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Background: High arterial oxygen saturation (SaO2) is associated with the development of retinopathy of prematurity (ROP), but difficult to avoid., Objective: To assess the association between severe ROP and a burden of cerebral and arterial hyperoxia., Methods: We retrospectively analyzed 225 preterm infants born ≤30 weeks' gestation. The cerebral oxygen saturation (rcSO2) and SaO2 were measured within the first 96 h after birth. We determined the burden of both cerebral and arterial hyperoxia, which was defined as the percentage of time spent at saturation thresholds exceeding 85 and 90%, respectively. Their association with severe ROP (prethreshold disease type 1) was tested using logistic regression analyses., Results: Median gestational age (GA) was 28.0 weeks (interquartile range 26.7-29.0) and mean birth weight 1,032 g (±281 SD). Eight infants developed severe ROP. Infants with severe ROP spent more time at cerebral hyperoxic levels than infants without severe ROP (medians 30 vs. 16%). Adjusted for GA, for every 10% increase in burden of cerebral hyperoxia, the OR for developing ROP was 1.50 (95% CI 1.09 - 2.06, p = 0.013). A burden of arterial hyperoxia was not associated with ROP. Infants with severe ROP experienced even less arterial hyperoxia, although not statistically significant., Conclusions: Cerebral hyperoxia may be a better early predictor of severe ROP than arterial hyperoxia. Moreover, under strict oxygen management, cerebral hyperoxia in these infants may result from cerebral immaturity rather than a high SaO2. Whether reducing cerebral hyperoxia is feasible and might prevent ROP needs to be further examined., (© 2019 The Author(s) Published by S. Karger AG, Basel.)