Comparative efficacy and safety of caffeine citrate and aminophylline in treating apnea of prematurity: A systematic review and meta-analysis

PLoS One. 2022 Sep 19;17(9):e0274882. doi: 10.1371/journal.pone.0274882. eCollection 2022.


Background: Methylxanthine, including caffeine citrate and aminophylline, is the most common pharmacologic treatment for apnea of prematurity. However, due to the lack of high-quality evidence, there are no clear recommendations or guidelines on how to choose between caffeine and aminophylline.

Objective: This meta-analysis aimed to assess the comparative efficacy and safety of caffeine and aminophylline for apnea of prematurity, and provide reliable evidence for clinical medication in the treatment for apnea of prematurity.

Methods: PubMed, Scopus, Embase, EBSCO, Web of Science, and Cochrane databases were systematically searched from May 1975 to June 2022.

Results: Ten studies including a total of 923 preterm infants were evaluated. Our results showed that there was no significant difference in the effective rate of 1-3days between caffeine and aminophylline (OR 1.05, 95%CI: 0.40-2.74, P = 0.914). However, for side effects such as tachycardia (OR 0.22, 95%CI: 0.13-0.37, P<0.001) and feeding intolerance (OR 0.40, 95%CI: 0.23-0.70, P = 0.001), the incidence rate was lower in the caffeine group compared with the aminophylline group. No significant difference was found in hyperglycemia (OR 0.45, 95%CI: 0.19-1.05, P = 0.064).

Conclusion: This meta-analysis reveals that caffeine citrate and aminophylline have similar therapeutic effectiveness on respiratory function, but caffeine has fewer side effects and should be considered first for treatment.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Aminophylline / adverse effects
  • Apnea / drug therapy
  • Caffeine / adverse effects
  • Citrates
  • Humans
  • Infant
  • Infant, Newborn
  • Infant, Newborn, Diseases* / drug therapy
  • Infant, Premature
  • Infant, Premature, Diseases* / drug therapy


  • Citrates
  • Aminophylline
  • Caffeine
  • caffeine citrate

Grants and funding

The author(s) received no specific funding for this work.