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Neonatal necrotizing enterocolitis

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Research and Reports in Neonatology
23 August 2011
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Akhil Maheshwari 1 Abstract: Necrotizing enterocolitis is the most common gastrointestinal emergency in
Laura L Corbin 2 preterm neonates and a major cause of morbidity and mortality in premature infants born
Robert L Schelonka 2 before 32 weeks of gestation or with a birth weight less than 1500 g. In this review, we discuss
predisposing factors, clinical manifestations, and the quality of evidence for various preventive
1
Division of Neonatology and
For personal use only.

Center for Neonatal and Pediatric and therapeutic strategies.

Gastrointestinal Disease, Department Keywords: necrotizing enterocolitis, inflammation, mucosa, pneumatosis, neonate
of Pediatrics, University of Illinois at
Chicago, IL, 2Division of Neonatology,
Department of Pediatrics, Oregon
Health and Sciences University,
Introduction
Portland, OR, USA Necrotizing enterocolitis (NEC), an inflammatory bowel necrosis of infants,1,2 is the
most common gastrointestinal emergency in preterm neonates and a major cause of
morbidity and mortality in neonatal intensive care units throughout the world.3,4 In
this review, we discuss pathophysiological factors that may predispose the developing
intestine to NEC, describe the clinical manifestations of this disease, and provide a
critical appraisal of therapeutic strategies.

Incidence and epidemiology

The incidence of NEC is estimated to be 1–3 per 1000 live births, with more than 90%
of all cases occurring in preterm infants.1 NEC occurs in 4%–11% of all premature
infants born with very low birth weight (,1500 g), and the frequency in this subgroup
is also inversely related to birth weight and gestational age.5,6 In the National Institute
of Child Health and Development cohort at neonatal research network centers, NEC
was recorded in 11.5%, 9%, 6%, and 4% of infants weighing 401–750 g, 751–1000 g,
1001–1250 g, and 1251–1500 g, respectively.7
The incidence of NEC varies significantly between neonatal intensive care units.8–11
Cases occur in each individual neonatal intensive care unit at an “endemic” rate specific
for that unit, which may show some seasonal fluctuation and may be punctuated by
Correspondence: Akhil Maheshwari minor epidemics.7,12–15 Although the reasons for these center differences are unclear,
Center for Neonatal and Pediatric
Gastrointestinal Disease, Children’s plausible explanation(s) include biological differences in patient populations and
Hospital of University of Illinois, distribution of birth weights, infectious milieu in the neonatal intensive care units,
University of Illinois at Chicago,
840 S Wood St, CSB 1257, UIC and consistency in labeling of cases that recover without requiring significant medical
m/c 856, Chicago, IL 60612, USA or surgical intervention.15
Tel +1 312 996 4185
Fax +1 312 355 5548
Despite improvements in neonatal intensive care and increased overall survival of
Email akhil1@[Link] critically ill premature neonates, mortality rates from NEC can reach 50%.5,16,17 Most

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deaths occur in extremely low birth weight infants, who risk).30 In contrast, NEC is not associated with most single
frequently develop severe disease and require surgery.5 nucleotide polymorphisms that have been linked with
Crohn’s disease and/or ulcerative colitis, such as those in the
Pathophysiology genetic sequences of tumor necrosis factor-alpha (TNF-α),
Although the etiopathogenesis of NEC remains unclear, IL-1, IL-4, IL-6, IL-8, and IL-10, CD14, toll-like receptor
­current epidemiological and experimental evidence18,19 4, caspase-recruitment domain 15, and nucleotide-binding
identifies several diverse risk factors and supports a multi- oligomerization domain containing 2.31–33
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factorial model of disease (summarized in Figure 1). NEC usually occurs in infants who are receiving enteral
Prematurity is the most important predictor of NEC. feedings. Although NEC can occur in neonates who have
Immaturity of the gastrointestinal tract, particularly in never been fed, 90%–95% of cases occur in infants with
the context of its motility, digestion, perfusion, barrier a history of recent volume advancement or reinitiation
function, and immune defense, is a major predisposing of enteral feedings.34,35 Besides the risk of direct osmotic
factor for NEC.20–22 The pathophysiological importance of injury to the gut mucosa, feedings may also alter splanchnic
prematurity is evident from the near exclusive occurrence blood flow and increase the risk of ischemic injury in
of NEC in preterm infants, even though events generally underperfused regions by increasing local oxygen needs.
considered to be critical in the pathogenesis of NEC, such In addition, immaturity of motility and digestion in the
as gut mucosal injury, altered barrier function, and bacterial developing intestine may leave undigested food in the lumen
translocation, are recorded frequently in critically ill patients for prolonged periods, promoting bacterial overgrowth and
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of all ages.23–25 translocation.36 Products of bacterial fermentation, such as

Evidence for genetic predisposition to NEC is modest. short chain fatty acids, can also injure the immature gut
Bhandari et al26 recorded NEC in one or both twins in nine of mucosa.37,38
63 (14%) pairs of monozygotic twins and in 29 of 189 (15%) Infants receiving formula feedings are at increased
pairs of dizygotic twins. After controlling for covariates, risk of NEC compared with exclusively breastfed
genetic factors did not account for any variance in liability neonates.39–46 Formula lacks both cellular as well as soluble
for NEC. NEC has been associated with single nucleotide immunoprotective factors, such as IgA and various natural
polymorphisms in the interleukin (IL)-4 receptor (+1902G, antimicrobials, and also has a propensity to alter the normal
protective),27 IL-18 (-607A, increased severity),28 vascular postnatal gut bacterial colonization.47–49 Recent studies
endothelial growth factor (+450C, increased risk),29 and the indicate that formula feeding in newborn animals may
carbamoyl-phosphate synthetase 1 genes (T450N, increased directly induce inflammatory changes in the gut mucosa.50

Host susceptibility Ischemia

Prematurity, immature barrier Placental insufficiency,
function, male gender, ethnic maternal cocaine, prenatal indocin,
predisposition polycythemia, hypoxic/ischemic injury,
cyanotic heart disease, anemia/blood
transfusions, single nucleotide
polymorphisms in CPS1
Gut mucosal injury

Inflammatory response
Bacterial flora
Enteral feedings Inflammatory cells, PAF, TNFα,
Luminal bacteria, endotoxins
Hypertonic feeds/meds, leukotrienes, interleukins
altered bacterial colonization
H2-blockers, malabsorption, single nucleotide polymorphisms in
H2 productiion, endotoxins, IL4R, IL18, VEGF
volatile organic acids

Figure 1 Current epidemiological and experimental information on necrotizing enterocolitis supports a multifactorial model of disease. Clinical and histopathological features
indicate that tissue ischemia, bacterial flora, a dysregulated inflammatory response, and enteral feedings may contribute to the pathogenesis of necrotizing enterocolitis in
premature infants.
Abbreviations: IL, interleukin; VEGF, vascular endothelial growth factor; PAF, plasminogen activating factor; TNFα, tumor necrosis factor alpha.

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In spite of a large body of data from physiological and end-arteries,70 also indicates that ischemia may be an
retrospective studies, a direct association between specific important pathophysiological event in NEC. Infants with
feeding regimens and/or the rapidity of advancement of feed NEC may have decreased endothelial nitric oxide synthase
volumes and NEC has not been conclusively proven.45,51 activity and decreased arteriolar nitric oxide production,
Several observational studies have suggested that delaying which can place the developing intestine at a higher risk of
the introduction of enteral feeds beyond the first few days ischemic injury.71 However, this association between hypoxia-
after birth, and using standardized regimes to increase the ischemia and NEC has not been clearly established in
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volume of feeds by less than about 24 mL/kg body weight clinical studies in preterm infants.72 Although minor transient
each day may be associated with a lower risk of NEC.35,52–56 episodes of hypoxia and/or hypotension are not uncommon
In the National Institute of Child Health and Development in premature neonates, major ischemic events are obvious in
neonatal research network, the incidence of NEC was only a minority of preterm infants with NEC,6,9,72,73 and tend
higher at centers where enteral feeding was introduced to occur early in the neonatal period rather than in postnatal
earlier and feeding volumes advanced rapidly.57 In a recent weeks 2–4 when NEC occurs.73,74
retrospective study from a multihospital system,58 fulminant In full-term infants, NEC tends to occur at an earlier
NEC characterized by massive bowel necrosis and rapid postnatal age than in preterm infants, and is more obviously
progression to death within 48  hours was associated with associated with factors that may conceivably cause splanchnic
advancement of feedings by more than 20 mL/kg/day and/or hypoperfusion. Many term or near-term infants with NEC
an increase in concentration of human milk fortifier within have a history of placental insufficiency and absence/reversal
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48 hours before developing NEC. However, the association of end-diastolic blood flow in the umbilical vessels in utero,
between aggressive enteral feeding and NEC has not been perinatal asphyxia, polycythemia, episodes of low cardiac
evident in randomized controlled trials comparing slow output or clinical shock, and congenital cyanotic heart
versus rapid advancement of feedings.51,59–61 A meta-analysis disease.80,83,84
based on these studies showed that cautiously advanced NEC is characterized by a severe, unregulated inflam-
enteral feedings are not only safe, but may also reduce matory response. It is characterized by a prominent leu-
other morbidities associated with prematurity.62 Similarly, kocyte infiltrate comprised of activated macrophages and
current trial data do not provide evidence that delayed neutrophils.63,65,75 Human and animal studies have demon-
introduction of progressive enteral feeds reduces the risk strated increased tissue expression of TNFα and platelet acti-
of NEC in very low birth weight infants. In a meta-analysis vating factor (PAF), which may propagate ongoing mucosal
of five randomized controlled trials (600  infants, delayed injury by triggering a cascade of inflammatory mediators,
introduction of feedings defined as later than 5–7 days after including IL-1, IL-6, IL-8, IL-10, IL-12, and IL-18.36,76–81
birth, and early introduction as less than 4 days after birth), Activation of the complement and coagulation cascades,
delayed introduction of feedings did not reduce the risk cytokines, reactive oxygen species, and nitric oxide further
of NEC (relative risk [RR] 0.89, 95% confidence interval amplify the mucosal injury.36 In infants with NEC, increased
[CI] 0.58–1.37) or all-cause mortality (RR 0.93, 95% CI expression of PAF may be coupled with reduced levels of
0.53–1.64). Infants who had delayed introduction of enteral PAF acetylhydrolase (the enzyme which degrades PAF),
feeds took significantly longer to establish full enteral feeding further augmenting its local inflammatory effects.36,77,82,83 In
(reported median difference 3 days). experimental animals, attempts to regulate the inflammatory
Mucosal injury may be an early event. Gut epithelial response by depletion of neutrophils or by using anti-TNFα
injury is believed to be an early event in NEC. Although the antibodies have successfully reduced the severity of tissue
causes of this initial epithelial injury remain unclear, primary damage.84,85
apoptotic and autophagic mechanisms have been invoked.63,64 Bacteria play an essential role in the pathogenesis of
This disruption of the epithelial barrier is presumed to NEC. Several lines of evidence emphasize the importance of
allow bacterial translocation, which in turn triggers a local bacterial flora in the pathogenesis of NEC: NEC occurs only
inflammatory response.63,65,66 after postnatal bacterial colonization of the gastrointestinal
Ischemia may play a role in NEC. Coagulative necrosis, tract; intestinal injury prior to colonization may cause
which is typically associated with ischemia, is a prominent strictures or atresia, but not NEC;86 pneumatosis intestinalis,
histopathological finding in NEC.67–69 The predilection the pathognomonic finding in NEC, reflects the entrapment
for the ileocecal region, a watershed area supplied by of the gaseous products of bacterial fermentation in affected

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tissues;87 enterally administered aminoglycosides can reduce antimicrobial peptides, such as defensins and cathelicidins,
the incidence of NEC;88 and NEC-like lesions do not develop are components of the biochemical barrier.
in germ-free animals.16,89 Bacteria play a key role in NEC Immaturity of Paneth cells, specialized crypt cells that
by activating the immune system in the mucosa and causing produce natural antimicrobials (such as enteric human
inflammatory injury.66 Bacterial products such as short chain defensins 5 and 6) and MD2 (a key component of the
fatty acids (acetate, butyrate) can also directly damage the lipopolysaccharide receptor complex), has been suggested to
epithelial barrier.38,90 contribute to the risk of NEC.99–102 Acute NEC is associated
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Cases of NEC are often temporally and spatially with a low number of Paneth cells, which show weak
clustered in neonatal intensive care units, suggesting that immunoreactivity or complete absence of lysozyme.103,104
NEC may be caused by a transmissible agent.91 However, During recovery from NEC, Paneth cell hyperplasia/
most studies, whether based on culture techniques or on metaplasia has been observed with increased expression of
polymerase chain reaction amplification of 16S ribosomal enteric defensins.99,101
RNA,92,93 have failed to consistently implicate a single agent. Secretory IgA (sIgA) antibodies are an important host
Cultures of blood and other sterile fluids from infants with defense mechanism, preventing luminal antigens and
NEC usually yield microorganisms that typically colonize microorganisms from entering the mucosa. In an adult human
critically ill preterm infants and the neonatal intensive care subject, 70%–80% of all Ig-producing cells in the body are
unit microenvironment. Because these microorganisms are located in the intestinal mucosa and most of these cells produce
not unique to neonatal intensive care units, the interaction of IgA.105,106 In contrast, neonates lack IgA immunocytes at birth
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bacteria and bacterial products with the immature intestine and the first sIgA may not appear in mucosal secretions until
tends to receive greater emphasis in the pathogenesis of NEC sometime between postnatal week 2 and 8.107 This deficiency
than the presence of specific bacterial pathogens.65 However, can be partially offset in breastfed infants by sIgA present in
some recent studies suggest that early duodenal colonization colostrum/milk;108 breastfed infants receive about 0.5–1.0 g/
with specific Enterobacteriaceae and Clostridia may predict day of antibodies in milk throughout lactation, which is
later development of NEC.93,94 Similarly, in a polymerase comparable with the 2.5 g daily production of antibodies by a
chain reaction-based comparison of fecal microbiota from 65 kg adult, and a source of passive immunity against antigens
preterm infants with and without NEC, Wang et al95 found a “seen” by the mother-infant dyad.109 In formula-fed premature
marked reduction in bacterial diversity and also an abnormal infants, the absence of milk-borne sIgA is a significant
pattern of bacterial colonization, with a relative abundance immunological disadvantage and a likely contributor to the
of gammaproteobacteria (which include Enterobacteriaceae increased risk of NEC.46
and Pseudomonadaceae) and reduced numbers of  Firmicutes. Compared with term infants, premature neonates have
The oligoclonality of gut microbiota and the disproportionate increased gut mucosal permeability, and this permeability
representation of Gram-negative bacilli may be related to is even greater in infants who subsequently develop NEC.110
administration of broad-spectrum antibiotics, delayed or Studies on human tissue samples and in rodent models show
interrupted feedings, and exposure to selected multidrug- that the intestinal epithelium is breached early during NEC
resistant nursery flora.96,97 Delayed or altered acquisition of through apoptosis or necrosis.63 In this process, excessive
intestinal microbiota by early prolonged antibiotic treatment nitric oxide production, either directly or through its
increases the risk for NEC. This was shown in a recent reactive nitrogen derivative, peroxynitrite, may accentuate
cohort analysis of 4039 extremely low birth weight infants. epithelial injury through membrane oxidation, induction
Infants who received at least 4  days of initial empirical of apoptosis, and direct mitochondrial damage.111–113 In
antibiotic treatment, with sterile body fluid cultures, had an preterm infants, a deficiency in the mucus layer may promote
increased risk of NEC with an odds ratio [OR] of 1.34 (95% bacterial adherence and increase gut mucosal permeability,
CI 1.04–1.73).98 The association of specific bacterial groups predisposing to mucosal injury. 114 The developmental
with NEC is intriguing and merits further evaluation. deficiency of epithelial trophic factors, such as the epidermal
Immaturity of intestinal barrier function may promote growth factor and heparin-binding epidermal growth factor-
bacterial translocation and increase the risk of NEC. Tight like growth factor, may further increase the risk of injury to
junctions and the glycoprotein mucin layer secreted by goblet the epithelial barrier.115–117
cells comprise the structural component of the intestinal Do red blood cell transfusions predispose to NEC? In
barrier, whereas IgA, lysozyme, phospholipase A2, and convalescing preterm infants, red blood cell transfusions have

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 Dovepress Neonatal necrotizing enterocolitis

been temporally associated with NEC.118,119 Red blood cell Gastrointestinal signs may include increased prefeed residuals
transfusions can dampen the normal postprandial increase in or delayed gastric emptying, emesis, abdominal distention,
mesenteric blood flow in premature infants, particularly in those tenderness, and/or ileus with hypoactive bowel sounds. Grossly
with a birth weight ,1250 g.120 Immaturity of ­vascular auto- bloody stools are seen in approximately 25% of infants.
regulation in extremely preterm infants is linked to defects in Clinical progression of NEC is commonly staged using the
endothelial nitric oxide synthesis68 and could plausibly explain modified Bell’s criteria (Table 1).125 Characteristically, NEC
a higher risk of mucosal injury following transfusions. follows an initial early stage of systemic inflammatory
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response, followed by a definite stage of localized peritonitis,

Pathology and finally, an advanced stage of generalized peritonitis.
The disease is commonly localized to the ileocolic region, In a recent study, Clark et  al126 described the clinical
although the colon may be frequently involved in term characteristics of infants who died of NEC. Compared with
infants.121 Some infants with severe, aggressive disease may 5594 infants who recovered from NEC and were discharged
develop total gut necrosis (NEC totalis). The four major histo- home, there were 1505  infants diagnosed with NEC who
pathological findings in NEC are coagulative necrosis, bacte- died. In multivariate analysis, lower gestational age, lower
rial overgrowth, pneumatosis intestinalis, and inflammation. birth weight, treatment with assisted ventilation on the day
of diagnosis of NEC, treatment with vasopressors at the
Clinical features time of diagnosis, and African-American ethnicity were
The presenting signs of NEC are protean and may be insidious associated with mortality. In another study,58 fulminant
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in onset or sudden and catastrophic. NEC typically presents NEC, characterized by massive bowel necrosis and rapid
at 2–4 weeks after birth, although the onset may be as late progression to death within 48  hours, was recorded in
as 3 months in some infants.16,72,122 The age of onset of NEC 7%–10% of all cases and was associated with lower birth
correlates inversely with gestational age at birth in a nonlinear weight (1088 ± 545 g versus 1652 ± 817 g), earlier gestational
(log-normal) relationship, where infants born at ,28 weeks’ age (27.5 ± 3.3 weeks versus 31.1 ± 4.4 weeks), radiographic
gestation tend to develop NEC at a disproportionately greater evidence of portal venous air, hematocrit ,22%, a history
postnatal age than their more mature counterparts.123,124 of advancement in feeding volume  .20 mL/kg/day, an
NEC often presents with nonspecific systemic signs, such immature to total neutrophil ratio .0.5, blood lymphocyte
as tachycardia, apnea, lethargy, and temperature instability. count ,4000/µL, and a history of increased concentration of

Table 1 Modified Bell’s staging criteria for necrotizing enterocolitis125

Stage Classification System signs Intestinal signs Radiological signs
IA Suspected NEC Temperature instability, apnoea, Increased pregavage residuals, Normal or intestinal
bradycardia, lethargy mild abdominal distention, dilation, mild ileus
emesis, guaiac-positive stool
IB Suspected NEC Same as above Bright-red blood from rectum Same as above
IIA Proven NEC – mildly ill Same as above Same as above, plus absent bowel Intestinal dilation, ileus,
sounds, with or without pneumatosis intestinalis
abdominal tenderness
IIB Proven NEC – moderately ill Same as above, plus mild Same as above, plus absent bowel Same as IIA, plus
metabolic acidosis and mild sounds, definite abdominal tenderness, portal vein gas, with
thrombocytopenia with or without abdominal cellulitis or without ascites
or right lower quadrant mass
IIIA Advanced NEC – severely ill, Same as lllB, plus hypotension Same as above, plus signs of Same as IIB, plus
bowel intact bradycardia, severe apnoea, generalized peritonitis, marked definite ascites
combined respiratory and tenderness, and distention of
metabolic acidosis, disseminated abdomen
intravascular coagulation,
and neutropenia
IIIB Advanced NEC – severely ill, Same as IIIA Same as IIIA Same as IIB, plus
bowel perforated pneumoperitoneum
Note: This table was published in Pediatric Clinics of North America, Vol 33, MC Walsh, RM Kliegman, Necrotizing enterocolitis: Treatment based on staging criteria, Pages
179–201, © Copyright Elsevier 1986.
Abbreviation: NEC, necrotizing enterocolitis.

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human milk fortifier within 48 hours before developing NEC. A B

In another study of NEC totalis,127 breast milk feeding was
noted to have a protective effect.
NEC in full-term infants differs from that seen in pre-
mature infants. Approximately 10% of infants with NEC
are born at term. Unlike preterm infants who develop NEC
in the second or third week of life (median 12 days), most
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term cases are seen within the first week (median 2 days) and
often have colonic involvement.121,128,129 NEC in term infants
is usually secondary, associated with conditions such as birth C D
asphyxia, polycythemia, congenital heart disease, rotavirus
infections, and Hirschsprung’s disease.121,128–134 Outcomes
are generally better than in preterm neonates, with mortality
rates of 0%–13%.121,135,136

Diagnosis
A high index of suspicion in diagnosing at-risk infants is
crucial. Most clinical antecedents prior to Bell stage III Figure 2 Abdominal radiographs with characteristic findings of necrotizing
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enterocolitis. (A) Diffuse pneumatosis intestinalis with a linear distribution in the

NEC are nonspecific for gastrointestinal pathology and left upper and middle quadrants. (B) Characteristic arborization pattern of portal
may not provide sufficient time to the clinician for early venous gas. (C) Free peritoneal gas with the falciform ligament visible (arrow).
(D) Free peritoneal gas seen in a left lateral decubitus view.
institution of treatment measures. In a recent retrospective
study, Christensen et al137 reviewed the medical records of
118  infants with stage III NEC. The earliest recognized Although intestinal perforation may occur within a few hours
antecedents of NEC were nonspecific, including apnea/ to as late as 8 days following the onset of NEC,142 more than
bradycardia, skin mottling, and irritability, which were first two-thirds of all perforations occur within 30–48  hours.143
noted at a mean of 2.8 ± 2.1, 4.5 ± 3.1, and 5.4 ± 3.7 hours, In some infants who present with bloody stools but minimal
respectively, prior to the diagnosis of NEC. The most systemic signs, pneumatosis may be limited to the colon and
frequently identified gastrointestinal antecedents were may indicate a relatively benign course.144
blood in the stools, increased abdominal girth, and elevated Most patients with NEC develop leukocytosis and
prefeeding gastric residuals or emesis, identified 2.0 ± 1.9, neutrophilia, although neutropenia can occur in advanced
2.8 ± 3.1, and 4.9 ± 4.0 hours before NEC was recognized. disease due to the migration of neutrophils into the peritoneal
No consistent laboratory antecedents were discovered. cavity.145 Blood cultures may grow organisms typically
Radiographic features remain the mainstay of definitive associated with late-onset sepsis. Thrombocytopenia may
diagnosis. The pathognomonic sign for NEC is pneumatosis occur in stage II and III, and patients with advanced NEC
intestinalis (Figure 2).138 These radiolucent shadows have a may have evidence of disseminated intravascular coagulation.
bubbly appearance when air is submucosal and become linear Breath hydrogen testing was initially heralded as a diagnostic
when subserosal. Portal venous gas has been associated with tool, but subsequent studies have shown it as lacking
a poor prognosis, although this association has recently been discriminant value.146
questioned.139 Sonographic appearance of portal air is an early The differential diagnosis of NEC includes infections
sign. In a prospective cohort study, sonographic portal air (systemic or intestinal), gastrointestinal obstruction, volvulus,
had a specificity of 86% for advanced NEC ($stage II), and and isolated intestinal perforation. Idiopathic focal intestinal
the sensitivity was lower at 45%.140 It is not known if portal perforations can occur spontaneously or in association with
venous gas visualized by ultrasound or on plain radiographs deficiency of the muscularis propria,147 early use of postnatal
has the same prognostic significance. Sonographic detection corticosteroids alone148 or with indomethacin,149 and with
of echoic free fluid and bowel wall thinning may also be more occult candidal infections.150 Pneumoperitoneum develops
sensitive for intestinal perforation than plain radiography.141 in such patients, but they are usually less ill than those with
Serial radiographs are invaluable in following the progression NEC. Some experts believe that isolated perforations may
of NEC, particularly in the first 48 hours after onset of disease. not be related to NEC.

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Treatment supportive care and prevention of further injury with cessation

Medical management of feeding, nasogastric decompression, and administration of
Rapid initiation of therapy is necessary for suspected as well intravenous fluids (see Table 2). Infants are usually made nil
as proven cases of NEC. There is no definitive treatment per os for a variable period of time, depending on the severity
for established NEC, and therefore treatment is directed at of disease. Parenteral antibiotics are widely used for the
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Table 2 Treatment and prevention of necrotizing enterocolitis

Therapeutic intervention Current status Evidence level Recommendation level
Treatment
Gastric/Intestinal Provide supportive care and prevent further injury with cessation III B
decompression and bowel rest of feeding, nasogastric decompression, and administration of
intravenous fluids. Infants stay nil per os for 3–5 days in stage I,
and 10–14 days in stages II and III.
Parenteral antibiotics Broad spectrum antibiotics should be administered based on II-3 C
local antibiotic sensitivity patterns. Anaerobic coverage should
be considered in infants with stage III NEC.
Primary peritoneal drainage Choices for surgical management in infants with NEC include I C
versus exploratory laparotomy peritoneal drain placement and exploratory laparotomy.
In unstable premature infants with perforated NEC, peritoneal
drainage can be cautiously considered as an alternative to
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exploratory laparotomy, although the best surgical approach

in these infants remains unresolved.
Prevention
Antenatal corticosteroids Small beneficial effect of antenatal steroids for reducing risk of NEC. I A
Minimal enteral (trophic) Infants receiving trophic feedings take less time to tolerate full I C
feedings enteral feeds and have a shorter duration of hospital stay,
without an effect on the incidence of necrotizing enterocolitis.
Slow advancement of feedings No evidence to suggest that slow advancement of enteral feed I D
volumes reduces the risk of NEC in very low birth weight infants.
Breast milk Although the mechanism of protection is not completely II-2 A
understood, there is strong evidence favoring the use of human
milk to reduce the risk of NEC in premature infants.
Oral immunoglobulins Data from available trials do not support oral administration of I D
immunoglobulin for the prevention of NEC.
Enteral antibiotics Enteral antibiotic treatment leads to a small reduction in I D
NEC risk; however, increase in antimicrobial-resistant intestinal
microbiota precludes routine use of this therapy.
Amino acid supplementation Data are insufficient at present to support supplemental I C
administration of parenteral L-arginine or glutamine to reduce
the risk of NEC.
Recombinant cytokines and Epidermal growth factor is a promising agent in preclinical studies. III I
growth factors In early clinical studies, enteral administration of a synthetic
amniotic fluid-like solution containing erythropoietin and
granulocyte-colony stimulating factor has shown an encouraging
safety and efficacy profile.
Probiotics Probiotics may reduce the risk of severe NEC and related I C
mortality; however, important questions remain regarding
optimal choice of agent(s) and dose.
Prebiotics Recent nonhuman animal experimental data suggest that NA* NA*
oligofructose prebiotics may be useful in protecting against
experimental NEC.
Notes: *Insufficient human data to determine evidence level or recommendation. Levels of evidence: I, Evidence obtained from at least one properly designed randomized,
controlled trial; II, evidence obtained from well-designed controlled trials without randomization (II 1), cohort or case-control analytic studies, (II 2) evidence obtained
from multiple time series with or without the intervention (II 3); III, opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert
committees. Levels of recommendations for clinical use: A, Good scientific evidence suggests that the benefits substantially outweigh the potential risks; B, at least fair
scientific evidence suggests that the benefits outweigh the potential risks; C, at least fair scientific evidence suggests that there are benefits provided, but the balance between
benefits and risks are too close for making general recommendations; D, at least fair scientific evidence suggests that the risks outweigh potential benefits; I, scientific evidence
is lacking, of poor quality, or conflicting, such that the risk–benefit balance cannot be assessed.
Abbreviation: NEC, necrotizing enterocolitis.

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treatment of NEC, but there is surprisingly sparse evidence within 28  days of peritoneal drainage or laparotomy
guiding the choice of antimicrobial agent and duration of (28/90 versus 30/95; typical RR 0.99, 95% CI 0.64–1.52;
therapy. One study comparing alternative treatment regimens n = 185), mortality by 90 days after the primary procedure
that included 90 infants with definite NEC, treated 46 cases (typical RR 1.05, 95% CI 0.71–1.55; n  =  185) and the
with ampicillin and gentamicin, while 44 cases received number of infants needing total parenteral nutrition for
cefotaxime and vancomycin. Infants $2200 g birthweight more than 90 days (typical RR 1.18, 95% CI 0.72–1.95;
had similar outcomes with either regimen. Smaller infants n = 116). Nearly 50% of infants in the peritoneal drainage
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given cefotaxime and vancomycin had a lower risk of group could avoid the need for laparotomy during the
culture-positive peritonitis (P = 0.01), and were less likely study period (44/90 versus 95/96; typical RR 0.49, 95%
to die (P = 0.048) or develop thrombocytopenia (P = 0.004). CI 0.39–0.61; n = 186). One study found that the time to
These data suggest that carefully chosen antibiotic regimens attain full enteral feeds in infants #1000 g was prolonged
can improve the outcome of NEC.151 Antibiotic coverage in the peritoneal drainage group (mean difference 20.77,
for anaerobes should be considered for infants with stage 95% CI 3.62–37.92).
III NEC. Although the immediate outcome following peritoneal
drainage or laparotomy appears to be similar, there are
Surgical management concerns about the risk of neurodevelopmental impairment
Approximately 20%–40% of patients with pneumatosis following peritoneal drainage. In a recent multicenter trial,
intestinalis will require surgical management. Indications peritoneal drainage was associated with increased risk
For personal use only.

for surgery include evidence of perforation seen on of death or neurodevelopmental impairment.155 A meta-
abdominal radiographs or positive abdominal paracentesis analysis of three prospective observational studies and two
(stool or organism on Gram stain from peritoneal fluid). randomized controlled trials suggested a significant excess
Failure of medical management, a single fixed bowel loop mortality of 55% associated with peritoneal drainage.156
on radiographs, abdominal wall erythema, or a palpable There is a need for better identification of patients who are
mass are all relative indications for surgery. In rare cases, less likely to tolerate laparotomy and who may benefit from
the entire intestine can be involved, precluding surgical peritoneal drainage as a temporizing strategy.
intervention. Ideally, surgery should be performed after the
development of bowel necrosis, but before perforation and Prevention
peritonitis occurs. The existing evidence shows a small beneficial effect of
In unstable premature infants with perforated NEC, antenatal steroids in reducing the risk of NEC (see Table 2).157
peritoneal drainage can be cautiously considered as an This may be accomplished by accelerating maturation of the
alternative to exploratory laparotomy, although the best gut epithelial barrier and by reducing the overall severity
surgical approach in these infants remains unresolved. In of illness via prevention of lung disease. When analyzed
the NECSTEPS trial,152 there was no statistically significant together, eight randomized controlled comparisons of ante-
difference in 90-day survival, dependence on parenteral natal corticosteroid administration with placebo or with no
nutrition, or length of hospital stay in 117 very low birth treatment, including 1675 infants, showed a risk reduction
weight infants randomly assigned to peritoneal drainage or in NEC of 0.46 (95% CI 0.29–0.74).157 Multiple courses of
laparotomy. However, other studies have raised important antenatal steroids do not appear to reduce the risk of NEC
concerns about the routine use of peritoneal drainage. In further. In a randomized trial of one to four weekly treat-
the NET trial,153 69 extremely low birth weight patients ments of antenatal steroids or placebo that included 1858
were randomized to peritoneal drainage or laparotomy, pregnant women, and the outcomes of 2304 infants, the rate
and no significant differences were noted in survival, of NEC, ie, 1%, was similar in both groups.158
length of hospital stay, ventilator dependence, or need
for parenteral nutrition. However, peritoneal drainage Minimal enteral (trophic) feedings
was effective as a definitive treatment in only 4/35 (11%) Initiating feeds by using small amounts of milk or formula
surviving neonates, and the rest either required a delayed may promote the maturation of peristaltic activity and
laparotomy (26/34, 74%) or died. In a recent meta-analysis, enzymatic systems, release of digestive hormones, and
Rao et al154 reviewed data from the NET and NECSTEPS augment intestinal blood flow. 3,43,159–162 However, in a
trials and detected no significant differences in mortality meta-analysis of nine randomized trials including 754

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 Dovepress Neonatal necrotizing enterocolitis

very low birth weight infants,163 early trophic feedings did Enteral antibiotics
not affect feed tolerance, growth rates, or the risk of NEC To determine the effect of enteral antibiotic prophylaxis and
(RR 1.07, 95% CI 0.67–1.70; risk difference 0.01, 95% subsequent development of NEC, five randomized controlled
CI -0.04–0.05). trials involving 456 infants were compared. Enteral antibiotic
administration resulted in a significant risk reduction for NEC
Slow advancement of feedings (RR 0.47, CI 0.28–0.78; risk difference -0.10, 0.16 to -0.04);
Meta-analyses of three randomized controlled trials in which number needed to treat 10 [6–25]). There was a statisti-
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a total of 396  infants were included found no significant cally significant reduction in NEC-related deaths (RR 0.32,
effects of feeding advancement on the risk of NEC (RR 0.96, 0.10–0.96; risk difference -0.07, CI -0.13–0.01) and number
95% CI 0.48–1.92) or all-cause mortality (RR 1.40, 95% needed to treat of 14 (8–100). However, concerns about the
CI 0.71–2.80).45 Infants who had slow rates of feed volume development of resistant bacteria remain, and meta-analysis
advancement took longer to regain birth weight (median revealed a borderline increase in antimicrobial-resistant intes-
difference 2–5  days) and to establish full enteral feeding tinal microbiota with enteral antibiotic treatment.88
(median difference 3–5  days). No statistically significant
effect on total duration of hospital stay was detected. The Amino acid supplementation
currently available data do not provide evidence that slow Nitric oxide augments gastrointestinal perfusion, barrier
advancement of enteral feed volumes reduces the risk of function, and mucosal repair.167 The supplementation of
NEC in very low birth weight infants. Of note, few partici- L-arginine, a major substrate for nitric oxide production,
For personal use only.

pants were extremely low birth weight or growth restricted, appears promising in small cohorts in reducing NEC but
so conclusions about infants at greatest risk for NEC cannot the data are insufficient at present to support a practice
be drawn from the available data. recommendation.168–170 Similarly, glutamine promotes gut
epithelial proliferation and barrier function in animal stud-
Breast milk ies, but a larger multicenter trial of parenteral glutamine
Experimental and clinical studies show a protective effect supplementation did not show a beneficial effect in reducing
of human milk feeds against NEC when compared with the incidence of NEC in preterm infants.171
formula.39–44,48,164,165 The protective effects of breast milk
against NEC are retained even in pasteurized, banked Probiotics
donor milk. In meta-analysis of data from five randomized Probiotics are living microorganisms which, when ingested,
trials,46 formula-fed infants were at higher risk of NEC than can exert a health benefit beyond basic nutrition. Probiotics
infants who received donor milk (RR 2.5, 95% CI 1.2–5.1; improve intestinal defense mechanisms, including mucosal
risk difference 0.03, 95% CI 0.01–0.06; number needed to IgA secretion, intestinal epithelial cell proliferation, and
harm 33, 95% CI 17–100). More recently, Sullivan et al166 barrier function, decrease inflammation and epithelial cell
showed that an exclusively human milk-based diet protected apoptosis,172 and may be useful in preventing NEC.173,174
extremely premature infants against NEC and surgical Alfaleh et  al 175 analyzed 16 eligible trials including
NEC when compared with a mother’s milk-based diet that 2842 infants.174,176–190 Included trials were highly variable with
included bovine milk-derived human milk fortifier and regard to enrollment criteria such as birth weight and gesta-
preterm formula. tional age, baseline risk of NEC in the control groups, timing,
dose, formulation of the probiotics, and feeding regimens.
Oral immunoglobulins Enteral probiotics significantly reduced the incidence of
Three trials, including a total of 2095 neonates, were reviewed severe NEC (stage II or more, typical RR 0.35, 95% CI 0.24–
together. Oral administration of IgG or an IgG/IgA combina- 0.52) and mortality (typical RR 0.40, 95% CI 0.27–0.60).
tion did not result in a significant reduction in incidence of Deshpande et  al191 selected 11 of these trials174,178–181,184–189
definite NEC (RR 0.84, 95% CI 0.57–1.25), suspected NEC involving 2176 neonates and reported a similar reduction
(RR 0.84, 95% CI 0.49–1.46), need for surgery (RR 0.21, in NEC. The frequency of NEC decreased from 6.56% (71
95% CI 0.02–1.75), or death from NEC (RR 1.10, 95% CI of 1082) in the control group to 2.37% (26 of 1094) in the
0.47–2.59).49 Based on the available trials, the evidence does probiotics-treated group. Meta-analysis using a fixed-effects
not support the administration of oral immunoglobulin for model showed reduction in risk of NEC in the probiotics-
the prevention of NEC. treated group (RR 0.35, 95% CI 0.23–0.55; P , 0.00001).

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 Maheshwari et al Dovepress

Only four of these trials reported a significantly higher risk Prognosis

for NEC in the control group.174,179,180,189 The number needed Mortality rates range between 20% and 50%. ­Approximately
to treat with probiotics to prevent one case of NEC was 25 27%–63% of affected infants may require surgery,1,16
(95% CI 17–34). Current evidence indicates that enteral and as many as 50% infants may die in the postoperative
supplementation with probiotics can prevent severe NEC period.1,15,17 Subacute complications include strictures,
and decrease all-cause mortality in preterm infants. However, dysmotility, malabsorption, and short gut syndrome.15
further study is needed before routine supplementation using Severe NEC has been associated with growth delay
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infant formulas with probiotics and also to determine the that can persist beyond infancy into childhood and poor
safety and efficacy of probiotic formulations in extremely ­neurodevelopmental outcome at a corrected gestational age
low birth weight infants.175,192 of 18–22 months.207

Prebiotics Summary
Prebiotics are nondigestible dietary supplements (usually Despite advances in the diagnosis and management of many
carbohydrates or mucins) which promote proliferation neonatal diseases, NEC remains a devastating condition
of beneficial commensal bacteria like Lactobacillus and for many infants. While it is established that very low
Bifidobacterium. Recent experimental data suggest that birth weight infants are at greatest risk for development of
­oligofructose prebiotics may be protective against NEC.193–196 NEC, human milk-feeding appears to be the single most
effective strategy to reduce, but not eliminate, this disease.
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Recombinant cytokines Current medical management of NEC is largely supportive

Epidermal growth factor, an important component of gut and likely does not modify the etiopathogenesis of the
secretions, human milk, and amniotic fluid, promotes disease. Controversies remain regarding optimal surgical
epithelial proliferation, migration, and mucosal repair management for this condition. Although there are important
following injury.197 Oral administration of recombinant gaps in our understanding of NEC, future research should
epidermal growth factor protects experimental animals against focus on prevention of the disease and early recognition that
NEC-like lesions.198 Other studies have similarly evaluated the occurs well before the onset of intestinal necrosis.
role of hematopoietic growth factors, such as erythropoietin
and granulocyte-colony stimulating factor. We have recently Acknowledgment
shown that transforming growth factor-β2 may protect mouse AM is supported by a National Institutes of Health award.
pups against NEC-like injury.66 These cytokines are present in
amniotic fluid and human milk, are swallowed by the fetus in Disclosure
large amounts,199,200 and have a demonstrated an in vitro and The authors report no conflicts of interest in this work.
in vivo protective effect on gut mucosa.201–206
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