The effects of caffeine on intermittent hypoxaemia in late preterm neonates

Abstract

Aim: Late preterm infants have higher rates of intermittent hypoxaemia in the first weeks after birth and worse long-term neurodevelopment than term-born babies. Caffeine reduces hypoxaemia and improves outcomes in very preterm infants. We aimed to establish the most effective dose of caffeine to reduce intermittent hypoxaemia in late preterm infants and to evaluate and synthesise the evidence for the use of caffeine in preterm infants. Method: We undertook a double-blind, five-arm, parallel, dose-finding randomised controlled trial to compare the effectiveness of oral caffeine citrate versus placebo in reducing intermittent hypoxaemia. Following the development of an appropriate oral formulation, we randomised 132 late preterm infants to 5, 10, 15 or 20mg.kg-1.day-1 caffeine citrate or placebo daily until term equivalent age, with a primary outcome of intermittent hypoxaemia, two weeks post-randomisation. Finally, we formally evaluated the evidence for the use of caffeine for apnoea and prevention of neurodevelopmental impairment in preterm infants through a systematic review and meta-analysis. Findings: At two weeks post-randomisation, caffeine citrate at doses of 10 and 20 mg.kg-1.day-1 reduced intermittent hypoxaemia compared to placebo, increased mean oxygen saturation (SpO2), and reduced time with SpO2<90%, with 20 mg.kg-1.day-1 being most effective. No adverse effects were observed on growth velocity or sleep at any dose, but tachycardia increased at two weeks with all doses, and persisted at term in the 5, 10 and 20 mg.kg-1.day-1 groups. The systematic review included 15 studies (3,530 infants). Caffeine possibly reduced apnoea (very low certainty evidence) and probably reduced bronchopulmonary dysplasia (moderate certainty evidence), with higher doses probably more effective. Only one trial reported neurodevelopmental outcomes beyond early childhood, with moderate-certainty evidence indicating a probable lack of effect on neurocognitive impairment in early childhood but possible benefit on motor function in middle childhood. Conclusion: Caffeine citrate 20 mg.kg-1.day-1 was most effective in reducing intermittent hypoxaemia in late preterm infants and was well tolerated. Further research is needed to determine if this dose improves neurodevelopmental outcomes; if it does, then use in this population could be rapidly adopted to improve outcomes by means of a simple intervention suitable for delivery outside the hospital setting.