Long-term effects of caffeine therapy for apnea of prematurity

N Engl J Med. 2007 Nov 8;357(19):1893-902. doi: 10.1056/NEJMoa073679.


Background: Methylxanthine therapy is commonly used for apnea of prematurity but in the absence of adequate data on its efficacy and safety. It is uncertain whether methylxanthines have long-term effects on neurodevelopment and growth.

Methods: We randomly assigned 2006 infants with birth weights of 500 to 1250 g to receive either caffeine or placebo until therapy for apnea of prematurity was no longer needed. The primary outcome was a composite of death, cerebral palsy, cognitive delay (defined as a Mental Development Index score of <85 on the Bayley Scales of Infant Development), deafness, or blindness at a corrected age of 18 to 21 months.

Results: Of the 937 infants assigned to caffeine for whom adequate data on the primary outcome were available, 377 (40.2%) died or survived with a neurodevelopmental disability, as compared with 431 of the 932 infants (46.2%) assigned to placebo for whom adequate data on the primary outcome were available (odds ratio adjusted for center, 0.77; 95% confidence interval [CI], 0.64 to 0.93; P=0.008). Treatment with caffeine as compared with placebo reduced the incidence of cerebral palsy (4.4% vs. 7.3%; adjusted odds ratio, 0.58; 95% CI, 0.39 to 0.87; P=0.009) and of cognitive delay (33.8% vs. 38.3%; adjusted odds ratio, 0.81; 95% CI, 0.66 to 0.99; P=0.04). The rates of death, deafness, and blindness and the mean percentiles for height, weight, and head circumference at follow-up did not differ significantly between the two groups.

Conclusions: Caffeine therapy for apnea of prematurity improves the rate of survival without neurodevelopmental disability at 18 to 21 months in infants with very low birth weight. (ClinicalTrials.gov number, NCT00182312 [ClinicalTrials.gov].).

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apnea / drug therapy*
  • Apnea / mortality
  • Body Size / drug effects
  • Caffeine / therapeutic use*
  • Central Nervous System Stimulants / therapeutic use*
  • Cerebral Palsy / epidemiology
  • Cerebral Palsy / prevention & control
  • Citrates / therapeutic use*
  • Developmental Disabilities / epidemiology
  • Developmental Disabilities / prevention & control
  • Epilepsy / epidemiology
  • Epilepsy / prevention & control
  • Female
  • Follow-Up Studies
  • Humans
  • Infant, Newborn
  • Infant, Premature / growth & development
  • Infant, Premature, Diseases / drug therapy*
  • Infant, Premature, Diseases / mortality
  • Infant, Very Low Birth Weight* / growth & development
  • Logistic Models
  • Male
  • Odds Ratio
  • Retinopathy of Prematurity / epidemiology
  • Survival Rate


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

Associated data

  • ClinicalTrials.gov/NCT00182312