PEDIATRICS Vol. 115 No. 1 January 2005, pp. 173-174 (doi:10.1542/10.1542/peds.2004-2360)
COMMENTARY |
Preventing Necrotizing Enterocolitis: What Works and How Safe?
Department of Pediatrics,
Carver College of Medicine,
University of Iowa,
Iowa City, IA 52242
Abbreviations: NEC, necrotizing enterocolitis VLBW, very low birth weight
Necrotizing enterocolitis (NEC) is a significant cause of morbidity and mortality among premature infants, affecting 4% to 13% of very low birth weight (VLBW) infants.1 The incidence varies among institutions and over time within each institution, occurring at times in outbreaks suggesting transmission among patients. The incidence of NEC varies inversely with pregnancy length, being more common in infants of younger gestational age. Reports of cases identified as NEC appeared in the 1960s,2 although apparent cases were reported much earlier, in the 19th century.3 A single cause has not been identified, suggesting that NEC results from various triggering events under certain predisposing conditions: a final common pathway. The leading theory is that NEC requires 3 coexisting elements: inadequate oxygen transport to the gut, potentially invasive pathogenic bacteria, and substrate in the form of enteral feedings.4 Early animal models of NEC are consistent with this theory.5 More recent thought adds the possible role of vasoconstriction in response to inflammatory or other stimuli.6
Despite our limited knowledge of the pathogenesis of NEC, various strategies have been tried in an effort to prevent NEC in high-risk infants (Table 1). Among these strategies is the enteral administration of probiotics, which are defined as live microorganisms that survive in the gastrointestinal tract and have beneficial effects on the host.7 Probiotics have been advocated for prevention or treatment of a variety of disorders including rotavirus infection, antibiotic-associated diarrhea, and travelers diarrhea. In this issue of Pediatrics, Lin et al report a randomized, clinical trial in which prophylactic administration of probiotics to VLBW infants reduced the incidence of NEC from 5.3% to 1.1%, a relative risk reduction of 79%.8 The probiotic group was given a commercial preparation (Infloran, Berna Biotech Ltd, Berne, Switzerland) containing Lactobacillus acidophilus and Bifidobacterium infantis. The absolute risk reduction was 4.2%, which means that 24 infants would need to be given probiotics to prevent 1 case of NEC.9
|
Probiotics have been shown to reduce NEC in a rat model,10 an infant study with historical controls,11 and 1 previous randomized clinical trial in VLBW infants using Lactobacillus GG.12 Dani et al12 found that infants given probiotic were less likely than control infants to develop NEC, 1.4% vs 2.8%, for a relative risk reduction of 50%; however, this reduction was not statistically significant. The use of 1 probiotic agent rather than 2 may explain, at least in part, the smaller treatment effect in this study compared with the study of Lin et al.8 Pooling the results of the 2 randomized trials, those of Lin et al and Dani et al, the relative risk reduction with administration of probiotics is 67%; the absolute risk is reduced by 2.5% (from 3.8% to 1.3%), yielding 40 as the number needed to treat (Table 1).
Other strategies that have been shown to reduce the risk of NEC are enteral antibiotics,1318 judicious administration of parenteral fluids,19 human milk feeding,20,21 enteral administration of IgG and IgA together22 but not IgG alone,2325 and antenatal corticosteroids26 (Table 1). Delayed or slow feeding has not been shown to reduce the incidence of NEC.27,28 In evaluating each of these strategies, it is necessary to look at the number needed to treat as a measure of the size of treatment effect but also at the risks and the size of these potentially harmful effects: the number needed to harm. Although the risks of enteral antibiotics have not been quantified, this strategy has never been widely adopted, despite its efficacy, because of concerns about the emergence of resistant bacteria and absorption of antibiotics from the gut.18 Human milk feeding, avoidance of excess fluid administration, and antenatal corticosteroid use are widely practiced. Combined use of enteral IgG and IgA has been examined in only 1 placebo-controlled trial. Replication of this result and more data on safety would help to clarify the role of this strategy for preventing NEC. Studies of IgG alone have not shown protection against NEC.
Enteral administration of probiotics is an appealing strategy for preventing NEC. Colonization of the gut with Lactobacillus and Bifidobacterium species is thought to be promoted by the feeding of human milk,29 which also decreases the risk of NEC in premature infants.20,21 This observation suggests that promotion of probiotic colonization may be among the mechanisms by which human milk protects against NEC. Milk leukocytes, immunoglobulins, and growth factors are other components proposed to contribute to the protective effect of human milk. The 3 clinical studies of probiotic administration to infants have reported no adverse effects including no cases of pathogenic infection caused by a probiotic organism.8,11,12 Bloodstream infection with Lactobacillus or Bifidobacterium species is rare.30
The human gut is a hospitable environment for bacteria and other microorganisms, most of which live there peacefully for the entire life of the host. The microbial flora are affected by what we eat and certain medications we take, both probiotics and antibiotics. Some of our healthiest and tastiest foods are produced with the help of bacteria or yeast (eg, yogurt, cheese, and wine). The study by Lin et al8 suggests that we may be able to help our premature infant patients by manipulating their intestinal flora with enterally administered probiotics. This promising intervention warrants additional examination of its safety and efficacy through larger clinical trials so that both the benefits and the risks of probiotics for premature infants can be better defined.
| FOOTNOTES |
|---|
Accepted Oct 27, 2004.
Address correspondence to Edward F. Bell, MD, Department of Pediatrics, Carver College of Medicine, University of Iowa, 200 Hawkins Dr, Iowa City, IA 52242. E-mail: edward-bell{at}uiowa.edu
No conflict of interest declared.
| REFERENCES |
|---|
|
|
|---|
- Lemons JA, Bauer CR, Oh W, et al. Very low birth weight outcomes of the National Institute of Child Health and Human Development Neonatal Research Network, January 1995 through December 1996. Pediatrics. 2001;107(1) . Available at: www.pediatrics.org/cgi/content/full/107/1/e1
- Berdon WE, Grossman H, Baker DH, Mizrahi A, Barlow O, Blanc WA. Necrotizing enterocolitis in the premature infant. Radiology. 1964;83 :879 887
- Santulli TV, Schullinger JN, Heird WC, et al. Acute necrotizing enterocolitis in infancy: a review of 64 cases.
Pediatrics. 1975;55
:376
387
[Abstract/Free Full Text] - Koloske AM. Pathogenesis and prevention of necrotizing enterocolitis: a hypothesis based on personal observation and a review of the literature.
Pediatrics. 1984;74
:1086
1092
[Abstract/Free Full Text] - Barlow B, Santulli TV, Heird WC, Pitt J, Blanc WA, Schullinger JN. An experimental study of acute neonatal enterocolitisthe importance of breast milk. J Pediatr Surg. 1974;9 :587 594[CrossRef][Web of Science][Medline]
- Reber KM, Nankervis CA, Nowicki PT. Newborn intestinal circulation. Physiology and pathophysiology. Clin Perinatol. 2002;29 :23 39[CrossRef][Web of Science][Medline]
- de Roos NM, Katan MB. Effects of probiotic bacteria on diarrhea, lipid metabolism, and carcinogenesis: a review of papers published between 1988 and 1998.
Am J Clin Nutr. 2000;71
:405
411
[Abstract/Free Full Text] - Lin HC, Su BH, Chen AC, et al. Oral probiotics reduce the incidence and severity of necrotizing enterocolitis in very low birth weight infants.
Pediatrics. 2005;115
:1
4
[Abstract/Free Full Text] - Sackett DL, Straus SE, Richardson WS, Rosenberg W, Haynes RB. Evidence Based Medicine: How to Practice and Teach EBM. 2nd Ed. Edinburgh, United Kingdom: Churchill Livingstone; 2000
- Caplan MS, Miller-Catchpole R, Kaup S, et al. Bifidobacterial supplementation reduces the incidence of necrotizing enterocolitis in a neonatal rat model. Gastroenterology. 1999;117 :577 583[CrossRef][Web of Science][Medline]
- Hoyos AB. Reduced incidence of necrotizing enterocolitis associated with enteral administration of Lactobacillus acidophilus and Bifidobacterium infantis to neonates in an intensive care unit. Int J Infect Dis. 1999;3 :197 202[CrossRef][Medline]
- Dani C, Biadaioli R, Bertini G, Martelli E, Rubaltelli FF. Probiotics feeding in prevention of urinary tract infection, bacterial sepsis and necrotizing enterocolitis in preterm infants. A prospective double-blind study. Biol Neonate. 2002;82 :103 108[CrossRef][Web of Science][Medline]
- Egan EA, Mantilla G, Nelson RM, Eitzman DV. A prospective controlled trial of oral kanamycin in the prevention of neonatal necrotizing enterocolitis. J Pediatr. 1976;89 :467 470[CrossRef][Web of Science][Medline]
- Boyle R, Nelson JS, Stonestreet BS, Peter G, Oh W. Alterations in stool flora resulting from oral kanamycin prophylaxis of necrotizing enterocolitis. J Pediatr. 1978;93 :857 861[Web of Science][Medline]
- Rowley MP, Dahlenburg GW. Gentamicin in prophylaxis of neonatal necrotising enterocolitis. Lancet. 1978;2(8088) :532
- Grylack LJ, Scanlon JW. Oral gentamicin therapy in the prevention of neonatal necrotizing enterocolitis.
Am J Dis Child. 1978;132
:1192
1194
[Abstract/Free Full Text] - Siu YK, Ng PC, Fung SCK, et al. Double blind, randomised, placebo controlled study of oral vancomycin in prevention of necrotising enterocolitis in preterm, very low birthweight infants.
Arch Dis Child Fetal Neonatal Ed. 1998;79
:F105
F109
[Abstract/Free Full Text] - Bury RG, Tudehope D. Enteral antibiotics for preventing necrotizing enterocolitis in low birthweight or preterm infants [review]. Cochrane Database Syst Rev. 2001;(1) :CD000405. doi:10.1002/14651858.CD000405
- Bell EF, Acarregui MJ. Restricted versus liberal water intake for preventing morbidity and mortality in preterm infants [review]. Cochrane Database Syst Rev. 2001;(3) :CD000503. doi:10.1002/14651858.CD000503
- Lucas A, Cole TJ. Breast milk and neonatal necrotising enterocolitis. Lancet. 1990;336 :1519 1523[CrossRef][Web of Science][Medline]
- Schanler RJ, Shulman RJ, Lau C. Feeding strategies for premature infants: beneficial outcomes of feeding fortified human milk versus preterm formula.
Pediatrics. 1999;103
:1150
1157
[Abstract/Free Full Text] - Eibl MM, Wolf HM, Fürnkranz H, Rosenkranz A. Prevention of necrotizing enterocolitis in low-birth-weight infants by IgA-IgG feeding. N Engl J Med. 1988;319 :1 7[Abstract]
- Rubaltelli FF, Benini F, Sala M. Prevention of necrotizing enterocolitis in neonates at risk by oral administration of monomeric IgG. Dev Pharmacol Ther. 1991;17 :138 143[Web of Science][Medline]
- Lawrence G, Tudehope D, Baumann K, et al. Enteral human IgG for prevention of necrotising enterocolitis: a placebo-controlled, randomised trial. Lancet. 2001;357 :2090 2094[CrossRef][Web of Science][Medline]
- Foster J, Cole M. Oral immunoglobulin for preventing necrotizing enterocolitis in preterm and low birth-weight neonates [review]. Cochrane Database Syst Rev. 2004;(1) :CD001816.pub2. doi:10.1002/14651858.CD001816.pub 2
- Crowley P. Prophylactic corticosteroids for preterm birth [review]. Cochrane Database Syst Rev. 1996;(1) :CD000065. doi:10.1002/14651858.CD000065
- Kennedy KA, Tyson JE, Chamnanvanikij S. Early versus delayed initiation of progressive enteral feedings for parenterally fed low birth weight or preterm infants [review]. Cochrane Database Syst Rev. 2000;(1) :CD001970. doi:10.1002/14651858.CD001970
- Kennedy KA, Tyson JE, Chamnanvanakij S. Rapid versus slow rate of advancement of feedings for promoting growth and preventing necrotizing enterocolitis in parenterally fed low-birth-weight infants [review]. Cochrane Database Syst Rev. 1999;(4) :CD001241. doi:10.1002/14651858.CD001241
- Orrhage K, Nord CE. Factors controlling the bacterial colonization of the intestine in breastfed infants [review]. Acta Paediatr Suppl. 1999;88(430) :47 57[CrossRef]
- Thompson C, McCarter YS, Krause PJ, Herson VC. Lactobacillus acidophilus sepsis in a neonate. J Perinatol. 2001;21 :258 260[CrossRef][Medline]
PEDIATRICS (ISSN 1098-4275). ©2005 by the American Academy of Pediatrics
This article has been cited by other articles:
![]() |
P. Oberdorfer, O. Louthrenoo, T. Puthanakit, V. Sirisanthana, and T. Sirisanthana Quality of Life Among HIV-Infected Children in Thailand J Int Assoc Physicians AIDS Care (Chic Ill), June 1, 2008; 7(3): 141 - 147. [Abstract] [PDF] |
||||
![]() |
C. L. Wang, C. Anderson, T. A. Leone, W. Rich, B. Govindaswami, and N. N. Finer Resuscitation of Preterm Neonates by Using Room Air or 100% Oxygen Pediatrics, June 1, 2008; 121(6): 1083 - 1089. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. Neu, M. Douglas-Escobar, and M. Lopez Microbes and the Developing Gastrointestinal Tract Nutr Clin Pract, April 1, 2007; 22(2): 174 - 182. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. Neu Gastrointestinal development and meeting the nutritional needs of premature infants Am. J. Clinical Nutrition, February 1, 2007; 85(2): 629S - 634S. [Abstract] [Full Text] [PDF] |
||||
![]() |
R J Schanler Probiotics and necrotising enterocolitis in premature infants. Arch. Dis. Child. Fetal Neonatal Ed., November 1, 2006; 91(6): F395 - F397. [Full Text] [PDF] |
||||
![]() |
N. Jesse and J. Neu Necrotizing Enterocolitis: Relationship to Innate Immunity, Clinical Features, and Strategies for Prevention NeoReviews, March 1, 2006; 7(3): e143 - e150. [Full Text] [PDF] |
||||
![]() |
A. Marini, G. Boehm, F. Negretti, and M. Agosti Probiotics, Prebiotics, or Both in a Very Low Birth Weight Infant Pediatrics, August 1, 2005; 116(2): 522 - 523. [Full Text] [PDF] |
||||
![]() |
Journal Watch Arch. Dis. Child., May 1, 2005; 90(5): 544 - 545. [Full Text] [PDF] |
||||
![]() |
Probiotics for Infants: Two Studies, Two Successes Journal Watch (General), February 11, 2005; 2005(211): 3 - 3. [Full Text] |
||||
![]() |
Probiotics in Infants: Two Studies, Two Successes Journal Watch Pediatrics and Adolescent Medicine, February 1, 2005; 2005(201): 2 - 2. [Full Text] |
||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||













