Necrotizing enterocolitis in neonates. Understanding pathophysiology, risk factors, and management strategies

Nº de DOI: 10.34896/RSI.2025.94.70.001

AUTHORS

1. Yuliana Elizabeth Guayanay Calva. General Practitioner. Attached to the Zumba Basic Hospital. Independent Researcher of the Department of Research and Teaching Matilde Hidalgo de Procel. Graduate of the Particular Technical University of Loja. (Loja-Ecuador). https://orcid.org/0009-0003-2717-9936
2. Marjorie Jocelyn Morales López. General Practitioner. Attached to the Archidona Health Center. Graduated from the Technical University of Ambato. (Ambato-Ecuador). https://orcid.org/0000-0001-9722-6660
3. Miryam Yolanda Japón Japón. General Practitioner. Attached to the Specialized Medical Center Runa Life. Graduated from the Catholic University of Cuenca. (Loja-Ecuador). https://orcid.org/0009-0008-9452-6615
4. Santiago Napoleón Chata García. General Practitioner. Attached to the Alfredo Noboa Provincial Hospital. Graduated from the University of Guayaquil. (Guaranda-Ecuador). https://orcid.org/0000-0002-9866-8118
5. Jessenia Estefanía Toalombo Lombeida. General Practitioner. Attached to the Alfredo Noboa Montenegro Hospital. Graduated from the Higher Polytechnic School of Chimborazo. (Guaranda-Ecuador). https://orcid.org/0000-0001-7926-9296
6. Michelle Stefanny Navarrete Cisneros. Medical Surgeon. Attached to the Río Verde Health Post. Graduated from UTE University. (Quito -Ecuador). https://orcid.org/0009-0001-7802-7137

ABSTRACT

This paper aims to provide a comprehensive overview of the pathophysiology, risk factors, and management strategies for necrotizing enterocolitis in neonates, thereby contributing to the ongoing discourse on improving outcomes for affected infants.

KEY WORDS

Necrotizing enterocolitis, NEC in neonates, intestinal inflammation in preterm infants, NEC risk factors, and management of NEC.

RESUMEN

Este artículo tiene como objetivo proporcionar una descripción general completa de la fisiopatología, los factores de riesgo y las estrategias de manejo de la enterocolitis necrotizante en recién nacidos, contribuyendo así al discurso actual sobre la mejora de los resultados para los bebés afectados.

PALABRAS CLAVE

Enterocolitis necrotizante, ECN en recién nacidos, inflamación intestinal en lactantes prematuros, factores de riesgo de ECN y tratamiento de la ECN.

Introduction

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disorder predominantly affecting premature neonates, characterized by the inflammation and necrosis of intestinal tissue. This complex condition poses significant challenges for neonatal care, as it can lead to severe morbidity and mortality. The pathophysiology of NEC involves a multifactorial interplay of various mechanisms, including the immaturity of the intestinal barrier, which predisposes neonates to bacterial invasion and inflammatory responses. Additionally, host-microbial interactions play a critical role, as disruptions in the gut microbiota may contribute to the disease’s onset and progression. Identifying the risk factors associated with NEC is crucial for prevention and management; both prenatal factors—such as maternal health and gestational age—and postnatal factors—like feeding practices and environmental influences—significantly increase the likelihood of developing NEC, particularly in infants with low birth weight, who are at a heightened risk. Moreover, genetic predispositions may further illuminate the heterogeneity observed in NEC cases. In response to the clinical challenges posed by this condition, various management strategies have been developed, encompassing medical interventions such as nutritional modifications and antibiotic therapies, alongside surgical options for severe cases where intestinal resection may be necessary. Understanding these management protocols and implementing effective preventive measures are vital to minimizing the incidence and impact of NEC in vulnerable neonatal populations.

OBJECTIVE

To provide an overview of the pathophysiology, risk factors and treatment strategies for necrotising enterocolitis in neonates.

METHODOLOGY

This scientific review aims to provide a comprehensive analysis of necrotizing enterocolitis (NEC) in neonates, focusing on its pathophysiology, risk factors, and management strategies. A systematic search of the literature is conducted using electronic databases such as PubMed, Scopus, and Web of Science. The search employs key terms including «necrotizing enterocolitis», «NEC in neonates», «intestinal inflammation in preterm infants», «NEC risk factors» and «management of NEC». The review focuses on articles published in the past two decades to incorporate the most current research and clinical practices.

Inclusion criteria focus on peer-reviewed articles, clinical studies, case reports, and meta-analyses that provide insights into the etiology of NEC, specifically the interplay between prematurity, gut immaturity, abnormal bacterial colonization, and inflammatory responses. Articles that discuss genetic predisposition, feeding practices, and the use of antibiotics are also considered. Studies highlighting clinical manifestations, such as abdominal distension, feeding intolerance, and systemic signs of sepsis, are included to provide a detailed understanding of the presentation of NEC in neonates.

The review also emphasizes risk factors associated with NEC, with particular attention to prematurity, low birth weight, formula feeding, and the impact of neonatal intensive care interventions, such as mechanical ventilation and the use of umbilical catheters. Research exploring protective factors, including breastfeeding, probiotics, and advances in antenatal and postnatal care, is reviewed to assess their role in reducing NEC incidence.

Management strategies are a key focus, with the review evaluating both preventive measures and active treatment approaches. Surgical and medical interventions, including the use of antibiotics, bowel rest, and resection of necrotic bowel, are examined based on their effectiveness and associated outcomes. Studies detailing advances in neonatal intensive care, such as non-invasive monitoring techniques and the application of probiotics in high-risk infants, are included to assess their role in improving prognosis and reducing complications. Special emphasis is placed on the long-term outcomes of NEC survivors, including neurodevelopmental impairment and gastrointestinal complications.

Selected studies are critically appraised for methodological rigor, sample size, and clinical relevance. Articles that lack comprehensive data or have small sample sizes are excluded from the review. The gathered data is organized into key themes, including the pathophysiology of NEC, risk factors, clinical presentation, and management strategies. Emerging therapies, such as the use of stem cells and personalized medicine approaches, are also considered in the review to identify potential future directions in the treatment of NEC.

RESULTS

Pathophysiology of Necrotizing Enterocolitis in Neonates:

What are the primary mechanisms that lead to necrotizing enterocolitis in neonates?

The primary mechanisms that lead to necrotizing enterocolitis (NEC) in neonates are multifaceted, involving a complex interplay of immune responses, microbial interactions, and physiological vulnerabilities. One of the central factors is the innate immune response to intestinal microbiota, which is particularly pronounced in premature infants. This response triggers inflammation and subsequent injury to the intestinal lining, a process that is critical to the pathogenesis of NEC¹. Formula feeding, especially those with high osmotic strength, exacerbates this condition by altering gut health, which may further predispose the neonate to NEC². Additionally, genetic factors are being recognized as contributors to the susceptibility of developing NEC, suggesting that certain infants may have an inherent predisposition to this severe condition². The method of delivery also influences the infant’s gut microbiota, with vaginal births generally promoting a more favourable microbiome compared to Cesarean sections, thus impacting the likelihood of NEC occurrence¹. Given the multi-dimensional nature of NEC, ongoing research is essential to develop targeted strategies for prevention and treatment, emphasizing the need for comprehensive approaches that address both immune and microbial factors in the neonatal gut environment³.

How does the immature intestinal barrier contribute to the development of NEC?

The immature intestinal barrier plays a crucial role in the pathogenesis of NEC in premature infants. The compromised epithelial barrier, due to intestinal immaturity, allows for the translocation of harmful luminal microbiota, leading to severe intestinal inflammation and potentially sepsis¹. This barrier dysfunction is exacerbated by the decreased number of mucus-producing goblet cells and immature tight junctions, which collectively impair the physical integrity of the gut⁴. Additionally, the underdeveloped immune defenses in premature infants further contribute to their heightened susceptibility to NEC¹. The synergistic effect of these factors, coupled with external influences such as formula feeding, antibiotic exposure, and Cesarean delivery, disrupts the luminal microbiota and magnifies the risks associated with an immature intestinal barrier¹. Consequently, this environment fosters a proinflammatory state within the gut, which facilitates bacterial translocation across the intestinal epithelium and exacerbates the development of NEC⁴. Addressing these multifaceted issues through targeted interventions, such as the use of probiotics to modulate the microbial environment, could potentially mitigate the adverse effects of the immature intestinal barrier in premature infants¹.

What role do host-microbial interactions play in the pathophysiology of NEC?

The role of host-microbial interactions in the pathophysiology of necrotizing enterocolitis (NEC) is multifaceted, with significant implications for both the immune response and the integrity of the intestinal barrier. Disruptions in the balance between host and microbial populations can lead to a cascade of events that increase the susceptibility to NEC, as observed in the composition of gut microbiota affecting immune activation⁵. For instance, the predominance of Gram-negative facultative bacteria, particularly before 27 weeks of gestation, has been closely associated with the development of NEC, highlighting the critical window during which microbial influence is most pronounced⁶. Additionally, the interaction of microbiota with Toll-like receptors (TLRs) mediates responses that can profoundly influence intestinal health, as these receptors play a key role in recognizing microbial components and initiating inflammatory responses⁵. This pathological activation of TLRs underscores the importance of regulated host-microbial interactions in preventing NEC, as unregulated TLR activation can lead to detrimental inflammation and tissue damage⁷. Therefore, understanding and modulating these interactions, potentially through interventions like probiotic therapy, could offer promising strategies to maintain a protective microbiota composition and mitigate the risks associated with NEC⁵.

Risk Factors for Necrotizing Enterocolitis:

What prenatal and postnatal factors increase the risk of NEC in neonates?

The risk of necrotizing enterocolitis (NEC) in neonates is influenced by a complex interplay of prenatal and postnatal factors, with prematurity emerging as the most significant determinant. The immature intestines of preterm newborns are particularly vulnerable to ischemic mucosal damage, which compromises the gut’s barrier function and predisposes them to NEC⁸. Additionally, the underdeveloped gut of these infants is more susceptible to infections and inflammation, further enhancing their risk for this devastating condition⁸. Gestational age is a pivotal factor; neonates born at full-term are significantly less likely to develop NEC compared to their preterm counterparts, underscoring the critical nature of in utero development in mitigating NEC risk⁸. Furthermore, premature rupture of membranes (PROM) exacerbates this vulnerability by exposing the fetus to bacteria in the vaginal canal, leading to potential infections and inflammation of the gastrointestinal tract post-birth⁸. The incidence of NEC is markedly higher among infants with the lowest birth weights, illustrating a direct correlation between low birth weight and NEC risk⁹. Prophylactic measures such as prenatal glucocorticoid administration and postnatal probiotic supplementation have shown promise in reducing the incidence of NEC, highlighting the need for targeted interventions to protect this highly susceptible population⁹. Collectively, these factors illustrate the importance of both prenatal care and postnatal management in mitigating the risk of NEC in neonates.

How does low birth weight correlate with the incidence of NEC?

Low birth weight (LBW) is a critical factor in the development of necrotizing enterocolitis (NEC) in neonates, with multiple interrelated domains influencing this correlation. One of the key predictors of NEC in LBW infants is gestational age, particularly between 28–32 weeks, and a birth weight less than 1,000 grams, highlighting the vulnerability of extremely low birth weight neonates¹⁰. These infants are often born with immature bowels that are highly sensitive and prone to infection, exacerbating the risk of NEC¹⁰. Moreover, the hypoxic-ischemic state induced by maternal preeclampsia plays a significant role in increasing susceptibility to NEC in LBW neonates. This condition leads to prolonged exposure to hypoxia, resulting in intestinal stasis, abnormal colonization, and bacterial overgrowth, all of which contribute to the pathogenesis of NEC¹⁰. Additionally, the challenges of blood and oxygen circulation, as well as digestion in LBW infants, further elevate their chances of developing NEC¹⁰. Given the multifactorial influences, including both maternal and neonatal factors, it is essential to develop targeted interventions that mitigate these risks. This could involve improved prenatal care to manage preeclampsia and strategies to enhance gut health and immune function in LBW infants. Addressing these interconnections holistically could significantly reduce the incidence and severity of NEC in this vulnerable population.

What are the genetic predispositions associated with NEC?

The genetic predispositions associated with NEC involve multiple single-nucleotide polymorphisms (SNPs) and candidate genes that have been studied for their potential role in the disease. Certain SNPs, such as those in carbamyl phosphate synthetase, interleukin-12 (p40 promoter CTCTAA/GC), vascular endothelial growth factor (C−2578A), and nuclear factor kappa B subunit 1, have been linked to NEC, suggesting these genetic variations could influence the inflammatory and immune pathways critical in the disease’s pathogenesis¹¹. Twin studies further support the genetic component of NEC, showing that genetic factors may account for approximately 50% of the variance in liability for NEC¹¹. This genetic influence is also reflected in epidemiological data, which indicates differences in the prevalence of NEC among different ethnic groups, thus hinting at a genetic basis for the varied susceptibility to the disease¹². However, the genetic research in NEC faces significant challenges, including the lack of adequately powered replication cohorts, which makes it difficult to validate the genetic discoveries related to NEC¹². This highlights the need for larger, more comprehensive studies to confirm these associations and advance our understanding of the genetic predispositions contributing to NEC.

Management Strategies for Necrotizing Enterocolitis:

What are the current medical management protocols for NEC in neonates?

The current medical management protocols for NEC in neonates are multifaceted, addressing both preventive and therapeutic strategies. Promoting the use of mother’s own milk (MOM) is a cornerstone of these protocols, as it significantly reduces the incidence of NEC due to its beneficial effects on the infant’s gut microbiome and immune system¹³. Standardized feeding protocols are also implemented to minimize the risk of NEC in preterm infants, ensuring that feedings are introduced gradually and safely¹³. In addition to nutritional strategies, antibiotic stewardship plays a critical role in managing NEC. Minimizing exposure to antibiotics helps prevent microbial dysbiosis, which is a major factor in the development of NEC¹³. Furthermore, avoiding acid-reducing medications is crucial, as these can disrupt the intestinal microbiome and increase the risk of NEC¹³. Transfusion protocols are also considered to reduce severe prolonged anemia, which may contribute to the risk of NEC¹³. While treatment options for NEC have not significantly changed, ongoing research is promising for developing earlier diagnostic and improved preventive and treatment strategies¹³. In summary, a comprehensive approach involving nutrition, antibiotic stewardship, and careful medication management is essential for effectively managing NEC in neonates.

How effective are surgical interventions in the treatment of NEC?

Despite the advancements in understanding the pathophysiology of NEC, the effectiveness of surgical interventions remains a complex and debated issue. Various studies have highlighted that the type of surgical management—whether peritoneal drainage or laparotomy—does not necessarily correlate with better outcomes, as evidenced by the similar rates of death or neurodevelopmental impairment (NDI) between these procedures¹⁴. This raises significant concerns, particularly when considering that initial peritoneal drainage may be associated with worse neurodevelopmental outcomes compared to laparotomy, although the findings are not statistically significant¹⁴. Moreover, a multicenter prospective cohort study involving extremely low birth weight (ELBW) infants illustrated alarmingly high rates of adverse outcomes, with 68% of infants in the laparotomy group and 84% in the peritoneal drainage group either dying or developing NDI by 18-22 months corrected age¹⁴. These findings underscore the pressing need for well-designed multicenter prospective studies, such as the Necrotizing Enterocolitis Surgery Trial (NEST), to better evaluate these surgical interventions and develop evidence-based guidelines¹⁴. Therefore, while surgical treatment is often necessary, particularly in cases of intestinal perforation, the medical community must prioritize further research to optimize the timing and type of surgical interventions for NEC patients¹⁵.

What preventive measures can be implemented to reduce the incidence of NEC?

To address the high incidence of NEC among premature infants, several preventive measures can be implemented, targeting various aspects of infant care and nutrition. One of the most emphasized strategies is the use of breast milk, which has been shown to offer protective benefits against NEC, although the degree of protection varies depending on factors such as storage and processing of the milk¹⁶. While exclusive human milk feeding is recommended, it is crucial to note that NEC can still occur, particularly if the milk undergoes refrigeration, freezing, or pasteurization, which may diminish its protective properties¹⁶. Consequently, feeding practices should be carefully monitored and modified, as evidence suggests that a significant percentage of infants with NEC had received milk feedings prior to disease onset¹⁶. Furthermore, incorporating donor human milk as an alternative to formula feeding has been shown to reduce the risk of NEC, providing an additional layer of protection for preterm infants¹⁷. In addition to human milk, the administration of probiotics has emerged as a promising preventive measure, with studies indicating that probiotics can reduce the risk of NEC by up to 40%–50%¹⁷. This substantial reduction underscores the potential of probiotics as a critical component of NEC prevention strategies. Moreover, maternal health care plays a pivotal role in preventing preterm birth, which is a significant risk factor for NEC. Ensuring optimal maternal health can help reduce the likelihood of preterm deliveries, thereby decreasing the incidence of NEC in neonates¹⁸. Implementing standardized enteral nutrition guidelines is another effective approach, as such guidelines have been proven to lower the incidence of NEC by providing a structured feeding regimen that minimizes risks associated with enteral feeding¹⁷. In conclusion, a multifaceted approach that includes the use of breast milk, donor human milk, probiotics, maternal health care, and standardized enteral nutrition guidelines is essential for effectively reducing the incidence of NEC in premature infants. By addressing the various factors that contribute to NEC, these preventive measures can work synergistically to protect this vulnerable population from the devastating effects of the disease.

DISCUSSION

The findings presented in this research paper underscore the intricate pathophysiology of necrotizing enterocolitis (NEC) in neonates, particularly highlighting the multifactorial risk factors that converge to heighten susceptibility, especially in premature infants. The interplay between innate immune responses and microbial interactions is pivotal, as premature infants exhibit an exaggerated immune response to their developing gut microbiota. This relationship is further complicated by various factors, including the mode of delivery and feeding practices, which can significantly influence gut health and microbiome composition. Notably, the advantages of vaginal birth over Cesarean section in promoting a favorable microbiome are evident, suggesting that delivery methods should be carefully considered in high-risk populations. Additionally, the detrimental effects of formula feeding, particularly those with high osmotic strength, on gut integrity and health necessitate a reevaluation of feeding protocols in neonatal care. The critical role of the immature intestinal barrier cannot be overstated, as it serves as a gateway for microbial translocation and subsequent inflammatory responses that characterize NEC. This highlights the urgent need for targeted interventions, such as the incorporation of probiotics and standardized enteral nutrition guidelines, which have demonstrated efficacy in mitigating the incidence of NEC. Moreover, the alarming correlation between low birth weight and NEC incidence emphasizes the necessity of tailored approaches that address the vulnerabilities of extremely low birth weight infants, particularly those born between 28 to 32 weeks gestational age. While the current management strategies reflect a comprehensive understanding of NEC, the limitations in the existing literature, including potential biases in study populations and the need for more robust clinical trials, point to areas where further research is essential. Future directions should focus on elucidating the genetic predispositions that contribute to NEC, optimizing maternal health interventions to reduce preterm births, and refining probiotic therapies to enhance gut resilience. By addressing these multifaceted issues holistically, we can pave the way for more effective preventative measures and therapeutic strategies, ultimately improving outcomes for this vulnerable population.

CONCLUSIONS

1. Necrotizing enterocolitis (NEC) remains a significant cause of morbidity and mortality in neonates, particularly in preterm infants. This complex disease results from a combination of factors, including gut immaturity, abnormal microbial colonization, inflammatory responses, and feeding practices, especially the use of formula. The pathophysiology of NEC is now better understood, with research highlighting the critical role of impaired intestinal barrier function and dysregulated immune responses in the development of the disease. However, despite advances in understanding these mechanisms, NEC continues to pose challenges in neonatal care, especially in early diagnosis and effective prevention.
2. The primary risk factors for NEC, including prematurity, low birth weight, and formula feeding, have been well established. Premature infants are particularly vulnerable due to the underdeveloped gastrointestinal and immune systems. On the other hand, breastfeeding has consistently been shown to provide protective effects against NEC, likely due to the beneficial microbiota and immunological components of human milk. Probiotics have also emerged as a potential preventative measure, with some studies showing reductions in NEC incidence, although there is still debate over their routine use in clinical practice.
3. Management of NEC requires a multidisciplinary approach, combining both medical and surgical interventions. In the early stages, conservative management with bowel rest, broad-spectrum antibiotics, and supportive care in the neonatal intensive care unit (NICU) is often employed. However, in severe cases, surgical intervention to remove necrotic bowel is necessary. Although survival rates have improved due to advancements in neonatal care, survivors of NEC often face long-term complications, including short bowel syndrome, neurodevelopmental delays, and feeding difficulties, highlighting the need for improved strategies for early intervention and prevention.
4. Despite progress in understanding the pathogenesis and risk factors of NEC, significant gaps remain in the development of effective preventive strategies and early diagnostic tools. Future research should focus on personalized approaches that consider the individual risk factors and biological markers of infants. The potential role of novel therapies, such as stem cells and targeted immunomodulation, also warrants further exploration.

FUTURE DIRECTIONS

Necrotizing enterocolitis continues to be a critical challenge in neonatal care, particularly for preterm infants. While significant strides have been made in understanding the disease and improving management techniques, further research is essential to reduce the incidence and improve the long-term outcomes of affected infants. Early diagnosis, preventative strategies such as breastfeeding, and multidisciplinary management remain key components of NEC care, but future innovations hold promise for more effective treatments and better prognosis for neonates at risk.

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