Approach Considerations

As many as 50% of all premature infants manifest feeding intolerance during their hospital
course, but less than one fourth of those infants develop necrotizing enterocolitis (NEC). As
with all neonatal care, the risks and benefits of various clinical approaches to NEC must be
considered carefully.

In a study of extremely low birth weight infants, standardized slow enteral feeding (SSEF)
was associated with a reduced risk of NEC compared with early enteral feeding. A total of
125 infants were treated with the SSEF protocol; these infants were compared with 294
historic controls. Days to full feeds ranged from 16 to 22 among controls, from 44 to 52 days
for babies weighing under 750 grams in the SSEF group, and from 32 to 36 days for infants
in the SSEF group weighing 750 to 1,000 grams at birth. [36, 37]

NEC occurred in 5.6% of infants in the SSEF group and 11.2% of infants in the control
group, and 1.6% of SSEF infants and 4.8% of controls required surgery for NEC. Among
infants weighing less than 750 grams at birth, the risk of NEC was 2.1% in the smallest SSEF
babies, compared to 16.2% for the smallest infants in the control group. Risk of combined
NEC and death was 12.8% for infants in the SSEF group weighing less than 750 grams, and
29.5% for small infants in the control group. Infants on the SSEF protocol who developed
NEC got sick at 60 days of age, on average, compared to 30 days for controls. Among
surviving infants, there was no difference between SSEF and control infants in discharge
weight or length. [36, 37]

Patients with mild (Bell stage II) NEC require gastrointestinal rest to facilitate resolution of
the intestinal inflammatory process. These babies are traditionally kept on a diet of nothing
by mouth (NPO) for 7-10 days, making parenteral hyperalimentation necessary. Many of
these babies have difficult intravenous (IV) access. Therefore, the need for prolonged
parenteral nutrition frequently requires placing central venous catheters, which have attendant
risks and complications that include thromboembolic events and nosocomial infections.

In a Cochrane review of 15 studies comprising 979 infants, investigators found similar safety
and efficacy between newer lipid emulsions (LE) from alternative lipid sources with reduced
polyunsaturated fatty acid (PUFA) content and that of conventional pure soybean oil–based
LEs that have high PUFA content for the parenteral nutrition of preterm infants. [38] There
were no statistically significant differences in clinically important outcomes including death,
growth, bronchopulmonary dysplasia, sepsis, retinopathy of prematurity of stage 3 or higher,
and parenteral nutrition–associated liver disease with the use of newer alternative LEs versus
the conventional pure soy oil–based LEs.

Cessation of feeding and initiation of broad-spectrum antibiotics in every baby with feeding
intolerance impedes proper nutrition and exposes the baby to unnecessary antibacterials that
may predispose to fungemia. However, failure to intervene appropriately for the baby with
early NEC may exacerbate the disease and worsen the outcome. Clearly, managing this
population requires a high degree of clinical suspicion for possible untoward events,
tempered by cautious watching and waiting.

Experimental and meta-analytical evidence suggests that exogenous administration of the

probiotics bifidobacteria and lactobacilli (nondigestible substances that selectively promote
the growth of beneficial, probioticlike bacteria normally present in the gut) may moderate the
risk and severity of NEC in preterm infants. [4, 39, 40, 41]

Placement of a peripheral arterial line may be helpful at the beginning of the patient's
treatment to facilitate serial arterial blood sampling and invasive monitoring.

Placement of a central venous catheter for administration of pressors, fluids, antibiotics, and
blood products is prudent because severely affected patients often have complications that
include sepsis, shock, and disseminated intravascular coagulation (DIC).

If the baby is rapidly deteriorating, with apnea and/or signs of impending circulatory and
respiratory collapse, airway control and initiation of mechanical ventilation is indicated.

Abdominal decompression

Decompression is essential at the first sign of abdominal pathology. Abdominal

decompression in infants with necrotizing enterocolitis is as follows:

 Use a large-bore catheter with multiple side holes and a second lumen to prevent
vacuum attachment to the stomach mucosa (eg, Replogle tube)
 Set the catheter for low, continuous or intermittent suction and monitor output; the
tube should be irrigated with several milliliters of normal saline to maintain patency
 If copious amounts of gastric/intestinal secretions are removed, consider IV
replacement with a physiologically similar solution; maintaining electrolyte balance
and intravascular volume is essential

Consultations

Consult with a pediatric surgeon at the earliest suspicion of developing necrotizing

enterocolitis. This may require transferring the patient to another facility where such services
are available.

Transfer

In the acute phase, patients with progressive NEC require pediatric surgical consultation.
During refeeding, patients with or without previous surgical history may demonstrate signs of
obstruction requiring surgical evaluation and/or intervention. Transfer the patient to a facility
offering pediatric surgical expertise, if it is not available at the current location.

Future possibilities

Lactoferrin appears to have potential for prevention of neonatal sepsis and NEC, but few
safety and efficacy studies are complete and available. [42]

Two Cochrane Database of Systematic Reviews studies discussed very promising but also
very preliminary treatments.

One evaluated lactoferrin supplementation in the milk of infants and suggests it shows
promising preliminary results in reducing the incidence of late-onset sepsis in infants
weighing less than 1500 g. When given alone, it did not reduce the incidence of NEC in
preterm neonates. Long-term neurologic outcomes were not assessed, and the authors stress
that dosing, duration, and type of lactoferrin prophylaxis need to be further studied. [43]

The other study found evidence that IV pentoxifylline as an adjunct to antibiotic therapy may
reduce mortality and duration of hospitalization in neonates with sepsis; no completed studies
were found confirming outcomes of treatment for patients with NEC. Although these results
also are promising, more research is needed to validate the findings. [44]

Stem cell therapy is being investigated, both for its potential protective as well as curative
effect. [45] Stem cells of various progenitors can be harvested from a number of sources,
including amniotic fluid, bone marrow and enteric sources. McCulloh et al has shown
promising results from more readily available amniotic fluid mesenchymal stem cells on gut
barrier integrity and permeability, decreasing both the incidence and severity of NEC in
experimental models. [46, 47]

Next:

Treatment by Stage
The mainstay of treatment for patients with stage I or II necrotizing enterocolitis (NEC) is
nonoperative management. The initial course of treatment consists of stopping enteral
feedings, performing nasogastric decompression, and initiating broad-spectrum antibiotics.
Historically, antibiotic coverage has consisted of ampicillin, gentamicin, and either
clindamycin or metronidazole, although the specific regimen used should be tailored to the
most common nosocomial organisms found in the particular neonatal intensive care unit.

Authors in some series have proposed the use of enteral aminoglycosides for the treatment of
NEC, but several prospective trials have shown no efficacy for this treatment. In addition, a
strong index of suspicion for fungal septicemia must be maintained, especially in the infant
with a deteriorating condition and negative bacterial cultures.

Bell stages IA and IB

The patient is kept on an NPO (nothing by mouth) diet with antibiotics for 3 days. IV fluids
are provided, including total parenteral nutrition (TPN).

Bell stages IIA and IIB

Treatment includes support for respiratory and cardiovascular failure, including fluid
resuscitation, NPO, and antibiotics for 14 days. Surgical consultation should be considered.
After stabilization, TPN should be provided during the period that the infant is NPO.

Bell stage IIIA

Treatment involves NPO for 14 days, fluid resuscitation, inotropic support, and ventilator
support. Surgical consultation should be obtained. TPN should be provided during the period
of NPO.

Bell stage IIIB

Surgical intervention, as outlined in the next section, is provided.

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Surgical Treatment
Indications

The principal indication for operative intervention in necrotizing enterocolitis (NEC) is

perforated or necrotic intestine. Infants with necrotic intestine are identified based on various
clinical, laboratory, and radiologic findings. The most compelling predictor of intestinal
necrosis indicating a need for operative intervention is pneumoperitoneum (see the image
below). Other relative indications for operative intervention are erythema in the abdominal
wall, gas in the portal vein, and positive paracentesis.

Pneumoperitoneum. Photo courtesy of the Department

of Pathology, Cornell University Medical College.
View Media Gallery

Surgery is generally indicated in the medically treated patient whose clinical condition
deteriorates. The signs of deterioration include worsening abdominal examination findings,
signs of peritonitis, worsening and intractable acidosis, persistent thrombocytopenia, rising
leukocytosis or worsening leukopenia, and hemodynamic instability.

Note that evaluation by a pediatric surgeon early in the course of NEC is important to avoid
any delay in operative intervention. Many infants may have isolated perforations or necrotic
tissue that wall off the abdominal cavity and do not show free intraperitoneal air. Knowing
whether these infants may benefit from early operative intervention is difficult.

Contraindications

Contraindications to surgical intervention include patients with stage I or stage II disease, for
whom nonoperative medical therapy is the treatment of choice. In addition, surgical
intervention should be deferred in patients with more severe disease whose condition
responds to initial medical management.

Patients who are extremely small and ill may not have the stability to tolerate laparotomy. If
free air develops in such a patient, one may consider inserting a peritoneal drain under local
anesthesia in the nursery.

Preoperative care

After the decision to proceed with surgery is made, the patient's general physiologic
condition should be optimized. Provide vigorous fluid replacement, correct any clinically
significant anemia or coagulopathy, and ensure adequate urine output of at least 1 mL/kg/h.
To minimize heat loss, place the infant on a heated air pad; in addition, a warmed operating
room and warmed IV and irrigation fluids should be used. The use of heated and humidified
oxygen and anesthetic gases may further minimize heat loss. Blood products should be
available during surgery.

Intraoperative details

The abdomen can be entered via a right transverse incision just below the umbilicus by using
electrocautery to ensure hemostasis. This incision provides adequate exposure away from a
frequently large liver and decreases the risk of retractor injury to the liver. Care must be taken
at the time of entry into the peritoneal cavity to avoid injury to dilated loops of intestine. If
any free intraperitoneal fluid is identified, samples may be taken for aerobic, anaerobic, and
fungal culture. Bloody peritoneal fluid is seen in necrosis and brown turbid fluid is found in
perforation.

The abdominal cavity is then systematically inspected for evidence of necrosis and
perforation. Particular attention is paid to the right lower quadrant because the terminal ileum
and proximal ascending colon are most commonly involved. The guiding principle of surgery
for NEC is to resect only perforated and unquestionably necrotic intestine and to make every
effort to preserve the ileocecal valve. (See the images below.)
 Normal (top) versus necrotic
section of bowel. Photo courtesy of the Department of Pathology, Cornell University Medical
College.
View Media Gallery

Resected portion of necrotic

bowel. Photo courtesy of the Department of Pathology, Cornell University Medical College.
View Media Gallery

White or gray bowel indicates ischemic necrosis. Hemorrhagic or edematous areas of bowel
may represent areas of mucosal ischemia and injury but do not necessarily indicate nonviable
bowel. Saccular protrusions of bowel wall have undergone mucosal, submucosal, and
muscularis necrosis and are covered only by a layer of serosa. These are areas of impending
intestinal perforation.

Palpation may also be helpful, because resilient pliable bowel is typically viable, and lax and
boggy bowel that indents on palpation is often necrotic. If the viability of remaining bowel is
significantly questionable, a second-look operation can be performed in 24-48 hours to assess
the viability of the remaining intestine.

If a single area of bowel is resected, a proximal ostomy and distal mucus fistula are created.
The viability of the bowel at the cut margins can be ascertained by whether the cut edges
bleed. The enterostomy and mucus fistula are brought out at opposite ends of the incision,
with the serosa sutured to the abdominal wall fascia with interrupted sutures. About 2 cm of
bowel is left to protrude above the abdominal wall, and the end of the ostomy is not matured.
If ostomy viability is in question postoperatively, the ends of the intestine may be excised and
observed for adequate bleeding.
Primary anastomosis is not generally advocated, because of the risk of ischemia at the
anastomosis, leading to increased incidence of leakage, stricture, fistula, or breakdown.
However, intestinal resection with primary anastomosis may be safely performed in select
cases. Patients must demonstrate a clearly demarcated small segment of injured bowel with
normal-appearing residual intestine and be in good general condition with no evidence of
sepsis, coagulopathy, or physiologic compromise.

If multiple segments of intestine are involved because of necrosis or perforation, a decision

must be made regarding the course of action. Historically, the individual segments of affected
intestine are resected, and multiple ostomies are created. However, a number of other surgical
options have been proposed. A single proximal stoma may be created and the distal bowel
segments anastomosed in continuity, thus avoiding multiple stomas.

Moore proposes a technique of patch, drain, and wait, which involves transverse, single-layer
repair of bowel perforations (patch); placement of 2 Penrose drains in the lower quadrants
(drain), and initiation of long-term parenteral nutrition (wait); however, this technique is not
widely advocated. The thin, distended bowel wall holds suture poorly, and the abdominal
cavity does not drain freely with open gravity drainage. In addition, this technique does not
address the source of intra-abdominal sepsis, because necrotic bowel is not resected.

In a small series, Vaughn describes a different technique of clip and drop-back. [48] The
unquestionably necrotic segments of intestine are resected and the transected ends are stapled
closed. A second-look operation is performed in 48-72 hours when the clips are removed, and
reanastomosis is performed without any ostomies.

NEC totalis occurs when less than 25% of the intestinal length is found to be viable at the
time of operation; this finding results in a number of grim treatment options. Simple closure
of the abdomen is supported by findings that show a 42-100% mortality rate in patients with
pan involvement. Massive resection with excision of the ileocecal valve requires at least 20
cm of residual bowel for any hope of adequate enteral nutrition. Patients with a decreased
bowel length require permanent parenteral nutrition.

Martin and Neblett describe a technique of enterostomy diversion proximal to the involved
bowel without bowel resection. [49] This technique may facilitate bowel healing by allowing
bowel decompression, reducing intestinal bacterial load, and decreasing metabolic demand.

After intestinal resection, the length of remaining viable bowel should be sequentially
measured along the antimesenteric border of the intestine and recorded.

Enterostomy closure

Timing of enterostomy closure to restore intestinal continuity is the principal follow-up issue
for infants who are surgically treated for NEC. This procedure is generally performed 1-2
months after the original operation, depending on weight gain and ostomy output, among
other factors. The argument against early ostomy closure is the difficulty of operating in a
peritoneal cavity replete with adhesions and resolving inflammation; the ideal time is
approximately 8 weeks.
If goal enteral feeds can be accomplished, there is some benefit in discharging the patient
home and performing a reanastamosis after several months. This gives the infant a chance to
grow and better tolerate an additional laparotomy.

Abnormally high ostomy output may indicate a need for early ostomy closure. A patient with
a high jejunostomy may have substantial loss of fluid and electrolytes, with consequences
such as failure to thrive and peristomal skin injury. These patients may benefit from early
ostomy closure with attendant colonic water absorption.

However, infants with a high ostomy and extensive ileal resection who undergo ostomy
closure may have considerable secretory diarrhea after the colon comes in contact with
unabsorbed bile salts. They may require treatment with a bile salt–binding agent, such as
cholestyramine. Sodium chloride supplementation (1-3 mcg/kg/day) has been recommended
to optimize growth in infants with small-bowel stomas.

All patients who have any remaining large intestine after an initial operation for NEC must be
examined with contrast-enhanced enema of the colon to identify any areas of stricture before
the ostomy is closed. If any such areas are present, they are resected when the enterostomy is
closed. In addition, some advocate a screening contrast enema study approximately 30 days
after recovery in infants who have been nonoperatively treated for NEC. Symptomatic
colonic strictures require treatment, whereas asymptomatic strictures may be observed.

Peritoneal drainage

Neonates who are extremely ill and unable to tolerate surgery may be treated by means of
peritoneal drainage in a technique described by Ein et al. [50] A right lower quadrant incision
is made at the bedside under local anesthesia, and a Penrose drain is inserted. The procedure
was initially intended as a means of temporizing with regard to surgical treatment, and
indeed, some infants survived with this procedure alone and did not require subsequent
laparotomy.

A multicenter, randomized clinical trial failed to show a significant difference in survival at

90 days between primary peritoneal drainage and laparotomy with resection for premature
infants with very low birth weight (<1500 g) and perforated NEC. [51]

Critically ill newborns with a relative contraindication to formal operative exploration may be
treated with the placement of a peritoneal drain. Although this is typically a temporizing
measure, these extremely ill infants may recover with drain placement alone and do not
require exploratory laparotomy.

Peritoneal drain placement may be the treatment of choice for extremely small (<600 g)
premature newborns. Such premature, critically ill infants cannot tolerate formal exploration,
and drain placement may be preferred and definitive. Nevertheless, many infants whose
condition is too unstable for formal exploration do not survive, regardless of intervention.

Postoperative details

After undergoing an operation for NEC, infants should continue to receive intravenous
antibiotics and total parenteral nutrition for at least 2 weeks. Supportive care, including
ventilatory support, fluid and electrolyte monitoring and replacement, and correction of
anemia and coagulopathy, should continue.

During surgery infants with NEC often develop a coagulopathy that continues after surgery
and can be difficult to manage. Blood can fill the abdominal cavity rapidly and create a
compartment syndrome that requires drainage. Any infants with continued clinical
deterioration must be evaluated for residual intestinal gangrene and possibly repeat surgical
exploration. Infants who improve postoperatively should not resume enteral feedings for at
least 10-14 days.

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Parenteral Nutrition
In patients with necrotizing enterocolitis (NEC), prolonged parenteral nutrition is essential to
optimize the baby's nutrition while the GI tract is allowed enough time to recover and return
to normal function. Central venous access is essential to facilitate parenteral delivery of
adequate calories and nutrients to the recovering premature baby to minimize catabolism and
promote growth.

Prolonged central venous access may be associated with an increased incidence of

nosocomial infection, predominately with skin flora such as coagulase-
negative Staphylococcus species, as well as methicillin-resistant S aureus (MRSA). A high
degree of clinical suspicion must be maintained to detect the subtle signs of such infection as
early as possible.

Parenteral administration of lipid formulations via central venous catheters is also associated
with an increased incidence of catheter-related sepsis.

Lipids coat the catheter's interior, allowing ingress of skin flora through the catheter lumen. A
high degree of clinical suspicion is required for early detection of such an infection.

If line infection is suspected, obtain a blood culture through the central line and from a
peripheral vein or artery. Antibiotics effective against skin flora, such as vancomycin, should
be administered (although prolonged broad-spectrum antibacterial therapy increases the
premature infant's risk for fungal sepsis). Persistently positive cultures require removal of the
central line. Remove the central line once sepsis and bacteremia are confirmed, because
eradication is almost impossible when the central line is kept in place.

Prolonged parenteral nutrition may be associated with cholestasis and direct

hyperbilirubinemia but may be less likely with use of a fish oil–based lipid
formulation. [52] This condition resolves gradually following initiation of enteral feeds.

Restarting enteral feedings

Enteral feedings are traditionally restarted 10-14 days after findings on abdominal
radiographs normalize in the case of nonsurgical NEC. However, balancing the risks and
benefits of NPO versus enteral feeds may alter this timeline. Reinitiating enteral feeds in
postsurgical babies may take longer and may also depend on issues such as the extent of
surgical resection, return of bowel motility, timing of reanastomosis, and preference of the
consulting surgical team.

Because of the high incidence of postsurgical strictures, some clinicians prefer to evaluate
intestinal patency via contrast studies prior to initiating enteral feeds. When feeds are
restarted, if human milk is not available, formulas containing casein hydrolysates, medium-
chain triglycerides, and safflower/sunflower oils (eg, Alimentum, Pregestimil, Nutramigen)
may be better tolerated and absorbed than standard infant formulas.

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Deterrence and Prevention

Feeding strategies

Breastfed babies have a lower incidence of necrotizing enterocolitis (NEC) than do formula-
fed infants, [53, 54] particularly in very low birth weight (VLBW) (≤1500 g) neonates. [55] In a
retrospective study of 550 VLBW neonates who received donor human milk, those who
received human milk on 50% or more of hospital days had equivalent growth outcomes but
significantly lower rates of NEC (3.4% NEC) compared to infants who received human milk
on fewer than 50% of hospital days (13.5% NEC). [55] Mortality was also reduced, although
this was not a significant difference (1.0% vs 4.2%, respectively).

Much anecdotal evidence details the role of feeding regimens in the etiology of NEC, but
clinical research does not demonstrate definitive evidence for either causation or prevention.
Although conventional wisdom recommends slow initiation and advancement of enteral feeds
for premature infants, random trials do not show an increased incidence of NEC in babies in
whom feeds have been started early in life versus after 2 weeks' chronologic age. [56, 57]

McKeown et al reported that rapid increase in feeding volume (>20 mL/kg/d) was associated
with higher risk of NEC. [29] Later, however, Rayyis et al showed no difference in the
occurrence of NEC Bell stage II or greater in patients advanced at 15 mL/kg/day compared
with those advanced at 35 mL/kg/day. [58] Similarly, a systematic review published by the
Cochrane Collaboration reported no effect on NEC from rapid feeding advancement for low
birth weight infants. [59, 60]

Antenatal and postnatal conditions that diminish intestinal blood flow may increase an
infant's risk of developing NEC. Antenatal conditions causing placental insufficiency, such as
hypertension, preeclampsia, or cocaine use, may justify a more cautious and vigilant
approach to enteral feeding in these infants. Similarly, postnatal conditions that diminish
splanchnic blood flow, such as patent ductus arteriosus (particularly when associated with
reversed aortic diastolic flow demonstrated on echocardiography), other cardiac disease, or
general hypotension/cardiovascular compromise, may increase the risk.

Because early presentation of NEC can be subtle, high clinical suspicion is important when
evaluating any infant with signs of feeding intolerance or other abdominal pathology. In
general, continuing to feed a baby with developing NEC worsens the disease.
Pharmacologic strategies

Efforts to reduce the incidence of NEC may target infection control in the newborn nursery,
augmentation of premature host defenses, stimulation of GI tract maturation, inhibition of
inflammatory mediators, and reduction of enteric bacterial load.

Enteral immunoglobulin A (IgA) is deficient in the premature gastrointestinal system, and

oral IgA supplementation reduces the incidence of NEC in rat models. In addition, a series in
human infants found that patients who received an oral IgG-IgA preparation were
significantly less likely to develop NEC than were control subjects.

The administration of prenatal glucocorticoids to mothers for fetal pulmonary maturation

significantly reduces the incidence of NEC. In addition, postnatal treatment decreases the
incidence of NEC, although not as effectively as prenatal treatment.

In laboratory models PAF antagonists reduced bowel injury. However, their role in the
prevention and treatment of NEC in humans has not been well established.

Nonabsorbable oral antibiotics have been used in attempts to reduce the intestinal bacterial
load and presumably inhibit the progression of NEC. However, several investigators found no
significant difference in outcome between infants receiving oral antibiotics and control
subjects.

A meta-analysis of 12 trials that included 10,800 premature neonates (5,144 receiving

prophylactic probiotics; 5,656 controls) revealed a significant reduction in the incidence of
NEC and mortality in the prophylactic probiotic group, although the incidence of sepsis did
not differ significantly between the groups. [41]

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Long-Term Monitoring
Following hospital discharge, caring for premature infants has shifted away from
neonatologists at regionalized centers to general pediatricians and other health care
providers in the community. Adequate interaction between subspecialists and
community providers and formulation of well-communicated health care plans for
these vulnerable babies are crucial to serving their best interest and to optimizing
their health outcome.

If a baby goes home with a colostomy, parents need thorough instruction regarding
the baby's care. Having the parent(s) room with the baby at the hospital for several
days prior to discharge is advisable so that they can learn and demonstrate
adequate caregiving skills.

Babies who have undergone intestinal resection may experience short-gut

syndrome. These babies require vigilant nutritional regimens to maintain adequate
calories and vitamins for optimum growth and healing.
Previous
Medication
Necrotizing Enterocolitis
Updated: Dec 27, 2017

 Author: Shelley C Springer, JD, MD, MSc, MBA, FAAP; Chief Editor:
Muhammad Aslam, MD more...

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Sections
Necrotizing Enterocolitis

 Sections Necrotizing Enterocolitis

 Overview
o Practice Essentials
o Background
o Etiology
o Epidemiology
o Prognosis
o Show All
 Presentation
o History
o Physical Examination
o Show All
 DDx
 Workup
o Approach Considerations
o Arterial Blood Gases
o Abdominal Radiography
o Abdominal Ultrasonography
o Upper Gastrointestinal Series
o Paracentesis
o Histologic Findings
o Staging of NEC
o Show All
 Treatment
o Approach Considerations
o Treatment by Stage
o Surgical Treatment
 o Parenteral Nutrition
o Deterrence and Prevention
o Long-Term Monitoring
o Show All
 Medication
o Medication Summary
o Antibiotics
o Vasopressors
o Volume Expanders
o Glucocorticosteroids
o Opioid Analgesics
o Antifungal Agents
o Probiotics
o Show All
 Media Gallery
 References

Overview

Practice Essentials
Necrotizing enterocolitis (NEC), which typically occurs in the second to third
week of life in premature, formula-fed infants, is characterized by variable damage
to the intestinal tract, ranging from mucosal injury to full-thickness necrosis and
perforation (see the image below). NEC affects close to 10% of infants who weigh
less than 1500 g, with mortality rates of 50% or more depending on severity, but
may also occur in term and near-term babies.

Normal (top) versus necrotic

section of bowel. Photo courtesy of the Department of Pathology, Cornell
University Medical College.
View Media Gallery

Signs and symptoms

In premature infants, onset of NEC is typically during the first several weeks after
birth, with the age of onset inversely related to gestational age at birth. In term
infants, the reported median age of onset is 1-3 days, but onset may occur as late as
age 1 month.

Initial symptoms may be subtle and can include 1 or more of the following:

 Vomiting
 Diarrhea
 Delayed gastric emptying
 Abdominal distention, abdominal tenderness, or both
 Ileus/decreased bowel sounds
 Abdominal wall erythema (advanced stages)
 Hematochezia

Systemic signs are nonspecific and can include any combination of the following:

 Apnea
 Lethargy
 Decreased peripheral perfusion
 Shock (in advanced stages)
 Cardiovascular collapse
 Bleeding diathesis (consumption coagulopathy)

Physical findings in patients with NEC can be primarily GI, primarily systemic,
indolent, fulminant, or any combination of these. Gastrointestinal signs can include
any or all of the following:

 Increased abdominal girth

 Visible intestinal loops
 Obvious abdominal distention and decreased bowel sounds
 Change in stool pattern
 Hematochezia
 Palpable abdominal mass
 Erythema of the abdominal wall

Systemic signs can include any of the following:

 Respiratory failure
 Decreased peripheral perfusion
 Circulatory collapse

See Clinical Presentation for more detail.

Diagnosis
Obtain radiographic studies if any concern about NEC is present. Pursue laboratory
studies, especially if the abdominal study findings are worrisome or the baby is
manifesting any systemic signs. A CBC with manual differential is usually
repeated at least every 6 hours if the patient's clinical status continues to
deteriorate. Relevant findings may include the following:

 WBC – Moderate to profound neutropenia (absolute neutrophil count

[ANC] <1500/μL) strongly suggests established sepsis
 Hematocrit and hemoglobin – Blood loss from hematochezia and/or a
developing consumptive coagulopathy can manifest as an acute decrease
in hematocrit; an elevated hemoglobin level and hematocrit may mark
hemoconcentration due to notable accumulation of extravascular fluid
 Platelet count – Thrombocytopenia may be present

Other laboratory findings

 Blood culture is usually negative

 Hyponatremia – An acute decrease in serum sodium (<130 mEq/dL) is
alarming
 Low serum bicarbonate (<20) may be seen in babies with poor tissue
perfusion, sepsis, and bowel necrosis
 Reducing substances may be identified in the stool of formula-fed infants
 A breath hydrogen test may be positive
 Arterial blood gas levels may indicate the infant's need for respiratory
support and can provide information on the acid-base status

Abdominal radiography

 The mainstay of diagnostic imaging

 An AP and a left lateral decubitus view are essential for initial evaluation
 Should be performed serially at 6-hour or greater intervals, depending on
presentation acuity and clinical course, to assess disease progression
 Characteristic findings on AP views include an abnormal gas pattern,
dilated loops, and thickened bowel walls
 A fixed and dilated loop that persists over several examinations is especially
worrisome
 Scarce or absent intestinal gas is more worrisome than diffuse distention
that changes over time

Other radiographic findings include the following:

 Pneumatosis intestinalis – Pathognomic of NEC

  Abdominal free air – Ominous; patients usually require emergency surgical
intervention
 Portal gas – A poor prognostic sign
 Distended loops of small bowel – Common but nonspecific
 Intraperitoneal free fluid

Abdominal ultrasonography

 Available at bedside
 Noninvasive
 Can identify areas of loculation and/or abscess consistent with a walled-off
perforation
 Excellent for identifying and quantifying ascites
 Limited availability at some medical centers
 Requires extensive training to discern subtle ultrasonographic appearance
of some pathologies
 Abdominal air can interfere with assessing intra-abdominal structures

See Workup for more detail.

Management

The initial course of treatment consists of the following:

 Stop enteral feedings

 Perform nasogastric decompression
 Initiate broad-spectrum antibiotics (eg, ampicillin, gentamicin, and
clindamycin or metronidazole)

Bell stages IA and IB – suspected disease

 NPO diet and antibiotics for 3 days

 IV fluids, including total parenteral nutrition (TPN)

Bell stages IIA and IIB – definite disease

Support for respiratory and cardiovascular failure, including fluid resuscitation

 NPO diet and antibiotics for 14 days

 Consider surgical consultation
 After stabilization, provide TPN while the infant is NPO

Bell stage IIIA – advanced disease

  NPO for 14 days
 Fluid resuscitation
 Inotropic support
 Ventilator support
 Obtain surgical consultation
 Provide TPN during the period of NPO
 Surgical intervention

Surgery

The principal indication for operative intervention in NEC is perforated or necrotic

intestine, which is most compellingly predicted by pneumoperitoneum. Other
indications include the following:

 Erythema in the abdominal wall

 Gas in the portal vein
 Positive paracentesis
 Clinical deterioration

See Treatment and Medication for more detail.

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Background
Necrotizing enterocolitis (NEC) is the most common gastrointestinal (GI)
medical/surgical emergency occurring in neonates. An acute inflammatory disease
with a multifactorial and controversial etiology, the condition is characterized by
variable damage to the intestinal tract ranging from mucosal injury to full-
thickness necrosis and perforation (see the image below). (See Etiology.)

Normal (top) versus necrotic

section of bowel. Photo courtesy of the Department of Pathology, Cornell
University Medical College.
View Media Gallery

Necrotizing enterocolitis represents a significant clinical problem and affects close

to 10% of infants who weigh less than 1500 g, with mortality rates of 50% or more
depending on severity. Although it is more common in premature infants, it can
also be observed in term and near-term babies. (See Epidemiology and Prognosis.)

NEC most commonly affects the terminal ileum and the proximal ascending colon.
However, varying degrees of NEC can affect any segment of the small intestine or
colon. The entire bowel may be involved and may be irreversibly damaged.

Numerous, vague reports in 19th-century literature report described infants who

died from peritonitis in the first few weeks of life. The first half of the 20th century
brought more reports of peritonitis with ileal perforation due to what was called
infectious enteritis. In 1953, Scmid and Quaiser called this condition newborn
NEC. [1] The first clear report of NEC did not appear until 1964, when Berdon from
the New York Babies Hospital described the clinical and radiographic findings of
21 infants with the disease. [2]

As neonatal intensive care has progressed and as premature newborns have come
to survive long enough for the disease to develop, the incidence of NEC in
neonatal intensive care units (NICUs) has increased. NEC remains one of the most
challenging diseases confronted by pediatric surgeons. It likely represents a
spectrum of diseases with variable causes and manifestations, and surgical care
must therefore be individualized. (See Etiology, Epidemiology, and Prognosis.)

NEC typically occurs in the second to third week of life in the infant who is
premature and has been formula fed. Although various clinical and radiographic
signs and symptoms are used to make the diagnosis, the classic clinical triad
consists of abdominal distension, bloody stools, and pneumatosis intestinalis.
Occasionally, signs and symptoms include temperature instability, lethargy, or
other nonspecific findings of sepsis. (See Presentation and Workup.)

Disease characteristics

Necrotizing enterocolitis affects the gastrointestinal tract and, in severe cases, can
cause profound impairment of multiple organ systems. Initial symptoms may be
subtle and can include 1 or more of the following (See Presentation.):

 Feeding intolerance
 Delayed gastric emptying
 Abdominal distention, abdominal tenderness, or both
 Ileus/decreased bowel sounds
 Abdominal wall erythema (advanced stages)
 Hematochezia
Systemic signs are nonspecific and can include any combination of the following:

 Apnea
 Lethargy
 Decreased peripheral perfusion
 Shock (in advanced stages)
 Cardiovascular collapse
 Bleeding diathesis (consumption coagulopathy)

Nonspecific laboratory abnormalities can include the following (See Workup.):

 Hyponatremia
 Metabolic acidosis
 Thrombocytopenia
 Leukopenia or leukocytosis with left shift
 Neutropenia
 Prolonged prothrombin time (PT) and activated partial thromboplastin time
(aPTT), decreasing fibrinogen, rising fibrin split products (in cases of
consumption coagulopathy)

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Etiology
Although the exact etiology of necrotizing enterocolitis (NEC) remains unknown,
research suggests that it is multifactorial; ischemia and/or reperfusion injury,
exacerbated by activation of proinflammatory intracellular cascades, may play a
significant role. Cases that cluster in epidemics suggest an infectious etiology.
Gram-positive and gram-negative bacteria, fungi, and viruses have all been
isolated from affected infants; however, many infants have negative culture
findings.

Furthermore, the same organisms isolated in stool cultures from affected babies
have also been isolated from healthy babies. Extensive experimental work in
animal models suggests that translocation of intestinal flora across an intestinal
mucosal barrier rendered vulnerable by the interplay of intestinal ischemia,
immunologic immaturity, and immunological dysfunction may play a role in the
etiology of the disease, spreading it and triggering systemic involvement. Such a
mechanism could account for the apparent protection breast-fed infants have
against fulminant NEC.

Animal model research studies have shed light on the pathogenesis of this disease.
Regardless of the triggering mechanisms, the resultant outcome is significant
inflammation of the intestinal tissues, the release of inflammatory mediators (eg,
leukotrienes, tumor necrosis factor [TNF], platelet-activating factor [PAF]) and
intraluminal bile acids, and downregulation of cellular growth factors, all of which
lead to variable degrees of intestinal damage.

Abnormal intestinal flora

In healthy individuals, the intestinal milieu is characterized by a predominance of

bifidobacteria. Such colonization is enhanced by the presence of oligofructose, a
component of human milk, in the intestinal lumen. Infants who receive formula
feedings without oligofructose as a constituent have been noted to have a
predominance of clostridial organisms.

Although infectious organisms have long been thought to play a key role in the
development of NEC, specifics regarding this role continue to be elusive. Whether
bacterial infection has a primary inciting role in NEC or whether an initial
intestinal mucosal injury allows secondary bacterial invasion is unclear. Is it a
straight-forward "infection" with a pathogenic organism that starts the disease
cascade, or is it more complex? Positive blood cultures are found in 30% of
patients; the most commonly identified organisms are Escherichia
coli and Klebsiella pneumoniae. Proteus mirabilis, Staphylococcus aureus, S
epidermidis, Enterococcus species, Clostridium perfringens, and Pseudomonas
aeruginosa have also been identified.

However, more recent research is focusing not on individual species but rather the
role of the premature gut microbiome as a risk factor. Unlike term infants, the
premature gut becomes colonized with a limited number of bacterial species, the
majority of which are gram-negative organisms in the Gammaproteobacteria
class. [3, 4] Termed "inappropriate colonization," or "dysbiosis," this class of
bacteria has been shown in animal models to produce short-chain fatty acids and
other bioactive substances, affecting epithelial cell health and integrity. How these
mediators impact the immature gut continues to be explored. [5] This line of inquiry
has been further supported by observational studies that have shown breastfed
infants (not breast-milk fed) and those advanced more quickly to full enteral feeds
were less likely to develop NEC than their counterparts. [5, 6]

E coli, Klebsiella species, Enterobacter cloacae, P aeruginosa,

Salmonella species, S epidermidis, C perfringens, C difficile, and C
butyricum commonly grow in stool cultures. Klebsiella species, E coli, S
epidermidis, and yeast are most commonly identified on peritoneal cultures.
Fungal infection is believed to be an opportunistic infection in the presence of an
altered host intestinal defense system.

New opportunistic and pathologic bacteria are being identified and speciated,
especially as the protective role of probiotics continues to be elucidated. [4] Infant
formulas contaminated with organisms such as Cronobacter species (previously
called Enterobacter sakazakii) [7] further complicate the picture as to whether the
formula or the bacteria are implicated in the disease or, conversely, whether the
breast milk or the bacteria are protective.

The observation of an epidemic or cluster of cases in a short period in one nursery

after sporadic cases supports the key role of infectious organisms in NEC. Nursery
personnel are known to experience acute gastrointestinal (GI) illnesses in
association with these outbreaks, and the institution of infection control measures
has accordingly reduced the rates of NEC.

Rat pups colonized with Staphylococcus aureus and Escherichia coli demonstrated
increased incidence and severity of necrotizing enterocolitis compared with those
whose intestines were populated with various bacterial species. [8] Toll-like receptor
signaling of intestinal mucosal transmembrane proteins is accomplished by binding
of specific bacterial ligands that mediate the inflammatory response; the character
of the intestinal bacterial milieu is thought to play a role in the up-regulation or
down-regulation of intestinal inflammation via toll-receptor signaling.

Many preterm infants receive frequent exposure to broad-spectrum antibacterial

agents, further altering the intra-intestinal bacterial environment. Advances in
genome sequencing of the gut microbiome of healthy as well as affected premature
infants, along with the roles of host molecular and immune factors, continue to
raise more questions than answers about the multifactorial etiology of this
devastating condition. [3, 5]

That NEC is related to gut colonization of pathogenic flora is supported by

findings showing administration of physiologic flora decreases the incidence of
NEC. The protective effect of breast milk is thought, in part, to be related to
delivery of Lactobacillus species that somehow repair the intestinal milieu. Work
by Blackwood, et al suggests that the mechanism is more elegant: Both in vitro and
in vivo models showed improved intestinal integrity in rat pups fed L
rhamnosus and L plantarum probiotics. [9] By increasing capillary tight junctions,
tested animals experienced less intestinal injury compared to control animals when
challenged with a known cellular toxin. [9]

Intestinal ischemia

Epidemiologically, some have noted that infants exposed to intrauterine

environments marked by compromised placental blood flow (ie, maternal
hypertension, preeclampsia, cocaine exposure) have an increased incidence of
NEC. Similarly, infants with postnatally diminished systemic blood flow, as is
found in patients with patent ductus arteriosus or congenital heart disease (both
considered risk factors for NEC), also have an increased incidence. Infants with
patent ductus arteriosus are at particularly high risk for developing NEC if
pharmacologic closure is attempted.

A retrospective analysis compared outcomes of NEC in patients with congenital

heart disease with outcomes of NEC in patients without congenital heart disease;
the study demonstrated improved outcomes in patients with heart disease. This
somewhat counterintuitive finding further emphasizes the multifactorial
pathophysiology underlying NEC. [10]

Animal models of induced intestinal ischemia have identified its significant role in
the development of NEC. Pathologically, ischemia induces a local inflammatory
response that results in activation of a proinflammatory cascade with mediators
such as PAF, TNF-a, complement, prostaglandins, and leukotrienes such as C4 and
interleukin 18 (IL-18). This potential role of perhaps even antenatal inflammation
in the eventual clinical occurrence of NEC is further supported by a recent
systematic review of the evidence showing a strong correlation between antenatal
clinical and/or histologic chorioamnionitis and subsequent NEC. [11]

Alterations in hepatobiliary cell junction integrity result in leakage of these

proinflammatory substances and bile acids into the intestinal lumen, increasing
intestinal injury. Cellular protective mechanisms such as epidermal growth factor
(EGF), transforming growth factor β1 (TGF-β1), and erythropoietin are down-
regulated, further compromising the infant's ability to mount a protective response.
Subsequent norepinephrine release and vasoconstriction result in splanchnic
ischemia, followed by reperfusion injury.

Intestinal necrosis results in breach of the mucosal barrier, allowing for bacterial
translocation and migration of bacterial endotoxin into the damaged tissue. The
endotoxin then interacts synergistically with PAF and a multitude of other
proinflammatory molecules to amplify the inflammatory response.

Activated leukocytes and intestinal epithelial xanthine oxidase may then produce
reactive oxygen species, leading to further tissue injury and cell death.
Experimental administration of PAF inhibitors in animal models has not been
shown to mitigate intestinal mucosal injury. Many other modulators of the
inflammatory response are being studied both in vivo in animal models and in vitro
in an attempt to mitigate or prevent the morbidity and mortality caused by
fulminant necrotizing enterocolitis.

Intestinal mucosal immaturity

NEC is principally a disease of premature infants. Although approximately 5-25%

of infants with NEC are born full term, studies have found a markedly decreased
risk of NEC with increasing gestational age. This finding suggests that maturation
of the GI system plays an important role in the development of NEC.
The premature neonate has numerous physical and immunologic impairments that
compromise intestinal integrity. Gastric acid and pepsin production are decreased
during the first month of life. Pancreatic exocrine insufficiency is associated with
low levels of enterokinase, the enzyme that converts trypsinogen to trypsin, which
allows hydrolysis of intestinal toxins. Mucus secretion from immature goblet cells
is decreased. Gut motility is impaired, and peristaltic activity is poorly coordinated.
Finally, secretory immunoglobulin A (IgA) is deficient in the intestinal tract of
premature infants not fed breast milk.

In the preterm infant, mucosal cellular immaturity and the absence of mature
antioxidative mechanisms may render the mucosal barrier more susceptible to
injury. Intestinal regulatory T-cell aggregates are a first-line defense against
luminal pathogens and may be induced by collections of small lymphoid
aggregates, which are absent or deficient in the premature infant.

Experimental and epidemiologic studies have noted that feeding with human milk
has a protective effect; however, donor human milk that has been pasteurized is not
as protective. Human milk contains secretory immunoglobulin A (IgA), which
binds to the intestinal luminal cells and prohibits bacterial transmural translocation.
Other constituents of human milk, such as IL-10, EGF, TGF-β1, and
erythropoietin, may also play a major role in mediating the inflammatory response.
Oligofructose encourages replication of bifidobacteria and inhibits colonization
with lactose-fermenting organisms.

Human milk has been found to contain PAF acetylhydrolase, which metabolizes
PAF; preterm human milk has higher PAF acetylhydrolase activity (as much as 5
times greater in one study [12] ) than milk collected from women who delivered at
term.

It has long been suspected that the initiation of early enteral feedings is associated
with NEC, sparked in part by the observation that unfed infants rarely develop
NEC. Some series have reported decreased rates of NEC when feeding volumes
are reduced, however, a more recent multicenter, matched case-control study
(EPIFLORE: Epidemiologic Study of Flora) comprising data from 64 neonatal
intensive care units, reported the opposite. [5] Earlier, in a prospective randomized
trial, Book et al found a significant increase in the development of NEC among
preterm infants fed a hyperosmolar elemental formula compared with those fed a
milk formula. [13] The complex relationship between feeding and NEC is further
confounded by the recognition that NEC is much more likely to occur in infants
who receive packed red blood cell (RBC) transfusion, especially in infants who are
enterally feeding. [14] Up to one third of all NEC cases in very low birth weight
infants may occur within 24-48 hours after RBC transfusion, with the highest risk
potentially in infants transfused with the most severe anemia. [15]

Innate genetic predisposition

Twin studies have suggested susceptibility to NEC may be affected by a genetic
component. [16] Given the frequent subtle and nonspecific nature of presenting
symptoms, identification of a biomarker for infants at higher risk of developing
necrotizing enterocolitis could have significant impact on morbidity and mortality
rates.

Animal models have focused on single-nucleotide polymorphisms (SNPs) that

negatively affect innate immune responses to bacterial antigens. One such SNP,
discovered in the gene that encodes carbamoyl-phosphate synthetase I (the rate-
limiting enzyme for the production of arginine), has been reportedly associated
with an increased risk of NEC. [17]

A more recent study of 184 neonates reported an association between the

functional SNP IL-6 (rs1800795) and the development of NEC (6-fold increase) as
well as an increased severity of NEC (7-fold increase in stage III disease) in white
neonates. [18] There was also an association between TRIM21 (rs660) (increased
incidence) and TGFβ-1 (rs2241712) (decreased incidence) with NEC- related
perforation. [18]

Infants with distinct genotypes of various cytokines have also been associated with
higher frequencies of NEC. Given the interplay of inherent, infectious, ischemic,
inflammatory, iatrogenic, and environmental factors, alterations in expression of
proinflammatory and/or anti-inflammatory mediators may play a role in neonatal
susceptibility to the disease. [19, 20]

Medications

Numerous medications have been implicated as a risk factor in NEC. Xanthine

derivatives, such as theophylline and aminophylline, slow gut motility and produce
oxygen free radicals during their metabolism to uric acid. Indomethacin, used to
treat patent ductus arteriosus, may cause splanchnic vasoconstriction leading to
impaired intestinal integrity. Vitamin E, used to treat retinopathy of prematurity, is
known to impair leukocyte function and has been associated with NEC. Inhibitors
of gastric acid secretion alter the pH of the intestinal milieu, which subsequently
affects the intestinal flora. Several recent studies, including meta-analysis, have
identified a higher incidence of NEC in infants exposed to gastric antacids. [21]

The results from a multicenter, prospective, observational study suggest that

ranitidine treatment in very low birth weight infants is associated with an increased
risk of infections, a 6.6-fold higher risk of NEC, and a significantly higher
mortality rate. [22]

Many of the most premature infants are exposed in utero to magnesium sulfate
(MgSO4) administered to the mother for a variety of obstetric indications. Data
exist suggesting a neuroprotective effect of MgSO4 on the extremely premature
infant has further increased its use, fueling concerns of an increased risk of NEC in
these infants. However, in a retrospective (2011-2014) cohort of over 4,000
extremely premature infants, no difference in odds ratios were seen for the risk of
NEC in MgSO4-treated infants (n = 2,055) compared to those without such
exposure (n = 2,300). [23]

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Epidemiology
Although some studies indicate a higher frequency of NEC in black babies than in
white babies, other studies show no difference based on race. Most studies indicate
that male and female babies are equally affected.

Occurrence in the United States

The frequency of necrotizing enterocolitis (NEC) varies among nurseries, without

correlation with season or geographic location. Outbreaks of NEC seem to follow
an epidemic pattern within nurseries, suggesting an infectious etiology, although a
specific causative organism has not been isolated.

Population studies conducted in the United States over the past 25 years indicate a
relatively stable incidence, ranging from 0.3-2.4 cases per 1000 live births. The
disease classically presents among the smallest preterm infants. Although it is
reported among term infants with perinatal asphyxia or congenital heart disease,
differences in severity and outcome suggest presentation in this population may
represent a distinct pathophysiologic entity. [10]

International occurrence

Population-based studies from other countries suggest a frequency similar to the

United States. However, nations with a lower rate of premature births than that in
the United States generally have a lower rate of NEC as well. For example, a large
study of NICUs in Japan identified a 0.3% incidence of NEC, which is
significantly lower than that in similar patient populations in the United States. [24]

An epidemiologic review of the disease in infants born at less than 32 weeks'

gestation who survived past 5 days of life in Canada reported an incidence of
6.4%. [25]

Age-related demographics
NEC is more prevalent in premature infants, with incidence inversely related to
birth weight and gestational age. Although specific numbers range from 4% to
more than 50%, infants who weigh less than 1000 g at birth have the highest attack
rates. This rate dramatically drops to 3.8 per 1000 live births for infants who weigh
1501-2500 g at birth. Similarly, rates profoundly decrease for infants born after 35-
36 weeks' postconceptional age.

The average age of onset in premature infants seems to be related to

postconceptional age, with babies born earlier developing NEC at a later
chronologic age. The average age of onset has been reported to be 20.2 days for
babies born at less than 30 weeks' estimated gestational age (EGA), 13.8 days for
babies born at 31-33 weeks' EGA, and 5.4 days for babies born after 34 weeks'
gestation.

Term infants develop necrotizing enterocolitis much earlier, with the average age
of onset within the first week of life or, sometimes, within the first 1-2 days of life.
Observational studies have suggested the etiology of the disease in term and near-
term infants may be different than that postulated in the premature infant and could
include entities such as cow's milk protein–induced enterocolitis and glucose-6-
phosphate dehydrogenase deficiency.

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Prognosis
With improved supportive intensive care, including ventilatory management,
anesthetic techniques, and total parenteral nutrition, the survival of infants with
necrotizing enterocolitis (NEC) has steadily improved since the late 20th century.
The improved prognosis is most notable in critically ill neonates younger than 28
weeks' gestational age who weigh less than 1000 g. However, these neonates are
still at significantly increased risk for pan involvement and are more likely than
other premature infants to require surgery.

The mortality rate in NEC ranges from 10% to more than 50% in infants who
weigh less than 1500 g, depending on the severity of disease, compared with a
mortality rate of 0-20% in babies who weigh more than 2500 g. Extremely
premature infants (1000 g) are still particularly vulnerable, with reported mortality
rates of 40-100%. One study comparing mortality rates for term versus preterm
infants reported rates of 4.7% for term infants and 11.9% for premature babies. [26]

The improvement in treatment efficacy in infants with NEC is underscored by the

fact that if patients with pan involvement are excluded, the survival in surgically
treated infants with NEC is 95%. However, comparison between reported series is
difficult because of wide variations in patient populations, extent of disease,
coexisting conditions, and severity categorization between centers.

Of those patients who survive, 50% develop a long-term complication. The 2 most
common complications are intestinal stricture and short-gut syndrome.

Intestinal stricture

This complication, the incidence of which is 25-33%, can develop in infants with
or without a preceding perforation. Intestinal stricture occurs when an area of
intestinal ischemia heals with resultant fibrosis and scar formation that impinges on
the diameter of the lumen. The most common site of stricture is the left colon,
followed by the terminal ileum.

Intestinal stricture is most common in infants treated nonoperatively, because

infants treated operatively commonly undergo contrast enema before closure of the
ostomy, and any area of stricture is resected when the ostomy is closed.

Intestinal stricture should be suspected in any infant who receives nonoperative

treatment for NEC and who fails to thrive and/or has bloody stools or bowel
obstruction. Symptoms of feeding intolerance and bowel obstruction typically
occur 2-3 weeks after recovery from the initial event.

Short-gut syndrome

Short-gut syndrome is the most serious postoperative complication in NEC,

occurring in as many as 23% of patients after intestinal resection. This is a
malabsorption syndrome resulting from the removal of excessive or critical
portions of small bowel necessary for absorption of essential nutrients from the
intestinal lumen.

Symptoms are most profound in babies who either have lost most of their small
bowel or have lost a smaller portion that includes the ileocecal valve. Loss of small
bowel can result in malabsorption of nutrients, as well as of fluids and electrolytes.

The neonatal gut grows and adapts over time, but long-term studies suggest that
this growth may take as long as 2 years to occur. During that time, maintenance of
an anabolic and complete nutritional state is essential for the growth and
development of the baby. This is achieved by parenteral provision of adequate
vitamins, minerals, and calories; appropriate management of gastric acid
hypersecretion; and monitoring for bacterial overgrowth. The addition of
appropriate enteral feedings during this time is important for gut nourishment and
remodeling.
Babies who can never successfully feed enterally and/or who develop life-
threatening hyperalimentation liver disease may be candidates for organ
transplantation. Centers specializing in neonatal and infant small bowel and liver
transplantation may consider referrals on a case-by-case basis.

Cholestatic liver disease

Cholestatic liver disease is a multifactorial condition caused by prolonged fasting

and total parenteral nutrition. It is characterized by hepatomegaly and elevated
aminotransferase and direct bilirubin levels. The treatment is initiation of enteral
feedings as early as possible to stimulate bile flow.

Recurrent NEC

Recurrent NEC is an uncommon complication that can occur after either operative
or nonoperative management of NEC. It is seen in only 4-6% of patients with
NEC. Recurrent NEC has not been associated with the method of managing the
initial episode, the timing of enteral feedings, or the site of initial disease.

Neurodevelopmental disorders

Infants who survive NEC are at increased risk for neurodevelopmental

disorders. [27] As many as 50% of infants who survive NEC have some abnormality
in intelligence and motor skills. However, the incidence of non-gastrointestinal
sequelae in matched cohorts with and without NEC are similar, implying that
neurodevelopmental problems may be a function of underlying prematurity rather
than of NEC itself.

Additional complications

A multicenter, retrospective study in Switzerland reported a 29% rate of catheter-

related sepsis in patients with Bell stage II kept on a diet of nothing by mouth
(NPO) for longer than 5 days. [28] Prolonged hyperalimentation and the absence of
enteral nutrition can cause cholestasis, direct hyperbilirubinemia, and other
metabolic complications.

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