Necrotizing enterocolitis

Necrotizing enterocolitis:
An update
Dr. S. Ismat Bukhari

• Necrotizing enterocolitis (NEC) is an inflammatory disease of
the intestine affecting 5% to 10% of premature infants born
weighing less than 1,500 g, with an associated mortality rate
of 10% to 50%.
• 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.

Pathophysiology
• In simple terms, the condition can be considered an aberrant
response of the immature gut and immune system in the
setting of enteral nutrition and the presence of bacteria.

FEEDING
• The introduction of enteral nutrition is a key component in the
pathogenesis of NEC.
• Unfed infants rarely develop the disease; indeed, 90% to 95% of infants
who develop NEC have been exposed to recent enteral volume
advancement. Enteral nutrition may predispose to NEC by disrupting
mucosal integrity, reducing gut motility, or altering gastrointestinal blood
flow.
• Appropriate feeding advancements have not been elucidated for preterm
infants, but it appears that aggressively increasing feedings increases the
risk of NEC.
• The type of feeding also is critical. Human milk appears to decrease the
risk of NEC compared with formula. The osmolality of formulas is
important, with those that have high osmotic loads being associated with
NEC.

BACTERIA/INFECTION
• Considerable attention has been directed to the relationship of intestinal
microbes and the pathogenesis of NEC.
• Bacteremia occurs in up to 35% of cases of NEC. It is unclear whether
bacteria play a primary role in the pathogenesis of NEC or bacterial
translocation occurs due to an already compromised intestinal barrier.
• No pathogen is found consistently in NEC.
• On the other hand, bacteria also play a primary role in normal intestinal
homeostasis.
• In the newborn period, the gut becomes colonized with E coli and
streptococci from the maternal vaginal flora.

• Bacteria reported to be associated with NEC include Escherichia coli,
Klebsiella, Enterobacter, Pseudomonas, Salmonella, Clostridium,
coagulase-negative Staphylococcus, and Enterococcus sp.
• Gram-positive organisms are more common in stages I and II disease, and
enteric organisms predominate in more severe cases.
• Viral pathogens, namely, rotavirus, coronavirus, and enteroviruses also
have been described in association with NEC.
• The type of nutrition that a baby receives appears to have an impact on
subsequent colonization patterns, with formula-fed infants showing an
early increase in Enterobacteriaceae colonization and the guts of breast-
fed infants colonized early with Enterobacteriaceae and Bifidobacterium.

IMMATURE GUT
• An immature gastrointestinal tract and immune response
predispose preterm infants to NEC.
• The preterm intestine demonstrates increased permeability to high
molecular weight molecules, decreased motility, and decreased
mucus production compared with the gastrointestinal tract of more
mature infants.
• Preterm infants show an inappropriate cellular and humoral
response to intestinal pathogens.
• The immature gastrointestinal tract shows impaired circulatory
dynamics in response to an enteral volume load.

Role of Hypoxia-Ischemia
• The relationship between hypoxicischemic events and NEC is
controversial.
• Hypoxia-ischemia was long believed to play a prominent role in the
pathogenesis of NEC, but much of the supporting evidence was anecdotal.
• Unfortunately, this has been one of the major reasons for neonatologists
withholding enteral feeding from babies who have experienced low or
even borderline low Apgar scores.
• The late occurrence of NEC in preterm infants who do not have preceding
evidence of ischemia argues against hypoxiaischemia as a primary
causative agent in the development of NEC.
• However, histologic examination does reveal coagulation necrosis,
suggesting the occurrence of ischemia, perhaps as a secondary event in
the pathogenesis of NEC.

• Several clinical situations in the preterm infant that increase
the risk of NEC are associated with compromised intestinal
blood flow.
• For example, patients who have an active patent ductus
arteriosus (PDA) associated with a large left-to-right shunt
have decreased gut perfusion and appear to have an
increased risk for NEC.

• Furthermore, patients treated with indomethacin to close the
PDA have an increased risk for NEC, presumably due to the
effect of the drug on the intestinal circulation.
• Finally, maternal cocaine abuse has been associated with an
increased incidence of NEC in several retrospective cohort
studies, and animal data suggest that intestinal blood flow is
reduced with cocaine exposure.

• Several mucosal enzymes and gastrointestinal hormones are
suppressed or deficient in preterm babies
• Many aspects of the intestinal host defense system are
deficient or dysfunctional in the preterm infant, including the
secretory immunoglobulin A (IgA) response, neutrophil
function, macrophage activation, cytokine production and
function, and activity of intestinal defensins.
• Furthermore, evidence suggests that autoregulation of the
microcirculation differs in preterm babies and the physiologic
mechanism in the prevention of bacterial overgrowth, is
dysfunctional as well.

Clinical findings
SPECIFIC GASTROINTESTINAL SIGNS:
• Early presenting signs:
– 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%)
– diarrhea (4% to 26%).
• As the disease progresses, abdominal findings become more severe.
Patients may develop marked abdominal distention 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.

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 3 109/L [,1,500 cells/cu mm]) has been reported in
37% of cases.
• It results from both decreased production and increased utilization of leukocytes.
• Thrombocytopenia is also common, seen in up to 87% of patients.
• In addition, patients may develop other coagulation abnormalities, including prolongation of
prothrombin time and hypofibrinogenemia.
• Glucose instability (hypoglycemia or hyperglycemia), metabolic acidosis, and electrolyte
imbalance may occur.
• Some patients have elevated C-reactive protein levels.
• Because no unique infectious agents have been incriminated in NEC, bacteriologic and fungal
cultures may prove helpful but not conclusive.

A plain antero-posterior radiograph
demonstrating pneumatosis.
Initial radiographic evaluation may
reveal a fixed, dilated loop of bowel.
The characteristic radiologic finding is
pneumatosis intestinalis, which is
believed to be intraluminal gas
produced by bacterial fermentation.
Pneumatosis intestinalis is found in
70% to 80% of confirmed cases of
NEC.
Portal venous gas or pneumo-
peritoneum may be seen with severe
cases.

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.

• Some authors have used other modes of imaging to diagnose NEC and
assist in the decision for surgical intervention.
• The use of ultrasonography, contrast radiography, and even magnetic
resonance imaging has been reported anecdotally, but their utility has not
been established.
• These studies never should delay otherwise indicated medical or surgical
management.

Photomicrograph of intestine with NEC.
The cystic areas below the severely
disrupted mucosal layer are pockets
of hydrogen gas that present
radiographically as pneumatosis.
HISTOLOGY/GROSS PATHOLOGY
Histologically, NEC is characterized by
mucosal edema, inflammation,
hemorrhage, coagulation necrosis, and
mucosal ulceration.
The terminal ileum and proximal
colon are the sections of bowel affected
most commonly, although more extensive
disease is possible from the stomach to
the rectum.

• Staging of NEC is according to a modification of the system
first proposed by Bell and colleagues in 1978.
• The staging system is based on clinical, laboratory, and
radiologic findings.
• Stage I signs are nonspecific and can be due to a number of
problems, including sepsis and simple feeding intolerance.
• Stage II and III criteria are more specific for NEC: pneumatosis
intestinalis, pneumoperitoneum, grossly bloody stools, DIC,
and metabolic acidosis.

Differential diagnosis
• Sepsis with ileus, in both term and preterm patients, can mimic
NEC.
• Both present with systemic signs of infection and abdominal
distention.
• Fortunately, the treatment for both conditions is similar: bowel rest,
antibiotic administration, and supportive care.
• Isolated gastric perforation can result in pneumo-peritoneum.
• Gastric perforation may be associated with administration of
indomethacin or corticosteroids.
• Iatrogenic gastric perforation from feeding tubes occurs rarely.
• Patients who have Hirschsprung enterocolitis or severe
gastroenteritis may present with pneumatosis.

Medical management
• Most patients who have NEC are treated non-operatively.
• The maxim of ABCs (airway, breathing, and circulation) holds in these
infants. Most require some mechanical ventilatory support.
• Peripheral arterial access should be established for accurate
measurement of systemic blood pressure and arterial blood gases.
• Many patients will be hypovolemic and require fluid resuscitation and
correction of acid base imbalance. The acidemia in NEC is often mixed,
with a respiratory component from hypoventilation as well as a metabolic
contribution from hypoperfusion.
• If there is evidence of coagulopathy, administration of platelets, fresh-
frozen plasma, or cryoprecipitate may be indicated.

• Sodium bicarbonate should be given in severe metabolic acidosis.
• Dopamine and epinephrine infusions may be necessary when
hypoperfusion does not respond to fluid administration.
• After obtaining blood cultures, broad-spectrum antimicrobial
therapy appropriate to cover bowel flora should be initiated.
• Ampicillin and gentamicin are possible choices, but the common
use of these antibiotics in the NICU typically results in the
development of resistant organisms.
• Antibiotic therapy may be guided by patterns of resistance in the
individual unit.
• In addition, VLBW infants are at risk for bacteremia from
coagulase-negative Staphylococcus.

• Accordingly, empiric treatment with vancomycin and a
third-generation cephalosporin is appropriate.
• Because anaerobic flora can be acquired as early as 1
week of age, a third agent to cover these organisms
may be warranted.
• The severity of the disease and the need for long-term
coverage with broad-spectrum antibiotics places
patients who have NEC at risk for fungal sepsis.
• Amphotericin, administered either empirically or
following proven culture, may be necessary later in the
course of treatment.

• Discontinuation of enteral feeding and gastric
decompression with a large-bore (10 or 12 French) orogastric
tube should be facilitated.
• Although fraught with imprecision, serial measurements of
the abdominal girth are warranted.
• More important is serial examination by the same examiner.

• Antimicrobial therapy and bowel rest should be continued for 7 to 14 days,
depending on the severity of the episode.
• At the end of this period, it is important to increase feedings gradually
over many days.
• Some patients who appear to respond successfully to medical treatment
will manifest increased gastric residuals, abdominal distention, and bilious
emesis as enteral feeds are advanced.

• This scenario suggests the development of intestinal strictures.
Strictures occur in areas of the intestine that suffered ischemia
without full-thickness necrosis.
• These areas heal by scarring, and contraction of the scar leads to
stricture. Strictures may occur anywhere in the intestine, but the
most common site is at the junction of the descending and sigmoid
colon. Radiographic studies reveal evidence of a partial bowel
obstruction, with intestinal dilatation on the anteroposterior view
and air-fluid levels on the dependent view.
• High suspicion of stricture warrants bowel rest until 6 weeks after
the initial diagnosis of NEC to allow complete fibrous healing.
• A contrast enema should be performed at the completion of this
period.
• If results of a lower gastrointestinal study are normal, an upper
gastrointestinal contrast study is indicated. If a stricture is
identified, it should be resected surgically.

Surgical management
• Even with aggressive and appropriate medical management, 34% to 50% of
patients who have NEC require surgical intervention.
• The operation of choice in patients weighing greater than 1,500 g is laparotomy
with resection of frankly necrotic bowel. In some cases, there is a well-defined
segment of dead bowel, with the remainder of the intestine appearing normal.
• In others, disease may be patchy, involving multiple segments of the intestine, or
large areas of intestine may be of questionable viability.
• The surgeon must resect all of the necrotic intestine yet avoid removing intestine
that ultimately could prove viable. A portion of viable intestine is used to create an
• enterostomy and mucous fistula. Once evidence of bowel function returns, enteral
feeds are introduced slowly.
• The period of time to bowel reanastomosis varies; 6 weeks is the minimal waiting
period.

• Primary resection and anastomosis of an isolated perforation has
been reported anecdotally, but this procedure is not widely
accepted.
• When multiple segments of bowel are affected, the surgeon
traditionally is forced to create multiple stomas.
• An alternative technique is the so-called “patch, drain, and wait”
approach. Each perforation is sutured closed, Penrose drains are
placed in the lower abdominal quadrant, and parenteral nutrition is
continued.
• For patients who have pan-necrosis with extensive involvement, the
appropriate surgical management is unclear.
• Resection of affected bowel results in severe short bowel
syndrome. Because of the poor outcomes seen in these patients,
some surgeons support the practice of foregoing any treatment.

• For patients weighing fewer than 1,500 g, the best operative management
is not known.
• Historically, the surgical management of VLBW neonates who had
perforated NEC was the same as that for larger babies: laparotomy,
resection, and stoma creation.
• However, applying classic surgical techniques in these very small babies
may increase mortality and morbidity.

Long term outcome
• In addition to post-NEC intestinal strictures, patients who undergo surgical
intervention for NEC have a high probability of long-term adverse
outcomes.
• The most common intestinal complication is short bowel syndrome (25%).
• In this condition, the amount of remaining intestine is not sufficient to
provide adequate absorption of enteral nutrients and fluid. Because the
bowel is not functional, the patient is dependent on parenteral nutrition.

• As many as 50% of patients who survive NEC develop
neurodevelopmental delay.
• Although NEC is not believed to be directly causative, any
condition that results in prolonged hospitalization has been
shown to place neonates at risk.

Predictive markers
• Individual markers that are elevated at presentation of clinical symptoms of NEC
that may be useful for supporting the diagnosis include serum amyloid A (SAA),
anaphylatoxin (C5a), urinary intestinal fatty acid–binding protein (I-FABP), claudin-
3, stool platelet-activating factor (PAF), and calprotectin.
• A decreased plasma level of inter-a-inhibitory protein (IaIp) appears to be a
reliable marker for the diagnosis of NEC.
• Serial measurement of C-reactive protein (CRP), SAA, and fecal calprotectin (FC) all
appear to be helpful in monitoring the response to therapy.
• Last, CRP, C5a, and I-FABP may be variably helpful in predicting severity of disease
and overall prognosis for poor outcomes (eg, death or perforation) related to NEC.
• Interestingly, plasma citrulline may predict dependence on total parenteral
nutrition (TPN) as a sign of morbidity related to NEC

Serum Amyloid A
• SAA is a rapidly acting acute-phase protein produced by hepatocytes in
response to activated monocytes/ macrophages.
• SAA has also been found to be elevated in infants who have NEC and levels
decrease rapidly after the initial peak with the resolution of disease.
• However, SAA levels remained elevated on days 3 and 7 of diagnosis in
patients who died, suggesting that persistent elevations in SAA may
predict higher mortality.

Anaphylatoxin
• The complement activation product, C5a is a strong
chemo-attractant peptide that helps to recruit
inflammatory cells and activates phagocytic cells.
• It has been reported as a contributing factor leading to
mesenteric ischemia/ reperfusion injury.
• C5a levels in the serum at the time of diagnosis were
more accurate than SAA, CRP, and interleukin-6 in
predicting severity of disease, for example, death.

Intestinal Fatty Acid–Binding Protein
• I-FABP is a cytosolic water-soluble protein released from mature
enterocytes in the small and large intestine when cell membrane
integrity is compromised.
• Because of its small size, I-FABP passes the glomerular filter and can
be detected in the urine quickly.
• Urinary I-FABP levels were higher in infants who had NEC versus
those infants without NEC, with specificity of 90% and a sensitivity
of 93% with a cutoff value of 2.20 pg/nmol creatinine.
• I-FABP may be useful as a predictor of disease severity in NEC.

Claudin-3
• Another marker specific to intestinal integrity loss is claudin-
3, which is an important tight junction protein.
• Urinary claudin-3 with a specificity of 81% and a sensitivity of
71%.
• However, this marker was not helpful as a predictor of
severity of NEC.

Platelet-Activating Factor
• PAF is an endogenous phospholipid mediator synthesized from plasma membrane
precursors, and is involved in many physiologic processes largely through local
paracrine effect.
• Levels of PAF are higher in infants with stage II and III NEC versus those without,
and levels steadily increased with progression of disease and returned to baseline
after recovery.
• In addition, fecal PAF has been shown to be elevated days before the clinical
appearance of NEC in human neonates.
• However, like other nonspecific markers of inflammation, PAF can be elevated in
conditions other than NEC, such as perinatal asphyxia, bronchopulmonary
dysplasia, persistent pulmonary hypertension of the newborn, and neonatal
sepsis, all common co-diagnoses in the population at risk for NEC.
• Nonetheless, because of the difficulty in measuring this nonprotein mediator, it is
unlikely that clinical laboratories will consider this suitable for routine use.

Calprotectin
• Calprotectin is a heterodimeric peptide that binds calcium and zinc and constitutes
up to 60% of the cytosolic content of neutrophils.
• In intestinal inflammation, neutrophils are sequestered into the gut wall.
• Calprotectin is extremely resistant to degradation by fecal bacteria, which allows
calprotectin to be reliably measured in fecal matter as a marker for gut wall
inflammation.
• FC levels have been useful for monitoring exacerbations of inflammatory bowel
disease in children.
• Levels did differ between well and sick infants based on their clinical condition,
with values greater than 350 mg/g stool noted in infants with signs of
gastrointestinal injury, that is, bloody stool or bowel perforation.
• FC levels appeared to decrease after the initiation of treatment, which may allow it
to be helpful in monitoring response to therapy.
• FC levels were not related to disease severity. In addition, fecal samples are not
always easily obtainable in infants who have NEC.

Inter a Inhibitor Proteins
• IaIps are serine protease inhibitors that play an important regulatory role
in systemic inflammation and are also an acute-phase reactant.
• IaIp downregulates endogenous serine proteases that can contribute to
epithelial cell necrosis and possibly to NEC.
• Normally, these proteins are found in high concentrations in human
plasma.
• In newborns and adults who have sepsis, a significant decrease in IaIp has
been demonstrated, and levels correlate with disease severity and
frequency of mortality.
• IaIp levels are also decreased in disease states such as neonatal sepsis, so
this marker may not be helpful in distinguishing infants who have
gastrointestinal ileus secondary to sepsis from infants who have NEC.

C-Reactive Protein
• CRP is perhaps one of the best studied and most widely used serological biomarkers used in
various diseases.
• CRP is an acute-phase reactant that increases in the serum in the face of inflammation from
infection or tissue injury.
• CRP may be helpful at the time of diagnosis for differentiating benign gastrointestinal
processes such as ileus from more severe NEC.
• However, an elevated CRP level may not be seen until 12 to 24 hours after clinical symptoms
because of a variable lag period, which makes it less helpful for making early diagnoses.
• However, CRP levels do decrease as the disease process is improved, so it may be helpful as a
marker of response to therapy.
• CRP is not helpful in distinguishing NEC alone from other inflammatory processes, or ileus
due to other infectious processes. Mean peak CRP value did not differ between infants with
stage II and stage III NEC, although time to reach peak CRP was shorter in NEC stage III versus
stage II.
• Persistently elevated levels may suggest the need to evaluate for complications or ongoing
disease that may indicate the need for surgical intervention.

Citrulline
• Citrulline is a nonprotein amino acid produced in the small intestine and serves as a
precursor of arginine, which is important in protein synthesis and nitric oxide production,
among other things.
• Historically, serum citrulline levels in various intestinal diseases have been shown to correlate
with functional intestinal mass. Specifically, in children who have short-bowel syndrome,
citrulline levels have been a fair marker of residual bowel length and TPN dependence.
• In infants who develop NEC, mean citrulline levels were lower than in controls at a
comparable day after birth and were reduced within 48 hours of symptoms, with an optimal
cutoff value of 17.75 mmol/L providing a sensitivity of 76% and a specificity of 87%.
• Although citrulline levels may not be helpful for early diagnosis based on a variable lag time,
further studies are needed to examine whether an acute decrease in serially measured levels
in healthy preterm infants may be used as an early indicator of compromised intestinal
function before the development of symptoms of NEC.
• Citrulline level at presentation of NEC correlated inversely with the duration of parenteral
nutrition needed.

Probiotics
• The interest in the use of probiotics for the prevention of NEC arose after several
observations:
(1) that genera such as Bifidobacterium and Lactobacillus are lower in hospitalized
infants than healthy term infants
(2) that probiotic bacteria are useful in other settings of gastrointestinal disease
(3) that bifidobacteria supplementation could reduce the risk of disease and
decrease the gut proliferation of Gram-negative enteric pathogens in a neonatal
rat model of NEC
(4) that probiotic bacteria downregulate the intestinal inflammatory response in a
variety of animal and cell culture models.
• More recent studies have demonstrated that probiotic bacterial products alone,
such as TLR ligands or CpG segments (areas of the genome with high
concentrations of cytosine linked to guanine by phosphodiester bonds, which
often are near gene promoter regions) of bacterial DNA, can activate anti-
inflammatory pathways via TLR9 binding, and may lessen the inflammatory
response seen in NEC.
• In addition, prebiotics, or nutrients that enhance the growth of beneficial
intestinal microbes, such as galactose, fructose, and lactulose, are being studied.

Human Milk
• Infants fed human milk, as opposed to formula-fed infants, have a lower
incidence of and less severe NEC.
• Infants fed more human milk than formula (>50%) versus infants fed more
formula than human milk (<50% human milk) had a threefold decreased
risk of NEC.
• However, mothers of premature infants often have difficulty in producing
enough milk to meet their infants’ needs.

Epidermal Growth Factor
• Epidermal growth factor (EGF) has been shown to have a role in gut
maturation and function, so it has been considered for its preventive
potential in NEC.
• Infants who have NEC, as well as premature infants, have lower levels of
salivary EGF.

Infection control
• Good hygiene practice (eg, handwashing) has been
demonstrated to be effective in controlling outbreaks of NEC.

Trophic Feedings
• Minimal enteral nutrition, also referred to as trophic, trickle, or
hypocaloric feedings, is the term applied to topical nutrition of the small
intestine administered in the first week or two after birth.
• During this time, enteral feedings are limited for several days, with most
nutrition provided parenterally. After this initial period, enteral feedings
are advanced judiciously.
• Infants exposed to minimal enteral feedings have not shown an increased
risk of NEC compared with infants kept NPO. This “gut priming” has been
shown to increase gut motility, reduce the incidence of cholestasis, and
improve tolerance of subsequent feedings.
• There is increasing evidence that not introducing at least small amounts of
food to the gastrointestinal tract results in atrophy and predisposes the
intestine to inflammation and likely translocation of bacteria.

Human Milk
• Enteral feeding with human milk has been shown to decrease the severity
of NEC compared with formula feeding.
• Fresh human milk contains many immunoprotective factors, such as
immunoglobulins (Igs), lactoferrin, neutrophils, lymphocytes, lysozyme,
and PAF acetylhydrolase (which inhibits PAF).
• Human milk also is believed to promote intestinal colonization with
Lactobacillus.

Antenatal Steroids
• Antenatal steroids are not administered to expectant mothers as
prophylaxis against NEC, but when administered to prevent
respiratory distress syndrome, antenatal steroids decrease the risk
for NEC.
• The mechanism by which steroids protect against NEC is unclear but
probably involves a decrease in inflammatory mediators, increased
activity of enzymes involved in digestion and absorption, and
potentially maturation of the microvillus membrane.
• A protective effect of postnatal glucocorticoids has not been
demonstrated clearly, although their long-term use to treat chronic
lung disease has been associated with adverse neuro-
developmental effects.

Oral Antibiotics
• Oral antibiotics, primarily aminoglycosides, clearly reduce the
incidence of NEC and death due to NEC.
• However, concerns regarding the emergence of bacterial
resistance have rendered oral antibiotic prophylaxis an
inappropriate intervention.

Probiotics
• The human gut is normally colonized with commensal organisms such as
Bifidobacterium and Lactobacillus sp.
• The widespread use of broadspectrum antibiotics in the NICU disrupts
development of normal microflora and allows for growth of pathogenic
organisms.
• Promising recent studies have shown that probiotic supplementation has a
positive impact on the incidence of NEC in preterm infants.
• Further study is necessary to determine which probiotic formulation
provides the maximal protection.
• Recent evidence suggests that probiotic bacteria may not need to be alive
to impart a positive effect; even bacterial products, such as TLR ligands or
CpG segments of DNA, may be effective in ameliorating inflammation in
the intestine.

Immunoglobulins
• Another possible preventive measure is oral supplementation
with Igs.
• A recent Cochrane review, which examined five studies on Ig
supplementation, found no significant difference in NEC or
death from NEC with IgG or IgA preparations.

Acidification
• Preterm infants have been shown to have
decreased gastric acid production in response to
enteral feeding.
• An acid environment is an important barrier to
many pathogenic microorganisms.
• A lower incidence of NEC is demonstrated in
infants whose enteral feedings were
supplemented with acid to keep the pH between
3 and 4.

Glutamine
• Glutamine has been shown to be important in
immunity and intestinal function.
• A couple of single-center studies in human neonates
have shown decreased sepsis and improved intestinal
function with glutamine supplementation.
• Other studies did not show a decrease in sepsis, but
the trial of enteral supplementation suggested a lower
prevalence of intraventricular hemorrhage and
periventricular leukomalacia.

Arginine
• Arginine is a substrate for nitric oxide, which demonstrates
vasodilatory and anti-inflammatory properties.
• Arginine also is a precursor for other amino acids that are
important in intestinal homeostasis, including glutamine and
glutamate.
• Although initial results suggest that arginine supplementation
may play a role in protecting against NEC.

Strictures
• Infants who survive episodes of NEC are at risk for serious
complications, the most common of which is stricture
formation.
• Up to 39% of affected patients develop stricture(s).
• Strictures may form as soon as 2 weeks following acute
disease. Most strictures are colonic.
• Occasionally, partial strictures may present with recurring
episodes of sepsis and feeding intolerance, which should be
ruled out with appropriate radiologic contrast studies.

Malabsorption/Short Gut
• Although short gut syndrome and malabsorption are expected when
significant amounts of bowel need to be resected, malabsorption also
occurs in cases of NEC that do not require resection.
• This may be due to persistent mucosal injury from an ongoing
inflammatory process.

Complications Associated with Total Parenteral Nutrition
• Most infants who have confirmed NEC require central catheterization for
prolonged parenteral nutrition.
• The catheters employed for total parenteral nutrition are associated with
significant risks of infection, vessel perforation, and iatrogenic pleural and
pericardial effusions.
• The use of parenteral nutrition and NPO status also place the patient at
risk for cholestasis and delay in intestinal maturation.

Recurrence
• As many as 6% of infants who develop NEC experience
disease recurrence.

Extraintestinal Complications
• Infants who recover from an episode of NEC have been shown to be at
increased risk of developing extraintestinal complications, such as sepsis,
bronchopulmonary dysplasia, and neurodevelopmental delay.
• A recent retrospective study found that infants who had experienced an
episode of NEC are at increased risk for microcephaly, short stature, and
serious developmental delay.
• An increased incidence of spastic diplegia and hemiplegia suggests
periventricular damage.

References
• The Pathophysiology of Necrotizing Enterocolitis
Michael S. Caplan, MD, and Tamas Jilling, MD
NeoReviews Vol.2 No.5 May 2001 e103
• Necrotizing Enterocolitis: Predictive Markers and Preventive Strategies
Alison Chu, MD, Joseph R. Hageman, MD, Michael S. Caplan, MD
NeoReviews Vol.14 No.3 March 2013 e113
• Clinical Management of Necrotizing Enterocolitis
Reed A. Dimmitt and R. Lawrence Moss
NeoReviews 2001;2;e110

Necrotizing enterocolitis

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