Necrotizing enterocolitis (NEC) is defined as inflammation and necrosis of the bowel. It is the final manifestation of vascular, mucosal, and metabolic insults to the immature intestine (1, 2). NEC is a common gastrointestinal emergency in newborns and one of the leading causes of morbidity and mortality in neonatal intensive care units (NICU), with a mortality rate of 15% to 30% (3, 4).
No single unifying theory exists for the pathogenesis of NEC that explains all the clinical observations associated with the disorder. Proposed mechanisms for the development of NEC include immature intestinal motility, digestion, circulatory regulation, barrier function, innate immunity, and abnormal bacterial colonization (2, 3).
The most frequent risk factors associated with NEC include prematurity and low birth weight. Over 90% of neonates who develop NEC are born preterm. Extremely low birth weight (<1000 g) infants <28 weeks' gestational age (GA) are the most susceptible. Other risk factors for the development of NEC include asphyxia, acute cardiopulmonary disease, polycythemia, hyperviscosity syndromes, exchange transfusions, aggressive enteral feeding, and abnormal colonization of the intestine with enteric pathogens (1–5).
Many nonspecific signs may trigger the suspicion of NEC, such as abdominal tenderness or distention, feeding intolerance, bloody stools, and apnea. The definite signs of NEC include pneumatosis intestinalis and portal venous gas, which are revealed by x-rays. Abdominal x-rays are performed to diagnose and determine progression of NEC. Laboratory values, such as complete blood count with differential, arterial blood gas measurements, and electrolytes, are measured as well as obtaining blood and stool cultures to look for other signs of NEC and rule out other conditions (2). To better classify and diagnose NEC using nonspecific and definite signs and symptoms of NEC, Bell's staging criteria were developed: suspected NEC is classified as stage 1, proven NEC as stage 2, and severe cases as stage 3 (1, 5) (Table 1).
Table 1.
Bell's staging criteria for necrotizing enterocolitis∗
| Stage | Systemic signs | Intestinal signs | Radiologic signs |
| 1A | Temperature instability Apnea Bradycardia Lethargy | Poor feeding ↑ Residuals Abdominal distention Emesis Stool guaiac (+) | Normal or Intestinal dilation Mild ileus |
| 1B | Same as 1A | Bright red blood from rectum | Same as 1A |
| 2A | Same as 1A and 1B | Same as 1B + Absent bowel sounds ± Abdominal tenderness | Intestinal dilation Ileus Pneumatosis intestinalis |
| 2B | Same as 2A + Metabolic acidosis Thrombocytopenia | Same as 2A + No bowel sounds Definite tenderness | Same as 2A + Portal vein gas Possible ascites |
| 3A | Same as 2B + Hypotension Respiratory acidosis Neutropenia | Same as 2B + Peritonitis Marked distention of abdomen | Same as 2B + Definite ascites |
| 3B | Same as 3A | Same as 3A | Same as 3A + Pneumoperitoneum |
MANAGEMENT OF NEC
No consensus exists for the most effective approach for the management of NEC. The goal of management is to prevent progression of disease, intestinal perforation, and shock. Medical management of NEC includes discontinuing oral feeding, starting intravenous fluids, performing nasogastric decompression, and monitoring and correcting laboratory values. Abdominal x-rays are performed to evaluate progression and/or resolution of NEC. Empiric antibiotics are often started along with a sepsis workup to rule out infection. In general, infants <7 days old are initiated on ampicillin and gentamicin, and infants ≥7 days old are initiated on tobramycin and vancomycin. If peritonitis or perforation is suspected, anaerobic coverage with metronidazole is started (1–3, 5–7).
In addition, if no significant improvement is seen in the infant despite adequate medical management, a surgical consultation is essential. Peritoneal drainage, exploratory laparotomy, and bowel resections are performed (1–3, 5, 6). Approximately 20% to 40% of infants with NEC undergo surgery. Up to 50% of cases are fatal during or after surgical intervention, with the highest rate in the smallest, least mature infants. Mortality is related to underlying clinical status, surgical treatment, and postoperative complications (8).
PREVENTION OF NEC
No approach for the prevention of NEC is proven effective. Common methods utilized to prevent NEC include breast-feeding and conservative and trophic feeding, which deliver small amounts of food at a time to prevent gut atrophy. Experimental methods include antenatal steroids, enteral antibiotics, prebiotics, probiotics, IgA supplementation, erythropoietin, and arginine supplementation. More research is needed to determine the effectiveness of these methods (1–3).
Intestinal colonization by commensal bacteria is an important protective mechanism of the intestine. Proposed benefits include maintenance of the gastrointestinal mucosal barrier integrity and regulation of appropriate bacterial colonization by preventing pathogenic bacteria from colonizing the intestine. Timing of intestinal colonization and microbial patterns depend on postnatal age, method of delivery, diet, environmental exposures, and antibiotic use. Since NEC does not occur in utero despite stress and fetal ingestion of amniotic fluid containing proteins, amniotic fluid containing proteins, carbohydrates, fat, immunoglobulin, and electrolytes, it is suggested that bacterial colonization is an important factor in the pathogenesis of this condition. In addition, the method of delivery dictates the rapidity of colonization, since the neonatal intestinal tract in utero is sterile. Vaginal delivery exposes the infant's intestinal tract to bacteria from the vaginal and fecal area, thus leading to colonization soon after birth. A more sterile method of delivery such as cesarean section can lead to delayed colonization and less diverse bacterial species (9, 10).
Probiotics are live exogenous microorganisms delivered enterally that improve mucosal defenses of the gastrointestinal tract. Prebiotics, on the other hand, are oligosaccharides that are delivered enterally and provide nutrients to the host bacteria that protect the intestinal tract (1, 3). Bifidobacterium spp., Streptococcus spp., Lactobacillus spp., and Saccharomyces spp., are the four main types of organisms studied for use as probiotics. Currently, the only US probiotic infant formulation is Good Start Natural Cultures infant formula with Bifidobacterium lactis for term infants (11). The Food and Drug Administration (FDA) requires infant formulas to be generally recognized as safe, with published studies available on the safety of the product (12). Probiotics have been found to be well tolerated; however, reports of sepsis due to translocation of the organism through the gastrointestinal mucosa have been published (13).
LITERATURE REVIEW: PROBIOTICS FOR NEC PREVENTION
Five prospective, randomized controlled trials using prevention of NEC as a primary outcome have been published (Table 2). Each is discussed individually.
Table 2.
Randomized controlled trials of probiotic use in the prevention of necrotizing enterocolitis
| Author/year | Design | Arms | Location | N | Gestational age (weeks) | Birth weight (g) |
| Dani et al, 2002 (14) | Double-blind, randomized placebo-controlled | (1) Lactobacillus rhamnosus GG; (2) placebo | 12 NICUs in Italy | 585 | 28.4–33.2 | 961–1729 |
| Bin-nun et al, 2005 (15) | Double-blind, randomized controlled | (1) Bifidobacteria infantis, Streptococcus thermophilus, B. bifidus; (2) milk alone | 1 NICU in Israel | 145 | 25–33.6 | 833–1414 |
| Lin et al, 2005 (16) | Randomized, masked, controlled | (1) L. acidophilus, B. infantis; (2) milk alone | 1 NICU in Taiwan | 367 | 25.7–31 | 828–1346 |
| Samanta et al, 2008 (17) | Randomized, double-blind controlled | (1) B. infantis, B. bifidum, B. longum, L. acidophilus; (2) milk alone | 1 NICU in India | 186 | 28.49–31.75 | 1029–1353 |
| Lin et al, 2008 (18) | Randomized, masked, controlled | (1) fibifidum, L. acidophilus; (2) milk alone | 7 NICUs in Taiwan | 443 | <34 | 783–1292 |
“Probiotics feeding in prevention of urinary tract infection, bacterial sepsis and necrotizing enterocolitis in preterm infants”
The objective of this 2002 trial by Dani et al (14) was to evaluate the effectiveness of Lactobacillus rhamnosus GG supplementation in reducing the incidence of urinary tract infection (UTI), bacterial sepsis, and NEC in preterm infants. This multicenter, randomized, double-blind placebo-controlled trial was performed in 12 NICUs in Italy and involved 585 infants with GA <33 weeks or birth weight <1500 g. The study group received Dicoflor (L. rhamnosus GG 6 × 109colony-forming units [cfu]) plus milk (either breast milk, formula, or mixed breast milk and formula), and the control group received milk plus placebo. The incidence of NEC stage 2 or 3 using Bell's staging criteria for diagnosis was defined as the primary outcome. Patients with major congenital malformations, death within the first 2 weeks of life, or the absence of parental consent were excluded.
The incidence of NEC was 1.4% (n = 4) in the study group compared with 2.8% (n = 8) in the control group, which was not statistically significant. The infants who developed NEC had a GA of 24 to 33 weeks and a weight of 760 to 1570 g. NEC was diagnosed at a mean age of 20 days in the study group compared with 15.5 days in the control group. Of the three infants with the youngest GA (one at 24 weeks and two at 26 weeks) that developed NEC, two infants died; both were in the control group. The incidence of UTI and bacterial sepsis was also found to be insignificant, and no cultures were positive for L. rhamnosus GG. The authors concluded that L. rhamnosus GG supplementation was not effective in reducing the incidence of NEC, UTI, and sepsis in preterm infants (14).
There was no statistically significant reduction in the incidence of NEC between the treatment and control groups; however, the results showed a trend toward probiotics delaying the onset of this disease. Furthermore, probiotics may provide a benefit in decreasing the incidence of death due to NEC in high-risk groups with a lower gestational age.
Strengths of this study included similar baseline characteristics between groups and the strong study design. Type of milk feeds, mode of delivery, GA, and length of probiotic or placebo supplementation were similar between groups. In addition, this study was a double-blind multicenter study performed at 12 locations and included all patients who were randomized to a group in the analysis (intent-to-treat analysis).
Nevertheless, fecal microbiological evaluations to assess L. rhamnosus GG intestinal colonization were stopped early due to technical difficulties and finances. Also, feeding titrations were not defined. A standard feeding protocol should be utilized, since a high rate of feeds may increase the risk of developing NEC. Lastly, although almost 600 patients were included in this study, conclusions on the use of probiotics and the incidence of NEC are difficult to make because the overall incidence of NEC was low.
“Oral probiotics prevent necrotizing enterocolitis in very low birth weight neonates”
This study was conducted in Israel by Bin-Nun et al (15) to evaluate the effect of normalization of the intestinal flora by prophylactic probiotic supplementation on the incidence and severity of NEC in preterm infants. Designed as a single-center, double-blind, randomized controlled trial, this study assessed the incidence and severity of NEC in 145 preterm infants with birth weight <1500 g. Infants were randomized to receive ABC Dophilus (B. infantis 0.35 × 109 cfu, Streptococcus thermophilus 0.35 × 109 cfu, B. bifidus 0.35 × 109 cfu) plus milk (breast milk or formula) or milk alone. Exclusion criteria were not mentioned.
The incidence of NEC was 4% in the study group compared with 16.4% in the control group (P = 0.03). A 75% relative risk reduction for the development of NEC was found with the use of probiotics compared with the control, with an absolute risk reduction of 12% with the use of probiotics. The number needed to treat (NNT) to prevent one case of NEC was 8 infants. Age at diagnosis of NEC was similar between groups (21 ± 9 days in the study group and 21 ± 14 days in the control group). The GA and birth weight of the infants that developed NEC were also similar, with a mean GA of 26.8 ± 1.6 weeks and 27.6 ± 1.9 weeks and a mean birth weight of 949 ± 223 g and 956 ± 223 g in the study and control groups, respectively. In addition, only 1% of the study group compared with 14% of the control group (P = 0.013) had clinically significant NEC indicated by a Bell's stage of 2 or 3. Three infants died in the study group compared with eight in the control group, which was not significant. No cases of sepsis or adverse events were reported due to probiotic supplementation. The authors concluded that B. infantis, S. thermophilus, and B. bifidus supplementation reduced the incidence and severity of NEC in preterm neonates (15).
As with Dani et al, this study was also a double-blind, intent-to-treat analysis in patients with similar baseline characteristics. Feeding titrations were not defined. This study was completed at only one center using a small sample size. In addition, no clear exclusion criteria were provided, creating difficulty in reproducing the study. Also, type of feeds, a potential confounder, was not differentiated in the infants who developed NEC to determine if breast milk had a protective effect.
“Oral probiotics reduce the incidence and severity of necrotizing enterocolitis in very low birth weight infants”
The incidence and severity of NEC with the use of probiotics was also evaluated in this study performed in Taiwan by Lin et al (16). A single-center, randomized, masked, controlled trial was conducted in 367 preterm infants with birth weight <1500 g. Infants were randomized to Infloran (L. acidophilus 1 × 106 cfu and B. infantis 1 × 106 cfu) 125 mg/kg twice daily plus milk (breast milk only) or milk alone. The primary outcome was defined as the incidence of death or NEC Bell's stage ≥2. Infants were excluded if death or NEC occurred within 7 days of birth or parental consent was not obtained.
The incidence of death or NEC was 5% in the study group compared with 12.8% in the control group (P = 0.009). Death occurred in 3.9% of the study group and 10.7% of the control group (P = 0.009). The NNT to prevent one death due to NEC was 31 infants. The incidence of NEC was 1.1% in the probiotic group compared with 5.3% in the control group (P = 0.04); the NNT to prevent one case of NEC was 27 infants. The mean age of onset of NEC was 19.5 ± 13.4 days and 16.4 ± 11.7 days in the study and control group, respectively. The difference was not significant. No cases of sepsis were attributed to probiotic use. The authors concluded that L. acidophilus and B. infantis supplementation reduced the incidence and severity of NEC in very low birth weight (VLBW) infants (16).
Strengths of this study include similar baseline characteristics between groups in a large sample size. This study was an intent-to-treat analysis, similar to the two prior studies. However, a defined feeding protocol was implemented to ensure similar progression of feeds. Since all patients received breast milk and the difference in the incidence of NEC was significant, this suggests that probiotics provide more benefit than breast milk alone. In spite of this, the study was conducted at only one center and the investigators were not blinded.
“Prophylactic probiotics for prevention of necrotizing enterocolitis in very low birth weight newborns”
The objective of this study by Samanta et al (17) was to evaluate the efficacy of probiotics in improving food tolerance and reducing the incidence and severity of NEC and death related to NEC in preterm VLBW infants. It was a single-center, randomized, double-blind controlled trial conducted in India. A total of 186 preterm infants <32 weeks GA with birth weight <1500 g were assigned to a probiotic mixture (B. infantis, B. bifidum, B. longum, and L. acidophilus at 2.5 × 109 cfu each) 125 g/kg twice daily plus milk (breast milk only) or milk alone. Outcome measures included time to full enteral feeding, length of hospital stay, NEC, sepsis, and death due to NEC or sepsis. Exclusion criteria included major congenital and gastrointestinal anomalies and death due to other neonatal illnesses.
NEC stage 2 or 3 occurred in 5 infants in the study group and 15 infants in the control group (P = 0.042). In fact, all outcome measures were significantly lower in the study group compared with the control group except severity of NEC, which was similar between groups. Death occurred in 4 infants in the study group compared with 14 infants in the control group (P = 0.032). No cases of sepsis were due to the administration of probiotics. The authors concluded that prophylactic probiotic supplementation reduced the incidence of NEC in VLBW neonates and shortened hospital stay and time to full feeds (17).
Strengths include similar baseline characteristics along with a strong study design using a double-blind, intent-to-treat analysis. However, an unclear dosing regimen was utilized. The study stated that the dosage of 125 g/kg twice daily was similar to the Lin et al trial published in 2005. Yet, Lin et al used 125 mg/kg twice daily with L. acidophilus 1 × 106 cfu and B. infantis 1 × 106 cfu. In addition, this trial was conducted in only one center using a small sample size without a defined feeding protocol.
“Oral probiotics prevent necrotizing enterocolitis in very low birth weight preterm infants: a multicenter, randomized, controlled trial”
Based on their pilot trial performed in 2005, Lin et al (18) performed a multicenter, randomized, masked, controlled trial to evaluate the efficacy of probiotics in preventing NEC in VLBW infants in Taiwan. A total of 443 preterm infants with birth weight <1500 g were randomized to Infloran (L. acidophilus 1 ×109 cfu and B. bifidum 1 ×109 cfu) 125 mg/kg twice daily plus milk (breast milk or mixed breast milk and formula) or milk alone. The manufacturer of Infloran changed the probiotic formulation from B. infantis to B. bifidum, and instead of only breast milk, mixed breast milk and formula or breast milk alone were utilized. Death or NEC stage 2 or 3 was defined as the primary outcome. The study excluded infants with severe asphyxia, fetal chromosomal anomalies, cyanotic congenital heart disease, congenital intestinal atresia, gastroschisis, omphalocele, exclusive formula feeding, and a history of fasting for >3 weeks.
Death or NEC stage 2 or 3 occurred in 4 of 217 infants in the study group and 20 of 217 in the control group (P = 0.002). NEC stage 2 or 3 developed in 4 infants in the study group compared with 14 infants in the control group (P = 0.02). The NNT to prevent one case of NEC was 20 infants. Death due to NEC occurred in two infants in the study group and three infants in the control group (P = 0.98). However, death due to other causes was reported in six infants in the control group and no infants in the study group (P = 0.04). The authors concluded that L. acidophilus and B. bifidum reduced the incidence of death or NEC in VLBW preterm infants (18).
Strengths of this study are that it was conducted in seven NICUs, had a defined feeding protocol, and had a large sample size. A composite endpoint was used as the primary outcome since death is a competing variable of NEC; however, since death due to other causes was significantly higher in the control group, the primary outcome showed a larger difference between groups. In addition, infants in the study group had a lower baseline birth weight at 1028.9 ± 246 g, compared with 1077.3 ± 214.4 g for the control group (P = 0.03). Infants that withdrew from the study after being randomized to a group were not included in the analysis. Moreover, the study was masked, with the investigators aware of patient assignments.
Summary
In summary, a reduction in the incidence of NEC was observed with the use of probiotics in preterm infants, especially in the >1000 g birth weight patient group. The severity of NEC was also decreased with the use of probiotics in some studies. In addition, a low incidence of adverse reactions was reported. Therefore, the risk of sepsis due to translocation of the probiotic through the intestinal wall was relatively low despite the immunocompromised condition of preterm infants. However, thus far, no trials have been conducted in preterm infants in the USA. A standard dose or strain of probiotic is not established as well. Infant formula is not strictly regulated by the FDA. Lastly, there is no available formula with a probiotic designed particularly for preterm neonates.
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