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Effect of nutritionally modified infant formula on academic performance: linkage of seven dormant randomised controlled trials to national education data

BMJ 2021; 375 doi: https://doi.org/10.1136/bmj-2021-065805 (Published 11 November 2021) Cite this as: BMJ 2021;375:e065805

Linked Editorial

Enriched formula milks and academic performance in later childhood

  1. Maximiliane L Verfürden, postdoctoral researcher1,
  2. Ruth Gilbert, professor1,
  3. Alan Lucas, professor1,
  4. John Jerrim, professor2,
  5. Mary Fewtrell, professor1
  1. 1UCL Great Ormond Street Institute of Child Health, London, UK
  2. 2UCL Institute of Education, London, UK
  1. Correspondence to: M L Verfürden m.verfuerden{at}alumni.ucl.ac.uk (or @DrMaxVerfuerden on Twitter)
  • Accepted 14 October 2021

Abstract

Objective To compare differences in academic performance between adolescents who were randomised in infancy to modified or standard infant formula.

Design Linkage of seven dormant randomised controlled trials to national education data.

Setting Five hospitals in England, 11 August 1993 to 29 October 2001, and schools in England, September 2002 to August 2016.

Participants 1763 adolescents (425 born preterm, 299 born at term and small for gestational age, 1039 born at term) who took part in one of seven randomised controlled trials of infant formula in infancy.

Interventions Nutrient enriched versus standard term formula (two trials), long chain polyunsaturated fatty acid (LCPUFA) supplemented versus unsupplemented formula (two trials), high versus low iron follow-on formula (one trial), high versus low sn-2 palmitate formula (one trial), and nucleotide supplemented versus unsupplemented formula (one trial).

Main outcome measures The primary outcome, determined by linkage of trial data to school data, was the mean difference in standard deviation scores for mandated examinations in mathematics at age 16 years. Secondary outcomes included differences in standard deviation scores in English (16 and 11 years) and mathematics (11 years). Analysis was by intention to treat with multiple imputation for participants missing the primary outcome.

Results 1607 (91.2%) participants were linked to school records. No benefit was found for performance in mathematics examinations at age 16 years for any modified formula: nutrient enriched in preterm infants after discharge from hospital, standard deviation score 0.02 (95% confidence interval −0.22 to 0.27), and nutrient enriched in small for gestational age term infants −0.11 (−0.33 to 0.12); LCPUFA supplemented in preterm infants −0.19 (−0.46 to 0.08) and in term infants −0.14 (−0.36 to 0.08); iron follow-on formula in term infants −0.12 (−0.31 to 0.07); and sn-2 palmitate supplemented formula in term infants −0.09 (−0.37 to 0.19). Participants from the nucleotide trial were too young to have sat their General Certificate of Secondary Education (GCSE) examinations at the time of linkage to school data. Secondary outcomes did not differ for nutrient enriched, high iron, sn-2 palmitate, or nucleotide supplemented formulas, but at 11 years, preterm and term participants randomised to LCPUFA supplemented formula scored lower in English and mathematics.

Conclusions Evidence from these randomised controlled trials indicated that the infant formula modifications did not promote long term cognitive benefit compared with standard infant formulas.

Footnotes

  • Contributors: MLV prepared the initial draft of the manuscript and protocol, and conducted the analyses. RG, JJ, and MF provided substantial intellectual input. AL and MF conducted the original trials and had access to the trial data and participant identifiers. All authors contributed to critical revisions of the manuscript and approved the final version for submission. MLV acts as guarantor of the manuscript. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria were omitted.

  • Funding: This work was supported by the Economic and Social Research Council UCL, Bloomsbury and East London Doctoral Training Partnership (ES/P000592/1) and a Great Ormond Street Hospital Charity Research starter grant (V0017). RG received funding from the National Institute for Health Research (NIHR) Children and Families Policy Research Unit and Health Data Research UK (grant LOND1). All research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The funders of the study had no role in design, data collection, analysis, or interpretation, or writing of the report. The investigators were independent from the funders. The corresponding author had final responsibility for the decision to submit for publication.

  • Competing interests: All authors have completed the ICMJE disclosure form at http://www.icmje.org/disclosure-of-interest/ and declare: support from the Economic and Social Research Council UCL, Bloomsbury and East London Doctoral Training Partnership and a Great Ormond Street Hospital Charity Research starter grant for the submitted work; the trials analysed in this manuscript were originally funded by research grants to AL and MF from the University of Cambridge or UCL from the manufacturers of the infant formulas (Farleys, Milupa, Nestle, Wyeth, Nutricia, and Heinz). The companies provided the infant formulas and funding for the initial studies but were not involved in this study. MF is a member of the Infant Nutrition Working Group at the European Food Safety Authority (EFSA) since 2013, is assistant officer (nutrition) at the Royal College of Paediatrics and Child Health (RCPCH) since 2017, and the general secretary of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) since June 2021. AL declares honoraria and travel support for academic lectures from Wyeth, Nestle, and Abbott; and consultancy advice to Wyeth on its educational programmes (none of these activities is linked to the current work); and a further consultancy with Prolacta Bioscience that has no relation to the original work or current manuscript. MLV declares support from the Economic and Social Research Council UCL Bloomsbury and East London Doctoral Training Partnership. MLV, RG, AL, and MF declare support from the Great Ormond Street Hospital Charity. All other authors declare no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work; no other relationships or activities that could appear to have influenced the submitted work. No funder had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

  • Patient consent: The study was conducted with support under section 251 of the NHS Act 2006 instead of participant consent to avoid bias caused by non-response that would arise because of difficulties locating participants in adolescence and adulthood (Health Research Authority (HRA) Confidentiality Advisory Group (CAG): IRAS ID: 212148/17CAG0051).

  • The lead author (the manuscript’s guarantor) 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.

  • Dissemination to participants and related patient and public communities: The results of this study will be disseminated to scientific, practitioner, and lay audiences at conferences, through open access papers, and a doctoral thesis. A lay summary of the results will be made available online (on GitHub and the UCL study website) and will be promoted on social media.

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

Data availability statement

Data are subject to data sharing agreements and are not publicly available. Data could be obtained on retrieving the relevant permissions from the Health Research Authority, Confidentiality Advisory Group, Department for Education, and UCL. All statistical code can be obtained here https://github.com/MaxVerfuerden/infant-formula-and-academic-performance

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