Necrotizing Enterocolitis

NECROTIZING ENTEROCOLITIS

ByAYMAN ABOU MEHREM, MD, CABP

Assistant ConsultantDepartment of pediatrics

King Abdulaziz Hospital, Al-Ahsa

November 25, 2007

Necrotizing Enterocolitis

DefinitionsEpidemiologyRisk FactorsPathogenesisPathophysiologyClinical PresentationDiagnosisManagementPrognosisPrevention

Definitions

Necrotizing Enterocolitis: an acquired neonatal acute intestinal necrosis of unknown etiologyNEC is neither a uniform nor a well-defined disease entity.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

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


DefinitionsAcquired 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:

NECSIPViral enteritis of infancyCow’s milk protein allergy


Epidemiology

Incidence: 0.3-2.4 / 1000 live births2-5 % of all NICU admissions5-10 % of VLBW infants

Over 90 % of cases occur in preterm babiesAbout 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 .

Sporadic or epidemic clustersSex, 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

Epidemiology

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 factorThe 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 Surg. 1991 Apr;26(4):414-8; discussion 419-21.

Familial:Fried and Vure (1974) reported a consanguineous Jewish Ashkenazi family in which three of four children died within a few weeks after birth from severe enterocolitis.5

Mégarbané and Sayad (2007) reported a Lebanese consanguineous family where three term sibs presented with severe early and lethal enterocolitis, all with delayed meconium passage.6

Risk Factors: Genetics

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 Genet. 2007 Jan;71(1):89-90.

Twins:Bhandari et al, in a multicenter retrospective study of 450 twin pairs born at < or =32 weeks of gestation, showed that intraventricular hemorrhage, necrotizing enterocolitis, and bronchopulmonary dysplasia are familial in origin.7

Risk Factors: Genetics

7 Bhandari et al. Familial and genetic susceptibility to major neonatal morbidities in preterm twins. Pediatrics. 2006 Jun;117(6):1901-6.

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

Risk Factors: Gene Polymorphism

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 enterocolitis. Pediatr Res. 2007 Aug;62(2):188-90.

Schutzman and Porat, in a retrospective study10, found:G6PD deficiency was significantly higher (27.8%) in infants with NEC compared with the 5.3% prevalence among NICU admissions (odds ratio = 6.9; 95% confidence interval = 2 to 23.5).G6PD deficiency also was found to be a marker for more severe NEC. G6PD deficiency should be considered a risk factor for NEC.

Risk Factors: G-6-PD Deficiency

10 Schutzman DL, Porat R. Glucose-6-phosphate dehydrogenase deficiency: another risk factor for necrotizing enterocolitis?. J Pediatr. 2007 Oct;151(4):435-7.

Maternal cocaine abuse increases the risk by 2.5 folds (95% CI = 1.17 to 5.32, P = 0.02) 11

Risk Factors: Cocaine

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.

Indomethacin for Tocolysis: Metaanalysis 2007Recent 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.

Risk Factors: Indomethacin

12 Amin SB et al. Metaanalysis of the effect of antenatal indomethacin on neonatal outcomes. Am J Obstet Gynecol. 2007 Nov;197(5):486.e1-10.

Risk Factors: Indomethacin

Indomethacin in Early Life:Associated with SIP 13

Prolonged versus Short Course of Indomethacin for the treatment of PDA in preterm infants: Systematic Review 14

o The reduction of transient renal impairment does not outweigh the increased risk of NEC associated with the prolonged course.

o Based on these results, a prolonged course of indomethacin cannot be recommended for the routine treatment of PDA in preterm infants.

13 Schmidt B et al. Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants. N Engl J Med 2001; 344: 1966–1972.

14 Herrera C et al. Prolonged versus short course of indomethacin for the treatment of patent ductus arteriosus in preterm infants. Cochrane Database Syst Rev. 2007 Apr 18;(2):CD003480.

Paquette et al showed that the combined use of indomethacin and dexamethasone increases the risk of SIP in VLBW neonates. 15

Risk Factors: Dexamethasone

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.

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

Risk Factors: H2-Blockers

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.

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)

Risk Factors: Co-amoxiclav

17 Kenyon S et al. Antibiotics for preterm rupture of membranes . Cochrane Database Syst Rev.2003;(2):CD001058 .

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.

Risk Factors: Acyclovir

18 Montjaux-Régis N et al. Necrotizing enterocolitis in a full-term infant. Is acyclovir involved?. Arch Pediatr. 2007 Oct 10.

Rugolotto et al., case report: 19

Necrotizing enterocolitis in a 850 gram infant receiving sorbitol-free sodium polystyrene sulfonateTheir case report shows that Kayexalate per se, and not necessarily suspended in sorbitol, can lead to gastrointestinal tract complications and NEC in preterm infants.

Risk Factors: Kayexalate

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.

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

Havranek et al.: Preprandial SMA BFV and postprandial SMA BFV responses to minimal enteral feedings were not affected by the presence of a UAC. 22

Risk Factors: UAC

20 Rand T et al. Effects of umbilical arterial catheterization on mesenteric hemodynamics. PediatrRadiol. 1996 Jul;26(7):435-8.

21 Barrington KJ. Umbilical artery catheters in the newborn: effects of position of the catheter tip. Cochrane Database Syst Rev. 2000;(2):CD000505.

22 Havranek T et al. Umbilical artery catheters do not affect intestinal blood flow responses to minimal enteral feedings. J Perinatol. 2007 Jun;27(6):375-9.

Butler-O'Hara et al. compared long-term (up to 28 days) and short-term (7-10 days) use of umbilical venous catheters in premature infants with birth weights of less than 1251 grams. 23

There were no differences in time to full feedings or to regain birth weight or in the incidence of necrotizing enterocolitis or death.

Risk Factors: UVC

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.

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.

Risk Factors: PDA

24 Patole SK et al. Does patent ductus arteriosus affect feed tolerance in preterm neonates?. Arch DisChild Fetal Neonatal Ed. 2007 Jan;92(1):F53-5.

Limited to those that have some underlying illness or condition requiring NICU admission.2

Congenital Heart DiseaseIntrauterine growth restrictionPolycythemiaHypoxic-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: in Term Babies

Dempsey and Barrington in a Systematic Review 25

showed:There is no evidence of long term benefit from partial exchange in polycythaemic infants.The incidence of gastrointestinal injury is increased. NEC (RR 8.68; 95% CI 1.06 to 71.1)

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.

Risk Factors: Exchange Transfusion

Pathogenesis

Pathophysiology

Hypoxic-Ischemic insultEnteral FeedingMicrobiologic FloraCytokines 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 meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2007 May;92(3):F169-75.

Enteral Feeding

Disadvantages of Formula:Higher osmolality ±Lack of immunoprotective factorsLack of growth factorsAltering intestinal flora

Microbiologic Flora and Infection

Several organisms have been accused, but non has been proven to be causative:

EnterobacteriaceaeEnterobacter sakazakiiCoagulase-negative staphylococci: SIPClosrtidium perfringensCandida species: SIPCytomegalovirusTorovirusHIVMucormycosis

Cytokines and Inflammatory Mediators

Platelet Activating Factor (PAF)Tumor Necrosis Factor (TNF)High-mobility group box 1 protein (HMGB 1)Interferon-gamma (INF-gamma)Interleukins (ILs)Matrix metalloproteinases (MMPs)

Inflammatory cascade. The inflammatory cascade results in the secretion of multiple proinflammatory and counterregulatory cytokines that eventually lead to the generation of toxic metabolites and destruction of the intestinal mucosa.29 Markel TA et al. Cytokines in necrotizing enterocolitis. Shock. 2006 Apr;25(4):329-37.

Pathophysiology, in summary

Ischemic or toxic mucosal damage

Loss of mucosal integrity Bacterial proliferation

Enteral feeding

Intramural gas

Transmural necrosis

Invasion of mucosa and submucosa

Perforation

Peritonitis

Pathology

Closeup of intestine of infant showing necrosis and pneumatosis intestinalis. Autopsy

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 muscularisthat only the serosa is intact.30 Epelman M et al. Necrotizing enterocolitis, review of state-of-the-art imaging findings with pathologic correlation. RadioGraphics 2007; 27:285–305.

Pathology

NEC induced by an intravenous injection of PAF in a rat model

Pathology

Microscopic images of (A) normal bowel and (B) characteristic findings of NEC, which illustrates hemorrhagic necrosis, beginning in the mucosa and extending to the muscular bowel wall, where the potential for perforation exists. NEC frequently involves the terminal ileum. Reprinted with permission from WebPath, courtesy of Edward C. Klatt, MD, Florida State University College of Medicine, Tallahassee, FL (http://medlib.med.utah.edu/WebPath).

Pathology

Parietal ileal pneumatosis in neonatal necrotizing enterocolitis

Clinical Presentation

Onset varies with gestational ageVLBW 14 – 20 daysTerm first week

Course of the diseaseFulminant presentationSlow, paroxysmal presentation

Clinical PresentationSystemic signs:

Respiratory distress, apnea, bradycardiaLethargy, irritabilityTemp. instabilityPoor feedingHypotensionAcidosisOligureaBleeding diathesis


Abdominal (enteric) signs:DistensionTendernessGastric aspirate, vomitingIleusAbdominal wall erythema, indurationAscitesAbdominal massBloody stool


Diagnosis

A high index of suspicion is required

Sometimes cannot be differentiated from sepsis

Diagnosis, Laboratory studies

No lab test is specific for NECThe most common triad (!):

ThrombocytopeniaPersistent metabolic acidosisSevere refractory hyponatremia

↑ WBC, ↓ WBC, ↓ PMNHyperkalemiaStool: reducing substances, occult blood

Diagnosis, Radiologic studies

Abdominal X-ray:Abnormal gas pattern, ileusBowel wall edemaPneumatosis intestinalisFixed position loopIntrahepatic portal venous gas ( in the absence of UVC)Pneumoperitonium, left lateral decubitus or cross-table lateral views


Supine radiograph of the abdomen of a normal neonate shows a normal bowel gas pattern. Gas is distributed throughout the small and large bowel, and it is difficult to differentiate the small bowel from the large bowel. Each loop causes impressions on adjacent loops, giving each loop a multifaceted appearance; the overall pattern resembles that of a mosaic. The loops are generally not rounded or elongated.30 Epelman M et al. Necrotizing enterocolitis, review of state-of-the-art imaging findings with pathologic correlation. RadioGraphics 2007; 27:285–305.


Pneumatosis intestinalis. Very obvious case. Tremendous amount of air in bowel walls

Reference:Radiology Cases In NeonatologyCopyright 1996, Loren Yamamoto


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 NeonatologyCopyright 1996, Loren Yamamoto


Pneumatosis intestinalis


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.30 Epelman M et al. Necrotizing enterocolitis, review of state-of-the-art imaging findings with pathologic correlation. RadioGraphics 2007; 27:285–305.


Free intraperitoneal gas is present anteriorly (arrows)30 Epelman M et al. Necrotizing enterocolitis, review of state-of-the-art imaging findings with

pathologic correlation. RadioGraphics 2007; 27:285–305.


NEC with perforation


Left lateral decubitus radiograph shows free air

Ref: Necrotizing Enterocolitis, emidicine.com, Beverly P Wood, MD, MS, PhD


Abdominal ultrasound:Thick-walled loops of bowel with hypomotility.Intraperitoneal fluid is often present.Intramural gas can be identified in early-stage NEC 31

In the presence of pneumatosis intestinalis, gas is identified in the portal venous circulation within the liver.Color Doppler US is more accurate than abdominal radiography in depicting bowel necrosis in NEC. 32

31 Kim WY et al. Sonographic evaluation of neonates with early-stage necrotizing enterocolitis. PediatrRadiol. 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.


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.30 Epelman M et al. Necrotizing enterocolitis, review of state-of-the-art imaging findings with pathologic correlation. RadioGraphics 2007; 27:285–305.


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.30 Epelman M et al. Necrotizing enterocolitis, review of state-of-the-art imaging findings with pathologic correlation. RadioGraphics 2007; 27:285–305.


Abdominal Doppler ultrasound:Murdoch et al., in a prospective cohort study, concluded that neonates with high resistance patterns of blood flow velocity in the superior mesenteric artery on the first day of life are at increased risk of developing necrotizing enterocolitis. 33

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 NECClinical signs and symptomsNo diagnostic radiograph


Stage II : Definite (confirmed) NECA: 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


Stage III: Advanced NECA: 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, pneumoniaSurgical abdominal catastrophesInfectious enterocolitisAllergic collitisFeeding intolerance

Management

The main principle of management of confirmed NEC is to treat it as an acute abdomen with impending or septic peritonitis

Isolation: cohort isolation in case of epidemic clusters

Management, Medical

Basic NEC protocol: for all stagesNPONGT with low pressure suctionClose monitoring of vital signs & abdominal girthRemove UAC and UVCSeptic workup: blood, urine, and stool culturesLP and CSF culture: controversialAntibiotics: ampicillin + gentemicin or cefotaximeadd metronidazole or clindamycin if peritonitis or perforation is suspected

Management, Medical

Basic NEC protocol …..continuedMonitor for GI bleedingFluid balance: maintain urine output 1-3 ml/kg/hrLab.: CBC, PLT, electrolytes q 8-12 hrs

PT, PTT, LFT’s as indicated CRP 34

Radiology: serial AXR q 6-8 hrs in the first 2-3 daysFamily support

34 Pourcyrous M et al. C-reactive protein in the diagnosis, management, and prognosis of neonatal necrotizing enterocolitis. Pediatrics. 2005 Nov;116(5):1064-9.

Management, Medical

Stage IBasic NEC protocolIf all cultures are negative, the infant improved clinically, and AXR is normal, antibiotics can be stopped after 2-3 days and feeding can be resumed.

Management, Medical

Stage IIBasic NEC protocolNPO for 14 daysTPN, 90-110 kcal/kg/dayAntibiotics for 14 daysRespiratory support± Inotropic supportSurgical consultation

Management, Medical

Stage IIIAs stage IIInotropic supportTreat anemia, thrombocytopenia, coagulopathySurgical intervention

Management, Surgical

Early Surgical ConsultationIndications for surgery:

Perforation: 20-30 % of cases12-48 hrs after onset

Full-thickness necrosisDeterioration despite aggressive medical treatment


Surgical Approach:Exploratory laparotomyPeritoneal drainage


Exploratory laparotomy:The most commonly used approach.Intestinal resection with enterostomy.Primary anastomosis. 35, 36

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 Surg. 2006 Apr;41(4):725-9.

Management, SurgicalPeritoneal drainage:

More conservative approach, Started in 1977Insertion of a peritoneal draine local anaesthesiaInitially, used for very sick premature babies, with weight ≤ 1000 gNow, it is used more commonly with larger and more stable babiesIt is used as a definite treatment in some centers


Algorithm for the treatment of necrotizing enterocolitis37 Xavier Demestre et al Peritoneal drainage as primary management in necrotizing enterocolitis: A

prospective study, J Pediatr Surg. 2002 Nov • Volume 37 • Number 11 • p1534 to p1539.


Laparoscopy:Clarck and Mackinaly reported the use of laparoscopy on day 30 of life in the treatment of a VLBW infant (900 g) with perforated NEC.38

Tan et al.: 4 babies (500-1000 g)Needlescopic diagnosis is feasible and appears to be safe, even in critically ill micropremmies less than 1000 g. The technique can provide useful information for surgical decision-making and allows for precise placement of a microlaparotomy incision over the site of perforation, thus minimizing the trauma from open surgery in this special group of patients. 39

38 Clark C, Mackinlay GA. Laparoscopy as an adjunct to peritoneal drainage in perforated necrotizing enterocolitis. J Laparoendosc Adv Surg Tech A. 2006 Aug;16(4):411-3.

39 Tan HL et al. The role of diagnostic laparoscopy in micropremmies with suspected necrotizing enterocolitis. Surg Endosc. 2007 Mar;21(3):485-7.

Prognosis and OutcomeNEC with perforation: mortality 20-40 %Recurrent NEC : rare complication, 4%Subacute or intermittent symptoms of bowel obstruction: strictures, 10-35 %Short-gut syndrome: FTT, high mortality.The type of operation (peritoneal drain vs. laparotomy) performed for perforated NEC does not influence survival or other clinically important early outcomes in preterm infants. 40

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 OutcomeRees 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 OutcomeAdesanya et al. Retrospective Study:Intestinal perforation caused by NEC, as compared to SIP, is associated with worse neurodevelopmentaloutcome 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, multicenterclinical 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.

PreventionBreast milkAntenatal Steroid therapyOral immunoglobulinsOral antibioticsProbiotics (Lactobacillus, Bifidobacterium)Feeding strategiesOral PAF antagonistsGlutamineArgininePolyunsaturated fatty acids (PUFA)LactoferinPentoxifylline

Prevention: Breast Milk

Formula vs. Donor Breast Milk: 27, 28

Breast milk is associated withlower risk of NECslower 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 meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2007 May;92(3):F169-75.

Antenatal corticosteroids for women at risk of preterm birth: Systematic Review 46

Decreased risk of NECRR 0.46, 95% CI 0.29 to 0.74, eight studies, 1675 infants

Prevention: Antenatal Steroids

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.

The evidence does not support the administration of oral immunoglobulin for the prevention of NEC. There are no randomised controlled trials of oral IgA alone for the prevention of NEC. 47

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.

Probiotics might reduce the risk of necrotisingenterocolitis 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 trialsUnanswered questions include the dose, duration, and type of probiotic agents (species, strain, single or combined, live or killed) used for supplementation. 48

Prevention: Probiotics

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 .

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

Prevention: Feeding Strategies

49 Pietz J et al. Prevention of necrotizing enterocolitis in preterm infants: a 20-year experience. Pediatrics. 2007 Jan;119(1):e164-70 .

The available data from good quality randomisedcontrolled trials suggest that glutamine supplementation does not confer clinically significant benefits for preterm infants. The narrow confidence intervals for the effect size estimates suggest that a further trial of this intervention is not a research priority. 50

Prevention: Glutamine

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.

The data are insufficient at present to support a practice recommendation. A multicentrerandomized controlled study of argininesupplementation in preterm neonates is needed, focusing on the incidence of NEC, particularly the more severe stages (2 or 3). 51

Prevention: Arginine

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 & WilkinsNeonatology, Tricia Gomella, 5th ed, 2004, McGraw HillA Manual of Neonatal Intensive Care, Rennie & Roberton, 4th ed, 2002, Arnold

Health & Medicine

Necrotizing Enterocolitis