Probiotics Reduce All-Cause Mortality and Necrotizing Enterocolitis: It Is Time to Change Practice William Odita Tarnow-Mordi

, Dominic Wilkinson, Amit Trivedi and Jesper Brok Pediatrics 2010;125;1068; originally published online April 19, 2010; DOI: 10.1542/peds.2009-2151

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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2010 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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Probiotics Reduce All-Cause Mortality and Necrotizing Enterocolitis: It Is Time to Change Practice
Delay in adopting effective treatment has serious consequences.1 Hundreds of thousands more infants could have lived had antenatal corticosteroids been introduced sooner after evidence to support their use was published in 1972.2,3 A systematic review, published in this issue of Pediatrics, by Deshpande et al4 of 11 randomized, controlled trials (RCTs) in 2176 infants of Ͻ34 weeks’ gestation revealed that oral probiotics reduced all-cause mortality and necrotizing enterocolitis (NEC) by more than half (P Ͻ .00001). These results suggest that current probiotics could prevent tens of thousands of deaths annually. The unusually large effect implies that most deaths or cases of NEC in eligible infants who are not given probiotics may, on balance of probability, be ascribed to that omission. Few infants receive probiotics outside RCTs. Should this practice change? After birth at term, the gut is colonized with probiotic organisms such as lactobacilli and bifidobacteria. Probiotics upregulate local and systemic immunity, increase anti-inflammatory cytokines and gut impermeability to bacteria and toxins, and suppress pathogens associated with NEC.5 Probiotics are susceptible to antibiotics, which could explain why prolonged antibiotic use is associated with NEC6,7 and death.7 The authors of a Cochrane review article recommended probiotics for infants of Ͼ1000 g birth weight but also recommended more research in smaller infants.8 However, in a subsequent trial,9 probiotics reduced death or NEC in infants with a birth weight of 500 to 750 g. Why is there still reservation about adopting probiotics? Probiotics are different from conventional drugs; there are many types, and optimum production, transport, dosage, and contraindications are unclear. There are theoretical concerns that probiotics could enhance transfer of antibiotic-resistance genes. However, RCTs that compare different probiotic regimens and ongoing surveillance will address these issues more efficiently than further placebo-controlled trials. Probiotic sepsis could have been missed. However, any adverse effects of this possibility are likely to be outweighed by the substantial reduction in mortality and NEC.4 There might be concerns about pooling different probiotic regimens in meta-analysis, but pooling trials of different treatments or doses is appropriate to determine if a class of therapy is effective.10 As with probiotics in preterm infants, pooling RCTs of different antibiotic regimens for colorectal surgery revealed that antibacterial prophylaxis reduced perioperative deaths by more than half.10 Comparisons of specific antibiotics were not significant because sample sizes were too small, yet prescribing an antibiotic is now standard care for colorectal surgery. Could this meta-analysis4 be misleading, as the highly significantly favorable meta-analyses of the early, small trials of magnesium in myocardial infarction proved to be after the later, larger ISIS-4 (Fourth
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AUTHORS: William Odita Tarnow-Mordi, BA(Cantab), MBChB, MRCP(UK), DCH, FRCPCH,a,b Dominic Wilkinson, MBChB, FRACP,c Amit Trivedi, MBChB, MD(Paed), FRACP,d and Jesper Brok, MDe,f
aWestmead International Network for Neonatal Education and Research (WINNER) Centre, bCentre for Newborn Care, Westmead Hospital, University of Sydney, Sydney, Australia; cOxford Uehiro Centre for Practical Ethics, University of Oxford, Oxford, United Kingdom; dGrace Centre for Newborn Care, Children’s Hospital at Westmead, Westmead, Sydney, New South Wales; eCopenhagen Trial Unit, Center for Clinical Intervention Research, Department 3344, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; and fPediatric Department, Hvidovre Hospital, Copenhagen, Denmark

ABBREVIATIONS RCT—randomized, controlled trial NEC—necrotizing enterocolitis RR—risk ratio Drs Tarnow-Mordi and Wilkinson drafted the commentary; Dr Trivedi performed the cumulative meta-analysis; Dr Brok performed the trial sequential analysis; and Drs Trivedi and Brok reviewed the commentary. Opinions expressed in this commentary are those of the author and not necessarily those of the American Academy of Pediatrics or its Committees. www.pediatrics.org/cgi/doi/10.1542/peds.2009-2151 doi:10.1542/peds.2009-2151 Accepted for publication Jan 15, 2010 Address correspondence to William Odita Tarnow-Mordi, BA(Cantab), MBChB, MRCP(UK), DCH, FRCPCH, Westmead Hospital WINNER Centre and Centre for Newborn Care, University of Sydney, Hawkesbury Road, Wentworthville, Sydney, New South Wales 2122, Australia. E-mail: williamtm@med.usyd.edu.au PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2010 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
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COMMENTARY

1068) to reasons for and against joining placebo-controlled trials. Clinicians and parents may wish to recruit infants at high risk who were previously excluded from placebocontrolled trials. Also, if approved products are lacking,22 joining placebo-controlled trials will maximize the number of infants who receive probiotics.
FIGURE 1
Cumulative meta-analysis of probiotics trials.

International Study of Infarct Survival) and MAGIC (Magnesium in Coronaries) trials?11–13 Unlike the earlier magnesium meta-analyses, 11–14 there was no evidence of funnel-plot asymmetry to suggest selection bias.4 Did this metaanalysis4 have a sufficient number of patients and events to be reliable? It depends on whether clinicians consider the observed risk ratio (RR) of 0.41 for all-cause mortality to be plausible, but even a benefit half as great would be important. If the true RR were 0.5, on trial sequential analysis the meta-analysis exceeds the optimum information size15 of 1372 patients needed to detect this RR with 90% power at 2p ϭ 0.05, assuming a control mortality rate of 8.6%.16 Last, what about the impact of probiotics on neurodevelopment? Preliminary data have been reassuring.17 It is important to note that NEC itself predisposes infants to excess neurodevelopmental impairment,18 so the substantial reREFERENCES
1. Chalmers I. The scandalous failure of science to cumulate evidence scientifically. Clin Trials. 2005;2:229 –231 2. Roberts D, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2006;(3): CD004454 3. Sinclair JC. Meta-analysis of randomized controlled trials of antenatal corticosteroids for the prevention of respiratory dis-

duction in cases of NEC4 makes it unlikely that probiotics will increase rates of survival with disability. Is more evidence needed before introducing this inexpensive, apparently safe and effective treatment? It is possible that further trials would overturn the evidence of benefit of probiotics, as occurred for magnesium in myocardial infarction.11,12 However, the evidence that probiotics reduce mortality rates4 is as conclusive16 as that for surfactant for respiratory distress syndrome,19 cooling for hypoxic ischemic encephalopathy,20 or antenatal corticosteroids for threatened preterm labor.2,3 Should placebo-controlled trials continue? If they do, parents should be informed about current evidence. To achieve balance in controversy, one approach is to give “equal air time”21 in information leaflets (available as supplemental information at www. pediatrics.org/content/full/125/5/

Where probiotics are licensed or available by special-access schemes, we recommend that parents of all infants who met eligibility criteria from earlier trials4 be offered probiotics, after adequate quality control of the reconstituted product. There is a strong case for informing parents that the strategy is new and will be used only with their consent. However, knowing what we now know, do we have the right to deny parents the option?23 Careful surveillance of mortality, NEC,24,25 and the emergence of resistant strains will be important. Clinicians, researchers, parents, consumers, ethics committees, and licensing authorities need to review the evidence4 carefully. History may not judge us kindly if we ignore it.1

ACKNOWLEDGMENTS We thank Sir Iain Chalmers, Nick Evans, Edmund Hey (now deceased), Jeremy Howick, Mickey Caplan, and Colin Morley for comment and criticism.

tress syndrome: discussion. Am J Obstet Gynecol. 1995;173(1):335– 444 4. Deshpande G, Rao S, Patole S, Bulsara M. Updated meta-analysis of probiotics for preventing necrotizing enterocolitis in preterm neonates. Pediatrics. 2010;125(5):921–930 5. Millar M, Wilks M, Costeloe K. Probiotics for preterm neonates? Arch Dis Child Fetal Neonatal Ed. 2003;88(5):F354 –F358 6. Kenyon SL, Taylor DL, Tarnow-Mordi WO; ORACLE Collaborative Group. Broad-

spectrum antibiotics for preterm, prelabour rupture of fetal membranes: the ORACLE I randomised trial [published correction appears in Lancet . 2001;358(9276):156]. Lancet. 2001;357: 979 –988 7. Cotten CM, Taylor S, Stoll B, et al; NICHD Neonatal Research Network. Prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely

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low birth weight infants. Pediatrics. 2009; 123(1):58 – 66 AlFaleh KM, Bassler D. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev. 2008;(1):CD005496 Lin HC, Hsu CH, Chen HL, et al. Oral probiotics prevent necrotizing enterocolitis in very low birth weight preterm infants: a multicenter, randomized, controlled trial. Pediatrics. 2008;122(4):693–700 Lau J, Schmid CH, Chalmers TC. Cumulative meta-analysis of clinical trials builds evidence for exemplary medical care. J Clin Epidemiol. 1995;48(1):45–57; discussion 59 – 60 Li J, Zhang Q, Zhang M, Egger M. Intravenous magnesium for acute myocardial infarction. Cochrane Database Syst Rev. 2007;(2): CD002755 Yusuf S, Flather M. Magnesium in myocardial infarction. BMJ. 1995;310(6982): 751–752 Nuesch E, Juni P. Commentary: which meta analyses are conclusive? Int J Epidemiol. 2009;38(1):298 –303 Egger M, Davey Smith G, Schneider M, Minder, C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997; 315(7109):629 – 634

15. Pogue J, Yusuf S. Overcoming the limitations of current meta-analysis of randomised controlled trials. Lancet. 1998; 351(9095):47–52 16. Brok J, Thorlund K, Wetterslev J, Gluud C. Apparently conclusive meta-analyses may be inconclusive: trial sequential analysis adjustment of random error risk due to repetitive esting of accumulating data in apparently conclusive neonatal metaanalyses. Int J Epidemiol. 2009;38(1): 287–298 17. Lin HC, Kuo HT, Chang JS, Su BH. Lack of effects of oral probiotics on growth and neurodevelopment outcomes of preterm very low birth weight infants at two years corrected age. In: Proceedings of the Pediatric Academic Societies Annual Meeting; May 2– 6, 2008 Hawaii, HI. Abstract 3420.4 18. Schulzke SM, Deshpande GC, Patole SK. Neurodevelopmental outcomes of very low birthweight infants with necrotizing enterocolitis: a systematic review of observational studies. Arch Pediatr Adolesc Med. 2007;161(6):583–590 19. Seger N, Soll R. Animal derived surfactant extract for treatment of respiratory distress syndrome. Cochrane Database Syst Rev. 2009;(2):CD007836 20. Jacobs SE, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns

with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev. 2007;(4): CD003311 21. Wilkinson D. Therapeutic hypothermia and the “equal air-time” solution for controversial randomised trials. J Paediatr Child Health. 2010; In press 22. Hibberd PL, Davidson L. Probiotic foods and drugs: impact of US regulatory status on design of clinical trials. Clin Infect Dis. 2008; 46(suppl 2):S137–S140; discussion S144 –S151 23. Hey E. Probiotics (comment): Has the time come to start using probiotics more widely? Neonatal Formulary 5. Available at: www.blackwellpublishing. com/medicine/bmj/nnf5/pdfs/comment/ prob࿝com࿝jul09.pdf. Accessed September 27, 2009 24. Hoyos AB. Reduced incidence of necrotizing enterocolitis associated with enteral administration of Lactobacillus acidophilus and Bifidobacterium infantum to neonates in an intensive care unit. Int J Infect Dis. 1999;3(4):197–202 25. Satoh Y, Shinohara K, Umezaki H, et al. Bifidobacterium prevents necrotizing enterocolitis and infection in preterm infants. Int J Probiotics Prebiotics. 2007; 2(2/3):149 –154

Work Hour Reductions Are Not Just for Residents: While much is being reported and published about the Institute of Medicine recommendations to reduce work hours for interns and residents (and the Accrediting Council on Graduate Medical Education’s response to those recommendations) an article in the Journal of the American Medical Association (Staiger DO, Auerbach DI, Buerhaus PI. Trends in the work hours of physicians in the United States. JAMA. 2010;303(8):747–753) notes that physicians have reduced their work hours from 55 to 51 hours per week from 1996 to 2008. Even when residents in training were removed from the analysis, the finding still holds with a 6% decline in work hours. The effect this decline will have on the overall physician workforce supply and demand remains to be seen. Noted by JFL, MD

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Probiotics Reduce All-Cause Mortality and Necrotizing Enterocolitis: It Is Time to Change Practice William Odita Tarnow-Mordi, Dominic Wilkinson, Amit Trivedi and Jesper Brok Pediatrics 2010;125;1068; originally published online April 19, 2010; DOI: 10.1542/peds.2009-2151
Updated Information & Services including high resolution figures, can be found at: http://pediatrics.aappublications.org/content/125/5/1068.full.h tml Supplementary material can be found at: http://pediatrics.aappublications.org/content/suppl/2010/04/15 /peds.2009-2151.DC1.html This article cites 17 articles, 8 of which can be accessed free at: http://pediatrics.aappublications.org/content/125/5/1068.full.h tml#ref-list-1 This article has been cited by 14 HighWire-hosted articles: http://pediatrics.aappublications.org/content/125/5/1068.full.h tml#related-urls This article, along with others on similar topics, appears in the following collection(s): Fetus/Newborn Infant http://pediatrics.aappublications.org/cgi/collection/fetus:newb orn_infant_sub Gastroenterology http://pediatrics.aappublications.org/cgi/collection/gastroenter ology_sub Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://pediatrics.aappublications.org/site/misc/Permissions.xht ml Information about ordering reprints can be found online: http://pediatrics.aappublications.org/site/misc/reprints.xhtml

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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2010 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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