|Necrotizing enterocolitis (NEC) is the most
common gastrointestinal emergency in newborn
infants. Despite improvement in other areas of
neonatal care, there have been no significant
advances in the prevention, incidence, or
mortality from NEC over the last several
decades. In fact, incidence of death from NEC
has actually increased, since advances in preand
postnatal care have resulted in a survival
of a greater number of very-low birth weight
Necrotizing enterocolitis remains a leading
cause of mortality, ranging from 10-50% and
nearly 100% in patients with the most severe
of the disease (pan-necrosis). Long-term
morbidity is also high, e.g. intestinal adhesions,
strictures and short gut syndrome, and poorer
neurodevelopmental outcome arising from a combination of factors including NEC-associated
infection, inflammation, delayed nutrition, and
commonly, complicating hypoperfusion.
Incidence is 0.9-2.4 infants per 1000 births,
with 1-5% of admissions to neonatal intensive
care units (NICUs). The disease involves mostly
premature infants, and is uncommon in term
infants (only 10% of the cases). Five to 15
percent of infants with a birth weight less
than 1500 g at birth develop NEC. Incidence
increases with decreasing gestational age,
and risk for NEC remains high until the
postconceptual age of 35-36 weeks.
A change in feeding tolerance with gastric
retention is a frequent early sign. Vomiting,
feeding intolerance, abdominal distension and periumbilical and flank erythema on the
abdominal wall, blood in the stools, lethargy,
apnea, and temperature instability; and in
severe cases, progressive systemic shock with
metabolic acidosis, oliguria, hypotension and
disseminated intravascular coagulation (DIC)
When NEC is suspected, serial abdominal
X-ray films are recommended to check for
the presence of pneumatosis intestinalis and
pneumoperitoneum and for assessing disease
progression. Occult blood in stool and sepsis
are evaluated in suspected cases. The presence
of abdominal distention, blood in stool, and
pneumatosis intestinals confirm the clinical
diagnosis of NEC. However, presence of occult
blood is not specific for NEC. At least one
positive occult blood is found in 58% of infants
<1800 g over a six-week period.
Pneumatosis intestinalis (gas bubbles within
the bowel walls) is thought to be produced
by bacterial fermentation of substrates and
diagnostic of NEC (present in 85% of cases).
In severe cases, portal air can be seen and is
associated with severe bowel necrosis in about
40% of the cases. However, radiological signs
may vary with gestational age; pneumatosis
intestinalis is present in 100% of full-term
infants and in 29% of infants whose gestational
ages are ≤26 weeks, while portal venous gas
is present in 47% and 10%, respectively.
Pneumoperitoneum is present in severe cases.
"Football sign" for free gas in the peritoneal
cavity is a large hypolucent area in the central
abdomen with markings from the falciparum
ligament. Pneumatosis coli (pneumatosis in the
colon without small intestinal involvement) is a
benign form of NEC. Sonographic findings are
also useful in predicting outcome and therefore
might help guide management.
The severity of the disease was categorized in
stages by Bell et al. in 1978, later modified
by Walsh and Kliegman in 1986. Briefly,
abdominal distention in stage I (mild),
pneumatosis intestinalis in stage II (moderate),
and pneumoperitoneum in stage III (severe)
are the diagnostic parameters. In 25% of cases,
NEC is suspected but not confirmed (stage I).
The symptoms resolve gradually in these
infants. In 25-40% of cases, the progression
of NEC is fulminant with sepsis, DIC, and
shock (stage III).
Predominant pathological lesion is coagulative
or ischemic necrosis and most commonly
involves the ileocecal region (insufficient blood
supply?). In about half of the cases, the necrosis
involves both the small and large intestines,
either continuous or segmental. In severe cases,
gas bubbles, which may be grossly visible in
the intestinal wall, involve the entire colon
more commonly in the term infant than in
Risk factors associated with NEC have been
suggested as small prematurity (infectious,
pathogenic bacteria/viral colonization of
lumen, sepsis), oxygen delivery - consumption
imbalance (perinatal hypoxia and ischemia,
congenital heart disease, anemia, abnormal
hemoglobins, polycythemia), and iatrogenic
(umbilical arterial or venous catheterization;
drugs - indomethacin, methylxanthines, H2
blockers; feeding regimens - advancing too fast,
high osmolality; feeding additives - calcium,
vitamin E; and formula feeding).
Pathogenesis of NEC is poorly understood. It
may be a multifactorial disorder: prematurity,
enteral feeding and uncontrolled inflammation
in the bowel are three important factors for
development of NEC.
Prematurity and ischemia-reperfusion injury
Highest incidence occurs during the first few
days of postnatal life in term babies, at the
end of the first week of life for neonates
greater than 33 weeks gestational age, during
the first two-and-a-half weeks in neonates
28-32 weeks and after more than four weeks
in neonates below 28 weeks gestational age.
In recent years, "late-onset" or "new" NEC is
proposed to define late-onset NEC developed
in VLBW infants.
Late-onset cases often affect "stable" growing
neonates who are often breathing without
assistance and are tolerating full enteral feeding
volumes, and who at diagnosis are completely
without any of the traditional risk factors other
than a history of extreme prematurity. These
cases probably arise from abnormal combination
of developmentally immature digestive tract
(reduced gastric acidity, reduced intestinal
peristalsis, thinner goblet cell secretions,
looser tight junctions between enterocytes, lesser amounts of secreted antimicrobial
factors such as lactoferrin, secretory IgA,
defensin, intestinal trefoil factor and lysozyme,
and fewer and less active Paneth cells),
pathogenic gut colonization, and dysregulation
of the gut-associated lymphoid system, causing
exaggerated and aberrant local and/or systemic
In older infants, any intestinal cellular
destruction may lead to diarrhea, followed
by epithelial regeneration from proliferating
intestinal crypt cells. However, in high-risk or
premature neonates whose regenerative capacity
may be compromised, epithelial cell necrosis
may not be counterbalanced by sufficient cellular
regeneration, and as a result, systemic bacterial
invasion or intestinal perforation may ensue.
Bowel ischemia is a suspected contributing
factor in NEC. Perinatal asphyxia, presence of
umbilical lines, polycythemia, hypotension, and
congenital heart disease such as hypoplastic left
heart and truncus arteriosus are risk factors
for developing intestinal ischemia. However,
epidemiologic studies have failed to confirm an
association between NEC and most of these
risk factors. Whether the implicated role of
ischemia is the cause or the end result of NEC
remains unknown, but according to the results
of an in vitro study with submucosal arterioles
harvested from human intestine for NEC, it is
unlikely that vascular events are the primary
or initiating factors in NEC pathogenesis.
Ischemia-reperfusion injury following perinatal
asphyxia and the prolonged state of low
flow perfusion in growth-retarded fetuses are
important risk factors to be proven.
Feeding and abnormal intestinal bacterial flora
Although the fetus ingests as much as 500 ml
daily by term, NEC does not occur in utero.
Ninety percent of cases occur after infants
have been fed. Human milk reduces the
incidence but does not prevent it entirely.
Infants often develop symptoms following
recent volume advancement or after reinitiating
feeds. Osmolality in damaging the intestine
have failed to support this. However, enteral
feeding, especially formula feeding, may cause
abnormal intestinal bacterial flora.
Healthy breast-milk fed neonates are colonized
with normal bacterial flora with a predominance
of the probiotic Bifidobacteria and Lactobacilli, whereas coliforms, enterococci and bacteroides
predominate in formula-fed infants. Intestinal
microbiota of the premature infant differs
greatly from that of the term infant due
to decreased contact with maternal flora
and increased exposure to broad-spectrum
antibiotics and nosocomial pathogens. Broad
spectrum antibiotics and delayed initiation
of enteral feeds contribute to abnormal
colonization. Intestinal bacterial colonization
of babies with NEC is abnormal.
Necrotizing enterocolitis usually does not occur
before bacterial colonization of the intestine.
The endemic cases of NEC are not consistently
associated with a single infectious agent.
Gram-negative bacteria are the most common,
followed by Gram-positive bacteria (Escherichia
coli, Klebsiella, Enterobacter, Pseudomonas,
Salmonella, Clostridium perfringens, Clostridium
difficile, Clostridium butyricum, coagulase-negative
staphylococci), but yeast and even viruses
(coronavirus, rotavirus, and enteroviruses) have
been implicated. Cases of NEC are usually
sporadic, but the many reports of clusters suggest
colonization with particularly virulent strains
may be important. Only 20-30% of infants will
have a positive blood culture, but bacteremia is
seen more often with advanced disease.
In the anaerobic environment of the colon,
bacteria rapidly ferment carbohydrates to
gases (hydrogen, carbon dioxide, and in some
cases, methane) and SCFAs (short chain fatty
acids - mainly acetic acid, propionic acid
and butyric acid). Pneumatosis intestinalis
most likely results from these gases. Bacterial
production of P-galactosidase, which reduces pH
by fermentation of lactose, has been suggested
to contribute to the development of intestinal
pneumatosis. However, the ability of colonizing
bacteria to ferment lactose is not correlated
with the production of NEC. Intraluminal
administration of lactic acid, the fermentation
product of lactic acid-producing probiotics, does
not induce intestinal mucosal injury.
In the premature infant who has a relative
lactase deficiency, lactose ingested in the form
of milk may be fermented into SCFAs and
subsequently absorbed. SCFA overproduction
may arise during periods of significant
carbohydrate malabsorption and/or bacterial
overgrowth. Overproduction or accumulation of SCFAs, but not lactic acid, in the proximal
colon and/or distal ileum may play a key role
in the pathogenesis of NEC.
Patients with NEC often have elevated
inflammatory mediators. Intestinal epithelial
cells produce many of the cytokines that are
implicated as mediators of intestinal inflammation
and injury. Intraepithelial lymphocytes are also
responsible for cytokine response. In the neonate,
the functions of intraepithelial lymphocytes may
be relatively depressed until "adequate" antigenic
exposure has occurred (minimum of two weeks
even in full-term babies). During that period,
especially in hypoxia or other perinatal insults,
dysregulated transfer of antigen (including
bacteria) across the intestinal epithelium may
occur, resulting in widespread activation of the
mucosal immune system.
Activated T cells can cause injury in the gut
by producing proinflammatory cytokines, by
direct epithelial damage, by stimulating local
release of inflammatory mediators that leads
to further tissue injury (enterocyte apoptosis)
and inhibition of tissue repair mechanisms
(enterocyte proliferation and migration), and by
recruiting additional blood-borne inflammatory
cells, which in turn become activated in the
inflammatory cytokine milieu. All these lead
to uncontrolled inflammatory response with
release of other mediators. The net effect is
further tissue destruction, intestinal perforation,
and sepsis. In small preterms, dysregulation of
the gut- associated lymphoid system, causing
exaggerated and aberrant local and/or systemic
immune response, may cause NEC.
Cytokine gene polymorphisms are characterized
by the overproduction of inflammatory mediators
or diminished expression of antiinflammatory
cytokines. Infants with NEC may have a "proinflammatory"
genotype, and polymorphism in
the cytokine gene may account for variation
of disease. Although mutant variants of
interleukin-4ra (IL-4ra) are less frequent in NEC,
no differences were found in tumor necrosis
factor (TNF), IL-1Β, IL-6, and IL-10 and TAP
(transferring antigen peptide) gene polymorphism
between NEC and controls[15-17]. However, further
studies with larger sample sizes are needed.
Platelet activating factor (PAF) is one of the
mediators most intensely studied. PAF is an
endogenous mediator of inflammation that is released during inflammatory states. It also
seems to be the endogenous mediator for
hypoxia-induced bowel injury. PAF is produced
by inflammatory cells, endothelial cells,
platelets and bacteria. The ileum is sensitive
to PAF, since the greatest receptor expression
is found in the ileum - the most common
site of involvement in NEC. Conversion by
PAF-acetylhydrolase renders it inactive; human
neonates have low or absent circulating PAFacetylhydrolase,
and human milk contains
significant quantities. Stool PAF levels in
infants with NEC are 3-4 times higher[18,19].
It is probably the most potent agent to
induce intestinal injury. Activation of the PAF
receptor induces the production of additional
molecules such as TNF-α, IL-6, and IL-8. PAF
activates pathways triggering apoptosis in
intestinal epithelial cells, increases gut mucosal
permeability, and may facilitate the entry of
bacterial products including lipopolysaccharides
(LPS) from the gut lumen into the tissues,
triggering the inflammatory cascade. PAF
also causes capillary leak, myocardial
dysfunction, renal dysfunction, neutropenia,
thrombocytopenia, and hypotension[18,19].
Toll-like receptors (TLRs) on the cell surface
act as sensors of microbial infection and play
a role in the initiation of the inflammatory and
immune defense response. LPS are a potent
"priming" agent for PAF secretion, and PAF
may be the endogenous mediator for LPSinduced
intestinal injury, since LPS-induced
intestinal injury is blocked by pretreatment
with PAF antagonists. Activation of TLRs does
result in cytokine activation and, potentially, a
considerable inflammatory response. Abnormal
TLR activation, perhaps via the influence of
PAF, in the developing neonate increases the
likelihood of developing NEC.
Tumor necrosis factor-α (TNF) has many
proinflammatory actions, such as inducing
leukocyte and endothelial adhesion molecules,
activating polymorphonuclear leukocytes
(PMNs) and endothelial cells, and causing
production of other cytokines, including TNF
itself, eicosanoids, and PAF. Both LPS and
PAF stimulate TNF gene expression. LPS
may induce TNF production via both PAFdependent
and -independent pathways. PAF
and LPS (partly mediated via PAF and TNF)
activate nuclear factor κB (NF-κB), a central transcription factor in the regulation of many
proinflammatory cytokines. Proinflammatory
cytokines cause PMN activation and tissue
inflammation. Neutrophils adhere to the
mesenteric endothelium, release further
inflammatory mediators, and cause further
intestinal inflammation and necrosis. The
complement system, especially C5, may also
participate in producing NEC.
The final step of intestinal injury is most likely
free oxygen radicals. These radicals can be released
by activated PMN, but the major source of free
oxygen radicals in the intestine is probably
the xanthine dehydrogenase/xanthine oxidase
complex (XD/XO). XD is the precursor of XO.
During ischemia/reperfusion, XD is converted
to XO. XO generates superoxide, which, in
the presence of iron, forms the potent tissue
damaging hydroxyl radicals. Pretreatment with
allopurinol, a XO inhibitor, largely prevents PAFinduced
bowel necrosis. Infusion of superoxide
dismutase plus catalase and antioxidant enzymes
also alleviates the injury.
Nitric oxide (NO) increases intestinal blood
flow. Inadequate NO leads to vasoconstriction
of the intestinal vessels, which may lead to
ischemia and a predisposition to NEC. It
also inhibits leukocyte adherence, modulates
the inflammatory responses in the intestine,
and acts as a neurotransmitter for enteric
non-adrenergic non-cholinergic neurons that
regulate peristalsis (lack or inadequacy of NO
can alter intestinal motility). It has been shown
that NO donors reduce PAF-induced bowel
injury. NO also protects against hypoxiainduced
Nitric oxide synthase (NOS) is essential in NO
synthesis. Degree of intestinal injury is inversely
related to the neuronal NOS (nNOS) activity,
and PAF rapidly decreases intestinal nNOS.
Tetrahydrobiopterin (BH4), a nNOS cofactor
essential for its action, protects rats from PAFinduced
intestinal ischemia and necrosis.
Local release of inflammatory mediators such
as interferon-γ and TNF by neighboring cells
leads to sustained upregulation of inducible
NOS (iNOS) and overproduction of NO, which
reacts with superoxide to produce peroxynitrite
radical (ONOO-). NO or ONOO- leads to
further tissue injury (enterocyte apoptosis)
and inhibition of tissue repair mechanisms
(enterocyte proliferation and migration).
In summary, trigger factors (i.e. perinatal
hypoxia, mild infection or formula feeding)
cause focal mild intestinal mucosal injury. In
the presence of proliferation of commensal
bacteria, local breakdown of mucosal barrier
may cause entry of bacterial products (e.g. LPS,
PAF?). Endothelial PAF and/or TNF and/
or direct stimulating effects of PMN cause
proinflammatory cascade and focal necrosis,
which increase the entry of large amounts of
bacterial LPS, and then severe NEC, sepsis,
and shock develop.
Therapies for the prevention of NEC that appear
to have some benefit are breastfeeding, antenatal
steroids, fluid restriction and enteral antibiotics.
Although enteral antibiotics have some
protective effect in prevention of progression
of NEC, they should not be used because of
the colonization of resistant bacteria.
Antenatal steroids have some protective effects
on fetal and neonatal intestine (e.g. increase
cardiovascular stability, decrease the incidence
of patent ductus arteriosus [PDA], have
anti-inflammatory effects, promote intestinal
maturation, increase the activity of PAFacetylhydrolase
that breaks PAF, and decrease
the activity of PAF-acetyltransferase, the key
enzyme in PAF biosynthesis).
Although it has been claimed in previous reports
that prenatal steroids reduce NEC in approximately
70%, a recent meta-analysis showed only a "nonsignificant"
trend of benefit.
Breast milk reduces the incidence of NEC 6-10
times compared to formula-feeding, although
it does not prevent it entirely. There are
no evidence-based feeding strategies for the
prevention of NEC or for optimal nutrition
during active and recovering NEC. Prospective
randomized controlled trials are needed to
evaluate safety and efficacy of age of initiation
of feeding (early versus delayed) and rates of
advancement (slow versus rapid) of feedings.
Most authors agree that 20 ml/kg/day is a safe
advancement rate. Many NICUs have a policy
of attempting "minimal enteral nutrition" or
"trophic feedings" to not increase the risk[29,30].
According to "experience-based practice¡", lateonset,
slow enteral feeding protocol may be
valuable in the prevention of NEC.
After the diagnosis of NEC, infants who
are re-fed sooner (median 4 days) reach full
enteral feedings sooner compared to infants
who are re-fed 10 days after diagnosis. In
cases with portal air, enteral feedings should
be initiated in infants when portal gas is
absent for three consecutive days on abdominal
Probiotics are living organisms, anaerobic
bacteria and yeast that promote maturation
of intestinal functions, reduce growth and
adherence of potentially pathogenic organisms,
stimulate the immune system to develop
a regulated immune response, and induce
dendritic cells to enhance the production of antiinflammatory
cytokines and secretory IgA.
A meta-analysis of seven randomized placebocontrolled
trials in VLBW infants to evaluate
probiotics in the prevention of NEC showed
that probiotics reduce the risk of NEC, shorten
the time (mean -2.7 days) to full feeding,
and reduce overall mortality without changing
the mortality due to NEC and sepsis. The
inconsistency of all measured outcomes may
raise concerns regarding the stage of NEC
and different probiotics. Although no side
effects are reported, Lactobacillus GG sepsis
and fungemia due to Saccharomyces boulardii
in premature infants have been reported.
Trials with heat-killed probiotics may solve
the problem in the near future.
Therapies for the prevention of NEC that
do not appear to be of benefit are enteral
immunoglobulin and polyunsaturated fatty
acids. There are also some reported novel
therapies as summarized below.
Local NO affects the intestinal blood flow
and potentially predisposes to NEC. Adequate
NO concentration may be achieved by
supplementing substrates such as arginine
for its precursor. The intestine is an important
source of arginine, and enteral glutamine is
catabolized by the small intestine and serves
as a major precursor for intestinal synthesis
of arginine. Arginine synthesis is low in preterm infants. Lower plasma arginine
levels were reported in NEC[41,42]. Although
prophylactic arginine (15 mmol/kg per day)
reduces NEC, multicenter trials are required
before arginine supplementation. However,
NO may also play a role in the generation of
peroxynitrites, and it has been reported that
arginine supplementation increases mortality
in sepsis in adults.
Nitric oxide production is regulated by the
DDAH/ADMA/NOS pathway. Normally,
ADMA (asymmetric dimethylarginine) is a NOS
inhibitor and decreases NO production and is
itself catabolized with DDAH (dimethylarginine
dimethyl aminohydrolase). Sepsis causes
increased ADMA levels in adults. However,
reduced ADMA levels and arginine: ADMA
ratios in NEC may cause increase in NO.
Therefore, overall nutrition covering arginine
and ADMA is important in the prevention of
catabolism-induced production of ADMA.
Glutamine is the most abundant amino acid
in the body and is a non-essential amino acid,
but during times of stress (e.g. sepsis), the
body may not be able to produce adequate
quantities of glutamine to meet increased
demands. Glutamine is approved by the Food
and Drug Administration (FDA) as a protein
supplement and is available in health food
stores. It is mainly used by body builders for
anabolic purposes. Glutamine is the principal
metabolic fuel for the small intestine and major
precursor for intestinal synthesis of arginine. It
stimulates crypt cell proliferation (a mitogenic
signal), increases the effects of growth factors
(i.e. epidermal, insulin-like, transforming -
EGF, IGF-1, TGF), and stimulates intestinal
salt and water absorption. Glutamine also has
some immunological functions: as nutrient
for immune cells, in improving gut barrier
function, as precursor of glutathione, which
plays a role in reducing oxidative stress by
scavenging free radicals, and as inhibitor of
the inflammatory response by preventing action
of NF-kB. Glutamine deprivation induces
apoptosis in intestinal cells. Although low
glutamine levels have been reported before
NEC, neither enteral (max. 0.3 g/kg/day) nor
parenteral glutamine supplementation makes a
difference in the rate of systemic infection or
of NEC in VLBW infants[53,54].
Many growth factors, including EGF, IGF-1,
TGF-α, erythropoietin, and granulocyte colonystimulating
factor (G-CSF), are present in
relatively high concentrations in the liquids
swallowed by the fetus and neonate, namely,
amniotic fluid, colostrum, and human milk, and
are relatively protected from digestion. Enterally
administered growth factors to neonates are not
absorbed. The receptors for growth factors are
also expressed on enterocytes of the fetus and
neonate, and induce growth and development
of the gastrointestinal tract.
The majority of epidermal growth factor (EGF) is
produced in the submaxillary salivary glands,
and lesser amounts in Brunner glands of the
duodenum and in the exocrine pancreas, and
it plays an important role in the function of
intestinal epithelial barrier function (i.e. matures
the intestinal mucosal barrier) by enhancing the
migration and proliferation of enterocytes in
response to mucosal injury; it also decreases
intestinal apoptosis and down-regulates the
proinflammatory response. EGF, which is the
major trophic factor for the developing intestine,
is found in many endogenous fluids bathing
the developing intestine (amniotic fluid, fetal
urine, breast milk, bile, saliva). In amniotic
fluid, the EGF levels increase as gestation
progresses55. Urinary EGF levels increase as
gestation progresses. In rabbits and Rhesus
monkeys, in utero EGF infusion accelerates the
maturation of intestinal enzymes and stimulates
intestinal growth. EGF-receptor knockout mice
die in utero or early in the neonatal period with
a hemorrhagic enteritis that is similar to human
NEC. Single nucleotide polymorphisms in the
human EGF gene may account for variation of
Human milk feeding is the only currently
accepted modality for NEC prevention. This
finding may be related to the presence of
EGF in human milk. Saliva also contains
EGF, which increases with gestational age
as well as with postnatal days, and small for
gestational age (SGA) infants and formula-fed
infants have lower salivary EGF levels. Infants
who developed NEC have lower salivary and
serum EGF levels in the first week, with a
greater increase in subsequent weeks; a two
to three times increase in sEGF levels may be
due to intestinal injury[62,63]. Supplementation
of formula with EGF reduces the incidence and severity of NEC in rats and mice[64,65].
Therefore, it may have a therapeutic value in
newborn infants with NEC.
In VLBW infants, erythropoietin (in a daily dose
of 200 U/kg intravenously as a continuous
infusion in the hyperalimentation solution
or as 400 U/kg subcutaneously, 3 days/
week) reduces the incidence of NEC (4.6% vs
10.8%, p=0.028). However, a FDA warning
(May 10, 2007) cautioned that erythropoietin
used to treat anemia caused by chemotherapy
has the potential for tumor promotion and
Recombinant human granulocyte colony-stimulating
factor (rhG-CSF) increases the absolute neutrophil
count and neutrophil functions. In VLBW
septic-neutropenic and even in preeclampsiaassociated
neonatal neutropenia, rhG-CSF causes
a significant increase in neutrophil cell number,
although the function of those cells remains suboptimal.
Intravenous rhG-CSF given at the time
of diagnosis decreases NEC mortality[68,69].
Enterally administered rhG-CSF likely has local
actions, and may reduce the severity of intestinal
damage or may lead to an acceleration in the
reparation of intestinal tissue or may control local
inflammation. In a preliminary study, it has
been shown that enteral rhG-CSF in stage I NEC
limits progression to more severe stages, which
is also supported by an animal study[71,72].
Pneumatosis typically occurs 12-48 hours after
presenting signs of NEC and 1-4 days prior
to perforation. Therefore, the presence of
pneumatosis intestinalis may be an objective
criterion for the initiation of rhG-CSF therapy.
Although responses to rhG-CSF begin as early as
a few hours, a peak response is seen in neonates
at 10-14 days following the initiation of a threeday
course of treatment. Therefore, the patient
must be able to survive long enough using
conventional support until any putative rhG-CSF
effects have sufficient time to occur.
Some drugs are used with caution for the
prevention of NEC. Hyperosmolar formulas
and drugs (e.g. multivitamins, phenobarbital,
theophylline) may cause predisposition to NEC.
Use of histamine type 2 receptor antagonists
(e.g. cimetidine, ranitidine, famotidine), which
eliminate the gastric barrier by reducing the
gastric pH in premature infants, increases the NEC risk by 1.7 times. Vitamin E may
increase risk for NEC because of a reduction of
antimicrobial defenses by excessive scavenging
of oxygen free radicals.
Patent ductus arteriosus is an independent
risk factor for the development of NEC in
VLBW infants. Therapy with indomethacin has
no significant effect on the risk for NEC.
However, if it is given with steroids, NEC risk
is 9.6 times higher. In addition, prolonged
use of indomethacin is associated with an
increased risk of NEC by 1.9 times. Enteral
feedings do not need to be interrupted when
on a course of indomethacin.
Management is determined by the specific
stage of the infant¡¯s disease. In stage I NEC,
intravenous antibiotics (ampicillin + amikacin for
sepsis, and metronidazole to reduce abnormally
colonized bacteria for 10-14 days, although blood
culture is positive in one-third of the patients),
no enteral feeding and nasogastric decompression
(2-3 days in suspected cases) are sufficient, and
serial abdominal radiographs are performed to
evaluate those that demonstrate radiographic
progression. Management in stage II includes
no enteral feeding and prolonged nasogastric
decompression (7-14 days). Surgical intervention
is generally recommended in stage III.
Portal venous gas had been thought to be a
predictor of poor outcome and an indication
for surgical intervention. However, there is no
difference in survival rates between those with
portal venous gas and those without (17% vs.
20%). Of the infants with portal venous gas,
those who are treated medically have a higher
survival rate than those treated surgically (91%
vs. 74%). Therefore, portal venous gas and
extensive pneumatosis are not accepted as a
Multiple retrospective analyses have been unable
to answer the question as to why some babies
with NEC recover uneventfully, while others
develop fulminant disease. Patients with NEC
who will not respond to medical therapy are
unpredictable. Nevertheless, intestinal perforation
is an absolute indication for operation. Intestinal
perforation (which is often multiple), occurs in
about 20% of those babies who develop NEC,
and mortality rate is 30-50% in babies with
intestinal perforation due to NEC. Unfortunately, abdominal radiographs are specific but not very
sensitive in the diagnosis of perforation.
Localized intestinal perforation (LIP) without
NEC also occurs in premature babies. It is only
about a third as common as in those affected
by NEC. Affected neonates appear to remain
clinically relatively well despite LIP until sudden
onset of abdominal distension, which coincides
with the onset of perforation. LIP is usually
in the terminal ileum and unlike in NEC the
remaining intestine appears normal. NEC and
LIP are different ends of a spectrum of the
same intestinal pathological disorder; LIP is
a more benign condition that responds well
to treatment and carries a good prognosis.
LIP is the isolated nature of the perforation.
Other aspects of these diseases (pathogenesis,
pathology, clinical presentation, morbidity,
mortality) are less obviously different.
Two commonly used methods for NEC with
intestinal perforation are laparotomy or primary
peritoneal drainage ("patch, drain and wait"). The
preferred method is controversial. Laparotomy
with surgical resection and enterostomy
formation has traditionally been considered the
safest method. Resection of gangrenous bowel
reduces bacterial translocation. Formation of
enterostomies allows for resolution of peritonitis
and further disease before reestablishing
continuity of the intestine.
According to the findings of a multicenter
randomized control trial, the type of intervention
(primary peritoneal drainage vs. laparotomy) for
perforated NEC does not influence survival,
dependence on parenteral nutrition, or length
of hospital stay in preterm infants. However,
long-term neurodevelopmental impairment is
not known in infants treated with primary
peritoneal drainage. The critical questions
regarding surgical care remain unanswered: what
is the optimal time for operative intervention;
what is the optimal strategy for intervention;
and what are the specific techniques that are
appropriate during that intervention?
1. Hsueh W, de Plaen IG, Caplan MS, Qu XW, Tan XD,
Gonzalez-Crussi W. Neonatal necrotizing enterocolitis:
clinical aspects, experimental models and pathogenesis.
World J Pediatr 2007; 3: 17-29.
2. Abramo TJ, Evans JS, Kokomoor FW, Kantak AD. Occult
blood in stools and necrotizing enterocolitis. Is there
a relationship? Am J Dis Child 1988; 142: 451-452.
3. Sharma R, Hudak ML, Tepas JJ, et al. Impact of
gestational age on the clinical presentation and surgical
outcome of necrotizing enterocolitis. J Perinatol 2006;
4. Silva CT, Daneman A, Navarro OM, et al. Correlation
of sonographic findings and outcome in necrotizing
enterocolitis. Pediatr Radiol 2007; 37: 274-282.
5. Bell MJ, Ternberg JL, Feigin RD, et al. Neonatal
necrotizing enterocolitis: therapeutic decisions based
upon clinical staging. Ann Surg 1978; 187: 1-7.
6. Walsh MC, Kliegman RM. Necrotizing enterocolitis:
treatment based on staging criteria. Pediatr Clin North
Am 1986; 33: 179-201.
7. Gibbs K, Lin J, Holzman IR. Necrotising enterocolitis: the
state of the science. Indian J Pediatr 2007; 74: 67-72.
8. Simmonds A, La Gamma EF. Addressing the "New"
NEC: Part I: rediscovering the basics. Indian J Pediatr
2006; 73: 1011-1018.
9. Salzman NH, Underwood MA, Bevins CL. Paneth cells,
defensins, and the commensal microbiota: a hypothesis
on intimate interplay at the intestinal mucosa. Semin
Immunol 2007; 19: 70-83.
10. Neu J, Chen M, Beierle E. Intestinal innate immunity:
how does it relate to the pathogenesis of necrotizing
enterocolitis. Semin Pediatr Surg 2005; 14: 137-144.
11. Anand RJ, Leaphart CL, Mollen KP, Hackam DJ. The
role of the intestinal barrier in the pathogenesis of
necrotizing enterocolitis. Shock 2007; 27: 124-133.
12. Nowicki PT. Ischemia and necrotizing enterocolitis: where,
when, and how. Semin Pediatr Surg 2005; 14: 152-158.
13. Nowicki PT, Caniano DA, Hammond S, et al.
Endothelial nitric oxide synthase in human intestine
resected for necrotizing enterocolitis. J Pediatr 2007;
14. Nafday SM, Chen W, Peng L, Babyatsky MW, Holzman
IR, Lin J. Short-chain fatty acids induce colonic mucosal
injury in rats with various postnatal ages. Pediatr Res
2005; 57: 201-204.
15. Treszl A, Kocsis I, Szathmari M, Schuler A, Tulassay
T, Vasarhelyi B. Genetic variants of the tumour
necrosis factor-alpha promoter gene do not influence
the development of necrotizing enterocolitis. Acta
Paediatr 2001; 90: 1182-1185.
16. Treszl A, Heninger E, Kalman A, Schuler A, Tulassay
T, Vasarhelyi B. Lower prevalence of IL-4 receptor
alpha-chain gene G variant in very-low-birth-weight
infants with necrotizing enterocolitis. J Pediatr Surg
2003; 38: 1374-1378.
17. Heresbach D, Alizadeh M, Bretagne JF, et al. TAP
gene transporter polymorphism in inflammatory bowel
diseases. Scand J Gastroenterol 1997; 32: 1022-1027.
18. Amer MD, Hedlund E, Rochester J, Caplan MS.
Platelet-activating factor concentration in the stool
of human newborns: effects of enteral feeding and
neonatal necrotizing enterocolitis. Biol Neonate 2004;
19. Caplan MS, Simon D, Jilling T. The role of PAF, TLR,
and the inflammatory response in neonatal necrotizing
enterocolitis. Semin Pediatr Surg 2005; 14: 145-151.
20. Pereira SG, Oakley F. Nuclear factor-kB1: regulation
and function. Int J Biochem Cell Biol (in press).
21. Qu XW, Rozenfeld RA, Huang W, Bulkley GB, Hsueh
W. The role of xanthine oxidase in platelet activating
factor induced intestinal injury in the rat. Gut 1999;
22. Qu XW, Rozenfeld RA, Huang W, Sun X, Tan XD,
Hsueh W. Roles of nitric oxide synthases in plateletactivating
factor-induced intestinal necrosis in rats.
Crit Care Med 1999; 27: 356-364.
23. Upperman JS, Potoka D, Grishin A, Hackam D, Zamora
R, Ford HR. Mechanisms of nitric oxide-mediated
intestinal barrier failure in necrotizing enterocolitis.
Semin Pediatr Surg 2005; 14: 159-166.
24. Qu XW, Thaete LG, Rozenfeld RA, et al. Tetrahydrobiopterin
prevents platelet-activating factor-induced intestinal
hypoperfusion and necrosis: role of neuronal nitric oxide
synthase. Crit Care Med 2005; 33: 1050-1056.
25. Ford HR. Mechanism of nitric oxide-mediated
intestinal barrier failure: insight into the pathogenesis
of necrotizing enterocolitis. J Pediatr Surg 2006;
26. Lee JS, Polin RA. Treatment and prevention of
necrotizing enterocolitis. Semin Neonatol 2003;
27. Crowley P. Prophylactic corticosteroids for preterm
birth. Cochrane Database Syst Rev 2000; (2):
28. Kennedy KA, Tyson JE, Chamnanvanakij S. Rapid versus
slow rate of advancement of feedings for promoting
growth and preventing necrotizing enterocolitis in
parenterally fed low-birth-weight infants. Cochrane
Database Syst Rev 2000; (2): CD001241.
29. Reynolds RM, Thureen PJ. Special circumstances: trophic
feeds, necrotizing enterocolitis and bronchopulmonary
dysplasia. Semin Fetal Neonatal Med 2007; 12: 64-70.
30. Tyson JE, Kennedy KA, Lucke JF, Pedroza C. Dilemmas
initiating enteral feedings in high risk infants: how can
they be resolved? Semin Perinatol 2007; 31: 61-73.
31. Pietz J, Achanti B, Lilien L, Stepka EC, Mehta SK.
Prevention of necrotizing enterocolitis in preterm
infants: a 20-year experience. Pediatrics 2007; 119:
32. Berseth CL. Feeding strategies and necrotizing
enterocolitis. Curr Opin Pediatr 2005; 17: 170-173.
33. Schanler RJ. Probiotics and necrotising enterocolitis
in premature infants. Arch Dis Child Fetal Neonatal
Ed 2006; 91: F395-397.
34. Deshpande G, Rao S, Patole S. Probiotics for prevention
of necrotising enterocolitis in preterm neonates with
very low birthweight: a systematic review of randomised
controlled trials. Lancet 2007; 369: 1614-1620.
35. Caffarelli C, Bernasconi S. Preventing necrotising
enterocolitis with probiotics. Lancet 2007; 369:
36. Bell EF. Preventing necrotizing enterocolitis: what
works and how safe? Pediatrics 2005; 115: 173-174.
37. Munoz P, Bouza E, Cuenca-Estrella M, et al. Saccharomyces
cerevisiae fungemia: an emerging infectious disease. Clin
Infect Dis 2005; 40: 1625-1634.
38. Foster J, Cole M. Oral immunoglobulin for preventing
necrotizing enterocolitis in preterm and low birthweight
neonates. Cochrane Database Syst Rev 2004;
39. Fewtrell MS, Morley R, Abbott RA, et al. Doubleblind,
randomized trial of long-chain polyunsaturated
fatty acid supplementation in formula fed to preterm
infants. Pediatrics 2002; 110: 73-82.
40. Wu G, Jaeger LA, Bazer FW, Rhoads JM. Arginine
deficiency in preterm infants: biochemical mechanisms
and nutritional implications. J Nutr Biochem 2004;
41. Zamora SA, Amin HJ, McMillan DD, et al. Plasma
L-arginine concentrations in premature infants with
necrotizing enterocolitis. J Pediatr 1997; 131: 226-232.
42. Becker RM, Wu G, Galanko JA, et al. Reduced serum
amino acid concentrations in infants with necrotizing
enterocolitis. J Pediatr 2000; 137: 785-793.
43. Neu J. Arginine supplementation and the prevention
of necrotizing enterocolitis in very low birth weight
infants. J Pediatr 2002; 140: 389-391.
44. Shah P, Shah V. Arginine supplementation for prevention
of necrotising enterocolitis in preterm infants. Cochrane
Database Syst Rev 2007; (3): CD004339.
45. Kalil AC, Danner RL. L-Arginine supplementation in
sepsis: beneficial or harmful? Curr Opin Crit Care
2006; 12: 303-308.
46. Heyland DK, Dhaliwal R, Drover JW, Gramlich L,
Dodek P; Canadian Critical Care Clinical Practice
Guidelines Committee. Canadian clinical practice
guidelines for nutrition support in mechanically
ventilated, critically ill adult patients. JPEN J Parenter
Enteral Nutr 2003; 27: 355-373.
47. O¡¯Dwyer MJ, Dempsey F, Crowley V, Kelleher DP,
McManus R, Ryan T. Septic shock is correlated with
asymmetrical dimethyl arginine levels, which may be
influenced by a polymorphism in the dimethylarginine
dimethylaminohydrolase II gene: a prospective
observational study. Crit Care 2006; 10: R139.
48. Richir MC, Siroen MP, van Elburg RM, et al. Low
plasma concentrations of arginine and asymmetric
dimethylarginine in premature infants with necrotizing
enterocolitis. Br J Nutr (in press).
49. Neu J. Arginine supplementation for neonatal
necrotizing enterocolitis: are we ready? Br J Nutr
2007; 97: 814-815.
50. Rhoads M. Glutamine is the gas pedal but not the ferrari.
J Pediatr Gastroenterol Nutr 2004; 38: 474-476.
51. Mates JM, Segura JA, Alonso FJ, Marquez J. Pathways
from glutamine to apoptosis. Front Biosci 2006; 11:
52. Becker RM, Wu G, Galanko JA, et al. Reduced serum
amino acid concentrations in infants with necrotizing
enterocolitis. J Pediatr 2000; 137: 785-793.
53. Bell SG. Immunomodulation. Part IV: Glutamine.
Neonatal Netw 2006; 25: 439-443.
54. Tubman TR, Thompson SW, McGuire W. Glutamine
supplementation to prevent morbidity and mortality
in preterm infants. Cochrane Database Syst Rev 2005;
55. Hirai C, Ichiba H, Saito M, Shintaku H, Yamano T,
Kusuda S. Trophic effect of multiple growth factors
in amniotic fluid or human milk on cultured human
fetal small intestinal cells. J Pediatr Gastroenterol Nutr
2002; 34: 524-528.
56. Warner BW, Warner BB. Role of epidermal growth
factor in the pathogenesis of neonatal necrotizing
enterocolitis. Semin Pediatr Surg 2005; 14: 175-180.
57. Scott SM, Guardian CM, Angelus P, Backstrom C.
Developmental pattern of urinary epidermal growth
factor in the premature infant and the influence of
gender. J Clin Endocrinol Metab 1991; 72: 588-593.
58. Buchmiller TL, Shaw KS, Chopourian HL, et al. Effect
of transamniotic administration of epidermal growth
factor on fetal rabbit small intestinal nutrient transport
and disaccharidase development. J Pediatr Surg 1993;
59. Miettinen PJ, Berger JE, Meneses J, et al. Epithelial
immaturity and multiorgan failure in mice lacking
epidermal growth factor receptor. Nature 1995;
60. Caplan M. Is EGF the Holy Grail for NEC? J Pediatr
2007; 150: 329-330.
61. Dvorak B, Fituch CC, Williams CS, Hurst NM, Schanler
RJ. Increased epidermal growth factor levels in human
milk of mothers with extremely premature infants.
Pediatr Res 2003; 54: 15-19.
62. Shin CE, Falcone RA, Stuart L, Erwin CR, Warner
BW. Diminished epidermal growth factor levels in
infants with necrotizing enterocolitis. J Pediatr Surg
2000; 35: 173-176.
63. Warner BB, Ryan AL, Seeger K, Leonard AC, Erwin
CR, Warner BW. Ontogeny of salivary epidermal
growth factor and necrotizing enterocolitis. J Pediatr
2007; 150: 358-363.
64. Dvorak B, Halpern MD, Holubec H, et al. Epidermal
growth factor reduces the development of necrotizing
enterocolitis in a neonatal rat model. Am J Physiol
Gastrointest Liver Physiol 2002; 282: G156-164.
65. Halpern MD, Holubec H, Clark JA, et al. Epidermal growth
factor reduces hepatic sequelae in experimental necrotizing
enterocolitis. Biol Neonate 2006; 89: 227-235.
66. Ledbetter DJ, Juul SE. Erythropoietin and the incidence
of necrotizing enterocolitis in infants with very low
birth weight. J Pediatr Surg 2000; 35: 178-181.
67. Khuri FR. Weighing the hazards of erythropoiesis
stimulation in patients with cancer. N Engl J Med
2007; 356: 2445-2428.
68. Kocherlakota P, La Gamma EF. Human granulocyte colonystimulating
factor may improve outcome attributable to
neonatal sepsis complicated by neutropenia. Pediatrics
1997; 100(1): E6.
69. Ahmad A, Laborada G, Bussel J, Nesin M. Comparison
of recombinant granulocyte colony-stimulating factor,
recombinant human granulocyte-macrophage colonystimulating
factor and placebo for treatment of septic preterm
infants. Pediatr Infect Dis J 2002; 21: 1061-1065.
70. Ido A, Numata M, Kodama M, Tsubouchi H. Mucosal
repair and growth factors: recombinant human hepatocyte
growth factor as an innovative therapy for inflammatory
bowel disease. J Gastroenterol 2005; 40: 925-931.
71. Canpolat FE, Yurdakok M, Ozsoy S, Haziroglu R, Korkmaz
A. Protective effects of recombinant human granulocyte
colony-stimulating factor in a rat model of necrotizing
enterocolitis. Pediatr Surg Int 2006; 22: 719-723.
72. Canpolat FE, Yurdakok M, Korkmaz A, Yigit S, Tekinalp
G. Enteral granulocyte colony-stimulating factor for the
treatment of mild (stage I) necrotizing enterocolitis:
a placebo-controlled pilot study. J Pediatr Surg 2006;
73. Simmonds A, La Gamma EF. Toward improving
mucosal barrier defenses: rhG-CSF plus IgG antibody.
Indian J Pediatr 2006; 73: 1019-1026.
74. Guillet R, Stoll BJ, Cotten CM, et al.; National Institute
of Child Health and Human Development Neonatal
Research Network. Association of H2-blocker therapy
and higher incidence of necrotizing enterocolitis
in very low birth weight infants. Pediatrics 2006;
75. Johnson L, Quinn GE, Abbasi S, et al. Effect of
sustained pharmacologic vitamin E levels on incidence
and severity of retinopathy of prematurity: a controlled
clinical trial. J Pediatr 1989; 114: 827-838.
76. Dollberg S, Lusky A, Reichman B. Patent ductus
arteriosus, indomethacin and necrotizing enterocolitis
in very low birth weight infants: a populationbased
study. J Pediatr Gastroenterol Nutr 2005;
77. Paquette L, Friedlich P, Ramanathan R, Seri I.
Concurrent use of indomethacin and dexamethasone
increases the risk of spontaneous intestinal perforation
in very low birth weight neonates. J Perinatol 2006;
78. Herrera C, Holberton J, Davis P. Prolonged versus
short course of indomethacin for the treatment of
patent ductus arteriosus in preterm infants. Cochrane
Database Syst Rev 2007; (2): CD003480.
79. Bellander M, Ley D, Polberger S, Hellstrom-Westas
L. Tolerance to early human milk feeding is not
compromised by indomethacin in preterm infants
with persistent ductus arteriosus. Acta Paediatr 2003;
80. Sharma R, Tepas JJ, Hudak ML, et al. Portal venous
gas and surgical outcome of neonatal necrotizing
enterocolitis. J Pediatr Surg 2005; 40: 371-376.
81. Boston VE. Necrotising enterocolitis and localized
intestinal perforation: different diseases or ends of
a spectrum of pathology. Pediatr Surg Int 2006;
82. Henry MC, Lawrence Moss R. Surgical therapy for
necrotizing enterocolitis: bringing evidence to the
bedside. Semin Pediatr Surg 2005; 14: 181-190.
83. Moss RL, Dimmitt RA, Barnhart DC, et al. Laparotomy
versus peritoneal drainage for necrotizing enterocolitis
and perforation. N Engl J Med 2006; 354: 2225-2234.