First described over a century ago, necrotising enterocolitis (NEC) is now the most common gastrointestinal emergency occurring in neonates.¹ Prematurity and low birthweight are the most important risk factors. This is particularly poignant because:

• It mainly affects premature infants who, having survived a difficult neonatal period, then confront a disease with high morbidity and mortality.
• With obstetric advances more very low birthweight infants survive the neonatal period, increasing the population at risk of NEC.

NEC is rare in term babies as a whole, but these account for 10% of cases. In term babies, the initiating events are different and it it often associated with underlying disorders.

Diagnosis and treatment remain very difficult and challenging.²

Epidemiology^2,3

• This is the most frequent gastrointestinal emergency in neonates.
• There are few population or multicentre studies but frequency ranges from 1% to 5% of neonatal intensive care unit (NICU) admissions.
• One American study found an incidence of. 0.3-2.4 cases per 1,000 live births. There is thought to be little global variation.
• Incidence and mortality increase in inverse proportion to birthweight and gestational age.
• 10% of necrotising enterocolitis (NEC) occurs in full-term infants.
• Patent ductus arteriosus is a risk factor in premature babies, especially if conservative closure using indometacin has been attempted.
• In full-term infants, NEC is usually associated with predisposing or underlying disorders:
  • Perinatal asphyxia.
  • Polycythaemia.
  • Respiratory distress.
  • Congenital anomalies (myelomeningocele, congenital heart disease).
  • Cows' milk protein-induced enterocolitis and glucose-6-phosphate dehydrogenase deficiency have been mooted as possible pathophysiological mechanisms.
• There is no consistent association between gender and rates of NEC.
• However, male very low birthweight (VLBW) babies have a higher mortality.
• Mortality is higher in black infants with NEC (even when matching for birthweight and other characteristics).
• The average yearly infant death rate from NEC has been reported as 12.4 deaths per 100,000 live births.
• An estimated 20-40% of infants with NEC undergo surgery.
• 95% of NEC occurs after enteral feeds have been introduced.
• Human milk is protective with a three- to ten-fold reduction in NEC (compared to formula-fed).
• There are no identified sex/race/seasonal/socio-economic status associations (other than above).
• Sporadic outbreaks seem to follow an epidemic pattern, suggesting an infectious aetiology.
• Outbreaks occur more commonly in crowded nurseries with more gastrointestinal illness among carers.
• Antibiotic treatment for more than 10 days has been reported as an independent risk factor.⁴

Pathophysiology³

Despite a lot of research over many years, the aetiology remains elusive. It involves serious intestinal injury following a combination of vascular, mucosal, toxic and possibly other insults to a relatively immature gut. A genetic predisposition may also play a part. Epidemic clusters have suggested an infective aetiology and viral, fungal and bacterial agents have all been isolated, although many infants have negative culture findings. The fact that organisms found in necrotising enterocolitis (NEC) babies are also found in healthy babies suggests that damage to the intestinal mucosa is the main underlying problem, resulting in spread of commensural organisms beyond their normal location. Colonisation by pathological organisms may also occur (e.g. Escherichia coli, Klebsiella spp., Salmonella spp., Staphylococcus epidermidis).

NEC does not occur in utero. Colonisation of the gut with either commensal or pathogenic bacteria may affect maturation of the innate immune system (pattern recognition receptors and microbial-associated molecular patterns). Hyperactive inflammation in infants, caused by inadequate or altered colonisation of the gut, may cause deficiencies in dampening of bacterially mediated inflammatory pathways.

Clinical presentation³

History

Onset is usually 3-10 days (extremes 1-90 days) after birth. Age at presentation is inversely related to gestational age at birth (that is, full-term infants with necrotising enterocolitis (NEC) present in the first few days). Early signs are nonspecific and sepsis may be suspected before NEC. It may be benign or catastrophic and since 1978 a system of staging has been used (see box).^5,6

Term infants may be systemically unwell due to an underlying condition (e.g. birth asphyxia, respiratory distress, congenital heart disease, metabolic abnormalities) or have a history of abnormal fetal growth pattern. There may be a history of maternal factors causing placental insufficiency, such as cocaine abuse or pregnancy-induced hypertension.

In premature babies there is often a history of initially making progress on enteral feeding. There is an increase in incidence after blood transfusion for asymptomatic anaemia. Feeding difficulties may be noted by nursing staff and there may be concerns about vomiting or abdominal distension.

Examination

• Abdominal distension with increasing gastric aspirates.
• Visible intestinal loops.
• Altered stool pattern.
• Bloody mucoid stool and bilious vomiting.
• Decreased bowel sounds with erythema of the abdomen.
• Palpable abdominal mass or ascites.
• Associated features are bradycardia, lethargy, shock, apnoea, respiratory distress, temperature instability.

Differential diagnosis ²

• Sepsis.
• Haemorrhagic disease of the newborn.
• Swallowed maternal blood.
• Volvulus/malrotation.
• Intussusception.
• Hirschsprung colitis.
• Pseudomembranous colitis.
• Stress ulcer.
• Meconium ileus.
• Metabolic or respiratory acidosis.
• Apnoea or prematurity.
• Bacteraemia.
• Candidiasis.
• Coarctation of the aorta.
• Enteroviral infection.
• Gastro-oesophageal reflux.
• Hirschsprung's disease.
• Hospital-acquired infections.
• Hypoplastic left heart syndrome.
• Omphalitis.
• Bacterial meningitis.
• Urinary tract infection.
• Focal intestinal perforation.

Investigations^3,7

• Blood lab tests are nonspecific but cultures, FBC, blood gas and baseline biochemistry should be taken and lend support to the diagnosis.
  • Severe or persistent thrombocytopenia, neutropenia, coagulopathy or acidosis indicate severe disease.
  • Serial C-reactive protein may be useful, with persistently high levels with complications (stricture, abscess).
  • Blood gases may assist in the diagnosis of respiratory distress or acute lactic acidosis.
• Diagnosis is confirmed by abdominal X-ray (AXR) - supine and decubitus/erect - and should be performed as soon as the diagnosis is suspected. Serial abdominal films are taken.
• The cardinal sign is pneumatosis intestinalis (gas in the bowel wall) which may be linear or cystic (and mistaken for faeces by the unwary).
• The X-rays may also show portal venous gas, free air, dilated intestinal loop, ileus, ascites, diffuse distention and asymmetric bowel gas pattern.
• Ultrasound scanning may also be useful, particularly in identifying portal air, areas of walled-off perforation or ascites.
• Other imaging techniques being developed include contrast radiography, portal vein ultrasonography, MRI and radionuclide scanning.
• Newly developed biomarkers may prove helpful in achieving early diagnosis. These have been suggested as screening tests for at-risk babies.^8,9,10
• Various non-invasive methods are also being developed.¹¹

Staging^5,6

Management^2,12

• Nil by mouth to rest the bowel.
• Nasogastric or orogastric tube to decompress the bowel with low intermittent orogastric suction.
• Intravenous (IV) fluids, total parenteral nutrition (TPN), and IV antibiotics for 10-14 days:
  • Ampicillin/gentamicin or cefotaxime.
  • Plus metronidazole or clindamycin.
• Antifungals should be considered for babies who have recently been on lengthy courses of antibiotics or are not responding to antibiotic treatment.
• Upper gastrointestinal small bowel follow-through is sometimes performed therapeutically in resolving necrotising enterocolitis (NEC) where intestinal obstruction develops as a result of a fibrous band or stricture.
• Paracentesis for ascites may be necessary.
• Treat shock, DIC, etc. Very ill babies may benefit from blood pressure support with vasopressors (e.g. naloxone, dopamine).
• Surgery if a deteriorating or perforated/necrotic bowel is suspected (e.g. free air on abdominal radiography).
• Peritoneal drainage appears to be of equal effectiveness to laparotomy, although further research is needed.¹³
• Intubation/ventilation for apnoea.
• Oral feeds can be restarted 7-10 days after pneumatosis clears.

Complications and prognosis^3,14

• Perforation.
• Acquired short bowel syndrome (following surgery).
• Stoma-related complications.¹⁵
• DIC.
• Sepsis and shock.
• Intestinal strictures (~30%).
• Enterocolic fistulae.
• Abscess formation.
• Recurrent necrotising enterocolitis (NEC) (rare)
• Iatrogenic complications - e.g. central venous catheter-related thrombotic events and nosocomial infections, metabolic complications secondary to prolonged hyperalimentation (a nutrient mixture given to premature babies before giving milk).
• The overall survival rate is 75% but mortality varies considerably according to birthweight (10-44% in infants less than 1,500 g, 0-20% in infants over 2,500 g).³

Other forms¹⁶

There is another necrotising enterocolitis (NEC) that affects older children and adults. It is known by different local names over the globe (for instance, 'Darmbrand' in Germany and 'pigbel' in Papua New Guinea).¹⁷

• Occurring either sporadically or in epidemics, it is thought to be due to food contaminated with different strains of Clostridium perfringens (type A for most sporadic cases and probably type C for larger outbreaks).¹⁸
• The disease course usually involves abdominal pain, vomiting, fever and bloody diarrhoea. In severe cases, shock follows and the mortality rates can be very high (30-100%).
• Treatment follows the same principles as the neonatal form (bowel rest, antibiotics +/- surgery) but would depend on available local medical and surgical services.

Prevention

Feeding with human milk is known to be an effective intervention in the prevention of necrotising enterocolitis (NEC).¹⁹ Other interventions have a limited evidence base but have focused on reducing the multiple contributing factors in a susceptible host.

Interventions that have been tried include:²

• Factors relating to feeding:
  • Correction of hypovolaemia, hyperviscosity and allowing adequate time for homeostatic mechanisms to mature before the enteral feeding challenge is begun.
  • Start feeds slowly using formulas of low volume.²⁰
  • Small increments (20 ml/kg/day) when increasing feeds.
  • Avoid hyperosmolar medications and feeds.
  • Conservative feeding.
  • Trophic feeding rather than extended bowel rest.²¹
• Some have suggested steroids for women in preterm labour.²¹
• Ig A supplementation (IV Ig prophylaxis of neonatal infections not protective).
• Arginine supplementation.
• Erythropoietin.
• Oral antibiotics.
• Probiotics.²²
• Implementation of strict infection-control measures to prevent faecal and oral spread of organisms.

Document references

1. Lahmiti S, Aboussad A; Neonatal necrotizing enterocolitis. ScientificWorldJournal. 2011 Mar 22;11:655-6. [abstract]
2. Lin PW, Stoll BJ; Necrotising enterocolitis. Lancet. 2006 Oct 7;368(9543):1271-83. [abstract]
3. Springer SC et al; Necrotizing Enterocolitis (Pediatric perspective), Medscape, May 2011
4. Alexander VN, Northrup V, Bizzarro MJ; Antibiotic exposure in the newborn intensive care unit and the risk of J Pediatr. 2011 Sep;159(3):392-7. Epub 2011 Apr 13. [abstract]
5. Bell MJ; Neonatal necrotizing enterocolitis. N Engl J Med. 1978 Feb 2;298(5):281-2.
6. Bell MJ, Ternberg JL, Feigin RD, et al; Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg. 1978 Jan;187(1):1-7. [abstract]
7. Wood BP; Necrotizing Enterocolitis (Imaging perspective) Medscape, May 2011
8. Neu J, Mshvildadze M, Mai V; A roadmap for understanding and preventing necrotizing enterocolitis. Curr Gastroenterol Rep. 2008 Oct;10(5):450-7. [abstract]
9. Young C, Sharma R, Handfield M, et al; Biomarkers for Infants at Risk for Necrotizing Enterocolitis: Clues to Prevention? Pediatr Res. 2009 Jan 28. [abstract]
10. Ng PC, Ang IL, Chiu RW, et al; Host-response biomarkers for diagnosis of late-onset septicemia and necrotizing J Clin Invest. 2010 Aug 2;120(8):2989-3000. doi: 10.1172/JCI40196. Epub 2010 Jul [abstract]
11. Oh S, Young C, Gravenstein N, et al; Monitoring technologies in the neonatal intensive care unit: implications for the J Perinatol. 2010 Nov;30(11):701-8. Epub 2010 Mar 25. [abstract]
12. Chen L; Necrotizing Enterocolitis (Surgical perspective) Medscape, Mar 2010
13. Rao SC, Basani L, Simmer K, et al; Peritoneal drainage versus laparotomy as initial surgical treatment for Cochrane Database Syst Rev. 2011 Jun 15;(6):CD006182. [abstract]
14. Clark RH, Gordon P, Walker WM, et al; Characteristics of patients who die of necrotizing enterocolitis. J Perinatol. 2011 May 19. [abstract]
15. Aguayo P, Fraser JD, Sharp S, et al; Stomal complications in the newborn with necrotizing enterocolitis. J Surg Res. 2009 Dec;157(2):275-8. Epub 2009 Jul 10. [abstract]
16. Zachariah SK; Adult necrotizing enterocolitis and non occlusive mesenteric ischemia. J Emerg Trauma Shock. 2011 Jul;4(3):430-2. [abstract]
17. Cooke RA; Pig Bel. Perspect Pediatr Pathol. 1979;5:137-52. [abstract]
18. Matsuda T, Okada Y, Inagi E, et al; Enteritis necroticans 'pigbel' in a Japanese diabetic adult. Pathol Int. 2007 Sep;57(9):622-6. [abstract]
19. Morgan JA, Young L, McGuire W; Pathogenesis and prevention of necrotizing enterocolitis. Curr Opin Infect Dis. 2011 Jun;24(3):183-9. [abstract]
20. Schurr P, Perkins EM; The relationship between feeding and necrotizing enterocolitis in very low birth weight infants. Neonatal Netw. 2008 Nov-Dec;27(6):397-407. [abstract]
21. Thompson AM, Bizzarro MJ; Necrotizing enterocolitis in newborns: pathogenesis, prevention and management. Drugs. 2008;68(9):1227-38. [abstract]
22. Frost BL, Caplan MS; Probiotics and prevention of neonatal necrotizing enterocolitis. Curr Opin Pediatr. 2011 Apr;23(2):151-5. [abstract]

Internet and further reading

• Claud EC; Neonatal Necrotizing Enterocolitis -Inflammation and Intestinal Immaturity. Antiinflamm Antiallergy Agents Med Chem. 2009 Sep;8(3):248-259. [abstract]
• Morowitz MJ, Poroyko V, Caplan M, et al; Redefining the role of intestinal microbes in the pathogenesis of necrotizing Pediatrics. 2010 Apr;125(4):777-85. Epub 2010 Mar 22. [abstract]