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http://dx.doi.org/10.2147/RRN.S23459
Neonatal necrotizing enterocolitis
Akhil Maheshwari
1
Laura L Corbin
2
Robert L Schelonka
2
1
Division of Neonatology and
Center for Neonatal and Pediatric
Gastrointestinal Disease, Department
of Pediatrics, University of Illinois at
Chicago, IL,
2
Division of Neonatology,
Department of Pediatrics, Oregon
Health and Sciences University,
Portland, OR, USA
Correspondence: Akhil Maheshwari
Center for Neonatal and Pediatric
Gastrointestinal Disease, Children’s
Hospital of University of Illinois,
University of Illinois at Chicago,
840 S Wood St, CSB 1257, UIC
m/c 856, Chicago, IL 60612, USA
Tel +1 312 996 4185
Fax +1 312 355 5548
Email akhil1@uic.edu
Abstract: Necrotizing enterocolitis is the most common gastrointestinal emergency in
preterm neonates and a major cause of morbidity and mortality in premature infants born
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
and therapeutic strategies.
Keywords: necrotizing enterocolitis, inflammation, mucosa, pneumatosis, neonate
Introduction
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
minor epidemics.
7,12–15
Although the reasons for these center differences are unclear,
plausible explanation(s) include biological differences in patient populations and
distribution of birth weights, infectious milieu in the neonatal intensive care units,
and consistency in labeling of cases that recover without requiring significant medical
or surgical intervention.
15
Despite improvements in neonatal intensive care and increased overall survival of
critically ill premature neonates, mortality rates from NEC can reach 50%.
5,16,17
Most
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Maheshwari et al
deaths occur in extremely low birth weight infants, who
frequently develop severe disease and require surgery.
5
Pathophysiology
Although the etiopathogenesis of NEC remains unclear,
current epidemiological and experimental evidence
18,19
identifies several diverse risk factors and supports a multi-
factorial model of disease (summarized in Figure 1).
Prematurity is the most important predictor of NEC.
Immaturity of the gastrointestinal tract, particularly in
the context of its motility, digestion, perfusion, barrier
function, and immune defense, is a major predisposing
factor for NEC.
20–22
The pathophysiological importance of
prematurity is evident from the near exclusive occurrence
of NEC in preterm infants, even though events generally
considered to be critical in the pathogenesis of NEC, such
as gut mucosal injury, altered barrier function, and bacterial
translocation, are recorded frequently in critically ill patients
of all ages.
23–25
Evidence for genetic predisposition to NEC is modest.
Bhandari et al
26
recorded NEC in one or both twins in nine of
63 (14%) pairs of monozygotic twins and in 29 of 189 (15%)
pairs of dizygotic twins. After controlling for covariates,
genetic factors did not account for any variance in liability
for NEC. NEC has been associated with single nucleotide
polymorphisms in the interleukin (IL)-4 receptor (+1902G,
protective),
27
IL-18 (-607A, increased severity),
28
vascular
endothelial growth factor (+450C, increased risk),
29
and the
carbamoyl-phosphate synthetase 1 genes (T450N, increased
risk).
30
In contrast, NEC is not associated with most single
nucleotide polymorphisms that have been linked with
Crohn’s disease and/or ulcerative colitis, such as those in the
genetic sequences of tumor necrosis factor-alpha (TNF-α),
IL-1, IL-4, IL-6, IL-8, and IL-10, CD14, toll-like receptor
4, caspase-recruitment domain 15, and nucleotide-binding
oligomerization domain containing 2.
31–33
NEC usually occurs in infants who are receiving enteral
feedings. Although NEC can occur in neonates who have
never been fed, 90%–95% of cases occur in infants with
a history of recent volume advancement or reinitiation
of enteral feedings.
34,35
Besides the risk of direct osmotic
injury to the gut mucosa, feedings may also alter splanchnic
blood flow and increase the risk of ischemic injury in
underperfused regions by increasing local oxygen needs.
In addition, immaturity of motility and digestion in the
developing intestine may leave undigested food in the lumen
for prolonged periods, promoting bacterial overgrowth and
translocation.
36
Products of bacterial fermentation, such as
short chain fatty acids, can also injure the immature gut
mucosa.
37,38
Infants receiving formula feedings are at increased
risk of NEC compared with exclusively breastfed
neonates.
39–46
Formula lacks both cellular as well as soluble
immunoprotective factors, such as IgA and various natural
antimicrobials, and also has a propensity to alter the normal
postnatal gut bacterial colonization.
47–49
Recent studies
indicate that formula feeding in newborn animals may
directly induce inflammatory changes in the gut mucosa.
50
Host susceptibility
Prematurity, immature barrier
function, male gender, ethnic
predisposition
Bacterial flora
Luminal bacteria, endotoxins
altered bacterial colonization
Enteral feedings
Hypertonic feeds/meds,
H
2
-blockers, malabsorption,
H
2
productiion, endotoxins,
volatile organic acids
Gut mucosal injury
Inflammatory response
Inflammatory cells, PAF, TNFα,
leukotrienes, interleukins
single nucleotide polymorphisms in
IL4R, IL18, VEGF
Ischemia
Placental insufficiency,
maternal cocaine, prenatal indocin,
polycythemia, hypoxic/ischemic injury,
cyanotic heart disease, anemia/blood
transfusions, single nucleotide
polymorphisms in CPS1
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 ora, a dysregulated inammatory 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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Neonatal necrotizing enterocolitis
In spite of a large body of data from physiological and
retrospective studies, a direct association between specific
feeding regimens and/or the rapidity of advancement of feed
volumes and NEC has not been conclusively proven.
45,51
Several observational studies have suggested that delaying
the introduction of enteral feeds beyond the first few days
after birth, and using standardized regimes to increase the
volume of feeds by less than about 24 mL/kg body weight
each day may be associated with a lower risk of NEC.
35,52–56
In the National Institute of Child Health and Development
neonatal research network, the incidence of NEC was
higher at centers where enteral feeding was introduced
earlier and feeding volumes advanced rapidly.
57
In a recent
retrospective study from a multihospital system,
58
fulminant
NEC characterized by massive bowel necrosis and rapid
progression to death within 48 hours was associated with
advancement of feedings by more than 20 mL/kg/day and/or
an increase in concentration of human milk fortifier within
48 hours before developing NEC. However, the association
between aggressive enteral feeding and NEC has not been
evident in randomized controlled trials comparing slow
versus rapid advancement of feedings.
51,59–61
A meta-analysis
based on these studies showed that cautiously advanced
enteral feedings are not only safe, but may also reduce
other morbidities associated with prematurity.
62
Similarly,
current trial data do not provide evidence that delayed
introduction of progressive enteral feeds reduces the risk
of NEC in very low birth weight infants. In a meta-analysis
of five randomized controlled trials (600 infants, delayed
introduction of feedings defined as later than 5–7 days after
birth, and early introduction as less than 4 days after birth),
delayed introduction of feedings did not reduce the risk
of NEC (relative risk [RR] 0.89, 95% confidence interval
[CI] 0.58–1.37) or all-cause mortality (RR 0.93, 95% CI
0.53–1.64). Infants who had delayed introduction of enteral
feeds took significantly longer to establish full enteral feeding
(reported median difference 3 days).
Mucosal injury may be an early event. Gut epithelial
injury is believed to be an early event in NEC. Although the
causes of this initial epithelial injury remain unclear, primary
apoptotic and autophagic mechanisms have been invoked.
63,64
This disruption of the epithelial barrier is presumed to
allow bacterial translocation, which in turn triggers a local
inflammatory response.
63,65,66
Ischemia may play a role in NEC. Coagulative necrosis,
which is typically associated with ischemia, is a prominent
histopathological finding in NEC.
67–69
The predilection
for the ileocecal region, a watershed area supplied by
end-arteries,
70
also indicates that ischemia may be an
important pathophysiological event in NEC. Infants with
NEC may have decreased endothelial nitric oxide synthase
activity and decreased arteriolar nitric oxide production,
which can place the developing intestine at a higher risk of
ischemic injury.
71
However, this association between hypoxia-
ischemia and NEC has not been clearly established in
clinical studies in preterm infants.
72
Although minor transient
episodes of hypoxia and/or hypotension are not uncommon
in premature neonates, major ischemic events are obvious in
only a minority of preterm infants with NEC,
6,9,72,73
and tend
to occur early in the neonatal period rather than in postnatal
weeks 2–4 when NEC occurs.
73,74
In full-term infants, NEC tends to occur at an earlier
postnatal age than in preterm infants, and is more obviously
associated with factors that may conceivably cause splanchnic
hypoperfusion. Many term or near-term infants with NEC
have a history of placental insufficiency and absence/reversal
of end-diastolic blood flow in the umbilical vessels in utero,
perinatal asphyxia, polycythemia, episodes of low cardiac
output or clinical shock, and congenital cyanotic heart
disease.
80,83,84
NEC is characterized by a severe, unregulated inflam-
matory response. It is characterized by a prominent leu-
kocyte infiltrate comprised of activated macrophages and
neutrophils.
63,65,75
Human and animal studies have demon-
strated increased tissue expression of TNFα and platelet acti-
vating factor (PAF), which may propagate ongoing mucosal
injury by triggering a cascade of inflammatory mediators,
including IL-1, IL-6, IL-8, IL-10, IL-12, and IL-18.
36,76–81
Activation of the complement and coagulation cascades,
cytokines, reactive oxygen species, and nitric oxide further
amplify the mucosal injury.
36
In infants with NEC, increased
expression of PAF may be coupled with reduced levels of
PAF acetylhydrolase (the enzyme which degrades PAF),
further augmenting its local inflammatory effects.
36,77,82,83
In
experimental animals, attempts to regulate the inflammatory
response by depletion of neutrophils or by using anti-TNFα
antibodies have successfully reduced the severity of tissue
damage.
84,85
Bacteria play an essential role in the pathogenesis of
NEC. Several lines of evidence emphasize the importance of
bacterial flora in the pathogenesis of NEC: NEC occurs only
after postnatal bacterial colonization of the gastrointestinal
tract; intestinal injury prior to colonization may cause
strictures or atresia, but not NEC;
86
pneumatosis intestinalis,
the pathognomonic finding in NEC, reflects the entrapment
of the gaseous products of bacterial fermentation in affected
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Maheshwari et al
tissues;
87
enterally administered aminoglycosides can reduce
the incidence of NEC;
88
and NEC-like lesions do not develop
in germ-free animals.
16,89
Bacteria play a key role in NEC
by activating the immune system in the mucosa and causing
inflammatory injury.
66
Bacterial products such as short chain
fatty acids (acetate, butyrate) can also directly damage the
epithelial barrier.
38,90
Cases of NEC are often temporally and spatially
clustered in neonatal intensive care units, suggesting that
NEC may be caused by a transmissible agent.
91
However,
most studies, whether based on culture techniques or on
polymerase chain reaction amplification of 16S ribosomal
RNA,
92,93
have failed to consistently implicate a single agent.
Cultures of blood and other sterile fluids from infants with
NEC usually yield microorganisms that typically colonize
critically ill preterm infants and the neonatal intensive care
unit microenvironment. Because these microorganisms are
not unique to neonatal intensive care units, the interaction of
bacteria and bacterial products with the immature intestine
tends to receive greater emphasis in the pathogenesis of NEC
than the presence of specific bacterial pathogens.
65
However,
some recent studies suggest that early duodenal colonization
with specific Enterobacteriaceae and Clostridia may predict
later development of NEC.
93,94
Similarly, in a polymerase
chain reaction-based comparison of fecal microbiota from
preterm infants with and without NEC, Wang et al
95
found a
marked reduction in bacterial diversity and also an abnormal
pattern of bacterial colonization, with a relative abundance
of gammaproteobacteria (which include Enterobacteriaceae
and Pseudomonadaceae) and reduced numbers of Firmicutes.
The oligoclonality of gut microbiota and the disproportionate
representation of Gram-negative bacilli may be related to
administration of broad-spectrum antibiotics, delayed or
interrupted feedings, and exposure to selected multidrug-
resistant nursery flora.
96,97
Delayed or altered acquisition of
intestinal microbiota by early prolonged antibiotic treatment
increases the risk for NEC. This was shown in a recent
cohort analysis of 4039 extremely low birth weight infants.
Infants who received at least 4 days of initial empirical
antibiotic treatment, with sterile body fluid cultures, had an
increased risk of NEC with an odds ratio [OR] of 1.34 (95%
CI 1.04–1.73).
98
The association of specific bacterial groups
with NEC is intriguing and merits further evaluation.
Immaturity of intestinal barrier function may promote
bacterial translocation and increase the risk of NEC. Tight
junctions and the glycoprotein mucin layer secreted by goblet
cells comprise the structural component of the intestinal
barrier, whereas IgA, lysozyme, phospholipase A2, and
antimicrobial peptides, such as defensins and cathelicidins,
are components of the biochemical barrier.
Immaturity of Paneth cells, specialized crypt cells that
produce natural antimicrobials (such as enteric human
defensins 5 and 6) and MD2 (a key component of the
lipopolysaccharide receptor complex), has been suggested to
contribute to the risk of NEC.
99–102
Acute NEC is associated
with a low number of Paneth cells, which show weak
immunoreactivity or complete absence of lysozyme.
103,104
During recovery from NEC, Paneth cell hyperplasia/
metaplasia has been observed with increased expression of
enteric defensins.
99,101
Secretory IgA (sIgA) antibodies are an important host
defense mechanism, preventing luminal antigens and
microorganisms from entering the mucosa. In an adult human
subject, 70%–80% of all Ig-producing cells in the body are
located in the intestinal mucosa and most of these cells produce
IgA.
105,106
In contrast, neonates lack IgA immunocytes at birth
and the first sIgA may not appear in mucosal secretions until
sometime between postnatal week 2 and 8.
107
This deficiency
can be partially offset in breastfed infants by sIgA present in
colostrum/milk;
108
breastfed infants receive about 0.5–1.0 g/
day of antibodies in milk throughout lactation, which is
comparable with the 2.5 g daily production of antibodies by a
65 kg adult, and a source of passive immunity against antigens
“seen” by the mother-infant dyad.
109
In formula-fed premature
infants, the absence of milk-borne sIgA is a significant
immunological disadvantage and a likely contributor to the
increased risk of NEC.
46
Compared with term infants, premature neonates have
increased gut mucosal permeability, and this permeability
is even greater in infants who subsequently develop NEC.
110
Studies on human tissue samples and in rodent models show
that the intestinal epithelium is breached early during NEC
through apoptosis or necrosis.
63
In this process, excessive
nitric oxide production, either directly or through its
reactive nitrogen derivative, peroxynitrite, may accentuate
epithelial injury through membrane oxidation, induction
of apoptosis, and direct mitochondrial damage.
111–113
In
preterm infants, a deficiency in the mucus layer may promote
bacterial adherence and increase gut mucosal permeability,
predisposing to mucosal injury.
114
The developmental
deficiency of epithelial trophic factors, such as the epidermal
growth factor and heparin-binding epidermal growth factor-
like growth factor, may further increase the risk of injury to
the epithelial barrier.
115–117
Do red blood cell transfusions predispose to NEC? In
convalescing preterm infants, red blood cell transfusions have
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Neonatal necrotizing enterocolitis
been temporally associated with NEC.
118,119
Red blood cell
transfusions can dampen the normal postprandial increase in
mesenteric blood flow in premature infants, particularly in those
with a birth weight ,1250 g.
120
Immaturity of vascular auto-
regulation in extremely preterm infants is linked to defects in
endothelial nitric oxide synthesis
68
and could plausibly explain
a higher risk of mucosal injury following transfusions.
Pathology
The disease is commonly localized to the ileocolic region,
although the colon may be frequently involved in term
infants.
121
Some infants with severe, aggressive disease may
develop total gut necrosis (NEC totalis). The four major histo-
pathological findings in NEC are coagulative necrosis, bacte-
rial overgrowth, pneumatosis intestinalis, and inflammation.
Clinical features
The presenting signs of NEC are protean and may be insidious
in onset or sudden and catastrophic. NEC typically presents
at 2–4 weeks after birth, although the onset may be as late
as 3 months in some infants.
16,72,122
The age of onset of NEC
correlates inversely with gestational age at birth in a nonlinear
(log-normal) relationship, where infants born at ,28 weeks’
gestation tend to develop NEC at a disproportionately greater
postnatal age than their more mature counterparts.
123,124
NEC often presents with nonspecific systemic signs, such
as tachycardia, apnea, lethargy, and temperature instability.
Gastrointestinal signs may include increased prefeed residuals
or delayed gastric emptying, emesis, abdominal distention,
tenderness, and/or ileus with hypoactive bowel sounds. Grossly
bloody stools are seen in approximately 25% of infants.
Clinical progression of NEC is commonly staged using the
modified Bell’s criteria (Table 1).
125
Characteristically, NEC
follows an initial early stage of systemic inflammatory
response, followed by a definite stage of localized peritonitis,
and finally, an advanced stage of generalized peritonitis.
In a recent study, Clark et al
126
described the clinical
characteristics of infants who died of NEC. Compared with
5594 infants who recovered from NEC and were discharged
home, there were 1505 infants diagnosed with NEC who
died. In multivariate analysis, lower gestational age, lower
birth weight, treatment with assisted ventilation on the day
of diagnosis of NEC, treatment with vasopressors at the
time of diagnosis, and African-American ethnicity were
associated with mortality. In another study,
58
fulminant
NEC, characterized by massive bowel necrosis and rapid
progression to death within 48 hours, was recorded in
7%–10% of all cases and was associated with lower birth
weight (1088 ± 545 g versus 1652 ± 817 g), earlier gestational
age (27.5 ± 3.3 weeks versus 31.1 ± 4.4 weeks), radiographic
evidence of portal venous air, hematocrit ,22%, a history
of advancement in feeding volume .20 mL/kg/day, an
immature to total neutrophil ratio .0.5, blood lymphocyte
count ,4000/µL, and a history of increased concentration of
Table 1 Modied Bell’s staging criteria for necrotizing enterocolitis
125
Stage Classication System signs Intestinal signs Radiological signs
IA Suspected NEC Temperature instability, apnoea,
bradycardia, lethargy
Increased pregavage residuals,
mild abdominal distention,
emesis, guaiac-positive stool
Normal or intestinal
dilation, mild ileus
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
sounds, with or without
abdominal tenderness
Intestinal dilation, ileus,
pneumatosis intestinalis
IIB Proven NEC – moderately ill Same as above, plus mild
metabolic acidosis and mild
thrombocytopenia
Same as above, plus absent bowel
sounds, denite abdominal tenderness,
with or without abdominal cellulitis
or right lower quadrant mass
Same as IIA, plus
portal vein gas, with
or without ascites
IIIA Advanced NEC – severely ill,
bowel intact
Same as lllB, plus hypotension
bradycardia, severe apnoea,
combined respiratory and
metabolic acidosis, disseminated
intravascular coagulation,
and neutropenia
Same as above, plus signs of
generalized peritonitis, marked
tenderness, and distention of
abdomen
Same as IIB, plus
denite ascites
IIIB Advanced NEC – severely ill,
bowel perforated
Same as IIIA Same as IIIA Same as IIB, plus
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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Maheshwari et al
human milk fortifier within 48 hours before developing NEC.
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
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
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
NEC are nonspecific for gastrointestinal pathology and
may not provide sufficient time to the clinician for early
institution of treatment measures. In a recent retrospective
study, Christensen et al
137
reviewed the medical records of
118 infants with stage III NEC. The earliest recognized
antecedents of NEC were nonspecific, including apnea/
bradycardia, skin mottling, and irritability, which were first
noted at a mean of 2.8 ± 2.1, 4.5 ± 3.1, and 5.4 ± 3.7 hours,
respectively, prior to the diagnosis of NEC. The most
frequently identified gastrointestinal antecedents were
blood in the stools, increased abdominal girth, and elevated
prefeeding gastric residuals or emesis, identified 2.0 ± 1.9,
2.8 ± 3.1, and 4.9 ± 4.0 hours before NEC was recognized.
No consistent laboratory antecedents were discovered.
Radiographic features remain the mainstay of definitive
diagnosis. The pathognomonic sign for NEC is pneumatosis
intestinalis (Figure 2).
138
These radiolucent shadows have a
bubbly appearance when air is submucosal and become linear
when subserosal. Portal venous gas has been associated with
a poor prognosis, although this association has recently been
questioned.
139
Sonographic appearance of portal air is an early
sign. In a prospective cohort study, sonographic portal air
had a specificity of 86% for advanced NEC ($stage II), and
the sensitivity was lower at 45%.
140
It is not known if portal
venous gas visualized by ultrasound or on plain radiographs
has the same prognostic significance. Sonographic detection
of echoic free fluid and bowel wall thinning may also be more
sensitive for intestinal perforation than plain radiography.
141
Serial radiographs are invaluable in following the progression
of NEC, particularly in the first 48 hours after onset of disease.
Although intestinal perforation may occur within a few hours
to as late as 8 days following the onset of NEC,
142
more than
two-thirds of all perforations occur within 30–48 hours.
143
In some infants who present with bloody stools but minimal
systemic signs, pneumatosis may be limited to the colon and
may indicate a relatively benign course.
144
Most patients with NEC develop leukocytosis and
neutrophilia, although neutropenia can occur in advanced
disease due to the migration of neutrophils into the peritoneal
cavity.
145
Blood cultures may grow organisms typically
associated with late-onset sepsis. Thrombocytopenia may
occur in stage II and III, and patients with advanced NEC
may have evidence of disseminated intravascular coagulation.
Breath hydrogen testing was initially heralded as a diagnostic
tool, but subsequent studies have shown it as lacking
discriminant value.
146
The differential diagnosis of NEC includes infections
(systemic or intestinal), gastrointestinal obstruction, volvulus,
and isolated intestinal perforation. Idiopathic focal intestinal
perforations can occur spontaneously or in association with
deficiency of the muscularis propria,
147
early use of postnatal
corticosteroids alone
148
or with indomethacin,
149
and with
occult candidal infections.
150
Pneumoperitoneum develops
in such patients, but they are usually less ill than those with
NEC. Some experts believe that isolated perforations may
not be related to NEC.
AB
CD
Figure 2 Abdominal radiographs with characteristic ndings of necrotizing
enterocolitis. (A) Diffuse pneumatosis intestinalis with a linear distribution in the
left upper and middle quadrants. (B) Characteristic arborization pattern of portal
venous gas. (C) Free peritoneal gas with the falciform ligament visible (arrow).
(D) Free peritoneal gas seen in a left lateral decubitus view.
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Neonatal necrotizing enterocolitis
Treatment
Medical management
Rapid initiation of therapy is necessary for suspected as well
as proven cases of NEC. There is no definitive treatment
for established NEC, and therefore treatment is directed at
supportive care and prevention of further injury with cessation
of feeding, nasogastric decompression, and administration of
intravenous fluids (see Table 2). Infants are usually made nil
per os for a variable period of time, depending on the severity
of disease. Parenteral antibiotics are widely used for the
Table 2 Treatment and prevention of necrotizing enterocolitis
Therapeutic intervention Current status Evidence level Recommendation level
Treatment
Gastric/Intestinal
decompression and bowel rest
Provide supportive care and prevent further injury with cessation
of feeding, nasogastric decompression, and administration of
intravenous uids. Infants stay nil per os for 3–5 days in stage I,
and 10–14 days in stages II and III.
III B
Parenteral antibiotics Broad spectrum antibiotics should be administered based on
local antibiotic sensitivity patterns. Anaerobic coverage should
be considered in infants with stage III NEC.
II-3 C
Primary peritoneal drainage
versus exploratory laparotomy
Choices for surgical management in infants with NEC include
peritoneal drain placement and exploratory laparotomy.
In unstable premature infants with perforated NEC, peritoneal
drainage can be cautiously considered as an alternative to
exploratory laparotomy, although the best surgical approach
in these infants remains unresolved.
I C
Prevention
Antenatal corticosteroids Small benecial effect of antenatal steroids for reducing risk of NEC. I A
Minimal enteral (trophic)
feedings
Infants receiving trophic feedings take less time to tolerate full
enteral feeds and have a shorter duration of hospital stay,
without an effect on the incidence of necrotizing enterocolitis.
I C
Slow advancement of feedings No evidence to suggest that slow advancement of enteral feed
volumes reduces the risk of NEC in very low birth weight infants.
I D
Breast milk Although the mechanism of protection is not completely
understood, there is strong evidence favoring the use of human
milk to reduce the risk of NEC in premature infants.
II-2 A
Oral immunoglobulins Data from available trials do not support oral administration of
immunoglobulin for the prevention of NEC.
I D
Enteral antibiotics Enteral antibiotic treatment leads to a small reduction in
NEC risk; however, increase in antimicrobial-resistant intestinal
microbiota precludes routine use of this therapy.
I D
Amino acid supplementation Data are insufcient at present to support supplemental
administration of parenteral L-arginine or glutamine to reduce
the risk of NEC.
I C
Recombinant cytokines and
growth factors
Epidermal growth factor is a promising agent in preclinical studies.
In early clinical studies, enteral administration of a synthetic
amniotic uid-like solution containing erythropoietin and
granulocyte-colony stimulating factor has shown an encouraging
safety and efcacy prole.
III I
Probiotics Probiotics may reduce the risk of severe NEC and related
mortality; however, important questions remain regarding
optimal choice of agent(s) and dose.
I C
Prebiotics Recent nonhuman animal experimental data suggest that
oligofructose prebiotics may be useful in protecting against
experimental NEC.
NA* NA*
Notes: *Insufcient 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 scientic evidence suggests that the benets substantially outweigh the potential risks; B, at least fair
scientic evidence suggests that the benets outweigh the potential risks; C, at least fair scientic evidence suggests that there are benets provided, but the balance between
benets and risks are too close for making general recommendations; D, at least fair scientic evidence suggests that the risks outweigh potential benets; I, scientic evidence
is lacking, of poor quality, or conicting, such that the risk–benet balance cannot be assessed.
Abbreviation: NEC, necrotizing enterocolitis.
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treatment of NEC, but there is surprisingly sparse evidence
guiding the choice of antimicrobial agent and duration of
therapy. One study comparing alternative treatment regimens
that included 90 infants with definite NEC, treated 46 cases
with ampicillin and gentamicin, while 44 cases received
cefotaxime and vancomycin. Infants $2200 g birthweight
had similar outcomes with either regimen. Smaller infants
given cefotaxime and vancomycin had a lower risk of
culture-positive peritonitis (P = 0.01), and were less likely
to die (P = 0.048) or develop thrombocytopenia (P = 0.004).
These data suggest that carefully chosen antibiotic regimens
can improve the outcome of NEC.
151
Antibiotic coverage
for anaerobes should be considered for infants with stage
III NEC.
Surgical management
Approximately 20%–40% of patients with pneumatosis
intestinalis will require surgical management. Indications
for surgery include evidence of perforation seen on
abdominal radiographs or positive abdominal paracentesis
(stool or organism on Gram stain from peritoneal fluid).
Failure of medical management, a single fixed bowel loop
on radiographs, abdominal wall erythema, or a palpable
mass are all relative indications for surgery. In rare cases,
the entire intestine can be involved, precluding surgical
intervention. Ideally, surgery should be performed after the
development of bowel necrosis, but before perforation and
peritonitis occurs.
In unstable premature infants with perforated NEC,
peritoneal drainage can be cautiously considered as an
alternative to exploratory laparotomy, although the best
surgical approach in these infants remains unresolved. In
the NECSTEPS trial,
152
there was no statistically significant
difference in 90-day survival, dependence on parenteral
nutrition, or length of hospital stay in 117 very low birth
weight infants randomly assigned to peritoneal drainage or
laparotomy. However, other studies have raised important
concerns about the routine use of peritoneal drainage. In
the NET trial,
153
69 extremely low birth weight patients
were randomized to peritoneal drainage or laparotomy,
and no significant differences were noted in survival,
length of hospital stay, ventilator dependence, or need
for parenteral nutrition. However, peritoneal drainage
was effective as a definitive treatment in only 4/35 (11%)
surviving neonates, and the rest either required a delayed
laparotomy (26/34, 74%) or died. In a recent meta-analysis,
Rao et al
154
reviewed data from the NET and NECSTEPS
trials and detected no significant differences in mortality
within 28 days of peritoneal drainage or laparotomy
(28/90 versus 30/95; typical RR 0.99, 95% CI 0.64–1.52;
n = 185), mortality by 90 days after the primary procedure
(typical RR 1.05, 95% CI 0.71–1.55; n = 185) and the
number of infants needing total parenteral nutrition for
more than 90 days (typical RR 1.18, 95% CI 0.72–1.95;
n = 116). Nearly 50% of infants in the peritoneal drainage
group could avoid the need for laparotomy during the
study period (44/90 versus 95/96; typical RR 0.49, 95%
CI 0.39–0.61; n = 186). One study found that the time to
attain full enteral feeds in infants #1000 g was prolonged
in the peritoneal drainage group (mean difference 20.77,
95% CI 3.62–37.92).
Although the immediate outcome following peritoneal
drainage or laparotomy appears to be similar, there are
concerns about the risk of neurodevelopmental impairment
following peritoneal drainage. In a recent multicenter trial,
peritoneal drainage was associated with increased risk
of death or neurodevelopmental impairment.
155
A meta-
analysis of three prospective observational studies and two
randomized controlled trials suggested a significant excess
mortality of 55% associated with peritoneal drainage.
156
There is a need for better identification of patients who are
less likely to tolerate laparotomy and who may benefit from
peritoneal drainage as a temporizing strategy.
Prevention
The existing evidence shows a small beneficial effect of
antenatal steroids in reducing the risk of NEC (see Table 2).
157
This may be accomplished by accelerating maturation of the
gut epithelial barrier and by reducing the overall severity
of illness via prevention of lung disease. When analyzed
together, eight randomized controlled comparisons of ante-
natal corticosteroid administration with placebo or with no
treatment, including 1675 infants, showed a risk reduction
in NEC of 0.46 (95% CI 0.29–0.74).
157
Multiple courses of
antenatal steroids do not appear to reduce the risk of NEC
further. In a randomized trial of one to four weekly treat-
ments of antenatal steroids or placebo that included 1858
pregnant women, and the outcomes of 2304 infants, the rate
of NEC, ie, 1%, was similar in both groups.
158
Minimal enteral (trophic) feedings
Initiating feeds by using small amounts of milk or formula
may promote the maturation of peristaltic activity and
enzymatic systems, release of digestive hormones, and
augment intestinal blood flow.
3,43,159–162
However, in a
meta-analysis of nine randomized trials including 754
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47
Neonatal necrotizing enterocolitis
very low birth weight infants,
163
early trophic feedings did
not affect feed tolerance, growth rates, or the risk of NEC
(RR 1.07, 95% CI 0.67–1.70; risk difference 0.01, 95%
CI -0.04–0.05).
Slow advancement of feedings
Meta-analyses of three randomized controlled trials in which
a total of 396 infants were included found no significant
effects of feeding advancement on the risk of NEC (RR 0.96,
95% CI 0.48–1.92) or all-cause mortality (RR 1.40, 95%
CI 0.71–2.80).
45
Infants who had slow rates of feed volume
advancement took longer to regain birth weight (median
difference 2–5 days) and to establish full enteral feeding
(median difference 3–5 days). No statistically significant
effect on total duration of hospital stay was detected. The
currently available data do not provide evidence that slow
advancement of enteral feed volumes reduces the risk of
NEC in very low birth weight infants. Of note, few partici-
pants were extremely low birth weight or growth restricted,
so conclusions about infants at greatest risk for NEC cannot
be drawn from the available data.
Breast milk
Experimental and clinical studies show a protective effect
of human milk feeds against NEC when compared with
formula.
39–44,48,164,165
The protective effects of breast milk
against NEC are retained even in pasteurized, banked
donor milk. In meta-analysis of data from five randomized
trials,
46
formula-fed infants were at higher risk of NEC than
infants who received donor milk (RR 2.5, 95% CI 1.2–5.1;
risk difference 0.03, 95% CI 0.01–0.06; number needed to
harm 33, 95% CI 17–100). More recently, Sullivan et al
166
showed that an exclusively human milk-based diet protected
extremely premature infants against NEC and surgical
NEC when compared with a mother’s milk-based diet that
included bovine milk-derived human milk fortifier and
preterm formula.
Oral immunoglobulins
Three trials, including a total of 2095 neonates, were reviewed
together. Oral administration of IgG or an IgG/IgA combina-
tion did not result in a significant reduction in incidence of
definite NEC (RR 0.84, 95% CI 0.57–1.25), suspected NEC
(RR 0.84, 95% CI 0.49–1.46), need for surgery (RR 0.21,
95% CI 0.02–1.75), or death from NEC (RR 1.10, 95% CI
0.47–2.59).
49
Based on the available trials, the evidence does
not support the administration of oral immunoglobulin for
the prevention of NEC.
Enteral antibiotics
To determine the effect of enteral antibiotic prophylaxis and
subsequent development of NEC, five randomized controlled
trials involving 456 infants were compared. Enteral antibiotic
administration resulted in a significant risk reduction for NEC
(RR 0.47, CI 0.28–0.78; risk difference -0.10, 0.16 to -0.04);
number needed to treat 10 [6–25]). There was a statisti-
cally significant reduction in NEC-related deaths (RR 0.32,
0.10–0.96; risk difference -0.07, CI -0.13–0.01) and number
needed to treat of 14 (8–100). However, concerns about the
development of resistant bacteria remain, and meta-analysis
revealed a borderline increase in antimicrobial-resistant intes-
tinal microbiota with enteral antibiotic treatment.
88
Amino acid supplementation
Nitric oxide augments gastrointestinal perfusion, barrier
function, and mucosal repair.
167
The supplementation of
L-arginine, a major substrate for nitric oxide production,
appears promising in small cohorts in reducing NEC but
the data are insufficient at present to support a practice
recommendation.
168–170
Similarly, glutamine promotes gut
epithelial proliferation and barrier function in animal stud-
ies, but a larger multicenter trial of parenteral glutamine
supplementation did not show a beneficial effect in reducing
the incidence of NEC in preterm infants.
171
Probiotics
Probiotics are living microorganisms which, when ingested,
can exert a health benefit beyond basic nutrition. Probiotics
improve intestinal defense mechanisms, including mucosal
IgA secretion, intestinal epithelial cell proliferation, and
barrier function, decrease inflammation and epithelial cell
apoptosis,
172
and may be useful in preventing NEC.
173,174
Alfaleh et al
175
analyzed 16 eligible trials including
2842 infants.
174,176–190
Included trials were highly variable with
regard to enrollment criteria such as birth weight and gesta-
tional age, baseline risk of NEC in the control groups, timing,
dose, formulation of the probiotics, and feeding regimens.
Enteral probiotics significantly reduced the incidence of
severe NEC (stage II or more, typical RR 0.35, 95% CI 0.24–
0.52) and mortality (typical RR 0.40, 95% CI 0.27–0.60).
Deshpande et al
191
selected 11 of these trials
174,178–181,184–189
involving 2176 neonates and reported a similar reduction
in NEC. The frequency of NEC decreased from 6.56% (71
of 1082) in the control group to 2.37% (26 of 1094) in the
probiotics-treated group. Meta-analysis using a fixed-effects
model showed reduction in risk of NEC in the probiotics-
treated group (RR 0.35, 95% CI 0.23–0.55; P , 0.00001).
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Only four of these trials reported a significantly higher risk
for NEC in the control group.
174,179,180,189
The number needed
to treat with probiotics to prevent one case of NEC was 25
(95% CI 17–34). Current evidence indicates that enteral
supplementation with probiotics can prevent severe NEC
and decrease all-cause mortality in preterm infants. However,
further study is needed before routine supplementation using
infant formulas with probiotics and also to determine the
safety and efficacy of probiotic formulations in extremely
low birth weight infants.
175,192
Prebiotics
Prebiotics are nondigestible dietary supplements (usually
carbohydrates or mucins) which promote proliferation
of beneficial commensal bacteria like Lactobacillus and
Bifidobacterium. Recent experimental data suggest that
oligofructose prebiotics may be protective against NEC.
193–196
Recombinant cytokines
Epidermal growth factor, an important component of gut
secretions, human milk, and amniotic fluid, promotes
epithelial proliferation, migration, and mucosal repair
following injury.
197
Oral administration of recombinant
epidermal growth factor protects experimental animals against
NEC-like lesions.
198
Other studies have similarly evaluated the
role of hematopoietic growth factors, such as erythropoietin
and granulocyte-colony stimulating factor. We have recently
shown that transforming growth factor-β
2
may protect mouse
pups against NEC-like injury.
66
These cytokines are present in
amniotic fluid and human milk, are swallowed by the fetus in
large amounts,
199,200
and have a demonstrated an in vitro and
in vivo protective effect on gut mucosa.
201–206
Lactoferrin
As an addition to antibiotics, lactoferrin has been considered
by some to enhance the response of the immune system
when faced with sepsis. Although immune enhancement
may play a role in the treatment of NEC, current data do
not support the use of lactoferrin as a single agent at this
time. Manzoni et al
182
randomized 472 very low birth weight
infants to receive either lactoferrin alone or in combination
with Lactobacillus rhamnosus GG. Prophylaxis with oral
lactoferrin alone did not reduce the incidence of NEC
(RR 0.33, 95% CI 0.09–1.17; risk difference -0.04, 95%
CI -0.0–0.00), but a significant reduction in NEC was noted
when lactoferrin was combined with L. rhamnosus GG (RR
0.05, 95% CI 0.0–0.90; risk difference -0.06, 95% CI -0.10
to -0.02; number needed to treat 17, 95% CI 10–50).
Prognosis
Mortality rates range between 20% and 50%. Approximately
27%–63% of affected infants may require surgery,
1,16
and as many as 50% infants may die in the postoperative
period.
1,15,17
Subacute complications include strictures,
dysmotility, malabsorption, and short gut syndrome.
15
Severe NEC has been associated with growth delay
that can persist beyond infancy into childhood and poor
neurodevelopmental outcome at a corrected gestational age
of 18–22 months.
207
Summary
Despite advances in the diagnosis and management of many
neonatal diseases, NEC remains a devastating condition
for many infants. While it is established that very low
birth weight infants are at greatest risk for development of
NEC, human milk-feeding appears to be the single most
effective strategy to reduce, but not eliminate, this disease.
Current medical management of NEC is largely supportive
and likely does not modify the etiopathogenesis of the
disease. Controversies remain regarding optimal surgical
management for this condition. Although there are important
gaps in our understanding of NEC, future research should
focus on prevention of the disease and early recognition that
occurs well before the onset of intestinal necrosis.
Acknowledgment
AM is supported by a National Institutes of Health award.
Disclosure
The authors report no conflicts of interest in this work.
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