Neonatal necrotizing enterocolitis: Clinical features and diagnosis

INTRODUCTION — Necrotizing enterocolitis (NEC) is one of the most common gastrointestinal emergencies in the newborn infant. It is a disorder characterized by ischemic necrosis of the intestinal mucosa, which is associated with severe inflammation, invasion of enteric gas forming organisms, and dissection of gas into the bowel wall and portal venous system [1]. Although early recognition and aggressive treatment of this disorder has improved clinical outcomes, NEC accounts for substantial long-term morbidity in survivors of neonatal intensive care, particularly in preterm very low birth weight (VLBW) infants (BW below 1500 g).

The clinical features and diagnosis of NEC are reviewed here. The pathology, pathogenesis, management, and prevention of this disorder are discussed separately. (See "Neonatal necrotizing enterocolitis: Pathology and pathogenesis" and "Neonatal necrotizing enterocolitis: Management and prognosis" and "Neonatal necrotizing enterocolitis: Prevention".)

EPIDEMIOLOGY — The true incidence of NEC is unknown because of insufficient reliable data due to inconsistencies in diagnosis and data collection of published studies [2]. In particular, it has been difficult to ascertain the prevalence of suspected or unproven NEC (eg, Bell stage I) (table 1) (see 'Severity of NEC: Modified Bell staging criteria' below). In the United States, the incidence of proven or severe NEC (Bell stage II and III) is estimated to be approximately 1 to 3 per 1000 live births [3,4].

More than 90 percent of cases occur in very low birth weight (VLBW) infants (BW <1500 g) born at <32 weeks gestation, and the incidence of NEC decreases with increasing gestational age (GA) and BW.

Preterm infants — The reported incidence of NEC in preterm infants with a GA <32 weeks varies globally from 2 to 7.5 percent across different neonatal intensive care units (NICUs) [5-7]. Although there is uncertainty of the cause(s) of this variability, it is speculated that the use of different definitions of NEC and variation in neonatal care are important contributing factors.

Despite the overall variability, data within studies from various parts of the world consistently show that the incidence increases with decreasing BW and GA [3,5,6,8]. Rates of NEC increase five-fold for extremely low birth weight (ELBW) infants (BW <1000 g) born extremely preterm (GA <28 weeks) compared with the overall incidence of VLBW preterm infants (GA <32 weeks) [5,6].

The effect of GA on the incidence of NEC was illustrated by a study from the from the National Institute of Child Health and Human Development (NICHD) neonatal network cohort of extremely preterm infants (GA 22 to 28 weeks) born in 2012 [3]. In this cohort with an overall incidence of NEC of 9 percent, rates of stage II and III NEC were inversely related to GA in infants who survived at or beyond 12 hours after delivery as follows:

●GA 22 weeks – 11 percent

●GA 23 weeks – 16 percent

●GA 24 weeks – 11 percent

●GA 25 weeks – 9 percent

●GA 26 weeks – 10 percent

●GA 27 weeks – 8 percent

●GA 28 weeks – 8 percent

In the United States, the incidence of NEC appears to be decreasing over a ten-year period from 2005 to 2014 [9]. In addition, over the same time period, the variation of NEC incidence amongst NICUs narrowed. These results may be due to quality improvement activities focused on reducing the risk of NEC [10-12]. (See "Neonatal necrotizing enterocolitis: Prevention".)

Reported mortality rates range from 15 to 30 percent and also are inversely related to GA and BW [13]. In the United States, the risk of developing NEC and of overall mortality is highest for preterm male infants born to African-American mothers [4,14,15].

Term infants — Although the majority of infants with NEC are preterm, approximately 10 percent of cases occur in term infants [16-18]. In retrospective studies, term infants who develop NEC typically receive non-human milk feeding and have a preexisting illness [16,19-23]. Associated conditions may affect intestinal perfusion and include congenital heart disease [24], primary gastrointestinal disorders, sepsis, fetal growth restriction, and perinatal hypoxia. (See "Neonatal necrotizing enterocolitis: Pathology and pathogenesis", section on 'Pathogenesis: Term infant'.)

CLINICAL PRESENTATION

Preterm infants

Clinical symptoms and signs — The majority of preterm infants who develop NEC are generally healthy, feeding well, and growing prior to developing NEC [25]. The most frequent sign of NEC is a sudden change in feeding tolerance.

Other potential presenting signs of NEC include nonspecific abdominal and systemic findings, such as abdominal wall erythema, crepitus, and induration [26,27]. Nonspecific systemic findings include apnea, respiratory failure, lethargy, or temperature instability. Hypotension resulting from septic shock may be present in the most severe cases. 20 to 30 percent of infants with NEC have associated bacteremia, which may contribute to these findings [28]. (See "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation", section on 'Clinical manifestations'.)

While gastric residuals are often seen in early NEC, there is no evidence that routine measurement of gastric residual volumes in asymptomatic infants is a useful guide to prevent or detect the onset of NEC, or help to advance feeds [1,29-31]. Many neonatal intensive care units, including our units, no longer routinely check for gastric residuals in healthy preterm infants. In a single-center study of 141 infants, 74 were randomized to undergo gastric residual checks while the other half did not have residuals checked. The no residual group were able to achieve faster feeding rates and had consumed more feedings at weeks 5 and 6. This group had higher mean weights and were discharged earlier than the residual check group. In addition, there were no differences in risk for NEC, late-onset sepsis, or death [31]. (See "Approach to enteral nutrition in the premature infant", section on 'Feeding intolerance'.)

Timing of presentation — The timing of the onset of symptoms varies and appears to be inversely related to gestational age (GA) [8,32]. There appears to be a bimodal distribution (early versus late onset) based on GA [8]. For example, the median age at onset of NEC in infants with a GA of less than 26 weeks was 23 days (late), and for those with a GA of greater than 31 weeks, the median age at onset was 11 days (early). It remains uncertain why there is an inverse relationship between GA and timing of the presentation of NEC. Proposed explanations include that very preterm infants take longer to begin enteral feeding and therefore longer to reach a critical amount of feeding mass needed for the development of NEC and that changes with development and exposures make an infant more prone to intestinal inflammation or immune dysregulation as they mature (eg, exposure to broad-spectrum antibiotics) resulting in microbial dysbiosis. (See "Neonatal necrotizing enterocolitis: Pathology and pathogenesis", section on 'Potential triggers and risk factors'.)

Laboratory findings — Laboratory findings of infants presenting with NEC often include anemia, thrombocytopenia, evidence of disseminated intravascular coagulopathy (DIC), and in 20 percent of cases a positive blood culture [28,33,34]. (See 'Laboratory evaluation' below.)

Term infants — There are limited data on the clinical presentation of NEC in term infants. Case series suggest that the NEC develops in term infants with a serious predisposing illness or condition (eg, congenital heart disease, sepsis) who are fed non-human milk [17-20,22,24,35-38]. Most term infants who develop NEC are already cared for in the neonatal intensive care unit (NICU) setting [35]. (See "Neonatal necrotizing enterocolitis: Pathology and pathogenesis", section on 'Pathogenesis: Term infant'.)

Presenting signs and symptoms of NEC are similar to those observed in preterm infants, including bilious gastric aspirate or emesis, abdominal distension, and rectal bleeding [35].

Term infants generally have earlier onset of NEC compared to preterm infants [18,35].

DIAGNOSIS — In general, the clinical diagnosis of NEC is based on the presence of the most characteristic clinical features (abdominal distention, bilious vomiting or gastric aspirate, and rectal bleeding [heme-positive or grossly bloody stools without anal fissure]), and the finding on abdominal imaging of intramural gas (pneumatosis intestinalis), pneumoperitoneum, or sentinel bowel loops [39]. A definite diagnosis of NEC is made from either intestinal surgical or postmortem specimens that demonstrate the histological findings of intestinal inflammation, infarction, and necrosis (see 'Clinical symptoms and signs' above and 'Characteristic findings of NEC' below and "Neonatal necrotizing enterocolitis: Pathology and pathogenesis", section on 'Pathology').

However, for the vast majority of survivors, a pathologic diagnosis is not available as they improve with medical management. In these patients, making a clinical diagnosis of NEC remains challenging due to the lack of a single pathognomonic sign or test. Although laboratory tests are not generally used to make a diagnosis of NEC due to their lack of specificity, they may be used to support a clinical diagnosis and staging of NEC. (See 'Laboratory evaluation' below.)

RADIOLOGIC EVALUATION

Abdominal imaging — As noted above, abdominal imaging is critical in making a clinical diagnosis of NEC. In particular, a finding of pneumatosis intestinalis on abdominal imaging is highly suggestive of NEC. Plain abdominal radiography is the preferred imaging modality as it has been the foundation for diagnosis and staging for NEC and is readily available. However, Doppler ultrasonography is increasingly used to diagnosis NEC especially when there are equivocal findings on abdominal radiography.

Abdominal radiography — Abdominal radiographs are usually used to confirm the diagnosis of NEC and follow the progression of the disease. However, they often lack sensitivity and specificity [1,40], so abdominal radiography cannot be used alone to make or rule out the diagnosis of NEC. Radiographic findings need to be interpreted in the context of the patient's other clinical findings. As a result, when there are equivocal radiographic findings, treatment decisions should be based upon clinical suspicion and findings. For example, an infant with marked distended abdomen with deteriorating hematologic and biochemical signs may still be considered a candidate for surgery regardless of the lack of evidence of intestinal perforation or pneumatosis intestinalis on abdominal radiograph.

In addition, abdominal radiography is not as sensitive in extremely preterm infants (gestational age [GA] <28 weeks) as radiologic findings vary by GA. In an observational series of 202 infants with NEC, intramural gas (pneumatosis intestinalis) was detected in all infants with a GA ≥37 weeks but was only present in 29 percent of infants with a GA ≤26 weeks [41]. Portal venous gas was also more common in infants ≥37 weeks compared with those ≤26 weeks gestation (47 versus 10 percent). Thus, abdominal radiography may not be as helpful in the most immature infants. Particularly in these infants, treatment decisions should be based upon clinical suspicion as confirmatory radiographic findings may not be present.

Characteristic findings of NEC — The following characteristic radiographic features are seen in the majority of infants with NEC (image 1) [27].

●An abnormal gas pattern with dilated loops of bowel that is consistent with ileus, and is typically seen in the early stages of NEC. This is a nonspecific pattern that can also be seen in other conditions such as septic ileus.

●Pneumatosis intestinalis (image 1), considered a hallmark of NEC, appears as bubbles of gas in the small bowel wall, and is seen in most patients with Bell stages II and III NEC (table 1) [42]. While there are other conditions aside from NEC where pneumatosis intestinalis may be present later in life (eg, typhlitis, ischemic bowel, cow's milk protein allergy, food protein intolerance enterocolitis syndrome [FPIES]), pneumatosis in the preterm infant is indicative of NEC until proven otherwise. However, this finding can be difficult to diagnose by radiograph as air-filled stool can mimic the appearance of pneumatosis.

●Pneumoperitoneum typically appears when bowel perforation occurs in patients with IIIB NEC. A substantial amount of intraperitoneal air may result in the "football" sign on a supine radiograph (image 2). This sign consists of a large hypolucent area in the central abdomen found to the right of midline overlying the liver with markings from the falciform ligament. Pneumoperitoneum is a nonspecific sign and can be seen in other bowel conditions such as spontaneous intestinal perforation (SIP).

●Sentinel loops, a loop of bowel that remains in fixed position and that can be seen in orthogonal views (anteroposterior and lateral), is suggestive of necrotic bowel and/or perforation in the absence of pneumatosis intestinalis.

●Portal venous gas is a transient sign of bacterial gas entering into the portal system that outlines branching segments of the vascular tree. It was previously thought to be a predictor of poor outcome and an indication for surgical intervention, but this was not supported by subsequent data [43].

Procedure — Abdominal radiographs are obtained in the supine position [44]. In infants with more advanced illness in whom pneumoperitoneum is suspected, films also are taken in the supine cross-table lateral view or in the lateral decubitus position with the left side down to detect free air in the abdomen, particularly overlying the liver. After the initial evaluation, we obtain serial radiographs to follow the course of the disease, usually every 8 to 12 hours during the first few days or until the infant improves.

Abdominal ultrasonography — Although in our center we primarily rely on radiography for diagnosis, abdominal ultrasonography is increasingly helpful in the diagnosis and management of NEC [45-51].

The benefits of ultrasonography over plain radiographs include [45,52]:

●Ultrasound is more sensitive in detecting fluid collections

●Doppler ultrasound is dynamic and permits real-time visualization of bowel wall thickness, peristalsis, and perfusion

However, the use of ultrasonography is limited by variability of operator expertise, lack of 24-hour availability, and insufficient data to accurately apply findings for management decisions (eg, surgery). Additional training for diagnostic imaging staff and radiologists and potential bedside providers is needed to derived possible benefits of repeated ultrasound evaluations to detect potentially ischemic bowel [52,53].

The following findings can be observed in infants with NEC. The presence of free air, focal fluid collections, and increased bowel wall thickness, and echogenicity are associated with more severe NEC [45,47,54].

●Changes in bowel wall thickness – Bowel wall thickening and increased blood flow are initial changes seen with increasing inflammation. Thinning bowel wall with a central echogenic focus and a hypoechoic rim (the pseudo-kidney sign) may indicate necrotic bowel and imminent perforation (picture 1 and figure 1).

●Increased bowel wall echogenicity is indicative of inflammation, swelling, and increased perfusion of the affected bowel.

●Presence of pneumatosis intestinalis – Ultrasound detection of small air bubbles in the bowel wall as in pneumatosis intestinalis can be spatially resolved from air bubbles in stool that can be misdiagnosed on radiographs. Ultrasonography also can detect intermittent gas bubbles in liver parenchyma and the portal venous system that are not detected by radiographs.

●Alterations in bowel wall perfusion – Color Doppler ultrasonography has also been used to diagnose NEC. In a small study, color Doppler ultrasonography was more sensitive than abdominal radiography in detecting bowel necrosis and alterations in bowel wall perfusion as confirmed at laparotomy (figure 1) [48].

●Bowel perforation – Evidence of free air, bowel wall thickening, and complex ascites strongly indicate signs of intestinal perforation.

Available data suggests that ultrasonography has high specificity but low sensitivity for many of these findings [55]. Additional studies are needed to determine the optimal radiologic modality or combination to confirm NEC in at-risk infants in all settings.

Contrast enema: Contraindicated — Contrast enemas are not recommended if NEC is suspected, as it may result in bowel perforation with extravasation of contrast material into the peritoneum.

LABORATORY EVALUATION — Although laboratory tests are not used to make the diagnosis of NEC, laboratory findings may support the diagnosis and staging of disease severity, and aid in the management of infants with NEC. (See "Neonatal necrotizing enterocolitis: Management and prognosis", section on 'Laboratory monitoring'.)

Blood tests — The following blood tests, although non-specific, may be used as supportive evidence for a diagnosis and aid in the management of NEC. In particular, low platelet count, metabolic acidosis, and an increasing serum glucose are associated with NEC [33,34].

●Complete blood count – A complete blood count and differential are performed when NEC is suspected. Alterations in the white blood count are nonspecific, although an absolute neutrophil count of less than 1500/microL is more commonly observed in patients with NEC and is associated with a poor prognosis [56,57]. Thrombocytopenia is a frequent finding and can result in significant bleeding. In the early course of NEC, declining platelet counts correlate with necrotic bowel and worsening disease, whereas a subsequent rise in platelet counts often signals improvement [33].

●Coagulation studies – Coagulation studies are not ordered routinely, but should be obtained if the infant has thrombocytopenia or bleeding, because disseminated intravascular coagulation (DIC) is a frequent finding in infants with severe NEC. DIC is confirmed by a decreased platelet count, prolonged prothrombin and partial thromboplastin times, decreased serum factor V and fibrinogen concentrations, and increased fibrin split products (D-dimer). In patients with DIC and significant bleeding, replacement therapy is administered. (See "Disseminated intravascular coagulation in infants and children".)

●Serum chemistries – Serum electrolytes, blood urea nitrogen, creatinine, and pH are routinely measured. Electrolyte abnormalities often are nonspecific. However, persistence of hyponatremia (serum sodium levels of less than 130 mEq/L), increasing glucose levels, and metabolic acidosis are suggestive of necrotic bowel or sepsis [34].

●Other tests:

•An arterial blood gas analysis is performed in infants with signs of respiratory compromise.

•Serial lactate levels may be used to follow metabolic acidosis as indicators of disease progression and healing.

Sepsis evaluation — A sepsis evaluation (blood culture, and if indicated, cerebral spinal fluid culture) is performed when NEC is suspected because sepsis is a common concomitant finding or one of the main differential diagnosis [58]. Culture results are used in guiding antibiotic therapy. (See "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation", section on 'Evaluation' and "Neonatal necrotizing enterocolitis: Management and prognosis", section on 'Antibiotic therapy' and "Bacterial meningitis in the neonate: Treatment and outcome", section on 'Antimicrobial therapy'.)

Peritoneal culture — A diagnostic abdominal paracentesis is infrequently needed to obtain fluid for culture and Gram stain in infants with severe ascites or when peritonitis is suspected. In these cases, the identification of enteric organisms in the peritoneal fluid supports the diagnosis of peritonitis from intestinal perforation and helps guide appropriate antibiotic coverage [59].

Stool tests: Generally not useful — Bedside stool tests (examination for occult blood and reducing substances, and measurement of alpha-1 antitrypsin) have not been clinically helpful as they are nonspecific findings [60]. For example, occult blood in the stool is commonly found in preterm infants. In a survey of infants <1800 g, 58 percent of infants had at least one positive occult blood in stool test over a six-week period [61].

Potential predictive biomarkers — There are a number of possible biomarkers that may assist in early prediction of NEC, diagnosing NEC, and/or determining the severity of NEC. However, none of these biomarkers have demonstrated sufficient specificity and sensitivity to be useful for early detection of NEC or monitoring disease progression [62-64]. Many of the promising biomarkers target nonspecific inflammatory factors (C-reactive protein, platelet activating factor, or cytokines such as interleukins [IL-6, IL-8] or tumor necrosis factor-beta) that are also elevated with sepsis and ileus [62]. There is still a need for an early biomarker to detect the earliest signs of developing NEC before severe outcomes occur.

Ongoing research efforts have been focused on the following potentially more specific marker for NEC:

●Intestinal fatty acid binding protein (IFABP) is a small cytoplasmic protein that is found in the enterocytes that support the uptake and transport of fatty acids. The cell death of enterocytes leads to the release of IFABP into the circulation. Although plasma IFABP levels is very specific to bowel injury it appears to have only medium sensitivity for NEC [65].

●Stool NEC biomarker – Early changes in the gut microbiome of infants who are at-risk for NEC may lead to identifying an important precursor that can aid in the diagnosis of early NEC, and perhaps become a potential preventative intervention [66,67]. For example, fecal calprotectin, found in intestinal inflammatory cells, is produced during intestinal inflammation. Levels of fecal calprotectin correlate well with NEC disease severity but have not been shown yet to be useful in early detection of NEC [68-70]. However, potential limitations include timing of stool collection, because stool sampling must be obtained at the time when NEC is suspected, and variation of normative value based on gestational age [71]. In addition, the utility of calprotectin may depend on the underlying pathogenesis.

●MicroRNAs have been suggested as possible biomarkers for gastrointestinal injury including NEC [72].

●Cord blood biomarkers (ie, glial fibrillary acidic protein (GFAP), glial-derived neurotrophic factor (GDNF), fatty acid-binding protein-2 (FABP-2)) are associated with higher risk of developing NEC in the first two weeks of life in preterm infants <1500 grams and <34 weeks gestation.

SEVERITY OF NEC: MODIFIED BELL STAGING CRITERIA — The modified Bell staging criteria provide a uniform clinical definition of NEC based upon the severity of systemic, intestinal, radiographic and laboratory findings, and are the most commonly used diagnostic and staging criteria in practice (table 1) [56,73]. These definitions are useful in comparing cases and studies; however, treatment is directed at the clinical signs rather than the particular stage of NEC. In addition, these criteria were developed in the 1970s, and concerns of overdiagnosis have been raised. For example, the diagnosis of intramural air is often incorrect and may be due to air contained in stool within the intestinal lumen.

Nevertheless, the Bell staging criteria is the standard that is used in most neonatal intensive care units (NICUs). Each advancing stage includes the characteristics of the previous stage plus additional findings due to increasing severity of the disease:

●Suspected NEC, stage I, is characterized by nonspecific systemic signs, such as temperature instability, apnea, and lethargy. Abdominal signs include increased gastric residuals, abdominal distention, emesis, and heme-positive stool. Abdominal radiographs may be normal or show dilation of the bowel consistent with mild ileus. Although therapy does not change, stage I cases are further divided by the absence (stage IA) or presence (stage IB) of grossly bloody stools. However, there is disagreement among experts in the field whether or not the entity described as Bell stage I is actually NEC, or nonspecific feeding intolerance/ileus of the preterm infant [74].

●Proven NEC, stage II, encompasses the signs of stage I plus absent bowel sounds with or without abdominal tenderness. Abdominal tenderness is present, and some infants have cellulitis of the abdominal wall or a mass in the right lower quadrant. Infants with stage IIA are mildly ill, whereas those with stage IIB NEC are moderately ill and also have mild metabolic acidosis and thrombocytopenia. Findings on abdominal imaging include intestinal dilation, ileus, ascites and pneumatosis intestinalis, which is the defining feature of stage II. (See 'Abdominal radiography' above.)

●Advanced NEC, stage III, is the most severe form. In stage IIIA, the bowel is intact, whereas stage IIIB is characterized by bowel perforation visualized as a pneumoperitoneum on the abdominal radiograph. Infants with advanced NEC are critically ill. In addition to the signs of less severe stages, they typically have hypotension, bradycardia, severe apnea, and signs of peritonitis (eg, abdominal distention and marked tenderness). Laboratory signs include a combined respiratory and metabolic acidosis, neutropenia, and disseminated intravascular coagulation (DIC).

In approximately one-third of cases, NEC is suspected but not confirmed (stage I), and symptoms resolve gradually in these infants. Of note, in many studies regarding incidence and outcome, patients with stage I are not included as it remains uncertain whether or not they had NEC. In 25 to 40 percent of cases, the progression of NEC is fulminant with signs of peritonitis and sepsis, and the rapid development of DIC and shock (stage III).

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of necrotizing enterocolitis (NEC) includes other conditions that cause rectal bleeding, abdominal distension, gastric retention, or intestinal perforation [75]. NEC is differentiated from these other diseases by the radiologic evidence of pneumatosis intestinalis, and the combined clinical findings of abdominal distention, bilious vomiting or gastric aspirate, and rectal bleeding (heme-positive or grossly bloody stools).

●Infectious enteritis – Pathogenic organisms, including Campylobacter, Clostridioides difficile, Salmonella, and Shigella sometimes cause infectious neonatal enterocolitis. These organisms are identified by stool cultures, although it is unclear whether they have a causative role. Viral enteritis of infancy is characterized by frequent and sometimes bloody stools, abdominal distension, and secondary sepsis. There may be a clustering of cases within a single unit. Common pathogens include rotavirus and enterovirus.

●Spontaneous intestinal perforation of the newborn is a single intestinal perforation that is typically found at the terminal ileum or colon. It occurs primarily in very low birth weight (VLBW) infants (BW <1500 g) similar to NEC. It is most commonly distinguished from NEC by the absence of pneumatosis intestinalis on abdominal imaging and the clinical findings of hypotension and abdominal distension, along with the classical bluish discoloration of the abdominal wall. This is in contrast to the more commonly observed physical findings of abdominal wall erythema, crepitus, and induration in infants with NEC. In addition, spontaneous intestinal perforation typically occurs earlier in extremely and very preterm infants (within the first week of life) and is independent of feeding, whereas NEC occurs later in life and after the initiation of enteral feeds. (See "Spontaneous intestinal perforation of the newborn".)

●Anatomic or functional conditions that cause intestinal obstruction can result in enterocolitis. These disorders include Hirschsprung disease, ileal atresia, volvulus [76], meconium ileus, and intussusception. Abdominal radiography distinguishes these entities from NEC. (See "Congenital aganglionic megacolon (Hirschsprung disease)" and "Intestinal malrotation in children" and "Intestinal atresia".)

●Anal fissures can result in rectal bleeding. This condition usually is benign, although the diagnosis of NEC must be strongly considered in any premature infant who has occult or gross blood in the stools. Physical examination of the anus confirms the diagnosis of fissures. (See "Lower gastrointestinal bleeding in children: Causes and diagnostic approach", section on 'Neonatal period'.)

●Neonatal appendicitis is a rare disorder with high morbidity and mortality, most likely due to a delay in diagnosis [77]. The presentation may be the same as NEC and the diagnosis may be made only at laparotomy. (See "Acute appendicitis in children: Clinical manifestations and diagnosis", section on 'Neonates (0 to 30 days)'.)

●Infants with sepsis can have an ileus that is difficult to distinguish from early signs of NEC (stage I). (See "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation", section on 'Clinical manifestations'.)

●Cow's milk protein intolerance is uncommon in preterm infants and rarely occurs before six weeks of age but may be misdiagnosed as NEC [78]. It is characterized by abdominal distention and increased stooling, which may progress to bloody stools, and in severe cases, pneumatosis may be present. It is often associated with frequent courses of parenteral nutrition with repeated feeding intolerance before symptoms resolve after changing feeds to a protein hydrolysate or crystalline amino acid formula. (See "Milk allergy: Clinical features and diagnosis".)

●Food protein-induced enterocolitis syndrome (FPIES) can mimic NEC in preterm infants, as both conditions may present with pneumatosis, low albumin, anemia, and inflammatory marker elevations [79]. However, patients with NEC commonly (but not always) have leukopenia and thrombocytopenia, whereas those with acute FPIES typically have thrombocytosis, leukocytosis, and eosinophilia. Patients with FPIES will have resolution of symptoms with modification of their diet to an extensively hydrolyzed or an amino acid-based formula. (See "Food protein-induced enterocolitis syndrome (FPIES)".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Newborn necrotizing enterocolitis (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Necrotizing enterocolitis (NEC) is one of the most common gastrointestinal emergencies in the newborn infant. It is estimated to occur in 1 to 3 per 1000 live births. More than 90 percent of cases occur in very low birth weight (VLBW) infants (BW <1500 g) born at <32 weeks gestation, and the incidence of NEC decreases with increasing gestational age (GA) and BW. The global incidence varies from 2 to 7 percent for VLBW infants. Term infants who develop NEC usually have a preexisting illness, such as congenital heart disease or sepsis. (See 'Epidemiology' above.)

●Clinical presentation – NEC primarily occurs in healthy, growing, and feeding VLBW preterm infants. It presents with sudden changes in feeding tolerance, with both nonspecific systemic signs (eg, apnea, respiratory failure, poor feeding, lethargy, or temperature instability) and abdominal signs (eg, abdominal distension, bilious gastric retention and/or vomiting, tenderness, rectal bleeding, and diarrhea). Physical findings may include abdominal wall erythema, crepitus, and induration. (See 'Clinical presentation' above.)

●Diagnosis – A clinical diagnosis of NEC is based on the presence of the characteristic clinical features of abdominal distension, bilious vomiting or gastric aspirate, and rectal bleeding (hematochezia), and the abdominal radiographic finding of pneumatosis intestinalis, pneumoperitoneum, or sentinel loops (image 1 and image 2). A definite diagnosis of NEC is not always possible, as this is made from either surgical or postmortem intestinal specimens that demonstrate the histological findings of inflammation, infarction, and necrosis. Treatment decisions should be based upon clinical suspicion and findings, as radiographic findings may be equivocal. (See 'Diagnosis' above.)

●Laboratory evaluation – Results of laboratory evaluation, including blood studies and stool analysis, are nonspecific, but may be supportive of the diagnosis of NEC. In particular, low platelet count, metabolic acidosis, and a heme-positive stool are associated with NEC. Once a diagnosis of NEC is made or suspected, a sepsis evaluation should be performed as bacteremia is a common concomitant finding in infants with NEC. (See 'Laboratory evaluation' above.)

●Severity – The severity of NEC is defined by the Bell staging criteria, which stages NEC based upon the severity of clinical findings (table 1). (See 'Severity of NEC: Modified Bell staging criteria' above.)

●Differential diagnosis – The differential diagnosis of NEC includes other conditions that cause rectal bleeding, abdominal distension, or intestinal perforation. These include spontaneous intestinal perforation of the newborn, infectious enterocolitis, and the usually benign diagnosis of anal fissure. NEC is usually differentiated from these conditions by its characteristic clinical features (healthy, growing, and feeding VLBW preterm infants who present with feeding intolerance and evidence of rectal bleeding) and abdominal radiographic findings (eg, pneumatosis intestinalis). (See 'Differential diagnosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Richard J Schanler, MD, who contributed to an earlier version of this topic review.