Long-term effects of caffeine therapy for apnea of prematurity

The methylxanthines - aminophylline, theophylline, and caffeine - have been administered to preterm infants as respiratory stimulants for more than 30 years. Despite their widespread use, these drugs have been evaluated only in few small, short-term studies. Therefore, it is uncertain whether these drugs might adversely affect the infants development. Methylxanthines are inhibitors of adenosine receptors; in animal models, adenosine protected the brain from energy failure and cell death during hypoxia and ischemia. On these basis, an American group conduced a large, international, randomized, placebo-controlled trial of caffeine to study the short- and long-term efficacy and safety of methylxanthine therapy for apnea of prematurity in infants with very low birth weight (VLBW). The purpose of this study in the long-term was to determine whether caffeine therapy for apnea of prematurity alters the rate of survival without neurodevelopmental disability at a corrected age of 18 to 21 months. The results regarding this outcome have recently been published on the New England Journal of Medicine. In total, VLBW infants were randomized to caffeine (n = 937) or placebo (n = 932) until therapy for apnea of prematurity was no longer needed. The primary outcome was a composite of death, cerebral palsy, cognitive delay (defined as a Mental Development Index score of <85 on the Bayley Scales of Infant Development), deafness, or blindness at a corrected age of 18 to 21 months. In the caffeine group, 377 of the 937 infants (40.2%) died or survived with a neurodevelopmental disability, as compared with 431 of the 932 infants (46.2%) in the placebo arm [odds ratio (OR): 0.77; 95% confidence interval (CI), 0.64 to 0.93; p = 0.008]. Caffeine reduced the incidence of cerebral palsy (4.4% vs 7.3%; OR: 0.58; 95% CI, 0.39 to 0.87; p = 0.009) and of cognitive delay (33.8% vs 38.3%; OR: 0.81; 95% CI, 0.66 to 0.99; p = 0.04) if compared to placebo. The rates of death, deafness, and blindness and the mean percentiles for height, weight, and head circumference at follow-up did not differ significantly between the two groups. A post-hoc analysis was conducted to explore possible mechanisms for the effect of caffeine on the rate of survival without neurodevelopmental disability. The analysis suggested that the earlier discontinuation of positive airway pressure in infants assigned to caffeine, as compared with placebo, was the most important intermediate variable, since it explained almost half of the effect of caffeine on the composite 18-month outcome. Globally, all the six intermediate variables identified, taken together, explained 55% of the observed benefit of caffeine therapy on the primary composite outcome at 18 months. Therefore, almost half of the effect of caffeine is still unexplained and other potential mechanisms for the improved long-term outcome of the study participants assigned to caffeine warrant further study. In conclusion, the present results, showing that caffeine significantly improved survival without neurodevelopmental disability at a corrected age of 18 to 21 months, provide strong evidence that the overall benefits of methylxanthine therapy outweigh any potential risks up to 2 years after very preterm birth.

Top