Prophylactic or very early initiation of continuous positive airway pressure (CPAP) for preterm infants

Abstract

Background

Cohort studies have suggested that nasal continuous positive airway pressure (CPAP) starting in the immediate postnatal period before the onset of respiratory disease (prophylactic CPAP) may be beneficial in reducing the need for intubation and intermittent positive pressure ventilation (IPPV), and in preventing bronchopulmonary dysplasia (BPD), in preterm or low birth weight infants.

Objectives

To determine if prophylactic nasal CPAP (started within the first 15 minutes) or very early nasal CPAP regardless of respiratory status (started within the first hour of life), reduces the use of mechanical ventilation and the incidence of bronchopulmonary dysplasia without any adverse effects in preterm infants.

Search methods

A comprehensive search was run on 6 November 2020 in the Cochrane Central Register of Controlled Trials (CENTRAL via CRS Web) and MEDLINE via Ovid. We also searched the reference lists of retrieved studies.

Selection criteria

We included all randomised controlled trials (RCTs) and quasi‐RCTs in preterm infants (under 37 weeks of gestation). We included trials if they compared prophylactic nasal CPAP (started within the first 15 minutes) or very early nasal CPAP (started within the first hour of life) in infants with minimal signs of respiratory distress with 'supportive care', such as supplemental oxygen therapy, standard nasal cannula, or mechanical ventilation. We excluded studies where prophylactic CPAP was compared with CPAP along with co‐interventions.

Data collection and analysis

We used the standard methods of Cochrane Neonatal, including independent study selection, assessment of trial quality, and extraction of data by two review authors.

Main results

We included eight trials (seven from the previous version of the review and one new study), recruiting 3201 babies, in the meta‐analysis. Four trials, involving 765 babies, compared CPAP with supportive care, and three trials (2364 babies) compared CPAP with mechanical ventilation. One trial (72 babies) compared prophylactic CPAP with very early CPAP. Apart from a lack of blinding of the intervention, we judged seven studies to have a low risk of bias. However, one study had a high risk of selection bias.

Prophylactic or very early CPAP compared to supportive care

There may be a reduction in failed treatment (risk ratio (RR) 0.6, 95% confidence interval (CI) 0.49 to 0.74; risk difference (RD) ‐0.16, 95% CI ‐0.34 to 0.02; 4 studies, 765 infants; very low certainty evidence). CPAP possibly reduces BPD at 36 weeks (RR 0.76, 95% CI 0.51 to 1.14; 3 studies, 683 infants, moderate certainty evidence); there may be little or no difference in death (RR 1.04, 95% CI 0.56 to 1.93; 4 studies, 765 infants; moderate certainty evidence). Prophylactic CPAP may reduce the composite outcome of death or BPD (RR 0.69, 95% CI 0.40 to 1.19; 1 study, 256 infants; low certainty evidence). There may be no difference in pulmonary air leak (pneumothorax) (RR 0.75, 95% CI 0.35 to 1.16; 3 studies, 568 infants; low certainty evidence), or intraventricular haemorrhage (IVH) Grade 3 or 4 (RR 0.96, 95% CI 0.39 to 2.37; 2 studies, 486 infants; moderate certainty evidence). Neurodevelopmental impairment was not reported in any of the studies.

Prophylactic or very early CPAP compared to mechanical ventilation

There was probably a reduction in the incidence of BPD at 36 weeks (RR 0.89, 95% CI 0.8 to 0.99; RD ‐0.04, 95% CI ‐0.08 to 0.00; 3 studies, 2150 infants; moderate certainty evidence); and death or BPD (RR 0.89, 95% CI 0.81 to 0.97; RD ‐0.05, 95% CI ‐0.09 to 0.01; 3 studies, 2358 infants; moderate certainty evidence). There was also probably a reduction in the need for mechanical ventilation (failed treatment) (RR 0.49, 95% CI 0.45 to 0.54; RD ‐0.50, 95% CI ‐0.54 to ‐0.45; 2 studies, 1042 infants; moderate certainty evidence). There was probably a reduction in the incidence of death (RR 0.82, 95% CI 0.66 to 1.03; 3 studies, 2358 infants; moderate certainty evidence); pulmonary air leak (pneumothorax) (RR 1.24, 95% CI 0.91 to 1.69; 3 studies, 2357 infants; low certainty evidence); and IVH Grade 3 or 4 (RR 1.09, 95% CI 0.86 to 1.39; 3 studies, 2301 infants; moderate certainty evidence). One study in this comparison reported that there was probably little or no difference between the groups in the incidence of neurodevelopmental impairment at 18 to 22 months (RR 0.91, 95% CI 0.62 to 1.32; 976 infants; moderate certainty evidence).

Prophylactic CPAP compared with very early CPAP

There was one study in this comparison. We are very uncertain whether there is any difference in the incidence of BPD (RR 0.5, 95% CI 0.05 to 5.27; very low certainty evidence). The combined outcome of death and BPD was not reported, and failed treatment was reported but without data. There may have been little to no effect on death (RR 0.75, 95% CI 0.29 to1.94; 1 study, 72 infants; very low certainty evidence). Intraventricular haemorrhage Grade 3 or 4 and neurodevelopmental outcomes were not reported in this study. Pulmonary air leak (pneumothorax) was reported in this study, but there were no events in either group.

Authors' conclusions

For preterm and very preterm infants, there is insufficient evidence to evaluate prophylactic CPAP compared to oxygen therapy and other supportive care. When compared to mechanical ventilation, prophylactic nasal CPAP in very preterm infants reduces the incidence of BPD, the combined outcome of death and BPD, and mechanical ventilation. There is probably no difference in neurodevelopmental impairment at 18 to 22 months of age.

When prophylactic CPAP is compared to early CPAP, we are very uncertain about whether there is any difference between prophylactic and very early CPAP.

There is no information about the effect of prophylactic or very early CPAP in late preterm infants.

There is one study awaiting classification.

Plain language summary

Can breathing support using continuous positive airway pressure (CPAP), given within the first hour of life, prevent death and illness in premature babies?

Key messages

Premature babies given breathing support within the first hour of life with continuous positive airway pressure (CPAP) – where air is pushed into the baby’s nose at a constant pressure and the baby breathes by itself – compared to oxygen alone, may be less likely to be put on a ventilator ‐ where a tube is inserted into the baby’s lungs and a machine breathes for the baby.

CPAP in the first hour after birth compared to a ventilator probably leads to less lung damage, fewer deaths, and less need for babies to be put on a ventilator.

One small study looked at the effect of the timing of CPAP after birth (up to 15 minutes compared to up to 1 hour), so there was not enough evidence to make a judgement regarding timing.

What is continuous positive airway pressure?

Continuous positive airway pressure (CPAP) helps people with breathing difficulties by pushing air into their lungs through the nose at a constant pressure. Air is delivered through a mask that fits over the nose, or prongs that sit in the nostrils. CPAP is less invasive than mechanical ventilation, when a tube is put down the throat into the lungs and a machine (a ventilator) ‘breathes’ for the patient. CPAP provides more breathing support than just giving oxygen. 

How does CPAP help premature babies?

Premature babies are those babies born before 37 weeks of development (gestation). They may have trouble breathing because their lungs are not fully developed. This is called ‘respiratory distress syndrome’ (RDS). Premature babies with non‐severe RDS may be treated with warmth, fluids, calories, and oxygen. Babies with severe RDS are given breathing support with CPAP or a ventilator. Babies breathe by themselves with CPAP, but the pressure of the stream of air that CPAP delivers keeps the baby’s airways open between breaths. Babies on CPAP avoid being put on ventilators, which can cause lung damage, such as bronchopulmonary dysplasia (BPD).

CPAP can be given within the first 15 minutes after birth (preventive CPAP), or up to an hour after birth as therapy if babies show early signs of RDS (very early CPAP). 

What did we want to find out?

We wanted to know if preventive CPAP and very early CPAP are effective in preventing RDS in premature babies. We were interested in:

‐ how many babies had BPD;
‐ whether CPAP successfully supported babies’ breathing, or if they needed to be put on a ventilator;
‐ how many babies died; and
‐ the combined number of babies who died or developed BPD.

What did we do? 
We searched for studies that investigated CPAP given to premature babies 15 minutes after birth, whether or not they showed signs of RDS, and to premature babies who showed early signs of RDS up to 1 hour after birth. Studies could look at:

‐ CPAP compared to supportive care, which includes supplemental oxygen;
‐ CPAP compared to putting babies on a ventilator; and
‐ preventive CPAP compared to very early CPAP.

What did we find?

We found 8 studies with 3201 babies in total ranging from 24 to 32 weeks gestation:

‐ 4 studies with 765 babies compared CPAP with supportive care;
‐ 3 studies with 2364 babies compared CPAP with ventilation; and
‐ 1 study with 72 babies compared preventive CPAP with very early CPAP.

Studies took place in high‐ and middle‐income countries: Argentina, Australia, Brazil, Canada, Chile, Italy, New Zealand, Paraguay, Peru, Uruguay, and the USA. Babies were very or extremely preterm, or very low birth weight (less than 1500 grams); no studies included late preterm babies or low birthweight babies.

Main results

Compared to supportive care, CPAP:

‐ makes little to no difference to BPD up to 28 days after birth;
‐ may result in fewer babies needing to be put on a ventilator; and
‐ probably makes little to no difference to combined numbers of deaths and BPD.

Compared to a ventilator, CPAP:

‐ probably reduces BPD up to 36 weeks after birth;
‐ probably reduces the need for babies to be put on a ventilator by almost half; and
reduces the combined numbers of deaths and BPD.

Due to insufficient evidence, we don't know whether preventive CPAP compared to very early CPAP makes any difference to BPD up to 28 days after birth, reduces or increases the number of deaths up to 28 days after birth, or reduces the need for babies to be put on a ventilator.

What are the limitations of the evidence?

We have limited evidence about CPAP compared to supportive care. CPAP compared to ventilators probably reduces BPD and combined numbers of death and BPD. We are very uncertain about the effect of preventive CPAP compared with very early CPAP because there was one small study that lacked the details we needed.

How up to date is this evidence?

This updates our previous review. The evidence is up to date to 6 November 2020.

Summary of findings

Summary of findings 1. Prophylactic or very early CPAP compared to supportive care for preventing morbidity and death at any time in preterm infants.

Prophylactic CPAP compared to supportive care for preventing morbidity and death at any time in preterm infants
Patient or population: preterm infants Settings: delivery room and neonatal intensive care unit Intervention: prophylactic or very early CPAP Comparison: supportive care
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Supportive care	Prophylactic CPAP
Failed treatment  defined as recurrent apnoea, hypoxia, hypercarbia (such as PaCO₂ > 60 mmHg), increasing oxygen requirement, or the need for mechanical ventilation	Study population		RR 0.60  (0.49 to 0.74)	765 (4 studies)	⊕⊝⊝⊝ very lowa,b,c	Outcome subjective and may be susceptible to lack of blinding
	392 per 1000	258 per 1000 (176 to 384)
Bronchopulmonary dysplasia at 36 weeks defined as oxygen dependency at 36 weeks postmenstrual age	Study population		RR 0.76  (0.51 to 1.14)	683 (3 studies)	⊕⊕⊕⊝ moderatec	Not downgraded for lack of blinding as outcome is objective and unlikely to be susceptible to lack of blinding
	124 per 1000	98 per 1000 (62 to 154)
Death at any time	Study population		RR 1.04  (0.56 to 1.93)	765 (4 studies)	⊕⊕⊕⊝ moderatec	Not downgraded for lack of blinding as outcome is objective and unlikely to be susceptible to lack of blinding
	50 per 1000	52 per 1000 (28 to 97)
Combined outcome of death and bronchopulmonary dysplasia defined as death at any time or oxygen dependency at 36 weeks' postmenstrual age	Study population		RR 0.69  (0.4 to 1.19)	256 (1 study)	⊕⊕⊝⊝ lowd	Not downgraded for lack of blinding as outcome is objective and unlikely to be susceptible to lack of blinding
	192 per 1000	134 per 1000 (79 to 232)
Pulmonary air leak  defined as pneumothorax	Study population		RR 0.75 (0.35 to 1.16)	568 (3 studies)	⊕⊕⊝⊝ lowe	Not downgraded for lack of blinding as outcome is objective and unlikely to be susceptible to lack of blinding
	50 per 1000	38 per 1000 (18 to 82)
Intraventricular haemorrhage grade 3 or 4	Study population		RR 0.96  (0.39 to 2.37)	486 (2 studies)	⊕⊕⊝⊝ lowe	Not downgraded for lack of blinding as outcome is objective and unlikely to be susceptible to lack of blinding. Downgraded for imprecision due to a very wide confidence interval
	38 per 1000	38 per 1000 (11 to 130)
Neurodevelopmental impairment	No study reported this outcome
*The basis for the assumed risk (e.g. the median control group risk across studies) is taken from the pooled estimates of the included studies. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; CPAP: continuous positive airway pressure; IVH: intraventricular haemorrhage; NICU; neonatal intensive care unit; RR: risk ratio
GRADE Working Group grades of evidence High certainty: further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty: we are very uncertain about the estimate.

^aDowngraded one level for serious risk of bias due to no blinding of intervention or outcome assessment.
^bDowngraded one level for serious inconsistency due to considerable unexplained heterogeneity across included studies (I² = 70%).
^cDowngraded one level due to serious imprecision because the 95% confidence interval includes both potential benefit and potential harm.
^dDowngraded two levels for very serious imprecision due to wide 95% confidence interval including both potential benefit and potential harm, as well as failure to meet the optimal information size (one study < 400 participants).
^eDowngraded two levels for very serious imprecision due to extremely wide 95% confidence interval including both potential benefit and potential harm.

Summary of findings 2. Prophylactic CPAP compared to mechanical ventilation for preventing morbidity and death at any time in preterm infants.

Prophylactic or ery early CPAP compared to mechanical ventilation for preventing morbidity and death in preterm infants
Patient or population: preterm infants < 37 weeks Settings: delivery room and neonatal intensive unit Intervention: prophylactic or very early CPAP Comparison: prophylactic or very early mechanical ventilation
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Mechanical ventilation	Prophylactic CPAP
Bronchopulmonary dysplasia at 36 weeks defined as oxygen dependency at 36 weeks' postmenstrual age	Study population		RR 0.89  (0.8 to 0.99)	2150 (3 studies)	⊕⊕⊕⊝ moderateb	Not downgraded for lack of blinding as outcome is objective and unlikely to be susceptible to lack of blinding
	381 per 1000	339 per 1000 (304 to 377)
Death Death at any time	Study population		RR 0.82  (0.66 to 1.03)	2358 (3 studies)	⊕⊕⊕⊝ moderateb	Not downgraded for lack of blinding as outcome is objective and unlikely to be susceptible to lack of blinding
	126 per 1000	103 per 1000 (83 to 130)
Combined outcome of death and bronchopulmonary dysplasia  defined as death at any time and oxygen dependency at 36 weeks' postmenstrual age	Study population		RR 0.89  (0.81 to 0.97)	2358 (3 studies)	⊕⊕⊕⊝ moderateb	Not downgraded for lack of blinding as outcome is objective and unlikely to be susceptible to lack of blinding
	470 per 1000	418 per 1000 (380 to 455)
Failed treatment defined as the need for mechanical ventilation	Study population		RR 0.49  (0.45 to 0.54)	1042 (2 studies)	⊕⊕⊕⊝ moderatea	Outcome subjective and may be susceptible to lack of blinding, although in one of the two studies, mechanical ventilation was mandatory in the control group
	982 per 1000	491 per 1000 (413 to 580)
Pulmonary air leak  defined as pneumothorax	Study population		RR 1.24  (0.91 to 1.69)	2357 (3 studies)	⊕⊕⊝⊝ lowb,c	Not downgraded for lack of blinding as outcome is objective and unlikely to be susceptible to lack of blinding. Considerable heterogeneity explained by subgroup differences
	58 per 1000	82 per 1000 (39 to 171)
Intraventricular haemorrhage grade 3 or 4	Study population		RR 1.09  (0.86 to 1.39)	2301 (3 studies)	⊕⊕⊕⊝ moderated	Not downgraded for lack of blinding as outcome is objective and unlikely to be susceptible to lack of blinding. Moderate heterogeneity ‐ not downgraded
	99 per 1000	97 per 1000 (63 to 148)
Neurodevelopmental impairment defined as cerebral palsy, developmental delay, intellectual impairment, blindness or sensorineural deafness at 18 to 22 months corrected age	Study population		RR 0.91 (0.62 to1.32)	976 (1 study)	⊕⊕⊕⊝ moderateb	Not downgraded for lack of blinding as outcome is objective and unlikely to be susceptible to lack of blinding
	95 per 1000	105 per 1000
*The basis for the assumed risk (e.g. the median control group risk across studies) taken from the pooled risk differences of the included studies. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; CPAP: continuous positive airway pressure; IVH: intraventricular haemorrhage; NICU; neonatal intensive care unit; RR: risk ratio
GRADE Working Group grades of evidence  High certainty: further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty: we are very uncertain about the estimate.

^aDowngraded one level for serious study limitations due to lack of blinding of intervention or outcome assessors.
^bDowngraded one level for serious imprecision because the 95% confidence interval includes both potential benefit and potential harm.
^cDowngraded one level for serious heterogeneity.
^dDowngraded one level for serious imprecision because the 95% confidence interval includes both potential benefit and potential harm.

Summary of findings 3. Prophylactic CPAP compared to very early CPAP for preventing morbidity and death at any time in preterm infants.

Prophylactic CPAP compared to very early CPAP for preventing morbidity and mortality in preterm infants
Patient or population: preterm infants Settings: delivery room and neonatal intensive care unit Intervention: prophylactic CPAP started within the first 15 minutes of life Comparison: very early CPAP started within the first 60 minutes of life
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Early CPAP	Prophylactic CPAP
Bronchopulmonary dysplasia at 28 days	Study population		RR 0.5 (0.05 to 5.27)	72 (1 study)	⊕⊝⊝⊝ very lowa,b,c,d	Not downgraded for lack of blinding as outcome is objective and unlikely to be susceptible to lack of blinding Downgraded for very serious imprecision
	56 per 1000	28 per 1000 (3 to 293)
Failed treatment	This outcome was reported, but there were no data
Death at any time (by 28 days)	Study population		RR 0.75 (0.29 to 1.94)	72 (1 study)	⊕⊝⊝⊝ very lowa,b,c,d	Not downgraded for lack of blinding as outcome is objective and unlikely to be susceptible to lack of blinding Downgraded for very serious imprecision
	222 per 1000	167 per 1000 (64 to 431)
Combined outcome of death and bronchopulmonary dysplasia	No study reported this outcome
Pulmonary air leak	The outcome was reported in one study (n = 72) but there were no events in either group
Intraventricular haemorrhage grade 3 or 4	No study reported this outcome
Neurodevelopmental impairment	No study reported this outcome
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; CPAP: continuous positive airway pressure; NICU: neonatal intensive care unit; RR: risk ratio
GRADE Working Group grades of evidence  High certainty: further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty: we are very uncertain about the estimate.

^aDowngraded one level for serious study limitations (selective outcome reporting).
^bDowngraded two levels for very serious imprecision including very important benefit and harm.
^cDowngraded one level for concerns about study limitations (lack of blinding and selective outcome reporting).
^dDowngraded one level for imprecision. Includes both substantial benefit and clinically unimportant benefit.

Background

Description of the condition

Respiratory distress syndrome (RDS) is the most common respiratory disorder of preterm infants. Rates are highest in the most immature infants, although more mature infants with delayed lung maturation of different aetiologies can also be afflicted. In RDS, the structurally immature, surfactant‐deficient lung has a tendency to collapse. Although the poorly ventilated areas may be relatively well perfused, this can result in the typical ventilation‐perfusion mismatch, leading to hypoxia and hypercarbia. If severe enough, there may be pulmonary vasoconstriction, leading to persistent pulmonary hypertension and more severe hypoxia. Histologically, RDS is characterised by leakage of proteinaceous fluid into the alveoli and hyaline membrane formation (Rodriguez 2002). While increased respiratory effort after birth is a common occurrence amongst preterm babies, some will stabilise after a period of respiratory support whereas others may go on to established respiratory distress syndrome (RDS). 

After 72 hours of age, most infants with RDS start the recovery phase. Respiratory rate and retractions decrease, and the partial pressure of oxygen (PaO₂₎ increases without evidence of further carbon dioxide (CO₂₎ retention. In infants of very low birth weight, even in the absence of severe RDS over the first few days, recovery may be prolonged. This may be attributed to impaired respiratory drive or respiratory muscle failure, persistent atelectasis not related to surfactant deficiency, nutritional compromise, intercurrent infection, congestive heart failure, or some combination of these interrelated factors (Fanaroff 2013).
 

Description of the intervention

In the early days of neonatal intensive care, the only available treatments for RDS were supportive ones, and included provision of warmth, fluid, calories, and oxygen. Two major modes of respiratory support became available in the 1960s and 1970s: mechanical ventilation via an endotracheal tube and continuous positive airway pressure (CPAP). Both could be given prophylactically to infants at risk of developing RDS or as rescue therapy to infants with signs of respiratory failure (Polin 2002). The timing of initiating CPAP could be irrespective of the respiratory status of the infant. Subsequently, two effective perinatal interventions – surfactant administered via an endotracheal tube (Seger 2009; Soll 1997; Soll 1998), and antenatal corticosteroids (McGoldrick 2020) – were evaluated and incorporated into supportive care.

Nasal CPAP (nCPAP) is a noninvasive method for applying a constant distending pressure to the lungs via the nostrils throughout the respiratory cycle to support spontaneously breathing newborn infants with lung disease. The goals of CPAP are to maintain the functional residual capacity of the lungs and to support gas exchange. This reduces apnoea, work of breathing, and lung injury. CPAP is most commonly delivered using binasal short prongs or a nasal mask. Pressure is generated using a variety of devices. CPAP pressure settings are measured in centimetres of water pressure or cm H₂O. CPAP is generally well tolerated, in part because infants are preferential or “obligatory nasal‐breathers” (Kattwinkel 1973). Recently, the delivery of surfactant to infants supported on CPAP using minimally invasive techniques, such as LISA (Less Invasive Surfactant Administration) or MIST(Minimally Invasive Surfactant Therapy), has been used (Olivier 2017). This procedure involves sedating the neonate with atropine and fentanyl. A laryngoscopy is performed while the baby is supported on nCPAP, and surfactant is administered after tracheal insertion of a 5 French sterile and flexible gavage tube with Magill forceps. If desaturation or bradycardia occurs, the procedure is temporarily interrupted. This means that CPAP need not be interrupted to administer surfactant.

CPAP is an attractive option for supporting neonates with respiratory distress, because it preserves spontaneous breathing, does not require endotracheal intubation, and may result in less lung injury than mechanical ventilation (Sweet 2007). Cohort studies of variations in practice between centres have suggested that early nasal CPAP may be beneficial in reducing the need for intubation for intermittent positive pressure ventilation (IPPV) and the incidence of bronchopulmonary dysplasia (BPD) (Avery 1987; Jonsson 1997). Therefore, CPAP needs to be compared with both supportive care and mechanical ventilation.

Cohort studies using historical controls have suggested that prophylactic or very early nasal CPAP initiated immediately after birth regardless of respiratory status in very low birth weight (VLBW) infants is effective in reducing the need for IPPV without worsening other measures of neonatal outcome (Gittermann 1997; Jacobsen 1993). These studies found no important decrease in the incidence of BPD in infants managed with elective CPAP.

How the intervention might work

Nasal CPAP has been adopted by many neonatal intensive care units (NICUs) as a way of reducing rates of bronchopulmonary dysplasia in preterm neonates, but assessment of its benefits is complicated by questions about the simultaneous effects of concomitant surfactant treatment and other NICU interventions (Patel 2008).

CPAP prevents end‐alveolar collapse, reduces the work of breathing, decreases ventilation‐perfusion mismatch, and may reduce adverse effects of mechanical ventilation (Rodriguez 2002). Therefore, giving it very early might prevent infants progressing to established RDS. However, not all infants with respiratory difficulties at birth will progress to established RDS.

CPAP might not work as well in less mature babies, such as those below 28 weeks' gestation whose lungs are less developed and who are more prone to apnoea and respiratory failure (Gerber 2012). CPAP might work better if given simultaneously with surfactant (Stevens 2007).

A feasibility pilot study by the United States' National Institutes of Health (NIH) network, in which early CPAP in the delivery room was used for infants less than 28 weeks' gestational age, showed that while nasal CPAP could be initiated early, only 80% of infants required intubation during the seven days after birth (Finer 2010).

Why it is important to do this review

There are several problems interpreting these observational studies. Comparisons between centres and between infants in different eras are confounded by variations in the characteristics of infants entering treatment programmes, such as the gestational age of cohorts based on birth weight (Avery 1987), and by variations in co‐interventions, such as antenatal steroid administration (Gittermann 1997). Furthermore, the definition of the major end‐point (failed CPAP) varies. The general approach towards intubation is often more 'restrictive' in centres which use the policy of elective CPAP as part of a package of minimal intervention and 'permissive hypercarbia'.

Randomised controlled trials are required to minimise bias and give a more precise measure of the effectiveness of prophylactic nasal CPAP (Lundstrom 1996). Bancalari 1992 carried out an earlier systematic review of this subject.

Cochrane Reviews have described a variety of uses of CPAP for the neonate. These include: CPAP compared with theophylline for apnoea prematurity (Henderson‐Smart 2001); CPAP compared with nasal intermittent positive pressure ventilation (Lemyre 2002); CPAP for respiratory distress (Ho 2020a; Ho 2020b); CPAP to reduce extubation failure after mechanical ventilation (Davis 2003); and CPAP compared with high flow nasal cannula (Wilkinson 2016). An existing review describes the use of surfactant during the course of CPAP (INtubate, SURfactant administration, Extubate; a technique or method known as INSURE) (Stevens 2007).

This review looks at the routine use of CPAP prior to the onset of respiratory disease and compares it with other forms of treatment. This review has been updated several times, and this update is needed because there are new studies.

Objectives

To determine if prophylactic nasal CPAP (started within the first 15 minutes) or very early nasal CPAP regardless of respiratory status (started within the first hour of life), reduces the use of mechanical ventilation and the incidence of bronchopulmonary dysplasia without any adverse effects in preterm infants.

Methods

Criteria for considering studies for this review

Types of studies

All trials using random or quasi‐random participant allocation in randomised controlled trials (RCTs) were eligible. We excluded cross‐over trials.

Types of participants

Preterm infants below 37 weeks' gestation at birth, regardless of respiratory status. We included studies where at least 80% of infants met this criterion. (See Differences between protocol and review for changes made in this update.)

Types of interventions

We included prophylactic nasal CPAP (started within the first 15 minutes) or very early nasal CPAP regardless of respiratory status (started within the first hour of life) in infants who appeared to need further respiratory stabilisation.

We defined prophylactic CPAP as CPAP commencing within the first 15 minutes of life regardless of respiratory status, and very early CPAP as CPAP usually started in the delivery room after the first 15 minutes but within the first 60 minutes of life, and prior to the onset of established respiratory distress syndrome. We included the following comparisons.

Prophylactic or very early CPAP compared to:

• supportive care which may have included supplemental oxygen delivered by head box or standard nasal canula;

• mechanical ventilation with or without surfactant started within the first 15 minutes of life usually in the delivery room;

• each other; that is, prophylactic CPAP compared to very early CPAP. If surfactant such as LISA or MIST was used, it should have been used in both groups in the same manner.

We excluded trials in which nasal CPAP was used early in the treatment of established respiratory distress syndrome because these trials were ineligible for this review and are considered in other reviews (Ho 2020a; Ho 2020b).

We excluded trials where CPAP was used along with surfactant administration followed by a brief period of mechanical ventilation. This is addressed in another review (Stevens 2007).

(See Differences between protocol and review for changes made in this update, including the addition of a third comparison.)

Types of outcome measures

 We have underlined below the critical outcomes that we have graded and presented in the summary of findings tables.

Primary outcomes

For comparison 1: prophylactic or very early CPAP started soon after birth compared to supportive care which may include supplemental oxygen delivered by head box or standard nasal canula.

• Failed treatment (defined as recurrent apnoea, hypoxia, hypercarbia (such as PaCO₂ > 60 mmHg), increasing oxygen requirement, or the need for mechanical ventilation)

• Bronchopulmonary dysplasia (BPD) using recognised definitions such as:

  • oxygen therapy at 28 days with or without an abnormal chest X‐ray (NIH 1979)

  • oxygen therapy at 36 weeks' postmenstrual age (Jobe 2001)

• Death at any time

• Combined outcome of BPD or death

For comparison 2: prophylactic or very early CPAP started soon after birth compared to mechanical ventilation with or without surfactant.

• BPD using recognised definitions such as:

  • oxygen therapy at 28 days with or without an abnormal chest X‐ray (NIH 1979)

  • oxygen therapy at 36 weeks' postmenstrual age (Jobe 2001)

• Death at any time

• Combined outcome of BPD and death

• Failed treatment (defined as the need for mechanical ventilation)

For comparison 3: prophylactic CPAP compared to very early CPAP.

• BPD using recognised definitions such as:

  • oxygen therapy at 28 days with or without an abnormal chest X‐ray (NIH 1979)

  • oxygen therapy at 36 weeks' postmenstrual age (Jobe 2001)

• Failed treatment (defined as recurrent apnoea, hypoxia, hypercarbia (such as PaCO₂ > 60 mmHg), increasing oxygen requirement, or the need for mechanical ventilation)

• Death at any time

• Combined outcome of BPD and death

Secondary outcomes

• Use of surfactant

• Pulmonary air leaks (pneumothorax, pneumomediastinum)

• Local trauma (nasal injury, subglottic stenosis, laryngeal injury)

• Feed intolerance (days to full feeds)

• Intraventricular haemorrhage (IVH)

• Periventricular leukomalacia (PVL)

• Necrotising enterocolitis (NEC, diagnosed by radiology or at surgery)

• Late‐onset systemic infection

• Retinopathy of prematurity (ROP)

• Health care resources

• Costs of care

• Duration of hospitalisation

• Neurodevelopmental impairment (moderate to severe) at two or more years of age, defined as: cerebral palsy (CP) or gross motor disability defined as level 2 or higher according to the Gross Motor Function Classification System (GMFCS) (Palisano 1997); developmental delay (Bayley or Griffith assessment > 2 standard deviations (SD) below the mean) (Bayley 1993; Bayley 2006; Griffiths 1954); or intellectual impairment (IQ > 2 SD below the mean), blindness (vision < 6/60 in both eyes), or sensorineural deafness requiring amplification.

• Combined outcome of neurodevelopmental impairment and death

We made a post hoc decision to include the combined outcome of death or neurodevelopmental impairment since this has been reported in the included studies, and we consider it a valid and important outcome.

Search methods for identification of studies

Electronic searches

We conducted a search for studies on 6 November 2020, including Cochrane Central Register of Controlled Trials (CENTRAL 2020, Issue 11) via CRS Web (crsweb.cochrane.org), and Ovid MEDLINE and Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Daily and Versions (from 1946 to 6 November 2020). We have included the search strategies for each database in Appendix 1. We did not apply date, language, or publication type restrictions.

We searched clinical trial registries for ongoing or recently completed trials. We searched the World Health Organization's International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en/), and the US National Library of Medicine’s ClinicalTrials.gov (clinicaltrials.gov), via Cochrane CENTRAL. Additionally, we searched the ISRCTN Registry (www.isrctn.com/), for any unique trials not found through the Cochrane CENTRAL search.

This is the fifth update of this review. Our previous search details are listed in Appendix 2 and Appendix 3.

Searching other resources

We searched the reference lists of any articles selected for inclusion in this review in order to identify additional relevant articles.

We searched the reference lists of related published reviews.

Data collection and analysis

Selection of studies

We used the standard review methods of Cochrane Neonatal. Two authors (PS and JJH) independently screened the search results. The three review authors (PS, JJH, PD) assessed for inclusion in the review all abstracts and published studies identified as potentially relevant by the literature search.

Data extraction and management

Each review author extracted data separately to a data extraction form. We then compared the information and resolved differences by consensus. One review author (PS) entered data into Review Manager 5 (RevMan 5; Review Manager 2020), and the other review author (JJH) cross‐checked the printout against her own data extraction forms. The discrepancies were discussed and resolved. For the studies identified as an abstract, we contacted the primary study author to obtain further information.

Assessment of risk of bias in included studies

Two review authors (PS and JJH) independently assessed the risk of bias (low, high, or unclear) of all included trials using the Cochrane risk of bias tool (Higgins 2011), for these domains:

• sequence generation (selection bias);

• allocation concealment (selection bias);

• blinding of participants and personnel (performance bias);

• blinding of outcome assessment (detection bias);

• incomplete outcome data (attrition bias);

• selective reporting (reporting bias);

• any other bias.

Measures of treatment effect

We performed statistical analyses using RevMan 5 (Review Manager 2020). We analysed categorical data using risk ratio (RR) and risk difference (RD).

Where the meta‐analysis for a primary outcome or adverse effect showed a benefit, we calculated the number needed to treat for an additional beneficial outcome (NNTB) or, where relevant, the number needed to treat for an additional harmful outcome (NNTH).

We reported the 95% confidence interval (CI) on all estimates. If we had encountered any continuous outcomes, we would have reported mean difference and 95% CI.

Unit of analysis issues

The unit of analysis was the individual newborn. For trials testing more than two study arms, if encountered, we intended to include only the relevant arms in the analysis. Where two or more study arms met our inclusion criteria for either the intervention or the control, we intended to combine those arms.

Dealing with missing data

We contacted the authors of studies with missing data that could be included in the analysis. For included studies, we have noted levels of attrition. If we had encountered studies with high levels of missing data in the overall assessment of treatment effect, we intended to explore the impact of this using sensitivity analysis. 

For all analyses carried out, where we had complete data, we used an intention‐to‐treat principle; that is, we included all participants in the analysis in the group to which they were randomised. Where data were not complete, we used an available case analysis where the denominator for each outcome was the number randomised minus any participants whose outcomes were known to be missing. 

Assessment of heterogeneity

First, we inspected each forest plot for any lack of overlap of confidence intervals as evidence of heterogeneity. Then, we assessed heterogeneity statistically with the I² statistical test. An I² estimate of more than 50% was considered moderate heterogeneity and more than 75% as substantial heterogeneity.

Assessment of reporting biases

If we had found 10 or more included studies, we intended to construct a funnel plot. We would have visually inspected the funnel plot for asymmetry and, if detected, we would have attempted to explain it using exploratory analyses (e.g. Rücker's arcsine test for dichotomous data and Egger's linear regression test for continuous data) to further investigate funnel plot asymmetry. A P value of less than 0.1 would have been considered as the level of statistical significance.

Data synthesis

We used the statistical package in Review Manager 5 (Review Manager 2020), provided by Cochrane. We used fixed‐effect meta‐analysis for combining data where it was reasonable to assume that studies were estimating the same underlying treatment effect: that is, where trials were examining the same intervention, and trial populations and methods were judged sufficiently similar.

Subgroup analysis and investigation of heterogeneity

We investigated heterogeneity by first attempting to explain it based on the trial characteristics and methods. We then performed a limited number of prespecified subgroup analyses as follows.

For the primary outcomes, subgroup analysis was planned to address the following hypotheses.

• Gestational age: late preterm (34 to 36 weeks), moderate preterm (32 to 33 weeks), very preterm (28 to 31 weeks), and extremely preterm (below 28 weeks).

• Birth weight (> 1500 grams, 1001 to 1500 grams, and < 1000 grams respectively).

• Higher versus lower CPAP pressure (e.g. 6 cm H₂0 or less, and more than 6 cm H₂0).

• Mode of CPAP delivery (e.g. binasal prong, nasal mask, nasopharyngeal tube, or other modes).

• Prophylactic versus very early CPAP (comparisons 1 and 2 only).

• Mechanical ventilation with or without surfactant (comparison 2 only).

• Usage of antenatal steroids (e.g. more than 50%).

Of these, we were not able to do subgroup analysis with regard to mode of CPAP or the use of antenatal steroids.

Sensitivity analysis

We planned to conduct a sensitivity analysis to explore differences in trial quality. In the first two versions of this review, we used the fixed‐effect model (Subramaniam 2002; Subramaniam 2005). For this version, to test this decision, we included sensitivity analysis using random‐effects meta‐analysis when we encountered moderate heterogeneity. We planned a sensitivity analysis to exclude studies where we judged the rate of missing data was sufficiently high to affect the outcome. 

Summary of findings and assessment of the certainty of the evidence

We used the GRADE approach, as outlined in the GRADE Handbook (Schünemann 2013), to assess the certainty of evidence for the critical (clinically relevant) outcomes listed above (see Types of outcome measures).

Two review authors (PS and JJH) independently assessed the certainty of the evidence for each of the outcomes described above. We considered evidence from RCTs as high certainty but downgraded the evidence one level for serious (or two levels for very serious) limitations based upon the following: design (risk of bias), consistency across studies, directness of the evidence, precision of estimates, and presence of publication bias. We used the GRADEpro GDT Guideline Development Tool to create three summary of findings tables to report the certainty of the evidence.

The GRADE approach results in an assessment of the certainty of a body of evidence in one of four grades:

• high certainty: further research is very unlikely to change our confidence in the estimate of effect;

• moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate;

• low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate;

• very low certainty: we are very uncertain about the estimate.

Results

Description of studies

See Figure 1.

1.

Study flow diagram: review update

Results of the search

For this update, we screened 2455 citations, and of these, we retrieved the full texts of four new citations. From these, we included one new study (Badiee 2013), and we excluded one study (Mwatha 2020). We identified two or further publications for one of the previously included studies (Finer 2010), which describe the outcomes of infants between 18 and 22 months old (Vaucher 2012 and Stevens 2014), and one was excluded (Mwatha 2020). With seven studies previously identified, this means that we have included a total of eight studies in this version of the review. One further study previously classified as 'waiting further assessment' in our 2016 review update (Subramaniam 2016), was excluded (Thomson 2002). In addition, we classified one study as awaiting classification (NCT04209946).

See Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification.

Included studies

We included one new study in this update (Badiee 2013). We included the two‐year follow‐up data from one existing study (Finer 2010 (Vaucher 2012 reference)).

In total, we included eight studies (3201 babies) in our updated review (Badiee 2013; Dunn 2011; Finer 2010; Gonçalves‐Ferri 2014; Han 1987; Morley 2008; Sandri 2004; Tapia 2012).  

Publication dates ranged from 1987 to 2014. All eight studies were parallel‐arm RCTs. One study had three arms, of which two were relevant to our study (Dunn 2011). We excluded the arm randomising infants to the INSURE technique [INtubate, SURfactant administration, Extubate]. Finer 2010 used a two‐by‐two factorial design to study two interventions (prophylactic CPAP versus control and oxygen saturation targeting 85% to 89% versus 91% to 95%). Outcomes, including neurodevelopmental impairment, were reported at two years.

Full details of the eight included studies are given in the Characteristics of included studies tables.

Comparison 1: prophylactic or very early CPAP compared to supportive care

This comparison included four studies (765 participants) in which the sample sizes ranged from 82 to 256 infants (Gonçalves‐Ferri 2014; Han 1987; Sandri 2004; Tapia 2012). Two of the studies were from high‐income countries: Italy and Canada (Han 1987; Sandri 2004).

Tapia 2012 was performed in high‐ and upper‐middle‐income countries (Argentina, Chile, Paraguay, Peru, and Uruguay). Gonçalves‐Ferri 2014, was performed in an upper‐middle‐income country (Brazil).

None of the studies were carried out in a low‐income setting.

Comparison 2: prophylactic or very early CPAP compared to mechanical ventilation

This comparison included three studies, involving 2358 babies (Dunn 2011; Finer 2010; Morley 2008). All three studies were multicentre studies conducted in high‐income countries, including Australia, New Zealand, United States, Canada, and Europe.

Comparison 3: prophylactic CPAP compared with very early CPAP

This comparison included one study involving 72 participants (Badiee 2013). This study was conducted in an upper‐middle‐income country (Iran).

Participants

Comparison 1: four studies included spontaneously breathing infants between 28 and 32 weeks' gestation with birth weights between 800 and 1500 grams (Gonçalves‐Ferri 2014; Han 1987; Sandri 2004; Tapia 2012). Antenatal steroids were given to between 82% to 90% of babies in two studies (Sandri 2004; Tapia 2012), and 63% to 67% of mothers in Gonçalves‐Ferri 2014. No mother was given any antenatal steroids in Han 1987. Three studies included the first twin (Gonçalves‐Ferri 2014; Han 1987; Sandri 2004). Tapia 2012 included both twins but did not state how they were randomised. However, there were equal proportions of twins distributed across the two intervention groups.

Comparison 2: comprised three studies that included infants between 24 and 30 weeks' gestation (Dunn 2011; Finer 2010; Morley 2008). Of these, Finer 2010 included infants with no known condition that might adversely affect breathing after birth, apart from prematurity, who were randomised prior to birth. Dunn 2011 randomised preterm babies at birth. Morley 2008 randomised preterm babies with no known condition that might adversely affect breathing after birth, apart from prematurity, and who were judged to require respiratory support at five minutes of age. The mean birth weights for the infants were between 825 and 1053 grams. Antenatal steroids were given to more than 94% of mothers.

Comparison 3: the one included trial studied infants of 25 to 30 weeks' gestation who had respiratory distress but were spontaneously breathing at five minutes of age and were judged to require respiratory support (Badiee 2013). The mean birth weights were 983 grams (SD 223.9) and 1070 grams (SD 184.6) for the prophylactic and very early CPAP groups, respectively. The use of antenatal steroids was not reported.

All studies excluded babies with major congenital malformations.

Intervention

Comparison 1: in Han 1987, the experimental group received nasal CPAP (nCPAP) via the nasopharyngeal route. CPAP pressure was determined by measuring pressure in the lower oesophagus (Tanswell 1980).

The other included studies used nCPAP delivered via binasal prongs. Sandri 2004 delivered 4 to 6 cm H₂O of nasal CPAP using the Infant Flow Driver system (EME Ltd, Brighton, Sussex, UK), within 30 minutes of birth. Tapia 2012 used a bubble CPAP system (Fisher & Paykel Healthcare), with a pressure of 5 cm H₂O from about five minutes of life. In Gonçalves‐Ferri 2014, CPAP was applied using a Neopuff manual ventilator with PEEP (Positive end expiratory pressure) at 5 cm H₂0 and was maintained with positive pressure for at least 48 hours. The authors did not report how CPAP was delivered after infants were moved from the delivery room to the neonatal unit. 

For the control groups, head box oxygen was used by two studies (Han 1987; Sandri 2004). In Tapia 2012, babies were initially managed with oxygen via nasal cannula before transferring to a head box.

In Gonçalves‐Ferri 2014, the control group received routine treatment, which included oxygen delivered by 'methods described in the AAP [American Academy of Pediatrics] AHA [American Heart Association guideline] (Kattwinkel 2010). After transfer to the NICU, infants were stabilised and ventilation parameters followed institutional protocols. Three of the four studies had access to surfactant (Gonçalves‐Ferri 2014; Sandri 2004; Tapia 2012). Surfactant was administered by the INSURE (Intubation, SURfactant administration, Extubation) method in two studies (Tapia 2012, Sandri 2004), and in Gonçalves‐Ferri 2014, surfactant was administered with or without mechanical ventilation, but the actual technique used was unclear.

Comparison 2: CPAP was administered by short single or binasal prongs in two studies (Dunn 2011; Morley 2008). Nasal CPAP was administered in the delivery room within 15 minutes of life in Dunn 2011. Both Dunn 2011 and Finer 2010 used CPAP pressures of 5 cm H₂O. In Dunn 2011, this could be increased to a maximum of 7 cm H₂O. In Finer 2010, the CPAP group was resuscitated according to the neonatal resuscitation program guideline. The infants then received nasal CPAP in the NICU via a ventilator, purpose‐built flow driver, or bubble CPAP circuit. Intubation was only performed after arrival in the NICU if the infant met strict predetermined criteria, and surfactant was administered if the infant was under 48 hours of life. Morley 2008 used a CPAP pressure of 8 cm H₂O with short single or double prong nasal CPAP. After admission to the nursery, a double prong was used and the CPAP pressure could be altered as required.

Intubation and mechanical ventilation were initiated only if strict criteria were met.

For the control groups, infants in all three studies received intubation and mechanical ventilation. Infants in both Finer 2010 and Dunn 2011 received surfactant in the delivery room after intubation. In Morley 2008, surfactant was not mandatory but could be administered to either treatment group after intubation.

Comparison 3: in Badiee 2013, the prophylactic group received CPAP in the delivery room, initiated five minutes after birth at a pressure of 6 cm H₂O, using a nasopharyngeal tube. After admission to the NICU, a binasal prong (Hudson prong) was used for delivering bubble CPAP. For the control group (very early CPAP group), oxygen was administrated by a head box until 30 minutes after birth. If the infants required oxygen for more than 30 minutes, nasal CPAP was administered at a pressure of 6 cm H₂O with a single nasopharyngeal tube. 

Surfactant (beractant, 100 mg/kg) was administered using the INSURE (INtubation, SURfactant, Extubation) method described by Stevens 2007, for those newborns who had arterial oxygen saturation (SPO₂)of less than 88% in spite of a fraction of inspired oxygen (FiO₂) of more than 0.6 [60%]. This was repeated every six hours up to four doses (each repetition of surfactant was done only if the newborns needed it to maintain FiO₂ more than 0.6) until 48 hours after birth. Intubation criteria were: arterial pH < 7.2, PaCO₂ > 65 mmHg, or recurrent apnoea unresponsive to methylxanthine therapy after initiation of nCPAP.

Outcomes

Comparison 1: all four studies reported failed treatment (Gonçalves‐Ferri 2014; Han 1987, Sandri 2004; Tapia 2012). They defined this as the need for mechanical ventilation. All four studies had their own fixed criteria for mechanical ventilation. None of the studies used other additional criteria for failed treatment, such as recurrent apnoea, hypoxia, hypercarbia (such as PaCO₂ > 60 mmHg), and increasing oxygen requirement.

Han 1987 did not include BPD as a primary outcome. However, the remaining three studies recorded BPD as oxygen dependency at 36 weeks' postmenstrual age, and none of them reported the numbers at 28 days (Gonçalves‐Ferri 2014; Sandri 2004; Tapia 2012).

Death at any time was reported by all four studies. One study reported death at any time within 28 days (Sandri 2004). Three studies reported death at any time during the hospital stay (Gonçalves‐Ferri 2014; Han 1987; Tapia 2012).

The authors of Han 1987 did not define a number of outcomes in the first published paper, but these were clarified by contact with Dr Han (see Characteristics of included studies).

The combined outcome of BPD and mortality was reported by one study (Tapia 2012).

Three studies reported the secondary outcomes, use of surfactant, pulmonary air leak (all reported only pneumothorax), and sepsis (Gonçalves‐Ferri 2014; Sandri 2004; Tapia 2012). Subglottic stenosis was reported in Han 1987 and nasal injury was reported in Tapia 2012. Necrotising enterocolitis (NEC) was reported in three studies (Han 1987; Sandri 2004; Tapia 2012), and periventricular leukomalacia (PVL) was reported in one study (Sandri 2004s). Intraventricular haemorrhage (IVH) (any grade) was reported in two studies (Han 1987: Tapia 2012), whereas Grades 3 and 4 IVH was reported in two studies (Sandri 2004; Tapia 2012). Sepsis was reported in three studies (Han 1987; Sandri 2004; Tapia 2012). Grades 3 and 4 retinopathy of prematurity (ROP) were reported in two studies (Han 1987; Sandri 2004).

None of the four studies reported feed intolerance, duration of hospitalisation, or neurodevelopmental impairment.

Comparison 2: all three studies (Dunn 2011; Morley 2008; Finer 2010), reported our primary outcomes of BPD at 36 weeks' postmenstrual age, death at any time by 36 weeks' postmenstrual age, and the combined outcome of death and BPD. Failed treatment, defined as the need for mechanical ventilation, was reported in two studies (Dunn 2011; Morley 2008). In this comparison, because all infants in the control group were treated with prophylactic or very early mechanical ventilation, it is recognised that all infants in this arm would be classified as having failed treatment.

The secondary outcomes reported in all three studies were use of surfactant, pulmonary air leak (all reported only pneumothorax), NEC, and IVH Grades 3 and 4. Dunn 2011 and Morley 2008 reported the number of babies with PVL. Sepsis and IVH (any grade) was reported by Dunn 2011.

One study reported neurodevelopmental impairment at two years corrected age, including abnormal neurodevelopment, moderate or severe cerebral palsy, bilateral blindness, hearing impairment, and a cognitive score of less than 70 (Finer 2010 (Vaucher 2012 reference)).

Comparison 3: in Badiee 2013, the primary outcome was the need for mechanical ventilation (in the first 48 hours after birth), death, and BPD (defined as the need for oxygen at 28 days).

The secondary outcomes were the use of surfactant, IVH (any grade), pulmonary air leak (pneumothorax), sepsis, and duration of hospitalisation. Some of the reported outcome data for this study was not usable. Attempts to contact Dr Badiee for further information were unsuccessful.

Further details of the included trials can be found in the table of Characteristics of included studies.

Awaiting classification

There is one study awaiting classification (NCT04209946). See Characteristics of studies awaiting classification for further information.

Excluded studies

In total, we excluded six studies, five from previous versions of the review and one additional exclusion in this update (Drew 1982; Mwatha 2020; Rojas 2009; Thomson 2002; Tooley 2003; Zaharie 2008). We give the reasons for exclusion in the Characteristics of excluded studies table.

Risk of bias in included studies

Details are given in the Characteristics of included studies, Figure 2 and Figure 3.

2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study

Allocation

Random sequence generation was adequate in five studies (Dunn 2011; Finer 2010; Morley 2008; Sandri 2004; Tapia 2012). It was unclear in two studies (Badiee 2013; Gonçalves‐Ferri 2014), and inadequate in one (Han 1987).

Allocation concealment was adequate in seven of the included studies and unclear in one (Gonçalves‐Ferri 2014).

Blinding

None of the included studies used blinding of the intervention to parents, caregivers, study personnel, or outcome assessors, with two exceptions. Han 1987 used blinding of assessors for a radiological diagnosis of BPD. In Finer 2010's follow‐up study of infants up to two years of age, the surviving infants underwent a comprehensive neurodevelopmental assessment performed by neurologic examiners and neurodevelopmental testers, who were unaware of the treatment assignments and were evaluated annually for testing reliability.

Incomplete outcome data

In the Han 1987 trial, there were complete follow‐up data for 90% of participants (two treatment and three control infants were excluded, two due to congenital abnormalities and three for protocol violations). Therefore, this trial reporting was not strictly according to intention‐to‐treat. There was complete follow‐up in five studies (Badiee 2013; Finer 2010; Gonçalves‐Ferri 2014; Sandri 2004; Tapia 2012). In Morley 2008, there was complete follow‐up in 98% of cases. In Dunn 2011, there was complete follow‐up in 99% of cases in the treatment group and 98% in the control group. 

We judged incomplete outcome data as low risk in all eight trials.

Selective reporting

Protocols were not available for three studies (Han 1987; Morley 2008; Sandri 2004). Morley and colleagues registered their trial retrospectively, but all expected outcomes were reported, so we did not judge this study to be at risk of selective outcome reporting. Protocols were available for three studies (Dunn 2011; Finer 2010; Tapia 2012). In Finer 2010, all the study's prespecified outcomes have been reported, some in the supplementary material. 

Badiee 2013 reported the results only as percentages. The primary outcome was reported last and usable data were not given. Means were reported without standard deviations (SDs). The conclusion given does not appear to be consistent with what data are available. (Authors state there is evidence that very early is better than early.) We judged this to be selective outcome reporting.

For Gonçalves‐Ferri 2014, data were stratified by gestation and the results were not reported. We judged this to be not selective reporting but probably used to reduce the risk of selection bias. There was a limited protocol available in the trial's registration document but all of the study's prespecified outcomes were reported. Mortality was not included in the protocol but was reported in the clinical report. However, since there was no reported difference in mortality, we do not suspect selective reporting of this outcome. 

Other potential sources of bias

Han 1987 was stopped early because of concerns that treatment outcomes were worse in the intervention group. We judged this to be high risk of bias.

No other potential sources of bias were reported in four studies (Dunn 2011; Finer 2010; Gonçalves‐Ferri 2014; Sandri 2004).

In Badiee 2013, infants were randomised at one minute of life. It is noted that the inclusion criteria would not be evident at one minute of life. Some infants randomised at one minute might not need CPAP at 30 minutes of life. We judged this to be unclear risk of bias.

Effects of interventions

See: Table 1; Table 2; Table 3

We included eight studies involving a total of 3201 infants in our updated review (Badiee 2013; Dunn 2011; Finer 2010; Gonçalves‐Ferri 2014; Han 1987; Morley 2008; Sandri 2004; Tapia 2012). We included four studies (765 infants) in the first comparison (CPAP versus supportive care) (Gonçalves‐Ferri 2014; Han 1987; Sandri 2004; Tapia 2012). We included three studies (2364 infants) in the second comparison (CPAP versus mechanical ventilation) (Dunn 2011; Finer 2010; Morley 2008), and one study (72 participants) in the third comparison (prophylactic versus very early CPAP) (Badiee 2013).

Comparison 1: prophylactic or very early CPAP versus supportive care

For details, see Table 1.

Failed treatment, use of mechanical ventilation (outcome 1.1)

Four trials (765 infants) reported on this outcome (Gonçalves‐Ferri 2014; Han 1987; Sandri 2004; Tapia 2012). For three studies, failed treatment was defined as the use of mechanical ventilation; and for one study, it was defined as use of rescue CPAP prior to the use of mechanical ventilation, surfactant, or both (Gonçalves‐Ferri 2014). In two studies (Han 1987; Sandri 2004), there was no difference in the use of mechanical ventilation between the CPAP and control groups. However, in two studies (Gonçalves‐Ferri 2014; Tapia 2012), there is very uncertain evidence that CPAP may reduce the rates of failed treatment compared to the supportive care group. The meta‐analysis of the four studies showed there may be a reduction in failed treatment (RR 0.60, 95% CI 0.49 to 0.74; RD ‐0.16, 95% CI ‐0.22 to ‐0.10; I² = 70%; 4 studies, 765 infants; very low certainty evidence; Analysis 1.1). Because we found substantial heterogeneity, on sensitivity analysis using the random‐effects model, we found that a reduction in failed treatment persisted (RR 0.66, 95% CI 0.45 to 0.98). Subgroup analysis by birth weight did not explain this heterogeneity (typical RR 0.70, 95% CI 0.41 to 1.18; I² = 77%) for infants over 1000 grams (RR 0.60, 95% CI 0.48 to 0.76; 4 trials, 716 infants), and infants under 1000 grams (RR 0.60, 95% CI 0.40 to 0.90; 1 trial, 49 infants) random‐effects, test for subgroup differences P = 0.98, I² = 0%. The available data did not permit the other planned subgroup analyses.

1.1. Analysis.

Comparison 1: Prophylactic CPAP vs supportive care, Outcome 1: Failed treatment

We downgraded this outcome to very low certainty evidence due to substantial heterogeneity, imprecision, and the outcome being susceptible to the lack of blinding of the intervention and outcome assessors.

Bronchopulmonary dysplasia (BPD) (outcomes 1.2, 1.3, 1.4)

Three studies reported that CPAP probably has little to no difference on the incidence of BPD at 28 days when compared to supportive care (RR 1.04, 95% CI 0.84 to 1.28; I² = 38%; 535 participants; moderate certainty evidence; Analysis 1.2) (Gonçalves‐Ferri 2014; Han 1987; Tapia 2012). We downgraded this outcome to moderate certainty because of serious imprecision. Subgroup analysis by birth weight showed no difference between the subgroups, P = 0.45, I²= 0%, for infants over 1000 grams (RR 1.07, 95% CI 0.83 to 1.37; 3 trials, 486 infants), and for infants under 1000 grams (RR 0.91, 95% CI 0.65 to 1.27; 1 trial, 49 infants). Subgroup analysis between the two trials (Han 1987; Tapia 2012), with data on antenatal steroids, one with no usage (82 infants) and one with high usage (256 infants), did not show a difference between the subgroups (test for subgroup differences: P = 0.10, I²= 63.1%; Analysis 1.3).

1.2. Analysis.

Comparison 1: Prophylactic CPAP vs supportive care, Outcome 2: Bronchopulmonary dysplasia at 28 days

1.3. Analysis.

Comparison 1: Prophylactic CPAP vs supportive care, Outcome 3: Bronchopulmonary dysplasia at 28 days

When compared to supportive care, CPAP probably results in a reduction in BPD at 36 weeks, but the confidence interval includes both benefit and harm (RR 0.76, 95% CI 0.51 to 1.14; I² = 14%; 3 studies, 683 infants; moderate certainty evidence; Analysis 1.4) (Gonçalves‐Ferri 2014; Sandri 2004; Tapia 2012). For infants over 1000 grams (RR 0.72, 95% CI 0.43 to 1.19; 3 studies, 634 infants), and infants under 1000 grams (typical RR 0.90, 95% CI 0.47 to 1.71; 1 study, 49 infants), there was no difference between the birth weight subgroups (test for subgroup differences: P = 0.60, I²= 0%).

1.4. Analysis.

Comparison 1: Prophylactic CPAP vs supportive care, Outcome 4: Bronchopulmonary dysplasia at 36 weeks

Death at any time (outcome 1.5)

Death at any time was reported by four studies (Gonçalves‐Ferri 2014; Han 1987; Sandri 2004; Tapia 2012). CPAP probably results in little or no difference in mortality when compared to supportive care (RR 1.04, 95% CI 0.56 to 1.93; I² = 0%; 4 studies, 765 infants; moderate certainty evidence; Analysis 1.5). We downgraded this outcome to moderate certainty because of serious imprecision.

1.5. Analysis.

Comparison 1: Prophylactic CPAP vs supportive care, Outcome 5: Death at anytime

Combined outcome of BPD and death at any time (outcome 1.6)

The combined outcome of BPD or death was reported only by Tapia 2012. CPAP may reduce the composite outcome of death or BPD (RR 0.69, 95% CI 0.40 to 1.19; 1 study, 256 infants; low certainty evidence; Analysis 1.6). We downgraded this outcome to low certainty due to imprecision and failure to reach the optimal information size.

1.6. Analysis.

Comparison 1: Prophylactic CPAP vs supportive care, Outcome 6: Death or bronchopulmonary dysplasia

Use of surfactant (outcome 1.7)

Three studies reported the use of surfactant in the two groups (Gonçalves‐Ferri 2014; Sandri 2004; Tapia 2012). The overall meta‐analysis, the evidence suggests that CPAP may result in a reduction in the use of surfactant when compared to the supportive care group (RR 0.75, 95% CI 0.58 to 0.96; I² = 50.6%; 3 studies, 683 infants; low certainty evidence; Analysis 1.7) (Tapia 2012). We judged this to be an outcome that could be influenced by lack of blinding, and therefore we downgraded the evidence to low certainty due to lack of blinding and imprecision. Subgroup analysis by birth weight did not explain the heterogeneity (test for subgroup differences: p = 0.15, I²= 50.6%). Data were not available for the other planned subgroup analyses.

1.7. Analysis.

Comparison 1: Prophylactic CPAP vs supportive care, Outcome 7: Use of surfactant

Pulmonary air leaks (outcome 1.8)

All three studies reported the rates of pneumothorax (Gonçalves‐Ferri 2014; Sandri 2004; Tapia 2012). There were no differences in the rates between CPAP and supportive care in any study and in the meta‐analysis. There may be no difference in the rates of pneumothorax when CPAP is compared to supportive care (RR 0.75, 95% CI 0.35 to 1.61; I² = 0%; 3 trials, 586 infants; low certainty evidence; Analysis 1.8). We judged the evidence to be of low certainty due to imprecision. We judged this to be an objective outcome so did not downgrade for lack of blinding.

1.8. Analysis.

Comparison 1: Prophylactic CPAP vs supportive care, Outcome 8: Pulmonary airleak (Pneumothorax)

Local trauma (outcome 1.9)

Subglottic stenosis was only reported by Han 1987. There was one case reported out of the 82 infants; it occurred in the supportive care group. No difference was reported. Tapia 2012 reported nasal injury in 11 out of 131 infants in the CPAP group, favouring supportive care (RR 21.95, 95% CI 1.31 to 368.65; RD 0.08, 95% CI 0.03 to 0.13; NNTH 13, 95% CI 33 to 8; 1 study, 256 infants; Analysis 1.9).

1.9. Analysis.

Comparison 1: Prophylactic CPAP vs supportive care, Outcome 9: Local trauma

Feed intolerance 

None of the studies in this comparison reported on this outcome.  

Intraventricular haemorrhage (IVH) (outcomes 1.10, 1.11)

Han 1987 and Tapia 2012 reported IVH of any grade. Both the individual studies and the meta‐analysis showed that CPAP likely results in little or no difference in the incidence of IVH (any grade) when compared to supportive care (RR 1.42, 95% CI 0.94 to 2.13; I² = 4%; 2 studies, 338 infants; Analysis 1.10). Both Sandri 2004 and Tapia 2012 reported IVH Grades 3 or 4. Both the individual studies and the meta‐analysis showed that CPAP probably results in little or no difference in IVH Grades 3 or 4 when compared to supportive care (RR 0.96, 95% CI 0.39 to 2.37; I² = 23%; 2 studies, 486 infants; low certainty evidence; Analysis 1.11). We downgraded the evidence to low certainty due to very serious imprecision.

1.10. Analysis.

Comparison 1: Prophylactic CPAP vs supportive care, Outcome 10: IVH (any grade)

1.11. Analysis.

Comparison 1: Prophylactic CPAP vs supportive care, Outcome 11: IVH grade 3 or 4

Periventricular leukomalacia (PVL) (outcome 1.12)

PVL was only reported by Sandri 2004. No data were presented. They reported no difference between the CPAP and control groups (Analysis 1.12).

1.12. Analysis.

Comparison 1: Prophylactic CPAP vs supportive care, Outcome 12: Periventricular leukomalacia

Necrotising enterocolitis (NEC) (outcome 1.13)

Three studies reported on NEC (Han 1987; Sandri 2004; Tapia 2012). The individual studies and the meta‐analysis showed that CPAP likely results in little or no difference in the incidence of NEC compared to supportive care (RR 0.91, 95% CI 0.55 to 1.50; I² = 34%; 3 studies, 568 infants; Analysis 1.13).

1.13. Analysis.

Comparison 1: Prophylactic CPAP vs supportive care, Outcome 13: Necrotising enterocolitis

Late‐onset systemic infection (outcome 1.14)

Rates of sepsis were reported in three studies (Han 1987; Sandri 2004; Tapia 2012). There were no differences in any of the individual studies and probably no difference in the meta‐analysis (RR 1.04, 95% CI 0.64 to 1.69, I² = 0%; 3 studies, 568 infants; Analysis 1.14).

1.14. Analysis.

Comparison 1: Prophylactic CPAP vs supportive care, Outcome 14: Late onset systemic infection

Retinopathy of prematurity (ROP) (outcome 1.15)

Rates of ROP Grades 3 or 4 were reported in two studies (Han 1987; Sandri 2004). There were no differences in either study and probably no difference in the meta‐analysis (RR 0.67, 95% CI 0.13 to 3.32; I² = 0%; 2 studies, 312 infants; Analysis 1.15).

1.15. Analysis.

Comparison 1: Prophylactic CPAP vs supportive care, Outcome 15: Retinopathy of prematurity grade 3 or 4

Use of healthcare resources, costs of care, and duration of hospitalisation

None of the studies in this comparison reported on these outcomes.

Neurodevelopment impairment 

None of the studies in this comparison reported on this outcome. 

Combined outcome of neurodevelopmental impairment and death 

None of the studies in this comparison reported on this outcome.

Comparison 2: prophylactic or very early CPAP versus mechanical ventilation

For details, see Table 2.

Bronchopulmonary dysplasia (BPD) (outcomes 2.1, 2.2, 2.3)

Three studies reported this outcome (Dunn 2011; Finer 2010; Morley 2008). One study, Morley 2008, reported BPD at 28 days, showing a reduction in the CPAP group (RR 0.81, 95% CI 0.70 to 0.94; 1 study, 610 infants; Analysis 2.1). None of the included studies showed a reduction in BPD at 36 weeks, but in the meta‐analysis, CPAP likely results in a reduction of BPD at 36 weeks when compared to mechanical ventilation (RR 0.89, 95% CI 0.80 to 0.99; RD ‐0.04, 95% CI ‐0.08 to 0.00; NNTB 25, 95% CI 13 to 100; I² = 0%; 3 studies, 2150 infants; moderate certainty evidence; Analysis 2.2; Analysis 2.3). We judged that this outcome would not be influenced by the lack of blinding of the intervention, but certainty would be influenced by imprecision. Subgroup analysis by gestational age of less than 28 weeks (3 studies, 1918 infants) and 28 weeks or more (1 study, 232 infants) did not reveal any difference (test for subgroup differences: P = 0.42, I² = 0%).  

2.1. Analysis.

Comparison 2: Prophylactic CPAP vs mechanical ventilation, Outcome 1: Bronchopulmonary dysplasia (BPD) at 28 days

2.2. Analysis.

Comparison 2: Prophylactic CPAP vs mechanical ventilation, Outcome 2: Bronchopulmonary dysplasia at 36 weeks

2.3. Analysis.

Comparison 2: Prophylactic CPAP vs mechanical ventilation, Outcome 3: Bronchopulmonary dysplasia at 36 weeks (subgroup analysis by CPAP pressure)

Death at any time (outcomes 2.4, 2.5)

Neonatal mortality was reported for a total of 2358 infants in the three studies (Dunn 2011; Finer 2010; Morley 2008). CPAP probably reduces mortality when compared with the ventilation groups (RR 0.82, 95% CI 0.66 to 1.03; I² = 0%; 2358 infants; moderate certainty evidence; Analysis 2.4; Analysis 2.5). We judged that this outcome would not be influenced by the lack of blinding of the intervention, but certainty would be influenced by imprecision.

2.4. Analysis.

Comparison 2: Prophylactic CPAP vs mechanical ventilation, Outcome 4: Death at anytime (subgroups by CPAP pressure)

2.5. Analysis.

Comparison 2: Prophylactic CPAP vs mechanical ventilation, Outcome 5: Death at anytime (subgroups by gestation)

Combined outcome of BPD and death at any time (outcomes 2.6, 2.7)

The combined outcome of BPD and death was reported by all three studies (2358 infants). CPAP likely results in a reduction in the rate of death and BDP when compared to mechanical ventilation (RR 0.89, 95% CI 0.81 to 0.97; RD ‐0.05, 95% CI ‐0.09 to ‐0.01; NNTB 20, 95% CI 11 to 100; I² = 0%; 3 studies, 2350 infants; moderate certainty evidence; Analysis 2.6; Analysis 2.7). We judged that this outcome would not be influenced by the lack of blinding of the intervention, but certainty would be influenced by imprecision.

2.6. Analysis.

Comparison 2: Prophylactic CPAP vs mechanical ventilation, Outcome 6: Death or bronchopulmonary dysplasia

2.7. Analysis.

Comparison 2: Prophylactic CPAP vs mechanical ventilation, Outcome 7: Death or bronchopulmonary dysplasia

Failed treatment (mechanical ventilation) (outcome 2.8)

Two studies reported failed treatment as the need for mechanical ventilation (Dunn 2011; Morley 2008). In both studies, mechanical ventilation was the intervention received by those allocated to the control group. Both studies reported a significant reduction in the need for mechanical ventilation. The meta‐analysis showed a reduction in the CPAP group. Although the meta‐analysis suggested moderate heterogeneity, in the overall meta‐analysis, CPAP likely resulted in a reduction in the use of mechanical ventilation (RR 0.49, 95% CI 0.45 to 0.54; P = 0.06, I² = 71%; 2 studies, 1042 infants; moderate certainty evidence; Analysis 2.8). The results were not substantially altered using a random‐effects model for the meta‐analysis. On subgroup analysis (5 cm versus 8 cm H₂O), there was a reduced need for mechanical ventilation in the trial using 8 cm H₂O (RR 0.46, 95% CI 0.41 to 0.52), compared with the trial using 5 cm H₂O (RR 0.54, 95% CI 0.48 to 0.62; test for subgroup differences: P = 0.07, I² = 70.5%) (Dunn 2011; Morley 2008). We downgraded the certainty of evidence for this outcome to moderate certainty because the decision to provide mechanical ventilation is a subjective outcome susceptible to the lack of blinding of the intervention and outcome assessors. 

2.8. Analysis.

Comparison 2: Prophylactic CPAP vs mechanical ventilation, Outcome 8: Failed Treatment (Mechanical Ventilation)

Use of surfactant (outcome 2.9)

For two studies, surfactant was mandatory in the control group (Dunn 2011; Finer 2010); and for one study, surfactant was not mandated (Morley 2008). All three studies allowed the use of surfactant in the treatment group if intubation was required (Dunn 2011; Finer 2010; Morley 2008). All three showed a reduction in the use of surfactant. When combined in the meta‐analysis, the evidence suggests that CPAP reduces the use of surfactant when compared to the ventilated group. However, there was substantial heterogeneity between the studies, so we are uncertain about the actual effect size (RR 0.60, 95% CI 0.57 to 0.63; RD ‐0.41, 95% CI ‐0.54 to ‐0.28; NNTB 2, 95% CI 1 to 6; P < 0.001, I² = 96%; 3 studies, 2354 infants; low certainty evidence; Analysis 2.9). We downgraded the certainty of the evidence due to lack of blinding and imprecision.

2.9. Analysis.

Comparison 2: Prophylactic CPAP vs mechanical ventilation, Outcome 9: Use of surfactant

Pulmonary air leaks (outcome 2.10)

All three studies reported the rates of pneumothorax, and there was no difference between groups (RR 1.24, 95% CI 0.91 to 1.69; I² = 75%; 3 studies, 2357 infants; Analysis 2.10). There was substantial heterogeneity. Sensitivity analysis using random‐effects meta‐analysis resulted in a similar result but with a wider confidence interval, incorporating a substantial benefit and substantial harm (RR 1.42, 95% CI 0.68 to 2.98). This could be explained on subgroup analysis by starting CPAP pressures (5 cm H₂O versus 8 cm H₂O). In the analysis of the studies receiving 5 cm H₂O (RR 0.96, 95% CI 0.67 to 1.37; I² = 0%; 2 studies, 1747 infants) (Dunn 2011; Finer 2010), and in the study using 8 cm H₂O (Morley 2008), there may have been an increase in pneumothorax in the CPAP group (RR 3.07, 95% CI 1.47 to 6.40; 1 study, 610 infants) (test for subgroup differences: P = 0.005, I² = 87.2%). However, due to the small number of studies in the subgroup analysis, this needs to be treated with caution. We judged this outcome to have low certainty evidence due to a wide confidence interval and heterogeneity. 

2.10. Analysis.

Comparison 2: Prophylactic CPAP vs mechanical ventilation, Outcome 10: Pulmonary airleak (pneumothorax)

Local trauma 

None of the studies in this comparison reported on this outcome.

Feed intolerance 

None of the studies in this comparison reported on this outcome.

Intraventricular haemorrhage (IVH) (outcomes 2.11, 2.12)

One study reported IVH of any grade (Dunn 2011), and it did not show any difference in the incidence of IVH (RR 0.95, 95% CI 0.66 to 1.36; Analysis 2.11). All three studies reported the incidence of IVH Grades 3 or 4. CPAP likely results in little to no difference in severe grades of IVH (Grades 3 or 4) when compared to mechanical ventilation (RR 1.09, 95% CI 0.86 to 1.39; I² = 52%; 3 studies, 2301 infants; Analysis 2.12). We judged this to be moderate certainty evidence due to imprecision.

2.11. Analysis.

Comparison 2: Prophylactic CPAP vs mechanical ventilation, Outcome 11: IVH (any grade)

2.12. Analysis.

Comparison 2: Prophylactic CPAP vs mechanical ventilation, Outcome 12: IVH grade 3 or 4

Periventricular leukomalacia (PVL) (outcome 2.13)

PVL was reported by both Dunn 2011 and Morley 2008. There was probably no difference between the CPAP and mechanical ventilation groups (RR 0.83, 95% CI 0.39 to 1.79; I² = 0%; 2 studies, 1006 infants; Analysis 2.13).

2.13. Analysis.

Comparison 2: Prophylactic CPAP vs mechanical ventilation, Outcome 13: Periventricular leukomalacia

Necrotising enterocolitis (NEC) (outcome 2.14)

There was probably no difference in the incidence of NEC (RR 1.19, 95% CI 0.92 to 1.55; I² = 0%; 3 studies, 2313 infants; Analysis 2.14).

2.14. Analysis.

Comparison 2: Prophylactic CPAP vs mechanical ventilation, Outcome 14: Necrotising enterocolitis

Late‐onset systemic infection (outcome 2.15)

Rates of sepsis were reported by Dunn 2011. There was no difference in the rate between the CPAP and control groups (RR 0.59, 95% CI 0.33 to 1.04; 425 infants; Analysis 2.15).

2.15. Analysis.

Comparison 2: Prophylactic CPAP vs mechanical ventilation, Outcome 15: Late onset systemic infection

Retinopathy of prematurity (ROP) (outcome 2.16)

Rates of ROP Grades 3 or 4 were reported by both Dunn 2011 and Finer 2010. There was no difference in the rates between the CPAP and mechanical ventilation group in either study, and probably no difference in the meta‐analysis (RR 1.03, 95% CI 0.77 to 1.39; I² = 39%; 2 studies, 1359 infants; Analysis 2.16).

2.16. Analysis.

Comparison 2: Prophylactic CPAP vs mechanical ventilation, Outcome 16: Retinopathy of prematurity grade 3 or 4

Use of healthcare resources, costs of care, and duration of hospitalisation

None of the studies in this comparison reported on these outcomes.

Neurodevelopmental impairment (outcome 2.17)

Finer 2010 reported in their follow‐up study (Vaucher 2012), that CPAP probably results in little to no difference in: neurodevelopmental impairment (RR 0.91, 95% CI 0.62 to 1.32); death or neurodevelopmental impairment at 18 to 22 months corrected age (RR 0.93, 95% CI 0.78 to 1.11; 1234 infants; moderate certainty evidence); cognitive score of less than 70 (RR 0.83, CI 0.53 to 1.29; 974 infants); moderate to severe cerebral palsy (RR 1.04, 95% CI 0.56 to 1.90; 990 infants); bilateral blindness (RR 0.54, 95% CI 0.16 to 1.82, 990 infants); or hearing impairment (RR 2.28, 95% CI 0.95 to 5.44). We downgraded the outcome to moderate certainty due to imprecision. 

Combined outcome of neurodevelopmental impairment and death 

None of the studies in this comparison reported on these outcomes.

Comparison 3: prophylactic versus very early CPAP

For details, see Table 3.

Bronchopulmonary dysplasia at 28 days (outcome 3.1)

In Badiee 2013, only 3 of the 72 infants were reported to have BPD at 28 days (RR 0.5, 95% CI 0.05 to 5.27; very low certainty evidence). Thus, we are very uncertain whether there is any difference in BPD between prophylactic and early CPAP groups.  

Failed treatment with CPAP

Although this was reported to be the primary outcome, data were not provided. The authors reported only a P value of 0.06 and stated that infants in the prophylactic CPAP group required less frequent intubation (Badiee 2013).

Death at any time (outcome 3.2)

In the one study (Badiee 2013), prophylactic CPAP may have little to no effect on neonatal mortality when compared to early CPAP, but the evidence is very uncertain (RR 0.75, 95% CI 0.29 to1.94; 72 infants; very low certainty evidence).  

Combined outcome of BPD and death at any time

The study in this comparison did not report on this outcome.  

Use of surfactant (outcome 3.3)

In Badiee 2013, the evidence suggests that prophylactic CPAP, compared to the early CPAP group, may result in a reduction in the use of surfactant (RR 0.64, 95% CI 0.44 to 0.93; 72 infants; low certainty evidence).  

Pulmonary air leaks

There were no cases of pneumothorax in either of the groups reported by the authors.

Local trauma

The study in this comparison did not report on this outcome.

Feed intolerance

The study in this comparison did not report on this outcome.

Intraventricular haemorrhage (IVH) (outcome 3.4)

The evidence suggests a reduction in IVH, any grade, in the prophylactic CPAP group compared to early CPAP (RR 0.70, 95% CI 0.51 to 0.96; 72 infants), but it is very uncertain. 

Periventricular leukomalacia (PVL) 

The study in this comparison did not report on this outcome. 

Necrotising enterocolitis (NEC)

The study in this comparison did not report on this outcome. 

Late‐onset systemic infection (outcome 3.5)

Badiee 2013 reported that there was a decrease in sepsis in the prophylactic CPAP group compared to the early CPAP group (RR 0.46, 95% CI 0.27 to 0.79), but the evidence is very uncertain.

Retinopathy of prematurity 

The study in this comparison did not report on this outcome. 

Use of healthcare resources, costs of care, and duration of hospitalisation

Badiee 2013 reported that there was no significant difference between the groups for the length of stay, but did not provide any useful data.

Neurodevelopmental impairment

The study in this comparison did not report on this outcome.

Combined outcome of neurodevelopmental impairment and death

The study in this comparison did not report on this outcome.

Sensitivity analysis

We did not perform sensitivity analysis by trial quality because all included studies were RCTs and all had lack of blinding of the intervention. We also did not do a sensitivity analysis for trials with missing data because data were almost complete for all outcomes except for neurodevelopmental impairment. For this outcome, there was only one included study. Sensitivity analysis looking at the choice of model for meta‐analysis is included under the relevant outcomes.

Discussion

Summary of main results

This update presents new information about the effects of prophylactic or very early CPAP. We have included one new trial (Badiee 2013), and added a third comparison (prophylactic CPAP compared with very early CPAP).

Comparison 1: prophylactic or very early CPAP compared to supportive care

There may be a reduction in the incidence of failed treatment in the CPAP group compared with the supportive care group, but the evidence is very uncertain.

CPAP may result in a reduction in the use of surfactant when compared to the supportive care group. Compared to supportive care, CPAP probably reduces BPD at 36 weeks. There is little to no difference in the outcomes of BPD at 28 days, death and BPD, pneumothorax, or Grades 3 to 4 IVH.

Comparison 2: prophylactic or very early CPAP compared to mechanical ventilation

Compared to mechanical ventilation, CPAP probably reduces the incidence of BPD at 36 weeks and the combined outcome of death and BPD.

Prophylactic or very early CPAP likely reduces the need for mechanical ventilation probably by almost half and substantially reduces the use of surfactant. Overall, CPAP, when compared with mechanical ventilation, likely results in little to no difference in outcome for the incidence of IVH (Grades 3 to 4), pneumothorax, or neurodevelopmental impairment at two years of age. However, there may be an increase in the incidence of pneumothorax, except in the small subgroup using CPAP applied at 8 cm H₂0.  Although, overall, CPAP may not increase pneumothorax, the test for subgroup differences was significant (P = 0.005), indicating that higher CPAP pressures of 8 cm H₂0 may increase the risk of pneumothorax compared with mechanical ventilation. There is probably no difference in IVH, NEC, ROP, PVL, or sepsis.

Comparison 3: prophylactic CPAP compared with very early CPAP

There is insufficient evidence to show whether prophylactic CPAP, compared with very early CPAP, has any effect on or no difference to the incidence of BPD or death (at 28 days or less). We are also very uncertain whether there may be a slight reduction in the need for mechanical ventilation with the use of prophylactic CPAP.

Overall completeness and applicability of evidence

Although we had insufficient studies to construct a funnel plot, we have no reason to believe that we have missed any studies. The studies were all identified from database searching by Cochrane Neonatal. Consultation with experts in the field, and examining the reference lists of included and excluded studies as well as other related systematic reviews, did not reveal any other studies, strongly suggesting that there is unlikely to be further studies. One multicentre study, Thomson 2002, met our inclusion criteria. However, it could not be included in our analysis because, from the report (in the form of an abstract), although the study's stated aim was to look at prophylactic CPAP, only about three‐quarters of the infants had been initiated on CPAP at six hours of age. By six hours of age, infants with respiratory distress are likely to have established RDS, and hence the use of CPAP would be treating rather than preventing it. The abstract reported no analysable data and the study has not been published in full. The authors reported that the use of CPAP with or without surfactant reduced the need for mechanical ventilation. Therefore, it is possible that if data from that trial could be included, it might affect our final conclusions for comparison 1: prophylactic CPAP compared to supportive care.

We are more confident about the overall completeness of the evidence for comparison 2: prophylactic CPAP compared to mechanical ventilation. The included studies were all large, multicentre studies. Any unidentified studies would likely be small, unpublished studies that would provide little weight in the meta‐analysis. The main clinically important outcomes were reported in all the included trials.

The included studies were from high‐ and upper‐middle‐income countries. We found no studies conducted in lower‐middle‐ or low‐income countries. Therefore, we are uncertain of the applicability of our findings in these settings. There were also little data on the effect of prophylactic or very early CPAP on infants at higher gestations and birth weights. All the included studies recruited only very or extremely preterm babies, or where birthweight was used as inclusion criteria, only very low birth weight infants were included. There were no data on late preterm or low birth weight infants. Such data would be important for low resourced settings. Antenatal steroids were used in more than 60% of mothers in six studies. In one study (Han 1987), no antenatal steroids were used, and in another study (Badiee 2013), the use of antenatal steroids was not reported.

Quality of the evidence

The trials were generally of low risk of selection bias, but due to the nature of the included interventions, all studies lacked blinding of the intervention. We judged that lack of blinding might influence the subjective outcomes (failed treatment, use of surfactant, and mechanical ventilation) but would be unlikely to affect outcomes such as BPD, death at any time, and the combined outcome of BPD and death, all of which have well‐recognised objective definitions. After applying the GRADE criteria, we judged all primary outcomes for the first two comparisons to be of moderate certainty, except 'failed treatment', which we judged to be very low certainty evidence. We downgraded in the following domains: lack of blinding, imprecision, and inconsistency. In the third comparison, we downgraded the primary outcomes of BPD and death to very low certainty because of lack of blinding, imprecision, and selective outcome reporting.

There were protocol‐driven definitions for failed CPAP in comparison 1 (prophylactic CPAP compared to supportive care and use of mechanical ventilation), and in comparison 2 (prophylactic CPAP compared to mechanical ventilation) in all studies. Although blinding of outcome assessors was not used, with these strictly controlled definitions, it could be argued that the lack of blinding is less important. Reported data were generally complete, and we did not find evidence of reporting biases, but the study protocols were not available for some studies.

We did not downgrade any of our outcomes for publication bias. We downgraded one outcome (failed treatment in comparison 1), for inconsistency. We also did not downgrade for indirectness of evidence. Most of our evidence applies to very or extremely preterm infants in upper‐middle‐ and high‐income countries. However, we do not have reason to believe at present that the results could not be applied in other settings.

The certainty of evidence in comparison 3 (prophylactic CPAP compared with very early CPAP) was generally very low due to selective outcome reporting, and serious and very serious imprecision.

Potential biases in the review process

The protocol was first written in 1997 (Subramaniam 1998), and since then, both the research questions about the use of prophylactic CPAP and the methods used for Cochrane Reviews have changed, and we have therefore updated our methods substantially. In addition, due to changes in the research questions about CPAP, we have subsequently had to add two additional comparisons. Comparison 2 was added in the previous update (Subramaniam 2016), and we have added the third comparison for this update. These post hoc changes might be viewed as potential biases in the review process.

We excluded one study that was reported in abstract format (Thomson 2002). Although it contained some usable data, we made a decision not to use these data as it was not clear that prophylactic CPAP was used in the study.

For the 2020 update, Embase, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) were not searched separately. This modification to our search methods may have reduced the retrieval of available studies on prophylactic CPAP. While trial records from Embase, ClincalTrials.gov and ICTPR are included in CENTRAL, we acknowledge a publishing delay from when study records are first available in their original sources and when they are available in CENTRAL. This publishing delay may have prevented recent trial records and reports from being identified for the 2020 update. Further, searching only CENTRAL for records from these sources may have lessened the likelihood of retrieving eligible studies due to the limited number of fields that are published in CENTRAL, compared to the original source databases. For future updates of this review, we will search Embase, ClinicalTrials.gov, and ICTRP separately to ensure maximum retrieval of eligible study records. 

We have included subgroup analyses where as few as a single study is used in one of the subgroups. We have included these because weight and gestation groups are commonly used in guideline development.

Agreements and disagreements with other studies or reviews

CPAP has been shown to be beneficial for preterm infants with RDS (Ho 2020b); and also at extubation from mechanical ventilation (Davis 2003). This review on prophylactic CPAP strengthens the body of evidence that CPAP is beneficial in the management of the preterm infant.

One systematic review studied a slightly different question (Schmolzer 2013): the effect of prophylactic or very early CPAP compared with either surfactant using the INSURE technique or mechanical ventilation. This review provides further evidence supporting a reduction in the outcome of BPD and the combined outcome of death and BPD with the use of prophylactic or very early CPAP.

Authors' conclusions

Implications for practice.

Continuous positive airway pressure (CPAP) compared to supportive care: in settings where the treatment choice is between CPAP and supportive care, this review provides very low certainty evidence that CPAP may reduce failure of treatment.

Prophylactic or very early CPAP compared to mechanical ventilation: there is moderate certainty evidence that CPAP applied prophylactically within the first 15 minutes of life or very early within the first hour of life, reduces the incidence of bronchopulmonary dysplasia (BPD), the combined outcome of death and BPD, as well as the need for mechanical ventilation.

Prophylactic CPAP compared to very early CPAP: we are very uncertain whether there is any difference between these two interventions.

Implications for research.

There is an urgent need to evaluate the cost and effectiveness of prophylactic or very early CPAP in both low‐ and lower‐middle‐income settings where surfactant therapy is limited. Prophylactic or very early CPAP should be compared with current methods of management available in these settings, such as low flow nasal oxygen, head box, or other forms of delivery of oxygen therapy that do not generate a positive pressure. Other supportive care, such as warmth and nutrition, if available, should be given to both comparison groups. Trials need to be stratified for weight or gestational age to determine if differences in effectiveness occur in lighter, less mature infants and also in late preterm infants. It would also be important to follow up infants into childhood where possible.

In high‐income countries, further trials to determine the best definition of CPAP failure and to evaluate alternative methods of surfactant delivery to babies managed on CPAP are required.

Feedback

Feedback from C Morley, 21 May 2009

Summary

If the review is “Prophylactic nasal continuous positive airway pressure for preventing morbidity and mortality in very preterm infants”, then I think you should include the COIN trial. The other situation where the word prophylactic is used is for surfactant. You can argue about the minutiae of the definition of prophylactic but the COIN trial was the largest RCT so far to enrol infants to nasal CPAP within 5 minutes of birth and therefore it really fulfils the definition of prophylactic.

Reply

Feedback Comment:
To be included in COIN, babies had to have some respiratory distress at 5 minutes of age Therefore this is treatment not prophylaxis. This included the subjective and inaccurate sign of cyanosis. The numbers of infants eligible by gestational age but excluded because they had no respiratory distress isn't captured in the paper and I don't think we have the unpublished data to tell. In practice, lack of respiratory distress was a very rare exclusion criteria at RWH where most of the babies were recruited. The spirit of the trial was that babies who were breathing at 5 minutes were randomised but they had signs of respiratory distress and or failure (cyanosis) which I guess makes it not suitable for inclusion in the prophylaxis review rather than the treatment review.

Contributors

Colin J Morley
David J Henderson‐Smart
Peter G Davis
Prema Subramaniam

What's new

Date	Event	Description
20 November 2020	New citation required and conclusions have changed	We included another study (Badiee 2013), in this review as a third comparison. We added no new studies to the existing two comparisons. We added follow‐up data to one of the existing comparisons. The objective has been defined in a more specific way without changing its meaning.
6 November 2020	New search has been performed	We reran the search to 6 November 2020.

History

Protocol first published: Issue 1, 1997
Review first published: Issue 4, 1998

Date	Event	Description
14 February 2019	Amended	Title amended. Inclusion criteria amended to include infants below 37 weeks. Intervention amended to include prophylactic and very early CPAP
16 February 2016	New search has been performed	This review updates the previous version published in Issue 1, 2009. The background section has been updated and a new search has resulted in the inclusion of five new studies. Another study previously awaiting further assessment has been included in the review but not in the analysis.The methods section has been modified to meet current standards of describing methods without any substantive change in the original methods used. This has lead to a more complete description of assessment of risk of bias, the methods used in the analysis and exploration of heterogeneity. This was done prior to performing the search and analysis.
16 February 2016	New search has been performed	In our original comparison, standard care was not defined. We therefore have clarified this by dividing standard care into two groups of comparisons ‐ supportive care and mechanical ventilation allowing us to do away with the term 'standard care'.
12 March 2009	New search has been performed	This review updates the existing review of 'Prophylactic nasal continuous positive airways pressure to prevent morbidity and mortality in preterm infants' published in The Cochrane Library Issue 3, 2005 (Subramaniam 2005). The updated search included two additional studies One of these studies, the COIN trial (Morley 2008), had previously been referenced as an "Ongoing study" has now been completed.
16 October 2008	Amended	Converted to new review format.
20 April 2005	New citation required but conclusions have not changed	Substantive amendment
20 April 2005	New search has been performed	This review updates the existing review of 'Prophylactic nasal continuous positive airways pressure to prevent morbidity and mortality in preterm infants' which was published in The Cochrane Library Issue 2, 2002 (Subramaniam 2002). The search revealed one new published eligible trial Sandri (2004). Author clarification regarding randomization and outcome definitions has been received for one trial (Han 1987) and added to the review. The completed trial by Thomson has not been published except in abstract form and is in the 'Trials awaiting assessment' section.

Appendices

Appendix 1. 2020 search methods

The RCT filters have been created using Cochrane's highly sensitive search strategies for identifying randomised trials (Higgins 2020). The neonatal filters were created and tested by the Cochrane Neonatal Information Specialist.

CENTRAL via CRS Web:

Date searched: 06 November 2020
Terms:
1 MESH DESCRIPTOR positive‐pressure respiration EXPLODE ALL AND CENTRAL:TARGET
2 MESH DESCRIPTOR Continuous Positive Airway Pressure EXPLODE ALL AND CENTRAL:TARGET
3 continuous positive airway pressure or continuous positive pressure or continuous distending airway pressure or continuous distending pressure or continuous positive transpulmonary pressure or continuous transpulmonary pressure or continuous inflating pressure or continuous negative distending pressure or continuous negative pressure or continuous airway pressure AND CENTRAL:TARGET
4 cpap or ncpap AND CENTRAL:TARGET
5 #1 OR #2 OR #3 OR #4
6 MESH DESCRIPTOR Infant, Newborn EXPLODE ALL AND CENTRAL:TARGET
7 infant or infants or infant's or "infant s" or infantile or infancy or newborn* or "new born" or "new born's" or "newly born" or neonate* or baby* or babies or premature or premature or prematurity or preterm or preterms or "pre term" or premies or "low birth weight" or "low birthweight" or VLBW or LBW or ELBW or NICU AND CENTRAL:TARGET
8 #7 OR #6 AND CENTRAL:TARGET
9 #5 AND #8

MEDLINE via Ovid ‐ Ovid MEDLINE(R) and Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Daily and Versions(R):

Date ranges: 1946 to 06 November 2020
Terms:
1. exp positive‐pressure respiration/ or exp continuous positive airway pressure/
2. (continuous positive airway pressure or continuous positive pressure or continuous distending airway pressure or continuous distending pressure or continuous positive transpulmonary pressure or continuous transpulmonary pressure or continuous inflating pressure or continuous negative distending pressure or continuous negative pressure or continuous airway pressure).mp.
3. (cpap or ncpap).mp.
4. 1 or 2 or 3 [Intervention terms]
5. exp infant, newborn/
6. (newborn* or new born or new born's or newly born or baby* or babies or premature or prematurity or preterm or pre term or low birth weight or low birthweight or VLBW or LBW or infant or infants or 'infant s' or infant's or infantile or infancy or neonat*).ti,ab.
7. 5 or 6 [Neonatal population terms]
8. randomised controlled trial.pt.
9. controlled clinical trial.pt.
10. randomized.ab.
11. placebo.ab.
12. drug therapy.fs.
13. randomly.ab.
14. trial.ab.
15. groups.ab.
16. or/8‐15
17. exp animals/ not humans.sh.
18. 16 not 17 [RCT Filter 1: Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity‐maximizing version (2008 revision); Ovid format ]

19. random?ed.ti,ab. or randomly.ti,ab. or trial.ti,ab. or groups.ti,ab. or ((single or doubl* or tripl* or treb*) and (blind* or mask*)).ti,ab. OR placebo*.ti,ab. 

20. limit 19 to yr="2019‐2020" [RCT filter 2: to capture recent studies not found by the Cochrane RCT filter per Line 18]
21. 4 and 7 and  (18 or 20) [CPAP AND Neonatal terms and RCT filters ]

ISRCTN:

Date searched: 06 November 2020
Terms:
Interventions: Continuous positive airway pressure AND Participant age range: Neonate
Interventions: Cpap AND Participant age range: Neonate

Appendix 2. 2017 search methods

In 2017, we conducted a comprehensive search including: Cochrane Central Register of Controlled Trials (CENTRAL 2020, Issue 6) in The Cochrane Library; MEDLINE via PubMed (01 January 2007 to 30 June 2020); Embase (01 January 2007 to 30 June 2020); and CINAHL (01 January 2007 to 30 June 2020) using the following search terms.

PubMed:

(continuous positive airway pressure[MeSH] OR continuous positive pressure OR continuous positive airway pressure OR CPAP OR continuous distending airway pressure OR continuous positive transpulmonary pressure OR continuous transpulmonary pressure OR continuous inflating pressure OR continuous negative distending pressure OR continuous negative pressure OR continuous airway pressure) AND ((infant, newborn[MeSH] OR infan* OR newborn OR neonat* OR premature OR low birth weight OR VLBW OR LBW) AND (randomised controlled trial [pt] OR controlled clinical trial [pt] OR randomised [tiab] OR placebo [tiab] OR drug therapy [sh] OR randomly [tiab] OR trial [tiab] OR groups [tiab]) NOT (animals [mh] NOT humans [mh]))

Embase:

((exp positive end expiratory pressure) OR (continuous positive pressure OR continuous positive airway pressure OR CPAP OR continuous distending airway pressure OR continuous positive transpulmonary pressure OR continuous transpulmonary pressure OR continuous inflating pressure OR continuous negative distending pressure OR continuous negative pressure OR continuous airway pressure)) AND ((exp infant) OR (infan* OR newborn or neonat* OR premature or very low birth weight or low birth weight or VLBW or LBW).mp AND (human not animal) AND (randomised controlled trial or controlled clinical trial or randomised or placebo or clinical trials as topic or randomly or trial or clinical trial).mp

CINAHL:

(continuous positive airway pressure OR continuous positive pressure OR CPAP OR continuous distending airway pressure OR continuous positive transpulmonary pressure OR continuous transpulmonary pressure OR continuous inflating pressure OR continuous negative distending pressure OR continuous negative pressure OR continuous airway pressure) AND (infan* OR newborn OR neonat* OR premature OR low birth weight OR VLBW OR LBW) AND (randomised controlled trial OR controlled clinical trial OR randomised OR placebo OR clinical trials as topic OR randomly OR trial OR PT clinical trial)

CRS:

(continuous positive airway pressure[MeSH]) OR (continuous positive airway pressure OR continuous positive pressure OR CPAP OR continuous distending airway pressure OR continuous positive transpulmonary pressure OR continuous transpulmonary pressure OR continuous inflating pressure OR continuous negative distending pressure OR continuous negative pressure OR continuous airway pressure) AND (infan* or newborn or neonat* or premature or preterm or very low birth weight or low birth weight or VLBW or LBW)

We did not apply language restrictions.

We searched clinical trials registries for ongoing or recently completed trials (clinicaltrials.gov; the World Health Organization’s International Trials Registry and Platform, and the ISRCTN Registry).

Appendix 3. Previous search methodology

We conducted a comprehensive search including: the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 1) in The Cochrane Library; MEDLINE via PubMed (1966 to 31 January 2016); Embase (1980 to 31 January 2016); and CINAHL (1982 to 31 January 2016). We used the following search terms: (respiratory distress syndrome OR hyaline membrane disease OR continuous distending pressure OR continuous distending airway pressure OR continuous positive airway pressure OR continuous positive transpulmonary pressure OR continuous transpulmonary pressure OR continuous inflating pressure OR continuous negative distending pressure OR continuous negative pressure OR continuous airway pressure OR CPAP), plus database‐specific limiters for RCTs and neonates:

PubMed: ((infant, newborn[MeSH] OR infan* OR newborn OR neonat* OR premature OR low birth weight OR VLBW OR LBW) AND (randomised controlled trial [pt] OR controlled clinical trial [pt] OR randomised [tiab] OR placebo [tiab] OR drug therapy [sh] OR randomly [tiab] OR trial [tiab] OR groups [tiab]) NOT (animals [mh] NOT humans [mh]))

Embase: ((exp infant) OR (infan* OR newborn or neonat* OR premature or very low birth weight or low birth weight or VLBW or LBW).mp AND (human not animal) AND (randomised controlled trial or controlled clinical trial or randomised or placebo or clinical trials as topic or randomly or trial or clinical trial).mp

CINAHL: (infan* OR newborn OR neonat* OR premature OR low birth weight OR VLBW OR LBW) AND (randomised controlled trial OR controlled clinical trial OR randomised OR placebo OR clinical trials as topic OR randomly OR trial OR PT clinical trial)

Cochrane Library: (infan* or newborn or neonat* or premature or preterm or very low birth weight or low birth weight or VLBW or LBW)

We did not apply language restrictions.

Appendix 4. Risk of bias tool

1. Sequence generation (checking for possible selection bias). Was the allocation sequence adequately generated?

For each included study, we categorised the method used to generate the allocation sequence as:

1. low risk (any truly random process e.g. random number table; computer random number generator);

2. high risk (any non‐random process e.g. odd or even date of birth; hospital or clinic record number); or

3. unclear risk.

2. Allocation concealment (checking for possible selection bias). Was allocation adequately concealed?

For each included study, we categorised the method used to conceal the allocation sequence as:

1. low risk (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);

2. high risk (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth); or

3. unclear risk.

3. Blinding of participants and personnel (checking for possible performance bias). Was knowledge of the allocated intervention adequately prevented during the study?

For each included study, we categorised the methods used to blind study participants and personnel from knowledge of which intervention a participant received. Blinding was assessed separately for different outcomes or class of outcomes. We categorised the methods as:

1. low risk, high risk or unclear risk for participants; and

2. low risk, high risk or unclear risk for personnel.

4. Blinding of outcome assessment (checking for possible detection bias). Was knowledge of the allocated intervention adequately prevented at the time of outcome assessment?

For each included study, we categorised the methods used to blind outcome assessment. Blinding was assessed separately for different outcomes or class of outcomes. We categorised the methods as:

1. low risk for outcome assessors;

2. high risk for outcome assessors; or

3. unclear risk for outcome assessors.

5. Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations). Were incomplete outcome data adequately addressed?

For each included study and for each outcome, we described the completeness of data including attrition and exclusions from the analysis. We noted whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported or supplied by the trial authors, we re‐included missing data in the analyses. We categorised the methods as:

1. low risk (< 20% missing data);

2. high risk (≥ 20% missing data); or

3. unclear risk.

6. Selective reporting bias. Are reports of the study free of suggestion of selective outcome reporting?

For each included study, we described how we investigated the possibility of selective outcome reporting bias and what we found. For studies in which study protocols were published in advance, we compared prespecified outcomes versus outcomes eventually reported in the published results. If the study protocol was not published in advance, we contacted study authors to gain access to the study protocol. We assessed the methods as:

1. low risk (where it is clear that all of the study's prespecified outcomes and all expected outcomes of interest to the review have been reported);

2. high risk (where not all the study's prespecified outcomes have been reported; one or more reported primary outcomes were not prespecified outcomes of interest and are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported); or

3. unclear risk.

7. Other sources of bias. Was the study apparently free of other problems that could put it at a high risk of bias?

For each included study, we described any important concerns we had about other possible sources of bias (for example, whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data‐dependent process). We assessed whether each study was free of other problems that could put it at risk of bias as:

1. low risk;

2. high risk; or

3. unclear risk.

If needed, we explored the impact of the level of bias through undertaking sensitivity analyses.

Data and analyses

Comparison 1. Prophylactic CPAP vs supportive care.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Failed treatment	4	765	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.49, 0.74]
1.1.1 Birth weight ≥ 1000 grams	4	716	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.48, 0.76]
1.1.2 Birth weight < 1000 grams	1	49	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.40, 0.90]
1.2 Bronchopulmonary dysplasia at 28 days	3	535	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.84, 1.28]
1.2.1 Birth weight ≥ 1000 grams	3	486	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.83, 1.37]
1.2.2 Birth weight < 1000 grams	1	49	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.65, 1.27]
1.3 Bronchopulmonary dysplasia at 28 days	2	338	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.78, 1.22]
1.3.1 Antenatal steroids	1	256	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.71, 1.13]
1.3.2 No antenatal steroids	1	82	Risk Ratio (M‐H, Fixed, 95% CI)	2.27 [0.77, 6.65]
1.4 Bronchopulmonary dysplasia at 36 weeks	3	683	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.51, 1.14]
1.4.1 Birth weight ≥ 1000 grams	3	634	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.43, 1.19]
1.4.2 Birth weight < 1000 grams	1	49	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.47, 1.71]
1.5 Death at anytime	4	765	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.60, 1.96]
1.5.1 Birth weight ≥ 1000 grams	4	716	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.52, 2.09]
1.5.2 Birth weight < 1000 grams	1	49	Risk Ratio (M‐H, Fixed, 95% CI)	1.22 [0.39, 3.79]
1.6 Death or bronchopulmonary dysplasia	1	256	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.40, 1.19]
1.6.1 Birth weight ≥ 1000 grams	1	207	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.29, 1.30]
1.6.2 Birth weight < 1000 grams	1	49	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.37, 1.82]
1.7 Use of surfactant	3	683	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.58, 0.96]
1.7.1 Birth weight > 1000 grams	3	634	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.61, 1.05]
1.7.2 Birth weight < 1000 grams	1	49	Risk Ratio (M‐H, Fixed, 95% CI)	0.51 [0.29, 0.89]
1.8 Pulmonary airleak (Pneumothorax)	3	568	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.35, 1.61]
1.9 Local trauma	2		Risk Difference (M‐H, Random, 95% CI)	Subtotals only
1.9.1 Subglottic stenosis	1	82	Risk Difference (M‐H, Random, 95% CI)	‐0.03 [‐0.09, 0.04]
1.9.2 Nasal injury	1	256	Risk Difference (M‐H, Random, 95% CI)	0.08 [0.03, 0.13]
1.10 IVH (any grade)	2	338	Risk Ratio (M‐H, Fixed, 95% CI)	1.42 [0.94, 2.13]
1.11 IVH grade 3 or 4	2	486	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.39, 2.37]
1.12 Periventricular leukomalacia	1	230	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.04, 3.16]
1.13 Necrotising enterocolitis	3	568	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.55, 1.50]
1.14 Late onset systemic infection	3	568	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.64, 1.69]
1.15 Retinopathy of prematurity grade 3 or 4	2	312	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.13, 3.32]

Comparison 2. Prophylactic CPAP vs mechanical ventilation.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Bronchopulmonary dysplasia (BPD) at 28 days	1	610	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.70, 0.94]
2.2 Bronchopulmonary dysplasia at 36 weeks	3	2150	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.80, 0.99]
2.2.1 Gestation < 28 weeks	3	1918	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.78, 0.98]
2.2.2 Gestation ≥ 28 weeks	1	232	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.64, 1.88]
2.3 Bronchopulmonary dysplasia at 36 weeks (subgroup analysis by CPAP pressure)	3	2150	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.79, 0.99]
2.3.1 CPAP started at 5 cmH2O	2	1540	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.80, 1.03]
2.3.2 CPAP started at 8 cmH2O	1	610	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.65, 1.06]
2.4 Death at anytime (subgroups by CPAP pressure)	3	2358	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.66, 1.03]
2.4.1 CPAP started at 5 cmH2O	2	1748	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.62, 0.99]
2.4.2 CPAP started at 8 cmH2O	1	610	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.59, 2.03]
2.5 Death at anytime (subgroups by gestation)	3	2358	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.66, 1.03]
2.5.1 Gestation < 28 weeks	3	2126	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.66, 1.04]
2.5.2 Gestation ≥ 28 weeks	1	232	Risk Ratio (M‐H, Fixed, 95% CI)	0.55 [0.13, 2.25]
2.6 Death or bronchopulmonary dysplasia	3	2358	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.81, 0.97]
2.6.1 CPAP started at 5 cmH2O	2	1748	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.81, 0.98]
2.6.2 CPAP started at 8 cmH2O	1	610	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.70, 1.07]
2.7 Death or bronchopulmonary dysplasia	3	2358	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.81, 0.97]
2.7.1 Gestation < 28 weeks	3	2126	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.80, 0.96]
2.7.2 Gestation ≥ 28 weeks	1	232	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.63, 1.68]
2.8 Failed Treatment (Mechanical Ventilation)	2	1042	Risk Ratio (M‐H, Fixed, 95% CI)	0.49 [0.45, 0.54]
2.8.1 CPAP started at 5 cmH2O	1	432	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.48, 0.62]
2.8.2 CPAP started at 8 cmH2O	1	610	Risk Ratio (M‐H, Fixed, 95% CI)	0.46 [0.41, 0.52]
2.9 Use of surfactant	3	2354	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.57, 0.63]
2.9.1 CPAP started at 5 cmH2O	2	1744	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.59, 0.66]
2.9.2 CPAP started at 8 cmH2O	1	610	Risk Ratio (M‐H, Fixed, 95% CI)	0.49 [0.42, 0.57]
2.10 Pulmonary airleak (pneumothorax)	3	2357	Risk Ratio (M‐H, Fixed, 95% CI)	1.24 [0.91, 1.69]
2.10.1 CPAP started at 5 cmH2O	2	1747	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.67, 1.37]
2.10.2 CPAP started at 8 cmH2O	1	610	Risk Ratio (M‐H, Fixed, 95% CI)	3.07 [1.47, 6.40]
2.11 IVH (any grade)	1	421	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.66, 1.36]
2.12 IVH grade 3 or 4	3	2301	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.86, 1.39]
2.13 Periventricular leukomalacia	2	1006	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.39, 1.79]
2.14 Necrotising enterocolitis	3	2331	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [0.92, 1.55]
2.15 Late onset systemic infection	1	425	Risk Ratio (M‐H, Random, 95% CI)	0.59 [0.33, 1.04]
2.16 Retinopathy of prematurity grade 3 or 4	2	1359	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.77, 1.39]
2.17 Neurodevelopmental Impairment at 18 to 22 months corrected age	1	976	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.62, 1.32]
2.18 Death or neurodevelopment impairment at 18 to 22 months corrected age	1	1234	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.78, 1.11]
2.19 Moderate or severe cerebral palsy	1	990	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.56, 1.90]
2.20 Bilateral blindness	1	990	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.16, 1.82]
2.21 Hearing Impairment	1	990	Risk Ratio (M‐H, Fixed, 95% CI)	2.28 [0.95, 5.44]
2.22 Cognitive score < 70	1	1044	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.53, 1.29]

2.17. Analysis.

Comparison 2: Prophylactic CPAP vs mechanical ventilation, Outcome 17: Neurodevelopmental Impairment at 18 to 22 months corrected age

2.18. Analysis.

Comparison 2: Prophylactic CPAP vs mechanical ventilation, Outcome 18: Death or neurodevelopment impairment at 18 to 22 months corrected age

2.19. Analysis.

Comparison 2: Prophylactic CPAP vs mechanical ventilation, Outcome 19: Moderate or severe cerebral palsy

2.20. Analysis.

Comparison 2: Prophylactic CPAP vs mechanical ventilation, Outcome 20: Bilateral blindness

2.21. Analysis.

Comparison 2: Prophylactic CPAP vs mechanical ventilation, Outcome 21: Hearing Impairment

2.22. Analysis.

Comparison 2: Prophylactic CPAP vs mechanical ventilation, Outcome 22: Cognitive score < 70

Comparison 3. Prophylactic vs very early CPAP.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Bronchopulmonary dysplasia at 28 days	1	72	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.05, 5.27]
3.2 Death at anytime	1	72	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.29, 1.94]
3.2.1 Gestation ≥ 28 weeks	1	72	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.29, 1.94]
3.3 Use of surfactant	1	72	Risk Ratio (M‐H, Fixed, 95% CI)	0.64 [0.44, 0.93]
3.3.1 CPAP started at 5 cmH2O	1	72	Risk Ratio (M‐H, Fixed, 95% CI)	0.64 [0.44, 0.93]
3.4 IVH (any grade)	1	72	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.51, 0.96]
3.5 Late onset systemic infection	1	72	Risk Ratio (M‐H, Fixed, 95% CI)	0.46 [0.27, 0.79]

3.1. Analysis.

Comparison 3: Prophylactic vs very early CPAP, Outcome 1: Bronchopulmonary dysplasia at 28 days

3.2. Analysis.

Comparison 3: Prophylactic vs very early CPAP, Outcome 2: Death at anytime

3.3. Analysis.

Comparison 3: Prophylactic vs very early CPAP, Outcome 3: Use of surfactant

3.4. Analysis.

Comparison 3: Prophylactic vs very early CPAP, Outcome 4: IVH (any grade)

3.5. Analysis.

Comparison 3: Prophylactic vs very early CPAP, Outcome 5: Late onset systemic infection

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Badiee 2013.

Study characteristics
Methods	Randomised controlled trial conducted from June 2009 to September 2010 at the Shahid Beheshti University Hospital, Isfahan, Iran
Participants	72 inborn neonates with gestational age between 25 and 30 weeks who received respiratory support because of RDS and breathing spontaneously at 5 minutes after birth were included. The diagnosis of RDS was based on at least 2 of the following classic symptoms: need of supplemental oxygen, tachypnoea, intercostal retraction, grunting, and exclusion of other causes of respiratory distress. The mean birth weights and gestations were 983 grams (SD 223.9) and 29.6 weeks (SD 1.8) in the early CPAP group and 1070 grams (SD 184.6) and 29.8 weeks (SD 1.70) in the late CPAP group. Infants that were excluded had major congenital malformation, demonstrated gasping respiration, or required endotracheal intubation due to respiratory failure (a partial pressure of CO2 more than 60 mmHg and a pH less than 7.25) immediately after birth.
Interventions	Experimental group: 36 preterm infants were given early CPAP, at a pressure of 6 cm H2O, using a nasopharyngeal tube in the delivery room. The infants were transported to the NICU and the nasopharyngeal tube was discarded and a binasal prong (equipped with Hudson‑prong) was used for delivering CPAP by bubble CPAP. Control group: 36 preterm infants were given early CPAP initiated 15 minutes after birth. Oxygen was administrated by an oxyhood until 30 minutes after birth. If the infants required oxygen for more than 30 minutes, then nCPAP was administered at a pressure of 6 cm H2O with a single nasopharyngeal tube. After NICU admission, short binasal prongs connected to a bubble CPAP at the same pressure were used.   For both groups, surfactant via INSURE (INtubation, SURfactant administration, Extubation) was given to infants if PO2 less than 88% in an FiO2 more than 0.6. Intubation criteria were arterial pH < 7.2, PaCO2 > 65 mmHg or recurrent apnoea unresponsive to methylxanthine therapy after initiation of nCPAP.
Outcomes	Reported 72 infants Primary outcome Need for mechanical ventilation in first 48 hours Secondary outcomes Death Pneumothorax Intraventricular haemorrhage Need for mechanical ventilation Bronchopulmonary dysplasia
Notes	Sepsis was defined according to the attending neonatologist BPD defined as need for any supplemental oxygen after 28 days from birth IVH was identified by serial ultrasound on days 3, 7 and 14. Hydrocephalus by bi‐weekly ultrasound in infants with IVH.   Source of funding was not stated. No declarations of interest among the primary researchers were available
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomised at one minute of life. Method of generation of random sequence not reported. Stratified by gestational age
Allocation concealment (selection bias)	Low risk	Sequentially numbered sealed envelopes
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Not reported
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete follow‐up
Selective reporting (reporting bias)	High risk	The results were reported only as percentages. The primary outcome was reported last and data were not given. Means were reported without SDs. Conclusion given does not appear to be consistent with the data. (Authors state there is evidence that very early is better than early.) Data was stratified by gestation. Results not reported.
Other bias	High risk	No baseline imbalance. Infants were randomised at one minute of life. It is noted that the inclusion criteria would not be evident at one minute of life. Some infants randomised at one minute might not need CPAP at 30 minutes of life.

Dunn 2011.

Study characteristics
Methods	The study was a multicentre randomised controlled trial conducted between September 2003 and March 2009 at 27 participating Vermont Oxford Network centres across North America (Canada and the USA). The trial consisted of 3 interventions, 2 of which were relevant to this review and included in the data analysis.
Participants	We included 432 of 656 infants. Neonates born between 26 weeks' gestation and 29 weeks 6 days' gestation were enrolled at participating Vermont Oxford Network centres. Infants could be excluded after randomisation only if found to be stillborn or to have a previously unrecognised life‐threatening congenital anomaly. The mean birth weights of the infants were 1053 grams (SD 252) and 1040 grams (SD 244) in the CPAP and surfactant groups, respectively, and the mean gestations were 28.1 weeks (SD 1.1) and 28 weeks (SD 1.1) in the CPAP and surfactant groups, respectively. Antenatal steroids were given to 98% of mothers.
Interventions	Experimental group: 223 infants were to be supported with nasal CPAP within 15 minutes after birth. Infants who received nCPAP were initially supported with a pressure of 5 cm H2O, which could be increased to a maximum of 7 cm H2O. These infants were intubated only if meeting 1 or more of the following criteria. More than 12 episodes of apnoea that required stimulation or more than 1 episode that required bagging in a 6‐hour period PaCO₂ > 65 mmHg on arterial or capillary blood gas Requirement for FiO₂ of > 0.4 to maintain oxygen saturation of 86% to 94% Intubation was discretionary if FiO₂ was 0.4 to 0.6 and mandatory if FiO₂ > 0.6. Control group: 209 infants were intubated 5 to 15 minutes after birth. These infants were then given surfactant and stabilised on mechanical ventilation for a minimum of 6 hours.
Outcomes	Reported 432 infants. Primary outcome Death or moderate to severe BPD at 36 weeks Secondary outcomes included number of infants who received surfactant use of postnatal steroids days on mechanical ventilation pneumothorax pulmonary haemorrhage PDA NEC IVH (severe) PVL ROP
Notes	Source of funding not stated. The authors have indicated they have no financial relationships relevant to the article. No declarations of interest among the primary researchers were available.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Investigators randomly allocated infants to the different treatment arms by drawing a card contained within a sealed envelope. Stratification and block randomisation was according to centre and according to gestational age. Block size not stated. Infants from multiple gestation pregnancies were randomly assigned as individual subjects. Infants from multiple gestations were assigned as a single infant.
Allocation concealment (selection bias)	Low risk	A sealed envelope was used.
Blinding (performance bias and detection bias) All outcomes	High risk	Blinding of intervention: no
Blinding of outcome assessment (detection bias) All outcomes	High risk	This was not used for IPPV
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete follow‐up, in 99% of cases in the treatment group and 98% in the control group, (1 treatment and 4 control infants excluded due to major birth defect; no consent; and 2 were stillborn)
Selective reporting (reporting bias)	Low risk	Protocol available. All of the study's prespecified outcomes have been reported.
Other bias	Low risk	None detected

Finer 2010.

Study characteristics
Methods	Multicentre study, randomised controlled trial conducted in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network, USA, from February 2005 to February 2009 Multifactorial design. Infants were randomised to low‐ and high‐oxygen saturation levels and then to the two interventions relevant to this review.
Participants	1316 infants with a gestational age at delivery between 24 weeks and 27 weeks 6 days without known malformations The mean birth weights were 834.6 grams (SD 188.2) and 825.5 grams (SD 198.1) for the CPAP and surfactant groups, respectively, and the mean gestations were 26.2 weeks (SD 1.1) in both groups. A single dose of antenatal steroids was given to 96% of mothers and a full course of steroids was given to 73.6% and 69.8% of mother whose babies were in the CPAP and surfactant groups, respectively. Inclusion criteria were: birth in a centre participating in the trial; a decision had been made to provide full resuscitation; written informed consent had been obtained from a parent or guardian. Infants who were excluded were those who received intubation for resuscitation on the basis of standard indications specified in the Neonatal Resuscitation Program guidelines or did not meet the eligibility criteria.
Interventions	Experimental group (n = 663) received nasal CPAP via a T‐piece resuscitator, a neonatal ventilator or an equivalent device with a recommended pressure of 5 cm H₂O in the delivery room irrespective of respiratory status. Infants were intubated if they met any of the following criteria for intubation: pH < 7.25, PaCO₂ > 65 mmHg, FiO₂ > 0.5 or haemodynamic instability defined as a blood pressure that was low for gestational age, poor perfusion, or both, requiring volume or pressure support for 4 hours or more. The allocated treatment was commenced soon after birth (n = 663). The control group (n = 653) were intubated within 1 hour of life in the delivery room and received surfactant. They could be extubated within 24 hours if they met prespecified criteria: PaCO₂ of less than 50 mmHg, pH > 7.30, FiO₂ ≥ 0.35, SpO₂ ≥ 88%, a mean arterial pressure of 8 cm H₂O or less, a ventilator rate ≥ 20 breaths/minute, amplitude < twice the mean arterial pressure if on high frequency ventilation, haemodynamic stability, without clinically significant patent ductus arteriosus (n = 653).
Outcomes	Reported a total of 1316 infants Primary outcome Death or BPD at 36 weeks Secondary outcomes 5 minute Apgar score % infants who died or had neurodevelopmental impairment at 18 to 22 months (BSID‐III cognitive composite score < 70, GMFCS score of ≥ 2, moderate or severe cerebral palsy, hearing impairment and blindness) Duration of mechanical ventilation during the entire NICU stay % infants alive and off ventilation by day 7 Proportion of infants receiving surfactant treatment Incidence of air leaks on admission and overall Incidence of BPD at 36 weeks using the physiologic definition of BPD Incidence of death Proportion of infants with severe IVH Proportion of infants with PVL Proportion with threshold ROP and requiring surgery for ROP Proportion requiring endotracheal intubation before 10 minutes of age Duration of oxygen supplementation Pulse oximetry values > 90% Incidence of blindness of at least 1 eye at 18 to 22 months' follow‐up Proportion who receive postnatal steroids to prevent or treat BPD Proportion who develop NEC
Notes	SUPPORT Study. Funding from National Institutes of Health (NIH) grants. Some information obtained from supplementary material on publisher's website. This study was reported in 3 publications, immediate outcomes to discharge and follow‐up data. The follow‐up paper on neurological outcomes is included here. Stevens 2014 reported only respiratory outcomes but did not include any outcomes relevant to this review. The disclosure forms attached to the published article did not reveal any conflict of interest among the primary researchers.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	By an independent statistician
Allocation concealment (selection bias)	Low risk	Stratified by centre and gestational age group Specially prepared double‐sealed envelopes opened just before the actual delivery. Included twin pairs were assigned to the same group.
Blinding (performance bias and detection bias) All outcomes	High risk	Not possible to blind staff who had to apply either CPAP or intubation. Data were collected on infants during intervention phase so not possible to blind outcome assessors for primary outcome
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Neurodevelopmental assessments were performed by neurologic examiners and neurodevelopmental testers who were unaware of the treatment assignments and were evaluated annually for testing reliability.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	All infants were accounted for and included in the analysis. There appeared to be a balance across the groups for infants who received the two ranges of oxygen targeting. 1. Group in which the target O₂ sat of 85% to 89%, 54 of 336 in intervention group and 60 of 318 in control group 2. Group in which the target O₂ sat of 91% to 95%, 40 of 327 in intervention group and 54 of 335 in control group
Selective reporting (reporting bias)	Low risk	The study protocol is available. All of the study's prespecified outcomes have been reported — some in the supplementary material.
Other bias	Low risk	None detected

Gonçalves‐Ferri 2014.

Study characteristics
Methods	Multicentre randomised controlled trial involving 5 public university hospitals in Brazil from June 2008 to December 2009. The infants were stratified according to birth weight (1000 to 1250 grams and 1251 to 1500 grams) in blocks of 4 and the cards were placed in opaque sealed envelopes. The mean birth weights and mean gestations were 1262 grams (SD 147) and 31.2 weeks (SD 2.2) in the CPAP group, and 1286 grams (SD 140) and 31.2 weeks (SD 2.2) in the control group. Antenatal steroids were given to 67.3% of mothers in the CPAP group and to 63.6% in the control group.
Participants	250 infants who were eligible for the study. 59 were excluded, of which: informed consent for 42 not obtained on time; 10 because their CPAP was not ready on time; and 7 infants' parents refused to participate. Preterm infants with a birth weight of 1000 to 1500 grams without major malformations or foetal hydrops. Only the first twin was included. These infants were not intubated or extubated in less than 15 minutes after birth.
Interventions	Experiment group (n = 98): positive pressure was applied using a Neopuff manual ventilator with a PEEP at 5 cm H₂O and 100% oxygen. Newborns were transferred to the NICU where, after stabilisation, ventilation parameters followed institutional protocols. The CPAP group was maintained with positive pressure for at least 48 hours. Control group (n = 99): infants who presented with central cyanosis, oxygen was started according to the techniques recommended by the guidelines of the AAP and AHA. According to the study protocol, infants in the control group who failed supportive therapy were to be administered CPAP prior to the use of mechanical ventilation.
Outcomes	A total of 256 infants were considered eligible, of which 197 patients were included in the study. Primary outcomes The need for mechanical ventilation or surfactant, or both, during the first 5 days of life Secondary outcomes The incidence of respiratory morbidity and mortality during the hospital stay
Notes	Funding supported by the State of São Paulo Research Foundation (FAPESP #2006/61388‐2). Clarification on method allocation and measurement of failed treatment was supplied by the authors along with data on mortality and BPD. No declarations of interest among the primary researchers were available
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation not described. Stratified into 2 weight strata in blocks of 4
Allocation concealment (selection bias)	Unclear risk	Cards placed in sealed opaque envelopes. Stratified into 2 weight strata (1000 to 1250 grams and 1251 to 1500 grams) and by centre using permuted blocks of 4 at a 1:1 ratio for intervention and control. Comment: since there was no blinding of the intervention and blocks of 4 were used, there is a possibility that the allocated intervention of each 4th infant could have been known prior to allocation.
Blinding (performance bias and detection bias) All outcomes	High risk	Family members not blinded. Not feasible to blind medical staff administering the treatment.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	No loss of participants to follow‐up
Selective reporting (reporting bias)	Low risk	Limited protocol available on trial registration document. All of the study's prespecified outcomes have been reported. Mortality was not included in the protocol but was reported in the clinical report. Comment: however, since there was no reported difference in mortality, we do not suspect selective reporting of this outcome.
Other bias	Low risk	None detected

Han 1987.

Study characteristics
Methods	Randomised controlled trial done in Canada over a period of 18 months
Participants	Characteristics: 87 infants were eligible. Preterm infants (n = 82) of 32 weeks' gestation or less and stratified by sex. 39 were in the control group and 43 were in the treatment group. Excluded were 5 infants for whom there was insufficient time to obtain parental consent before birth, major congenital abnormalities and primary apnoea at birth necessitating immediate intubation and IPPV. The mean birth weights and mean gestation ages of the infants were 1290 grams (SD 390) and 29.4 weeks (SD 2.0) in the CPAP group, and 1400 grams (SD 310) and 30 weeks (SD 1.9) in the control group. None of the mothers received antenatal steroids.
Interventions	Experimental group: nasopharyngeal CPAP of 6 cm H₂O pressure applied at birth. Infants who failed to improve (PaO₂ < 50 mmHg in optimal CPAP (see notes) and FiO₂ > 0.8, apnoeas) were managed with endotracheal (ET) CPAP and then IPPV as indicated by PaO₂ < 50 mmHg in FiO₂ > 0.9, or pH < 7.2 mainly due to PaCO₂ > 60 mmHg, apnoea (severity not defined) not controlled by ETCPAP Control group: oxygen in a head box. Nasal CPAP given when PaO₂ < 50 mmHg in FiO₂ > 0.5, or apnoea (given to 33%). Subsequent management similar to treatment group. Both groups of infants received an initial FiO₂ ranging from 0.3 to 0.6.
Outcomes	Reported on 82 infants. Failed treatment included use of IPPV and other treatment BPD at 28 days (oxygen therapy + abnormal chest X‐ray ‐ blindly assessed) Death Pulmonary air leaks (no breakdown by pneumothorax vs other available) PDA Any IVH (breakdown by grade not available) Subglottic stenosis Neonatal sepsis (blood culture positive) NEC (Bell stage 2 or more) RLF (ROP grade 3 or 4)
Notes	Additional information provided by the author in July 2002 on randomisation, timing of deaths, definitions of outcomes ‐ sepsis, BPD, RLF, air leaks and diagnosis of IVH. Optimal CPAP was measured according to the method described by Tanswell 1980 in which a lower oesophageal pressure is used to demonstrate opening of small airways. No mother received antenatal corticosteroids and postnatal surfactant therapy was not available. 280 subjects planned, sequential descriptive analysis (stopped early because of possible worse outcomes in treatment group). The trial dates were not stated in the paper. Source of funding not stated. No declarations of interest among the primary researchers were available
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Quote: "This stratification ensured distribution of boys and girls in equal numbers in the two study groups. Separate cards were prepared by a statistician for both sexes, for both study groups. Each card was placed in an envelope and provided the patient’s number in the study and his or her allocation to treatment or control group which had been determined from a table of random numbers. Group assignment was made by pulling the next envelope in sequence from the appropriate box as soon as the sex was known at birth".
Allocation concealment (selection bias)	Low risk	Opaque sealed envelopes were used.
Blinding (performance bias and detection bias) All outcomes	High risk	Blinding of intervention ‐ no
Blinding of outcome assessment (detection bias) All outcomes	High risk	Yes for chest X‐Rays and no for IPPV
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete follow‐up for 90% of participants (2 treatment and 3 control infants excluded, 2 due to congenital abnormalities and 3 for protocol violations). Therefore, not strictly according to intention to treat
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	High risk	Trial stopped early because of concerns that treatment outcomes were worse in the intervention group

Morley 2008.

Study characteristics
Methods	International multicentre randomised controlled trial between 27 April 1999 and 23 March 2006 in Australia, New Zealand, USA, Canada and Europe
Participants	Inclusion criteria: infants (n = 616) with a gestational age at delivery between 25 weeks and 28 weeks 6 days with no known condition that might adversely affect breathing after birth apart from prematurity. The mean birth weights and mean gestational ages were 964 grams (SD 212) and 26.91 weeks (SD1.0) in the CPAP group, and 952 grams (SD 217) and 26.87 weeks (SD 1.0) in the Intubated group. Antenatal steroids were used in 94% of mothers in both groups. Birth in a hospital participating in the trial. Ability to breath at 5 minutes after birth but needing respiratory support because of increased respiratory effort, grunting respiration, or cyanosis. Exclusion criteria: infants who were intubated before randomisation. Infants who did not require any respiratory support or oxygen.
Interventions	Experiment group (n = 307): infants were assigned to receive nasal CPAP started at 8 cm H₂O with short single or double prong and continued until met criteria for extubation according to local protocol or until met criteria for intubation (pH < 7.25, PaCO₂ > 60 mmHg, FiO₂ > 0.6 or apnoea). Control group (n = 303): infants were intubated and ventilated at 5 minutes of age. The allocated treatment was commenced within 5 minutes of life in both groups. Surfactant was not mandatory but could be administered to either treatment group after intubation.
Outcomes	Reported on 610 neonates Primary outcome Death or BPD (oxygen at 36 weeks) Loss of participants to follow‐up: 6 of 310 in intervention group and 6 of 306 in control group
Notes	COIN trial. Funding by NHMRC, Australia. Dr. Morley reports being a member of the Australian Resuscitation Council, serving as a coeditor of the Australian Neonatal Resuscitation Guidelines, and serving on the International Liaison Committee on Resuscitation and assisting with the 2005 International Guidelines for Neonatal Resuscitation. No other potential conflict of interest relevant to this article was reported.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	This was done by an independent statistician using a random number table and block randomisation with variable block sizes. Randomisation was stratified according to centre and gestational age, 25 to 26 and 27 to 28 weeks
Allocation concealment (selection bias)	Low risk	Sequentially numbered sealed opaque envelopes
Blinding (performance bias and detection bias) All outcomes	High risk	Not possible to blind staff who had to apply either CPAP or intubation
Blinding of outcome assessment (detection bias) All outcomes	High risk	Not possible to blind outcome assessors for primary outcome
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete follow‐up in 98% of cases
Selective reporting (reporting bias)	Low risk	Protocol not available. All of the study's prespecified outcomes have been reported.
Other bias	Unclear risk	Study was registered retrospectively with the Australian Clinical Trials Register

Sandri 2004.

Study characteristics
Methods	Multicentre randomised controlled trial conducted in 17 NICUs in Italy between November 1999 to December 2000.
Participants	Characteristics: preterm infants (n = 230) between 28 and 31.6 weeks' gestation. The mean gestation and mean birth weights were 30 weeks (SD 1.0) and 1370 grams (SD 356) in the prophylactic CPAP group and 29.9 weeks (SD 1.0) and 1339 grams (335) in the control group. 83.3% and 82.4% of mothers in the CPAP and control groups, respectively, received antenatal steroids.
Interventions	Experimental group: prophylactic nasal CPAP of 4 to 6 cm H₂O applied within 30 minutes of birth (n = 115) Control group : received nasal CPAP when the fraction of inspired oxygen (FiO₂) in the hood was > 0.4 for more than 30 minutes (n= 115), to maintain transcutaneous oxygen saturation (SpO₂) at the right hand between 93% and 96%. Nasal CPAP was given through nasal prongs using the Infant Flow Driver system (n = 115). Newborns receiving nasal CPAP at a pressure of 6 cm water pressure, requiring a FiO₂ > 0.4 for more than 30 minutes to maintain SpO₂ in the range 93% to 96% and showed radiological signs of RDS were endotracheally intubated, treated with surfactant and manually ventilated for 2 to 5 minutes. The infants were then extubated and placed on nasal CPAP if they had a good respiratory drive and maintained a satisfactory SpO₂ value. Criteria for mechanical ventilation (IPPV) were: persistence of a FiO₂ requirement of > 0.4 on nasal CPAP after surfactant administration, severe apnoea, PaCO₂ > 70 mmHg and pH < 7.2, or FiO₂ rapidly increasing above 0.8 even before 30 minutes.
Outcomes	Failed treatment included: the use of surfactant; the need for IPPV within 7 days; air leaks; death at or before 7 days; death between 8 to 28 days; death; IVH > grade 2; PVL; NEC; sepsis; chronic lung disease at 36 weeks; PDA.
Notes	The source of funding was not stated. No declarations of interest among the primary researchers were available
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated number list
Allocation concealment (selection bias)	Low risk	Computer‐generated numbers stratified for each week of gestational age. Randomised in blocks of 6. However, the study does not appear to be stratified by centre so the risk of knowing the allocation of each 6th participant within each stratum would have been low. For twin pairs, only the first twin was randomised.
Blinding (performance bias and detection bias) All outcomes	High risk	Blinding of treatment ‐ no
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not stated
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete follow‐up ‐ yes
Selective reporting (reporting bias)	Unclear risk	Protocol not available. All of the study's prespecified outcomes have been reported.
Other bias	Low risk	None detected. Souce of funding not stated.

Tapia 2012.

Study characteristics
Methods	Randomised, controlled, multicentre trial conducted in 12 tertiary neonatal intensive care units from 5 South American countries: Argentina, Chile, Paraguay, Peru, and Uruguay from 2 November 2006 to 19 September 2009.
Participants	256 preterm infants with birth weight 800 to 1500 grams who were spontaneously breathing at 5 minutes of life. Birth in a hospital participating in the trial. Ability to breath at 5 minutes after birth but needing respiratory support because of increased respiratory effort, grunting respiration, or cyanosis. The mean birth weights and mean gestations were 1196 grams (SD 194.8) and 29.8 weeks (SD 2.4) in the CPAP group, and 1197 grams (SD 189.2) and 29.5 weeks (SD 2.2) in the control group. 90.8% and 88% of mothers in the CPAP and control groups, respectively, received antenatal steroids.
Interventions	Experiment group: 131 infants were given CPAP (as soon as possible after allocation) using a bubble CPAP system (Fisher & Paykel Healthcare) with a distending pressure of 5 cm H₂O. The short binasal prongs included with the CPAP system were used. Before the nasal prongs were inserted, CPAP was maintained at 5 cm H₂O through a mask connected to a T‐piece resuscitator, ensuring that the infants in this group were maintained on CPAP from the time of enrolment. Infants with an FiO₂ > 0.35 to maintain SpO₂ in the target range and X‐ray findings compatible with RDS were intubated and given surfactant following the INSURE protocol. Control group: 125 infants randomised to the Oxygen/MV group who were initially managed with oxygen via low flow nasal cannula were transferred to an oxyhood. A chest X‐ray was obtained within the first 2 hours of life if there was clinical evidence of respiratory distress. In infants with RDS and an FiO₂ > 0.35 on oxyhood therapy and with compatible X‐ray findings, surfactant was administered followed by mechanical ventilation.
Outcomes	Reported in 256 neonates. Primary outcome Any requirement for mechanical ventilation between study enrolment and hospital discharge Secondary outcomes Death BPD Death/BPD Use of surfactant Pneumothorax IVH (Grades 3 or 4) PDA Late‐onset sepsis ROP Nasal damage
Notes	CPAP equipment was donated by Fisher & Paykel Healthcare, Inc. The authors did not declare any conflicts of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	A computerised randomisation system was used. The infants were stratified by birth weight (800 to 999 grams and 1000 to 1500 grams) and by centre.
Allocation concealment (selection bias)	Low risk	Allocation obscured in a sealed opaque envelope
Blinding (performance bias and detection bias) All outcomes	High risk	Not possible to blind staff who had to apply either CPAP or intubation
Blinding of outcome assessment (detection bias) All outcomes	High risk	Not possible for IPPV and surfactant use
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete follow‐up
Selective reporting (reporting bias)	Low risk	Protocol available. All of the study's prespecified outcomes have been reported.
Other bias	Low risk	Trial was prospectively registered.

AAP: American Academy of Pediatrics; AHA: American Heart Association; BPD: bronchopulmonary dysplasia; BSID: Bayley Scales of Infant and Toddler Development; CPAP: continuous positive airway pressure; ET: endotracheal; FAPESP: the State of São Paulo Research Foundation; GMFCS: Gross Motor Function Classification System; IPPV: intermittent positive pressure ventilation; INSURE: INtubation, SURfactant administration, Extubation; IVH: intraventricular haemorrhage; MV: mechanical ventilation; nCPAP: nasal continuous positive airway pressure; NEC: necrotising enterocolitis; NICU: neonatal intensive care unit; PDA: patent ductus arteriosus; PEEP: positive end‐expiratory pressure; PVL: periventricular leukomalacia; RDS: respiratory distress syndrome; RLF:retrolental fibroplasia; ROP: retinopathy of prematurity; SD: standard deviation; vs: versus

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Drew 1982	This study examined elective intubation at birth followed by CPAP via the endotracheal tube versus selective intubation on clinical grounds. This intervention is not prophylactic or very early CPAP.
Mwatha 2020	This study examined babies who presented with one or more signs of respiratory distress, including tachypnoea (> 60 breaths/min), chest retraction, nasal flaring, grunting, or cyanosis. This is not prophylactic CPAP.
Rojas 2009	Infants were randomly assigned at between 15 and 60 minutes of birth and nasal CPAP was compared with INSURE. The control intervention is inappropriate. This study is included in a separate review.
Thomson 2002	Study only available in abstract form. This study was a multicentre RCT on prophylactic CPAP with 4 arms and 237 participants. 2 groups received prophylactic CPAP (one with and one without prophylactic surfactant) and the authors state that in the 2 groups of infants, early nasal CPAP with prophylactic surfactant (group 1), early nasal CPAP +/‐ rescue surfactant (group 2), 76% and 79% of the participants were on prophylactic CPAP by 6 hours of life. Therefore it is highly unlikely that this study meets our inclusion criteria of prophylactic CPAP starting within 15 minutes of life, or very early CPAP starting within the first hour of life. Several attempts have been made to communicate with the authors but we have not received any response.
Tooley 2003	This study examined preterm babies with RDS who were electively intubated and given one dose of surfactant within 20 minutes or less after birth. These infants were then randomised to either continue with mechanical ventilation or to be extubated to nasal CPAP within 1 hour after birth. This is not prophylactic or very early CPAP because all infants received mechanical ventilation during the first hour of life.
Zaharie 2008	This was an observational study examining preterm babies between 28 and 32 weeks' gestational age who were given either early or prophylactic CPAP. There was no blinding or randomisation.

CPAP: continuous positive airway pressure; INSURE: INtubation, SURfactant administration, Extubation; RCT: randomised controlled trial; RDS: respiratory distress syndrome; vs: versus

Characteristics of studies awaiting classification [ordered by study ID]

NCT04209946.

Methods	After 5 minutes of life, consented infants that are assessed by a provider as clinically stable (i.e. HR > 100 bpm) and spontaneously breathing on CPAP will be randomised by computer generated randomisation cards placed in opaque envelopes. For infants not consented prior to birth, after 5 minutes of life and before 2 hours of life, postnatal consent may be obtained for any eligible infant admitted to the NICU and must be randomised and receive treatment prior to 2 hours of age. Randomisation will be stratified by gestational age (24 to 26+6 weeks and 27 to 29+6 weeks) and labelled as such on each envelope. Multiples will be randomised to the same treatment group for ease of consent and family considerations. Infants randomised to LISA will receive surfactant (Curosurf 2.5 mL/kg, based on estimated fetal weight) given in the first 2 hours of life using a conventional or video laryngoscope and a small flexible 16 gauge angiocatheter. All sites have agreed on using senior level physicians or practitioners that have prior experience with the LISA method. An orogastric tube will be placed into the stomach prior to laryngoscopy and the contents aspirated after the procedure to document any oesophageal surfactant administration. Infants randomised to early CPAP will be managed according to unit practice for preterm infants on CPAP.
Participants	Infants born between 24 to 29+6 weeks gestation
Interventions	After 5 minutes of life, consented infants that are assessed by a provider as clinically stable (i.e. HR > 100 bpm) and spontaneously breathing on CPAP. Infants will continue on early CPAP or be randomised to LISA where they will receive surfactant (Curosurf 2.5 mL/kg, based on estimated fetal weight) given in the first 2 hours of life using a conventional or video laryngoscope and a small flexible 16 gauge angiocatheter.
Outcomes	Primary outcome The need for mechanical ventilation in the first 72 hours of life Secondary outcomes include Duration of mechanical ventilation and/or CPAP Oxygen at 36 weeks' corrected age Frequency of all‐grade intraventricular haemorrhage Need for repeat surfactant dosing
Notes	Estimated study completion date: June 2025 NCT04209946

bpm: beats per minute; CPAP: continuous positive airway pressure; HR: heart rate; LISA: less invasive surfactant administration; NICU: neonatal intensive care unit;

Differences between protocol and review

• The initial protocol compared prophylactic CPAP with 'standard methods of treatment'. We have since retired the term 'standard treatment' and instead added two comparisons: comparison 1 is CPAP versus supportive care, and comparison 2 is CPAP versus mechanical ventilation.

• Types of interventions: the initial version of this review (Subramaniam 2002), included only one comparison (CPAP versus standard care). In the 2016 update (Subramaniam 2016), we included a second comparison (CPAP versus mechanical ventilation) and we discontinued the use of the term 'standard care' in preference for the term 'supportive care', which may include supplemental oxygen.

• In the last version of the review (Subramaniam 2016), we changed the inclusion criteria, in Types of participants, from 32 to 37 weeks' gestation. This is because all preterm infants are susceptible to RDS.

• The title of the previous version of the published review was “Prophylactic nasal continuous positive airway pressure for preventing morbidity and mortality in very preterm infants” (Subramaniam 2016). We have changed the title to “Prophylactic or very early initiation of continuous positive airway pressure (CPAP) for preterm infants”.

• We made a post hoc decision to include the combined outcome of death or neurodevelopmental impairment since this has been reported in the literature, and we consider it a valid and important outcome.

At the request of the World Health Organization (WHO), this review was updated in 2020/2021.

The methods have been updated as follows for the 2020/2021 update.

• The definition of the intervention has been expanded to include a third comparison.

• Modification of both primary and secondary outcomes measures in consultation with authorship team and WHO.

• Modification of selected subgroup analyses in consultation with authorship team and WHO.

• Modification of outcomes selected for summary of findings tables.

• CINAHL, Embase, ClinicalTrials.gov, and WHO ICTRP were included in the protocol and searched in previous versions of this review, but were not searched for the 2020 update as assessments suggested no unique included studies would be contributed from these sources.

Contributions of authors

PS along with the late DHS (see Acknowledgements) developed the protocol; JJH did not participate in the development of the protocol but was involved in post hoc changes to the protocol made in the previous update. All authors evaluated the studies and extraction of the data.
PS and JJH wrote the text of this update with PGD's input.
The search update was carried out by PS and JJH.
All review authors participated in evaluation of the new trials, data extraction and contributed to updating the review.

Sources of support

Internal sources

• Northwest Hospital and Health Services (Mount Isa Hospital), Australia

  Clinical Appointment for P Subramaniam

• RCSI & UCD Malaysia Campus (formerly Penang Medical College), Malaysia

  University Appointment for J Ho

• Royal Women's Hospital, Melbourne, Australia

  Clinical Appointment for P Davis

• Department of Paediatrics, Ipoh Hospital, Ipoh, Malaysia

  Clinical appointments for two authors (P Subramaniam and J Ho)  during previous versions of the review

External sources

• Vermont Oxford Network, USA

  Cochrane Neonatal Reviews are produced with support from Vermont Oxford Network, a worldwide collaboration of health professionals dedicated to providing evidence‐based care of the highest quality for newborn infants and their families.

Declarations of interest

Prema Subramaniam has declared no conflicts.

Jacqueline J Ho has worked as a Consultant Neonatologist for the Ministry of Health, Malaysia, as a Neonatal Unit Director.

Peter G Davis is a Neonatologist who receives project and salary support from the Australian National Health and Medical Research Council. He was involved in conducting an included study, the COIN trial (Morley 2008). This study was funded by the Australian National Health and Medical Research Council. JJH and PS independently extracted the data from the COIN study.
 

New search for studies and content updated (conclusions changed)