Abstract PEDIATRICS Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOP-ROP), a Randomized, Controlled Trial, I: Primary Outcomes The STOP-ROP Multicenter Study Group Objective To determine the efficacy and safety of supplemental therapeutic oxygen for infants with prethreshold retinopathy of prematurity (ROP) to reduce the probability of progression to threshold ROP, and therefore the need for peripheral retinal ablation. Methods: Premature infants with confirmed prethreshold ROP in at least 1 eye and median pulse oximetry less than 94% saturation were randomized to a Conventional oxygen arm with pulse oximetry targeted at 89% to 94% saturation, or a Supplemental arm with pulse oximetry targeted at 96% to 99% saturation, for at least 2 weeks, and until both eyes were at study endpoints. Certified examiners masked to treatment assignment conducted weekly eye examinations until each study eye reached ophthalmic endpoint. An adverse ophthalmic endpoint for an infant was defined as reaching threshold criteria for laser or cryotherapy in at least 1 study eye. A favorable ophthalmic endpoint was regression of the ROP into zone III for at least 2 consecutive weekly examinations, or full retinal vascularization. At 3 months after the infant's due date, ophthalmic findings, pulmonary status, growth, and interim illnesses were again recorded. Results: Six hundred forty-nine infants (325 Conventional, 324 Supplemental) were enrolled from 30 centers over 5 years. Five hundred ninety-seven (92.0%) infants attained known ophthalmic endpoints, and 600 (92%) completed the ophthalmic 3-month assessment. The rate of progression to threshold in at least 1 eye was 48% in the Conventional arm, and 41% in the Supplemental arm. After adjustment for baseline ROP severity stratum, plus disease, race and gestational age, the odds ratio (Supplemental vs Conventional) for progression was 0.72 (95% confidence interval [CI], 0.52-1.01). Final structural status of all study eyes at 3 months' corrected age showed similar rates of severe sequelae in both treatment arms: retinal detachments or folds (4.4% Conventional vs 4.1% Supplemental), and macular ectopia (3.9% Conventional vs 3.9% Supplemental). Within the prespecified ROP severity strata, ROP progression rates were lower with Supplemental oxygen than with Conventional oxygen, but the differences were not statistically significant. A post hoc subgroup analysis of plus disease (dilated and tortuous vessels in at least 2 quadrants of the posterior pole) suggested that infants without plus disease may be more responsive to supplemental therapy (46% progression in the Conventional arm vs 32% in the Supplemental arm, P = .004) than infants with plus disease (52% progression in Conventional vs 57% in Supplemental, P = .484). Pneumonia and/or exacerbations of chronic lung disease (CLD) occurred in more infants in the Supplemental arm (8.5% Conventional vs 13.2% Supplemental, P = .066). Also, at 50 weeks' post menstrual age, fewer Conventional than Supplemental infants remained hospitalized (6.8% vs 12.7%, P = .012), on oxygen (37.0% vs 46.8%, P = .020), and on diuretics (24.4% vs 35.8%, P = .002). Growth and developmental milestones did not differ between the two arms. Conclusions: Use of Supplemental oxygen at pulse oximetry saturations of 96% to 99% did not cause further progression of prethreshold ROP, but also did not significantly reduce the number of infants requiring peripheral ablative surgery. A subgroup analysis suggested a benefit of Supplemental oxygen among infants who have prethreshold ROP without plus disease, but this finding requires further study. Supplemental oxygen increased the risk of adverse pulmonary events including pneumonia and/or exacerbations of CLD, and the need for oxygen, diuretics, and hospitalization at 3 months' corrected age. While the relative risk/benefit of Supplemental oxygen for each infant must be individually considered, clinicians need no longer be concerned that supplemental oxygen, as used in this study, will exacerbate active prethreshold ROP. Pediatrics. 2000;105:295-310. Commentary THE ROLE of supplemental oxygen in the development of retinopathy of prematurity (ROP) is complex. Early investigations into the cause of ROP, prior to continuous pulse oximetry monitoring, identified high inhaled concentrations of oxygen during early life as a risk factor for development of ROP.1 This knowledge, along with the known toxic effects of oxygen to the neonatal lungs and advances in monitoring, has led to the current practice standards targeting pulse oximetry levels in the range of 80% to 92% for premature infants requiring oxygen.2 The possibility that higher levels of oxygenation later in the course of treatment, after ROP has developed, might reverse ROP or prevent its progression has been supported by studies in animal models3 and case reports of premature infants with prethreshold ROP treated with supplemental oxygen.4,5 The Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOP-ROP) trial tested the hypothesis that increasing the target pulse oximetry levels for infants with prethreshold ROP might reduce the progression in these infants to threshold and improve functional outcomes. Unlike previous clinical case series, the STOP-ROP trial used prospective randomization and novel monitoring data to analyze oxygenation, and outcomes assessments were masked.6 A reduction in progression of ROP to a threshold of 7.6% (48.5% in control vs 40.9% in supplemental treatment group) was measured. Although this difference was not statistically significant (P = .03, 1-tailed t test), the power of the study was limited by enrollment, which was lower than the prestudy design. Stratification of eyes by ophthalmic findings suggests that the treatment is most beneficial for eyes without plus disease (45.6% vs 32.3%, P = .004). Medical outcomes were slightly worse in the supplemental group with an increased rate of exacerbation of chronic lung disease, pneumonia, use of diuretics or steroids, and prolonged oxygen requirements and hospitalization, although these differences were small. The authors' subgroup analysis of the patients by pulmonary status prior to randomization suggests that this difference occurred only in those patients with the worst preexisting lung disease. No difference was seen in developmental or growth measurements or survival. How can we use the results of the STOP-ROP trial to improve the care of infants with ROP? These data failed to demonstrate a clear advantage to supplemental oxygen and do not support the uniform application of higher target levels for pulse oximetry in all prethreshold infants. The trend toward improved ophthalmic outcomes does seem to be clinically relevant in some groups of patients, but risks of worsening medical complications must be considered. By weighing the potential risks and benefits in each patient individually, ophthalmologists and neonatologists can create a treatment plan that may include supplemental oxygen. In premature infants with prethreshold ROP and without severe lung disease, especially those with less than 2 quadrants of plus disease, treatment with supplemental oxygen should be considered. Corresponding author: Dale L. Phelps, MD, Children's Hospital at Strong, University of Rochester School of Medicine and Dentistry, Pediatrics, Box 651, 601 Elmwood Ave, Rochester, NY 14642 (e-mail: email@example.com). Accepted for publication March 27, 2000. This study was supported by grants from the National Eye Institute, the National Institute of Child Health and Human Development, the National Institute of Nursing Research, and the National Institutes of Health General Clinical Research Centers, Bethesda, Md, plus local funding sources at many participating centers. Corresponding author: Monte D. Mills, MD, Division of Ophthalmology, Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104-4399. References 1. Kinsey VEJacobus JTHemphill F Retrolental fibroplasia: cooperative study of retrolental fibroplasia and the use of oxygen. Arch Ophthalmol. 1956;56481- 547Google ScholarCrossref 2. American Academy of Pediatrics, Fetus and Newborn Committee, Clinical considerations in the use of oxygen. Freeman RKPoland RLHauth JCMerenstein GBeds. Guidelines for Perinatal Care Chicago, Ill American Academy of Pediatrics1992;197- 203Google Scholar 3. Pierce EFoley EDSmith LE Regulation of vascular endothelial growth factor by oxygen in a model of retinopathy of prematurity. Arch Ophthalmol. 1996;1141219- 1228Google ScholarCrossref 4. Gaynon MWStevenson DKSunshine PFleischer BELanders MB Supplemental oxygen may decrease progression of prethreshold retinopathy of prematurity. J Perinatol. 1997;17434- 438Google Scholar 5. Sieberth VLinderkamp OAkkoyun-Vardarli IJendritza WVoegele C Oxygen therapy in acute retinopathy of prematurity stage 3 [abstract]. Invest Ophthalmol Vis Sci. 1998;39S820Google Scholar 6. 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;105295- 310Google ScholarCrossref
Archives of Ophthalmology – American Medical Association
Published: Aug 1, 2000
Keywords: oxygen,oximetry, pulse,retinopathy of prematurity,diuretics,pneumonia,lung disease, chronic,surrogate endpoints,lasers,ophthalmic examination and evaluation,ablation,surgical procedures, operative,cryotherapy,ectopic tissue,retinal detachment,eye,infant,infant, premature,lung
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