Intermittent hypoxia and caffeine in infants born preterm: the ICAF Randomized Clinical Trial

Objective To determine whether extending caffeine therapy through 43 weeks’ postmenstrual age (PMA) decreases intermittent hypoxia (IH) in convalescing preterm infants. Secondary objectives were to assess caffeine effects on changes in inflammation-related plasma biomarkers and brain MRI. Design Multicentre masked randomised trial. Setting 16 US hospitals. Patients Infants at <30 weeks + 6 days gestational age on caffeine between 32 weeks and 36+5 days PMA in room air with routine caffeine discontinuation prior to 36 weeks +6 days. Intervention Randomisation to caffeine or placebo and treated through 42 completed weeks. Pulse oximetry was recorded from enrolment through 1 week after stopping study drug. Blood for 12 inflammation-related biomarkers obtained at enrolment and 38 weeks’ PMA and brain imaging after enrolment or <3 days of randomisation, and study end. Main outcome measure Seconds/hour of oxygen saturation <90% from randomisation to study end. Results Randomised 160 subjects, 78 placebo, 82 caffeine. IH was less at every PMA with caffeine treatment from 34 (172.7 (123.4, 241.7); 84.7 (64.4, 111.4, p<0.01) through 41 weeks (73.0 (51.3, 103.7); 26.6 (18.5, 38.2, p<0.001). Adjusted TNF-α levels were 23% lower at follow-up in the caffeine group compared with placebo (p<0.02), without other biomarker differences. Paired brain imaging found no significant differences. Conclusions Extended caffeine reduced the burden of IH in very preterm infants and may reduce inflammation. Further study is needed to determine if this effect of caffeine is associated with reduced risk of adverse outcomes.