Published online January 3, 2005
PEDIATRICS Vol. 115 No. 1 January 2005, pp. 173-174 (doi:10.1542/10.1542/peds.2004-2360)
This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via ISI Web of Science (17)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bell, E. F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bell, E. F.
Related Collections
Right arrow Infectious Disease & Immunity
Right arrowRelated AAP Red Book topics:
Yersinia enterocolitica and...
Rotavirus Infections
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

COMMENTARY

Preventing Necrotizing Enterocolitis: What Works and How Safe?

Edward F. Bell, MD

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 traveler’s 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


View this table:
[in this window]
[in a new window]
  		TABLE 1. Proposed Strategies for Prevention of Necrotizing Enterocolitis.

 
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,13–18 judicious administration of parenteral fluids,19 human milk feeding,20,21 enteral administration of IgG and IgA together22 but not IgG alone,23–25 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
TOP
 REFERENCES
 

  1. 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
  2. Berdon WE, Grossman H, Baker DH, Mizrahi A, Barlow O, Blanc WA. Necrotizing enterocolitis in the premature infant. Radiology. 1964;83 :879 –887
  3. 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]
  4. 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]
  5. Barlow B, Santulli TV, Heird WC, Pitt J, Blanc WA, Schullinger JN. An experimental study of acute neonatal enterocolitis—the importance of breast milk. J Pediatr Surg. 1974;9 :587 –594[CrossRef][Web of Science][Medline]
  6. Reber KM, Nankervis CA, Nowicki PT. Newborn intestinal circulation. Physiology and pathophysiology. Clin Perinatol. 2002;29 :23 –39[CrossRef][Web of Science][Medline]
  7. 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]
  8. 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]
  9. 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
  10. 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]
  11. 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]
  12. 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]
  13. 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]
  14. 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]
  15. Rowley MP, Dahlenburg GW. Gentamicin in prophylaxis of neonatal necrotising enterocolitis. Lancet. 1978;2(8088) :532
  16. 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]
  17. 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]
  18. 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
  19. 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
  20. Lucas A, Cole TJ. Breast milk and neonatal necrotising enterocolitis. Lancet. 1990;336 :1519 –1523[CrossRef][Web of Science][Medline]
  21. 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]
  22. 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]
  23. 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]
  24. 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]
  25. 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
  26. Crowley P. Prophylactic corticosteroids for preterm birth [review]. Cochrane Database Syst Rev. 1996;(1) :CD000065. doi:10.1002/14651858.CD000065
  27. 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
  28. 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
  29. 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]
  30. 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

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Facebook Facebook   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:


Home page
 J Int Assoc Physicians AIDS Care (Chic Ill)Home page
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]

Home page
 PediatricsHome page
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]

Home page
 Nutr Clin PractHome page
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]

Home page
 Am. J. Clin. Nutr.Home page
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]

Home page
 Arch. Dis. Child. Fetal Neonatal Ed.Home page
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]

Home page
 NeoReviewsHome page
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]

Home page
 PediatricsHome page
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]

Home page
 Arch. Dis. Child.Home page
Journal Watch
Arch. Dis. Child., May 1, 2005; 90(5): 544 - 545.
[Full Text] [PDF]

Home page
 JWatch GeneralHome page
Probiotics for Infants: Two Studies, Two Successes
Journal Watch (General), February 11, 2005; 2005(211): 3 - 3.
[Full Text]

Home page
 JWatch PediatricsHome page
Probiotics in Infants: Two Studies, Two Successes
Journal Watch Pediatrics and Adolescent Medicine, February 1, 2005; 2005(201): 2 - 2.
[Full Text]

This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via ISI Web of Science (17)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bell, E. F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bell, E. F.
Related Collections
Right arrow Infectious Disease & Immunity
Right arrowRelated AAP Red Book topics:
Yersinia enterocolitica and...
Rotavirus Infections
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?