Chapter III.14. Necrotizing Enterocolitis
Erika K. Ryckman
August 2022

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The editors and current author would like to thank and acknowledge the significant contribution of the previous author of this chapter from the 2004 first edition, Dr. Kelly S. Yamasato. This current third edition chapter is a revision and update of the original author's work.


This is a 14 day old infant female born to a 24 year old G1P1 mother at 30 weeks gestation via spontaneous vaginal delivery. Birthweight was 1340 g. Apgar scores were 6 and 7 at 1 and 5 minutes. Her early hospital course was remarkable for respiratory distress syndrome and patent ductus arteriosus. Recent problems include apnea and bradycardia of prematurity and feeding intolerance. Her nutritional needs have been met by advancing enteral feedings of preterm formula supplemented with parenteral hyperalimentation. On the day prior to the onset of symptoms, she had advanced to full feeds and was weaned off of parenteral hyperalimentation. Today she had developed abdominal distention and bilious vomiting. Her stool color has darkened and her urine output is reduced. She is also having more apnea and bradycardia events.

Exam: VS T36, HR 180, RR 60, BP 63/40, current weight 1425 g. She is lethargic and poorly responsive on exam with delayed capillary refill and mottled appearance. Cardiac exam demonstrates tachycardia and no murmurs. Lungs are clear. Her abdomen is distended, tender, with hypoactive bowel sounds and an overlying bluish hue to the abdominal skin with visibly distended veins. Stool is guaiac positive.

Abdominal radiographs demonstrate pneumatosis intestinalis. She is made NPO and a nasogastric tube is placed to suction for gastric decompression. Following an intravenous fluid bolus of normal saline, her tachycardia resolves and she is placed on maintenance intravenous fluids at 120 cc/kg/day. Empiric antibiotic therapy with ampicillin and gentamicin is started. Serial abdominal radiographs and examinations are regularly performed. She begins to show improvement and enteral feeding is reintroduced 10 days later. Her feedings are slowly advanced and tolerated without difficulty. She is discharged from the hospital at 6 weeks of age.


Necrotizing enterocolitis (NEC) is a potentially fulminant syndrome causing bowel wall inflammation, air in the intestinal wall, intestinal necrosis, and air in the portal venous system and/or peritoneal cavity (1,2). It occurs in 1% to 8% of neonatal intensive care unit admissions and is the most common GI emergency in neonates (3). NEC may affect the gastrointestinal (GI) tract from the stomach to the rectum, although the distal ileum and proximal colon are most commonly involved (4). The incidence of this disease is 1 to 3 per 1000 live births (3), with 90% of cases occurring in premature infants (2,4). There is an inverse relationship between age of onset and gestational age. Onset is common between 14-25 days for extremely to moderate preterm babies and 5 to 13 days for late preterm to full term babies (5,6). The overall mortality rate in NEC is estimated to be about 20% to 40%. The rate increases in those who require surgery or those with lower birthweight (2,6).

Prematurity and low birthweight (<1500 grams) are important risk factors for NEC (4,7). Enteral feeding is also a suspected risk factor, as more than 90% of infants who develop NEC have been enterally fed (3). Research efforts have long investigated the most optimal feeding strategies to minimize NEC risk. Some studies show no difference in NEC risk whether enteral feeding is increased daily by small or large increments (8). Studies are also trying to determine if delaying enteral feeds decreases the risk of developing NEC (9,10). The use of formula rather than breast milk is particularly associated with increased NEC incidence (1,2). Other suggested risk factors include conditions that lead to reduced intestinal blood flow, hypoxia, or gut dysbiosis including polycythemia, congenital heart disease, sepsis, perinatal asphyxia, and respiratory distress (6,11,12).

NEC is a multifactorial disease with an unclear pathophysiology. The pathogenesis of NEC is believed to involve factors such as immature intestinal functions, intestinal ischemia, bacterial colonization, and formula feeding (2,11,13,14). Premature infants display under-developed immunologic and digestive functions, increasing their risk of intestinal infection. Decreased small intestine motility may contribute to NEC by facilitating bacterial overgrowth (11,13). Premature infants may have deficiencies in protective cells such as Paneth cells which secrete defensins or trefoil factor peptides (2,11). Immature goblet cells do not secrete as much mucus, which is necessary for protection and the growth of friendly microorganisms (2,13).

An excessive immune response can contribute to the damage of NEC (14). It is believed that increased toll-like receptor 4 (TLR4) expression plays a large role in NEC pathogenesis. Activation from gram-negative bacteria lipopolysaccharide can lead to an increase in epithelial cell apoptosis, proinflammatory mediators, and decreased cell regeneration (2,11,13). This epithelial and mucosal layer damage can initiate bacterial translocation, necrosis, and gut perforation (13). Some other mediators suspected to play a role include platelet activating factor, tumor necrosis factor, and interleukin-1, 6, and 8 (2).

Factors contributing to intestinal hypoxia (which may be secondary to hemodynamically significant patent ductus arteriosus or congenital heart disease) can lead to decreased gut perfusion and ischemic injury which is further worsened by the overactive immune response mentioned previously (11,12). Factors such as mode of delivery, feeding methods, use of antibiotics or central lines, and hospital environment can all contribute to bacterial colonization (11,13). Although bacteria such as Proteobacteria, Klebsiella, Escherichia coli, Clostridium, and Staphylococcus epidermidis are suspected to have a role in NEC, no pathogen has been identified as the primary cause (11,13). Breast milk feedings may decrease the risk of NEC by promoting the integrity of the intestinal mucosal layer and the growth of commensal intestinal bacterial populations, thus decreasing the risk of pathological bacterial translocation (2,13).

Early signs and symptoms of NEC may include abdominal distention or discoloration, apneic episodes, vomiting, and hematochezia (2,3,4). NEC often progresses rapidly and may quickly lead to bowel perforation, shock, and septicemia (1,4).

NEC was originally most commonly classified using the 3 stages proposed by the 1978 Bell staging system. This system classified NEC based on severity, symptoms, and imaging signs. These stages were later modified by Kliegman in 1986 (15). The Modified Bellís Staging Criteria is summarized as follows (11,15,16):

Stage IA: NEC is suspected due to a wide range of nonspecific symptoms such as mild abdominal distention, apnea, guaiac-positive stools, lethargy, and bradycardia.

Stage IB: Findings are the same as those in IA with the addition of bright red rectal blood.

Stage IIA: Patient is mildly ill with NEC, proven primarily by the detection of intestinal dilatation, pneumatosis intestinalis, and ileus through abdominal radiography. Findings are the same as those in IA and IB, with the addition of decreased bowel sounds and possible tenderness in the abdomen.

Stage IIB: Patient is moderately ill with NEC. This is proven by the same imaging signs as those seen in IIA with the addition of possible portal venous gas and ascites. Other findings include an abdominal mass, low platelet count, and metabolic acidosis.

Stage IIIA: Patient has advanced NEC with an intact bowel. Findings build on what is seen in IIB, adding low neutrophils, disseminated intravascular coagulation, and combined respiratory and metabolic acidosis. There is likely an increase in abdominal tenderness and distention.

Stage IIIB: Patient has advanced NEC with a perforated bowel causing a pneumoperitoneum on imaging. The patient will likely experience abrupt deterioration and worsening of findings seen in IIIA.

One of the primary diagnostic tools in NEC is the abdominal radiograph (17,18,19). Many of the imaging signs are caused by the accumulation of gas produced by invading bacteria (19). Infants suspected of NEC should have serial abdominal radiographs performed to monitor the development of NEC and possible progression to bowel perforation (18). Curvilinear or bubble shaped lucencies within the bowel wall can indicate pneumatosis intestinalis and fixed, dilated bowel loops can show necrosis. Radiographs can also be used to look for branching lucencies near the liver showing portal venous gas or a circular lucency in the upper abdomen showing free intraperitoneal air (17,18,19). The abdominal radiograph may be used to detect nonspecific early signs of NEC, such as asymmetric bowel gas patterns or dilated bowel loops (17,18). Pneumatosis intestinalis or gas in the bowel wall is a radiographic finding diagnostic of NEC and is estimated to occur in about 50% to 75% of cases (4). Portal venous gas, another pathognomonic sign, is usually associated with more severe disease (11). Pneumoperitoneum resulting from bowel perforation can also be seen with radiographic imaging in severe cases (3,4).

In addition, studies are investigating the use of bedside point of care ultrasound to evaluate for NEC and transmural air by examining bowel shape, thickness of bowel wall, accumulation of fluid, and changes in peristalsis or blood flow (20). Changes in vascularity seen with a color doppler can indicate necrosis and nonviable bowel (18,20).

The differential diagnosis of NEC includes systemic and intestinal infections, congenital intestinal obstruction (e.g., volvulus, intussusception, meconium ileus, atresia, Hirschsprung disease), spontaneous intestinal perforation, and protein induced enterocolitis syndrome (4,6,14).

Aggressive treatment is indicated in all suspected cases of NEC (1). The initial goals include bowel rest, stabilizing cardiorespiratory function, regulating body temperature, and intravenous fluid resuscitation (6,11). Initial medical treatment of NEC includes making the infant NPO, placing a gastric tube to suction for decompression, and supplementing excessive gastrointestinal fluid losses with fluid resuscitation on top of parenteral nutrition. (1,4,11). After collecting blood cultures and considering the local antibiotic sensitivity patterns, systemic antibiotics should be given for 7 to 14 days (4,6). Antibiotics that broadly cover gram-negative and anaerobic bacteria associated with the gut should be chosen (6). Sequential and positional abdominal radiographs should be obtained frequently to follow NEC progression (4,6). Changes in physical exam, respiratory status, hemodynamics, and fluid balance should be monitored carefully (4).

Early consultation with a surgeon is advised in all cases of NEC because 30% of infants may fail medical treatment and will require surgical intervention (1). Surgical intervention may include peritoneal drain placement for infants with intestinal perforation or abdominal compartment syndrome, or exploratory laparotomy with necrotic bowel resection. Indications for surgical intervention include pneumoperitoneum , failure of medical management, signs of worsening necrosis (e.g., fixed intestinal loop, ascites, worsening lactic acidosis), and worsening cardiorespiratory function (11). Mortality rates in NEC cases requiring surgery range from 20% to 50% (2,11).

The elusiveness of the etiology of NEC has made it difficult to establish effective preventive measures. Studies are being conducted to find the most optimal standardized feeding protocols (6). The use of total parenteral nutrition with gradual progression to enteral feeding may be beneficial (14). Limiting the use of medications such as anti-acids and antibiotics that affect gut microbiota can be another helpful measure (6). Giving prophylactic probiotics to preterm infants might reduce NEC risk (12). The use of exclusive human breast milk feeds instead of formula, may be beneficial in protecting against NEC by providing growth factors, anti-inflammatory cytokines, immunoglobulins, and oligosaccharides that increase the number of goblet cells (6,12).

NEC has a recurrence rate of about 5% (21). About 10% to 36% of patients will develop intestinal strictures, most commonly in the colon (6,21). Severe cases of NEC requiring significant intestinal resection may lead to short bowel syndrome causing long-term malabsorption, malnutrition, and failure to thrive (4,11,21). Infants with short bowel syndrome requiring prolonged parenteral nutrition are at risk for central venous catheter related sepsis and cholestatic liver disease (4,6,21). Infants with NEC should be managed and cared for by a multi-disciplinary team including neonatology, pediatric surgery, dietary, and rehabilitation therapists.


Questions
1. True/False: NEC can affect full term infants.

2. Complications of NEC include (select all that apply):
   a. long-term malnutrition
   b. increased peristalsis
   c. intestinal strictures
   d. short bowel syndrome
   e. excess growth

3. True/False: Formula should be used over breastmilk to reduce the risk of developing NEC.

4. How is the reduced intestinal motility of premature infants thought to contribute to the development of NEC?

5. A premature infant is suspected to have NEC. Name three initial treatment measures that should be employed.


Related x-rays
Newborn radiographs: Available online at: www.hawaii.edu/medicine/pediatrics/neoxray/neoxray.html

NEC radiographs: Yamamoto LG. Hematemesis in a 6-Day Old Infant. In: Yamamoto LG, Inaba AS, DiMauro R (eds). Radiology Cases In Pediatric Emergency Medicine, 1995, volume 2, case 14. Available online at: www.hawaii.edu/medicine/pediatrics/pemxray/v2c14.html

Older infant with pneumatosis intestinalis: Yamamoto LG. Bloody Diarrhea and Dehydration In a 5-Month Old. In: Yamamoto LG, Inaba AS, DiMauro R (eds). Radiology Cases In Pediatric Emergency Medicine, 1999, volume 6, case 14. Available online at: www.hawaii.edu/medicine/pediatrics/pemxray/v6c14.html


References
1. Lima AA, Warren CA, Guerrant RL. Chapter 99. Acute Dysentery Syndromes (Diarrhea With Fever). In: Bennett JE, Dolin R, Blaser MJ (eds). Mandell, Douglas, and Bennettís Principles and Practice of Infectious Diseases, 9th edition, 2020. Elsevier, Philadelphia, PA. pp:1357-1364.
2. Kudin O, Neu J. Chapter 85. Neonatal Necrotizing Enterocolitis. In: Martin RJ, Fanaroff AA, Walsh MC (eds). Fanaroff and Martinís Neonatal-Perinatal Medicine, 2-Volume Set, 11th edition. 2020. Elsevier, Philadelphia, PA. pp: 1571, 1581.
3. Marcdante KJ, Kliegman RM, Schuh AM. Chapter 63. Necrotizing Enterocolitis. In: Marcdante KJ, Kliegman RM, Schuh AM (eds). Nelson Essentials of Pediatrics, 9th edition. 2023. Elsevier, Philadelphia, PA. pp:267-268.
4. Kliegman RM, St Geme JW, Blum NJ, et al. Chapter 123. Digestive System Disorders. In: Kliegman RM, St. Geme JW, Blum NJ, et al (eds). Nelson Textbook of Pediatrics, 21st edition. 2020, Elsevier, Philadelphia, PA. pp:949-961.
5. Nair J, Longendyke R, Lakshminrusimha S. Necrotizing Enterocolitis in Moderate Preterm Infants. Biomed Res Int. 2018;2018:4126245. doi:10.1155/2018/4126245
6. Wertheimer F, Arcinue R, Niklas V. Necrotizing Enterocolitis: Enhancing Awareness for the General Practitioner. Pediatr Rev. 2019;40(10):517-527. doi:10.1542/pir.2017-0338
7. Alsaied A, Islam N, Thalib L. Global incidence of Necrotizing Enterocolitis: a systematic review and Meta-analysis. BMC Pediatr. 2020;20(1):344. doi:10.1186/s12887-020-02231-5
8. Oddie SJ, Young L, McGuire W. Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database Syst Rev. 2021;8(8):CD001241. doi:10.1002/14651858.CD001241.pub8
9. Young L, Oddie SJ, McGuire W. Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database Syst Rev. 2022;1(1):CD001970. doi:10.1002/14651858.CD001970.pub6
10. Masoli D, Dominguez A, Tapia JL, Uauy R, Fabres J. NEOCOSUR Collaborative Network. Enteral Feeding and Necrotizing Enterocolitis: Does Time of First Feeds and Rate of Advancement Matter? J Pediatr Gastroenterol Nutr. 2021;72(5):763-768. doi:10.1097/MPG.0000000000003069
11. Iben S, Rodriguez RJ. Chapter 45. Neonatal Necrotizing Enterocolitis. In:Wyllie R, Hyams JS, Kay M (eds). Pediatric Gastrointestinal and Liver Disease, 6th Edition. 2021. Elsevier Inc. pp: 500-509. doi:10.1016/B978-0-323-67293-1.00045-1
12. Alganabi M, Lee C, Bindi E, Li B, Pierro A. Recent advances in understanding necrotizing enterocolitis. F1000Res. 2019;8:F1000 Faculty Rev-107. doi:10.12688/f1000research.17228.1
13. Andrews RE, Coe KL. Clinical Presentation and Multifactorial Pathogenesis of Necrotizing Enterocolitis in the Preterm Infant. Adv Neonatal Care. 2021;21(5):349-355. doi:10.1097/ANC.0000000000000880
14. Neu J. Necrotizing Enterocolitis: The Future. Neonatology. 2020;117(2):240-244. doi:10.1159/000506866
15. Patel RM, Ferguson J, McElroy SJ, Khashu M, Caplan MS. Defining necrotizing enterocolitis: current difficulties and future opportunities. Pediatr Res. 2020;88(Suppl 1):10-15. doi:10.1038/s41390-020-1074-4
16. Walsh MC, Kliegman RM. Necrotizing Enterocolitis: Treatment Based on Staging Criteria. Pediatr Clin North Am. 1986;33(1):179-201. doi:10.1016/S0031-3955(16)34975-6
17. Herring W. Chapter 28. Recognizing Pediatric Diseases. In: Herring W (eds). Learning Radiology: Recognizing the Basics, 4th Edition, 2020. Elsevier, Philadelphia, PA. pp:324-338. doi:10.1016/B978-0-323-56729-9.00028-2
18. Merrow AC, Hariharan S. Necrotizing Enterocolitis. In: Merrow AC, Hariharan S (eds). Imaging in Pediatrics, 1st edition, 2018. Elsevier, Philadelphia, PA. pp: 130-131. doi:10.1016/B978-0-323-47778-9.50098-2
19. Soni R, Katana A, Curry JI, Humphries PD, Huertas-Ceballos A. How to use abdominal X-rays in preterm infants suspected of developing necrotising enterocolitis. Arch Dis Child Educ Pract Ed. 2020;105(1):50-57. doi:10.1136/archdischild-2018-315252
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Answers to questions
1. True
2. a,c,d
3. False
4. Reduced intestinal motility increases the chances of bacterial overgrowth.
5. Acceptable answers include: 1) making the infant NPO, 2) placing a gastric tube to low suction for decompression, 3) fluid resuscitation on top of parenteral nutrition, 4) systemic antibiotics, 5) respiratory status, hemodynamics, and fluid balance monitoring, 6) early consultation with a surgeon


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