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Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) - Outcome Study of Cryotherapy for Retinopathy of Prematurity

Purpose | Background | Description | Patient Eligibility | Recruitment Status | Current Status | Results | Publications | Resource Centers | NEI Representative

Purpose

Background

ROP is a disease of the eyes of prematurely born infants in which the retinal blood vessels increase in number and branch excessively, sometimes leading to hemorrhage or scarring. Before the establishment of this study in 1985, more than 500 infants annually were blinded by ROP in the United States alone.

More than 40 years ago, the National Institutes of Health sponsored a clinical trial that showed that if premature babies are given oxygen only as needed, the number of infants who develop ROP drops dramatically. Subsequently, hospitals cut back on giving excessive oxygen routinely to premature babies. But, with improvements in neonatal care over the last three decades, the number of babies at risk has increased as survival rates for smaller premature infants improve. The lower the birth weight, the higher the incidence and severity of ROP.

In a more recent NEI-supported study at the University of Miami, blood oxygen levels of very low birth-weight infants were monitored continuously by use of transcutaneous measurements as long as oxygen therapy was needed. The study showed that there is no statistically significant difference between the rates of ROP in infants monitored on continuous oxygen therapy and in those monitored only when they were receiving oxygen in excess of 40 percent.

The Supplemental Therapeutic Oxygen for Prethreshold ROP (STOP-ROP) trial, also funded by the NEI, studied whether a slight increase in oxygen therapy would prevent the progression of moderate ROP to ROP severe enough to require surgical treatment. This intervention made little or no difference in outcomes.

Likewise, another NEI-sponsored clinical trial (LIGHT-ROP) demonstrated absence of protective effect on ROP by limiting light exposure to newborn premature infants. These studies have led to the conclusion that factors other than oxygen or light exposure must be involved in causing ROP.

Description

In most infants who develop ROP, the disease spontaneously subsides, permitting development of normal vision. But other infants who progress to a severe form of ROP are in danger of becoming permanently blind. Although the cause of ROP is not fully explained, scientists are seeking ways to treat ROP successfully and to find the right time in the progression of the disease to use treatment. Cryotherapy, which destroys the fringe of the retina through freezing, is the only treatment so far that has been proven to provide substantial benefit to these eyes.

The multicenter trial of cryotherapy for ROP enrolled more than 4,000 premature infants who weighed no more than 1,250 grams at birth. This category of infants has the greatest risk of developing ROP. The eyes of the infants enrolled in the study were examined at predetermined intervals while the subjects were still in the intensive care nursery. After the pupils were dilated with eye drops, the eyes were examined by an ophthalmologist using a binocular indirect ophthalmoscope to visualize the developing retina. The natural history of the condition of each infant's retina was recorded. When examination disclosed the severe form of ROP (threshold ROP) in both eyes, and the parents gave informed consent, one of the infant's eyes was randomly selected to receive cryotherapy. In this technique, a cryoprobe was used to freeze and thus destroy the peripheral extent of the retina, thereby arresting the development of the blood vessels growing wildly toward it.

Outcome of the therapy was assessed at 3 months and 12 months following randomization by an extensive examination that included photography of the interior of both the treated and the control eyes. The 12-month exam also measured visual function with preferential-looking techniques. Such measurements allowed correlations between fundus photographs and visual function and a comparison of visual function for treated versus control eyes. Neither the trained photograph readers who evaluated the pictures from both eyes nor the specially trained vision testers knew which eyes had received cryotherapy. Additional assessments of visual acuity and retinal status have been made approximately each year through age 10, with a final examination at age 15 for patients in the randomized trial of cryotherapy who did not have bilateral total retinal detachment and blindness.

Patient Eligibility

Premature infants of either gender who were eligible for the natural history study had weighed less than 1,251 grams at birth and had survived the first 28 days of life. They had no major ocular or systemic congenital anomalies. Infants who met these criteria and also had a threshold level of ROP (defined as stage 3+ of the International Classification of Retinopathy of Prematurity occupying five or more contiguous or eight cumulative 30° sectors [clock hours] of stage 3 ROP in zone I or II in the presence of plus disease) could be referred for examination to determine eligibility for entry to the cryotherapy trial.

Patient Recruitment Status

Recruitment, which began in January 1986, was stopped January 22, 1988.

Current Status of Study

The 15-year examination period has ended, and all clinical study centers are now closed. Currently, data from this final study examination are being analyzed to determine if the benefits of cryotherapy are sustained in adolescence, when late structural complications and loss of visual acuity have been reported to occur. A comparison will be made between treated and untreated eyes for many conditions, such as late retinal detachment, macular degeneration, and vision failure. This information will be used for evaluating the overall outcome for these teenagers. A manuscript reporting the results of this examination is in process.

Results

The Cryotherapy for Retinopathy of Prematurity Cooperative Group reported preliminary results in 1988. This study registered 9,751 infants with birth weights less than 1,251 grams at 23 study centers. Of these infants, 4,099 were systematically examined. The defined threshold severity of ROP developed in 291 infants.

Cryotherapy was performed in half the eligible eyes of the 291 infants. Twelve months after randomization, the results of masked grading of fundus photographs of the posterior pole indicated an unfavorable outcome in 25.7 percent of the eyes that had received cryotherapy and in 47.4 percent of the control eyes. Masked Teller Acuity Card assessment of grating acuity indicated an unfavorable functional outcome in 35 percent of the treated eyes, compared with 56.3 percent of the control eyes. These results indicate that cryotherapy reduces the risk of unfavorable retinal and functional outcome from threshold ROP.

Although the surgery was stressful, no major complications occurred during or following treatment. Physicians' diagnoses and the unbiased photograph gradings were statistically similar. These data support the efficacy of cryotherapy in reducing by approximately one-half the risk of unfavorable retinal outcome from threshold ROP.

At 3½ years following randomization, functional outcome was evaluated by masked assessment of visual acuity (using only the letters H, O, T, and V) and of grating acuity (using the Teller Acuity Card procedure). Structural outcome was evaluated by the physician's assessment of ROP residua in the posterior pole. All three outcome measures showed a reduction of unfavorable outcomes in treated versus control eyes: 46.6 percent versus 57.5 percent (p < 0.01) for letter acuity, 52.4 percent versus 65.6 percent (p < 0.001) for grating acuity, and 26.1 percent versus 45.4 percent (p < 0.001) for posterior pole status.

At 5½ years following randomization, Snellen visual acuity was measured by masked testers. Again, structural outcome was evaluated by the physician's assessment of ROP residua in the posterior pole. Both visual acuity and fundus structure continued to show fewer unfavorable outcomes in treated versus control eyes: 47.1 percent versus 61.7 percent (p < 0.005) for visual acuity, and 26.9 percent versus 45.4 percent (p < 0.001) for fundus status. detailed analysis of visual acuity outcomes for all eyes revealed that while fewer treated eyes (31.5 percent) than control eyes (47.7 percent) were blind (p < 0.001), there was a slight trend toward fewer eyes with a visual acuity of 20/40 or better in the treated (12.6 percent) versus control (16.7 percent) groups (p = 0.19).

Results at 3½ years and 5½ years following randomization continue to support the long-term efficacy and safety of cryotherapy in the treatment of severe ROP. Although the 5½-year data suggested that cryotherapy could reduce the chance of normal vision in some cases, nevertheless findings from the 10-year examination showed fewer unfavorable outcomes for both visual acuity and structure in treated vs untreated eyes. For distance visual acuity, 44.4 percent of treated eyes had unfavorable outcomes versus 62.1 percent of control eyes (p < 0.001). similarly, for near visual acuity, 42.5 percent of treated eyes versus 61.6 percent of control eyes had unfavorable outcomes (p < 0.001). the fundus status results showed that 27.2 percent of treated eyes versus 47.9 percent of control eyes had unfavorable outcomes (p < 0.001). eyes that received cryotherapy were at least as likely as control eyes to have 20/40 or better visual acuity.

The examination at age 10 included measurement of contrast sensitivity and visual fields. Results of contrast sensitivity testing demonstrated no evidence of adverse treatment effects in eyes that received cryotherapy: 39.7 percent of treated eyes had unfavorable outcomes versus 59.3 percent of control eyes (p < 0.001). the findings for visual field testing with goldmann perimetry showed a visual field area that was 24 percent to 26 percent larger in treated eyes versus untreated eyes, when blind eyes were included and assigned a score of 0. when blind eyes were excluded, visual field area was 5 percent smaller for treated eyes than for untreated eyes, indicating that cryotherapy slightly reduces the visual field area in eyes with severe rop. this small reduction in visual field area in treated eyes is minor when compared with the much greater risk that an eye will be blind without treatment. however, this and any other possible adverse side effects are important considerations in determining whether to treat milder cases of rop that have a relatively good prognosis for vision without treatment.

Cryotherapy is now recommended for both eyes whenever stage 3+ retinopathy of prematurity involves approximately half the circumference in either zone I or zone II. There are, as yet, insufficient data to mandate cryotherapy in any method different from the one used in this trial, or to apply it to patients with less severe disease. Following the publication of the positive results of this study in 1988, the U.S. pattern of care changed rapidly to embrace these guidelines as standard practice.

Laser therapy has been shown to have similar value to cryotherapy. Currently the risk data from the CRYO-ROP study are being used to test the value of earlier intervention in selected high risk eyes, in the Early Treatment for ROP study (ETROP).

Publications

Reynolds JD, Dobson V, Quinn GE, Fielder AR, Palmer EA, Saunders RA, Hardy RJ, Phelps DL, Baker JD, Trese MT, Schaffer DB, Tung B, for the CRYO-ROP and LIGHT-ROP Cooperative Groups: Evidence-based screening criteria for retinopathy of prematurity: natural history data from the CRYO-ROP and LIGHT-ROP studies. Arch Ophthalmol 120: 1470-1476, 2002.

Editorial Committee, for the Cryotherapy for Retinopathy of Prematurity Cooperative Group: Multicenter trial of cryotherapy for retinopathy of prematurity: Natural history ROP: Ocular outcome at 5 1/2 years in premature infants with birth weights less than 12. Arch Ophthalmol 120: 595-599, 2002.

Cryotherapy for Retinopathy of Prematurity Cooperative Group: Contrast sensitivity at age 10 years in children who had threshold retinopathy of prematurity. Arch Ophthalmol 119: 1129-1133, 2001.

Cryotherapy for Retinopathy of Prematurity Cooperative Group: Effect of retinal ablative therapy for threshold retinopathy of prematurity. Arch Ophthalmol 119: 1120-1125, 2001.

Cryotherapy for Retinopathy of Prematurity Cooperative Group: Multicenter trial of cryotherapy for retinopathy of prematurity: Ophthalmological outcomes at 10 years. Arch Ophthalmol 119: 1110-1118, 2001.

Quinn GE, Dobson V, Siatkowski RM, Hardy RJ, Kivlin J, Palmer EA, Phelps DL, Repka MX, Summers CG, Tung B, Chan W, for the Cryotherapy for Retinopathy of Prematurity Cooperative Group: Does cryotherapy affect refractive error? Results from treated versus control eyes in the cryotherapy for retinopathy of prematurity trial. Ophthalmology 108: 343-347, 2001.

Repka MX, Palmer EA, Tung B, on Behalf of the Cryotherapy for Retinopathy of Prematurity Cooperative Group: Involution of retinopathy of prematurity. Arch Ophthalmol 118: 645-649, 2000.

Msall ME, Phelps DL, DiGaudio KM, Dobson V, Tung B, McClead RE, Quinn GE, Reynolds JD, Hardy RJ, Palmer EA: Severity of neonatal retinopathy of prematurity (ROP) is predictive of neurodevelopmental functional outcome at age 5.5 years. Pediatrics 106: 998-1005, 2000.

Dobson V, Quinn GE, Siatkowski RM, Baker JD, Hardy RJ, Reynolds JD, Trese MT, Tung B, for the Cryotherapy for Retinopathy of Prematurity Cooperative Group: Agreement between grating acuity at age 1 year and Snellen acuity at age 5.5 years in the preterm child. Invest Ophthalmol Vis Sci 40: 496-503, 1999.

Harvey ME, Dobson V, Quinn GE, Tung B, Hardy RJ: Interobserver agreement for grating acuity and letter acuity assessment in 1- to 5.5-year-olds with severe retinopathy of prematurity. Invest Ophthalmol Vis Sci 40: 1565-1576, 1999.

Quinn GE, Dobson V, Kivlin J, Kaufman LM, Repka MX, Reynolds JD, Gordon RA, Hardy RJ, Tung B, Stone RA, for the Cryotherapy for Retinopathy of Prematurity Cooperative Group: Prevalence of myopia between 3 months and 5½ years in preterm infants with and without retinopathy of prematurity. Ophthalmology 105: 1292-1300, 1998.

Bremer DL, Palmer EA, Fellows RR, Baker JD, Hardy RJ, Tung B, Rogers GL: Strabismus in premature infants in the first year of life. Arch Ophthalmol 116: 329-333, 1998.

Repka MX, Summers CG, Palmer EA, Dobson V, Tung B, Davis B, on behalf of the Cryotherapy for Retinopathy of Prematurity Cooperative Group: The incidence of ophthalmological interventions in children with birth weights less than 1251 grams: Results through 5½ years. Ophthalmology 105: 1621-1627, 1998.

Hardy RJ, Palmer EA, Schaffer DB, Phelps DL, Davis BR, Cooper CJ, CRYO-ROP Cooperative Group: Outcome-based management of retinopathy of prematurity. JAAPOS 1: 46-54, 1997.

Saunders RA, Christmann LM, Donohue M, Pakalnis VA, Phelps DL, Tung B: Racial variation in retinopathy of prematurity. Arch Ophthalmol 115: 604-608, 1997.

Bartholomew PA, Chao J, Evans JL, Hammel AM, Trueb AL, Verness JL, Dobson V, Quinn GE: Acceptance/Use of the Teller acuity card procedure in the clinic. Am Orthoptic J 46: 100-106, 1996.

Cryotherapy for Retinopathy of Prematurity Cooperative Group: Multicenter Trial of Cryotherapy for Retinopathy of Prematurity: Snellen acuity and structural outcome at 5½ years. Arch Ophthalmol 114(4): 417-424, 1996.

Dobson V, Quinn GE, Abramov I, Hardy RJ, Tung B, Siakowski RM, Phelps DL, Cryotherapy for Retinopathy of Prematurity Group: Color vision measured with standard pseudoisochromatic plates at 5½ years in eyes of children from the CRYO-ROP study. Inv Ophthalmol Vis Sci 37: 2467-2474, 1996.

Gilbert WS, Quinn GE, Dobson V, Reynolds J, Hardy RJ, Palmer EA, CRYO-ROP Cooperative Group: Partial retinal detachment at 3 months after threshold retinopathy of prematurity: Long term structural and functional outcome. Arch Ophthalmol 114: 1085-1091, 1996.

Kivlin JD, Biglan AW, Gordon RA, Dobson V, Hardy RA, Palmer EA, Tung B, Gilbert W, Spencer R, Cheng KP, Buckley E: Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) Cooperative Group: Early retinal vessel development and iris vessel dilatation as factors in retinopathy of prematurity. Arch Ophthalmol 114: 150-154, 1996.

Quinn GE, Dobson V, Barr CC, Davis BR, Palmer EA, Robertson J, Summers CG, Trese MT, Tung B, Cryotherapy for Retinopathy of Prematurity Cooperative Group: Visual acuity of eyes after vitrectomy for ROP: Follow-up at 5½ years. Ophthalmology 103(4): 595-600, 1996.

Quinn GE, Dobson V, Hardy RJ, Phelps DL, Tung B, Palmer EA, CRYO-ROP Cooperative Group: Visual fields measured with double-arc perimetry in eyes with threshold retinopathy of prematurity (ROP) from the CRYO-ROP trial. Ophthalmology 103(9): 1432-1437, 1996.

Dobson V, Quinn GE, Saunders RA, Spencer R, Davis BR, Risser J, Palmer EA, Cryotherapy for Retinopathy of Prematurity Group: Grating acuity in eyes with retinal residua of retinopathy of prematurity (ROP). Arch Ophthalmol 113: 1172-1177, 1995.

Dobson V, Quinn GE, Tung B, Palmer EA, Reynolds JD, Cryotherapy for Retinopathy of Prematurity Cooperative Group: Comparison of recognition and grating acuities in very low birth weight children with and without retinal residua of retinopathy of prematurity (ROP). Invest Ophthalmol Vis Sci 36: 692-702, 1995.

Kivlin JD, Biglan AW, Gordon RA, Dobson V, Hardy RA, Palmer EA, Tung B, Gilbert W, Spencer R, Cheng KP, Buckley E, Cryotherapy for Retinopathy of Prematurity Group: Early retinal vessel development as a factor in retinopathy of prematurity and its functional sequelae. Arch Ophthalmol 114: 150-154, 1995.

Quinn GE, Dobson V, Biglan A, Evans J, Plotsky D, Hardy RJ, Cryotherapy for Retinopathy of Prematurity Cooperative Group: Correlation of retinopathy of prematurity in fellow eyes in the CRYO-ROP study. Arch Ophthalmol 113: 469-473, 1995.

Cryotherapy for Retinopathy of Prematurity Cooperative Group: The natural ocular outcome of premature birth and retinopathy: Status at one year. Arch Ophthalmol 112: 903-912, 1994.

Dobson V, Quinn GE, Summers CG, Saunders RA, Phelps DL, Tung B, Palmer EA, Cryotherapy for Retinopathy of Prematurity Cooperative Group: Effect of acute-phase retinopathy of prematurity on grating acuity development in the very low birth weight infant. Invest Ophthalmol Vis Sc 35: 4236-4244, 1994.

Cryotherapy for Retinopathy of Prematurity Cooperative Group: Multicenter Trial of Cryotherapy for Retinopathy of Prematurity: 3½ year outcome—structure and function. Arch Ophthalmol 111: 339-344, 1993.

Evans MS, Wallace PR, Palmer EA: Fundus photography in small infants. J Ophthal Photography 15(1): 38-39, 1993.

Reynolds J, Dobson V, Flynn JT, Gilbert WS, Quinn GE, Tung B, Robertson J, Cryotherapy for Retinopathy of Prematurity Cooperative Group: Prediction of visual function in eyes with mild to moderate posterior pole residua of retinopathy of prematurity. Arch Ophthalmol 111(8): 1050-1056, 1993.

Schaffer DB, Palmer EA, Plotsky DF, Metz HS, Flynn JT, Tung B, Hardy RJ, Cryotherapy for Retinopathy of Prematurity Cooperative Group: Prognostic factors in the natural course of retinopathy of prematurity (ROP). Ophthalmology 100(2): 230-236, 1993.

Gilbert WS, Dobson V, Quinn GE, Reynolds J, Tun B, Flynn JT, Cryotherapy for Retinopathy of Prematurity Cooperative Group: The correlation of visual function with posterior retinal structure in severe retinopathy of prematurity. Arch Ophthalmol 110: 625-631, 1992.

Quinn GE, Dobson V, Repka MX, Reynolds J, Kivlin J, Davis B, Buckley E, Flynn JT, Palmer EA, Quinn GE, Dobson V, Repka MX, Reynolds J, kivlin J, Davis B, Buckley E, Flynn JT, Palmer EA, Cryotherapy for Retinopathy of Prematurity Cooperative Group: Development of myopia in infants with birth weights less than 1251 grams. Ophthalmology 99: 329-340, 1992.

Summers GC, Phelps DL, Tung B, Palmer EA, Cryotherapy for Retinopathy of Prematurity Cooperative Group: Ocular cosmesis in retinopathy of prematurity. Arch Ophthalmol 110: 1092-1097, 1992.

Trueb L, Evans J, Hammel A, Bartholomew P, Dobson D: Assessing visual acuity of visually impaired children using the Teller acuity cards. Am Orthoptic J 42: 149-154, 1992.

Hardy RJ, Davis BR, Palmer EA, Tung B, Cryotherapy for Retinopathy of Prematurity Cooperative Group: Statistical considerations in the early termination of the multicenter trial of cryotherapy for retinopathy of prematurity. Controlled Clin Trials 12: 293-303, 1991.

Palmer EA, Flynn JT, Hardy RJ, Phelps DL, Phillips CL, Schaffer DB, Tung B, Cryotherapy for Retinopathy of Prematurity Cooperative Group: Incidence and early course of retinopathy of prematurity. Ophthalmology 98: 1628-1640, 1991.

Palmer EA, Hardy RJ, Mowery R, Davis BR, Tung B, Phelps DL, Schaffer DB, Flynn JT, Cryotherapy for Retinopathy of Prematurity Cooperative Group: Operational aspects of early termination of the multicenter trial of cryotherapy for retinopathy of prematurity. Controlled Clin Trials 12: 277-292, 1991.

Phelps DL, Brown DR, Tung B, Cassady G, McClead RE, Purohit DM, Palmer EA, Cryotherapy for Retinopathy of Prematurity Cooperative Group: 28-day survival rates of 6676 neonates with birth weights of 1250 grams or less. Pediatrics 87: 7-17, 1991.

Quinn GE, Dobson V, Barr CC, Davis BR, Flynn JT, Palmer EA, Robertson J, Trese MT: Visual acuity in infants after vitrectomy for severe retinopathy of prematurity. Ophthalmology 98: 5-13, 1991.

Cryotherapy for Retinopathy of Prematurity Cooperative Group: Multicenter Trial of Cryotherapy for Retinopathy of Prematurity. Three-month outcome. Arch Ophthalmol 108: 195-204, 1990.

Dobson V, Quinn GE, Biglan AW, Tung B, Flynn JT, Palmer EA, Cryotherapy for Retinopathy of Prematurity Cooperative Group: Acuity card assessment of visual function in the Cryotherapy for Retinopathy of Prematurity trial. Invest Ophthalmol Vis Sci 31: 1702-1708, 1990.

Watzke RC, Robertson JE, Palmer EA, Wallace PR, Evans MS, Soldevilla JED, Cryotherapy for Retinopathy of Prematurity Cooperative Group: Photographic grading in the retinopathy of prematurity trial. Arch Ophthalmol 108: 950-955, 1990.

Cryotherapy for Retinopathy of Prematurity Cooperative Group: Multicenter Trial of Cryotherapy for Retinopathy of Prematurity. Preliminary results. Arch Ophthalmol 106: 471-479, 1988.

Cryotherapy for Retinopathy of Prematurity Cooperative Group: Multicenter Trial of Cryotherapy for Retinopathy of Prematurity. Preliminary results. Pediatrics 81: 697-706, 1988.

NEI Representative

Donald F. Everett, M.A.
National Eye Institute
National Institutes of Health
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Telephone: (301) 496-5983
Fax: (301) 402-0528

Last Updated: 11/4/2003



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