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' 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.

Conflict of interest statement

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.

Figures

Figure 1.. Participant Flow Diagram

aMajor disability was prespecified (published in the Neonatal Oxygenation Prospective Meta-analysis protocol; Supplement 1) and includes any of the following: Bayley-III developmental assessment cognitive score of less than 85, language score of less than 85, or both; severe visual impairment; cerebral palsy with Gross Motor Function Classification System (GMFCS) level 2 or higher, at age 18 to 24 months corrected for prematurity; or deafness requiring hearing aids. bThe maximum number of infants available for major disability assessment at 18 to 24 months was 3971 because 902 infants were known to have died prior to the age of 18 to 24 months. There were an additional 92 infants with unknown death status at this time point who could not be assessed for major disability outcomes.

Figure 2.. Effect of Oxygen Saturation as Measured by Pulse Oximetry (Spo2) Target Levels on Composite Primary Outcome of Death or Major Disability

Box sizes correspond to precision; therefore, the more precise the larger the box. Precision was ascertained by calculating the inverse of the variance for each estimate. aDefined as a composite outcome of death or major disability by the age of 18 to 24 months, which was corrected for prematurity and prespecified in the published Neonatal Oxygenation Prospective Meta-analysis protocol (Supplement 1). bIncluded using alternative sources of information for classifying major disability as used within individual trials. This may have included a Bayley-II major disability score of less than 70, another validated assessment tool (eg, the Griffiths test), a pediatrician assessment, or parent-reported measure of neurodevelopmental impairment (eg, able to speak <5-10 words), or other measures. cDefined per protocol. dDefined using supplementary data as noted in the “b” footnote. eDevelopmental assessment for cognition or language. fDefined by Gross Motor Function Classification System level 2 or greater (higher levels = functioning more impaired) or cerebral palsy diagnosed but score unknown. gRequiring hearing aids or worse. hDefined by the trial investigators.

Figure 3.. Effect of Oxygen Saturation as Measured by Pulse Oximetry (Spo2) Target Levels on Secondary Outcomes

Box sizes correspond to precision; therefore, the more precise the larger the box. Precision was ascertained by calculating the inverse of the variance for each estimate. aDenominators include the total number of infants with a known outcome. bDiagnosed by ultrasound during initial hospitalization. cTreated with surgery or leading to death during initial hospitalization. dData on postmenstrual age when ceased use of home oxygen can only be calculated using the 537 infants who received home oxygen and for whom the postmenstrual age when ceased use is known.

Figure 4.. Subgroup Analyses of Primary Outcome Composite of Death or Major Disability

Box sizes correspond to precision; therefore, the more precise the larger the box. Precision was ascertained by calculating the inverse of the variance for each estimate. Spo2 indicates oxygen saturation as measured by pulse oximetry. aDenominators include the total number of infants with a known outcome. bExcluded 74 infants in the Canadian Oxygen Trial who were exposed to both the original and revised software. cInborn defined as born inside the treating center; outborn, born outside the treating center (eg, transferred from another hospital). dLess than 10th percentile using charts from Kramer et al.

Figure 5.. Subgroup Analysis by Oximeter Software Type

Box sizes correspond to precision; therefore, the more precise the larger the box. Precision was ascertained by calculating the inverse of the variance for each estimate. Spo2 indicates oxygen saturation as measured by pulse oximetry. This subgroup analysis excludes 74 infants in the Canadian Oxygen Trial who were exposed to both the original and revised software. aDenominators include the total number of infants with a known outcome. bDevelopmental assessment cognitive or language score of less than 85. cDefined by Gross Motor Function Classification System level 2 or greater (higher levels = functioning more impaired) or cerebral palsy diagnosed but score unknown. dRequiring hearing aids or worse. eDefined by the trial investigators. fDiagnosed by ultrasound. gTreated with surgery or leading to death during initial hospitalization.