. 2021 Oct 13:375:n2202.

doi: 10.1136/bmj.n2202.

Conduct and reporting of formula milk trials: systematic review

Bartosz Helfer^{1

2}, Jo Leonardi-Bee³, Alexandra Mundell⁴, Callum Parr¹, Despo Ierodiakonou⁵, Vanessa Garcia-Larsen^{1

6}, Cynthia M Kroeger⁷, Zhaoli Dai^{7

8}, Amy Man¹, Jessica Jobson¹, Fatemah Dewji¹, Michelle Kunc¹, Lisa Bero⁹, Robert J Boyle^{10

11}

Affiliations

¹ National Heart and Lung Institute, Imperial College London, London, UK.
² Institute of Psychology, University of Wroclaw, Wroclaw, Poland.
³ Centre for Evidence Based Healthcare, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, UK.
⁴ Imperial College Healthcare NHS Trust, London, UK.
⁵ Department of Primary Care and Population Health, University of Nicosia Medical School, Nicosia, Cyprus.
⁶ Program in Human Nutrition, Department of International Health, Johns Hopkins University, Baltimore, MD, USA.
⁷ Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
⁸ Australian Institute of Health Innovation, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia.
⁹ Center for Bioethics and Humanities, Schools of Medicine and Public Health, University of Colorado Anschutz Medical Center, Aurora, CO, USA.
¹⁰ National Heart and Lung Institute, Imperial College London, London, UK r.boyle@imperial.ac.uk.
¹¹ Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, UK.

PMID: 34645600
PMCID: PMC8513520
DOI: 10.1136/bmj.n2202

Conduct and reporting of formula milk trials: systematic review

Bartosz Helfer et al. BMJ. 2021.

. 2021 Oct 13:375:n2202.

doi: 10.1136/bmj.n2202.

Authors

Affiliations

¹ National Heart and Lung Institute, Imperial College London, London, UK.
² Institute of Psychology, University of Wroclaw, Wroclaw, Poland.
³ Centre for Evidence Based Healthcare, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, UK.
⁴ Imperial College Healthcare NHS Trust, London, UK.
⁵ Department of Primary Care and Population Health, University of Nicosia Medical School, Nicosia, Cyprus.
⁶ Program in Human Nutrition, Department of International Health, Johns Hopkins University, Baltimore, MD, USA.
⁷ Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
⁸ Australian Institute of Health Innovation, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia.
⁹ Center for Bioethics and Humanities, Schools of Medicine and Public Health, University of Colorado Anschutz Medical Center, Aurora, CO, USA.
¹⁰ National Heart and Lung Institute, Imperial College London, London, UK r.boyle@imperial.ac.uk.
¹¹ Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, UK.

PMID: 34645600
PMCID: PMC8513520
DOI: 10.1136/bmj.n2202

Erratum in

Conduct and reporting of formula milk trials: systematic review.
[No authors listed] [No authors listed] BMJ. 2021 Nov 24;375:n2890. doi: 10.1136/bmj.n2890. BMJ. 2021. PMID: 34819301 Free PMC article. No abstract available.

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.

PubMed Disclaimer

Conflict of interest statement

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.

Figures

**Fig 1**
Primary outcomes for formula trials with a superiority aim published between 2015 and 2020. Standardised mean difference and 95% confidence intervals for the primary outcome of the 68 formula trials designed with the aim of showing that the intervention was better than the comparator, where standardised mean difference could be calculated

**Fig 2**
Funnel plot for formula trials with a superiority aim published between 2015 and 2020. Effect size, expressed as standardised mean difference, is shown as a purple dot for each trial primary outcome, against the corresponding standard errors. Colours indicate regions of statistical significance (top panel). Unadjusted pooled standardised mean difference is 0.51 (0.34 to 0.68), Egger’s test for funnel plot asymmetry=4.111, P<0.001. White dots represent standardised mean difference imputed with Duval and Tweedie’s trim-and-fill procedure until funnel plot symmetry is reached (bottom panel). Adjusted standardised mean difference is 0.19 (−0.03 to 0.41)

**Fig 3**
Primary outcomes for formula trials designed to show adequate infant growth, published between 2015 and 2020. Data are mean differences (95% confidence intervals) and mean differences (90% confidence intervals) in weight gain between intervention and control formula during the intervention period, for the 23 trials that were designed according to guidance of Food and Drug Administration for demonstrating adequate growth. Equivalence margins of 3 g/day weight gain are indicated by dotted lines. Authors interpreted the primary outcome as favourable in 22 (96%) trials

See this image and copyright information in PMC

References

1. Baker P, Santos T, Neves PA, et al. . First-food systems transformations and the ultra-processing of infant and young child diets: The determinants, dynamics and consequences of the global rise in commercial milk formula consumption. Matern Child Nutr 2021;17:e13097. 10.1111/mcn.13097. - DOI - PMC - PubMed
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1. Infant formula requirements pertaining to current good manufacturing practice, quality control procedures, quality factors, records and reports, and notifications. Electronic Code of Federal Regulations, Title 21, Chapter IB, Part 106.
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Conduct and reporting of formula milk trials: systematic review

Affiliations

Conduct and reporting of formula milk trials: systematic review

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

Figures

References

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LinkOut - more resources

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