What is necrotizing enterocolitis, particularly in premature or low birth weight newborn infants?

Necrotizing Enterocolitis (NEC): Overview

Definition and Epidemiology

Necrotizing enterocolitis is an inflammatory necrosis of the intestinal tract, most commonly affecting the terminal ileum and proximal ascending colon, that predominantly occurs in premature and very low birth weight infants. 1

• NEC affects 5-12% of very low birth weight neonates and is the leading cause of death from gastrointestinal disease in this population 2
• Risk is inversely proportional to gestational age and birth weight 3
• While primarily a disease of prematurity (affecting infants <37 weeks gestation), NEC can occasionally occur in term neonates, though with different clinical characteristics 4, 5

Pathophysiology

The disease requires three essential components for development 1:

• Substrate for bacterial growth (enteral feedings)
• Infectious agent (usually bacterial)
• Bowel injury event such as decreased blood flow causing vascular compromise and mucosal injury 1

This triad leads to mucosal injury, pneumatosis intestinalis (gas in the bowel wall), bacterial overgrowth, and potential progression to full-thickness bowel necrosis and perforation 1. Distinct fecal microbiota signatures exist in infants with NEC compared to healthy preterm infants, suggesting dysbiosis plays a critical role 1

Clinical Presentation

Classic Presentation in Premature Infants

The typical presentation includes 1, 6:

• Increased episodes of apnea and bradycardia as initial warning signs
• Abdominal distension (often the most prominent finding)
• Bloody stools (grossly bloody or occult positive)
• Bilious emesis indicating intestinal obstruction
• Focal abdominal wall erythema may develop
• Portal venous gas on imaging

Systemic Signs

• Signs of sepsis including thrombocytopenia and neutropenia 1, 6
• Metabolic acidosis if bowel ischemia is present 1
• Severe hypotension and hemodynamic instability 5

Unique Features in Term Neonates

When NEC occurs in term infants, the presentation differs significantly 4:

• Earlier onset: 50% present within first 48 hours of life, 90% within first 4 days (versus later onset in preterm infants)
• Birth weight typically >2.7 kg
• Traditional risk factors (asphyxia, hypoglycemia, polycythemia, respiratory distress) absent in 60% of cases
• Severe colonic involvement is characteristic, with perforation occurring in 71% of surgical cases
• Higher surgical intervention rate (70% vs lower rates in preterm infants)

Initial Management

Immediate Interventions

All neonates with suspected or confirmed NEC require immediate bowel rest, nasogastric decompression, fluid resuscitation, and broad-spectrum antibiotics 6, 7, 8:

• Complete cessation of enteral feeds and strict bowel rest 7
• Nasogastric tube placement for bowel decompression 6, 7
• Aggressive fluid resuscitation to address hemodynamic instability and third-spacing 6
• Hemodynamic monitoring with management of sepsis/septic shock 6

Antibiotic Therapy

First-line antibiotic regimens include 6, 7:

• Ampicillin + gentamicin + metronidazole (most commonly used triple therapy)
• Ampicillin + cefotaxime + metronidazole (alternative triple therapy)
• Meropenem monotherapy (single-agent option with broad coverage)

Special Antibiotic Considerations

• For suspected MRSA or ampicillin-resistant enterococcal infection: substitute vancomycin for ampicillin 6
• For suspected fungal infection: add fluconazole or amphotericin B, particularly in extremely low birth weight infants (<1000g) 6
• Avoid anticholinergic, antidiarrheal, or opioid agents as they may mask clinical deterioration and worsen ileus 6

Laboratory Monitoring

Essential monitoring includes 6:

• Serial complete blood counts for thrombocytopenia and neutropenia
• Metabolic panels for acidosis
• Blood cultures prior to antibiotic initiation
• Serial abdominal radiographs to assess for pneumatosis, portal venous gas, or free air

Surgical Management

Indications for Surgery

Urgent surgical consultation is mandatory when perforation is evident or when clinical deterioration occurs despite maximal medical therapy 6, 7:

• Pneumoperitoneum (free air indicating perforation) - absolute indication 6
• Clinical deterioration despite maximal medical management 6
• Peritonitis on examination 4
• Abdominal mass suggesting abscess or extensive necrosis 4

Surgical Options

The surgical approach depends on infant size and clinical status 6:

• Laparotomy with resection of necrotic bowel followed by either:
  • Creation of ostomies (safer in unstable patients)
  • Primary anastomosis (if bowel viable and patient stable)
• Peritoneal drainage as either:
  • Temporizing measure in very low birth weight neonates prior to definitive surgery
  • Definitive treatment in select extremely premature infants 1, 6

Intraoperative Gram stains and cultures must be obtained to guide antimicrobial therapy 6

Critical Pitfall to Avoid

Never delay surgical consultation when perforation or clinical deterioration is evident - failure to remove necrotic bowel in these severely compromised patients is often fatal 6

Nutritional Support During Acute Phase

During the period of bowel rest, parenteral nutrition is essential 7, 8:

• Minimum amino acid intake of 1.0 g/kg/day to prevent negative nitrogen balance 8
• Provide 30-40 kcal per 1g amino acids to ensure amino acid utilization 8
• Taurine should be included in amino acid solutions 8
• Consider arginine supplementation when reintroducing feeds to potentially prevent recurrence 8
• Glutamine supplementation is NOT recommended for infants up to two years of age 8
• Monitor for parenteral nutrition-associated complications including cholestasis 7

Transfusion Considerations

For significant gastrointestinal bleeding causing anemia or hemodynamic compromise 7:

• Consider blood transfusion as clinically indicated
• Withhold enteral nutrition during and immediately after transfusion to reduce risk of transfusion-associated NEC (TANEC)

Prevention Strategies

Probiotic Supplementation

Combinations of Lactobacillus species and Bifidobacterium species have high-quality evidence for reducing severe NEC and all-cause mortality in preterm infants 1:

Specific effective combinations include:

• L. rhamnosus ATCC 53103 + B. longum subsp infantis
• L. casei + B. breve
• L. acidophilus + B. longum subsp infantis
• L. acidophilus + B. bifidum
• Four-strain combination: L. acidophilus, B. bifidum, B. animalis subsp lactis, B. longum subsp longum

These combinations showed:

• 44% reduction in all-cause mortality (OR 0.56; 95% CI 0.39-0.80) 1
• 65% reduction in severe NEC (stage II or higher) (OR 0.35; 95% CI 0.20-0.59) 1

Single-strain probiotics with moderate-to-high quality evidence:

• B. animalis subsp lactis (OR 0.31 for NEC reduction) 1
• L. reuteri DSM 17938 or ATCC 55730 (OR 0.55 for NEC reduction) 1
• L. rhamnosus (OR 0.44 for NEC reduction) 1

Other Preventive Measures

• Human breast milk feeding is strongly protective 9
• Standardized feeding protocols reduce NEC incidence 9
• Lactoferrin alone or with Lactobacillus may reduce late-onset sepsis including Candida 6
• Antifungal prophylaxis may be considered for extremely low birth weight infants (<1000g) 6

Risk Factors to Minimize

Avoid or minimize when possible 9:

• Early broad-spectrum antibiotic exposure (alters microbiota)
• Proton pump inhibitors and H2 receptor antagonists (increase NEC risk)
• Formula feeding when breast milk available

Prognosis and Outcomes

Overall Survival

The survival rate for NEC is approximately 95% when disease is localized 1, 6, 7, 8:

• When NEC involves the entire bowel (occurs in ~25% of cases), mortality increases dramatically to 40-90% 1, 6, 7, 8
• Nonoperative management is successful in approximately 70% of cases 1, 7
• Mortality among neonates requiring surgery is estimated at 20-30% 2

Long-term Sequelae

Survivors face significant long-term complications 1:

• Short bowel syndrome requiring prolonged parenteral nutrition
• Parenteral nutrition-associated liver injury and cholestasis
• Impaired neurodevelopment affecting cognitive outcomes
• Intestinal strictures requiring delayed surgical intervention (seen in some medically managed cases) 4

Follow-up Considerations

• All surviving patients with surgical intervention should have intestinal continuity restored when stable 4
• Monitor for development of strictures even in medically managed patients
• Some patients require resection of additional NEC strictures prior to reanastomosis 4
• No late complications were reported in successfully treated term infants in one series 4

Key Clinical Pearls

• Term infants with NEC present earlier and have more severe colonic disease than preterm infants 4
• Close monitoring is essential - children treated without catheter removal (in context of central line infections) or without surgery require frequent clinical evaluation and repeat cultures 1
• The disease can present insidiously with feeding intolerance as an early sign, mandating high clinical suspicion 2
• Biomarker development is critical - non-invasive biomarkers to predict NEC before clinical onset would allow maximal preventative interventions 2