aDivision of Emergency Medicine, McMaster University, Hamilton, Ontario, Canada; bHamilton Health Sciences, Centre for Paramedic Education and Research, Hamilton, Ontario, Canada; cDepartment of Critical Care Nursing, Graduate School of Human Health Science, Kyoto University, Kyoto, Japan; dDivision of Neonatalogy, National Center for Child Health and Development, Tokyo, Japan; eNeonatal Services, The Royal Women’s Hospital and University of Melbourne, Melbourne, Australia; fPediatrics and Communicable Diseases, University of Michigan and C. S. Mott Children’s Hospital, Ann Arbor, Michigan; gMedical Sciences Division, Department of Paediatrics, University of Oxford, Oxford, United Kingdom; hNewborn Services, John Radcliffe Hospital, Oxford University Hospitals, National Health Service Foundation Trust, Oxford, United Kingdom; iDivision of Neonatal-Perinatal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; jDepartment of Pediatrics, University of Calgary, Calgary, Alberta, Canada; and kAlberta Children’s Hospital Research Institute, Calgary, Alberta, Canada

To cite: Welsford M, Nishiyama C, Shortt C, et al. Room Air for Initiating Term Newborn Resuscitation: A Systematic Review With Meta-analysis. Pediatrics. 2019;143(1):e20181825

CONTEXT: The International Liaison Committee on Resuscitation prioritized to rigorously review the initial fraction of inspired oxygen (Fio2) during resuscitation of newborns.OBJECTIVE: This systematic review and meta-analysis provides the scientific summary of initial Fio2 in term and late preterm newborns (≥35 weeks’ gestation) who receive respiratory support at birth.DATA SOURCES: Medline, Embase, Evidence Based Medicine Reviews, and Cumulative Index to Nursing and Allied Health Literature were searched between January 1, 1980 and August 10, 2018.STUDY SELECTION: Studies were selected by pairs of independent reviewers in 2 stages, with a Cohen’s κ of 0.8 and 1.0.DATA EXTRACTION: Pairs of independent reviewers extracted data, appraised risk of bias, and assessed Grading of Recommendations Assessment, Development and Evaluation certainty of evidence.RESULTS: Five randomized controlled trials (RCTs) and 5 quasi RCTs included 2164 patients. Room air (Fio2 0.21) was associated with a statistically significant benefit in short-term mortality compared with 100% oxygen (Fio2 1.0) (7 RCTs; n = 1469; risk ratio [RR] = 0.73; 95% confidence interval [CI]: 0.57 to 0.94). No significant differences were observed in neurodevelopmental impairment (2 RCTs; n = 360; RR = 1.41; 95% CI: 0.77 to 2.60) or hypoxic-ischemic encephalopathy (5 RCTs; n = 1315; RR = 0.89; 95% CI: 0.68 to 1.18).LIMITATIONS: The Grading of Recommendations Assessment, Development and Evaluation certainty of evidence was low for short-term mortality and hypoxic-ischemic encephalopathy and very low for neurodevelopmental impairment.CONCLUSIONS: Room air has a 27% relative reduction in short-term mortality compared with Fio2 1.0 for initiating neonatal resuscitation ≥35 weeks’ gestation.

Room Air for Initiating Term Newborn Resuscitation: A Systematic Review With Meta-analysisMichelle Welsford, BSc, MD, FRCPC, a, b Chika Nishiyama, RN, PhD, c Colleen Shortt, PhD, b Tetsuya Isayama, MD, MSc, PhD, d Jennifer Anne Dawson, RN, PhD, e Gary Weiner, MD, f Charles Christoph Roehr, MD, PhD, g, h Myra H. Wyckoff, MD, i Yacov Rabi, MD, j, k on behalf of the International Liaison Committee on Resuscitation Neonatal Life Support Task Force

abstract

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Resuscitation guidelines published before 2000 recommended a 100% inspired concentration of oxygen (fraction of inspired oxygen [Fio2] 1.0) for respiratory support of newborns, regardless of gestation.1 However, evidence has emerged over the past decades recognizing that administration of high Fio2 leads to free radical formation and is toxic to the newly born lungs, eyes, brain, and other organs.2 Excess oxygen can be toxic; however, too little oxygen can also lead to harm from hypoxia. The Resair-2 study revealed that using room air (Fio2 0.21) during initial respiratory support in term newborns at birth did not increase mortality or long-term neurodevelopmental impairment (NDI) and resulted in a quicker time to first breath compared with Fio2 1.0.3, 4 A Cochrane systematic review in 2005 confirmed reduction in short-term mortality for newborns initially resuscitated with Fio2 0.21 compared with 1.0.5

The International Liaison Committee on Resuscitation (ILCOR) reviews evidence on important clinical practice questions regarding resuscitation. The review process includes rigorous evaluation of relevant science by a team of multidisciplinary experts culminating in a consensus on the science with treatment recommendations (CoSTRs). In 2010, ILCOR recommended using Fio2 0.21 rather than 1.0 for newborns born at term who received respiratory support at birth; however, this was before the incorporation of Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment into CoSTRs.6 The 2015 ILCOR guidelines continued to recommend the use of room air during initial resuscitation for term newborns but did not provide an updated review.7 Recently, ILCOR has moved from a 5 year review cycle to a continuous evaluation process, and this provided an opportunity to

perform an updated analysis on this topic by using rigorous methodology including GRADE.

This systematic review and meta-analysis is the core that serves as the “consensus on science” for the ILCOR CoSTRs. This scientific summary was completed in parallel and in collaboration with ILCOR and is published separately from the ILCOR CoSTRs, which will be published in the fall of 2019 and will focus on the treatment recommendations. In cooperation with the ILCOR Neonatal Life Support (NLS) task force, we investigate in this meta-analysis initiating resuscitation with lower compared with higher Fio2 on mortality and morbidity among term and late preterm newborns (≥35 weeks’ gestation) who receive respiratory support at birth. The primary outcome is short-term mortality. Secondary outcomes include long-term mortality, NDI, and the proportion of neonates with hypoxic-ischemic encephalopathy (HIE).

METHODS

Protocol

This systematic review and meta-analysis was conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for meta-analysis in health care interventions.8, 9 The protocol was registered in advance of article selection with the Prospective Register of Systematic Reviews (registered January 8, 2018; CRD42018084902; see Supplemental Information). The protocol included term and preterm newborns as predetermined subgroups, and these were separated into different analyses after initial article selection. Studies were included in this systematic review if >75%

of the newborns were ≥35 weeks’ gestation. The cutoff at 35 weeks’ gestation was chosen on the basis of the experience of our clinical experts that late preterm infants were more similar physiologically to term infants than the population of very premature infants enrolled in the preterm randomized controlled trials (RCTs) and pragmatically based on the knowledge of the enrollment criteria for previous studies.

Outcomes

The selection and importance rating of patient-oriented outcomes for term and late preterm newborns ≥35 weeks’ gestation were determined in advance through discussion and consensus with the ILCOR NLS task force.10 The outcomes centered on all-cause mortality and neurologic impairment.10 When available, we collected all-cause mortality at 2 time intervals: short-term (primary outcome, in-hospital or up to 30 days postnatal) and long-term (1–3 years); and neurologic impairment at 2 time intervals: short-term HIE (Sarnat Stage II–III), and long-term NDI (moderate to severe at 1–3 years).11 NDI is commonly defined as having at least 1 of cerebral palsy, cognitive impairment, visual impairment, or hearing impairment and is categorized by severity. Where available, we extracted data for moderate to severe NDI at 1 to 3 years based on the Gross Motor Function Classification System and Bayley Scales of Infant and Toddler Development, Third Edition.12, 13

Search Strategy

Ovid Medline, Embase, all Evidence Based Medicine Reviews (including Cochrane CENTRAL and others), and EBSCOhost Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched for relevant neonatal literature between January 1, 1980, and December 11, 2017, without language restrictions. The search was updated from December

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1, 2017, to August 10, 2018, before publication (Supplemental Tables 6 and 7). The searches were limited to the last 4 decades because no pertinent studies were expected before this. An iterative approach was used to ensure that key articles (identified by content experts and in previous systematic review articles) were found. Additionally, we searched the first 200 hits on Google Scholar, references of systematic reviews on the topic, references of the ILCOR 2010 and 2015 CoSTRs, and trial registries (clinicaltrials.gov; the International Standard Randomized Controlled Trial Number Registry, isrctn.com; and the EU Clinical Trials Register, clinicaltrialsregister.eu; last searched August 10, 2018).

Study Selection and Data Extraction

Covidence software was used for study selection in 2 steps (Covidence systematic review software; Veritas Health Innovation, Melbourne, Australia; www. covidence. org). Pairs of independent reviewers screened titles and abstracts. In the event of a disagreement at abstract screening, the full text was reviewed. Independent reviewers subsequently completed full-text review for eligibility in duplicate. A third reviewer was involved for disagreements at the full-text stage, and final decisions were determined by consensus. The first reason for exclusion was captured according to a predetermined, ordered list of exclusions. Interrater agreement for article selection was assessed by using Cohen’s κ coefficient at the abstract and full-text stages.

RCTs, quasi randomized controlled trials (qRCTs), and nonrandomized (observational) studies were eligible if they included comparison of low with high initial oxygen concentration for respiratory support at birth. Review articles, editorials, comments, case reports, and small case series (≤10 patients) were

excluded. We excluded studies that were focused on oxygen use beyond the initial stabilization in the delivery room or studies that were focused on oxygen saturation targeting and not initial oxygen concentration. To avoid publication bias, the protocol was amended to include data from conference abstracts (not otherwise published) in a sensitivity analysis if the authors provided enough information to confirm the methods, key patient characteristics, and outcomes.

Data Collection, Bias, and Quality Assessment

For each study, pairs of authors independently extracted predetermined study characteristics and study outcomes and then achieved consensus. Pairs of independent authors evaluated risk of bias (RoB) in individual studies using the Cochrane Risk of Bias Tool for RCTs and the Risk of Bias in Non-Randomized Studies of Interventions tool for observational studies.8, 14 Similarly, 2 authors assessed the certainty of evidence (confidence in the estimate of effect) for each outcome on the basis of the GRADE framework, including calculating the optimal information size to assess imprecision (GRADEpro Guideline Development Tool, McMaster University, Ontario, Canada; available at gradepro.org).15 The RoB and GRADE assessments were then reviewed by ILCOR content experts who are also authors to achieve consistency and consensus.

Data Analysis

Covidence, GRADEpro, and Review Manager software (RevMan 5.3; The Nordic Cochrane Centre, Copenhagen, Denmark) were used to abstract, summarize, and analyze the data, respectively.

Meta-analyses were performed if ≥2 studies were available. Heterogeneity was measured by using the I2 statistic.16 Because multiple small

studies (<250 patients) were anticipated, a random effects model was used for analysis. We report pooled unadjusted risk ratios (RRs) and corresponding 95% confidence intervals (CIs) using the Mantel-Haenszel method for dichotomous variables. Forest plots were used for graphical representation of RRs. To assess for publication bias, we visually inspected funnel plots where >8 studies were available. The absolute risk difference and number needed to treat (NNT) were calculated where the pooled estimate from RCTs revealed a statistically significant benefit by using the method recommended by the Cochrane Collaboration.17

Sensitivity analyses were completed where inclusion of 1 or more studies was uncertain because of a high RoB, incongruent allocation, mixture of adjusted and nonadjusted analyses, or significant heterogeneity.

Prespecified subgroup analyses were planned if >2 studies were available with relevant outcome information related to gestational ages (≥35 and ≥37 weeks’ gestation), specific Fio2 ranges, or oxygen saturation targeting as a cointervention.

RESULTS

Literature Search and Study Selection

Using this search strategy, we identified a total of 2366 records; after removing 967 duplicates, 1399 records were screened by title and abstract. Five additional studies (abstracts) were found via reference searches and added to full-text screening. A total of 59 full-text articles were assessed for eligibility, and 12 publications on term or late preterm newborns were included.2 – 4, 18 – 26 The Cohen’s κ coefficient, a measure of interrater agreement, was 0.81 (excellent) at the abstract stage and 1.0 (full agreement) at the full-text stage.

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See Fig 1 for the PRISMA study selection diagram including the reasons for article exclusion.

Of the additional studies found via reference searches, 1 study published in Romanian with an English abstract was originally excluded because it did not include outcomes of interest.22 However, the publication included a full description of methods and the first author provided additional relevant outcome data; therefore, the full-text of the study was translated and included. Three additional titles by the same first author were identified but were only published as conference abstracts.23 – 25 The author provided additional information regarding methodology, patient characteristics, and outcomes for all 3 of these studies and thus they were included in sensitivity analysis.

Another article of note included both randomized and observational data for 830 term newborns over a 6-year time period (1994–1999) at a single center.19 Some of the randomly assigned patients overlapped with

other included publications.3, 20 The first author provided additional information and outcomes for a subset of 537 patients who were randomly assigned but not published in other included studies. Thus, the study was included in the systematic review and considered for the meta-analysis.

Lastly, a search of clinical trial registries (www. clinicaltrials. gov, www. isrctn. com, and www. clinicaltrialsreg ister. eu) revealed no additional published or unpublished term or late preterm studies.

Study Characteristics

In Table 1, we summarize the characteristics of the included studies and highlight these differences. Of the 12 included articles, there were 10 original studies and 2 publications of follow-up data. Five were quasi randomized on the basis of alternating days and 5 were RCTs, but only 2 were fully randomized with blinding of allocation and intervention. No eligible

observational cohort studies were identified. Ten studies contained reports of short-term mortality (in hospital or up to 30 days postnatal), 7 contained reports of HIE (Sarnat Stage II–III), 1 contained a report of long-term mortality (1–3 years), and 3 contained reports of NDI (moderate to severe, 1–3 years).

A total of 2164 patients were included in studies ranging from 44 to 609 patients. Most studies were from India and Europe; they were published between 1993 and 2007, with patient recruitment from 1990 to 2007. In 4 of 10 studies, the authors reported multicenter data. The authors of all the included studies compared initiating Fio2 0.21 with Fio2 1.0.

The Resair-2 study was a large, nonblinded, multicenter qRCT (allocated by even and odd days). There were 10 sites, which were predominantly low-resource settings with high event rates.3 The authors of the original study indicated that the researchers enrolled 609 patients but subsequently determined data from 18 neonates had been duplicated.4 The authors reported that the corrected demographics and outcomes revealed no difference. As the specific outcome and demographic data for the corrected numbers was not available, the original data were used. The follow-up data at 18 to 24 months used the corrected numbers, but only some of the original centers were included, and there was significant loss to follow-up such that only 66% had follow-up data.

Although the reporting of mortality was similar, the definition of NDI was different among the 3 studies that contained reports of it. In the Resair-2 follow-up publication, they evaluated whether the neonates had developed normally using an unvalidated simple assessment tool.4 In Bajaj et al, 21 NDI assessment was performed by using the Baroda development screening

WELSFORD et al4

FIGURE 1PRISMA flow diagram of study selection. EBM, evidence-based medicine.

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test (modified Bayley), and <97% score on the development screening test was defined as neurologically abnormal. In Toma et al, 22 they assessed NDI using the Bayley Scales of Infant and Toddler Development, Third Edition and divided neonates into 3 categories: high, moderate, and low according to a total score. Where available, we extracted information on moderate to high NDI. Additionally, HIE reported in Ramji et al26 required clarification, and the data used in our analysis were confirmed with the authors.

Patient Characteristics

In Table 2, we outline the patient characteristics of the included studies. The intervention and comparator groups were similar in most of the key prognostic variables (although patient characteristics was not available for 1 study).19 Eight of the 10 studies included either term or late preterm newborns (≥35 weeks’ gestation), 1 study included newborns ≥34 weeks’ gestation, and 1 study (including follow-up publication) included some preterm patients but <25% were <35 weeks’ gestation (median 38, interquartile range [IQR] 31–42 weeks’ gestation).3, 4, 22 The gestational age mean and median ranged from 35.3 to 40.5 weeks with well-matched intervention and comparator groups. The birth weight mean and median ranged from 2319 to 3536 g and were also well matched. Researchers did not routinely report sex, but those that did reported a slight male sex predominance (49%–60%). Intubation and mechanical ventilation were not routinely reported but ranged from 10% to 51%. Apgar scores were well matched between the 2 comparators.

RoB

The RoB assessment for each study is summarized in Table 3. Only 2 studies were fully randomized and blinded for participants, personnel, and assessors;

PEDIATRICS Volume 143, number 1, January 2019 5

TABL

E 1

Stud

y Ch

arac

teri

stic

s

Term

(≥

35 w

k) R

ando

miz

ed a

nd q

RCTs

Stud

ySt

udy

Char

acte

rist

ics

Tota

l Pa

tient

sGe

stat

iona

l Age

Patie

nts

by

Oxyg

en L

evel

s,

n

Oxyg

en L

evel

De

finiti

on, %

O 2 Sat

Ta

rget

Outc

omes

Year

s of

Re

crui

tmen

tCo

untr

y of

Re

crui

tmen

tM

ulti-

or

Sing

le

Cent

er

Stud

y De

sign

Blin

ding

of

Gas

<35

wk

≥35

w

kLo

wHi

ghST

MLT

MND

IHI

E

Ram

ji et

al18

1990

–199

1In

dia

Sing

leqR

CT b

y da

teNo

84—

Yes

4242

Low

, 21;

hig

h, 1

00No

Yes

——

Yes

Saug

stad

et a

l319

94–1

996

Mul

tiM

ulti

qRCT

by

date

No60

9<2

5%Ye

s28

832

1Lo

w, 2

1; h

igh,

100

NoYe

s—

—Ye

s

Vent

o et

al19

a19

94–1

999

Spai

nSi

ngle

qRCT

by

date

No53

7—

Yes

300

237

Low

, 21;

hig

h, 1

00No

Yes

——

—

Ram

ji et

al26

1995

–199

7In

dia

Mul

tiqR

CT b

y da

teNo

431

—Ye

s21

022

1Lo

w, 2

1; h

igh,

100

NoYe

s—

—Ye

s

Saug

stad

et a

l419

94–1

996

Mul

tiM

ulti

qRCT

by

date

No41

0<2

5%Ye

s91

122

Low

, 21;

hig

h, 1

00No

——

Yes

—

Vent

o et

al20

2000

–200

1Sp

ain

Sing

leRC

TYe

s10

6—

Yes

5155

Low

, 21;

hig

h, 1

00No

Yes

——

—Ba

jaj e

t al21

2001

–200

2In

dia

Sing

leqR

CT b

y da

teNo

204

—Ye

s10

797

Low

, 21;

hig

h, 1

00No

Yes

—Ye

sYe

s

Vent

o et

al2

1999

–200

2Sp

ain

Sing

leRC

TYe

s39

—Ye

s17

22Lo

w, 2

1; h

igh,

100

NoYe

s—

——

Tom

a et

al22

2006

Rom

ania

Sing

leRC

TNo

44≥

34 w

kYe

s20

24Lo

w, 2

1; h

igh,

100

NoYe

s—

—Ye

sTo

ma

et a

l23a

2005

Rom

ania

Mul

tiRC

TNo

54—

Yes

2727

Low

, 21;

hig

h, 1

00No

Yes

——

Yes

Tom

a et

al25

a20

06–2

007

Rom

ania

Mul

tiRC

TNo

56—

Yes

3026

Low

, 21;

hig

h, 1

00No

Yes

——

Yes

Tom

a et

al24

a20

05Ro

man

iaSi

ngle

RCT

No54

—Ye

s27

27Lo

w, 2

1; h

igh,

100

No—

Yes

Yes

—

LTM

, lon

g-te

rm m

orta

lity;

STM

, sho

rt-te

rm m

orta

lity;

—, n

ot a

pplic

able

.a

Stud

y w

as o

nly

incl

uded

in s

ensi

tivity

ana

lysi

s.

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WELSFORD et al6

the majority of the studies were determined to have a high RoB.

The 3 articles that were published as conference abstracts were determined to have a critical RoB and thus were included in the sensitivity analysis but not the primary meta-analysis.11, 24, 25 Additionally, although outcome data were provided for the

randomly assigned subset of patients from Vento et al, 20 the demographic information for this subset was not available, and the imbalance in the numbers randomly assigned to each group was unexplained (300 compared with 237). For these reasons, this study was found to have a critical RoB and only included in

the sensitivity analysis and not the primary meta-analysis.

Outcome Analysis

Results of the meta-analysis are detailed below and shown in the Figs 2–5 forest plots.

TABLE 2 Patient Characteristics

Study Oxygen Level Gestational Age, wk

Male Sex, % Birth Wt, g Apgar Score at 5 min

Cesarean Delivery, %

Intubation and Mechanical

Ventilation, %

Chest Compressions, %

Ramji et al18 Low 38.4 (1.9)a N/A 2410 (540)a 8 (7–9)b 24 14 N/AHigh 38.1 (2.6)a N/A 2410 (660)a 7 (6–8)b 21 33 N/A

Saugstad et al3 Low 38 (32–42)b 54 2600 (1320–4078)b 8 (4–9)c 41 25 N/AHigh 38 (31–42)b 59 2560 (1303–3900)b 7 (3–9)c 37 26 N/A

Vento et al19,d Low N/A N/A N/A N/A N/A N/A N/AHigh N/A N/A N/A N/A N/A N/A N/A

Ramji et al26 Low 37.9 (2.9)a N/A 2400 (563)a 7 (3–10)b 83 N/A N/AHigh 38.1 (2.6)a N/A 2529 (629)a 7 (2–10)b 88 N/A N/A

Saugstad et al4 Low 38 (32–42)b 49 2650 (1490–4240)b 8 (4.6–9.0)c N/A N/A N/AHigh 39 (33–42)b 60 2800 (1560–4300)b 8 (4.1–9.0)c N/A N/A N/A

Vento et al20 Low 38.9 (1.6)a N/A 3160 (240)a 6 (5–8)c 69 10 N/AHigh 40.5 (1.1)a N/A 3220 (168)a 6 (4–8)c 75 13 N/A

Bajaj et al21 Low 38.3 (2.8)a 54 2461 (602)a 6.8 (2.0)a 50 51 7High 37.4 (3.5)a 58 2319 (614)a 7.1 (1.6)a 41 35 0

Vento et al2 Low 39.6 (1.6)a N/A 3320 (180)a 5 (3–5)b N/A 41 N/AHigh 39.2 (1.1)a N/A 3110 (90)a 4 (3–5)b N/A 36 N/A

Toma et al22 Low 36.0 (2.69)a N/A 2684 (1013)a N/A N/A N/A N/AHigh 35.3 (2.22)a N/A 2468 (685)a N/A N/A N/A N/A

Toma et al23, 24,d Low 39.1 (1)a N/A 3536 (519)a 8 (3.4–10.0)a N/A N/A N/AHigh 39.2 (0.7)a N/A 3530 (337)a 8 (2.4–10.0)a N/A N/A N/A

Toma et al25d Low 38.8 (0.78)a N/A 3172 (599)a N/A N/A N/A N/AHigh 38.6 (0.58)a N/A 3200 (200)a N/A N/A N/A N/A

N/A, not available (not collected in original study).a Reported as mean (SD).b Reported as median (IQR).c Reported as median (5th–95th percentile).d Study was only included in sensitivity analysis.

TABLE 3 RoB According to Cochrane RCTs Criteria

Cochrane RoB for RCTs

Study Sequence Generation

Allocation Concealment

Blinding of Participants

and Personnel

Blinding of Outcome

Assessors

Incomplete Outcome Data

Selective Outcome Reporting

Other Sources of Bias

Overall Bias

Ramji et al18 High High High High Low Low Unclear HighSaugstad et al3 High High High High Low Low Unclear HighVento et al19a High High High High Unclear High High CriticalRamji et al26 High High High Unclear Unclear Unclear Low HighSaugstad et al4 High High High Unclear High Unclear Unclear HighVento et al20 Low Low Low Unclear Low Unclear Low UnclearBajaj et al21 High High High Low Low Low Low HighVento et al2 Low Low Low Unclear Low Low Unclear UnclearToma et al22 Low High High High Unclear Low High HighToma et al23,a Low High High High Unclear Low High CriticalToma et al24,a Low High High High Unclear Unclear High CriticalToma et al25,a Low High High High Unclear Unclear High Critical

a Denotes articles of critical RoB and only included in sensitivity analysis.

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Short-term Mortality

Seven RCTs and qRCTS involving 1469 term and late preterm newborns (≥35 weeks’ gestation) containing reports on short-term mortality (in-hospital or up to 30 days postnatal) were included in the meta-analysis.2, 3, 19, 21– 23 The pooled estimate demonstrated a statistically significant reduction in

mortality for Fio2 0.21 compared with 1.0 (RR = 0.73; 95% CI: 0.57 to 0.94; I2 = 0%). The absolute survival benefit (absolute risk difference) is 4.6% (95% CI: 1.0% to 7.3%) and the relative survival benefit is 27%. Based on an assumed control risk of 17.0% (from the mortality rate of the comparison group), the NNT with room air to have 1 additional survivor (short-term) is

22 (95% CI: 14 to 99). The forest plot is presented in Fig 2A. Heterogeneity was low as evidenced by the low I2 = 0%, visual inspection of the forest plot, and similarities in the included populations. Although the CIs from the included studies crossed the null effect line, all studies trended in the same direction (favoring room air), and the summary estimate from the

PEDIATRICS Volume 143, number 1, January 2019 7

FIGURE 2Summary of results: term newborns receiving respiratory support comparing Fio2 0.21 with 1.0. A, Short-term mortality (in-hospital or up to 30 days).

FIGURE 3Summary of results: term newborns receiving respiratory support comparing Fio2 0.21 with 1.0 (continued). B, Short-term mortality (in-hospital or up to 30 days) sensitivity analysis demonstrating studies that are blinded, unblinded, and at critical RoB.

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meta-analysis provides confirmation that initial room air improves survival.

To explore the reasons for heterogeneity, a sensitivity analysis was conducted for the primary outcome of short-term mortality to compare studies that were blinded, unblinded, and those at a critical RoB (Fig 3B).19, 23, 25 Inclusion of data from the studies at a critical RoB to the meta-analysis (additional 647 neonates from 3 studies) made no appreciable change in the outcome estimate for short-term mortality, favoring an Fio2 0.21 compared with 1.0 (RR = 0.71; 95% CI: 0.56 to 0.91; I2 = 0%).

Long-term Mortality

Long-term mortality (1–3 years) was reported in 1 abstract with a critical RoB, involving a total of 54 patients with no deaths in either group.24

NDI

NDI (moderate to severe, 1–3 years) was reported in 2 qRCTs involving

360 term and late preterm newborns (≥35 weeks’ gestation, Table 2). The summary estimate from meta-analysis revealed no difference in initiating respiratory support with Fio2 0.21 compared with 1.0 (RR = 1.41; 95% CI: 0.77 to 2.60; I2 = 0%).4, 21

The sensitivity analysis for NDI involving 1 additional study that was determined to be at a critical RoB (414 patients from 3 studies), still demonstrated no statistically significant difference (RR = 1.24; 95% CI: 0.73 to 2.10; I2 = 0%) for Fio2 0.21 compared with 1.0.24

HIE

HIE (Sarnat Stage II–III) was reported in 5 RCT and/or qRCTs involving 1315 term and late preterm newborns (≥35 weeks’ gestation) receiving respiratory support at birth included in the meta-analysis and revealed no statistically significant difference in Fio2 0.21 compared with

1.0 (RR = 0.90; 95% CI: 0.71 to 1.14; I2 = 8%) (Fig 5D).3, 18, 21, 22, 26

Sensitivity analysis for HIE (Sarnat Stage II–III) was performed with 3 additional studies that were determined to be at a critical RoB. Data from these 8 studies and 2006 neonates did not change the RR appreciably and still demonstrated no statistically significant difference (RR = 0.89; 95% CI: 0.73 to 1.10; I2 = 0%) for Fio2 0.21 compared with 1.0.19, 23, 25

Subgroup Analyses

The authors of all studies compared Fio2 0.21 with 1.0, and thus subgroup analysis according to different initial oxygen concentrations was not possible. There were no data for the planned subgroups analyses related to different gestational ages and whether oxygen saturation targeting was included as a cointervention.

The GRADE summary of quality evaluation for the primary outcomes is presented in Table 4. RCTs start at high

WELSFORD et al8

FIGURE 4Summary of results: term newborns receiving respiratory support comparing Fio2 0.21 with 1.0 (continued). C, Long-term NDI (1–3 years).

FIGURE 5Summary of results: term newborns receiving respiratory support comparing Fio2 0.21 with 1.0 (continued). D, HIE (Sarnat Stage II–III). df, degrees of freedom; M-H, Mantel-Haenszel method; Random, random effects.

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certainty. Because of concerns with RoB, inconsistency, and imprecision, the certainty of the results was downgraded. The ILCOR NLS Task Force provided the expert opinion that it was unlikely that there were any additional unpublished studies on this topic given the intense clinical interest in this topic, the international reach and involvement of the committee, and the extensive search including uncovering abstracts and conference proceedings. Therefore, the outcomes were not downgraded for publication bias. The GRADE certainty was determined to be low for short-term mortality and HIE and very low for NDI because of serious concerns with RoB and imprecision. The ratings of the importance of outcomes for the GRADE analysis were all “critical” and ranged from 7 to 9 on the 9-point scale.

DISCUSSION

In this systematic review and meta-analysis involving 2164 neonates ≥35 weeks’ gestation, we demonstrate a 27% relative survival benefit and 4.6% absolute survival benefit (short-term) when initial room air is compared with Fio2 1.0 for neonates receiving respiratory support at birth. This corresponds to an NNT with room air to have 1 additional survivor (short-term) of 22. There were no statistically significant differences for HIE and NDI. The GRADE certainty of evidence was low for short-term mortality and HIE and very low for NDI.

The last ILCOR analysis of initial oxygen use for term neonatal resuscitation was completed in 2010 before the adoption of the GRADE methodology for ILCOR reviews. The ILCOR 2010 NLS CoSTR stated, “In term infants receiving resuscitation at birth with positive pressure ventilation, it is best to begin with air rather than 100% oxygen. If despite effective ventilation there is no increase in heart rate or if oxygenation (guided by oximetry) remains unacceptable, use of a

PEDIATRICS Volume 143, number 1, January 2019 9

TABL

E 4

GRAD

E Su

mm

ary

of F

indi

ngs

Cert

aint

y As

sess

men

tNo

. Pat

ient

sEf

fect

Cert

aint

yIm

port

ance

(R

atin

g Sc

ale)

No.

Stud

ies

Stud

y De

sign

RoB

Inco

nsis

tenc

yIn

dire

ctne

ssIm

prec

isio

nOt

her

Room

Air

Ev

ents

/n (

%)

100%

Ev

ents

/n,

(%)

Rela

tive

(95%

CI)

Abso

lute

(9

5% C

I)

Shor

t-ter

m m

orta

lity

(in-

hosp

ital o

r 30

d

post

nata

l)

7RC

TSe

riou

saNo

t ser

ious

Not s

erio

usSe

riou

sbNo

nec

89/7

14 (

12.5

)12

8/75

5 (1

7.0)

RR 0

.73

(0.5

7 to

0.

94)

−46

of 1

000

(−10

to

−73

)

⨁⨁

◯◯

Lo

wCr

itica

l (9)

NDI (

mod

erat

e-se

vere

, 1–3

y)

2RC

TVe

ry s

erio

usd

Not s

erio

usNo

t ser

ious

Very

se

riou

seNo

nec

20/1

68 (

11.9

)17

/192

(8

.9)

RR 1

.41

(0.7

7 to

2.

60)

36 o

f 100

0 (−

20 to

−

42)

⨁◯

◯◯

Ve

ry L

owCr

itica

l (8)

HIE

(Sar

nat S

tage

II–

III)

5RC

TSe

riou

sfNo

t ser

ious

Not s

erio

usSe

riou

sgNo

nec

117/

661

(17.

7)13

7/69

8 (1

9.6)

RR 0

.90

(0.7

1 to

1.

14)

−20

of 1

000

(27

to

−57

)

⨁⨁

◯◯

Lo

wCr

itica

l (7)

a Fi

ve o

ut o

f 7 s

tudi

es h

ave

a hi

gh r

isk

of “

allo

catio

n se

quen

ce, ”

“allo

catio

n co

ncea

lmen

t, ” a

nd “

blin

ding

.” Th

ese

dom

ains

may

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the

outc

ome.

b To

tal n

umbe

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s (1

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less

than

OIS

(21

46).

c The

ILCO

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S Ta

sk F

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vide

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it w

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stud

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bias

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Both

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ris

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indi

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alth

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rrow

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ngra

de im

prec

isio

n on

ce.

by guest on January 21, 2021www.aappublications.org/newsDownloaded from

higher concentration of oxygen should be considered.” 6 After the release of this CoSTR, there was widespread adoption of initial room-air resuscitation worldwide. The Neonatal Resuscitation 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations did not update the CoSTR.7

The ILCOR NLS Task Force prioritized this research question in 2017 because of the strong desire to have the existing evidence subjected to a methodologically rigorous review including GRADE analysis of confidence in effect. In Table 5, we compare this analysis to key previously published meta-analyses.5, 27 – 30 The results are fairly consistent across the meta-analyses, with the largest number of patients included in the current publication’s sensitivity analysis and the Saugstad et al27 publication.

There have been no new publications of term studies on this topic since 2007; therefore, we are left with these few older studies from a different era, with their inherent differences to current state-of-the-art neonatal resuscitation to reflect on the evidence for current care. This previous evidence, despite low and very low confidence in the point effect estimates, has low statistical heterogeneity and consistent short-term mortality excess with Fio2 1.0. The findings of the current systematic review and meta-analysis are similar to the 2010 ILCOR review and indicate benefit in short-term mortality by initiating respiratory support at birth for term and late preterm newborns (≥35 weeks’ gestation), with room air compared with Fio2 1.0. There are no identified term or late preterm studies comparing outcomes at any intermediate oxygen concentration between these 2 extremes. However, given that practice has changed to initiating resuscitation

WELSFORD et al10

TABL

E 5

Com

pari

son

of M

eta-

anal

yses

This

stu

dyTh

is s

tudy

aSa

ugst

ad e

t al27

,bRa

bi e

t al28

,cTa

n et

al5,

dSa

ugst

ad e

t al29

,eDa

vis

et a

l30,f

Shor

t-ter

m m

orta

lity

RR 0

.73

RR 0

.71

RR 0

.69

RR 0

.63

RR 0

.71

OR 0

.59

RR 0

.75

(0.5

7–0.

94)

(0.5

6–0.

91)

(0.5

4–0.

88)

(0.4

2–0.

94)

(0.5

4–0.

94)

(0.4

0–0.

87)

(0.5

6–1.

0)n

= 14

69N

= 21

16n

= 21

33n

= 13

76n

= 12

75n

= 15

02n

= 65

9ND

I (1–

3 y)

RR 1

.41

RR 1

.24

——

RR 1

.56

—RR

1.5

6(0

.77–

2.66

)(0

.73–

2.10

)—

—(0

.76–

3.22

)—

(0.7

6–3.

22)

n =

360

n =

414

——

n =

213

—n

= 12

2HI

E (S

arna

t Sta

ge II

–III)

RR 0

.90

RR 0

.89

RR 0

.88

RR 0

.86

RR 0

.84

—RR

0.8

4(0

.71–

1.14

)(0

.74–

1.10

)(0

.72–

1.08

)(0

.65–

1.14

)(0

.65–

1.08

)—

(0.6

5–1.

08)

n =

1359

n =

2006

n =

2133

n =

693

n =

1124

—n

= 58

4

RR <

1 fa

vors

Fio2 0

.21

com

pare

d w

ith 1

.0. —

, not

app

licab

le.

a Se

nsiti

vity

ana

lysi

s in

clud

ing

3 ad

ditio

nal s

tudi

es.

b In

clud

ed V

ento

et a

l19 a

nd 2

Tom

a ab

stra

cts24

, 25.

c Sho

rt-te

rm m

orta

lity

defin

ed a

s m

orta

lity

at 1

mo.

d De

ath

at la

test

follo

w-u

p, a

bnor

mal

dev

elop

men

t at 1

8–24

mo.

e Res

ults

rep

orte

d as

odd

s ra

tio n

ot R

R.f S

hort

-term

mor

talit

y de

fined

as

deat

h in

firs

t wk;

NDI

defi

ned

as a

bnor

mal

dev

elop

men

t.

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with room air and using oxygen saturation monitoring to adjust oxygen administration, the precise initial Fio2 may have become less important, and it is unlikely that there will be any future studies on this topic.

In this systematic review and meta-analysis, we include a prespecified protocol, broad search strategy, additional unpublished data from authors, unpublished studies (abstracts) included in sensitivity analyses, use of GRADE to describe certainty in effect estimate, a team of expert systematic reviewers coupled with international multidisciplinary experts in neonatology, and adherence to PRISMA reporting.

However, several limitations are worth noting. First, out of 10 trials, all but 2 had high RoB, 5 studies used a quasi-randomized design (alternating days), and 8 did not have allocation concealment or personnel blinding. This serious RoB, as well as imprecision, make the certainty of the evidence low or very low. In addition, the mortality incidence was vastly different between studies. Short-term mortality ranged from 1.5% in Vento et al19 (Spain) to 15% in Ramji et al26 (India), and 18% in Saugstad et al3 (patients were mostly from India, Egypt, and Philippines). Studies with high mortality are more heavily weighted in the meta-analyses, and thus caution is needed to ensure similar results are found in countries with lower newborn mortality. Furthermore, all of the studies were conducted >10 years ago and before continuous oxygen saturation monitoring and oxygen titration during delivery room resuscitation were routine. Therefore, it is not clear whether the same results would be found in the setting of current clinical practice in which the inspired oxygen concentration is titrated to achieve targeted levels of oxygen saturation.7 The evidence in which

long-term NDI was evaluated was limited because of the small sample size included in the 2 eligible trials and 1 abstract. We assessed HIE as a short-term neurologic outcome as oxygen administration was historically investigated as a treatment; however, the pathogenesis of HIE starts in utero and HIE may not accurately predict important long-term neurologic outcomes.31 Lastly, all the trials included in this review compared initial room air with Fio2 1.0; therefore, whether room air is superior to other low or intermediate Fio2 (eg, Fio2 0.30) is not known.

CONCLUSIONS

With this systematic review and meta-analysis, we confirm a statistically significant reduction in short-term mortality (without statistically significant differences in short- and long-term neurologic outcomes) by using initial room air compared with Fio2 1.0 (100% oxygen) for term and late preterm newborns (≥35 weeks’ gestation) receiving respiratory support at birth. The certainty of effect is low (short-term mortality); however, the results are consistent across studies with no evidence of statistical heterogeneity and represent the best available evidence to answer this important question.

ACKNOWLEDGMENTS

The authors would like to express their appreciation to the following for contributing valuable support to improve this review: Laurie J. Morrison (ILCOR Continuous Evidence Evaluation Working Group Liaison), and Carolyn Ziegler (St. Michael’s Hospital Information Specialist) and Andrei Harabor (article translation). The authors would also like to highlight the following researchers who kindly contributed valuable information and data from

their studies to improve this review: Naveen Bajaj, Ola Saugstad, Adrian Toma, and Maximo Vento.

Besides the authors Tetsuya Isayama, Charles Christoph Roehr, Myra H. Wyckoff, and Yacov Rabi, members of the International Liaison Committee on Resuscitation Neonatal Life Support Task Force include: Jonathan Wyllie, Jeffrey M. Perlman, Khalid Aziz, Ruth Guinsburg, Maria Fernanda de Almeida, Vishal Kapadia, Daniele Trevisanuto, Sithembiso Velaphi, Lindsay Mildenhall, Helen Liley, Shigeharu Hosono, Han-Suk Kim, and Edgardo Szyld.

PEDIATRICS Volume 143, number 1, January 2019 11

ABBREVIATIONS

CI:  confidence intervalCINAHL:  Cumulative Index to

Nursing and Allied Health Literature

CoSTR:  consensus on the science with treatment recommendation

Fio2:  fraction of inspired oxygen

GRADE:  Grading of Recommendations Assessment, Development and Evaluation

HIE:  hypoxic-ischemic encephalopathy

ILCOR:  International Liaison Committee on Resuscitation

IQR:  interquartile rangeNDI:  neurodevelopmental

impairmentNLS:  Neonatal Life SupportNNT:  number needed to treatPRISMA:  Preferred Reporting

Items for Systematic Reviews and Meta-Analyses

qRCT:  quasi randomized controlled trial

RCT:  randomized controlled trial

RoB:  risk of biasRR:  risk ratio

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WELSFORD et al12

Dr Welsford prepared the protocol, screened studies, abstracted data, completed risk of bias and Grading of Recommendations Assessment, Development and Evaluation (GRADE) evaluations, completed the analysis, and prepared the first draft of the manuscript; Dr Nishiyama reviewed the protocol, screened studies, abstracted data, completed risk of bias and GRADE evaluations, reviewed the analysis, and prepared the first draft of the manuscript; Dr Shortt reviewed the protocol, screened studies, abstracted data, prepared the tables, and was involved in writing and editing the manuscript; Drs Isayama and Dawson reviewed the protocol, completed risk of bias and GRADE evaluations, reviewed the analysis, and were involved in writing and editing the manuscript; Drs Weiner, Roehr, Wyckoff, and Rabi were involved in reviewing the protocol, reviewing the analysis, and writing and editing the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

This trial has been registered with PROSPERO (https:// www. crd. york. ac. uk/ PROSPERO) (identifier CRD42018084902).

DOI: https:// doi. org/ 10. 1542/ peds. 2018- 1825

Accepted for publication Sep 11, 2018

Address correspondence to Michelle Welsford, BSc, MD, FRCPC, Division of Emergency Medicine, McMaster University, Centre for Paramedic Education and Research, Hamilton General Hospital, McMaster Clinic, 237 Barton St E., Room 253, Hamilton, ON L8L 2X2, Canada. E-mail: welsford@mcmaster.ca

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2019 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: Funded by the American Heart Association on behalf of the International Liaison Committee on Resuscitation. The funder was involved in the International Liaison Committee on Resuscitation process but had no role in this systematic review study design, data collection and analysis, or preparation of the article.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

COMPANION PAPER: Companions to this article can be found online at www. pediatrics. org/ cgi/ doi/ 10. 1542/ peds. 2018- 1828 and www. pediatrics. org/ cgi/ doi/ 10. 1542/ peds. 2018- 3365.

by guest on January 21, 2021www.aappublications.org/newsDownloaded from

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With Meta-analysisRoom Air for Initiating Term Newborn Resuscitation: A Systematic Review

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DOI: 10.1542/peds.2018-1825 originally published online December 21, 2018; 2019;143;Pediatrics 

Support Task Forceon behalf of the International Liaison Committee on Resuscitation Neonatal Life

Dawson, Gary Weiner, Charles Christoph Roehr, Myra H. Wyckoff, Yacov Rabi and Michelle Welsford, Chika Nishiyama, Colleen Shortt, Tetsuya Isayama, Jennifer Anne

With Meta-analysisRoom Air for Initiating Term Newborn Resuscitation: A Systematic Review

http://pediatrics.aappublications.org/content/143/1/e20181825located on the World Wide Web at:

The online version of this article, along with updated information and services, is

http://pediatrics.aappublications.org/content/suppl/2018/12/17/peds.2018-1825.DCSupplementalData Supplement at:

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