Strategies for caffeine administration in preterm infants: route, dosing, monitoring, and adjunctive interventions - a systematic review

Abstract Introduction Caffeine is widely used in preterm infants, yet the optimal administration strategy remains unclear. This systematic review aims to evaluate different caffeine administration approaches, including route, frequency, dose modifications, and co-administration with surfactant in preterm infants. Methods We searched three databases and two trial registries up to October 2024. Data collection and analysis followed Cochrane methodology; certainty of evidence was assessed using GRADE; and reporting followed PRISMA. Results Three RCTs were identified, two provided data for analyses: one study (38 infants) on route of administration (intravenous versus oral caffeine) and one study (40 infants) on frequency of administration (once versus twice daily). The evidence is very uncertain about the effects of intravenous versus oral administration on: mortality (RR 0.14, 95% CI 0.01–2.59); mechanical ventilation duration (MD 1.00, 95% CI -8.05 to 10.05); hospital stay (MD 8.00, 95%CI -5.35-21.35); severe intraventricular hemorrhage (RR 1.00, 95%CI 0.29–3.43); and chronic lung disease (RR 5.00, 95%CI 0.26–97.70). The evidence is very uncertain about the effects of twice-daily versus once-daily caffeine on: mortality (RR 1.00, 95%CI 0.29–3.45); ventilation duration (MD 0.81, 95%CI -7.56-9.18); and hospital stay (MD -2.70, 95%CI -8.12-2.72). We found no studies on caffeine dose modifications and co-administration with surfactant. Two trials on adjusting caffeine dose and route of administration are ongoing. Conclusion Although caffeine clearly benefits preterm infants, evidence guiding optimal administration strategies, such as route, frequency, and dose modifications, is limited. High-quality studies are urgently needed to inform clinical practice and guidelines.