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Two-year outcomes of a randomised trial of prophylactic granulocyte-macrophage colony stimulating factor (GM-CSF) to reduce sepsis in extremely preterm, small for gestational age babies (the PROGRAMS trial)

Presented at the Neonatal Society 2011 Spring Meeting.

Marlow N1, Morris TP2, Brocklehurst P3, Carr R4, Cowan F5, Redshaw M3, Modi N5, Doré CJ2

1 UCL Institute for Women’s Health, London, UK
2 MRC Clinical Trials Unit, London, UK
3 National Perinatal Epidemiology Unit, Oxford, UK
4 Department of Haematology, Guy’s and St Thomas’ Hospital, London, UK
5 Section of Neonatal Medicine, Chelsea & Westminster campus, Imperial College London, UK

Background: Neutropenia is a recognised risk factor for sepsis. The PROGRAMS trial (ISRCTN42553489), approved by South Thames Multicentre Research Ethics Committee, addressed the hypothesis that prophylactic GM-CSF by preventing neutropenia would reduce neonatal systemic infection and infection related mortality. Small for gestational age babies born at ≤31 weeks gestation, were randomly allocated to receive 5 daily doses of 10μg/kg GM-CSF subcutaneously commencing within 72h of birth or routine care. Prophylactic GM-CSF resulted in elevation of the neutrophil count but there was no difference in sepsis-free survival to 14 days from trial entry (1). As part of the original design of the project we hypothesized that there might be benefits to long-term outcomes. Here we describe outcomes at age 2-years.

Methods: Babies recruited to the PROGRAMS trial received follow-up assessments at age 2-years adjusted for prematurity by trained examiners blinded to treatment allocation; these comprised measures of growth, formal clinical and neurological examination and the Bayley Scales of Infant Development, 2nd edition (BSID-II). Parents completed a questionnaire with health and socioeconomic details and the Parent Report of Child Abilities. Outcomes were classified as severe disability, other disabilities or no disability (2). All analyses were done on an intention to treat basis.

Results: Of 280 babies entered into the PROGRAMS trial, 64 died, 13 were lost to follow-up and 203 received 2-year evaluations. In the GM-CSF and control arms 87 (65%) vs 87 (66%) children survived to 2 years without severe disability (RR 1.0, 95%CI 0.7 to 1.3). Bayley II Infant Development MDI and PDI scores and the pattern of disabilities were similar in the two groups. Marginally more children in the GM-CSF arm were reported to have cough (RR 1.7, 95%CI 1.1 to 2.6) and had Harrison’s sulcus (RR 2.0, 95%CI 1.0 to 3.9) though this was not reflected in the use of bronchodilators or excess need for hospital readmission for respiratory disease. Parent report of child development showed no differences between groups; growth deficits were similar in both groups (mean SDS, GM-CSF vs control: weight -1.7, -1.8; height -1.6, -1.7; head circumference -2.1, -2.1).

Conclusion: The administration of GM-CSF is not associated with either improved or adverse neurodevelopmental outcomes at age 2-years. The implication of the increase in respiratory findings in the GM-CSF group is uncertain. These were not pre-specified trial outcomes, and the differences may have arisen by chance. In contradistinction, 16 children in the GM-CSF arm compared to 23 in the control arm were discharged home with supplemental oxygen. As the stability between 2-year assessments and childhood measures of cognitive performance has been questioned it will be important to evaluate more predictive outcomes in the 5-year assessments that are currently ongoing, before the hypothesis that GM-CSF has no benefit in this very high-risk population can be rejected.

Corresponding author: n.modi@imperial.ac.uk

References
1. Carr R, Brocklehurst P, Doré CJ, Modi N. Granulocyte-macrophage colony stimulating factor administered as prophylaxis for reduction of sepsis in extremely preterm, small for gestational age neonates (the PROGRAMS trial): a single-blind, multicentre, randomised controlled trial. Lancet 2009; 373:226-33
2. Report of two working groups. Disability and perinatal care: Measurement of health status at two years. National Perinatal Epidemiology Unit and Oxford Health Authority1995

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