Necrotising Enterocolitis (NEC)

First described over a century ago necrotising enterocolitis (NEC) is now the most common gastrointestinal emergency occurring in neonates. It is an acquired disorder with a mortality as high as 50% (10-44% in infants less than 1500 g, 0-20% in infants over 2500 g). 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 birth weight 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. 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.¹ Diagnosis and treatment remain very difficult and challenging.²

• The most frequent gastrointestinal emergency in neonates³
• Few population or multicentre studies but frequency ranges from 1% to 5% of neonatal intensive care unit (NICU) admissions.
• Incidence of 0.5 to 5 patients per 1000 live births.
• Incidence and mortality increase in inverse proportion to birthweight and gestational age.²
• Only one study has reported a decline in the rate of disease in very low birth weight (VLBW) infants.⁴
• 10% of NEC occurs in full term infants.
• In full term infants NEC is usually associated with predisposing or underlying disorders:
  • Perinatal asphyxia.
  • Polycythaemia.
  • Respiratory distress.
  • Congenital anomalies (myelomeningocoele, congenital heart disease).
• There is no consistent association between gender and rates of NEC.
• However male VLBW babies have a higher mortality.
• Mortality is higher in black infants with NEC (even when matching for birthweight and other characteristics).
• 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).
• No identified sex/race/seasonal/socioeconomic status associations (other than above).
• Currently no known genetic links (although there is promising research offering hope of specific treatments or preventive strategies).
• 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.

The aetiology is unknown and the pathophysiology poorly understood. Premature infants are at risk because of immaturity of:

• Gastrointestinal motility. Slower motility also occurs in fetal hypoxia and perinatal asphyxia.
• Digestive ability. Impaired ability to digest and absorb nutrients may contribute to intestinal injury.
• Circulatory regulation. Hypoxic-ischaemic injury may play a part. One hypothesis is that there is reflex diversion of blood supply away from gut and towards heart and brain (the diving reflex) and that this together with other factors (feeding and bacteria) might lead to intestinal hypoxia.
• Intestinal barrier function. If this is immature, or reduced, bacteria are able to penetrate the mucosal barrier and cause inflammation more easily. Immature goblet cells and an immature mucin layer may lead to increased permeability and breaching of the intestinal epithelial barrier. Immature paneth cells and biochemical defences may also reduce defenses (less able to secrete antimicrobial peptides).
• Immune defence. A series of events contribute to the inflammatory response characterising NEC (mucosal oedema, coagulation necrosis, haemorrhage). Various inflammatory mediators are implicated in what may be an exaggerated response by immature intestinal cells. Another hypothesis is that an inadequate immune response allows bacterial overgrowth. Either excessive or hypoactive immune responses may therefore be implicated in the pathogenesis.

Other contributory factors include:

• Hypoxic-ischaemic injury
• Formula feeding and formula composition (human milk is protective)
• Colonisation by pathological bacteria

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.
Note also that:

• Polycythaemia, drugs, cardiac defects, exchange transfusions, RDS may contribute to the hypoxic-ischaemic injury.
• Blood cultures are positive in 20-30% of cases reflecting the reduced defense to bacterial invasion (E. coli, Klebsiella spp., Salmonella spp., S. epidermidis).
• Several groups have shown that upregulation of nitric oxide plays an integral role in the development of epithelial injury in NEC.⁵

Onset usually 3-10 days (extremes 1 to 90 days) after birth. Age at presentation is inversely related to gestational age at birth (that is full term infants with NEC present in the first few days). Early signs are non-specific 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).^6,7

• Abdominal distension with increasing gastric aspirates
• 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

• Sepsis
• Haemorrhagic disease of the newborn
• Swallowed maternal blood
• Volvulus/malrotation
• Intussusception
• Hirschsprung colitis
• Pseudomembranous colitis
• Stress ulcer
• Meconium ileus
• Focal intestinal perforation⁸

• Blood lab tests are non-specific, but cultures, full blood count, 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).
• Diagnosis is confirmed on abdominal x-ray (supine and decubitus/erect). 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 hepatic venous gas, free air, dilated intestinal loop, ileus, ascites, diffuse distention and asymetric bowel gas pattern.
• USS may also be useful.
• Newly developed biomarkers may prove helpful in achieving early diagnosis. These have been suggested as screening tests for at risk babies.^9,10

• Nil by mouth to rest the bowel.
• NG or OG tube to decompress the bowel with low intermittent orogastric suction.
• IV fluids, TPN, and IV antibiotics for 10-14 days:
  • Ampicillin/gentamicin or cefotaxime.
  • Plus metronidazole or clindamycin.
• Treat shock, DIC, etc.
• Surgery if deteriorating or perforated/necrotic bowel suspected.
• Intubation/ventilation for apnoea.
• Serial bloods and abdominal x-rays.
• Can restart oral feds 7-10 days after pneumatosis clears.

• Perforation
• Acquired short bowel syndrome (following surgery)
• DIC
• Sepsis and shock
• Intestinal strictures (~30%)
• Enterocolic fistulae
• Abscess formation
• Recurrent NEC (rare)
• Death (20-40%)

There is another necrotising enterocolitis that affects older children and adults. It is known by different local names over the globe (for instance darmbrand in Germany and pig-bel in Papua New Guinea).

• 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).
• 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.¹

Focus on reducing the multiple contributing factors in a susceptible host.
Suggestions include:²

• Factors relating to feeding:
  • Correction of hypovolaemia, hyperviscosity and allowing adequate time for homeostatic mechanisms to mature before enteral feeding challenge is begun.
  • Start feeds slowly using formulas of low volume.^13,14
  • Small increments (20 ml/kg/day) when increasing feeds.
  • Exclusive use of (expressed) human milk seems to protect.¹⁵ Donor human milk may not be as protective)¹⁴
  • Avoid hyperosmolar medications and feeds.
  • Conservative feeding.
  • Trophic feeding rather than extended bowel rest.¹⁵
• Some have suggested steroids for women in preterm labour.¹⁵
• Ig A supplementation (IV Ig prophylaxis of neonatal infections not protective).
• Arginine supplementation.
• Erythropoietin.
• Oral antibiotics.
• Probiotics.¹⁵
• Implementation of strict infection-control measures to prevent faecal and oral spread of organisms.