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Treatment of almost all medical conditions has been affected by the COVID-19 pandemic. NICE has issued rapid update guidelines in relation to many of these. This guidance is changing frequently. Please visit https://www.nice.org.uk/covid-19 to see if there is temporary guidance issued by NICE in relation to the management of this condition, which may vary from the information given below.
What is necrotising enterocolitis
First described over a century ago, necrotising enterocolitis (NEC) is now the most common gastrointestinal emergency occurring in neonates. Prematurity and low birth weight are the most important risk factors.
- Necrotising enterocolitis mainly affects premature infants who, having survived a difficult neonatal period, then confront a disease with high morbidity and mortality.
- With obstetric advances more infants of very low birth weight (VLBW) survive the neonatal period, increasing the population at risk of NEC.
NEC is rare in term babies as a whole; however, these account for 10% of cases. In term babies, the initiating events are different and it it often associated with underlying disorders.
The diagnosis and treatment of this condition remain very difficult and challenging.
- It is estimated that it affects 5-7% of all preterm neonates but 10-12% of infants born weighing less than 1500 g (VLBW)[1, 2].
- In a 2017 UK study, the incidence of NEC was 11% in those born at 24 weeks of gestation and decreased to 0.5% for infants born at 31 weeks of gestation.
- Full-term and near-term infants also develop the disease but much less often.
A recent systematic review on the incidence of NEC in high-income countries found variation in the incidence of the disease based on GA, birth weight, and country.
Overall, NEC incidence was highest among the most preterm infants. In infants born at a gestational age (GA) of <28 weeks, the lowest reported incidence of NEC was in Japan (2%) and the highest in Australia, Canada, and Italy (7-9%). In neonates with a GA of between 28 and 31 weeks, reported NEC incidence was also lowest in Japan (0.2%), while other developed nations had incidence rates ranging from 2-3%. Similarly, for VLBW infants, NEC incidence ranged from 2% in Japan to 6-7% in the USA and 9% in Poland.
- Maternal risk factors include illicit drug abuse, infection with chorioamnionitis, and HIV-positive status.
- Fetal factors in addition to prematurity and low birth weight include congenital abnormalities, especially those affecting the heart and/or GI, such as congenital heart disease, patent ductus arteriosus, and gastroschisis. Gut dysbiosis is also thought to be important and this is a disruption of gut microbiota development and its homeostasis. This pathological process involves a lack of beneficial commensal microbes combined with a low diversity of bacteria, which allows the overgrowth of pathogenic bacteria that induce an inflammatory response
- Risk factors that occur during birth include low flow and perfusion states due to perinatal events, such as placental abruption, leading to neonatal shock which is characterised by hypovolaemia and academia.
- Neonatal care factors include respiratory support, feeding type, and pharmacological interventions. Studies have also shown that breast milk feeding is protective and when maternal breast milk is unavailable, preterm formula, compared to donor breast milk, increases the risk of NEC (RR 2.61).
In full-term infants, NEC is usually associated with predisposing or underlying disorders:
- Perinatal asphyxia.
- Respiratory distress.
- Congenital anomalies (myelomeningocele, congenital heart disease).
- Cow's milk protein-induced enterocolitis and glucose-6-phosphate dehydrogenase deficiency have been mooted as possible pathophysiological mechanisms.
Necrotising enterocolitis pathophysiology
NEC pathophysiology is generally thought to be multi-factorial; in addition to the common risk factors that include low gestational age at birth, low birth weight, chorioamnionitis, and mechanical ventilation, there are many more that are implicated. Research has uncovered risk factors such as genetic predisposition, intestinal immaturity, changes in microvascular tone, and abnormal microbial colonisation. Although no studies have found a clear genetic phenotype associated strongly with NEC, studies have also found a familial predisposition for the disease.
Preterm neonates are also more susceptible to intestinal injury due to the underdeveloped nature of their intestine. Specifically, preterm neonates lack several GI defence mechanisms such as gastric acid, digestive enzymes, production of mucus, peristalsis, and polymeric immunoglobulin A (IgA).
The classical form of NEC usually occurs in preterm neonates, most commonly in the third week of life. The signs are often highly variable, nonspecific and subtle.
In premature babies there is often a history of initially making progress on enteral feeding. There is an increase in necrotising enterocolitis incidence after blood transfusion for asymptomatic anaemia. Feeding difficulties may be noted by nursing staff and there may be concerns about vomiting or abdominal distension.
- Abdominal distension with increasing gastric aspirates.
- Visible intestinal loops.
- Altered stool pattern.
- Bloody mucoid stool and bilious vomiting.
- Decreased bowel sounds with erythema of the abdomen.
- Palpable abdominal mass or ascites.
- Associated features are bradycardia, lethargy, shock, apnoea, respiratory distress, and temperature instability.
GutCheckNEC is a toolkit designed to create a composite risk score for NEC and was designed using a cohort of over 58,000 infants. It found that there were nine independent risk factors for developing NEC.
- Haemolytic disease of the newborn.
- Swallowed maternal blood.
- Pseudomembranous colitis.
- Stress ulcer.
- Meconium ileus.
- Metabolic or respiratory acidosis.
- Apnoea or prematurity.
- Coarctation of the aorta.
- Enteroviral infection.
- Gastro-oesophageal reflux.
- Hirschsprung's disease.
- Hospital-acquired infections.
- Hypoplastic left heart syndrome.
- Bacterial meningitis.
- Urinary tract infection.
- Focal intestinal perforation.
- Blood laboratory tests are nonspecific but cultures, FBC, blood gas and baseline biochemistry should be taken and monitored 12-hourly (blood tests) and 4-6 hourly (blood gases/lactates):
- Severe or persistent thrombocytopenia, neutropenia, coagulopathy or acidosis indicate severe disease.
- Serial C-reactive protein may be useful, with persistently high levels associated with complications (stricture, abscess).
- Blood gases may assist in the diagnosis of respiratory distress or acute lactic acidosis.
- Diagnosis is confirmed by abdominal X-ray (AXR) - supine and decubitus/erect - and should be performed as soon as the diagnosis is suspected. Serial abdominal films are taken. Bowel wall thickening, persistent bowel loops that are filled with gas, and overall gaseous distention may suggest NEC but these X-ray findings are not specific.
- Ultrasound scanning may also be useful and have some advantages over X-ray as it can depict bowel wall thickness and echogenicity, free and focal fluid collections, peristalsis, and the presence or absence of bowel wall perfusion using Doppler imaging. An additional benefit is the absence of ionising radiation.
- Other imaging techniques being developed include contrast radiography, portal vein ultrasonography, MRI and radionuclide scanning.
- Modern technology has aided the discovery of numerous proteins and other products of metabolism that are capable of differentiating between NEC and non-NEC conditions, with some of them being able to predict NEC development, days and weeks prior to the appearance of clinical manifestations. However, so far, there is no consensus among researchers for a distinct metabolomic/proteomic profile specific for NEC, due to the significant inconsistency of findings among studies.
- Stage I - suspected NEC:
- Systemic: nonspecific signs such as temperature instability, lethargy, apnoea, bradycardia.
- Gastrointestinal tract (GIT): gastric residuals, occult blood in stool.
- AXR: normal/nonspecific changes.
- Stage IIA - definite and mild NEC:
- Systemic: nonspecific signs.
- GIT: abdominal distension ± tenderness, absent bowel sounds, frank blood in stool.
- AXR: ileus, focal pneumatosis intestinalis.
- Stage IIB - definite and moderate NEC:
- Systemic: mild acidosis, thrombocytopenia.
- GIT: abdominal wall oedema, tenderness ± mass.
- AXR: extensive pneumatosis intestinalis, early ascites, ± intrahepatic portal gas.
- Stage IIIA - advanced NEC:
- Systemic: respiratory/metabolic acidosis, apnoea, hypotension, decreasing urine output, leukopenia, disseminated intravascular coagulation (DIC).
- GIT: spreading oedema, erythema, induration of the abdomen.
- AXR: prominent ascites ± persistent sentinel loop, no perforation.
- Stage IIIB - advanced NEC:
- Systemic: deteriorating vital signs, shock, electrolyte imbalance.
- GIT and AXR: signs of perforation.
- Nil by mouth to rest the bowel.
- Nasogastric or orogastric tube to decompress the bowel with low intermittent orogastric suction.
- Intravenous (IV) fluids, total parenteral nutrition (TPN) and triple IV antibiotics for 10-14 days according to local guidance.
- Antifungals should be considered for babies who have recently been on lengthy courses of antibiotics or are not responding to antibiotic treatment.
- Consider analgesia - paracetamol and/or morphine.
- Upper gastrointestinal small bowel follow-through is sometimes performed therapeutically in resolving NEC where intestinal obstruction develops as a result of a fibrous band or stricture.
- Paracentesis for ascites may be necessary.
- Treat shock, DIC, etc. Very ill babies may benefit from blood pressure support with vasopressors (eg, naloxone, dopamine).
- Surgery if a deteriorating or perforated/necrotic bowel is suspected (eg, free air on abdominal radiography). Up to 50% of infants with severe NEC will need surgical intervention.
- Peritoneal drainage appears to be of equal effectiveness to laparotomy, although further research is needed.
- Intubation/ventilation for apnoea.
- Oral feeds can be restarted 7-10 days after pneumatosis clears.
There is substantial long-term morbidity in survivors, especially those with a birth weight of <1500 g; namely intestinal failure and functional neurodevelopmental delay, which contribute significantly towards increased health needs.
- Perforation. Where severe disease causes full-thickness destruction of the intestinal wall which leads to perforation and peritonitis, mortality approaches 100%.
- Acquired short bowel syndrome (following surgery).
- Stoma-related complications.
- Sepsis and shock.
- Intestinal strictures (~30%).
- Enterocolic fistulae.
- Abscess formation.
- Recurrent NEC (rare)
- Iatrogenic complications - eg, central venous catheter-related thrombotic events and nosocomial infections, metabolic complications secondary to prolonged hyperalimentation (a nutrient mixture given to premature babies before giving milk).
- In neonates with NEC who require surgery to resect the perforated portions of bowel, the mortality rate is estimated between 20% and 30%, the highest mortality rate is foundamong neonates requiring surgery.
There is another NEC that affects older children and adults. It is known by different local names over the globe (for instance, 'Darmbrand' in Germany and 'pigbel' in Papua New Guinea).
- Occurring either sporadically or in epidemics, it is thought to be due to food contaminated with different strains of Clostridium perfringens (type A for most sporadic cases and probably type C for larger outbreaks).
- The disease course usually involves abdominal pain, vomiting, fever and bloody diarrhoea. In severe cases, shock follows and the mortality rates can be very high (30-100%).
- Treatment follows the same principles as the neonatal form (bowel rest, antibiotics +/- surgery) but would depend on available local medical and surgical services.
Feeding with human milk is known to be an effective intervention in the prevention of NEC. Other interventions have a limited evidence base but have focused on reducing the multiple contributing factors in a susceptible host.
A 2020 summary of evidence from systematic reviews of randomised controlled trials (RCTs) showed moderate certainty evidence for a reduction in NEC following administration of a combination of species of probiotics, probiotics (any), antenatal corticosteroids in pregnant women at risk of preterm birth, and ibuprofen versus indomethacin for treatment of patent ductus arteriosus (PDA). For surgical NEC, moderate certainty evidence showed an increased risk with lower (85-89%) oxygen saturation target levels, compared with higher (91-95%) oxygen saturation target levels.
There has been a lot of research on how to feed neonates with NEC but a 2021 Cochrane review reported that there was poor evidence to support the use of small increments (<24 ml/kg/day) when increasing feeds.
Further reading and references
Meister AL, Doheny KK, Travagli RA; Necrotizing enterocolitis: It's not all in the gut. Exp Biol Med (Maywood). 2020 Jan245(2):85-95. doi: 10.1177/1535370219891971. Epub 2019 Dec 6.
Battersby C, Santhalingam T, Costeloe K, et al; Incidence of neonatal necrotising enterocolitis in high-income countries: a systematic review. Arch Dis Child Fetal Neonatal Ed. 2018 Mar103(2):F182-F189. doi: 10.1136/archdischild-2017-313880. Epub 2018 Jan 9.
Battersby C, Longford N, Mandalia S, et al; Incidence and enteral feed antecedents of severe neonatal necrotising enterocolitis across neonatal networks in England, 2012-13: a whole-population surveillance study. Lancet Gastroenterol Hepatol. 2017 Jan2(1):43-51. doi: 10.1016/S2468-1253(16)30117-0. Epub 2016 Nov 8.
Pammi M, Cope J, Tarr PI, et al; Intestinal dysbiosis in preterm infants preceding necrotizing enterocolitis: a systematic review and meta-analysis. Microbiome. 2017 Mar 95(1):31. doi: 10.1186/s40168-017-0248-8.
Rose AT, Patel RM; A critical analysis of risk factors for necrotizing enterocolitis. Semin Fetal Neonatal Med. 2018 Dec23(6):374-379. doi: 10.1016/j.siny.2018.07.005. Epub 2018 Aug 1.
Ginglen JG, Butki N; Necrotizing Enterocolitis
Gephart SM, Wetzel C, Krisman B; Prevention and early recognition of necrotizing enterocolitis: a tale of 2 tools--eNEC and GutCheckNEC. Adv Neonatal Care. 2014 Jun14(3):201-10
Neu J; Necrotizing Enterocolitis: The Future. Neonatology. 2020117(2):240-244. doi: 10.1159/000506866. Epub 2020 Mar 10.
Guidelines for the management of Necrotising Enterocolitis; Wales Neonatal Network, 2017
Neu J; Necrotizing enterocolitis: the mystery goes on. Neonatology. 2014106(4):289-95. doi: 10.1159/000365130. Epub 2014 Aug 20.
Chen S, Hu Y, Liu Q, et al; Application of abdominal sonography in diagnosis of infants with necrotizing enterocolitis. Medicine (Baltimore). 2019 Jul98(28):e16202. doi: 10.1097/MD.0000000000016202.
Agakidou E, Agakidis C, Gika H, et al; Emerging Biomarkers for Prediction and Early Diagnosis of Necrotizing Enterocolitis in the Era of Metabolomics and Proteomics. Front Pediatr. 2020 Dec 88:602255. doi: 10.3389/fped.2020.602255. eCollection 2020.
Gregory KE, Deforge CE, Natale KM, et al; Necrotizing enterocolitis in the premature infant: neonatal nursing assessment, disease pathogenesis, and clinical presentation. Adv Neonatal Care. 2011 Jun11(3):155-64
Rao SC, Basani L, Simmer K, et al; Peritoneal drainage versus laparotomy as initial surgical treatment for perforated necrotizing enterocolitis or spontaneous intestinal perforation in preterm low birth weight infants. Cochrane Database Syst Rev. 2011 Jun 15(6):CD006182.
Baelum JK, Rasmussen L, Qvist N, et al; Enterostomy complications in necrotizing enterocolitis (NEC) surgery, a retrospective chart review at Odense University Hospital. BMC Pediatr. 2019 Apr 1319(1):110. doi: 10.1186/s12887-019-1488-5.
Matsuda T, Okada Y, Inagi E, et al; Enteritis necroticans 'pigbel' in a Japanese diabetic adult. Pathol Int. 2007 Sep57(9):622-6.
Xiong T, Maheshwari A, Neu J, et al; An Overview of Systematic Reviews of Randomized-Controlled Trials for Preventing Necrotizing Enterocolitis in Preterm Infants. Neonatology. 2020117(1):46-56. doi: 10.1159/000504371. Epub 2019 Dec 13.
Oddie SJ, Young L, McGuire W; Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database Syst Rev. 2021 Aug 248:CD001241. doi: 10.1002/14651858.CD001241.pub8.