Early Caffeine Use in Very Low Birth Weight Infants and Neonatal Outcomes: A Systematic Review and Meta-Analysis

J Korean Med Sci. 2015 Dec;30(12):1828-35. doi: 10.3346/jkms.2015.30.12.1828. Epub 2015 Nov 30.


The use of caffeine citrate for treatment of apnea in very low birth weight infants showed short-term and long-term benefits. A systematic review and meta-analysis of the literature was undertaken to document the effect providing caffeine early (0-2 days of life) compared to providing caffeine late (≥3 days of life) in very low birth weight infants on several neonatal outcomes, including bronchopulmonary dysplasia (BPD). We searched MEDLINE, the EMBASE database, the Cochrane Library, and KoreaMed for this meta-analysis. The quality of the included studies was assessed using the Newcastle-Ottawa Scale and Jadad's scale. Studies were included if they examined the effect of the early use of caffeine compared with the late use of caffeine. Two reviewers screened the candidate articles and extracted the data from the full-text of all of the included studies. We included a total of 59,136 participants (range 58,997-59,136; variable in one study) from a total of 5 studies. The risk of death (odds ratio [OR], 0.902; 95% confidence interval [CI], 0.828 to 0.983; P=0.019), bronchopulmonary dysplasia (BPD) (OR, 0.507; 95% CI, 0.396 to 0.648; P<0.001), and BPD or death (OR, 0.526; 95% CI, 0.384 to 0.719; P<0.001) were lower in the early caffeine group. Early caffeine use was not associated with a risk of necrotizing enterocolitis (NEC) and NEC requiring surgery. This meta-analysis suggests that early caffeine use has beneficial effects on neonatal outcomes, including mortality and BPD, without increasing the risk of NEC.

Keywords: Bronchopulmonary Dysplasia; Caffeine; Infant, Newborn; Outcome; Very Low Birth Weight.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Apnea / drug therapy*
  • Bronchopulmonary Dysplasia / drug therapy
  • Caffeine / administration & dosage*
  • Caffeine / adverse effects
  • Citrates / administration & dosage*
  • Citrates / adverse effects
  • Enterocolitis, Necrotizing / etiology
  • Humans
  • Infant
  • Infant Mortality
  • Infant, Newborn
  • Infant, Very Low Birth Weight
  • Risk Factors
  • Treatment Outcome


  • Citrates
  • Caffeine
  • caffeine citrate