Extended Caffeine Therapy and Intermittent Hypoxia in Prematurity

Source: Eichenwald E, Corwin M, McEntire B, et al. Intermittent hypoxia and caffeine in infants born preterm: the ICAF randomized clinical trial. Arch Dis Child Fetal Neonatal Ed. 2025:fetalneonatal-2025-329230; doi: 10.1136/archdischild-2025-329230.Investigators from multiple institutions conducted a randomized controlled trial to assess the effect of prolonged treatment with caffeine on intermittent hypoxia (IH), plasma inflammatory markers, and brain MRI in very preterm infants. Study participants were infants born at <30 weeks +6 days gestational age who were treated at 16 US sites and received caffeine when they were 32 to <37 weeks postmenstrual age (PMA). Only patients who were on room air were enrolled. Study participants who were ready to discontinue routine caffeine treatment prior to 37 weeks PMA were randomized to either continue caffeine or to receive placebo. Those in the caffeine treatment group were treated with caffeine base 5 mg/kg/day until they were 36 weeks PMA, and 5 mg/kg/day twice daily until 42 weeks +6 days. Continuous pulse oximetry data were collected on all study infants until 43 weeks PMA. The primary study outcome was number of seconds/hour for which oxygen saturation was <90%. Number of seconds/hour for which oxygen saturation was <85% and <80% were secondary outcomes. Mixed effects regression, with adjustment for confounders, was used to compare these outcomes at each PMA week (33 through 42) in participants randomized to caffeine or placebo. Blood samples were obtained on study infants at 38 weeks PMA or discharge, and levels of multiple pro-inflammatory biomarkers among those in each of the treatment groups compared. Brain MRIs were performed at 10 study sites on participants 43 to 46 weeks PMA, with MRI outcomes in those receiving caffeine or placebo compared.A total of 170 preterm infants were enrolled and 160 randomized, with 82 assigned to the caffeine group and 78 to placebo. Mean gestational age at birth was 28.4 ±1.6 and 28.5 ±1.8 weeks, respectively, for infants in the 2 treatment groups. The number of seconds/hour of oxygen saturation <90% was significantly lower at each PMA week from 34 to 41 weeks for infants receiving caffeine than in those randomized to placebo, with a median reduction of 60%. Number of seconds/hour of oxygen saturation <85% and <80% also were significantly lower in participants receiving caffeine. TNF-a levels were measured in 133 participants and were 23% lower in those randomized to caffeine than in those receiving placebo (P = 0.02). There were no significant differences between groups in levels of multiple other proinflammatory biomarkers or in brain MRI findings (obtained on 43 infants randomized to caffeine and 45 placebo recipients).The authors conclude that prolonged administration of caffeine reduced the burden of IH in very preterm infants.Dr King has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.Caffeine therapy remains one of the most rigorously studied and effective interventions in neonatal medicine. Since the publication of the CAP trial nearly 2 decades ago,1 caffeine has been shown to improve short-term respiratory outcomes and confer durable neurodevelopmental benefits extending into late childhood.2 Yet despite this strong evidence base, fundamental questions regarding the optimal duration of caffeine therapy have persisted, and there is wide variability in the timing of caffeine discontinuation in clinical practice.3The current trial is the second published within a year4 that aims to explore benefits of prolonged caffeine use. Prior observational work5 demonstrated that IH persists beyond termequivalent age in infants born preterm, often without obvious clinical correlates. These clinically inapparent events raise concern, because IH has been linked to oxidative stress, inflammation, and adverse neurodevelopmental outcomes in both animal models and human cohorts.6The results of the current trial provide evidence that extended caffeine reduces IH burden through approximately 42–44 weeks PMA, but whether reducing this burden translates into improved outcomes remains uncertain. Secondary analyses from the Canadian Oxygen Trial suggest that neurodevelopmental risk is most strongly associated with prolonged (>1 minute) hypoxemic episodes below 80% saturation,7 and data from the current trial suggest these types of severe events are rare, particularly post-discharge, when the duration of hypoxia drops substantially. The clinical significance of attenuating these milder events, particularly in relation to brain development, remains to be determined. Future studies powered for neurodevelopmental endpoints, potentially enriched for infants with higher IH burden, will be essential to determine whether extending caffeine therapy beyond current norms yields meaningful long-term benefit.Continuing caffeine through discharge for preterm infants reduces the burden of IH events, but clinical benefits are uncertain.