According to an article published in The Lancet this week, the prophylactic administration of a blood cell growth factor to premature babies does not improve survival or reduce sepsis (systemic infection), despite raising immune cell counts.

The study was carried out by Dr. Robert Carr, Guy's and St. Thomas' Hospital NHS Trust, London, England, and team from the National Perinatal Epidemiology Unit, Medical Research Council and Imperial College London, UK.

Systemic infection continues to be a main cause of mortality among newborn infants, the authors explain. A premature baby is even more vulnerable - many premature infants who do survive often face developmental delay and neurological problems because of brain damage.

Underweight and premature babies tend to suffer from neutropenia (low white blood cell counts), further raising their risk of infection. The researchers had hoped that by increasing their white blood cell numbers they might boost a premature baby's chances of survival. This did not happen.

It had previously been demonstrated that the use of blood growth factors such as granulocyte-macrophage colony stimulating factor (GM-CSF) were effective in raising white blood cell numbers and reducing the elevated risk of infection. Cancer patients, whose white blood cell count are depleted after chemotherapy benefit from this strategy.

Therefore, it was expected that these agents would raise the white blood cell counts and lower infection in premature infants. As these blood growth factors had only been used intermittently in treating premature babies, without any confirmation of their efficacy, the researchers initiated the PROGRAMS trial. The PROGRAMS trial aimed to find out whether prophylactic administration of GM-CSF to extremely preterm, small newborn babies would reduce sepsis and mortality.

In this randomised, controlled trial the researchers studied 280 babies from 26 centres around the United Kingdom. All the babies had been born at 31 weeks gestation or earlier, and in the lowest 10% birthweight for their gestational age - in other words, babies at especially high risk of infection. 139 of them randomly received a GM-CSF injection once daily for the first five days after they were born, while the other 141 received standard management.

White blood cell counts among the babies receiving GM-CSF did go up faster, compared to the control group, said the researchers. However, no significant difference in infection-free survival was detected between the two groups. A meta-analysis combining the results of the PROGRAMS study with earlier trials also showed no survival benefit for prophylactic administration of GM-CSF.

"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," the authors concluded. 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."

"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 Frank Shann, Intensive Care Unit, Royal Children's Hospital, Melbourne, Australia, wrote in an accompanying Comment.

Main Article
"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."
Robert Carr FRCPath, Prof Peter Brocklehurst FRCOG, Caroline J Doré BSc, Prof Neena Modi FRCPCH
The Lancet, Volume 373, Issue 9659, Pages 226 - 233, 17 January 2009
Click here to view Abstract online

Accompanying Comment
"Sepsis in babies: should we stimulate the phagocytes."
Frank Shann
The Lancet, Volume 373, Issue 9659, Pages 188 - 190, 17 January 2009
Click here to read first paragraph online