The International Classification of ROP describes the disorder by location (zones 1 to 3), severity (stages 1 to 4), amount of disease (clock hours) and presence or absence of venous dilatation and arteriolar tortuosity ("plus" disease) (ICROP 1984). In addition, infants have been categorised as either having pre-threshold disease (zone 1 disease of any stage or zone 2, stage 2 with "plus" disease or zone 2, stage 3) or threshold disease (five contiguous or eight cumulative clock hours of stage 3 ROP in zone 1 or 2 with "plus" disease) (CRYO-ROP 1988). Infants with threshold disease, prior to the introduction of surgery to halt the progression of ROP, were predicted to have an almost 50% risk of blindness (CRYO-ROP 1988).
Retrolental fibroplasia (stage 3 ROP with plus disease(Reese 1953))has been associated with supplemental oxygen administration since the 1950's when it was shown that unrestricted oxygen exposure for premature infants regardless of clinical requirement resulted in an increase in retrolental fibroplasia (Askie 2002). A meta-analysis has shown that the relative restriction of oxygen resulted in a greater than 70% decrease in ROP (Watts 1992; Askie 2002). Following this discovery there was a period where supplemental oxygen was severely restricted and ROP rates fell. In retrospect, however, many of the infants at greatest risk of developing ROP did not survive (Cross 1973) . From retrospective studies in England and Wales and the United States, Cross concluded that for every case of blindness prevented there was an excess of 16 deaths from hypoxia. Analysis of arterial oxygen tension became available in the 1960's and, later, continuous estimations of arterial oxygen levels could be measured with transcutaneous oxygen monitoring and pulse oximetry. Despite rigorous monitoring of oxygen, preterm infants who are at risk still develop ROP today. There have been reports of infants who developed ROP who never received supplemental oxygen (Adamkin 1977) and of infants who did not develop ROP despite very high oxygen levels (Aranda 1974). It is currently thought that retinopathy of prematurity is a multifactorial disease.
Current treatment for severe retinopathy is invasive and involves ablation
of the avascular retina by cryotherapy or laser photocoagulation (Chan-Ling 1995). The CRYO-ROP trial showed
that cryotherapy achieved an initial reduction in unfavourable outcome of
50% (CRYO-ROP 1988). However, even after invasive
treatment of the avascular portion of the retina next to the abnormal vessels,
retinal detachment and blindness still occur in some infants. Also retinal
ablation while beneficial is not without complication. There have been
reports of iris atrophy, cataracts and hypotony following this procedure
(Kaiser 2001).
Non-invasive treatments of ROP have been postulated. One of these is
supplemental oxygen therapy aimed at targeting higher oxygen levels in
the blood. However there is little consensus as to the appropriate normal
levels of oxygen for maximising short or long term benefits whilst minimising
harmful effects. Uncertainty exists as to the range of blood oxygen levels
that should be targeted in preterm and low birthweight infants (Askie 2002). Different methods are used to monitor
oxygen levels such as arterial blood gas sampling (intermittent), transcutaneous
oxygen monitoring (intermittent or continuous) or pulse oximetry (intermittent
or continuous). Pulse oximeters can be further divided into two types,
those that include fractional or those that include functional saturation
in their algorithms. These differences in algorithms can lead to differences
in saturation of at least 2-3 percent (Grieve
1997), with functional oximeters reading higher than oximeters using
a fractional oxygen saturation algorithm.
The physiology behind the postulation that supplemental oxygen can halt
and reverse the progression of ROP is as follows. In the first phase of
ROP exposure of the extremely preterm infant to the relatively hyperoxic
extra-uterine environment after birth leads to down regulation of vascular
endothelial growth factor (VEGF) production and the cessation of normal blood
vessel growth (Pierce 1996). The density of
blood vessels in the retina is then insufficient once the metabolic demand
from the avascular retina increases. A rebound overproduction of VEGF to
compensate for the tissue metabolic imbalance leads to the abnormal vascularization
typical of ROP (Chan-Ling 1995). Kittens
with hyperoxia-induced ROP that recovered in 28% oxygen had less severe
retinopathy than those recovered in room air (Phelps
1988). Unfortunately the animal models of ROP do not progress to full
detachment and blindness as ROP does in some infants and therefore may not
completely reflect the pathophysiology in humans (Phelps 1988).
Supplemental oxygen for the treatment of prethreshold ROP is hypothesised
to reduce the retinal neovascularization that causes the ROP by controlling
the rate of revascularization. However increasing the oxygen given to these
infants may result in other problems such as increased length of stay in
the hospital and chronic lung disease (Frank 1985).
Primary:
Progression to threshold ROP and/or retinal ablation surgery
Blindness or severe visual impairment (visual acuity 20/200 or worse)
Secondary:
Visual function (visual acuity, refraction and structural outcome) -
short and long term
Length of hospital stay (days)
Number of days of supplemental oxygen
Mortality before hospital discharge
Chronic lung disease (oxygen requirement at 36 weeks postmenstrual age
[PMA]) /bronchopulmonary dysplasia (chest x-ray changes at 36 weeks PMA),
pneumonia and other significant respiratory morbidities
Growth/weight gain - short and long term
The following search strategy was used to search MEDLINE and was modified
as necessary for EMBASE and CINAHL
1 exp Retinopathy of Prematurity/
2 (retinopathy adj5 prematur$).mp.
3 retrolental fibroplasia.mp.
4 or/1-3
5 exp Oxygen Inhalation Therapy/
6 supplemental oxygen.mp
7 oxygen saturation.mp.
8 exp Monitoring, Physiologic/
9 exp Blood Gas Analysis/
10 or/5-9
11 clinical trial.pt.
12 (random$ or trial$ or double blind$ or placebo$).mp.
13 or/11-12
14 4 and 10 and 13
Selection of trials:
The standard methods set out by The Cochrane Neonatal Review Group were
used to select trials. Two reviewers looked at titles and abstracts to identify
potentially relevant trials using the selection criteria. Trials that clearly
failed to meet the inclusion criteria were not reviewed. Those that could
not be excluded were reviewed in full text. In all instances, differences
of opinion were resolved by discussion.
Quality of trials:
The methodological quality of the included trial was assessed independently
by two reviewers with discrepancies resolved by discussion. Quality was
based on concealment of randomisation and allocation, blinding of intervention
and outcome assessment, follow up rates and power calculation. Additional
information was sought from the authors when necessary. Studies having greater
than 20% attrition for the primary outcome were to be excluded from analysis.
Data extraction:
Data were extracted by two reviewers using a standardised data form.
Levels of agreement between the reviewers were greater than 90%.
Statistical analysis:
The standard method of the Cochrane Neonatal Review Group was used. Categorical
data were expressed as relative risk and risk difference with 95% confidence
interval and number needed to treat or harm as appropriate. Continuous
data were analysed using weighted mean difference with 95% confidence intervals.
A fixed effects model was to be used for meta-analysis. In order to assess
the effect of missing data on the primary outcome, progression to threshold
ROP, analyses of best case/worst case scenarios were undertaken.
In this review the analyses were performed on all enrollees according to the assigned treatment arm (sensitivity analysis on failure to complete the primary endpoint assessment).
Sub-group analysis:
A priori sub-group analysis was to be performed for infants with birthweights
less than 1500g or less than 1000g or infants with a gestational age at
birth less than 32 weeks or less than 28 weeks. Other secondary analyses
to be performed were those using different monitors to measure the oxygen
levels, for example pulse oximeters (including brands of pulse oximeters)
and transcutaneous monitors, and intermittent versus continuous monitoring.
One trial, STOP-ROP 2000, assessing the use of supplemental oxygen in the treatment of prethreshold retinopathy of prematurity (ROP), met the inclusion criteria . Between February 1994 and March 1999, this trial enrolled 649 preterm infants with prethreshold ROP (see Additional Table 01 for definitions) and randomly assigned them to target a fractional oxygen saturation range of either 96-99% (experimental, supplemental or higher oxygen saturation range group) or 89-94% (control, conventional or normal oxygen saturation range group) for a minimum of two weeks or until the primary ophthalmic outcomes were reached. The mean birthweight and gestational age of the enrolled infants were 726 grams and 25.4 weeks respectively. The mean age at randomisation was 35.6 weeks PMA. Randomisation was stratified by severity of eye disease (severe versus less severe ROP, see Additional Table 02 for definitions). Infants were not considered for randomisation if their median pulse oximetry saturations were greater than 94% in room air after four hours continuous monitoring or they had lethal anomalies or congenital anomalies of the eye. The primary outcome measure in this trial was progression to threshold ROP by three months corrected age as assessed by study accredited ophthalmologists who were masked to the infants' treatment allocation. Several other clinically important secondary outcomes were also assessed. A more detailed description of this study can be found in the Characteristics of Included Studies table.
There was no blinding of the intervention, with bedside nurses, attending clinicians and parents aware of treatment allocation. Due to the nature of the intervention it would have been difficult to blind these caregivers, therefore it was deemed to be appropriate. There was, however, blinding of outcome assessment.
The infants in the control and experimental arms were similar at baseline with respect to birthweight, gestational age, pulmonary status, gender, race, medications and socioeconomic status.
Loss to follow-up with respect to the primary eye endpoint (no data for primary study outcome of progression to threshold ROP) occurred in twenty six (8%) infants in the control group (nine withdrew from the study, two had early ablative surgery and 15 missed eye exams) and twenty six (8%) infants in the experimental group (two died, nine withdrew from the study, three had early ablative surgery and 12 missed eye exams). Ophthalmic outcome data were incomplete at three months corrected age for twenty four (7%) infants in the control group (seven died, 16 withdrew and one was lost to follow-up) and twenty five (8%) infants in the experimental group (nine died, 15 withdrew and one was lost to follow-up).
Ophthalmic outcomes
The results of the one trial included in this review (STOP-ROP 2000) indicate that there was a trend
for supplemental oxygen to reduce the progression to threshold ROP but
this did not reach statistical significance (RR 0.84, 95%CI 0.70, 1.02).
The number needed to treat for this outcome was 14.5. There was no significant
difference in blindness or severe visual impairment between the infants
having higher oxygen saturation targets compared with the control infants
(RR 1.08, 95%CI 0.52, 2.26). Blindness or severe visual impairment in this
study refers to partial or total retinal detachment, retinal folds or obstruction
of the visual axis. There was also no significant effect on the anatomic
finding of macular ectopia at three months corrected age (RR 1.00, 95%CI
0.47, 2.13).
A best case/worst case analysis, accounting for the possible effects of missing outcome data, shows that the relative risk for progression to threshold ROP must be between 0.72 (0.60, 0.85) and 1.02 (0.86, 1.21). See Table 03. So assuming all missing patients in the supplemental arm did not progress to threshold ROP and all the missing infants in the control arm progressed to threshold ROP (best case), then treatment of prethreshold ROP with higher oxygen saturations would significantly reduce the number of infants progressing to threshold disease.
A subgroup analysis of progression to threshold ROP by presence or absence of plus disease was not a prespecified outcome of the reviewers or the study authors. However, the reviewers felt that the result was of clinical importance and had biological plausibility so the results have been included in this review. Caution, however, should be taken when interpreting results from post hoc analyses as the results could be due to random error. In infants with plus disease, there was no significant difference in progression to threshold ROP between the treatment groups (RR 1.09, 95%CI 0.85, 1.40). However, significantly fewer infants with no plus disease at randomisation progressed to threshold ROP in the experimental group (RR 0.70, 95%CI 0.54, 0.90).
Mortality
Mortality was an infrequent outcome in the STOP-ROP 2000 study and hence the power was
insufficient to assess clinically important differences. No evidence of
effect was found, either in all cause mortality (RR 1.30, 95%CI 0.48, 3.53)
or deaths from pulmonary causes (RR 1.68, 95%CI 0.40, 7.10) by three months
corrected age.
Pulmonary sequelae
Our pre-specified outcome of chronic lung disease (CLD) and/or bronchopulmonary
dysplasia (BPD) was not specifically reported in the one included trial.
As the mean age at randomisation was 35.6 weeks PMA and the intervention
involved targeting either oxygen saturation range for a minimum of two weeks,
it is likely that virtually all enrolled infants would have been oxygen-dependent
at 36 weeks PMA, rendering the reporting of this outcome in the included
trial meaningless.
Another pre-specified outcome, pneumonia, was also not reported as a single outcome in the included STOP-ROP 2000 trial. However, the composite and clinically meaningful outcome of pneumonia/CLD events was reported. This was defined as probable or definite pneumonia, an acute exacerbation of CLD, or some combination of these two events such that the study neonatologist could not distinguish between them. There was no significant difference in the number of infants with pneumonia/CLD events (RR 1.52, 95%CI 0.94, 2.47) between the two treatment groups in the one included trial.
The final pre-specified pulmonary outcome was other significant respiratory morbidities. The included trial reported this outcome as adverse pulmonary events by three months corrected age. An adverse pulmonary event was defined in the STOP-ROP 2000 trial as any one or more of the following by three months corrected age: remaining hospitalised; remaining on study equipment, oxygen, steroids, methylxanthines, or diuretics. There was a significant increase in the number of adverse pulmonary events in the supplemental oxygen group (RR 1.24, 95%CI 1.06, 1.44). Using number to harm this equates to one extra infant with an adverse pulmonary event for every nine infants treated with higher target oxygen saturations. However, there was no significant difference in another important respiratory morbidity, the number of infants rehospitalized for pulmonary reasons (RR 0.89, 95%CI 0.60, 1.32). The individual components of the composite adverse pulmonary events outcome were also reported in the included trial. Significantly more of the infants in the supplemental group were still in hospital (RR 1.86 95%CI 1.12, 3.10), were receiving diuretics (RR 1.47, 95% CI 1.16, 1.87) and remained on supplemental oxygen (RR 1.26, 95%CI 1.05, 1.51) at three months corrected age.
Growth
There was no significant difference in weight gain either during the
first two weeks of the study intervention (MD -13.00 grams, 95%CI -34.55,
8.55) or by three months corrected age (MD -80.00 grams, 95%CI -237.77,
77.77).
A priori sub-group analysis
A priori sub-group analysis could not be performed for infants with
birthweights less than 1500g or less than 1000g, or infants with a gestational
age at birth less than 32 weeks or less than 28 weeks in the one eligible
trial because these data were not available. Therefore the secondary goals
of the sub-group analysis, to determine whether the effectiveness of the
treatment and its safety were different in infants of differing birthweight
and gestational age, could not be achieved. Other secondary analyses to
be performed were those using different monitors to measure the oxygen
levels, for example pulse oximeters (including brands of pulse oximeters)
and transcutaneous monitors, and intermittent versus continuous monitoring.
The only trial eligible for this review targeted higher versus normal oxygen
saturation ranges using continuous pulse oximetry. No studies meeting the
entry criteria were found that used alternative methods for oxygen monitoring
and/or different target ranges for oxygen levels.
The STOP-ROP 2000 study concluded, as did the authors of this review, that there was a trend to a reduced rate of progression from prethreshold to threshold ROP in infants with higher targeted oxygen saturation. This only reached statistical significance in infants who did not have plus disease at randomisation (post hoc analysis). As stated in the results, this was not a prespecified sub-group analysis of this review and the results must be interpreted with caution. However, a possible explanation is that hyperoxia causes down regulation of VEGF production by the avascular retina leading to the reduction in blood vessel growth. In plus disease (dilation and tortuosity of the retinal blood vessels) the rate and density of vascularization may not be susceptible to this process. Plus disease therefore may be an indicator that ROP is more advanced and less likely to respond to treatment. However, data from an excluded non-randomised retrospective study by Gaynon 1997 showed a benefit of increased oxygen saturation on ROP progression despite all enrolled infants having at least two quadrants of plus disease (part of the eligibility criteria).
The two excluded studies in this review (Gaynon 1997; Seiberth 1998) looked at increased oxygen saturation levels for infants with prethreshold ROP. They both showed a decrease in progression to threshold ROP in infants with increased oxygen saturation levels compared to infants who had normal oxygen saturation levels. There are many reasons, in addition to differences in study design, why these two small observational studies, using historical controls, may have had different results from that of the randomised trial included in this review, including lower disease severity, heavier infants and improvements in care and outcomes over time. These studies used higher minimum oxygen saturation levels than STOP-ROP 2000 and did not have an upper oxygen saturation limit. However, they used a different type of pulse oximeter (saturation readings approximately 1.6 saturation points higher than the STOP-ROP 2000 oximeter), and adding this difference to the STOP-ROP 2000 supplemental range results in very similar target saturation levels making this an unlikely reason for any difference. The Gaynon 1997 study examined their infants weekly compared to every two weeks in the STOP-ROP 2000 study centres prior to the diagnosis of prethreshold disease, so infants were probably placed in increased oxygen earlier than the STOP-ROP 2000 trial. Also, in the STOP-ROP 2000 trial there was some delay in starting the treatment due to confirming the diagnosis with a second ophthalmologist and obtaining informed consent. Fifty percent of infants in the trial were not randomised in the first 24 hours as the authors had initially intended. Increasing oxygen saturation levels earlier, by starting oxygen immediately after diagnosis, examining the infants more often to diagnose significant disease earlier or changing the definition of prethreshold ROP, may improve the outcome and reduce the need for peripheral retinal ablation. There is a study currently enrolling infants (ETROP) that is comparing ablation of the unvascularized retina prior to the eye reaching threshold disease with the current practice of treatment once threshold is reached with the hypothesis that fewer infants in the early treatment arm will have adverse eye outcomes. The same hypothesis could also be relevant re the timing of higher oxygen levels for the treatment of ROP.
The only randomised controlled trial (STOP-ROP 2000) looking at the use of higher oxygen levels to treat prethreshold ROP failed to enroll the prespecified number of infants. Therefore, there is the possibility of a type II error, that is, the study may have missed a significant effect because of reduced enrollment and a subsequent decrease in statistical power (from 90% to approximately 80%).
This study did not demonstrate that increased oxygen saturation levels are deleterious as far as established ROP is concerned. However, these data do not support the use of higher saturation levels for more immature infants where ROP is not already established. To date, the only randomised trial that has attempted to assess the effect of higher oxygen saturation target ranges on longer term growth and development (BOOST 2002) found no significant difference in growth, development or adverse eye outcomes for those targeting a higher oxygen saturation range. A secondary hypothesis of the STOP-ROP 2000 study was that higher oxygen saturations would benefit infants with CLD resulting in increased growth and lung function. However, the results show that increasing the fractional oxygen saturation range from 89%-94% to 96%-99% had no significant effect on short term growth, neurodevelopment, rehospitalisation for pulmonary reasons, pneumonia/CLD exacerbations or mortality. More infants in the higher oxygen saturation group, however, were still on supplemental oxygen and in hospital at three months corrected age and had more adverse pulmonary events. Any benefit in the trend to reduce the number of infants with threshold disease and therefore reduce the number needing ablative surgery needs to be weighed against the number of infants still needing oxygen and hospital care at three months corrected age and the effect that this may have on family and cost of care. If the number needing ablative surgery can be reduced this will also benefit those infants with CLD by avoiding a general anaesthesia.
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| STOP-ROP 2000 | Random allocation - yes, stratified by severity of disease and participating center. See Table 02. Concealed allocation - yes Baseline comparablity - yes Blind assessors - yes, study-certified ophthalmologists who assessed eligibility, progression of ROP and study endpoints were blinded to treatment allocation by covering the pulse oximeter and computer during examination. Blind parents/guardians - no Blind bedside nurses and attending neonatologists - no Adequate follow-up - yes (> 90%) Length of follow-up - 3 months corrected age (52 weeks post menstral age - target of 50 - 54 weeks PMA). Some infants (number not stated) were examined after 54 weeks PMA. Intention to treat analysis - no for eye endpoints (corrected in the review), yes for other outcomes Between group comparisons - ?no Point estimates and variablility - yes Eligibility criteria - yes |
Study enrollment occurred between February 1994 and March 1999. 1213 Premature infants (definition not stated) with prethreshold ROP in at least one eye confirmed by a second ophthalmologist were potentially eligible for the study. For definitions of threshold and prethreshold ROP used in the STOP-ROP study see Additional Table 01. Infants were excluded if after 4 hours continuous monitoring their median pulse oximetry saturations were greater than 94% in room air or they had lethal anomalies or congenital anomalies of the eye. 649 infants were enrolled in the trial and randomised to the control or experimental group. The mean BW was 721g and 731g in the control and experimental groups respectively. The mean gestational age was 25.4 weeks in both groups. The ranges for gestational age or birthweight were not stated. The mean PMA at randomisation was 35.6 weeks. | Infants were placed on continuous pulse oximetry monitors (Ohmeda 3740) to maintain saturations between 89% and 94% (n = 325) in the control group and 96% to 99% (n =324) in the experimental group. Laptop computers were connected to the pulse oximeters to monitor, record and report trends in oxygen saturation for each infant. It was the intention of the study authors that the intervention start within 24 hours of the diagnosis of prethreshold ROP. However only 33% of infants were randomised less than 24 hours after diagnosis and 27% were not randomised until more than 48 hours after diagnosis. The enrolled infants were examined weekly until both eyes reached ophthalmic endpoints and again at 3 months PMA. Target saturation levels were maintained for 2 weeks even if primary ophthalmic outcomes were reached sooner. After 2 weeks assigned treatment ceased after both eyes reached primary ophthalmic outcomes. Parents were permitted to take infants home on study equipment. At least one of the 2 study ophthalmologists for study entry in each centre had to be certified by the STOP-ROP study. For adverse eye endpoint, both examiners had to be certified. | Progression to threshold ROP Weight gain Length gain Head circumference increase PMA at discharge home PMA to achieve oral feeding Number of infants with CLD/pneumonia, sepsis and apnoea or bradycardia. Outcomes at 3 months PMA:- number of infants hospitalised, rehospitalised, rehospitalised for pulmonary reasons,on study equipment, on oxygen, on steroids, on diuretics, on methylxanthines, all deaths, room saturations too low to test, room air oxygen saturations, developmental assessment |
Intially a sample size of 880 infants was required to provide 90% power with an overall type 1 error rate of 0.025 to detect a one third reduction in pregression to threshold disease or a 10% absolute reduction based on a predicted rate of progression in the control arm of 30%. Power calculations were revised due to poor enrollment after 3.3 years. It was calculated that an enrollment of 633 infants completing the study would provide 83% power to detect a fall in progression rate from 30% to 20%. The final number of 597 infants with ophthalmic endpoints resulted in a power of approximately 80% to detect a fall in rate of progression of 10%. | A |
| Study | Reason for exclusion |
| Gaynon 1997 | This was a non-randomised retrospective cohort study. Oxygen saturation levels for infants with prethreshold ROP were increased in a stepwise fashion (target minimum 92%-99%) over a number of years (1985-1993). Patient allocation was not randomised and thus the study was excluded from the review. |
| Seiberth 1998 | Preterm infants with stage 3 ROP between 1994 an 1996 were treated with supplemental oxygen to maintain pulse oximetry saturations above 98%. The incidence of threshold ROP was compared to a historical control group of preterm infants born between 1991 and 1993. Patients were not randomly allocated to a treatment and therefore this non-randomised, retrospective cohort study was excluded from the review. |
The STOP-ROP Multicenter Study Group. Supplemental therapeutic oxygen for prethreshold retinopathy of prematurity (STOP-ROP), a randomized, controlled trial. I: Primary outcomes. Pediatrics 2000;105:295-310.
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.
Seiberth 1998 {published data only}
Seiberth V, Linderkamp O, Vardarli I, Jendritza W, Vogele C, Knorz MC. Oxygen therapy in acute retinopathy of prematurity Stage 3. Invest Ophthalmol Vis Sci 1998;39:S820.
* indicates the primary reference for the study
Adamkin DH, Shott RJ, Cook LN, Andrews BF. Nonhyperoxic retrolental fibroplasia. Pediatrics 1977;60:828-830.
Aranda JV, Sweet AY. Sustained hyperoxemia without cicatricial retrolental fibroplasia. Pediatrics 1974;54:434-437.
Askie LM, Henderson-Smart DJ. Restricted versus liberal oxygen exposure for preventing morbidity and mortality in preterm or low birth weight infants (Cochrane review). In: The Cochrane Library, Issue 4, 2002. Oxford: Update Software.
Askie LM, Henderson-Smart DJ, Irwig L, Simpson JM. The effect of differing oxygen saturation targeting ranges on long term growth and development of extremely preterm, oxygen dependent infants: the BOOST Trial [abstract]. In: Pediatr Res. Vol. 51. 2002:378A.
Chan-Ling T, Gock B, Stone J. Supplemental oxygen therapy: basis for noninvasive treatment of retinopathy of prematurity. Invest Ophthalmol Vis Sci 1995;36:1215-1230.
Cross KW. Cost of preventing retrolental fibroplasia. Lancet 1973;2:954-956.
CRYO-ROP Cooperative Group. Multicentre trial of cryotherapy for retinopathy of prematurity. Arch Ophthalmol 1988;106:471-479.
CRYO-ROP Cooperative Group. The natural ocular outcome of premature birth and retinopathy: status at 1 year. Arch Ophthalmol 1994;112:903-912.
Donoghue D, ANZNN. The report of the Australian and New Zealand Neonatal Network 2000. Sydney: ANZNN, 2002.
Good WV, Hardy RJ. The multicenter study of early treatment for retinopathy of prematurity (ETROP). Ophthalmology 2001;108:1013-1014.
Frank L. Effects of oxygen on the newborn. Federation Proc 1985;44:2328-2334.
Grieve SH, McIntosh N, Laing IA. Comparison of two different pulse oximeters in monitoring preterm infants. Crit Care Med 1997;25:2051-2054.
ICROP. An International Classification of Retinopathy of Prematurity. Pediatrics 1984;74:127-133.
Kaiser RA, Trese MT. Iris atrophy, cataracts and hypertony following peripheral ablation for threshold retinopathy of prematurity. Arch Ophthalmol 2001;119:615-617.
The Laser ROP Study Group. Laser therapy for retinopathy of prematurity. Arch Ophthalmol 1994;112:154-156.
Phelps DL. Reduced severity of oxygen-induced retinopathy in kittens recovered in 28% oxygen. Pediatr Res 1988;24:106-109.
Pierce EA, Foley ED, Smith LEH. Regulation of vascular endothelial growth factor by oxygen in a model of retinopathy of prematurity. Arch Ophthalmol 1996;114:1219-1254.
Reese AB, King M, Owens WC. A classification of retrolental fibroplasia. Am J Ophthalmol 1953;36:1333-1335.
Watts JL. Retinopathy of prematurity. In: Sinclair JC, Bracken MB, editor(s). Effective care of the newborn infant. New York: Oxford University Press, 1992:617-638.
01.01 Progression to threshold ROP by 3 months corrected age
01.02 Blindness or severe visual impairment at 3 months corrected age
01.03 Macular ectopia at 3 months corrected age
01.04 Mortality between randomization and 3 months corrected age
01.05 Remained in hospital at 3 months corrected age
01.06 Remained on supplemental oxygen at 3 months corrected age
01.07 Pulmonary morbidities at or by 3 months corrected age
01.08 Growth / weight gain
01.09 Sensitivity analysis for progression to threshold ROP
| Threshold ROP | |
| Zone II | Presence of posterior pole dilation/tortuosity in at least 2 posterior pole quadrants (plus disease), and stage 3 ROP for at least 5 contiguous clock hours or 8 non-contiguous clock hours |
| Zone I | ROP (any stage) with posterior pole dilation/tortuosity in at least 2 posterior pole quadrants (plus disease), or stage 3 ROP with or without plus disease |
| Beyond Threshold | Stage 4 ROP, stage 5 ROP, or massive vitreal haemorrhage obscuring the view of the fundus |
| Prethreshold ROP | |
| Zone II | Any number of clock hours of stage 3 ROP less than threshold severity, or any stage 2 ROP with at least 2 quadrants of posterior pole dilation/tortuosity disease (plus disease |
| Zone I | Any ROP less than threshold severity. |
| Stratum A (severe ROP) | Either study eye having 1 or more clock hours of any stage ROP in zone I, or when the fellow eye was already at threshold or worse |
| Stratum B (less severe ROP) | Zone II prethreshold ROP in both eyes or in the second eye at less than prethreshold |
| Experimental group | Control group | RR (95%CI) | |
| Number of infants enrolled | 324 | 325 | |
| Number of missing infants | 26 | 26 | |
| Reported | 122/298 | 145/299 | 0.84 (0.71,1.01) |
| Worst case | 148/324 | 145/325 | 1.02 (0.86,1.21) |
| Best case | 122/324 | 171/325 | 0.72 (0.60,0.85) |
| Comparison or outcome | Studies | Participants | Statistical method | Effect size |
|---|---|---|---|---|
| 01 Higher versus normal target oxygen saturation levels | ||||
| 01 Progression to threshold ROP by 3 months corrected age | 2 | 649 | RR (fixed), 95% CI | 0.84 [0.70, 1.02] |
| 02 Blindness or severe visual impairment at 3 months corrected age | 1 | 649 | RR (fixed), 95% CI | 1.08 [0.52, 2.26] |
| 03 Macular ectopia at 3 months corrected age | 1 | 649 | RR (fixed), 95% CI | 1.00 [0.47, 2.13] |
| 04 Mortality between randomization and 3 months corrected age | RR (fixed), 95% CI | Subtotals only | ||
| 05 Remained in hospital at 3 months corrected age | 1 | 649 | RR (fixed), 95% CI | 1.86 [1.12, 3.10] |
| 06 Remained on supplemental oxygen at 3 months corrected age | 1 | 649 | RR (fixed), 95% CI | 1.26 [1.05, 1.51] |
| 07 Pulmonary morbidities at or by 3 months corrected age | RR (fixed), 95% CI | Subtotals only | ||
| 08 Growth / weight gain | WMD (fixed), 95% CI | Subtotals only | ||
| 09 Sensitivity analysis for progression to threshold ROP | RR (fixed), 95% CI | Subtotals only | ||
Dr Jeremy Smith
Ophthalmologist
Ophthalmology
Westmead Hospital
Westmead AUSTRALIA
2145
Telephone 1: +61 2 9745 6166
E-mail: revelwood@myoffice.net.au
Prof William O Tarnow-Mordi
Professor of Neonatal Medicine, Westmead and The Children's Hospitals
Department of Neonatal Medicine
Westmead Hospital
Corner of Hawksberry and Darcy Road
Westmead
NSW AUSTRALIA
2145
Telephone 1: +61 2 98455555 extension: 8911
Facsimile: +61 2 98457490
E-mail: williamt@westgate.wh.usyd.edu.au
