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The n e w e ng l a n d j o u r na l of m e dic i n e

review article

medical progress

Necrotizing Enterocolitis
Josef Neu, M.D., and W. Allan Walker, M.D.

ecrotizing enterocolitis is among the most common and dev- From the Department of Pediatrics, Uni-
astating diseases in neonates. It has also been one of the most difficult to versity of Florida, Gainesville (J.N.); Har-
vard Medical School, Boston (W.A.W.);
eradicate1 and thus has become a priority for research.2 Conditions closely and the Department of Pediatrics, Massa-
resembling necrotizing enterocolitis were described before the 1960s, but the en- chusetts General Hospital for Children,
tity was not widely recognized until after the advent of modern neonatal intensive Charlestown (W.A.W.). Address reprint
requests to Dr. Walker at the Mucosal Im-
care.1 Since that time, the incidence of necrotizing enterocolitis and the associated munology Laboratory, Department of
morbidity and mortality have remained unchanged because of ever-improving sur- Pediatrics, Massachusetts General Hospi-
vival of the smallest infants; in some instances, these rates have actually increased. tal for Children, 114 16th St., Boston, MA
02129-4404, or at
On the basis of large, multicenter, neonatal network databases from the United
States and Canada, the mean prevalence of the disorder is about 7% among infants N Engl J Med 2011;364:255-64.
with a birth weight between 500 and 1500 g.3-6 The estimated rate of death associ- Copyright © 2011 Massachusetts Medical Society.

ated with necrotizing enterocolitis ranges between 20 and 30%, with the highest
rate among infants requiring surgery.7
The excessive inflammatory process initiated in the highly immunoreactive
intestine in necrotizing enterocolitis extends the effects of the disease systemi-
cally, affecting distant organs such as the brain and placing affected infants at
substantially increased risk for neurodevelopmental delays.8,9 Indeed, an infant re-
covering from necrotizing enterocolitis may have nearly a 25% chance of micro-
cephaly and serious neurodevelopmental delays that will transcend concerns that
pertain to the gastrointestinal tract.10 In many centers, concern that enteral feeding
is associated with the development of necrotizing enterocolitis has resulted in an
increased duration of intravenous nutrition in infants, potentially increasing the
risk of infectious complications and the length of hospitalization.11
The financial cost of necrotizing enterocolitis is substantial; the total annual
estimated cost of caring for affected infants in the United States is between $500
million and $1 billion. In one study,12 infants with necrotizing enterocolitis were
hospitalized 60 days longer than unaffected preterm infants if surgery was required
and more than 20 days longer if surgery was not necessary. The need for bowel
resection is one of the most common severe complications of necrotizing entero-
colitis and is the major cause of the short-bowel syndrome in pediatric patients.
The total mean cost of care over a 5-year period for a child with the short-bowel
syndrome has been estimated to be nearly $1.5 million.13

Differ en t i a l Di agnosis

There are multiple necrotizing enterocolitis−like conditions with various presenta-
tions. However, the most typical initial signs and symptoms of “classic” necrotizing
enterocolitis in a preterm infant include feeding intolerance, abdominal distention
(Fig. 1A), and bloody stools after 8 to 10 days of age. The pathognomonic findings
on abdominal radiography are pneumatosis intestinalis, portal venous gas, or both
(Fig. 1B). Early imaging signs that should raise the suspicion of necrotizing entero-
colitis include dilated loops of bowel, a paucity of gas, and gas-filled loops of bowel

n engl j med 364;3  january 20, 2011 255
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preventive strat- egies have remained elusive for several decades. the term “necrotizing entero- colitis” often reflects a spectrum of intestinal conditions that differ with respect to pathogene- sis and the strategies required for prevention and treatment. All rights reserved.. David Kays. . intestinal anomalies (e. 2011 The New England Journal of Medicine Downloaded from nejm. but it differs C from that seen in preterm infants in that it is more often associated with other problems. the upper arrow points to portal january 20. intestinal perforation. Ex. 1C). Symp.) In Panel C. University of Florida. or both (Fig. often within hours. spontaneous intestinal perforations have at times been categorized as necrotizing enterocolitis but probably represent a different disease entity with a different pathogenesis. and peritonitis. as evidenced by low levels of serum inflam- toms may progress rapidly. Jonathan Williams. Despite considerable research. For personal use only. and perinatal stress that may affect mes- enteric blood flow. 2012. (Photograph courtesy of Dr. (Radiograph courtesy of Dr. Al- though necrotizing enterocolitis is considered to be a disease that primarily affects preterm in- fants. David Kays. spontaneous intestinal perfora- tions.) B from subtle signs to abdominal discoloration.g. It has been associated with 256 n engl j med 364. Copyright © 2011 Massachusetts Medical Society.) In the radiograph shown in Panel B. which is indicative of pneumatosis intestinalis.15 Among preterm infants. No other uses without permission. Three forms of neonatal intestinal in- jury occur most often: conditions primarily seen in term infants. This disorder is characterized by traluminal air (“free air”) outside the bowel is a only minimal intestinal inflammation and necro- sign of advanced necrotizing at DUKE MEDICAL CENTER LIBRARY on October 5.14.17 Spontaneous intes- tinal perforation usually occurs in the first sev- eral days after birth and is not associated with that are unaltered on repeated examinations. sis. Thus. the disease usually occurs in the first week after birth. Department of Pediatric Surgery. Panel A shows an infant with a shiny.3 nejm.16. congenital heart disease. and classic necrotizing enterocolitis. matory cytokines. and the lower arrow points to a ring of intramural gas. In these more mature neonates. The n e w e ng l a n d j o u r na l of m e dic i n e Figure 1. enteral feeding. such as maternal illicit drug use. Department of Pediatric Surgery. Uni- versity of Florida. Department of Pediatric Pathology. aganglionosis or atresias). Clinical and Radiographic Features of Necro- A tizing Enterocolitis. surgical support. University of Florida. reflecting the lack of a clear delineation of what constitutes the diagnosis of classic necrotizing enterocolitis. distended abdomen with periumbilical erythema. leading to systemic hypotension that requires intensive med- ical support. the arrow points to an area of necrotic bowel in a patient with necrotizing enterocolitis. necrotizing enterocolitis−like symptoms also occur in term and late preterm infants. (Photograph courtesy of Dr.

quent laparotomy. be a spontaneous intestinal perforation or cal procedures may involve drain placement. with a failure to intervene early enough. A more reliable staging approach that allows for cocorticoids such as dexamethasone or hydrocor. mild abdominal disten.. Surgi- fact. such as difficult to establish the diagnosis. which may or may not be associ.18. cal presentation (Table 1). was first most do not have necrotizing enterocolitis. . Surgical inter- may be hard to detect on radiographs. with the absence of peritoneal drainage very often required a subse- anal fissures. feeding intolerance. No other uses without permission. A systematic abdominal distention. The imaging findings include pneu. Medical intervention clude feeding intolerance. sion of necrotizing enterocolitis. classic necro. peritoneal drainage was used for this purpose..27 The first concluded radiographic findings.26. heme-positive stools. bow- tion. or both. All rights reserved. not be clear in individual patients. neutrophil count. but it tisone. which and intravenous hyperalimentation. but ing system described by Bell et al. intestinal perforation or deteriorating clinical or forated viscus. whether necrosis is actually present may bowel. tizing enterocolitis. the later this condition occurs after birth. or both). The more premature the infant. and it showed no improvement when to those of the criteria described by Bell et al. hepatobiliary gas. One of ventions are generally required in patients with the most important criteria for stage 3 is a per. biochemical status (e. a systematic review of several studies surgery can develop in patients even though suggested mortality was increased by more than pneumatosis intestinalis or portal gas has not 50% with peritoneal drainage as compared with been detected on imaging. the latter study examined whether peritoneal moperitoneum. and pneu. The clinical findings include bilious gastric nificant differences in outcomes between the aspirate or emesis. ical or surgical management based on the clini- ria are highly nonspecific findings and may in. that may cause  january 20. or neurodevelopmental impairment among those n engl j med 364. Stage 1 crite. which involves an inflamma- tory intestinal condition in prematurely born at DUKE MEDICAL CENTER LIBRARY on October 5. comes. De- published in 1978 and subsequently refined. abdominal distention. in platelet count.3  nejm. 2012. vanced necrotizing enterocolitis with intestinal ization and histopathological evaluation. exploratory laparotomy with resection of diseased more. findings such as pneumatosis intestinalis. cur r en t T r e atmen t S t r ategie s fants. the Vermont−Oxford drainage improved the patient’s immediate clin- diagnostic approach has shortcomings similar ical status.20 The lack of Almost all very-low-birth-weight infants have in- universally reliable diagnostic criteria makes it termittent gastrointestinal symptoms. These patients may laparotomy. benefits of these methods have been controver- lished in the Vermont Oxford Network Manual of sial. groups. typically includes abdominal decompression. Stage 2 criteria are radiographic el rest.26 The second study also showed no sig- litis.g. The relative necrotizing enterocolitis more specifically is pub. months in infants who had undergone surgery luminal bowel gas. broad-spectrum intravenous antibiotics. since perito. on presentation. with one or more of each that the type of procedure does not influence type of finding (clinical or radiographic) required survival or other clinically important early out- to establish a diagnosis of necrotizing enteroco.23 perforation are laparotomy and primary perito- Another classification system used to define neal drainage without laparotomy. and oc.24 This manual describes clinical and address this controversy.28 Follow-up examinations at 18 to 22 only have abdominal distention. 2011 257 The New England Journal of Medicine Downloaded from nejm.19 will probably require the development of bio- The remainder of this review focuses on the markers that accurately predict the full expres- most common form of the disease. Copyright © 2011 Massachusetts Medical Society. dissected air from the pleural cavity. the for necrotizing enterocolitis in the neonatal peri- ominous progression of the disease may be od showed a significantly reduced risk of death missed. Two commonly used methods for treating ad- neal drains may be placed without direct visual. and description of necrotizing enterocolitis.25 Thus. aggressive preventive measures is needed.22 finitive necrotizing enterocolitis may require med- This system includes three stages. but it showed that infants treated with cult gross blood in the stool. However. the stag. Further. without intra.21. and enterostomy with creation of a stoma. For personal use only.27 Further analysis of data from matosis intestinalis. medical progress the administration of indomethacin and with glu..24 since severe necrotizing enterocolitis requiring In addition. Two large multicenter studies attempted to Operations. shock or a decreasing ated with intestinal necrosis and which could.

g. For personal use only.g. and platelet intestine and ileus patterns are not pathognomonic counts (sudden decreases suggest progression of but should be treated as such disease).. the hu- predisposing factors (Fig. abdominal ra- diograph (anteroposterior and left lateral decubi- tus). 2011 The New England Journal of Medicine Downloaded from nejm. Extensive basic mucosal zation in the intestine and a highly immunoreac. absorption. or both feedings for approximately 7–10 days Other radiographic signs such as fixed..21 and Walsh and Kliegman. gastric acid secretion is limited in the pre- required.22 who had undergone a laparotomy as compared lation probably predispose the preterm infant to with those who had undergone peritoneal at DUKE MEDICAL CENTER LIBRARY on October 5. immune sion of toll-like receptor 4 (TLR4) appears to be defenses.29 These studies indicate that once surgery is ple. an increased risk of intestinal injury. testinal explants. or free tention and feeding intolerance intraperitoneal air Unexpected onset of feeding intolerance Consideration of bowel decompression and brief dis- continuation of feeding (e. consideration of blood cultures and short course of intravenous antibiotics Definitive medical necrotizing enterocolitis Abdominal distention with pneumatosis intestinalis. sive inflammatory response to luminal microbial balance in microvascular tone. and circulatory regu. and radio. riers in the  january 20. 2012. However. immunologic studies31. monitoring of white-cell. barrier function. Placement of drain graphs that show an absence of bowel gas. The expres- Immature motility. enterocolitis and in human fetal-cell cultures. blood culture and intravenous antibiotics for 7–10 days. notification of surgical team Surgical necrotizing enterocolitis Free intraperitoneal air on abdominal radiograph after Exploratory laparotomy with resection if necessary initial medical signs and symptoms Persistent ileus pattern. particularly among infants with gastric acid se- Patho gene sis cretion that is further limited by the administra- tion of H2 blockers. a finding that term infant.32 indicate that after its tive intestinal mucosa. close monitoring of abdominal radio- graphs (anteroposterior and left lateral decubitus). the outcome may be poor. and an im. differential. differential. to an increased risk of necrotizing enterocolitis. portal venous gas. No other uses without permission. . such responses alter the protective bar- strong likelihood of abnormal microbial coloni. The n e w e ng l a n d j o u r na l of m e dic i n e Table 1. intestinal immaturity. epi. 24 hr). Copyright © 2011 Massachusetts Medical Society. All rights reserved. Diagnostic Criteria for and Treatment of Necrotizing Enterocolitis. coupled with deteriorating clinical and laboratory values (e.* Diagnosis and Signs and Symptoms Treatment Strategy Suspected necrotizing enterocolitis Abdominal distention without radiographic evidence of Close clinical observation for increased abdominal dis- pneumatosis intestinalis.4 The pathophysiology of classic necrotizing entero. leads to a confluence of initial postnatal microbial colonization. abdominal distention. and plate- let counts (sudden decreases suggest progression of disease). and this limitation has been linked underscores the need for effective prevention. dilated loops of Close monitoring of white-cell.3  nejm. 2). in- demiologic observations strongly suggest a multi. decreasing neutrophil and platelet counts) * Adapted from Bell et al. accompanied by a stimuli.30 For exam- age. increased in a fetal cell line as compared with an 258 n engl j med 364. The combination of a genetic that the fetus and preterm infant have an exces- predisposition. Observations in animal models of necrotizing colitis is incompletely understood. digestion. man intestine adapts to the increased microbial stimulation by means of modifications in the Intestinal Immaturity epithelial innate immune response. and xenografts have suggested factorial cause. Bowel decompression and discontinuation of enteral portal venous gas.

adult cell line. Copyright © 2011 Massachusetts Medical Society.40 and infants with necrotizing en- affected preterm infants. and an excessive inflammatory response. TLR denotes toll-like receptor. Among these increased terocolitis frequently have concomitant bacteremia cytokines.3  nejm. Pathophysiology of Necrotizing Enterocolitis. Another hypothesis is that inappropriate initial tion of initial postnatal colonization.34 Such differ.30. the increase in interleukin-8 and the ex- ences between the fetal and the mature intestine cessive inflammatory response produced by fetal may be the basis for the excessive and inappro.41 Although specific pathogens epithelial cells and mediates the migration of have been cultured in outbreaks of necrotizing n engl j med 364. Furthermore. neutrophils to the site of inflammation and their tor (IκB) for the transcription factor nuclear fac. 2011 259 The New England Journal of Medicine Downloaded from nejm. For personal use only.38 that enterocytes in the preterm infant. interleukin-8. These observations suggest preterm infant to necrotizing enterocolitis. can cause necrosis and increased pro- tor κB (NF-κB). Microbial Colonization ment. . are not prepared for the excessive stimula. including altered microbiota. No other uses without permission.36 which is produced by and endotoxemia. which have resided in a germ-free intrauterine environ. microbial colonization in preterm infants is an Several clinical observations also implicate important risk factor for necrotizing enterocoli- excessive inflammation in response to intestinal tis. medical progress Figure 2. cytes are consistent with the vulnerability of the tizing enterocolitis. These factors contribute to the severe necrosis of the small intestine that is characteristic of this disease. 2012. Thus. which affects  january 20. experimental matory cells have been reported to be higher in necrotizing enterocolitis does not occur in germ- patients with necrotizing enterocolitis than in un­ free animals. activation.35. does not occur until at least 8 to 10 days post jury. at a time when anaerobic bacteria have cytokines and chemokines that recruit inflam. the serum levels of several at DUKE MEDICAL CENTER LIBRARY on October 5. inadequate intestinal barrier function. colonized the gut. All rights reserved. enterocytes as compared with mature entero- priate inflammatory response that leads to necro.36 For example.33 and an important regulatory fac.37 developmentally underexpressed. is duction of acute-phase proteins in the gut. Factors conferring a predisposition to necrotizing enterocolitis include genetic factors and several immature characteristics of the fetal intestine.39 particularly since necrotizing enterocolitis stimuli in the development of this intestinal in.

53 enterocolitis.34 The excessive immature inflamma. For personal use only. nal microbial species and an overall reduction in the diversity of microbiota.51 but the way in which transfusion might necrotizing enterocolitis. which probably has consistently been implicated.48 has recently been questioned. The de- creased microbial diversity and alteration in the Numerous approaches have been proposed for the microbial species may reduce colonization resis. cade that leads to necrotizing enterocolitis. this approach appears prom- ered to be the primary contributor to necrotizing ising. stems from clinical experience and retrospective pears to be mediated by a developmental imma. previously consid.49 exclusive use of human milk plus a human It is now considered to be unlikely that major milk−derived fortifier may result in a lower inci- perinatal hypoxic−ischemic events contribute sub. reviews suggesting that a rapid increase in feed- turity in the expression of IκB (the molecule that ings increases the likelihood of necrotizing en- inhibits the activation of cytokines by transcrip. in a cultured human enterocyte model. risk of necrotizing enterocolitis.52 More recent data suggest that com- tion factor NF-κB).47.43 enterocolitis. prevention of necrotizing enterocolitis (Table 2).58. hypoxia and ischemia mod. no organism as nitric oxide and endothelin. The Human play a downstream role in the pathogenic cas- Microbiome Project was initiated in 2007 42 in con.54-56 A recent study suggested that the enterocolitis. In administering probiotic agents. and administering various growth fac- commensal bacteria as well as pathogens have tors. prebiotic agents.57 stantially to the pathogenesis of necrotizing en. using enteral antibiotics. All rights reserved. been shown to evoke an excessive inflammatory The widespread practice of withholding enteral response in fetal human enterocytes as compared feedings in infants with necrotizing enterocolitis with mature enterocytes. The findings of several small studies suggest terocolitis. 2012. tory response associated with abnormal intestinal and late-onset sepsis. use of umbilical catheters has not been causally ect have strengthened the evidence supporting associated with the pathogenesis of necrotizing the colonization hypothesis. especially when there Pr e v en t i v e A pproache s has been prolonged antibiotic therapy. or both.49 junction with technological advances that allow for the molecular identification of a vast array of Other Contributing Factors microbes that are difficult or impossible to cul.46 because the usually rich diversity among These approaches include withholding enteral colonizing intestinal microflora. No other uses without permission. A current alternative attempt at the prevention of necrotizing enterocolitis is to provide enteral Hypoxia−Ischemia feedings of small amounts of the mother’s ex- The role of hypoxia−ischemia. However. tance. which protects feedings. Although of wide concern in neonatology.53 It is thought that a delay microbiota is currently considered to be the most in feeding may actually increase the severity of likely basis for the pathogenesis of necrotizing necrotizing enterocolitis if it occurs.45 suggest that the be related to alterations in intestinal blood flow disorder is associated with both unusual intesti.34 This difference ap. parenteral nutrition. The n e w e ng l a n d j o u r na l of m e dic i n e enterocolitis in single institutions. as well as some infants in whom between the elective transfusion of packed red necrotizing enterocolitis developed and from cells and necrotizing enterocolitis has been re- whom samples were obtained before and during ported. or hypoxia−ischemia is at DUKE MEDICAL CENTER LIBRARY on October 5. dence of necrotizing enterocolitis. providing further evidence plete withholding of feedings may be a dangerous that the premature gut is unprepared to interact practice because it leads to the prolonged use of with colonizing bacteria in the extrauterine en. as well as to intestinal atro- vironment. that the administration of enteral aminoglyco- ulate the balance in microvascular tone related to sides might be a promising preventive strate- the relative production of vascular regulators such gy.59 but most neonatal intensive care units 260 n engl j med 364. and parenteral nutrition through an Preliminary studies using molecular methods umbilical-artery catheter does not increase the to evaluate fecal microbiota from unaffected pre. 2011 The New England Journal of Medicine Downloaded from nejm. anticytokine agents. Copyright © 2011 Massachusetts Medical Society. is lacking.3  nejm. feeding the the host against hospital-acquired pathogens that infant with the mother’s expressed breast milk. the ture from the intestine. . and glucocorticoids.50 An association term infants. phy. can cause intestinal inflammation. pressed breast milk. addition. terocolitis. The findings of this  january 20. increased permeability and inflammation.

For example. caution in the Microbial Components that Modulate use of probiotics seems wise. despite a recent Inflammation commentary suggesting the routine use of probi. More recent studies the oligosaccharides inulin.74 an important cellular signaling step blind trial. theoretical benefit of such preparations has been litis but did not decrease mortality from necro. lactulose. but they Prospective randomized trials during the past require an initial appropriate colonization of the decade have evaluated the effects of various pro. the cells continued to respond Prebiotic Agents to lipopolysaccharide.creased may have had an increased risk of intes- ents that enhance the growth of potentially benefi. primary intestinal epithelial cells from fetal and maceutical standards. For personal use only. Furthermore. it would be important to have evidence in ter vaginal birth in the newborn.69 The decreased the incidence of necrotizing enteroco. If the pups were delivered by cesarean at DUKE MEDICAL CENTER LIBRARY on October 5. which decreased af- ogists. Before routine probiotic neonatal mice and reported high lipopolysaccha- prophylaxis could be recommended to neonatol. 1 (IRAK-1). Studies in epithelial cells and in a model of rats otics on the basis of current data. ride reactivity in the fetus. galactose. Prebiotics enhance the proliferation of Probiotic Agents endogenous flora such as bifidobacteria. not be reproducible according to drug or phar.67 nous antibiotics (a very common practice in Although these compounds appear to alter the NICUs) actually results in an increased incidence consistency and frequency of  january 20.2 and Neu. n-3 fatty acids Arginine * Adapted from Grave et al. may be as effective as live microbes in modulating ministration of a microorganism in preterm in. . suggest that prolonged empirical use of intrave. excessive inflammatory stimuli. randomized. their efficacy of necrotizing enterocolitis.60 in the prevention of necrotizing enterocolitis is unclear. n engl j med 364. although ing could also be effective.66 Prebiotic agents include croorganisms often emerge. medical progress Table 2. prevention of necrotizing enterocolitis. pro. probiotic products have not tal data suggest that specific microbial compo- been subjected to rigorous manufacturing quality nents that affect toll-like receptor (TLR) signal- control. may involving a mouse model used isolated. and combinations of these nutrients. gut.65 The Food and fed infant formula suggest that dead microbes Drug Administration has not approved the ad.70-73 Experimen- fants. suggesting that those neo- Another proposed preventive strategy is to supple. Copyright © 2011 Massachusetts Medical Society. All rights reserved. there appears to be available to provide support for a benefit in the a higher incidence of sepsis among infants receiv. single-protocol.20 (NICUs) avoid this practice because resistant mi.66 but little information is currently tizing enterocolitis.nates in which IRAK-1 expression was not de- ment feedings with so-called prebiotics.64 especially in those with a birth weight of less than 750 g. reviewed.tinal inflammation and injury.68 Oligosaccharides in hu- The most recently reported multicenter trial of man milk have been proposed as alternatives to probiotics suggested that the probiotic approach plant-based and synthetic prebiotic agents. cial intestinal microbes. No other uses without permission. presumably support of such use from at least one large. or nutri.61-63 weight preterm infants. in inflammation.3  nejm. fructose. double. 2012. Thus. ing probiotics. studies they appear to be safe in individual studies. However. Measures to Prevent Necrotizing Enterocolitis. purified.* Evidence of Efficacy Evidence of Efficacy Evidence of Efficacy in Animal Proposed Efficacy and Safety but Questionable Safety Models but Not in Humans but Lacking Evidence Breast-milk feeding Enteral aminoglycosides Anticytokines Prebiotics (derived from plants and breast milk) Nonaggressive enteral Probiotics Growth factors Microbial components and feeding toll-like-receptor agonists Glucocorticoids Glutamine. through interleukin-1 receptor−associated kinase spective. which appears to be lacking in very-low-birth- biotics to prevent necrotizing enterocolitis. The contents of such products. 2011 261 The New England Journal of Medicine Downloaded from nejm.

Badger GJ. atr Surg at DUKE MEDICAL CENTER LIBRARY on October 5. Grave GD. ciency to prevent bronchopulmonary dys- ble-blind.96:203-10. E. Cole CH. higher incidence of necrotizing enteroco. Preventive approaches are likely to yield better tion. Sankaran K. Necrotizing enterocolitis 3. Copyright © 2011 Massachusetts Medical Society. these criteria would include the development of testinal inflammation. 15. or near-term infants: risk factors. Tyson JE.. J Perinatol 2004. Swanson JR.76.” 17. to differentiate between necrotizing enterocolitis term infants or animals without necrotizing en. Enhanced Impact of necrotizing enterocolitis on 19. Emerging trends in acquired Perinat Epidemiol 2006. Pediatrics 2002. basolateral.19:101-4. For personal use only. Ludwig-Auser HM. Gordon PV. Horbar JD. 114:1649-57. Necrotizing enterocoli. et al. sistent diagnostic criteria may also be helpful in extracellular.77 The location of TLRs highly sensitive specific biomarkers78 and new on the surface or within the enterocyte may also techniques for detecting factors that confer a limit activation by colonizing bacteria. pressed by birth weight categories. et al. 9. Perlman JM. J Med 2001. Specific preventive interven- and the type of microbes colonizing the intes. Steiner CA. N Engl 6. Sun D. controlled trial. 11. Raboei EH. Neonatal Research Network. plasia: a multicenter trial. et al. fants after necrotizing enterocolitis. Erasmus HD.110:285-91. Prophylaxis of early adrenal insuffi- lactase-treated feeds: a randomized. Ching Y. 12. Pediatrics 2002. apical vs. and in relation evaluating the effects of different clinical prac- to whether intercellular junctions are open or tices among NICUs and then applying strategies closed). Barnett M. for very low birth weight infants. Gordon PV. Attridge JT.32 The role and therapeutic potential of fants in studies that focus on enhancing innate pharmaceutical or dietary interventions that may immunity with human milk or avoiding manip- alter the accessibility of colonizing bacteria to ulations that may alter normal microbial ecology TLRs and other receptors require additional elu. No other uses without permission. J Pedi. Silver L.117(2):e137-e142. Spencer AU.71:292-8. Pediatrics 2004. intracellular vs. such as spontaneous intesti- terocolitis. Obladen M. tions may be applied to the most susceptible in- tine. Trends in mortality and morbidity neonates: the experience of the NICHD 18. Gerdes JS. ing enterocolitis hospitalisations among Broyles R. et al. neous intestinal perforations. low birth weight infants <1000 g. Necrotizing enterocolitis and 16. 13. Carpenter JH. Schonberger LB. in full-term neonates: is it aganglionosis? KL. such as the unnecessary use of cidation. Yu D. References 1. there are now tools that may lead toward the goal of eradicating this disease. Stoll BJ. ing clinical literature relevant to sponta- atrics 2006. Berseth CL. Cotten CM. After decades of insufficient prog- ress in the prevention and treatment of necrotiz- F u t ur e C onsider at ions ing enterocolitis. Neonate 1997. Watterberg KL. et al. Guillet R. Pediatrics Adverse effects of early dexamethasone in 1999. 262 n engl j med 364.3  nejm. Fitzgibbons SC.344:95-101. neonates in the United States. Strategies for establishing and applying associated with necrotizing enterocolitis or in. J Pediatr 2002.24:534-40. low birth weight infants. Nelson SA. 2011 The New England Journal of Medicine Downloaded from nejm.76 Studies both in these models and in results. TLRs have predisposition to necrotizing enterocolitis. J Peri. Hansen N. Stoll BJ. syndrome: the cost of comprehensive care. Bancalari New therapies and preventive approaches 8.24:531-3. Stoll BJ. Stoll BJ. 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Copyright © 2011 Massachusetts Medical Society. et al. 2011 The New England Journal of Medicine Downloaded from nejm. No other uses without permission.179:4808-20. J Pediatr Gastroenterol Nutr 74. des Robert C. Russell WM. Lopez M. Chen HL. litis. 73. Br J Nutr epithelial cells. lating intestinal injury and repair.177:3273-82. Lu J. Zhang L. Jilling T. View an image. crease tumor necrosis factor-alpha-induced rine models of necrotizing enterocolitis. randomized. Human milk oligosac. The Image Challenge app is available at the iTunes App Store. rat model. 65. Caicedo R. Douglas-Escobar vating factor-induced phosphatidylinosi- Br J Nutr 1998. M. for the detection of necrotizing enteroco- 2002. neonatal intensive care unit: implications term infants. All rights  january 20. Neu J. Am J Physiol et al.82:103-8.80:S209-S212. Biomarkers for infants at 28. 84. age-related bifidogenic effects of ­galacto. Probiotics reduce all-cause Lactobacillus rhamnosus GG decreases sis of necrotizing enterocolitis by modu- mortality in necrotizing enterocolitis: it is lipopolysaccharide-induced systemic in. 264 n engl j med 364. and chil. Jilling T. Li N. Handfield M.] Neu J. 2009. Cabana M.42:545-52. Lopez M.30:701-8. Leaphart CL. J Nutr 2008. For personal use only. Hornef MW. The Image Challenge app randomly selects from 300 challenging clinical photos published in NEJM. Sharma R. A critical role for TLR4 in the pathogene- vedi A. et al. interleukin-8 production in Caco-2 cells. Zhang L. Biol Neonate 2002. Monitoring technologies in the and fructooligosaccharides in formula-fed in Caco-2 cells. Potential roles and clinical utility of effects on proinflammatory and anti-­ Gastrointest Liver Physiol 2008. and see how others answered. roles of bacteria and TLR4 in rat and mu- tis in very low birth weight preterm in. Dos. choose your answer. 2012. Moro G. Gribar SC. Alive 75. trolled trial.294:G1181- prebiotics in newborns. J Pediatr Gastroenterol Nutr 77. Minoli I.156:344.34:291-5. Postnatal acquisi. Live and ultraviolet-inactivated prevention? Pediatr Res 2009. inflammatory cytokines/chemokines in G1190. infants. . et al. Li N. Islam S. summit meeting. June 27. Ménard S. 69. J Exp Med at DUKE MEDICAL CENTER LIBRARY on October 5. Gibson GR. 64. 2009. the Image Challenge app lets you test your diagnostic skills anytime. Donovan SM. The probiotics prevent necrotizing enterocoli. charides — the plot thickens. 76. Live and tol 3 kinase/Akt-mediated apoptosis in 67. Simon D. Hsu CH. Dietary modulation of the 2006. Lin HC. Oh S. Cavallo J. Pediatrics 2010.135:1752-6. Tri­ 71. 68.138:2264-8. et al. J Im- time to change practice. unsaturated fatty acids block platelet-acti- human gut microflora using prebiotics.155:S61-S70. Gravenstein N. Lactobacillus rhamnosus GG decrease 79. Sherman PM. dren: proceedings from a global prebiotic gastrostomy-fed infant rats. Gütle D.101:1267-9. Kataria J. with a new image added each week. Neu J. Brok J. Poly- 66. Russell M. Walther S. Caplan MS. 125:1068-70. Mosca M. Young C. J Pediatr 2009. Lotz M. new nejm application for iphone The NEJM Image Challenge app brings a popular online feature to the smartphone. 2008.3  nejm. J Immunol 2006. tion of endotoxin tolerance in intestinal Copyright © 2011 Massachusetts Medical Society. Young C. anywhere. flagellin-induced interleukin-8 production Neu J. fants: a multicenter. Li D. Tarnow-Mordi WO.66:203-7. 72. Lu J. and dead Lactobacillus rhamnosus GG de. medical progress in preterm infants: a prospective double. heat-killed Lactobacillus rhamnosus GG: intestinal epithelial cells. risk for necrotizing enterocolitis: clues to ratum. Hauser N. J Nutr 2005. Wilkinson D. J Pediatr 2010. [Er. Pediatrics 2008. get immediate feedback.203:973- blind study. New York City.65:91R-97R. Bogdan C. flammation in a gastrostomy-fed infant munol 2007. con. Li N. Oral 70. Optimized for viewing on the iPhone and iPod Touch. Mai V. Pediatr Res 78. et al. Neu J. Li N. J Perinatol 2010. Gibson GR.122:693-700.