Necrotising enterocolitis

What is necrotising enterocolitis

First described in 1828 and formally recognised in 1944,¹ necrotising enterocolitis (NEC) is now the most common life-threatening condition occurring in neonates. Prematurity and low birth weight are the most important risk factors.

Epidemiology

• It is estimated that it affects 1% of all neonates but 11% of all low-weight neonates (less than 1500 g at birth) and up to 22% of extremely low birthweight infants (less than 1000 g at birth).²¹

• UK data shows an incidence of 11% in those born before 24 weeks' gestation and 0.5% of those born after 31 weeks.¹

• The incidence has remained stable over the past decade.¹

• A recent systematic review on the incidence of necrotising enterocolitis in high-income countries found variation in the incidence of the disease based on GA, birth weight, and country.³

  Overall, necrotising enterocolitis incidence was highest among the most preterm infants. In infants born at a gestational age of <28 weeks, the lowest reported incidence of necrotising enterocolitis was in Japan (2%) and the highest in Australia, Canada, and Italy (7-9%). In neonates with a gestational age of between 28 and 31 weeks, reported necrotising enterocolitis incidence was also lowest in Japan (0.2%), while other developed nations had incidence rates ranging from 2-3%. Similarly, for infants with a low birthweight, NEC incidence ranged from 2% in Japan to 6-7% in the USA and 9% in Poland.

Risk factors¹⁴

• Prematurity. This is the most significant risk factor with 9 out of 10 cases of necrotising enterocolitis occurring in babies born prematurely.⁵

• Low birthweight. Babies who are small for gestational age have double the risk of developing necrotising enterocolitis.

• Congenital heart disease in the infant.

• Prolonged rupture of the membranes (PROM) or chorioamnionitis.

• Infants with low APGAR scores or those who need ventilation.

• Infants requiring a blood transfusion.

• Hispanic ethnicity and Black ethnicity are both associated with higher rates of necrotising enterocolitis in the United States, independent of other risk factors.

• There may be genetic risk factors. The twin of an infant with necrotising enterocolitis has a higher risk of developing necrotising enterocolitis. It is also more common in the UK, Ireland and the USA compared with Japan, Taiwan, Switzerland, and Austria.

• There are many reports of "clusters" of necrotising enterocolitis occurring which may suggest specific bacterial strains in the environment though these have not been isolated.

Protective factors¹

Breast milk has been shown to significantly reduce the risks of necrotising enterocolitis when compared with formula or mixed feeding.

Pathophysiology¹²⁶

Whilst this is incompletely understood, it is thought that the impaired immunity of the low birthweight or premature infant makes them more susceptible to intestinal insults, either from hypoperfusion or from formula feeding. Their intestines are immature with a reduced gut microbiome,⁷poor peristalsis, but high permeability and low secretion of gastric acid, and digestive enzymes. Bacteria can therefore proliferate, damaging the intestinal mucosa and causing inflammation, leading to intestinal injury, necrosis, and perforation. This in turn leads to systemic inflammation, causing complications, such as neurodevelopmental disorders and lung damage. In addition, local ischemia and hypoxia and/or impaired microcirculation, disturbances in the intestinal flora, and formula feeding (necrotising enterocolitis occurs almost always in infants who have been formula fed) are also major pathogenic factors.

Clinical presentation

The clinical presentation of necrotising enterocolitis is highly variable. There may be a future role in using biomarkers to predict who is likely to develop necrotising enterocolitis, but these are not yet effective.² Early symptoms tend to be nonspecific but typically necrotising enterocolitis presents with sudden onset of feeding intolerance, abdominal distension, bloody stools, and nonspecific systemic changes around 2-3 weeks after birth.⁸

There are various clinical staging tools though the most commonly used is the modified Bell's scale which classifies necrotising enterocolitis into 3 stages based on clinical and radiological findings.⁸

• Stage 1 (suspected):

  • Mild gastrointestinal disturbances.

  • Normal to mild intestinal dilation on imaging.

  • Nonspecific systemic signs, including temperature instability, tachycardia, bradycardia, apnoea, and lethargy.

• Stage 2 (definite):

  • Worsening systemic signs.

  • Abdominal distension and tenderness.

  • Absent bowel sounds.

  • Evidence of gas in the bowel wall on imaging.

  • Mild metabolic acidosis.

  • Thrombocytopaenia.

• Stage 3 (advanced):

  • Worsening symptoms.

  • Hypotension.

  • Disseminated intravascular coagulation.

  • Intestinal perforation in severe cases.

  • Pneumoperitoneum.

Differential diagnosis

• Sepsis.

• Haemolytic disease of the newborn.

• Swallowed maternal blood.

• Volvulus/malrotation.

• Intussusception.

• Pseudomembranous colitis.

• Stress ulcer.

• Meconium ileus.

• Metabolic or respiratory acidosis.

• Bacteraemia.

• Candidiasis.

• Coarctation of the aorta.

• Enteroviral infection.

• Gastro-oesophageal reflux.

• Hirschsprung's disease.

• Hospital-acquired infections.

• Hypoplastic left heart syndrome.

• Omphalitis.

• Bacterial meningitis.

• Urinary tract infection.

• Focal intestinal perforation.

Treatment and management⁸

Treatment options remain limited but include:

• Nil by mouth with intravenous (IV) fluids, total parenteral nutrition (TPN) and IV antibiotics according to local guidance.

• Nasogastric tube to relieve abdominal distension by removing air and fluid from the gastrointestinal tract.

• Frequent x-rays and blood tests to monitor for patient stability and determine disease progression.

• Surgical interventions are required in cases of intestinal perforation and sometimes for failure of medical management.

• Various recent drug trials have shown no statistically significant improvement in outcomes in necrotising enterocolitis.

• Various non-surgical interventions including nitrous oxide inhalation, gastric aspiration prior to feeding, and the use of feeding tubes, have shown some evidence of benefit though none of this was statistically significant. Researchers recommend further investigations into these and other interventions.

• Dietary supplements: Donor breast milk has been shown to be beneficial with statistically significant benefits. Probiotics may also be of value in both the prevention and treatment of necrotising enterocolitis.

• Use of prophylactic antibiotics in infants born below 33 weeks' gestation increased the risks of necrotising enterocolitis.

• Use of maternal antibiotics had no impact on the risk of necrotising enterocolitis.

Complications and prognosis

• Mortality rates in infants diagnosed with necrotising enterocolitis are 23.5%, rising to 50.9% in extremely low birthweight infants with necrotising enterocolitis who undergo surgery.²⁹

• There is substantial long-term morbidity in survivors, especially those with a birth weight of <1500 g; neurodevelopmental disorders and intestinal failure are the most serious complications, occurring in 24.8% and 15.2% of all children with necrotising enterocolitis, and in 59.3% and 35.3% of children with necrotising enterocolitis requiring surgery, respectively.⁸There is a suggestion that early surgery may reduce the risks of neurodevelopmental disorders although this is unproven.⁷

• Necrotising enterocolitis is an independent risk factor for neurodevelopmental delays and poor neurocognition in infants born prematurely. Neurological and motor dysplasia are apparent at around 2 years of age, and cognitive deficits can persist into school age.⁸

• Acquired short bowel syndrome (following surgery).

• Stoma-related complications.

• DIC.

• 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).

Other forms

There is another necrotising enterocolitis 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).¹⁰

• 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.

Prevention⁷¹¹

Feeding with human milk is known to be an effective intervention in the prevention of necrotising enterocolitis. Other interventions have a limited evidence base but have focused on reducing the multiple contributing factors in a susceptible host. The use of probiotics may also play a role although studies suggested increased incidence of sepsis in infants treated with probiotics so, although studies continue across the world, they are currently advised against in the United States.⁸

Recent studies have made significant progress in discovering more about the molecular mechanisms underlying the pathophysiology of necrotising enterocolitis. There is hope that this research will improve treatment options and outcomes in the future.⁵