Initial Oxygen Concentration for Preterm Newborn Resuscitation: NLS 5400 TF SR

Conflict of Interest Declaration

The ILCOR Continuous Evidence Evaluation process is guided by a rigorous ILCOR Conflict of Interest policy.

The following Task Force members and other authors declared an intellectual conflict of interest, and this was acknowledged and managed by the Task Force Chairs and Conflict of Interest committees:

• Co-author Schmölzer is a co-author on the NetMotion study {Sotiropoulos 2024 774} and was excluded from decisions about adolopment and bias assessment of this study.
• Co-author Schmölzer is a co-author of one study eligible for inclusion {Law 2021 942} and was excluded from decisions about inclusion and risk of bias assessment for this study.
• The following Task Force members have no conflicts of interest to declare: Helen Liley, Gary Weiner, Anne Lee Solevåg, Jennifer Dawson, Joe Fawke, Daniela Testoni Costa-Nobre, Daniele Trevisanuto.
• The following Content Experts have no conflicts of interest to declare: Daniel Ibarra, Charles Roehr, Jenny Bua, Alex Staffler.

SAC reviewer Yacov Rabi is also co-author on the NetMotion study {Sotiropoulos 774} and has undertaken that any critical comments or recommendations related to that study will be passed to the SAC chair.

CoSTR Citation

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Methodological Preamble and Link to Published Systematic Review

A previous ILCOR systematic review {Welsford 2019 1} reported; “Ten randomized controlled studies and 4 cohort studies included 5697 patients. There are no statistically significant benefits of or harms from starting with lower compared with higher FiO₂ in short-term mortality (n = 968; risk ratio = 0.83 [95% confidence interval 0.50 to 1.37]), long-term mortality, neurodevelopmental impairment, or other key preterm morbidities. A sensitivity analysis in which 1 study with a high RoB was excluded failed to reveal a reduction in mortality with initial low FiO₂ (n = 681; risk ratio = 0.63 [95% confidence interval 0.38 to 1.03])”.

As a result of these findings, the Task Force recommended that; “We suggest starting with a lower oxygen concentration (21-30%) compared to higher oxygen concentration (60-100%) for preterm (<35 weeks’ gestation) newborns who receive respiratory support at birth with subsequent titration of oxygen concentration using pulse oximetry (weak recommendation, very low certainty of evidence. {Soar 2019 e826}

Since publication of the 2019 ILCOR systematic review, an individual patient data network meta-analysis (IPD NWMA) {Sotiropoulos 2024 774} has been published. NetMotion included 8 {Armanian 2012 25, Boronat 2016 e 20161405, Kapadia 2013 e1488, Lundstrøm 1995 F81, Oei 2017 26, Rabi 2011 e374, Vento 2009 e439, Wang 2008 1083} of the 12 RCTs included in {Welsford 2019 1} and 4 additional trials. {Dekker 2019 10.3389/fped.2019.00504, Finer 2018 , Kaban 2022 104, Liyakat 2023 794} NetMotion obtained patient data for 1055 infants and concluded that; “High initial FiO2 (0.90) may be associated with reduced mortality in preterm infants born at less than 32 weeks’ gestation compared to low initial FiO2 (low certainty). High initial FiO2 is possibly associated with reduced mortality compared to intermediate initial FiO2 (very low certainty) but more evidence is required”.

Three of the 4 additional trials included in NetMotion were not published at the time of the previous ILCOR systematic review. {Dekker 2019 10.3389/fped.2019.00504, Kaban 2022 104, Liyakat 2023 794} For an additional study, the NetMotion investigators obtained unpublished results (not eligible for inclusion in the ILCOR systematic review) from study authors. {Finer 2018 } To avoid duplication of results, one additional trial that enrolled 42 infants was not included in the previous ILCOR systematic review, {Escrig 2008 875} because it was a pilot/feasibility study and most data were reported in a subsequent larger trial that was included in the review. {Vento 2009 e439}

The previous ILCOR systematic review {Welsford 2019 1} also included 4 observational studies {Dawson 2009 F87, Kapadia 2017 35, Rabi 2015 252, Soraisham 2017 1141} that were ineligible for NetMotion. {Sotiropoulos 2023 372}

Due to the discordance between the conclusions of these two systematic reviews (conducted at different times and using different methods) the Task Force concluded that an updated ILCOR systematic review was required, to consider three types of evidence:

1. Evidence from eligible randomized controlled trials included in {Welsford 2019 1} and any published since the last search date for that review (10th August 2018).
2. Evidence from large (preferably population-based) observational studies that is adjudicated using GRADE methods to provide similar or higher certainty of evidence to the RCTs.
3. Results of the IPD NWMA NetMotion {Sotiropoulos 2024 774}, by adolopment, considering the evidence therein but using it to develop the Task Force’s own conclusions about the Consensus on Science and Treatment recommendations, in combination with the evidence from study level metanalysis of RCTs and observational studies.

Systematic Review

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PICOST

The PICOST (Population, Intervention, Comparator, Outcome, Study Designs and Timeframe)

Population: Newborn infants <35 weeks’ estimated gestational age who receive respiratory support at delivery.

Intervention: Lower initial oxygen concentration (FiO2 ≤0.5).

Comparators: Higher initial oxygen concentration (FiO2 >0.5).

Outcomes:

• All-cause mortality in-hospital or 28 days (critical);
• All-cause mortality before 1-3 years (critical)
• Neurodevelopmental impairment at 1 to 3 years of age (critical);
• Major intraventricular hemorrhage (IVH) (grade III or IV) (critical);
• Retinopathy of prematurity (critical);
• Necrotizing enterocolitis stage II or III (critical);
• Bronchopulmonary dysplasia (Chronic Neonatal Lung Disease) (important);
• Number with heart rate (HR) > 100 at 5 mins; time from birth to SpO2 ≥80% (important);
• Advanced resuscitation (chest compressions with or without epinephrine (adrenaline)) (important).

Study Designs: Randomized controlled trials (RCTs) and non-randomized studies (non-randomized controlled trials, interrupted time series, controlled before-and-after studies, cohort studies) were eligible for inclusion. Individual patient data systematic reviews were eligible for inclusion. As previous reviews have found sufficient randomized trials and cohort studies to draw conclusions, case series were excluded. Unpublished studies (e.g., conference abstracts, trial protocols) were excluded. Animal studies were excluded. All relevant publications in any language were included as long as there is an English abstract.

Timeframe: Since August 10^th, 2018 (last date of literature review for previous Systematic Review on this question). The literature search was done on August 7^th, 2024.

PROSPERO Registration CRD42017080475

DEFINITIONS

Neurodevelopmental impairment; as defined by study authors but including at least 1 of the following (categorized by severity, based on standardized tests):

• cerebral palsy
• motor impairment other than cerebral palsy
• cognitive impairment
• visual impairment
• hearing impairment

Intraventricular hemorrhage:

• Graded according to criteria of Papile et al. {Papile 1978 529}

Retinopathy of prematurity:

• Severity as defined in the International Classification of Retinopathy of Prematurity {Chiang 2021 e51} or on the basis of whether the infant received intravitreal or surgical treatment

Necrotizing enterocolitis (NEC) stage II or III

• defined as modified Bell’s stage II (pneumatosis) or III (surgical) {Patel 2020 10}

Bronchopulmonary dysplasia (BPD) or Chronic Neonatal Lung Disease (CNLD)

• As defined by the Eunice Kennedy Shriver National Institute of Child Health and Human Development {Jobe 2001 1723} or
• As defined by study authors
• Or on the basis of receiving supplemental oxygen at 36 weeks’ corrected gestational age

Time to heart rate (HR) >100 beats per minute from birth (time measured from birth)

• if not available, HR (expressed as mean [SD] or median [interquartile range (IQR)]) at 1, 5, and/or 10 minutes

Time from birth to SpO2 ≥80% (time measured from birth)

• if not available, SpO2 at 5 minutes from birth or proportion of infants with SpO2 ≥80% at 5 minutes

Advanced resuscitation (chest compressions with or without epinephrine (adrenaline)

A PRIORI SUBGROUPS

Gestational age:

• preterm 28-34+6 weeks gestation
• <28 weeks

Level of initial supplemental oxygen delivered:

• 21% (ambient air)
• >21% to 30%
• 31% to 50%
• 66% to 80%
• 81% to <100%
• 100%

Oxygen saturation targeting:

• No explicit saturation targeting
• Oxygen saturation targeting as an integral part of the study methods

Umbilical cord management method

• Immediate cord clamping
• Deferred/delayed cord clamping
• Umbilical cord milking or stripping

A sensitivity analysis will also be conducted by high vs low risk of bias

RISK OF BIAS

• Randomized controlled trials were assessed using the Cochrane Risk of Bias 2 instrument for each outcome {Sterne 2019 l4898}
• Observational non-randomized studies were assessed using the ROBINS-I tool for each study {Sterne 2016 i4919}
• The NetMotion IPD NWMA was evaluated using the AMSTAR2 checklist {Shea 2017 j4008}. We concluded that the NETMOTION IPD NWMA was of overall high quality. Shortcomings included a lack of information about the included studies as the paper did not report individual study outcomes, funding etc. The authors did not justify including only RCTs and only papers written in English and did not provide a list of excluded studies. (The study level meta-analysis also excluded papers not written in English and no additional non-RCTs were found).

NetMotion used IPD which allowed adjustment for various important modifiers such as gestation at birth and birthweight, so should have greater precision of estimates than the study-level meta-analysis. {Sotiropoulos 2023 372} There is such extensive overlap of included data that it is unlikely that differences in the results of NetMotion and the updated study level meta-analysis are accounted for by study exclusions. Of note, there is some indirectness of NetMotion compared to our PICOST, because it included only infants <32 weeks' gestation, and therefore does not inform a decision about infants 32 to 34+6 weeks' gestation. However, for infants <32 weeks' gestation, the results were considered by the Task Force to be more precise than those of the study level meta-analysis even though the overall certainty of evidence was similar.

Consensus on Science

The IPD NWMA NetMotion {Sotiropoulos 2024 774} evaluated 1055 infants from 12 out of 13 eligible studies (one study omitted because individual patient data could not be obtained from study authors). {Aguar 2013 , Dekker 2019 10.3389/fped.2019.00504, Escrig 2008 875, Finer 2018 , Kapadia 2017 35, Liyakat 2023 794, Oei 2017 26, Rabi 2011 e374, Rook 2014 1322, Vento 2009 e439, Wang 2008 1083}

The study-level meta-analysis (new search plus studies included in {Welsford 2019 1}) identified 16 studies reporting RCTs involving 1804 infants. {Aguar 2013 , Armanian 2012 25, Boronat 2016 e 20161405, Dekker 2019 10.3389/fped.2019.00504, Harling 2005 F401, Kaban 2022 104, Kapadia 2013 e1488, Kapadia 2017 35, Law 2021 942, Liyakat 2023 794, Lundstrøm 1995 F81, Oei 2017 26, Rabi 2011 e374, Rook 2014 1322, Thamrin 2018 55, Vento 2009 e439, Wang 2008 1083}

The updated systematic literature search identified for inclusion in the study-level meta-analysis the 3 RCTs that had been included in NetMotion {Sotiropoulos 2024 774}) that had been published after the previous ILCOR systematic review. {Welsford 2019 1} The search found one additional RCT {Law 2021 942}) which had not been included in NetMotion because it was cluster-randomized. The study-level meta-analysis therefore included 1289 infants (compared to the 1007 included in the previous ILCOR meta-analysis. {Welsford 2019 1} Of the included studies, three reported aspects of a single two-country trial {Aguar 2013 , Boronat 2016 e 20161405, Rook 2014 1322}, one included most data from a previous pilot study {Escrig 2008 875, Vento 2009 e439}, and one reported neurodevelopmental follow-up data and late mortality {Thamrin 2018 55} from another trial. {Oei 2017 26}

From the individual patient network meta-analysis:

For the critical primary outcome of all-cause mortality (in hospital or by 28 days) the NetMotion IPD NWMA) compared low (≤0.3), intermediate (0.5-0.65) and high (≥0.9) initial FiO2. {Sotiropoulos 2024 774, Sotiropoulos 2023 372}

• High initial FiO2 (≥ 0.90) reduced all-cause mortality (in-hospital or within 28 days) compared to low initial FiO2 (0.21-0.30) (adjusted odds ratio (aOR) 0.45, 95% credible interval (CrI) 0.23-0.86, number needed to benefit (NNTB) 16 (95% CrI 10-66) ARD 67 more infants per 1000 survived with high initial FiO2 (95% CrI 15 more to 100 more), low certainty evidence from direct comparison of 833 patients included in 8 studies. {Dekker 2019 10.3389/fped.2019.00504, Kapadia 2013 e1488, Liyakat 2023 794, Oei 2017 26, Rabi 2011 e374, Vento 2009 e439, Wang 2008 1083}
• For intermediate initial FiO2 (0.50-0.65) compared to low FiO2 (0.21-0.30) clinical benefit or harm could not be excluded (aOR 1.33, 95% CrI 0.54-3.15), very low certainty evidence from direct comparison of 352 participants in 4 studies. {Aguar 2013 , Finer 2018 , Kaban 2022 104, Rook 2014 1322}
• For high (≥0.90) compared to intermediate initial FiO2 (0.50-0.65) there was possible clinical benefit (aOR 0.34; 95% CrI 0.11-0.99; NNTB 11; 95% CrI, 4-1514) very low certainty evidence from an indirect comparison. (No studies compared high vs intermediate FiO2). {Sotiropoulos 2024 774}

The prediction intervals (i.e., range between which results of a future study would be expected to fall) crossed the line of no effect for the high vs. low comparison (prediction interval 0.44, 95%CrI 0.15-1.34) and high vs. intermediate comparison (prediction interval 0.33, 95% CrI 0.08-1.40), which was considered to be evidence of inconsistency and thereby reduced certainty of evidence. {Sotiropoulos, 2024 #1}

For the critical outcome of severe intraventricular hemorrhage clinical benefit or harm could not be excluded (OR 0.56, 95% CrI 0.10-1.82), very low certainty evidence from 809 infants included in 8 studies. {Dekker 2019 10.3389/fped.2019.00504, Escrig 2008 875, Kapadia 2013 e1488, Liyakat 2023 794, Oei 2017 26, Rabi 2011 e374, Vento 2009 e439, Wang 2008 1083}

For the following important outcomes, the comparison between high (>0.90) and low (≤0.30) FiO2 could not exclude benefit or harm (in each case, the evidence was of very low certainty):

• chronic lung disease (aOR 1.17, 95% CrI 0.55-2.52) from 783 infants included in 8 studies {Dekker 2019 10.3389/fped.2019.00504, Escrig 2008 875, Kapadia 2013 e1488, Liyakat 2023 794, Oei 2017 26, Rabi 2011 e374, Vento 2009 e439, Wang 2008 1083}
• retinopathy of prematurity (OR 1.17, 95% CrI 0.58-2.20), 767 infants included in 8 studies {Dekker 2019 10.3389/fped.2019.00504, Escrig 2008 875, Kapadia 2013 e1488, Liyakat 2023 794, Oei 2017 26, Rabi 2011 e374, Vento 2009 e439, Wang 2008 1083}

The comparisons between high (>0.90) and intermediate (0.50 to 0.65) FiO2 included 483, 519 and 480 infants respectively from 4 included studies and have even greater imprecision due to smaller numbers of included infants, so are not presented. {Sotiropoulos 2024 774}

Other critical and important outcomes of the PICOST were not reported.

From the study-level meta-analysis:

Comparison of lower initial oxygen concentration (FiO2 ≤0.5) to higher initial oxygen concentration (FiO2>0.5)

• For the critical primary outcome of all-cause mortality (in hospital or by 28 days) clinical benefit or harm could not be excluded (Relative risk (RR); 1.12, 95% confidence intervals (95% CI); 0.84 to 1.49), very low certainty evidence from 1289 infants included in 14 RCTs {Aguar 2013 , Armanian 2012 25, Dekker 2019 10.3389/fped.2019.00504, Harling 2005 F401, Kaban 2022 104, Kapadia 2013 e1488, Law 2021 942, Liyakat 2023 794, Lundstrøm 1995 F81, Oei 2017 26, Rabi 2011 e374, Rook 2014 1322, Vento 2009 e439, Wang 2008 1083} The certainty of evidence was downgraded for risk of bias and very serious imprecision.
• For the critical secondary outcome of long term all-cause mortality (1-3 years) clinical benefit or harm could not be excluded (RR 1.04, 95% CI 0.42-2.58) very low certainty evidence from 515 infants included in 2 RCTs. {Boronat 2016 e 20161405, Thamrin 2018 55} The certainty of evidence was downgraded for serious risk of bias and very serious imprecision. (These results are essentially the same as those reported in the previous ILCOR systematic review, but are replicated with updated assessment using Cochrane RoB2 and GRADE CoE, and using the denominator of infants included in each study, rather than the denominator of only those for whom follow-up was achieved).
• For the critical secondary outcome of neurodevelopmental impairment (1-3 years) clinical benefit or harm could not be excluded (RR;1.14, 95% 95% CI; 0.78 to 1.67), very low certainty evidence from 389 infants who were able to be followed up from 2 RCTs. {Boronat 2016 e 20161405, Thamrin 2018 55} The certainty of evidence was downgraded for risk of bias and very serious imprecision. (These results are essentially the same as those reported in the previous ILCOR systematic review, but are replicated with updated assessment using Cochrane RoB2 and GRADE CoE).
• For the critical secondary outcome of major IVH (grade III or IV) clinical benefit or harm could not be excluded (RR; 1.10, 95%; 0.81 to 1.49), very low certainty evidence from 1129 infants included in 11 RCTs. {Boronat 2016 e 20161405, Dekker 2019 10.3389/fped.2019.00504, Harling 2005 F401, Kaban 2022 104, Kapadia 2013 e1488, Law 2021 942, Liyakat 2023 794, Lundstrøm 1995 F81, Oei 2017 26, Vento 2009 e439, Wang 2008 1083} The certainty of evidence was downgraded for very serious risk of bias and for imprecision.
• For the critical secondary outcome of severe retinopathy of prematurity clinical benefit or harm could not be excluded (RR; 1.06, 95% CI; 0.62 to 1.82), very low certainty evidence from 1046 infants included in 9 RCTs. {Boronat 2016 e 20161405, Harling 2005 F401, Kaban 2022 104, Kapadia 2013 e1488, Law 2021 942, Liyakat 2023 794, Lundstrøm 1995 F81, Oei 2017 26, Vento 2009 e439} The certainty of evidence was downgraded for risk of bias and very serious imprecision.
• For the critical secondary outcome of necrotizing enterocolitis (grade 2 or 3) clinical benefit or harm could not be excluded (RR; 1.07, 95% CI; 0.58 to 2.00), very low certainty evidence from 1007 infants included in 9 RCTs. {Boronat 2016 e 20161405, Harling 2005 , Kaban 2022 104, Kapadia 2013 e1488, Law 2021 , Liyakat 2023 794, Lundstrøm 1995 , Oei 2017 26, Vento 2009 e439} The certainty of evidence was downgraded for very serious risk of bias and very serious imprecision.
• For the important secondary outcome of bronchopulmonary dysplasia clinical benefit or harm could not be excluded (RR; 1.04, 95% CI; 0.70 to 1.56), very low certainty evidence from 921 infants included in 8 RCTs. {Boronat 2016 e 20161405, Harling 2005 F401, Kaban 2022 104, Kapadia 2013 e1488, Law 2021 942, Lundstrøm 1995 F81, Oei 2017 26, Vento 2009 e439} The certainty of evidence was downgraded for very serious risk of bias, inconsistency and very serious imprecision.
• For the important secondary outcome of advanced resuscitation (chest compressions with or without epinephrine (adrenaline)) clinical benefit or harm could not be excluded (RR; 0.84, 95% CI; 0.24 to 2.90), very low certainty evidence from 772 infants included in 7 RCTs {Escrig 2008 875, Kaban 2022 104, Kapadia 2013 e1488, Liyakat 2023 794, Oei 2017 26, Rabi 2011 e374, Wang 2008 1083} The certainty of evidence was downgraded for serious risk of bias, and extremely serious imprecision.
• For other important outcomes of the review, they were not reported or there was insufficient evidence for meaningful analysis (e.g. outcome reported in only one small study with high risk of bias for the outcome).

OBSERVATIONAL STUDIES

There were no new observational studies found for inclusion in this updated review. The previous ILCOR systematic review included 4 observational studies and reported for long-term mortality that "two observational cohort studies involving 1225 preterm newborns receiving respiratory support at birth revealed a statistically significant benefit of starting with lower compared to higher FiO2 (RR 0.77, 95% CI 0.59 to 0.99; I 2 =6%)". {Kapadia 2017 35, Soraisham 2017 1141} These studies were deemed to be at "unclear" overall risk of bias using ROBINS-I assessment. {Welsford 2019 1}

For neurodevelopmental impairment, two studies including 930 infants "revealed no statistically significant difference in starting with lower compared with higher FiO2 (RR = 0.89 [95% CI 0.66 to 1.20]; I2 = 59%. {Kapadia 2017 35, Soraisham 2017 1141} These studies were deemed to be at "unclear" overall risk of bias using ROBINS-I assessment {Welsford 2019 1}

SUBGROUP CONSIDERATIONS

From the individual patient network meta-analysis:

The authors noted that in regard to pre-specified subgroup analysis for the NetMotion study “there was no evidence of differential effects of treatment across gestational ages or according to infant sex (post hoc, primary outcome only) when examining treatment-covariate interactions” and that there was limited statistical power to detect such interactions. {Sotiropoulos 2024 774} The authors of that study also reported that there was an insufficient number of trials and participants from low-or middle-income countries to perform prespecified subgroup analysis according to country income classification and the considered that oxygen concentration titration strategies were too heterogenous to explore faster vs slower titration. {Sotiropoulos 2024 774}

From the study-level meta-analysis:

Oxygen level use for low oxygen group and titration strategy:

Most studies included detailed provisions for titrating or changing FiO2 depending on response to oxygen saturation (SpO2) measured using pulse oximetry and utilizing early and frequent observations and adjustments. The remaining studies had provisions for crossover or adjustments in certain circumstances, or after a specified time interval. It seems likely that the better the adherence to these strategies, the greater the likelihood that any differential in study outcomes between high and low initial oxygen concentrations would be reduced. However, the effect on short-term mortality of low oxygen vs high oxygen in those studies that used no or late titration (RR 1.10, 95% CI 0.81 to 1.60) {Harling 2005 F401, Law 2021 942, Liyakat 2023 794, Rabi 2011 e374, Wang 2008 1083} was very similar to that in studies that used early titration (RR 1.25, 95% CI 0.65-2.40). {Armanian 2012 25, Boronat 2016 e 20161405, Dekker 2019 10.3389/fped.2019.00504, Kaban 2022 104, Kapadia 2013 e1488, Lundstrøm 1995 F81, Oei 2017 26, Rabi 2011 e374, Vento 2009 e439} The test for subgroup differences was not significant: Chi2 = 0.14 df = 1, p = 0.71 I2 = 0%.

(Note that in this comparison, one study is included twice and the low FiO2 group is represented twice because it was a 3-arm study, one high FiO2 group with titration (managed by the study investigator) and one with no titration. {Rabi 2011 e374}).

One trial compared FiO2 0.30 to 0.50, both of which are within our definition of "low", and the difference between these oxygen concentrations may have been small enough to mask an overall difference between low and high. {Kaban 2022 104} However, removing this trial from the analysis resulted in confidence intervals that still crossed the line of no effect.

For short term mortality, there was also no apparent influence of the level of oxygen used in the low oxygen group; with effect sizes being:

• RR 1.12, 95% CI 0.76 to1.64 for studies that used FiO2 0.21 as the low oxygen group. {Kapadia 2013 e1488, Liyakat 2023 794, Lundstrøm 1995 F81, Oei 2017 26, Rabi 2011 e374, Wang 2008 1083}
• RR 1.46 95% CI 0.73 to 2.88 for studies that used FiO2 0.30 as the low oxygen group {Aguar 2013 , Armanian 2012 25, Dekker 2019 10.3389/fped.2019.00504, Kaban 2022 104, Law 2021 942, Rook 2014 1322, Vento 2009 e439}
• RR 0.80 95% CI 0.24 to 2.65 for the one study that used FiO2 0.50 as the low oxygen group. {Harling 2005 F401}

The test for subgroup differences was not significant: Chi2 = 11.76, df = 11, p = 0.47, I2 = 0%.

Thus, for short term mortality, the results did not show differences by or pre-specified subgroup analyses, (or by gestation - see Subgroup Considerations below).

For short term mortality, in our study-level post-hoc analysis by NetMotion subgroups:

• RR 1.73, 95%CI 0.53-5.58 for studies that compared intermediate vs low initial FiO2 (0.5-0.65 vs ≤0.3) {Aguar 2013 , Harling 2005 F401, Kaban 2022 104, Law 2021 942, Rook 2014 1322}
• RR 1.29 95% CI 0.89 to 1.87 for studies that used high vs low initial FiO2 (≥0.9 vs ≤0.3) {Armanian 2012 25, Dekker 2019 10.3389/fped.2019.00504, Kapadia 2013 e1488, Liyakat 2023 794, Oei 2017 26, Rabi 2011 e374, Vento 2009 e439, Wang 2008 1083}

The test for subgroup differences was not significant; Chi2 = 0.21, df = 1, p = 0.65 I2 = 0%

Gestation groups

The effect size for short term mortality was similar for studies reporting infants (or subgroups) < 28 weeks' (or mostly <28 weeks') gestation or 28 to 34+6 weeks' gestation.

• <28 weeks' gestation RR 1.67 95% CI 0.88 to 3.15 {Escrig 2008 875, Law 2021 942, Oei 2017 26, Vento 2009 e439}
• 28 to 34+6 weeks gestation RR 1.19 95% CI 0.77 to 1.83 {Armanian 2012 25, Liyakat 2023 794, Oei 2017 26}

The test for subgroup differences was not significant; Chi2 = 0.75, df = 1, p = 0.339, I2 = 0%.

Note - one study is listed twice because a breakdown was provided by gestation subgroups. {Oei 2017 26} For the higher gestation group, the analysis attached heavy weighting to a study done in a low-resource setting where no titration of oxygen was possible and overall mortality was high. {Liyakat 2023 794}

Method of umbilical cord management

There were insufficient data distinguishing infants by method of umbilical cord management to conduct this preplanned subgroup analysis.

Treatment Recommendations

Among newborn infants <32 weeks’ gestation, it is reasonable to begin resuscitation with more than 30% oxygen. (Weak recommendation, low COE).

For infants born at 32 to 34+6 weeks' gestation, there is insufficient evidence to make a recommendation.

Subsequent titration of oxygen concentration using pulse oximetry is advised. (Weak recommendation, very low certainty evidence).

The uncertainty over the optimal initial oxygen concentration means that it is reasonable to study a full range of oxygen concentrations (21-100%) within a research protocol.

Justification and Evidence to Decision Framework Highlights

The previous ILCOR treatment recommendation (2020) was:

We suggest starting with a lower oxygen concentration (21-30%) compared to higher oxygen concentration (60-100%) for preterm (<35 weeks’ gestation) newborns who receive respiratory support at birth with subsequent titration of oxygen concentration using pulse oximetry (weak recommendation, very low certainty of evidence). {Soar 2019 e826}

This was based on (1) evidence from RCTs appraised at the time that for all critical and important outcomes of the review, there was no benefit or harm of using either lower or higher oxygen concentrations for commencing resuscitation, (2) evidence from observational studies suggesting benefit of lower oxygen concentrations for long term mortality and (3) the evidence from "decades of research (that) demonstrate that oxygen exposure is a determinant of critical neonatal outcomes in preterm infants. Concern remains that oxygen concentrations to which preterm infants are exposed if they need resuscitation immediately after birth may be a critical contributor to outcomes regardless of subsequent oxygen exposure". {Soar 2019 e826}

The NetMotion individual patient network meta-analysis, the evidence from which was included by adolopment, suggested benefit of higher concentrations and that 90-100% may result in the lowest mortality. {Sotiropoulos 2024 774} However, the Task Force concluded that the overall certainty of evidence was very low, mainly because of concerns that the total sample for each comparison was substantially below the optimal information size for all outcomes. The updated study-level meta-analysis found that benefit or harm could not be excluded for lower vs. higher concentrations of oxygen for commencing resuscitation, with low certainty of evidence for all outcomes.

Concerns persist regarding unmeasured adverse effects of hyperoxia and hypoxia, and most very preterm infants whose resuscitation has started in 21% or 100% will need prompt adjustments of inspired oxygen concentration, and as a result, two pending multicenter trials are utilizing 30% vs 60% oxygen for their treatment arms.

Whichever initial oxygen concentration was used, oxygen saturation monitoring and individualized adjustments of inspired oxygen concentration were used in most of the clinical trials and are likely to be needed to optimize outcomes.

Knowledge Gaps

• Human factors aspects of resuscitation performance depending on initial oxygen concentration for commencing resuscitation.

• Comparison of targets and strategies for oxygen saturation levels in the first 10-20 min after birth in preterm infants.

• Optimal oxygen concentration for commencing resuscitation in preterm newborn infants (noting that two trials comparing FiO2's of 0.30 to 0.60 are expected).

• Effect of initial oxygen concentrations and titration strategies on biomarkers of both hypoxic and hyperoxic injury to organs including the brain, lungs and retina.

ETD summary table

References

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Boronat N, Aguar M, Rook D, Iriondo M, Brugada M, Cernada M, et al. Survival and Neurodevelopmental Outcomes of Preterms Resuscitated With Different Oxygen Fractions. Pediatrics. 2016;138(6)e 20161405.

Chiang MF, Quinn GE, Fielder AR, Ostmo SR, Paul Chan RV, Berrocal A, et al. International Classification of Retinopathy of Prematurity, Third Edition. Ophthalmology. 2021;128(10)e51-e68.

Dawson JA, Kamlin CO, Wong C, te Pas AB, O'Donnell CP, Donath SM, et al. Oxygen saturation and heart rate during delivery room resuscitation of infants <30 weeks' gestation with air or 100% oxygen. Arch Dis Child Fetal Neonatal Ed. 2009;94(2)F87-91.

Dekker J, Martherus T, Lopriore E, Giera M, McGillick EV, Hutten J, et al. The Effect of Initial High vs. Low FiO2 on Breathing Effort in Preterm Infants at Birth: A Randomized Controlled Trial. Frontiers in Pediatrics. 2019;7.

Escrig R, Arruza L, Izquierdo I, Villar G, Saenz P, Gimeno A, et al. Achievement of targeted saturation values in extremely low gestational age neonates resuscitated with low or high oxygen concentrations: a prospective, randomized trial. Pediatrics. 2008;121(5)875-81.

Finer N, Vento M, Saugstad OD. Study of room air versus 60%oxygen for resuscitation of premature infants (PRESOX). NCT01773746 2018 [

Harling AE, Beresford MW, Vince GS, Bates M, Yoxall CW. Does the use of 50% oxygen at birth in preterm infants reduce lung injury? Arch Dis Child Fetal Neonatal Ed. 2005;90(5)F401-5.

Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2001;163(7)1723-9.

Kaban RK, Aminullah A, Rohsiswatmo R, Hegar B, Sukadi A, Davis PG. Resuscitation of very preterm infants with 30% vs. 50% oxygen: a randomized controlled trial. Paediatrica Indonesiana. 2022;62(2)104-114.

Kapadia VS, Chalak LF, Sparks JE, Allen JR, Savani RC, Wyckoff MH. Resuscitation of preterm neonates with limited versus high oxygen strategy. Pediatrics. 2013;132(6)e1488-96.

Kapadia VS, Lal CV, Kakkilaya V, Heyne R, Savani RC, Wyckoff MH. Impact of the Neonatal Resuscitation Program-Recommended Low Oxygen Strategy on Outcomes of Infants Born Preterm. J Pediatr. 2017;19135-41.

Law BHY, Asztalos E, Finer NN, Yaskina M, Vento M, Tarnow-Mordi W, et al. Higher versus Lower Oxygen Concentration during Respiratory Support in the Delivery Room in Extremely Preterm Infants: A Pilot Feasibility Study. Children (Basel). 2021;8(11).

Liyakat NA, Kumar P, Sundaram V. Room air versus 100% oxygen for delivery room resuscitation of preterm neonates in low resource settings: A randomised, blinded, controlled trial. J Paediatr Child Health. 2023;59(6)794-801.

Lundstrøm KE, Pryds O, Greisen G. Oxygen at birth and prolonged cerebral vasoconstriction in preterm infants. Arch Dis Child Fetal Neonatal Ed. 1995;73(2)F81-6.

Oei JL, Saugstad OD, Lui K, Wright IM, Smyth JP, Craven P, et al. Targeted Oxygen in the Resuscitation of Preterm Infants, a Randomized Clinical Trial. Pediatrics. 2017;139(1)26‐26.

Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr. 1978;92(4)529-34.

Patel RM, Ferguson J, McElroy SJ, Khashu M, Caplan MS. Defining necrotizing enterocolitis: current difficulties and future opportunities. Pediatr Res. 2020;88(Suppl 1)10-15.

Rabi Y, Lodha A, Soraisham A, Singhal N, Barrington K, Shah PS. Outcomes of preterm infants following the introduction of room air resuscitation. Resuscitation. 2015;96252-9.

Rabi Y, Singhal N, Nettel-Aguirre A. Room-air versus oxygen administration for resuscitation of preterm infants: the ROAR study. Pediatrics. 2011;128(2)e374-81.

Rook D, Schierbeek H, Vento M, Vlaardingerbroek H, van der Eijk AC, Longini M, et al. Resuscitation of preterm infants with different inspired oxygen fractions. J Pediatr. 2014;164(6)1322-6.e3.

Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran J, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017;358j4008.

Soar J, Maconochie I, Wyckoff MH, Olasveengen TM, Singletary EM, Greif R, et al. 2019 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations: Summary From the Basic Life Support; Advanced Life Support; Pediatric Life Support; Neonatal Life Support; Education, Implementation, and Teams; and First Aid Task Forces. Circulation. 2019;140(24)e826-e880.

Soraisham AS, Rabi Y, Shah PS, Singhal N, Synnes A, Yang J, et al. Neurodevelopmental outcomes of preterm infants resuscitated with different oxygen concentration at birth. J Perinatol. 2017;37(10)1141-1147.

Sotiropoulos JX, Oei JL, Schmölzer GM, Libesman S, Hunter KE, Williams JG, et al. Initial Oxygen Concentration for the Resuscitation of Infants Born at Less Than 32 Weeks' Gestation: A Systematic Review and Individual Participant Data Network Meta-Analysis. JAMA Pediatr. 202410.1001/jamapediatrics.2024.1848.

Sotiropoulos JX, Schmolzer GM, Oei JL, Libesman S, Hunter KE, Williams JG, et al. PROspective Meta-analysis Of Trials of Initial Oxygen in preterm Newborns (PROMOTION): Protocol for a systematic review and prospective meta-analysis with individual participant data on initial oxygen concentration for resuscitation of preterm infants. Acta Paediatr. 2023;112(3)372-382.

Sterne JA, Hernan MA, Reeves BC, Savovic J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355i4919.

Sterne JAC, Savovic J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366l4898.

Thamrin V, Saugstad OD, Tarnow-Mordi W, Wang YA, Lui K, Wright IM, et al. Preterm Infant Outcomes after Randomization to Initial Resuscitation with FiO2 0.21 or 1.0. Journal of Pediatrics. 2018;20155‐61.e1.

Vento M, Moro M, Escrig R, Arruza L, Villar G, Izquierdo I, et al. Preterm resuscitation with low oxygen causes less oxidative stress, inflammation, and chronic lung disease. Pediatrics. 2009;124(3)e439-49.

Wang CL, Anderson C, Leone TA, Rich W, Govindaswami B, Finer NN. Resuscitation of preterm neonates by using room air or 100% oxygen. Pediatrics. 2008;121(6)1083-9.

Welsford M, Nishiyama C. Initial Oxygen Use for Preterm Newborn Resuscitation: A Systematic Review With Meta-analysis. Pediatrics. 2019;143(1)1-17.

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Appendix: Literature searches

PubMed

("Infant"[Mesh] OR "Premature Birth"[MeSH] OR "Term Birth"[MeSH] OR "Live Birth"[MeSH] OR "Intensive Care, Neonatal"[MeSH] OR "Intensive Care Units, Neonatal"[Mesh] OR "Delivery Rooms"[MeSH] OR "Respiratory Distress Syndrome, Newborn"[MeSH] OR "Asphyxia Neonatorum"[MeSH] OR "Bronchopulmonary Dysplasia"[MeSH] OR "Infant, Premature, Diseases"[MeSH] OR "Neonatal Nursing"[MeSH] OR "Persistent Fetal Circulation Syndrome"[MeSH] OR "Gestational Age"[MeSH] OR

"delivery room*"[tiab] OR newborn*[tiab] OR new-born*[tiab] OR neonat*[tiab] OR prematur*[tiab] OR preterm[tiab] OR pre-term[tiab] OR infant*[tiab] OR baby[tiab] OR babies[tiab] OR birth[tiab] OR "gestational age"[tiab])

AND

("Resuscitation"[Mesh] OR "Oxygen Inhalation Therapy"[Mesh] OR "Oxygen/administration and dosage"[Mesh] OR resuscitat*[tiab] OR "respiratory support"[tiab:~2] OR "cardiorespiratory support"[tiab:~2] OR "artificial respiration"[tiab:~2] OR "oxygen supplementation"[tiab:~2] OR "supplementing oxygen"[tiab:~2] OR "supplement oxygen"[tiab:~2])

AND
("high oxygen"[tiab:~2] OR "higher oxygen"[tiab:~2] OR "highflow oxygen"[tiab:~2] OR "100% oxygen"[tiab] OR "one hundred percent oxygen"[tiab] OR "100 percent oxygen"[tiab] OR

"high O2"[tiab:~2] OR "higher O2"[tiab:~2] OR "highflow O2"[tiab:~2] OR "100% O2"[tiab] OR "one hundred percent O2"[tiab] OR "100 percent O2"[tiab] OR

"high O(2)"[tiab:~2] OR "higher O(2)"[tiab:~2] OR "highflow O(2)"[tiab:~2] OR "100% O(2)"[tiab] OR "one hundred percent O(2)"[tiab] OR "100 percent O(2)"[tiab] OR

"high Fio2"[tiab:~2] OR "higher Fio2"[tiab:~2] OR "highflow Fio2"[tiab:~2] OR "100% Fio2"[tiab] OR "one hundred percent Fio2"[tiab] OR "100 percent Fio2"[tiab] OR

((Air[MeSH] OR "room air"[tiab]) AND (oxygen[tiab] OR O2[tiab] OR "O(2)"[tiab] OR Fio2[tiab])) OR

"low oxygen"[tiab:~2] OR "lower oxygen"[tiab:~2] OR "limited oxygen" [tiab:~2] OR "reduced oxygen" [tiab:~2] OR "reduction oxygen" [tiab:~2] OR

"low O2"[tiab:~2] OR "lower O2"[tiab:~2] OR "limited O2" [tiab:~2] OR "reduced O2" [tiab:~2] OR "reduction O2" [tiab:~2] OR

"low O(2)"[tiab:~2] OR "lower O(2)"[tiab:~2] OR "limited O(2)" [tiab:~2] OR "reduced O(2)" [tiab:~2] OR "reduction O(2)" [tiab:~2] OR

"low Fio2"[tiab:~2] OR "lower Fio2"[tiab:~2] OR "limited Fio2" [tiab:~2] OR "reduced Fio2" [tiab:~2] OR "reduction Fio2" [tiab:~2] OR

"oxygen concentration"[tiab:~2] OR "oxygen concentrations"[tiab:~2] OR "oxygen fraction"[tiab:~2] OR "oxygen fractions"[tiab:~2] OR "target oxygen"[tiab:~2] OR "targets oxygen"[tiab:~2] OR "targeted oxygen"[tiab:~2] OR "oxygen saturation"[tiab:~2] OR
"optimal oxygen"[tiab:~2] OR "oxygen differences"[tiab:~2] OR

"O2 concentration"[tiab:~2] OR "O2 concentrations"[tiab:~2] OR "O2 fraction"[tiab:~2] OR "O2 fractions"[tiab:~2] OR "target O2"[tiab:~2] OR "targets O2"[tiab:~2] OR "targeted O2"[tiab:~2] OR
"O2 saturation"[tiab:~2] OR "optimal O2"[tiab:~2] OR "O2 differences"[tiab:~2] OR

"O(2) concentration"[tiab:~2] OR "O(2) concentrations"[tiab:~2] OR "O(2) fraction"[tiab:~2] OR "O(2) fractions"[tiab:~2] OR "target O(2)"[tiab:~2] OR "targets O(2)"[tiab:~2] OR "targeted O(2)"[tiab:~2] OR "O(2) saturation"[tiab:~2] OR "optimal O(2)"[tiab:~2] OR "O(2) differences"[tiab:~2] OR

"Fio2 concentration"[tiab:~2] OR "Fio2 concentrations"[tiab:~2] OR "Fio2 fraction"[tiab:~2] OR "Fio2 fractions"[tiab:~2] OR "target Fio2"[tiab:~2] OR "targets Fio2"[tiab:~2] OR "targeted Fio2"[tiab:~2] OR "Fio2 saturation"[tiab:~2] OR "optimal Fio2"[tiab:~2] OR "Fio2 differences"[tiab:~2]

)
NOT (animals[MeSH] NOT humans[MeSH])

NOT (letter[pt] OR comment[pt] OR editorial[pt] OR "case reports"[pt] OR congress[pt] OR "clinical conference"[pt])

AND 2018/08/01:2024/12/31 [crdt]

MEDLINE (Ovid)

(exp "Infant"/ OR exp "Premature Birth"/ OR exp "Term Birth"/ OR exp "Live Birth"/ OR exp "Intensive Care, Neonatal"/ OR exp "Intensive Care Units, Neonatal"/ OR exp "Delivery Rooms"/ OR exp "Respiratory Distress Syndrome, Newborn"/ OR exp "Asphyxia Neonatorum"/ OR exp "Bronchopulmonary Dysplasia"/ OR exp "Infant, Premature, Diseases"/ OR exp "Neonatal Nursing"/ OR exp "Persistent Fetal Circulation Syndrome"/ OR exp "Gestational Age"/ OR "delivery room*".tw. OR newborn*.tw. OR new-born*.tw. OR neonat*.tw. OR prematur*.tw. OR preterm.tw. OR pre-term.tw. OR infant*.tw. OR baby.tw. OR babies.tw.OR birth.tw. OR "gestational age".tw.)
AND

(exp Resuscitation/ OR exp "Oxygen Inhalation Therapy"/ OR exp "Oxygen"/ad OR resuscitat*.tw. OR (respiratory ADJ3 support).tw. OR (cardiorespiratory ADJ3 support).tw. OR (artificial ADJ3 respiration).tw. OR (oxygen ADJ3 supplement*).tw.)

AND
(

((high OR higher OR highflow OR 100% OR "one hundred percent" OR "100 percent" OR low OR lower OR limited OR reduced OR reduction OR concentration OR concentrations OR fraction OR fractions OR target OR targets OR targeted OR saturation OR optimal OR differences) ADJ3 (oxygen OR O2 OR "O(2)" OR Fio2)).tw. OR
((exp Air/ OR "room air".tw.) AND (oxygen.tw. OR O2.tw. OR "O(2)".tw. OR Fio2.tw.))

)
NOT (exp animals/ NOT exp humans/)

NOT (letter.pt. OR comment.pt. OR editorial.pt. OR "case reports".pt. OR congress.pt. OR "clinical conference".pt.)

Embase (via Embase.com)

('infant'/exp OR 'prematurity'/exp OR 'term birth'/exp OR 'live birth'/exp OR 'newborn intensive care'/exp OR 'neonatal intensive care unit'/exp OR 'delivery room'/exp OR 'neonatal respiratory distress syndrome'/exp OR 'newborn hypoxia'/exp OR 'lung dysplasia'/exp OR 'newborn nursing'/exp OR 'persistent pulmonary hypertension'/exp OR 'gestational age'/exp OR 'delivery room*':ti,ab OR newborn*:ti,ab OR new-born*:ti,ab OR neonat*:ti,ab OR prematur*:ti,ab OR preterm:ti,ab OR pre-term:ti,ab OR infant*:ti,ab OR baby:ti,ab OR babies:ti,ab OR birth:ti,ab OR 'gestational age':ti,ab)

AND

(resuscitation/exp OR 'oxygen therapy'/exp OR resuscitat*:ti,ab OR (respiratory NEAR/3 support):ti,ab OR (cardiorespiratory NEAR/3 support):ti,ab OR (artificial NEAR/3 respiration):ti,ab OR (oxygen NEAR/3 supplement*):ti,ab)

AND

(

((high OR higher OR highflow OR 100% OR 'one hundred percent' OR '100 percent' OR low OR lower OR limited OR reduced OR reduction OR concentration OR concentrations OR fraction OR fractions OR target OR targets OR targeted OR saturation OR optimal OR differences) NEAR/3 (oxygen OR O2 OR 'O(2)' OR Fio2)):ti,ab OR

(('ambient air'/exp OR 'room air':ti,ab) AND (oxygen:ti,ab OR O2:ti,ab OR 'O(2)':ti,ab OR Fio2:ti,ab))

)
NOT (('animal experiment'/de OR animal/exp) NOT ('human experiment'/de OR 'human'/exp))

NOT ('conference abstract'/it)

AND [embase]/lim

AND [01-08-2018]/sd

CENTRAL (via the Cochrane Library)

([mh "Infant"] OR [mh "Premature Birth"] OR [mh "Term Birth"] OR [mh "Live Birth"] OR [mh "Intensive Care, Neonatal"] OR [mh "Intensive Care Units, Neonatal"] OR [mh "Delivery Rooms"] OR [mh "Respiratory Distress Syndrome, Newborn"] OR [mh "Asphyxia Neonatorum"] OR [mh "Bronchopulmonary Dysplasia"] OR [mh "Infant, Premature, Diseases"] OR [mh "Neonatal Nursing"] OR [mh "Persistent Fetal Circulation Syndrome"] OR [mh "Gestational Age"] OR ("delivery" NEXT room*):ti,ab OR newborn*:ti,ab OR new-born*:ti,ab OR neonat*:ti,ab OR prematur*:ti,ab OR preterm:ti,ab OR pre-term:ti,ab OR infant*:ti,ab OR baby:ti,ab OR babies:ti,ab OR birth:ti,ab OR "gestational age":ti,ab)

AND

([mh Resuscitation] OR [mh "Oxygen Inhalation Therapy"] OR resuscitat*:ti,ab OR (respiratory NEAR/2 support):ti,ab OR (cardiorespiratory:ti,ab NEAR/2 support:ti,ab) OR (artificial:ti,ab NEAR/2 respiration:ti,ab) OR (oxygen:ti,ab NEAR/2 supplement*:ti,ab))

AND

(

((high:ti,ab OR higher:ti,ab OR highflow:ti,ab OR 100%:ti,ab OR "one hundred percent":ti,ab OR "100 percent":ti,ab OR low:ti,ab OR lower:ti,ab OR limited:ti,ab OR reduced:ti,ab OR reduction:ti,ab OR concentration:ti,ab OR concentrations:ti,ab OR fraction:ti,ab OR fractions:ti,ab OR target:ti,ab OR targets:ti,ab OR targeted:ti,ab OR saturation:ti,ab OR optimal:ti,ab OR differences:ti,ab) NEAR/2 (oxygen:ti,ab OR O2:ti,ab OR "O(2)":ti,ab OR Fio2:ti,ab)) OR

(([mh Air] OR "room air":ti,ab) AND (oxygen:ti,ab OR O2:ti,ab OR "O(2)":ti,ab OR Fio2:ti,ab))

)

Limited by 'Date added to CENTRAL trials database' to 01/08/2018 to 31/12/2024

CINAHL (EBSCOHost)

(MH "Infant+" OR MH "Childbirth, Premature" OR MH "Term Birth" OR MH "Childbirth+" OR MH "Intensive Care, Neonatal+" OR MH "Intensive Care Units, Neonatal" OR MH "Delivery Rooms+" OR MH "Respiratory Distress Syndrome, Newborn+" OR MH "Asphyxia Neonatorum" OR MH "Bronchopulmonary Dysplasia" OR MH "Infant, Premature, Diseases+" OR MH "Neonatal Nursing+" OR MH "Persistent Fetal Circulation Syndrome" OR MH "Gestational Age" OR TI "delivery room*" OR AB "delivery room*" OR TI newborn* OR AB newborn* OR TI new-born* OR AB new-born* OR TI neonat* OR AB neonat* OR TI prematur* OR AB prematur* OR TI preterm OR AB preterm OR TI pre-term OR AB pre-term OR TI infant* OR AB infant* OR TI baby OR AB baby OR TI babies OR AB babies OR TI birth OR AB birth OR TI "gestational age" OR AB "gestational age")

AND

(MH "Resuscitation+" OR MH "Oxygen Therapy+" OR TI resuscitat* OR AB resuscitat* OR ((TI respiratory OR AB respiratory) N3 (TI support OR AB support)) OR ((TI cardiorespiratory OR AB cardiorespiratory) N3 (TI support OR AB support)) OR ((TI artificial OR AB artificial) N3 (TI respiration OR AB respiration)) OR ((TI oxygen OR AB oxygen) N3 (TI supplement* OR AB supplement*)))

AND

(

((TI high OR AB high OR TI higher OR AB higher OR TI highflow OR AB highflow OR TI 100% OR AB 100% OR TI "one hundred percent" OR AB "one hundred percent" OR TI "100 percent" OR AB "100 percent" OR TI low OR AB low OR TI lower OR AB lower OR TI limited OR AB limited OR TI reduced OR AB reduced OR TI reduction OR AB reduction OR TI concentration OR AB concentration OR TI concentrations OR AB concentrations OR TI fraction OR AB fraction OR TI fractions OR AB fractions OR TI target OR AB target OR TI targets OR AB targets OR TI targeted OR AB targeted OR TI saturation OR AB saturation OR TI optimal OR AB optimal OR TI differences OR AB differences) N2 (TI oxygen OR AB oxygen OR TI O2 OR AB O2 OR TI "O(2)" OR AB "O(2)" OR TI Fio2 OR AB Fio2)) OR

((MH "Air+" OR TI "room air" OR AB "room air") AND (TI oxygen OR AB oxygen OR TI O2 OR AB O2 OR TI "O(2)" OR AB "O(2)" OR TI Fio2 OR AB Fio2))

)

NOT ((MH animals+ OR MH (animal studies) OR TI (animal model*)) NOT MH (human))

NOT (PT "Case Study" OR PT "Conference Proceeding" OR PT "Proceeding" OR PT "Proceedings")

AND
EM 20180801-

Clinicaltrials.gov
(
("neonatal intensive care" OR "NICU" OR "Delivery Rooms" OR "Respiratory Distress Syndrome, Newborn" OR "Asphyxia Neonatorum" OR "Bronchopulmonary Dysplasia" OR "Persistent Fetal Circulation Syndrome" OR "delivery room" OR newborn OR newborns OR new-borns OR new-borns OR neonates OR neonatal OR premature OR prematurity OR prematurely OR preterm OR pre-term OR infant OR infants OR baby OR babies OR birth OR "gestational age")

AND
(resuscitation OR resuscitated OR resuscitating OR "oxygen inhalation" OR "respiratory support" OR "cardiorespiratory support" OR "artificial respiration" OR "oxygen supplementation" OR "supplementing oxygen" OR "supplementing with oxygen" OR "supplement with oxygen" OR "supplemented with oxygen" OR "supplemental oxygen")
)
Searched in other terms box

(oxygen OR O2 OR "O(2)" OR Fio2))

Searched in intervention/treatment box

The two search boxes described above were used in a single search, and the results were limited by 'first posted' to 08/01/2018 to 12/31/2024 (US date format)

ISRCTN
("neonatal intensive care" OR "NICU" OR "Delivery Rooms" OR "Respiratory Distress Syndrome, Newborn" OR "Asphyxia Neonatorum" OR "Bronchopulmonary Dysplasia" OR "Persistent Fetal Circulation Syndrome" OR "delivery room" OR newborn OR newborns OR new-borns OR new-borns OR neonates OR neonatal OR premature OR prematurity OR prematurely OR preterm OR pre-term OR infant OR infants OR birth OR "gestational age")

AND

(resuscitation OR resuscitated OR resuscitating OR "oxygen inhalation" OR "respiratory support" OR "cardiorespiratory support" OR "artificial respiration" OR "oxygen supplementation" OR "supplementing oxygen" OR "supplementing with oxygen" OR "supplement with oxygen" OR "supplemented with oxygen" OR "supplemental oxygen")

AND

(

((high OR higher OR highflow OR 100% OR "one hundred percent" OR "100 percent" OR low OR lower OR limited OR reduced OR reduction OR concentration OR concentrations OR fraction OR fractions OR target OR targets OR targeted OR saturation OR optimal OR differences) AND (oxygen OR O2 OR "O(2)" OR Fio2)) OR

("room air" AND (oxygen OR O2 OR "O(2)" OR Fio2))

)

Searched in simple search box

Results were downloaded into a CSV file then, then filtered by registration date to 1/08/2018 onwards