Methylxanthine treatment for apnea in preterm infants
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Updated: Oct 16, 2026
A Swine Model of Neonatal Asphyxia
Published on: October 11, 2011
1NSW Centre for Perinatal Health Services Research, Queen Elizabeth II Institute for Mothers and Infants, Building DO2, University of Sydney, Sydney, NSW, Australia, 2006. dhs@mail.usyd.edu.au
Insights
Methylxanthine treatment effectively reduces apnea and the need for mechanical ventilation in preterm infants within the first week. Caffeine is recommended due to lower toxicity, but long-term effects require further study.
Area of Science:
- Neonatal Medicine
- Pharmacology
Background:
- Recurrent apnea is prevalent in preterm infants, potentially causing hypoxemia and bradycardia requiring resuscitation.
- Methylxanthines are utilized to stimulate breathing and mitigate apnea in neonates.
Purpose of the Study:
- To assess the efficacy of methylxanthine treatment in reducing apnea and intermittent positive pressure ventilation (IPPV) in preterm infants.
- To evaluate the clinical significance of methylxanthine side effects in this population.
Main Methods:
- Systematic review of randomized and quasi-random trials comparing methylxanthines (theophylline, caffeine) with placebo or no treatment.
- Searches included major databases (MEDLINE, EMBASE, Oxford Database of Perinatal Trials) and conference proceedings.
- Data analysis involved calculating relative risk (RR), risk difference (RD), and number needed to treat (NNT).
Main Results:
- Four trials involving 110 preterm infants demonstrated that methylxanthine therapy reduces apnea and IPPV use within 2-7 days.
- Insufficient data exist to evaluate side effects or effects across different gestational ages.
- Long-term effects of methylxanthine treatment have not been assessed in trials.
Conclusions:
- Methylxanthines are effective in decreasing apneic episodes and the need for mechanical ventilation in preterm infants shortly after treatment initiation.
- Caffeine is the preferred methylxanthine due to its lower toxicity profile.
- Future research should stratify by gestational age and assess long-term outcomes, including growth and development.
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. Methylxanthines have been used to stimulate breathing and prevent apnea and its consequences.
Objectives:
The objective of this review is to determine if methylxanthine treatment in preterm infants with recurrent apnea leads to a clinically important reduction in apnea and use of intermittent positive pressure ventilation (IPPV), without clinically important side effects.
Search Strategy:
Searches were made of the Oxford Database of Perinatal Trials, MEDLINE, EMBASE, previous reviews including cross references, abstracts of conferences and symposia proceedings, expert informants, journal handsearching mainly in the English language.
Selection Criteria:
All trials utilising random or quasi-random patient allocation, in which methylxanthine (theophylline or caffeine) was compared with placebo or no treatment for apnea in preterm infants, were included.
Data Collection And Analysis:
Methodological quality was assessed independently by the two authors. Data were extracted independently by the two authors. Treatment effects were expressed as relative risk (RR) and risk difference (RD) and their 95% confidence intervals, using a fixed effect model. For significant results, the inverse of the risk difference (1/RD) was used to calculate the number needed to treat (NNT).
Main Results:
The results of four trials which enrolled a total of 110 preterm infants with apnea indicate that methylxanthine therapy leads to a reduction in apnea and use of IPPV in the first 2 - 7 days. There are insufficient data to evaluate side effects and no data to examine effects within different gestational age groups. There are no trial data which examine long term effects.
Reviewer'S Conclusions:
Methylxanthines are effective in reducing the number of apneic attacks and the use of mechanical ventilation in the two to seven days after starting treatment. In view of its lower toxicity, caffeine would be the preferred drug. Although the safety of methylxanthine therapy has been suggested in cohort studies, there are no trial data on longterm outcome. In order to indicate which infants are likely to benefit from treatment, there is a need for stratification by gestation and/or other risk factors in future studies. In any future studies the longer term effects of treatment on growth and development should be evaluated.
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