Prophylactic methylxanthine for prevention of apnea in preterm infants

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Abstract
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 and its associated hypoxemia and bradycardia. In preterm infants, does prophylactic treatment with methylxanthine lead to less apnea, bradycardia, episodes of hypoxemia and use of mechanical ventilation, without clinically important side effects? The standard strategy of the Cochrane Neonatal Review Group was used. This included searches of the Oxford Database of Perinatal Trials, previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants and journal handsearching mainly in the English language. A search of MEDLINE was made in October 1998 covering the years 1966 -1998. 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, side effects such as tachycardia or feed intolerance, as well as longer term abnormal growth and development. 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 author. Each reviewer 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). 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. 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, length of hospital stay and long term development.