Necrotizing enterocolitis (NEC) is the most common, and most serious gastrointestinal emergency in newborn infants. The pathophysiologic mechanism(s) leading to NEC are complex, and remain somewhat elusive. It is characterized by severe inflammation of the intestinal mucosa, invasion of enteric bacteria, and dissection of gas that can extend into the portal venous system and result in perforation. There is associated intestinal ischemia, and the most severe cases are characterized by extensive ischemic necrosis.
Clinical presentation of NEC can be variable. Onset can be subtle, starting with simple abdominal distension, followed by insidious progression. Alternatively, there can be an abrupt and devastating presentation that includes rapid necrosis of the intestines with cardiovascular and respiratory collapse.
The most important and consistent risk factor for developing NEC is prematurity. NEC incidence has consistently been shown to be inversely proportional to gestational age at delivery. The trend is similar with birth weight, which is highly correlated with gestational age at delivery. NEC is rare in term infants, and usually associated with congenital anomalies that have affected development of the intestines, and/or limit perfusion and oxygenation of the bowel, such as congenital heart disease.
Major improvements in care of premature infants have resulted in improved survival, especially for those born near the limit of viability, and decreases in many of the prematurity-related morbidities. Unfortunately, morbidity and mortality related to NEC continue to be significant. Despite a great deal of clinical experience with, and research about NEC, there has been very little change in the approach to diagnosis and treatment. Medical treatment is largely supportive (bowel rest, intestinal decompression, antibiotics, cardiorespiratory support, parenteral nutrition support), with a focus on monitoring for intestinal necrosis/perforation requiring surgical intervention (peritoneal drain placement or laparotomy and excision of necrotic bowel). Reported mortality rates vary, but it continues to be substantial; mortality rate for those requiring surgery for NEC is still as high as 50%. Associated complications and morbidities in survivors remain significant, including short bowel syndrome, intestinal strictures and adhesions, cholestasis, failure to thrive, and neurodevelopment delay and disability.
Risk factors:
NEC is a complex, multifactorial problem. In addition to prematurity, many other risk factors have been identified in the prenatal, antenatal, and neonatal periods. Many of these risk factors, such as maternal morbidities, prematurity, intrauterine growth restriction, and genetic predisposition cannot be modified after delivery.
Some modifiable risk factors have been identified, and preventative measures have been successfully implemented in many NICUs:
- Human milk feeding vs. formula feeding
- Restriction of use of therapies that suppress gastric acid
- Restriction of empiric use of antibiotics
- Standardized feeding protocols (Gephard, et al 2017)
There is also strong evidence in multiple studies that probiotics are effective in NEC prevention. Dysbiosis of the intestinal flora is a significant factor in the development of NEC, and probiotics likely attenuate this process. However, the studies are heterogeneous in nature. Different types of probiotics were used. There are also safety concerns, as probiotics are not regulated, and there’s potential for sepsis in a host with an immature immune system. (Barbian 2023)
Diagnosis/Risk identification:
There have been developments in the use of ultrasound for the diagnosis and monitoring of NEC in recent years. In patients with NEC, ultrasound can detect pneumatosis and other bowel wall abnormalities, portal venous air, intraperitoneal air and fluid collections.
Hypoperfusion of the intestines, and decreased tissue oxygenation is part of the complex pathophysiology leading to NEC. Ultrasound can be used to monitor superior mesenteric artery blood flow. Certain blood flow characteristics, such as increased differential between peak systolic velocity and end diastolic velocity, and higher resistive index that represent decreased perfusion have been shown to be predictive of NEC. The use of ultrasound for identifying babies who could be at risk for NEC, and monitoring progress of the disease is increasing, but remains limited as it requires specialized technical expertise.
Near infrared spectroscopy (NIRS) is another non-invasive method of assessing tissue oxygenation. Clinically, in the pediatric/neonatal population, NIRS is primarily used for monitoring brain oxygenation, for which there are developed algorithms. Cerebral oxygenation has been considered a proxy for systemic oxygenation. In one study, having lower cerebral oxygen saturations in the first 48 hours of life is associated with a higher prevalence of NEC. Using NIRS to monitor splanchnic circulation, decreased tissue oxygenation, and increased fractional tissue oxygenation extraction have both been identified in babies prior to the onset of NEC. Work is being done to better monitor and understand tissue oxygenation in the intestines, which is more variable at baseline than brain oxygenation.
Biomarkers:
Research advances have led to improved understanding of different pathophysiologic processes that can lead to NEC, and has prompted investigation of potential associated biomarkers that could identify babies at risk for NEC, and facilitate earlier diagnosis.
There are biomarkers under investigation with promising results that can be tested in serum, urine, and stool.
Biomarkers under investigation for clinical use represent these processes associated with the development of NEC:
- Inflammation and inflammatory regulation – calprotectin (stool), S100A12 (stool), serum amyloid A (serum, urine); anti-inflammatory Inter-alpha inhibitor proteins (serum) absolute monocyte count (blood).
- Breakdown of intestinal homeostasis caused by hypoperfusion – intestinal alkaline phosphatase (stool), Intestinal fatty acid binding proteins (blood and urine), cystolic beta glucosidase (serum).
- Intestinal dysbiosis, colonization with pathogenic bacteria – Volatile organic compounds (stool).
There has been tremendous dedication to basic science and clinical research about NEC, and implementation of practices that reduce the risk of NEC. In recent years, collaboration among disciplines involved in the care of premature infants, and among institutions has been essential for advancing our understanding of this devastating complication. As a result, tools for identifying babies at high risk for NEC, and identifying the process earlier in the course of the illness are emerging. Research focusing on the pathophysiology, and ways to prevent, interrupt, and/or attenuate the cascade of events leading to NEC continues to be a priority.
Elizabeth Cristofalo, MD, MPH is a neonatologist who trained at the University of Pennsylvania, Children’s Hospital Los Angeles, and Johns Hopkins. She has served as a faculty member in Divisions of Neonatology at Johns Hopkins and Yale University, and as a clinician in those, and other NICUs throughout the country. Dr. Cristofalo‘s research has focused primarily on breast milk, and neurodevelopment of at-risk newborns.
References:
Prevention:
Gephart SM, Hanson C, Wetzel CM, Fleiner M, Umberger E, Martin L, Rao S, Agrawal A, Marin T, Kirmani K, Quinn M, Quinn J, Dudding KM, Clay T, Sauberan J, Eskenazi Y, Porter C, Msowoya AL, Wyles C, Avenado-Ruiz M, Vo S, Reber KM, Duchon J. NEC-zero recommendations from scoping review of evidence to prevent and foster timely recognition of necrotizing enterocolitis. Matern Health Neonatol Perinatol. 2017 Dec 18;3:23. doi: 10.1186/s40748-017-0062-0. PMID: 29270303; PMCID: PMC5733736.
Gephart SM, Newnam K, Wyles C, Bethel C, Porter C, Quinn MC, Canvasser J, Umberger E, Titler M. Development of the NEC-Zero Toolkit: Supporting Reliable Implementation of Necrotizing Enterocolitis Prevention and Recognition. Neonatal Netw. 2020 Jan 1;39(1):6-15. doi: 10.1891/0730-0832.39.1.6. PMID: 31919288.
Probiotics:
Wang H, Meng X, Xing S, Guo B, Chen Y, Pan YQ. Probiotics to prevent necrotizing enterocolitis and reduce mortality in neonates: A meta-analysis. Medicine (Baltimore). 2023 Feb 22;102(8):e32932. doi: 10.1097/MD.0000000000032932. PMID: 36827026.
Barbian ME, Patel RM. Probiotics for prevention of necrotizing enterocolitis: Where do we stand? Semin Perinatol. 2023 Feb;47(1):151689. doi: 10.1016/j.semperi.2022.151689. Epub 2022 Dec 21. PMID: 36621416.
Sharif S, Meader N, Oddie SJ, Rojas-Reyes MX, McGuire W. Probiotics to prevent necrotising enterocolitis in very preterm or very low birth weight infants. Cochrane Database Syst Rev. 2020 Oct 15;10(10):CD005496. doi: 10.1002/14651858.CD005496.pub5. PMID: 33058137; PMCID: PMC8094746.
Ultrasound:
Cuna AC, Reddy N, Robinson AL, Chan SS. Bowel ultrasound for predicting surgical management of necrotizing enterocolitis: a systematic review and meta-analysis. Pediatr Radiol. 2018 May;48(5):658-666. doi: 10.1007/s00247-017-4056-x. Epub 2017 Dec 19. PMID: 29260286; PMCID: PMC5895673.
Cuna AC, Lee JC, Robinson AL, Allen NH, Foley JE, Chan SS. Bowel Ultrasound for the Diagnosis of Necrotizing Enterocolitis: A Meta-analysis. Ultrasound Q. 2018 Sep;34(3):113-118. doi: 10.1097/RUQ.0000000000000342. PMID: 29369246.
Gao HX, Yi B, Mao BH, Li WY, Bai X, Zhang Y, Tang JM, Liu PQ, Cheng K. Efficacy of abdominal ultrasound inspection in the diagnosis and prognosis of neonatal necrotizing enterocolitis. Clinics (Sao Paulo). 2021 Mar 26;76:e1816. doi: 10.6061/clinics/2021/e1816. PMID: 33787653; PMCID: PMC7978842.
Guang Y, Ying D, Sheng Y, Yiyong F, Jun W, Shuqiang G, Rong J. Early Doppler Ultrasound in the Superior Mesenteric Artery and the Prediction of Necrotizing Enterocolitis in Preterm Neonates. J Ultrasound Med. 2019 Dec;38(12):3283-3289. doi: 10.1002/jum.15064. Epub 2019 Jun 19. PMID: 31218729.
NIRS:
Cortez J, Gupta M, Amaram A, Pizzino J, Sawhney M, Sood BG. Noninvasive evaluation of splanchnic tissue oxygenation using near-infrared spectroscopy in preterm neonates. J Matern Fetal Neonatal Med. 2011 Apr;24(4):574-82. doi: 10.3109/14767058.2010.511335. Epub 2010 Sep 9. PMID: 20828232.
Schat TE, van Zoonen AGJF, van der Laan ME, Mebius MJ, Bos AF, Hulzebos CV, Boezen HM, Hulscher JBF, Kooi EMW. Early cerebral and intestinal oxygenation in the risk assessment of necrotizing enterocolitis in preterm infants. Early Hum Dev. 2019 Apr;131:75-80. doi: 10.1016/j.earlhumdev.2019.03.001. Epub 2019 Mar 11. PMID: 30870625.
Palleri E, Wackernagel D, Wester T, Bartocci M. Low Splanchnic Oxygenation and Risk for Necrotizing Enterocolitis in Extremely Preterm Newborns. J Pediatr Gastroenterol Nutr. 2020 Sep;71(3):401-406. doi: 10.1097/MPG.0000000000002761. PMID: 32404748.
All prediction:
Wu S, Di S, Liu T, Shi Y. Emerging prediction methods for early diagnosis of necrotizing enterocolitis. Front Med (Lausanne). 2022 Sep 16;9:985219. doi: 10.3389/fmed.2022.985219. PMID: 36186788; PMCID: PMC9523100.
