Methylxanthines for the prevention or treatment of intermittent hypoxemia or respiratory insufficiency in late preterm infants.

rationaleLate preterm infants (34 0/7 to 36 6/7 weeks' gestation, i.e. 34 weeks and 0 days to 36 weeks and 6 days) are at increased risk of intermittent hypoxemia and respiratory insufficiency due to physiological immaturity, compared to full-term infants. Methylxanthines, most frequently caffeine, are used to improve respiratory function and long-term outcomes in very preterm infants. However, the use of methylxanthines in late preterm infants for preventing or treating intermittent hypoxemia and respiratory insufficiency needs to be assessed, also to avoid the risk of over-treatment.

objectivesTo assess the benefits and harms of methylxanthines in preventing or treating intermittent hypoxemia or respiratory insufficiency in late preterm infants. SEARCH

methodsSearches were conducted up to December 2025 in MEDLINE, CENTRAL, Embase, Epistemonikos, and two clinical trial registries. We also screened the reference lists of relevant reviews and included studies. ELIGIBILITY CRITERIA: We included randomized controlled trials enrolling late preterm infants, comparing any methylxanthine (aminophylline, theophylline, or caffeine) with placebo or no methylxanthine. Studies with a cross-over design were excluded. OUTCOMES: Critical outcomes were the number of intermittent hypoxemia episodes and apnea after 24 hours and over one week from starting treatment, and major neurodevelopmental disability. Important outcomes included respiratory support, duration of hospital stay, all-cause mortality prior to discharge, and adverse effects leading to treatment discontinuation. RISK OF BIAS: We assessed risk of bias using the Cochrane RoB 2 tool. SYNTHESIS

methodsWe used a fixed-effect model to calculate risk ratios (RRs) with 95% confidence intervals (CIs) for the outcomes: respiratory support, all-cause mortality before discharge, and adverse effects leading to treatment discontinuation. For intermittent hypoxemia and duration of hospital stay, we calculated ratios of geometric means. We assessed the certainty of the evidence using GRADE methods. Study authors were contacted for additional data when required. INCLUDED STUDIES: We included one randomized controlled trial involving 132 late preterm infants in New Zealand. Infants were assigned to receive either caffeine or placebo for the prevention of intermittent hypoxemia. Reported outcomes included episodes of intermittent hypoxemia, respiratory support, duration of hospital stay, all-cause mortality, and adverse effects leading to treatment discontinuation. No eligible studies assessed methylxanthines for the treatment of intermittent hypoxemia, apnea, or respiratory insufficiency. We identified five ongoing trials: the largest is expected to enroll 478 late preterm infants and to be completed in 2026. SYNTHESIS OF

resultsThe included study did not report the critical outcome of the number of episodes of intermittent hypoxemia after 24 hours from starting treatment (i.e. from day two through the end of the first week). Methylxanthines may reduce the number of episodes of intermittent hypoxemia over one week from starting treatment compared to placebo or no treatment (ln [ratio of geometric means] -0.58, 95% CI -1.14 to -0.02; I² not applicable; 1 study, 132 participants; low-certainty evidence). The evidence is very uncertain about the effect of methylxanthines on respiratory support after 24 hours from starting treatment (RD 0.00, 95% CI -0.05 to 0.05; I² not applicable; 1 study, 132 participants; very low-certainty evidence); on duration of hospital stay (ln [ratio of geometric means] 0.23, 95% CI -0.01 to 0.47; I² not applicable; 1 study, 132 participants; very low-certainty evidence); and on any adverse effects leading to treatment discontinuation at the end of study compared to placebo or no treatment (RR 2.57, 95% CI 0.65 to 10.22; I² not applicable; 1 study, 132 participants; very low-certainty evidence). Methylxanthines may result in little to no difference in all-cause mortality prior to hospital discharge compared to placebo or no treatment (RD 0.00, 95% CI -0.05 to 0.05; I² not applicable; 1 study, 132 participants; low-certainty evidence). No studies reported on apnea or major neurodevelopmental disability. The certainty of the evidence is limited by the inclusion of only one study, with all outcomes downgraded for serious or very serious imprecision. For most outcomes, we also downgraded the certainty of the evidence due to some concerns about the risk of bias. These findings should be considered preliminary and are likely to change with future research. AUTHORS'

conclusionsOverall, methylxanthine therapy in late preterm infants may reduce the number of intermittent hypoxemia episodes over one week from starting treatment, but likely results in little to no difference in all-cause mortality prior to hospital discharge. The effects of methylxanthines on other important outcomes, such as respiratory support, duration of hospital stay and adverse effects, remain highly uncertain due to limited and low-certainty evidence. A few outcomes were not reported, and no studies addressed the treatment of established intermittent hypoxemia or respiratory insufficiency. Current evidence is limited, and further high-quality trials are needed to clarify the efficacy and safety of methylxanthines in late preterm infants. The identified ongoing trials are planning to recruit over 900 infants, with the largest (n = 478) expected to be completed in 2026.

fundingThis Cochrane review was supported by Cochrane Sweden, Region Skåne and Skåne University Hospital, Lund University, and Vermont Oxford Network. No dedicated funding was received. REGISTRATION: Protocol (2024) DOI: 10.1002/14651858.CD016113.