Introduction
On our most recent podcast, episode 48, I discussed human breast milk and reviewed all of its beneficial properties – for ALL infants, but especially those born premature or critically ill. I briefly mentioned and described necrotizing enterocolitis (NEC) because research has consistently shown that human breast milk, especially maternal breast milk, to reduce the incidence of NEC. So for our 49th episode, I reviewed what exactly NEC is, what is thought to cause it, which infants are at an increased risk to develop NEC, what symptoms infants may present with (both the common and more subtle symptoms), the staging system used to define the severity of each case, what the management and treatment typically is, what preventative measures are being used commonly in NICUs and finally I close out the episode discussing the prognosis for infants who have been diagnosed with NEC.
The month of May is NEC Awareness Month, so what better time to learn more about necrotizing enterocolitis than now! This particular episode will be beneficial for parents and NICU clinicians, so stay tuned and get ready to be empowered – you do not want to miss this episode!
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Episode 49
What is Necrotizing Enterocolitis?
Necrotizing Enterocolitis (NEC) is an ischemic and inflammatory condition of the bowel that affects infants with an occurrence rate around 1-3 per 1000 live births. It is more predominant in preterm infants and occurs in 5% of very low birth weight(VLBW) infants, or those with a birthweight of less than 1500 grams. Only about 10% of NEC cases occur in term infants, many of which have a preexisting condition. Unfortunately, for infants that do develop NEC, it is a life-threatening condition with a mortality rate of 50%.
The word “necrotizing” means the process of tissue death and the word “enterocolitis” means inflammation of the small intestine or colon. The pathophysiology or the physiologic processes associated with NEC includes inflammation of the intestinal lining that leads to bacterial invasion and it results in cellular damage and death to the intestinal wall which causes necrosis of the colon and intestine. Unfortunately, as NEC progresses, it can lead to an intestinal perforation – basically cause a hole to develop in the intestine that can result in spillage of the intestinal contents, or stool into the peritoneum and may result in peritonitis or inflammation of the abdomen, followed by sepsis, and/or death.
What causes Necrotizing Enterocolitis?
Necrotizing enterocolitis is a complex disease and despite decades of research, it is still not well understood. Mostly, because there has not been one particular culprit identified that results in NEC. Some of the risk factors that have been identified include prematurity, low birth weight, formula feeding, ischemia, and altered intestinal microbiota.
The disease is multifactorial in nature, which means there are several factors that attribute to the pathogenesis of NEC. The majority of evidence continues to support the concurrent presence of several factors. Infants, especially those born prematurely, have an immature intestinal tract with an immature mucosal barrier that allows for increased permeability and bacterial penetration. Therefore, the preterm infant’s gut allows bacteria to more easily penetrate than that of a term infant. Additionally, a preterm infant’s gut motility and function are also immature which can result in delayed transit time or mobility of stool. The delayed transit of stool allows an increase in bacterial overgrowth in the intestine. Premature infants also have an immature immune system which increases their susceptibility. All of these factors in combination with a trigger is what is thought to lead to a disruption of the normal intestinal bacterial flora or microbiome.
Some of the identified triggers include non-human milk feedings, circulatory instability, anemia or a deficiency in red blood cells, and medications like antibiotics. Antibiotics cause intestinal mucosal injury or result in an enhanced microbial overgrowth. The combination of the infant’s immature intestinal tract plus a trigger results in an increased growth of bacteria, and eventually causes an exaggerated and altered inflammatory host response. Premature infants have immature local host defenses too and may have an imbalance between pro- and anti-inflammatory factors which results in a cascade of abnormal mediator responses.
There is an inverse relationship between the risk of NEC and gestational age. Meaning, the younger the gestational age, the increased risk of developing NEC. More than 90% of NEC cases occur in VLBW infants.
Luckily, according to Kim from Up-to-date, the incidence of NEC does appear to be decreasing over the last 10 years in the United States. The decrease in cases is attributed to the quality improvement activities that have focused on reducing the risk of NEC.
As I previously stated, the majority of NEC cases occur in VLBW infants, but 10% of the NEC cases do occur in term infants. Term cases of NEC typically occur in infants who have received non-human milk feeding and have a preexisting illness. Infants with congenital heart disease, primary gastrointestinal disorders, sepsis, fetal growth restriction, and/or perinatal hypoxia. These conditions all affect the intestinal perfusion which places these infants at risk for developing NEC.
Clinical Presentation – What symptoms do infants present with?
NEC typically occurs in the 2nd or 3rd week of life or around a post-menstrual age of 30 to 32 weeks. Unfortunately, the majority of preterm infants who develop NEC are generally healthy, tolerating feedings, and growing well prior to presenting with symptoms. NEC is very rare in unfed infants. Additionally, the signs and symptoms are highly variable, nonspecific and they may be subtle.
Parents often notice and report a decrease in their baby’s activity with fatigue. The most frequent sign of NEC is a sudden change in feeding tolerance which may present with abdominal distention, tenderness of the abdomen, vomiting, diarrhea, rectal bleeding or blood noted in the stool, or bilious drainage from the feeding tube. Although an increase in gastric residuals may be indicative of early NEC, there is not evidence to support the routine measurement of gastric residual volumes in asymptomatic infants (this used to be a common practice in NICUs). Many NICUs no longer routinely check for gastric residuals prior to feedings in well-appearing preterm infants.
Some additional non-specific findings may include apnea or pauses in breathing, respiratory failure, temperature instability, and lethargy or decreased responsiveness as I mentioned before. Hypotension or low blood pressures may occur from septic shock in severe cases.
On the physical exam, the infant’s abdomen may appear distended, will be tender to palpation, and there may be visible loops of bowel, decreased bowel sounds, and/or abdominal redness.
What findings to look for on X-Ray
Once findings suspicious for NEC are observed an abdominal X-Ray will be ordered STAT. There will be a series of films done to include an anterior-posterior X-Ray and left lateral decubitus. Generally, clinical diagnosis of NEC is based on the presence of common clinical features and the X-Ray finding of intramural gas or small amounts of air noted within the wall of the bowel otherwise known as pneumatosis intestinalis. There may also be an abnormal gas pattern with dilated loops of bowel consistent with an ileus. Sentinel loops or a loop of bowel that remains in a fixed position may also be present which suggests necrotic bowel or possibly a perforation. The X-ray may also show portal venous gas which is not universally present with NEC, but is a transient sign of bacterial gas entering into the portal system. There may also be free air present in the abdomen when a perforation has occurred. Serial X-rays will be done frequently every 6 to 12 hours to monitor for free air in the abdomen or pneumoperitoneum because there is an increased risk for bowel perforation within 48 to 72 hours of disease onset.
An absolute definitive diagnosis of NEC can only be made from either an intestinal surgery or postmortem findings. The radiographic findings, or X-Rays need to be interpreted in the context of the patient’s other clinical findings and the overall clinical picture.
Common labs to assist with the diagnosis of NEC
Laboratory findings will not make the diagnosis of NEC, but they may help support the suspected diagnosis and help to stage the severity of the disease. Typically a complete blood count (CBC) will be drawn with a differential to monitor for alterations in the white blood cell (WBC) count and the absolute neutrophil count (ANC). An ANC of less than 1500/microL is common in patients with NEC and indicative of a poor prognosis. The CBC may also show a low platelet count or thrombocytopenia, which is a frequent finding in patients affected by NEC. Trending the platelet count may also be helpful as a declining count early in the course of NEC correlates with necrotic bowel or worsening disease whereas a rise in the platelet count may signal an improvement.
A C-reactive protein (CRP) may also be drawn. If the CRP value is elevated, it is indicative of inflammation. Although the initial number may not be incredibly helpful, CRP values are typically trended every 12-24 hours to monitor the progression.
A chemistry panel will likely be drawn to monitor serum electrolytes, specifically monitoring for hyponatremia or low sodium levels.
A blood culture will be drawn because sepsis often accompanies NEC and will help guide antibiotic therapy if the culture is positive.
A blood gas may be done as well to evaluate for metabolic acidosis and any respiratory compromise.
Coagulation studies may also be indicated, especially if thrombocytopenia or low platelets are present. The coagulation studies also help to monitor for disseminated intravascular coagulation (DIC) which is a frequent finding in infants with severe NEC. DIC is a condition that causes abnormal clotting throughout the body.
Bell Staging Criteria
The staging system used for patients with NEC is called the Bell Staging Criteria. It helps to provide a uniform clinical definition of NEC based on the severity of the systemic, intestinal, radiographic, and laboratory findings. There are 3 stages:
Stage I: Suspected NEC
Stage I is characterized by nonspecific signs that may include temperature instability, apnea, and lethargy. On exam, the infant’s abdomen may be distended, there is an increase in gastric residuals, emesis, and/or blood in the stool. By X-ray, the images may be normal or show dilation of the bowel consistent with a mild ileus.
Stage II: Proven NEC
With stage II, it encompasses all of the signs of stage I plus absent bowel sounds either with or without abdominal tenderness. Some infants have cellulitis of the abdominal wall or a mass in the right lower quadrant. Additional findings may include metabolic acidosis and thrombocytopenia or a low platelet count. On X-Ray, pneumatosis intestinalis is apparent which is the defining feature of stage II and it may be with or without portal venous gas. The X-ray may also show intestinal dilation, an ileus, and/or ascites.
Stage III: Advanced NEC
Infants with stage III NEC are critically ill. In stage IIIA, the bowel is intact; whereas stage IIIB is characterized by bowel perforation that is visualized on X-ray. The signs at this stage encompass the less severe stages (stage I and stage II), plus the infants may have severe respiratory and metabolic acidosis, respiratory failure, hypotension, oliguria, bradycardia, severe apnea, shock, neutropenia, and DIC. The abdomen is likely tense and discolored with spreading erythema or redness.
In approximately ⅓ of the cases, NEC is suspected, but not confirmed and the symptoms gradually resolve. In 24-40% of the cases, the progression of NEC is fierce with signs of peritonitis and sepsis followed by the rapid development of DIC and shock.
Treatment and Management
With NEC, early recognition and aggressive treatment have been shown to improve clinical outcomes. Necrotizing Enterocolitis does impact the long-term morbidity amongst its survivors.
The main goal of treatment is to provide bowel rest and prevent progression of the disease to intestinal perforation and severe symptoms. As I stated previously, NEC is very rare in infants that have not been fed.
For medical management, one of the initial steps is to stop feedings and make the infant NPO. The gastrointestinal rest is usually for 10-14 days. Infants with NEC have a loss of gut motility due to the inflammation in the bowel, so bowel rest with cessation of feedings lessens the stress on the gut.
Next, gastric decompression is initiated. A large bore oral or nasogastric tube, often referred to as a Replogle is placed into the stomach with intermittent suction until the ileus is resolved and pneumatosis is no longer visualized on the X-Ray.
Infants with NEC will also need total parenteral nutrition (TPN) that may be given through a PIV, but more than likely will require a central line due to the need for prolonged IV nutrition, medication administration, and antibiotic therapy. TPN helps to provide appropriate caloric intake until feedings are resumed.
Assessment and management of the cardiovascular and respiratory systems is crucial. Infants with NEC may need fluid replacement, inotropic support to maintain a normal blood pressure, and respiratory support based on the infant’s blood gas results, respiratory status, and clinical condition.
Antibiotics used to treat NEC
Infants with suspected or confirmed NEC will be started on antibiotics. It is recommended to start with a broad spectrum antibiotic that covers pathogens that cause late-onset sepsis in premature infants until the culture identifies a specific pathogen.
Each institution may initiate different antibiotics, but in general, the suggested antibiotic regimen includes ampicillin, gentamicin, and either clindamycin or metronidazole otherwise known as Flagyl. Some institutions may utilize monotherapy with Zosyn or Meropenem. Additionally, if the infant had a central line in place at the onset of the NEC diagnosis or if there is a NICU with a high prevalence of MRSA or ampicillin-resistant enterococcal infections, Vancomycin should be used in place of Ampicillin.
The antibiotic regimen will be modified based on the results of the blood culture or any peritoneal fluid that was sent to pathology as well as surgical specimens. For infants with Bell stage I, the NICU team in collaboration with pediatric surgery, may decide to stop antibiotics a little early and resume feedings based on the clinical course, but every unit may differ in their practice and every infant’s clinical condition will also vary.
Surgical Intervention
As I stated previously, X-rays will be followed closely as well as labs and the infant’s clinical exam to monitor the course for improvement or deterioration. If there is considerable progression of the disease with a lack of response to the medical management, surgical intervention may need to be considered.
Typically once NEC is suspected in an infant, a consultation will be placed for Pediatric Surgery so the peds surgical team can closely follow the infant’s condition and collaborate on their care. A surgical consult is especially necessary for infant’s with stage II or III NEC, if the disease is rapidly progressing, or if there is evidence of an intestinal perforation. The decision for surgical intervention is made collaboratively between the neonatology team and the surgical team, with the inclusion of the parents in all of the decision-making. The presence of a pneumoperitoneum is the only absolute indication for surgical intervention, otherwise the decision is made based on each infant’s complete clinical picture. The goals of surgical intervention are to remove the unviable necrotic intestine and control enteric spillage while preserving as much of the viable intestine as possible.
The surgical procedures for the management of NEC include exploratory laparotomy and primary peritoneal drain placement. The preferred procedural choice varies among institutions, will likely vary based on the surgeon’s recommendation and preference, but is mostly chosen based on each infant’s clinical condition.
The exploratory laparotomy involves the infant going to the operating room and being put under general anesthesia. The surgeon examines or explores the bowel thoroughly and resects the necrotic segments. A portion of the viable bowel is typically used for creation of a proximal enterostomy (usually an ileostomy) and distal mucous fistula. Most infants undergo reanastomosis or reconnection of the bowel anywhere between 4-12 weeks after the initial surgery depending on the infant’s clinical condition.
Unfortunately, for some infants, once the bowel is visualized by the surgeon during the exploratory laparotomy, there may be diffuse ischemia, necrosis, and pneumatosis intestinalis that involves both the small and large intestine. This condition is called NEC totalis and it is severe and fatal. If this is found during the surgery, most infants are given comfort care.
The peritoneal drain placement is typically performed at the infant’s bedside in the NICU. A penrose drain is threaded into the abdomen and secured. The primary purpose of the procedure is to relieve the pressure by evacuation of air and stool through the drain. Placement of the drain also provides additional time to allow some bowel to recover before resection of the non-viable bowel is performed. A peritoneal drain may also be placed for infants who are too critical or those who are too clinically unstable to be transported to the operating room for an exploratory laparotomy.
Post-operatively, these infants need supportive care with fluid replacement, TPN, antibiotics, and bowel rest for 10-14 days. Around two weeks post-op, if the infant is doing well clinically and intestinal motility has returned, small feedings of breast milk may be resumed.
Prevention of NEC
Exclusive Use of Human Breast Milk
As I stated previously, due to quality improvement initiatives throughout NICUs, the focus has been shifted from treatment to prevention of NEC. Research has shown repeatedly that the use of human milk prevents NEC in premature and high risk infants. We know that the use of maternal milk is always preferred. But, if you need a refresher on all of the amazing benefits of maternal milk as well as how the composition of human milk varies when you compare term breastmilk, preterm breast milk and donor breast milk, go back and listen to episode 48. Listening to the episode will help you understand just how specific and wonderful maternal milk is for all infants, but especially preterm infants. But, when maternal milk is not available, rather than feed preterm infants formula, they are given donor human milk instead to reduce the risk of NEC.
Standardized Feeding Protocols
The use of standardized feeding regimens or protocols has also been shown to decrease the incidence of NEC. Therefore, once minimal enteral or trophic feedings are initiated, their advancement is guided by a protocol specific to their gestational age or weight. With feeding protocols in place, there is more consistency in how slowly or quickly feedings are advanced based on the different populations of preterm infants among all providers in the NICU.
Probiotics
The use of probiotics may also be beneficial in preventing NEC. Probiotics promote colonization of the gut with beneficial organisms, preventing colonization by pathogens and improving the maturity and function of the gut mucosal barrier. In a 2022, Dickison and Gonzalez-Shalaby found statistically significant reductions in necrotizing enterocolitis rates after supplementation with probiotics without any reports of adverse effects in their literature review. But, because probiotics are not considered a medication, they are not regulated by the US Food and Drug Administration so there are not any established regimens with the optimal strain and dosing. The use of probiotics in the NICU will be based on each unit’s preference and the parents will be involved in the discussion and ultimately the decision-making process. Prebiotics have also been proposed as a preventative strategy, but more research is needed.
Avoid unnecessary antibiotic administration
Additionally, it is recommended to avoid the use of prolonged and/or unnecessary antibiotic administration. Antibiotics alter the gut flora and ultimately promote the growth of pathogens, especially in susceptible preterm infants.
NEC Mortality Rate
Despite preventative strategies and aggressive treatment, NEC accounts for approximately 10% of infant deaths in the NICU. In a systematic review of literature, the overall mortality rate for infants with confirmed NEC (Bell stage II and III), was 23.5%. The mortality rate increased to 40% for infants who underwent surgery and up to 51% for infants less than 28 weeks who were affected by NEC. Unfortunately, the mortality rate is highest for extremely premature infants who undergo surgical intervention, likely due to the severity of the disease.
Infants that have undergone extensive resection of the bowel may develop short bowel syndrome which requires specific treatment and management with some infants who ultimately require an intestinal transplant. Additionally, about half of the infants that survive NEC have long-term sequelae including gastrointestinal complications, impaired growth, and impaired neurodevelopment. In systematic reviews, infants with NEC were twice as likely to be developmentally impaired when compared to age-matched children without NEC. Survivors of NEC are at an increased risk for cerebral palsy, cognitive and visual impairments.
NEC Society
The NEC society is a charitable organization led by families who have been personally affected by the disease. If you’d like any additional information or would like to support their mission which is to build a world without NEC by advancing research, education, and advocacy, head to necsociety.org or find the link in our show notes.
Closing
I hope you enjoyed this review of necrotizing enterocolitis. As I stated previously, the research findings and preventative measures being utilized in the NICUs today have demonstrated a decrease in the number of NEC cases overall. During my professional career in the NICU, I have seen a reduction myself from when I started out as a NICU nurse 20 years ago (I actually can’t believe it’s been that long). Sadly, back then, we used to see more cases of NEC than what we do now. But today, with the use of human milk feedings and more regimented feeding protocols, although there are still occasional cases, the incidence is less than before.
But, despite the overall reduction, NEC does still affect around 5% of the VLBW infants and the mortality rate for infants with NEC remains 50%.
Whether you are a NICU parent or clinician, I hope you learned some new information. For parents, if you ever notice that your infant is more lethargic and not as responsive, or if their abdomen appears more distended than before, point it out to your baby’s nurse or provider. You know your baby the best and will likely pick up on the subtle cues more than anyone! For NICU nurses, if you notice any of the common symptoms or even if the baby you’re caring for is having some temperature instability with an increase in apnea or bradycardia, or their abdomen appears distended with some erythema, please let the provider know. Remember, the sooner the aggressive treatment begins, the better!
As always, please consider sharing this episode with anyone who may gain some value from it!
References
Altobelli, E., Angeletti, P., Verrotti, A., & Petrocelli, R. (2020). The impact of human milk on necrotizing enterocolitis: A systematic review and meta-analysis. Nutrients, 12(5), https://doi.org/10.3390/nu12051322
Cleveland Clinic. (n.d.) Necrotizing Enterocolitis. https://my.clevelandclinic.org/health/diseases/10026-necrotizing-enterocolitis
Dickison, L. & Gonzalez-Shalabary, C. Reducing Risk Factors for Necrotizing Enterocolitis. Advances in Neonatal Care, 22(6), 513-522.
Eichenwald, E. Hansen, A., Martin, C., & Stark, A. (2017). Cloherty and Stark’s Manual of Neonatal Care, Eight Edition. Wolters Kluwer.
Gardner, S., Carter, B., Enzman-Hines, M., & Niermeyer, S. (2021). Merenstein & Garner’s Handbook of Neonatal Intensive Care Nursing: An Interprofessional Approach, Ninth Edition. Elsevier.
Ginglen, J. & Butki, N. (2022, August 8). Necrotizing Enterocolitis. National Library of Medicine. https://www.ncbi.nlm.nih.gov/books/NBK513357/
Gomella, T., Eyal, F., & Bany-Mohammed, F. (2020). Gomella’s Neonatology: Management, Procedures, On-Call Problems, Diseases, and Drugs, 8th Edition. McGraw-Hill.
Kim, J. (2023, May 11). Neonatal Necrotizing Enterocolitis: Clinical Features and Diagnosis. Up To Date. https://www.uptodate.com/contents/neonatal-necrotizing-enterocolitis-clinical-features-and-diagnosis
Kim, J. (2023, May 9). Neonatal Necrotizing Enterocolitis: Management and Prognosis. Up To Date. https://www.uptodate.com/contents/neonatal-necrotizing-enterocolitis-clinical-features-and-diagnosis
Kim, J. (2023, May 10). Neonatal Necrotizing Enterocolitis: Pathology and Pathogenesis. Up To Date. https://www.uptodate.com/contents/neonatal-necrotizing-enterocolitis-pathology-and-pathogenesis
NEC Society (n.d.) What is NEC? https://necsociety.org/nec-now/
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