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Sex-specific effects of nutritional supplements in infants born early or small: protocol for an individual participant data meta-analysis (ESSENCE IPD-MA)
  1. Luling Lin,
  2. Caroline Crowther,
  3. Greg Gamble,
  4. Frank Bloomfield,
  5. Jane E Harding
  6. The ESSENCE IPD-MA Group
    1. Liggins Institute, The University of Auckland, Auckland, New Zealand
    1. Correspondence to Professor Jane E Harding; j.harding{at}


    Introduction Preterm and small for gestational age (SGA) infants are at increased risk of poor growth, disability and delayed development. While growing up they are also at increased risk of obesity, diabetes and later heart disease. The risk of such adverse outcomes may be altered by how preterm and SGA infants are fed after birth. Faltering postnatal growth is common due to failure to achieve recommended high energy and protein intakes, and thus preterm and SGA infants are often provided with supplemental nutrition soon after birth. Enhanced nutrition has been associated with improved early growth and better cognitive development. However, limited evidence suggests that faster growth may increase the risk for later adiposity, metabolic and cardiovascular disease, and that such risks may differ between girls and boys.

    Methods and analysis We will search Ovid MEDLINE, Embase, Cochrane CENTRAL, Cochrane Database of Systematic Reviews,, and for randomised trials that studied the effects of macronutrient supplements for preterm and SGA infants on (i) developmental and metabolic and (ii) growth outcomes after hospital discharge. The outcomes will be (i) cognitive impairment and metabolic risk (co-primary) and (ii) body mass index. Individual participant data (IPD) from all available trials will be included using an intention-to-treat approach. A one-stage procedure for IPD meta-analysis (MA) will be used, accounting for clustering of participants within studies. Exploratory subgroup analyses will further investigate sources of heterogeneity, including sex and size of infants, different timing, duration and type of supplements.

    Ethics and dissemination This IPD-MA is approved by the University of Auckland Human Participants Ethics Committee (reference number: 019874). Individual studies have approval from relevant local ethics committees. Results will be disseminated in a peer-reviewed journal and presented at international conferences.

    PROSPERO registration number CRD42017072683

    • preterm
    • small-for-gestational-age
    • development
    • metabolic
    • individual participant data meta-analysis

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    • Collaborators The ESSENCE IPD-MA Group

      ESSENCE-IPD Project Team: This is the project Steering Group which is responsible for the day-to-day management of the IPD. This group has drafted the IPD protocol, will liaise with trialists and prepare the draft publications. J.E. Harding (chair of ESSENCE-IPD project); L Lin; C.A. Crowther; F.H. Bloomfield and G Gamble.

      ESSENCE-IPD Management Group: This group is convened by the Chair of the Project Team and comprises the IPD-MA statistician and data manager who will be responsible for the collection, checking, storage and analyses of data. J.E. Harding (chair of ESSENCE-IPD project); L Lin; C.A. Crowther and G Gamble.

      ESSENCE-IPD Trialist Group: This group includes investigators from all eligible trials who have agreed to share their data for the IPD.

      M Agosti (Division of Neonatology and Neonatal Intensive Care Unit, 'F. Del Ponte' Hospital, Varese, Italy); S.A. Atkinson (Department of Pediatrics, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.); A Biasini (Donor Human Milk Bank Italian Association (AIBLUD), Milan, Italy); R.D.S Da Cunha (Hospital Universitário da Universidade Federal do Maranhão - Brasil); N.D. Embleton (Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK); M Faraz (Department of Pediatrics, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.); M.S Fewtrell (Childhood Nutrition Research Centre, UCL Great Ormond Street Institute of Child Health, London, UK); F Lamy Filho (Departamento de Medicina, Universidade Federal do Maranhão (UFMA), São Luís, MA, Brazil); C. Fusch (Department of Pediatrics, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada and Department of Pediatrics, Nuremberg General Hospital, Paracelsus Medical University, 90471 Nuremberg, Germany); M.L. Gianni (Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, via Commenda 12, 20122 Milan, Italy); H.G. Kanmaz (Department of Neonatology, NICU, Zekai Tahir Burak Education andResearch Hospital, Ankara, Turkey); W.WK. Koo (Department of Nutrition and Food Science, Wayne State University, Detroit, MI, USA); I Litmanovitz (Department of Neonatology, Meir Medical Center, Kfar Saba, Israel); A Lucas (MRC Childhood Nutrition Research Centre, Institute of Child Health, University College London, London, UK); C Morgan (Department of Neonatology, Liverpool Women’s Hospital, Liverpool, UK); K Mukhopadhyay (Department of Pediatrics, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.); E Neri (Department of Psychology, University of Bologna, Bologna, Italy); J Picaud (Division of Neonatology, Hôpital de la Croix-Rousse, Lyon, France); E.V Rafael (Departamento de Enfermagem da Universidade Federal do Maranhão, Brasil); P Roggero (Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, via Commenda 12, 20122 Milan, Italy); A Singhal (Department of Nutrition, Institute of Child Health, London, UK); K Stroemmen (Department of Neonatal Intensive Care, Division of Pediatric and Adolescent Medicine, Rikshospitalet, Oslo University Hospital, Oslo, Norway); M.J. Tan (Department of Developmental Paediatrics, Alder Hey Children's NHS Foundation Trust, Liverpool, UK); F.M. Tandoi (Division of Neonatology and Neonatal Intensive Care Unit, “F. Del Ponte” Hospital, Varese, Italy); C.L. Wood (Institute of Genetic Medicine, Newcastle University, Newcastle, UK); G Zachariassen (H.C. Andersen Children’s Hospital, Odense University Hospital and University of Southern Denmark, Odense, Denmark).

    • Contributors The Chair of the ESSENCE-IPD Project Team (J.E. Harding) wrote the first draft of the ESSENCE-IPD protocol. L Lin revised the subsequent versions of the ESSENCE-IPD protocol and prepared the initial draft of the manuscript. The ESSENCE-IPD Project Team and the ESSENCE-IPD Management Group participated in the protocol development and commented on all drafts of the manuscript. The ESSENCE-IPD Trialist Group participated in the development of the IPD protocol and have read and approved the final draft of the manuscript.

    • Funding The ESSENCE-IPD project is supported by the Health Research Council (HRC) of New Zealand (16/605). The analysis will be included as part of the doctoral thesis of Luling Lin, who is supported by Agnes Paykel PhD Scholarship. None of the funders are involved in any other aspect of the project, such as the design of the protocol and analysis plan, the collection and analysis of the data or the interpretation and publication of the study results.

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Ethics approval The ESSENCE-IPD project has been approved by University Of Auckland Human Participants Ethics Committee. Participants in the individual trials have previously given informed consent to participate in their respective trials. The data for these projects are to be used for the purpose for which they were originally collected and are available through an agreement between all trialists of the collaborative group. These trialists remain custodians of their original trial data at all times. A data sharing agreement will be signed by a representative of the institution that owns the data and a representative of University of Auckland.

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

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