Different forms of intestinal injury: Moving beyond NEC

Key points

1.
Necrotizing enterocolitis (NEC) is a poorly defined umbrella diagnosis for what is more likely a heterogenous group of acquired neonatal intestinal injuries.
2.
Multiple criteria exist for NEC, of varying sensitivities and specificities. However, much of the research is clouded by inaccurate definitions and diagnoses.
3.
Classic preterm NEC likely has a multifactorial pathophysiology with intestinal immaturity, immune immaturity, and microbial dysbiosis all contributing toward a reduced intestinal barrier and resultant inflammatory response.
4.
Feeding with human milk is a protective factor against the development of NEC.
5.
Spontaneous intestinal perforation (SIP) tends to occur at a younger postnatal age and in smaller infants compared to classic preterm NEC. SIP presents as isolated pneumoperitoneum resulting from focal perforation of the intestinal muscularis propria layer without intestinal necrosis.
6.
Cardiac-induced mesenteric hypoperfusion syndrome associated with insufficient systemic blood flow to the intestines can result in necrotizing intestinal injury. It more commonly involves the large intestine, which is more prone to watershed injury.
7.
Preterm infants often demonstrate slow gastrointestinal motility that can present with similar signs to other serious acquired intestinal injuries.
8.
More research is needed to better define different types of acquired neonatal intestinal injuries and to develop tailored diagnostic and treatment strategies.

Introduction

Despite decades of hypotheses and research, there has been a recognized stagnation surrounding advancements in diagnosing and treating necrotizing enterocolitis (NEC). This is partly attributable to an overly inclusive diagnosis that amalgamates a host of disease processes under a single label. While NEC has previously been described as a heterogeneous disease with various presentations, it is time for the field to go beyond adherence to an outdated umbrella diagnosis and move toward reclassifying and redefining distinctly different types of acquired intestinal injuries, each of which requires a unique treatment approach. ^, To that end, we herein describe a myriad of neonatal intestinal pathologies that are increasingly recognized as unique entities rather than points along a single disease spectrum.

Necrotizing enterocolitis background

NEC, as per our current understanding, is one of the most critical clinical encounters neonatologists experience in the NICU, with an overall mortality rate of 32%. Unfortunately, it is also one of the most prevalent, with an incidence of 5% to 12% in very-low-birth-weight infants (born <1500 g). It is a very costly disease that significantly increases length of stay and hospitalization charges. First classified by Mizrahi and colleagues in 1964–1965, NEC has for decades perniciously remained a single diagnosis for a heterogeneous group of diseases with heterogeneous pathophysiologies. ^, Martin Bell proposed the first widely used staging system for NEC in 1978, a laudable attempt at describing a diverse disease process. Bell’s staging classified NEC into three stages of increasing severity: stage I consisted of suspected NEC, stage II was indicative of “definite” NEC, and stage III was indicative of advanced NEC requiring surgical attention. However, Bell’s staging had significant limitations. The original paper cited concerns that stage I criteria were overly inclusive and likely contributing to incorrect diagnoses of NEC that were not genuinely present.

In 1986, Walsh and Kliegman introduced a modified version of Bell’s staging criteria, subdividing each of the original stages into two subcategories classified as A and B. With these subdivisions, more specific criteria were included and organized by systemic signs, intestinal signs, and radiographic signs, and the recommended treatment was outlined for each stage ( Table 10.1 ). However, growing experience with an evolving patient population of younger neonates with a diverse range of neonatal intestinal injuries has created a greater emphasis on improving the definition of what we are labeling as necrotizing enterocolitis. Multiple attempts at improved diagnostic criteria were developed over recent years including VON (Vermont Oxford Network), CDC (Centers for Disease Control and Prevention), Stanford in 2014, UK (United Kingdom Neonatal Collaborative) in 2017, 2of3 Rule in 2018, and INC (International Neonatal Consortium) criteria in 2019 ( Table 10.2 ). Though it remains unclear which set of criteria may be superior in sensitivity and specificity, no single set of criteria has yet emerged as the gold standard across the field. Many sets of criteria continue to include nonspecific signs such as abdominal distension and thrombocytopenia that occur with other illnesses and could contribute to the overdiagnosis of NEC.

TABLE 10.1

Walsh and Kliegman’s Modified Bell’s Staging

Stage	Systemic Signs	Intestinal Signs	Radiologic Signs	Treatment
IA – Suspected NEC	Temperature instability, apnea, bradycardia, lethargy	Elevated pre-gavage residuals, mild abdominal distention, emesis, guaiac-positive stool	Normal or intestinal dilation, mild ileus	NPO, antibiotics × 3d pending culture
IB – Suspected NEC	Same as above	Bright red blood from rectum	Same as above	Same as above
IIA – Definite NEC Mildly ill	Same as above	Same as above, plus absent bowel sounds, ± abdominal tenderness	Intestinal dilation, ileus, pneumatosis intestinalis	NPO, antibiotics × 7–10 d if exam is normal in 24–48 h
IIB – Definite NEC Moderately ill	Same as above, plus mild metabolic acidosis, mild thrombocytopenia	Same as above, plus absent bowel sounds, definite abdominal tenderness, ± abdominal cellulitis or RLQ mass	Same as IIA, plus portal vein gas, ± ascites	NPO, antibiotics × 14 d, NaHCO ₃ for acidosis
IIIA – Advanced NEC Severely ill, bowel intact	Same as IIB, plus hypotension, bradycardia, severe apnea, combined respiratory and metabolic acidosis, DIC, neutropenia	Same as above, plus signs of generalized peritonitis, marked tenderness, and distension of abdomen	Same as IIB, plus definite ascites	Same as above, plus 200 + mL/kg fluids, inotropic agents, ventilation, therapy, paracentesis
IIIB – Advanced NEC Severely ill, bowel perforated	Same as IIIA	Same as IIIA	Same as IIB, plus pneumoperitoneum	Same as above, plus surgical intervention

d , Days; DIC , disseminated intravascular coagulation; h , hours; NEC , necrotizing enterocolitis; NPO , nil per os; RLQ , right lower quadrant..

TABLE 10.2

Comparison Criteria for Necrotizing Enterocolitis

Adapted from Patel RM, Ferguson J, McElroy SJ, Khashu M, Caplan MS. Defining necrotizing enterocolitis: current difficulties and future opportunities. Pediatr Res . 2020;88(suppl 1):10-15. doi:10.1038/S41390-020-1074-4 .

	UK	VON	CDC	2of3	Stanford	INC
Risk Grouping
Gestational age	+			+		+
Postnatal age				+	+	+
Gender					+
Ethnicity					+
Exclusion Criteria
SIP	+	+		+		+
Congenital anomaly				+		+
Fed <80 mL/kg/d				+
GA ≥36 weeks				+		+
Systemic Signs
Thrombocytopenia				+	+	+
Acidosis					+
DIC						+
Ventilated					+
Intestinal Signs
Poor feeding					+
Emesis		+	+
Pre-gavage residuals	+
Bilious aspirates	+	+	+
Abdominal distension	+	+	+	+		+
Rectal bleeding	+	+	+	+		+
Abdominal tenderness	+
Abdominal discoloration	+				+
Radiographic Signs
Ileus					+
Pneumatosis intestinalis	+	+	+	+	+	+
Portal venous gas	+	+	+	+	+	+
Pneumoperitoneum	+	+	+
Fixed bowel loop	+

2of3 , 2of3 Rule in 2018; CDC , Centers for Disease Control and Prevention; DIC , disseminated intravascular coagulation; GA , gestational age; INC , International Neonatal Consortium; SIP , spontaneous intestinal perforation; VON , Vermont Oxford Network; UK , United Kingdom Neonatal Collaborative.

Meanwhile, Bell’s staging continues to be most frequently utilized in research, with studies often including only Bell’s stage II and stage III in their definitions of NEC. However, it is increasingly clear that what has previously been called “NEC” represents more than one disease process. A lack of consensus and an inability to establish effective and exclusive criteria have contributed to nonspecific datasets inclusive of pathologies other than necrotizing intestinal injuries. In the absence of clear definitions, it has proved challenging to develop precise predictive and diagnostic biomarkers and has hindered advancement in preventive and therapeutic strategies. Future research into better defining distinct types of neonatal intestinal injuries and their corresponding markers is needed. Nevertheless, to discuss pathologies that are not necrotizing intestinal injuries, we will first review what is generally considered “classic NEC.”

Classic preterm enterocolitis

Clinical presentation and diagnosis

Despite shortcomings in specific diagnostic criteria, there is a severe and fulminant form of necrotizing neonatal intestinal injury, herein described as classic preterm NEC. Affected infants may present with several nonspecific signs including abdominal distension, feeding intolerance, bilious emesis, and bloody stools while receiving enteral feeds. However, differentiating these signs from signs seen with other types of intestinal injuries remains a diagnostic hurdle. Radiographic evidence of pneumatosis intestinalis and portal venous gas are prominent features that likely represent fermentation by bacteria translocated through the intestinal wall ( Fig. 10.1 ). Unfortunately, identifying pneumatosis intestinalis remains subjective and challenging for accurate diagnosis, especially considering pneumatosis may occasionally be present with other pathology. ^, Overdiagnosis of NEC is likely to accompany frequent X-rays obtained for signs of feeding intolerance and abdominal distension that may be secondary to other causes such as continuous positive airway pressure (CPAP). Presentation is often abrupt and rapidly progressive to intestinal perforation, severe shock, and death. If surgery is performed, necrosis of the bowel is visualized, and this is currently the only indisputable method of diagnosis.

Fig. 10.1, Radiographic evidence of pneumatosis intestinalis (yellow arrows) and portal venous gas (blue arrow) .

Pathophysiology

While NEC has been reported across the gamut from extremely preterm infants to full-term infants, its incidence peaks around 30 weeks corrected gestational age. The pathophysiology is likely multifactorial with interplaying factors of intestinal immaturity, immune immaturity, and microbial dysbiosis all contributing. The intestinal mucosal lining provides a vital barrier of protection against pathogens, but it is underdeveloped in the preterm infant and is significantly impacted by the developing microbiome. A symbiotic microbiome, including Bifidobacterium , aids in establishing a healthy mucosal lining and immune tolerance.

However, a relative shift in the fecal microbiome prior to the development of NEC has been demonstrated, with gram-positive Firmicutes and gram-negative Bacteroidetes becoming notably less abundant and gram-negative Proteobacteria becoming more abundant. This shift also occurs around 30 weeks corrected gestational age (similar to the peak incidence of NEC) and is impacted by perinatal antibiotic exposure. ^, This is significant as Firmicutes contribute to increased butyrate, which is essential for maintaining tight junctions and intestinal mucosal integrity. ^, Conversely, Proteobacteria have significant lipopolysaccharide in the cell wall that is recognized by toll-like receptor 4 (TLR4), which is increased in the preterm intestinal tract. ^, This suggests that a proinflammatory effect of Proteobacteria in addition to a compromised intestinal mucosal layer (affected by a decrease in Firmicutes ) could contribute to the pathogenesis of NEC. Furthermore, bacteria from the vaginally derived Bacteroidetes phylum have been shown to contribute to immune tolerance, suggesting that a reduction in these bacteria may also contribute to a proinflammatory state involved in the pathogenesis of the disease.

As with many disease states, it is also reasonable to hypothesize that there may be an underlying genetic predisposition. While some genetic variants have been identified as areas of interest, confirming their role in the pathogenesis of NEC requires continued research as none have been definitively implicated.

Prevention

There are recognized protective factors and risk factors for the development of disease. In many years of research, only a handful have had evidence to support the decreased risk of NEC including increasing the delivery of mother’s own milk, standardization of feeding regimens, antenatal steroids, and delayed cord clamping.

Human milk, including both mother’s expressed breast milk and donor milk, is an important protective factor that is readily accessible in most modern NICUs. Human milk contains antioxidants essential in reducing oxidative stress and avoiding increased intestinal barrier permeability that is induced by bovine-based formulas. ^, However, whether human milk–based fortification of breast milk helps reduce NEC compared with bovine-based fortification is less clear, as the data do not consistently support the routine use of one over the other. ^, Slow progression of incremental feeding volume has been a traditional approach to feeding advancement in the NICU. While this strategy may still be helpful for general feeding intolerance associated with prematurity, it has not been shown to reduce the rate of NEC. Furthermore, early fortification does not seem to significantly impact NEC incidence compared to late fortification. ^, Delaying the introduction of feeds has also not proven to prevent NEC. ^,

Routine surveillance of gastric residuals was a previously widespread practice, with large residuals raising concern for early signs of NEC. However, monitoring gastric residuals has no impact on reducing the incidence of NEC, and many NICUs have largely abandoned this long-held practice due to the potential associated risks of prolonging time to full feeds and increasing the duration of hospitalization.

There have been numerous studies focused on the use of probiotics for the reduction of NEC, and a review of multiple meta-analyses supports a consensus that probiotics, precisely a combination of Lactobacillus and Bifidobacteria , likely reduce the incidence of NEC and death. However, there remain significant obstacles into implementing routine probiotic use in the NICU. There are clinically impactful differences between unique bacterial strains among the same genus, and identifying the optimal combination of strains deserves more study. Furthermore, probiotics are classified as dietary supplements, which do not undergo the same rigorous review by the US Food and Drug Administration (FDA) as pharmaceuticals for safety and efficacy. The American Academy of Pediatrics (AAP) Committee on the Fetus and Newborn has examined this issue closely and raised concerns. The consistency of probiotics is decidedly variable among manufacturers and ensuring a quality probiotic for our patient population remains a challenge. As such, any use of probiotics to reduce NEC remains off-label and should be used with caution. ^, Furthermore, according to AAP recommendations, “current evidence does not support the routine universal administration of probiotics to preterm infants, particularly those with a birth weight of less than 1000 g.” Therefore probiotic administration for the reduction of NEC remains controversial.

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