Necrotising Enterocolitis (NEC)

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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
Epidemiology2
The most frequent gastrointestinal emergency in neonates 3
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:
o Perinatal asphyxia.
o Polycythaemia.
o Respiratory distress.
o 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.

Pathophysiology2
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
Clinical presentation
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

Differential diagnosis
Sepsis
Haemorrhagic disease of the newborn
Swallowed maternal blood
Volvulus/malrotation
Intussusception
Hirschsprung colitis
Pseudomembranous colitis
Stress ulcer
Meconium ileus
Focal intestinal perforation8
Investigations
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.
o Severe or persistent thrombocytopenia, neutropenia, coagulopathy or acidosis
indicate severe disease.
o 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
Staging6,7
Stage I - Suspected NEC
o Systemic: Non-specific signs such as temperature instability, lethargy, apnoea, bradycardia
o GIT: Gastric residuals, occult blood in stool
o AXR: Normal/non-specific changes
Stage IIA -Definite and mild NEC
o Systemic: Non-specific signs
o GIT: Abdominal distension tenderness, absent bowel sounds, frank blood in stool
o AXR: Ileus, focal pneumatosis intestinalis
Stage IIB - Definite and moderate NEC
o Systemic: Mild acidosis, thrombocytopenia
o GIT: Abdominal wall oedema, tenderness mass
o AXR: Extensive pneumatosis intestinalis, early ascites, intrahepatic portal gas
Stage IIIA - Advanced NEC
o Systemic: Respiratory/metabolic acidosis, apnoea, hypotension, decreasing urine output, leukopenia, DIC
o GIT: Spreading oedema, erythema, induration of the abdomen
o AXR: Prominent ascites persistent sentinel loop, no perforation
Stage IIIB - Advanced NEC
o Systemic: Deteriorating vital signs, shock, electrolyte imbalance
o GIT and AXR: Signs of perforation
Management2,11,12
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:
o Ampicillin/gentamicin or cefotaxime.
o 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.

Complications and prognosis

Perforation
Acquired short bowel syndrome (following surgery)
DIC
Sepsis and shock
Intestinal strictures (~30%)
Enterocolic fistulae
Abscess formation
Recurrent NEC (rare)
Death (20-40%)
Other forms
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 (30100%).
Treatment follows the same principles as the neonatal form (bowel rest, antibiotics +/surgery), but would depend on available local medical and surgical services. 1
Prevention
Focus on reducing the multiple contributing factors in a susceptible host.
Suggestions include:2
Factors relating to feeding:
o Correction of hypovolaemia, hyperviscosity and allowing adequate time for
homeostatic mechanisms to mature before enteral feeding challenge is begun.
o Start feeds slowly using formulas of low volume.13,14
o Small increments (20 ml/kg/day) when increasing feeds.
o Exclusive use of (expressed) human milk seems to protect. 15 Donor human milk
may not be as protective)14
o Avoid hyperosmolar medications and feeds.
o Conservative feeding.
o 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.

Document references
1. Warrell D, Cox TM, Firth JD, Benz E. Oxford Textbook of Medicine, 4th edition. 2004.
OUP. ISBN 0198529988
2. Lin PW, Stoll BJ; Necrotising enterocolitis. Lancet. 2006 Oct 7;368(9543):1271-83.
[abstract]
3. Pellegrini M, Lagrasta N, Garcia Garcia C, et al; Neonatal necrotizing enterocolitis: a
focus on. Eur Rev Med Pharmacol Sci. 2002 Jan-Feb;6(1):19-25. [abstract]
4. Luig M, Lui K; Epidemiology of necrotizing enterocolitis--Part II: Risks and susceptibility
of premature infants during the surfactant era: a regional study. J Paediatr Child
Health. 2005 Apr;41(4):174-9. [abstract]
5. Guner YS, Chokshi N, Petrosyan M, et al; Necrotizing enterocolitis--bench to bedside:
novel and emerging strategies. Semin Pediatr Surg. 2008 Nov;17(4):255-65. [abstract]
6. Bell MJ; Neonatal necrotizing enterocolitis. N Engl J Med. 1978 Feb 2;298(5):281-2.
7. 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]
8. Okuyama H, Kubota A, Oue T, et al; A comparison of the clinical presentation and
outcome of focal intestinal perforation and necrotizing enterocolitis in very-low-birthweight neonates. Pediatr Surg Int. 2002 Dec;18(8):704-6. Epub 2002 Dec 17. [abstract]
9. Neu J, Mshvildadze M, Mai V; A roadmap for understanding and preventing necrotizing
enterocolitis. Curr Gastroenterol Rep. 2008 Oct;10(5):450-7. [abstract]
10. 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]
11. Nadler EP, Upperman JS, Ford HR; Controversies in the management of necrotizing
enterocolitis. Surg Infect (Larchmt). 2001 Summer;2(2):113-9; discussion 119-20.
[abstract]
12. Burkitt HG and Quick CRG. Essential Surgery 3rd edition Churchill Livingstone 2002.
13. Berseth CL, Bisquera JA, Paje VU; Prolonging small feeding volumes early in life
decreases the incidence of necrotizing enterocolitis in very low birth weight infants.
Pediatrics. 2003 Mar;111(3):529-34. [abstract]
14. 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]
15. Thompson AM, Bizzarro MJ; Necrotizing enterocolitis in newborns: pathogenesis,
prevention and management. Drugs. 2008;68(9):1227-38. [abstract]