Caffeine citrate: a review of its use in apnoea of prematurity

Paediatr Drugs. 2001;3(1):61-79. doi: 10.2165/00128072-200103010-00005.


Apnoea of prematurity is a common condition in neonates born at less than 37 weeks' gestational age; it affects approximately 90% of premature neonates weighing under 1000 g at birth, and 25% of infants with a birthweight of less than 2500 g. Caffeine, a methylxanthine which occurs naturally in many plants, has been used for over 20 years to treat apnoea of prematurity. In a recent double-blind, placebo-controlled trial, apnoea was eliminated or reduced by at least 50% in significantly more neonates receiving caffeine citrate as first-line treatment than those receiving placebo. In a nonblind trial, caffeine citrate was more effective at reducing apnoeic episodes when compared with neonates receiving no treatment. Caffeine as first-line treatment demonstrated similar efficacy to theophylline or aminophylline (theophylline ethylenediamine) in 4 small randomised studies. Caffeine citrate was generally well tolerated in short term clinical trials, with very few adverse events reported. Caffeine was associated with fewer adverse events than theophylline in randomised trials. No differences in the incidence of individual adverse events were reported between caffeine citrate and placebo in a double-blind, randomised trial. Long term tolerability data are not yet available.

Conclusions: Caffeine citrate was generally well tolerated by neonates in clinical trials and it decreased the incidence of apnoea of prematurity compared with placebo. It has demonstrated similar efficacy to theophylline, but is generally better tolerated and has a wider therapeutic index. Caffeine citrate should, therefore, be considered the drug of choice when pharmacological treatment of apnoea of prematurity is required.

Publication types

  • Review

MeSH terms

  • Apnea / drug therapy*
  • Apnea / metabolism
  • Brain / drug effects
  • Brain / metabolism
  • Caffeine / chemistry
  • Caffeine / pharmacokinetics
  • Caffeine / therapeutic use*
  • Central Nervous System Stimulants / pharmacokinetics
  • Central Nervous System Stimulants / therapeutic use*
  • Citrates / chemistry
  • Citrates / pharmacokinetics
  • Citrates / therapeutic use*
  • Drug Combinations
  • Heart Rate / drug effects
  • Heart Rate / physiology
  • Humans
  • Infant, Newborn
  • Infant, Premature* / physiology
  • Randomized Controlled Trials as Topic* / methods
  • Respiration / drug effects


  • Central Nervous System Stimulants
  • Citrates
  • Drug Combinations
  • Caffeine
  • caffeine citrate