Effects of caffeine on intermittent hypoxia in infants born prematurely: a randomized clinical trial

JAMA Pediatr. 2014 Mar;168(3):250-7. doi: 10.1001/jamapediatrics.2013.4371.


Importance: Preterm infants have immature respiratory control and resulting intermittent hypoxia (IH). The extent of IH after stopping routine caffeine treatment and the potential for reducing IH with extended caffeine treatment are unknown.

Objectives: To determine (1) the frequency of IH in premature infants after discontinuation of routine caffeine treatment and (2) whether extending caffeine treatment to 40 weeks' postmenstrual age (PMA) reduces IH.

Design, setting, and participants: A prospective randomized clinical study was conducted at 16 neonatal intensive care units in the United States, with an 18-month enrollment period. Preterm infants (<32 weeks' gestation) previously treated with caffeine were randomized to extended caffeine treatment or usual care (controls) at a PMA of at least 34 weeks but less than 37 weeks. Continuous pulse oximeter recordings were obtained through 40 weeks' PMA. Oximeter data were analyzed by persons masked to patient group.

Intervention: Continued treatment with caffeine.

Main outcomes and measures: Number of IH events and seconds with less than 90% hemoglobin oxygen saturation (Sao2) per hour of recording.

Results: Our analysis included 95 preterm infants. In control infants, the mean (SD) time at less than 90% Sao2 at 35 and 36 weeks' PMA was 106.3 (89.0) and 100.1 (114.6) s/h, respectively. The number of IH events decreased significantly from 35 to 39 weeks' PMA (P = .01). Extended caffeine treatment reduced the mean time at less than 90% Sao2 by 47% (95% CI, -65% to -20%) to 50.9 (48.1) s/h at 35 weeks and by 45% (95% CI, -74% to -17%) to 49.5 (52.1) s/h at 36 weeks.

Conclusions and relevance: Substantial IH persists after discontinuation of routine caffeine treatment and progressively decreases with increasing PMA. Extended caffeine treatment decreases IH in premature infants.

Trial registration: clinicaltrials.gov Identifier: NCT01875159.

Publication types

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

MeSH terms

  • Caffeine / therapeutic use*
  • Central Nervous System Stimulants / therapeutic use*
  • Female
  • Gestational Age
  • Humans
  • Hypoxia / drug therapy*
  • Infant, Newborn
  • Infant, Premature
  • Infant, Premature, Diseases / drug therapy*
  • Male
  • Oxygen / blood
  • Prospective Studies
  • Treatment Outcome
  • United States


  • Central Nervous System Stimulants
  • Caffeine
  • Oxygen

Associated data

  • ClinicalTrials.gov/NCT01875159