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Meta-Analysis
. 2017 Apr 11;4(4):CD011190.
doi: 10.1002/14651858.CD011190.pub2.

Effects of targeting lower versus higher arterial oxygen saturations on death or disability in preterm infants

Lisa M Askie  1 , Brian A Darlow  2 , Peter G Davis  3 , Neil Finer  4 , Ben Stenson  5 , Maximo Vento  6 , Robin Whyte  7
Affiliations
Meta-Analysis

Effects of targeting lower versus higher arterial oxygen saturations on death or disability in preterm infants

Lisa M Askie et al. Cochrane Database Syst Rev. .

Abstract

Background: The use of supplemental oxygen in the care of extremely preterm infants has been common practice since the 1940s. Despite this, there is little agreement regarding which oxygen saturation (SpO₂) ranges to target to maximise short- or long-term growth and development, while minimising harms. There are two opposing concerns. Lower oxygen levels (targeting SpO₂ at 90% or less) may impair neurodevelopment or result in death. Higher oxygen levels (targeting SpO₂ greater than 90%) may increase severe retinopathy of prematurity or chronic lung disease.The use of pulse oximetry to non-invasively assess neonatal SpO₂ levels has been widespread since the 1990s. Until recently there were no randomised controlled trials (RCTs) that had assessed whether it is better to target higher or lower oxygen saturation levels in extremely preterm infants, from birth or soon thereafter. As a result, there is significant international practice variation and uncertainty remains as to the most appropriate range to target oxygen saturation levels in preterm and low birth weight infants.

Objectives: 1. What are the effects of targeting lower versus higher oxygen saturation ranges on death or major neonatal and infant morbidities, or both, in extremely preterm infants?2. Do these effects differ in different types of infants, including those born at a very early gestational age, or in those who are outborn, without antenatal corticosteroid coverage, of male sex, small for gestational age or of multiple birth, or by mode of delivery?

Search methods: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 4), MEDLINE via PubMed (1966 to 11 April 2016), Embase (1980 to 11 April 2016) and CINAHL (1982 to 11 April 2016). We also searched clinical trials databases, conference proceedings and the reference lists of retrieved articles for randomised controlled trials.

Selection criteria: Randomised controlled trials that enrolled babies born at less than 28 weeks' gestation, at birth or soon thereafter, and targeted SpO₂ ranges of either 90% or below or above 90% via pulse oximetry, with the intention of maintaining such targets for at least the first two weeks of life.

Data collection and analysis: We used the standard methods of Cochrane Neonatal to extract data from the published reports of the included studies. We sought some additional aggregate data from the original investigators in order to align the definitions of two key outcomes. We conducted the meta-analyses with Review Manager 5 software, using the Mantel-Haenszel method for estimates of typical risk ratio (RR) and risk difference (RD) and a fixed-effect model. We assessed the included studies using the Cochrane 'Risk of bias' and GRADE criteria in order to establish the quality of the evidence. We investigated heterogeneity of effects via pre-specified subgroup and sensitivity analyses.

Main results: 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.

Authors' conclusions: 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.

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Conflict of interest statement

Six members of the authorship team were investigators in the included studies and the NeOProM Collaboration. One member was included for his expertise in the field but had no affiliation with the included studies.

Lisa Askie is a member of the BOOST II Australia writing committee and the NeOProM Collaboration. Brian Darlow is a member of the BOOST‐NZ trial management committee, the BOOST II Australia trial management committee, and the NeOProM Collaboration. Peter Davis is a member of the BOOST‐II Australia trial management committee and the NeOProM Collaboration. Neil Finer is a member of the SUPPORT trial management committee and the NeOProM Collaboration. Ben Stenson is a member of the BOOST‐II UK steering committee and the NeOProM Collaboration. Maximo Vento has no conflicts of interest to declare. Robin Whyte is a member of the COT trial management committee and the NeOProM Collaboration.

Figures

1
1
Study flow diagram
2
2
Participant flow chart for the combined five NeOProM trials
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Oximeter offset to achieve masking as used in the five NeOProM trials
1.1
1.1. Analysis
Comparison 1 Lower versus higher targeted oxygen saturations (no subgroups), Outcome 1 Death or major disability by 18 to 24 months corrected age (aligned definition).
1.2
1.2. Analysis
Comparison 1 Lower versus higher targeted oxygen saturations (no subgroups), Outcome 2 Death or major disability by 18 to 24 months corrected age (trialist defined).
1.3
1.3. Analysis
Comparison 1 Lower versus higher targeted oxygen saturations (no subgroups), Outcome 3 Death to 18 to 24 months corrected age.
1.4
1.4. Analysis
Comparison 1 Lower versus higher targeted oxygen saturations (no subgroups), Outcome 4 Major disability by 18 to 24 months corrected age (aligned definition).
1.5
1.5. Analysis
Comparison 1 Lower versus higher targeted oxygen saturations (no subgroups), Outcome 5 Major disability by 18 to 24 months corrected age (trialist defined).
1.6
1.6. Analysis
Comparison 1 Lower versus higher targeted oxygen saturations (no subgroups), Outcome 6 Death to discharge.
1.7
1.7. Analysis
Comparison 1 Lower versus higher targeted oxygen saturations (no subgroups), Outcome 7 Severe retinopathy of prematurity or retinal therapy (trialist defined).
1.8
1.8. Analysis
Comparison 1 Lower versus higher targeted oxygen saturations (no subgroups), Outcome 8 Patent ductus arteriosus requiring medical or surgical treatment.
1.9
1.9. Analysis
Comparison 1 Lower versus higher targeted oxygen saturations (no subgroups), Outcome 9 Necrotising enterocolitis.
1.10
1.10. Analysis
Comparison 1 Lower versus higher targeted oxygen saturations (no subgroups), Outcome 10 Cerebral palsy with GMFCS level 2 or higher at 18 to 24 months corrected age.
1.11
1.11. Analysis
Comparison 1 Lower versus higher targeted oxygen saturations (no subgroups), Outcome 11 Blindness.
1.12
1.12. Analysis
Comparison 1 Lower versus higher targeted oxygen saturations (no subgroups), Outcome 12 Severe hearing loss.
1.13
1.13. Analysis
Comparison 1 Lower versus higher targeted oxygen saturations (no subgroups), Outcome 13 Proportion of infants re‐admitted to hospital up to 18 to 24 months corrected age.
1.14
1.14. Analysis
Comparison 1 Lower versus higher targeted oxygen saturations (no subgroups), Outcome 14 Weight (grams) at discharge home.
1.15
1.15. Analysis
Comparison 1 Lower versus higher targeted oxygen saturations (no subgroups), Outcome 15 Weight (kilograms) at 18 or 24 months corrected age.
1.16
1.16. Analysis
Comparison 1 Lower versus higher targeted oxygen saturations (no subgroups), Outcome 16 Days of endotracheal intubation.
1.17
1.17. Analysis
Comparison 1 Lower versus higher targeted oxygen saturations (no subgroups), Outcome 17 Days of CPAP.
1.18
1.18. Analysis
Comparison 1 Lower versus higher targeted oxygen saturations (no subgroups), Outcome 18 Days of supplemental oxygen.
1.19
1.19. Analysis
Comparison 1 Lower versus higher targeted oxygen saturations (no subgroups), Outcome 19 Supplemental oxygen requirement at 36 weeks postmenstrual age.
1.20
1.20. Analysis
Comparison 1 Lower versus higher targeted oxygen saturations (no subgroups), Outcome 20 Days on home oxygen.
1.21
1.21. Analysis
Comparison 1 Lower versus higher targeted oxygen saturations (no subgroups), Outcome 21 Quantitative Bayley III scores (Composite Cognitive Score (CCS)).
1.22
1.22. Analysis
Comparison 1 Lower versus higher targeted oxygen saturations (no subgroups), Outcome 22 Quantitative Bayley III scores (Composite Language Score (CLS)).
2.1
2.1. Analysis
Comparison 2 Lower versus higher targeted oxygen saturations (primary outcome, subgrouped by gestational age), Outcome 1 Death or major disability by 18 to 24 months corrected age (trialist defined).
3.1
3.1. Analysis
Comparison 3 Lower versus higher targeted oxygen saturations (primary outcome, subgrouped by sex), Outcome 1 Death or major disability by 18 to 24 months corrected age (trialist defined).
4.1
4.1. Analysis
Comparison 4 Lower versus higher targeted oxygen saturations (primary outcome, subgrouped by multiples), Outcome 1 Death or major disability by 18 to 24 months corrected age (trialist defined).
5.1
5.1. Analysis
Comparison 5 Lower versus higher targeted oxygen saturations (primary outcome, subgrouped by oximeter calibration software), Outcome 1 Death or major disability by 18 to 24 months corrected age (aligned definition).
5.2
5.2. Analysis
Comparison 5 Lower versus higher targeted oxygen saturations (primary outcome, subgrouped by oximeter calibration software), Outcome 2 Death or major disability by 18 to 24 months corrected age (trialist defined).
6.1
6.1. Analysis
Comparison 6 Lower versus higher targeted oxygen saturations (secondary outcomes, subgrouped by oximeter calibration software), Outcome 1 Death by 18 to 24 months corrected age.
6.2
6.2. Analysis
Comparison 6 Lower versus higher targeted oxygen saturations (secondary outcomes, subgrouped by oximeter calibration software), Outcome 2 Major disability by 18 to 24 months corrected age (aligned definition).
6.3
6.3. Analysis
Comparison 6 Lower versus higher targeted oxygen saturations (secondary outcomes, subgrouped by oximeter calibration software), Outcome 3 Major disability by 18 to 24 months corrected age (trialist defined).
6.4
6.4. Analysis
Comparison 6 Lower versus higher targeted oxygen saturations (secondary outcomes, subgrouped by oximeter calibration software), Outcome 4 Death to discharge.
6.5
6.5. Analysis
Comparison 6 Lower versus higher targeted oxygen saturations (secondary outcomes, subgrouped by oximeter calibration software), Outcome 5 Severe retinopathy of prematurity or retinal therapy.
7.1
7.1. Analysis
Comparison 7 Lower versus higher targeted oxygen saturations (secondary outcomes, subgrouped by gestational age), Outcome 1 Death by 18 to 24 months corrected age.
7.2
7.2. Analysis
Comparison 7 Lower versus higher targeted oxygen saturations (secondary outcomes, subgrouped by gestational age), Outcome 2 Major disability by 18 to 24 months corrected age (trialist defined).
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Update of

References

References to studies included in this review

BOOST‐II Australia 2016 {published data only}
    1. Stenson BJ, Tarnow‐Mordi WO, Darlow BA, Simes J, Juszczak E, Askie L, et al. BOOST II United Kingdom Collaborative Group, BOOST II Australia Collaborative Group, BOOST II New Zealand Collaborative Group. Oxygen saturation and outcomes in preterm infants. New England Journal of Medicine 2013;368(22):2094‐104. [DOI: 10.1056/NEJMoa1302298; PUBMED: 23642047 ] - DOI - PubMed
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BOOST‐II UK 2016 {published data only}
    1. BOOST II United Kingdom Collaborative Group, BOOST II Australia Collaborative Group, BOOST II New Zealand Collaborative Group, Stenson BJ, Tarnow‐Mordi WO, Darlow BA, Simes J, Juszczak E, Askie L, et al. Oxygen saturation and outcomes in preterm infants. New England Journal of Medicine 2013;368(22):2094‐104. - PubMed
    1. BOOST‐II Australia and United Kingdom Collaborative Groups, Tarnow‐Mordi W, Stenson B, Kirby A, Juszczak E, Donoghoe M, Deshpande S, et al. Outcomes of two trials of oxygen‐saturation targets in preterm infants. New England Journal of Medicine 2016;374(8):749‐60. - PubMed
BOOST NZ 2014 {published and unpublished data}
    1. BOOST II United Kingdom Collaborative Group, BOOST II Australia Collaborative Group, BOOST II New Zealand Collaborative Group, Stenson BJ, Tarnow‐Mordi WO, Darlow BA, Simes J, Juszczak E, Askie L, et al. Oxygen saturation and outcomes in preterm infants. New England Journal of Medicine 2013;368(22):2094‐104. - PubMed
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Schmidt 2013 {published and unpublished data}
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Vaucher 2012 {published and unpublished data}
    1. Carlo WA, Finer NN, Walsh MC, Rich W, Gantz MG, Laptook AR, et al. SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network. Target ranges of oxygen saturation in extremely preterm infants. New England Journal of Medicine 2010;362(21):1959‐69. [DOI: 10.1056/NEJMoa0911781; NCT00233324] - DOI - PMC - PubMed
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Arora 2013 {published data only}
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