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Identifying effect modifiers of systemic hydrocortisone treatment initiated 7–14 days after birth in ventilated very preterm infants on long-term outcome: secondary analysis of a randomised controlled trial
  1. Nienke Marjolein Halbmeijer1,2,
  2. Michel Sonnaert3,
  3. Renate M Swarte4,
  4. Corine Koopman-Esseboom5,
  5. Margriet van Stuijvenberg6,
  6. Susanne Mulder-de Tollenaer7,
  7. Ratna N G B Tan8,
  8. Thilo Mohns9,
  9. Els Bruneel10,
  10. Katerina Steiner11,
  11. Boris W Kramer12,13,
  12. Anne Debeer14,
  13. Mirjam M van Weissenbruch2,15,
  14. Yoann Marechal16,
  15. Henry Blom17,
  16. Katleen Plaskie18,
  17. Martin Offringa1,19,
  18. Maruschka P Merkus20,
  19. Wes Onland1,2,
  20. Aleid G Leemhuis1,2,
  21. Anton H van Kaam1,2
  22. SToP-BPD Study group
    1. 1 Neonatology, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
    2. 2 Research Institute, Amsterdam Reproduction and Development, Amsterdam, The Netherlands
    3. 3 Neonatology, Universitair Ziekenhuis Brussel, Brussels, Belgium
    4. 4 Neonatology, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands
    5. 5 Neonatology, University Medical Centre Utrecht/Wilhelmina Children's Hospital, Utrecht, The Netherlands
    6. 6 Neonatology, University Medical Centre Groningen, Beatrix Children's Hospital, Groningen, The Netherlands
    7. 7 Neonatology, Isala Medical Centre, Zwolle, The Netherlands
    8. 8 Neonatology, Leiden University Medical Center, Leiden, The Netherlands
    9. 9 Neonatology, Maxima Medical Centre, Women Mother and Child Centre, Veldhoven, The Netherlands
    10. 10 Neonatology, Ziekenhuis Oost-Limburg, Genk, Belgium
    11. 11 Neonatology, Radboudumc Institute for Health Sciences, Amalia Children's Hospital, Nijmegen, The Netherlands
    12. 12 School of Women’s and Infants’ Health, University of Western Australia, Crawley, Western Australia, Australia
    13. 13 Research & Development, Neuroplast BV, Maastricht, The Netherlands
    14. 14 Neonatology, University Hospitals Leuven, Leuven, Belgium
    15. 15 Neonatology, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
    16. 16 Neonatology, Centre Hospitalier Universitaire de Charleroi, Charleroi, Belgium
    17. 17 Neonatology, Universitair Ziekenhuis Antwerpen, Edegem, Belgium
    18. 18 Neonatology, St Augustinus ziekenhuis, Antwerp, Belgium
    19. 19 Neonatology and Child Health Evaluative Sciences, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
    20. 20 Epidemiology and Data Science, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
    1. Correspondence to Professor Anton H van Kaam, Neonatology, Amsterdam UMC location University of Amsterdam, PO Box 22700; 1100 DD Amsterdam, The Netherlands; a.h.vankaam{at}amsterdamumc.nl

    Abstract

    Objective To explore clinical effect modifiers of systemic hydrocortisone in ventilated very preterm infants for survival and neurodevelopmental outcome at 2 years’ corrected age (CA).

    Design Secondary analysis of a randomised placebo-controlled trial.

    Setting Dutch and Belgian neonatal intensive care units.

    Patients Infants born <30 weeks’ gestational age (GA), ventilator-dependent in the second week of postnatal life.

    Intervention Infants were randomly assigned to systemic hydrocortisone (cumulative dose 72.5 mg/kg; n=182) or placebo (n=190).

    Main outcome measures The composite of death or neurodevelopmental impairment (NDI) at 2 years’ CA and its components. Candidate effect modifiers (GA, small for GA, respiratory index, sex, multiple births, risk of moderate/severe bronchopulmonary dysplasia or death) were analysed using regression models with interaction terms and subpopulation treatment effect pattern plots.

    Results The composite outcome was available in 356 (96.0%) of 371 patients (one consent withdrawn). For this outcome, treatment effect heterogeneity was seen across GA subgroups (<27 weeks: hydrocortisone (n=141) vs placebo (n=156), 54.6% vs 66.2%; OR 0.61 (95% CI 0.38 to 0.98); ≥27 weeks: hydrocortisone (n=30) vs placebo (n=31), 66.7% vs 45.2%; OR 2.43 (95% CI 0.86 to 6.85); p=0.02 for interaction). This effect was also found for the component death (<27 weeks: 20.1% vs 32.1%; OR 0.53 (95% CI 0.32 to 0.90); ≥27 weeks: 28.1% vs 16.1%; OR 2.04 (95% CI 0.60 to 6.95); p=0.049 for interaction) but not for the component NDI. No differential treatment effects were observed across other subgroups.

    Conclusion This secondary analysis suggests that in infants <27 weeks’ GA, systemic hydrocortisone may improve the outcome death or NDI, mainly driven by its component death. There was insufficient evidence for other selected candidate effect modifiers.

    • Neonatology
    • Infant Development
    • Respiratory Medicine

    Data availability statement

    Data are available upon reasonable request. Deidentified individual participant data (including data dictionaries) will be made available, in addition to study protocol, the statistical analysis plan and the analytical code. The data will be made available upon publication to researchers who provide a methodologically sound proposal for use in achieving the goals of the approved proposal. Proposals should be submitted to Professor Anton van Kaam (email: a.h.vankaam@amsterdamumc.nl).

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    Data availability statement

    Data are available upon reasonable request. Deidentified individual participant data (including data dictionaries) will be made available, in addition to study protocol, the statistical analysis plan and the analytical code. The data will be made available upon publication to researchers who provide a methodologically sound proposal for use in achieving the goals of the approved proposal. Proposals should be submitted to Professor Anton van Kaam (email: a.h.vankaam@amsterdamumc.nl).

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    Footnotes

    • Presented at The results of this study were shown at the Ninth Congress of the European Academy of Pediatric Societies 2022, Barcelona, Spain; poster viewing: 7–11 October 2022.

    • Collaborators SToP-BPD Study group members: Debbie H Nuytemans, Moniek van de Loo (Department of Neonatology, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands); Filip Cools, Ingrid van Limberghen (Department of Neonatology, Universitair Ziekenhuis Brussel, Brussels, Belgium); Andre Kroon, Nienke Rietema, Annette van der Kaa (Department of Neonatology, Sophia Children’s Hospital, Erasmus MC, Rotterdam, the Netherlands); Ingrid C van Haastert, Henriette Swanenburg de Veye, Rian Eijsermans (Department of Neonatology, University Medical Center, Utrecht, the Netherlands); Ellen de Kort, Marieke Vervoorn (Department of Neonatology, Maxima Medical Center Veldhoven, the Netherlands); Eric Cavartorta, Anne Rassart (Department of Neonatology, Centre Hospitalier Universitaire Marie Curie, Charleroi, Belgium); An Eerdekens, Isabelle Hermans, Julie Messiaen (Department of Neonatology, Universitair ziekenhuis Leuven, Leuven, Belgium); Peter H Dijk, Anne E den Heijer (Department of Neonatology, University Medical Center Groningen, Beatrix Children’s Hospital, University of Groningen, Groningen, the Netherlands); Anjo Janssen, Nienke M Maas-van Schaaijk, Wendy Jansen (Department of Neonatology, Radboud University Medical Center-Amalia Children's Hospital, Nijmegen, the Netherlands); Hendrik Niemarkt, Ilse van Hattum (Department of Neonatology, Medical University Center Maastricht, Maastricht, the Netherlands); Astrid Giezen, Henrica L van Straaten, (Department of Neonatology, Isala Medical Center, Zwolle, the Netherlands); Arjan B Te Pas, Romy Berkhout (Department of Neonatology, Leiden University Medical Center, Leiden, the Netherlands); Claire Theyskens (Department of Neonatology, Ziekenhuis Oost-Limburg, Genk, Belgium); Inge Zonnenberg (Department of Neonatology, Emma Children’s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands); Elke Dierckx (St Augustinus ziekenhuis, Antwerp, Belgium). All members contributed to the design of the study protocol, data collection and data reporting. They received no compensation for their contributions.

    • Contributors MS, RMS, CK-E, MvS, SM-dT, RNGBT, TM, EB, KS, BWK, AD, MMvW, YM, HG, KP, MO and AGvW-L are local investigators at the participating centres, and made substantial contributions to the concept and design of the study, and interpretation of data. NMH performed the statistical analyses, prepared the data tables, drafted the initial manuscript and revised the manuscript. MPM participated in the statistical analyses, and critically reviewed and revised the manuscript for important intellectual content. WO and AHvK are local investigators who made substantial contributions to the concept and design of the study, had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis, and critically reviewed the manuscript for important intellectual content. All authors approved the final manuscript as submitted. AHvK is the guarantor.

    • Funding The SToP-BPD Study was funded by a project grant from the Netherlands Organization for Health Research and Development (ZonMW) Priority Medicines for Children (no. 11-32010-02).

    • Competing interests AHvK reports grants from the Netherlands Organization for Health Research and Development (ZonMW) during the conduct of the study. No other disclosures were reported.

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

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.