Appropriate Oxygen Levels for Extremely Preterm Infants: a Prospective Meta-analysis (NeOProM)

Appropriate Levels of Oxygen Saturation for Extremely Preterm Infants: Prospective Individual Patient Data Meta-analysis

University of Otago, University of Oxford, University of Pennsylvania, University of California, San Diego

The primary question to be addressed by this study is: compared with a functional oxygen saturation level (SpO2) of 91-95%, does targeting SpO2 85-89% in extremely preterm infants from birth or soon after, result in a difference in mortality or major disability in survivors by 2 years corrected age (defined as gestational age plus chronological age)?

Oxygen has been used in the care of small and sick newborn babies for over 60 years. However, to date there has been no reliable evidence to guide clinicians regarding what is the best level to target oxygen saturation in preterm infants to balance the four competing risks of mortality, lung disease, eye damage and developmental disability. Five high quality randomised controlled trials are now underway assessing two different levels of oxygen saturation targeting (USA - SUPPORT; Australia - BOOST II; New Zealand - BOOST NZ; UK - BOOST II UK; Canada - COT). The value of these gold-standard trials can be further enhanced when, with careful planning, they are synthesised into a prospective meta-analysis (PMA). A PMA is one where trials are identified for inclusion in the analysis before any of the individual results are known. We have established the Neonatal Oxygenation Prospective Meta-analysis (NeOProM) Collaboration, comprising the investigators of these five trials and a methodology team. The trials are sufficiently similar with respect to design, participants and intervention and, with planning, will have enough common outcome measures to enable their results to be prospectively meta-analysed. Together they have a combined sample size of almost 5000 enrolled infants.

Infant, Premature, Diseases, Bronchopulmonary Dysplasia, Retinopathy of Prematurity, Infant, Newborn, Diseases, Infant, Very Low Birth Weight

Higher (SpO2 91-95%) functional oxygen saturation target range from birth, or soon thereafter, for durations as specified in each trial protocol.

Lower (SpO2 85-89%) functional oxygen saturation target range from birth, or soon thereafter, for durations as specified in each trial protocol.

Major disability is defined as any of the following: Bayley-III Developmental Assessment cognitive score <85 and/or language score <85 Severe visual loss Cerebral palsy with Gross Motor Function Classification System (GMFCS) level 2 or higher or Manual Ability Classification System (MACS) level 2 or higher at 18-24 months postmenstrual age Deafness requiring hearing aids

Retinopathy of prematurity (ROP) treatment by laser photocoagulation or cryotherapy or anti-VEGF injection

• Measures of respiratory support, including the following separate outcomes a. supplemental oxygen requirement at 36 weeks postmenstrual age, b. postmenstrual age ceased endotracheal intubation, c. postmenstrual age ceased continuous positive airway pressure (CPAP), d. postmenstrual age ceased supplemental oxygen, e. postmenstrual age ceased home oxygen (if received).

Severe visual impairment (cannot fixate or is legally blind:<6/60 vision , 1.3 logMAR in both eyes or equivalent as defined by trial)

Subgroups: Gestational age less than 26 weeks greater than or equal to 26 weeks Inborn or outborn Use of any antenatal corticosteroids = yes if any of the following incomplete, less than 24 hours before birth complete more than 7 days before birth started less than 24h before birth started 24h or more before birth Male or female gender Small for gestation age birth weight below trialist defined cut-point birth weight less than 10th percentile using WHO centile charts Multiple or singleton birth Mode of delivery Vaginal if any of the following: vaginal, vaginal-cephalic, vaginal-breech Caesarean if any of the following: caesarean, caesarean section before onset of labour, caesarean section after onset of labour, caesarean section Time of intervention commencement less than 6 hours after birth 6 hours or more after birth Oximeter calibration software original revised

Askie LM, Brocklehurst P, Darlow BA, Finer N, Schmidt B, Tarnow-Mordi W; NeOProM Collaborative Group. NeOProM: Neonatal Oxygenation Prospective Meta-analysis Collaboration study protocol. BMC Pediatr. 2011 Jan 17;11:6. doi: 10.1186/1471-2431-11-6.

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; Neonatal Oxygenation Prospective Meta-analysis (NeOProM) Collaboration. Association Between Oxygen Saturation Targeting and Death or Disability in Extremely Preterm Infants in the Neonatal Oxygenation Prospective Meta-analysis Collaboration. JAMA. 2018 Jun 5;319(21):2190-2201. doi: 10.1001/jama.2018.5725. Erratum In: JAMA. 2018 Jul 17;320(3):308.