- Compared to no treatment or a placebo (inactive) medicine, methylxanthines probably lead to fewer apnea episodes (pauses in breathing), probably reduce the need for breathing machines, and do reduce lung injury in preterm babies.
- Methylxanthines probably make little or no difference to the risk of preterm babies dying before leaving hospital. There was little evidence about side effects of methylxanthines.
- More research is needed on the long-term effects of these medicines.
What is apnea of prematurity?
Apnea of prematurity is when babies born too early (preterm babies) stop breathing for at least 20 seconds during sleep. More than half of all preterm babies have apnea. Episodes of apnea can result in low heart rate and low blood oxygen, leading to the need for support with a breathing machine (mechanical ventilation). Preterm babies, especially those born before 28 weeks in the womb (gestation), have a higher risk of dying or having lung disease, intellectual disabilities, blindness, or deafness than babies born at or near their due date.
How is apnea in preterm babies treated?
It is commonly treated with methylxanthines – substances found in tea, coffee, and chocolate. Three types of methylxanthines are caffeine, aminophylline, and theophylline. They act as mild stimulants to speed up the body’s systems and make breathing easier. Doctors give methylxanthines to babies for 3 main reasons: (1) to prevent apnea episodes; (2) to treat/reduce apnea episodes and thus avoid the need for mechanical ventilation; and (3) to increase the chance that babies who are on breathing machines can successfully be ‘weaned’ or taken off those machines (extubation) and breathe on their own. In all cases, the aim is to minimize the chances of babies developing the problems described above.
What did we want to find out?
We wanted to find out if giving methylxanthines to preterm infants for any of the reasons described above reduces apnea episodes and the risk of death and improves the long-term development of preterm babies.
What did we do?
We searched for studies that gave methylxanthines to preterm newborns at risk for or with apnea of prematurity. We compared and summarized the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
We found 18 studies that involved 2705 preterm babies with or at risk for apnea. The biggest and longest-running study included 2006 babies from 9 countries over 5 years, and reported on outcomes for some of the babies until they were teenagers. The remaining 17 studies were much smaller, ranging from 18 to 86 babies; these studies were conducted in the USA (6 studies), UK (3 studies), Canada, Iran (2 studies each country), Australia, France, Spain, and Switzerland (1 study in each country). Most of these studies focused on immediate and short-term outcomes and did not look at the babies’ long-term development. Of the 18 studies, 14 were conducted in the 1980s and 1990s.
The studies’ methylxanthine use varied: 6 studies explored apnea prevention; 5 studies explored apnea treatment; 6 studies investigated methylxanthine for weaning from breathing machines (extubation); and 1 study (the biggest one) investigated methylxanthine given for all 3 reasons.
Compared to giving no treatment or a placebo (inactive) medicine, giving preterm babies methylxanthines for any reason:
- probably leads to a reduction in the risk of apnea episodes;
- probably increases the number of babies who have fewer apnea episodes after 2 to 7 days;
- probably reduces the need for breathing machines after treatment has started;
- reduces bronchopulmonary dysplasia, a form of lung injury.
The single large study demonstrated that giving methylxanthines (specifically, caffeine) improves children’s development at 18 to 24 months of age.
What are the limitations of the evidence?
Our confidence in the evidence varies. The big study used robust methods: it assigned the babies at random to treatment groups, and it ‘masked’ researchers collecting outcome information, meaning they did not know the babies’ group assignments. These methods tend to produce high-quality evidence. This study dominated the review and provided the only evidence about babies’ brain development in infancy and childhood. The remaining studies’ methods were of variable quality. Many did not mask the researchers, and most reported on outcomes that are not critical to babies’ long-term development. However, we had no reason to believe that these studies wrongly withheld any information or reported only favorable results, despite not reporting longer-term outcomes, such as death.
How up to date is this evidence?
The evidence is current to November 2022.
Caffeine probably reduces the risk of death, major neurodevelopmental disability at 18 to 24 months, and the composite outcome DMND at 18 to 24 months. Administration of any methylxanthine to preterm infants for any indication probably leads to a reduction in the risk of any apneic episodes, failed apnea reduction after two to seven days, cerebral palsy, developmental delay, and may reduce receipt of positive-pressure ventilation after institution of treatment. Methylxanthine used for any indication reduces chronic lung disease (defined as the use of supplemental oxygen at 36 weeks' postmenstrual age).
Very preterm infants often require respiratory support and are therefore exposed to an increased risk of chronic lung disease and later neurodevelopmental disability. Although methylxanthines are widely used to prevent and treat apnea associated with prematurity and to facilitate extubation, there is uncertainty about the benefits and harms of different types of methylxanthines.
To assess the effects of methylxanthines on the incidence of apnea, death, neurodevelopmental disability, and other longer-term outcomes in preterm infants (1) at risk for or with apnea, or (2) undergoing extubation.
We searched CENTRAL, MEDLINE, Embase, two other databases, and three trial registers (November 2022).
We included randomized trials in preterm infants, in which methylxanthines (aminophylline, caffeine, or theophylline) were compared to placebo or no treatment for any indication (i.e. prevention of apnea, treatment of apnea, or prevention of re-intubation).
We used standard Cochrane methods and GRADE to assess the certainty of evidence.
We included 18 studies (2705 infants), evaluating the use of methylxanthine in preterm infants for: any indication (one study); prevention of apnea (six studies); treatment of apnea (five studies); and to prevent re-intubation (six studies).
Death or major neurodevelopmental disability (DMND) at 18 to 24 months. Only the Caffeine for Apnea of Prematurity (CAP) study (enrolling 2006 infants) reported on this outcome. Overall, caffeine probably reduced the risk of DMND in preterm infants treated with caffeine for any indication (risk ratio (RR) 0.87, 95% confidence interval (CI) 0.78 to 0.97; risk difference (RD) -0.06, 95% CI -0.10 to -0.02; number needed to treat for an additional beneficial outcome (NNTB) 16, 95% CI 10 to 50; 1 study, 1869 infants; moderate-certainty evidence). No other trials reported DMND.
Results from the CAP trial regarding DMND at 18 to 24 months are less precise when analyzed based on treatment indication. Caffeine probably results in little or no difference in DMND in infants treated for prevention of apnea (RR 1.00, 95% CI 0.80 to 1.24; RD -0.00, 95% CI -0.10 to 0.09; 1 study, 423 infants; moderate-certainty evidence) and probably results in a slight reduction in DMND in infants treated for apnea of prematurity (RR 0.85, 95% CI 0.71 to 1.01; RD -0.06, 95% CI -0.13 to 0.00; NNTB 16, 95% CI 7 to > 1000; 1 study, 767 infants; moderate-certainty evidence) or to prevent re-intubation (RR 0.85, 95% CI 0.73 to 0.99; RD -0.08, 95% CI -0.15 to -0.00; NNTB 12, 95% CI 6 to >1000; 1 study, 676 infants; moderate-certainty evidence).
Death. In the overall analysis of any methylxanthine treatment for any indication, methylxanthine used for any indication probably results in little or no difference in death at hospital discharge (RR 0.99, 95% CI 0.71 to 1.37; I2 = 0%; RD -0.00, 95% CI -0.02 to 0.02; I2 = 5%; 7 studies, 2289 infants; moderate-certainty evidence).
Major neurodevelopmental disability at 18 to 24 months. In the CAP trial, caffeine probably reduced the risk of major neurodevelopmental disability at 18 to 24 months (RR 0.85, 95% CI 0.76 to 0.96; RD -0.06, 95% CI -0.10 to -0.02; NNTB 16, 95% CI 10 to 50; 1 study, 1869 infants; moderate-certainty evidence), including a reduction in the risk of cerebral palsy or gross motor disability (RR 0.60, 95% CI 0.41 to 0.88; RD -0.03, 95% CI -0.05 to -0.01; NNTB 33, 95% CI 20 to 100; 1 study, 1810 infants; moderate-certainty evidence) and a marginal reduction in the risk of developmental delay (RR 0.88, 95% CI 0.78 to 1.00; RD -0.05, 95% CI -0.09 to -0.00; NNTB 20, 95% CI 11 to > 1000; 1 study, 1725 infants; moderate-certainty evidence).
Any apneic episodes, failed apnea reduction after two to seven days (< 50% reduction in apnea) (for infants treated with apnea), and need for positive-pressure ventilation after institution of treatment. Methylxanthine used for any indication probably reduces the occurrence of any apneic episodes (RR 0.31, 95% CI 0.18 to 0.52; I2 = 47%; RD -0.38, 95% CI -0.51 to -0.25; I2 = 49%; NNTB 3, 95% CI 2 to 4; 4 studies, 167 infants; moderate-certainty evidence), failed apnea reduction after two to seven days (RR 0.48, 95% CI 0.33 to 0.70; I2 = 0%; RD -0.31, 95% CI -0.44 to -0.17; I2 = 53%; NNTB 3, 95% CI 2 to 6; 4 studies, 174 infants; moderate-certainty evidence), and may reduce receipt of positive-pressure ventilation after institution of treatment (RR 0.61, 95% CI 0.39 to 0.96; I2 = 0%; RD -0.06, 95% CI -0.11 to -0.01; I2 = 49%; NNTB 16, 95% CI 9 to 100; 9 studies, 373 infants; low-certainty evidence).
Chronic lung disease. Methylxanthine used for any indication reduces chronic lung disease (defined as the use of supplemental oxygen at 36 weeks' postmenstrual age) (RR 0.77, 95% CI 0.69 to 0.85; I2 = 0%; RD -0.10, 95% CI -0.14 to -0.06; I2 = 18%; NNTB 10, 95% CI 7 to 16; 4 studies, 2142 infants; high-certainty evidence).
Failure to extubate or the need for re-intubation within one week after initiation of therapy. Methylxanthine used for the prevention of re-intubation probably results in a large reduction in failed extubation compared with no treatment (RR 0.48, 95% CI 0.32 to 0.71; I2 = 0%; RD -0.27, 95% CI -0.39 to -0.15; I2 = 69%; NNTB 4, 95% CI 2 to 6; 6 studies, 197 infants; moderate-certainty evidence).