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Research

Conduct and reporting of formula milk trials: systematic review

BMJ 2021; 375 doi: https://doi.org/10.1136/bmj.n2202 (Published 14 October 2021) Cite this as: BMJ 2021;375:n2202

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  1. Bartosz Helfer, postdoctoral researcher1 2,
  2. Jo Leonardi-Bee, professor of medical statistics and epidemiology3,
  3. Alexandra Mundell, senior house officer4,
  4. Callum Parr, medical student1,
  5. Despo Ierodiakonou, assistant professor5,
  6. Vanessa Garcia-Larsen, assistant professor1 6,
  7. Cynthia M Kroeger, postdoctoral researcher7,
  8. Zhaoli Dai, research fellow7 8,
  9. Amy Man, senior house officer1,
  10. Jessica Jobson, senior house officer1,
  11. Fatemah Dewji, senior house officer1,
  12. Michelle Kunc, senior house officer1,
  13. Lisa Bero, professor9,
  14. Robert J Boyle, reader in paediatrics1 10
  1. 1National Heart and Lung Institute, Imperial College London, London, UK
  2. 2Institute of Psychology, University of Wroclaw, Wroclaw, Poland
  3. 3Centre for Evidence Based Healthcare, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, UK
  4. 4Imperial College Healthcare NHS Trust, London, UK
  5. 5Department of Primary Care and Population Health, University of Nicosia Medical School, Nicosia, Cyprus
  6. 6Program in Human Nutrition, Department of International Health, Johns Hopkins University, Baltimore, MD, USA
  7. 7Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
  8. 8Australian Institute of Health Innovation, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia
  9. 9Center for Bioethics and Humanities, Schools of Medicine and Public Health, University of Colorado Anschutz Medical Center, Aurora, CO, USA
  10. 10Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, UK
  1. Correspondence to: R J Boyle r.boyle{at}imperial.ac.uk
  • Accepted 25 August 2021

Abstract

Objective To systematically review the conduct and reporting of formula trials.

Design Systematic review.

Data sources Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched from 1 January 2006 to 31 December 2020.

Review methods Intervention trials comparing at least two formula products in children less than three years of age were included, but not trials of human breast milk or fortifiers of breast milk. Data were extracted in duplicate and primary outcome data were synthesised for meta-analysis with a random effects model weighted by the inverse variance method. Risk of bias was evaluated with Cochrane risk of bias version 2.0, and risk of undermining breastfeeding was evaluated according to published consensus guidance. Primary outcomes of the trials included in the systematic review were identified from clinical trial registries, protocols, or trial publications.

Results 22 201 titles were screened and 307 trials were identified that were published between 2006 and 2020, of which 73 (24%) trials in 13 197 children were prospectively registered. Another 111 unpublished but registered trials in 17 411 children were identified. Detailed analysis was undertaken for 125 trials (23 757 children) published since 2015. Seventeen (14%) of these recently published trials were conducted independently of formula companies, 26 (21%) were prospectively registered with a clear aim and primary outcome, and authors or sponsors shared prospective protocols for 11 (9%) trials. Risk of bias was low in five (4%) and high in 100 (80%) recently published trials, mainly because of inappropriate exclusions from analysis and selective reporting. For 68 recently published superiority trials, a pooled standardised mean difference of 0.51 (range −0.43 to 3.29) was calculated with an asymmetrical funnel plot (Egger’s test P<0.001), which reduced to 0.19 after correction for asymmetry. Primary outcomes were reported by authors as favourable in 86 (69%) trials, and 115 (92%) abstract conclusions were favourable. One of 38 (3%) trials in partially breastfed infants reported adequate support for breastfeeding and 14 of 87 (16%) trials in non-breastfed infants confirmed the decision not to breastfeed was firmly established before enrolment in the trial.

Conclusions The results show that formula trials lack independence or transparency, and published outcomes are biased by selective reporting.

Systematic review registration PROSPERO 2018 CRD42018091928.

Footnotes

  • Contributors: RJB, JL-B, DI, and BH designed the study, with advice and input from LB, VGL, CMK, and ZD. BH, RJB, AM, MK, FD, JJ, and CP developed and piloted the study search, data extraction, and coding tools. BH conducted the search. BH, RJB, AM, MK, FD, and JJ screened titles, extracted data, and coded outcomes. BH, JL-B, and DI undertook the statistical analyses. RJB wrote the first draft of the manuscript. All authors critically reviewed and revised the manuscript and approved the final manuscript. RJB acts as guarantor of the manuscript. AM and CP made equal contributions to the study. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

  • Funding: This work was funded by Imperial Health Charity, grant FA1920_05. Imperial Health Charity had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report or decision to submit the article for publication. BH and RJB had full access to all of the study data. Final responsibility for the decision to submit for publication was made by RJB and the funder was not involved.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare support from Imperial Health Charity: RJB received personal fees from Cochrane, DBV Technologies, and Prota Therapeutics, and from expert witness work in cases of food anaphylaxis and class actions related to infant formula health claims, outside the submitted work, and received personal fees from Public Health England as a member of the UK Nutrition and Health Claims Committee and the Maternal and Child Nutrition Subgroup of the Scientific Advisory Committee on Nutrition. JL-B received fees from Danone Nutricia Research and the Food Standards Agency, outside of the submitted work. The University of Colorado receives remuneration for LB’s work as senior editor, Cochrane, which is outside the submitted work. The authors report no other relationships or activities that could appear to have influenced the submitted work.

  • RJB affirms that this 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 registered have been explained.

  • Dissemination to participants and related patient and public communities: The findings of this study will be disseminated to regulators, industry clinical trials departments, and charities which support and advise parents and other carers of young children in making feeding decisions.

  • Provenance and peer review: Not commissioned, externally peer reviewed.

Data availability statement

All data collected for this study, including detailed responses to ROB2, breastfeeding, and conflict of interest signalling questions, are in the data supplement (web appendix 2). All other data are in the public domain or publication databases, except for trial protocols and statistical analysis plans received from authors and funders. We have not been given permission to share trial protocols and statistical analysis plans outside of our study team, but they can be requested directly from the trial authors and funders, as indicated in supplementary table 5.

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