Download PDF
Am J Perinatol
DOI: 10.1055/a-2483-5736
Review Article

Bedside Utilization of Intestinal Pathology in Preterm Infants with Surgical Necrotizing Enterocolitis

Padma P. Garg
1   Department of Pediatrics, University of Mississippi Medical Center, Jackson, Mississippi
,
Victoria G. Weis
2   Wake Forest Institute for Regenerative Medicine, Atrium Health Wake Forest Baptist, Wake Forest School of Medicine, Winston-Salem, North Carolina
,
Jeffrey Shenberger
3   Department of Pediatrics/Neonatology, Connecticut Children's, Hartford, Connecticut
,
Jared A. Weis
4   Department of Biomedical Engineering, Wake Forest School of Medicine, Winston-Salem, North Carolina
,
Anna McDonald
5   Department of Pathology, Atrium Health Wake Forest Baptist, Wake Forest School of Medicine, Winston-Salem, North Carolina
,
Parvesh M. Garg
6   Department of Pediatrics/Neonatology, Atrium Health Wake Forest Baptist, Wake Forest School of Medicine, Winston-Salem, North Carolina
› Author Affiliations
Funding P.M.G. is partially supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number U54GM115428 and the department of pediatrics at Wake Forest School of Medicine.The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
› Further Information
Also available at
   Permissions and Reprints

Abstract

Necrotizing enterocolitis (NEC) is one of the most common conditions requiring emergency surgery in the neonatal intensive care unit and is associated with multiorgan dysfunction, multiple systemic morbidities, and mortality. The resected bowel commonly shows evidence of coagulative necrosis, inflammation, interstitial hemorrhages, and reparative changes on the pathology examination. The severity of these pathological abnormalities may correlate with the disease's severity and pace of progression and may assist in the prediction of clinical outcomes. This review presents current evidence about the clinical utility of intestinal pathology in bedside decision-making, accurate diagnosing, prediction of outcomes, and the prognostication of preterm infants with surgical NEC. Developing refined and validated noninvasive methods to diagnose the extent of bowel injury and monitoring tissue repair throughout disease progression is paramount to mitigate the long-term morbidities in preterm infants with surgical NEC. Improved imaging methods such as targeted bowel ultrasound capable of assessing the inflammation and necrosis in real time will greatly advance care and provide focus for the temporal framework of surgical interventions.

Key Points

  • The degree and severity of intestinal pathological changes are associated with different outcomes.

  • Bedside utilization of the intestinal pathological changes may help improve outcomes.

  • Targeted noninvasive methods to diagnose the extent of bowel injury in real time are greatly needed.

Keywords

neonate - surgical NEC - histology - outcomes

Authors' Contributions

P.M.G. conceptualized the idea. P.P.G., V.G.W., J.A.W., A.M., J.S., and P.M.G. wrote and approved the manuscript.




Publication History

Received: 28 August 2024

Accepted: 22 November 2024

Accepted Manuscript online:
25 November 2024

Article published online:
24 December 2024

© 2024. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med 2011; 364 (03) 255-264
    CrossrefPubMedSearch in Google Scholar
  • 2 Sjoberg Bexelius T, Ahle M, Elfvin A, Björling O, Ludvigsson JF, Andersson RE. Intestinal failure after necrotising enterocolitis: incidence and risk factors in a Swedish population-based longitudinal study. BMJ Paediatr Open 2018; 2 (01) e000316
    CrossrefPubMedSearch in Google Scholar
  • 3 Allin BSR, Long AM, Gupta A, Lakhoo K, Knight M. British Association of Paediatric Surgeons Congenital Anomalies Surveillance System Necrotising Enterocolitis Collaboration. One-year outcomes following surgery for necrotising enterocolitis: a UK-wide cohort study. Arch Dis Child Fetal Neonatal Ed 2018; 103 (05) F461-F466
    CrossrefPubMedSearch in Google Scholar
  • 4 Knell J, Han SM, Jaksic T, Modi BP. Current status of necrotizing enterocolitis. Curr Probl Surg 2019; 56 (01) 11-38
    CrossrefPubMedSearch in Google Scholar
  • 5 Stoll BJ, Hansen NI, Bell EF. et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993-2012. JAMA 2015; 314 (10) 1039-1051
    CrossrefPubMedSearch in Google Scholar
  • 6 Sántulli TV, Schullinger JN, Heird WC. et al. Acute necrotizing enterocolitis in infancy: a review of 64 cases. Pediatrics 1975; 55 (03) 376-387
    CrossrefPubMedSearch in Google Scholar
  • 7 Mowitz ME, Dukhovny D, Zupancic JAF. The cost of necrotizing enterocolitis in premature infants. Semin Fetal Neonatal Med 2018; 23 (06) 416-419
    CrossrefPubMedSearch in Google Scholar
  • 8 Ganapathy V, Hay JW, Kim JH, Lee ML, Rechtman DJ. Long term healthcare costs of infants who survived neonatal necrotizing enterocolitis: a retrospective longitudinal study among infants enrolled in Texas Medicaid. BMC Pediatr 2013; 13: 127
    CrossrefPubMedSearch in Google Scholar
  • 9 Ravisankar S, Tatum R, Garg PM, Herco M, Shekhawat PS, Chen YH. Necrotizing enterocolitis leads to disruption of tight junctions and increase in gut permeability in a mouse model. BMC Pediatr 2018; 18 (01) 372
    CrossrefPubMedSearch in Google Scholar
  • 10 Garg P, Weitkamp JH, McDonald AG. et al. Placenta and intestinal injury in preterm infants. Am J Perinatol 2024; Jul 11. Epub ahead of print. PMID: 38889889.
    Thieme ConnectPubMedSearch in Google Scholar
  • 11 Garg P, Pinotti R, Lal CV, Salas AA. Transfusion-associated necrotizing enterocolitis in preterm infants: an updated meta-analysis of observational data. J Perinat Med 2018; 46 (06) 677-685
    CrossrefPubMedSearch in Google Scholar
  • 12 Bowker RM, Yan X, De Plaen IG. Intestinal microcirculation and necrotizing enterocolitis: The vascular endothelial growth factor system. Semin Fetal Neonatal Med 2018; 23 (06) 411-415
    CrossrefPubMedSearch in Google Scholar
  • 13 Scheese DJ, Sodhi CP, Hackam DJ. New insights into the pathogenesis of necrotizing enterocolitis and the dawn of potential therapeutics. Semin Pediatr Surg 2023; 32 (03) 151309
    CrossrefPubMedSearch in Google Scholar
  • 14 Sampath V, Martinez M, Caplan M, Underwood MA, Cuna A. Necrotizing enterocolitis in premature infants-A defect in the brakes? Evidence from clinical and animal studies. Mucosal Immunol 2023; 16 (02) 208-220
    CrossrefPubMedSearch in Google Scholar
  • 15 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
    CrossrefPubMedSearch in Google Scholar
  • 16 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 (09) 755-762
    CrossrefPubMedSearch in Google Scholar
  • 17 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 (01) 163-170
    CrossrefPubMedSearch in Google Scholar
  • 18 Fernández R, Garate J, Lage S. et al. Identification of biomarkers of necrosis in xenografts using imaging mass spectrometry. J Am Soc Mass Spectrom 2016; 27 (02) 244-254
    CrossrefPubMedSearch in Google Scholar
  • 19 Tata A, Woolman M, Ventura M. et al. Rapid detection of necrosis in breast cancer with desorption electrospray ionization mass spectrometry. Sci Rep 2016; 6: 35374
    CrossrefPubMedSearch in Google Scholar
  • 20 Garg PM, O'Connor A, Ansari MAY. et al. Hematological predictors of mortality in neonates with fulminant necrotizing enterocolitis. J Perinatol 2021; 41 (05) 1110-1121
    CrossrefPubMedSearch in Google Scholar
  • 21 Garg PM, Paschal JL, Zhang M. et al. Brain injury in preterm infants with surgical necrotizing enterocolitis: clinical and bowel pathological correlates. Pediatr Res 2022; 91 (05) 1182-1195
    CrossrefPubMedSearch in Google Scholar
  • 22 Yan X, Managlia E, Tan XD, De Plaen IG. Prenatal inflammation impairs intestinal microvascular development through a TNF-dependent mechanism and predisposes newborn mice to necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 2019; 317 (01) G57-G66
    CrossrefPubMedSearch in Google Scholar
  • 23 Garg PM, Lett K, Ansari MAY. et al. Outcomes by disease onset, sex, and intervention in neonates with SIP and surgical NEC. Pediatr Res 2024; 95 (04) 1009-1021
    CrossrefPubMedSearch in Google Scholar
  • 24 Maheshwari A. Immunologic and hematological abnormalities in necrotizing enterocolitis. Clin Perinatol 2015; 42 (03) 567-585
    CrossrefPubMedSearch in Google Scholar
  • 25 Garg PM, Pippin M, Zhang M. et al. Clinical correlates of moderate-to-severe bronchopulmonary dysplasia in preterm infants following surgical necrotizing enterocolitis. Am J Perinatol 2024; 41 (10) 1348-1358
    Thieme ConnectPubMedSearch in Google Scholar
  • 26 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 (03) e17776
    CrossrefPubMedSearch in Google Scholar
  • 27 Jilling T, Simon D, Lu J. et al. The roles of bacteria and TLR4 in rat and murine models of necrotizing enterocolitis. J Immunol 2006; 177 (05) 3273-3282
    CrossrefPubMedSearch in Google Scholar
  • 28 Yu W, Haque I, Venkatraman A. et al. SIGIRR mutation in human necrotizing enterocolitis (NEC) disrupts STAT3-dependent microRNA expression in neonatal gut. Cell Mol Gastroenterol Hepatol 2022; 13 (02) 425-440
    CrossrefPubMedSearch in Google Scholar
  • 29 Garg PM, Middleton C, Zhang M. et al. Clinical and histopathological correlates of intestinal repair in preterm infants following surgical necrotizing enterocolitis. J Matern Fetal Neonatal Med 2022; 35 (26) 10565-10576
    CrossrefPubMedSearch in Google Scholar
  • 30 Koh TJ, DiPietro LA. Inflammation and wound healing: the role of the macrophage. Expert Rev Mol Med 2011; 13: e23
    CrossrefPubMedSearch in Google Scholar
  • 31 Meszaros AJ, Reichner JS, Albina JE. Macrophage phagocytosis of wound neutrophils. J Leukoc Biol 1999; 65 (01) 35-42
    CrossrefPubMedSearch in Google Scholar
  • 32 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 (06) 951-961
    CrossrefPubMedSearch in Google Scholar
  • 33 Daley JM, Reichner JS, Mahoney EJ. et al. Modulation of macrophage phenotype by soluble product(s) released from neutrophils. J Immunol 2005; 174 (04) 2265-2272
    CrossrefPubMedSearch in Google Scholar
  • 34 Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest 1998; 101 (04) 890-898
    CrossrefPubMedSearch in Google Scholar
  • 35 Qureshi FG, Leaphart C, Cetin S. et al. Increased expression and function of integrins in enterocytes by endotoxin impairs epithelial restitution. Gastroenterology 2005; 128 (04) 1012-1022
    CrossrefPubMedSearch in Google Scholar
  • 36 Leaphart CL, Qureshi F, Cetin S. et al. Interferon-gamma inhibits intestinal restitution by preventing gap junction communication between enterocytes. Gastroenterology 2007; 132 (07) 2395-2411
    CrossrefPubMedSearch in Google Scholar
  • 37 Sheng Q, Lv Z, Cai W. et al. Human β-defensin-3 promotes intestinal epithelial cell migration and reduces the development of necrotizing enterocolitis in a neonatal rat model. Pediatr Res 2014; 76 (03) 269-279
    CrossrefPubMedSearch in Google Scholar
  • 38 Neal MD, Richardson WM, Sodhi CP, Russo A, Hackam DJ. Intestinal stem cells and their roles during mucosal injury and repair. J Surg Res 2011; 167 (01) 1-8
    CrossrefPubMedSearch in Google Scholar
  • 39 Reynolds A, Wharton N, Parris A. et al. Canonical Wnt signals combined with suppressed TGFβ/BMP pathways promote renewal of the native human colonic epithelium. Gut 2014; 63 (04) 610-621
    CrossrefPubMedSearch in Google Scholar
  • 40 Rager TM, Olson JK, Zhou Y, Wang Y, Besner GE. Exosomes secreted from bone marrow-derived mesenchymal stem cells protect the intestines from experimental necrotizing enterocolitis. J Pediatr Surg 2016; 51 (06) 942-947
    CrossrefPubMedSearch in Google Scholar
  • 41 Garg PM, Ravisankar S, Bian H, Macgilvray S, Shekhawat PS. Relationship between packed red blood cell transfusion and severe form of necrotizing enterocolitis: a case control study. Indian Pediatr 2015; 52 (12) 1041-1045
    CrossrefPubMedSearch in Google Scholar
  • 42 MohanKumar K, Namachivayam K, Song T. et al. A murine neonatal model of necrotizing enterocolitis caused by anemia and red blood cell transfusions. Nat Commun 2019; 10 (01) 3494
    CrossrefPubMedSearch in Google Scholar
  • 43 Bubberman JM, van Zoonen A, Bruggink JLM. et al. Necrotizing enterocolitis associated with congenital heart disease: a different entity?. J Pediatr Surg 2019; 54 (09) 1755-1760
    CrossrefPubMedSearch in Google Scholar
  • 44 Frid G, Reppucci M, Lum T, Paul M, Seiden H, Coakley BA. Comparison of necrotizing enterocolitis in pre-mature infants vs. term-born infants with congenital heart disease. Front Pediatr 2021; 9: 802607
    CrossrefPubMedSearch in Google Scholar
  • 45 Elgendy MM, Othman HF, Heis F, Qattea I, Aly H. Spontaneous intestinal perforation in premature infants: a national study. J Perinatol 2021; 41 (05) 1122-1128
    CrossrefPubMedSearch in Google Scholar
  • 46 Swanson JR, Hair A, Clark RH, Gordon PV. Spontaneous intestinal perforation (SIP) will soon become the most common form of surgical bowel disease in the extremely low birth weight (ELBW) infant. J Perinatol 2022; 42 (04) 423-429
    CrossrefPubMedSearch in Google Scholar
  • 47 Ang JL, Rath CP, Tan H, Patole S, Rao SC. Mortality and neurodevelopmental outcomes of infants with spontaneous intestinal perforation: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed 2023; 108 (03) 256-266
    CrossrefPubMedSearch in Google Scholar
  • 48 Keane OA, Dantes G, Dutreuil VL. et al. Comparison of preoperative and intraoperative surgeon diagnosis and pathologic findings in spontaneous intestinal perforation vs necrotizing enterocolitis. J Perinatol 2024; 44 (04) 568-574
    CrossrefPubMedSearch in Google Scholar
  • 49 Garg PM, Lett K, Ansari MAY. et al. Postoperative outcomes, and growth and brain injury outcomes in spontaneous intestinal perforation vs surgical necrotizing enterocolitis in preterm infants. Indian Pediatr 2023; 60 (11) 922-926
    CrossrefPubMedSearch in Google Scholar
  • 50 Garg PM, Riddick R, Ansari MAY, Pittman I, Hillegass W. Clinical impact of timing of surgery on outcomes in preterm infants with surgical necrotizing enterocolitis. Res Sq 2023; rs.3.rs- 3084887
    PubMedSearch in Google Scholar
  • 51 Garg PM, Garg PP, Shenberger JS. Is necrotizing enterocolitis and spontaneous intestinal perforation part of same disease spectrum - new insights?. Curr Pediatr Rev 2024;
    CrossrefPubMedSearch in Google Scholar
  • 52 Blakely ML, Tyson JE, Lally KP. et al; Eunice Kennedy Shriver National Institute of Child Health, Human Development Neonatal Research Network. Initial laparotomy versus peritoneal drainage in extremely low birthweight infants with surgical necrotizing enterocolitis or isolated intestinal perforation: a multicenter randomized clinical trial. Ann Surg 2021; 274 (04) e370-e380
    CrossrefPubMedSearch in Google Scholar
  • 53 Benjamin JL, Dennis R, White Jr S. et al. Improved diagnostic sensitivity of bowel disease of prematurity on contrast-enhanced ultrasound. J Ultrasound Med 2020; 39 (05) 1031-1036
    CrossrefPubMedSearch in Google Scholar
  • 54 Lindner JR, Song J, Xu F. et al. Noninvasive ultrasound imaging of inflammation using microbubbles targeted to activated leukocytes. Circulation 2000; 102 (22) 2745-2750
    CrossrefPubMedSearch in Google Scholar
  • 55 Jing XX, Wang ZG, Ran HT. et al. Evaluation of renal ischemia-reperfusion injury in rabbits using microbubbles targeted to activated neutrophils. Clin Imaging 2008; 32 (03) 178-182
    CrossrefPubMedSearch in Google Scholar
  • 56 Weis VG, Cruz-Diaz N, Rauh JL. et al. Photoacoustic imaging as a novel non-invasive biomarker to assess intestinal tissue oxygenation and motility in neonatal rats. J Pediatr Surg 2024; 59 (03) 528-536
    CrossrefPubMedSearch in Google Scholar