Key messages

• Caffeine is an effective medication used to decrease the risk of death or avoid serious lung damage in premature babies, but more research is necessary to fully understand when this therapy should be started.

• The evidence is uncertain when caffeine therapy should be started in preterm babies.

• Upcoming studies should examine different timeframes and different reasons for giving caffeine to preterm infants because, based on current studies, we cannot draw a solid conclusion.

What is caffeine?

Caffeine is the most popular medication used in preterm infants for apnea (pauses in breathing) and to decrease risk of death and other consequences of preterm birth.

Why is caffeine important for preterm babies in the neonatal intensive care unit (NICU)?

Preterm infants requiring special and intensive care usually have problems with breathing, leading to organ damage, including brain damage. Caffeine helps preterm infants to breathe and decreases the risk of death or avoids serious lung damage in premature babies.

What did we find out?

We wanted to know what the best time and reason to start therapy with caffeine is in preterm infants, and how does it affects:

• baby death for any reason;

• long-term lung disease;

• any negative effects of caffeine use that lead to stopping the therapy;

• how long a baby may have to be ventilated;

• how long a baby may need to stay in hospital;

• the number of infants with at least one episode of apnea;

• intermittent hypoxemia (short drops in oxygen levels).

What did we do?

We checked 11 studies that used caffeine within different timeframes and for different reasons, that is to say, caffeine given:

• within two hours of life versus 2 to 24 hours;

• within 72 hours of life versus after 72 hours of life;

• within 72 hours of life versus treatment of infants with sympthoms;

• with minimal symptoms versus caffeine started with serious apnea (who needed help to start breathing again with touch or breathing support);

• during treatment with respirator versus caffeine started at the time of extubation (removal of the breathing tube).

We analyzed and summarized the results of studies and graded our confidence in the evidence, based on how studies were conducted and their size.

What we did find?

We included 11 studies with 774 babies, published between 2014 and 2023. We found seven ongoing studies.

What are the main results?

• The evidence is very uncertain for outcomes reported in comparisons: caffeine within two hours of life versus 2 to 24 hours, and caffeine within 72 hours of life versus after 72 hours of life. However, caffeine within 72 hours of life is likely to reduce the risk for apnea and long-term lung disease.

• Caffeine given within 72 hours of life is likely to reduce the risk of long-term lung disease compared to treating infants who have symptoms. We have little confidence or are not confident in the other outcomes in this comparison, because there are not enough studies to be certain about the results of our outcomes.

• No studies compared caffeine started in infants with minimal symptoms in comparison to caffeine started with serious apnea (handled with stimulation or ventilation).

• Caffeine started while on mechanical ventilation may result in a large reduction in how long babies have to be ventilated and may reduce the risk for long-term lung disease compared to caffeine started at the time of removal of the breathing tube.

What are the limitations of the evidence?

We did not find any studies comparing caffeine started in infants with minimal symptoms to caffeine started with serious apnea (handled with stimulation or ventilation). No studies reported intermittent hypoxemia (short drops in oxygen levels). The results of upcoming studies could change the outcomes of this review.

How up to date is this evidence?

The evidence is current to 23 April 2025.