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ENTEROCOLITIS
By
AYMAN ABOU MEHREM, MD, CABP
Assistant Consultant
Department of pediatrics
King Abdulaziz
Hospital, Al-Ahsa
1 Gordon PV et al, Emerging trends in acquired neonatal intestinal disease: is it time to abandon Bell's
criteria?, J Perinatol. 2007 Nov;27(11):661-71.
Definitions
Isolated spontaneous intestinal perforation
(SIP): ill-defined clinical syndrome of undetermined
cause resembling NEC with less systemic involvement
and a less severe clinical course. It may present a variant
of classical NEC.
The National Institute of Child Health and Human
Development Neonatal Network (NICHD): intestinal
perforation without evidence of pneumatosis since 2002.1
1 Gordon PV et al, Emerging trends in acquired neonatal intestinal disease: is it time to abandon Bell's
criteria?, J Perinatol. 2007 Nov;27(11):661-71.
Definitions
Acquired neonatal intestinal diseases (ANIDs)1
Wider umbrella includes different pathologies affecting
gastrointestinal tract in preterm and term infants. Some
which do lead to the common final pathology of NEC and
some which do not.
Includes:
NEC
SIP
Viral enteritis of infancy
Cow’s milk protein allergy
1 Gordon PV et al, Emerging trends in acquired neonatal intestinal disease: is it time to abandon Bell's
criteria?, J Perinatol. 2007 Nov;27(11):661-71.
Epidemiology
Incidence: 0.3-2.4 / 1000 live births
2-5 % of all NICU admissions
5-10 % of VLBW infants
Over 90 % of cases occur in preterm
babies
About 10 % occur in term newborns: essentially
limited to those that have some underlying illness or
condition requiring NICU admission.2
2 Lambert DK et al. Necrotizing enterocolitis in term neonates: data from a multihospital health-care
system . J Perinatol. 2007 Jul;27(7):437-43 .
Epidemiology
Sporadic or epidemic clusters
Sex, race, geography, climate, season: No role
Holman et al.3:
o Male VLBW infants are at greater risk of death.
o Black infants: increased risk of NEC, and its
associated mortality
3 Holman RC et al. The epidemiology of necrotizing enterocolitis infant mortality in the United States.
Am J Public Health 1997; 87: 2026–31.
Risk Factors: Prematurity
Prematurity is the single greatest risk
factor
The risk is inversely related to birth
weight and gestational age.4
4 Lin PW, Stoll BJ. Necrotizing enterocolitis. Lancet. 2006 Oct 7;368(9543):1271-83.
5 Czyrko C et al. Maternal cocaine abuse and necrotizing enterocolitis: outcome and survival. J Pediatr
5 Fried K, Vure E. A lethal autosomal recessive entero-colitis of early infancy. Clin Genet 1974 (6),
195-196.
6 Mégarbané A, Sayad R. Early lethal autosomal recessive enterocolitis: report of a second family. Clin
7 Bhandari et al. Familial and genetic susceptibility to major neonatal morbidities in preterm twins.
Pediatrics. 2006 Jun;117(6):1901-6.
Risk Factors: Gene Polymorphism
Vascular endothelial growth factor:
Bányász et al suggest that VEGF G+405C polymorphism might be
associated with a higher risk of preterm birth and that VEGF C-
2578A polymorphism may participate in the development of
perinatal complications such as NEC and ARF.8
Carbamoyl phosphate synthetase:
Moonen et al suggested that the CPS1 T1405N polymorphism may
be associated with the risk of NEC in preterm infants.9
8 Bányász et al. Genetic polymorphisms for vascular endothelial growth factor in perinatal
complications. Eur Cytokine Netw. 2006 Dec;17(4):266-70.
9 Moonen RM et al. Carbamoyl phosphate synthetase polymorphisms as a risk factor for necrotizing
10 Schutzman DL, Porat R. Glucose-6-phosphate dehydrogenase deficiency: another risk factor for
necrotizing enterocolitis?. J Pediatr. 2007 Oct;151(4):435-7.
Risk Factors: Cocaine
Maternal cocaine abuse increases the risk by
2.5 folds (95% CI = 1.17 to 5.32, P = 0.02) 11
11 Czyrko C et al. Maternal cocaine abuse and necrotizing enterocolitis: outcome and survival. J
Pediatr Surg. 1991 Apr;26(4):414-8; discussion 419-21.
Risk Factors: Indomethacin
Indomethacin for Tocolysis: Metaanalysis 2007
Recent exposure (within 48 hours of delivery) to
antenatal indomethacin was associated with
necrotizing enterocolitis (OR, 2.2; 95% CI; 1.1-4.2). 12
Some limitations.
arteriosus in preterm infants. Cochrane Database Syst Rev. 2007 Apr 18;(2):CD003480.
Risk Factors: Dexamethasone
Paquette et al showed that the combined use of
indomethacin and dexamethasone increases the
risk of SIP in VLBW neonates. 15
15 Paquette et al. Concurrent use of indomethacin and dexamethasone increases the risk of spontaneous
intestinal perforation in very low birth weight neonates. J Perinatol. 2006 Aug;26(8):486-92.
Risk Factors: H2-Blockers
Guillet et al, in large case control study using
NICHD Neonatal Research Network, showed
that “Antecedent H2-blocker use was associated
with an increased incidence of NEC.
(OR 1.71, 95% CI 1.34-2.19, P < .0001) 16
16 Guillet R et al. Association of H2-blocker therapy and higher incidence of necrotizing enterocolitis in
very low birth weight infants. Pediatrics. 2006 Feb;117(2):e137-42.
Risk Factors: Co-amoxiclav
Kenyon et al. in a Systematic Review:
Co-amoxiclav should be avoided in women at
risk of preterm delivery because of the increased
risk of neonatal necrotising enterocolitis. 17
(RR 4.60, 95% CI 1.98 to 10.72)
17 Kenyon S et al. Antibiotics for preterm rupture of membranes . Cochrane Database Syst Rev.
2003;(2):CD001058 .
Risk Factors: Acyclovir
Montjaux-Régis et al, case report: 18
Term baby, developed NEC after receiving
prophylactic acyclovir.
Mother had herpes genitalis and pROM at 32 wks of
GA, treated with acyclovir until vaginal delivery.
Acyclovir treatment in utero and after birth is
discussed as a possible cause of necrotizing
enterocolitis in the infant.
19 Rugolotto S et al. Necrotizing enterocolitis in a 850 gram infant receiving sorbitol-free sodium
polystyrene sulfonate (Kayexalate): clinical and histopathologic findings. J Perinatol. 2007
Apr;27(4):247-9.
Risk Factors: UAC
Rand et al. suggested that UAC cause a decrease in mesenteric blood
flow. Therefore, their use in hemodynamically unstable neonates or
in those with gastrointestinal disease should be very carefully
considered. 20
High vs. low UAC: necrotising enterocolitis are not more frequent
with high compared to low catheters. 21
23 Butler-O'Hara M et al. A randomized trial comparing long-term and short-term use of umbilical
venous catheters in premature infants with birth weights of less than 1251 grams. Pediatrics. 2006
Jul;118(1):e25-35.
Risk Factors: PDA
Patole et al., in prospective observational study,
reported that: 24
No association between significant PDA and NEC.
The age at starting feed and full enteral feed was
significantly delayed in infants with significant PDA.
24 Patole SK et al. Does patent ductus arteriosus affect feed tolerance in preterm neonates?. Arch Dis
Child Fetal Neonatal Ed. 2007 Jan;92(1):F53-5.
Risk Factors: in Term Babies
Limited to those that have some underlying
illness or condition requiring NICU admission.2
Congenital Heart Disease
Intrauterine growth restriction
Polycythemia
Hypoxic-ischemic events
2 Lambert DK et al. Necrotizing enterocolitis in term neonates: data from a multihospital health-care
system. J Perinatol. 2007 Jul;27(7):437-43.
Risk Factors: Exchange Transfusion
25 Dempsey EM, Barrington K. Short and long term outcomes following partial exchange transfusion in
the polycythaemic newborn: a systematic review. Arch Dis Child Fetal Neonatal Ed. 2006
Jan;91(1):F2-6.
Pathogenesis
Pathophysiology
Hypoxic-Ischemic insult
Enteral Feeding
Microbiologic Flora
Cytokines and Inflammatory Mediators
Hypoxic-ischemic insult
Hypoxia-Reoxygenation.
Ischemia-Reperfusion.
Intramural microcirculation.
Balance between Endothelin-1 and Nitric Oxide.26
26 Nowicki PT. Ischemia and necrotizing enterocolitis, Where, when, and how. Seminars in Pediatric
Surgery (2005) 14, 152-158.
Enteral Feeding
Formula vs. Donor Breast Milk: 27, 28
Formula is associated with higher risk of
NEC
27 Quigley M et al. Formula milk versus donor breast milk for feeding preterm or low birth weight
infants. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD002971.
28 Boyd CA et al. Donor breast milk versus infant formula for preterm infants: systematic review and
Intramural gas
Transmural necrosis
Perforation
Peritonitis
Pathology
Postmortem photograph of bowel involved with severe NEC. The arrows indicate areas of the bowel
wall where there has been so much necrosis and sloughing of the mucosa, submucosa, and muscularis
that only the serosa is intact.
30 Epelman M et al. Necrotizing enterocolitis, review of state-of-the-art imaging findings with
Pneumatosis intestinalis.
Very obvious case.
Tremendous amount of
air in bowel walls
Reference:
Radiology Cases In Neonatology
Copyright 1996, Loren Yamamoto
Diagnosis, Radiologic studies
Pneumatosis intestinalis.
Note the air visible in
the bowel wall. The air
dissects the bowel wall
giving it a double lined
appearance (ie., railroad
tracks without the ties)
Reference:
Radiology Cases In Neonatology
Copyright 1996, Loren Yamamoto
Diagnosis, Radiologic studies
Pneumatosis intestinalis
Diagnosis, Radiologic studies
Supine AXR, The bowel is mildly dilated with gas, mainly on the left side. The bubbly pattern of
gas seen mainly in the right lower quadrant represents intramural gas.
Epelman M et al. Necrotizing enterocolitis, review of state-of-the-art imaging findings with
30
31 Kim WY et al. Sonographic evaluation of neonates with early-stage necrotizing enterocolitis. Pediatr
Radiol. 2005 Nov;35(11):1056-61.
32 Faingold R et al. Necrotizing Enterocolitis: Assessment of Bowel Viability with Color Doppler US,
Radiology 2005;235:587-594.
Diagnosis, Radiologic studies
Sonogram of a bowel loop shows differentiation of intraluminal gas from intramural gas.
The intraluminal gas (L) is surrounded by a thickened bowel wall. Within the bowel wall
are multiple hyperechoic foci (arrows), which represent intramural gas.
Epelman M et al. Necrotizing enterocolitis, review of state-of-the-art imaging findings with
30
Sonogram shows a bowel loop with a large amount of intramural gas (arrows) in the more
dependent and vertically oriented parts of the loop. This gives the bowel wall a typical
granular appearance and causes a posterior artifact.
Epelman M et al. Necrotizing enterocolitis, review of state-of-the-art imaging findings with
30
33 Murdoch EM et al. Doppler flow velocimetry in the superior mesenteric artery on the first day of life
in preterm infants and the risk of neonatal necrotizing enterocolitis. Pediatrics. 2006
Nov;118(5):1999-2003.
Modified Bell’s Staging Criteria
Stage I : Suspected NEC
Clinical signs and symptoms
No diagnostic radiograph
Modified Bell’s Staging Criteria
Stage II : Definite (confirmed) NEC
A: Mild NEC
• Sign & symptoms, absent B/S, gross blood in stool
• AXR: ileus, focal areas of pneumatosis intestinalis
B: Moderate NEC
• Systemically ill
• AXR: extensive pneumatosis intestinalis, early
ascites, possible intrahepatic portal venous
gas
Modified Bell’s Staging Criteria
Stage III: Advanced NEC
A: Severe NEC without perforation
• Critically ill
• Abdominal wall induration, extensive erythema
• AXR: prominent ascites, paucity of bowel gas,
persistent fixed loop
B: Severe NEC with perforation
Differential Diagnosis
Systemic infection: sepsis, pneumonia
Surgical abdominal catastrophes
Infectious enterocolitis
Allergic collitis
Feeding intolerance
Management
The main principle of management of
confirmed NEC is to treat it as an
acute abdomen with impending or
septic peritonitis
35 Hall NJ et al. Resection and primary anastomosis is a valid surgical option for infants with
necrotizing enterocolitis who weigh less than 1000 g. Arch Surg. 2005 Dec;140(12):1149-51.
36 Singh m et al. Surgery for intestinal perforation in preterm neonates: anastomosis vs stoma. J Pediatr
40 Moss RL et al. Laparotomy versus Peritoneal Drainage for Necrotizing Enterocolitis and Perforation.
N Engl J Med. 2006 May 25;354(21):2225-34.
Neurodevelopmental Outcome
Soraisham et al.: Preterm infants who develop
NEC are at a significantly higher risk for
developing neurodevelopmental disability. 41
41 Soraisham AS et al. Does necrotising enterocolitis impact the neurodevelopmental and growth
outcomes in preterm infants with birthweight < or =1250 g?. J Paediatr Child Health. 2006
Sep;42(9):499-504.
Neurodevelopmental Outcome
Rees et al. Systematic Review (UK):
NEC is associated with significantly worse
neurodevelopmental outcome than prematurity alone.
Presence of advanced NEC and need for surgery increase
the risk of neurological impairment. 42
Schulzke et al. Systematic Review (Australia):
Survivors of stage II or higher NEC are at risk for long-
term neurodevelopmental impairment, especially if
they require surgery for the illness. 43
42 Rees CM et al. Neurodevelopmental outcomes of neonates with medically and surgically treated
necrotizing enterocolitis. Arch Dis Child Fetal Neonatal Ed. 2007 May;92(3):F193-8.
43 Schulzke SM et al. Neurodevelopmental outcomes of very low-birth-weight infants with necrotizing
enterocolitis: a systematic review of observational studies. Arch Pediatr Adolesc Med. 2007
Jun;161(6):583-90.
Neurodevelopmental Outcome
Adesanya et al. Retrospective Study:
Intestinal perforation caused by NEC, as compared to
SIP, is associated with worse neurodevelopmental
outcome at 1 year. 44
Blakely et al. Retrospective Study:
the risk-adjusted odds ratio favoring laparotomy for death
or impairment, indicate the need for a large, multicenter
clinical trial to assess the effect of the initial surgical
therapy on outcome at > or =18 months. 45
44 Adesanya OA et al. Intestinal perforation in very low birth weight infants: growth and
neurodevelopment at 1 year of age. J Perinatol. 2005 Sep;25(9):583-9.
45 Blakely ML et al. Laparotomy versus peritoneal drainage for necrotizing enterocolitis or isolated
intestinal perforation in extremely low birth weight infants: outcomes through 18 months adjusted
age. 2006 Apr;117(4):e680-7.
Prevention
Breast milk
Antenatal Steroid therapy
Oral immunoglobulins
Oral antibiotics
Probiotics (Lactobacillus, Bifidobacterium)
Feeding strategies
Oral PAF antagonists
Glutamine
Arginine
Polyunsaturated fatty acids (PUFA)
Lactoferin
Pentoxifylline
Prevention: Breast Milk
Formula vs. Donor Breast Milk: 27, 28
Breast milk is associated with
lower risk of NEC
slower growth in the early postnatal period
27 Quigley M et al. Formula milk versus donor breast milk for feeding preterm or low birth weight
infants. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD002971.
28 Boyd CA et al. Donor breast milk versus infant formula for preterm infants: systematic review and
46 Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at
risk of preterm birth. Cochrane Database Syst Rev. 2006 Jul 19;3:CD004454.
Prevention: Oral Immunoglobulin
47 Foster J et al, Oral immunoglobulin for preventing necrotizing enterocolitis in preterm and low birth-
weight neonates. Cochrane Database Syst Rev. 2004;(1):CD001816.
Prevention: Probiotics
Probiotics might reduce the risk of necrotising
enterocolitis in preterm neonates with less than 33 weeks'
gestation (relative risk 0.36, 95% CI 0.20-0.65)
the short-term and long-term safety of probiotics needs to
be assessed in large trials
Unanswered questions include the dose, duration, and
type of probiotic agents (species, strain, single or
combined, live or killed) used for supplementation. 48
48 Deshpande G et al. Probiotics for prevention of necrotising enterocolitis in preterm neonates with
very low birthweight: a systematic review of randomised controlled trials. Lancet. 2007 May
12;369(9573):1614-20 .
Prevention: Feeding Strategies
Pietz et al. reported 20-year experience, in
Fairview Hospital, Cleveland, Ohio, with 1239
very low birth weight infants suggests strongly
that the late-onset, slow, continuous drip feeding
protocol and avoidance of indomethacin and
early dexamethasone treatment contribute to the
prevention of necrotizing enterocolitis. 49
50 Tubman TR et al, Dalziel S. Glutamine supplementation to prevent morbidity and mortality in preterm
infants. Cochrane Database Syst Rev. 2005 Jan 25;(1):CD001457.
Prevention: Arginine
The data are insufficient at present to support a
practice recommendation. A multicentre
randomized controlled study of arginine
supplementation in preterm neonates is needed,
focusing on the incidence of NEC, particularly
the more severe stages (2 or 3). 51
51 Shah P, Shah V., Arginine supplementation for prevention of necrotising enterocolitis in preterm
infants. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD004339 .
References
Manual of Neonatal Care, Cloherty, 5th ed, 2004,
Lippincott Williams & Wilkins
Neonatology, Tricia Gomella, 5th ed, 2004,
McGraw Hill
A Manual of Neonatal Intensive Care, Rennie &
Roberton, 4th ed, 2002, Arnold