Analyzing data on the use of caffeine for the prevention of complications in premature infants to fill knowledge gaps and expand the FDA labeling.


Caffeine citrate is the most commonly used non-antimicrobial medication in the newborn intensive care unit and one of the top 10 medications used in the NICU. However, the FDA label for caffeine does not support an indication for the reduction of important morbidities of prematurity or neurodevelopmental impairment. Moreover, the labeled dose, duration, and safety information reflects older data. Deficiencies in the current label include:

• Omission of data from the landmark Caffeine for Apnea of Prematurity (CAP) study
• Exclusion of infants <28 weeks of age
• Indication for short-term treatment only
• An unsupported warning regarding a risk for necrotizing enterocolitis

Furthermore, caffeine’s actual dose and duration do not match the FDA label: clinicians routinely use higher doses for a duration well beyond the 10 days recommended on the label. In fact, nearly all infants born at gestational age <28 weeks develop apnea of prematurity and are treated off-label with caffeine citrate. This is because caffeine reduces time on the ventilator, the risk of bronchopulmonary dysplasia, and the risk of severe retinopathy. Most importantly, caffeine citrate reduces the risk of death or disability, including cerebral palsy, measured at 18–22 months of life. The goal of this study is to bridge the knowledge gap between the FDA label and the off-label use of caffeine citrate.

Using a multi-pronged retrospective study design, the PTN plans to provide data that will support extending the labeled indication of apnea of prematurity to infants as young as 23 weeks and expanding treatment duration beyond short-term use. Data will be culled from various sources, including a systematic literature review, the CAP trial, and the electronic medical record of the Pediatrix Medical Group. Additionally, a retrospective cohort study of approximately 400 infants will be conducted at up to 6 clinical sites. Safety signals will also be reviewed, and, if the data support it, we will challenge the association between necrotizing enterocolitis and the use of caffeine citrate in infants which is currently included in the label. We also hope to provide evidence that caffeine is useful for prevention of bronchopulmonary dysplasia.


Analysis ongoing

Principal Investigator:
P. Brian Smith, MD, MPH, MHS
Duke Health, Durham, NC