Neonatal necrotizing enterocolitis: Management and prognosis

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 intestinal wall and portal venous system. Although early recognition and aggressive treatment of this disorder have improved clinical outcomes, NEC accounts for substantial long-term morbidity in survivors of neonatal intensive care, particularly in very low birth weight (VLBW) preterm infants (BW <1500 g and gestational age [GA] <32 weeks).

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

OVERVIEW — Management of NEC encompasses medical management for all patients, and in some cases, surgical intervention. However, there is no clear evidence-based consensus on which patients require surgery, with the exception of those with evidence of bowel perforation. Most experts in the field continue to base decisions on the severity of illness using the modified Bell staging criteria (table 1). However, this commonly used classification schema, which is helpful in defining NEC for research and quality improvement purposes, has not been validated for clinical management, including for determining when surgery should be performed.

The following management approach is based on severity of disease:

●Supportive medical management alone is provided for patients with Bell stage I (unproven) and most cases of II (proven but not advanced disease) NEC.

●Surgical intervention is provided to patients with Bell stage III NEC (advanced disease and bowel perforation). Surgery is also performed in patients with Bell stage II who fail to respond to medical management [1]. (See 'Referral and indications for surgery' below.)

Care for the infant with (or suspected to have) NEC is best provided by a multidisciplinary team that includes surgical consultation to assist the neonatology team in the evaluation and management of the infant and decide if and when surgery is needed [1]. In centers where surgical care is not available, anticipatory transfer to a center with a higher level of care should be planned before infants are too unstable for transfer.

MEDICAL MANAGEMENT — Medical management for all infants with NEC should be initiated promptly when necrotizing enterocolitis (NEC) is suspected. It consists of the following:

●Supportive care

●Empiric antibiotic therapy

●Serial examinations and close laboratory and radiologic monitoring

Supportive care and antibiotic therapy are focused on limiting the progression of the disease and are initiated in all patients, including those who are likely to require surgical intervention. Serial examination and laboratory and radiologic studies monitor the course of the disease and are used to help determine whether there is clinical improvement or progressive deterioration.

Supportive care — Supportive care includes the following:

●Bowel rest with discontinuation of enteral feedings – Because patients with NEC have a loss of gut motility (ileus) due to bowel inflammation and bowel wall thickening, bowel rest (cessation of feeding) is an important element of management as it lessens the stress on the gut by limiting luminal content during a time of intestinal stasis. The typical duration of bowel rest parallels the antibiotic treatment course of 10 to 14 days. Enteral feedings are resumed gradually as the infant's clinical condition improves.

●Gastric decompression using intermittent nasogastric suction – Gastric decompression enhances bowel rest, and nasogastric suction is provided until the ileus resolves and pneumatosis is no longer seen on the abdominal radiograph.

●Total parenteral nutrition – During bowel rest, parenteral nutrition is required until adequate enteral feeds are resumed. This may require a central venous catheter to provide sufficient caloric intake. (See "Parenteral nutrition in premature infants".)

●Fluid replacement – Parenteral fluids are required to correct third space losses as transmural bowel inflammation invariably leads to capillary leak and loss of intravascular fluid. (See "Fluid and electrolyte therapy in newborns".)

●Cardiovascular and respiratory support – Assessment and support of both the cardiovascular (eg, inotropic support in addition to fluid replacement [resuscitation]) and respiratory systems (eg, supplemental oxygen and mechanical ventilation) as needed. Critically ill infants frequently require both cardiovascular and respiratory support. (See "Overview of mechanical ventilation in neonates" and "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn".)

●Other measures – Some infants may require additional correction of hematologic (eg, disseminated intravascular coagulation) and metabolic abnormalities (eg, metabolic acidosis). (See "Disseminated intravascular coagulation in infants and children", section on 'Management'.)

Antibiotic therapy — For all infants with suspected or established NEC, we suggest initiating broad-spectrum antibiotics after obtaining appropriate specimens for culture.

Rationale — Although antibiotic therapy has not been evaluated in clinical trials, it has been a mainstay of routine therapy for NEC based on clinical experience and the following observational data [2-6]:

●Documented bacteremia in 20 to 30 percent of NEC cases

●Recovery of pathogenic bacteria in pathologic specimens and peritoneal fluid from NEC cases

●Presence of intramural gas produced by pathogenic bacteria in the bowel

●Efficacy of antibiotic agents in experimental animal models for intra-abdominal sepsis and NEC

●Efficacy of enteral versus parenteral antibiotics in preventing NEC

●Evidence of altered gut microbiome prior to infants developing NEC

These issues are discussed in greater detail separately. (See "Neonatal necrotizing enterocolitis: Pathology and pathogenesis", section on 'Microbial dysbiosis' and "Neonatal necrotizing enterocolitis: Pathology and pathogenesis", section on 'Primary infection'.)

Choice and duration of antibiotic regimen

●Initial empiric antibiotic therapy – The empiric antibiotic regimen should provide broad-spectrum coverage, including coverage for common causes of late-onset neonatal sepsis, which are summarized in the table (table 2), and discussed in greater detail separately. (See "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation", section on 'Pathogens in LOS'.)

The choice is also guided by the local susceptibility patterns (ie, the local antibiogram in a particular neonatal intensive care unit [NICU]).

Acceptable empiric regimens include, but are not limited to, the following [7,8]:

•Ampicillin plus gentamicin (or amikacin) plus metronidazole

•Ampicillin plus gentamicin (or amikacin) plus clindamycin

•Ampicillin plus an expanded-spectrum cephalosporin (eg, cefotaxime [where available], ceftazidime, or cefepime) plus metronidazole

•Monotherapy with piperacillin-tazobactam

•Monotherapy with meropenem

Vancomycin should be included in the regimen (ie, replacing ampicillin or added to monotherapy) in centers where there is a high prevalence of methicillin-resistant Staphylococcus aureus (MRSA) or ampicillin-resistant enterococcal infections. Centers with significant gentamicin resistance patterns should consider amikacin in place of gentamicin.

We do not recommend the use of oral aminoglycosides because this treatment can result in the development of resistant bacterial strains, and has not been shown to be more beneficial than standard care [9,10].

While the use of broad-spectrum antibiotic therapy in this setting is widely accepted as standard practice, consensus is lacking regarding the preference for a specific regimen [11]. A systematic review of antimicrobial regimens did not show any regimen to be superior to ampicillin and gentamicin in decreasing mortality and preventing clinical deterioration in NEC [12]. In particular, it is uncertain whether anaerobic coverage is necessary. Based on available data, it is our practice to include anaerobic coverage routinely in the treatment of neonates with suspected or established NEC. Others include anaerobic coverage only when intestinal perforation is suspected (based on the presence of signs of peritonitis or radiologic evidence of pneumoperitoneum) [13]. In one retrospective multicenter cohort study, mortality rates and complication rates (ie, intestinal strictures) were similar between patients who received anaerobic antimicrobial therapy compared with matched controls who did not receive anaerobic antibiotic coverage [14]. Among infants who underwent a surgical procedure, mortality was lower in the group receiving anaerobic antimicrobial therapy (odds ratio 0.71, 95% CI 0.52-0.95). However, this study had some major limitations because matching was challenging, resulting in the exclusion of nearly 60 percent of the sample population.

●Suspected fungal infection – Fluconazole or amphotericin B should be used when fungal infection is suspected, as discussed separately. (See "Treatment of Candida infection in neonates", section on 'Invasive infection'.)

●Subsequent adjustments and duration – Antibiotic regimens are modified based upon the results of cultures of blood, peritoneal fluid, or surgical specimens. For cases of Bell stage 1 NEC, due to the wide variation in presentations, we may choose to stop antibiotics early and resume feeds depending on the course of the disease (table 1). For Bell stage 2 or above, even if culture results are negative, we continue therapy to complete a course of antibiotics for a total of 10 or 14 days. A 10- to 14-day course usually is sufficient unless the course is complicated by abdominal abscess formation. (See 'Rare complications' below.)

Monitoring response to therapy — Serial physical examination, and laboratory and radiologic studies monitor the course of the disease and are used to help determine whether there is clinical improvement or deterioration. If there is considerable progression of disease with a failure to respond to medical management, surgical intervention may be considered.

Serial physical examinations — Careful serial physical evaluations are an essential part of the management of suspected NEC since the clinical signs of NEC may change rapidly. In particular, recognizing changes in vital signs (increased heart rate and respiratory rate, variability in blood pressure) and the abdominal examination may indicate progression of illness and prompt earlier radiologic and surgical assessment. Changes that suggest possible bowel perforation, such as abdominal erythema or bruising, marked abdominal distension, and increased tenderness should lead to further urgent evaluation and therapeutic changes in management. The frequency of exams should be guided by the infant's clinical course and rate of NEC progression. Abdominal examinations are generally performed every two hours. However, any major changes in heart rate and respiratory patterns, and/or blood pressure should prompt further evaluation, including abdominal examination, laboratory testing and imaging studies, and increased frequency of abdominal examinations.

Laboratory monitoring — Laboratory monitoring depends upon the results of the initial evaluation and the clinical condition of the infant. Once NEC is suspected (Bell stage I) or the diagnosis is established (Bell stage II and III), we obtain a complete blood count and differential, platelet count, serum electrolyte and creatinine measurements, blood urea nitrogen, and acid-base studies that include lactate levels. These tests are repeated every 12 to 24 hours depending on the severity of the illness. (See "Neonatal necrotizing enterocolitis: Clinical features and diagnosis", section on 'Laboratory evaluation'.)

Low platelet count, metabolic acidosis, low monocyte count, and increased blood glucose are associated with NEC. If these studies are initially abnormal, normalization suggests improvement in the infant's condition and response to medical therapy. Conversely, persistently abnormal or worsening results suggest failure to respond to medical therapy and potential deterioration of the patient's clinical condition. Specific abnormalities, such as thrombocytopenia, may require more frequent testing to evaluate the need for and response to treatment.

In our center, we use a conservative threshold for platelet transfusion (platelet count below 25,000 counts/mL), as concerns have been raised for higher thresholds as well as potential risk of the accumulation of proinflammatory mediators in stored platelets [15-17]. (See "Neonatal thrombocytopenia: Clinical manifestations, evaluation, and management", section on 'Platelet transfusion'.)

Some clinicians monitor stools for blood to follow the course of the disease but there is no confirmatory evidence that this approach is predictive of outcome. In our center, we have not found monitoring stools for blood helpful for ongoing management decisions.

Abdominal imaging

Radiography — Although abdominal radiographic monitoring is a relatively insensitive guide to the diagnosis and progression of the disease (image 1), serial studies are used to assist in ongoing evaluation of bowel viability and dysfunction in conjunction with the clinical monitoring described above. We obtain an abdominal radiograph in the supine position every 6 to 12 hours during the initial phase of illness, and more frequently if there are physical signs suggesting further clinical deterioration.

Radiologic views that can be obtained depending on the status of the infant include the following.

●Anterior-posterior [AP].

●Lateral decubitus to detect free air – The infant is placed on their left side down in order to visualize the presence of free air over the liver.

●Supine cross-table lateral view – If the infant does not tolerate being moved and pneumoperitoneum is suspected, a supine cross-table lateral view is substituted to detect the presence of free air.

●Orthogonal views (right angle, and lateral views) – To identify fixed (sentinel) loops, in addition to the AP view.

Radiographic features that are monitored for progression of disease include increasing bowel distension, especially fixed dilatation (sentinel loop) which is highly suspicious for threatened bowel perforation, increased bowel wall thickening, presence of ascites, and frank perforation. Infants with severe intestinal inflammation may have a radiographic appearance of a gasless abdomen. This may conceal other changes, including occult bowel perforation and extensive tissue necrosis.

Radiographic changes are a component of Bell staging (table 1):

●Stage I – Normal dilatation, mild ileus

●Stage II

•Stage II A – Intestinal dilatation, ileus, pneumatosis intestinalis

•Stage II B – Same as II A plus ascites

●Stage III

•Stage III A – Same as stage II A plus ascites

•Stage III B – Same as II A plus ascites and pneumoperitoneum

Improvements in the abdominal radiograph typically correlate with improvements in other clinical signs and symptoms. For these patients, radiographs are obtained less frequently and discontinued when there is resolution of pneumatosis intestinalis and bowel gas pattern normalizes.

Ultrasonography — Ultrasonography is used at some centers as a supplement to serial radiography, however, it is not universally due to the shortage of adequately trained ultrasonographers. Ultrasonography provides real-time information regarding bowel architecture and function including bowel wall thickness, distension, regional blood flow, and detection of pneumatosis intestinalis, free fluid, and non-viable bowel loops infants with NEC [18]. The dynamic nature of bowel ultrasound can assess motility and perfusion, which is not detected by static imaging. As a result ultrasound may be useful to identify patients with severe necrosis who are at risk for bowel perforation and are candidates for surgical intervention (figure 1) [19]. In our center, ultrasound is used to monitor changes in bowel structure (bowel wall thickness/distention) and function. (See "Neonatal necrotizing enterocolitis: Clinical features and diagnosis", section on 'Abdominal ultrasonography'.)

SURGICAL MANAGEMENT — The goals of surgical intervention are to remove unviable necrotic intestine and control enteric spillage while maximizing the length of viable intestine [1].

Referral and indications for surgery — The decision and timing of surgical intervention in a critically ill neonate requires considerable judgment. Consultation with a pediatric surgeon should be requested at the time when the diagnosis of NEC is suspected or confirmed. The decision for surgical intervention is made collaboratively by the multidisciplinary team, with input from the neonatology team, surgeon, and others involved in care.

In our center, we determine the need for surgical intervention by assessing the response to medical therapy as follows:

●We make a global assessment of the infant, considering physical findings (eg, hypotension, abdominal mass), laboratory findings (persistent thrombocytopenia and acidosis), and imaging findings (eg, new finding of ascites, fixed loop of bowel, and including ultrasonographic signs of decreased or absent peristalsis and diminished intestinal perfusion) that indicate a poor or no response to medical therapy.

●We serially monitor the abdominal ultrasound to assess for changes in bowel structure, motility, and perfusion. Other centers may use serial abdominal radiographs for this purpose. The advantages of serial ultrasound imaging include reduced radiation exposure and better detail regarding perfusion and changes in the bowel wall [18]. Use of this modality in managing neonates with NEC is steadily increasing. (See 'Ultrasonography' above.)

●Surgical intervention is performed when there is evidence of perforation (ie, pneumoperitoneum on abdominal imaging) or if the neonate continues to clinically deteriorate despite optimal medical management.

Evidence of pneumoperitoneum on abdominal imaging indicates intestinal perforation due to severe necrosis. This finding is a clear indicator that surgical intervention is warranted. However, detecting intestinal perforation is not straightforward, as perforation can occur without evidence on abdominal radiograph [1,20,21].

Surgery is also appropriate for infants with severe irreversible necrosis who are at high risk for perforation or other severe complications of NEC. However, in clinical practice, it is difficult to identify such infants. Based on clinical experience, it is presumed these patients have continued clinical deterioration despite maximal medical support.

It would be desirable to identify at-risk patients for perforation. Some risk factors such as low gestational age, no antenatal corticosteroids, early onset of NEC, and low serum bicarbonate, have been associated with a greater chance of developing NEC requiring surgery [22,23]. However, no single indicator has been shown to be sensitive and specific enough to accurately identify at-risk patients who require surgical intervention. As a result, clinical scoring systems that include multiple indicators have been developed to better define "clinical deterioration" and identify patients with irreversible severe necrosis [21,24,25]. Studies using these scoring systems report that patients with multiple persistent clinical (eg, abdominal erythema, palpable abdominal mass, hypotension), radiologic (eg, fixed bowel loop and severe pneumatosis intestinalis) and laboratory abnormalities (eg, positive blood culture, acidosis, bandemia, thrombocytopenia, hyponatremia, or neutropenia) are most likely to need surgical intervention [21,24,25]. However, further prospective studies are required to validate these scoring systems in the absence of pneumoperitoneum prior to recommending their routine use in clinical care.

Procedures

Choice of surgical procedure — Surgical procedures for treatment of NEC include:

●Exploratory laparotomy with resection of the affected intestinal region(s) (see 'Laparotomy' below), or

●Primary peritoneal drainage (PPD) (see 'Primary peritoneal drainage' below)

The choice of intervention varies among institutions and is based on the clinical experience and preferences of the surgical staff and center. Although laparotomy is more commonly performed, the available evidence suggests that outcomes are comparable with either approach. (See 'Comparison of procedures' below.)

In our practice, when the decision is made to proceed with surgical intervention, the preferred procedure typically consists of primary exploratory laparotomy with creation of stomas for the recovering bowel. Infants who are too unstable to undergo laparotomy are managed with PPD, which can be performed at the bedside. Most infants who initially undergo PPD require a subsequent surgery (when stable) to remove nonviable bowel and create stomas for the recovering bowel.

Neonates who undergo surgery should also receive ongoing medical management, including supportive care and antibiotics. (See 'Medical management' above.)

After the infant has successfully undergone surgery and is improving clinically, a contrast enema is obtained to evaluate for stricture formation prior to initiating feeds. This is particularly important in infants managed with PPD alone because their bowel will not have been visually examined. If feeding problems arise during follow up, the infant should be evaluated for bowel stricture. (See 'Stricture formation' below.)

For patients who fail to respond appropriately after initial surgical intervention and optimal medical care, additional surgical intervention may be needed to remove residual necrotic bowel.

Laparotomy — Laparotomy usually involves resection of the affected bowel segment (picture 1), and placement of a proximal enterostomy (usually an ileostomy) and distal mucous fistula. It usually requires transport to the operating room and general anesthesia. Most infants will require reanastomosis, which is usually performed four to six weeks after the initial procedure, depending upon the infant's clinical condition. A contrast enema is generally performed before the reanastomosis to detect intestinal strictures. (See 'Stricture formation' below.)

If NEC affects only a short segment of bowel and the resection is limited, some surgeons perform a primary anastomosis. This procedure avoids the development of complications associated with ileostomies, including fluid and electrolyte abnormalities, delayed resumption of oral feedings, poor growth, stenosis of the enterostomy site, and a second surgical procedure for reanastomosis. An alternative approach is placement of a peritoneal drain instead of resection and enterostomy [26].

When a substantial length of bowel is affected, resection is restricted to segments of definite necrosis or perforation to avoid the risk of short bowel syndrome. If the potential viability of some segments is uncertain, one approach is to place peritoneal drains and plan a second operation in two to three days to reexamine the bowel and excise necrotic segments.

Primary peritoneal drainage — PPD is performed at the bedside in the neonatal intensive care unit (NICU). The primary purpose of this procedure is to provide pressure relief with some evacuation of air and stool contaminated ascites, as well as gaining additional time to allow some bowel to recover before resection of nonviable bowel. In particular, PPD may be the preferred initial surgical procedure in extremely low birth weight (ELBW) infants (BW <1000 g), who tend to be sicker, because it can be performed at the bedside under local anesthesia. PPD is associated with somewhat higher mortality than laparotomy, perhaps because PPD is typically performed in the sickest patients who cannot be transported to the operating room [27].

After the administration of pain medication, the abdomen is prepped and local anesthesia is administered. A small transverse incision is made at McBurney's point (midway between the umbilicus and the anterior superior iliac crest in the right lower quadrant). The layers of the abdominal wall are bluntly dissected to enter the peritoneal cavity. In many cases, there will be a rush of air and the presence of meconium encountered. Cultures are taken, the peritoneal cavity is copiously irrigated with warm saline solution, and a Penrose drain is gently threaded into the abdomen and secured.

The drain site is observed over the subsequent days. When there is no evidence of persistent intestinal or meconium drainage from the drain site, the drain is backed out daily until it is removed. After the return of bowel function, a trial of feeding can be started or the patency of the gastrointestinal tract can be determined with a contrast study.

Comparison of procedures — The available data, including ameta-analysis, suggest that the two surgical procedures (primary laparotomy and PDD) result in comparable outcomes [28-35]. Thus, the choice of intervention is based upon the expertise of the surgical staff and center.

The largest trial examining this question was the Necrotizing Enterocolitis Surgery Trial (NEST), in which 310 neonates were randomized to initial laparotomy or PPD [34]. Mortality was similar in both groups (28 and 30 percent, respectively). Among survivors, rates of neurodevelopmental impairment (NDI) at 18 to 22 months corrected age were also similar in both groups (54 and 53 percent, respectively). However, in a prespecified subgroup analysis, laparotomy was associated with a nonsignificant trend towards lower rates of death or NDI in neonates whose preoperative diagnosis was NEC (adjusted relative risk [aRR] 0.81, 95% 0.64-1.04); whereas there was no apparent advantage of laparotomy over PDD in neonates whose preoperative diagnosis was isolated intestinal perforation (aRR 1.11, 95% CI 0.95-1.31). Surgical management of isolated intestinal perforation is discussed separately. (See "Spontaneous intestinal perforation of the newborn", section on 'Surgical treatment'.)

A meta-analysis reported similar rates of mortality between PPD and laparotomy as initial surgical interventions [35]. An earlier systematic review and meta-analysis identified two trials (185 infants) comparing laparotomy and PPD and found no differences in mortality within 28 days of the primary procedure (RR 0.99, 95% CI 0.64-1.52) or at 90 days (RR 1.05, 95% 0.71-1.55) [28-30]. Approximately one-half of the PPD group failed to improve and subsequently underwent laparotomy.

Observational studies have also reported similar mortality rates in infants undergoing laparotomy or PDD [32,33]. In one study, PPD was associated with an increased risk of NDI at 18 to 22 months postmenstrual age [32]. However, given the observational nature of the study, this finding could be explained, at least in part, by selection bias (ie, sicker patients were more likely to undergo PDD).

COMPLICATIONS

Acute complications — NEC is associated with the following significant complications during the acute stage of the disease and immediate post-recovery stage.

●Infectious complications – Sepsis, meningitis, peritonitis, and abscess formation

●Disseminated intravascular coagulation, which contributes to intestinal or extraintestinal bleeding

●Respiratory and cardiovascular complications – Hypotension, shock, and respiratory failure

●Metabolic complications – Hypoglycemia and metabolic acidosis

Late gastrointestinal complications — The most common late gastrointestinal complications of NEC are intestinal narrowing (ie, due to stricture formation) and short bowel syndrome.

In particular, gastrointestinal complications are frequent in survivors who underwent surgery for NEC. In a review of the literature of gastrointestinal sequelae in 4260 patients surviving surgery for NEC, the following findings and frequency were noted [36]:

●Strictures – 24 percent (95% CI 17-31 percent)

●Intestinal failure – 13 percent (95% CI 3-15 percent)

●Recurrent NEC – 8 percent (95% CI 7-19 percent)

●Adhesion ileus – 6 percent (95% CI 4-9 percent)

Stricture formation — Although some areas of intestinal narrowing resolve spontaneously, others become more stenotic and form strictures, which require surgical resection.

Intestinal strictures occur in 9 to 36 percent of infants treated medically or surgically and are unrelated to the severity of NEC, the presence of pneumatosis intestinalis, or gestational age (GA) [22,37-40]. The majority of strictures occur in the colon, although the ileum and jejunum also are affected, and strictures at multiple sites are common [41]. Strictures typically develop within two to three months of the acute episode, but are sometimes detected as late as 20 months.

Infants with intestinal strictures may also develop bacterial overgrowth in the small bowel. As a result of bacterial overgrowth and the strictures themselves, patients may have repeated infections, bloody stools, failure to thrive, and symptoms of bowel obstruction.

Strictures are more common following enterostomy compared with primary anastomosis [36]. As a result, contrast enemas are performed to detect intestinal narrowing or strictures before closure of an enterostomy and reanastomosis of the bowel (typically performed four to six weeks after the acute episode of NEC), or if feeding intolerance develops [22,42,43].

Short bowel syndrome — Neonatal short bowel syndrome, defined as less than 25 percent of the normal small bowel length [44], occurs in approximately 9 percent of infants who undergo surgery for NEC, and results in significant malabsorption [38]. The incidence of short bowel increases with decreasing GA [45].

NEC is the most common cause of neonatal onset intestinal failure due to short bowel syndrome [46]. These infants are also at risk for sepsis [47] and intestinal failure-associated liver disease due to the chronic need and administration of total parenteral nutrition. Intestinal and liver transplantations have been performed as life-saving procedures in patients with these complications. The pathophysiology, management, and complications of short bowel syndrome are discussed separately. (See "Pathophysiology of short bowel syndrome" and "Management of short bowel syndrome in children" and "Chronic complications of short bowel syndrome in children".)

In a multicenter prospective study, the following factors predicted increased risk of short bowel syndrome in infants following surgery for NEC [48]:

●Parenteral antibiotics on the day NEC is diagnosed.

●Birth weight (BW) <750 g.

●Mechanical ventilation on the day NEC is diagnosed.

●Exposure to enteral feeds before the diagnosis of NEC.

●Substantial small bowel resection, as measured by a composite score based upon the actual percentage of small bowel resected, whether a diverting jejunostomy was created, and the duration of its use.

Rare complications — Rare complications of NEC include enterocele, enterocolic fistula, and intra-abdominal abscess.

OUTCOME

Mortality — Advances in neonatal intensive care, earlier diagnosis, and aggressive treatment have improved the outcome of infants with NEC. However, NEC accounts for approximately 10 percent of deaths of infants cared for in neonatal intensive care units [27,49]. In a systematic review of the literature, the overall mortality rate for infants with confirmed NEC (Bell stage II and III) (table 1) was 23.5 percent [49]. The risk increased for infants who underwent surgery (40 percent mortality) and extremely preterm (EPT) infants (gestational age <28 weeks) (51 percent mortality).

Preterm infants — Mortality increases with decreasing gestational age and for those who undergo surgical intervention [27,45,49-52]. The mortality is greatest for EPT infants who undergo surgery with a death rate of 50 percent [49].

The increase in mortality rate due to increased prematurity was demonstrated by a retrospective study from the Vermont Oxford Network [50]. In this study, 71,808 preterm infants who were born between January 2005 and December 2006 were divided by 250 g increments into four weight categories. The risk of NEC and mortality in patients with NEC decreased with increasing BW as follows:

●Birth weight (BW) 501 to 750 g – 12 percent risk, 42 percent mortality with NEC

●BW 751 to 1000 g – 9 percent risk, 29 percent mortality with NEC

●BW 1001 to 1250 g – 6 percent risk, 21 percent mortality with NEC

●BW 1251 to 1500 g – 3 percent risk, 16 percent mortality with NEC

In addition to lower BW, earlier gestation, and surgical intervention, other reported risk factors include mechanical ventilation, treatment with vasopressor agents, and Black ethnicity [53]. Risk factors for fulminant disease (rapid progression to death within 48 hours of onset) included portal venous air, anemia, rapid feeding escalation, a high immature to total (I/T) neutrophil ratio, a low lymphocyte count [54].

Term infants — Retrospective data show a reported mortality rate of 11 percent for infants with NEC and BWs >2500 g [55]. The relatively high mortality in these infants is attributed to associated risk factors, which include major congenital anomalies, chromosomal abnormalities, and sepsis.

Long-term sequelae — Approximately one-half of survivors of NEC have no long-term sequelae. However the remaining survivors may have impaired growth and neurodevelopmental outcomes, as well as gastrointestinal complications [49,56]. (See 'Late gastrointestinal complications' above.)

●Sequelae in relation to NEC treatment — Although the literature is conflicting on whether medically or surgically treated NEC leads to better long-term outcomes overall, it seems that long-term complications are more common in surgically treated infants than in those treated medically.

•Growth – In general, infants treated surgically have poorer outcomes than those treated medically. Infants who have persistent stomas after discharge are at higher risk of growth impairment [57]. However, the literature remains uncertain if NEC treated either surgically or medically is associated with poor long-term growth for extremely low birth weight (ELBW) infants (BW <1000 g).

In a large multicenter study from the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network, ELBW infants who underwent surgery were more likely to have significant growth delay compared with infants without NEC [58]. ELBW infants who were medically treated did not differ in growth compared with those without NEC.

In contrast, data from the Vermont Oxford Network showed that rates of severe growth failure (defined as <3^rd percentile weight-for-age) were higher among infants with NEC treated either medically (56 percent) or surgically (61 percent) compared with those without NEC (36 percent) [59]. By 18 to 24 months follow-up, rates were similar for the three groups, although one-quarter of the cohort had severe growth failure.

•Neurodevelopmental impairment – Survivors of NEC treated either medically or surgically are at risk for impaired neurodevelopmental outcome detectable up to school age [49,58,60-63]. In systematic reviews, infants with NEC were twice as likely to be developmentally impaired compared with age-matched controls without NEC [60,62,64]. Infants with NEC were at increased risk for cerebral palsy, and cognitive and severe visual impairment. Patients who were surgically treated had poorer neurodevelopmental outcome than those treated medically.

Results from a small study of 48 preterm infants (gestational age <30 weeks) suggested that the poorer neurodevelopmental outcome associated with NEC may be related to lower cerebral tissue oxygenation throughout the neonatal intensive care unit stay [65]. However, further investigations are needed to verify these findings and determine if there is any causality.

•Functional gastrointestinal disorders – An observational study reported that survivors of NEC have a higher incidence of functional gastrointestinal disorders later in childhood, particularly constipation, compared with preterm counterparts who did not have NEC [66].

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SUMMARY AND RECOMMENDATIONS

●Management approach – The management of necrotizing enterocolitis (NEC) depends upon the severity of illness (table 1). Care for the infant with suspected or established NEC is provided by a multidisciplinary team, which includes surgical consultation that assists the neonatology team in the evaluation and management of the infant. (See 'Overview' above.)

●Medical management – Medical management should be initiated promptly when NEC is suspected (see 'Medical management' above):

•Supportive care – Supportive care includes bowel rest with discontinuation of enteral intake, gastric decompression with intermittent nasogastric suction, initiation of parenteral nutrition, correction of metabolic, fluid/electrolyte, and hematologic abnormalities, and stabilization of the cardiac and respiratory function. (See 'Supportive care' above.)

•Antibiotic therapy – For all infants with suspected or established NEC, we suggest initiating antibiotics after obtaining appropriate specimens for culture (Grade 2C). The empiric regimen should provide broad-spectrum coverage taking into consideration resistance patterns at the individual institution. Acceptable regimens include any of the following (see 'Antibiotic therapy' above):

-Ampicillin plus gentamicin (or amikacin) plus metronidazole

-Ampicillin plus an expanded-spectrum cephalosporin (eg, cefotaxime [where available], ceftazidime, or cefepime) plus metronidazole

-Ampicillin plus gentamicin (or amikacin) plus clindamycin

-Monotherapy with piperacillin-tazobactam

-Monotherapy with meropenem

Vancomycin should be included in the regimen (ie, replacing ampicillin or added to monotherapy) in centers where there is a high prevalence of methicillin-resistant Staphylococcus aureus (MRSA) or ampicillin-resistant enterococcal infections.

•Ongoing monitoring – The clinical status is monitored to see if the patient responds to medical management, or if NEC continues to progress, and to determine if (and when) surgical intervention is required. Monitoring entails serial physical examinations and abdominal radiographs, and ongoing laboratory testing (eg, white cell and platelet count, and serum bicarbonate and glucose measurements). (See 'Monitoring response to therapy' above.)

●Surgical management – Surgical intervention is required either when intestinal perforation occurs or when there is unremitting clinical deterioration despite medical management, which suggests extensive and irreversible necrosis. Limited data suggest that the two available surgical procedures (primary laparotomy (picture 1) and primary peritoneal drainage [PPD]) have similar results. As a result, the choice of intervention is based on the expertise and preference of the surgical staff at the center. In our center, primary laparotomy is the initial surgical intervention for NEC, but PPD at the bedside is sometimes performed, especially in extremely low birth weight (ELBW) infants (BW <1000 g) who are hemodynamically unstable. (See 'Surgical management' above.)

●Outcome – Prognosis of NEC has improved with earlier recognition and treatment, with survival rates of approximately 70 to 80 percent of affected infants. The risk of death increases with decreasing gestational age. Long-term, approximately one-half of the survivors have no significant sequelae. For the remainder, long-term sequelae include gastrointestinal complications (eg, short bowel syndrome, intestinal strictures, and increased frequency of bowel movements with loose stools, functional gastrointestinal disorders) and impairment of growth and neurodevelopmental outcome. (See 'Outcome' above and 'Complications' above.)

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