A randomised trial of granulocyte-macrophage colony-stimulating factor for neonatal sepsis: outcomes at 2 years
- Neil Marlow1,
- Timothy Morris2,
- Peter Brocklehurst3,
- Robert Carr4,
- Frances M Cowan5,
- Nishma Patel6,
- Stavros Petrou7,
- Maggie E Redshaw8,
- Neena Modi9,
- Caroline Dore2
- 1Institute for Womens Health, University College London, London, UK
- 2MRC Clinical Trials unit, London, UK
- 3Institute for Women's Health, University College London, London, UK
- 4Department of Haematology, Kings College London, London, UK
- 5Department of Paediatrics, Imperial College (Hammersmith Hospital), London, UK
- 6National Perinatal Epidemiology Unit, University of Oxford, Oxford, UK
- 7CTU, University of Warwick, Coventry, UK
- 8Policy Research Unit in Maternal Health & Care, National Perinatal Epidemiology Unit, University of Oxford, Oxford, UK
- 9Department of Neonatal Medicine, Imperial College London, London, UK
- Correspondence to Neil Marlow, Institute for Womens Health, 74 Huntley Street, University College London WC1E 6AU, UK;
Contributors Investigators NMo, RC, PB and CJD formulated the hypothesis and design of the primary PROGRAMS trial; NMo, RC, PB, CJD and NMa formulated the hypothesis and design of the follow-up study. TM analysed the data with supervision by CJD. SP and NP were responsible for the economic analysis and interpretation. NMa wrote the first draft of this paper and coordinated manuscript revisions and submission. All investigators with FC and MR were involved in management of the 2-year follow-up study, interpretation of data, and writing the report. All the authors have seen and approved the final version. Two-year outcome study oversight committees: Data Monitoring Committee: D Field, J Hutton, S Saigal, C Bennett; Follow-up Trial Steering Committee Independent Members: M Chiswick, M Deans, S Riddell, M Weindling. Trial hospitals and investigators: Brighton, Royal Sussex County (H Rabe, F Weir); Bristol, Southmead (D Evans), Bristol, St Michaels (P Cairns, A Jain); Cambridge, the Rosie (A Ogilvy-Stuart); Cardiff, University of Wales (S Barr, P Cartlidge); Dundee, Ninewells (P Fowlie); Gillingham, Medway Maritime (B Jani); Glasgow, Princess Royal (A Powls), Ipswich (K O’Neill); Liverpool Women's (C Morgan, M Weindling), London, Chelsea and Westminster (D Acolet, E Ogundipe); London, Guy's & St Thomas' (M Campbell, G Fox, J Rissik); London, Hammersmith (N Murray); London, Hillingdon (M Cruwys); London, Homerton (E Maalouf); London, Newham General (V Gopinathan); London, Northwick Park (R Nicholl); London, University College (J Hawdon); Manchester, St Mary's (A Emmerson); Norwich, Norfolk & Norwich University (P Clarke, J Eason); Nottingham, Queens (S Wardle); Plymouth, Derriford (J Lilley); Portsmouth, St Mary's (R Thwaites); Slough, Wexham Park (R Jones); Swansea, Singleton (J Mathers); Woolwich, Queen Elizabeth (B Al-Rubeyi). Two-year Outcome Study Assessors: Amanda Cundy, Angela Huertas, Huw Jones, Louise Watson, Sajjad Rahman, Andrew Cheew, Ann Humphreys, Leigh Dyet, Angela D’Amore, Georgie Siggers, Lesley McDonald, Nick Wood, Sam Johnson.
- Received 30 November 2011
- Accepted 22 February 2012
- Published Online First 27 April 2012
Objective The authors performed a randomised trial in very preterm small-for-gestational age (SGA) babies to determine if prophylaxis with granulocyte-macrophage colony-stimulating factor (GM-CSF) improves outcomes (the PROGRAMS trial). Despite increased neutrophil counts following GM-CSF, the authors reported no significant difference in neonatal sepsis-free survival.
Patients and methods 280 babies born <31 weeks of gestation and SGA were entered into the trial. Outcome was determined at 2 years to determine neurodevelopmental and general health outcomes, including economic costs.
Results The authors found no significant differences in health outcomes or health and social care costs between the trial groups. In the GM-CSF arm, 87 of 134 (65%) babies survived to 2 years without severe disability compared with 87 of 131 (66%) controls (RR: 1·0, 95% CI 0·8 to 1·2). Marginally, more children receiving GM-CSF were reported to have cough (RR 1·7, 95% CI 1·1 to 2·6) and had signs of chronic respiratory disease (Harrison's sulcus; RR 2·0, 95% CI 1·0 to 3·9) though this was not reflected in bronchodilator use or need for hospitalisation for respiratory disease. Overall, the rate of neurologic abnormality (7%–9%) was similar but mean overall developmental scores were lower than expected for gestational age.
Conclusions The administration of GM-CSF to very preterm SGA babies is not associated with improved or more adverse outcomes at 2 years of age. The apparent excess of developmental impairment in the entire PROGRAMS cohort, without corresponding increase in neurological abnormality, may represent diffuse brain injury attributable to intrauterine growth restriction.
Funding Action Medical Research and the Wellcome Trust; Neil Marlow receives part funding from the Department of Health's NIHR Biomedical Research Centres funding scheme at UCLH/UCL. Robert Carr received part funding from the NIH Biomedical Research Centre at King's College London.
Competing interests None.
Ethics approval South Thames Multicentre Research Ethics Committee.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Data from this study are still under analysis as a 5-year outcome study is now under way. The database is available for researchers following application to the chief investigator (N Modi) subject to review by the investigators group.
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