Introduction

Necrotizing enterocolitis (NEC) is one of the most common and severe digestive emergencies in newborns, particularly affecting preterm and very low birth weight (VLBW) infants. It is characterized by acute intestinal inflammation, bacterial invasion, gas formation within the intestinal wall (pneumatosis), and coagulative necrosis, often leading to multiorgan involvement.¹

Despite advances in early recognition and aggressive treatment, NEC remains associated with high mortality (20–30%), especially in the most premature infants or those requiring surgery. Survivors often experience significant long-term morbidity, including delayed brain development and digestive issue.²

NEC affects the body in a complicated way, involving several factors such as intestinal immaturity, microbial dysbiosis, feeding practices, immature immune responses, and ischemia, leading to intestinal barrier breakdown and systemic inflammation.³

Because current therapies cannot fully reverse NEC’s effects, early prevention is critical. Preventive strategies aim to stop the disease process  early to reduce NEC incidence and improve outcomes.³

Risk factors and pathogenesis

Prematurity and low birth weight

Decreasing gestational age and birth weight are well-established risk factors for NEC particularly VLBW infants (BW <1500 g).⁴ A UK national study found NEC incidence was highest (11%) in infants born at 24 weeks gestation, dropping to 0.5% at 31 weeks. Similar findings were reported in a large U.S. study, which also linked lower gestational age and birth weight to higher NEC-related mortality.⁵

Formula feeding vs. breast milk

Feeding is often delayed in very preterm or low birth weight infants due to concerns about gut immaturity. Risks linked to feeding in NEC include using different feeding methods and not managing feeding issues properly, causing care to vary from baby to baby.Formula feeding has been repeatedly linked to a higher NEC risk, while the use of breast milk fortifiers, especially those derived from bovine sources, may also pose additional risks compared to human milk-based alternatives.⁶

Gut microbiome imbalance

 Keeping the gut healthy is helpful in preventing NEC because an imbalance in gut bacteria plays a big role in causing the disease. In preterm infants, gut colonization is influenced by several factors, and common NICU interventions, such as antibiotic use and antacid administration, can disrupt microbial balance, thereby increasing NEC risk.^7,8

Hypoxia-ischemia and intestinal immaturity

 Lack of oxygen and breathing issues are closely linked to how NEC starts and how serious it later becomes. During anoxic (lack of oxygen) states, such as those caused by pneumonia or respiratory distress, the body redistributes blood flow to prioritize vital organs, leading to intestinal vasoconstriction (constriction of arteries and veins) and reduced gut perfusion. This results in intestinal hypoxia and mucosal injury, which significantly increases the risk of NEC.⁹

Inflammatory cascade and bacterial invasion

When bacteria enters the wall of the intestine, they can cause inflammation and damage to the tissues in the intestine. In serious cases, there is usually a widespread inflammation in the whole body, which releases harmful substances that can affect the lining of the intestine. Alongside this, bacterial toxins and endotoxins directly harm intestinal epithelial cells, contributing to intestinal necrosis (death of the cells).^3,9

Early identification and risk stratification

Use of clinical scoring systems

Since the original Bell staging system introduced in 1978, several updated definitions of NEC have emerged to improve diagnostic consistency. Commonly used criteria include the Vermont Oxford Network (VON) definition, the CDC definition, and the "Two of Three" rule, which typically require clinical signs such as abdominal distention, ileus, or bloody stools, along with at least two diagnostic findings, such as pneumatosis intestinalis (air within the bowel walls) and/or portal venous gas (presence of air or gas within the veins from digestive system to liver) visible on x-ray or ultrasound.¹⁰

Biomarkers under investigation (e.g., fecal calprotectin, I-FABP)

Recent research has focused on identifying biomarkers for the early prediction, diagnosis, and severity assessment of NEC. While many cytokines and proteins measured in blood, urine, and stool lack sufficient specificity, some promising markers have emerged such as Inter-alpha inhibitor proteins, Intestinal fatty acid-binding protein (I-FABP). Combining biomarkers improves diagnostic accuracy, e.g., urine I-FABP, fecal calprotectin, and urine serum amyloid A along with intestinal microbiome profiling may aid in identifying bacterial patterns specific to NEC, offering another valuable diagnostic tool.⁸

Role of early screening and monitoring in NICUs

Early recognition of NEC symptoms and aggressive treatment is paramount.⁴ It is strongly linked to active physician involvement within interdisciplinary teams. These teams commonly include physicians, nurses, neonatal nutritionists, and lactation specialists, and sometimes extend beyond the NICU to involve obstetric staff. For example, collaboration with obstetrics was key in implementing practices like delayed cord clamping for infants born at less than 30 weeks, highlighting the value of cross-disciplinary cooperation in NEC prevention efforts.⁷

Nutritional strategies

Exclusive human milk feeding

Benefits of maternal breast milk

Breast milk supports the growth of healthy bacteria in your digestive system, and is known as the safest food for babies. It provides important nutrients and antibody that enhance the immune function, suppress how your body responds to inflammation and promotes healing in the intestinal walls and this contribute to the lowering the risk and severity of NEC.⁷  

Breast milk helps in growing healthy gut bacteria and is the safest, most natural food for babies. It gives important nutrients and antibodies that enhance the immune function, suppress inflammation and help heal the gut lining and this contributes to lowering the risk and severity of NEC.⁷

Donor human milk as an alternative

Donor human milk (DHM), often sourced from mothers of term infants, contains lower levels of macro- and micronutrients than preterm mother’s own milk (MOM). When MOM is unavailable or contraindicated, DHM is recommended for preterm infants, as it significantly reduces the risk of NEC compared to formula. However, DHM may not provide the full range of benefits associated with MOM.^1,7

Human milk fortifiers

Although human milk (HM) is the gold standard for infant nutrition, preterm infants have higher needs for calories, protein, minerals, and electrolytes. To meet these needs, HM is often fortified using either bovine milk-based fortifiers, formula, or donor human milk (DHM)-based fortifiers. While an HM diet clearly reduces the risk of NEC, current evidence does not show added protective benefit of DHM-based fortifiers over bovine-based fortifiers.¹

Standardized feeding protocols

A Standard Feeding Protocol (SFP) should include slow and graded feeding advancements along with close monitoring for feeding intolerance. Key components of an SFP include the initiation and duration of trophic feeds, prioritization of HM, and clearly defined guidelines for the rate of feeding advancement and timing of fortification. Implementing such a protocol has been shown to support optimal infant growth and reduce the incidence of NEC.¹

Microbiome-based interventions

Probiotics

Research suggests that probiotics, particularly those containing Bifidobacterium and Lactobacillus species, are effective in preventing certain neonatal complications. A wide variety of probiotic preparations have been studied, including Bacillus, Lactobacillus, and Saccharomyces species, as well as various probiotic combinations. Among these, the most commonly used preparations were Lactobacillus spp., Bacillus spp., or a combination of both. Most randomized controlled trials (RCTs) evaluated the effects of probiotic supplementation compared to placebo or no supplementation. Probiotics are live bacterial supplements and, while generally safe, can pose risks such as lactic acidosis and probiotic-associated sepsis, especially in vulnerable populations.Hence proper monitoring should be ensured.¹¹

Infection control and hygiene practices

In the NICU, strict hand hygiene, sterile techniques, and minimizing invasive procedures are critical strategies to reduce the risk of NEC. Preventing the overuse of antibiotics is equally important to maintain microbiome integrity. Studies have shown that prolonged empiric antibiotic use, especially in extremely low birth weight infants with sterile cultures, is associated with an increased risk of NEC and death. Antibiotics disrupt normal microbial colonization, promoting the growth of potentially pathogenic bacteria. Notably, each additional day of empiric antibiotic treatment has been linked to a 7% increase in the odds of developing NEC.^1,7

Use of non-invasive monitoring tools

Near-infrared spectroscopy for gut perfusion

Near-infrared spectroscopy (NIRS) is a noninvasive bedside tool used to monitor regional tissue oxygenation by measuring oxygenated and deoxygenated hemoglobin, with applications in assessing oxygen balance in organs such as the brain, gut, and kidneys. Given the role of impaired intestinal perfusion in the pathogenesis of NEC, particularly in infants with congenital heart disease (CHD). NIRS has emerged as a promising modality for early detection of gut perfusion.¹² 

Abdominal ultrasound for early signs

Abdominal ultrasound (aUS) is increasingly recognized as a valuable tool in the diagnosis of NEC, gradually surpassing abdominal radiography (aXR) in clinical utility. The International Neonatal Consortium’s 2018 recommendation included abdominal ultrasound as part of the "two out of three" diagnostic model for preterm NEC. Most importantly, it helps in distinguishing infants with NEC from neonates with CHD.¹² 

Regular clinical assessments

Regular clinical assessments such as Peripheral oxygen saturation (SpO2), Doppler flowmetry, blood pressure, heart rate variability etc, are also some of the invasive bedside tools which can be used to diagnose and monitor the condition of infants with NEC.¹² 

Emerging and investigational strategies

Anti-inflammatory agents (e.g., lactoferrin, epidermal growth factor)

Several RCTs have evaluated the effects of oral lactoferrin, a natural glycoprotein with antimicrobial and immunomodulatory properties. A meta-analysis of four RCTs involving 750 infants demonstrated a protective effect of oral lactoferrin compared to placebo or no intervention. Similar benefits were observed when lactoferrin was combined with probiotics.⁵ Epidermal growth factor, which helps protect against NEC by limiting ileal damage from bile acids, is naturally present in breast milk but absent in formula.⁶

Personalized nutrition and microbiome modulation

Personalized nutrition and microbiome modulation aim to tailor dietary interventions based on an individual infant’s unique gut microbiota composition. By optimizing nutrition and using targeted probiotics or prebiotics, this approach seeks to promote healthy microbial balance, support gut development, and potentially reduce the risk of conditions like NEC.¹¹

Artificial intelligence for early NEC prediction

Machine learning (ML) research on NEC has shown promising results in early diagnosis, prognosis, and biomarker identification. However, many studies are limited by small sample sizes and single-center data. To enhance ML’s potential, collaboration between clinicians, researchers, and data scientists is essential to develop larger, cleaner, and more generalizable datasets. With improved data quality, ML and AI could greatly advance early detection and treatment of NEC.¹³

Multidisciplinary team approach

The prevention of NEC requires a multidisciplinary approach involving neonatologists, nurses, dietitians, and parents. Standardized care bundles, combined with ongoing staff education, help ensure consistent, evidence-based practices in the NICU. Active parental involvement, especially in feeding decisions and kangaroo care, not only strengthens bonding but also contributes to improved feeding tolerance and reduced risk of NEC.

Summary

• NEC remains a significant cause of morbidity and mortality in preterm and VLBW infants, with complex multifactorial pathogenesis involving immaturity, dysbiosis, and inflammation.
  
• Early identification through clinical scoring, biomarkers, and noninvasive monitoring tools is crucial for timely intervention and improved outcomes.
  
• Nutritional strategies prioritizing exclusive human milk feeding, standardized feeding protocols, and microbiome modulation with probiotics are key preventive measures.
  
• Infection control, including strict hygiene and cautious antibiotic use, helps preserve microbiome integrity and reduce NEC risk.
  
• A multidisciplinary approach involving healthcare teams and parental engagement ensures consistent care, education, and support critical for effective NEC prevention.