Pathophysiology 21 (2014) 3–12

Neonatal necrotizing enterocolitis: Clinical challenges, pathophysiology

and management
Shehzad Huda a , Shabnum Chaudhery b , Hassan Ibrahim c , Arun Pramanik c,∗
a Department of Neonatal-Perinatal Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
b Department of Pathology, LSU-Health, Shreveport, LA, United States
c Department of Pediatrics, LSU-Health, Shreveport, LA, United States

Abstract
NEC remains a major concern for neonatologists, surgeons, and gastroenterologists due to its high morbidity and mortality. These infants
often have poor developmental outcome, and contribute to significant economic burden resulting in marked stress in these families. By
developing and adhering to strict feeding protocols, encouraging human milk feeding preferably from the infant’s mother, use of probiotics,
judicious antibiotic use, instituting blood transfusion protocols, the occurrence of NEC may possibly be reduced. However, because of its
multifactorial etiology, it cannot be completely eradicated in the NICUs, particularly in the extremely premature infants. Ongoing surveillance
of NEC and quality improvement projects may be beneficial.
© 2014 Published by Elsevier Ireland Ltd.

Keywords: Necrotizing enterocolitis; Preterm infant; Prevention

1. Introduction (NICU). It is the commonest gastrointestinal emergency

The first case report of necrotizing enterocolitis (NEC)
probably dates back to 1823 when Charles Billard used the
term “gangrenous enterocolitis” or “malignant enteritis” to
describe necrosis and inflammation of the intestinal tract in
a small infant. This was followed by a report of 25 patients
with “gangrenous enterocolitis” in 1850 [1]. During the early
part of 20th century, there were more reports of peritonitis
with ileal perforation due to what was then called “infectious
enteritis”. In 1953, Schmidt and Quaiser coined the term
“Newborn NEC” [2]. However, the clinical and radiological
features of NEC as currently used were first described in 21
such infants by Berndon from New York Babies hospital in
1964 [3].
Necrotizing enterocolitis, an inflammatory bowel disease
of newborn infants attributed to multifactorial etiology often
presents unexpectedly in the Neonatal Intensive Care Unit
∗ Corresponding author at: Department of Pediatrics, Louisiana State Uni-
versity Health, PO Box 33932, Shreveport, LA 71115, United States.
E-mail address: aprama@lsuhsc.edu (A. Pramanik).
with high morbidity and mortality, particularly in extremely
premature infants. The terminal ileum and the proximal colon
are the most commonly affected sites although any segment
of the small or large intestine may be involved. In a subset
of patients it has a rapid and fulminating course wherein the
entire bowel is irreversibly damaged which has been termed
as ‘NEC totalis’. The exact mechanism initiating the inflam-
mation and injury to the gut is poorly understood despite
extensive clinical and basic research on NEC in the last few
decades. The lack of clinically significant progress, and the
unchanged prevalence rate of NEC have been attributed to a
variety of factors which include: increased survival of smaller
and sicker premature infants at higher risk of NEC with the
advent of modern NICU practices, our inability to differenti-
ate this disease early from ‘feeding intolerance’, alterations
in gut flora with use of antibiotics and feeding practices, a
possible risk of increased NEC due to blood transfusions
during feeding, and our inability to create an animal model
closely simulating human disease. NEC is estimated to affect
approximately one out of 10 premature infants with birth
weights less than 1000 g and results in significant morbidity
and mortality, particularly in extremely premature infants.

0928-4680/$ – see front matter © 2014 Published by Elsevier Ireland Ltd.

http://dx.doi.org/10.1016/j.pathophys.2013.11.009
4 S. Huda et al. / Pathophysiology 21 (2014) 3–12
Fig. 1. Pathophysiological risk factors for necrotizing enterocolitis.
In premature infants, it usually presents several weeks after
birth and the age of onset is inversely proportional to the
gestational age at birth, with an exponential increase in its
rate in infants weighing less than 1000 g. Because NEC has
not been described in a fetus, several investigators have sug-
gested that postnatal factors likely contribute to its etiology.
More than 90% of neonates were enterally fed prior to the
onset of NEC. NEC may occur in full term infants in whom it
clinically presents earlier in life due to a variety of underlying
disease states listed below under epidemiology. Although
the exact mechanism of gut injury remains controversial,
factors that have been attributed in infants at greater risk are:
immature gut mucosal and barrier function or dysmotility,
tissue ischemia secondary to underlying diseases, excessive
pro-inflammatory cytokines, enteral feeding or medications
altering gut flora, and enhanced inflammatory response
(Fig. 1). Tissue hypoxia of the affected intestine may further
decrease gut motility, and with continuation of feeding gut
flora are possibly altered and overgrowth resulting in gut
mucosal damage which may be followed by translocation
of gut bacteria into the systemic circulation with resulting
septicemia in up to 30% of NEC patients [4]. Here we will
review the epidemiology, clinical features, pathophysiology,
management and prevention of NEC.
2. Epidemiology
NEC prevalence varies amongst NICUs. In a report from
the NICHD Neonatal Research Network, NEC had a mean
prevalence of 7% in infants with birth weight less than 1500 g,
rising to 15% in infants weighing less than 750 g, with 50%
of them receiving surgical intervention [5]. Overall, NEC
results in significant morbidity [6–8], and the mortality rates
range from 5 to 24% [9–13]. On rare occasions, NEC may
occur in infants born at near-term or term gestation in whom
it presents earlier. These term infants may have asphyxia,
congenital heart disease, polycythemia, exchange transfusion
or underlying surgical condition (e.g. Hirschprung’s disease)
suggesting a different mechanism of gut injury.
 S. Huda et al. / Pathophysiology 21 (2014) 3–12 5

Table 1
Stage Clinical Laboratory Radiological Management
Ia Temperature instability, apnea, Unremarkable Unremarkable Asses frequently to rule out if due to
bradycardia, ↓ SaO2 , ↑ gastric prematurity, CPAP or sepsis, hold feeds if
residuals, abdominal distension, green tinged, increase feeds cautiously
stool-occult blood +ve
Ib Same as above Same as above + bloody Unremarkable Above + rule out fissures. Consider
stools antibiotics to be discontinued in 2 days if
CRP and blood cultures are normal
IIa Stage I + decreased or absent Mild metabolic acidosis, mild Dilated bowel loops, NPO, gastric decompression, X-ray
bowel sound, guarding thrombocytopenia sentinel loops, abdomen q 6–8 h including left lateral
pneumatosis intestinalis decubitus, inform surgeons. Start
antibiotics × 7–10 days after sepsis work-up
IIb Stage I & IIa + absent bowel Metabolic acidosis, IIA + portal venous gas Same as above + supportive treatment
sounds, marked guarding, thrombocytopenia, shadows
abdominal wall discoloration or hyponatremia
cellulitis, Rt. lower quadrant mass
IIIa Stage I & II + hypotension, DIC Respiratory acidosis, Stage II + ascites Same as above + insure adequate coverage
metabolic acidosis, for gram negative bacteria and anaerobes
neutropenia, increased
PT/PTT/INR, D-dimer,
increase CRP
IIIb Same as above Same as above Stage II & Above + emergency surgery
IIIa + pneumoperitoneum

3. Clinical features
In 1978 Bell et al. [14] suggested staging of NEC depend-
ing on its severity, which was subsequently modified by
Walsh and Kliegman [15]. Table 1 lists the staging along
with suggested management strategies. Feeding intolerance
is a common presentation of NEC which is also observed
in premature infants with septicemia, decreased gut motil-
ity, use of caffeine or indomethacin, and gastro-esophageal
reflux, thus resulting in over-diagnosis of stage I NEC. In
order to diagnose NEC early, a high index of suspicion should
be maintained in premature infants, particularly those with
birth weights less than 1 kg, and in infants with unstable peri-
natal events who should be monitored closely. Non-specific
laboratory findings reported in NEC patients are: neutrope-
nia, leukocytosis, thrombocytopenia [16,17], hyponatremia,
acidosis or hyperglycemia. Radiological findings of fixed
dilated bowel loops or ‘sentinel loop sign’ (Fig. 2), pneu-
matosis intestinalis (white arrows: Fig. 3), portal venous gas
shadow (black arrows: Fig. 3) and pneumoperitoneum which

Fig. 2. X-rays KUB with markedly dilated sausage shaped loop (white Fig. 3. X-rays KUB with black arrow depicts portal venous gas shadow and
arrow) and umbilical venous catheter in place. white arrow depicts pneumatosis intestinalis.
6 S. Huda et al. / Pathophysiology 21 (2014) 3–12
Fig. 4. Football sign – black arrow depicts free air under the diaphragm and
white arrow depicts falciform ligament.
may present as ‘football sign’ (Fig. 4; white arrows: free
air, black arrows: falciform ligament) are helpful in diagno-
sis of NEC. In some patients, pneumatosis, portal venous
gas and pneumoperitoneum are seen in advanced stage of
NEC with gut necrosis or ‘NEC totalis’ with poor progno-
sis. Pneumoperitoneum represents bowel perforation and is
a surgical emergency. Isolated spontaneous intestinal perfo-
ration (SIP) is also occasionally seen in premature infants
who have received postnatal corticosteroids, indomethacin,
or were hypotensive, and these patients have a relatively better
prognosis. The diagnosis of SIP is difficult to make with-
out laparotomy, and thus some epidemiological studies may
have overestimated the prevalence of NEC. High resolution
ultrasonography has been used to asses gut injury, wherein
echogenic dots or dense granular echogenic spots are seen
in the bowel wall [18], and color Doppler imaging has been
used to diagnose pneumatosis [19], but these techniques have
not received wide acceptance. Some investigators believe that
due to our failure to diagnose NEC early, infants have seri-
ous adverse outcome with enormous impact on their families
who have to make frequent hospital visits, care for a hand-
icapped infant and deal with financial burden [20]. Hence
many NICUs adhere to strict feeding protocols, which have
been considered to possibly decrease the occurrence of NEC.
However, randomized, prospective studies with adequate sta-
tistical power to control for multiple factors in the extremely
premature infants, particularly those with fetal compromise
Fig. 5. Congested, discolored and thickened bowel due to edema and inflam-
mation.
and/or critically ill at birth are lacking. Therefore, we sug-
gest a conservative approach in these high-risk infants by
encouraging breast milk feeding (total or partial), to cau-
tiously increase feeds and frequently assess them to minimize
the occurrence of NEC, and diagnose NEC earlier when it
does occur.
4. Pathology (gross and histopathology)
NEC commonly affects the terminal ileum followed by
colon and other segments of the small intestine [21,22].
Since pathological specimens are obtained from surgery or
during autopsy, early stages of NEC are not usually acces-
sible for pathological examination. On gross examination,
as the disease process continues, the intestines appear con-
gested, discolored and thickened (Fig. 5) due to edema and in
advanced cases gas-filled cysts may be visible. These areas
can progress to appear dark, gray and gangrenous (Fig. 6)
and may perforate. Intestinal pneumatosis, the formation of
gas bubbles within the intestinal wall is a characteristic find-
ing seen in most patients with NEC, likely resulting from
fermentation and gas production by bacteria. The intestinal
wall perforates when the disease is severe with transmural
involvement.
 S. Huda et al. / Pathophysiology 21 (2014) 3–12
Fig. 6. Dark, gray gangrenous bowel with hemorrhagic foci.
Microscopic examination shows early changes of
microvascular thrombi, submucosal gas-filled cysts (intesti-
nal pneumatosis), vascular congestion, edema and a variable
inflammatory infiltrate in the mucosal and submucosal areas.
The inflammatory component may appear relatively less
compared to the degree of necrosis. Late changes include
coagulation necrosis with hemorrhage and gangrenous bowel
wall susceptible to perforation [23] (Fig. 7a–e).
Although there is no histological grading of NEC in
humans, using an animal model, Jilling et al. have described
grading from 0 to 4 with grade 0 representing intact mor-
phology, grade 1 showing sloughing of the tip of villi, grade
2 with mild necrosis of villi, grade 3 with loss of villi, and
grade 4 representing complete destruction of the intestinal
mucosa [24].
5. Pathophysiology
5.1. Mechanism of injury
This has been described in other chapters. We have sum-
marized some of the salient features below.
7
5.1.1. Decrease in mucin production
In NEC, the onset of the inflammatory process may be
gradual, but may have a rapid progression, thus making it
difficult to ascertain the time of its origin. Since most prema-
ture infants do not develop NEC despite immature intestines,
it has been suggested that there may be genetic predisposition
with fewer mucin-producing goblet cells in some infants. The
goblet cells are expressed as early as 9 weeks of gestation,
with peak expression at 23 weeks of gestation. The develop-
mental expression of mucin goes through various stages of
maturation with adult pattern layer observed between 23 and
27 weeks of gestation. Mucin protects the intestinal epithelial
lining and prevents the translocation of the gut microbes into
the circulation [6,25–28].
5.1.2. Cytokines and chemokines
The role of cytokines and chemokines in inflammation
leading to gut injury in NEC has been extensively studied. The
initial process of inflammation in gut injury likely begins with
ischemia leading to the dysmotility of the intestine followed
by excessive distension leading to the damage of the intestinal
mucosal epithelial cells leading to the proliferation of proin-
flammatory bacteria. Lipopolysaccharide (LPS) [29–31] (an
endotoxin present in the outer wall of the gram negative bacte-
ria) may trigger the activation of the inflammatory cascade by
engaging the toll like receptors (TLR), leading to the release
of various cytokines and chemokines, e.g. interferon gamma,
Interleukin-6, interleukin-8, interleukin-12, interleukin-18,
tumor necrosis factor-alpha. These cytokines and chemokines
are regulated by the transcription factor nuclear factor-kB,
which regulates the leukocyte adhesion molecules. The role
of cytokines and toll receptors has been discussed in other
chapters in this issue.
5.1.3. Role of endothelium
Several researchers have proposed that NEC is an
ischemia–reperfusion injury with significant reduction in
intestinal blood flow leading to inflammation followed by
cellular necrosis. With compromised blood flow, the tissue
is deprived of oxygen and nutrients. Endothelium, which
lines the microvessels plays a pivotal role in controlling
the blood flow to the intestinal tissues via regulation of
endothelin-1 (ET-1) and endothelial nitric oxide (eNO). ET-1
is a potent vasoconstrictor [32], which acts via binding with
ETA receptor and eNO, a potent vasodilator, which acts via
ETB receptor. Nankervis and Nowicki postulated that this
results from imbalance between vasoconstriction and vaso-
dilatation properties of the endothelin leading to ischemia of
the affected tissue causing NEC [33]. Thus vascular endothe-
lial cells also play a major role in inflammatory cascade and
acts as an immunomodulator.
5.1.4. Role of feeding
Although NEC has never been reported in a fetus, Nan-
thakumar et al. found evidence suggesting gut inflammation
in aborted fetuses [34]. They postulated that because of
8 S. Huda et al. / Pathophysiology 21 (2014) 3–12

Fig. 7. (a) H&E-stained histological sections of a macroscopically unaffected segment, showing early signs of epithelial degeneration at villous tips and
thrombus formation (arrow head) in an underlying vessel, hematoxylin–eosin stain, 100×. (b) Pathologic findings in NEC. Histologic sections of small bowel
showing early stage of intestinal injury with hyperemia of mucosa and loss of epithelial cells at the villus tips (1). Intramural gas is seen as rounded bubbles in
the submucosa (arrows), hematoxylin–eosin stain, 100×. (c) Here the bowel is affected much more severely. There is necrosis of the mucosa and submucosa
with intraluminal necrotic debris on the mucosal side of the bowel wall (m) and loss of villi. The histologic characteristics of NEC include coagulative necrosis
(1), bacterial overgrowth with inflammatory cell infiltration (2), mucosal edema and ulceration (3), hematoxylin–eosin stain, 100× with insert at 400×. (d)
High magnification of a histological section of the necrotic small bowel mucosa showing characteristic vascular thrombi (arrowhead) and necrosis (arrow),
hematoxylin–eosin stain, 200×. (e) Transmural necrosis of mucosa, submucosa, and muscularis propria extending to serosa with potential for perforation.
s = serosal surface of bowel wall.

excessive cytokine production, immature human enterocytes
may be prone to necrosis. In more than 90% of patients, NEC
occurs in neonates who received enteral feeds. Although
there is lack of consensus amongst neonatologists regarding
the timing of initiation and the rate of increase of enteral
feedings in premature infants, most physicians administer
trophic feeds which are increased cautiously in extremely
premature infants, particularly those who had absent diastolic
flow in fetal period, had hypotension or severe intrauterine
growth retardation. Also, it has been suggested that in utero,
these infants produce meconium by swallowing amniotic
fluid, which possibly has protective chemicals with a role in
preventing intestinal injury after birth. Christensen et al. fed
a small group of 10 very low birth weight infants weighing
750–1250 g with formula having composition similar to the
amniotic fluid and found no significant adverse effects in all
these VLBW infants [35]. They suggested that amniotic fluid
contents including erythropoietin and granulocyte-colony
stimulating factor have antiapoptotic effects. Feeding prac-
tices in many NICUs are dependent on the clinician caring
for the infant. However many neonatologists consider that
if the infant does not have a large Patent Ductus Arteriosus
or hypotension requiring vasopressors, minimal enteral
nutrition, i.e. trophic feedings should be initiated once the
infant is stable. This concept of priming the gut epithelium
and develop adaptability may also help in decreasing feeding
 S. Huda et al. / Pathophysiology 21 (2014) 3–12
intolerance. Clinical trials have been conducted by keeping
these infants Nil Per Os (NPO) for a week followed by
introduction of the feeds with no differences observed in the
incidence of NEC in infants weighing greater than750 g at
birth. The Cochrane Systematic Review evaluating 9 trials
does not suggest that the practice of minimal enteral nutrition
either increases (or decreases) the risk of definite NEC,
with a typical relative risk of 1.07 (95% confidence interval
0.67, 1.70); typical risk difference of 0.01 (95% confidence
interval −0.04, 0.05) [36]. Premji et al. reviewed data from
seven different trials in 571 infants on the effectiveness of
continuous feedings in premature infants weighing less than
1500 g and concluded that there was no significant difference
in the time to achieve the full feeds, somatic growth and the
incidence of the NEC [37]. A consensus should be developed
amongst neonatologists regarding the postnatal age to start
trophic feeds, and the rate of increase of enteral feeds in
various subgroups of premature infants. Although studies
have been conducted on rapidity of increasing enteral feeds
in premature infants, there is paucity of data in infants with
birth weight of less than 750 g, and in those with varying
degrees of illness. Since VLBW have a poor gut barrier
and motility, they are prone to develop feeding intolerance.
Under such circumstances, with an increase in gastric
residuals even an experienced neonatologist may miss the
early signs of NEC and although radiological evidence to
support the diagnosis [38,39] and other criteria listed in table
have been used, they are not definitive.
5.1.5. Infant formula and breast milk
The next question is which form of enteral nutrition should
be used, i.e. cow milk-based infant formula or human milk
(either mother’s breast milk or donor breast milk)? The Amer-
ican Academy of Pediatrics endorses the use of human milk
[40]. With the use of human milk, a decrease in the inci-
dence of the NEC has been reported [41–44]. Lactoferrin, an
iron-binding protein is suggested to be an important factor
providing protective barrier and boosting the immune system
by stimulating the infant’s innate immunity [4]. It is high-
est in colostrum (7 g/dL) compared to mature milk (1 g/dL)
and is lowest in the mid-lactation milk (0.1 g/dL) [45–47].
Although in the fetus the gut is sterile, it is colonized by
variety of microbes in the post-natal period. Gut microbiota
is also altered by the type of feeding the newborn infant
receives, i.e. breast fed infants get lactobacilli or bifidoba-
teria in comparison to formula fed infants that are colonized
with enterobacteria and other gram negative organisms [48].
In a double-blind placebo controlled randomized trial con-
ducted at eleven tertiary care NICUs involving 472 very low
birth weight infants (VLBW) infants who were given bovine
lactoferrin (BLF) and BLF plus Lactobacillus rhamnosus GG
(LGG) from birth to 30 days of life, Manzoni et al. concluded
that BLF supplementation alone or in combination with LGG
reduced the incidence of a first episode of late onset sepsis
in VLBW neonates [49]. Additionally, with the use of pro-
longed use of antibiotics and/or H2-blockers, the gut loses its
9
normal flora and may develop resistant microbes which may
result in NEC and sepsis [34]. Carrion and Egan reported that
by maintaining an acidic gastric pH less than 3.0 in breast
milk, PM 60/40 and PF20, the incidence of NEC decreased,
in contrast to higher gastric enteric bacterial colony counts
which strongly correlated with gastric pH greater than 4.0
[50]. It is unclear whether the absence of harmful contents,
or the presence of anti-inflammatory factors in the human
milk prevents NEC. It is also postulated that unknown proin-
flammatory substances in artificial formula milk aggravate
gut injury in infants with a genetic predisposition.
Several probiotic strains have been used by researchers
including: Bifidobacterium bifidus, breve, infantis, lactis and
longus; Lactobacillus acidophilus, casei, rhamnosus GG,
plantarum and sporogenes; Streptococcus thermophillus and
Saccharomyces boulardii.
Although clinical trials have demonstrated favorable result
with use of probiotics treatment, several concerns remain,
such as their side effects, optimal organism, dosages and the
immature immune response of premature infants. Since, the
actual dosage of pre, pro and postbiotics are unknown, com-
plications may occur which could be dose related [1,51].
Rationale for the use of prebiotics and postbiotics in pre-
venting NEC has been discussed by Dr. Panigrahi and Dr.
Denning in this issue.
5.1.6. Transfusion associated gut injury
Agwu et al. in 2005 in a case report suggested that blood
transfusion may be a risk factor in inducing gut injury in pre-
mature infants leading to NEC. Subsequently several studies
documented an increase in NEC among premature infants
receiving enteral feeding during transfusion [52–56]. Stritzke
et al. in 2013 conducted a retrospective chart review of 927
patients with NEC and reported an association of transfusion
associated NEC (TANEC). They noted that 5.5% of patients
received transfusion two days prior to the diagnosis of NEC.
Majority of these TANEC patients were critically ill during
their initial hospital admission, and developed NEC between
23 and 37 days of life [57].
5.2. Long-term outcome
The prevalence of NEC varies amongst NICUs. Ladd
et al. conducted a retrospective study of 249 NEC patients
who underwent surgery to analyze the factors possibly
impacting long-term survival and growth. They reported
that survivors were more mature, increased birth weight
and postnatal age at the time of surgery. There were 112
deaths with 36% having NEC totalis, and an additional
30% died of septicemia. The average postoperative survival
was 46.9 ± 91.5 days. Significant mortality was observed in
neonates ≤30 weeks gestation (53%). In NEC, those patients
who received surgical intervention had longer hospital stays
in comparison to medical NEC. All such babies go through
prolonged periods of parenteral nutrition but the majority
are on enteral nutrition at the time of discharge. Although
10 S. Huda et al. / Pathophysiology 21 (2014) 3–12
duration of prolonged parenteral nutrition duration depends
on the intact ileocecal valve, it is also dependent on the
length of the intestine resected. In general, those in whom
>20 cm has been resected, go through prolong parenteral
nutrition [58]. These infants go through a prolonged period
of intestinal rehabilitation, depending on the size of viable
gut remaining. The consequences of short gut have been
discussed by Dr. Peter Minneci in this issue of the journal.
Growth and development remains a major concern in
infants surviving NEC. Sonntag et al. reported significant
neurodevelopmental delay at 12 and 20 months in a small
group of VLBW survivors of NEC [59]. Salhab et al. reported
similar findings with neurodevelopmental assessment done
at 18–22 months [60]. In a large NICHD study cohort, Hintz
et al. hypothesized that ELBW infants with surgically man-
aged NEC are at greater risk for poor neurodevelopmental
and growth outcomes than in NEC patients managed med-
ically and those infants did not have NEC. They evaluated
2948 infants at 18–22 months. Amongst them, 124 survived
after surgery of NEC, and 121 managed medically. Infants
with NEC who had surgery had more cystic periventricu-
lar leukomalacia, bronchopulmonary dysplasia and stunted
growth in comparison to those in whom the NEC was man-
aged with medical therapy and those who did not develop
NEC [61]. Whereas Schulzke et al. after reviewing eleven
non-randomized studies including 5 with matched control
patients reported similar neurodevelopmental impairment in
the NEC survivors requiring surgical intervention compared
to those requiring medical therapy [62].
5.3. Management
Patients with NEC managed medically should be NPO
along with gastric decompression (using large-bore Repogle
tube), given total parenteral nutrition, receive appropriate
antibiotic coverage (to cover anaerobic, gram negative and
positive organisms), and receive close clinical and laboratory
monitoring with serial abdominal X-rays (antero-posterior
and left lateral decubitus views) done every 6–8 h to detect
intestinal perforation. Emergency surgical intervention is
undertaken in all cases of pneumoperitoneum, and in some
patients with abdominal cellulitis (i.e. peritonitis), and in
those with persistent thrombocytopenia suggesting necrotic
bowel. Whether infection is the primary cause or occurs
secondary to the ischemic gut initiating the inflammatory cas-
cade remains controversial. Cole et al. reported that patients
with NEC had late onset sepsis [63]. There are no clini-
cal features or diagnostic tests which enable the clinician
to halt the inflammatory process which leads to gut injury
and necrosis. When pneumoperitoneum is detected, gan-
grenous changes in the intestines may have occurred in some
instances, hence surgeons must be consulted in all suspected
patients with NEC to minimize the time to surgery after pneu-
moperitoneum is diagnosed (Fig. 4). In addition, surgical
intervention is also indicated if the infant is clinically dete-
riorating despite maximal medical treatment, if abdominal
mass is detected, has signs of persistent intestinal obstruc-
tion, sepsis, or has intestinal stricture. Relative indications for
surgery are: increased abdominal tenderness, distension, dis-
coloration, or the persistence of portal vein gas [64]. Surgical
interventions include primary peritoneal drainage, laparo-
tomy with resection and enterostomy, resection with primary
anastomosis, proximal diverting jejunostomy, and “Clip and
Drop” technique. Najaf et al. reported that 24% of their 124
infants with >Stage II NEC developed bowel perforation
with a median interval of 1 day from the appearance of the
symptoms [65]. In another review of 147 patients with NEC,
Kosloske concluded that in addition to pneumoperitoneum
which remains the definitive indication for surgery, portal
venous gas and greater than 0.5 mL of brown fluid and/or
bacterial growth in the fluid at paracentesis, surgical interven-
tion should be considered [66]. Dr. Moss has elaborated on
the surgical management of patients with NEC in this issue.
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