ROP Clinical Trials
The clinical trials (Figure 9) that have had the greatest impact on the understanding, and the treatment of ROP are the Trial of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) and the Early Treatment in Retinopathy of Prematurity (ETROP) Study. Other important studies reviewed below have evaluated the merits of cryoablation versus laser photoablation of the peripheral retina, the impact of oxygen, light and dietary supplementation on ROP. Remote digital fundus imaging (RDFI) for ROP surveillance and pharmacotherapy with anti-VEGF agents are discussed elsewhere.
Most of our understanding as to risk factors, clinical course, treatment and outcome of ROP is based on data from the multicenter prospective CRYO-ROP study. This study included 4099 premature infants with a birth-weight less than 1251 grams from 23 study centers prospectively screened between January 1,1986 to November 30,1987, of which 291 babies with threshold ROP were randomized to either peripheral retinal ablation with cryotherapy or observation.
The CRYO-ROP Study demonstrated that, at a threshold of disease defined by 5 contiguous or 8 noncontiguous clock-hours of stage 3 retinopathy of prematurity in zones 1 or 2 with plus disease in four quadrants, peripheral retinal ablation effectively reduced unfavorable outcomes (posterior retinal fold, retinal detachment in zone 1, or retrolental tissue mass obscuring the view of the posterior pole) by 49.3%.
Though outcomes with treatment at threshold in the CRYO-ROP Study were superior to the untreated natural history of disease, they were far short of ideal. Even in treated patients, outcomes were frequently poor, and many eyes (21.8%) progressed to macular distortion or retinal detachment with long-term vision loss. Over the longer term, even eyes with favorable anatomic outcomes still had poor vision. This was particularly true for eyes with ROP located in zone 1. Younger gestational age, multiple births, out of nursery birth, low birth weight, white race, plus disease, stage3, >6 clock hour stage 3, and iris vessel dilatation also were noted to be associated with an unfavorable anatomic outcome.
Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity. Preliminary results. Arch Ophthalmol 1988;106:471-479
Cryotherapy for Retinopathy of Prematurity Cooperative group. Multicenter trial of cryotherapy for retinopathy of prematurity. Three-month outcome. Arch Ophthalmol 1990;108: 195-204.
Cryotherapy for Retinopathy of Prematurity Cooperative group. Multicentric trial of cryotherapy for retinopathy of prematurity. One year outcome-structure and function. Arch Ophthalmol 1990;108:1408-1416.
Cryotherapy for Retinopathy of Prematurity Cooperative group. Multicentric trial of cryotherapy for retinopathy of prematurity: natural history ROP: ocular outcome at 5 ½ years in premature infants with birth weight less than 1251 g. Arch Ophthalmol 2002;120:595-599.
Peripheral Retinal Ablation: Laser vs. Cryopexy
Although the merit of cryopexy versus laser retinopexy for ROP was hotly debated, laser is the current standard for treating ROP. Ng et al and Connolly et al reported long-term structural and functional outcomes using laser superior to those obtained with cryotherapy. The difference is perhaps most dramatic in eyes with posterior ROP; favorable anatomic results have been reported in 83% of eyes treated with laser, whereas cryotherapy, by contrast, provided favorable outcomes in only 25% of eyes with zone I disease. In view of the superiority of laser in the management of posterior ROP it is likely that at least part of the difference in structural and functional outcomes in the ETROP study (below) as compared to the CRYO-ROP study accrued not only by virtue of earlier treatment, but also due to the shift from cryopexy to laser ablation. Additional advantages of laser photoablation over cryoablation include reduced postoperative inflammation and lower risk of systemic complications. While laser has largely supplanted cryopexy in the treatment of ORP, cryopexy remains a viable alternative for ROP treatment when poor fundus visualization precludes effective laser, if laser is unavailable, or when the treating physician is not facile with indirect laser photocoagulation.
Ng EY, Connolly BP, McNamara JA et al. A comparison of laser photocoagulation with cryotherapy for threshold retinopathy of prematurity at 10 years: part 1. Visual function and structural outcome. Ophthalmology 2002;109(5):928-934
Connolly BP, Ng EY, McNamara JA et al. A comparison of laser photocoagulation with cryotherapy for threshold retinopathy of prematurity at 10 years: part 2. Refractive outcome. Ophthalmology 2002;109(5):936-941.
Current role of cryotherapy in retinopathy of prematurity: a report by the American Academy of Ophthalmology. Simpson JL, Melia M, Yang MB, Buffenn AN, Chiang MF, Lambert SR. Ophthalmology. 2012 Apr;119(4):873-7. doi: 10.1016/j.ophtha.2012.01.003. Epub 2012 Mar 3.
While infants treated in the CRYO-ROP fared better than their untreated peers, visual outcomes were still unsatisfactory: 44% if treated infants were legally blind at 10 years, and zone I eyes almost always progressed to threshold. For these reasons the benefits of earlier treatment were investigated in the Early Treatment for Retinopathy of Prematurity (ETROP) study. The ETROP demonstrated a statistically significant benefit to earlier treatment, particularly for eyes with the most posterior disease. The clinical algorithm recommended peripheral retinal ablation should be considered for any eye with Type I ROP, defined as:
- Zone I, any stage ROP with plus disease or
- Zone I, stage 3, with or without plus disease or
- Zone II, stage 2 or 3 ROP, with plus disease
Note that plus disease is defined as dilation and tortuosity of the posterior retinal blood vessels in at least two quadrants.
Serial examinations (a “watch and wait” approach) were recommended for Type II ROP, defined as:
- Zone I, stage 1 or 2 with no plus disease or
- Zone II, stage 3 with no plus disease
9-month data demonstrated a reduction in unfavorable visual acuity outcomes with earlier treatment from 19.5% to 14.5%, and a reduction in unfavorable structural outcomes (defined as retinal folds or detachment) from 15.4% to 9.1% in eyes that received early treatment. The 6-year data confirmed the visual benefit of early treatment for infants with Type I ROP. Of note, 52% of Type II prethreshold eyes (zone I stage 1 or 2 ROP without plus disease, or zone II stage 3 ROP without plus disease) underwent regression of ROP without treatment.
Good WV; Early Treatment for Retinopathy of Prematurity Cooperative Group.: Final results of the Early Treatment for Retinopathy of Prematurity (ETROP) randomized trial. Trans Am Ophthalmol Soc. 2004;102:233-48
Early Treatment for Retinopathy of Prematurity Cooperative Group, Good WV, Hardy RJ, Dobson V, Palmer EA, Phelps DL, Tung B, Redford M. Final visual acuity results in the early treatment for retinopathy of prematurity study. Arch Ophthalmol. 2010 Jun;128(6):663-71.
The Role of Oxygen:
During the 50s when ROP was initially described, high, unregulated oxygen at the time of birth was found to be a significant factor that led to severe ROP. Efforts to reduce oxygen concentration led to reduced blindness, but also increased pulmonary and cerebral morbidity. The Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOP-ROP) evaluated supplemental oxygen as a strategy to prevent threshold ROP. Premature infants with prethreshold ROP and median pulse oximetry <94% saturation were randomized to pulse oximetry targeted at 89% to 94% saturation or 96% to 99% saturation. A trend for supplemental oxygen to reduce the progression to threshold ROP did not reach statistical significance, however supplemental oxygen increased the risk of adverse pulmonary events
The HOPE-ROP study (The high oxygen percentage in retinopathy of prematurity study) enrolled infants that were compared to STOP-ROP infants. The patients had prethreshold disease in at least in one eye and a median SaO2 >94%. When covariates (race, gestational age, post menstrual age, zone 1 disease, plus disease) were controlled for, the results were not significant (p>0.05).
A recent meta-analysis suggests the effect of oxygen on the development and progression of ROP is not straight forward – with early low and late high oxygen saturation associated with a reduced risk for severe ROP among preterm infants with a gestational age of < or = 32 week.
The SUPPORT study sought to test the hypothesis that a lower target range of oxygen saturation (85 to 89%), as compared with a higher target range (91 to 95%), would reduce the incidence of ROP or death among very preterm infants (between 24 weeks 0 days of gestation and 27 weeks 6 days of gestation). The rate severe retinopathy or death before discharge did not differ significantly between the two oxygen saturation groups. However, the lower target range of oxygen saturation increased the risk of in-hospital death and substantially reduced the risk of severe retinopathy among survivors. This study underscored the fact that caution should be exercised regarding a strategy of targeting levels of oxygen saturation in the low range for preterm infants to minimize ROP severity, since it may lead to increased mortality. Ongoing investigation is necessary to understand the relationships among oxygen concentration, variability in oxygen concentration, and timing of oxygen delivery.
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(2):295-310
McGregor ML, Bremer DL, Cole C et al. 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. Pediatrics 2002;110(3):540-544
Chen ML, Guo L, Smith LE, Dammann CE, Dammann O. High or low oxygen saturation and severe retinopathy of prematurity: a meta-analysis. Pediatrics. 2010 Jun;125(6):e1483-92.
SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network. Target ranges of oxygen saturation in extremely preterm infants. N Engl J Med 2010;362:1959-1969.
The Role of Light Exposure (Light-ROP)
Light was proposed as a causative factor in ROP because light leads to a release of free radicals that can cause oxidative damage, death of endothelial cells and a release of angiogenic compounds. Expression of tumor necrosis factor alpha (TNF-alpha) and vascular endothelial growth factor (VEGF) during retinal neovascularization can be initiated by lipid hydroperoxides. The Light-ROP study was designed to test the effect of reduced light to the preterm infant’s retina on the development of ROP. Infants were randomized to either a group in which infants wore goggles that reduced ultra-violet light exposure within 24 hours of birth or a group in which infants did not. There was no evidence that reduced light exposure had an effect on the incidence of ROP or the severity of ROP when it developed.
Armstrong D, Ueda T, Ueda T et al. Expression of TNF-alpha and VEGF during retinal neovascularization is initiated by lipid hydroperoxide. Angiogenesis 1997;2:174-184
Reynolds JD, Hardy RJ, Kennedy KA et al. Lack of efficacy of light reduction in preventing retinopathy of prematurity. New Eng J Med 1998;338:1572-1576
Oxidative stress has been linked to ROP through a number of mechanisms related to oxygen delivery to retinal tissue in the premature infant. A number of early studies tested the use of antioxidants, such as vitamin E, to reduce ROP in infants. A meta-analysis of six of these studies found a 52% overall reduction in the incidence of intravitreous neovascularization in ROP when infants were given vitamin E. Sepsis or late-onset necrotizing enterocolitis reported in earlier vitamin E studies did not occur in a later study performed by the same group and was attributed to improved immunologic function with ongoing development of the preterm infant. Vitamin E therapy has also been reported in association with a greater incidence of intraventricular hemorrhage in the premature infant. Additional study is necessary to determine the possible efficacy of vitamin E in preventing ROP.
There is active interest in the influence of early postnatal nutrition – such as increased dietary intake of omega-3-polyunsaturated fatty acids - on retinopathy of prematurity in extremely low birth weight infants.
Raju TNK, Langenberg P, Bhutani V et al. Vitamin E prophylaxis to reduce retinopathy of prematurity: A reappraisal of published trials. J Pediatr 1997;131(6):844-850
Johnson L, Quinn GE, Abbasi S et al. Severe retinopathy of prematurity in infants with birth weights less than 1250 grams: Incidence and outcome of treatment with pharmacologic serum levels of vitamin E in addition to cryotherapy from 1985 to 1991. J Pediatr 1995;127:632-639
Phelps DL, Rosenbaum AL, Isenberg SJ et al. Tocopherol efficacy and safety for preventing retinopathy of prematurity: A randomized, controlled, double-masked trial. Pediatrics 1987;79:489-500
Connor KM, SanGiovanni JP, Lofqvist C, Aderman CM, Chen J, Higuchi A, Hong S, Pravda EA, Majchrzak S, Carper D, Hellstrom A, Kang JX, Chew EY, Salem N Jr, Serhan CN, Smith LE. Increased dietary intake of omega-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis. Nat Med. 2007 Jul;13(7):868-73.