A pilot randomized trial of high-dose caffeine therapy in preterm infants

Pediatr Res. 2015 Aug;78(2):198-204. doi: 10.1038/pr.2015.72. Epub 2015 Apr 9.


Background: Standard-dose caffeine improves white matter microstructural development assessed by diffusion magnetic resonance imaging (MRI). We hypothesized that early high-dose caffeine would result in further improvement in white matter microstructural development.

Methods: Seventy-four preterm infants (≤30 wk gestational age) were randomly assigned to either a high (80 mg/kg i.v.) or standard (20 mg/kg i.v.) loading dose of caffeine citrate in the first 24 h of life. MRI and neurobehavioral testing were undertaken at term equivalent age. Infants returned at 2 y of age for developmental testing.

Results: Clinical characteristics were similar between groups, with the exception of higher maternal age in the high-dose caffeine group. There was an increased incidence of cerebellar hemorrhage in infants randomized to high-dose caffeine (36 vs. 10%, P = 0.03). Infants in the high-dose caffeine group also demonstrated more hypertonicity (P = 0.02) and more deviant neurologic signs (P = 0.04) at term equivalent age. Diffusion measures at term equivalent age and developmental outcomes at 2 y of age did not differ between groups.

Conclusion: Preterm infants randomized to early high-dose caffeine had a higher incidence of cerebellar injury with subsequent alterations in early motor performance. The results of this pilot trial discourage a larger randomized controlled trial.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caffeine / administration & dosage*
  • Dose-Response Relationship, Drug
  • Humans
  • Infant, Newborn
  • Infant, Premature*
  • Magnetic Resonance Imaging
  • Pilot Projects
  • White Matter / drug effects


  • Caffeine