William Odita Tarnow-Mordi, Dominic Wilkinson, Amit Trivedi and Jesper Brok

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; originally published online April 19, 2010;
DOI: 10.1542/peds.2009-2151
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/early/2010/04/19/peds.2009-2151.citation
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.
Downloaded from pediatrics.aappublications.org by guest on June 9, 2014
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 ⬍34 weeks’ gestation revealed that oral probiotics reduced all-cause mortality and necrotizing enterocolitis (NEC)
by more than half (P ⬍ .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 ⬎1000 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
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: [email protected]
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.
+
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
1068
TARNOW-MORDI et al
Downloaded from pediatrics.aappublications.org by guest on June 9, 2014
COMMENTARY
●●●) 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 Infant 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 ⫽ 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 re-
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.
REFERENCES
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-
PEDIATRICS Volume 125, Number 5, May 2010
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
Downloaded from pediatrics.aappublications.org by guest on June 9, 2014
1069
8.
9.
10.
11.
12.
13.
14.
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㛭com㛭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
1070
TARNOW-MORDI et al
Downloaded from pediatrics.aappublications.org by guest on June 9, 2014
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; 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/early/2010/04/19
/peds.2009-2151.citation
Supplementary Material
Supplementary material can be found at:
http://pediatrics.aappublications.org/content/suppl/2010/04/15
/peds.2009-2151.DC1.html
Citations
This article has been cited by 14 HighWire-hosted articles:
http://pediatrics.aappublications.org/content/early/2010/04/19
/peds.2009-2151.citation#related-urls
Permissions & Licensing
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
Reprints
Information about ordering reprints can be found online:
http://pediatrics.aappublications.org/site/misc/reprints.xhtml
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.
Downloaded from pediatrics.aappublications.org by guest on June 9, 2014