Prophylactic administration to premature babies of a blood cell growth factor raises immune cell counts but does not reduce systemic infection (sepsis) or improve survival. The findings are reported in an Article in this week's edition of The Lancet, written by Dr Robert Carr, Guy's and St Thomas' Hospital NHS Trust, London, UK, and colleagues from the National Perinatal Epidemiology Unit, Medical Research Council and Imperial College London, UK.
Systemic infection remains a major cause of death in newborn babies. Premature babies are particularly vulnerable and those that survive can face developmental delay and neurological problems due to brain damage. Premature babies and particularly those who have a lower than normal birth weight for their degree of prematurity, are prone to low white blood cell counts (neutropenia) and this further increases the risk of infection. Hence treatments to increase white blood cell numbers have been considered a promising therapeutic approach.
The use of blood growth factors such as granulocyte-macrophage colony stimulating factor (GM-CSF) has been shown to be effective for increasing white blood cell numbers and reducing the high risk of infection. This strategy has been used in cancer patients who have had chemotherapy treatment which has depleted their white blood cell count. Thus it was hoped these agents could increase white blood cell counts and reduce infection in premature babies. However, to date these blood growth factors have been used sporadically in treating premature babies without evidence of their efficacy. In this study – the PROGRAMS trial —the researchers assessed whether prophylactic administration of GM-CSF to extremely preterm, small newborn babies would reduce sepsis and mortality.
This randomised controlled trial studied 280 babies from 26 UK centres, all born at 31 weeks gestation or earlier and in the lowest 10% of birthweight for their gestational age — and thus a group at extremely high risk of infection. Babies were randomised to receive an injection of GM-CSF once a day for the first five days after delivery (139 babies) or standard management (141 babies). The researchers found that, although white blood cell counts rose more rapidly in infants given GM-CSF than in control infants, there was no significant difference in infection-free survival between the two groups. A meta-analysis combining the results of the PROGRAMS study with previous trials also showed no survival benefit for prophylactic administration of GM-CSF.
The authors conclude: "Early postnatal prophylactic GM-CSF corrects neutropenia but does not reduce sepsis or improve survival and short-term outcomes in extremely preterm neonates...We believe that, before embarking on future single agent clinical trials, we should consider if this is too simplistic an approach to sepsis prevention in the preterm infant, whose immune system appears compromised in many different ways. Knowledge of the functional characteristics of neonatal innate immunity remains limited and needs continued research effort. Successful future stratagems will need a wider view of their antibacterial defences."
They add*: "Treatments that are effective in adults cannot be assumed to be effective in premature babies. The majority of medications used in premature babies have not been specifically evaluated in them."
In an accompanying Comment, Dr Frank Shann, Intensive Care Unit, Royal Children's Hospital, Melbourne, Australia, says: "G-CSF and GM-CSF should no longer be used routinely in neonatal intensive care without further evidence from randomised trials. Unfortunately, funding is difficult to get for trials of treatments that will be used in very few patients, or that are not under patent."
Dr Robert Carr, Guy's and St Thomas' Hospital NHS Trust, London, UK T) +44 (0) 7732 773 798 E) robert.carr@gstt.nhs.uk
Dr Frank Shann, Intensive Care Unit, Royal Children's Hospital, Melbourne, Australia contact by e-mail only E) frank.shann@rch.org.au / shannf@netspace.net.au
*Notes to editors: quote direct from authors and cannot be found within the text of the Article.
For full Article and Comment see: http://press.thelancet.com/programs.pdf
Journal
The Lancet