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Treating infant colic with the probiotic Lactobacillus reuteri: double blind, placebo controlled randomised trial

BMJ 2014; 348 doi: https://doi.org/10.1136/bmj.g2107 (Published 01 April 2014) Cite this as: BMJ 2014;348:g2107
  1. Valerie Sung, paediatrician123,
  2. Harriet Hiscock, associate professor123,
  3. Mimi L K Tang, professor123,
  4. Fiona K Mensah, statistician123,
  5. Monica L Nation, honours student23,
  6. Catherine Satzke, research fellow23,
  7. Ralf G Heine, paediatric gastroenterologist/allergist123,
  8. Amanda Stock, paediatrician1,
  9. Ronald G Barr, professor4,
  10. Melissa Wake, professor123
  1. 1Royal Children’s Hospital, Parkville, Victoria, Australia
  2. 2Murdoch Childrens Research Institute Victoria, Australia
  3. 3The University of Melbourne, Parkville, Victoria, Australia
  4. 4Developmental Neurosciences and Child Health, Child and Family Research Institute, Vancouver, BC, Canada
  1. Correspondence to: V Sung Centre for Community Child Health, Royal Children’s Hospital, Parkville, Vic 3052, Australia valerie.sung{at}rch.org.au
  • Accepted 3 March 2014

Abstract

Objective To determine whether the probiotic Lactobacillus reuteri DSM 17938 reduces crying or fussing in a broad community based sample of breastfed infants and formula fed infants with colic aged less than 3 months.

Design Double blind, placebo controlled randomised trial.

Setting Community based sample (primary and secondary level care centres) in Melbourne, Australia.

Participants 167 breastfed infants or formula fed infants aged less than 3 months meeting Wessel’s criteria for crying or fussing: 85 were randomised to receive probiotic and 82 to receive placebo.

Interventions Oral daily L reuteri (1×108 colony forming units) versus placebo for one month.

Main outcomes measures The primary outcome was daily duration of cry or fuss at 1 month. Secondary outcomes were duration of cry or fuss; number of cry or fuss episodes; sleep duration of infant at 7, 14, and 21 days, and 1 and 6 months; maternal mental health (Edinburgh postnatal depression subscale); family functioning (paediatric quality of life inventory), parent quality adjusted life years (assessment of quality of life) at 1 and 6 months; infant functioning (paediatric quality of life inventory) at 6 months; infant faecal microbiota (microbial diversity, colonisation with Escherichia coli), and calprotectin levels at 1 month. In intention to treat analyses the two groups were compared using regression models adjusted for potential confounders.

Results Of 167 infants randomised from August 2011 to August 2012, 127 (76%) were retained to primary outcome; of these, a subset was analysed for faecal microbial diversity, E coli colonisation, and calprotectin levels. Adherence was high. Mean daily cry or fuss time fell steadily in both groups. At 1 month, the probiotic group cried or fussed 49 minutes more than the placebo group (95% confidence interval 8 to 90 minutes, P=0.02); this mainly reflected more fussing, especially for formula fed infants. The groups were similar on all secondary outcomes. No study related adverse events occurred.

ConclusionsL reuteri DSM 17938 did not benefit a community sample of breastfed infants and formula fed infants with colic. These findings differ from previous smaller trials of selected populations and do not support a general recommendation for the use of probiotics to treat colic in infants.

Trial registration Current Controlled Trials ISRCTN95287767.

Footnotes

  • Murdoch Childrens Research Institute is supported by the Victorian government’s operational infrastructure support programme. The following authors were supported by Australian National Health and Medical Research Council fellowships: VS (postgraduate scholarship 607447), HH (career development award 607351), MW (career development award 546405 and senior research fellowship 1046518), and FM (capacity building grant 436914 and early career fellowship 1037449). RGB is supported by a Canada research chair in community child health research and by the Child and Family Research Institute of BC Children’s Hospital. We thank all families, maternal and child health nurses, doctors, paediatricians, and research assistants (Elissa York, Jane Sheehan, Saga Arthursson, Sally Robinson) who took part in the trial, and Dawn Mount for independent coding and analysis of the diary measures. We also thank Eileen Dunne for her work in the microbiological analysis of the faecal samples.

  • Contributors: All authors had full access to all of the data (including statistical reports and tables) in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis. VS is the guarantor, had final responsibility for the decision to submit for publication, and takes overall responsibility for all aspects of the trial and this manuscript. VS, HH, and MW conceived the trial with MT, RH, and FM. VS, HH, and MW designed the intervention, with advice from MT, RH, and RGB, who also advised on measures and their interpretation. FM advised on statistical issues. AS contributed to recruitment procedures. MT advised on laboratory outcome measures and their interpretation, with input from CS and MN. MN developed and performed laboratory assays with advice and oversight from CS. All authors contributed to, read, and approved the final manuscript.

  • Funding: This trial was supported by the Georgina Menzies Maconachie Charitable Trust administered by Equity Trustees. BioGaia Sweden supplied the investigational product and placebo at no cost. Calpro AS supplied CalproLab ELISA kits for the analysis of calprotectin levels at no cost. BioGaia, Calpro AS, and Equitee Trustees were independent of the trial and its researchers and played no role in the trial design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare that: VS, HH, FM, and MW have support from the Australian National Health and Medical Research Council for the submitted work; RB is supported by a Canada research chair in community child health research and by the Child and Family Research Institute of BC Children’s Hospital; MT is a member of the Nestlé Nutrition Institute Medical Advisory Board Oceania and the Nutricia Medical Advisory Board Australasia, received honorariums for speaking at symposiums sponsored by Nestlé Nutrition Institute and Nutricia (Danone), and received probiotic and placebo research products from Nestlé Research Centre Switzerland and Dicofarm Italy for studies unrelated to this trial; RH is a member of the Nestlé Nutrition Institute Medical Advisory Board Oceania and the Nutricia Medical Advisory Board Australasia and received honorariums for speaking at symposiums sponsored by Nestlé Nutrition Institute and Nutricia (Danone); the authors’ spouses, partners, or children have no financial relationships that may be relevant to the submitted work; and the authors have no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: This trial was approved by the Royal Children’s Hospital human research ethics committee (HREC 30111). All participants gave written informed consent before taking part.

  • Data sharing: The study’s technical appendix is available with open access at www.rch.org.au/ccch/for_researchers/Baby_Biotics/. The statistical code is available, and anonymous patient level data may be available, from the corresponding author (valerie.sung@rch.org.au) subject to the study’s material transfer agreement. Consent from participants for data sharing was not obtained but the presented data are anonymised and risk of identification is low.

  • Transparency: VS affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

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