Use of Methylxanthine Therapies for the Treatment and Prevention of Apnea of Prematurity

Katherine Schoen, Tian Yu, Chris Stockmann, Michael G. Spigarelli, Catherine M. T. Sherwin

Apnea of prematurity (AOP) is a common complication of preterm birth, which affects more than 80 % of neonates with a birth weight less than 1,000 g. Methylxanthine therapies, including caffeine and theophylline, are a mainstay in the treatment and prevention of AOP. Despite their frequent use, little is known about the long-term safety and efficacy of these medications. In this review, we systematically evaluated the literature on neonatal methylxanthine therapies and found that caffeine is associated with fewer adverse effects and a wider therapeutic window when compared with theophylline. When used as a therapeutic agent, larger doses of caffeine citrate have been shown to improve acute neonatal outcomes when administered promptly, although further studies are needed to assess the long-term neurological consequences associated with the use of large loading doses. In a secondary analysis of data obtained from a randomized controlled trial, the prophylactic use of caffeine was associated with substantial cost savings and improved clinical outcomes. However, there remains a paucity of well-controlled, randomized clinical trials that have examined the use of caffeine as a prophylactic agent, and further prospective trials are needed to determine if caffeine is a safe and effective prophylactic agent. Additionally, measuring plasma concentrations longitudinally as a marker of therapeutic efficacy and/or toxicity has not been shown to be clinically useful in neonates who are responsive to treatment and exhibit no signs or symptoms of toxicity. However, in cases where toxicity is of concern or for neonates with congenital or pathophysiologic process that may alter the pharmacokinetics of these drugs, therapeutic drug monitoring may be warranted to monitor for methylxanthine toxicity.