Prophylactic administration of caffeine reduces bronchopulmonary dysplasia in very preterm infants: a single center, randomized controlled trial

Caffeine has been widely used to prevent apnea in very preterm infants (VPIs), but it is not clear whether prophylactic administration of caffeine can prevent bronchopulmonary dysplasia (BPD) in VPIs. This single-center, randomized clinical trial recruited very preterm neonates (< 32 + 0 weeks’ gestational age [GA]) born and admitted to the neonatal intensive care unit between September 1, 2016 and January 28, 2024. Neonates were randomly assigned to two groups and received either prophylactic caffeine administration (PCA, caffeine citrate dosage, 20 mg/kg loading, 10 mg/kg maintenance daily) or therapeutic caffeine administration (TCA) when apnea was diagnosed (dosage the same as PCA) as the control. The primary outcome was the composite occurrence of BPD at 36 weeks’ postmenstrual age (PMA) and/or death by discharge (BPD/death). Secondary outcomes included duration of mechanical and noninvasive ventilation (days), duration of oxygen administration (days), number of blood transfusions, incidence of NEC, intraventricular hemorrhage (IVH), retinopathy of prematurity (ROP), and late-onset sepsis (LOS), medical costs and hospital stay. A total of 372 VPIs were enrolled. BPD/death occurred in 37.1% (69/186) of the PCA group versus 47.3% (88/186) in the TCA group (RR = 0.77, 95% CI 0.62–0.95, P = 0.013). The effect remained robust in five sensitivity analysis models, and was more pronounced among female, received antenatal steroids, were not intubated at birth or only had noninvasive ventilation after birth. Blood transfusion frequency was higher in the PCA group (MD = 0.42, 95% CI 0.05–0.79, P = 0.027). No significant differences was observed in other serious complications between groups. Prophylactic administration of caffeine reduced the risk of death/BPD compared with therapeutic administration under clinical indications in VPIs. The study was registered in the Chinese Clinical Trial Registry (ChiCTR-INR- 16009243) on September 22nd, 2016. (retrospectively registered) https://www.chictr.org.cn/bin/project/edit?pid=15684 .