Methylxanthines: The Major Impact of Caffeine in Clinical Practice in Patients Diagnosed with Apnea of Prematurity.

Background: Apnea of prematurity affects at least 85% of infants born before 34 weeks' gestation and represents a significant clinical challenge in neonatal intensive care. Methylxanthines, including caffeine, theophylline, and aminophylline, have emerged as the primary pharmacological intervention for this condition. Objective: To conduct a comprehensive systematic review of the use of methylxanthine in the treatment and prevention of apnea episodes in preterm infants, evaluating efficacy, safety, and long-term outcomes. Methods: We searched multiple databases including PubMed, Embase, Web of Science for randomized controlled trials, retrospective studies, or case-control studies of methylxanthine effects in preterm apnea. Risk of bias was assessed using the Cochrane Risk of Bias tool. Results were summarized narratively and grouped by methylxanthine type, study design, and primary outcomes (reduction in frequency and severity of apnea episodes, success of extubation, risk of bronchopulmonary dysplasia). Results: Twenty-five studies (n = 4599 preterm infants) were included. The landmark Caffeine for Apnea of Prematurity (CAP) trial (n = 2006) demonstrated that caffeine therapy significantly reduced bronchopulmonary dysplasia (36.3% vs. 46.9%, adjusted OR 0.63) and facilitated the earlier discontinuation of positive airway pressure (median 1 week earlier). Studies with a smaller number of cases have consistently demonstrated the efficacy of methylxanthines in reducing the incidence of bronchopulmonary dysplasia and apneic episodes and in supporting successful extubation. Long-term follow-up at 11 years showed improved pulmonary function (FEV1 z-score -1.00 vs. -1.53). Discussion: Limitations of this review include heterogeneity in outcome definitions, small sample sizes in early studies, and the dominance of evidence from the CAP trial. Methylxanthines, particularly caffeine, are an evidence-based intervention used for apnea of prematurity, with demonstrated benefits that extend beyond reducing the frequency and severity of apnea episodes, including decreasing the risk of bronchopulmonary dysplasia as well as reducing the need for mechanical ventilation. No external funding was received for this review. No registration record exists for this systematic review.