Effects of targeting higher versus lower arterial oxygen saturations on death or disability in preterm infants

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

  1. What are the effects of targeting higher versus lower oxygen ranges on death or major neonatal and infant morbidities, or both, in extremely preterm infants?

  2. Do these effects differ in different types of infants, including those born at a very early gestational age, outborn, without antenatal corticosteroid coverage, male gender, small for gestational age, multiple birth or by mode of delivery?

Background

Description of the condition

The administration of supplemental oxygen has a long history in neonatal care (Wilson 1942; Tin 2007). Oxygen was used liberally for the first time in neonates in the 1930s when an oxygen unit was described for preterm infants (Raju 1999). The use of oxygen in preterm and low birth weight infants suffering respiratory insufficiency has resulted in significant healthcare benefits, such as reduced mortality and spastic diplegia (Avery 1960; McDonald 1963), but has also been associated with significant deleterious effects such as retinopathy of prematurity and lung toxicity (Duc 1992).

Improvements in technology in the past few decades have led to the increased survival of preterm and low birth weight infants. One of these advances is the ability to measure oxygen levels more accurately. Despite the exceedingly common use of supplemental oxygen in this population of infants, there is little consensus as to the optimal levels of oxygen for maximising short- or long-term growth and development, while minimising harmful effects (Poets 1998; McIntosh 2001; Silverman 2004). 

ADVERSE CONSEQUENCES OF LIBERAL AND RESTRICTED USE OF OXYGEN

The adverse consequences of liberal oxygen use were recognised in the early 1940s. Terry 1944 described a type of blindness in preterm infants characterised by thick fibrotic membrane in the retrolental space. In 1951 the role of supplemental oxygen in the aetiology of 'retrolental fibroplasia' (RF) was first suggested (Campbell 1951). By 1954, RF had blinded about 10,000 infants (Silverman 1980; Silverman 2004). From 1954 to 1956, three randomised trials (Lanman 1954; Patz 1954; Kinsey 1956), enrolling 341 infants, proved that breathing unrestricted concentrations of inspired oxygen was a major cause of RF (Askie 2009). Throughout this period, oxygen administration was guided by the clinical observations of skin colour, as well as the rate, regularity and work of breathing. It was not until the 1960s and 1970s that sampling of blood gases, transcutaneous oxygen monitoring and later pulse oximetry became available for more precise monitoring of oxygen levels (Walsh 2009). An early prospective cohort study, reported in 1977, was unable to establish a causal relationship between arterial oxygen tension and (what is now known as) retinopathy of prematurity (ROP), but did reveal that the most relevant factors for developing ROP were birth weight less than 1200 grams and length of exposure to supplemental oxygen (Kinsey 1977).

As a consequence of the RF blindness epidemic in the 1960s, the use of oxygen was drastically limited, usually to less than 40% inspired oxygen, even for preterm infants with respiratory distress, allowing them to become severely hypoxaemic and leading to a substantial increase in the incidence of cerebral palsy (Usher 1961). In the next 20 years over 150,000 premature babies died of hypoxic respiratory failure (Avery 1960; McDonald 1964; Cross 1973; Bolton 1974). It is estimated that for every infant whose sight was saved, 16 died (Avery 1960; Silverman 2004) and many others developed spastic diplegia (McDonald 1964).

Description of the intervention

Multiple attempts have been made to establish the optimal oxygen levels in preterm infants, using a variety of technologies, in order to circumvent the adverse consequences of either restricted or liberal use of supplemental oxygen.

However, what constitutes an 'appropriate' level of oxygen for infants born preterm, who would otherwise be in-utero, remains unknown. The foetus is relatively hypoxic with haemoglobin (Hb) oxygen saturations of 65%, 55%, and 45% in the aorta, pulmonary artery and pulmonary vein, respectively. However it should be noted that foetal blood contains almost only foetal haemoglobin (HbF) which has an extraordinary affinity for oxygen and is therefore  capable of capturing sufficient oxygen from the intervillous space to support foetal growth and metabolism (Gao 2010; Vento 2013). 

In the 1980s and early 1990s the use of transcutaneous oxygen monitoring became available.  A study of transcutaneous oxygen monitoring (TcO₂) in preterm infants confirmed that ROP occurred more often when longer periods of time were spent with a TcO₂ above 80 mm Hg, but did not determine if another limit was safer (Flynn 1992). A partial pressure of arterial oxygen (PaO₂) range of 50 to 80 mmHg became widely accepted as an appropriate level to target (AAP 1988; McIntosh 2001; AAP 2002), but this was based on professional consensus rather than on evidence.

In the 1990s the use of pulse oximetry became a standard of care and continuous monitoring has allowed more frequent titration of the oxygen concentration administered. Pulse oximetry (SpO₂) refers to the estimation of the oxygen saturation of arterial blood using a device that measures the pulsatile changes in light transmission across a tissue bed. Pulse oximeters work on the principle that desaturated haemoglobin and oxygenated haemoglobin absorb light of different wavelengths (red and infrared). The oximeter emits light of these two wavelengths and measures absorption in the pulsatile element of the blood flow, thus producing a measure of the oxygen saturation of arterial blood separate from the non-pulsatile venous blood (Williams 1998). Pulse oximeters lack the heat-related side effects of transcutaneous oxygen monitors.

Despite the ease of use of pulse oximeters, translation of SpO₂ values into PaO₂ can be difficult to establish. The correlation between SpO₂ and PaO₂ is dependent on various physiologic circumstances such as affinity of Hb for oxygen which is significantly greater in foetal Hb. Thus, the higher the foetal Hb concentration the higher the SpO₂ would be for any given PaO₂ value. Castillo 2008 reported that in preterm infants for oxygen saturation values between 85% and 93%, the mean measured PaO₂ was 56 ± 14.7 mm Hg. Within this SpO₂ range, 87% of the samples had PaO₂ values of 40 to 80 mm Hg, 8.6% had values of less than 40 mm Hg, and 4.6% had values greater than 80 mm Hg. When the SpO₂ was greater than 93% the mean PaO₂ was 107.3 ± 59.3 mm Hg with 60% of values greater than 80 mm Hg.

The Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity trial (STOP ROP 2000) used pulse oximetry to target a lower (89% to 94%) or higher (96% to 99%) oxygen saturation range in 649 preterm infants with prethreshold ROP who were 35 weeks postmenstrual age at randomisation. The higher range caused more adverse respiratory events including pneumonia, chronic lung disease requiring oxygen, and diuretic therapy. There was no statistically significant difference in the rate of progression to threshold ROP. The results of this trial are included in a separate Cochrane review entitled: Supplemental oxygen for the treatment of pre-threshold retinopathy of prematurity (Lloyd 2003). In the Benefits of Oxygen Saturation Targeting (BOOST) trial (Askie 2003), 358 infants born at less than 30 weeks’ gestation were randomly assigned, from three weeks or more after birth (at 32 weeks’ postmenstrual age) until they breathed air, to target an SpO₂ range of either 91% to 94% or 95% to 98% using offset oximeters. This trial found no evidence that higher SpO₂ targeting improved growth or development, but it did increase days of oxygen therapy and use of healthcare resources. Masked oximeters were adjusted to display values 2% lower or 2% higher than actual SpO₂ values. Staff were unaware of actual SpO₂ and targeted a masked range of 93% to 96%. The authors concluded that further large randomised trials were needed to determine how targeting different SpO₂ levels from the day of birth affects ROP, chronic lung disease, growth, disability and mortality (Askie 2003; Silverman 2004).

In transposing oxygen tensions of 50 to 80 mm Hg into equivalent arterial oxygen saturation, most clinicians have targeted functional SpO₂ 90% to 95% with a minimum acceptable SpO₂ of 85% (Anderson 2004). Hence the dichotomising of SpO₂ into 'higher' or 'lower' target ranges above or below a cut point of 90% appears reasonable. In the early 2000s, there were several observational studies that found lower SpO₂ was associated with less severe ROP; improved short-term respiration, growth and development outcomes; and either no apparent effect or a decrease in mortality (Tin 2001; Chow 2003; Anderson 2004). It should also be recognised that an intention to target a certain SpO₂ range does not guarantee that an infant's actual SpO₂ will always be maintained within that range. Most studies report that preterm infants receiving supplemental oxygen in a specified target range only remain in that range for about 30% to 50% of the time (Hagadorn 2006; Lim 2014).

To address the continuing uncertainty regarding the appropriate levels of oxygen saturation targeting for preterm infants with sufficient statistical reliability, the NeOProM Collaboration was formed in 2003. NeOProM is a prospective meta-analysis collaboration (Askie 2011) that includes five randomised trials (ACTRN12605000055606; ACTRN12605000253606; NCT00233324; ISRCTN00842661; ISRCTN62491227). These five trials prospectively (i.e. before the results of any of the trials were known) agreed to undertake their trials using very similar protocols, and have made a commitment to combine their individual participant data once their own trial's results are published. Representatives from each of these five trials and the NeOProM Collaboration are authors of this Cochrane Review.

SUMMARY

There are two opposing concerns. Less inspired oxygen (targeting SpO₂ at 90% or less) may increase patent ductus arteriosus, pulmonary vascular resistance and apnoea, and may impair neurodevelopment (Newburger 1984; Skinner 1999; Subhedar 2000). More inspired oxygen (targeting SpO₂ greater than 90%) may increase severe ROP (Hellstrom 2013) and chronic lung disease (Warner 1998; Tin 2001; Sun 2002; Chow 2003; Anderson 2004). However, uncertainty remains as to the most appropriate range to target blood oxygen levels in preterm and low birth weight infants.

Two other related Cochrane reviews have summarised the findings on gradual versus abrupt (Askie 2001a) and early versus late discontinuation of oxygen therapy (Askie 2001b) in preterm or low birth weight infants. A meta-analysis of the available aggregate data from the five NeOProM trials was published by Saugstad 2014.

How the intervention might work

Oxygen is the most common therapy used in the care of very preterm infants. It has been associated with significant improvements in neonatal survival and reduced disability (Avery 1960). However, preterm infants are highly sensitive to the harmful biochemical and physiological effects of supplemental oxygen. Toxic oxygen radicals are increased in hyperoxia (Hellstrom 2001) and in re-oxygenation after hypoxaemia. Preterm infants are vulnerable to oxidative stress because they lack antioxidant protection (Hellstrom 2001) from plasma radical scavengers such as beta- carotene, antioxidant enzymes, such as glutathione peroxidase, and their red blood cells and cells of other organs (e.g. lungs) lack superoxide dismutase.

Targeting a higher oxygen level contributes to bronchopulmonary dysplasia (Warner 1998; Jobe 2001; Vento 2009; Kapadia 2013). Relatively recent epidemiological/observational studies (Tin 2001; Sun 2002; Chow 2003; Anderson 2004) and small randomised trials from the 1950s (Askie 2009) have suggested that targeting lower oxygen saturation levels may reduce severe ROP. The effects on death or neurodisability of targeting either lower or higher oxygen saturation levels from birth have not yet been fully assessed.

Why it is important to do this review

Extreme prematurity of less than 28 weeks’ gestation affects approximately 1% of births (Centre for Epi 2012). Although approximately 80% of these infants are discharged home alive (Chow 2013), they often sustain severe morbidity (Doyle 2010), including chronic lung disease, poor growth, respiratory illness, hospital re-admissions, visual deficits, cerebral palsy, neurodevelopmental disability and cognitive, educational and behavioural impairment (Anderson 2003). It is essential to determine whether the range of targeted SpO₂ levels affects the occurrence of such outcomes and, if possible, to determine the optimal range for management of the very vulnerable preterm infant. Very preterm infants account for a high proportion of the costs and disability from neonatal intensive care (Sutton 1999). Reducing these morbidities would enhance quality of life for these infants and benefit their families and communities (Saigal 2000).

Objectives

  1. What are the effects of targeting higher versus lower oxygen ranges on death or major neonatal and infant morbidities, or both, in extremely preterm infants?

  2. Do these effects differ in different types of infants, including those born at a very early gestational age, outborn, without antenatal corticosteroid coverage, male gender, small for gestational age, multiple birth or by mode of delivery?

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised controlled trials. We will exclude quasi-randomised trials and cluster-randomised trials.

Types of participants

Participants in the eligible trials will be infants either inborn or outborn before 28 weeks’ gestation.

Types of interventions

The intervention will target either a lower (SpO₂ less than or equal to 90%) or higher (SpO₂ greater than 90%) oxygen saturation range by 24 hours after birth, with the intention to target these ranges for at least the first two weeks of life, via the use of pulse oximetry. There is no minimum required level of compliance for keeping within the target ranges. Oxygen targeting can be achieved by either manual or machine-assisted methods.

Types of outcome measures

We will assess longer-term outcomes in infancy from 18 months corrected age (gestational age plus chronological age) onwards, depending on the measurement time point used by individual trials.

Primary outcomes
  • Composite outcome of death or major disability by 18 to 24 months corrected age (gestational age plus chronological age)

Secondary outcomes
  • Death (to discharge, to 18 to 24 months follow-up)

  • Major disability by 18 to 24 months corrected age (gestational age plus chronological age)

  • Retinopathy of prematurity (ROP) treatment by laser photocoagulation, cryotherapy or bevacizumab treatment (performed if threshold ROP occurs)

  • Measures of respiratory support, defined as (a) supplemental oxygen requirement at 36 weeks postmenstrual age, (b) days of endotracheal intubation, (c) days of continuous positive airway pressure (CPAP), (d) days of supplemental oxygen, (e) days on home oxygen

  • Patent ductus arteriosus diagnosed by ultrasound

  • Patent ductus arteriosus requiring medical treatment (defined as using cyclo-oxygenase inhibitors)

  • Patent ductus arteriosus requiring surgical treatment

  • Necrotising enterocolitis (any, requiring surgery or causing death)

  • Weight at 36 weeks postmenstrual age, discharge home and 18 or 24 months corrected age (gestational age plus chronological age)

  • Proportion of infants re-admitted to hospital up to 18 to 24 months corrected age (gestational age plus chronological age)

  • Cerebral palsy with Gross Motor Functioning Classification System (GMFCS) level 2 or higher, or Manual Ability Classification System (MACS) level 2 or higher at 18 to 24 months corrected age (gestational age plus chronological age)

  • Blindness

  • Deafness requiring hearing aids

  • Quantitative Bayley III scores (Composite Cognitive Score (CCS) and Composite Language Score (CLS) scores)

Search methods for identification of studies

We will use the standard search methods of the Cochrane Neonatal Review Group.

Electronic searches

We will search CENTRAL, MEDLINE (via PubMed), Cinahl, and Embase using the following terms: (oxygen OR oxygen saturation OR hypoxia OR retinopathy of prematurity OR retrolental fibroplasia OR hyperoxia) AND ((infant, newborn OR newborn OR neonate OR neonatal OR premature OR low birth weight OR VLBW OR LBW or infan* or neonat*) AND (randomized controlled trial OR controlled clinical trial OR Clinical Trial OR randomized OR placebo OR clinical trials OR randomly OR trial) NOT (animals NOT humans)).

We will search for any ongoing or recently completed and unpublished trials, using the World Health Organization portal www.who.int/ictrp.

We will not include any language, date or publication status restrictions.

Searching other resources

We will search previous reviews and cross-references, abstracts, conference and symposia proceedings, expert informants, and journal handsearching. We will search abstracts of the relevant perinatal meetings (including Society for Pediatric Research, Neonatal Register) for the years 1985 to the present, using the following key word: 'oxygen saturation'. For abstract books that do not include keywords, we will limit the search to relevant sections such as pulmonology and neonatology.

Data collection and analysis

We will use the methods of the Cochrane Neonatal Review Group for data collection and analysis.

Selection of studies

We will include all randomised controlled trials that meet the selection criteria described in the previous section. LA and BD will independently review the results of the search and select studies for inclusion. We will resolve any disagreement by discussion, or by recourse to other members of the review author team.

Data extraction and management

We will use a data extraction form specifically designed for this review. Three review authors (LA, RW, MV) will separately extract, assess and code all data for each included study. We will collect information on the following outcome variables: composite outcome of death or major disability by 18 to 24 months corrected age (gestational age plus chronological age); death (to discharge, to 18 to 24 months follow-up); major disability by 18 to 24 months corrected age (gestational age plus chronological age); ROP treatment by laser photocoagulation, cryotherapy or bevacizumab treatment (performed if threshold ROP occurs); measures of respiratory support, defined as (a) supplemental oxygen requirement at 36 weeks postmenstrual age, (b) days of endotracheal intubation (c) days of CPAP, (d) days of supplemental oxygen, (e) days on home oxygen; patent ductus arteriosus diagnosed by ultrasound; patent ductus arteriosus requiring medical treatment (defined as using cyclo-oxygenase inhibitors); patent ductus arteriosus requiring surgical treatment; necrotising enterocolitis (any, requiring surgery or causing death); weight at 36 weeks postmenstrual age, discharge home and 18 and 24 months corrected age; re-admissions to hospital up to 18 to 24 months corrected age; cerebral palsy with GMFCS level 2 or higher or MACS level 2 or higher at 18 to 24 months corrected age; blindness (< 6/60 vision, 1.3 logMAR in both eyes); deafness requiring hearing aids; quantitative Bayley III scores.

We will resolve differences in assessment by discussion or by involving the remaining review authors.

For each study, one review author (LA) will enter final data into Review Manager 5 (RevMan 2012), and a second review author (RW) will check them for accuracy. We will resolve discrepancies through discussion or by involving the remaining review authors. We will attempt to contact authors of the original reports to provide further details when information regarding any of the above was unclear.

Assessment of risk of bias in included studies

Criteria for assessing the methodological quality of the studies:

We will use the standard method of the Cochrane Neonatal Review Group. LA and PD will independently assess the risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreement by discussion or by involving the remaining review authors. 

We will assess the methodological quality of the studies using the following criteria: 

  1. Sequence generation (checking for possible selection bias): For each included study, we will categorise 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);

    3. unclear risk. 

  2. Allocation concealment (checking for possible selection bias): For each included study, we will categorise 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);

    3. unclear risk.

  3. Blinding (checking for possible performance bias): For each included study, we will categorise the methods used to blind study participants and personnel from knowledge of which intervention a participant received. We will assess blinding separately for different outcomes or classes of outcomes. We will categorise the methods as:

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

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

    3. low risk, high risk or unclear risk for outcome assessors. 

  4. Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations): For each included study and for each outcome, we will describe the completeness of data including attrition and exclusions from the analysis. We will note 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 is reported or supplied by the trial authors, we will re-include missing data in the analyses. We will categorise the methods as:

    1. low risk (less than 20% missing data);

    2. high risk (20% or more missing data);

    3. unclear risk.

  5. Selective reporting bias: For each included study, we will describe how we investigated the possibility of selective outcome reporting bias and what we found. We will assess 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 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);

    3. unclear risk.

  6. Other sources of bias: For each included study, we will describe 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 or interim analyses issues, or both). We will assess whether each study was free of other problems that could put it at risk of bias as:

    1. low risk ; high risk ; unclear risk.  

  7. Overall risk of bias [described in Table 8.5c in the Cochrane Handbook (Higgins 2011)]. 

We will make explicit judgements regarding whether studies were at high risk of bias, according to the criteria given in the Cochrane Handbook (Higgins 2011). With reference to (1) to (6) above, we will assess the likely magnitude and direction of the bias and whether we consider it is likely to impact on the findings. If need be, we plan to explore the impact of the level of bias through undertaking sensitivity analyses (see 'Sensitivity analysis' below).

Measures of treatment effect

We will use the standard methods of the Neonatal Review Group to analyse data.

We will perform statistical analyses using Review Manager 5 software (RevMan 2012). We will analyse dichotomous data using the risk ratio (RR), risk difference (RD) and the number needed to treat for an additional beneficial outcome (NNTB) or number needed to treat for an additional harmful outcome (NNTH). We will include the 95% confidence interval (CI) for all estimates. For the purposes of the analysis, we will consider the lower target range group to be the treatment or experimental group and the higher target range group to be the controls.

We will analyse continuous data using weighted mean difference (WMD), or the standardised mean difference (SMD) to combine trials that measure the same outcome but use different methods.

Unit of analysis issues

The unit of analysis will be each infant randomised.

Dealing with missing data

For included studies, we will note levels of attrition. We will explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect, using sensitivity analyses.

We will analyse all outcomes on an intention-to-treat basis, i.e. we will include all participants randomised to each group in the analyses. The denominator for each outcome in each trial will be the number randomised minus any participants whose outcomes were known to be missing.

Assessment of heterogeneity

We will examine heterogeneity between trials by first assessing differences in trial methodologies and clinical heterogeneity. We will then inspect the forest plots and quantify the impact of heterogeneity using the I² statistic (less than 25%, no heterogeneity; 25% to 49% low heterogeneity; 50% to 74%, moderate heterogeneity; and 75% or more, high heterogeneity) (Higgins 2003; Higgins 2011). If heterogeneity is detected, we plan to explore the possible causes of statistical heterogeneity using prespecified subgroup analysis (for example, differences in study quality, participant or intervention characteristics).

Assessment of reporting biases

We will assess possible publication bias and other biases using symmetry/asymmetry of funnel plots, if there are sufficient trials to allow these analyses.

For included trials that were recently performed (and therefore prospectively registered), we will explore possible selective reporting of study outcomes by comparing the primary and secondary outcomes in the reports with the primary and secondary outcomes proposed at trial registration, using the website www.who.int/ictrp. If we find such discrepancies, we plan to contact the primary investigators to obtain missing data on outcomes prespecified at trial registration.

Data synthesis

If meta-analysis is judged to be appropriate, we will conduct the analysis using Review Manager 5 software (RevMan 2012), supplied by the Cochrane Collaboration. We will use the Mantel-Haenszel method for estimates of typical risk ratio and risk difference. We plan to analyse any continuous measures using the inverse variance method. We will use the fixed-effect model for all meta-analyses.

Subgroup analysis and investigation of heterogeneity

The effect of the intervention (higher versus lower oxygen saturation targeting) may be different due to certain characteristics of either the infant or the way the intervention was delivered. If possible, we will explore these effects by the following subgroup analyses.

a. Participant baseline characteristics:

  • gestational age (less than 26 weeks / 26 weeks or more);

  • inborn or outborn status;

  • antenatal steroids (any: yes/no);

  • gender (male/female);

  • small for gestational age (yes/no);

  • multiples (singleton/multiple);

  • mode of delivery (vaginal/caesarean).

b. Intervention characteristics:

  • oximeter calibration algorithm (original or revised).

We will limit subgroup analyses to the primary outcome (death or major disability); the individual components of the primary outcome (death, major disability); and two key secondary outcomes (necrotising enterocolitis, severe retinopathy of prematurity).

Sensitivity analysis

We plan sensitivity analyses for situations where this might affect the interpretation of significant results (for example, where there are risks of bias associated with the quality of some of the included trials or missing outcome data).

Declarations of interest

Lisa Askie is a member of the BOOST II Australia writing committee and the NeOProM Collaboration.
Brian Darlow is a member of the BOOST-NZ trial management committee and the NeOProM Collaboration.
Peter Davis is a member of the BOOST-II Australia trial management committee and the NeOProM Collaboration.
Neil Finer is a member of the SUPPORT trial management committee and the NeOProM Collaboration.
Ben Stenson is a member of the BOOST-II UK steering committee and the NeOProM Collaboration.
Maximo Vento has no conflicts of interest to declare.
Robin Whyte is a member of the COT trial management committee and the NeOProM Collaboration.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA.

    Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C.

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