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Necrotizing enterocolitis in newborns: update in pathophysiology and newly emerging therapeutic strategies

  • Choi, Young Youn (Department of Pediatrics, Chonnam National University Hospital, Chonnam National University Medical School)
  • Received : 2014.07.25
  • Accepted : 2014.10.07
  • Published : 2014.12.10

Abstract

While the survival of extremely premature infants with respiratory distress syndrome has increased due to advanced respiratory care in recent years, necrotizing enterocolitis (NEC) remains the leading cause of neonatal mortality and morbidity. NEC is more prevalent in lower gestational age and lower birth weight groups. It is characterized by various degrees of mucosal or transmural necrosis of the intestine. Its exact pathogenesis remains unclear, but prematurity, enteral feeding, bacterial products, and intestinal ischemia have all been shown to cause activation of the inflammatory cascade, which is known as the final common pathway of intestinal injury. Awareness of the risk factors for NEC; practices to reduce the risk, including early trophic feeding with breast milk and following the established feeding guidelines; and administration of probiotics have been shown to reduce the incidence of NEC. Despite advancements in the knowledge and understanding of the pathophysiology of NEC, there is currently no universal prevention measure for this serious and often fatal disease. Therefore, new potential techniques to detect early biomarkers or factors specific to intestinal inflammation, as well as further strategies to prevent the activation of the inflammatory cascade, which is important for disease progression, should be investigated.

Keywords

References

  1. Mizrahi A, Barlow O, Berdon W, Blanc WA, Silverman WA. Necrotizing enterocolitis in premature infants. J Pediatr 1965;66: 697-705.
  2. Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg 1978;187:1-7.
  3. Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am 1986;33:179-201.
  4. Caplan MS. Neonatal necrotizing enterocolitis: clinical observations, pathophysiology, and prevention. In: Martin RJ, Fanaroff AA, Walsh MC, editors. Fanaroff & Martin's neonatal-perinatal medicine. 9th ed. Missouri: Elsevier Mosby, 2010:1431-42.
  5. Maheshwari A, Carlo WA. Neonatal necrotizing enterocolitis. In: Kliegman RM, Stanton BF, St. Geme JW III, Schor NF, Behrman RE, editors. Nelson textbook of pediatrics. 19th ed. Philadelphia: Elsevier Saunders, 2011:601-3.
  6. Fanaroff AA, Stoll BJ, Wright LL, Carlo WA, Ehrenkranz RA, Stark AR, et al. Trends in neonatal morbidity and mortality for very low birthweight infants. Am J Obstet Gynecol 2007;196:147.e1-8.
  7. Stoll BJ, Hansen NI, Bell EF, Shankaran S, Laptook AR, Walsh MC, et al. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics 2010;126:443-56.
  8. Martin CR, Walker WA. Intestinal immune defences and the inflammatory response in necrotising enterocolitis. Semin Fetal Neonatal Med 2006;11:369-77.
  9. Kamitsuka MD, Horton MK, Williams MA. The incidence of necrotizing enterocolitis after introducing standardized feeding schedules for infants between 1250 and 2500 grams and less than 35 weeks of gestation. Pediatrics 2000;105:379-84.
  10. Tyson JE, Kennedy KA. Minimal enteral nutrition for promoting feeding tolerance and preventing morbidity in parenterally fed infants. Cochrane Database Syst Rev 2000;(2):CD000504.
  11. Lin J, Nafday SM, Chauvin SN, Magid MS, Pabbatireddy S, Holzman IR, et al. Variable effects of short chain fatty acids and lactic acid in inducing intestinal mucosal injury in newborn rats. J Pediatr Gastroenterol Nutr 2002;35:545-50.
  12. Halpern MD, Holubec H, Saunders TA, Dvorak K, Clark JA, Doelle SM, et al. Bile acids induce ileal damage during experimental necrotizing enterocolitis. Gastroenterology 2006;130:359-72.
  13. Wold AE, Adlerberth I. Breast feeding and the intestinal microflora of the infant--implications for protection against infectious diseases. Adv Exp Med Biol 2000;478:77-93.
  14. Walker WA. Mechanisms of action of probiotics. Clin Infect Dis 2008;46 Suppl 2:S87-91.
  15. Mehall JR, Kite CA, Saltzman DA, Wallett T, Jackson RJ, Smith SD. Prospective study of the incidence and complications of bacterial contamination of enteral feeding in neonates. J Pediatr Surg 2002;37:1177-82.
  16. van Acker J, de Smet F, Muyldermans G, Bougatef A, Naessens A, Lauwers S. Outbreak of necrotizing enterocolitis associated with Enterobacter sakazakii in powdered milk formula. J Clin Microbiol 2001;39:293-7.
  17. Ballance WA, Dahms BB, Shenker N, Kliegman RM. Pathology of neonatal necrotizing enterocolitis: a ten-year experience. J Pediatr 1990;117(1 Pt 2):S6-13.
  18. Nowicki PT, Nankervis CA. The role of the circulation in the pathogenesis of necrotizing enterocolitis. Clin Perinatol 1994;21:219-34.
  19. Dollberg S, Lusky A, Reichman B. Patent ductus arteriosus, indomethacin and necrotizing enterocolitis in very low birth weight infants: a population-based study. J Pediatr Gastroenterol Nutr 2005;40:184-8.
  20. Mally P, Golombek SG, Mishra R, Nigam S, Mohandas K, Depalhma H, et al. Association of necrotizing enterocolitis with elective packed red blood cell transfusions in stable, growing, premature neonates. Am J Perinatol 2006;23:451-8.
  21. More K, Athalye-Jape G, Rao S, Patole S. Association of inhibitors of gastric acid secretion and higher incidence of necrotizing enterocolitis in preterm very low-birth-weight infants. Am J Perinatol 2013;30:849-56.
  22. Radulescu A, Yu X, Orvets ND, Chen Y, Zhang HY, Besner GE. Deletion of the heparin-binding epidermal growth factor-like growth factor gene increases susceptibility to necrotizing enterocolitis. J Pediatr Surg 2010;45:729-34.
  23. Stark AR, Carlo WA, Tyson JE, Papile LA, Wright LL, Shankaran S, et al. Adverse effects of early dexamethasone in extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network. N Engl J Med 2001;344:95-101.
  24. Davey AM, Wagner CL, Cox C, Kendig JW. Feeding premature infants while low umbilical artery catheters are in place: a prospective, randomized trial. J Pediatr 1994;124(5 Pt 1):795-9.
  25. Neal MD, Sodhi CP, Dyer M, Craig BT, Good M, Jia H, et al. A critical role for TLR4 induction of autophagy in the regulation of enterocyte migration and the pathogenesis of necrotizing enterocolitis. J Immunol 2013;190:3541-51.
  26. Richter JM, Schanbacher BL, Huang H, Xue J, Bauer JA, Giannone PJ. LPS-binding protein enables intestinal epithelial restitution despite LPS exposure. J Pediatr Gastroenterol Nutr 2012;54:639-44.
  27. Terrin G, Scipione A, De Curtis M. Update in pathogenesis and prospective in treatment of necrotizing enterocolitis. Biomed Res Int 2014;2014:543765.
  28. Leaphart CL, Cavallo J, Gribar SC, Cetin S, Li J, Branca MF, et al. A critical role for TLR4 in the pathogenesis of necrotizing enterocolitis by modulating intestinal injury and repair. J Immunol 2007;179:4808-20.
  29. Sodhi CP, Shi XH, Richardson WM, Grant ZS, Shapiro RA, Prindle T Jr, et al. Toll-like receptor-4 inhibits enterocyte proliferation via impaired beta-catenin signaling in necrotizing enterocolitis. Gastroenterology 2010;138:185-96.
  30. Huang W, Tang Y, Li L. HMGB1, a potent proinflammatory cytokine in sepsis. Cytokine 2010;51:119-26.
  31. Afrazi A, Sodhi CP, Good M, Jia H, Siggers R, Yazji I, et al. Intracellular heat shock protein-70 negatively regulates TLR4 signaling in the newborn intestinal epithelium. J Immunol 2012;188:4543-57.
  32. Good M, Siggers RH, Sodhi CP, Afrazi A, Alkhudari F, Egan CE, et al. Amniotic fluid inhibits Toll-like receptor 4 signaling in the fetal and neonatal intestinal epithelium. Proc Natl Acad Sci U S A 2012;109:11330-5.
  33. Tran L, Ferris M, Norori J, Stark M, Craver R, Dowd S, et al. Necrotizing enterocolitis and cytomegalovirus infection in a premature infant. Pediatrics 2013;131:e318-22.
  34. Stewart CJ, Marrs EC, Magorrian S, Nelson A, Lanyon C, Perry JD, et al. The preterm gut microbiota: changes associated with necrotizing enterocolitis and infection. Acta Paediatr 2012;101:1121-7.
  35. Smith B, Bode S, Petersen BL, Jensen TK, Pipper C, Kloppenborg J, et al. Community analysis of bacteria colonizing intestinal tissue of neonates with necrotizing enterocolitis. BMC Microbiol 2011;11:73.
  36. Mai V, Young CM, Ukhanova M, Wang X, Sun Y, Casella G, et al. Fecal microbiota in premature infants prior to necrotizing enterocolitis. PLoS One 2011;6:e20647.
  37. Warner BB, Ryan AL, Seeger K, Leonard AC, Erwin CR, Warner BW. Ontogeny of salivary epidermal growth factor and necrotizing enterocolitis. J Pediatr 2007;150:358-63.
  38. Perrone S, Tataranno ML, Negro S, Cornacchione S, Longini M, Proietti F, 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.
  39. Ng EW, Poon TC, Lam HS, Cheung HM, Ma TP, Chan KY, et al. Gut-associated biomarkers L-FABP, I-FABP, and TFF3 and LIT score for diagnosis of surgical necrotizing enterocolitis in preterm infants. Ann Surg 2013;258:1111-8.
  40. Neu J. Neonatal necrotizing enterocolitis: an update. Acta Paediatr Suppl 2005;94:100-5.
  41. Grave GD, Nelson SA, Walker WA, Moss RL, Dvorak B, Hamilton FA, et al. New therapies and preventive approaches for necrotizing enterocolitis: report of a research planning workshop. Pediatr Res 2007;62:510-4.
  42. Sullivan S, Schanler RJ, Kim JH, Patel AL, Trawoger R, Kiechl-Kohlendorfer U, et al. An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J Pediatr 2010; 156:562-7.e1.
  43. Nair RR, Warner BB, Warner BW. Role of epidermal growth factor and other growth factors in the prevention of necrotizing enterocolitis. Semin Perinatol 2008;32:107-13.
  44. Shiou SR, Yu Y, Chen S, Ciancio MJ, Petrof EO, Sun J, et al. Erythropoietin protects intestinal epithelial barrier function and lowers the incidence of experimental neonatal necrotizing enterocolitis. J Biol Chem 2011;286:12123-32.
  45. Kuschel CA, Harding JE. Multicomponent fortified human milk for promoting growth in preterm infants. Cochrane Database Syst Rev 2004;(1):CD000343.
  46. Meinzen-Derr J, Poindexter B, Wrage L, Morrow AL, Stoll B, Donovan EF. Role of human milk in extremely low birth weight infants' risk of necrotizing enterocolitis or death. J Perinatol 2009;29:57-62.
  47. Polycarpou E, Zachaki S, Tsolia M, Papaevangelou V, Polycarpou N, Briana DD, et al. Enteral L-arginine supplementation for prevention of necrotizing enterocolitis in very low birth weight neonates: a double-blind randomized pilot study of efficacy and safety. JPEN J Parenter Enteral Nutr 2013;37:617-22.
  48. Terrin G, Berni Canani R, Passariello A, Messina F, Conti MG, Caoci S, et al. Zinc supplementation reduces morbidity and mortality in very-low-birth-weight preterm neonates: a hospital-based randomized, placebo-controlled trial in an industrialized country. Am J Clin Nutr 2013;98:1468-74.
  49. Wallin RP, Lundqvist A, More SH, von Bonin A, Kiessling R, Ljunggren HG. Heat-shock proteins as activators of the innate immune system. Trends Immunol 2002;23:130-5.
  50. Hoyos AB. Reduced incidence of necrotizing enterocolitis associated with enteral administration of Lactobacillus acidophilus and Bifidobacterium infantis to neonates in an intensive care unit. Int J Infect Dis 1999;3:197-202.
  51. Dani C, Biadaioli R, Bertini G, Martelli E, Rubaltelli FF. Probiotics feeding in prevention of urinary tract infection, bacterial sepsis and necrotizing enterocolitis in preterm infants. A prospective double-blind study. Biol Neonate 2002;82:103-8.
  52. Lin HC, Su BH, Chen AC, Lin TW, Tsai CH, Yeh TF, et al. Oral probiotics reduce the incidence and severity of necrotizing enterocolitis in very low birth weight infants. Pediatrics 2005;115:1-4.
  53. Bin-Nun A, Bromiker R, Wilschanski M, Kaplan M, Rudensky B, Caplan M, et al. Oral probiotics prevent necrotizing enterocolitis in very low birth weight neonates. J Pediatr 2005;147:192-6.
  54. Lin HC, Hsu CH, Chen HL, Chung MY, Hsu JF, Lien RI, et al. Oral probiotics prevent necrotizing enterocolitis in very low birth weight preterm infants: a multicenter, randomized, controlled trial. Pediatrics 2008;122:693-700.
  55. Samanta M, Sarkar M, Ghosh P, Ghosh Jk, Sinha Mk, Chatterjee S. Prophylactic probiotics for prevention of necrotizing enterocolitis in very low birth weight newborns. J Trop Pediatr 2009;55:128-31.
  56. Sari FN, Dizdar EA, Oguz S, Erdeve O, Uras N, Dilmen U. Oral probiotics: lactobacillus sporogenes for prevention of necrotizing enterocolitis in very low-birth weight infants: a randomized, controlled trial. Eur J Clin Nutr 2011;65:434-9.
  57. Mihatsch WA, Braegger CP, Decsi T, Kolacek S, Lanzinger H, Mayer B, et al. Critical systematic review of the level of evidence for routine use of probiotics for reduction of mortality and prevention of necrotizing enterocolitis and sepsis in preterm infants. Clin Nutr 2012;31:6-15.
  58. AlFaleh K, Anabrees J. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev 2014;4:CD005496.
  59. Sherman PM, Cabana M, Gibson GR, Koletzko BV, Neu J, Veereman-Wauters G, et al. Potential roles and clinical utility of prebiotics in newborns, infants, and children: proceedings from a global prebiotic summit meeting, New York City, June 27-28, 2008. J Pediatr 2009;155:S61-70.
  60. Backhed F, Fraser CM, Ringel Y, Sanders ME, Sartor RB, Sherman PM, et al. Defining a healthy human gut microbiome: current concepts, future directions, and clinical applications. Cell Host Microbe 2012;12:611-22.
  61. Reyes J, Bueno J, Kocoshis S, Green M, Abu-Elmagd K, Furukawa H, et al. Current status of intestinal transplantation in children. J Pediatr Surg 1998;33:243-54.
  62. Nucci A, Burns RC, Armah T, Lowery K, Yaworski JA, Strohm S, et al. Interdisciplinary management of pediatric intestinal failure: a 10-year review of rehabilitation and transplantation. J Gastrointest Surg 2008;12:429-35.
  63. Guner YS, Chokshi N, Petrosyan M, Upperman JS, Ford HR, Grikscheit TC. Necrotizing enterocolitis: bench to bedside: novel and emerging strategies. Semin Pediatr Surg 2008;17:255-65.

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