Early versus late discontinuation of oxygen in preterm or low birth weight infants

Abstract

Background

It has been hypothesized that the duration of supplemental oxygen administration, independent of the oxygen concentration, gestational age and/or birth weight, is influential in the development of severe retinopathy of prematurity (ROP). Concern regarding the possible deleterious effects of prolonged oxygen supplementation has lead many clinicians to wean infants from oxygen therapy as early as possible. However, recent work in feline models has suggested that visual outcomes may be improved by continuing oxygen supplementation during the recovery phase of ROP. The effect of duration of oxygen supplementation on the long‐term growth and development of preterm or low birth weight infants remains unclear.

Objectives

To determine the effect of early versus late weaning from supplementary oxygen on mortality, retinopathy of prematurity, lung function, growth or development in preterm or low birth weight infants.

Search methods

The standard search strategy of the Neonatal Review Group was used. This included searches of the Oxford Database of Perinatal Trials, MEDLINE, previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, journal handsearching mainly in the English language. An additional literature search of the MEDLINE and CINAHL databases was conducted in order to locate any trials in addition to those provided by the Cochrane Controlled Trials Register (CENTRAL/CCTR).

Selection criteria

All trials utilising random or quasi‐random patient allocation in which early weaning was compared with late discontinuation of supplemental oxygen in preterm or low birth weight infants were eligible for inclusion.

Data collection and analysis

The degree of selection, performance, attrition and detection bias was assessed independently by each review author. Data regarding clinical outcomes including mortality, retinopathy of prematurity, and long‐term growth and development were extracted and reviewed independently by each review author. Results were compared and differences resolved as required. Data analysis was conducted according to the standards of the Cochrane Neonatal Review Group.

Main results

In the single eligible trial of 99 infants with birth weights less than 1650 g, there were no significant differences in neonatal death rates or retrolental fibroplasia (any grade or severe) for all infants, or among infants with birth weights of less than 1000 g. No other outcome measures specified a priori as clinically meaningful were reported in enough detail or with satisfactory follow‐up rates to include in the analysis (early death, chronic lung disease, long‐term growth, development, lung or visual function).

Authors' conclusions

The results of this systematic review do not provide strong evidence for either the benefits or harms of early oxygen weaning in preterm/LBW infants. Future research should be directed toward addressing the question of what are the most appropriate target levels of oxygenation, in both the early and late neonatal periods, rather than whether oxygen should be weaned early or late.

Plain language summary

Early versus late discontinuation of oxygen in preterm or low birth weight infants

Not enough evidence to show the benefits or adverse effects of early oxygen weaning in preterm or low birthweight babies. Babies born either prematurely (before 37 weeks) or with a low birthweight often have breathing problems and need extra oxygen. Oxygen supplementation has provided many benefits for these babies and the ability to measure oxygen levels accurately can help reduce adverse effects. The correct time to wean babies off oxygen supplementation has been unclear but is usually measured by their age, weight gain and breathing ability. The review did not find enough evidence from trials to show the benefits or adverse effects of early oxygen weaning in preterm or low birth weight babies. More research is needed.

Background

The administration of supplemental oxygen has a long history in neonatal care. The use of oxygen in preterm and low birth weight infants suffering respiratory insufficiency has resulted in significant health care benefits, such as reductions in 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 both the increased survival of preterm and low birth weight infants and an ability to measure their 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 mode of administration and appropriate levels of oxygen for maximising short or long‐term growth and development, while minimising harmful effects (Poets 1998; Tin 2001; McIntosh 2001).

Several authors (Kinsey 1956; Kinsey 1977; Gunn 1980; Shahinian 1978) have hypothesised that the duration of supplemental oxygen administration, independent of the oxygen concentration, gestational age and/or birth weight, is influential in the development of severe retinopathy of prematurity. Concern regarding the possible deleterious effects of prolonged oxygen supplementation has lead many clinicians to wean infants from oxygen therapy as early as possible. However, work by Phelps (Phelps 1988) has suggested that visual outcomes may be improved by continuing oxygen supplementation during the recovery phase in kittens with ROP. The effect of duration of oxygen supplementation on the long‐term growth and development of preterm or low birth weight infants remains unclear (Duc 1992).

Objectives

To determine the effect of early vs. late weaning from supplementary oxygen on mortality, retinopathy of prematurity, lung function and growth or development in preterm or low birth weight infants.

A priori subgroup analyses:

• Infants born at different gestational age and birth weight subgroups (as there are differing baseline risks of the outcome measures in these subgroups)

• Gradual vs. abrupt discontinuation of oxygen (as this is hypothesised to influence outcome measures) (Chan‐Ling 1995)

Methods

Criteria for considering studies for this review

Types of studies

Trials utilising random or quasi‐random patient allocation were eligible for inclusion.

Types of participants

Preterm (< 37 weeks gestation) or low birth weight (< 2500g) infants receiving supplemental oxygen.

Types of interventions

Early vs. late weaning of supplemental oxygen.

Types of outcome measures

• Retinopathy of prematurity ‐ any, severe (Stage 3 or greater)

• Retrolental fibroplasia ‐ vascular (any, severe)

• Retrolental fibroplasia ‐ cicatricial (any, severe)

• Mortality ‐ any, early, in neonatal period

• ROP (severe) or death (any)

• RLF (severe) or death (any)

• Apnoea of prematurity

• Chronic lung disease/bronchopulmonary dysplasia

• Growth ‐ neonatal period, long‐term

• Neurodevelopment ‐ long‐term

• Visual function ‐ long‐term

It was determined a priori that outcome data with attrition rates greater than 20% were not to be included in analyses. The only outcome data that were reported in the one eligible trial (Engle 1955) were retrolental fibroplasia and neonatal mortality. No other outcome measures deemed a priori to be clinically important (as listed above) were examined in the one eligible trial included in this review.

Search methods for identification of studies

The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of the Cochrane Controlled Trials Register (CENTRAL/CCTR), the Oxford Database of Perinatal Trials, MEDLINE, previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, journal handsearching mainly in the English language.

An additional literature search of the MEDLINE (1966 ‐ January 2008) and CINAHL (1982 ‐ January 2008) databases was conducted using OVID software in order to locate any trials in addition to those provided by the Cochrane Controlled Trials Register (CENTRAL/CCTR). The search strategy involved various combinations of the following keywords, using the search fields of abstract, MeSH subject heading, exploded subject heading, floating subject heading, publication type, registry number word, subject heading word, text word, and title: oxygen, preterm, premature, neonate, newborn, infant, oxygen saturation, hypoxia, retinopathy of prematurity, retrolental fibroplasia, low birth weight, very low birth weight, extremely low birth weight, randomized controlled trial, controlled clinical trial, clinical trial, random allocation, placebo. No further trials, either eligible for inclusion or excluded trials, were identified by the additional literature search.

Data collection and analysis

The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used to select trials, assess quality and to extract and synthesise data. Each review author independently assessed the methodologic quality and extracted the data from the one eligible trial. Results were compared and differences resolved as required. Level of agreement between the two review authors was greater than 90%. The one eligible trial was assessed for the degree of selection, performance, attrition and detection bias.

Results

Description of studies

The systematic review found only one randomized trial pertaining to the question of early vs. late oxygen weaning (Engle 1955). Another study, Simoes 1997, was excluded from analysis as it did not involve random allocation of patients to the intervention under review.

Participants: 
 The Engle 1955 trial was conducted during an early era of neonatal care 1950 ‐ 1952. Ninety‐nine infants with birthweights less than 1650g were enrolled, and of these only a small number (n = 9) had birthweights under 1000g.

Intervention: 
 All infants in this trial received oxygen for at least 5 days. Blood oxygen levels were not measured in either group. Criteria for the weaning of oxygen were day of life, weight or other clinical signs such as cyanosis and respiratory pattern.

Seven of the infants who were allocated to receive the experimental treatment, early weaning, were unable to receive that treatment due to poor clinical condition. The authors reported most results with these infants included as a third treatment group. In this review, this third group has been analysed as part of their original group allocation (intention‐to‐treat analysis). An additional but uncertain number of infants in the early weaning group were returned to oxygen for periods of time. Hence, the treatments actually received by both groups overlapped considerably (see Effects of Interventions below).

Outcomes: 
 Eye outcome data were reported using retrolental fibroplasia (RLF) classifications (Kinsey 1956). Active (vascular) RLF stage 1 and cicatricial grade A correspond approximately with retinopathy of prematurity (ROP) stage 3 plus, using the International Classification of Retinopathy of Prematurity system, Committee for the Classification of Retinopathy of Prematurity commonly used today (ROP Committee 1984; ROP Committee 1987). Ascertainment of RLF in the included trial was by direct ophthalmoscope, visualising the posterior pole only. The only findings that could be identified using this method were dilation and tortuosity of the retinal vessels ("plus disease", using the 1984 and 1987 classifications). The more common findings in the more anterior retina that today can be visualised with indirect ophthalmoscopy were unable to be identified. Hence, the eye outcomes reported in this review equate with what today would be described as severe ROP.

The authors reported some results for short‐term outcomes such as mean growth measures, weight gain, days in oxygen, and blood transfusions. These data were not reported in sufficient detail to enable inclusion in this review. Attempts were made to follow infants for up to two years. Unfortunately, losses were significant (24% at six months, 50% at 12 months) and, in complying with our a priori criteria not to report outcomes with greater than 20% attrition, growth and development outcomes are not included in this review.

No data were reported on any other outcome measures that were deemed a priori as clinically important, such as late mortality, apnoea of prematurity, chronic lung disease, or long‐term visual function.

Risk of bias in included studies

The single eligible trial, Engle 1955, used a modified random allocation technique (although the method of randomization was not stated), had at least one clinically meaningful outcome, and was thus included in the analysis.

Allocation concealment was unclear in this trial. It is not known what proportion of eligible infants were randomized, or if any were excluded prior to randomization. There was no blinding of the intervention, and it is unclear whether or not outcome assessments were blinded. Attrition within six weeks of treatment allocation was minimal; four survivors lost to follow‐up. Hence, early eye and mortality outcomes are reported. Long term losses to follow up were significant (24% at six months, 50% at 12 months) and therefore long‐term outcome measures are not reported in this review.

Effects of interventions

There were no significant differences in neonatal death rates or retrolental fibroplasia (any grade or severe) for all infants, or among infants with birth weights of less than 1000 g, in this small randomized trial comparing early vs. late oxygen weaning. No other outcome measures specified a priori as clinically meaningful were reported in enough detail or with satisfactory follow‐up rates to include in the analysis (chronic lung disease; and long‐term growth, development, lung or visual function).

As there was only one eligible trial (Engle 1955), an evaluation of heterogeneity and sensitivity analyses were not possible.

All infants in this trial received oxygen for at least 5 days, hence the effect of early vs. late weaning on early mortality could not be assessed in this study design. Seven infants allocated to the early weaning group did not receive this treatment due to poor clinical condition. An additional but uncertain number of infants in the early weaning group were returned to oxygen for periods of time. Hence, the treatments actually received by both groups overlapped considerably, as demonstrated by the range of days of supplemental oxygen: 5 ‐ 81 days for early weaning group, and 8‐60 days for the late weaned group.

Discussion

The hypothesis underlying the investigation of the effect of early vs. late weaning of supplemental oxygen in preterm/LBW infants was that the duration of supplemental oxygen administration, independent of ambient oxygen concentration, was causally related to RLF (Kinsey 1956, Kinsey 1977, Gunn 1980, Shahinian 1978).

This hypothesis has been tested in only one published randomized controlled trial comparing early vs. late oxygen weaning (Engle 1955). Although infants were randomly allocated within this trial. The overall methodological quality of the trial was poor with unclear allocation concealment, no blinding of intervention or outcome assessment, and significant long term losses to follow‐up. This, coupled with the fact that the duration of oxygen exposure in the two group was similar, and infants were exposed to a considerable period of unrestricted oxygen prior to enrolment, means that the results of this analysis should be regarded with caution. The wide confidence intervals suggest a lack of statistical power to demonstrate any real effect of early oxygen weaning should such an effect truly exist.

This trial was conducted during an early era of neonatal care 1950 ‐ 1952, and had only a small number of infants with birth weights under 1000 g, the group of infants who contribute most to significant mortality and morbidity (e.g. ROP) seen in preterm/LBW infants today. Blood oxygen levels were not measured in this trial. Criteria for the weaning of oxygen were day of life, weight or other clinical signs such as cyanosis and respiratory pattern. Such methods of assessing oxygen requirements would not be appropriate in modern neonatal intensive care settings where continuous, non‐invasive oxygen monitoring is now the norm.

Thus, the results of this systematic review do not provide strong evidence for either the benefits or harms of early vs. late oxygen weaning in preterm/LBW infants.

While of historic interest, the non‐significant results of this systematic review have little implication for current practice as the unmeasured, unrestricted method of oxygen administration used in this trial is no longer considered appropriate.

Authors' conclusions

Implications for practice.

The results of this systematic review do not provide evidence for either the benefits or harms of early vs. late oxygen weaning in preterm/LBW infants.

Implications for research.

In light of improved oxygen administration and monitoring techniques since the included trial was conducted, the question of duration of oxygen therapy has been superseded by the question of what are appropriate target oxygen levels. Future research should thus be directed toward addressing the question of what are the most appropriate levels of oxygenation to be targeted, in both the early and late neonatal periods, rather than whether oxygen should be weaned early or late.

What's new

Date	Event	Description
12 August 2009	Amended	Minor change in text of Characteristics of Included Studies table.

History

Protocol first published: Issue 2, 1998
 Review first published: Issue 4, 1998

Date	Event	Description
7 August 2008	New search has been performed	This review updates the existing review "Early versus late discontinuation of oxygen in preterm or low birth weight infants" published in the Cochrane Database of Systematic Reviews. Updated search found no new trials. No changes to conclusions.
15 February 2008	Amended	Converted to RevMan 5 format.
13 July 2001	New citation required and conclusions have changed	Substantive amendment

Data and analyses

Comparison 1. Early vs late oxygen weaning (all preterm/LBW infants).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death (neonatal period)	1	99	Risk Ratio (M‐H, Fixed, 95% CI)	3.06 [0.13, 73.34]
2 RLF (vascular, any stage) in examined survivors	1	94	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.69, 1.29]
3 RLF (cicatricial, any grade) in examined survivors	1	94	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.36, 1.68]
4 RLF (cicatricial, severe grades) in examined survivors	1	94	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.19, 3.31]
5 RLF (severe) or death (neonatal)	1	99	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.27, 3.85]

1.1. Analysis.

Comparison 1 Early vs late oxygen weaning (all preterm/LBW infants), Outcome 1 Death (neonatal period).

1.2. Analysis.

Comparison 1 Early vs late oxygen weaning (all preterm/LBW infants), Outcome 2 RLF (vascular, any stage) in examined survivors.

1.3. Analysis.

Comparison 1 Early vs late oxygen weaning (all preterm/LBW infants), Outcome 3 RLF (cicatricial, any grade) in examined survivors.

1.4. Analysis.

Comparison 1 Early vs late oxygen weaning (all preterm/LBW infants), Outcome 4 RLF (cicatricial, severe grades) in examined survivors.

1.5. Analysis.

Comparison 1 Early vs late oxygen weaning (all preterm/LBW infants), Outcome 5 RLF (severe) or death (neonatal).

Comparison 2. Early vs late oxygen weaning (BW <1000g).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 RLF (vascular, any stage) in examined survivors	1	9	Risk Ratio (M‐H, Fixed, 95% CI)	1.2 [0.69, 2.07]
2 RLF (cicatricial, any grade) in examined survivors	1	9	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.08, 4.66]
3 RLF (cicatricial, severe grades) in examined survivors	1	9	Risk Ratio (M‐H, Fixed, 95% CI)	0.4 [0.02, 7.82]

2.1. Analysis.

Comparison 2 Early vs late oxygen weaning (BW <1000g), Outcome 1 RLF (vascular, any stage) in examined survivors.

2.2. Analysis.

Comparison 2 Early vs late oxygen weaning (BW <1000g), Outcome 2 RLF (cicatricial, any grade) in examined survivors.

2.3. Analysis.

Comparison 2 Early vs late oxygen weaning (BW <1000g), Outcome 3 RLF (cicatricial, severe grades) in examined survivors.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Engle 1955.

Methods	Randomization was by a modified random allocation technique (method not stated), so it is assumed that infants were truly randomized. It appears there was no blinding of either the intervention or outcome assessment. No power calculations were done. There was a 77% follow up rate at 6 months, but only 51% of infants underwent developmental assessment at 12 months age.
Participants	Infants less than 1650g birth weight were eligible to participate. 99 infants were randomized. Of these only 9 were <1000g BW. Birth weight range: 800‐1650g. Gestational age range: 26‐40 weeks. Infants 1000g or less were randomized at 14 days, those with birth weights 1001‐1361 at 7 days, and those 1362‐1650g at 2 days.
Interventions	All infants received supplementary oxygen for at least 5 days. Experimental group (early weaning): were assigned at Day 2, 7, or 14 (depending on birth weight) to be weaned from oxygen gradually over 3‐4 days. Thus removal from oxygen was at approximately 5, 10 or 17 days. Control group (late weaning): infants were given unrestricted oxygen until they reached 1600g, and were then weaned gradually over 3‐4 days.
Outcomes	Mortality (any) RLF (vascular, any stage) RLF (cicatricial, any grade) RLF (cicatricial, severe grades) Valid mortality and eye outcome data only available to 6 weeks of age. There was 1 death on day 11 (early weaning group), and four losses to follow up by 6 weeks (2 in each group). The loss to follow up rates at 6 and 12 months were 24% and 50% respectively. Hence long term developmental outcomes were not analysed for this review.
Notes	Authors reported results in three groups: experimental (group II, early weaning), control (group I, late weaning), and a group that were randomized to the experimental group but received the control intervention (group II ‐> I). The analyses for this review were undertaken on an intention‐to‐treat basis i.e. those in group II ‐> I were analysed as they were originally randomized in group II.
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Modified random allocation. It was unclear how this method worked.
Allocation concealment?	High risk	It was not stated whether allocation concealment was used.
Blinding? All outcomes	High risk	It was impossible to blind participants to early and late discontinuation of oxygen (or assisted ventilation).
Incomplete outcome data addressed? All outcomes	High risk	There were 9 tables of results and analysed data that reported on all outcomes, but there was only a 77% follow up rate at 6 months, and only 51% of infants underwent developmental assessment at 12 months age.

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Simoes 1997	Neonates not randomly assigned to treatment groups.

Differences between protocol and review

Some results for short‐term outcomes such as mean growth measures, weight gain, days in oxygen, and blood transfusions were reported, but not reported in sufficient detail to enable inclusion in this review. Attempts were made to follow infants for up to two years. Unfortunately, losses were significant (24% at six months, 50% at 12 months) and, in complying with our a priori criteria not to report outcomes with greater than 20% attrition, growth and development outcomes are not included in this review.

No data were reported on any other outcome measures that were deemed a priori as clinically important, such as late mortality, apnoea of prematurity, chronic lung disease, or long‐term visual function.

There was no subgroup analysis of infants born at different gestational age due to no adequate data on this aspect.

Contributions of authors

Askie and Henderson‐Smart developed the original protocol for this review, as well as undertaking the original literature search, background, data analysis, discussion and conclusions sections. 
 Askie and Henderson‐Smart reviewed the updated literature search and the GRADE Summary of Findings tables created by Ko which will be published with this review at a future date.

Sources of support

Internal sources

• NHMRC Clinical Trials Centre, University of Sydney, Australia.

• Centre for Perinatal Health Services Research, University of Sydney, Australia.

External sources

• No sources of support supplied

Declarations of interest

The authors of this review are currently conducting a randomized, controlled trial of the effect of higher versus standard oxygen saturation targeting on long term growth and development of preterm infants.

Edited (no change to conclusions)