Association between oxygen saturation targeting and death or disability in extremely preterm infants in the neonatal oxygenation prospective meta-analysis collaboration

Lisa M. Askie; Brian A. Darlow; Neil Finer; Barbara Schmidt; Ben Stenson; William Tarnow-Mordi; Peter G. Davis; Waldemar A. Carlo; Peter Brocklehurst; Lucy C. Davies; Abhik Das; Wade Rich; Marie G. Gantz; Robin S. Roberts; Robin K. Whyte; Lorrie Costantini; Christian Poets; Elizabeth Asztalos; Malcolm Battin; Henry L. Halliday; Neil Marlow; Win Tin; Andrew King; Edmund Juszczak; Colin J. Morley; Lex W. Doyle; Val Gebski; Kylie E. Hunter; Robert J. Simes

doi:10.1001/jama.2018.5725

Association between oxygen saturation targeting and death or disability in extremely preterm infants in the neonatal oxygenation prospective meta-analysis collaboration

Lisa M. Askie, Brian A. Darlow, Neil Finer, Barbara Schmidt, Ben Stenson, William Tarnow-Mordi, Peter G. Davis, Waldemar A. Carlo, Peter Brocklehurst, Lucy C. Davies, Abhik Das, Wade Rich, Marie G. Gantz, Robin S. Roberts, Robin K. Whyte, Lorrie Costantini, Christian Poets, Elizabeth Asztalos, Malcolm Battin, Henry L. HallidayNeil Marlow, Win Tin, Andrew King, Edmund Juszczak, Colin J. Morley, Lex W. Doyle, Val Gebski, Kylie E. Hunter, Robert J. Simes

Medicine

Research output: Contribution to journal › Article › peer-review

347 Citations (Scopus)

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 (SpO₂) 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 SpO₂ 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 SpO₂ target range and 2485 to the higher SpO₂ 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 SpO₂ target group and 1150 of 2229 infants (51.6%) in the higher SpO₂ 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 SpO₂ target group, and 3 significantly favored the higher SpO₂ target group. Death occurred in 484 of 2433 infants (19.9%) in the lower SpO₂ target group and 418 of 2440 infants (17.1%) in the higher SpO₂ 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 SpO₂ target group and 308 of 2065 infants (14.9%) in the higher SpO₂ 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 SpO₂ target group and 170 of 2465 infants (6.9%) in the higher SpO₂ 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 SpO₂ target range compared with a higher SpO₂ target range on the primary composite outcome of death or major disability at a corrected age of 18 to 24 months. The lower SpO₂ target range was associated with a higher risk of death and necrotizing enterocolitis, but a lower risk of retinopathy of prematurity treatment.

Original language	English
Pages (from-to)	2190-2201
Number of pages	12
Journal	JAMA - Journal of the American Medical Association
Volume	319
Issue number	21
DOIs	https://doi.org/10.1001/jama.2018.5725
Publication status	Published - Jun 5 2018

Bibliographical note

Funding Information:
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.

Funding Information:
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.

Funding Information:
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.

Publisher Copyright:
© 2018 American Medical Association. All rights reserved.

ASJC Scopus Subject Areas

General Medicine

Access to Document

10.1001/jama.2018.5725

Cite this

Askie, L. M., Darlow, B. A., Finer, N., Schmidt, B., Stenson, B., Tarnow-Mordi, W., Davis, P. G., Carlo, W. A., Brocklehurst, P., Davies, L. C., Das, A., Rich, W., Gantz, M. G., Roberts, R. S., Whyte, R. K., Costantini, L., Poets, C., Asztalos, E., Battin, M., ... Simes, R. J. (2018). Association between oxygen saturation targeting and death or disability in extremely preterm infants in the neonatal oxygenation prospective meta-analysis collaboration. JAMA - Journal of the American Medical Association, 319(21), 2190-2201. https://doi.org/10.1001/jama.2018.5725

Association between oxygen saturation targeting and death or disability in extremely preterm infants in the neonatal oxygenation prospective meta-analysis collaboration. / Askie, Lisa M.; Darlow, Brian A.; Finer, Neil et al.
In: JAMA - Journal of the American Medical Association, Vol. 319, No. 21, 05.06.2018, p. 2190-2201.

Research output: Contribution to journal › Article › peer-review

Askie, LM, Darlow, BA, Finer, N, Schmidt, B, Stenson, B, Tarnow-Mordi, W, Davis, PG, Carlo, WA, Brocklehurst, P, Davies, LC, Das, A, Rich, W, Gantz, MG, Roberts, RS, Whyte, RK, Costantini, L, Poets, C, Asztalos, E, Battin, M, Halliday, HL, Marlow, N, Tin, W, King, A, Juszczak, E, Morley, CJ, Doyle, LW, Gebski, V, Hunter, KE & Simes, RJ 2018, 'Association between oxygen saturation targeting and death or disability in extremely preterm infants in the neonatal oxygenation prospective meta-analysis collaboration', JAMA - Journal of the American Medical Association, vol. 319, no. 21, pp. 2190-2201. https://doi.org/10.1001/jama.2018.5725

@article{632dc9a41bcb4e9f9e0603a422d2a5c7,

title = "Association between oxygen saturation targeting and death or disability in extremely preterm infants in the neonatal oxygenation prospective meta-analysis collaboration",

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 (SpO2) 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{\textquoteright} gestation. EXPOSURES SpO2 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 SpO2 target range and 2485 to the higher SpO2 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 SpO2 target group and 1150 of 2229 infants (51.6%) in the higher SpO2 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 SpO2 target group, and 3 significantly favored the higher SpO2 target group. Death occurred in 484 of 2433 infants (19.9%) in the lower SpO2 target group and 418 of 2440 infants (17.1%) in the higher SpO2 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 SpO2 target group and 308 of 2065 infants (14.9%) in the higher SpO2 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 SpO2 target group and 170 of 2465 infants (6.9%) in the higher SpO2 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 SpO2 target range compared with a higher SpO2 target range on the primary composite outcome of death or major disability at a corrected age of 18 to 24 months. The lower SpO2 target range was associated with a higher risk of death and necrotizing enterocolitis, but a lower risk of retinopathy of prematurity treatment.",

author = "Askie, {Lisa M.} and Darlow, {Brian A.} and Neil Finer and Barbara Schmidt and Ben Stenson and William Tarnow-Mordi and Davis, {Peter G.} and Carlo, {Waldemar A.} and Peter Brocklehurst and Davies, {Lucy C.} and Abhik Das and Wade Rich and Gantz, {Marie G.} and Roberts, {Robin S.} and Whyte, {Robin K.} and Lorrie Costantini and Christian Poets and Elizabeth Asztalos and Malcolm Battin and Halliday, {Henry L.} and Neil Marlow and Win Tin and Andrew King and Edmund Juszczak and Morley, {Colin J.} and Doyle, {Lex W.} and Val Gebski and Hunter, {Kylie E.} and Simes, {Robert J.}",

note = "Funding Information: 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{\textquoteright}s National Institute for Health Research Biomedical Research Centre{\textquoteright}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. Funding Information: 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{\textquoteright}s National Institute for Health Research Biomedical Research Centre{\textquoteright}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. Funding Information: 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. Publisher Copyright: {\textcopyright} 2018 American Medical Association. All rights reserved.",

year = "2018",

month = jun,

day = "5",

doi = "10.1001/jama.2018.5725",

language = "English",

volume = "319",

pages = "2190--2201",

journal = "JAMA - Journal of the American Medical Association",

issn = "0098-7484",

publisher = "American Medical Association",

number = "21",

}

TY - JOUR

T1 - Association between oxygen saturation targeting and death or disability in extremely preterm infants in the neonatal oxygenation prospective meta-analysis collaboration

AU - Askie, Lisa M.

AU - Darlow, Brian A.

AU - Finer, Neil

AU - Schmidt, Barbara

AU - Stenson, Ben

AU - Tarnow-Mordi, William

AU - Davis, Peter G.

AU - Carlo, Waldemar A.

AU - Brocklehurst, Peter

AU - Davies, Lucy C.

AU - Das, Abhik

AU - Rich, Wade

AU - Gantz, Marie G.

AU - Roberts, Robin S.

AU - Whyte, Robin K.

AU - Costantini, Lorrie

AU - Poets, Christian

AU - Asztalos, Elizabeth

AU - Battin, Malcolm

AU - Halliday, Henry L.

AU - Marlow, Neil

AU - Tin, Win

AU - King, Andrew

AU - Juszczak, Edmund

AU - Morley, Colin J.

AU - Doyle, Lex W.

AU - Gebski, Val

AU - Hunter, Kylie E.

AU - Simes, Robert J.

N1 - Funding Information: 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. Funding Information: 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. Funding Information: 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. Publisher Copyright: © 2018 American Medical Association. All rights reserved.

PY - 2018/6/5

Y1 - 2018/6/5

N2 - 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 (SpO2) 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 SpO2 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 SpO2 target range and 2485 to the higher SpO2 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 SpO2 target group and 1150 of 2229 infants (51.6%) in the higher SpO2 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 SpO2 target group, and 3 significantly favored the higher SpO2 target group. Death occurred in 484 of 2433 infants (19.9%) in the lower SpO2 target group and 418 of 2440 infants (17.1%) in the higher SpO2 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 SpO2 target group and 308 of 2065 infants (14.9%) in the higher SpO2 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 SpO2 target group and 170 of 2465 infants (6.9%) in the higher SpO2 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 SpO2 target range compared with a higher SpO2 target range on the primary composite outcome of death or major disability at a corrected age of 18 to 24 months. The lower SpO2 target range was associated with a higher risk of death and necrotizing enterocolitis, but a lower risk of retinopathy of prematurity treatment.

AB - 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 (SpO2) 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 SpO2 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 SpO2 target range and 2485 to the higher SpO2 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 SpO2 target group and 1150 of 2229 infants (51.6%) in the higher SpO2 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 SpO2 target group, and 3 significantly favored the higher SpO2 target group. Death occurred in 484 of 2433 infants (19.9%) in the lower SpO2 target group and 418 of 2440 infants (17.1%) in the higher SpO2 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 SpO2 target group and 308 of 2065 infants (14.9%) in the higher SpO2 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 SpO2 target group and 170 of 2465 infants (6.9%) in the higher SpO2 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 SpO2 target range compared with a higher SpO2 target range on the primary composite outcome of death or major disability at a corrected age of 18 to 24 months. The lower SpO2 target range was associated with a higher risk of death and necrotizing enterocolitis, but a lower risk of retinopathy of prematurity treatment.

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U2 - 10.1001/jama.2018.5725

DO - 10.1001/jama.2018.5725

M3 - Article

C2 - 29872859

AN - SCOPUS:85048270550

SN - 0098-7484

VL - 319

SP - 2190

EP - 2201

JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

IS - 21

ER -

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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