Abstract: Five trials, which together enrolled 4965 infants, were eligible for inclusion. The investigators of these five trials had prospectively planned to combine their data as part of the NeOProM (Neonatal Oxygen Prospective Meta-analysis) Collaboration. We graded the quality of evidence as high for the key outcomes of death, major disability, the composite of death or major disability, and necrotising enterocolitis; and as moderate for blindness and retinopathy of prematurity requiring treatment. When an aligned definition of major disability was used, there was no significant difference in the composite primary outcome of death or major disability in extremely preterm infants when targeting a lower (SpO₂ 85% to 89%) versus a higher (SpO₂ 91% to 95%) oxygen saturation range (typical RR 1.04, 95% confidence interval (CI) 0.98 to 1.10; typical RD 0.02, 95% CI -0.01 to 0.05; 5 trials, 4754 infants) (high-quality evidence). Compared with a higher target range, a lower target range significantly increased the incidence of death at 18 to 24 months corrected age (typical RR 1.16, 95% CI 1.03 to 1.31; typical RD 0.03, 95% CI 0.01 to 0.05; 5 trials, 4873 infants) (high-quality evidence) and necrotising enterocolitis (typical RR 1.24, 95% 1.05 to 1.47; typical RD 0.02, 95% CI 0.01 to 0.04; 5 trials, 4929 infants; I² = 0%) (high-quality evidence). Targeting the lower range significantly decreased the incidence of retinopathy of prematurity requiring treatment (typical RR 0.72, 95% CI 0.61 to 0.85; typical RD -0.04, 95% CI -0.06 to -0.02; 5 trials, 4089 infants; I² = 69%) (moderate-quality evidence). There were no significant differences between the two treatment groups for major disability including blindness, severe hearing loss, cerebral palsy, or other important neonatal morbidities. A subgroup analysis of major outcomes by type of oximeter calibration software (original versus revised) found a significant difference in the treatment effect between the two software types for death (interaction P = 0.03), with a significantly larger treatment effect seen for those infants using the revised algorithm (typical RR 1.38, 95% CI 1.13 to 1.68; typical RD 0.06, 95% CI 0.01 to 0.10; 3 trials, 1716 infants). There were no other important differences in treatment effect shown by the subgroup analyses using the currently available data. In extremely preterm infants, targeting lower (85% to 89%) SpO₂ compared to higher (91% to 95%) SpO₂ had no significant effect on the composite outcome of death or major disability or on major disability alone, including blindness, but increased the average risk of mortality by 28 per 1000 infants treated. The trade-offs between the benefits and harms of the different oxygen saturation target ranges may need to be assessed within local settings (e.g. alarm limit settings, staffing, baseline outcome risks) when deciding on oxygen saturation targeting policies.

Plain-language summary: The studies we included were randomised trials that enrolled babies born at less than 28 weeks' gestation, at birth or soon thereafter, and targeted oxygen saturation (SpO₂) ranges of either 85% to 89% or 91% to 95%, for at least the first two weeks of life. We included five trials, which together enrolled 4965 infants, in this review. There were benefits and harms associated with both the target ranges tested. Neither the lower nor the higher target range had a significant effect on the rate of death or major disability (the main outcome), on major disability alone or on blindness. However, infants in whom the lower oxygen range was targeted had, on average, a 2.8% increased risk of death, compared to the infants in whom the higher oxygen range was targeted. They also had a 2.2% increase in the rate of a serious bowel condition known as necrotising enterocolitis. Conversely, the infants in whom the lower oxygen range was targeted had a 4.2% decrease in the rate of a serious eye problem, retinopathy of prematurity, requiring surgery or other treatments. The trade-offs between these benefits and harms may need to be assessed within local settings when deciding on oxygen saturation targeting policies. We rated the quality of the evidence as high for the key outcomes of death, major disability, the composite of death or major disability, and necrotising enterocolitis. We rated the quality of evidence as moderate for the two eye-related outcomes (blindness, retinopathy of prematurity requiring treatment), giving us confidence that the overall results are reliable.