Association Between Oxygen Saturation Targeting and Death or Disability in Extremely
      Preterm Infants in the Neonatal Oxygenation Prospective Meta-analysis Collaboration

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Key Points

Question

For extremely preterm infants, is targeting a lower oxygen saturation (85%-89%) compared with a higher saturation (91%-95%) associated with a difference in death or major disability by a corrected age of 24 months?

Findings

In a prospectively designed meta-analysis of individual participant data from 4965 infants in 5 randomized clinical trials, there was no significant difference in the primary composite outcome of death or major disability between those treated with lower vs higher oxygen saturations (53.5% vs 51.6%, respectively). Lower oxygen targets were associated with increased death and necrotizing enterocolitis but reduced retinopathy of prematurity treatment.

Meaning

Among extremely preterm infants, there was no significant difference between lower and higher oxygen saturation targets on a composite of death or major disability; secondary end points may need to be considered in decision making.

Abstract

Importance

There are potential benefits and harms of hyperoxemia and hypoxemia for extremely preterm infants receiving more vs less supplemental oxygen.

Objective

To compare the effects of different target ranges for oxygen saturation as measured by pulse oximetry (Sp o ₂) on death or major morbidity.

Design, Setting, and Participants

Prospectively planned meta-analysis of individual participant data from 5 randomized clinical trials (conducted from 2005-2014) enrolling infants born before 28 weeks’ gestation.

Exposures

Sp o ₂ target range that was lower (85%-89%) vs higher (91%-95%).

Main Outcomes and Measures

The primary outcome was a composite of death or major disability (bilateral blindness, deafness, cerebral palsy diagnosed as ≥2 level on the Gross Motor Function Classification System, or Bayley-III cognitive or language score <85) at a corrected age of 18 to 24 months. There were 16 secondary outcomes including the components of the primary outcome and other major morbidities.

Results

A total of 4965 infants were randomized (2480 to the lower Sp o ₂ target range and 2485 to the higher Sp o ₂ range) and had a median gestational age of 26 weeks (interquartile range, 25-27 weeks) and a mean birth weight of 832 g (SD, 190 g). The primary outcome occurred in 1191 of 2228 infants (53.5%) in the lower Sp o ₂ target group and 1150 of 2229 infants (51.6%) in the higher Sp o ₂ target group (risk difference, 1.7% [95% CI, −1.3% to 4.6%]; relative risk [RR], 1.04 [95% CI, 0.98 to 1.09], P = .21). Of the 16 secondary outcomes, 11 were null, 2 significantly favored the lower Sp o ₂ target group, and 3 significantly favored the higher Sp o ₂ target group. Death occurred in 484 of 2433 infants (19.9%) in the lower Sp o ₂ target group and 418 of 2440 infants (17.1%) in the higher Sp o ₂ target group (risk difference, 2.8% [95% CI, 0.6% to 5.0%]; RR, 1.17 [95% CI, 1.04 to 1.31], P = .01). Treatment for retinopathy of prematurity was administered to 220 of 2020 infants (10.9%) in the lower Sp o ₂ target group and 308 of 2065 infants (14.9%) in the higher Sp o ₂ target group (risk difference, −4.0% [95% CI, −6.1% to −2.0%]; RR, 0.74 [95% CI, 0.63 to 0.86], P < .001). Severe necrotizing enterocolitis occurred in 227 of 2464 infants (9.2%) in the lower Sp o ₂ target group and 170 of 2465 infants (6.9%) in the higher Sp o ₂ target group (risk difference, 2.3% [95% CI, 0.8% to 3.8%]; RR, 1.33 [95% CI, 1.10 to 1.61], P = .003).

Conclusions and Relevance

In this prospectively planned meta-analysis of individual participant data from extremely preterm infants, there was no significant difference between a lower Sp o ₂ target range compared with a higher Sp o ₂ target range on the primary composite outcome of death or major disability at a corrected age of 18 to 24 months. The lower Sp o ₂ target range was associated with a higher risk of death and necrotizing enterocolitis, but a lower risk of retinopathy of prematurity treatment.

Abstract

This meta-analysis uses individual participant data from 5 randomized clinical trials to compare the effects of lower vs higher oxygen saturation target ranges on death or major morbidity among infants born before 28 weeks’ gestation.

Related collections

Most cited references 25

Record: found
Abstract: found
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A new and improved population-based Canadian reference for birth weight for gestational age.

M Kramer, R W Platt, S Wen … (2001)

Existing fetal growth references all suffer from 1 or more major methodologic problems, including errors in reported gestational age, biologically implausible birth weight for gestational age, insufficient sample sizes at low gestational age, single-hospital or other non-population-based samples, and inadequate statistical modeling techniques. We used the newly developed Canadian national linked file of singleton births and infant deaths for births between 1994 and 1996, for which gestational age is largely based on early ultrasound estimates. Assuming a normal distribution for birth weight at each gestational age, we used the expectation-maximization algorithm to exclude infants with gestational ages that were more consistent with 40-week births than with the observed gestational age. Distributions of birth weight at the corrected gestational ages were then statistically smoothed. The resulting male and female curves provide smooth and biologically plausible means, standard deviations, and percentile cutoffs for defining small- and large-for-gestational-age births. Large-for-gestational age cutoffs (90th percentile) at low gestational ages are considerably lower than those of existing references, whereas small-for-gestational-age cutoffs (10th percentile) postterm are higher. For example, compared with the current World Health Organization reference from California (Williams et al, 1982) and a recently proposed US national reference (Alexander et al, 1996), the 90th percentiles for singleton males at 30 weeks are 1837 versus 2159 and 2710 g. The corresponding 10th percentiles at 42 weeks are 3233 versus 3086 and 2998 g. This new sex-specific, population-based reference should improve clinical assessment of growth in individual newborns, population-based surveillance of geographic and temporal trends in birth weight for gestational age, and evaluation of clinical or public health interventions to enhance fetal growth. fetal growth, birth weight, gestational age, preterm birth, postterm birth.

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Abstract: found
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Retinopathy of prematurity.

Ann Hellström, Lois E. H. Smith, Olaf Dammann (2013)

The immature retinas of preterm neonates are susceptible to insults that disrupt neurovascular growth, leading to retinopathy of prematurity. Suppression of growth factors due to hyperoxia and loss of the maternal-fetal interaction result in an arrest of retinal vascularisation (phase 1). Subsequently, the increasingly metabolically active, yet poorly vascularised, retina becomes hypoxic, stimulating growth factor-induced vasoproliferation (phase 2), which can cause retinal detachment. In very premature infants, controlled oxygen administration reduces but does not eliminate retinopathy of prematurity. Identification and control of factors that contribute to development of retinopathy of prematurity is essential to prevent progression to severe sight-threatening disease and to limit comorbidities with which the disease shares modifiable risk factors. Strategies to prevent retinopathy of prematurity will depend on optimisation of oxygen saturation, nutrition, and normalisation of concentrations of essential factors such as insulin-like growth factor 1 and ω-3 polyunsaturated fatty acids, as well as curbing of the effects of infection and inflammation to promote normal growth and limit suppression of neurovascular development. Copyright © 2013 Elsevier Ltd. All rights reserved.

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Target ranges of oxygen saturation in extremely preterm infants.

Waldemar A Carlo, Neil N Finer, Michele C Walsh … (2010)

Previous studies have suggested that the incidence of retinopathy is lower in preterm infants with exposure to reduced levels of oxygenation than in those exposed to higher levels of oxygenation. However, it is unclear what range of oxygen saturation is appropriate to minimize retinopathy without increasing adverse outcomes. We performed a randomized trial with a 2-by-2 factorial design to compare target ranges of oxygen saturation of 85 to 89% or 91 to 95% among 1316 infants who were born between 24 weeks 0 days and 27 weeks 6 days of gestation. The primary outcome was a composite of severe retinopathy of prematurity (defined as the presence of threshold retinopathy, the need for surgical ophthalmologic intervention, or the use of bevacizumab), death before discharge from the hospital, or both. All infants were also randomly assigned to continuous positive airway pressure or intubation and surfactant. The rates of severe retinopathy or death did not differ significantly between the lower-oxygen-saturation group and the higher-oxygen-saturation group (28.3% and 32.1%, respectively; relative risk with lower oxygen saturation, 0.90; 95% confidence interval [CI], 0.76 to 1.06; P=0.21). Death before discharge occurred more frequently in the lower-oxygen-saturation group (in 19.9% of infants vs. 16.2%; relative risk, 1.27; 95% CI, 1.01 to 1.60; P=0.04), whereas severe retinopathy among survivors occurred less often in this group (8.6% vs. 17.9%; relative risk, 0.52; 95% CI, 0.37 to 0.73; P<0.001). There were no significant differences in the rates of other adverse events. A lower target range of oxygenation (85 to 89%), as compared with a higher range (91 to 95%), did not significantly decrease the composite outcome of severe retinopathy or death, but it resulted in an increase in mortality and a substantial decrease in severe retinopathy among survivors. The increase in mortality is a major concern, since a lower target range of oxygen saturation is increasingly being advocated to prevent retinopathy of prematurity. (ClinicalTrials.gov number, NCT00233324.) 2010 Massachusetts Medical Society

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Author and article information

Journal

Journal ID (nlm-ta): JAMA

Journal ID (iso-abbrev): JAMA

Journal ID (pmc): JAMA

Title: JAMA

Publisher: American Medical Association

ISSN (Print): 0098-7484

ISSN (Electronic): 1538-3598

Publication date (Electronic): 5 June 2018

Publication date (Print): 5 June 2018

Publication date (Corrected, electronic): 17 July 2018

Publication date PMC-release: 5 December 2018

Volume: 319

Issue: 21

Pages: 2190-2201

Affiliations

[1 ]National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia

[2 ]Department of Paediatrics, University of Otago, Christchurch, New Zealand

[3 ]Department of Pediatrics, University of California, San Diego

[4 ]Division of Neonatology, University of Pennsylvania, Philadelphia

[5 ]Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada

[6 ]Department of Neonatology, Royal Infirmary of Edinburgh, Edinburgh, Scotland

[7 ]Newborn Research, Royal Women’s Hospital, Departments of Obstetrics and Gynaecology, and Paediatrics, University of Melbourne, Melbourne, Australia

[8 ]Clinical Sciences, Murdoch Children’s Research Institute, Melbourne, Australia

[9 ]Department of Pediatrics, University of Alabama, Birmingham

[10 ]Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, England

[11 ]National Perinatal Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, England

[12 ]Statistics and Epidemiology Unit, RTI International, Rockville, Maryland

[13 ]Statistics and Epidemiology Unit, RTI International, Research Triangle Park, North Carolina

[14 ]Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada

[15 ]Department of Neonatology, Tuebingen University Hospital, Tuebingen, Germany

[16 ]Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada

[17 ]Newborn Services, Auckland City Hospital, Auckland, New Zealand

[18 ]Royal Maternity Hospital, Belfast, Ireland

[19 ]Department of Child Health, Queen’s University, Belfast, Ireland

[20 ]EGA Institute for Women’s Health, University College London, London, England

[21 ]Department of Neonatal Medicine, James Cook University, Middlesbrough, England

[22 ]University of Cambridge, Department of Obstetrics and Gynaecology, Cambridge, England

Author notes

Article information

Group Information: Information about the members of the Neonatal Oxygenation Prospective Meta-analysis (NeOProM) Collaboration appears at the end of the article.

Corresponding Author: Lisa M. Askie, PhD, National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Medical Foundation Building, Level 6, 92-94 Parramatta Rd, Camperdown, NSW 2050, Australia ( lisa.askie@ 123456ctc.usyd.edu.au ).

Accepted for Publication: April 30, 2018.

Correction: This article was corrected on July 17, 2018, to fix data errors in Figure 3 for the row “z score for infant body weight at postmenstrual age of 36 wk” and the transposition of the male and female labels in Figure 4.

Author Contributions: Dr Askie and Ms Davies had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Askie, Darlow, Schmidt, Stenson, Davis, Carlo, Davies, Simes.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Askie, Davies, Gebski.

Obtained funding: Askie, Darlow, Schmidt, Tarnow-Mordi, Carlo, Brocklehurst, Gebski, Simes.

Administrative, technical, or material support: All authors.

Supervision: Askie, Gebski, Simes.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Askie reported receiving honoraria from the Nemours Foundation (Hot Topics in Neonatology). Dr Schmidt reported receiving honoraria from several US academic institutions, the Nemours Foundation (Hot Topics in Neonatology), and the Vermont Oxford Network for lectures on the topic of oxygen saturation targeting in extremely preterm infants. Dr Tarnow-Mordi reported receiving honoraria from the Nemours Foundation (Hot Topics in Neonatology) and the Vermont Oxford Network for speaking on topics related to the care of premature infants. Dr Davis reported receiving a fellowship from the Australian National Health and Medical Research Council. Dr Brocklehurst reported receiving personal fees from the UK Medical Research Council. Mr Rich reported receiving personal fees from Windtree Therapeutics Inc. Dr Poets reported receiving honoraria from Chiesi Farmaceutici. Dr Halliday reported being an advisor to Chiesi Farmaceutici and the joint editor-in-chief of Neonatology. Dr Marlow reported serving as a consultant to Shire. No other disclosures were reported.

Funding/Support: The data analysis was supported by grant R03HD 079867 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services . Support for staff of the National Health and Medical Research Council (NHMRC) Clinical Trials Centre (University of Sydney, Sydney, Australia) was partly funded by NHMRC program grant 1037786. Dr Marlow receives funding from the UK Department of Health’s National Institute for Health Research Biomedical Research Centre’s funding scheme at University College London Hospital and the University College London. The SUPPORT trial was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Heart, Lung, and Blood Institute, and from the National Institutes of Health (U10 HD21364, U10 HD21373, U10 HD21385, U10 HD21397, U10 HD27851, U10 HD27853, U10 HD27856, U10 HD27880, U10 HD27871, U10 HD27904, U10 HD34216, U10 HD36790, U10 HD40461, U10 HD40492, U10 HD40498, U10 HD40521, U10 HD40689, U10 HD53089, U10 HD53109, U10 HD53119, and U10 HD53124); and by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, cofunding from the National Heart, Lung, and Blood Institute, and grants from the National Institutes of Health (M01 RR30, M01 RR32, M01 RR39, M01 RR44, M01 RR54, M01 RR59, M01 RR64, M01 RR70, M01 RR80, MO1 RR125, M01 RR633, M01 RR750, M01 RR997, M01 RR6022, M01 RR7122, M01 RR8084, M01 RR16587, UL1 RR25008, UL1 RR24139, UL1 RR24979, and UL1 RR25744). The Canadian Oxygen Trial was funded by the Canadian Institutes of Health Research (MCT-79217). The BOOST New Zealand trial was funded by th New Zealand Health Research Council (05/145) and the Child Health Research Foundation. The BOOST II UK trial was funded by the UK Medical Research Council and managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership. The BOOST II Australia trial was supported by Australian NHMRC project grant 352386.

Role of the Funder/Sponsor: None of the listed funders or the Masimo Corporation had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: All authors are members of the Neonatal Oxygenation Prospective Meta-analysis (NeOProM) Collaboration.

Additional Contributions: We thank the many people who have contributed to this project (none of whom received financial compensation for their role in the study) including: William Silverman, MD (Columbia-Presbyterian Medical Center, New York, NY), Jack Sinclair, MD (McMaster University, Hamilton, Ontario, Canada), Edmund Hey, MD, DPhil (Princess Mary Maternity Hospital, Newcastle, England), and David Henderson-Smart, PhD (University of Sydney, Sydney, Australia), who are deceased. We also thank Cynthia Cole, MD, MPH (Boston University School of Medicine, Boston, Massachusetts), who was instrumental in forming the initial collaboration; Dale Phelps, MD (University of Rochester School of Medicine and Dentistry, Rochester, New York), for advice regarding the oximeter masking; and Marion Fournier, MSc, Adrienne Kirby, MSc, Mark Donoghoe, PhD, Luke Buizen BSc(Hons), Rebecca Asher, MSc, and Anna Lene Seidler MSc (all employees of the NHMRC Clinical Trials Centre, University of Sydney, Australia), for statistical advice and preparation of the manuscript figures and tables. We also acknowledge and thank the dedicated staff who worked on the included trials and the families of the enrolled infants for giving of their time.

Article

Accession ID: PMC6583054 Pmcid ID: PMC6583054 Pmc-uid ID: 6583054 Publisher ID: joi180046

DOI: 10.1001/jama.2018.5725

PMC ID: 6583054

PubMed ID: 29872859

SO-VID: 37316520-8783-45f6-8576-56b5b490e763

History

Date received : 30 December 2017

Date: 25 April 2018

Date accepted : 30 April 2018

Funding

Funded by: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services

Funded by: National Health and Medical Research Council (NHMRC)

Funded by: UK Department of Health’s National Institute for Health Research Biomedical Research Centre’s

Funded by: Eunice Kennedy Shriver National Institute of Child Health and Human Development,

Funded by: National Heart, Lung, and Blood Institute

Funded by: National Institutes of Health

Funded by: Kennedy Shriver National Institute of Child Health and Human Development

Funded by: National Heart, Lung, and Blood Institute

Funded by: National Institutes of Health

Funded by: Canadian Institutes of Health Research

Funded by: New Zealand Health Research Council

Funded by: UK Medical Research Council

Funded by: Australian NHMRC

Association Between Oxygen Saturation Targeting and Death or Disability in Extremely Preterm Infants in the Neonatal Oxygenation Prospective Meta-analysis Collaboration

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Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Exposures

Main Outcomes and Measures

Results

Conclusions and Relevance

Abstract

Related collections

UCL: UN SDG 03 Good Health and Well-Being

Most cited references 25

A new and improved population-based Canadian reference for birth weight for gestational age.

Retinopathy of prematurity.

Target ranges of oxygen saturation in extremely preterm infants.

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Article

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