Multicenter Trial of Cryotherapy for Retinopathy of Prematurity: Natural History ROP: Ocular Outcome at 5½ Years in Premature Infants With Birth Weights Less Than 1251 g

Objective  To present ophthalmological outcome data at 5½ years after full term from a natural history cohort of infants who had a birth weight less than 1251 g and were enrolled at 5 centers of the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (ROP), including eyes without ROP and with a full range of ROP severity.

Design  Of the 1199 surviving children in the cohort, 1068 (89.1%) were examined. Study-certified ophthalmologists assessed ROP residua and conducted cycloplegic refractions. Visual acuity was measured by study-trained testers using the Early Treatment for Diabetic Retinopathy Study charts. Eyes that had developed ROP were categorized by the lowest (most posterior) zone and highest (most severe) stage reached during the acute phase of the disease. No eyes that received cryotherapy are included; data analysis included one untreated eye per patient. Fundus outcomes were classified as "unfavorable" if there was macular compromise by retinal folding (more severe than ectopia) or stage 4B or 5 retinal detachment. Visual acuity outcomes of 20/200 or worse were classified as unfavorable.

Results  Unfavorable fundus structural outcome occurred in 33 (3.1%) of the 1068 eyes; all 33 eyes had a history of severe ROP. Specifically, unfavorable fundus structure occurred in 62.5% (10/16) of eyes with zone I ROP and in 44.2% (23/52) of eyes with zone II ROP, stage 3+ disease involving more than six 30°-sectors. There were no unfavorable fundus outcomes among eyes that had fewer than 7 clock-hours of stage 3+ ROP in zone II in this cohort. Snellen visual acuity was tested in 1059 eyes, and 5.1% were unfavorable at 20/200 or worse; these unfavorable outcomes were correlated with more severe ROP. In eyes that had zone I ROP, 68.8% (11/16) had unfavorable acuity, and for eyes that had zone II ROP, 7.5% (36/481) had unfavorable acuity results. For eyes with ROP observed only in zone III, 1.8% (2/110) had unfavorable acuity of 20/200 or worse.

Conclusions  Premature infants with birth weights less than 1251 g seldom have poor structural and functional outcomes (3.1% and 5.1%, respectively). All unfavorable fundus structural outcomes and nearly all unfavorable acuity outcomes occurred in eyes with zone I ROP or zone II ROP involving more than 6 sectors of stage 3+ disease.

PREMATURE INFANTS whose eyes develop retinopathy of prematurity (ROP) during the neonatal period are known to be subject to various ocular and visual sequelae such as retinal abnormalities, myopia, and reduced visual acuity at long-term follow-up.^1-7 The Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) was designed to prospectively examine premature infants who have a birth weight less than 1251 g to detect ROP severe enough for enrollment in a randomized trial of cryotherapy. This involved serial monitoring of all eligible infants, including those who never developed severe ROP. The study provides sufficient numbers of subjects to permit evaluation of the relation between the acute-phase ROP severity classification during infancy and the ocular sequelae present in later childhood. We previously have reported first-year observations from the resulting "natural history" cohort of 4099 infants,^8-11 and we now report the final natural history ocular outcomes from examinations carried out at 5 centers when the children were approximately 6 years old and able to cooperate for standard visual acuity testing.

The CRYO-ROP study enrolled 4099 infants with birth weights of less than 1251 g to be monitored prospectively at 23 study centers. Each infant underwent a series of eye examinations at specified 1- to 2-week intervals during the neonatal period.^8-10 Detailed information on the location and severity of any ROP that developed was recorded using the international classification system.¹²

Previous reports have documented the incidence and consequences of ROP up to the age of 1 year.^8,10 For this report, the eligible patients were the 1208 survivors enrolled at the 5 CRYO-ROP study centers selected to conduct an extended natural history follow-up. These centers were located in Minneapolis, Minn; Philadelphia, Pa; Columbus, Ohio; Portland, Ore; and upstate New York. The sample represented by this cohort of children constitutes 29.5% of the CRYO-ROP study's original natural history group of 4099 children enrolled between January 1, 1986, and November 30, 1987. Informed consent was obtained twice from the parents or legal guardians—once before enrollment and again before enrollment into the extended follow-up program.

Complete details concerning the organization of the CRYO-ROP study have been published.^8-10,13,14 This article concerns the ocular outcome for 1068 of 1208 eligible children in the extended follow-up cohort who completed the 5½-year examination. Data are analyzed from the untreated eye of those patients who also participated in the randomized trial of cryotherapy (n = 66) and one randomly selected eye from each of the nonrandomized patients (n = 1002).

Outcomes were correlated with the severity of acute-phase ROP in the history. In the serial examinations conducted when the children were infants, study-certified ophthalmologists determined location, stage, and extent of ROP as well as the presence or absence of plus disease (ie, tortuosity and engorgement of the posterior retinal vasculature) according to the international classification system for ROP.^12-14 For data analysis, ROP was categorized first by the most posterior (lowest) zone in which it occurred, and then by the highest stage of active ROP (up to stage 3+) that occurred in that zone. Retinal detachment was excluded from the acute course of ROP, but retinal detachments are included in the outcome category.

Acute-phase categories used are as follows:

• ROP present, subdivided as: zone I, all stages, with and without plus disease; zone II, stage 3+: 10 to 12 sectors, 7 to 9 sectors, 4 to 6 sectors, and 1 to 3 sectors, or stage 3 (no plus disease), stage 2, or stage 1; and zone III, all stages.

• Other ROP, including eyes showing evidence of ROP sequelae without previously documented acute ROP.

• No ROP observed.

Study-certified ophthalmologists performed a comprehensive eye examination for each child. Residua of ROP were then summarized for each eye, primarily based on the appearance of the posterior pole of the retina.¹⁵ Fundus outcome categories are described and listed in Table 1. The examining ophthalmologist also estimated visual function by noting the presence or absence of normal fixation behavior.

Cycloplegic retinoscopy was performed by a standardized method.¹⁵ Whenever it was possible to improve visual acuity by subjective refinement, the best refractive correction was used. For this article, refractive errors were converted to the spherical equivalent, then categorized over the full range from severe hyperopia to severe myopia. Refractive data from eyes with aphakia resulting from lensectomy (n = 19) were excluded.(Note: Other data from eyes with aphakia were included in this article.) Distributions of refractive error were compared for eyes in several severity categories: zone II, stage 3+; zone II, stage 3 without plus disease; and zone II, stages 1 and 2 combined; zone III ROP; and no ROP. Zone I is excluded from comparison because there were few eyes (n = 7) that could be refracted.

Monocular visual acuity was quantified by study-certified visual acuity testers who were masked to each eye's treatment status. Testers measured best-corrected recognition acuity using the Early Treatment for Diabetic Retinopathy Study charts.¹⁶ Children were categorized as blind in both eyes and exempted from acuity testing if: (1) the examining physician and the parents agreed that the child had no light perception in either eye, or (2) the examining physician and parents agreed that the child's vision was, at best, light perception, and both eyes had total retinal detachment or phthisis bulbi. Further details of the 5½-year examination have been published.¹⁷

Results are reported as percentages of unfavorable outcomes and are stratified by the status of the acute-phase ROP. Eyes in the "favorable" category of better than 20/200 were subdivided into the following visual acuity groups:(1) better than or equal to 20/40; (2) worse than 20/40 but better than or equal to 20/60; and (3) worse than 20/60 but better than 20/200. Eyes considered to have unfavorable vision outcomes had Snellen acuity scores of 20/200 or worse, or were blind eyes exempted from visual acuity testing. Eyes in the unfavorable category were subdivided into those with and without acuity scores that were quantifiable using the Early Treatment for Diabetic Retinopathy Study charts. Eyes without quantifiable visual acuity included those with and without light perception, those with minimal pattern vision that was too poor to be quantified with the Early Treatment for Diabetic Retinopathy Study charts at either the 4-m or 1-m test distance, and those exempt from visual acuity testing because of blindness.

Baseline characteristics are described by providing the mean, SD, and frequency. For outcome results, one eye of each subject is the unit of statistical analysis. Eyes were categorized as having favorable or unfavorable retinal outcomes according to the scoring system listed in Table 1. Unfavorable visual acuity was defined as acuity scores of 20/200 or worse. Subgroup analysis based on the acute phase of ROP is also provided.

Nine enrolled patients at these 5 centers died between the 1-year and the 5½-year examinations. Of the remaining 1199 natural history patients, 1068 (89.1%) completed the 5½-year examination. The missing 131 examinations were impossible to perform because of parental refusal (n = 39) or loss of contact with the family (n = 92). In Table 2, baseline characteristics of 2759 patients who completed the 1-year examination at all 23 centers are compared with characteristics of the 1068 patients who completed the 5½-year examination at the 5 centers selected for this extended follow-up study. The proportion of racial minority patients was smaller in this reduced study group; the 2 groups were comparable for birth weight, gestational age, sex, multiple births, and percentage born in a study-affiliated hospital.

Table 3 presents anatomical outcomes stratified by the most posterior zone and highest stage of ROP documented during infancy. Outcomes are not included for 4 eyes because they were uncategorizable(peripheral retinal scarring and retinal pigment epithelial changes in zone II, stage 2 eye; optic atrophy in eye without ROP), or because they were unobtainable(parents refused the examination for a zone II, stage 1 eye; difficulties examining an autistic child who had an eye without ROP). About half of the eyes (50.6%) had zone II ROP. Unfavorable outcomes occurred in 3.1% of the total group, and only in eyes with the most severe ROP: zone I (62.5% unfavorable outcome); zone II, stage 3+ in 10 to 12 sectors (46.3%); and zone II, stage 3+ in 7 to 9 sectors (36.4%). No unfavorable outcomes occurred in this cohort in eyes with fewer than 7 sectors of stage 3+ in zone II (18 patients).

Of the 1068 eyes studied, 19 with aphakia from lensectomy were excluded from refraction analysis. Refraction measurements were attempted on all remaining eyes (n = 1049), but 11 of the eyes were unable to be refracted for the following reasons: 30% (3/10) of eyes that had experienced zone I ROP and 18% (7/40) of eyes that had had zone II, stage 3+ in 7 through 12 sectors were unable to be refracted due to poor ocular anatomical status. One eye with no history of ROP could not be refracted, because the parent refused permission for the administration of eyedrops.

Hyperopia was present in 799 (77.0%) of 1038 refractable eyes. Overall, most eyes (63.4%) were clustered in the low hyperopic range (+2.00 diopters[D] or less), and 13.6% were in the higher hyperopic range (more than +2.00 D). Myopia was found in 16.2% (n = 168) of eyes; 8.5% were in the low myopic range (−2.00 D), 7.7% were in the higher myopic range (-2.00 D or more), and 5.3% (n = 55) had myopia greater than −3.75 D. Higher myopes had experienced more severe ROP.^18,19

Figure 1 shows the spherical equivalent refractive error outcomes for eyes without ROP and with zone II and zone III ROP, showing the distributions of the refractive errors for each category of severity of ROP and for infants with no ROP. Zone I is excluded from comparison because there were few eyes (n = 7) that could be refracted. Eyes with more severe ROP tended to have more myopic refractive errors as well as more variability in refractive error outcomes (larger boxes representing 90% of outcomes). The median refractive error was myopic for eyes with zone II, stage 3+ disease, but all other categories of severity had slightly hyperopic medians, as did eyes with no ROP. In the group of eyes with no ROP observed, 2 eyes with normal structure and fixation had severe myopia (−15.50 and −20.63 D).

Table 4 gives fixation behavior outcomes stratified by severity of ROP. Of 1053 eyes examined, 64 (6.1%) had abnormal fixation. There was a strong correlation between the percentage of eyes with abnormal fixation and the severity of ROP. There was an abrupt decrease in observed abnormal fixation behavior when severity of acute phase ROP was less than 7 sectors of stage 3+ ROP in zone II.

Results of recognition acuity testing are provided for all but 9 of the 1068 eyes that were examined by the ophthalmologist; data for those 9 are missing because the child was unable to cooperate (n = 6) or because of insurmountable schedule conflicts (n = 3). For various reasons, usually relating to neurodevelopmental impairment, visual acuity could not be measured satisfactorily for 100 eyes. Fixation behavior was normal in 78 of those eyes, as judged by the examining ophthalmologist (Table 5), and this suggests that visual acuity outcomes were generally favorable in those eyes. This study was not designed to determine if visual impairment was caused by cerebral cortical or optic nerve abnormalities, rather than ROP sequelae. The Snellen acuity outcomes are listed in Table 6, according to category of prior ROP. Unfavorable visual acuity outcome was found in 5.1% of the eyes, and this was strongly correlated with the severity of ROP. The highest percentage of unfavorable outcomes occurred among eyes that had zone I ROP (68.8%) or zone II ROP with 7 clock-hours or more of stage 3+ (59.2%). All other ROP severity categories had less than 3% unfavorable outcomes.

This article provides 5½-year natural history data on the structural and functional outcome of premature eyes that had the full range of possible ocular abnormalities, from none to the most severe. Unfavorable outcomes were correlated strongly with the severity of ROP that occurred during infancy, yet even eyes with stage 3+ ROP in zone II tended to have good natural outcomes when stage 3+ ROP involved half or less of the retinal circumference. None of the 18 eyes with zone II, stage 3+ ROP of fewer than 7 sectors had unfavorable visual acuity or fundus outcomes. It deserves mention, however, that in the larger overall CRYO-ROP cohort reported at 1 year, there were several unfavorable structural outcomes in this group.¹⁰ Among the 536 eyes with less than stage 3+ ROP in which visual acuity could be assessed, 9 had unfavorable visual acuity outcomes but favorable fundus outcomes. These poor visual acuity outcomes may be related to factors other than ROP, for example, cortical visual impairment.

Most of the 16 eyes with zone I ROP had unfavorable retinal outcomes(n = 10; 62.5%) and visual acuity measured at 20/200 or worse (n = 11; 68.8%). Remarkably, four of the remaining 5 zone I ROP eyes with favorable outcomes developed visual acuity of 20/40 or better. The overall visual acuity outcome was good for all other categories of ROP except for zone II, stage 3+ that involved more than 6 clock-hour sectors. In zone II, stage 3+ ROP extending 7 through 12 sectors, about 60% of eyes had an outcome visual acuity of 20/200 or worse.

These results provide additional data that can bring perspective to ROP management. Only 5% of the overall group had visual acuity of 20/200 or worse. Fortunately, we can reduce the incidence of the worst outcomes by means of surgical ablation of the nonvascularized peripheral retina in appropriate cases. Surgeons are advised to consider the generally good spontaneous outcomes that tend to occur in untreated eyes with less than threshold ROP.^13,14

Submitted for publication May 17, 2001; final revision received January 6, 2002; accepted January 18, 2002.

The CRYO-ROP Study is supported by cooperative agreement EY05874 from the National Eye Institute, National Institutes of Health, Bethesda, Md.

Corresponding author and reprints: Earl A. Palmer, MD, CRYO-ROP Headquarters, Casey Eye Institute, Oregon Health & Science University, 3375 SW Terwilliger Blvd, Portland, OR 97201-4197 (e-mail: palmere@ohsu.edu).