Necrotizing enterocolitis (NEC) is the most common severe intestinal emergency that affects predominantly premature infants. It is associated with a mortality between 20% to 30%1 and also has high associated morbidity, which includes short gut syndrome, severe cholestasis, and significant neurodevelopmental delays.2 The precise etiology of NEC remains enigmatic despite considerable research over the past four decades.3 The mean prevalence of NEC is approximately 7% in very low birth weight infants in the United States and Canada.4 Of interest, at least in one country where NEC prevalence was previously thought to be extremely low, it appears to be increasing, possibly because of more aggressive intensive care for the most at-risk infants.5
Clinical signs, laboratory, and radiologic features at the initial presentation of NEC are highly unreliable and nonspecific. Differentiating early NEC from simple feeding intolerance or late onset sepsis is difficult.6 What has been lumped into one disease termed "NEC" is also becoming recognized as probably representing more than one disease. The pathogenesis of even the most classic forms of NEC is multifactorial and this makes it a difficult target for uniform preventive strategies.7
The most common reasons provided for susceptibility to NEC in the preterm infant relate to various factors of intestinal immaturity.8 These include immature motility, digestion, absorption, barrier function, immune defense, and circulatory regulation. Examination of the bowel and blood from infants with NEC shows an excessive inflammatory response with elevation of proinflammatory cytokines and chemokines.9 Another major predisposing factor relates to alterations in intestinal colonization prior to the development of the disease.10 With the advent of the Human Microbiome project and technological advances that allow for the molecular identification of many more microbes than can be cultured from the intestine, new evidence is being provided pertaining to specific microbial ecologic patterns as well as their effects on the host prior to the development of the disease.11-15 This will be critical for the subsequent preventive measures using microbial therapeutic techniques.
Clinical signs for the development of NEC include the wide array of presentations. These may include feeding intolerance, emesis, abdominal distention, and bloody stools. As the degree of illness advances, the abdomen becomes progressively more distended, shiny and erythematous. Systemic signs with advancing NEC include lethargy, pallor, increased episodes of apnea and bradycardia, hypotension, worsening of respiratory function, and hemodynamic compromise.6 Unfortunately these signs cannot be distinguished from late onset sepsis. Commonly used tests include radiographs, which are still considered the "gold standard." Pneumatosis intestinalis (air in the bowel wall), portal venous gas, and free air in the peritoneal cavity are signs that are highly associated with NEC. Unfortunately, free air in the peritoneal cavity may also indicate spontaneous intestinal perforations that are actually a different disease process with a different pathogenesis. Because of this and the fact that NEC can proceed very rapidly from first signs to death, it is imperative to develop better techniques for early detection of this disease.
Current medical management consists primarily of stopping enteral feedings, applying gastric intestinal decompression, and initiating broad-spectrum antibiotics. Frequent evaluation of blood counts, acid-base balance, and abdominal radiographs are used to determine whether the disease is progressing. Free intraperitoneal air is often an indicator for surgical intervention. Current surgical interventions include laparotomy with bowel resection when known necrotic intestine is present or primary peritoneal drainage. Which of these techniques should be used first remains controversial.16,17
Several strategies have been attempted to prevent NEC, but the one that is based on the best evidence appears to be human milk.18 It is thought that the baby's own mother's milk may provide advantages over donor milk, but donor milk is now commonly used when baby's own mother's milk is not available. Various feeding regimens have been attempted, and it is thought that very rapid advancement of feedings may exacerbate the likelihood of NEC,19,20 but the enteral route for careful introduction of nutrition remains highly recommended..21
Various other strategies have been suggested for prevention, but many of them remain highly questionable or understudied. Animal models for NEC and evaluation of the preventative modalities in these models remains questionable because some of the most commonly used models rely on procedures that do not closely mimic the timing and presentation of the disease as seen in preterm human infants.22 More recently numerous studies and meta-analyses of these studies using probiotics have been conducted in an attempt to prevent NEC.23 Some of the approaches appear promising, but many questions remain about the use of these agents and how to best employ them safely for preventing the disease and what kind of quality standards should be used to adequately protect the infant from potential harm by the live microbial agents. A rigorous, prospective trial that is properly powered for NEC, using an agent that meets standards of quality required by the FDA for a pharmacologic agent to prevent a specific disease (NEC) is needed.24
If potentially useful preventive or treatment strategies for NEC are developed, then we need strong diagnostic or predictive tests, such as biomarkers, of the disease.25 To identify which babies are at the highest risk for the development or progression of the disease, such tests must be highly sensitive, specific, and accurate —and have the ability to differentiate NEC from other common inflammatory processes such as sepsis or pneumonia.
In summary, NEC is more than one disease. Preventive strategies must be developed that are specific for the most common forms of NEC. Use of the baby's own mother's milk should be strongly encouraged in neonatal intensive care of these babies. Methods to optimize the quality of donor milk so that it is more highly similar to baby's own mother's milk are needed. Since the microbial ecology prior to the development of NEC appears to be perturbed, a clear understanding of this phenomenon could lead to microbial therapeutic techniques or the use of microbial products that may aid in the prevention of NEC
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