03/11/2005
Caffeine therapy in preterm infants: old questions, new answers
An international placebo controlled CAP trial will give new insights into long-term efficacy and safety of methilxantine treatment in premature children.

Very preterm infants are still considered at high risk of disability development. Recent studies show that, among premature infants, 20% had major disabilities at the age of 5 years and that only 20% was free of disability 6 years after birth. Moreover, preterm children have a greater occurrence of attention deficit, hyperactivity disorder and other abnormal behaviours. These findings suggest that the medical treatment in preterm infants could still be improved, not only by developing new drugs but also by rigorously evaluating common therapies for long-term efficacy and safety.
For instance, methilxantines (such as caffeine, the methilxantine of choice) have been prescribed for 35 years to reduce frequency of apnea. At present, they are one of the most prescribed drugs in neonatal medicine for the treatment of apnea and for the reduction of the needed mechanical ventilation in preterm infants. But treatment with these drugs still needs a deeper insight for long-term efficacy and safety. In fact, methilxantines are non-specific inhibitors of two of the four known adenosine receptors causing negative effects on growth and on brain development. Moreover, experimental findings in animal models demonstrate that methilxantine therapy alters permanently the expression of adenosine receptors in the brain, thus determining behavioural problems. Therefore, a long-term and rigorous study on these questions is necessary.
The international Caffeine for Apnea of Prematurity (CAP) trial may shed some light on this debate. In this trial, over 2,000 infants from North America, Europe and Australia, with birth weights 500–1,250 g have been randomised to caffeine or placebo to examine the long-term efficacy and safety of methilxantine therapy for the management of apnea. The randomisation was finished in 2004 and the follow-up will last 5 years. The primary outcome is survival to 18 months without neurodevelopmental disability. At this time, it is determined if the child died or survived with cerebral palsy, cognitive deficit, bilateral blindness and severe hearing loss. However, several long-term consequences of methilxantine therapy may not become evident until pre-school age. The follow-up has thus been extended to 5 years. The main outcome at this time will be a composite of death or survival with severe disability in at least one of six domains, namely cognition, neuromotor function, vision, hearing, behaviour, and general health. Severe disability has been defined as the need for constant supervision because of a particular deficit. The results of CAP trial will probably answer to some of the many questions still surrounding long-term efficacy and safety of methilxantine therapy in preterm infants. After this trial, caffeine will become one of the deepest-evaluated neonatal therapies.