ArticlesGranulocyte-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
Introduction
Systemic sepsis remains a major cause of death in newborn babies. Survivors of sepsis are at a substantially increased risk of developmental delay and neurocognitive impairment through damage to cerebral white matter and other brain injury induced by the systemic inflammatory response.1, 2 Bacterial sepsis doubles the risk of death and periventricular leucomalacia, a major form of preterm white matter brain injury.2, 3 Strategies to reduce neonatal sepsis have been disappointing and sepsis-related mortality remains high. The most important risk factor is the degree of immaturity, with sepsis rates in extremely preterm neonates ranging from 25% to 65%.2, 3 Neutropenia, which occurs frequently in preterm and intrauterine growth restricted infants,4, 5 is believed to increase the risk further.6, 7
Immunological immaturity plays an important part in the preterm infant's susceptibility to bacterial sepsis. The fetal and newborn innate immune system is unable to produce adequately the proinflammatory (TH1) cytokines, such as interferon gamma, that are believed to be necessary for effective antimicrobial defence.8 Preterm infants have reduced neutrophil production and marrow stores,9, 10 predisposing them to neutropenia during sepsis,11 and neonate neutrophils, particularly in preterm babies, are less effective at killing bacteria than in older infants.12, 13
Since the haemopoietic growth factors, granulocyte colony stimulating factor (G-CSF), and granulocyte-macrophage colony stimulating factor (GM-CSF) became available and were shown to be effective for neutropenia-related infection in cancer patients after chemotherapy,14, 15 their potential to reduce systemic sepsis in newborn babies has seemed an attractive therapeutic strategy.16 GM-CSF seemed particularly promising for use in preterm infants since it promotes TH1 immune responses and primes neutrophils and monocytes for enhanced bactericidal activity, as well as stimulating proliferation of neutrophil progenitors.17, 18, 19, 20 GM-CSF therefore has the potential to enhance antibacterial immunity in both neutropenic and non-neutropenic infants. The haemopoietic growth factors have entered into sporadic use in neonatal medicine for prophylaxis and treatment of sepsis in the presence of neutropenia without adequate evidence.
In rodent models of experimental sepsis, both G-CSF and GM-CSF reduce mortality, but are more effective when given before bacterial inoculation, supporting the potential benefit of early postnatal prophylaxis.21, 22 Studies in humans, in which G-CSF or GM-CSF were administered as prophylaxis for up to 5 days, showed a promising reduction in systemic sepsis in small-for-gestation neonates23 and those with established early postnatal neutropenia.24 However, both studies were small, and in a Cochrane review we concluded that there was inadequate evidence for the adoption of prophylactic colony stimulating factors into clinical practice.25
In the PROGRAMS trial we aimed to test the hypothesis that prophylactic GM-CSF, given for a short period after birth to preterm neonates at high risk of neutropenia and sepsis, would lead to a clinically significant reduction in systemic infection, mortality, and later disability. Here we present short-term outcomes to hospital discharge and a meta-analysis combining PROGRAMS and previous trial data.
Section snippets
Participants
Infants were eligible if born at a gestational age of less than or equal to 31 completed weeks and with a birthweight below the 10th centile (UK 1990 Growth Reference). An infant was not eligible if there was an immediately life-threatening congenital abnormality, or a strong likelihood of early onset sepsis, indicated by maternal pyrexia exceeding 38°C on two occasions during labour.
Study design and procedures
We undertook a single-blind, multicentre, randomised controlled trial of the effect of prophylactic GM-CSF in
Results
We recruited 280 neonates into the PROGRAMS trial between June, 2000, and June, 2006. Recruitment ceased when funding ended. There was an enforced break in recruitment between October, 2002, and October, 2004, between the discontinuation of Leucomax supply and Leukine becoming available in the UK. There were two protocol deviations: an infant above the 10th centile for birthweight and an infant who received only 2 days of GM-CSF treatment. All recruited infants were included in the analysis. No
Discussion
The findings of the PROGRAMS trial indicate that prophylactic GM-CSF significantly raises neutrophil counts in a population at high risk of postnatal neutropenia but does not result in a reduction in systemic sepsis, mortality, or short-term clinical morbidity.
Two previous small studies of CSF prophylaxis given soon after birth to infants who were neutropenic or small for gestational age showed benefit,23, 24 with a combined odds ratio for the prevention of sepsis of 0·2 (95% CI 0·05–0·84;
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