necrotizing enterocolitis in the asphyxiated full-term infant. Am J Perinatol  1983; 1(1): 40-2.
[http://dx.doi.org/10.1055/s-2007-1000050] [PMID:  6680650] 
[8] 
Gaynes RP, Palmer S, Martone WJ, et al. The role of host factors in an outbreak of necrotizing enterocolitis. Am J Dis Child  1984; 138(12): 1118-20.
[http://dx.doi.org/10.1001/archpedi.1984.02140500024007] [PMID:  6507393] 
[9] 
Patel RM, Knezevic A, Shenvi N, et al. Association of red blood cell transfusion, anemia, and necrotizing enterocolitis in very lowbirth- weight infants. JAMA  2016; 315(9): 889-97.
[http://dx.doi.org/10.1001/jama.2016.1204] [PMID:  26934258] 
[10] 
Patel RM, Kandefer S, Walsh MC, et al. Causes and timing of death in extremely premature infants from 2000 through 2011. N Engl J Med  2015; 372(4): 331-40.
[http://dx.doi.org/10.1056/NEJMoa1403489] [PMID:  25607427] 
[11] 
MohanKumar K, Nanachivayam K, Song T, et al. . A murine neonatal model of necrotizing enterocolitis caused by anemia and red blood cell transfusions. Nat Commun  2019; 10(1): 3494.
[http://dx.doi.org/10.1038/s41467-019-11199-5] [PMID:  31375667] 
[12] 
Garg PM, Bernieh A, Hitt MM, et al. Incomplete resection of necrotic bowel may increase mortality in infants with necrotizing enterocolitis. Pediatr Res  2021; 89(1): 163-70.
[http://dx.doi.org/10.1038/s41390-020-0975-6] [PMID:  32438367] 
[13] 
Garg PM, Hitt MM, Blackshear C, Maheshwari A. Clinical determinants of postoperative outcomes in surgical necrotizing enterocolitis. J Perinatol  2020; 40(11): 1671-8.
[http://dx.doi.org/10.1038/s41372-020-0728-8] [PMID:  32669645] 
[14] 
Remon JI, Amin SC, Mehendale SR, et al. Depth of bacterial invasion in resected intestinal tissue predicts mortality in surgical necrotizing enterocolitis. J Perinatol  2015; 35(9): 755-62.
[http://dx.doi.org/10.1038/jp.2015.51] [PMID:  25950918] 
[15] 
Remon J, Kampanatkosol R, Kaul RR, Muraskas JK, Christensen RD, Maheshwari A. Acute drop in blood monocyte count differentiates NEC from other causes of feeding intolerance. J Perinatol  2014; 34(7): 549-54.
[http://dx.doi.org/10.1038/jp.2014.52] [PMID:  24674979] 
[16] 
Ballance WA, Dahms BB, Shenker N, Kliegman RM. Pathology of neonatal necrotizing enterocolitis: a ten-year experience. J Pediatr  1990; 117(1 Pt 2): S6-S13.
[http://dx.doi.org/10.1016/S0022-3476(05)81124-2] [PMID:  2362230] 
[17] 
Santulli TV, Schullinger JN, Heird WC, et al. Acute necrotizing enterocolitis in infancy: A review of 64 cases. Pediatrics  1975; 55(3): 376-87.
[PMID:  1143976] 
[18] 
MohanKumar K, Kaza N, Jagadeeswaran R, et al.. Gut mucosal injury in neonates is marked by macrophage infiltration in contrast to pleomorphic infiltrates in adult: Evidence from an animal model. Am J Physiol Gastrointest Liver Physiol  2012; 303(1): G93-G102.
[http://dx.doi.org/10.1152/ajpgi.00016.2012] [PMID:  22538401] 
[19] 
Mohankumar KM, Perry JK, Kannan N, et al. Transcriptional activation of signal transducer and activator of transcription (STAT) 3 and STAT5B partially mediate homeobox A1-stimulated oncogenic transformation of the immortalized human mammary epithelial cell. Endocrinology  2008; 149(5): 2219-29.
[http://dx.doi.org/10.1210/en.2007-1320] [PMID:  18276758] 
[20] 
Pender SL, Braegger C, Gunther U, et al. Matrix metalloproteinases in necrotising enterocolitis. Pediatr Res  2003; 54(2): 160-4.
[http://dx.doi.org/10.1203/01.PDR.0000072326.23442.C3] [PMID:  12736398] 
[21] 
Bomelburg T, von Lengerke HJ. Sonographic findings in infants with suspected necrotizing enterocolitis. Eur J Radiol  1992; 15(2): 149-53.
[http://dx.doi.org/10.1016/0720-048X(92)90143-W] [PMID:  1425753] 
[22] 
Cuna AC, Lee JC, Robinson AL, Allen NH, Foley JE, Chan SS. Bowel ultrasound for the diagnosis of necrotizing enterocolitis: A Meta-analysis. Ultrasound Q  2018; 34(3): 113-8.
[http://dx.doi.org/10.1097/RUQ.0000000000000342] [PMID:  29369246] 
[23] 
MohanKumar K, Namachivayam K, Cheng F, et al. Trinitrobenzene
	sulfonic acid-induced intestinal injury in neonatal mice activates
transcriptional networks similar to those seen in human necrotizing	enterocolitis. Pediatr Res 2016; 81(1-1): 99-112.. 
[http://dx.doi.org/10.1038/pr.2016.189] [PMID: 27656771] 
[24] 
Namachivayam K, Blanco CL. , MohanKumar K, et al. Smad7 inhibits autocrine expression of TGF-β2 in intestinal epithelial cells in baboon necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol  2013; 304(2): G167-80.
[http://dx.doi.org/10.1152/ajpgi.00141.2012] [PMID:  23154975] 
[25] 
Namachivayam K, Blanco CL, Frost BL, et al. Preterm human milk contains a large pool of latent TGF-β which can be activated byexogenous neuraminidase. Am J Physiol Gastrointest Liver Physiol  2013; 304(12): G1055-65.
[http://dx.doi.org/10.1152/ajpgi.00039.2013] [PMID:  23558011] 
[26] 
Namachivayam K, Coffing HP, Sankaranarayanan NV, et al. Transforming growth factor-β2 is sequestered in preterm human milk by chondroitin sulfate proteoglycans. Am J Physiol Gastrointest Liver Physiol  2015; 309(3): G171-80.
[http://dx.doi.org/10.1152/ajpgi.00126.2015] [PMID:  26045614] 
[27] 
Maheshwari A, Kelly DR, Nicola T, et al. TGF-β2 suppresses macrophage cytokine production and mucosal inflammatory responses in the developing intestine. Gastroenterology  2011; 140(1): 242-53.
[http://dx.doi.org/10.1053/j.gastro.2010.09.043] [PMID:  20875417] 
[28] 
Bowker RM, Yan X, Managlia E, et al. Dimethyloxalylglycine preserves the intestinal microvasculature and protects against intestinal injury in a neonatal mouse NEC model: Role of VEGF signaling. Pediatr Res  2018; 83(2): 545-53.
[http://dx.doi.org/10.1038/pr.2017.219] [PMID:  29068435] 
[29] 
Managlia E, Liu SXL, Yan X, et al. Blocking NF-κB activation in Ly6c+ monocytes attenuates necrotizing enterocolitis. Am J Pathol  2019; 189(3): 604-18.
[http://dx.doi.org/10.1016/j.ajpath.2018.11.015] [PMID:  30593820] 
[30] 
Yan X, Managlia E, Liu SX, et al. Lack of VEGFR2 signaling causes maldevelopment of the intestinal microvasculature and facilitates necrotizing enterocolitis in neonatal mice. Am J Physiol Gastrointest Liver Physiol  2016; 310(9): G716-25.
[http://dx.doi.org/10.1152/ajpgi.00273.2015] [PMID:  26950855] 
[31] 
Wang Y, Hoenig JD, Malin KJ, et al. 16S rRNA gene-based analysis of fecal microbiota from preterm infants with and without necrotizing enterocolitis. ISME J  2009; 3(8): 944-54.
[http://dx.doi.org/10.1038/ismej.2009.37] [PMID:  19369970] 
[32] 
Brower-Sinning R, Zhong D, Good M, et al. Mucosa-associated bacterial diversity in necrotizing enterocolitis. PLoS One  2014; 9(9), e105046.
[http://dx.doi.org/10.1371/journal.pone.0105046] [PMID:  25203729] 
[33] 
Morrow AL, Lagomarcino AJ, Schibler KR, et al. Early microbial and metabolomic signatures predict later onset of necrotizing enterocolitis in preterm infants. Microbiome  2013; 1(1): 13.
[http://dx.doi.org/10.1186/2049-2618-1-13] [PMID:  24450576] 
[34] 
Torrazza RM, Ukhanova M, Wang X, et al. Intestinal microbial ecology and environmental factors affecting necrotizing enterocolitis. PLoS One  2013; 8(12), e83304.
[http://dx.doi.org/10.1371/journal.pone.0083304] [PMID:  24386174] 
[35] 
Hsueh W, Caplan MS, Tan X, MacKendrick W, Gonzalez-Crussi F. Necrotizing enterocolitis of the newborn: pathogenetic concepts in perspective. Pediatr Dev Pathol  1998; 1(1): 2-16.
[http://dx.doi.org/10.1007/s100249900002] [PMID:  10463267] 
[36] 
Gonzalez-Rivera R, Culverhouse RC, Hamvas A, Tarr PI, Warner BB. The age of necrotizing enterocolitis onset: an application of Sartwell’s incubation period model. J Perinatol  2011; 31(8): 519-23.
[http://dx.doi.org/10.1038/jp.2010.193] [PMID:  21273988] 
[37] 
Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med  2011; 364(3): 255-64.
[http://dx.doi.org/10.1056/NEJMra1005408] [PMID:  21247316] 
[38] 
Holman RC, Stoll BJ, Clarke MJ, Glass RI. The epidemiology of necrotizing enterocolitis infant mortality in the United States. Am J Public Health  1997; 87(12): 2026-31.
[http://dx.doi.org/10.2105/AJPH.87.12.2026] [PMID:  9431297] 
[39] 
Guner YS, Friedlich P, Wee CP, Dorey F, Camerini V, Upperman JS. State-based analysis of necrotizing enterocolitis outcomes. J Surg Res  2009; 157(1): 21-9.
[http://dx.doi.org/10.1016/j.jss.2008.11.008] [PMID:  19615694] 
[40] 
Maheshwari A, Schelonka RL, Dimmitt RA, et al. Cytokines associated with necrotizing enterocolitis in extremely-low-birth-weight infants. Pediatr Res  2014; 76(1): 100-8.
[http://dx.doi.org/10.1038/pr.2014.48] [PMID:  24732104] 
[41] 
Jones IH, Hall NJ. Contemporary outcomes for infants with necrotizing enterocolitis-a systematic review. J Pediatr  2020; 220: 86-92.e3.
[http://dx.doi.org/10.1016/j.jpeds.2019.11.011] [PMID:  31982088] 
[42] 
MohanKumar K, Namachivayam K, Chapalamadugu KC, et al.. Smad7 interrupts TGF-β signaling in intestinal macrophages and promotes inflammatory activation of these cells during necrotizing enterocolitis. Pediatr Res  2016; 79(6): 951-61.
[http://dx.doi.org/10.1038/pr.2016.18] [PMID:  26859364] 
[43] 
Bhandari V, Bizzarro MJ, Shetty A, et al. Familial and genetic susceptibility to major neonatal morbidities in preterm twins. Pediatrics  2006; 117(6): 1901-6.
[http://dx.doi.org/10.1542/peds.2005-1414] [PMID:  16740829] 
[44] 
Detlefsen B, Boemers TM, Schimke C. Necrotizing enterocolitis in premature twins with twin-to-twin transfusion syndrome. Eur J Pediatr Surg  2008; 18(1): 50-2.
[http://dx.doi.org/10.1055/s-2007-965788] [PMID:  18302071] 
[45] 
Wiswell TE, Hankins CT. Twins and triplets with necrotizing enterocolitis. Am J Dis Child  1988; 142(9): 1004-6.
[http://dx.doi.org/10.1001/archpedi.1988.02150090102035] [PMID:  3414612] 
[46] 
Tepas JJ III, Sharma R, Leaphart CL, Celso BG, Pieper P. Esquivia- Lee V. Timing of surgical intervention in necrotizing enterocolitis can be determined by trajectory of metabolic derangement. J Pediatr Surg  2010; 45(2): 310-3.
[http://dx.doi.org/10.1016/j.jpedsurg.2009.10.069] [PMID:  20152342] 
[47] 
Ashburner M, Ball CA, Blake JA, et al. Gene ontology: tool for the unification of biology. Nat Genet  2000; 25(1): 25-9.
[http://dx.doi.org/10.1038/75556] [PMID:  10802651] 
[48] 
Briones-Orta MA, Sosa-Garrocho M, Moreno-Alvarez P. Fonseca- Sanchez MA, Macias-Silva M. SnoN co-repressor binds and represses smad7 gene promoter. Biochem Biophys Res Commun  2006; 341(3): 889-94.
[http://dx.doi.org/10.1016/j.bbrc.2006.01.041] [PMID:  16442497] 
[49] 
Jahchan NS, Luo K. SnoN in mammalian development, function and diseases. Curr Opin Pharmacol  2010; 10(6): 670-5.
[http://dx.doi.org/10.1016/j.coph.2010.08.006] [PMID:  20822955] 
[50] 
Ausio J, van Holde KE. Histone hyperacetylation: Its effects on nucleosome conformation and stability. Biochemistry  1986; 25(6): 1421-8.
[http://dx.doi.org/10.1021/bi00354a035] [PMID:  3964683] 
[51] 
Prajapati S, Gaynor RB. Regulation of Ikappa B kinase (IKK)gamma/NEMO function by IKKbeta -mediated phosphorylation. J Biol Chem  2002; 277(27): 24331-9.
[http://dx.doi.org/10.1074/jbc.M201393200] [PMID:  11971901] 
[52] 
Huang W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc  2009; 4(1): 44-57.
[http://dx.doi.org/10.1038/nprot.2008.211] [PMID:  19131956] 
[53] 
Jilling T, Lu J, Jackson M, Caplan MS. Intestinal epithelial apoptosis initiates gross bowel necrosis in an experimental rat model of neonatal necrotizing enterocolitis. Pediatr Res  2004; 55(4): 622-9.
[http://dx.doi.org/10.1203/01.PDR.0000113463.70435.74] [PMID:  14764921] 
[54] 
Wright K, Kolios G, Westwick J, Ward SG. Cytokine-induced apoptosis in epithelial HT-29 cells is independent of nitric oxide formation. Evidence for an interleukin-13-driven phosphatidylinositol 3-kinase-dependent survival mechanism. J Biol Chem  1999; 274(24): 17193-201.
[http://dx.doi.org/10.1074/jbc.274.24.17193] [PMID:  10358077] 
[55] 
Waterhouse CC, Joseph RR, Stadnyk AW. Endogenous IL-1 and type II IL-1 receptor expression modulate anoikis in intestinal epithelial cells. Exp Cell Res  2001; 269(1): 109-16.
[http://dx.doi.org/10.1006/excr.2001.5303] [PMID:  11525644] 
[56] 
Bucher BT, McDuffie LA, Shaikh N, et al. Bacterial DNA content in the intestinal wall from infants with necrotizing enterocolitis. J Pediatr Surg  2011; 46(6): 1029-33.
[http://dx.doi.org/10.1016/j.jpedsurg.2011.03.026] [PMID:  21683193] 
[57] 
Chen G, Li Y, Su Y, et al. Identification of candidate genes for necrotizing enterocolitis based on microarray data. Gene  2018; 661: 152-9.
[http://dx.doi.org/10.1016/j.gene.2018.03.088] [PMID:  29605607] 
[58] 
Jung K, Koh I, Kim JH, et al. RNA-Seq for gene expression profiling of human necrotizing enterocolitis: a pilot study. J Korean Med Sci  2017; 32(5): 817-24.
[http://dx.doi.org/10.3346/jkms.2017.32.5.817] [PMID:  28378556] 
[59] 
Egan CE, Sodhi CP, Good M, et al. Toll-like receptor 4-mediated	lymphocyte influx induces neonatal necrotizing enterocolitis. J Clin
	Invest 2016; 126(2): 495-508.. 
[http://dx.doi.org/10.1172/JCI83356] [PMID: 26690704] 
[60] 
Fukata M, Michelsen KS, Eri R, et al. Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis. Am J Physiol Gastrointest Liver Physiol  2005; 288(5): G1055-65.
[http://dx.doi.org/10.1152/ajpgi.00328.2004] [PMID:  15826931] 
[61] 
Meng D, Zhu W, Shi HN, et al. Toll-like receptor-4 in human and mouse colonic epithelium is developmentally regulated: A possible role in necrotizing enterocolitis. Pediatr Res  2015; 77(3): 416-24.
[http://dx.doi.org/10.1038/pr.2014.207] [PMID:  25521917] 
[62] 
Leaphart CL, Cavallo J, Gribar SC, et al. A critical role for TLR4 in the pathogenesis of necrotizing enterocolitis by modulating intestinal injury and repair. J Immunol  2007; 179(7): 4808-20.
[http://dx.doi.org/10.4049/jimmunol.179.7.4808] [PMID:  17878380] 
[63] 
Richardson WM, Dai S, Dyer M, Russo A. Toll like receptor-4 activation links enterocyte autophagy with apoptosis via the stress response gene ATG 16 in the pathogenesis of necrotizing enterocolitis. J Surg Res  2010; 158: 209.
[http://dx.doi.org/10.1016/j.jss.2009.11.113] 
[64] 
Le Mandat Schultz A, Bonnard A, Barreau F, et al. Expression of TLR-2, TLR-4, NOD2 and pNF-kappaB in a neonatal rat model of necrotizing enterocolitis. PLoS One  2007; 2(10), e1102.
[http://dx.doi.org/10.1371/journal.pone.0001102] [PMID:  17971865] 
[65] 
Cuna A, Yu W, Menden HL, et al. NEC-like intestinal injury is ameliorated by Lactobacillus rhamnosus GG in parallel with SIGIRR and A20 induction in neonatal mice. Pediatr Res  2020; 88(4): 546-55.
[http://dx.doi.org/10.1038/s41390-020-0797-6] [PMID:  32053825] 
[66] 
Sampath V, Menden H, Helbling D, et al. SIGIRR genetic variants in premature infants with necrotizing enterocolitis. Pediatrics  2015; 135(6): e1530-4.
[http://dx.doi.org/10.1542/peds.2014-3386] [PMID:  25963006] 
[67] 
Nanthakumar N, Meng D, Goldstein AM, et al. The mechanism of excessive intestinal inflammation in necrotizing enterocolitis: an immature innate immune response. PLoS One  2011; 6(3), e17776.
[http://dx.doi.org/10.1371/journal.pone.0017776] [PMID:  21445298] 
[68] 
Sampath V, Bhandari V, Berger J, et al. A functional ATG16L1 (T300A) variant is associated with necrotizing enterocolitis in premature infants. Pediatr Res  2017; 81(4): 582-8.
[http://dx.doi.org/10.1038/pr.2016.260] [PMID:  27893720] 
[69] 
Caplan MS, Simon D, Jilling T. The role of PAF, TLR, and the inflammatory response in neonatal necrotizing enterocolitis. Semin Pediatr Surg  2005; 14(3): 145-51.
[http://dx.doi.org/10.1053/j.sempedsurg.2005.05.002] [PMID:  16084401] 
[70] 
Caplan MS, Sun XM, Hsueh W, Hypoxia PAF. Hypoxia, PAF, and necrotizing enterocolitis. Lipids  1991; 26(12): 1340-3.
[http://dx.doi.org/10.1007/BF02536562] [PMID:  1819729] 
[71] 
Muguruma K, Gray PW, Tjoelker LW, Johnston JM. The central role of PAF in necrotizing enterocolitis development. Adv Exp Med Biol  1997; 407: 379-82.
[http://dx.doi.org/10.1007/978-1-4899-1813-0_56] [PMID:  9321979] 
[72] 
Sun XM, Hsueh W, Torre-Amione G. Effects of in vivo ‘priming’ on endotoxin-induced hypotension and tissue injury. The role of PAF and tumor necrosis factor. Am J Pathol  1990; 136(4): 949-56.
[PMID:  2327475] 
[73] 
De Plaen IG, Liu SX, Tian R, et al. Inhibition of nuclear factorkappaB ameliorates bowel injury and prolongs survival in a neonatal rat model of necrotizing enterocolitis. Pediatr Res  2007; 61(6): 716-21.
[http://dx.doi.org/10.1203/pdr.0b013e3180534219] [PMID:  17426653] 
[74] 
Kumar A, Chatterjee I, Gujral T, et al. Activation of nuclear Factor- κB by tumor necrosis factor in intestinal epithelial cells and mouse intestinal epithelia reduces expression of the chloride transporter SLC26A3. Gastroenterology  2017; 153(5): 1338-1350.e3.
[http://dx.doi.org/10.1053/j.gastro.2017.08.024] [PMID:  28823863] 
[75] 
Li ZW, Chu W, Hu Y, et al. The IKKbeta subunit of IkappaB kinase (IKK) is essential for nuclear factor kappaB activation and prevention of apoptosis. J Exp Med  1999; 189(11): 1839-45.
[http://dx.doi.org/10.1084/jem.189.11.1839] [PMID:  10359587] 
[76] 
Lichanska AM, Browne CM, Henkel GW, et al. Differentiation of the mononuclear phagocyte system during mouse embryogenesis: the role of transcription factor PU.1. Blood  1999; 94(1): 127-38.
[http://dx.doi.org/10.1182/blood.V94.1.127.413k07_127_138] [PMID:  10381505] 
[77] 
Liu SX, Tian R, Baskind H, Hsueh W, De Plaen IG. Plateletactivating factor induces the processing of nuclear factor-kappaB p105 into p50, which mediates acute bowel injury in mice. Am J Physiol Gastrointest Liver Physiol  2009; 297(1): G76-81.
[http://dx.doi.org/10.1152/ajpgi.00053.2009] [PMID:  19460845] 
[78] 
Lotan R, Clifford JL. Nuclear receptors for retinoids: mediators of retinoid effects on normal and malignant cells. Biomed Pharmacother  1991; 45(4-5): 145-56.
[http://dx.doi.org/10.1016/0753-3322(91)90102-Y] [PMID:  1657236] 
[79] 
Miller JE, Whitman GJ, Iozzo RV, Jacobs DO, Ziegler MM. Early diagnosis of experimental necrotizing enterocolitis using proton nuclear magnetic resonance. J Surg Res  1985; 39(4): 322-30.
[http://dx.doi.org/10.1016/0022-4804(85)90110-6] [PMID:  3876481] 
[80] 
Musemeche C, Caplan M, Hsueh W, Sun X, Kelly A. Experimental necrotizing enterocolitis: The role of polymorphonuclear neutrophils. J Pediatr Surg  1991; 26(9): 1047-9.
[http://dx.doi.org/10.1016/0022-3468(91)90671-F] [PMID:  1941482] 
[81] 
Qualls JE, Kaplan AM, van Rooijen N, Cohen DA. Suppression of experimental colitis by intestinal mononuclear phagocytes. J Leukoc Biol  2006; 80(4): 802-15.
[http://dx.doi.org/10.1189/jlb.1205734] [PMID:  16888083] 
[82] 
Claud EC, Lu L, Anton PM, Savidge T, Walker WA, Cherayil BJ. Developmentally regulated IkappaB expression in intestinal epithelium and susceptibility to flagellin-induced inflammation. Proc Natl Acad Sci USA  2004; 101(19): 7404-8.
[http://dx.doi.org/10.1073/pnas.0401710101] [PMID:  15123821] 
[83] 
Maheshwari A. Role of cytokines in human intestinal villous development. Clin Perinatol  2004; 31(1): 143-55.
[http://dx.doi.org/10.1016/j.clp.2004.03.003] [PMID:  15183663] 
[84] 
Viscardi RM, Lyon NH, Sun CC, Hebel JR, Hasday JD. Inflammatory cytokine mRNAs in surgical specimens of necrotizing enterocolitis and normal newborn intestine. Pediatr Pathol Lab Med  1997; 17(4): 547-59.
[http://dx.doi.org/10.1080/15513819709168731] [PMID:  9211547] 
[85] 
Caplan MS, Sun XM, Hseuh W, Hageman JR. Role of platelet activating factor and tumor necrosis factor-alpha in neonatal necrotizing enterocolitis. J Pediatr  1990; 116(6): 960-4.
[http://dx.doi.org/10.1016/S0022-3476(05)80661-4] [PMID:  2348301] 
[86] 
Tan X, Hsueh W, Gonzalez-Crussi F. Cellular localization of tumor necrosis factor (TNF)-alpha transcripts in normal bowel and in necrotizing enterocolitis. TNF gene expression by Paneth cells, intestinal eosinophils, and macrophages. Am J Pathol  1993; 142(6): 1858-65.
[PMID:  8506954] 
[87] 
McILwain RB, Timpa JG, Kurundkar AR, et al.. Plasma concentrations of inflammatory cytokines rise rapidly during ECMO-related SIRS due to the release of preformed stores in the intestine. Lab Invest  2010; 90(1): 128-39.
[http://dx.doi.org/10.1038/labinvest.2009.119] [PMID:  19901912] 
[88] 
Carlo WA, McDonald SA, Tyson JE, et al. Cytokines and neurodevelopmental outcomes in extremely low birth weight infants. J Pediatr  2011; 159(6): 919-25.e3.
[http://dx.doi.org/10.1016/j.jpeds.2011.05.042] [PMID:  21798559] 
[89] 
Harris MC, Costarino AT Jr, Sullivan JS, et al. Cytokine elevations in critically ill infants with sepsis and necrotizing enterocolitis. J Pediatr  1994; 124(1): 105-11.
[http://dx.doi.org/10.1016/S0022-3476(94)70264-0] [PMID:  8283358] 
[90] 
Edelson MB, Bagwell CE, Rozycki HJ. Circulating pro- and counterinflammatory cytokine levels and severity in necrotizing enterocolitis. Pediatrics  1999; 103(4 Pt 1): 766-71.
[http://dx.doi.org/10.1542/peds.103.4.766] [PMID:  10103300] 
[91] 
Ford HR, Sorrells DL, Knisely AS. Inflammatory cytokines, nitric oxide, and necrotizing enterocolitis. Semin Pediatr Surg  1996; 5(3): 155-9.
[PMID:  8858761] 
[92] 
Ng PC, Li K, Wong RP, et al. Proinflammatory and antiinflammatory cytokine responses in preterm infants with systemic infections. Arch Dis Child Fetal Neonatal Ed  2003; 88(3): F209-13.
[http://dx.doi.org/10.1136/fn.88.3.F209] [PMID:  12719394] 
[93] 
Harris MC, D’Angio CT, Gallagher PR, Kaufman D, Evans J, Kilpatrick L. Cytokine elaboration in critically ill infants with bacterial sepsis, necrotizing entercolitis, or sepsis syndrome: correlation with clinical parameters of inflammation and mortality. J Pediatr  2005; 147(4): 462-8.
[http://dx.doi.org/10.1016/j.jpeds.2005.04.037] [PMID:  16227031] 
[94] 
Benkoe T, Baumann S, Weninger M, et al. Comprehensive evaluation of 11 cytokines in premature infants with surgical necrotizing enterocolitis. PLoS One  2013; 8(3), e58720.
[http://dx.doi.org/10.1371/journal.pone.0058720] [PMID:  23472217] 
[95] 
Lodha A, Asztalos E, Moore AM. Cytokine levels in neonatal necrotizing enterocolitis and long-term growth and neurodevelopment. Acta Paediatr  2010; 99(3): 338-43.
[http://dx.doi.org/10.1111/j.1651-2227.2009.01600.x] [PMID:  19922507] 
[96] 
Benkoe T, Reck C, Pones M, et al. Interleukin-8 predicts 60-day mortality in premature infants with necrotizing enterocolitis. J Pediatr Surg  2014; 49(3): 385-9.
[http://dx.doi.org/10.1016/j.jpedsurg.2013.05.068] [PMID:  24650462] 
[97] 
Bhatia AM, Stoll BJ, Cismowski MJ, Hamrick SE. Cytokine levels in the preterm infant with neonatal intestinal injury. Am J Perinatol  2014; 31(6): 489-96.
[http://dx.doi.org/10.1055/s-0033-1353437] [PMID:  23966125] 
[98] 
Sharma R, Tepas JJ III, Hudak ML, et al. Neonatal gut barrier and multiple organ failure: Role of endotoxin and proinflammatory cytokines in sepsis and necrotizing enterocolitis. J Pediatr Surg  2007; 42(3): 454-61.
[http://dx.doi.org/10.1016/j.jpedsurg.2006.10.038] [PMID:  17336180] 
[99] 
Tremblay E, Ferretti E, Babakissa C, Burghardt KM, Levy E, Beaulieu JF. IL-17-related signature genes linked to human necrotizing enterocolitis. BMC Res Notes  2021; 14(1): 82.
[http://dx.doi.org/10.1186/s13104-021-05489-9] [PMID:  33663574] 
[100] 
Szpecht D. , Neumann-Klimasińska N, Błaszczyński M, et al. Candidate gene analysis in pathogenesis of surgically and nonsurgically treated necrotizing enterocolitis in preterm infants. Mol Cell Biochem  2018; 439(1-2): 53-63.
[http://dx.doi.org/10.1007/s11010-017-3135-5] [PMID:  28770467] 
[101] 
Henderson G, Craig S, Baier RJ, Helps N, Brocklehurst P, McGuire W. Cytokine gene polymorphisms in preterm infants with necrotising enterocolitis: Genetic association study. Arch Dis Child Fetal Neonatal Ed  2009; 94(2): F124-8.
[http://dx.doi.org/10.1136/adc.2007.119933] [PMID:  17768156] 
[102] 
Miettinen PJ, Berger JE, Meneses J, et al. Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor. Nature  1995; 376(6538): 337-41.
[http://dx.doi.org/10.1038/376337a0] [PMID:  7630400] 
[103] 
Clark JA, Doelle SM, Halpern MD, et al. Intestinal barrier failure during experimental necrotizing enterocolitis: protective effect of EGF treatment. Am J Physiol Gastrointest Liver Physiol  2006; 291(5): G938-49.
[http://dx.doi.org/10.1152/ajpgi.00090.2006] [PMID:  16798726] 
[104] 
Clark JA, Lane RH, Maclennan NK, et al. Epidermal growth factor reduces intestinal apoptosis in an experimental model of necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol  2005; 288(4): G755-62.
[http://dx.doi.org/10.1152/ajpgi.00172.2004] [PMID:  15528252] 
[105] 
Dvorak B, Halpern MD, Holubec H, et al. Epidermal growth factor reduces the development of necrotizing enterocolitis in a neonatal rat model. Am J Physiol Gastrointest Liver Physiol  2002; 282(1): G156-64.
[http://dx.doi.org/10.1152/ajpgi.00196.2001] [PMID:  11751169] 
[106] 
Halpern MD, Holubec H, Clark JA, et al. Epidermal growth factor reduces hepatic sequelae in experimental necrotizing enterocolitis. Biol Neonate  2006; 89(4): 227-35.
[http://dx.doi.org/10.1159/000090015] [PMID:  16319449] 
[107] 
Warner BB, Ryan AL, Seeger K, Leonard AC, Erwin CR, Warner BW. Ontogeny of salivary epidermal growth factor and necrotizing enterocolitis. J Pediatr  2007; 150(4): 358-63.
[http://dx.doi.org/10.1016/j.jpeds.2006.11.059] [PMID:  17382110] 
[108] 
Good M, Siggers RH, Sodhi CP, et al. Amniotic fluid inhibits Tolllike receptor 4 signaling in the fetal and neonatal intestinal epithelium. Proc Natl Acad Sci USA  2012; 109(28): 11330-5.
[http://dx.doi.org/10.1073/pnas.1200856109] [PMID:  22733781] 
[109] 
Kalliomaki M, Ouwehand A, Arvilommi H, Kero P, Isolauri E. Transforming growth factor-beta in breast milk: A potential regulator of atopic disease at an early age. J Allergy Clin Immunol  1999; 104(6): 1251-7.
[http://dx.doi.org/10.1016/S0091-6749(99)70021-7] [PMID:  10589009] 
[110] 
Letterio JJ, Geiser AG, Kulkarni AB, Roche NS, Sporn MB, Roberts AB. Maternal rescue of transforming growth factor-beta 1 null mice. Science  1994; 264(5167): 1936-8.
[http://dx.doi.org/10.1126/science.8009224] [PMID:  8009224] 
[111] 
Lebman DA, Edmiston JS. The role of TGF-beta in growth, differentiation, and maturation of B lymphocytes. Microbes Infect  1999; 1(15): 1297-304.
[http://dx.doi.org/10.1016/s1286-4579(99)00254-3] [PMID:  10611758] 
[112] 
Hawkes JS, Bryan DL, James MJ, Gibson RA. Cytokines (IL- 1beta, IL-6, TNF-alpha, TGF-beta1, and TGF-beta2) and prostaglandin E2 in human milk during the first three months postpartum. Pediatr Res  1999; 46(2): 194-9.
[http://dx.doi.org/10.1203/00006450-199908000-00012] [PMID:  10447115] 
[113] 
Rautava S, Nanthakumar NN, Dubert-Ferrandon A, Lu L, Rautava J, Walker WA. Breast milk-transforming growth factor-β₂  specifically attenuates IL-1β-induced inflammatory responses in the immature human intestine via an SMAD6- and ERK-dependent mechanism. Neonatology  2011; 99(3): 192-201.
[http://dx.doi.org/10.1159/000314109] [PMID:  20881435] 
[114] 
Frost BL, Jilling T, Lapin B, Maheshwari A, Caplan MS. Maternal breast milk transforming growth factor-beta and feeding intolerance in preterm infants. Pediatr Res  2014; 76(4): 386-93.
[http://dx.doi.org/10.1038/pr.2014.96] [PMID:  24995914] 
[115] 
Maheshwari A. Immunologic and hematological abnormalities in necrotizing enterocolitis. Clin Perinatol  2015; 42(3): 567-85.
[http://dx.doi.org/10.1016/j.clp.2015.04.014] [PMID:  26250918] 
[116] 
Dahle C, Kvarnstrom M, Ekerfelt C, Samuelsson M, Ernerudh J. Elevated number of cells secreting transforming growth factor beta in Guillain-Barre syndrome. Acta Pathol Microbiol Scand Suppl  2003; 111(12): 1095-104.
[http://dx.doi.org/10.1111/j.1600-0463.2003.apm1111204.x] [PMID:  14678018] 
[117] 
Jain SK, Baggerman EW, Mohankumar K, et al. Amniotic fluidborne hepatocyte growth factor protects rat pups against experimental necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol  2014; 306(5): G361-9.
[http://dx.doi.org/10.1152/ajpgi.00272.2013] [PMID:  24407592] 
[118] 
Siggers J, Ostergaard MV, Siggers RH, et al. Postnatal amniotic fluid intake reduces gut inflammatory responses and necrotizing enterocolitis in preterm neonates. Am J Physiol Gastrointest Liver Physiol  2013; 304(10): G864-75.
[http://dx.doi.org/10.1152/ajpgi.00278.2012] [PMID:  23518680] 
[119] 
Calhoun DA, Christensen RD. Hematopoietic growth factors in neonatal medicine: the use of enterally administered hematopoietic growth factors in the neonatal intensive care unit. Clin Perinatol  2004; 31(1): 169-82.
[http://dx.doi.org/10.1016/j.clp.2004.03.001] [PMID:  15183665] 
[120] 
Christensen RD, Havranek T, Gerstmann DR, Calhoun DA. Enteral administration of a simulated amniotic fluid to very low birth weight neonates. J Perinatol  2005; 25(6): 380-5.
[http://dx.doi.org/10.1038/sj.jp.7211306] [PMID:  15830001] 
[121] 
Christensen RD, Lambert DK, Barney CK, Calhoun DK, Maheshwari A, Lima-Rogel V. Update on the SAFEstart clinical trials. Hematologica Rep  2006; 2(10): 457.
[http://dx.doi.org/10.4081/hmr.v2i10.457] 
[122] 
Banyasz I, Bokodi G, Vasarhelyi B, et al. Genetic polymorphisms for vascular endothelial growth factor in perinatal complications. Eur Cytokine Netw  2006; 17(4): 266-70.
[PMID:  17353160] 
[123] 
Lugering N, Kucharzik T, Gockel H, Sorg C, Stoll R, Domschke W. Human intestinal epithelial cells down-regulate IL-8 expression in human intestinal microvascular endothelial cells; role of transforming growth factor-beta 1 (TGF-beta1). Clin Exp Immunol  1998; 114(3): 377-84.
[http://dx.doi.org/10.1046/j.1365-2249.1998.00718.x] [PMID:  9844046] 
[124] 
Vuorela P, Andersson S, Carpen O, Ylikorkala O, Halmesmaki E. Unbound vascular endothelial growth factor and its receptors in breast, human milk, and newborn intestine Am J Clin Nutr 2000;
	72(5): 1196-201. 
[http://dx.doi.org/10.1093/ajcn/72.5.1196] [PMID: 11063449] 
[125] 
Sabnis A, Carrasco R, Liu SX, et al. Intestinal vascular endothelial growth factor is decreased in necrotizing enterocolitis. Neonatology  2015; 107(3): 191-8.
[http://dx.doi.org/10.1159/000368879] [PMID:  25659996] 
[126] 
Gao X, Ma F, Hao H, et al. Association of VEGFA polymorphisms with necrotizing enterocolitis in Chinese Han population. Pediatr Neonatol  2019; 60(2): 129-34.
[http://dx.doi.org/10.1016/j.pedneo.2018.07.002] [PMID:  30100520] 
[127] 
Besner G, Higashiyama S, Klagsbrun M. Isolation and characterization of a macrophage-derived heparin-binding growth factor. Cell Regul  1990; 1(11): 811-9.
[http://dx.doi.org/10.1091/mbc.1.11.811] [PMID:  2088527] 
[128] 
Feng J, Besner GE. Heparin-binding epidermal growth factor-like growth factor promotes enterocyte migration and proliferation in neonatal rats with necrotizing enterocolitis. J Pediatr Surg  2007; 42(1): 214-20.
[http://dx.doi.org/10.1016/j.jpedsurg.2006.09.055] [PMID:  17208569] 
[129] 
Feng J, El-Assal ON, Besner GE. Heparin-binding epidermal growth factor-like growth factor reduces intestinal apoptosis in neonatal rats with necrotizing enterocolitis. J Pediatr Surg  2006; 41(4): 742-7.
[http://dx.doi.org/10.1016/j.jpedsurg.2005.12.020] [PMID:  16567187] 
[130] 
Feng J, El-Assal ON, Besner GE. Heparin-binding epidermal growth factor-like growth factor decreases the incidence of necrotizing enterocolitis in neonatal rats. J Pediatr Surg  2006; 41(1): 144-9.
[http://dx.doi.org/10.1016/j.jpedsurg.2005.10.018] [PMID:  16410124] 
[131] 
Yu X, Radulescu A, Zorko N, Besner GE. Heparin-binding EGFlike growth factor increases intestinal microvascular blood flow in necrotizing enterocolitis. Gastroenterology  2009; 137(1): 221-30.
[http://dx.doi.org/10.1053/j.gastro.2009.03.060] [PMID:  19361505] 
[132] 
Wei J, Besner GE. M1 to M2 macrophage polarization in heparinbinding epidermal growth factor-like growth factor therapy for necrotizing enterocolitis. J Surg Res  2015; 197(1): 126-38.
[http://dx.doi.org/10.1016/j.jss.2015.03.023] [PMID:  25913486] 
[133] 
Roberge JN, Brubaker PL. Secretion of proglucagon-derived peptides in response to intestinal luminal nutrients. Endocrinology  1991; 128(6): 3169-74.
[http://dx.doi.org/10.1210/endo-128-6-3169] [PMID:  2036983] 
[134] 
Vegge A, Thymann T, Lund P, et al. Glucagon-like peptide-2 induces rapid digestive adaptation following intestinal resection in preterm neonates. Am J Physiol Gastrointest Liver Physiol  2013; 305(4): G277-85.
[http://dx.doi.org/10.1152/ajpgi.00064.2013] [PMID:  23764891] 
[135] 
Benight NM, Stoll B, Olutoye OO, Holst JJ, Burrin DG. GLP-2 delays but does not prevent the onset of necrotizing enterocolitis in preterm pigs. J Pediatr Gastroenterol Nutr  2013; 56(6): 623-30.
[http://dx.doi.org/10.1097/MPG.0b013e318286891e] [PMID:  23343934] 
[136] 
Nakame K, Kaji T, Mukai M, Shinyama S, Matsufuji H. The protective and anti-inflammatory effects of glucagon-like peptide-2 in an experimental rat model of necrotizing enterocolitis. Peptides  2016; 75: 1-7.
[http://dx.doi.org/10.1016/j.peptides.2015.07.025] [PMID:  26551873] 
[137] 
Prencipe G, Azzari C, Moriondo M, et al. Association between mannose-binding lectin gene polymorphisms and necrotizing enterocolitis in preterm infants. J Pediatr Gastroenterol Nutr  2012; 55(2): 160-5.
[http://dx.doi.org/10.1097/MPG.0b013e31824e5f7a] [PMID:  22331020] 
[138] 
Demmert M, Schaper A, Pagel J, et al. FUT 2 polymorphism and outcome in very-low-birth-weight infants. Pediatr Res  2015; 77(4): 586-90.
[http://dx.doi.org/10.1038/pr.2015.1] [PMID:  25642664] 
[139] 
Perrone S, Tataranno ML, Santacroce A, Negro S, Buonocore G. The role of oxidative stress on necrotizing enterocolitis in very low birth weight infants. Curr Pediatr Rev  2014; 10(3): 202-7.
[http://dx.doi.org/10.2174/1573396309666140101235126] [PMID:  25088341] 
[140] 
Perrone S, Tataranno ML, Negro S, et al. May oxidative stress biomarkers in cord blood predict the occurrence of necrotizing enterocolitis in preterm infants? J Matern Fetal Neonatal Med  2012; 25(Suppl. 1): 128-31.
[http://dx.doi.org/10.3109/14767058.2012.663197] [PMID:  22339378] 
[141] 
Akduman H, Tayman C, Korkmaz V, et al. Astaxanthin Reduces the severity of intestinal damage in a neonatal rat model of necrotizing enterocolitis. Am J Perinatol 2021.
[http://dx.doi.org/10.1055/s-0041-1727156] [PMID:  33853144] 
[142] 
Cuna A, George L, Sampath V. Genetic predisposition to necrotizing enterocolitis in premature infants: Current knowledge, challenges, and future directions. Semin Fetal Neonatal Med  2018; 23(6): 387-93.
[http://dx.doi.org/10.1016/j.siny.2018.08.006] [PMID:  30292709] 
[143] 
Zamora SA, Amin HJ, McMillan DD, et al. Plasma L-arginine concentrations in premature infants with necrotizing enterocolitis. J Pediatr  1997; 131(2): 226-32.
[http://dx.doi.org/10.1016/S0022-3476(97)70158-6] [PMID:  9290608] 
[144] 
Neu J. Arginine supplementation and the prevention of necrotizing enterocolitis in very low birth weight infants. J Pediatr  2002; 140(4): 389-91.
[http://dx.doi.org/10.1067/mpd.2002.124306] [PMID:  12006949] 
[145] 
Shah P, Shah V. Arginine supplementation for prevention of necrotising enterocolitis in preterm infants. Cochrane Database Syst Rev  2007; CD004339(3), CD004339.
[http://dx.doi.org/10.1002/14651858.CD004339.pub3] [PMID:  17636753] 
[146] 
Kosik K, Szpecht D, Al-Saad SR, et al. Single nucleotide vitamin D receptor polymorphisms (FokI, BsmI, ApaI, and TaqI) in the pathogenesis of prematurity complications. Sci Rep  2020; 10(1): 21098.
[http://dx.doi.org/10.1038/s41598-020-78125-4] [PMID:  33273558] 
[147] 
George L, Menden H, Xia S, et al. ITGB2 (Integrin β2) immunomodulatory gene variants in premature infants with necrotizing enterocolitis. J Pediatr Gastroenterol Nutr  2021; 72(2): e37-41.
[http://dx.doi.org/10.1097/MPG.0000000000002941] [PMID:  32925548] 
[148] 
Talavera MM, Jin Y, Zmuda EJ, et al. Single nucleotide polymorphisms in the dual specificity phosphatase genes and risk of necrotizing enterocolitis in premature infant. J Neonatal Perinatal Med  2020; 13(3): 373-80.
[http://dx.doi.org/10.3233/NPM-190302] [PMID:  31985475] 
[149] 
Gorreja F, Rush ST, Kasper DL, Meng D, Walker WA. The developmentally regulated fetal enterocyte gene, ZP4, mediates antiinflammation by the symbiotic bacterial surface factor polysaccharide A on Bacteroides fragilis. Am J Physiol Gastrointest Liver Physiol  2019; 317(4): G398-407.
[http://dx.doi.org/10.1152/ajpgi.00046.2019] [PMID:  31314571] 
[150] 
Wei J, Tang D, Lu C, et al. Irf5 deficiency in myeloid cells prevents necrotizing enterocolitis by inhibiting M1 macrophage polarization. Mucosal Immunol  2019; 12(4): 888-96.
[http://dx.doi.org/10.1038/s41385-019-0169-x] [PMID:  31086271] 
[151] 
Ho TTB, Groer MW, Kane B, et al. Dichotomous development of the gut microbiome in preterm infants. Microbiome  2018; 6(1): 157.
[http://dx.doi.org/10.1186/s40168-018-0547-8] [PMID:  30208950] 
Rights & Permissions Print Cite
Article Metrics
80
1
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/1573396318666220204113858	Print ISSN 1573-3963
Publisher Name Bentham Science Publisher	Online ISSN 1875-6336
Current Pediatric Reviews

Necrotizing Enterocolitis: Clinical Features, Histopathological Characteristics, and Genetic Associations

Abstract

Related Journals

Related Books

Related Articles
