eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Neonatology

Necrotizing Enterocolitis

Author: Shelley C Springer, MD, MBA, MSc, FAAP, JD LS-3, Clinical Instructor, Department of Pediatrics, University of Wisconsin; Neonatologist, Pediatrix Medical Group; Assistant Clinical Professor, Department of Pediatrics, University of North Texas Science Center; Assistant Clinical Professor, Department of Pediatrics, Texas A & M University
Coauthor(s): David J Annibale, MD,, Professor of Pediatrics, Director of Neonatology, Director of Fellowship Training Program in Neonatal-Perinatal Medicine, Department of Pediatrics, Medical University of South Carolina
Contributor Information and Disclosures

Updated: Sep 22, 2009

Introduction

Background

Necrotizing enterocolitis (NEC) is the most common GI medical/surgical emergency occurring in neonates. 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. Despite intensive study over the past 30 years, its etiology remains elusive.

Normal (top) versus necrotic section of bowel. Ph...

Normal (top) versus necrotic section of bowel. Photo courtesy of the Department of Pathology, Cornell University Medical College.

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Normal (top) versus necrotic section of bowel. Ph...

Normal (top) versus necrotic section of bowel. Photo courtesy of the Department of Pathology, Cornell University Medical College.


Pathophysiology

Necrotizing enterocolitis affects the GI tract and, in severe cases, can cause profound impairment of multiple organ systems.

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

  • 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:

  • 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)

Although the exact etiology 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 pathogenesis of the disease, spreading it and triggering systemic involvement. Such a mechanism could account for the apparent protection breast-fed infants have against fulminant necrotizing enterocolitis.

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 down-regulation of cellular growth factors, all of which lead to variable degrees of intestinal damage.

Although the pathogenesis of necrotizing enterocolitis remains uncertain, a large body of evidence suggests a multifactorial etiology, including the presence of abnormal bacterial flora, intestinal ischemia, reperfusion injury with activation of proinflammatory cellular cascades, and intestinal mucosal immaturity/dysfunction.

  • 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.
    • 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.1 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.
    • Experimental and meta-analytical evidence suggests that exogenous administration of the probiotics bifidobacteria and lactobacilli or probiotics (nondigestible substances that selectively promote the growth of beneficial probioticlike bacteria normally present in the gut) may moderate the risk and severity of necrotizing enterocolitis in preterm infants.2,3
  • 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 necrotizing enterocolitis. Similarly, infants with postnatally diminished systemic blood flow, such as is found in patients with patent ductus arteriosus or congenital heart disease, also have an increased incidence. However, a recent retrospective analysis compared outcomes of necrotizing enterocolitis in patients with congenital heart disease with outcomes of necrotizing enterocolitis 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 necrotizing enterocolitis.4
    • Animal models of induced intestinal ischemia have identified its significant role in the development of necrotizing enterocolitis. 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 IL-18. Alterations in hepatobiliary cell junction integrity results 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 results 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
    • 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 to 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 interleukin (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 study5 ) than milk collected from women who delivered at term.
  • Innate genetic predisposition
    • Twin studies have suggested susceptibility to necrotizing enterocolitis may be affected by a genetic component. 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 necrotizing enterocolitis.6
    • Infants with distinct genotypes of various cytokines have also been associated with higher frequencies of necrotizing enterocolitis. 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.7,8

Frequency

United States

Frequency varies among nurseries, without correlation with season or geographic location. Outbreaks of necrotizing enterocolitis 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.4

International

Population-based studies from other countries suggest a frequency similar to the United States. 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%.9

Mortality/Morbidity

The mortality rate 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 particularly vulnerable, with reported mortality rates of 40-100%. One study compared mortality rates for term versus preterm infants and reported rates of 4.7% for term infants and 11.9% for premature babies.10

Survivors can have significant short-term and long-term morbidities. Patients with mild disease (see Bell stage II under Medical Care) require GI 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.

A recent multicenter, retrospective study in Switzerland reported a 29% rate of catheter-related sepsis in patients with Bell stage II kept NPO for longer than 5 days.11 Prolonged hyperalimentation and the absence of enteral nutrition can cause cholestasis, direct hyperbilirubinemia, and other metabolic complications.

Patients who are severely affected may require intestinal resection during the acute phase of their disease. Any patient can develop strictures, as part of the healing process, which require surgical intervention. In rare and severe necrotizing enterocolitis cases, the entire intestine can be involved, precluding surgical intervention. Depending on the location and extent of the bowel removed, long-term morbidities can include the need for ileostomy and/or colostomy, repeated surgical procedures, prolonged parenteral nutrition, short gut and malabsorption syndromes, failure to thrive due to suboptimal nutrition, and multiple hospitalizations. Intestinal transplantation for babies with severe short-gut syndrome is becoming more common. Combination liver and small bowel transplantation may be necessary for severely affected infants who have also acquired life-threatening hyperalimentation hepatitis.

Race

Although some studies indicate a higher frequency in black babies than in white babies, other studies show no difference based on race.

Sex

Most studies indicate that male and female babies are equally affected.

Age

Necrotizing enterocolitis 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.

Average age at onset in premature infants seems to be related to postconceptional age, with babies born earlier developing necrotizing enterocolitis 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.

Infants with patent ductus arteriosus are at higher risk for developing the disease, particularly if pharmacologic closure is attempted. These infants may develop the disease sooner than infants without patent ductus arteriosus.

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 pathophysiology 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.

The recently reported finding that affected term infants with congenital heart disease, another known risk factor, have decreased risk of major short and long-term adverse outcomes further supports an alternative pathogenetic model.4

Clinical

History

In patients with necrotizing enterocolitis (NEC), epidemiologic studies demonstrate that demographics, risk factors, patient characteristics, and clinical course differ significantly between term and preterm infants.

  • Term baby
    • Compared with a preterm infant, the term baby with necrotizing enterocolitis presents at a younger age, with a reported median age of onset that ranges from 1-3 days of life in the immediate postnatal period, but may appear as late as one month of age.
    • The term neonate who is immediately affected postnatally is usually systemically ill with other predisposing conditions, such as birth asphyxia, respiratory distress, congenital heart disease, metabolic abnormalities, or has a history of abnormal fetal growth pattern.
    • Maternal risk factors that reduce fetal gut blood flow, such as placental insufficiency from acute disease (eg, pregnancy-induced hypertension), chronic disease (eg, diabetes), or maternal cocaine abuse, can increase the baby's risk for developing necrotizing enterocolitis.
    • Specific signs and symptoms that may be part of the history include bilious vomiting or gastric aspirates, abdominal distention, passage of blood per rectum, abdominal radiographs that reveal dilated loops of bowel, pneumatosis intestinalis, free abdominal air, and other signs of systemic infection, including shock and acidosis.
  • Premature baby
    • Premature babies are at risk for developing necrotizing enterocolitis for several weeks after birth, with the age of onset inversely related to gestational age at birth.
    • Premature infants with patent ductus arteriosus are at higher risk of developing necrotizing enterocolitis earlier in life, particularly if treated with indomethacin for pharmacologic closure. However, patients with persistent patent ductus arteriosus that ultimately required surgical ligation had a higher necrotizing enterocolitis mortality rate than those whose patent ductus arteriosus were successfully closed without surgery.
    • Patients are typically advancing on enteral feedings or may have achieved full-volume feeds when symptoms develop.
    • Increased incidence in the posttransfusion period has been reported in otherwise healthy premature babies who are feeding enterally and undergo blood transfusion for asymptomatic anemia of prematurity.
    • Presenting symptoms may include subtle signs of feeding intolerance that progresses over several hours to a day, subtle systemic signs that may be reported enigmatically by the nursing staff as "acting different," and, in advanced disease, a fulminant systemic collapse and consumption coagulopathy.
    • Symptoms of feeding intolerance can include abdominal distention/tenderness, delayed gastric emptying as evidenced by increasing gastric residuals, and, occasionally, vomiting.
    • Systemic symptoms can insidiously progress to include nonspecific signs and symptoms, such as increased apnea and bradycardia, lethargy, and temperature instability representing the primary manifestation(s).
    • Patients with fulminant necrotizing enterocolitis present with profound apnea, rapid cardiovascular and hemodynamic collapse, and shock.
    • The baby's feeding history can help increase the index of suspicion for early necrotizing enterocolitis. Babies who are breastfed have a lower incidence of necrotizing enterocolitis NEC than formula-fed babies.
    • Rapid advancement of formula feeding has been associated with an increased risk of necrotizing enterocolitis.12 However, multiple subsequent studies have failed to substantiate this finding.

Physical

  • The pertinent physical findings in patients who develop necrotizing enterocolitis can be primarily GI, primarily systemic, indolent, fulminant, or any combination of these. A high index of clinical suspicion is essential to minimize potentially significant morbidity or mortality.
  • GI 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
    • A palpable abdominal mass
    • Erythema of the abdominal wall
  • Systemic signs can include any of the following:
    • Respiratory failure
    • Decreased peripheral perfusion
    • Circulatory collapse
    • With insidious onset, the clinical signs may be mild, whereas patients with fulminant disease can present with severe clinical abnormalities.
  • If abdominal signs are present, surgical consultation may be advisable. Disease progression ranges from indolent to fulminant, and early and expeditious involvement of surgical colleagues can be helpful, especially if appropriate surgical care requires transfer to another facility.

Causes

More on Necrotizing Enterocolitis

Overview: Necrotizing Enterocolitis
Differential Diagnoses & Workup: Necrotizing Enterocolitis
Treatment & Medication: Necrotizing Enterocolitis
Follow-up: Necrotizing Enterocolitis
Multimedia: Necrotizing Enterocolitis
References
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Further Reading

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Keywords

necrotizing enterocolitis, NEC, inflammation of the intestinal tissues, enteral feeding, sepsis, feeding intolerance, delayed gastric emptying, abdominal wall erythema, hematochezia, apnea, decreased peripheral perfusion, cardiovascular collapse, bleeding diathesis, hyponatremia, consumption coagulopathy, metabolic acidosis, thrombocytopenia, leukopenia, leukocytosis, neutropenia, oligofructose, Staphylococcus aureus, Escherichia coli, intestinal ischemia, maternal hypertension, preeclampsia, cocaine exposure, patent ductus arteriosus, congenital heart disease, splanchnic ischemia, perinatal asphyxia, thromboembolic events, nosocomial infections, cholestasis, direct hyperbilirubinemia, strictures, hyperalimentation hepatitis, cow's milk protein–induced enterocolitis, glucose-6-phosphate dehydrogenase deficiency,  birth asphyxia, respiratory distress, abnormal fetal growth pattern, anemia of prematurity

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Contributor Information and Disclosures

Author

Shelley C Springer, MD, MBA, MSc, FAAP, JD LS-3, Clinical Instructor, Department of Pediatrics, University of Wisconsin; Neonatologist, Pediatrix Medical Group; Assistant Clinical Professor, Department of Pediatrics, University of North Texas Science Center; Assistant Clinical Professor, Department of Pediatrics, Texas A & M University
Shelley C Springer, MD, MBA, MSc, FAAP, JD LS-3 is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, and Minnesota Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

David J Annibale, MD,, Professor of Pediatrics, Director of Neonatology, Director of Fellowship Training Program in Neonatal-Perinatal Medicine, Department of Pediatrics, Medical University of South Carolina
David J Annibale, MD, is a member of the following medical societies: American Academy of Pediatrics and National Perinatal Association
Disclosure: Nothing to disclose.

Medical Editor

Oussama Itani, MD, FAAP, FACN, Clinical Associate Professor of Pediatrics and Human Development, Michigan State University; Medical Director, Department of Neonatology, Borgess Medical Center
Oussama Itani, MD, FAAP, FACN is a member of the following medical societies: American Academy of Pediatrics, American College of Nutrition, American College of Physician Executives, and American Heart Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

David A Clark, MD, Chairman, Professor, Department of Pediatrics, Albany Medical College
David A Clark, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Pediatric Society, Christian Medical & Dental Society, Medical Society of the State of New York, New York Academy of Sciences, and Society for Pediatric Research
Disclosure: Nothing to disclose.

CME Editor

Carol L Wagner, MD, Professor of Pediatrics, Medical University of South Carolina
Carol L Wagner, MD is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American Medical Women's Association, American Public Health Association, American Society for Bone and Mineral Research, American Society for Clinical Nutrition, Massachusetts Medical Society, National Perinatal Association, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Chief Editor

Ted Rosenkrantz, MD, Professor, Departments of Pediatrics and Obstetrics/Gynecology, Division of Neonatal-Perinatal Medicine, University of Connecticut School of Medicine
Ted Rosenkrantz, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Pediatric Society, Connecticut State Medical Society, Eastern Society for Pediatric Research, and Society for Pediatric Research
Disclosure: Nothing to disclose.

 
 
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