PEDIATRICS Vol. 110 No. 3 September 2002, pp. 540-544
Retinopathy of Prematurity Outcome in Infants With Prethreshold Retinopathy of Prematurity and Oxygen Saturation >94% in Room Air: The High Oxygen Percentage in Retinopathy of Prematurity Study
* Department of Ophthalmology, The Ohio State University, Columbus, Ohio
Department of Pediatrics, Tufts University School of Medicine, Boston, Massachusetts
Department of Pediatrics, The Ohio State University, Columbus, Ohio
|| Departments of Pediatrics and Ophthalmology, University of Rochester, Rochester, New York
¶ The EMMES Corporation, Rockville, Maryland
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONAPPENDIXREFERENCES |
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Objectives. To determine the rate of progression from prethreshold to threshold retinopathy of prematurity (ROP) in infants excluded from Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOP-ROP) because their median arterial oxygen saturation by pulse oximetry (SpO2) values were >94% in room air at the time of prethreshold diagnosis and to compare them with infants who were enrolled in STOP-ROP and had median SpO2
94% in room air. Methods. Fifteen of the 30 centers that participated in STOP-ROP elected to participate in the High Oxygen Percentage in Retinopathy of Prematurity study (HOPE-ROP) from January 1996 to March 1999. Infants were followed prospectively from the time prethreshold ROP was diagnosed until ROP either progressed to threshold in at least 1 study eye (adverse outcome) or resolved (favorable outcome).
Results. A total of 136 HOPE-ROP infants were compared with 229 STOP-ROP infants enrolled during the same time period from the same 15 hospitals. HOPE-ROP infants were of greater gestational age at birth (26.2 ± 1.8 vs 25.2 ± 1.4 weeks) and greater postmenstrual age at the time of prethreshold ROP diagnosis (36.7 ± 2.5 vs 35.4 ± 2.5 weeks). HOPE-ROP infants progressed to threshold ROP 25% of the time compared with 46% of STOP-ROP infants. After gestational age, race, postmenstrual age at prethreshold diagnosis, zone 1 disease, and plus disease at prethreshold diagnosis were controlled for, logistic regression analysis showed that HOPE-ROP infants progressed from prethreshold to threshold ROP less often than STOP-ROP infants (odds ratio: 0.607; 95% confidence interval: 0.359–1.026).
Conclusions. The mechanisms that result in better ROP outcome for HOPE-ROP versus STOP-ROP are not fully understood. It seems that an infant’s SpO2 value at the time of prethreshold diagnosis is a prognostic indicator for which infants may progress to severe ROP. When other known prognostic indicators are factored in, the SpO2 is of borderline significance.
Key Words: retinopathy of prematurity • retinal neovascularization • oxygen inhalation therapy • gestational age • disease progression
Abbreviations: ROP, retinopathy of prematurity • CRYO-ROP, Multicenter Trial of Cryotherapy for Retinopathy of Prematurity • PMA, postmenstrual age • STOP-ROP, Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity • SpO2, arterial oxygen saturation by pulse oximetry • HOPE-ROP, High Oxygen Percentage Retinopathy of Prematurity • OR, odds ratio • CI, confidence interval
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONAPPENDIXREFERENCES |
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Retinopathy of prematurity (ROP) is a retinal vascular disorder frequently seen in very premature infants. Much has been learned about the epidemiology, natural history, and pathogenesis of ROP during the past 15 years, particularly from the natural history portion of the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP).1–5 Although the majority of infants who develop ROP have spontaneous resolution of the process without retinal detachment or cicatricial sequelae, approximately 6% of low birth weight infants (<1251 g) develop severe ROP that requires treatment to prevent visual loss.2 Numerous ophthalmic and nonophthalmic prognostic factors have been identified to be associated with increased risk of unfavorable ROP outcome.2, 3,5 The CRYO-ROP Natural History study showed that one third of the infants who developed prethreshold ROP progressed to threshold ROP.2 The risk of progression from prethreshold ROP to threshold ROP varied according to ophthalmic and nonophthalmic factors.6 Ophthalmic characteristics such as postmenstrual age (PMA) at onset of ROP, ROP in zone 1 at first examination at which ROP was observed, rate of progression of ROP to prethreshold, and the presence of plus disease at the first prethreshold examination were significant. The only nonophthalmic factor found to be significant was race (black race was protective against threshold disease). Thus, not all prethreshold ROP is equal in its risk of progression to threshold ROP.
During the first year of the multicenter, masked, randomized, controlled trial Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOP-ROP),7 several centers noted a difference in the rate of progression to threshold ROP in oxygen-dependent infants eligible for and enrolled in the STOP-ROP study compared with infants clinically ineligible for STOP-ROP because their arterial oxygen saturation by pulse oximetry (SpO2) in room air was >94% at the time prethreshold ROP was first diagnosed. The Executive Committee and Data and Safety Monitoring Committee for STOP-ROP approved an ancillary study to test the hypothesis that fewer High Oxygen Percentage Retinopathy of Prematurity (HOPE-ROP) infants would progress to threshold ROP as compared with STOP-ROP infants. The hypothesis was tested by 1) determining the rate of prethreshold ROP progression to threshold ROP in HOPE-ROP infants and 2) comparing ophthalmic outcomes of HOPE-ROP infants with STOP-ROP infants.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONAPPENDIXREFERENCES |
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Fifteen of the 30 centers that participated in STOP-ROP elected to participate in HOPE-ROP from January 1, 1996, to March 31, 1999. These centers examined premature infants for ROP according to a screening schedule supported by the Fetus and Newborn Committee of the American Academy of Pediatrics8 and approved by STOP-ROP Study Headquarters. The diagnosis of prethreshold ROP had to be confirmed independently by a second examiner. At least 1 of the 2 examiners had to be certified by the STOP-ROP study; usually both were. Findings were recorded according to international classification of ROP convention.9 When prethreshold ROP was diagnosed (Table 1), the infant’s oxygen saturation status was evaluated according to STOP-ROP protocol.7 Infants whose median oxygen saturations in room air were >94% at the time prethreshold ROP was first diagnosed were ineligible for STOP-ROP. These infants were then eligible for enrollment in HOPE-ROP. This was the only time infants were HOPE-ROP eligible. STOP-ROP-eligible infants who were not enrolled after the first prethreshold examination and were found on subsequent examinations to have SpO2 >94% in room air could not be enrolled in HOPE-ROP. HOPE-ROP protocol dictated that if a HOPE-ROP infant’s respiratory status changed such that oxygen was required to maintain saturations >94%, then the infant was to be removed from the study cohort and then would become eligible for enrollment in STOP-ROP. (This circumstance never occurred.) Written parental consent was obtained when required by local Institutional Review Boards.
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Baseline neonatal and ophthalmic characteristics were recorded for all infants on enrollment. Neonatal variables included birth weight, gestational age, gender, race, and PMA at the time of prethreshold ROP diagnosis. PMA was defined as the infant’s gestational age at birth plus the chronologic age. Gestational dating was based on early ultrasound or good dating, or on the new Ballard score if neither of these was available.10 Each study eye was prethreshold at the time of enrollment. When an eye was less than prethreshold, already at threshold, or became prethreshold at a later date, it was not considered a study eye. Baseline ophthalmic characteristics included lowest zone and highest stage of ROP, number of sectors of stage 3, and the presence or absence of plus disease at the time prethreshold ROP was diagnosed. Plus disease was defined as at least 2 quadrants of dilated and tortuous vessels.
HOPE-ROP infants were followed according to standard ophthalmic guidelines: weekly until all study eyes reached threshold or signs of regression were noted. Once regression was noted, HOPE-ROP infants were not required to be examined weekly but were followed according to the ophthalmologist’s usual practice until ophthalmic endpoints were reached. STOP-ROP infants who showed signs of regression were followed weekly until they reached ophthalmic endpoint.
Threshold ROP (unfavorable endpoint for a study eye) for HOPE-ROP was the same as defined by the STOP-ROP study (Table 1). Favorable endpoints for HOPE-ROP study eyes were defined as 1) fully vascularized within 1 disk diameter of the ora temporally (may be quiescent old disease present), 2) ROP in zone 3 for the second time or more (with or without signs of regression), and 3) less than prethreshold ROP showing regression in zones 2 or 3 after 42 weeks’ PMA. Favorable endpoints for the STOP-ROP cohort included only 1 and 2.
For this study, an infant was classified as having an adverse outcome when at least 1 study eye reached threshold ROP (unfavorable endpoint). For an infant to be classified as having a favorable outcome, spontaneous resolution of ROP (favorable endpoint) had to occur in each eye (symmetrical cases) or in the only study eye (asymmetrical cases).
Statistical Analysis
Analyses were performed on all HOPE-ROP and STOP-ROP infants from hospitals in the 15 centers that contributed patients to both studies. Group differences of continuous factors were compared with Student’s t test and Wilcoxon rank-sum test when the data were not normally distributed. Categorical differences were compared using 
2 tests. Logistic regression was used for adjustment of covariates. All P values were 2-sided, and P <.05 was considered statistically significant. Analyses were conducted using SAS software. 11
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONAPPENDIXREFERENCES |
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A total of 139 infants were enrolled in HOPE-ROP. ROP outcome information was obtained on 136 infants. Two infants died and 1 was lost to follow-up before final eye endpoint could be determined. No HOPE-ROP infants exited because they became STOP-ROP eligible. During the same time period at the HOPE-ROP study centers, 237 STOP-ROP infants were enrolled and 229 were followed to ophthalmic outcome.
Baseline demographic characteristics were compared for these 2 groups (Table 2). HOPE-ROP infants were of greater gestational age at birth (26.2 ± 1.8 vs 25.2 ± 1.4 weeks; P < .001) and greater PMA at time of prethreshold ROP diagnosis (36.7 ± 2.5 vs 35.4 ± 2.5 weeks; P < .001). Baseline ophthalmic characteristics are shown in Table 3. Compared with STOP-ROP infants, the HOPE-ROP cohort had significantly fewer infants with zone 1 ROP and a greater proportion of infants with zone 2 disease at the time of prethreshold diagnosis. There was no difference in the incidence of plus disease at baseline examination between the 2 groups.
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Ophthalmic outcome data are presented in Table 4. HOPE-ROP infants with prethreshold disease progressed to threshold ROP in at least 1 study eye 25% of the time as compared with 46% of STOP-ROP infants from the same centers (odds ratio [OR]: 0.39; 95% confidence interval [CI]: 0.24–0.64; P = .001). Subgroup analysis of HOPE-ROP infants without plus disease revealed that these infants had a significantly reduced risk of progression to threshold ROP compared with STOP-ROP infants (HOPE-ROP, 19%; STOP-ROP, 40%; P = .001). Progression to threshold ROP was also less in HOPE-ROP infants with plus disease compared with STOP-ROP infants, although this difference was of borderline statistical significance (HOPE-ROP, 38%; STOP-ROP, 56%; P = .06). After black race, gestational age, PMA at prethreshold diagnosis, zone 1 disease, and plus disease at prethreshold diagnosis (baseline) were controlled for, logistic regression analysis of the tendency to progress to threshold showed that HOPE-ROP infants progressed from prethreshold to threshold ROP less often than STOP-ROP infants (P = .0623; OR: 0.607; 95% CI: 0.359–1.026), but this finding was only marginally significant. Within "plus" and "no plus" groups considered separately, the P value is clearly not statistically significant (plus P = .3721, OR: 0.661; "nonplus" P = .1107, OR: 0.581).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONAPPENDIXREFERENCES |
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HOPE-ROP is an observational study that cannot differentiate between the HOPE-ROP and STOP-ROP infants except for baseline O2 requirements at study entry. The HOPE-ROP study provides new information regarding the risk of prethreshold ROP progressing to threshold based on the infant’s SpO2 values at the time prethreshold was first diagnosed. These findings demonstrate that progression from prethreshold to threshold ROP occurs less often in infants whose pulmonary status is "better at enrollment" (oxygen saturation is higher in room air) than infants who require supplemental oxygen to maintain median pulse oximetry >94%. Subgroup analysis showed that this especially held true for infants without plus disease (Table 4). HOPE-ROP infants with plus disease also progressed to threshold less often than STOP-ROP infants did, although this difference was of borderline statistical significance. The significance of difference in progression rates disappears after adjusting for covariates for the complete cohort as well as the subgroup analyses.
That the risk of progression from prethreshold to threshold ROP is not equal for all infants was shown previously in the CRYO-ROP study.6 This risk is influenced by both ophthalmic and nonophthalmic factors. STOP-ROP tried to alter the rate of progression from prethreshold to threshold. It modified the SpO2 levels of oxygen-dependent infants but demonstrated a difference between "conventional" and "supplemental" treatment groups that was not statistically significant. HOPE-ROP showed that the infant’s respiratory status is a clinical feature that predicts with borderline statistical significance the progression from prethreshold to threshold ROP. It did not control for chronic lung disease, days on oxygen, or days on ventilator. Thus, HOPE-ROP can not draw any conclusions about the infant’s pulmonary status to complement other studies that suggest that prolonged oxygen requirement (a proxy for chronic lung disease), increased oxygenation lability, and more complicated clinical courses are associated with greater risk of severe ROP. 12–16
The HOPE-ROP study’s observed progression from prethreshold to threshold ROP (25%) is less than that reported in the CRYO-ROP study (33%), which is less than that reported for STOP-ROP (46%). One reason for this may be that the CRYO-ROP study did not measure SpO2 levels at the time of prethreshold diagnosis. Their cohort of prethreshold infants contained a mixture of infants with varying degrees of lung disease. Making comparisons between the STOP-ROP/HOPE-ROP studies and the CRYO-ROP study is made more difficult because the definition of threshold ROP in zone 1 and the criteria for plus disease differed from those used in CRYO-ROP. STOP-ROP determined that any amount of neovascularization (stage 3), or plus disease, with any ROP in zone 1 constituted threshold, whereas CRYO-ROP held to 5 contiguous or 8 total clock hours of stage 3 with plus disease in zone 1. These modifications to the definition of threshold in the STOP-ROP protocol were made in response to the almost uniformly poor outcomes of threshold ROP in zone 1 in the CRYO-ROP study. STOP-ROP further specified that at least 2 quadrants of the retina must have dilated and tortuous vessels to be called plus disease, whereas the number of quadrants was not specified in CRYO-ROP. These changes might account for some of the observed differences in progression among these studies.
The pathogenesis of ROP involves a complex relationship among avascular retina, immature retinal vessels, oxygen levels, and chemical signals.4 In the inductive phase of ROP, prolonged hyperoxic exposure or other severe physiologic stress causes vasoconstriction and obliteration of the developing capillary endothelial meshwork. Subsequent fibrovascular proliferation of new retinal vessel growth is induced by chemical messengers (eg, vascular endothelial growth factor) from the hypoxic, avascular retina.17, 18 The hypoxic stimulus for retinal neovascularization was first proposed in 1948.19 Clinical observations,20, 21 case-control studies, 22, 23 and animal research24, 25 have provided evidence that supports the hypoxic-stimulus model of ROP. This information provided the background evidence for STOP-ROP to study prevention of severe ROP by maintaining higher oxygen saturation levels to reduce the hypoxic stimulus of the avascular retina. The purpose of the STOP-ROP trial was to evaluate whether supplemental oxygen therapy reduced the progression of prethreshold ROP to threshold ROP.7 A subgroup analysis of the STOP-ROP cohort revealed that infants who had "prethreshold ROP without plus disease" and were randomized to the supplemental (higher O2 saturation) study group had significantly lower progression to threshold ROP than similar infants in the conventional group (supplemental, 32%; conventional, 46%; P = .004).
The mechanisms that result in better ROP outcome for HOPE-ROP versus STOP-ROP infants are not understood but probably relate, in part, to the fact that infants who still require oxygen at the time prethreshold ROP is diagnosed are younger at birth and have more severe ROP, as evidenced by a higher proportion of zone 1 ROP at prethreshold diagnosis. In addition, an infant’s respiratory status, as reflected by SpO2 levels at the time of prethreshold diagnosis, may be a surrogate indicator of some deeper underlying mechanism that influences progression to threshold. Additional studies are needed to improve our understanding of the ophthalmic and nonophthalmic factors that have an impact on an infant’s risk of ROP progression and the influence of greater oxygen dependency on ROP outcome. This information could lead to more effective strategies to prevent ROP progression.
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APPENDIX |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONAPPENDIXREFERENCES |
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Boston Consortium (Cynthia Cole, MD, PI; and Brenda MacKinnon, RNC, SCC): New England Medical Center, Children’s Hospital Medical Center, Brigham and Women’s Hospital, Beth Israel Hospital, Beverly Hospital, South Shore Hospital, Good Samaritan Hospital, Winchester Hospital, Lowell General Hospital. Columbus Consortium (Richard E. McClead, MD, PI; and Rae Fellows, MEd, SCC): Columbus Children’s Hospital, Ohio State University Hospital. Philadelphia Consortium (Alan R. Spitzer, MD, PI; Josh Fosnot, BA; and Bill Holt, RTT, RN, SCCs): Thomas Jefferson University Hospital. University of Louisville (Charles C. Barr, MD, PI; and Greg Whittington, PsyS, SCC): Norton’s Hospital, Kosair Children’s Hospital. Indiana University (James A. Lemons, MD, PI; and Dee Dee Appel, RN, SCC): James Whitcomb Riley Methodist Hospital. Stanford University (David K. Stevenson, MD, PI; and Bethany Ball, BS, CCRC, SCC): Stanford University Medical Center. University of Cincinnati (Edward Donovan, MD, PI; and Marcia Mersmann, RN, SCC): University of Cincinnati, Children’s Hospital of Cincinnati. Magee-Womens Hospital (Beverly S. Brozanski, MD, PI; and Judith Jones, BSN, RNC, SCC): Magee-Womens Hospital. University of Rochester (Dale L. Phelps, MD, PI; and Scott Shutts, BA, SCC): Strong Memorial Hospital and Buffalo Children’s Hospital. SUNY Stony Brook (Pamela A. Weber, MD, PI; and Adriann Combs, RNC, SCC): University Hospital at Stony Brook. Oregon Consortium (Raul C. Banagale, MD, PI; and Nancy G. Dolphin, RN, BSN, SCC): Legacy Emanuel Children’s Hospital. Sheridan Children’s Health Care Systems (Mitchell E. Stern, MD, PI; Brenda Weinstein, RNC; and Kay Wigton, RNC, MSN, Co-SCCs): Plantation General Hospital. University of Maryland (Mark W. Preslan, MD, PI; and Tamara Tanbusch, RN, BSN, SCC): University of Maryland Medical Center, Mercy Medical Center. Minnesota Consortium (Terri L. Young, MD, PI; and Sally M. Cook, BA, SCC): University of Minnesota Hospital/Fairview-Riverside. Cook Institute for Research and Education (Patrick J. Droste, MD, PI; Lynnette Johnson, RN; and Sue Mescar, BSN, NNP, SCCs): Spectrum Health-Downtown Campus.
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ACKNOWLEDGMENTS |
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The HOPE-ROP study is an ancillary study of STOP-ROP, which was supported by grants from the National Eye Institute, the National Institute of Child Health and Human Development, the National Institute of Nursing Research, several National Institutes of Health General Clinical Research Centers, and local funding sources at many centers. These include the following: in Rochester, NY, the Delta Gamma Sorority, the Rhea and Raymond White donation, the Research to Prevent Blindness; and in Boston, MA, support for home oxygen provided by Chartwell Home Therapy. The New England Medical Center received support from the National Institutes of Health General Clinical Research Center Grant M01-RR00054; Stanford University received additional support from National Institutes of Health RR-00-070 and National Institutes of Health HD-27-880.
We acknowledge the assistance of Beverly Brozanski, MD, Anne Lindblad, PhD, Brenda MacKinnon, RNC, and Earl A. Palmer, MD, who reviewed the manuscript.
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FOOTNOTES |
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Received for publication Sep 18, 2001; Accepted Mar 7, 2002.
Reprint requests to (M.L.M.) Children’s Hospital, Department of Ophthalmology, 700 Children’s Dr, Columbus, OH 43205. E-mail: mcgregom{at}chi.osu.edu
a See the appendix for group participants. 
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