The Politics of Probiotics

Annie Janvier and John Lantos and I have just published a ‘different view’ article in Acta Paediatrica, which has just appeared on-line. For various reasons we were asked to remove the references, so I list the references that we based our article on below.

Our contention in the article is that probiotics are an innovation in neonatology which is fundamentally different to other innovations such as inhaled nitric oxide, ECMO, or antenatal surgery. The major difference being that you can go and buy probiotics easily anywhere, and many people already do, so denying them to preterm infants is perverse, especially given the preponderance of evidence of benefit in the preterm.

We think that parents should be informed. We think that they should know about the medical evidence. We think they should have the right to choose an intervention that is probably beneficial, and which is easily available to all. We recognize also that there are docs who wish to perform further placebo controlled trials, even if I lost equipoise several years ago, and they want to ask parents for consent for those trials.

For some trials, it is reasonable to prohibit use of the intervention outside of the trial, for probiotics this is not reasonable.

Our final paragraph summarizes our view of the current situation.

‘We think that doctors should allow parents to choose probiotics, no probiotics, or randomization… Parents should be fully informed of the data from completed trials, including a clear description of the reduced mortality and lack of adverse effects in those trials. They should then be allowed to choose whether or not to give their baby probiotics or, alternatively, whether to enrol their baby in a randomized trial. Enrolment in a randomized trial should not be a condition for getting probiotics. This approach -allowing on-going trials to continue but permitting treatment off-protocol- would protect the best interests of babies (they would either get probiotics or they would get randomized to a possibility of getting them), preserve parental autonomy, and be consistent with professional equipoise… Probiotics may be in a regulatory purgatory, but we should not curtail parents’ reasonable choices or allow babies to die as a result of our regulatory paralysis.’

The references follow, and then a table with some details of all the RCTs published so far, which we also had to remove as it was too long otherwise.

Systematic reviews:

Alfaleh K, Anabrees J, Bassler D, Al-Kharfi T. Probiotics for prevention of necrotizing enterocolitis in preterm infants.  Cochrane Database Syst Rev. 2011 Mar 16;(3):CD005496.

Wang Q, Dong J, Zhu Y. Probiotic supplement reduces risk of necrotizing enterocolitis and mortality in preterm very low-birth-weight infants: an updated meta-analysis of 20 randomized, controlled trials. J Pediatr Surg 2012;47(1):241-8.

Deshpande G, Rao S, Patole S, Bulsara M. Updated Meta-analysis of Probiotics for Preventing Necrotizing Enterocolitis in Preterm Neonates. Pediatrics. 2010;125(5):921-30.

Other review articles:

Stenger MR, Reber KM, Giannone PJ, Nankervis CA. Probiotics and prebiotics for the prevention of necrotizing enterocolitis. Curr Infect Dis Rep. 2011;13:13-20.

Thomas DW, Greer FR; American Academy of Pediatrics Committee on Nutrition; American Academy of Pediatrics Section on Gastroenterology, Hepatology, and Nutrition.  Probiotics and prebiotics in pediatrics. Pediatrics. 2010;126:1217-31.

Frost BL, Caplan MS.   Probiotics and prevention of neonatal necrotizing enterocolitis.  Curr Opin Pediatr. 2011 Apr;23(2):151-5.

Degnan FH. The US Food and Drug Administration and probiotics: regulatory categorization. Clin Infect Dis.2008;46 Suppl 2:S133-6; discussion S144-51.

Opinion pieces and editorials about probiotic use:

Soll RF. Probiotics: Are We Ready for Routine Use? Pediatrics 2010;125(5):1071-2.

Neu J, Shuster J. Nonadministration of Routine Probiotics Unethical—Really? Pediatrics. 2010;126(3):e740-e1.

Garland SM, Jacobs SE, Tobin JM, group on behalf of the ProPrems study group. A Cautionary Note on Instituting Probiotics Into Routine Clinical Care for Premature Infants. Pediatrics 2010;126(3):e741-e2.

Beattie LM, Hansen R, Barclay AR. Probiotics for Preterm Infants: Confounding Features Warrant Caution. Pediatrics 2010;126(3):e742-e3.

Millar M, Wilks M, Fleming P, Costeloe K. Should the use of probiotics in the preterm be routine? Archives of Disease in Childhood – Fetal and Neonatal Edition 2010.

Cohort studies of Probiotic use in NICU

Hunter C, Dimaguila MA, Gal P, Wimmer J, Ransom JL, Carlos R, Smith M, Davanzo C: Effect of routine probiotic, lactobacillus reuteri dsm 17938, use on rates of necrotizing enterocolitis in neonates with birthweight < 1000 grams: A sequential analysis. BMC Pediatrics 2012, 12(1):142.

Bonsante F, Iacobelli S, Gouyon JB: Routine probiotic use in very preterm infants: Retrospective comparison of two cohorts. Am J Perinatol 2012(EFirst).

New RCTs, too recent to be in the table below

Fernández-Carrocera LA, Solis-Herrera A, Cabanillas-Ayón M, Gallardo-Sarmiento RB, García-Pérez CS, Montaño-Rodríguez R, Echániz-Aviles MOL: Double-blind, randomised clinical assay to evaluate the efficacy of probiotics in preterm newborns weighing less than 1500 g in the prevention of necrotising enterocolitis. Archives of Disease in Childhood – Fetal and Neonatal Edition 2012.

Publications about Other innovative therapies:

Lantos JD, Frader J.  Extracorporeal membrane oxygenation and the ethics of clinical research in pediatrics.  N Engl J Med. 1990 Aug 9;323(6):409-13.

Hanney S, Mugford M, Grant J, Buxton M.  Assessing the benefits of health research: lessons from research into the use of antenatal corticosteroids for the prevention of neonatal respiratory distress syndrome. Soc Sci Med. 2005;60:937-47.

Barrington KJ, Finer N. Inhaled nitric oxide for respiratory failure in preterm infants.Cochrane Database Syst Rev. 2010 Dec 8;(12)

Wilkinson DJ, Thayyil S, Robertson NJ.  Ethical and practical issues relating to the global use of therapeutic hypothermia for perinatal asphyxial encephalopathy. Arch Dis Child Fetal Neonatal Ed. 2011;96(1):F75-8.

First Author Date Eligibility criterion Total N Age at start Probiotic strain Duration
Kitajima 1997 <1500g 97 <24h B. breve 28 d
Dani 2002 <33wk, <1500g 585 First feed L. GG (?rhamnosus) Until discharge
Costalos 2003 28-32 wks 87 Mean 3d Saccharomyces Boulardii 30 d
Li 2004 <2500g 30 >24h B. breve Until discharge
Bin-Nun 2005 <1500g 145 First feed B. infantis, B. bifidus, Streptococcus thermophilus To 36 wk post-menstrual age
Lin 2005 <1500g 367 7d B. infantis, L. acidophilus 6 wk
Manzoni 2006 <1500g 80 ❤ d L. rhamnosus 6 wk or until discharge
Mohan 2007 <37wk 69 <24h B. lactis 21d
Stratiki 2007 27-36wk 41 B.lactis 30d
Ke 2008 <32 wk 189 Bifidobacteria
Lin 2008 <1500g 434 First feed B. bifidum, L. acidophilus 6 wk
Samanta 2008 <32wk or <1500g 186 When stable, >48h B. infantis,B. bifidum, B. longumL. acidophilus, Until discharge
Huang 2009 <32 wk and <1500 g 183 Bifidobacteria
Manzoni 2009 <1500g 304 Day 3 L. rhamnosus (and lactoferrin) 6wk (<1000g) or 4 wk
Rouge 2009 <32 wk and <1500g 94 First feed B. longum, L. rhamnosus Until discharge
Underwood 2009 <35 wk and 750-2000g 90 <7 days L. rhamnosus or L. acidophilusB. longum, B. bifidum and B infantis 28 days or discharge
Awad 2010 Preterm and term 150 Day 1 L. rhamnosus (live or heat-killed)
Mihatsch 2010 <30wk 183 Mean day 5 of feeds B. lactis Uncertain
Ren 2010 <33wk and 1000-1800g 150 Bifidobacteria
Sari 2010 <33wk or <1500g 221 Day of 1st feed L. sporogenes Until discharge
Braga 2011 750 to 1500g 231 Day 2 L. casei, B. breve 30d
Romeo 2011 <37 wk and <2500g 249 Mean 1.4d L. reuteri, or L. rhamnosus 6 wk or until discharge
Lozano 2012 <2000g 750 <48h L. reuteri Until discharge

About keithbarrington

I am a neonatologist and clinical researcher at Sainte Justine University Health Center in Montréal
This entry was posted in Neonatal Research and tagged , , . Bookmark the permalink.

2 Responses to The Politics of Probiotics

  1. Madge says:

    let me know exactly where do I get them

    • That depends where you are in the world. In Canada, we have the natural products directorate of Health Canada, which does not approve probiotics for this purpose, but does have probiotic preparations which are produced according to Good Manufacturing Practices, and which have registered DNA profiles. SO you are giving what you think you are giving.
      In other countries the situation is different.
      The Australian trial used ABCDophilus, which is available in many countries, and which would be a good start.

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