Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs
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 but can cause damage to the eyes (retinopathy) and lungs. The review of trials found that unrestricted oxygen supplementation has these potential adverse effects without any clear benefits. Restricted oxygen significantly reduces these risks. More research is needed to find the best level of supplementation.
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, whilst minimising harmful effects (Poets 1998, McIntosh 2001).
Uncertainty remains as to the most appropriate range to target blood oxygen levels in preterm and low birth weight infants. Usher (Usher 1973) examined the effect of targeting a lower versus higher range of PaO2 on death, the need for mechanical ventilation and other clinical outcomes and concluded there was no benefit in targeting a higher range, and there may in fact be deleterious respiratory effects (Coates 1982). A cohort study by Tin et al (Tin 2001) also suggested adverse respiratory outcomes and a significant increase in the incidence of ROP when higher O2 ranges were targeted in preterm infants. However, Phelps and Rosenbaum (Phelps 1984) demonstrated significantly more severe retinopathy in kittens recovering from hyperoxic-induced disease when allowed to recover in lower levels of ambient oxygen, suggesting that targeting higher blood oxygen levels may be beneficial to visual outcomes. The STOP-ROP trial (STOP-ROP 2000) found that higher O2 targeting did not significantly decrease the incidence of pre-threshold ROP progression, but did cause an exacerbation of adverse pulmonary events. The results of this trial will be included in a separate Cochrane review entitled: "Supplemental oxygen for the treatment of pre-threshold retinopathy of prematurity" (Lloyd J, Askie LM, Smith J, Tarnow-Mordi WO). The effects of either policy of oxygen administration on long term growth and development in preterm or low birth weight infants remains unknown.
A priori sub-group analyses:
- Method of oxygen monitoring.
- Infants born at different gestational age and birth weight subgroups:
as there are differing baseline risks of the outcome measures in these
subgroups.
- Time of discontinuation: early versus late discontinuation as this
is hypothesized to influence outcome measures (Gunn
1980).
- Method of discontinuation: gradual versus abrupt discontinuation
as this is hypothesized to influence outcome measures (Chan-Ling
1995).
Outcome data with attrition rates greater than 20% were not included in analyses.
An additional literature search, using OVID software, was conducted of the MEDLINE (1966-July 2001) and CINAHL (1982-July 2001) databases 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.
Meta-analyses were carried out with use of relative risk (RR) and risk difference (RD). When appropriate, number needed to treat (1/RD) was calculated. The fixed effects "assumption free" model was used. Evaluation of heterogeneity, subgroup and sensitivity analyses were undertaken as appropriate.
Participants:
The enrolment period for the five included studies was between 1951-1969.
This was during an early era of neonatal care, with therapies and practices
quite different from modern "intensive" care, and included only small numbers
of survivors with birth weights under 1000g who today carry the greatest
mortality and morbidity burden. There was a wide range of birth weights
amongst trial participants, from less than 1000 to 2500g. The largest trial
(Kinsey 1956) only enrolled infants who survived
beyond 48 hours, whilst the other four trials randomized infants on admission
to the neonatal nursery. All trials used birthweight as an inclusion criteria.
Two trials also selected infants for inclusion based on a diagnosis of
respiratory distress syndrome (Usher 1973) or
hypoxia/acidemia (Sinclair 1968).
Intervention:
Two trials (Usher 1973; Sinclair
1968) administered oxygen based on actual arterial or capillary blood
oxygen levels. The other three trials were conducted in an era before accurate
blood oxygen monitoring in infants was possible. As such, these trials
could only test the effects of cruder measures of oxygenation, such as
ambient oxygen concentration, and even these in only general terms, labelled
"liberal" and "restricted" oxygen administration in this review.
All the included trials commenced the intervention in the early neonatal period, but continued it for a wide range of time: from 1 day to 7 weeks. As such, it is not possible from the data available to investigate the effect of the intervention in the early neonatal period (less than 1 week life) compared with the later neonatal period (1 week - 1 month age). When oxygen weaning was indicated, it was done so gradually in 2 trials, abruptly in 1 trial, and the method not specified in the remaining 2 trials.
Outcomes:
Outcome measures were assessed at time periods ranging from 2 days
to 6 months. None of the included trials reported any valid short or long
term effects of the interventions on either growth, neurodevelopment, lung
function, or chronic lung disease. Coates 1982 reported some long term
outcomes on infants from Usher's 1973 study. Unfortunately, he was only
able to obtain outcome data for 23% of survivors, and in keeping with our
a priori specification of only including outcome measures with 80% or greater
ascertainment, these data are not included in the review.
The only eye outcome data reported in the included trials used the retrolental fibroplasia (RLF) classifications (Reese 1953). Vascular RLF stage 1 and cicatricial RLF grade II correspond approximately with retinopathy of prematurity (ROP) stage 3 plus and stage 4 respectively, using the International Classification of Retinopathy of Prematurity system (Committee for the Classification of Retinopathy of Prematurity 1984, 1987) commonly used today. Ascertainment of RLF in the included trials 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, as above). The more common findings in the anterior pole that can today be identified with indirect ophthalmoscopy were unable to be identified. Hence, even the least severe eye outcomes reported in this review equate with what today would be described as "threshold" ROP.
The largest trial (Kinsey 1956, n = 212) only enrolled infants who survived beyond 48 hours. Unfortunately, the second largest trial (Patz 1954, n = unknown, but greater than 120) did not report any mortality data and these data are not retrievable (Duc 1992 pp181-182).
Two of the trials had adequate allocation concealment: Kinsey 1956 used central telephone randomisation, and Sinclair 1968 used a method of sealed envelopes. Allocation concealment is unclear in the other three trials. Patz 1954 used quasi-random patient allocation. The other four trials were truly randomized. No trials blinded the intervention. Only Kinsey 1956 reported power calculations a priori. Four of the included studies had adequate short term outcome measure ascertainment. The Patz 1954 trial did not report deaths or losses, but it is assumed that outcome data were reported only on survivors and assessed by 6 months age.
Neither restricted oxygen compared with liberal administration, nor
lower versus higher PaO2, had significant independent effects on death
rates, either in all preterm/LBW infants or in a sub-group of infants with
birth weights less then 1250g. Restricted compared with liberal oxygen
administration did, however, significantly reduce a combined measure of
adverse outcome, death or RLF (vascular, any stage) (RR 0.59, CI 0.48-0.72).
Thus, one would need to treat only 3 infants with restricted oxygen to
prevent one infant from having the adverse outcome of death or RLF (NNT
= 1/RD = 1/0.310 = 3.2). Restricted compared with liberal oxygen administration
also reduced the more severe measure of adverse outcome, death or RLF (cicatricial,
any grade) (RR 0.77, CI 0.56-1.07), although this result was not statistically
significant.
No other outcome measures specified a priori as clinically meaningful
were reported in enough detail or with satisfactory follow-up rates to
be included in the analysis (chronic lung disease, long term growth, development,
lung or visual function).
Sub-group analyses:
Only two of the a priori stated sub-group analyses were possible with
the available data. The only reported effect of restricted versus liberal
oxygen administration on infants with BW less than 1000g was a non-significant
decrease in RLF (cicatricial, severe) in the Patz
1954 trial. This analysis was based on very small numbers, with uneven
denominators in each group. This may reflect a difference in the number
of survivors in the two groups resulting from deaths which were not accounted
for by Patz 1954. This result should thus be interpreted
with caution as the small numbers in this sub-group (as reflected by the
wide confidence intervals) and non-reported deaths make any meaningful
interpretation of these data difficult. A comparison of the effect of lower
versus higher PaO2 in a sub-group of infants with BW less than 1250g demonstrated
a result consistent with that in the group as a whole, i.e. no significant
difference in death rates. It was not possible to undertake any of the
other a priori specified sub-group analyses such as time or method of oxygen
weaning, or method of oxygen monitoring, due to insufficient data.
Evaluation of heterogeneity:
No statistical heterogeneity was demonstrated in any of the outcome
measures analysed that included more than one trial.
There was a degree of clinical heterogeneity amongst the five trials included in this review. All included trials contained a wide range of birthweights, followed infants for similar periods (all in the short term), used similar definitions of outcome measures, and implemented the interventions in the early neonatal period. However, there was a very wide range of exposure to the interventions under review (1 day - 7 weeks). Moreover, there were two distinct intervention comparisons included in the review (hence the division of comparisons into restricted versus liberal oxygen exposure and low versus high PaO2). The Kinsey 1956; Lanman 1954 and Patz 1954 trials were conducted in an early era of neonatal care where methods of oxygen monitoring and administration were crude in comparison to today's techniques and thus only restricted versus liberal oxygen exposure could be compared in these trials. The Usher 1973 and Sinclair 1968 trials used more modern techniques (including umbilical artery catheterisation, arterialised capillary sampling, micromethods for blood gases and acid-base) and thus comparisons of low versus high oxygen levels were possible with data from these trials.
Sensitivity analyses:
The results of the meta-analyses were tested for robustness with regard
to study quality. We had stated a priori that trials containing outcome
measures with greater than 20% attrition would not be included in the analysis.
In one trial, Patz 1954, it was unclear whether
outcome ascertainment was complete as attrition due to losses to followup
and deaths were not reported. This, plus the fact that it was the only
trial using a quasi-random method of patient allocation, led us to test
the results without the inclusion of this trial.
There were three outcome measures that included data from the Patz 1954 trial. One was a sub-group analysis of RLF (cicatricial, severe) in infants with birthweights less than 1000g. Data from the Patz trial were the only data contributing to this analysis, so removing this trial would mean that there were no data for this outcome measure. The other two outcomes to which the Patz trial contributed were RLF (vascular, any stage) and RLF (cicatricial, severe grades). The results for neither of these outcome measures were significantly affected by the exclusion of the Patz trial. Hence, the results of these meta-analyses were not sensitive to the effect of study quality.
Surprisingly, to date only one randomized trial (Usher 1973) has attempted to address this question directly. Sinclair 1968 assessed the effects of low versus high PaO2 and other co-interventions in a group of hypoxic, acidemic low birth weight infants. The related, but now historic, question of restricted versus liberal oxygen administration was addressed by three randomized trials in an era before accurate and/or continuous monitoring of infant blood oxygen levels was possible. Both interventions were included in this review, which addresses the general question of the effect of oxygen dose on outcomes for LBW/preterm infants.
Restricting oxygen exposure significantly reduced the incidence and severity of RLF without unduly increasing death rates in this meta-analysis. It should be noted, however, that the trial contributing the most data to this result (Kinsey 1956) did not enrol infants until at least 48 hours of age. The effect of restricted oxygen administration on early neonatal death cannot be reliably ascertained from the available data. The results of this trial have often been misinterpreted, with the resulting extrapolation of aggressive restriction of oxygen from birth leading to a substantial increase in mortality rates amongst preterm/low birthweight infants in the years following its publication (Cross 1973). It should also be noted that the second largest trial, Patz 1954, did not report any mortality data and this information is not retrievable (Duc 1992, pp 181-182). Unfortunately, the confidence intervals around the point estimate for this outcome are quite wide (RR 1.20, CI 0.80-1.80), and the addition of the Patz 1954 mortality data would have been most helpful in resolving this issue. It is possible that the difference in retrolental fibroplasia rates seen in survivors may be influenced by the trend toward excess deaths caused by the restricted oxygen policy.
The two trials (Sinclair 1968, Usher 1973) that addressed the question of lower versus higher PaO2 found no effect on death, but did not report (in sufficient detail to warrant inclusion) the effect of this intervention on eye or other outcomes. The effects of either of these oxygen administration policies on other clinically meaningful outcomes, including chronic lung disease, and long term growth, neurodevelopment, lung or visual function, were not reported in any of the available trials.
Since the publication of these trials, other authors have attempted to further investigate the association between RLF and PaO2 levels. A large, prospective, non-randomised study (Kinsey 1977) involving a detailed survey across five collaborating centres in the USA was undertaken between 1969 and 1972. No definitive relationship between PaO2 and the occurrence of RLF could be established. It should be noted that this analysis was undertaken using the limited information available from intermittent blood gas sampling. The study did find, however, an association between susceptibility to RLF and decreasing birthweight and increasing time in oxygen. However, no guidelines for the optimal range of PaO2 were suggested by this study.
The role of careful, continuous monitoring of oxygen levels on the incidence of retinopathy of prematurity has also been investigated by several authors since the publication of the studies included in this review. Bancalari and co-workers (Bancalari 1987a; Bancalari 1987b; Flynn 1987) conducted the only large randomized trial of continuous transcutaneous PO2 monitoring to date. This study showed no significant difference in the incidence or severity of ROP, mortality or chronic lung disease in the continuously monitored infants compared with those who received standard (intermittent) monitoring of PO2 levels. The utility of pulse oximetry monitoring in preventing adverse neonatal outcomes remains largely untested. The only controlled trial reported to date established the value of pulse oximetry in reducing major hypoxic events during anaesthesia among 152 children undergoing surgery (Cote 1988). No other experimental reports to date have assessed the effects of pulse oximetry monitoring on other neonatal outcomes.
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Kinsey 1956 | Central telephone randomisation ensured adequate allocation concealment. The ratio of experimental group : control group was 2:1 in first 3 months of enrolment. Following that, 574 infants were consecutively allocated to the experimental group and had no concurrent controls. These infants are not included in this review. The number of infants excluded before randomization is not known. Randomization was stratified by birth weight categories and institution. The intervention was not blinded, and the blinding of outcome assessments is unclear. The followup rate for outcome measures was 97%. There were detailed power calculations. | 212 infants with BW <1500g who survived to 48 hours. Enrolment commenced in July 1953. The mean BW in the two groups was 1242g (restricted) and 1234g (liberal) respectively. Infants were followed until 2.5 months of age. | Experimental group (restricted O2): received oxygen only if clinical
condition indicated and maximum FiO2 permitted was 0.5.
Control group (liberal O2): received supplemental oxygen in excess of 50% for a minimum of 28 days, and were then weaned over 3 days. |
Vascular RLF (any stage) in survivors
Vascular RLF (severe stages) in survivors Cicatricial RLF (any grade) in survivors Cicatricial RLF (severe grades) in survivors Mortality (48 hours-40 days) Of the 144 infants assigned to the restricted O2 group, 36 died before 40 days and 4 were lost to followup. There were 15 deaths and no losses to followup amongst the 68 infants allocated to the liberal O2 group. |
A | |
| Lanman 1954 | Infants were randomized by random numbers, method unspecified, and thus allocation concealment is unclear. There was no blinding of the intervention, and it is unknown if outcome assessments were done blinded to treatment allocation. There was only one loss to followup of the 86 infants enrolled. Power calculations were inadequate with the completion of the study being determine by a date specified one year in advance. | 86 infants with BW 1000-1850g, admitted within 12 hours of birth. Infants were followed until 3 months age. | Experimental group (restricted oxygen): only received oxygen when cyanosed,
at a maximum FiO2 of 0.5. The mean FiO2 received by this group was 0.38.
Control group (liberal oxygen): received supplemental oxygen for a minimum of 2 weeks or until reaching 1500g, and were then weaned abruptly. The mean FiO2 received by this group was 0.69. |
Vascular RLF (any stage) in survivors
Cicatricial RLF (any grade) in survivors Mortality (12 hours-3 months) |
B | |
| Patz 1954 | Quasi-random treatment allocation, based on alternate admission basis. Allocation concealment was thus inadequate. There was no blinding of the intervention and it is unclear whether outcome assessments were blinded to treatment allocation. Attrition due to deaths or losses to followup are not reported, so it is unclear whether there was complete outcome measure ascertainment. No power calculations were reported. | An unknown number of very low birthweight infants (</= 1500g) were enrolled from Jan 1951 to May 1953. 120 infants survived and had eye outcome assessments completed by 6 months age and were included in the analysis. | Experimental group (restricted oxygen): infants received oxygen only
for clinical indications, and to a maximum FiO2 of 0.4. The range of duration
of oxygen in this group was 1 day - 2 weeks. Once weaning was indicated,
it proceeded over 1-3 days.
Control group (liberal oxygen): infants were placed in supplemental oxygen of 60-70% for 4-7 weeks, then weaned over one week. |
Vascular RLF (any stage) in survivors
Cicatricial RLF (severe grades) in survivors Cicatricial RLF (severe grades), BW <1000g, in survivors There are no data available, either published or unpublished, on mortality rates. The number of infants allocated to each group was not reported, hence outcome data can only be expressed in relation to the surviving infants presenting for followup assessment. |
C | |
| Sinclair 1968 | Randomized to one of 4 treatment groups, using sealed envelopes and thus allocation concealment was adequate. There was no blinding of treatment intervention, and it is unclear whether there was blinding of outcome assessments. No power calculations were reported. Short term follow up was complete. | 20 infants with BW 1000-2500g, less than 24 hours age, who were hypoxic and acidemic were included. | Infants were randomized to one of four treatment groups including combinations
of the following treatments: restricted vs liberal ambient oxygen, rapid
vs slow alkali infusion, assisted vs spontaneous ventilation. There was
random allocation of the other two treatments within the two oxygen therapy
groups, hence the data from this trial were included in the review.
Experimental group (restricted oxygen): supplemental oxygen, to a maximum of 35%, to keep PaO2 50-120 mmHg. If PaO2 fell below 40 mmHg or infant became bradycardic, could give unlimited oxygen and would be considered as a treatment failure. Control group (liberal oxygen): received 100% headbox oxygen for first 2 hours, then aimed to maintain PaO2 at 50-120 mmHg using any FiO2 needed. |
Mortality (any)
Physiological measures including: - acid-base balance - PaO2 levels - percentage right-left shunt - serum electrolytes, blood urea nitrogen, serum lactate - urinary net acid excretion - plasma bicarbonate - "apparent" bicarbonate space Long term neurological assessments reported as "in progress" in the paper were never completed (personal communication J. Sinclair, July 1998). |
A | |
| Usher 1973 | Infants were randomized by a stratified random sampling technique. Allocation concealment is unclear. There was no blinding of the intervention. One author was unblinded to the treatment allocation, but is unclear whether this author was involved in outcome assessments. No power calculations were reported. Early outcome data were reported completely. However, long term outcome data included only 15% of the enrolled infants and thus have not been included in this review. | 150 infants with a diagnosis of respiratory distress syndrome or BW <1000g were eligible for inclusion. The numbers excluded prior to randomization are not reported. | Experimental group (low PaO2): infants received oxygen only if their
PaO2 fell below 40 mmHg or PcapO2 fell below 35 mmHg. Sufficient oxygen
was used to maintain these tensions.
Control group (high PaO2): infants were kept in a minimum of 40% oxygen for 72 hours. Aim was to maintain PaO2 80-120 mmHg or PcapO2 50-60 mmHg. Mechanical ventilation was not available to either group. |
Mortality (any)
Mortality (respiratory) Descriptive results of respiratory failure measures were reported (such as retractions, grunting, respiratory pattern and rate, chest Xray changes). |
B |
| Study | Reason for exclusion |
| Bard 1996 | Infants were not randomly assigned to target two different arterial blood oxygen saturations (90% and 95%). Infants acted as their own controls. This was not a random or quasi-random trial and was thus excluded from the review. |
| Cunningham 1995 | This nonrandomised, retrospective study assessed the effects of variability of oxygen levels, as measured by transcutaneous oxygen monitoring, on the incidence of retinopathy of prematurity. Patient allocation was not randomised, and thus the study was excluded from the review. |
| Engleson 1958 | This nonrandomised trial addressed a different question from that under review. It examined the effects of keeping preterm infants at oxygen concentrations below that of room air, and was thus not included in the review. |
| Gaynon 1997 | The study was a retrospective analysis of different target ranges of oxygen saturation on the incidence of ROP. There was no random allocation of patients to different treatment groups, thus the trial was excluded from the review. |
| Kitchen 1978 | This study was a randomized trial of a "package" of intensive care, including intravenous glucose, umbilical arterial catheterisation, bicarbonate infusion, and high PaO2 levels, versus the standard neonatal care regimen of the late 1960s. The trial was excluded from the review because the entire "package" of interventions, rather than the separate elements within it, was the randomized intervention. Thus, other interventions that could affect clinical outcomes were unbalanced between oxygen exposure groups. |
| Lundstrom 1995 | This randomised trial addressed a different question from that under review. It compared the use of atmospheric air versus 80% oxygen for preterm infants during initial stabilization in the delivery room, and was thus excluded from the review. |
| Mendicini 1971 | This study was a randomised trial of a "package" of intensive care, including intravenous glucose, bicarbonate infusion, and high PaO2 levels, versus the standard neonatal care regimen of the late 1960s. The trial was excluded from the review because the entire "package" of interventions, rather than the separate elements within it, was the randomized intervention. Thus, other interventions that could affect clinical outcomes were unbalanced between oxygen exposure groups. |
| Schulze 1995 | This was a nonrandomised, crossover trial comparing the effects of two different oxygen saturation target ranges on cardiac output, oxygen extraction, and oxygen consumption in mechanically ventilated, low birth weight infants. As treatment allocation was not random or quasi-random, the trial was excluded from the review. |
| STOP-ROP 2000 | This trial included preterm/LBW infants with pre-threshold ROP. The intervention tested was supplemental oxygen for the treatment of pre-threshold ROP, not a preventative strategy. The results of this trial will be included in a separate Cochrane review entitled: "Supplemental oxygen in the treatment of pre-threshold retinopathy of prematurity" (Lloyd J, Askie LM, Smith J, Tarnow-Mordi WO). |
| Weintraub 1956 | The planned scheme of quasi-random, alternate allocation was not adhered to, resulting in the possibility of substantial selection bias, and the study was thus excluded from the review. |
| Study | Trial name or title | Participants | Interventions | Outcomes | Starting date | Contact information | Notes |
| BOOST (Australia) | Benefits of oxygen saturation targeting trial | Infants < 30 weeks pma, still O2 dependent at 32 weeks pma | Higher (Fn SpO2 95-98%) vs standard (Fn SpO2 91-94%) O2 targeting | Growth and development at one year corrected age, other secondary outcomes | September 1996 | lisa.askie@perinatal.usyd.edu.au | Primary results expected by early 2002. |
Kinsey VE. Cooperative study of retrolental fibroplasia and the use of oxygen. Arch Ophthalmol 1956;56:481-543.
Lanman 1954 {published data only}
Lanman JT, Guy LP, Dancis J. Retrolental fibroplasia and oxygen therapy. JAMA 1954;155:223-226.
Patz 1954 {published data only}
* Patz A. Oxygen studies in retrolental fibroplasia. IV. Clinical and experimental observations. Am J Ophthalmol 1954;38:291-308.
Patz A, Hoeck LE, Cruz E De La. Studies on the effect of high oxygen administration in retrolental fibroplasia. I. Nursery observations. Am J Ophthalmol 1952;36:1248-1253.
Patz A. The role of oxygen in retrolental fibroplasia. Pediatrics 1957;19:504-524.
Sinclair 1968 {published data only}
Sinclair JC, Engel K, Silverman WA. Early correction of hypoxemia and acidemia in infants of low birth weight. A controlled trial of oxygen breathing, rapid alkali infusion and assisted ventilation. Pediatrics 1968;42:565-589.
Usher 1973 {published data only}
* Usher RH. Treatment of respiratory distress syndrome. In: Winters RW, editor(s). The Body Fluids in Pediatrics. Boston & Toronto: Little, Brown and Company, 1974:303-337.
Coates AL, Desmond K, Willis D, Nogrady MB. Oxygen therapy and long-term pulmonary outcome of respiratory distress syndrome in newborns. Am J Dis Child 1982;136:892-895.
Bard H, Belanger S, Fouron J. Comparisons of effects of 95% and 90% oxygen saturations in respiratory distress syndrome. Arch Dis Child 1996;75:F94-F96.
Cunningham 1995 {published data only}
Cunningham S, Fleck BW, Elton RA, McIntosh N. Transcutaneous oxygen levels in retinopathy of prematurity. Lancet 1995;346:1464-1465.
Engleson 1958 {published data only}
* Engleson, G, Rooth G, Sjostedt S. Treatment of premature infants with 15% oxygen. Acta Paediatr Scand 1958;(118 Suppl):47-49.
Sjostedt S, Rooth G. Low oxygen tension in the management of newborn infants. Arch Dis Child 1957;32:397-400.
Rooth G, EnglesonG, Tornblom M. A follow-up study of premature infants treated with low oxygen tension. Acta Paediatr Scand 1966;55:85-87.
Gaynon 1997 {published data only}
Gaynon, MW, Stevenson DK, Sunshine P, Fleisher BE, Landers MB. Supplemental oxygen may decrease progression of prethreshold disease to threshold retinopathy of prematurity. J Perinatol 1997;17:434-438.
Kitchen 1978 {published data only}
* Kitchen WH, Ryan MM, Rickards A, Gaudry E, Brenton AM, Billson FA, Fortune DW, Keir EH, Lundahl-Hegedus EE. A longitudinal study of very low birthweight infants. I. Study design and mortality rates. Dev Med Child Neurol 1978;20:605-618.
Kitchen WH, Rickards A, Ryan MM, McDougall AB, Billson FA, Keir EH, Naylor FD. A longitudinal study of very low-birthweight infants. II. Results of controlled trial of intensive care and incidence of handicaps. Dev Med Child Neurol 1979;21:582-589.
Kitchen WH, Campbell DG. Controlled trial of intensive care for very low birth weight infants. Pediatrics 1971;48:711-714.
Lundstrom 1995 {published data only}
* Lundstrom KE, Pryds O, Greisen G. Oxygen at birth and prolonged cerebral vasoconstriction in preterm infants. Arch Dis Child 1995;73:F81-F86.
Lundstrom KE, Pryds O, Greisen G. 80% oxygen administration to newborn premature infants causes prolonged cerebral vasoconstriction [abstract]. Pediatr Res 1994;35:275.
Lundstrom KE, Larsen PB, Brendstrup L, Skov L, Greisen G. Cerebral blood flow and left ventricular output in spontaneously breathing, newborn preterm infants treated with caffeine or aminophylline. Acta Paediatrica 1995;84:6-9.
Mendicini 1971 {published data only}
Mendicini M, Scalamandre A, Savignoni PG, Picece-Bucci S, Esuperanzi R, Bucci G. A controlled trial on therapy for newborns weighing 750-1250g. I. Clinical findings and mortality in the newborn period. Acta Paediatr Scand 1971;60:407-416.
Schulze 1995 {published data only}
Schulze A, Whyte RK, Way RC, Sinclair JC. Effect of the arterial oxygenation level on cardiac output, oxygen extraction, and oxygen consumption in low birth weight infants receiving mechanical ventilation. J Pediatr 1995;126:777-784.
STOP-ROP 2000 {published data only}
The STOP-ROP Multicenter Study Group. Supplemental theraputic oxygen for prethreshold retinopathy of prematurity (STOP-ROP), a randomized, controlled trial. I: Primary outcomes. Pediatrics 2000;105:295-310.
Weintraub 1956 {published data only}
Weintraub DH, Tabankin A. Relationship of retrolental fibroplasia to oxygen concentration. J Pediatr 1956;49:75-79.
Askie LM, Henderson-Smart DJ, Irwig L, Simpson J. NSW Centre for Perinatal Health Services Research Building D02 University of Sydney. NSW. 2006. AUSTRALIA Telephone: +61 2 9351 7739 Fax: +61 2 9351 7742 Email: laskie@mail.usyd.edu.
* indicates the primary reference for the study
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02 Restricted versus liberal oxygen therapy (BW<1000g)
02.01 Cicatricial RLF (severe grades)
in survivors
03 Restricted versus liberal oxygen therapy (all preterm/LBW infants)
excluding Patz 1954
03.01 Vascular RLF (any stage) in survivors
03.02 Cicatricial RLF (severe grades)
in survivors
04 Low versus high PaO2 (all preterm/LBW infants)
04.01 Death (any)
05 Low versus high PaO2 (BW <1250g)
05.01 Death (any)