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 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.
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, 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 in their neonatal course. 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).
A priori sub-group 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).
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.
An additional literature search of the MEDLINE (1966-July 2001) and CINAHL (1982-July 2001) 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.
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 Results).
Outcomes:
Eye outcome data were reported using retrolental fibroplasia (RLF)
classifications (Kinsey 1956, p536). 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 1984, 1987) commonly used
today. 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, as above). 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 2 years. Unfortunately, losses were significant (24% at 6 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.
Allocation concealment was unclear in this trial. It is not known what proportion of eligible infants were randomised, 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 - 4 survivors lost to follow up. Hence, early eye and mortality outcomes are reported. Long term losses to follow up were significant (24% at 6 months, 50% at 12 months) and therefore long term outcome measures are not reported in this review.
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 versus 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.
This hypothesis has been tested in only one published randomized controlled trial comparing early versus late oxygen weaning (Engle 1955). Although infants were randomly allocated within this trial, its overall methodological quality was poor with unclear allocation concealment, no blinding of intervention or outcome assessment, and significant long term losses to followup. 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 1000g, which today are the group of infants who contribute most to significant mortality and morbidity (e.g. ROP) seen in preterm/LBW infants. 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 versus late oxygen weaning in preterm/LBW infants.
Whilst 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.
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Engle 1955 | 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. | 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. | 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. | 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. |
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. | B |
| Study | Reason for exclusion |
| Simoes 1997 | Neonates not randomly assigned to treatment groups. |
* Engle MA, Levine SZ. Response of small premature infants to restriction of supplementary oxygen. Am J Dis Child 1955;89:316-324.
Engle MA, Baker DH, Baras I, Freemond A, Laupus WE, Norton EW. Oxygen administration and retrolental fibroplasia. Am J Dis Child 1955;89:399-413.
Simoes EAF, Rosenberg AA, King SJ, Groothius JR. Room air challenge: prediction for successful weaning of oxygen-dependent infants. J Perinatol 1997;17:125-129.
* indicates the primary reference for the study
Avery ME, Oppenheimer EH. Recent increase in mortality from hyaline membrane disease. J Pediatr 1960;57:553.
Chan-Ling T, Gock B, Stone J. Supplemental oxygen therapy. Basis for noninvasive treatment of retinopathy of prematurity. Investig Ophthalmol Visual Sci 1995;36:1215-1230.
Duc G, Sinclair JC. Oxygen administration. In: Sinclair JC, Bracken MB, editor(s). Effective Care of the Newborn Infant. Oxford: Oxford University Press, 1992:178-98.
Gunn TR, Easdown J, Outerbridge EW, Aranda JV. Risk factors in retrolental fibroplasia. Pediatrics 1980;65:1096-1100.
Kinsey V. Retrolental fibroplasia. Cooperative study of retrolental fibroplasia and the use of oxygen. Arch Ophthalmol 1956;56:481-543.
Kinsey VE, Arnold HJ, Kalina RE, Stern L, Stahlman M, Odell G, Driscoll JM, Elliott JH, Payne J, Patz A. PaO2 levels and retrolental fibroplasia: a report of the cooperative study. Pediatrics 1977;60:655-668.
McDonald AD. Cerebral palsy in children of low birth weight. Arch Dis Child 1963;38:579.
McIntosh N, Marlow N. High or low oxygen saturation for the preterm baby. Arch Dis Child Fetal Neonatal Edition 2001;84:F149-F150.
Phelps DL. Reduced severity of oxygen-induced retinopathy in kittens recovered in 28% oxygen. Pediatr Res 1988;24:106-109.
Poets CF. When do infants need additional inspired oxygen? A review of the current literature. Pediatr Pulmonol 1998;26:424-428.
Committee for the Classification of Retinopathy of Prematurity. An international classification of retinopathy of prematurity. Br J Ophthalmol 1984;68:690-697.
Committee for the Classification of Retinopathy of Prematurity. An international classification of retinopathy of prematurity. II The classification of retinal detachment. Arch Ophthalmol 1987;105:906-912.
Shahinian L Jr, Malachowski N. Retrolental fibroplasia: a new analysis of risk factors based on recent cases. Arch Ophthalmol 1978;96:70-74.
Tin W, Milligan DWA, Pennefather P, Hey E. Pulse oximetry, severe retinopathy, and outcome at one year in babies of less than 28 weeks gestation. Arch Dis Child Fetal Neonatal Edition 2001;84:F106-F110.
AskieLM, Henderson-Smart DJ. Early versus late discontinuation of oxygen in preterm or low birth weight infants (Cochrane Review). In: The Cochrane Library, Issue 4, 1998. Oxford: Update Software.
02 Early vs late oxygen weaning (BW <1000g)
02.01 RLF (vascular, any stage) in examined
survivors
02.02 RLF (cicatricial, any grade) in
examined survivors
02.03 RLF (cicatricial, severe grades)
in examined survivors