|Year : 2016 | Volume
| Issue : 2 | Page : 79-90
Necrotizing enterocolitis - Some things old and some things new: A comprehensive review
Khalid N Haque
Reader in Neonatal Medicine (retired), University of London, UK, International Faculty Professor, Children's Hospital and Institute of Child Health, Lahore, Pakistan
|Date of Web Publication||8-Apr-2016|
Khalid N Haque
276, Club Drive, San Carlos, California 94070, USA
Source of Support: None, Conflict of Interest: None
Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency encountered in particular the preterm infants and less often in term and near-term infants. Since its description in the late 1950's and early 1960's, its incidence along with its associated mortality and morbidity has remained unchanged. In babies born < 1500 g or before to 32 weeks of gestation, its incidence ranges between 3% and 12% and mortality is between 20 and 30%, with highest among those requiring surgery. With better understanding of etiology and pathophysiology, it is now being increasingly recognized that "NEC" as diagnosed by most clinicians in clinical practice may not be a single disease but a spectrum of diseases that present with similar signs and symptoms. NEC is currently thought to be due to dysbiosis of the intestinal microbiome and an uncontrolled exuberant inflammatory response to this microbial imbalance. This comprehensive review discusses the differences between NEC as seen in term and near-term babies as opposed to that seen classically in preterm infants. It also discusses the epidemiology, pathogenesis, and newer diagnostic modalities for the diagnosis of NEC in great depth, because it is only by understanding and appreciation of these dynamics that is likely to lead to the development of successful strategies for prevention, diagnosis, treatment, and improved outcome.
Keywords: Dysbiosis, gastrointestinal, microbiome
|How to cite this article:|
Haque KN. Necrotizing enterocolitis - Some things old and some things new: A comprehensive review. J Clin Neonatol 2016;5:79-90
| Introduction|| |
Necrotizing enterocolitis (NEC) by one name or the other has been recognized since 1828 when preterm infants started being housed in specialized hospital units. Schmidt and Quaiser reported its pathological characterization in 1952.  They called it "enterocolitis ulcerosa necroticans." Initially, the condition was reported to occur in "epidemics" thus suggesting an infectious etiology. However, it was gradually recognized that NEC is an "endemic" condition that is seen in almost all neonatal units worldwide.
NEC has a highly variable geographical incidence, e.g., the incidence in Japan is reported to be low (1.5%). The overall incidence reported from most parts of the world varies between 3 and 12%  with some countries reporting a falling incidence while others reporting an increasing trend.  Some reports have suggested seasonal variation in the incidence of NEC with higher incidence during the winter months. 
In USA and Canada, where the incidence of NEC is among the highest (7-12%) in babies weighing between 500 and 1500 g, approximately 20-30% of these babies die  and nearly quarter of survivors go on to develop microcephaly and are substantially at a greater risk of developing neurodevelopmental delay and other morbidities such as cholestasis and short gut syndrome. ,, It is estimated that in the USA, the cost of caring for infants with NEC is between 500 million and 1 billion dollars per year.  Length of stay in hospital is also increased by 20-60 days compared to infants without NEC. 
Though the precise etiology of NEC remains elusive and debatable, it has become clear that what has been classically defined as NEC is more than one disease. Initially, as NEC occurred in clusters, it was thought to have an infectious etiology by organisms such as Pseudomonas spp., Clostridium perfringens, various virus or infection by nosocomial organisms. Based on animal studies, Mizrahi  and others in the 60's postulated mesenteric hypoperfusion as the main etiological factor of NEC rather than infection. By the 70's, it became clear that NEC did not have a monocasual etiology but a multi-factorial one that included the immaturity of the preterm intestine, bowel ischemia, intestinal infection/infiltration with enterotoxin-producing pathogens, formula, and/or hyperosmolar feeding but till this date, the sequence or the interplay of these factors remains blurred. Till, we are able to clearly delineate the exact pathogenesis of NEC, strategies to prevent and manage NEC would remain a matter of continued and intense research. Hence, a review such as this is needed and will need to be updated from time to time.
| Epidemiology|| |
As indicated earlier, NEC is perhaps the most common gastrointestinal emergency in the preterm infant. Its true incidence is unknown as even now a number of gastrointestinal conditions are "lumped" under the term "NEC". Over decades, in countries where smaller and smaller babies of lower and lower gestation are surviving the incidence of NEC has increased while some other countries have reported a decrease in NEC.  Incidence in USA and Canada is reported to be between 7 and 12% of all preterm births. ,,,, Gordon et al.  have clearly shown that there is an inverse relationship between the onset of NEC and gestational age, i.e., the lower the gestational age, the later the onset of NEC. Using a very large national data set (Pediatrix), they also showed that the incidence of "classic NEC" peaked around the postgestational age of 29-31 weeks, whereas earlier presentation suggested a diagnosis of spontaneous intestinal perforation (SIP). Hunter et al.  suggest that the peak incidence of NEC occurs approximately 3 weeks after birth in infants born before 32 weeks of gestation, 2 weeks after birth in infants born between 32 and 36 weeks of gestation, and under a week in infants born after 36 weeks of gestation.
Earlier studies suggested that there were no geographical, seasonal, or racial differences in the incidence of NEC;  recent studies have challenged this view. There is evidence that Afro-American neonates have a higher incidence of NEC than their white counterparts and that NEC is slightly more frequent during the winter months. ,, Lower frequency of NEC is reported from Japan, Switzerland, Italy, and Austria whilst higher frequency of the disease is reported from Ireland, UK, USA, and Canada. ,,, It is unclear whether these differences are due to care strategies, environment, climate, ethnic background, or genetics. Unfortunately, robust data from developing countries is not available to give comparative figures.
Hull et al.  in a very large study from 55 neonatal units in the USA involving 215,057 very low birth weight infants found that the overall incidence of NEC was 9% of which approximately half were thought to have "medical NEC" and the other half to have "surgical NEC," i.e., those potentially requiring surgery. They reported an overall mortality of 28%. For "medical NEC," mortality in this cohort was 21%, which is much higher than the 6-10% reported from other studies. ,,, Mortality in babies with NEC who required surgery was 30%. 
In one of the largest studies of its kind, Ahle et al.  using the Swedish National Data Base studied the epidemiology and trends of NEC in Sweden between the years 1987 and 2009. They reported data from 2,381,318 live births and found the incidence of NEC to be 3.4/10,000 live births, boys having more NEC than girls (3.7 vs. 3.0/10,000 live births, P = 0.02, relative risk [RR] =1.2, 95% confidence interval [CI]: 1.06-1.40, P = 0.005) this difference remained when adjusted for birth weight, gestational age, birth year. They also observed a consistent seasonal variation with NEC peaking in November with a trough in May. They concluded by stating, "after an initial decrease, the incidence of NEC has increased in Sweden."
| Differential Diagnosis|| |
Prior to discussing the pathogenesis of NEC, it is important to "de-lump" the other conditions that hitherto have been included within the diagnosis of NEC. These conditions not only differ in their pathogenesis but also in strategies to prevent or treat them. They share NEC-like symptoms but usually occur in late preterm or term infants during the 1 st week of life as opposed to true NEC that is seen in very preterm (<32 weeks gestation) infants and occurs during the second or 3 rd week of life.
In term and near-term infants, the NEC-like symptoms may be due to perinatal stress (birth associated events like asphyxia) where mesenteric blood flow is affected, ,, cyanotic heart disease, aganglionosis, intestinal anomalies, maternal substance abuse (cocaine), formula feeding, rapid advancement of feeds, polycythemia with hyperviscosity or maternal chorioamnionitis. The pathogenesis in all these conditions is triggered by mesenteric hypoxia and ischemia that by activating platelet aggravating factor (PAF) and toll-like receptor TLR-4 expression in enterocytes initiates the cascade of apoptosis leading to intestinal mucosal necrosis.
Spontaneous intestinal perforation
This is the major differential diagnosis that has been confused with NEC. The main differentiating features between NEC and SIP are that SIP occurs within the first few days of life in premature infants and is not associated with inflammation or feeding, but a correlation has been reported with steroid and or Indomethacin therapy. ,, SIP has a nonischemic pathology  and histology showing thinned or segmental necrosis of the muscularis interna a common end point of NEC but SIP histology lacks coagulative necrosis and focal hemorrhage seen in NEC. Histologically and biochemically, there is no or minimal inflammation and activation of proinflammatory molecules (cytokines and chemokines) in SIP in contrast to NEC where inflammation and activation of pro-inflammatory molecules is massive. Clinically, it is difficult to differentiate between SIP and NEC though Gordon et al. have suggested a classification system to do this but that classification is not universally used.
Infants with severe sepsis sometimes develop intestinal ileus. The signs and symptoms are that of sepsis along with vomiting or abdominal distension with absence of bowel sound on auscultation. Diagnosis is confirmed by plain X-ray of abdomen. X-ray examination usually shows multiple fluid levels with distended bowel loops but no evidence of pneumatosis or biliary gas.
Viral enterocolitis is another condition that is often confused with NEC. It occurs at any gestation, at any age and is usually seen in clusters. Interestingly, it is characterized by early lymphocytosis something that is not seen with classical NEC.
Food-protein induced enterocolitis syndrome
Food-protein induced enterocolitis syndrome is an uncommon condition more likely to be seen in Asian and African infants who are more prone to have cow's milk intolerance.  The disease is not associated with a robust IgE response but increase in eosinophils into the intestine recruited by elevated interleukin (IL)-5.  Challenge with cow's milk antigen causes them to release their granules. Since preterm infants do not have the capacity to develop true allergy, they have low levels of mucosal necrosis when overchallenged by excessive antigens (cow's milk proteins). Hence, it is suggested that neonatal cow's milk allergy associated NEC is milder with low mortality.  Treatment here is total avoidance of not only cow's milk but also maternal milk as mother's milk may have sufficient cow antigen from their diet to sustain the allergic response in their babies. 
| Pathophysiology/Pathogenesis|| |
Neonatologists have known since the first descriptions of NEC that while prematurity was the major determinant but for NEC to develop it requires other factors such as decreased intestinal barrier function, or an event that compromises its integrity,  impairs intestinal immune defense plus the inflammatory propensity of the premature gut, , and the presence of food and bacteria in the gut [Figure 1].
Understanding 'that pathophysiology of NEC is evolving and is not yet fully understood. The main factor other than the immature motility and absorptive capacity of the newborn's intestine in the first few weeks of life after birth is its dependence on innate rather than adaptive immunity though the two are intertwined. The innate system that consists of cells and their receptors act as "first responders," i.e., they respond rapidly to microbes while the immune system activation requires prior exposure to antigenic stimuli. In the newborn, the adaptive system is significantly underdeveloped thereby increasing the risk of developing NEC. Immunologically, the vulnerability of the preterm infant to NEC is related to the transition from innate to adaptive immune function both systemically and locally in the gut itself. In the gut, once the mucosal barrier (which is poor in the preterm infant due to reduced mucin-producing goblet cells and weak "tight junctions" in between mucosal cells) is disrupted leading to invasion by organisms causing an imbalance between TLR-4 (proinflammatory) and TLR-9 (anti-inflammatory), which are thought to be the main immunological drivers in the development of NEC.
In the neonatal intestine, the TLR-4 gradually increases in expression with increasing gestational age till term when their number falls rapidly along with their surface expression. TLR-4 signaling regulates the balance between injury and repair in the newborn intestine. TLR-4 receptors are important because they sense macromolecules of pathogens, e.g., lipopolysaccharide (LPS)  and are an important regulatory factor for transcription of nuclear factor kappa-B (NFkB), which is underexpressed in the newborn. , Activated TLR-4 increases apoptosis and reduces enterocyte proliferation  and migration. Thus, TLR-4 activation within the intestinal epithelium exerts a deleterious effect on the intestinal mucosa by causing injury and reducing repair.
Enterocyte apoptosis is one of the first histopathological events in the development of NEC. Physiologically, TLR-4 expression gradually increases in the naοve newborn's gut with gestational age until term, when its abundance precipitously falls and its surface expression is also actively downregulated in few weeks after birth. In the preterm, the TLR-4 (numbers and expression) does not fall for a few weeks after birth and are activated secondary to colonization of the gut by both commensal and pathogenic organisms. This continued expression of TLR-4 maybe responsible for the timing of NEC in the preterm infant. The more the TLR-4 is expressed, the more vigorous the apoptosis and severity of the NEC. Unlike in the adults, the tendency of the preterm intestines toward inflammation is not only due to an abundance of TLR-4 receptors but also the intestinal epithelial cells expressing human leukocyte antigen (HLA1) and HLA-DR that accentuate local inflammatory response by acting as antigen presenting cells. , Fetal and neonatal intestinal epithelial cells also produce more cytokines such as IL-1, IL-6, IL-8, and tumor necrosis factor alpha (TNF-α) and PAF when triggered leading to the activation and migration of neutrophils and macrophages making the preterm infants intestine vulnerable to NEC. ,,,,,,
The role of adaptive immunity has not been well studied in NEC. However, we know that T-cells are present in the fetal gut and their numbers and activation is increased in chorioamnionitis… a risk factor for the development of NEC. A subset of T-cells is the T regulatory (Treg) cells are in abundance in the intestinal mucosa of preterm infants. They are responsible for preventing excessive activation of innate and adaptive immune systems in the intestinal tract.  Treg cells act through cytolysis of effector T-cells, secretion of inhibitory cytokines such as IL-10, IL-35, transforming growth factor-beta, and by other ways. , Thus, Treg cells regulate response to limit intestinal injury and inflammation by enhancing adaptive immunity in the gut. 
In summary, NEC is a disease that is characterized by impaired signaling in response to colonization of the gut of the newborn. Prematurity, endotoxemia, and hypoxia all lead to persistent upregulation of intestinal TLR-4. NEC reflects the inability of the newborns intestine to downregulate TLR-4 signaling to become tolerant of intestinal microflora.
Role of intestinal microbiota in necrotizing enterocolitis
Microbial dysbiosis (alteration of intestinal microbial composition) and excessive intestinal inflammatory response associated with it is currently thought to be the most likely pathogenic mechanism for the development of NEC. Intestinal microbiota are involved in regulating the multiple pathways giving rise to an interactive host-microbiota metabolic, signaling, and immune inflammatory process between the gut and other organs including the brain leading to systemic and long-term effects of NEC.
Fetal and newborn infants intestine physiologically and rapidly acquire commensal microbiota during and soon after birth. The composition of this community of intestinal microbiota is derived from maternal colonic and vaginal flora (Enterobacteriae, Enterococci, Staphylococci).  This microbiota further develops in its diversity and is altered by factors such as feeding (breast milk vs. formula milk), use of antibiotics or histamine type 2 (H2) blockers, and the neonatal unit environment itself.
Physiologically, there is a physical separation between the intestinal epithelial cells and the microorganisms maintained by the gel-like mucus layer lining the intestinal epithelium. This layer inhibits bacterial contact with the mucosal surface by My88 dependent secretion of bactericidal C-peptide lectin RegIIIg from the Paneth cells.  In the preterm, this protective mechanism is inefficient and along with poor tight junctions allows the microbes to enter through the mucosal surface. Once in the mucosa, the intestinal (pattern recognition receptors, e.g., TLR-4) are able to specifically recognize (microbial-associated molecular patterns, e.g., LPS or peptoglycans) to setup inflammation. Two other elements of innate immunity that can induce NEC or increase its severity are (PAF, also an upregulator of TLR-4) that senses the metabolic stress caused by the microbial burden and eosinophil's that have the capacity to sense a bacterial specific metabolite N-formyl-methionyl-leucyl-phenylalanine , while some TLRs are proinflammatory that increase cytokine-mediated (IL-8) inflammatory response in the gut.  Nanthakumar et al.  and others , have suggested that the exaggerated inflammatory response in the preterm gut is due to deficient expression of inhibitors of NFkB inflammatory pathway. Furthermore, immature intestine may develop inflammatory responses as the microbial colonization increases with feeding and down-regulation of IL-1 receptor associated with kinase 1, which is an essential component of TLR-4 signaling.  In the intestine, there are other receptors that help maintain intestinal homeostasis by supporting cytoprotection. They secrete antimicrobial peptides and activate commensal (friendly) bacteria. ,, TLR-9 has the opposite effect to TLR-4 it is able to sense the CpG (CpG sites are relatively rare (~1%) on vertebrate genomes in comparison to bacterial genomes or viral DNA) repeats within the DNA of commensal bacteria helping them proliferate.  In brief, intestinal expression of TLR-4 and TLR-9 is reciprocally related during development. TLR-4 within the intestine is functionally active, and that TLR-9 activation with CpG-DNA can limit TLR-4 signaling in enterocytes via a mechanism that requires IRAK-M, thus preventing the development of NEC by limiting TLR-4 induced enterocyte apoptosis and bacterial translocation.
To summarize, the newborn intestine should be able to tolerate beneficial commensal bacteria and other microbes without causing inflammation and injury despite its hyperinflammatory bias. It does that by recognition of friendly commensal bacteria by TRLs or by balancing the proinflammatory and anti-inflammatory TRLs (TRL-4 versus TRL-9) and downregulating NFkB pathway. Other friendly (probiotic) bacteria also reduce inflammation by blocking the degradation of IkB, an inhibitor of NFkB.
Another family of proteins that is generating interest in NEC research is Heparin-binding epithelial growth factor (HB-EGF). It is a naturally occurring glycoprotein produced by monocytes and macrophages. It is also expressed by endothelial, epithelial, and muscle cells and is present in significant quantities in the amniotic fluid and breast milk. HB-EGF is a repair protein that has proliferative and anti-inflammatory properties that are upregulated in response to tissue damage.  HB-EGF acts via several pathways to cytoprotect, i.e., as a growth factor, it stimulates enterocytes to proliferate and migrate and repair intestinal injury.  It protects epithelial cells from TLR-4 induced apoptosis and decreases the production of injurious mediators such as nitric oxide and free radicals. , HB-EGF also decreases neutrophil-endothelial adhesion thus preventing tissue destruction and intestinal injury from activated neutrophils. ,,
| Who is at Risk of Getting Necrotizing Enterocolitis?|| |
While preterm infants < 31 weeks of gestation are at greatest risk of developing NEC, nearly 10% of term or near-term infants also develop NEC. Interestingly, the risk factors in the two groups are different; the very preterm are more likely to develop NEC due to intestinal immaturity, whereas term and near-term infants usually develop NEC secondary to multiple triggering factors.
Prenatal risk factors
Any maternal condition that stimulates the fetal intestinal inflammatory cascade such as maternal hypertension, pregnancy induced hypertension, maternal infection, problems related to placental blood flow or recreational drug use (cocaine) with resultant damage to the vasculature in the watershed areas may lead to mucosal damage and NEC. ,,, Recently, the association between HIV-positive mothers and NEC in their preterm infants has been described.  Histological chorioamnionitis with associated vasculitis increases the risk of infant developing NEC 2.5 fold (odds ratio [OR] 2.6, P = 0.02). 
Intrapartum risk factors
The major intrapartum risk factor is hypoxic-ischemic compromise.  Though unlikely to be a major cause of NEC in the very preterm infant, hypoxia, and ischemia are known to modulate the balance of microvascular tone and production of vascular regulators such as endothelin and epidermal growth factor  that play a role in the development of NEC.
Delivery by cesarean section where the opportunity for the baby to acquire colonization by friendly maternal vaginal commensal bacteria is lost,  which increases the chances of the infant developing NEC particularly if not breastfed. Gregory  have shown that babies who require bag-mask resuscitation (P ≤ 0.002), intubation (P ≤ 0.001), hemodynamic support (P ≤ 0.0001), require inotropic support (P ≤ 0.0001), or had hypotensive episode (P ≤ 0.0001) in the delivery room were between 6.4 and 28.6 times more likely to develop NEC than those who did not require any of the above. Gregory went on to conclude that the "infant most at risk for developing NEC is one weighing between 500 and 1500 g, is <28 weeks in gestation and who requires resuscitation in the delivery room.
Risk factors in the early neonatal period
Several factors in early neonatal care cause intestinal dysbiosis in the gut of the newborn. Antibiotic therapy soon after birth reduces microbial diversity and the growth of friendly commensal bacteria such as Bifidobacter and adversely affects the intestinal innate and adaptive immune systems thus increasing the risk of NEC. ,,,, There is good evidence that lack of antibiotic exposure or reduced duration of exposure to antibiotics reduces the risk of NEC  and conversely the longer the antimicrobial therapy, the greater the risk of NEC.  Chong et al.,  in a recent study, showed a tenfold reduction in the rate of NEC in two centers who changed to using piperacillin and tazobactam as their first-line empirical antibiotic therapy from ampicillin and gentamicin.
Hemodynamically, significant patent ductus arteriosus (PDA) and its treatment with indomethacin have been shown to increase the risk of NEC , while treatment of PDA with ibuprofen is associated with a risk reduction of 0.68% (95% CI: 0.47-0.99). 
Neonatologists often use H2 blockers. H2 blockers by reducing gastric acidity potentiate bacterial growth in the gut. Their use is associated with increasing the risk of infant developing NEC (OR = 1.71, 95% CI: 1.34-2.19, P ≤ 0.0001). ,
It is widespread practice that feeding is withheld once a diagnosis of NEC is considered. Recent thinking suggests that complete withholding of feeds may lead to intestinal atrophy, increased translocation of microbes through the intestinal mucosa increasing the risk of NEC and its severity and systemic infection. 
There is a total consensus that infants who are breastfed given breast milk fortified feeds are 6-10 times less likely to develop NEC compared to formula fed infants. , However, there is debate about the use of trophic feeds and the rate of increase of feeds. Cochrane systemic review by Bombell and McGuire  showed no effect of early trophic feeding versus no feeding on the incidence of NEC (RR 1.07; 95% CI: 0.067-1.70) and the risk difference of 0.01 (95% CI: 0.04-0.05). Similarly, Morgan et al.  in another Cochrane review found no difference in the risk of NEC when feeds were advanced slowly (15-20 ml/kg/day) versus when advanced at the rate of 30-35 ml/kg/day.
Currently, many units are using formula milk containing probiotics. Probiotics are live commensal bacteria that help colonize the gut with friendly bacteria, improve gut motility, quality of intestinal mucus, and control the production of inflammatory cytokines.  Meta-analysis of over two thousand infants has shown that probiotics reduce the risk of NEC by 65% (number to treat 25 infants to save 1 case of NEC).  Wang et al.  in a meta-analysis of 20 randomized controlled trials has shown that probiotics containing both Lactobaccillus and Bifidobacter reduced both the incidence and mortality from NEC whereas probiotic containing only Bifidobacter reduces the incidence of NEC but has no effect on mortality. Role of prebiotics in prevention or treatment has not been fully evaluated. Mother's milk with its many cellular and immunological benefits is also the best to colonize the gut with friendly bacteria. Therefore, it should be the first choice and if it is not available then pasteurized donor milk should be used and only if neither of these are available then feeding with cow's milk formula containing both Bifidobacter and Lactobacillus should be used.
Gastric residuals suggest feeding intolerance; however, it only indicates compromise of intestinal integrity when either the residuals are bloody or in excess of 30-50% of the previous feed. ,,
Other risk factors that have been associated with increased risk of NEC include red blood cell transfusion. This is most often seen in premature infants who are fully formula fed and have AB blood group. , Posttransfusion NEC occurs usually 12-48 h after red blood cell transfusion and is often severe  with approximately 38% of infants with posttransfusion NEC requiring surgery.  The association with AB blood group suggest that AB blood group epitopes that are known to be expressed on the neonatal enterocytes  may be vulnerable to serum antibodies in blood products. Similarly, the use of high-dose immunoglobulins for hemolytic disease has been associated with NEC (OR = 31.66; 95% CI: 3.25-308.57).  This is possibly due to severe opsonization effect of using anti-AB immunoglobulins. Recently, NEC has been associated with cow's milk intolerance due to increased intestinal eosinophil's induced transmigration. ,
Though genetic factors have not been involved in the causation of NEC, a number of genes have been implicated in either affecting the outcome or modifying the disease severity.  Single nucleotide polymorphism in several genes, e.g., IL-4 receptor (+1902G) (protective), IL-8 (−607A) (severity), vascular EGF (+450C) (increased risk), and carbamoyl-phosphate synthetase 1 (T450N) (increased risk), and Sampath et al. have identified the NFkB1 (g-24519 del ATTG promoter polymorphism) variant in all cases of NEC. ,,,,, Bhandari et al.  have reported NEC in either one or both twins in 9 (14%) of 63 pairs of monozygotic twins and in 29 (15%) of 189 dizygotic twins. Thus, the genetic association needs to be further investigated, as does the racial factor NEC being more common in African American infants. 
| Clinical Presentation|| |
The initial presentation of NEC may not be very dissimilar to the presentation of neonatal sepsis. The infant is usually 31 weeks or less in gestation, is stable and feeding well on formula milk who insidiously over a few days starts showing nonspecific symptoms such as temperature instability (7-20%), apnea and bradycardia (32-60%), fluctuating blood pressure with hypotensive episodes (20-80%), increasing gastric residuals (50-90%), emesis (30-40%) abdominal wall redness, tenderness, and distension (10-70%), absent bowel sounds (20-40%), lower right quadrant mass (1-2.7%), and blood in stools (14-40%) (Figures quoted here are averages from a number of studies). Occasionally, the presentation may be acute with sudden collapse and shock-like symptoms with blood in stools; this presentation is more often seen in term or near-term infants who have endured a hypoxic-ischemic event.
Since Bell et al.  first published a staging system in 1978, it has been refined many times, ,,, but all classifications have similar shortcomings of the original Bells's system. NEC can develop without any radiological evidence of pneumatosis or intraluminal or portal gas (prerequisite for the diagnosis of NEC in the staging systems) thus; progression from one stage to another can be missed.  A more reliable staging system perhaps including specific biomarkers is needed. The author prefers to use a more clinical based user-friendly staging system as shown in [Table 1].
|Table 1: Staging of necrotizing enterocolitis based on clinical signs and symptoms |
Click here to view
Laboratory and radiological markers of necrotizing enterocolitis
Though radiology is considered the gold standard diagnostic tool for the diagnosis of NEC, quite often infants with NEC do not have any specific radiological findings. Often infants with NEC or those developing NEC develop nonspecific metabolic or respiratory acidosis, thrombocytopenia, and neutropenia  but if they show lymphocytosis, then rotavirus-associated NEC is very likely.  Blood culture is positive in less than a third of cases, and it is unclear whether this is as a result of bacterial translocation or systemic blood stream infection leading to NEC.
Radiological findings of an ileus or thickened (fixed loop) are nonspecific but finding of intraluminal (Pneumatosis intestinalis) or portal gas which is present in 50-75% of cases is considered diagnostic. Shebrya et al.  have shown that abdominal ultrasound is more sensitive than plain X-ray abdomen. Till date, serial plain X-ray abdomen and cross table lateral X-ray with a horizontal beam are the most often used technologies to detect subtle early collection of free air in the abdomen. , Urboniene et al.  have evaluated the RI and the PI of the superior mesenteric artery in preterm infants and found 96.3% of infants with NEC had an RI of >0.75 (sensitivity 96.3%, specificity 90.9%, OR = 260) whereas 88.9% of infants with NEC had a PI > 1.85 (sensitivity 88.9%, specificity 78.7%, OR = 29) suggesting Doppler measurements of intestinal blood flow as a useful bedside tool for predicting and diagnosing NEC.
| Other Tests|| |
Breath hydrogen sampling has been used for early detection of NEC  but has not gained popularity due to technical difficulties of doing the test in preterm infants and its poor predictive value.
Given the genetic predisposition toward NEC explained earlier, researchers have searched for genetic markers that could predict the diagnosis of NEC. Single-neucleotide polymorphism of CD-14, TLR-4 or caspase-recruitment domain 15, gene that encodes carbamoyl-phosphate synthase 1 and IL-18 AA genotype have been found useful, ,,,, but they lack sensitivity and specificity.
Infants who develop NEC have microbial dysbiosis compared to those who do not. Culture-based studies have clearly demonstrated these differences in fecal bacteria up to 72 h before the onset of NEC.  These changes include increase in Enterobacter and Escherichia More Details Coli with concomitant decrease in Streptococcus faecalis and other Staphylococcus species. Recent nonculture molecular 16S ribosomal RNA-based studies have shown changes in the prevalence of C. perfringens, Firmicutes, Proteobacteria, and Enterobacter prior to the onset of NEC , and decrease in Bifidobacter and changes in unidentified strains similar to Klebsiella.  These changes occur rapidly within the first few weeks of postnatal age , explaining the timeline for the development of NEC in preterm infant. Availability of nonculture molecular 16S ribosomal RNA-based studies offer a great potential for predicting NEC.
As described earlier, the pathogenesis of NEC involves a pathway that includes endogenous inflammatory mediators that cause intestinal injury, e.g., TNF-α, IL-8, PAF, and TLR-4 plus many cytokines and chemokines. Measurements of these mediators on their own have not achieved high sensitivity or specificity. Acute-phase reactants such as C-reactive protein or procalcitonin are raised in stage II and III of NEC but do not offer much in the way of sensitivity and specificity.
Fecal calprotectin is established screening test for the diagnosis of inflammatory bowel disease  in adults. Houston and Morgan  have shown that in the newborn, particularly the preterm infant, it overestimates the risk of NEC and thus should not be used to diagnose or predict NEC.
Intestinal fatty acid binding protein (I-FABP) is a specific indicator of early enterocyte death and is liberated into the blood stream as soon as the integrity of the enterocyte cell membrane is compromised.  Guthmann et al.  measured both I-FABP and liver FABP (L-FABP) and found that though L-FABP was more sensitive of intestinal injury, urinary I-FABP greater than 2 pg/nmol to creatinine ratio clearly distinguishes NEC from other conditions. Also associated with NEC are low levels of arginine and glutamine, but their measurement has not been found useful.
Interestingly, salivary derived epidermal growth factor which is physiologically low in preterm infants shows a very rapid rise during the 1 st week of life in infants who go on to develop NEC. 
New molecular techniques such as mass spectrometry, transcriptomics, and proteomics have emerged in developing new and novel biomarkers. Ng et al.  using proteomic techniques have found that proapolipoprotein CII and des-arginine variant of serum amyloid A as the most promising biomarkers for the diagnosis of NEC (sensitivity 90%, specificity 95%) but their study has to be validated from other institutions using larger cohort of patients.
Thus, advances in molecular diagnostic technologies in particular gene sequencing, mass spectrometry, and proteomics offer greater hope for diagnostic test for NEC. However, until these tests are made available, we have to contend with nonspecific tests with poor sensitivity and specificity.
| Management/Treatment Of Necrotizing Enterocolitis|| |
Management of a case of NEC and treatment has not changed over last three decades. It is based on the principles of resting the bowel by stopping feeds (there is no consensus for how long to stop feeds for), gastric decompression by placing an oral-gastric tube, management to support nutritional needs by parenteral nutrition and supporting the metabolic, cardiovascular, and respiratory effects of systemic disease.  Antibiotics (there is no consensus on which ones to use or for how long) are always given for possible infective etiology (though <10-15% of cases have positive blood culture) or complications. Often antianaerobics or antifungals are added if perforation is suspected or confirmed. , Small studies have shown enteral aminoglycoside therapy may prevent NEC, but risk of resistance development has prevented the adoption of this strategy.
Frequent radiological and laboratory assessments (there is again no consensus on how frequent) are done to monitor the progress of the disease.
As soon as the diagnosis of NEC is considered, most clinicians would inform their surgical team. Surgeons either use peritoneal drainage or laparotomy with bowel resection to decompress the gut and/or remove necrotic bowel. Infants who have peritoneal drainage often go on to require laparotomy.  Systematic reviews suggest that mortality may be 50% higher with peritoneal drainage compared with laparotomy.  Despite this, there is still debate whether primary peritoneal drainage has a role in critically ill preterm with NEC.  In babies who develop pancolitis (NEC totalis), then jejunostomy has shown some benefit compared to total bowel resection. 
| Prevention Strategies|| |
The major advance that has taken place in the management of NEC has been in the development of strategies to prevent or reduce the incidence of NEC. These include the following:
- Exclusive breastfeeding
- Promoting, preserving, and restoring healthy gut flora
- Use of standardized feeding protocols (SFPs)
- Limiting the use of anti-microbial therapy in the early neonatal period.
As stated earlier that the benefits of feeding the preterm infants, his/her own mother's milk have been shown over and over again to protect the baby from developing NEC. ,, For every 10 babies fed on mother's breast milk, one case of NEC is prevented.  If mother's milk is unavailable, then feeding donor breast milk will reduce the risk of NEC by 80% compared with formula milk feeding (RR = 0.21; 95% CI: 0.06-0.76).  If neither mother's milk nor donor breast milk is available, then preterm infants should be fed on preterm formula containing probiotics (Bifidobacter plus Lactobacillus).
Despite nine randomized controlled trials showing inconclusive evidence for trophic feeding,  this practice appears to be safe  and should be started as early as possible  keeping in mind that the premature intestine starts showing signs of atrophy if no feeds are given for 3 or more days.
Promoting, preserving, and restoring health gut flora
This can be achieved to a great extent by using probiotics in the feeds, i.e., using milk that contains Bifidobacter or Lactobacillus or both. In a large meta-analysis, Yang et al.  analyzed a total of 6655 preterm infants and found that probiotic supplementation reduced the risk of Bell Stage I and Stage II NEC (RR = 0.35, 95%, CI: 0.27-0.44, P ≤ 0.00001) and (RR = 0.34, 95% CI: 0.25-0.48, P ≤ 0.00001), respectively. The risk was also reduced for mortality from NEC without any increase in the risk for sepsis. There is not enough robust evidence for the benefits or otherwise of using prebiotics.
Use of standardized feeding protocol
Christensen et al.  in their article "Can we cut the incidence of NEC in half today?" suggested that one of the measures that can reduce the incidence of NEC is the institution of "SFPs." Patole and de Klerk  in a meta-analysis of 3762 infants weighing <1500 g described an approximate reduction in NEC up to 85% when SFP was used. A number of other researchers have shown that regardless of the protocol used the advantages of using SFPs outweighs using no SFP's in the prevention of NEC. 
Limiting the use of antimicrobial therapy in early neonatal period
Avoiding or limiting the use of empirical antibiotic therapy improves the healthy balance, quantity, and diversity of commensal bacteria in the neonatal gut offering the immunological advantages eluded to earlier in this review. In USA, the median duration of empiric antimicrobial treatment in neonates ranges from 3 to 9.5 days.  This study showed that the odds for developing NEC was 40% higher for infants receiving 7 versus 2 days empiric antibiotic therapy for culture negative or suspected early onset sepsis. ,
| Future|| |
With the use of "omic" technologies, it is hoped that sensitive and specific markers of NEC would be developed.
Lately, with evidence of HB-EGF having a role in cytoprotection and growth activity of the enterocytes and intestinal repair, Phase I and Phase II clinical trials are either underway or planned to establish the therapeutic use of HB-EGF to prevent and reduce the incidence of NEC.
| Conclusion|| |
A challenge that a comprehensive review of this magnitude poses is in providing a large amount of information and at the same time to provide the jobbing clinician advice/knowledge that is helpful in their daily practice.
It is now beyond doubt that NEC as clinically diagnosed today is not a single disease but an amalgam of conditions whose end point is injury to the premature gut. Thus, attempts should be made to clearly differentiate true NEC from other conditions masquerading as NEC. While the current diagnostic and management strategies and the outcome have not changed over many years, there have been advances made or are being made in understanding the pathogenesis of NEC and developing newer and unique biomarkers to predict or make early diagnosis so that robust treatment strategies could be adopted.
The greatest challenge is to bring this understanding of the pathogenesis and diagnostic tools together so that the clinician can diagnose and treat NEC better than before.
I am very grateful to Dr. Irfan Waheed and Dr. Talal Waqar for reviewing the manuscript and for their helpful suggestions.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Obladen M. Necrotizing enterocolitis-150 years of fruitless search for the cause. Neonatology 2009;96:203-10.
Ahle M, Drott P, Andersson RE. Epidemiology and trends of necrotizing enterocolitis in Sweden: 1987-2009. Pediatrics 2013;132:e443-51.
Fitzgibbons SC, Ching Y, Yu D, Carpenter J, Kenny M, Weldon C, et al.
Mortality of necrotizing enterocolitis expressed by birth weight categories. J Pediatr Surg 2009;44:1072-5.
Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med 2011;364:255-64.
Hintz SR, Kendrick DE, Stoll BJ, Vohr BR, Fanaroff AA, Donovan EF, et al.
Neurodevelopmental and growth outcomes of extremely low birth weight infants after necrotizing enterocolitis. Pediatrics 2005;115:696-703.
Bedrick AD. Necrotizing enterocolitis: Neurodevelopmental "risky business". J Perinatol 2004;24:531-3.
Mizrahi A, Barlow O, Berdon W, Blanc WA, Silverman WA. Necrotizing enterocolitis in premature infants. J Pediatr 1965;66:697-705.
Hull MA, Fisher JG, Gutierrez IM, Jones BA, Kang KH, Kenny M, et al.
Mortality and management of surgical necrotizing enterocolitis in very low birth weight neonates: A prospective cohort study. J Am Coll Surg 2014;218:1148-55.
Gordon PV, Clark R, Swanson JR, Spitzer A. Can a national dataset generate a nomogram for necrotizing enterocolitis onset? J Perinatol 2014;34:732-5.
Hunter CJ, Podd B, Ford HR, Camerini V. Evidence vs experience in neonatal practices in necrotizing enterocolitis. J Perinatol 2008;28 Suppl 1:S9-13.
Holman RC, Stoll BJ, Clarke MJ, Glass RI. The epidemiology of necrotizing enterocolitis infant mortality in the United States. Am J Public Health 1997;87:2026-31.
Yee WH, Soraisham AS, Shah VS, Aziz K, Yoon W, Lee SK; Canadian Neonatal Network. Incidence and timing of presentation of necrotizing enterocolitis in preterm infants. Pediatrics 2012;129:e298-304.
Kawase Y, Ishii T, Arai H, Uga N. Gastrointestinal perforation in very low-birthweight infants. Pediatr Int 2006;48:599-603.
Guner YS, Friedlich P, Wee CP, Dorey F, Camerini V, Upperman JS. State-based analysis of necrotizing enterocolitis outcomes. J Surg Res 2009;157:21-9.
Lambert DK, Christensen RD, Henry E, Besner GE, Baer VL, Wiedmeier SE, et al.
Necrotizing enterocolitis in term neonates: Data from a multihospital health-care system. J Perinatol 2007;27:437-43.
Maayan-Metzger A, Itzchak A, Mazkereth R, Kuint J. Necrotizing enterocolitis in full-term infants: Case-control study and review of the literature. J Perinatol 2004;24:494-9.
Ostlie DJ, Spilde TL, St Peter SD, Sexton N, Miller KA, Sharp RJ, et al.
Necrotizing enterocolitis in full-term infants. J Pediatr Surg 2003;38:1039-42.
Stark AR, Carlo WA, Tyson JE, Papile LA, Wright LL, Shankaran S, et al.
Adverse effects of early dexamethasone in extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network. N Engl J Med 2001;344:95-101.
Gordon PV, Young ML, Marshall DD. Focal small bowel perforation: An adverse effect of early postnatal dexamethasone therapy in extremely low birth weight infants. J Perinatol 2001;21:156-60.
Attridge JT, Clark R, Walker MW, Gordon PV. New insights into spontaneous intestinal perforation using a national data set: (2) Two populations of patients with perforations. J Perinatol 2006;26:185-8.
Gordon PV, Swanson JR, Attridge JT, Clark R. Emerging trends in acquired neonatal intestinal disease: Is it time to abandon Bell's criteria? J Perinatol 2007;27:661-71.
Feuille E, Nowak-Wegrzyn A. Definition, etiology, and diagnosis of food protein-induced enterocolitis syndrome. Curr Opin Allergy Clin Immunol 2014;14:222-8.
Lupp C, Robertson ML, Wickham ME, Sekirov I, Champion OL, Gaynor EC, et al.
Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae
. Cell Host Microbe 2007;2:119-29.
Coviello C, Rodriquez DC, Cecchi S, Tataranno ML, Farmeschi L, Mori A, et al.
Different clinical manifestation of cow's milk allergy in two preterm twins newborns. J Matern Fetal Neonatal Med 2012;25 Suppl 1:132-3.
Gordon PV, Clark R. In response to the case report of allergic enterocolitis in a preterm neonate: How prevalent is systemic eosinophilia with NEC? J Perinatol 2011;31:297-8.
Sharma R, Tepas JJ 3 rd
, Hudak ML, Mollitt DL, Wludyka PS, Teng RJ, et al.
Neonatal gut barrier and multiple organ failure: Role of endotoxin and proinflammatory cytokines in sepsis and necrotizing enterocolitis. J Pediatr Surg 2007;42:454-61.
Lin PW, Nasr TR, Stoll BJ. Necrotizing enterocolitis: Recent scientific advances in pathophysiology and prevention. Semin Perinatol 2008;32:70-82.
Nanthakumar NN, Fusunyan RD, Sanderson I, Walker WA. Inflammation in the developing human intestine: A possible pathophysiologic contribution to necrotizing enterocolitis. Proc Natl Acad Sci U S A 2000;97:6043-8.
Good M, Sodhi C, Siggers R, Prindle T, Branca M, Russo A, et al
. Epithelial growth factor attenuates the severity of experimental necrotizing enterocolitis and inhibits toll-like receptor 4 signaling in Enterocytes. E-PAS 2011:2720-3.
Fusunyan RD, Nanthakumar NN, Baldeon ME, Walker WA. Evidence for an innate immune response in the immature human intestine: Toll-like receptors on fetal enterocytes. Pediatr Res 2001;49:589-93.
Claud EC, Lu L, Anton PM, Savidge T, Walker WA, Cherayil BJ. Developmentally regulated IkappaB expression in intestinal epithelium and susceptibility to flagellin-induced inflammation. Proc Natl Acad Sci U S A 2004;101:7404-8.
Rognum TO, Thrane S, Stoltenberg L, Vege A, Brandtzaeg P. Development of intestinal mucosal immunity in fetal life and the first postnatal months. Pediatr Res 1992;32:145-9.
Emami CN, Mittal R, Wang L, Ford HR, Prasadarao NV. Role of neutrophils and macrophages in the pathogenesis of necrotizing enterocolitis caused by Cronobacter sakazakii
. J Surg Res 2012;172:18-28.
Martin CR, Walker WA. Intestinal immune defences and the inflammatory response in necrotising enterocolitis. Semin Fetal Neonatal Med 2006;11:369-77.
Uhlig HH, Powrie F. The role of mucosal T lymphocytes in regulating intestinal inflammation. Springer Semin Immunopathol 2005;27:167-80.
Neu J, Chen M, Beierle E. Intestinal innate immunity: How does it relate to the pathogenesis of necrotizing enterocolitis. Semin Pediatr Surg 2005;14:137-44.
Cong Y, Feng T, Fujihashi K, Schoeb TR, Elson CO. A dominant, coordinated T regulatory cell-IgA response to the intestinal microbiota. Proc Natl Acad Sci U S A 2009;106:19256-61.
Claud EC, Walker AW. The intestinal microbiota and the microbiome. New York: Saunders; 2008.
Vaishnava S, Yamamoto M, Severson KM, Ruhn KA, Yu X, Koren O, et al.
The antibacterial lectin Reg III gamma promotes the spatial segregation of microbiota and host in the intestine. Science 2011;334:255-8.
Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 2004;118:229-41.
Abreu MT. Toll-like receptor signalling in the intestinal epithelium: How bacterial recognition shapes intestinal function. Nat Rev Immunol 2010;10:131-44.
Cario E, Gerken G, Podolsky DK. Toll-like receptor 2 controls mucosal inflammation by regulating epithelial barrier function. Gastroenterology 2007;132:1359-74.
Nanthakumar N, Meng D, Goldstein AM, Zhu W, Lu L, Uauy R, et al.
The mechanism of excessive intestinal inflammation in necrotizing enterocolitis: An immature innate immune response. PLoS One 2011;6:e17776.
Lotz M, Gütle D, Walther S, Ménard S, Bogdan C, Hornef MW. Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells. J Exp Med 2006;203:973-84.
Michalsky MP, Lara-Marquez M, Chun L, Besner GE. Heparin-binding EGF-like growth factor is present in human amniotic fluid and breast milk. J Pediatr Surg 2002;37:1-6.
Feng J, El-Assal ON, Besner GE. Heparin binding epidermal growth factor-like growth factor decreases the incidence of necrotizing enterocolitis in rats with NEC. J Pediatr Surg 2007;42:214-20.
Feng J, El-Assal ON, Besner GE. Heparin-binding epidermal growth factor-like growth factor decreases the incidence of necrotizing enterocolitis in neonatal rats. J Pediatr Surg 2006;41:144-9.
Kuhn MA, Xia G, Mehta VB, Glenn S, Michalsky MP, Besner GE. Heparin-binding EGF-like growth factor (HB-EGF) decreases oxygen free radical production in vitro
and in vivo
. Antioxid Redox Signal 2002;4:639-46.
Rocourt M, Mehta V, Besner G. Heparin binding EGF-like growth factor (HB-EGF) decreases neutrophil-endothelial cell interaction. J Pediatr Surg 2007;139:269-73.
El-Assal ON, Besner GE. Heparin-binding epidermal growth factor-like growth factor and intestinal ischemia-reperfusion injury. Semin Pediatr Surg 2004;13:2-10.
El-Assal ON, Radulescu A, Besner GE. Heparin-binding EGF-like growth factor preserves mesenteric microcirculatory blood flow and protects against intestinal injury in rats subjected to hemorrhagic shock and resuscitation. Surgery 2007;142:234-42.
Neish AS. Molecular aspects of intestinal epithelial cell-bacterial interactions that determine the development of intestinal inflammation. Inflamm Bowel Dis 2004;10:159-68.
Hand IL, Noble L, McVeigh TJ, Kim M, Yoon JJ. The effects of intrauterine cocaine exposure on the respiratory status of the very low birth weight infant. J Perinatol 2001;21:372-5.
Bashiri A, Zmora E, Sheiner E, Hershkovitz R, Shoham-Vardi I, Mazor M. Maternal hypertensive disorders are an independent risk factor for the development of necrotizing enterocolitis in very low birth weight infants. Fetal Diagn Ther 2003;18:404-7.
Ogunyemi D, Murillo M, Jackson U, Hunter N, Alperson B. The relationship between placental histopathology findings and perinatal outcome in preterm infants. J Matern Fetal Neonatal Med 2003;13:102-9.
Desfrere L, de Oliveira I, Goffinet F, El Ayoubi M, Firtion G, Bavoux F, et al.
Increased incidence of necrotizing enterocolitis in premature infants born to HIV-positive mothers. AIDS 2005;19:1487-93.
Nowicki PT, Nankervis CA. The role of the circulation in the pathogenesis of necrotizing enterocolitis. Clin Perinatol 1994;21:219-34.
Warner BB, Ryan AL, Seeger K, Leonard AC, Erwin CR, Warner BW. Otogeny of salivery epidermal growth factor and necrotizing enterocolitis. J Pediatr 2007;150:358-60.
Westerbeek EA, van den Berg A, Lafeber HN, Knol J, Fetter WP, van Elburg RM. The intestinal bacterial colonisation in preterm infants: A review of the literature. Clin Nutr 2006;25:361-8.
Gregory KE. Clinical predictors of necrotizing enterocolitis in premature infants. Nurs Res 2008;57:260-70.
Cotten CM, Taylor S, Stoll B, Goldberg RN, Hansen NI, Sánchez PJ, et al.
Prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely low birth weight infants. Pediatrics 2009;123:58-66.
Kuppala VS, Meinzen-Derr J, Morrow AL, Schibler KR. Prolonged initial empirical antibiotic treatment is associated with adverse outcomes in premature infants. J Pediatr 2011;159:720-5.
Alexander VN, Northrup V, Bizzarro MJ. Antibiotic exposure in the newborn intensive care unit and the risk of necrotizing enterocolitis. J Pediatr 2011;159:392-7.
Chong E, Reynolds J, Shaw J, Forur L, Delmore P, Uner H, et al.
Results of a two-center, before and after study of piperacillin-tazobactam versus ampicillin and gentamicin as empiric therapy for suspected sepsis at birth in neonates ≤1500 g. J Perinatol 2013;33:529-32.
Dollberg S, Lusky A, Reichman B. Patent ductus arteriosus, indomethacin and necrotizing enterocolitis in very low birth weight infants: A population-based study. J Pediatr Gastroenterol Nutr 2005;40:184-8.
Ohlsson A, Shah SS. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database of Systematic Reviews 2011, Issue 7. Art. No.: CD004213. DOI: 10.1002/14651858.CD004213.pub3.
Patole S, McGlone L, Muller R. Virtual elimination of necrotising enterocolitis for 5 years - reasons? Med Hypotheses 2003;61:617-22.
Gantz M, Roy J, Guillet R. Analyzing retrospective data with time-varying exposure: A cautionary tale of H2 blockers in ELBW neonates. Am J Perinatol 2008;25:93-100.
Moss RL, Kalish LA, Duggan C, Johnston P, Brandt ML, Dunn JC, et al.
Clinical parameters do not adequately predict outcome in necrotizing enterocolitis: A multi-institutional study. J Perinatol 2008;28:665-74.
Chauhan M, Henderson G, McGuire W. Enteral feeding for very low birth weight infants: Reducing the risk of necrotising enterocolitis. Arch Dis Child Fetal Neonatal Ed 2008;93:F162-6.
Lucas A, Cole JJ. Breast milk and neonatal necrotising enterocolitis. Lancet 1990;336:1519-23.
Bombell S, McGuire W. Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database Syst Rev 2008. Issue 2. Art. No.: CD001970. DOI: 10.1002/14651858.CD001970.pub2.
Morgan J, Young L, McGuire W. Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database Syst Rev 2011. Issue 12. Art. No.: CD001970. DOI: 10.1002/14651858.CD001970.pub5.
Tarnow-Mordi WO, Wilkinson D, Trivedi A, Brok J. Probiotics reduce all-cause mortality and necrotizing enterocolitis: It is time to change practice. Pediatrics 2010;125:1068-70.
Deshpande G, Rao S, Patole S, Bulsara M. Updated meta-analysis of probiotics for preventing necrotizing enterocolitis in preterm neonates. Pediatrics 2010;125:921-30.
Wang Q, Dong J, Zhu Y. Probiotic supplement reduces risk of necrotizing enterocolitis and mortality in preterm very low-birth-weight infants: An updated meta-analysis of 20 randomized, controlled trials. J Pediatr Surg 2012;47:241-8.
Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics 2012;129:e827-41.
Bertino E, Giuliani F, Prandi G, Coscia A, Martano C, Fabris C. Necrotizing enterocolitis: Risk factor analysis and role of gastric residuals in very low birth weight infants. J Pediatr Gastroenterol Nutr 2009;48:437-42.
Gephart SM, McGrath JM, Effken JA, Halpern MD. Necrotizing enterocolitis risk: State of the science. Adv Neonatal Care 2012;12:77-87.
Thomson T, Habeeb O, Dechristopher PJ, Glynn L, Yong S, Muraskas J. Decreased survival in necrotizing enterocolitis is significantly associated with neonatal and maternal blood group: The AB isoagglutinin hypothesis. J Perinatol 2012;32:626-30.
Christensen RD, Lambert DK, Henry E, Wiedmeier SE, Snow GL, Baer VL, et al.
Is "transfusion-associated necrotizing enterocolitis" an authentic pathogenic entity? Transfusion 2010;50:1106-12.
Singh R, Visintainer PF, Frantz ID 3 rd
, Shah BL, Meyer KM, Favila SA, et al.
Association of necrotizing enterocolitis with anemia and packed red blood cell transfusions in preterm infants. J Perinatol 2011;31:176-82.
Figueras-Aloy J, Rodríguez-Miguélez JM, Iriondo-Sanz M, Salvia-Roiges MD, Botet-Mussons F, Carbonell-Estrany X. Intravenous immunoglobulin and necrotizing enterocolitis in newborns with hemolytic disease. Pediatrics 2010;125:139-44.
Moshfegh A, Lothian C, Halldén G, Marchini G, Lagercrantz H, Lundahl J. Neonatal eosinophils possess efficient Eotaxin/IL-5- and N-formyl-methionyl-leucyl-phenylalanine-induced transmigration in vitro
. Pediatr Res 2005;58:138-42.
Treszl A, Héninger E, Kálmán A, Schuler A, Tulassay T, Vásárhelyi B. Lower prevalence of IL-4 receptor alpha-chain gene G variant in very-low-birth-weight infants with necrotizing enterocolitis. J Pediatr Surg 2003;38:1374-8.
Carter BM, Holditch-Davis D. Risk factors for necrotizing enterocolitis in preterm infants: How race, gender, and health status contribute. Adv Neonatal Care 2008;8:285-90.
Héninger E, Treszl A, Kocsis I, Dérfalvi B, Tulassay T, Vásárhelyi B. Genetic variants of the interleukin-18 promoter region (-607) influence the course of necrotising enterocolitis in very low birth weight neonates. Eur J Pediatr 2002;161:410-1.
Bányász I, Bokodi G, Vásárhelyi B, Treszl A, Derzbach L, Szabó A, et al.
Genetic polymorphisms for vascular endothelial growth factor in perinatal complications. Eur Cytokine Netw 2006;17:266-70.
Moonen RM, Paulussen AD, Souren NY, Kessels AG, Rubio-Gozalbo ME, Villamor E. Carbamoyl phosphate synthetase polymorphisms as a risk factor for necrotizing enterocolitis. Pediatr Res 2007;62:188-90.
Sampath V, Le M, Lane L, Patel AL, Cohen JD, Simpson PM, et al.
The NFKB1 (g.-24519delATTG) variant is associated with necrotizing enterocolitis (NEC) in premature infants. J Surg Res 2011;169:e51-7.
Bhandari V, Bizzarro MJ, Shetty A, Zhong X, Page GP, Zhang H, et al.
Familial and genetic susceptibility to major neonatal morbidities in preterm twins. Pediatrics 2006;117:1901-6.
Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, et al.
Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg 1978;187:1-7.
Walsh MC, Kliegman RM. Necrotizing enterocolitis: Treatment based on staging criteria. Pediatr Clin North Am 1986;33:179-201.
Lee JS, Polin RA. Treatment and prevention of necrotizing enterocolitis. Semin Neonatol 2003;8:449-59.
Rees CM, Eaton S, Khoo AK, Kiely EM; Members of NET Trial Group, Pierro A. Peritoneal drainage does not stabilize extremely low birth weight infants with perforated bowel: Data from the NET Trial. J Pediatr Surg 2010;45:324-8.
Epelman M, Daneman A, Navarro OM, Morag I, Moore AM, Kim JH, et al.
Necrotizing enterocolitis: Review of state-of-the-art imaging findings with pathologic correlation. Radiographics 2007;27:285-305.
Gregory KE, Deforge CE, Natale KM, Phillips M, Van Marter LJ. Necrotizing enterocolitis in the premature infant: Neonatal nursing assessment, disease pathogenesis, and clinical presentation. Adv Neonatal Care 2011;11:155-64.
Sharma R, Garrison RD, Tepas JJ 3 rd
, Mollitt DL, Pieper P, Hudak ML, et al.
Rotavirus-associated necrotizing enterocolitis: An insight into a potentially preventable disease? J Pediatr Surg 2004;39:453-7.
Shebrya NH, Amin SK, El-Shinnawy MA, Imam SS. Abdominal ultrasonography in preterm necrotizing enterocolitis. Is it superior to plain radiography? The Egyptian Journal of Radiology and Nuclear Medicine 2012;43:457-63.
Jayakumar S, Patwardhan N. Characteristic radiological findings in preterm infants with missed intestinal perforation. J Neonatal Surg 2014;3:27.
Kamali K, Hosseini SR, Ardakani SM, Farnoodi MR. Complementory value of sonography in early evaluation of necrotizing enterocolitis. Pol J Radiol 2015;80:317-23.
Urboniene A, Palepsaitis A, Uktveris R, Barauskas V. Doppler flowmetry of the superior mesenteric artery and portal vein: Impact for the early prediction of necrotizing enterocolitis in neonates. Pediatr Surg Int 2015;31:1061-6.
Cheu HW, Brown DR, Rowe MI. Breath hydrogen excretion as a screening test for the early diagnosis of necrotizing enterocolitis. Am J Dis Child 1989;143:156-9.
Hoy C, Millar MR, MacKay P, Godwin PG, Langdale V, Levene MI. Quantitative changes in faecal microflora preceding necrotising enterocolitis in premature neonates. Arch Dis Child 1990;65:1057-9.
Morrow AL, Lagomarcino AJ, Schibler KR, Taft DH, Yu Z, Wang B, et al.
Early microbial and metabolomic signatures predict later onset of necrotizing enterocolitis in preterm infants. Microbiome 2013;1:13.
Mai V, Young CM, Ukhanova M, Wang X, Sun Y, Casella G, et al.
Fecal microbiota in premature infants prior to necrotizing enterocolitis. PLoS One 2011;6:e20647.
Torrazza RM, Ukhanova M, Wang X, Sharma R, Hudak ML, Neu J, et al.
Intestinal microbial ecology and environmental factors affecting necrotizing enterocolitis. PLoS One 2013;8:e83304.
Moles L, Gómez M, Heilig H, Bustos G, Fuentes S, de Vos W, et al.
Bacterial diversity in meconium of preterm neonates and evolution of their fecal microbiota during the first month of life. PLoS One 2013;8:e66986.
D'Incà R, Dal Pont E, Di Leo V, Benazzato L, Martinato M, Lamboglia F, et al
. Can calprotectin predict relapse in inflammatory bowel disease? Am J Gastroenterol 2008;103:2007-14.
Houston JF, Morgan JE. Question 2: Can faecal calprotectin be used as an effective diagnostic aid for necrotising enterocolitis in neonates? Arch Dis Child 2015;100:1003-6.
Thuijls G, Derikx JP, van Wijck K, Zimmermann LJ, Degraeuwe PL, Mulder TL, et al.
Non-invasive markers for early diagnosis and determination of the severity of necrotizing enterocolitis. Ann Surg 2010;251:1174-80.
Guthmann F, Börchers T, Wolfrum C, Wustrack T, Bartholomäus S, Spener F. Plasma concentration of intestinal- and liver-FABP in neonates suffering from necrotizing enterocolitis and in healthy preterm neonates. Mol Cell Biochem 2002;239:227-34.
Warner BB, Ryan AL, Seeger K, Leonard AC, Erwin CR, Warner BW. Ontogeny of salivary epidermal growth factor and necrotizing enterocolitis. J Pediatr 2007;150:358-63.
Ng PC, Ang IL, Chiu RW, Li K, Lam HS, Wong RP, et al.
Host-response biomarkers for diagnosis of late-onset septicemia and necrotizing enterocolitis in preterm infants. J Clin Invest 2010;120:2989-3000.
Patole S. Prevention and treatment of necrotising enterocolitis in preterm neonates. Early Hum Dev 2007;83:635-42.
Rees CM, Eaton S, Kiely EM, Wade AM, McHugh K, Pierro A. Peritoneal drainage or laparotomy for neonatal bowel perforation? A randomized controlled trial. Ann Surg 2008;248:44-51.
Sola JE, Tepas JJ 3 rd
, Koniaris LG. Peritoneal drainage versus laparotomy for necrotizing enterocolitis and intestinal perforation: A meta-analysis. J Surg Res 2010;161:95-100.
Pierro A, Eaton S, Rees CM, De Coppi P, Kiely EM, Peters MJ, et al.
Is there a benefit of peritoneal drainage for necrotizing enterocolitis in newborn infants? J Pediatr Surg 2010;45:2117-8.
Thyoka M, Eaton S, Kiely EM, Curry JI, Drake DP, Cross KM, et al.
Outcomes of diverting jejunostomy for severe necrotizing enterocolitis. J Pediatr Surg 2011;46:1041-4.
Renfrew MJ, Craig D, Dyson L, McCormick F, Rice S, King SE, et al.
Breastfeeding promotion for infants in neonatal units: A systematic review and economic analysis. Health Technol Assess 2009;13:1-146, iii-iv.
Sullivan S, Schanler RJ, Kim JH, Patel AL, Trawöger R, Kiechl-Kohlendorfer U, et al.
An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J Pediatr 2010;156:562-7.e1.
Boyd CA, Quigley MA, Brocklehurst P. Donor breast milk versus infant formula for preterm infants: Systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed 2007;92:F169-75.
Smith JR. Early enteral feeding for the very low birth weight infant: The development and impact of a research-based guideline. Neonatal Netw 2005;24:9-19.
Yang Y, Guo Y, Kan Q, Zhou XG, Zhou XY, Li Y. A meta-analysis of probiotics for preventing necrotizing enterocolitis in preterm neonates. Braz J Med Biol Res 2014;47:804-10.
Christensen RD, Gordon PV, Besner GE. Can we cut the incidence of necrotizing enterocolitis in half - Today? Fetal Pediatr Pathol 2010;29:185-98.
Patole SK, de Klerk N. Impact of standardised feeding regimens on incidence of neonatal necrotising enterocolitis: A systematic review and meta-analysis of observational studies. Arch Dis Child Fetal Neonatal Ed 2005;90:F147-51.
Gephart SM, Hanson CK. Preventing necrotizing enterocolitis with standardized feeding protocols. Ad Neonatal Care 2013;13:48-54.
|This article has been cited by|
||Necrotizing Enterocolitis Presented at birth in a Full-Term Baby Born to a Mother with Chorioamnionitis
| ||Husam Salama,Alaa Al.fakharani,Salem Mammoo |
| ||Neonatology Today. 2020; 15(12): 24 |
|[Pubmed] | [DOI]|
||Multidisciplinary evaluation of Clostridium butyricum clonality isolated from preterm neonates with necrotizing enterocolitis in South France between 2009 and 2017
| ||Michel Hosny,Jacques Yaacoub Bou Khalil,Aurelia Caputo,Rita Abou Abdallah,Anthony Levasseur,Philippe Colson,Nadim Cassir,Bernard La Scola |
| ||Scientific Reports. 2019; 9(1) |
|[Pubmed] | [DOI]|
||Early Biomarkers in Neonatal Necrotizing Enterocolitis: A Pilot Study
| ||Mohamed Shawky Elfarargy,Mohamed S. El Farargy,Marwa Mohamed Atef,Omnia Safwat El-Deeb,Radwa Mahmoud Elsharaby,Hany Abd Elfattah Elhady |
| ||Journal of Population Therapeutics & Clinical Pharmacology. 2019; 26(3): e1 |
|[Pubmed] | [DOI]|