PreviousTopicNew SearchClinical features and diagnosis of necrotizing enterocolitis in newborns

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INTRODUCTION — Necrotizing enterocolitis (NEC) is one of the most commongastrointestinal emergencies in the newborn infant. It is a disorder characterized byischemic necrosis of the intestinal mucosa, which is associated with inflammation,invasion of enteric gas forming organisms, and dissection of gas into the muscularisand portal venous system [1]. Although early recognition and aggressive treatment ofthis disorder has improved clinical outcomes, NEC accounts for substantial long-termmorbidity in survivors of neonatal intensive care, particularly in premature very low birthweight infants (birth weight 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 "Pathology and pathogenesis of necrotizing enterocolitis in newborns" and"Management of necrotizing enterocolitis in newborns" and "Prevention of necrotizingenterocolitis in newborns".)

EPIDEMIOLOGY — Necrotizing enterocolitis (NEC) occurs in 1 to 3 per 1000 live birthsand 1 to 7.7 percent of admissions to neonatal intensive care units (NICUs) [2].

Preterm infants — The incidence decreases with increasing gestational age (GA) andbirth weight (BW), and is about 6 to 7 percent in very low birth weight (VLBW) infants(BW less than 1500 g) [3-5].

This was illustrated in one study of VLBW infants born between 1999 and 2001 from theNational Institute of Child Health and Human Development (NICHHD) neonatal networkcohort [3]. The overall rate of NEC was about 7 percent. Rates were inversely related toBW as follows:

●BW between 401 to 750 g – 11.5 percent●BW between 751 to 1000 g – 9 percent●BW between 1001 to 1250 g – 6 percent●BW between 1251 to 1500 g – 4 percentAlthough unadjusted rates of NEC varied among the 362 NICUs, there were nosignificant differences when risk was adjusted for confounding variables. However, onelimitation of this study is that it most likely included infants with spontaneous intestinalperforation, which may alter these rates. (See "Spontaneous intestinal perforation of the

newborn".)

Similar trends were observed in two more current studies from the United Kingdom andCanada:

●In a survey from the United Kingdom of 10,946 admissions to the NICU during summerand winter study periods in 2005 and 2006, the reported prevalence rate was 2 percent[6]. The risk of NEC increased with decreasing BW and GA with a 14 percent prevalencefor infants with BW <1000 g and a GA <26 weeks. Males and females are affectedequally. NEC affects black and white infants more than Hispanic infants, but the racialpatterns reflect the populations served by neonatal centers.●In a population-based Canadian study of 16,669 preterm infants (gestational age <33weeks) admitted to 25 NICUs, the incidence of NEC was 5.1 percent [7].Reported mortality rates range from 15 to 30 percent and also are inversely related togestational age and birth weight [8]. The estimated yearly infant death rate in the UnitedStates from 1979 to 1992 was 12.4 deaths per 100,000 live births. The death rate fromNEC was highest in black VLBW male infants.

Term infants — Although the majority of infants with NEC are born prematurely,approximately 13 percent of cases occur in term infants [9]. Term infants who developNEC typically have a preexisting illness [10-12]. This was illustrated by the followingstudies:

●In one report, predisposing conditions were identified in 16 of 26 term infants with NEC[11]. Among these, 6 had congenital heart disease and 10 had other disorders, includingsepsis, seizures, hypoglycemia, severe intrauterine growth restriction, hypercoagulablestate, gastroschisis, and congenital herpes infection.●In another study, a preexisting condition was found in all 30 infants greater than 36weeks gestation with NEC cared for in a regional multiple-center healthcare system from2001 to 2006 [12]. Diagnoses included congenital heart disease (n = 8), respiratorydistress (n = 8), sepsis (n = 4), birth anoxia (n = 4), and polycythemia (n = 2). None of thepatients were exclusively breastfed. (See "Pathology and pathogenesis of necrotizingenterocolitis in newborns", section on 'Human milk'.)●In a case series of 39 term patients (gestational age ≥37 weeks) born between 1990and 2012, 15 infants were born to mothers with prenatal risk factors (eg, illegalsubstance use, intrapartum infection, maternal diabetes, and pregnancy-inducedhypertension) [13]. Two-thirds of the cohort also had perinatal and neonatal disordersincluding infection (n = 25), hypoxic event (n = 11), congenital heart disease (n = 9), andgenetic disorders (n = 9). Overall mortality was 18 percent.CLINICAL PRESENTATION — The majority of premature infants who develop necrotizingenterocolitis (NEC) are healthy, feeding well, and growing [14]. A change in feedingtolerance with gastric retention is a frequent early sign. The timing of the onset ofsymptoms varies and appears to be inversely related to gestational age [7,15]. Overall,25 percent of cases present later than 30 days after birth. The median age at onset in

infants with a gestational age of less than 26 weeks was 23 days, and for those with agestational age of greater than 31 weeks, the median age at onset was 11 days.

The clinical presentation of NEC consists of systemic and abdominal signs.

●Systemic signs are nonspecific and include apnea, respiratory failure, lethargy, poorfeeding, or temperature instability. Hypotension resulting from septic shock may bepresent in the most severe cases. Twenty to 30 percent of infants with NEC haveassociated bacteremia, which may contribute to these findings [16].●Abdominal signs include distention, gastric retention (residual milk in the stomachbefore a feeding), tenderness, vomiting, diarrhea, rectal bleeding (hematochezia), andbilious drainage from enteral feeding tubes [17,18].Bell staging criteria — The Bell staging criteria provide a uniform definition of NEC basedupon the severity of systemic, intestinal, and radiographic findings, and is the mostcommonly used criteria in practice (table 1) [1,19]. These definitions are useful incomparing cases and studies; however, treatment is directed at the clinical signs ratherthan the particular stage of NEC. Each advancing stage includes the characteristics ofthe previous stage plus additional findings due to increasing severity of the disease.

●Stage I, or suspected NEC, is characterized by nonspecific systemic signs, such astemperature instability, apnea, and lethargy. Abdominal signs include increased gastricresiduals, abdominal distention, emesis, and heme-positive stool. Abdominalradiographs 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 isdisagreement among experts in the field whether or not the entity described as Bellsstage I is actually necrotizing enterocolitis, or nonspecific feeding intolerance/ileus ofthe preterm infant [20].●Stage II, or proven NEC, encompasses the signs of stage I plus absent bowel soundswith or without abdominal tenderness. Abdominal tenderness is present, and someinfants 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 illand also have mild metabolic acidosis and thrombocytopenia. Abdominal radiographfindings include intestinal dilation, ileus, pneumatosis intestinalis, and ascites. (See'Abdominal radiography' below.)●Stage III, or advanced NEC, is the most severe form. In stage IIIA, the bowel is intact,whereas stage IIIB is characterized by bowel perforation visualized as apneumoperitoneum on the abdominal radiograph. Infants with advanced NEC arecritically ill. In addition to the signs of less severe stages, they typically havehypotension, bradycardia, severe apnea, and signs of peritonitis (eg, abdominaldistention and marked tenderness). Laboratory signs include a combined respiratoryand metabolic acidosis, neutropenia, and disseminated intravascular coagulation (DIC).In about one-third of cases, NEC is suspected but not confirmed (stage I), andsymptoms resolve gradually in these infants. In 25 to 40 percent of cases, the

progression of NEC is fulminant with signs of peritonitis and sepsis, and the rapiddevelopment of DIC and shock (stage III).

DIAGNOSIS — The diagnosis of necrotizing enterocolitis (NEC) is based on the presenceof the characteristic clinical features of abdominal distention and rectal bleeding(heme-positive or grossly bloody stools), and the abdominal radiographic finding ofpneumatosis intestinalis.

Assessment of infants with suspected NEC includes abdominal imaging, blood studies,stool analysis, and sepsis evaluation. Although the results of this evaluation often arenonspecific, certain findings are supportive of the diagnosis of NEC, and in the case ofabdominal imaging (ie, pneumatosis intestinalis), may be diagnostic.

Radiographic studies

Abdominal radiography — Abdominal radiographs confirm the diagnosis of NEC andfollow the progression of the disease. Of note, although abdominal radiography isusually useful in making the diagnosis of NEC, when there are equivocal radiographicfindings, treatment decisions should be based upon clinical suspicion.

Abdominal radiographs are obtained in the supine position [21]. In infants with moreadvanced illness in whom pneumoperitoneum is suspected, films also are taken in thesupine cross-table lateral view or in the lateral decubitus position with the left side downto detect free air in the abdomen. After the initial evaluation, we obtain serialradiographs to follow the course of the disease, usually every 8 to 12 hours during thefirst few days or until the infant improves.

The following characteristic radiographic features are seen in the majority of infantswith suspected NEC (image 1) [18].

●An abnormal gas pattern with dilated loops of bowel that is consistent with ileus, and istypically seen in the early stages of NEC.●Pneumatosis intestinalis, the hallmark of NEC, appears as bubbles of gas in the smallbowel wall, and is seen in most patients with stages II and III NEC [22].●Pneumoperitoneum typically appears when bowel perforation occurs in patients withIIIB NEC. A substantial amount of intraperitoneal air may result in the "football" sign on asupine radiograph. This sign consists of a large hypolucent area in the central abdomenwith markings from the falciform ligament.●Sentinel loops, a loop of bowel that remains in fixed position, is suggestive of necroticbowel and/or perforation in the absence of pneumatosis intestinalis.Portal venous gas (PVG) had been thought to be a predictor of poor outcome and anindication for surgical intervention. However, subsequent data do NOT support theseassumptions. This was illustrated in a prospective study of 194 infants with NEC treatedat a single center from 1991 to 2003 [23]. There was NO difference in survival rates

between those patients with PVG and those without (17 versus 20 percent) [23]. Of theinfants with PVG, those who were treated medically had a higher survival rate than thosetreated surgically (91 versus 74 percent).

Radiological findings may vary by gestational age. This was illustrated in oneobservational series of 202 infants with NEC [24]. Although intramural gas was detectedin all infants ≥37 weeks gestation with NEC, it was only present in 29 percent of those≤26 weeks gestation. In addition, portal venous gas was more common in infants ≥37weeks compared with those ≤26 weeks gestation (47 versus 10 percent). Thus,abdominal radiography may not be as helpful in the most immature infants. Particularlyin these infants, treatment decisions should be based upon clinical suspicion asconfirmatory radiographic findings may not be present.

Abdominal ultrasonography — Although we currently rely on radiographs, abdominalultrasonography has been increasingly used in the diagnosis of NEC [25-28]. Thesonographic appearance of bowel wall with a central echogenic focus and a hypoechoicrim (the pseudo-kidney sign) may indicate necrotic bowel and imminent perforation.Ultrasonography also can detect intermittent gas bubbles in liver parenchyma and theportal venous system that are not detected by radiographs. Free gas, focal fluidcollections, and increased bowel wall thickness and echogenicity are associated withmore severe NEC [26,28,29].

Color Doppler ultrasonography has also been used to diagnose NEC. In a small study,color Doppler ultrasonography was more sensitive than abdominal radiography indetecting bowel necrosis and alterations in bowel wall perfusion as confirmed atlaparotomy [30]. Additional studies are needed to determine the optimal radiologicmodality to confirm NEC in at-risk infants in all settings.

Contrast enema — Contrast enemas are NOT recommended if NEC is suspected, as itmay result in bowel perforation with extravasation of contrast material into theperitoneum.

LABORATORY EVALUATION

Blood tests — Although blood tests are not used in the diagnostic and staging criteria fornecrotizing enterocolitis (NEC), laboratory findings may support the diagnosis and aid inthe management of infants with NEC. In particular, low platelet count, metabolicacidosis, and an increasing serum glucose are associated with NEC [31,32].

●Complete blood count – A complete blood count and differential are performed whenNEC is suspected. Alterations in the white blood count are nonspecific, although anabsolute neutrophil count of less than 1500/microL is associated with a poor prognosis[1]. Thrombocytopenia is a frequent finding and can result in significant bleeding. In theearly course of NEC, declining platelet counts correlate with necrotic bowel and

worsening disease, whereas a subsequent rise in platelet counts often signalsimprovement [31].●Coagulation studies – Coagulation studies are not ordered routinely, but should beobtained if the infant has thrombocytopenia or bleeding, because disseminatedintravascular coagulation (DIC) is a frequent finding in infants with severe NEC. DIC isconfirmed by a decreased platelet count, prolonged prothrombin and partialthromboplastin times, decreased serum factor V and fibrinogen concentrations, andincreased fibrin split products (D-dimer). (See "Disseminated intravascular coagulationin infants and children".)●Serum chemistries – Serum electrolytes, blood urea nitrogen, creatinine, and pH areroutinely measured. An arterial blood gas analysis is performed in infants with signs ofrespiratory compromise. Electrolyte abnormalities often are nonspecific. However,persistence of hyponatremia (serum sodium levels of less than 130 mEq/L), increasingglucose levels, and metabolic acidosis are suggestive of necrotic bowel or sepsis [32].●Other nonspecific findings in infants with NEC include increased levels of C-reactiveprotein [33], lysosomal acid hydrolase, and alpha-1-acid glycoprotein (orosomucoid).Sepsis evaluation — A sepsis evaluation is performed when NEC is suspected becauseof sepsis is a common concomitant finding [34]. Culture results may be used in guidingantibiotic therapy. (See "Management of necrotizing enterocolitis in newborns", sectionon 'Antibiotic therapy'.)

Blood, stool, and, if indicated, cerebrospinal fluid cultures are obtained. Cultures of thestool typically reveal enteric flora. If Clostridium difficile is suspected, specific culturesand assays for its toxins are performed (see "Clostridium difficile infection in children:Approach to diagnosis"). Stool is cultured for viral or fungal organisms if theseinfectious agents are suspected.

A diagnostic abdominal paracentesis occasionally is performed to obtain fluid forculture and Gram stain in infants with severe ascites or when peritonitis is suspectedbecause of progressive clinical deterioration and an unchanging radiographic bowel gaspattern. In these cases, the identification of enteric organisms in the peritoneal fluidsupports the diagnosis of peritonitis from intestinal perforation and helps guideappropriate antibiotic coverage [35].

Other tests — In an infant suspected of having NEC, stool may be positive for occultblood. A positive finding may increase the diagnostic suspicion, but it is not specific forthe disease, as occult blood in stool is commonly found in premature infants. In a surveyof infants <1800 g, 58 percent of infants had at least one positive occult blood in stooltest over a six-week period [36].

Other stool tests have been studied, but are not performed routinely. As an example,many infants with NEC have carbohydrate malabsorption, reflected by the presence ofreducing substances in the stool or a positive breath hydrogen test [37,38]. In one study,breath hydrogen excretion increased 8 to 28 hours before clinical signs of NEC were

detected [37].

Other nonspecific findings in infants with NEC include increased levels of stool alpha-1antitrypsin, and urinary D-lactate (a carbohydrate fermentation metabolite produced byenteric microflora).

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of necrotizing enterocolitis(NEC) includes other conditions that cause rectal bleeding, abdominal distension,gastric retention, or intestinal perforation. In addition, infants with sepsis can have anileus that is difficult to distinguish from early signs of NEC.

●Pneumatosis coli is a rare and benign form of NEC that affects premature infants [39].Affected infants typically have gastric retention and vomiting, apnea and lethargy, mildabdominal distention, and bloody stools. In contrast to typical NEC, intramural bowelgas occurs in the colon rather than in the small bowel. Infants recover within three dayswithout sequelae [40].●Pathogenic organisms, including Campylobacter, C difficile, Salmonella, and Shigellasometimes cause infectious enterocolitis. These organisms are identified by stoolcultures, although their causative role in NEC is uncertain.●Anatomic or functional conditions that cause intestinal obstruction can result inenterocolitis. These disorders include Hirschsprung disease, ileal atresia, volvulus,meconium ileus, and intussusception.●Spontaneous intestinal perforation of the newborn is a single intestinal perforation thatis typically found at the terminal ileum. It also occurs primarily in very low birth weight(VLBW) infants (birth weight <1500 g) similar to NEC. It is distinguished from NEC by theclinical findings of hypotension and abdominal distension, with the classical bluishdiscoloration of the abdominal wall in the absence of abdominal wall erythema, crepitus,and induration commonly seen in NEC, and the absence of NEC radiographic findings ofpneumatosis intestinalis, transient thickening of the intestinal wall, and fixed dilatedsmall bowel loops. (See "Spontaneous intestinal perforation of the newborn".)●Anal fissures can result in rectal bleeding. This condition usually is benign, althoughthe diagnosis of NEC must be strongly considered in any premature infant who hasoccult or gross blood in the stools.●Neonatal appendicitis is a rare disorder with high morbidity and mortality, most likelydue to a delay in diagnosis [41]. The presentation may be the same as NEC and thediagnosis may be made only at laparotomy.Diagnostic guidelines — New guidelines in premature infants with birth weight <1250 ghave been proposed to distinguish four of the acquired neonatal intestinal diseases(ANID) from one another [42].

●Ischemic NEC is characterized by increased abdominal distension, radiologic evidenceof pneumatosis, bloody stools, mild acidosis and disseminated coagulopathy, and onsetmost common with rapid advances of enteral feeds. Congenital heart disease,polycythemia, growth restriction, or hypoxic-ischemic event are risk factors associated

with ischemic NEC.●Viral enteritis of infancy is characterized by frequent and sometimes bloody stools,abdominal distention, and secondary sepsis. There may be a clustering of cases withina single unit. Common pathogens include rotavirus and enterovirus.●Cow's milk protein allergy is rare in preterm infants and rarely occurs before six weeksof age. It is characterized by abdominal distention and increased stooling, which mayprogress to bloody stools, and in severe cases, pneumatosis may be present. (See "Foodprotein-induced proctitis/colitis and enteropathy of infancy".)●Spontaneous intestinal perforation, as discussed above, is not associated withpneumatosis, occurs within the first week of life, and is independent of feeding. (See"Spontaneous intestinal perforation of the newborn".)INFORMATION FOR PATIENTS — UpToDate offers two types of patient educationmaterials, “The Basics” and “Beyond the Basics.” The Basics patient education piecesare written in plain language, at the 5th to 6th grade reading level, and they answer thefour or five key questions a patient might have about a given condition. These articlesare best for patients who want a general overview and who prefer short, easy-to-readmaterials. Beyond the Basics patient education pieces are longer, more sophisticated,and more detailed. These articles are written at the 10th to 12th grade reading level andare best for patients who want in-depth information and are comfortable with somemedical jargon.

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

●Basics topic (see "Patient information: Newborn necrotizing enterocolitis (TheBasics)")SUMMARY AND RECOMMENDATIONS

●Necrotizing enterocolitis (NEC) is one of the most common gastrointestinalemergencies in the newborn infant [1]. It occurs in 1 to 3 per 1000 live births. Theincidence decreases with increasing gestational age and birth weight (BW), and is about6 to 7 percent in very low birth weight infants (BW less than 1500 g). Term infants whodevelop NEC usually have a preexisting illness, such as congenital heart disease orsepsis. (See 'Epidemiology' above.)●NEC primarily occurs in healthy, growing, and feeding premature infants. It presentswith both nonspecific systemic signs (eg, apnea, respiratory failure, poor feeding,lethargy, or temperature instability) and abdominal signs (eg, distension, gastricretention, tenderness, vomiting, rectal bleeding, and diarrhea). (See 'Clinical presentation'above.)●The Bell staging criteria defines the different stages of NEC based upon the severity ofclinical findings (table 1). (See 'Bell staging criteria' above.)●The diagnosis of NEC is based upon the presence of the characteristic clinical features

of abdominal distention and rectal bleeding (hematochezia), and the abdominalradiographic finding of pneumatosis intestinalis. At times, radiographic findings may beequivocal and treatment decision should be based upon clinical suspicion and findings.(See 'Diagnosis' above.)●Results of laboratory evaluation, including blood studies and stool analysis, arenonspecific, but may be supportive of the diagnosis of NEC. In particular, low plateletcount, metabolic acidosis, and a heme-positive stool are associated with NEC. (See'Laboratory evaluation' above.)●The differential diagnosis of NEC includes other conditions that cause rectal bleeding,abdominal distension, or intestinal perforation. These include spontaneous intestinalperforation of the newborn, infectious enterocolitis, and the usually benign diagnoses ofpneumatosis coli and anal fissures. NEC is differentiated from these conditions by theabdominal radiographic finding of pneumatosis intestinalis. (See 'Differential diagnosis'above.)

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