Pathology and pathogenesis of necrotizing enterocolitis in newborns

Author
Richard J Schanler, MD
Section Editor
Steven A Abrams, MD
Deputy Editor
Melanie S Kim, MD
Disclosures: Richard J Schanler, MD Consultant/Advisory Boards: Medela [Breastfeeding (Breast pumps,
collection kits)]. Steven A Abrams, MD Grant/Research/Clinical Trial Support: Mead-Johnson [Nutrition (Infant
formulas)]. Melanie S Kim, MD Nothing to disclose.
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All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Jun 2015. | This topic last updated: Jun 02, 2015.
INTRODUCTION Necrotizing enterocolitis (NEC), the most common gastrointestinal emergency
in the newborn infant, is a disorder manifested by ischemic necrosis of the intestinal mucosa [1]. It
is associated with inflammation, invasion of enteric gas forming organisms, and dissection of gas
into the muscularis and portal venous system.
NEC occurs in 1 to 3 per 1000 live births and is seen predominately in premature infants with an
incidence of about 6 to 7 percent in very low birth weight (VLBW) infants (birth weight <1500 g).
Although early recognition and aggressive treatment of this disorder has improved clinical
outcomes, NEC accounts for substantial long-term morbidity in survivors of neonatal intensive care,
particularly in VLBW infants.
First described in 1965, the etiology of NEC remains uncertain [2-4]. The pathology and the current
understanding of the pathogenesis of NEC are reviewed here. The clinical features, management,
and prevention of this disorder are discussed separately. (See "Clinical features and diagnosis of
necrotizing enterocolitis in newborns" and "Management of necrotizing enterocolitis in newborns"
and "Prevention of necrotizing enterocolitis in newborns".)
PATHOLOGY The pathology of necrotizing enterocolitis (NEC) is primarily due to changes from
intestinal infarction [5]. The specific findings vary and depend upon the progression of the disease
and the presence of underlying pathogenic factors. The terminal ileum and colon are involved in the
majority of cases, although the entire gastrointestinal tract is affected in severe cases.
On gross examination, the bowel appears distended and hemorrhagic. Subserosal collections of
gas occasionally are present along the mesenteric border. Gangrenous necrosis occurs on the
antimesenteric border, and perforation may be present. As the gut heals, thickening of the bowel
wall, fibrinous adhesions, and areas of stenosis appear.

The major histologic findings in NEC are mucosal edema, hemorrhage, and transmural bland
necrosis. Other findings include acute inflammation, secondary bacterial infiltration, and collections
of gas. Vascular thrombi are rare.
PATHOGENESIS The pathogenesis of necrotizing enterocolitis (NEC) remains unknown, but it is
probably a heterogeneous disease resulting from multiple factors that result in mucosal injury in a
susceptible host. The following factors have been implicated in the pathogenesis of NEC (figure 1):
Prematurity
Microbial bowel overgrowth
Milk feeding
Impaired mucosal defense
Circulatory instability of the intestinal tract
Medications that cause intestinal mucosal injury or enhance microbial overgrowth
Currently, epidemiologic studies have identified prematurity and milk feeding as consistent risk
factors for NEC [4,6].
Prematurity About 90 percent of NEC cases occur in premature infants born who have been fed
enterally. The following factors due to immaturity of the gastrointestinal tract and immune system
are thought to predispose the preterm infant to NEC (figure 2) [7,8].
Immature mucosal barrier with increased permeability and bacterial penetration into the
intestinal wall (translocation) compared with term infants. (See 'Impaired mucosal
defense' below.)
Immature local host defenses with diminished concentrations of secretory IgA, mucosal
enzymes (eg, pepsin and proteases), and other protective agents (eg, lactoferrin), and
increased gastric pH, which promotes bacterial overgrowth.
Immature bowel motility and function. Premature infants have decreased small bowel
motility, resulting in delayed transit time, which increases bacterial proliferation and
overgrowth [9].
Bacterial overgrowth and increased intestinal permeability are factors that contribute to greater
bacterial translocation from the intestinal lumen into the intestinal tissue leading to an inflammatory
response with activation of cytokines [9]. (See 'Inflammation' below.)
Exposure to glucocorticoids matures intestinal barrier function, and antenatal treatment has been
proposed to reduce the incidence of NEC [10,11]. (See "Antenatal corticosteroid therapy for
reduction of neonatal morbidity and mortality from preterm delivery", section on 'Reduction of IVH,
NEC, NNM, infection'.)
Term infants NEC in term infants is generally associated with predisposing or underlying
conditions, such as congenital heart disease, perinatal asphyxia, polycythemia, sepsis, and

respiratory disease. (See "Clinical features and diagnosis of necrotizing enterocolitis in newborns",
section on 'Epidemiology'.)
Milk feeding More than 90 percent of infants who develop NEC have received milk feeding,
although NEC also occurs in infants who have never been fed [12]. Enteral feeding may contribute
to the pathogenesis of NEC because human milk and commercial formulas serve as substrates for
bacterial proliferation in the gut.
Newborns, especially premature infants, have not developed the ability to completely digest and
absorb nutrients. As a result, bacterial fermentation products of incompletely digested
carbohydrates and lipids (eg, reducing substances, organic acids, short chain fatty acids, carbon
dioxide, and hydrogen gas) in the intestine of premature infants may cause mucosal injury. Delayed
transient time due to impaired motility in the premature infant exacerbates this process. Supportive
data was provided by a study using an animal model that demonstrated a mixture of casein, organic
acids, and low pH led to mucosal injury with infiltration of cellular elements and vasoactive
compounds [13].
Although NEC is associated with enteral feeds, it remains uncertain whether feeding-related factors
are important in the development of NEC:
Rate of advancement In a 2011 systematic review, available data demonstrated that
slow advancement of feeds was not associated with a reduced risk of NEC and was
associated with a delay in regaining birth weight and establishing full enteral feeds
compared with faster rates of advancement [14].
Timing of initial feeding A meta-analysis demonstrated that a delay in the introduction
of enteral feeds (after four days of age) was not associated with a reduced risk of NEC
and that the delay is associated with a longer time to establish full enteral feeds [15].
Providing minimal enteral or trophic feeding does not increase the incidence of NEC
[16-18].
Human milk Human milk, compared with formula, is more protective against NEC in premature
infants. Factors present in human milk may play a role in this protection by reducing inflammation or
the introduction of foreign antigens in the gastrointestinal tract (figure 3). Human milk feeding is
associated with a lower intestinal pH to facilitate the growth of nonpathogenic bacteria, which
counteract pathogenic bacteria. The mucus coat of the intestine is less affected by human milk, and
growth factors within human milk (such as epidermal growth factors) repair disruptions in this layer.
Human milk improves intestinal motility, which avoids milk stasis and decreases intestinal
permeability. Human milk also stimulates the mucosal defense system so that local immune
activation is thwarted. Protective factors within human milk include platelet activating factor
acetylhydrolase, secretory Immunoglobulin A, cytokines (IL-10, IL-11), epidermal growth factor [19],
nucleotides, glutamine, and antioxidants such as vitamin E, carotene, and glutathione. The benefits
of human milk compared with formula in reducing the risk of NEC in premature infants are

discussed elsewhere. (See "Human milk feeding and fortification of human milk for premature
infants" and "Infant benefits of breastfeeding", section on 'Gastrointestinal function'.)
Microbial colonization Bacterial colonization is believed to play a pivotal role in the
development of NEC because NEC does not occur in utero when the gut is sterile. After delivery,
rapid colonization of the intestinal tract by commensal bacteria from the maternal rectovaginal flora
occurs. These bacteria play a symbiotic role with the intestine through toll-like receptors by
regulating the expression of genes involved in intestinal physiology, postnatal maturation, and
function (eg, barrier, digestion, angiogenesis, and production of IgA), and protection against more
pathologic organisms [8,20-22]. Pathologic host-bacterial interactions may induce proinflammatory
and proapoptotic responses in the intestinal host cells mediated by signaling pathways, such as the
NF-kappa B pathway [8,21,23].
Although there are limited data regarding these roles of bacteria in prenatal and postnatal intestinal
development, intestinal noncommensal bacterial overgrowth, especially with coagulase-negative
staphylococci, appears to be associated with NEC [24]. Overgrowth of noncommensal bacteria may
cause mucosal injury by affecting intestinal maturation, increasing inflammation and apoptosis, and
releasing endotoxin. This appears to occur in the absence of a primary infection, particularly in most
sporadic cases of NEC in which infectious agents play a secondary role in the disease process [8].
Most very preterm infants (gestational age less than 28 weeks) are colonized by Staphylococci
species and very few by Bifidobacterium, commensal intestinal bacterium [25]. Approximately 20 to
30 percent of infants with NEC have associated bacteremia, which is often caused by coagulasenegative staphylococci and is most likely seeded by intestinal bacteria translocated through the
damaged intestinal mucosa [4]. In some cases, especially in outbreaks of NEC, primary infection by
pathogenic bacteria may occur [8].
The use of probiotic therapy has been proposed to reduce bacterial overgrowth of more invasive
bacteria and promote commensal intestinal bacteria, which inhibit inflammatory pathways, thereby
decreasing the risk of NEC [8,21]. However, the current use of probiotics should be limited to clinical
trials until there is unequivocal evidence that confirms the efficacy and safety of probiotic therapy
compared with other preventive modalities, and establishes the most effective regimen for
premature infants (ie, bacterial strain, dosing, and timing and duration of therapy). (See "Prevention
of necrotizing enterocolitis in newborns", section on 'Probiotics'.)
In contrast, empiric antibiotic therapy greater than five days duration is associated with an increased
risk of NEC or death, most likely due to a change in the bacterial colonization of the gastrointestinal
tract [8,26,27].
Primary infection NEC may be due to primary invasions of the gut by pathogenic enteric
bacteria. Bacterial organisms usually found in the distal gastrointestinal tract have been recovered
from the blood and peritoneal cavities of patients with NEC. These organisms include Escherichia
coli, Klebsiella pneumoniae, Pseudomonas, and Clostridium difficile [28-30]. In particular,

Clostridium species, toxin-producing bacteria that are associated with pseudomembrane formation,
submucosal and subserosal gas blebs, and intestinal gangrene, have been associated with more
severe NEC [31,32].
In addition to these bacteria, viral and fungal pathogens have been isolated in some sporadic cases
of NEC and in epidemic outbreaks [33,34]. Virus particles have been isolated from the stools of
infants with NEC and their caregivers, including their mothers, the midwives, and the nursery
nursing staff. Injury caused by infectious agents may be aggravated by inflammatory mediators.
(See 'Inflammation' below.)
The use of molecular techniques may prove to be a useful tool in evaluating the role of infection in
the pathogenesis of NEC. In a small prospective study, stool samples from 12 infants less than 34
weeks gestation who were admitted to the neonatal intensive care unit were analyzed using
polymerase chain reaction (PCR) and gel electrophoresis [35]. Clostridium perfringens was
recognized during the first two weeks of life in the three infants who later developed NEC, but not in
the nine infants who did not.
Impaired mucosal defense Premature infants are susceptible to the development of NEC
because immunologic and gastrointestinal immaturity results in altered host resistance. The
impairment of the mucosal barrier allows bacteria to gain access to deeper tissues resulting in
inflammation. (See 'Inflammation' below.)
Mucosal defense in the gut is mediated by several interrelated components, some of which provide
a physical barrier and others a biochemical and immunologic barrier [36,37]. Factors that contribute
to innate resistance include luminal pH, enzymes, mucins, epithelial barriers, and gut motility, as
well as nonspecific antimicrobial factors, such as lactoferrin and lysozyme.
Premature infants have lower concentrations or more immature function of contributing mucosal
defense factors than do term infants and adults [4].
The intestinal mucin barrier, which hampers bacterial epithelial binding and enhances
bacterial removal, is not fully developed in very premature infants. An immature mucin
layer increases bacterial intestinal penetration and adherence, which may result in injury
or cause inflammation. As a result, premature infants are more susceptible to enteric
infections or mucosal inflammation [1,21].
Secretory IgA, the major gastrointestinal immunoprotective antibody, is absent from the
human intestinal mucosa at birth.
Paneth cells are secretory enterocytes located at the base of the small intestinal crypts
that release lysozyme, phospholipase A2, and antimicrobial peptides (defensins and
cathelicidins), that help regulate the intestinal bacterial populations. Animal and human
studies suggest that the expression of defensins and number of Paneth cells are lower in
premature infants and fetuses than in term infants and adults [21,38].

Tight junctions between epithelial cells maintain the semipermeable property of the
intestinal tract. In premature infants, there is increased permeability most likely due to
immaturity of the composition and function of the tight junctions [38]. Further disruption of
these tight junctions occurs because of alterations in host-bacterial interactions, which
may induce inflammation. (See 'Microbial colonization' above and 'Inflammation' below.)
Growth factors, such as epidermal growth factor (EGF), are important in intestinal
development and preservation of gut barrier function [39]. Animal models and studies in
humans suggest a predictive or protective role for EGF in the pathogenesis of NEC. In
one study, an EGF receptor mice knockout model demonstrated hemorrhagic necrosis, a
pathologic finding similar to that seen in infants with NEC [40]. Another animal study
showed EGF supplementation reduced the incidence of NEC in a neonatal rat model of
NEC [41-44].
In a study of human neonates with gestational ages 32 weeks gestation, infants who developed
NEC had lower salivary epidermal growth factor (sEGF) levels at one week of age when compared
with infants without NEC [45]. In infants with NEC compared with those without NEC, there was also
a greater increase in sEGF levels from week one to week two of life.
Further investigations on the role of EGF in the pathogenesis of NEC are required to determine
whether there is a role for EGF in either predicting or preventing NEC [19].
Circulatory instability Ischemic insult to the gastrointestinal tract has been proposed as a major
contributor to NEC, although most infants with NEC have not had an obvious perinatal hypoxicischemic event [28,46,47]. Circulatory events that have been implicated in the development of NEC
include perinatal asphyxia [48], recurrent apnea, hypoxia from severe respiratory distress
syndrome, hypotension, congenital heart disease [49,50], patent ductus arteriosus, heart failure,
umbilical arterial catheterization, anemia, polycythemia [51,52], and red blood cell [53-55] and
exchange transfusions [56]. A diminished blood supply to the gut may contribute to the
pathogenesis of NEC in infants exposed to cocaine [57].
Many of these observations have occurred in term infants. In premature infants with NEC, the
predisposing role of circulatory instability remains unproven [28,47]. In case-controlled studies,
episodes of hypoxia and/or hypotension occur with the same frequency in premature infants with or
without NEC [58]. In addition, other manifestations of hypoxic-ischemic injury (eg, acute tubular
necrosis and intraventricular hemorrhage) do not correlate with the development of NEC.
These findings have led to the hypothesis that a subtle reduction in blood flow and subsequent
reperfusion occurring in response to hypoxia may contribute to bowel injury. Although the regulation
of mesenteric blood flow in the newborn is poorly understood, one small prospective trial reported
that high vascular resistance of the superior mesenteric artery determined by Doppler flow velocity
on the first day of life was associated with an increased risk of NEC [59]. In a prospective casecontrolled study of term infants with congenital heart disease, persistent diastolic flow reversal in the
abdominal aorta was associated with increased risk of NEC [49].

RBC transfusions Red blood cell (RBC) transfusions given after the first weeks of life have
been reported to be associated with an increased risk of NEC. However, it is unclear whether RBC
transfusions play a pathogenetic role in the development of NEC or whether it is an epiphenomenal
marker of imminent NEC [60].
Several retrospective studies and a systematic review have reported an association between RBC
transfusions and NEC [53-55,60-63]. In the systematic review of 11 case-control studies and one
cohort study, the following findings were noted [63]:
There was a temporal relationship between recent RBC transfusions and episodes of
NEC.
Infants with transfusion-associated NEC were more premature (mean difference in
gestational age, -1.5 weeks, 95% CI -0.9 to -2.1 weeks), had lower birth weight (mean
difference -528 g, 95% CI -496 to -560), and were more likely to have a patent ductus
arteriosus (odds ratio [OR] 2.68, 95% CI 1.81-2.97) or receive ventilatory support (OR
3.16, 95% CI 1.6-6.22) than infants with NEC not associated with RBC transfusion.
Infants with transfusion-associated NEC had a higher risk of mortality, but this analysis
was not adjusted for confounding factors.
In six of the studies, transfusion-associated NEC was delayed, occurring at an older
postnatal age than NEC not associated with transfusion.
However, the authors caution that these results do not establish a cause-effect relationship between
RBC transfusions and NEC, as the included studies were retrospective in nature and did not adjust
for confounding risk factors (ie, prematurity, birth weight, ventilatory status, and the presence of a
patent ductus arteriosus). In addition, the rationale for the blood transfusion is infrequently
mentioned so it furthers the confusion of this association.
Similar results were reported in a large Canadian case-control study of 927 preterm infants with
NEC and 2781 control patients without NEC matched by gestational age (GA) [64]. In this study,
exposure to transfusion in the previous two days was higher in NEC cases compared with controls
(15.5 versus 7.7 percent, adjusted odds ratio 2.44, 95% CI 1.87-3.18). The definition of exposure in
NEC cases was defined as receiving a transfusion within two calendar days before the diagnosis of
NEC and in the control cases as receiving an RBC transfusion within two calendar days before the
median age of diagnosis among NEC cases with the same GA. In this cohort, infants with NEC
were more likely to be small for gestational age and were sicker based on higher initial illness
severity scores compared with controls. In addition, infants with NEC that was associated with
transfusion exposure were also of lower birth weight and GA, and had higher illness severity scores
than those with NEC that was not associated with transfusion.
Proponents of a causal relationship between RBC transfusion and NEC have proposed the
following pathologic mechanisms [60]:

RBC transfusion results in immunologic injury to the intestine similar to what is seen in
transfusion-related acute lung injury.
Components of stored RBCs may cause intestinal injury due to impaired blood flow due
to vasoconstriction and thrombus formation. Known abnormalities associated with stored
RBCs include reduced RBC deformability, increased RBC adhesion and aggregation,
prothrombotic effects, and decreased nitric oxide stores.
It has been proposed that withholding of feeds during transfusion may reduce the risk of NEC;
however, data are also inadequate to determine whether or not this practice has any effect on the
prevalence of NEC [65]. In one small study of 17 preterm infants (<33 weeks gestation), mean
mesenteric tissue oxygenation during RBC transfusion was not affected by feeding status [66].
However, mean mesenteric tissue oxygenation was lower up to 15 hours post-transfusion in infants
who were fed during RBC transfusion compared with those who were not fed. Further data are
needed to confirm this finding and determine its clinical significance.
In our practice, we do not currently withhold feedings during a transfusion, as the data regarding the
benefit of withholding feeds are insufficient. However, other centers do withhold feeds during and for
several hours after RBC transfusion. Because of the concerns of complications involved with RBC
transfusion, the indications for intervention prior to administrating a RBC transfusion should always
be carefully considered. (See "Red blood cell transfusions in the newborn", section on 'Indications'.)
In contrast, a retrospective study in a neonatal intensive care unit (NICU) with a liberal transfusion
practice reported no association between RBC transfusions and NEC [67]. The authors suggest an
alternative explanation for the reported association of RBC transfusions in previous studies is that
transfusion is an incidental marker for clinically significant anemia in infants with incipient NEC.
Because of their liberal transfusion practice, infants in their practice did not reach the threshold of
significant anemia requiring transfusion. This degree of anemia is postulated to result in further
intestinal injury due to impaired oxygen delivery.
Because of the lack of evidence, further research is required including prospective clinical trials to
test the hypothesis of a relationship between RBC transfusion and NEC. These studies need to
carefully document indications for RBC transfusion and see whether they correlate with the onset of
symptoms associated with NEC. Data from such studies would be helpful in determining whether or
not RBC transfusions or anemia contribute to the pathogenesis of NEC. Until more definitive data
are available, we have not changed our practice regarding transfusion.
Medications The administration of hyperosmolar medications and/or formulas can cause
mucosal injury and may result in NEC [68]. Oral medications such as theophylline, multivitamins, or
phenobarbital contain hypertonic additives that might irritate the intestinal mucosa. Instillation of
hyperosmolar contrast agents into the bowel for diagnostic radiographic studies also can cause
mucosal injury because of fluid shifts, bowel distention, and ischemia. Isotonic contrast agents
should be used to avoid this complication. Hyperosmolar formulas, such as those concentrated

above recommended strengths or containing multiple additives, should be avoided in the first few
weeks after birth.
Histamine type 2 receptor (H2)-antagonists, such as cimetidine, ranitidine, and famotidine, are
associated with higher rates of NEC. This was illustrated in a report from the National Institute of
Child Health and Human Development (NICHHD) Neonatal Research Network [69]. In this study of
11,072 premature infants (birth weight 401 to 1500 g) from 1998 to 2001, the incidence of NEC was
7.1 percent. Infants with NEC compared with matched controls were more likely to have received
H2-antagonists (OR 1.71, 95% CI 1.34-2.19). A possible explanation for this finding is that gastric
acidity, which may reduce the risk of NEC by inhibiting bacterial growth [70], was lowered by the
use of H2-antagonists.
Inflammation Inflammatory mediators induced by ischemia, infectious agents, or mucosal
irritants may further aggravate mucosal injury [21,71]. These soluble inflammatory cytokines,
including tumor necrosis factor (TNF), interleukins (IL-1, IL-6, IL-8, IL10, IL12, and IL-18), and
platelet activating factor (PAF), increase vascular permeability and attract inflammatory cells. Levels
of these cytokines are increased in premature infants with NEC and correlate with the severity of
the disease [21,72-75].
This cascade of cellular events may be mediated at least in part by PAF, which is synthesized by
many cell types, including macrophages, neutrophils, eosinophils, and endothelial cells [76]. In
animals, administration of PAF causes intestinal necrosis as well as systemic hypotension, capillary
leakage, pulmonary hypertension, neutropenia, and thrombocytopenia [76].
These observations may be applicable to humans. Plasma concentrations of PAF are higher in
infants taking milk feedings, although the acetylhydrolase present in human milk breaks down PAF
[76]. Plasma acetylhydrolase activity is lower in infants with NEC compared with controls and may
contribute to the increased concentrations of PAF [72].
Medications or conditions that affect cytokines or oxygen-free radicals can contribute to the
development of NEC [76]. For example, a deficiency of magnesium or copper can increase the
synthesis or activity of cytokines and oxygen-free radicals, leading to intestinal injury [77]. In
addition, in a trial of vitamin E administration to prevent retinopathy of prematurity, NEC occurred
more often in treated infants with high levels of serum tocopherol (greater than 3.5 mg/dL) [78]. The
mechanism may be due to a reduction of antimicrobial defenses by excessive scavenging of
oxygen-free radicals. On the other hand, treatment with vitamin E is not associated with NEC in
infants with lower serum tocopherol concentrations.
Chorioamnionitis Chorioamnionitis is an antenatal proinflammatory process involving the
placenta and fetal membrane, which may play a contributing role in the pathogenesis of NEC.
However, data are inconclusive whether it is a significant clinical risk factor, as illustrated by a
systematic review of the literature [79]. The following findings were noted:

Meta-analysis of studies examining the relationship between NEC and chorioamnionitis

confirmed by histology found no significant association between histologic-confirmed
chorioamnionitis (HC) and NEC. However, a subgroup analysis demonstrated an
association between NEC and HC that included fetal involvement.
In another meta-analysis, clinically diagnosed chorioamnionitis was associated with an
increased risk of NEC.
However, there are several methodological issues that affect the interpretation of these findings
causing heterogeneity of results. These include not controlling for confounding factors such as
gestational age (incidence of chorioamnionitis and NEC is inversely related to gestational age) and
a lower rate of breastfeeding in mothers with chorioamnionitis (human milk is protective against
NEC); and differences among studies in inclusion and exclusion criteria, and criteria for the clinical
diagnosis of chorioamnionitis.
Further investigation is needed to determine whether there is a significant clinical role of
chorioamnionitis in the pathogenesis of NEC.
Intestinal vascular resistance Mucosal injury and inflammation may alter the balance of
endogenous vasoactive agents, which may contribute to the development of NEC with changes in
the intestinal vascular resistance and microcirculation [37,80-82]. Data are limited on the roles of
nitric oxide, the primary vasodilator, and endothelin-1, a potent vasoconstrictor, in the pathogenesis
of NEC.
Endothelin -1 (ET-1) In a pathologic study of resected intestinal specimens from
infants with suspected NEC, there were increased levels of ET-1 in areas that
demonstrated histological findings consistent with NEC as compared with unaffected
tissue from the same specimen [82]. In addition, arterioles showed increased
vasoconstriction in affected compared with unaffected tissue that was reversed by an
endothelin receptor antagonist.
Nitric oxide (NO) The limited data available on the role of NO are conflicting. In one
report, inducible NO synthase (iNOS) gene and protein expression were detected more
often in apical enterocytes in infants undergoing surgical resection for NEC than for
intestinal atresia or other noninflammatory conditions [81]. These results would suggest
that increased NO may contribute to failure of gut barrier function, bacterial translocation,
and direct intestinal damage.
In contrast, another study reported that although endothelial NO synthase (eNOS) was present in
specimens from infants undergoing surgical resection for NEC and control patients with intestinal
atresia, eNOS function was impaired, resulting in decreased NO production in arterioles from NEC
specimens compared with controls [41]. Arterioles from patients with NEC failed to normally dilate in
response to acetylcholine stimulation or increased arteriolar.

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The
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Basics topic (see "Patient information: Newborn necrotizing enterocolitis (The Basics)")
SUMMARY Necrotizing enterocolitis (NEC), the most common gastrointestinal emergency in the
newborn infant, is a disorder manifested by ischemic necrosis of the intestinal mucosa associated
with inflammation, invasion of enteric gas forming organisms, and dissection of gas into the
muscularis and portal venous system.
The pathologic findings of NEC vary depending upon the progression of the disease. In
general, the bowel appears distended and hemorrhagic on gross examination. The major
histologic findings include mucosal edema, hemorrhage, and transmural bland necrosis.
(See 'Pathology' above.)
Although the pathogenesis of NEC remains unknown, it is probably caused by multiple
factors in a susceptible host. Prematurity and milk feeding are established risk factors for
NEC, with 90 percent of cases occurring in enterally fed premature infants. Immaturity of
the gastrointestinal tract appears to predispose premature infants to NEC because it
results in impaired mucosal defense, and intestinal motility and function. These factors
result in microbial overgrowth and an increased likelihood of mucosal injury leading to
inflammation, ischemia, and necrosis, and the development of NEC. (See 'Pathogenesis'
above.)
Use of UpToDate is subject to the Subscription and License Agreement.
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Topic 4991 Version 26.0

Contributing mechanisms to the pathogenesis of necrotizing

enterocolitis in neonates

Adapted from: Kliegman RM, Pediatr Res 1993; 34:701.

Graphic 74897 Version 3.0

Necrotizing enterocolitis: Susceptibility of premature infants

Immaturity of the intestinal epithelial barrier and the neonatal mucosal immune system
predispose the premature infant to microbial invasion, which triggers the sequence of
events leading to necrotizing enterocolitis (NEC). Stimulation of pro-inflammatory cytokines
compromises intestinal defenses. An imbalance between epithelial cell injury and repair
leads to a cycle of bacterial invasion, immune activation, uncontrolled inflammation, and
gut barrier failure.
NO: nitric oxide; TNF-: tumor necrosis factor - alpha.
Reprinted by permission from Macmillan Publishers Ltd: Pediatric Research. Hunter CJ,
Upperman JS, Ford HR, Camerini V. Understanding the Susceptibility of the Premature Infant to
Necrotizing Enterocolitis (NEC). Pediatr Res 2008; 63:117. Copyright 2008.
www.nature.com/pr
Graphic 68015 Version 10.0

The beneficial effect of human milk on reducing pathogenetic

risk factors for necrotizing enterocolitis (NEC)

(A) Immaturity of the intestinal epithelial barrier and neonatal mucosal immune system
predispose the premature infant to bacterial invasion, which triggers the sequence of NEC.
Stimulation of pro-inflammatory cytokines compromises intestinal defenses. Imbalance
between epithelial cell injury and repair leads to a cycle of bacterial invasion, immune
activation, uncontrolled inflammation, and gut barrier failure.
(B) Human milk provides oligosaccharides, acetylhydrolase, and mucosal immune
components; alters bacterial flora; affects mucus coat; decreases epithelial permeability;
increases peristalsis (motility); and lowers gastric pH, which enhances barrier function.
NICU: neonatal intensive care unit; NO: nitric oxide; TNF-: tumor necrosis factor-alpha.
Reprinted by permission from Macmillan Publishers Ltd: Pediatric Research. Hunter CJ,
Upperman JS, Ford HR, Camerini V. Understanding the Susceptibility of the Premature Infant to

Necrotizing Enterocolitis (NEC). Pediatr Res 2008; 63:117. Copyright 2008.

www.nature.com/pr.
Graphic 90314 Version 2.0