Prophylactic methylxanthine for prevention of apnea in preterm infants

Background

Recurrent apnea is common in preterm infants, particularly at very early gestational ages. These episodes of loss of effective breathing can lead to hypoxemia and bradycardia which may be severe enough to require resuscitation including use of positive pressure ventilation. In infants with apnea, methylxanthines have been successful as treatment to prevent further episodes. It is possible that prophylactic therapy, given to all very preterm infants from soon after birth, might prevent apnea, its associated hypoxemia and bradycardia and need for added ventilatory support.

Objectives

To determine the effect of prophylactic treatment with methylxanthine on apnea, bradycardia, episodes of hypoxemia, use of mechanical ventilation, and morbidity in preterm infants at risk for apnea of prematurity

Search strategy

The standard search strategy of the Neonatal Review Group was used. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2008), Oxford Database of Perinatal Trials, MEDLINE (1966 - June 2008), CINAHL (1982 - June 2008) and EMBASE (1988 - June 2008) using MeSH term infant-newborn, and text terms methylxanthines, caffeine, theophylline, apnea, and premature as well as a search of previous reviews including cross references, and conference proceedings including abstracts from the Society for Pediatric Research meeting 2001 - 2008.

Selection criteria

All trials utilising random or quasi-random patient allocation, in which prophylactic methylxanthine (caffeine or theophylline) was compared with placebo or no treatment were eligible. Outcomes sought included the rate of apnea, bradycardia, hypoxemic episodes, use of IPPV, morbidity and side effects such as tachycardia or feed intolerance, as well as longer term abnormal growth and development.

Data collection and analysis

The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. The methodological quality of each trial was reviewed independently by each review author. Each review author extracted data separately, then results were compared and differences resolved. The standard method of the Cochrane Neonatal Review Group was used to analyze the data, utilizing relative risk (RR) and risk difference (RD) .

Main results

Two studies examining a total of 104 infants were found. Both studied the effects of prophylactic caffeine. There were no meaningful differences between the caffeine and placebo groups in the number of infants with apnea, bradycardia, hypoxemic episodes, use of IPPV or side effects in either of the studies. Only two outcomes (use of IPPV and tachycardia) were common to the two studies and meta-analysis showed no substantive differences between the groups. One large trial (CAP Trial 2006) of caffeine therapy in a heterogeneous group of infants at risk for and having apnea of prematurity has demonstrated an improved rate of survival without developmental disability at 18 - 21 months of age and is awaiting assessment for inclusion in this review.

Authors' conclusions

The results of this review do not support the use of prophylactic caffeine for preterm infants at risk of apnea, bradycardia or hypoxemic episodes.

Any future studies need to examine the effects of prophylactic methylxanthines in preterm infants at higher risk of apnea, bradycardia or hypoxemic episodes. This should include examination of important clinical outcomes such as need for IPPV, neonatal morbidity, length of hospital stay and long-term development. Much of this data will be available on further subgroup analysis of the Caffeine for Apnea of Prematurity Trial (CAP Trial 2006).