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Enterocolitis Necrotizante

The article discusses the clinical management of necrotizing enterocolitis (NEC), a serious intestinal condition primarily affecting preterm infants. It outlines risk factors, symptoms, diagnostic methods, and staging criteria for NEC, emphasizing the importance of early recognition and management. The document also details medical and surgical interventions, highlighting that most cases are treated non-operatively with supportive care and antibiotics.

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Enterocolitis Necrotizante

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Clinical Management of Necrotizing Enterocolitis

Reed A. Dimmitt and R. Lawrence Moss

Neoreviews 2001;2;e110
DOI: 10.1542/neo.2-5-e110

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Article gastroenterology

Clinical Management of
Necrotizing Enterocolitis
Reed A. Dimmitt, MD,*
Objectives After completing this article, readers should be able to:
and R. Lawrence Moss,
MD† 1. List the major risk factor for developing necrotizing enterocolitis (NEC).
2. Describe the presenting symptoms and physical findings of NEC.
3. Describe the initial steps in stabilizing an infant who has NEC.
4. Delineate the current recommendations for surgical intervention in NEC.

Introduction
Necrotizing enterocolitis (NEC) is the most common intestinal emergency in the preterm
infant, occurring in 1% to 5% of patients admitted to the neonatal intensive care unit
(NICU) and in 1 to 3 per 1,000 live births. Data from the National Center for Health
Statistics and individual institutions suggest an incidence of 1,200 to 9,600 cases per year
in the United States that result in more than 2,600 deaths annually.
The incidence of NEC correlates strongly with the degree of prematurity. Only a
handful of patients were reported as having NEC in the 1960s when very low-birthweight
(VLBW) infants did not survive long enough to acquire the disease. The incidence of NEC
is lower in countries that have decreased rates of prematurity. The routine use of both
antenatal steroids and prophylactic surfactant has resulted in the survival of greater
numbers of VLBW babies, and these extremely preterm infants present the greatest
challenge in the clinical management of NEC.
Over the past decade, advances in neonatal management have decreased the mortality
and morbidity associated with most conditions of prematurity, as demonstrated by a recent
report of the incidence of chronic lung disease during the postsurfactant administration
years of 1996 to 1998. VLBW patients who had birthweights of 801 to 900 g had only a
25% incidence of chronic lung disease; the incidence was only 15% among those weighing
901 to 1,000 g. In comparison, a study in 1975 of mechanically ventilated VLBW patients
reported survival in only 32%, all of whom had bronchopulmonary dysplasia. In contrast,
during this same period, the mortality rate of patients who had perforated NEC remained
largely unchanged, ranging from 35% to 50%. Infants who survive have a high prevalence
of adverse intestinal sequelae, including short bowel syndrome and total parenteral
nutrition-induced cholestasis. Additionally, a multicenter cohort study found a strong
association between NEC and adverse neurodevelopmental outcomes.

Diagnosis
Clinical Findings
Infants who have NEC usually display specific gastrointestinal signs. Early presenting signs
are abdominal distention (70% to 98%), feeding intolerance with increased gastric residuals
(!70%), emesis (!70%), gross blood per rectum (25% to 63%), occult gastrointestinal
bleeding (22% to 59%), and occasionally diarrhea (4% to 26%). As the disease progresses,
abdominal findings become more severe. Patients may develop marked abdominal disten-
tion due to increased intestinal dilation and ascites. Abdominal wall erythema may be
caused by necrotic bowel loops abutting the thin abdominal wall. When the intestine is
perforated, the abdomen may develop a bluish cast as intraperitoneal meconium is seen
through the abdominal wall.
Early systemic signs among patients who have NEC are typically nonspecific; they are

*Fellow in Pediatrics, Division of Neonatal and Developmental Medicine.

†
Assistant Professor of Surgery, Division of Pediatric Surgery, Stanford University School of Medicine, Palo Alto, CA.

e110 NeoReviews Vol.2 No.5 May 2001

similar to those seen with other causes of deterioration

and sepsis. Initially, patients may exhibit only lethargy
and temperature instability. This is followed by worsen-
ing cardiorespiratory function that ranges from episodes
of apnea and bradycardia to severe cardiovascular decom-
position. The signs of ileus due to systemic sepsis may be
difficult to distinguish from NEC, but the initial man-
agement is the same for both conditions.
Most cases of NEC are associated with prematurity,
although 10% of affected patients are term infants. These
infants have an earlier onset of NEC than do preterm
infants, and the disease can be fulminant.

Laboratory Findings
A patient who has NEC can present with an abnormal
white blood cell count. It may be elevated, but more
commonly it is depressed. A severely low white blood cell
count ("1.5 # 109/L ["1,500 cells/cu mm]) has been
reported in 37% of cases. It results from both decreased
production and increased utilization of leukocytes. Some
authors have shown an association between leukopenia
and gram-negative bacteremia in NEC. Thrombocyto-
penia is also common, seen in up to 87% of patients. In
addition, patients may develop other coagulation abnor-
malities, including prolongation of prothrombin time
and hypofibrinogenemia. Glucose instability (hypoglyce-
mia or hyperglycemia), metabolic acidosis, and electro-
lyte imbalance may occur. Some patients have elevated Figure 1. A plain anteroposterior radiograph demonstrating
C-reactive protein levels. Because no unique infectious pneumatosis. Note the extensive cystic pneumatosis (arrow) as
well as linear pneumatosis in the right upper quadrant.
agents have been incriminated in NEC, bacteriologic and
fungal cultures may prove helpful but not conclusive.

Radiology
Radiographic imaging is essential for diagnosing sus-
pected NEC. Plain anteroposterior abdominal and left
lateral recumbent radiographs are the studies of choice.
These allow the clinician an excellent view of the intesti-
nal gas pattern and the ability to identify free abdominal
air. Intestinal ileus is the most common early finding.
Other early findings include dilation and thickening of
bowel loops with air-fluid levels on the decubitus view.
The pathognomonic radiographic finding in NEC is
intramural gas (pneumatosis intestinalis) (Fig. 1). The
gas is present between the subserosal and muscularis
layers of the bowel (Fig. 2). Pneumatosis is caused by
hydrogen production from pathogenic bacteria. Two
radiographic patterns of pneumatosis are described. The
cystic pattern results from bubbles of air in the submu-
cosa and can mimic fecal material in the large bowel. The Figure 2. Photomicrograph of intestine with NEC. The cystic
linear pattern is formed by coalesced air bubbles and areas below the severely disrupted mucosal layer are pockets
courses parallel to the bowel lumen. of hydrogen gas that present radiographically as pneumatosis.

NeoReviews Vol.2 No.5 May 2001 e111

Figure 3. A left lateral decubitus radiograph demonstrating

free air (arrow) between the body wall and the liver. A
dependent radiographic view is required to visualize this small
amount of free air.

The most serious complications of NEC are intestinal

necrosis and perforation, which occur in up to one third
of patients. Identifying the development of a perforation
can be challenging. When free air is seen on abdominal
radiographs, the diagnosis is clear. Pneumoperitoneum is
the only absolute indication for surgical intervention.
Free air is best visualized on a dependent radiograph (left
lateral decubitus or cross table lateral). The air migrates
Figure 4. An anteroposterior radiograph showing extensive
to the nondependent portion of the abdomen and is seen free air. This so-called “football sign” is a dramatic but
between the body wall and hepatic silhouette (Fig. 3). uncommon finding in perforated NEC.
Less commonly, the pneumoperitoneum can be seen as a
large central collection of free air on an anteroposterior
abdominal film. This so-called “football sign” occurs
when free abdominal air outlines the falciform ligament bowel. In the original report of this finding, loops that
and umbilical arteries (Fig. 4). remained unchanged for 24 to 36 hours were associated
Some patients who have NEC and perforation or with transmural necrosis. Some reports have shown an
necrosis will not manifest radiographic evidence of free association between fixed loops and pan-necrosis, al-
air. Free air is the only absolute indication for surgery, though almost 50% of these patients recover without
but other findings may suggest the need for surgical operation. NEC can present as a distended, gasless ab-
intervention. When intramural air in the bowel is abdomen, and it can cause ascites. Increased intraperitoneal
sorbed into the mesenteric venous circulation, it may fluid can appear as a dense peripheral shadow surround-
result in the phenomenon termed portal venous gas ing gas-filled bowel loops in the center of the abdomen
(PVG). Some have argued that the gas is actually in the on plain radiographic studies. The finding of ascites with
hepatic lymphatics rather than the portal vein. PVG PVG has been associated with high mortality.
appears as thin, linear, air-dense areas overlying the liver. Some authors have used other modes of imaging to
PVG with extensive pneumatosis is a poor prognostic diagnose NEC and assist in the decision for surgical
sign, but PVG alone or with little pneumatosis is seen intervention. The use of ultrasonography, contrast radi-
frequently among patients who eventually recover with- ography, and even magnetic resonance imaging has been
out surgical intervention. reported anecdotally, but their utility has not been estab-
Occasionally, patients who have NEC have radio- lished. These studies never should delay otherwise indi-
graphic evidence of a fixed or persistent dilated loop of cated medical or surgical management.

e112 NeoReviews Vol.2 No.5 May 2001

Table 1. Modified Bell Staging Criteria for NEC*

Stage Systemic Signs Intestinal Signs Radiographic Signs
I: Suspected NEC Temperature instability, apnea, Elevated gastric residuals, mild Normal or mild ileus
bradycardia abdominal distention, occult
blood in stool
IIA: Mild NEC Similar to Stage I Prominent abdominal distention ! Ileus, dilated bowel loops
tenderness, absent bowel with focal
sounds, grossly bloody stools pneumatosis
IIB: Moderate NEC Mild acidosis and Abdominal wall edema and Extensive pneumatosis,
thrombocytopenia tenderness ! palpable mass early ascites, ! PVG
IIIA: Advanced NEC Respiratory and metabolic acidosis, Worsening wall edema and Prominent ascites,
mechanical ventilation, erythema with induration persistent bowel loop,
hypotension, oliguria, DIC no free air
IIIB: Advanced NEC Vital sign and laboratory evidence Evidence of perforation Pneumoperitoneum
of deterioration, shock
PVG$portal venous gas, DIC$disseminated intravascular coagulopathy
*Reprinted with permission from Kleigman RM, Walsh MC. Neonatal necrotizing enterocolitis: pathogenesis, classification, and spectrum of disease. Curr
Probl Pediatr. 1987;17:213.

NEC Staging Clinical Management

In 1973, Bell et al first attempted to categorize NEC by Medical Management
presentation and severity. These criteria were modified in Most patients who have NEC are treated nonoperatively.
1978 to include therapeutic and prognostic aspects of The maxim of ABCs (airway, breathing, and circulation)
the disease (Table 1). Although staging of NEC would holds in these infants. Most require some mechanical
appear to be helpful in determining appropriate treat- ventilatory support. If necessary, tracheal intubation is
ment, each patient’s condition supersedes category preferred to continuous positive airway pressure to pre-
guidelines. vent aerophagia and subsequent greater bowel disten-
tion. Peripheral arterial access should be established for
accurate measurement of systemic blood pressure and
Differential Diagnosis arterial blood gases. Many patients will be hypovolemic
Sepsis with ileus, in both term and preterm patients, can and require fluid resuscitation and correction of acid-
mimic NEC. Both present with systemic signs of infec- base imbalance. The acidemia in NEC is often mixed,
tion and abdominal distention. The absence of pneuma- with a respiratory component from hypoventilation as
tosis on plain radiographs argues against NEC, but does well as a metabolic contribution from hypoperfusion.
Initially, isotonic crystalloid fluid (0.9% sodium chloride
not rule it out. Fortunately, the treatment for both
or lactated Ringer solution) is recommended, but colloid
conditions is similar: bowel rest, antibiotic administra-
use may become necessary following capillary leak and
tion, and supportive care. In VLBW infants, inspissated
subsequent hypoalbuminemia with third space fluid ac-
meconium syndrome results in distended intestinal
cumulation. If there is evidence of coagulopathy, admin-
loops. However, these babies typically present with ob-
istration of platelets, fresh-frozen plasma, or cryoprecip-
structive signs without evidence of sepsis. Isolated gastric itate may be indicated. Sodium bicarbonate should be
perforation can result in pneumoperitoneum. Gastric given in severe metabolic acidosis. Dopamine and epi-
perforation may be associated with administration of nephrine infusions may be necessary when hypoperfusion
indomethacin or corticosteroids. Iatrogenic gastric per- does not respond to fluid administration.
foration from feeding tubes occurs rarely. Although pa- After obtaining blood cultures, broad-spectrum anti-
tients who have gastric perforation present with pneu- microbial therapy appropriate to cover bowel flora
moperitoneum, they are not as systemically ill as patients should be initiated. Ampicillin and gentamicin are possi-
who have NEC. Patients who have Hirschsprung entero- ble choices, but the common use of these antibiotics in
colitis or severe gastroenteritis may present with pneu- the NICU typically results in the development of resis-
matosis. tant organisms. Because NEC usually is acquired in the

NeoReviews Vol.2 No.5 May 2001 e113

NICU, antibiotic therapy may be guided by patterns of well-defined segment of dead bowel, with the remainder
resistance in the individual unit. In addition, VLBW of the intestine appearing normal. In others, disease may
infants are at risk for bacteremia from coagulase-negative be patchy, involving multiple segments of the intestine,
Staphylococcus. Accordingly, empiric treatment with van- or large areas of intestine may be of questionable viabil-
comycin and a third-generation cephalosporin is appro- ity. The surgeon must resect all of the necrotic intestine
priate. Because anaerobic flora can be acquired as early as yet avoid removing intestine that ultimately could prove
1 week of age, a third agent to cover these organisms may viable. A portion of viable intestine is used to create an
be warranted. The severity of the disease and the need for enterostomy and mucous fistula. Once evidence of bowel
long-term coverage with broad-spectrum antibiotics function returns, enteral feeds are introduced slowly.
places patients who have NEC at risk for fungal sepsis. The period of time to bowel reanastomosis varies;
Amphotericin, administered either empirically or follow- 6 weeks is the minimal waiting period.
ing proven culture, may be necessary later in the course Primary resection and anastomosis of an isolated per-
of treatment. foration has been reported anecdotally, but this proce-
Discontinuation of enteral feeding and gastric decom- dure is not widely accepted. When multiple segments of
pression with a large-bore (10 or 12 French) orogastric bowel are affected, the surgeon traditionally is forced to
tube should be facilitated. Although fraught with impre- create multiple stomas. An alternative technique is the
cision, serial measurements of the abdominal girth are so-called “patch, drain, and wait” approach. Each perfo-
warranted. More important is serial examination by the ration is sutured closed, Penrose drains are placed in the
same examiner. Frequent abdominal radiographs are lower abdominal quadrant, and parenteral nutrition is
needed to monitor disease progression. continued. For patients who have pan-necrosis with ex-
Antimicrobial therapy and bowel rest should be con-
tensive involvement, the appropriate surgical manage-
tinued for 7 to 14 days, depending on the severity of the
ment is unclear. Resection of affected bowel results in
episode. At the end of this period, it is important to
severe short bowel syndrome. Because of the poor out-
increase feedings gradually over many days. Some pa-
comes seen in these patients, some surgeons support the
tients who appear to respond successfully to medical
practice of foregoing any treatment.
treatment will manifest increased gastric residuals, ab-
For patients weighing fewer than 1,500 g, the best
dominal distention, and bilious emesis as enteral feeds
operative management is not known. Historically, the
are advanced. This scenario suggests the development of
surgical management of VLBW neonates who had per-
intestinal strictures. Strictures occur in areas of the intes-
forated NEC was the same as that for larger babies:
tine that suffered ischemia without full-thickness necro-
laparotomy, resection, and stoma creation. However,
sis. These areas heal by scarring, and contraction of the
scar leads to stricture. Strictures may occur anywhere in applying classic surgical techniques in these very small
the intestine, but the most common site is at the junction babies may increase mortality and morbidity. In 1977,
of the descending and sigmoid colon. Radiographic Ein and colleagues reported the use of primary peritoneal
studies reveal evidence of a partial bowel obstruction, drainage (PPD) for perforation in VLBW infants. PPD
with intestinal dilatation on the anteroposterior view and involved making a right lower quadrant incision, irrigat-
air-fluid levels on the dependent view. High suspicion of ing the peritoneal cavity, and placing a small Penrose
stricture warrants bowel rest until 6 weeks after the initial drain in the abdomen. The authors treated five patients
diagnosis of NEC to allow complete fibrous healing. weighing 760 to 1,600 g who were described as septic
A contrast enema should be performed at the completion and unstable. Surprisingly, three of these five “mori-
of this period. If results of a lower gastrointestinal study bund” babies survived. One of the three developed an
are normal, an upper gastrointestinal contrast study is intestinal stricture that was repaired electively 6 weeks
indicated. If a stricture is identified, it should be resected later. The two infants who did not survive died of causes
surgically. unrelated to NEC, and their gastrointestinal tracts were
intact at autopsy. The success of PPD in this anecdotal
Surgical Management report was impressive compared with the 35% to 55%
Even with aggressive and appropriate medical manage- mortality associated with conventional surgical treat-
ment, 34% to 50% of patients who have NEC require ment, but the technique was widely criticized in the
surgical intervention. The operation of choice in patients pediatric surgical community. This led to a comment
weighing greater than 1,500 g is laparotomy with resec- from the authors that PPD should be used only as a
tion of frankly necrotic bowel. In some cases, there is a temporizing procedure in the “sickest” preterm infants

e114 NeoReviews Vol.2 No.5 May 2001

Type of Operation, Gestational Age (GA), Birthweight (BW), and

Table 2.

Survival With Perforated NEC: Published Data*

PPD LAP
Author n GA(wk)† BW(g)† Survival n GA(wk)† BW(g)† Survival
Cheu 51 29 1,158 18 (35%) 41 32 1,875 31 (76%)
Takamatsu 4 27 808 4 (100%) — — — —
Morgan 29 27 994 23 (79%) 20 32 1,854 18 (90%)
Azarow 44 28 1,100 27 (61%) 42 31 1,700 24 (57%)
Snyder 12 29 1,134 3 (25%) 91 31 1,628 52 (57%)
Lessin 9 25 615 6 (67%) — — — —
Ahmed 23 27 910 10 (43%) 22 35 2,271 19 (86%)
Rovin 18 28 1,118 16 (89%) 10 29 1,274 9 (90%)
Downard 24 26 794 19 (79%) 9 30 1,510 7 (78%)
Dimmitt 17 25 677 7 (41%) 9 26 807 5 (56%)
Total 231 27 (0.5) 931 (63.2) 133 (58%) 244 31 (0.9) 1,615 (155) 165 (68%)
PPD$primary peritoneal drainage, LAP$laparotomy, †Means (standard error of the means)
*Reprinted with permission from Moss RL, Dimmitt RA, Henry MC, et al. A meta-analysis of peritoneal drainage and laparotomy in perforated necrotizing
enterocolitis. J Pediatr Surg. in press.

to stabilize the baby until formal laparotomy could be Long-term Outcome

performed safely. In addition to post-NEC intestinal strictures, patients
As experience with PPD increased, many babies who undergo surgical intervention for NEC have a high
treated with this “temporizing” procedure did not ap- probability of long-term adverse outcomes. The most
pear to need a subsequent laparotomy. The institution common intestinal complication is short bowel syn-
originating the procedure reported their updated expe- drome (25%). In this condition, the amount of remain-
rience in 1980, describing 15 patients who underwent ing intestine is not sufficient to provide adequate absorp-
PPD with the intention of proceeding to laparotomy in tion of enteral nutrients and fluid. This syndrome occurs
24 to 48 hours. Forty percent of these patients improved in up to 25% of patients postoperatively. Because the
so markedly that laparotomy was not performed, and bowel is not functional, the patient is dependent on
they recovered completely without further intervention.
parenteral nutrition. The most serious sequela of pro-
PPD has never been investigated in a controlled or
longed parenteral nutrition is parenteral nutrition-
comparative trial with laparotomy. In fact, every center
associated cholestasis with resultant cirrhosis and liver
using PPD reports selection bias in patient assignment.
failure. A study in 1986 reported cholestasis in 20 of 60
A recent review of the published experience for perfo-
patients undergoing surgical intervention for NEC.
rated NEC revealed that patients undergoing PPD were
significantly smaller and more preterm than those under- Twelve of these 20 patients ultimately died from liver
going laparotomy (Table 2). Using techniques of meta- failure. Recurrent central venous catheter sepsis is also
analysis, these data were pooled. Because of the marked common. A few centers have reported anecdotal success
selection bias and the lack of published information with combined small bowel/liver transplantation, but
explaining why patients were assigned to PPD versus the mortality rate of small infants undergoing this proce-
laparotomy, the effectiveness of the two techniques dure remains unacceptably high.
could not be determined. The principle investigators As many as 50% of patients who survive NEC develop
from each institution employed PPD in patients who had neurodevelopmental delay. Although NEC is not be-
a greater expected mortality. The fact that this “sicker” lieved to be directly causative, any condition that
group of patients did better than predicted raises the results in prolonged hospitalization has been shown to
question of whether PPD may be superior to laparotomy. place neonates at risk. In a matched cohort study, no
To answer this question, a multicenter, randomized, difference in the Bailey Scales of Infant Development
controlled clinical trial is currently accruing patients. was seen among patients surviving severe NEC com-
Results of this trial may determine the best treatment for pared with patients who had similar hospital stays
this severe disease of preterm infants. without NEC.

NeoReviews Vol.2 No.5 May 2001 e115

Summary enterocolitis: therapeutic decisions based upon clinical staging.

Despite tremendous advancements in neonatal and pedi- Ann Surg. 1978;187:1–7
Dimmitt RA, Meier AH, Skarsgard ED, et al. Salvage laparotomy
atric surgical management, the mortality and morbidity
for failure of peritoneal drainage in necrotizing enterocolitis in
associated with NEC, especially in VLBW patients, re- extremely low birth weight infants. J Pediatr Surg. 2000;35:
mains great. Most patients present with specific gastro- 856 – 859
intestinal symptoms and nonspecific signs of sepsis. The Ein SH, Marshall DG, Gervan D. Peritoneal drainage under local
most serious complication is intestinal perforation, re- anesthesia for perforations from necrotizing enterocolitis.
J Pediatr Surg. 1977;12:963–967
quiring surgical intervention. The preferred operation
Holman RC, Stoll BJ, Clarke MJ, et al. The epidemiology of
for VLBW patients is currently being investigated in a necrotizing enterocolitis infant mortality in the United States.
randomized clinical trial. Am J Public Health. 1997;87:2026 –2031
Ultimately, the answer to improved outcomes for Kosloske AM, Musemeche CA. Necrotizing enterocolitis of the
VLBW infants is prevention of NEC. This will require a neonate. Clin Perinatol. 1989;16:97–111
Moss RL, Dimmitt RA, Henry MC, et al. A meta-analysis of
better understanding of the developmental biology of
peritoneal drainage and laparotomy in perforated necrotizing
the preterm intestine and the pathogenesis of the disease. enterocolitis. J Pediatr Surg. In press.
As demonstrated in the accompanying paper by Caplan, Moss RL, Das JB, Raffensperger JG. Necrotizing enterocolitis and
these are active areas of current research. total parenteral nutrition associated cholestasis. Nutrition.
1996;12:340 –343
Morgan JL, Shochat SJ, Hartman GE. Peritoneal drainage as pri-
mary management of perforated NEC in the very low birth
Suggested Reading weight infant. J Pediatr Surg. 1994;29:310 –315
Albanese CT. Necrotizing enterocolitis. In: O’Neill, Rowe MI, Snyder CL, Gittes GK, Murphy JP, et al. Survival after necrotizing
Grosfeld JL, et al, eds. Pediatric Surgery. 5th ed. St. Louis, Mo: enterocolitis in infants weighing less than 1,000 g: 25 years’
Mosby-Year Book, Inc; 1998:1297–1320 experience at a single institution. J Pediatr Surg. 1997;32:
Bell MJ, Ternberg JL, Feigin RD, et al. Neonatal necrotizing 434 – 437

e116 NeoReviews Vol.2 No.5 May 2001

NeoReviews Quiz
5. The incidence of necrotizing enterocolitis (NEC) is higher among infants hospitalized in the neonatal
intensive care unit (NICU) than among infants in the general population. Of the following, this increase in
the incidence of NEC is most likely to be by a factor of:
A. 2.
B. 5.
C. 10.
D. 50.
E. 100.

6. Infants who have NEC typically manifest gastrointestinal and other signs and symptoms. Of the following,
the most common early manifestation of NEC is:
A. Abdominal distension.
B. Abdominal wall erythema.
C. Diarrhea.
D. Gastric residuals.
E. Gastrointestinal bleeding.

7. Results of laboratory studies are often abnormal for infants who have NEC. Of the following, the most
common laboratory finding in early NEC is:
A. Coagulopathy.
B. Glucose instability.
C. Leukocytosis.
D. Metabolic acidosis.
E. Thrombocytopenia.

8. A 2-week-old infant, who weighted 750 g at birth, has recurrent apnea and bradycardia, unstable body
temperature, and grossly bloody stools. His abdomen is distended and tender, and bowel sounds are
absent. Abdominal radiography reveals dilated loops of bowel and focal pneumatosis intestinalis. This
description of NEC is most consistent with Bell staging of:
A. I.
B. IIA.
C. IIB.
D. IIIA.
E. IIIB.

9. Early diagnosis and treatment of NEC is associated with a favorable outcome. Of the following, the most
accurate statement regarding the treatment of NEC in its early stages is that:
A. Amphotericin B is the antimicrobial of choice because of prevalent fungal sepsis.
B. Cryoprecipitate treatment for coagulopathy often is warranted.
C. Dopamine infusion frequently is necessary for the treatment of poor perfusion.
D. Endotracheal intubation is preferred to continuous positive airway pressure for ventilatory support.
E. Most patients need exploratory laparotomy or primary peritoneal drainage.

10. Ischemic necrosis of the gut associated with NEC often results in gastrointestinal strictures at one or more
sites. Of the following, the most common site for such a stricture is the junction between the:
A. Ascending and transverse colon.
B. Descending and sigmoid colon.
C. Duodenum and jejunum.
D. Ileium and cecum.
E. Jejunum and ileum.
NeoReviews Vol.2 No.5 May 2001 e117
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Clinical Management of Necrotizing Enterocolitis
Reed A. Dimmitt and R. Lawrence Moss
Neoreviews 2001;2;e110
DOI: 10.1542/neo.2-5-e110

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The Pathophysiology of
Necrotizing Enterocolitis
Michael S. Caplan, MD,*
Objectives After completing this article, readers should be able to:
and Tamas Jilling, MD†
1. Describe the basic epidemiologic aspects of neonatal enterocolitis (NEC).
2. List the major risk factors that predispose neonates to NEC.
3. Delineate the current views on the mechanisms involved in the pathogenesis of NEC.
4. Discuss the various models used to study NEC.
5. List the major mediators believed to be involved in the pathogenesis of NEC.

Introduction
Despite many years of clinical observation and experimental investigation, the pathogen-
esis of neonatal enterocolitis (NEC) remains elusive. The multifactorial theory suggests
that four key risk factors—prematurity, formula feeding, intestinal ischemia, and bacterial
colonization—are important prerequisites to the initiation of intestinal injury in neonates
(Figure). Current hypotheses suggest that these risk factors stimulate activation of the
inflammatory cascade that ultimately results in the final common pathway of bowel
necrosis that is the hallmark of neonatal NEC.

Prematurity
Prematurity is the most consistent and important risk factor associated with neonatal NEC.
The disease occurs in 10% of babies born in the United States who weigh less than 1,500
g, but it is extraordinarily infrequent among term newborns and almost never is diagnosed
in older infants or children. Furthermore, data clearly show that the more preterm the
infant, the higher the risk of NEC. Nonetheless, the specific reason(s) for this particular
predisposition are not well understood.
Evidence from animal and human studies have shown significant differences between
term and preterm neonates in several aspects of intestinal development and function. The
mucosal barrier matures throughout gestation and even remains deficient in the term
neonate during the first few weeks of life. It is well known that several mucosal enzymes
and gastrointestinal hormones are suppressed or deficient in preterm animals/humans.
Many aspects of the intestinal host defense system, a complex and important cascade
responsible for limiting the invasion of multiple pathogens, are deficient or dysfunctional
in the preterm infant, including the secretory immunoglobulin A (IgA) response, neutro-
phil function, macrophage activation, cytokine production and function, and activity of
intestinal defensins. Furthermore, evidence suggests that autoregulation of the microcir-
culation differs in newborns compared with older animals and that peristalsis, a key
physiologic mechanism in the prevention of bacterial overgrowth, is dysfunctional in the
preterm neonate. As will be discussed later, preterm infants hospitalized in the neonatal
intensive care unit (NICU) develop marked differences in the pattern of intestinal bacterial
colonization compared with term newborns, which may contribute to the initiation of
NEC. Nonetheless, the specific factors responsible for the peculiar epidemiology of this
disease affecting preterm infants remain unclear.

Formula Feeding
More than 90% of patients diagnosed with NEC have been fed enterally. Much debate and
investigation over the past 30 years pertains to the role of enteral nutrition on the initiation

*Associate Professor.
†
Assistant Professor, Department of Pediatrics, Northwestern University Medical School, Chicago, IL.

NeoReviews Vol.2 No.5 May 2001 e103

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gastroenterology necrotizing enterocolitis

development of neonatal NEC. In a recent randomized,

controlled trial of four feeding groups that included
human milk and preterm formula and compared contin-
uous nasogastric feeds, nasogastric bolus and early prim-
ing, and no early trophic feeding, no differences were
documented in the incidence of NEC. Furthermore,
additional morbidities were fewer with human milk, and
the rate to acquisition of full feedings was faster with the
bolus method. This study underscores that feeding ap-
proaches differ among NICUs and that clear standards of
care for feeding preterm infants are lacking.
Although most neonatologists assume that human
milk feedings reduce the incidence of NEC, only a few
scientific reports address this clinical effect. More than
Figure. Schematic of NEC pathomechanism. 20 years ago, the effectiveness of human milk supple-
mentation was examined in two retrospective analyses. In
of bowel injury. Hypotheses have considered the impor- one study of 109 cases of NEC, the findings identified
tance of formula osmolality and strength; the rate of daily several cases fed fresh human milk exclusively and were
feeding volume advancement; the provision of nutrition unable to identify specific risk factors peculiar to any of
by the nasogastric or nasojejunal route; cycling as bolus the three feeding classes, which included human milk,
or continuous infusion of formula; and the differences milk and formula, and formula alone. In another study,
between preterm formula, term formula, and human many fewer cases of NEC were analyzed according to
milk. Only breastfeeding clearly shows a beneficial role in feeding type, and the authors concluded (based on soft
reducing the incidence of NEC compared with alterna- data) that frozen human milk was beneficial to all infants,
tive food sources. but that it did not protect fully against the disease in the
A careful feeding regimen that was believed to reduce highest risk, lowest birthweight groups. To assess better
the risk of NEC markedly in preterm infants was de- the beneficial effect of human milk, a multicenter, pro-
scribed several years ago. Since that time, most neonatol- spective, controlled trial was conducted that was ran-
ogists advance feeding volumes slowly and cautiously, domized for some infants. Among the randomized pa-
although few studies have confirmed the benefit of this tients, donor milk reduced the incidence of NEC
technique. A recent report has shown that careful feeding compared with preterm formula, although inadequate
decreased the rate of NEC substantially in an NICU. power precluded statistical significance (1% versus 5% of
Despite the use of historical controls and lack of random- confirmed cases). Nonetheless, in the nonrandomized
ization, this study highlighted the diversity with which groups, donor milk reduced the incidence of NEC in all
preterm newborns are fed and the impact that such birthweight subcategories. Despite the flaws in study
variety might have on their developing intestines. In a design, these data suggest a beneficial role for human
randomized, controlled, prospective trial, preterm in- milk. Although physicians empirically assume that fresh
fants weighing less than 1,500 g were randomized to human milk may provide greater benefit than frozen or
receive either “slow” feeding advancement of 15 mL/kg pasteurized preparations, specific randomized trials have
per day or “fast” advancement at 35 mL/kg per day. The not confirmed this supposition.
authors found no difference in the incidence of NEC Several potent bioactive factors in human milk, which
between the groups (13% with the slow regimen versus are absent in preterm formula preparations, may play a
9% with the fast regimen), but the group randomized to role in modulating the inflammatory cascade and influ-
fast advancement regained their birthweights more rap- encing the incidence of NEC. For example, human milk
idly. These unexpected findings suggest that very low- contains neonatal antigen-specific antibodies (IgA, IgM,
birthweight infants may not require as much caution in and IgG), leukocytes, enzymes, lactoferrin, growth fac-
their feeding regimen as previously suggested, but few tors, hormones, oligosaccharides, polyunsaturated fatty
neonatologists currently advance feedings rapidly in pre- acids, nucleotides, and specific glycoproteins. All of these
term infants. compounds have been postulated to alter the mucosal
In addition to feeding volume, several studies suggest environment, thereby reducing the risk for neonatal
that the food source and feeding approach affect the NEC. Despite the enormous work pursuing these impor-

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gastroenterology necrotizing enterocolitis

tant human milk components, their specific importance Bacterial Colonization

on the intestinal milieu requires additional investigation. Before birth, the fetus has a sterile intestinal environ-
ment, and cases of NEC have not been described in
Intestinal Ischemia utero. It is presumed that intestinal stenosis or atresia
It is theorized that compromised intestinal blood flow in results from the onset of severe ischemia prior to birth. It
the fetus and neonate contributes to the pathophysiology follows that bacterial colonization is a prerequisite for the
of neonatal NEC. Multiple experimental models have initiation of inflammatory bowel necrosis and the clinical
been designed to evaluate the importance of intestinal presentation of NEC. Following delivery, intestines are
ischemia in the developing animal, and several observa- colonized rapidly with bacteria, resulting in a large array
tions from the human neonate have contributed to our of microorganisms that include the anaerobic bacteria
understanding. It is generally understood that most term bifidobacteria and lactobacilli among breastfed infants.
newborns who develop intestinal necrosis have associ- Preterm infants hospitalized in an NICU who are not
ated conditions that compromise the intestinal circula- exposed early to human milk typically exhibit different
tion, including polycythemia/hyperviscosity, birth as- intestinal microflora than healthy term infants. In a study
phyxia, exchange transfusion, congenital heart disease, or of stool microflora from extremely low-birthweight in-
intrauterine growth restriction with reversed end- fants, investigators found: 1) a paucity of bacterial species
diastolic flow in the umbilical artery. In these situations, in most cases (fewer than three by the 10th day of life),
the presentation and clinical progression of disease may 2) increased species diversity with human milk feeding,
be quite different from that which is observed in preterm 3) reduced species number with antibiotic therapy, and
neonates who have NEC. 4) only 1 in 29 infants colonized by anaerobic bacteria
Several clinical situations in the preterm infant that (eg, bifidobacteria or lactobacilli). Although epidemics
increase the risk of NEC are associated with compro- of NEC due to specific microorganisms have been de-
mised intestinal blood flow. For example, patients who scribed, most cases of NEC are isolated, and recent data
have an active patent ductus arteriosus (PDA) associated suggest that specific bacterial species do not cause NEC.
with a large left-to-right shunt have decreased gut perfu- These findings imply that these high-risk infants are
sion and appear to have an increased risk for NEC. In a susceptible to overgrowth of specific pathogens that
provocative randomized trial evaluating the effect of could initiate the inflammatory cascade that results in
prophylactic ductal ligation in the first day of life in NEC.
preterm infants weighing less than 1,000 g, investigators
in Alabama documented a significantly lower incidence
of NEC in treated infants compared with standard man- Experimental Models for Assessing the
agement controls. Furthermore, patients treated with Pathogenesis of NEC
indomethacin to close the PDA have an increased risk for Comparative analysis of data derived from healthy neo-
NEC, presumably due to the effect of the drug on the nates and those affected by NEC has provided valuable
intestinal circulation. Significant controversy over the information and served as a stepping stone for various in
years has surrounded the importance of umbilical artery vivo animal experiments and in vitro model systems.
catheters on the incidence of NEC, and some neonatol- Studies in the laboratory further contributed to the un-
ogists are reluctant to feed these patients enterally for fear derstanding of the pathogenesis of NEC and allowed the
of this disease. It is hypothesized that the presence of design of various preventive strategies.
umbilical artery catheters reduces intestinal circulation or Analysis of human samples typically extends to serum
allows for emboli to traverse the superior mesenteric samples, stool samples, and surgical or pathologic speci-
artery. Nonetheless, the data are not convincing that mens of the small intestine. Other, less typical parameters
umbilical artery catheters alter the incidence of NEC. collected from other sources or via noninvasive imaging
Although apnea and bradycardia spells are frequent in techniques include duodenal aspirate and Doppler or
the preterm infant and may compromise the intestinal near-infrared imaging of abdominal circulation.
microcirculation, no convincing data suggest that these Analysis of these parameters uncovered a potential
events modulate the pathophysiology of NEC. Finally, role for compromised mesenteric circulation, increased
maternal cocaine abuse has been associated with an in- mucosal inflammation, and intestinal epithelial apoptosis
creased incidence of NEC in several retrospective cohort as contributing mechanisms and identified platelet-
studies, and animal data suggest that intestinal blood activating factor (PAF) as a potential key molecule in the
flow is reduced with cocaine exposure. pathogenesis of NEC.

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gastroenterology necrotizing enterocolitis

Mesenteric Blood Flow lenge without significantly affecting circulatory changes.

Mesenteric circulation is extremely vulnerable to hemo- Furthermore, in piglets whose mesenteric blood flow can
dynamic challenges. As is well known from the phenom- be precisely monitored with Doppler ultrasonography,
enon of “diver’s reflex,” the mesenteric blood flow is very PAF has been shown to cause only a transient effect on
low on the priority list when perfusion is limited or splanchnic circulation via a cardiotoxic effect. These find-
oxygenation has to be redirected to vital organs. In the ings suggest that the well-documented role of PAF in the
presence of compromised hemodynamics or compro- pathogenesis of NEC probably is independent of its
mised oxygenation in the systemic circulation, increased effect on mesenteric circulation.
vascular resistance reduces blood flow in the mesenteric
circulation. Consequently, several studies addressed the
effects of various conditions affecting the systemic circu- PAF
lation or oxygenation on mesenteric blood flow, either PAF has emerged as a primary mediator in the pathogen-
by using Doppler ultrasonography or near-infrared spec- esis of NEC. Gonzalez-Crussi and Hsueh have shown
troscopy. Apneic episodes, PDA, extracorporeal mem- that intra-aortic injection of PAF results in experimental
brane oxygenation, umbilical arterial catheterization, bowel necrosis that is similar to NEC. This model has
and hypothermia during cardiac surgery have been been widely used to investigate the molecular and cellu-
shown to reduce splanchnic blood flow, and these lar events that lead to experimental bowel necrosis. Find-
changes correlate with compromised mucosal barrier ings from human samples validated the role of PAF in
function and a subsequently increased incidence of NEC, NEC. Plasma levels of PAF-acetylhydrolase, the PAF-
even in term neonates. The hemodynamics of the mes- degrading enzyme, have been shown to be significantly
entery are even more at risk in preterm neonates. In one lower in preterm neonates, and PAF levels in stool in-
remarkable study, the critical limits of mesenteric circu- crease following the initiation of enteral feeding. A neo-
lation and oxygen delivery have been described on an natal rat model of NEC employing common risk factors
isolated segment of human small intestine that was re- for NEC, such as hypoxic stress and formula feeding, also
moved during transplantation. With perfusion rates has been used to investigate the role of PAF in NEC. In
greater than 30 mL/min per 100 g intestinal tissue, this model, formula feeding and hypoxia stress synergis-
oxygen consumption was flow-independent; below these tically increased the intestinal expression of phospho-
rates, oxygen consumption became flow-limited. lipase A2 and PAF receptor mRNA. Conversely, PAF re-
Findings from these clinical observations have been ceptor antagonists or PAF-acetylhydrolase mixed in the
validated using various animal models, including rats, formula prevented the development of experimental NEC.
piglets, and rabbits. These experiments allowed even Because evidence indicating a central role for PAF in
more detailed characterization of the mechanisms by NEC was so strong, the various effects of PAF on epithe-
which mesenteric blood flow is regulated and enabled lial cells had to be evaluated. Given that ion transport has
researchers to test various preventive strategies to aug- been implicated in various forms of intestinal pathology,
ment mesenteric blood flow or to prevent the conse- we investigated the regulation of ion transport properties
quences of reduced perfusion under conditions that pre- of cultured intestinal epithelial cells by PAF. We mounted
dispose an infant to compromised splanchnic circulation. monolayers of HT29-CL19A cells (ie, colonic adenocarci-
Among other mediators, epinephrine, cocaine, endo- noma cells) in Ussing chambers and measured vectorial
thelin-1, tumor necrosis factor-alpha, and endotoxin transepithelial ion transport. PAF stimulated secretory chlo-
have been shown to play a role in regulating pathologic ride transport across epithelial cell monolayers, but only
mesenteric circulation, with the latter two acting when cells were exposed to PAF from the luminal side. The
through nitric oxide metabolism. An experimental pre- validity of this surprising observation was verified by the
ventive strategy was designed to ameliorate the conse- detection of PAF receptors in the apical plasma mem-
quences of reduced mesenteric blood flow during cardiac brane. It is yet to be determined whether the stimulation
surgery by perfusing intestinal lumen with oxygenated of ion transport by PAF represents physiologic regulation
fluorocarbons during hypoxic episodes. or it is responsible for PAF-induced pathology.
Although reduced splanchnic blood flow certainly can
act as a predisposing factor for NEC, it cannot be viewed Intestinal Mucosal Barrier and Apoptosis of
as a sole cause of the disease. In a rat model of NEC, PAF Epithelial Cells
antagonism prevented necrotic changes in the small in- It has been postulated that one primary reason for the
testine induced by lipopolysaccharide plus hypoxia chal- increased risk for NEC in preterm neonates is an unde-

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gastroenterology necrotizing enterocolitis

veloped mucosal barrier, which may allow the transloca- Bacterial Colonization
tion of bacteria and unprocessed food antigens into the Inappropriate colonization of the intestine with entero-
lamina propria that, in turn, might activate inflammatory pathogenic bacteria has been thought to play a role in
cells. The mucosal barrier consists of a single layer of NEC. Nonates fed human milk tend to colonize their
epithelial cells that line the lumen of the intestine and are intestine with bifidobacteria and lactobacilli (facultative
sealed together by tight junctions. Consequently, in anaerobes); formula-fed neonates develop an intestinal
addition to the inherently premature barrier, mucosal flora abundant with potentially pathogenic gram-
permeability may be augmented further by damage to negative bacteria. These distinct colonization profiles
the integrity of the epithelial layer. Epithelial cells turn might affect susceptibility to NEC. Because enterococci
over naturally by the removal of some cells via pro- and lactobacilli use lactose as their primary energy
source, successful colonization with these gram-positive
grammed cell death (apoptosis) and by replacement of
organisms exhausts the primary energy source that would
the dying cells with proliferating cells in the crypts.
allow the growth of pathogenic organisms. Furthermore,
Abundant apoptosis is a logical first step that might cause
facultative anaerobes generate metabolic byproducts
a breach in the mucosal barrier, thereby initiating a
such as the short-chain fatty acids, acetate, propionate,
cascade of events consisting of bacterial translocation
and butyrate that promote differentiation of intestinal
into the submucosa and the activation of an inflamma- epithelial cells. These bacteria also are believed to interact
tory cascade. directly with complex carbohydrates on apical surfaces of
Ford and associates detected the presence of abun- epithelial cells, initiating signal transduction and differ-
dant apoptotic nuclei in the epithelial cells of bowel entiation. In the absence of colonization with these
specimens derived from bowel resections of patients who beneficial gram-positive bacteria, various enteropatho-
had NEC. To investigate systematically the involvement genic gram-negative organisms may overgrow in the
of epithelial apoptosis in the pathogenesis of experimen- intestinal milieu. In an animal model, an NEC-like his-
tal NEC, we evaluated the presence of epithelial apopto- tology was achieved by filling rabbit ileal loops with
sis in a neonatal rat model of NEC. Formula feeding and enteropathogenic Escherichia coli. Release of endotoxins
hypoxia stress caused an abundance of apoptosis in the from these gram-negative organisms might contribute
intestinal epithelium, and apoptosis preceded the gross both to accelerated apoptosis and to compromised
morphologic damage to the intestinal wall. Further stud- splanchnic hemodynamics. We have found that bacterial
ies need to evaluate whether a specific blockade of apo- lipopolysaccharide is a potent activator of epithelial apo-
ptosis can prevent NEC in this model and verify that ptosis, and others have found that it can severely reduce
apoptosis is an underlying cause of further damage. Nev- mesenteric blood flow.
ertheless, existing data suggest that accelerated apoptosis These findings suggest that early colonization of the
might be an important early event in NEC pathogenesis gut might have an important role in developing suscep-
and might set the stage for subsequent bacterial translo- tibility to NEC. Accordingly, the supplementation of
cation and activation of the inflammatory cascade. The infant formula with probiotics might be a feasible pre-
vention strategy to reduce the incidence of NEC in
abundance of inflammatory mediators might further ac-
high-risk populations. In an experimental model of NEC
celerate epithelial apoptosis, thus completing a vicious
in quails and in the aforementioned neonatal rat model of
circle.
NEC, supplementation of formula with live bifidobacte-
To evaluate a possible connection between altered
ria prevented the development of NEC. Using the neo-
PAF metabolism and aberrantly high epithelial apoptosis,
natal rat model of NEC, we have performed a preliminary
we studied the regulation of apoptosis by PAF and other characterization of the mechanisms by which bifidobac-
inflammatory mediators in tissue culture models of the teria prevented NEC. Circulating plasma endotoxin lev-
developing intestine. PAF is a potent stimulator of apo- els were 10-fold lower in formula-fed and asphyxia
ptosis in cultured intestinal epithelial cells, and it pro- stressed animals that received bifidobacteria. Further-
motes apoptosis in epithelial cells via the activation of more, bifidobacteria supplementation of formula pre-
caspase 8 and caspase 3. Accordingly, caspase inhibitors vented the increase of PLA2-II gene expression by for-
efficiently block PAF-induced apoptosis in epithelial mula feeding and asphyxia stressing in the neonatal
cells. Based on these results, we are currently evaluating intestine. These findings in the animal model offer en-
whether caspase inhibition can prevent experimental couragement for future clinical trials to determine
NEC in the neonatal rat model. whether bifidobacteria can prevent NEC in humans.

NeoReviews Vol.2 No.5 May 2001 e107

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gastroenterology necrotizing enterocolitis

Summary Gonzalez-Crussi F, Hsueh W. Experimental model of ischemic

Although the precise mechanisms that are responsible for bowel necrosis. The role of platelet-activating factor and endo-
toxin. Am J Pathol. 1983;112:127–135
the development of NEC remain elusive, a basic under-
Grosfeld JL, Chaet M, Molinari F, et al. Increased risk of necrotiz-
standing of the key risk factors and the major steps that ing enterocolitis in premature infants with patent ductus arteri-
lead to this disease is developing. Based on this initial osus treated with indomethacin. Ann Surg. 1996;224:350 –355
evidence, several novel prevention strategies are being Holman RC, Stoll BJ, Clarke MJ, Glass RI. The epidemiology of
evaluated that might help to reduce the incidence of necrotizing enterocolitis infant mortality in the United States.
Am J Public Health. 1997;87:2026 –2031
NEC.
Kamitsuka MD, Horton MK, Williams MA. The incidence of
necrotizing enterocolitis after introducing standardized feeding
schedules for infants between 1250 and 2500 grams and less
Suggested Reading than 35 weeks of gestation. Pediatrics. 2000;105:379 –384
Caplan MS, Hedlund E, Adler L, Hsueh W. Role of asphyxia and Kilic N, Buyukunal C, Dervisoglu S, Erdil TY, Altiok E. Maternal
feeding in a neonatal rat model of necrotizing enterocolitis. cocaine abuse resulting in necrotizing enterocolitis. An experi-
Pediatr Pathol. 1994;14:1017–1028 mental study in a rat model. II. Results of perfusion studies.
Caplan MS, Miller-Catchpole R, Kaup S, et al. Bifidobacterial Pediatr Surg Int. 2000;16:176 –178
supplementation reduces the incidence of necrotizing enteroco- Kliegman RM, Pittard WB, Fanaroff AA. Necrotizing enterocolitis
litis in a neonatal rat model. Gastroenterology. 1999;117: in neonates fed human milk. J Pediatr. 1979;95:450 – 453
577–583 MacKendrick W, Hill N, Hsueh W, Caplan M. Increase in plasma
Fatica C, Gordon S, Mossad E, McHugh M, Mee R. A cluster of platelet-activating factor levels in enterally fed preterm infants.
necrotizing enterocolitis in term infants undergoing open heart Biol Neonate. 1993;64:89 –95
surgery. Am J Infect Control. 2000;28:130 –132 Walker WA. Breast milk and the prevention of neonatal and preterm
Ford HR, Sorrells DL, Knisely AS. Inflammatory cytokines, nitric gastrointestinal disease states: a new perspective. Chung Hua
oxide, and necrotizing enterocolitis. Semin Pediatr Surg. 1996; Min Kuo Hsiao Erh Ko I Hsueh Hui Tsa Chih. 1997;38:
5:155–159 321–331

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gastroenterology necrotizing enterocolitis

NeoReviews Quiz
1. Prematurity is the most consistent and important risk factor in the epidemiology of necrotizing
enterocolitis (NEC). Of the following, the estimated incidence of NEC among very low-birthweight
(<1,500 g) infants is closest to:
A. 5%.
B. 10%.
C. 15%.
D. 20%.
E. 30%.

2. Enteral feeding is one of the prerequisites for initiating intestinal injury that results in NEC. Of the
following, the factor most likely to be protective against NEC is:
A. Continuous orogastric infusion.
B. Early gut priming (trophic feedings).
C. Exclusive human milk feeding.
D. Low caloric density of milk.
E. Slow advancement of feeding volume.

3. A compromised intestinal blood flow in the fetus and/or the neonate contributes to the pathogenesis of
NEC. Of the following, the most convincing cause of intestinal ischemia is:
A. Anemia of prematurity.
B. Indomethacin treatment.
C. Partial exchange transfusion.
D. Recurrent apnea and bradycardia.
E. Umbilical artery catheterization.

4. Intestinal epithelial apoptosis contributes to the pathogenesis of NEC. Of the following, the medication
most likely to cause intestinal epithelial apoptosis is:
A. Endothelin-1.
B. Endotoxin.
C. Epinephrine.
D. Platelet-activating factor.
E. Tumor necrosis factor.

NeoReviews Vol.2 No.5 May 2001 e109

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The Pathophysiology of Necrotizing Enterocolitis
Michael S. Caplan and Tamas Jilling
NeoReviews 2001;2;e103
DOI: 10.1542/neo.2-5-e103

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The Pathophysiology of Necrotizing Enterocolitis
Michael S. Caplan and Tamas Jilling
NeoReviews 2001;2;e103
DOI: 10.1542/neo.2-5-e103

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International Journal of Medical Science and Clinical Research Studies
ISSN (print): 2767-8326, ISSN (online): 2767-8342
Volume 04 Issue 12 December 2024
Page No: 2484-2497
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Necrotizing Enterocolitis: A Literature Review of Basic Concepts, Diagnosis

and Treatment Options
Israel Estrada Marroquín1, María Fernanda Ibarra Guerrero2, Claudia Lemba Moreno Díaz3, Alexis Emir
Noguera Echeverría4, Alison Mariel Ruz Alcocer5, David Altamirano Ramírez4, Enzo Alejandro Herrera
Villaseñor5, Jonathan Remigio Sansores Bello6, Ambar Sahian Domínguez de la Cruz7, Erendira Helena Reyes
Koyoc7, Natalia Aleli Gómez Marfil7
1
MD. Clínica Hospital Mérida, ISSSTE. Facultad de Medicina de la Universidad Autónoma de Yucatán.
2
Pediatrics Resident. Clínica Hospital Mérida, ISSSTE. Facultad de Medicina de la Universidad Autónoma de Yucatán.
3
Neonatologist. Clínica Hospital Mérida, ISSSTE. Facultad de Medicina de la Universidad Autónoma de Yucatán.
4
Surgical Resident. Facultad de Medicina de la Universidad Autónoma de Yucatán.
5
Social Service MD Intern. Universidad Anáhuac Mayab.
6
Medical Intern. Universidad Anáhuac Mayab.
7
Medical Intern. Universidad para el Bienestar Benito Juárez García.

ABSTRACT ARTICLE DETAILS

Necrotizing enterocolitis (NEC) is a severe inflammatory bowel condition that causes intestinal Published On:
tissue ischemia in premature newborns, mainly due to their underdeveloped intestinal and immune 25 December 2024
systems. NEC develops through both maternal and infant-related factors, including weak immune
defenses, reduced transfer of maternal immunity, and various molecular factors such as
epigenetics and blood vessel development. Feeding problems are the earliest sign, often
accompanied by breathing pauses, slow heart rate, and unstable body temperature. Initial treatment
is focused on bowel rest, nutritional support, and antibiotics. Surgery becomes necessary in about
30% of cases, especially in younger patients. Preventing NEC is crucial for reducing
complications, medical costs, and long-term developmental problems that affect both quality of
life and healthcare resources.
Available on:
KEYWORDS: Necrotizing enterocolitis, premature newborns, bowel rest, antibiotics, surgery, https://ijmscr.org/
complications.

INTRODUCTION. microbiome to prevent disease. The successful adaptation of

Necrotizing enterocolitis (NEC) is an inflammatory bowel the neonatal gut is critical for survival. (3)
disease associated with high levels of inflammation and In twelve high-income countries, the reported rates for NEC
intestinal necrosis involving the Ileum, jejunum, and colon. in preterm newborns of 32 weeks of gestation is calculated at
This disease affects preterm newborns due to the intestinal 2% to 7%; in infants weighing less than 1000 g, the rate is 5
and immune system’s prematurity, with multifactorial - 22%. Approximately 2% to 5% of admissions to the
characteristics. NEC is considered a life-threatening surgical Neonatal Intensive Care Unit (NICU) can be attributed to
condition that affects premature newborns. (1, 2) NEC, with up to 85% of those cases occurring in premature
The gastrointestinal system undergoes dynamic, biochemical, newborns; late preterm newborns contribute 7% to 15%. (2)
structural, and functional changes to accomplish its functions In The United States, out of 480,000 preterm newborns every
in nutrition, immunity, and self-repair. The immature bowel year, it is estimated that NEC affects close to 9,000; with the
faces many challenges, such as acquiring the ability to digest most premature or lowest weight newborns presenting a
and absorb nutrients to maintain somatic and brain growth, greater risk, approximately 7% of very low birth weight
and the development of a symbiotic relationship with the newborns develop NEC, with a high mortality rate of up to

2484 Volume 04 Issue 12 December 2024 Corresponding Author: Israel Estrada Marroquín
Necrotizing Enterocolitis: A Literature Review of Basic Concepts, Diagnosis and Treatment Options
40 to 50%. Whereas in Mexico, the incidence reports range transfusion, congenital heart disease, respiratory distress
between 10% to 19.2%. (4, 5, 6, 7) syndrome, premature birth, and pneumonia. On the other
The global incidence of NEC varies between 0.3 to 2.4 hand, the protective factors to reduce the risk of neonates
newborns for every 1,000 births, with up to 70% of cases developing NEC were breastfeeding, probiotic intake, and the
occurring in preterm neonates born before 36 weeks of administration of prenatal glucocorticoids. (15)
gestation. (8)
Lately, there have been great improvements in neonatal PATHOPHYSIOLOGY
intensive care, reducing mortality and thus increasing the The pathophysiology of NEC is highly complex since it
incidence of NEC. (9) involves multiple factors, from both the mother and the
Infant formula-based nutrition and bacterial exposure, newborn. The risk of developing the disease cannot be
without a history of perinatal asphyxia, do not result as the attributed to a singular factor. Various factors contribute to
sole injury mechanism for the development of NEC, with the physiology of NEC, some of these include the immature
perinatal asphyxia having a crucial role in the development of host with dysfunction and poor maturation of innate and
NEC. (10) adaptive immune defense mechanisms, a significant
In a literature review carried out in Latin America in 2023, it reduction in the adaptive immune system transferred by the
was determined that there are maternal and prenatal risk mother, and molecular considerations such as epigenetic
factors for the development of NEC, which included factors, regulatory elements, microvasculature, and
premature rupture of membranes (PROM), preeclampsia, nucleotide polymorphisms, which all play a critical role in the
maternal HIV, and gestational diabetes. As for the perinatal development of NEC. (16, 17)
and labor risks, prematurity was determined as the main risk Perinatal asphyxia plays an important role, influenced by
factor; other risk factors were low birthweight, low various intrauterine environmental factors and fetal birth
gestational age, and cesarean delivery. Early neonatal and processes. Any condition affecting blood flow or gas
postnatal risk factors included respiratory distress syndrome, exchange between the mother and fetus can lead to hypoxia
pneumonia, mechanical ventilation, neonatal asphyxia, and, eventually, perinatal asphyxia. The risk is heightened in
anemia, red blood cell transfusion, neonatal sepsis, congenital low-birth-weight neonates and mothers with preeclampsia or
heart disease, patent ductus arteriosus, antibiotic therapy, eclampsia. (18, 19)
feeding with infant formula and prolonged parenteral feeding, Premature newborns with very low birth weight are highly
low Apgar scores, oxidative stress and the use of central susceptible to postnatal asphyxia because of their
umbilical catheters. (11) underdeveloped respiratory and neurological systems, which
limits their ability to initiate and maintain breathing at birth.
Preeclampsia, PROM, perinatal asphyxia, prematurity (28-32 This does not allow for an effective gaseous exchange to take
WG), and low birth weight are considered the main risk place, often leading to intensive resuscitation or mechanical
factors for the development of NEC. Newborns are known to ventilation. Exposure to low oxygen concentrations triggers
have weak metabolic and immune function, with inadequate blood flow redistribution to vital organs like the brain,
circulatory regulation that increases susceptibility to myocardium, and adrenal glands, at the expense of reduced
infections and complications. (11, 12) flow to organs such as the kidneys and intestines, this triggers
The usage of an umbilical arterial catheter with a duration a strong vasoconstriction of the mesenteric blood vessels,
greater than 5 days has been significantly associated with an which in turn causes hypoxia and ischemia of intestinal
increase in the risk for NEC, most likely secondary to the epithelial cells, and, in severe cases causing degeneration and
release of the microthrombi, vasospasm of splanchnic blood necrosis, culminating in NEC. (20, 21)
vessels, and reduction in the diameter of the abdominal In comparison with full-term neonates, the microflora of
aorta’s lumen due to the presence of the catheter, which can preterm neonates is characterized by a delay in colonization
lead to diminished blood flow. (13) and limited microbial diversity, with diminished levels of
The exposure to HIV during fetal life, as well as the use of commensal anaerobic bacteria and increased levels of
zidovudine, can contribute to the development of NEC due to facultative anaerobic bacteria with pathogenic potential. This,
secondary effects that could favor the colonization of in addition to the environmental factors seen in hospital
opportunistic microorganisms and other gastrointestinal settings, greatly influences intestinal bacterial colonization.
effects, such as hypoperistalsis and intestinal pseudo- (22)
obstruction, predominantly when the administration of the Intestinal microbiota can be altered by antibiotic use, the
drugs is enteral. (14) absence of breastfeeding, parenteral nutrition, and invasive
In a meta-analysis conducted in China in which a total of 52 procedures; these are strongly associated with an incomplete
studies were included, out of which 48 were cases and microbial barrier in the intestinal mucosa, which plays a
controls, and 4 were cohort studies; it was determined that the critical role in the pathogenesis of NEC and early-onset
main risk factors for NEC were: gestational diabetes, PROM, neonatal sepsis. Moreover, prolonged antibiotic exposure for
low birthweight, small for gestational age, septicemia, blood

2485 Volume 04 Issue 12 December 2024 Corresponding Author: Israel Estrada Marroquín
Necrotizing Enterocolitis: A Literature Review of Basic Concepts, Diagnosis and Treatment Options
more than 10 days has been linked to a two- to three-fold markers. This demonstrates that hyperosmolar formula
increased risk of developing NEC. (23, 24, 25) feeding induces mucosal hypoxia and ischemia, significantly
The abnormal pattern of intestinal bacterial colonization, increasing the risk of developing NEC. (29)
characterized by disrupted bacterial homeostasis (dysbiosis),
results in bacterial over-reactivity, accompanied by an CLINICAL PRESENTATION
abundance of pro-inflammatory interleukin-producing cells Clinical manifestations of NEC include non-specific systemic
in the intestinal mucosa of preterm newborns with risk and abdominal findings including abdominal distension,
factors, contributing to excessive intestinal inflammation and bilious vomiting, biliary drainage through enteral feeding
bacterial invasion. As the disease progresses, the tissue shows tubes, gastric residue, erythema of the abdominal wall,
signs of ischemia, followed by necrosis and finally diminished bowel sounds, crackles, induration; and as the
perforation, which can range from micro-perforation to overt ischemic disease progresses, bloody stools and perforation of
perforation. Micro perforations can lead to pneumatosis the gastrointestinal tract with free peritoneal fluid and free gas
intestinalis, the presence of gas within the intestinal walls. (4, in the abdominal cavity are found. Abnormal physiological
26) parameters can also be present, such as apnea, bradycardia,
Intestinal immaturity is a key factor in which pathogenic and hemodynamic changes, thermal instability, respiratory
commensal bacteria penetrate the mucus layer to interact with failure, and cyanosis. The most frequent sign is a sudden
pattern recognition receptors (PRRs) on epithelial cells and change in the patient’s feeding tolerance. (8, 32, 33, 34, 35)
trigger an immune response. The most common PRR in the The symptom onset can vary between preterm and full-term
intestines is Toll-like receptor 4 (TLR4), which is expressed neonates, being inversely related to the number of weeks of
at higher levels in the intestines of preterm neonates. (27) life, showing a later onset in preterm neonates. Typically, the
TLR4 belongs to a family of pattern-recognition receptors first symptoms in preterm newborns appear 2 or 3 weeks after
expressed by the immune system. They have an essential role birth, on the other hand, full-term newborns symptoms can
in recognizing pathogen-associated molecules, such as manifest themselves during the first week of life; this is
lipopolysaccharides from gram-negative microorganisms. probably related to the slower progress in enteral feeding seen
TLR4 activation is associated with endothelial damage, in the more premature patients and with a critical
inflammation, inhibition of enterocyte proliferation, reduced developmental window of greater susceptibility that
intestinal microcirculation, and intestinal ischemia. (28, 29) coincides with deregulated intestinal or systemic immune
The role of intestinal blood flow is crucial, and it is modulated responses and exaggerated inflammatory responses to
primarily by vasodilators and vasoconstrictors, with nitric bacteria or pathogens. Furthermore, there is an association of
oxide (NO) acting as a vasodilator and endothelin-1 (ET-1) presentation in full-term neonates linked to congenital
as a vasoconstrictor. Preterm newborns exhibit significantly malformations and genetic diseases, with a lower prevalence
reduced levels of arginine, a precursor of nitric oxide, when compared to appearance in preterm newborns. (36, 37,
resulting in limited capacity to regulate intestinal blood flow. 38)
which in turn leads to an insufficient blood supply thus The severity of the disease is inversely proportional to the
causing hypoxia, ischemic areas in the intestine, and a gestational age and birth weight. NEC can progress rapidly,
cascade of inflammatory events that result in intestinal injury. from the initial symptoms to a fully established disease that
(29, 30) can lead to death in the first 24-48 hours of symptom onset,
The caloric requirements necessary to maintain fetal growth therefore it is critical to make the diagnosis during the early
trajectories after birth in preterm newborns cannot be met stages. (39, 40)
through breastfeeding alone, requiring external fortification.
However, these fortifiers increase osmolarity, which, DIFFERENTIAL DIAGNOSES
combined with the immature intestinal mucosa and slow The absence of a clear definition, diffuse diagnostic criteria
small intestine peristalsis, leads to inadequate digestion, and lack of available biomarkers have conditioned for
causing the intestine to retain food residues that, upon numerous intestinal diseases to be diagnosed as NEC, for this
fermentation, create an environment conducive to bacterial reason, a reevaluation of the different forms of intestinal
overgrowth, further damaging intestinal mucosa. (11, 31) injury and dysfunction in neonates is necessary, which can
Feeding with hyperosmolar formula exerts excessive distinguish between differential diagnoses. (41)
digestive stress and increases oxygen consumption in the Spontaneous intestinal perforation (SIP), also known as focal
immature intestine, significantly increasing the expression of intestinal perforation (FIP), is an abdominal pathology that is
hypoxia markers (GLUT-1 and PHD-1). This effect, found in an isolated manner and that does not precede
associated with osmolarity or high caloric density, pneumatosis intestinalis and gas in the portal vein, as it is
compromises the intestinal mucosa, exclusively in preterm described in the classic form of NEC. Both presentations
neonates with immature intestinal microvasculature and manifest with abdominal distension and free air in the
limited ability to regulate blood flow. In contrast, abdominal cavity, and the surgical treatment is the same for
breastfeeding does not cause such damage or elevate hypoxia both cases, consisting of the placement of peritoneal

2486 Volume 04 Issue 12 December 2024 Corresponding Author: Israel Estrada Marroquín
Necrotizing Enterocolitis: A Literature Review of Basic Concepts, Diagnosis and Treatment Options
drainage. This entity has a different etiology than NEC, with term newborns is associated with congenital malformations
focal intestinal perforation (FIP) being found earlier, using or disorders, such as those previously mentioned. (48)
the age of onset to differentiate between NEC and FIP, with
a cut-off point of 14 days. Classifying the onset before 14 DIAGNOSIS
days of age as FIP, and after 14 days as NEC, nevertheless, In 1978 Dr. Martin Bell proposed the clinical staging criteria
both pathologies can be found before and after the cut-off for NEC, which was later modified in 1986 by Dr. Walsh and
point, therefore relevant history and other variables must be Dr. Kliegman. They expanded Bell's staging criteria to
considered to discern between both etiologies. (41, 42) include additional severity stages, designed to categorize the
Congenital heart disease increases the prevalence of NEC, disease into three stages based on severity and to guide
finding a prevalence of 3.7% with significant variation clinical management. The criteria consist of radiographic,
between different diseases of cardiac origin, most frequently clinical, and laboratory findings. (37, 49)
associated with hypoplastic left heart syndrome, truncus The modified Bell classification categorizes NEC into three
arteriosus, single ventricle defects, and interrupted aortic stages based on severity. Stage I represents suspected disease
arch, and less frequently seen in transposition of the great and is subdivided into IA and IB. Stage IA includes mild
arteries. (43) systemic signs such as apnea, bradycardia, temperature
The bowel injury is secondary to mesenteric hypoperfusion, instability, and lethargy, along with mild intestinal signs like
hypoxia-induced inflammation, and surgical stress-inducing abdominal distension, bilious gastric residuals, and occult
factors. The gravity of the ischemic lesion associated with blood in the stool, with radiographic findings being normal or
congenital heart disease can vary from ileus to enteritis and nonspecific. Stage IB adds visible blood in the stool to these
cardiac NEC. Cardiac NEC is an entity that is found with a signs. Stage II represents confirmed disease and is divided
higher incidence in full-term babies, with involvement in the into IIA and IIB. Stage IIA exhibits moderate systemic signs,
most distal regions of the intestine. (34) and intestinal findings such as abdominal tenderness and
Food protein-induced enterocolitis syndrome (FPIES) is a diminished bowel sounds, as well as specific radiographic
rare non-IgE-mediated food allergy that typically occurs in findings including intestinal dilation, ileus, and pneumatosis
preterm neonates with symptoms resembling NEC, including intestinalis. Stage IIB includes the signs of IIA along with
rectal bleeding, irritability, abdominal pain, occasional analytical abnormalities such as metabolic acidosis,
vomiting, an eczema-like rash, and pneumatosis intestinalis. leukopenia, and thrombocytopenia, additional abdominal
There are no specific diagnostic tests available. findings like cellulitis, and radiographic evidence of portal
Thrombocytopenia and elevated C-reactive protein are more venous gas can manifest themselves too. Stage III signifies
commonly found in NEC compared to FPIES. FPIES follows advanced disease and can also be divided into IIIA and IIIB.
a benign course, and the diagnosis is based on the resolution Stage IIIA consists of a non-perforated intestine with severe
of symptoms after eliminating milk from the diet. Cow’s milk systemic involvement, with hypotension, clear signs of
protein allergy and intolerance can be classified based on the shock, clinical signs of peritonitis, radiographic findings of
presence of IgE, non-IgE, or T-cell-mediated mechanisms, ascites, and laboratory abnormalities such as metabolic and
with the severity of adverse food reactions ranging from mild respiratory acidosis, leukopenia, neutropenia,
gastrointestinal symptoms to severe sepsis-like episodes. (44, thrombocytopenia, disseminated intravascular coagulation,
45, 46) and elevated C-reactive protein. Stage IIIB includes all the
Hirschsprung’s disease is a congenital disorder defined by the findings of IIIA but adds intestinal perforation, with
absence of ganglion cells in Meissner’s submucosal plexus radiographic evidence of severe findings such as
and Auerbach's myenteric plexus in the terminal rectum, pneumoperitoneum. (50, 51)
extending proximally to a variable distance. This happens The identification of potential early biomarkers as diagnostic
because of the interruption of the migration and tools enhances and increases the accuracy of diagnosis in
differentiation process of neural crest cells within the enteric high-risk populations, providing an opportunity for early
nervous system during gestation, resulting in an aganglionic intervention and significantly mitigating the disease. (52, 53)
intestinal segment with impaired relaxation, leading to Biomarkers can be classified into hematological indices, such
intestinal obstruction and inflammation. (47) as total white blood cell count, absolute neutrophil count,
Enterocolitis associated with Hirschsprung's disease is a platelet count, and immature-to-total white blood cell ratio;
potentially life-threatening complication with a variable acute-phase reactants, including C-reactive protein,
clinical presentation which ranges from fever, lethargy, procalcitonin, platelet-activating factor, and hepcidin; and
abdominal distension, and explosive diarrhea to intestinal immunological markers, such as cytokines, chemokines,
perforation. This can occur secondary to increased adhesion molecules, intracellular signaling molecules, and
intraluminal pressure, transmural inflammation, and vascular growth factors. (54)
events leading to ischemia and subsequent perforation. Various biochemical alterations can be observed, including
Unlike classic NEC, which typically occurs in preterm an increase or decrease in white blood cell count,
neonates with risk factors, the occurrence of this entity in full- thrombocytopenia, metabolic acidosis, glucose instability,

2487 Volume 04 Issue 12 December 2024 Corresponding Author: Israel Estrada Marroquín
Necrotizing Enterocolitis: A Literature Review of Basic Concepts, Diagnosis and Treatment Options
and elevated C-reactive protein levels. However, none of other biomarkers and laboratory analyses could improve its
these laboratory parameters demonstrate precise sensitivity specificity. (64, 65)
and specificity. The severity of thrombocytopenia has been A scoring system has been developed to assist in the
correlated with the clinical stages of Bell. (55, 56) differential diagnosis between NEC and spontaneous
Epidermal growth factors play a crucial role in the intestinal perforation (SIP), This system considers the
development of the gastrointestinal tract. Their levels are presence of abdominal distension, ileus, and/or bloody stools,
significantly reduced in the saliva and serum of patients with along with at least two of the following criteria: pneumatosis
NEC compared to healthy individuals, while urinary levels and/or portal air detected via X-ray or abdominal ultrasound,
show no significant difference. (56) persistent platelet consumption (platelet count <150,000 for
Fatty acid-binding proteins (FABPs) are small intracellular three days following diagnosis), and onset after the tenth day
proteins that increase under conditions of inflammation and of life. These findings are more consistent with NEC than
ischemia. They are in gastric epithelial cells and the intestinal with SIP. (66)
mucosa and are released into the bloodstream following
enterocyte injury or death and they can be measured in IMAGING STUDIES
plasma (I-FABPp) and urine (I-FABPu). Significantly higher Various clinical staging systems for NEC incorporate
concentrations of I-FABPp and I-FABPu have been observed abdominal radiographic findings. In Bell stage I (suspected
six hours after the suspicion of NEC compared to healthy NEC), radiographs typically show nonspecific signs such as
neonates. (57, 58) mild intestinal dilation or ileus. Stage II (definitive NEC)
There is a statistically significant increase in serum requires more specific features like pneumatosis intestinalis
concentrations of I-FABPp corresponding to the severity and and/or gas in the portal vein. Finally, Bell stage III (advanced
progression of the disease, with a diagnostic cutoff value NEC) includes findings such as pneumoperitoneum or free
greater than 131.8 ng/mL, offering 90% sensitivity and 100% air. (67)
specificity. Since NEC is a progressive disease, consecutive Supine abdominal radiographs are the cornerstone of NEC
measurements are recommended to provide detailed diagnosis. Common findings include asymmetrically dilated
information about the disease course rather than relying on a intestinal loops, intestinal wall edema, pneumatosis
single measurement at the onset of symptoms. (59) intestinalis, gas in the portal vein, pneumoperitoneum, and air
Blood lactate is an important marker that reflects tissue on both sides of the intestine (Rigler’s sign). For follow-up,
hypoxia as well as low perfusion. It is significantly associated supine and lateral projections are recommended during the
with hospital mortality, showing a mortality increase of up to first 48 hours, as most perforations occur in this period. If
40-45% for every 1 mmol/L increase in lactic acid levels. It perforation is clinically suspected but not initially evident on
is used as a predictor of poor outcomes, with values linked to a supine abdominal radiograph, additional views such as left
severe NEC, both at the onset of the disease and during its lateral decubitus or supine horizontal beam imaging improve
progression. (60, 61) sensitivity. Severe imaging findings, such as
The most used nonspecific biomarker is C-reactive protein pneumoperitoneum, gas in the portal vein, and
(CRP). Nevertheless, it has proven to have limitations, seroperitoneum, are more common in patients with a
including low specificity and a delayed increase of 12-24 fulminant disease course. (67, 68, 69)
hours after the onset of NEC. CRP levels may also be elevated The primary limitations of Bell’s staging criteria include the
due to other inflammatory causes, making it unable to low diagnostic accuracy of radiographs and the nonspecific
distinguish between NEC and sepsis. (62) symptoms in preterm infants, with no radiographic changes
Non-invasive fecal markers have been used as a diagnostic evident in the early stages of the disease. Radiographs have
tool and for monitoring the progression of the disease, low sensitivity for detecting pneumatosis (44%), portal
however, the difficulty in obtaining stool samples from venous gas (13%), and free intraperitoneal air (52%), though
neonates suffering from ileus secondary to NEC exhibits a specificity ranges from 92% to 100%. (70, 71)
significant drawback. (63) All these limitations impede early clinical interventions
The quantitative increase of fecal calprotectin, a non-invasive aimed at risk reduction and possible prevention of NEC. As a
fecal marker, is correlated with an increase in leukocytes result, new algorithms incorporating additional clinical
within the intestinal barrier, and with migration of variables for diagnosing and assessing NEC have recently
granulocytes into the intestinal lumen. Higher levels have gained traction. Promising modalities such as ultrasound and
been observed in preterm neonates compared to term near-infrared spectroscopy (NIRS) are increasingly utilized
neonates, associated with an early NEC diagnosis and in neonatal intensive care units. (72)
prediction of the severity of the disease, with sensibility and Near-infrared spectroscopy (NIRS) allows for monitoring
specificity rates of up to 76%-100% and 39%-96.4% regional oxygen saturation and calculating oxygen extraction
respectively; nonetheless, as calprotectin is a nonspecific in tissues. By monitoring splanchnic circulation, NIRS can
inflammatory marker for NEC, a combined approach with detect hypoxic-ischemic injuries that traditional
hemodynamic examinations are not able to identify. It is

2488 Volume 04 Issue 12 December 2024 Corresponding Author: Israel Estrada Marroquín
Necrotizing Enterocolitis: A Literature Review of Basic Concepts, Diagnosis and Treatment Options
considered a non-invasive tool for identifying preterm infants associated enterocolitis, and congenital gastrointestinal tract
at risk for NEC development. In early NEC, intestinal oxygen malformations. (79)
saturation levels decrease, with more pronounced reductions Early treatment is crucial to prevent devastating
observed in severe cases compared to mild-to-moderate consequences, through conservative approaches such as
cases. (73, 25) fasting, parenteral nutrition, fluid resuscitation, antibiotic
Ultrasound offers diagnostic capabilities beyond radiographs, regimens, and maintaining acid-base balance. However,
such as detecting peristalsis and blood flow, with higher some cases require surgical intervention. Most neonates are
sensitivity and specificity. It supports initial diagnosis and managed with conservative treatment, but approximately
patient monitoring. Early findings include intestinal 30% progress to requiring surgery. Newborns diagnosed at a
distension, hypervascularity, and echogenic mucosa. As the younger postnatal age are more likely to require surgical
disease progresses, intestinal wall thickening (ranging from treatment. (80, 81, 82)
2.5–2.7 mm) is commonly observed. In advanced stages, the The management of NEC depends on the severity of the
intestinal wall thins, the lumen dilates, and blood flow may disease, which is defined by the modified Bell staging
become undetectable. (35, 74) criteria. Treatment decisions are guided by the extent of
The main limitations include challenges in evaluating deeper disease, the surgeon's preference, and the physiological state
structures due to intestinal gas. High-frequency ventilation of the newborn. (83)
may also cause vibratory motion, creating interference, Antibiotics are a cornerstone of NEC treatment, with broad-
especially when assessing intestinal perfusion and peristalsis. spectrum regimens recommended to target both aerobic and
Reduced intestinal perfusion can be observed in patients with anaerobic bacteria. Although no specific microorganism has
low cardiac output or those receiving vasoconstrictive been definitively linked to NEC, common protocols include
medications; however, these findings should not be ampicillin or vancomycin for gram-positive coverage,
interpreted as indicative of primary intestinal pathology. (75) combined with aminoglycosides such as amikacin or
Another alternative radiological method is abdominal gentamicin, or cephalosporins like cefotaxime for gram-
computed tomography, which has demonstrated sensitivity, negative bacteria. In the setting of confirmed intestinal
specificity, positive predictive value, and negative predictive perforation, metronidazole is used for anaerobic coverage.
value of up to 100%. However, instability, the difficulty of Antibiotic selection is tailored to disease severity, with most
mobilizing the patient, and the high levels of ionizing NEC treatment regimens based on ampicillin and
radiation involved, result in the contraindication of this aminoglycosides, which act synergistically. Adjustments to
method in daily practice. (76) antibiotic therapy are made based on blood culture results.
The duration of antibiotic treatment is also determined by
BACTERIOLOGY Bell staging criteria, with Stage Ia requiring 48–72 hours of
Microorganisms associated with NEC are challenging to treatment followed by clinical reassessment, Stage Ib-II
isolate through blood cultures, with positive results in only requiring a 10-day course, and Stage III potentially requiring
25% of cases. The most identified pathogens include more than 10 days of therapy depending on the progression
Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, of the disease and the patient’s clinical condition. (84, 85, 86)
Enterobacter cloacae, Clostridium perfringens, and Nutritional management of NEC begins with intestinal rest,
Pseudomonas aeruginosa. (77) during which non-nutritive sucking may be initiated to
In a 2019 study with a 5-year follow-up, 1163 fecal promote intestinal motility and mesenteric blood flow.
metagenomes from 31 preterm neonates who developed NEC Enteral nutrition should be resumed as soon as NEC is
and 126 preterm neonates without NEC were analyzed, resolved to mitigate the adverse effects of prolonged
averaging 7.2 samples per neonate. The intestinal gastrointestinal rest and parenteral nutrition, such as an
microbiome of all neonates was dominated by Proteobacteria. increased risk of sepsis, cholestasis, growth impairment,
The study found an increase in Enterobacteriaceae and a neurocognitive deficits, and extended hospital stays.
deficiency in Actinobacteria and Bacteroides. Klebsiella Following recovery from conservative or less severe surgical
pneumoniae was the most strongly associated bacterium with NEC, an initial enteral feeding volume of 10–20 ml/kg/day is
NEC, detected in 52% of samples before NEC diagnosis recommended, with evidence showing that advancing by 20
compared to 23% in controls. Additionally, a daily increase ml/kg/day is generally well-tolerated without negative
in bacterial replication was observed three days before and up outcomes. However, caution should be exercised based on the
to the diagnosis, potentially contributing to the disease's severity of the disease and the extent of surgical resection.
onset. (78) Bolus feeding is thought to better stimulate intestinal
adaptation than continuous infusion. However, continuous
TREATMENT feeding provides a slower administration of nutrients, which
The choice of treatment can be challenging due to the wide may improve absorption and feeding tolerance, particularly
range of conditions resembling NEC, such as intestinal in infants with short bowel syndrome. (87)
perforation, ischemic intestinal necrosis, protein intolerance-

2489 Volume 04 Issue 12 December 2024 Corresponding Author: Israel Estrada Marroquín
Necrotizing Enterocolitis: A Literature Review of Basic Concepts, Diagnosis and Treatment Options
Neonates with NEC should begin early parenteral nutrition to The type of treatment serves as a significant prognostic
maintain a positive nutrient balance, support weight gain, and factor, with higher morbidity and mortality observed in
facilitate tissue repair. Parenteral nutrition should be patients who underwent surgical intervention compared to
discontinued once the inflammatory process resolves and those managed with conservative treatment. (97)
enteral feeding becomes sufficient to meet the neonate's
nutritional needs, thus reducing the risk of complications. PREVENTION
(88) Since the pathogenesis of NEC is multifactorial, multiple
While the only absolute indication for surgery is radiologic interventions have been studied for its prevention. These
evidence of intestinal perforation, manifesting as include optimal feeding strategies that prioritize human milk,
pneumoperitoneum on abdominal X-rays, emerging evidence microbial optimization approaches (probiotics, prebiotics,
suggests that early surgical intervention based on ultrasound and symbiotics), immunomodulatory strategies, and
findings—such as intestinal wall thickening and deficient nutritional strategies. (98)
intestinal peristalsis—can significantly improve therapeutic In a retrospective study examining the impact of mixed
outcomes and reduce mortality and complications, even feeding with different proportions of breast milk and formula,
before perforation occurs. (35, 76, 89, 90) 303 very low birth weight neonates were included, each
The main surgical goal is to minimize contamination by following a different feeding plan for two weeks. They were
controlling intestinal perforation and resecting nonviable divided into three groups: one group was fed with a higher
bowel segments. Several surgical approaches exist, including proportion (greater than 54%) of breast milk, a second group
peritoneal drainage, laparotomy with or without bowel with a lower proportion (less than 54%) of breast milk, and a
resection, and the formation of either a stoma or a primary third group was exclusively fed formula. This study found a
anastomosis. (91) significantly higher NEC incidence in the last two groups in
comparison with the group fed with a higher proportion of
COMPLICATIONS breast milk, concluding that a higher intake of breast milk was
Out of the neonates who survive, approximately 50% will more effective than a lower intake in preventing NEC due to
develop long-term complications, and around 10% of these bioactive components that shape intestinal immune
will experience late-onset gastrointestinal problems. development and promote healthy intestinal colonization,
Meanwhile, the remaining 50% will not have any long-term thus preventing intestinal inflammation and providing strong
sequelae. (92) protection against the development of NEC. Breastfeeding
In a 20-year follow-up study of neonates who had NEC (68% was considered the most effective preventive strategy. (99,
Bell stage I, 25% stage II, and 7% stage III), compared with 100)
neonates of the same gestational age, birth weight, and The protective effect of breastfeeding has been linked to an
birthdate, it was found that weight gain was significantly enzyme called PAF-acetylhydrolase (PAF-AH-102) that
lower in those who experienced NEC in comparison with the works by inhibiting the platelet-activating factor involved in
control group. No significant differences in height were the inflammatory process, possibly providing a protective
observed. (93) effect depending on the amount of breast milk received by the
NEC is associated with a higher incidence of preterm-infant. A meta-analysis found that the risk of NEC
neurodevelopmental impairment. Among neonates requiring was reduced by nearly half with human breast milk feeding,
surgery, greater neurological compromise was observed whether from the mother or a donor, compared to formula
compared to those treated conservatively, reflecting feeding. (101, 102)
multifactorial impacts, including inflammatory responses, Historically, it was believed that delaying the initiation of
hemodynamic changes in the brain, hypotension, reduced enteral feeding would minimize the incidence of NEC.
cerebral blood flow, hypoxia, and ischemia. However, no higher incidence of NEC has been found when
Neurodevelopmental impairment remains a significant early trophic feeding (within the first 96 hours of birth) is
concern, with an overall rate of 56% among survivors at 18 started and continued for one week, compared to fasting and
to 22 months of corrected age. This impairment is starting enteral feeding at seven or more days of life in very
characterized by moderate to severe cerebral palsy, severe preterm neonates (<32 weeks) or very low birthweight
bilateral visual impairment (vision below 20/200), or neonates (<1500 grams). (103)
permanent hearing loss. (94, 95) In a 2019 meta-analysis that included neonates between 28-
The most frequent gastrointestinal complications include 36 weeks of gestational age and weighing between 1000-
adhesions in 10% of cases and short bowel syndrome (SBS), 1500 grams, the safety of starting total enteral feedings at 80
which is considered the most common cause of intestinal ml/kg/day was compared to starting enteral feedings at the
failure. SBS is characterized by a reduction in intestinal conventional volume of 20 ml/kg/day, supplemented with
function and/or mass below the minimum required to sustain intravenous fluids. No difference was found in the incidence
growth, hydration, and electrolyte balance, with a 26% of NEC or feeding intolerance when total early enteral
occurrence rate secondary to NEC. (96) feedings were initiated. (104, 105)

2490 Volume 04 Issue 12 December 2024 Corresponding Author: Israel Estrada Marroquín
Necrotizing Enterocolitis: A Literature Review of Basic Concepts, Diagnosis and Treatment Options
vulnerable population, identified with risk factors, requires
A meta-analysis concluded that, for infants with very low careful monitoring.
birthweight, a faster advancement of feeding (30 to 40 This disease presents with nonspecific clinical signs and lacks
ml/kg/day compared to 15 to 24 ml/kg/day) did not increase pathognomonic symptoms, making complementary studies
the risk of NEC and showed benefits in recovering such as imaging and laboratory tests essential for early
birthweight and shortening hospital stay. However, the use of detection, accurate diagnosis, and timely medical
this practice should be individualized for newborns with risk intervention. New techniques and promising biomarkers have
factors. (106, 107) been introduced; however, an ideal biomarker that combines
Probiotics may positively contribute to modulating immune high specificity, sensitivity, low cost, and non-invasive
responses such as inflammation, improving the function of characteristics capable of differentiating NEC from similar
the intestinal mucosal barrier, modulating host gene pathologies is still lacking. Future research is needed to
expression, and preventing colonization by pathogenic determine its usefulness in everyday clinical practice. This
bacteria. Probiotics are not routinely administered in all area holds great potential for the development of new
centers, but where they are used, they are started as soon as molecular techniques that could positively impact the
possible once the patient receives enteral nutrition. (108, 109) prediction, diagnosis, timely treatment, and, consequently,
Moderate to high-certainty evidence shows the superiority of prognosis, reducing short- and long-term sequelae.
combinations of one or more Lactobacillus spp. and one or Overdiagnosis leads to the interruption of enteral feeding,
more Bifidobacterium spp. over alternative single and with the administration of prolonged courses of antibiotics
multiple probiotic treatments. The two combinations of and parenteral nutrition, and medical practices that, while
Bacillus spp. and Enterococcus spp., and Bifidobacterium necessary, are not benign.
spp. and S. salivarius thermophilus, may provide a greater NEC is a potentially fatal disease, with increased morbidity
reduction in the development of NEC, with low to very low and mortality in patients who undergo surgical treatment.
evidence certainty. A large, high-quality trial in Australia Various variables affect outcomes, including birth weight,
determined that the probiotic combination with hemodynamic status, comorbidities, available resources,
Bifidobacterium infantis, Streptococcus thermophilus, and B. intraoperative findings, and the attending physician's
lactis demonstrated a reduction in the risk of NEC. (110, 111) preferences.
The use of antenatal steroids for preterm birth reduces It is crucial to implement preventive measures to reduce the
perinatal death, neonatal death, and the most severe events incidence of NEC, lessen the economic burden on healthcare
associated with prematurity, including necrotizing systems, decrease severe complications, shorten
enterocolitis. It has the potential effect of accelerating hospitalization times, and avoid long-term sequelae and even
intestinal maturation, evidenced by decreased bacterial death. Long-term complications and neurodevelopmental
translocation, greater absorption of macromolecules, a sequelae are associated with poor quality of life and a
protective effect against intestinal injury and severity, significant increase in financial resource utilization.
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Enterocolitis Necrotizante

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Enterocolitis Necrotizante

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Clinical Management of Necrotizing Enterocolitis

Reed A. Dimmitt and R. Lawrence Moss

Data Supplement (unedited) at:

*Fellow in Pediatrics, Division of Neonatal and Developmental Medicine.

e110 NeoReviews Vol.2 No.5 May 2001

similar to those seen with other causes of deterioration

NeoReviews Vol.2 No.5 May 2001 e111

Figure 3. A left lateral decubitus radiograph demonstrating

The most serious complications of NEC are intestinal

e112 NeoReviews Vol.2 No.5 May 2001

Table 1. Modified Bell Staging Criteria for NEC*

NEC Staging Clinical Management

NeoReviews Vol.2 No.5 May 2001 e113

e114 NeoReviews Vol.2 No.5 May 2001

Type of Operation, Gestational Age (GA), Birthweight (BW), and

Survival With Perforated NEC: Published Data*

to stabilize the baby until formal laparotomy could be Long-term Outcome

NeoReviews Vol.2 No.5 May 2001 e115

Summary enterocolitis: therapeutic decisions based upon clinical staging.

e116 NeoReviews Vol.2 No.5 May 2001

NeoReviews Vol.2 No.5 May 2001 e103

development of neonatal NEC. In a recent randomized,

e104 NeoReviews Vol.2 No.5 May 2001

tant human milk components, their specific importance Bacterial Colonization

NeoReviews Vol.2 No.5 May 2001 e105

Mesenteric Blood Flow lenge without significantly affecting circulatory changes.

e106 NeoReviews Vol.2 No.5 May 2001

NeoReviews Vol.2 No.5 May 2001 e107

Summary Gonzalez-Crussi F, Hsueh W. Experimental model of ischemic

e108 NeoReviews Vol.2 No.5 May 2001

NeoReviews Vol.2 No.5 May 2001 e109

Downloaded from http://neoreviews.aappublications.org/ at The University Of Calgary on May 27, 2015

Data Supplement at:

Downloaded from http://neoreviews.aappublications.org/ at The University Of Calgary on May 27, 2015

Necrotizing Enterocolitis: A Literature Review of Basic Concepts, Diagnosis

ABSTRACT ARTICLE DETAILS

INTRODUCTION. microbiome to prevent disease. The successful adaptation of

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