Indian Pediatrics 2002; 39:229-237  

Necrotizing Enterocolitis–An Unconquered Disease

Background and Incidence

Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in the newborn infant. Although it is pre-dominatly a disease of the preterm infant, about 10% of cases occur in term babies. Data from the National Institute of Child Health and Human Development Neonatal Research Network (NICHD) in the USA show that proven NEC occurred in approximately 10% of babies born with birthweights less than 1500 grams and NEC was suspected in 17% of the babies(1). In a later report proven NEC occurred in 7% of babies of this weight group(2). Population studies from India on this condition are not widely publicised and to do this will require definition criteria as many cases of NEC might get coded as ‘sepsis’. In one such report from a single center the incidence of NEC in babies less than 32 weeks gestation was 5.2%(3). Mortality rates vary across centers and range from 10-40% depending on gestational age of the baby(4-7). Those who survive may show significant complications both in short and long term including neurodevelopmental impairment for which NEC is an independent risk factor(8,9). Despite several decades of research its etiology and pathogenesis remains elusive. With reduced respiratory mortality in the surfactant era its importance as a cause of neonatal mortality and morbidity has increased.

Despite our awareness of NEC since the middle of the last century as a disease that predominantly affects preterm babies its pathophysiology is not clearly understood. Several trials and epidemiological studies have been undertaken to unravel this mystery and some common observations can be derived.

Prematurity is the single most important risk factor for the development of NEC accounting for 90% of all cases. Babies less than 1000 grams or 28 weeks gestational age are at the highest risk. Age of onset of NEC in premature infants is related to postconceptual age with babies born more premature developing NEC at a later chronological age. Preterm babies are therefore at risk for developing NEC for several weeks after birth. Although NEC can occur in sick ventilated preterm babies many cases occur in babies who are advancing on enteral feeds or may have established full feeds when symptoms develop. Proposed factors in the premature gut predisposing to NEC include lack of immunologic factors such as decreased IgA secretion, immaturity of the intestinal barrier and luminal factors such as less acid output by the stomach and low enzyme activity(10-13).

Hypoxia and ischemia is a major contributing factor for developing NEC in term and near term infants. Typically term babies will develop NEC in the first week of life with some studies reporting median age of onset from 1-3 days(14-16). Term babies can become unwell with other conditions such as birth asphyxia or congenital heart disease or may have an abnormal fetal growth pattern due to maternal risk factors such as placental insufficiency(15,17-19). The physiological explanation for the link of hypoxia and NEC is the shunting of blood away from the gut at times of hypoxia (diving reflex) leading to ischemic changes. On the other hand epi-demiological studies suggest that hypoxia and ischemia are not necessarily the underlying mechanisms for the development of NEC in preterm babies(20,21).

The histopathological changes of ischemia in NEC may be secondary to other factors such as inflammatory mediators released, which cause vasoconstriction and lead to ischemia(22).

Micro-organisms have been implicated in the pathogenesis of NEC(23). The disease does not occur in a micro-organism free setting for example in utero. The occurrence of epidemics of NEC in nurseries also point towards an infectious origin and infection control measures have been thought to be effective in many NEC epidemics(24,25). The gas in pneumatosis intestinalis (intraluminal air-a hallmark of the disease) is thought to be derived from products of bowel bacterial fermentation. The frequent use of antibiotics in sick preterm infants can alter the normal bowel flora leading to colonisation with resistant strains of bacteria. It is unclear however if this has a central role in the pathogenesis of NEC.

Many of the organisms implicated are non-invasive commensals including gram negative rods(26). Clostridium difficile(27) and Staph. epidermidis(28), which are commonly found in the intestines of even healthy infants(29). Also, no common and consistent pathogen has been identified in most outbreaks. It may be that a variety of these organisms found in the babies’ gut possess common virulence factors which predispose to or initiate the patho-physiologic cascade of NEC.

Type of feeding is also thought to be related to risk of developing NEC with breast milk associated with a lower risk as compared to formula milk(30). This may be due to the presence of protective antibodies and enzymes in human milk, which protects against infections and NEC(31).

The rate of advance of feeds has also been implicated in the pathogenesis of NEC with aggressive increase in feeds associated with a higher incidence of NEC(1,32). However randomized trials comparing different rates of advance of feeds have been reviewed for the Cochrane database and the evidence so far suggests that among babies with more rapid advancement of feeds the incidence of NEC was not higher and these infants had an overall reduction in the number of days to regain their birthweight. The confidence intervals for the incidence of NEC were however wide and the reviewers concluded that more rapid rates of feeding could not be considered safe for implementation in clinical practice(33). Certainly the stimulation of the gut with minimal or trophic feeding to prime the GI tract has not been associated with an increased incidence of NEC(34).

Inflammatory mediators have been implicated in the development of NEC. These mediators are part of a final common pathway causing intestinal injury and the development of NEC.

• Platelet aggregation factor (PAF): NEC is associated with increased levels of Platelet aggregation factor(35) and PAF receptor antagonists reduce risk of NEC in experimental animals(36). Human milk contains PAF antagonists.

• Imbalance between pro and counter in-flammatory cytokines. Studies have shown excessive expression of IL-8 a pro-inflammatory cytokine from immature human enterocytes after inflammatory stimuli(37). It has been suggested that an imbalance between protective and pro- inflammatory cytokines is important in the development of NEC. Others have shown by serial sampling of infants that severity of NEC is not related to deficiency of counter-regulatory cytokines(38).

• Nitric Oxide is thought to have an important role in the final common pathway of NEC as shown in both animal models and studies from enterocytes of babies with NEC(39,40).

• Gut trophic and growth factors have also been studied.

Epidermal growth factor that promotes mucosal barrier function in the intestine has been shown to be deficient in premature infants with NEC(41). Erythropoietin has been shown to protect against apoptosis and programmed cell death. Leadbetter et al. showed in a retrospective review that babies who had been treated with erythropoietin for anaemia of prematurity had a lower incidence of NEC(42). Intestinal trefoil factor a peptide secreted by the goblet cells, which protects the gut against microbial invasion has been shown to be deficient in immature gut of rats(43).

Initial symptoms can be so non specific and subtle that they lead to the common observation of the baby simply appearing ‘not to be right’. In such cases a high index of suspicion is necessary in order to detect the problem early. On the other hand some babies develop fulminant NEC with one or a combi-nation of the features listed below and develop intestinal necrosis and perforation early.

Gastrointestinal symptoms include: (i) Abdominal distension and poor bowel sounds with visible intestinal loops; (ii) Abdominal wall erythema and tenderness (a sign easily elicited when examined carefully); (iii) Vomiting and feed intolerance with bilious or blood stained aspirates; (iv) Diarrhea; (v) Abdominal mass; (vi) Hematochezia; (vii) Blue/black discoloration of abdomen and ascites.

Systemic signs include: (i) Apnea and respiratory failure; (ii) Hypotension and poor perfusion; (iii) Bradycardia; (iv) Bleeding diathesis with consumption coagulopathy.

Laboratory abnormalities are commonly seen but are non-specific, and include: (i) Acidosis; (ii) Thrombocytopenia - Rapid fall in platelet count and platelet count less than 100,000 has been suggested as predictor of intestinal nec-rosis in cases of NEC but has low sensitivity and specificity(44); (iii) Leucocytosis and leucopenia; (iv) Coagulopathy; (v) Hypergly-cemia; (vi) Hyponatremia.

Abdominal X-rays are the mainstay for the diagnosis and following the course of NEC and may have to be performed serially. A left lateral decubitus film (baby lying on side with right side up) may be necessary to exclude a perforation as an air leak on an A-P film in a supine position can be missed. Other than peforation, X-ray findings include dilated bowel loops with thickened bowel wall, fixed and dilated loop that persists over serial films, abnormal gas patterns and even scant or absent abdominal gas. Intramural gas seen as train track lucency (pneumatosis intestinalis) is pathognomonic of NEC. Abdominal free air seen as the ‘football sign’ over the liver with outlining of the falciform ligament suggests perforation and requires surgical intervention. Gas in the portal venous system may be seen. Ascites may be seen in children where perforation has occurred and is a late finding. Rehan et al found low inter observer and intra observer agreements on the signs of NEC on X-rays, experienced observers did better than trainee observers(45).

Severity of NEC has been classified by Bell into three stages with stage I corresponding to non-specific symptoms, Stage 2 definite disease with clinical signs and symptoms and pneumatosis intestinalis on X- ray and stage 3 corresponding to advanced disease with critically ill infant associated with perforation or near perforation.

Differential diagnosis includes other surgical emergencies such as volvulus, obstruction, and spontaneous perforation as well as medical conditions like sepsis and inborn errors of metabolism.

Abdominal ultrasound may be used for evaluating NEC. It can identify free gas; areas of loculation and abscess seen in walled off perforation and ascites. Orientation of the superior mesenteric vasculature can give information about possibility of malrotation, which is an important differential diagnosis.

Recently MRI scan has been studied as a tool to help in the diagnosis of NEC by picking of intestinal necrosis but this is not easily available for routine clinical practice(46).

Initial management is conservative. Medical treatment consists of stopping feeds and providing enteric decompression. As sep-sis is an important differential diagnosis blood cultures and peritoneal fluid if available, should be obtained before broad-spectrum antibiotics are started. The value of routinely obtaining CSF and fungal cultures is question-able. Although no definitive infectious etiology is known to cause NEC, antibiotic treatment is started for the threat of sepsis. Broad-spectrum cover against gram positive and negative organisms as well as anaerobic cover is commonly provided although data to support the use of antianaerobic drugs in medical phase of disease is lacking. Many combination of drugs can be used and commonly used one includes metronidazole, cefotaxime and gentamicin. Clindamycin is used in many units to provide anaerobic cover and it is also effective against many staphylococcal species. Careful monitoring for complications and serial radiographs will be needed initially. Infection control steps should be initiated if more than two infants develop NEC in the unit at one time. Nutrition is provided parenterally during the period of bowel rest which is usually 10-14 days in non-surgical NEC. The critically ill infants need intensive care including ventilation, circulatory support and monitoring and appropriate action against multi organ failure.

Surgical treatment is required for per-foration and intestinal necrosis. Other indications remain controversial. Laparotomy with visual inspection of the bowel to identify any necrosis areas is performed. Bowel lavage may be performed and peritoneal fluid is obtained for culture. After resection of necrotic areas an enterostomy is usually performed with subsequent reanastomosis.

Beside peritoneal drains have been successfully employed in VLBW babies with salvage laparotomy reserved for those who deteriorate on this. Over recent years the surgical approach has been slowly changing towards this method in many units(47,48). Feeds are restarted in the convalescent phase. Where malabsorption is a problem dilute hydrolysate formula with MCT and no lactose may be needed.

The two commonest long-term complica-tions seen in survivors are intestinal strictures and short gut syndrome. Strictures are most commonly seen in the terminal ileum but can also involve the colon. Contrast enemas are used to diagnose strictures. Short gut syndrome results from malabsorption of nutrients and electrolytes secondary to removal of large amount or critical portions of the bowel. The gut may adapt and grow over time but during this period children will need close follow up with parenteral nutrition and appropriate enteral feeding.

Other complications include dumping syndrome, abscess and fistula formation, stoma problems, TPN related problems (cholestasis, infection) and growth and poor weight gain.

Intestinal transplantation is being evaluated as an approach for severe cases of short bowel syndrome(49).

1. Breastfeeding reduces the incidence of NEC as already outlined. The benefit of pooled and banked refrigerated milk is less clear.

2. Aggressive increase in the feeds of preterm infants has been implicated in NEC although the evidence for this is not definite. On the other hand it is important to remember that an overtly cautious approach may only be postponing the occurrence of NEC and may cause atrophy of the intestinal mucosa.

3. Enteral aminoglycosides: Several studies have addressed the issue of prophylactic oral aminoglycosides for reducing the incidence of NEC. The Cochrane group who looked at all randomized-controlled trials addressing this issue found that the administration of prophylactic antibiotics resulted in a statistically significant reduction in NEC and a reduction in the incidence of NEC related deaths of borderline significance. However, there was an increase in the incidence of colonization with resistant bacteria and reviewers concluded that there was insufficient evidence for use of enteral antibiotic prophylaxis for NEC in clinical practice(50).

In outbreaks of NEC, strict infection control measures to prevent spread of the disease are effective in curtailing the problem. Oral antibiotics have been suggested for contacts but again this risks the emergence of resistant strains(51).

4. Probiotics such as lactobacillus and bifidobacterium have been used to prevent NEC. They are thought to work, as the gut of premature infants is deficient in an-aerobic bacteria, which leads to the overgrowth of pathogenic strains. Although some trials using animal models as well as infants with NEC have shown that these anaerobic bacteria may have a protective role these findings have yet to be confirmed in larger tials(52,53).

5. Enteral immunoglobulins have been tried in the prevention of NEC. Eibl et al. reported protective effect of enteral IgG and IgA(54). Subsequent studies have failed to confirm this benefit(55). No difference was noted in a large randomized placebo controlled blinded multicenter trial(56).

6. Antenatal glucocorticoids are not used for the prevention of NEC but are routinely used to enhance fetal lung matruration. Data are suggestive of their benefit in the prevention of NEC. Early postnatal steroids have also been suggested but there are serious concerns regarding the inci-dence of side effects and their use cannot be justified on the current evidence.

Jaideep Singh,
Clinical Research Fellow,
Directorate of Neonatology,
James Cook University Hospital,
Morton Road, Middlesbrough, TS4 3BW, UK.

Sunil Sinha,
Professor of Pediatrics & Neonatology,
James Cook University Hospital,
Morton Road, Middlesbrough,TS4 3BW, UK.

Correspondence to:
Prof. S. Sinha,
E-mail: [email protected]

Funding: None.

Competing interests: None stated.

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