Caffeine and Preterm Heart: Molecular Mechanisms, Clinical Evidence, and Future Directions

Caffeine is the most widely used methylxanthine in the neonatal intensive care unit, and its application has expanded from the treatment of apnea in premature infants to the prevention of bronchopulmonary dysplasia (BPD) and beyond. The neonatal heart is one of the targets of caffeine. However, the cardiac effects of caffeine, spanning molecular pharmacology, developmental physiology, and clinical hemodynamics, have not been comprehensively reviewed. This article synthesizes the evidence on the effects of caffeine on the preterm heart and is organized around four dimensions: animal models and mechanisms, clinical studies, current controversies, and knowledge gaps. At the basic animal level, the cardiac effects are mainly mediated through nonselective antagonism of adenosine A1/A2A receptors, suggesting a biphasic pattern that depends on developmental stage and concentration; this pattern is inferred across studies differing in species, stage, exposure and outcomes, not demonstrated within a single experimental framework. In clinical terms, the standard dose of caffeine has been associated with acute hemodynamic changes, most consistently an increase in blood pressure and systemic vascular resistance, whereas effects on cardiac output and stroke volume are inconsistent; a reduced need for PDA treatment has been reported with standard dosing. However, in infants with patent ductus arteriosus, there may be a transient window period during which there is an increase in arterial duct shunting and a reduction in systemic perfusion. Tachycardia is the most common cardiac adverse event and is concentration-dependent. Although long-term data are reassuring, medium- and long-term cardiovascular-specific outcomes remain almost entirely unexplored. We identified eight priority knowledge gaps and proposed research designs to fill them. Considering the multiple factors of developmental stage, dose, and clinical condition, we should comprehensively consider the advantages and disadvantages of caffeine on the preterm heart and take cardiovascular outcomes as the core focus in the clinical use of it.