Incidence and Early Course of Retinopathy of Prematurity.

In the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (ROP), 4099 infants weighing less than 1251 g at birth underwent sequential ophthalmic examinations, beginning at age 4 to 6 weeks, to monitor the incidence and course of ROP. Overall, 65.8% of the infants developed ROP to some degree; 81.6% for infants of less than 1000 g birth weight. As expected, ROP incidence and severity were higher in lower birth weight and gestational age categories. Black infants appeared less susceptible to ROP, of all severity categories, than nonblack infants. The timing of retinal vascular events correlated more closely with postconceptional age than with postnatal age, implicating the level of maturity more than postnatal environmental influences in governing the timing of these vascular events. These results include the current incidence of various severity stages of ROP found in the United States and provide new. insight into the development of ROP.

Prevalence and course of strabismus through age 6 years in participants of the Early Treatment for Retinopathy of Prematurity randomized trial.

PURPOSE: To present strabismus data for children who participated in the Early Treatment for Retinopathy of Prematurity (ETROP) randomized trial. METHODS: The prevalence of strabismus, categorized as present or absent, was tabulated for all children with history of high-risk prethreshold retinopathy of prematurity (ROP) who participated in the ETROP randomized trial and were examined at 9 months to 6 years of age. Relationships among strabismus and demographic measures, eye characteristics, and neurodevelopmental factors were analyzed. RESULTS: Among the 342 children evaluated at 6 years, the prevalence of strabismus was 42.2%. Even with favorable acuity scores in both eyes, the prevalence of strabismus was 25.4%, and with favorable structural outcomes in both eyes the prevalence of strabismus was 34.2%. Of children categorized as visually impaired as the result of either ocular or cerebral causes, 80% were strabismic at the 6-year examination. Of 103 study participants who were strabismic at 9 months, 77 (74.8%) remained so at 6 years. Most strabismus was constant at both the 9-month (62.7%) and the 6-year examination (72.3%). After multiple logistic regression analysis, risk factors for strabismus were abnormal fixation behavior in one or both eyes (P < 0.001), history of amblyopia (P < 0.003), unfavorable structural outcome in one or both eyes (P = 0.025), and history of anisometropia (P = 0.04). Strabismus surgery was performed for 53 children. By 6 years, the cumulative prevalence of strabismus was 59.4%. CONCLUSIONS: Most children with a history of high-risk prethreshold ROP develop strabismus at some time during the first 6 years of life.

Visual field extent at 6 years of age in children who had high-risk prethreshold retinopathy of prematurity.

OBJECTIVE: To compare monocular visual field extent at 6 years of age in eyes with high-risk prethreshold retinopathy of prematurity (ROP) randomized to early treatment (ET) with eyes that underwent conventional management (CM) and were treated at threshold or regressed without treatment. METHODS: Subjects were 370 surviving study participants who developed high-risk prethreshold ROP and were enrolled in the Early Treatment for Retinopathy of Prematurity Study between October 1, 2000, and September 30, 2002. When the participants were 6 years of age, vision testers unaware of ROP status used white-sphere kinetic perimetry to measure visual field extent along the superotemporal, inferotemporal, inferonasal, and superonasal meridians. RESULTS: The extent of the visual field was 0.1° to 3.7° larger in ET eyes when blind eyes were assigned a score of 0°. When data were examined from eyes of participants with 1 sighted ET eye and 1 sighted CM eye, ET eyes showed a small (1.3°-3.1°) reduction, which was statistically significant only along the superonasal meridian (P = .005). In bilaterally sighted children, visual field extent was not significantly reduced for high-risk type 1 ET eyes (-0.9° to 1.8°). However, in ET eyes with high-risk type 2 disease, visual field extent was significantly smaller compared with that of CM eyes (3.6°-8.7° superonasal field [P = .003]; inferonasal field [P < .001]). CONCLUSION: Early treatment preserves peripheral vision, with only a small reduction of visual field extent. APPLICATION TO CLINICAL PRACTICE: Early treatment for high-risk prethreshold ROP does not adversely affect visual field extent clinically.

Retinopathy of prematurity in infants weighing less than 500 grams at birth enrolled in the early treatment for retinopathy of prematurity study.

PURPOSE: To describe patient characteristics, classification, and onset of prethreshold retinopathy of prematurity (ROP), and ocular findings at 6 months corrected age in infants with birth weights <500 g who were enrolled in the Early Treatment for Retinopathy of Prematurity (ETROP) Study. DESIGN: Multicenter randomized clinical trial. PARTICIPANTS: Sixty-three infants with birth weights <500 g who developed ROP and were enrolled in the ETROP Study. METHODS: Infants <1251 g at birth were logged at 26 study centers from October 1, 2000, to September 30, 2002, and underwent examinations for ROP. Infants who developed ROP and whose parents/legal guardians consented were enrolled in the ETROP Study. Infants who developed high-risk prethreshold ROP were randomized; 1 eye was treated early with peripheral retinal ablation and the other eye was managed conventionally, or, in asymmetric cases, the high-risk eye was randomized to early peripheral retinal ablation or conventional management. All eyes reaching prethreshold ROP were examined when infants reached 6 months corrected age. MAIN OUTCOME MEASURES: Retinopathy of prematurity incidence, characteristics, and ocular findings among participants. RESULTS: Thirty-four infants reached prethreshold or worse severity in 1 or both eyes. Retinopathy of prematurity was located in zone I in 43.3% of all prethreshold eyes, and plus disease was present in 46.7%. Median postmenstrual age for diagnosis of all prethreshold ROP was 36.1 weeks, but earlier (35.1 weeks) for eyes that developed high-risk prethreshold ROP. In the 27 surviving infants with prethreshold ROP, ophthalmic examination at 6 months corrected age showed a normal posterior pole in 22 (81.5%), a favorable structural outcome with posterior pole abnormalities in 4 (14.8%), and an unfavorable structural outcome (stage 4B) in 1 (3.7%). One infant developed amblyopia, 4 infants developed nystagmus, 4 infants developed strabismus, and 8 infants developed myopia >-5.00 diopters. CONCLUSIONS: This is the first report on characteristics of prethreshold ROP in infants with birth weights <500 g. These infants are at high risk for developing prethreshold ROP, although many initially achieve a favorable structural outcome. They are at risk of developing strabismus, nystagmus, high myopia, and abnormal retinal structure and should therefore receive continued long-term follow-up. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Final visual acuity results in the early treatment for retinopathy of prematurity study.

OBJECTIVE: To compare visual acuity at 6 years of age in eyes that received early treatment for high-risk prethreshold retinopathy of prematurity (ROP) with conventionally managed eyes. METHODS: Infants with symmetrical, high-risk prethreshold ROP (n = 317) had one eye randomized to earlier treatment at high-risk prethreshold disease and the other eye managed conventionally, treated if ROP progressed to threshold severity. For asymmetric cases (n = 84), the high-risk prethreshold eye was randomized to either early treatment or conventional management. The main outcome measure was ETDRS visual acuity measured at 6 years of age by masked testers. Retinal structure was assessed as a secondary outcome. RESULTS: Analysis of all subjects with high-risk prethreshold ROP showed no statistically significant benefit for early treatment (24.3% vs 28.6% [corrected] unfavorable outcome; P = .15). Analysis of 6-year visual acuity results according to the Type 1 and 2 clinical algorithm showed a benefit for Type 1 eyes (25.1% vs 32.8%; P = .02) treated early but not Type 2 eyes (23.6% vs 19.4%; P = .37). Early-treated eyes showed a significantly better structural outcome compared with conventionally managed eyes (8.9% vs 15.2% unfavorable outcome; P < .001), with no greater risk of ocular complications. CONCLUSIONS: Early treatment for Type 1 high-risk prethreshold eyes improved visual acuity outcomes at 6 years of age. Early treatment for Type 2 high-risk prethreshold eyes did not. Application to Clinical Practice Type 1 eyes, not Type 2 eyes, should be treated early. These results are particularly important considering that 52% of Type 2 high-risk prethreshold eyes underwent regression of ROP without requiring treatment. Trial Registration clinicaltrials.gov Identifier: NCT00027222.

Severe visual impairment in children with mild or moderate retinal residua following regressed threshold retinopathy of prematurity.

PURPOSE: To describe clinical features of patients from the Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) trial who, after developing severe ROP in infancy, had minimal or moderate retinal residua in at least one eye but a visual acuity of worse than 20/200 in both eyes at the 10 year examination. METHODS: Data from the 10 year CRYO-ROP Trial follow-up exams were evaluated to identify all patients with retinal outcomes of no retinopathy of prematurity (ROP) residua, straightened temporal vessels, or macular heterotopia in at least one eye, but visual acuity less than 20/200 in both eyes. Presence of optic atrophy, nystagmus, and optic disk cupping and developmental survey results were examined. RESULTS: Of 247 patients examined at 10 years, 16 met our inclusion criteria. At the last age at which the following data were recorded, seven had optic atrophy at the 10 year examination, one had optic disk cupping >0.5 at the 5(1/2) year examination, and eight had nystagmus under binocular conditions at the 24 month examination. Nine patients had a below-normal developmental test score on the Functional Independence Measure for Children (WeeFIM). After clinical data interpretation, we concluded that the predominant cause of visual impairment was postgeniculate disease in five patients, ROP in six patients, and combined anterior and posterior visual pathway disease in two patients; in three patients data were insufficient to make a determination. CONCLUSIONS: Poor visual function with mild to moderate retinal residua of severe ROP in at least one eye is relatively rare. In such patients, anterior, posterior, or combined visual pathway disease can occur.

Costenbader Lecture. The factor of time in retinopathy of prematurity.

PURPOSE: To analyze and discuss the relationship between the factor of time and our understanding of retinopathy of prematurity (ROP). METHODS: The author calls upon 30 years of experience in clinical investigations of ROP to critically synthesize selected literature on ROP, with attention to the broad theme of time. Future opportunities for clinical research are also considered. RESULTS: Although retinopathy of prematurity (ROP) ultimately is self-limited in its course, it is highly variable in its severity and outcome. Both the CRYO-ROP and the ETROP studies paid close attention to the chronology of ROP events; however, they approached the question of when to randomize eyes for treatment not simply according to a time definition, but rather according to disease severity characteristics. Still, results of both these studies can be reviewed from a time perspective, and indeed the pace of progression was one of the risk variables considered for ETROP randomization. The optimal schedule under which to perform eye examinations for active ROP is changing, as our understanding of this disease continues to improve. DISCUSSION: The factor of time is interwoven throughout the clinical course of ROP. Randomized clinical trials have proven to be an extremely efficient scientific method of comparing alternative treatment strategies. In looking toward the future, further randomized clinical trials are needed to investigate rational clinical management of cases in which retinal ablative therapy fails to arrest ROP's progression.

Prevalence and course of strabismus in the first year of life for infants with prethreshold retinopathy of prematurity: findings from the Early Treatment for Retinopathy of Prematurity study.

OBJECTIVE: To present strabismus data for premature infants with prethreshold retinopathy of prematurity (ROP) enrolled in the Early Treatment for Retinopathy of Prematurity study. DESIGN: The prevalence of strabismus was tabulated for all of the infants with high-risk prethreshold disease who participated in the randomized trial of the Early Treatment for Retinopathy of Prematurity study and were examined at 6 and/or 9 months' corrected age as well as for all of the infants with low-risk prethreshold disease who were examined at 6 months' corrected age. MAIN OUTCOME MEASURES: Presence or absence of strabismus at 6 and 9 months' corrected age. RESULTS: The prevalence of strabismus at 6 months was higher for infants with high-risk prethreshold ROP than for those with low-risk prethreshold ROP (20.3% vs 9.6%, respectively; P<.001). Risk factors associated with the development of strabismus at 9 months include abnormal fixation behavior, presence of amblyopia, and outborn birth status (ie, born outside of a study-affiliated hospital). At 9 months, 30% of infants with high-risk prethreshold ROP had strabismus, although only 42% showed strabismus at 6 months. Thirty percent of infants with strabismus at 6 months showed normal alignment at 9 months. CONCLUSIONS: Infants with high-risk prethreshold ROP show significant variability in the presence vs absence of strabismus in the first year of life; thus, conservative management is recommended. APPLICATION TO CLINICAL PRACTICE: Ophthalmologists managing strabismus in infants who have high-risk prethreshold ROP should be aware of the significant variability in ocular alignment during the first year of life.

Proceedings of the Third International Symposium on Retinopathy of Prematurity: an update on ROP from the lab to the nursery (November 2003, Anaheim, California).

The Third International Symposium on Retinopathy of Prematurity (ROP) was convened with the aim of cross fertilizing the horizons of basic and clinical scientists with an interest in the pathogenesis and management of infants with ROP. Ten speakers in the clinical sciences and ten speakers in the basic sciences were recruited on the basis of their research to provide state of the art talks. The meeting was held November 9, 2003 immediately prior to the American Academy of Ophthalmology meeting; scholarships were provided for outreach to developing countries and young investigators. This review contain the summaries of the 20 platform presentations prepared by the authors and the abstracts of presented posters. Each author was asked to encapsulate the current state of understanding, identify areas of controversy, and make recommendations for future research. The basic science presentations included insights into the development of the human retinal vasculature, animal models for ROP, growth factors that affect normal development and ROP, and promising new therapeutic approaches to treating ROP like VEGF targeting, inhibition of proteases, stem cells, ribozymes to silence genes, and gene therapy to deliver antiangiogenic agents. The clinical presentations included new insights into oxygen management, updates on the CRYO-ROP and ETROP studies, visual function in childhood following ROP, the neural retina in ROP, screening for ROP, management of stage 3 and 4 ROP, ROP in the third world, and the complications of ROP in adult life. The meeting resulted in a penetrating exchange between clinicians and basic scientists, which provided great insights for conference attendees. The effect of preterm delivery on the normal cross-talk of neuroretinal and retinal vascular development is a fertile ground for discovering new understanding of the processes involved both in normal development and in retinal neovascular disorders. The meeting also suggested promising potential therapeutic interventions on the horizon for ROP.

The early treatment for ROP (ETROP) randomized trial: study results and nursing care adaptations.

The Early Treatment for Retinopathy of Prematurity (ETROP) study, funded by the National Eye Institute, has shown that early treatment of high-risk prethreshold retinopathy of prematurity (ROP) improves retinal and visual outcomes at 9 months corrected age. These favorable study results have yielded new guidelines for treatment of infants with ROP This paper reviews the study methodology and results and outlines the neonatal and ophthalmic nursing interventions influenced by this new treatment schedule. Four critical phases, screening/examination, treatment, evaluation, and follow-up, are identified, and key nursing objectives and tasks are discussed.

The incidence and course of retinopathy of prematurity: findings from the early treatment for retinopathy of prematurity study.

OBJECTIVES: To estimate the incidence of retinopathy of prematurity (ROP) in the Early Treatment for Retinopathy of Prematurity (ETROP) Study and compare these results with those reported in the Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) Study. METHODS: The ETROP Study, as part of its protocol, screened 6998 infants at 26 centers throughout the United States. Serial eye examinations were conducted for infants born weighing <1251 g, making it possible to estimate the frequency of ROP in different birth weight and gestational age categories. ROP was categorized according to the International Classification for ROP. RESULTS: The incidence of any ROP was 68% among infants of <1251 g. The findings were compared with those for infants born in 1986 and 1987 in the CRYO-ROP Study. The overall incidences of ROP were similar in the 2 studies, but there was more zone I ROP in the ETROP Study. Among infants with ROP, more-severe ROP (prethreshold) occurred for 36.9% of infants in the ETROP Study and 27.1% of infants in the CRYO-ROP Study. The gestational age of onset of ROP of different severities has changed very little since the CRYO-ROP Study was conducted. CONCLUSIONS: ROP remains a common important problem among infants with birth weights of <1251 g. The incidence of ROP, time of onset, rate of progression, and time of onset of prethreshold disease have changed little since the CRYO-ROP natural-history study.

15-year outcomes following threshold retinopathy of prematurity: final results from the multicenter trial of cryotherapy for retinopathy of prematurity.

OBJECTIVE: To report the ocular structure and visual acuity outcomes at age 15 years, and the incidence of retinal detachment between 10 and 15 years of age, for patients in the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP). METHODS: Subjects were 254 survivors from 291 preterm children with birth weights less than 1251 g and severe (threshold) retinopathy of prematurity (ROP) in one or both eyes, who participated in the CRYO-ROP trial. At age 15 years, unfavorable ocular structure was posterior retinal fold or worse judged by study-certified ophthalmologists. Unfavorable distance visual acuity was 20/200 or worse measured by study-certified testers using Early Treatment of Diabetic Retinopathy Study recognition acuity charts. RESULTS: Thirty percent of treated eyes and 51.9% of control eyes (P<.001) had unfavorable structural outcomes. Between 10 and 15 years of age, new retinal folds, detachments, or obscuring of the view of the posterior pole occurred in 4.5% of treated and 7.7% of control eyes. Unfavorable visual acuity outcomes were found in 44.7% of treated and 64.3% of control eyes (P<.001). CONCLUSION: The benefit of cryotherapy for treatment of threshold ROP, for both structure and visual function, was maintained across 15 years of follow-up. New retinal detachments, even in eyes with relatively good structural findings at age 10 years, suggest value in long-term, regular follow-up of eyes that experience threshold ROP.

Health-related quality of life at age 10 years in very low-birth-weight children with and without threshold retinopathy of prematurity.

OBJECTIVE: To describe parental perspectives on health status and health-related quality of life (HRQL) at age 10 years in children with birth weights less than 1251 g who participated in the multicenter Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) study. METHODS: In 244 participants in the randomized CRYO-ROP trial and 102 CRYO-ROP participants who did not develop ROP, the Health Utilities Index (HUI) system was used to characterize health status for the following 8 attributes: vision, hearing, speech, ambulation, dexterity, emotion, cognition, and pain. Using a utility formula, HRQL was determined for each child on a scale from 0.0 (dead) to 1.00 (perfect health). RESULTS: The proportion of the ROP-randomized group with limitations in 4 attributes or more was 20.6% compared with 2.0% for the no-ROP group. Within the ROP-randomized group, the proportion of "sighted" children with limitations in 4 attributes or more was 6.4% vs 46.5% in the "blind/low vision" group. The median HRQL score for the ROP-randomized children was lower than for the no-ROP children (0.72 vs 0.97, P<.001); the median HRQL score for the sighted-randomized children was 0.87 vs 0.27 for the blind/low vision children (P<.001). CONCLUSIONS: Threshold ROP was associated with functional limitations in health attributes and reduction in HRQL scores at age 10 years. Furthermore, among children who developed threshold ROP, a greater reduction in HRQL scores was found among children with a poor visual outcome compared with those with better sight.

Multicenter trial of early treatment for retinopathy of prematurity: study design.

The Early Treatment for Retinopathy of Prematurity (ETROP) study was a randomized, prospective multicenter trial comparing the safety and efficacy of earlier vs. conventionally timed ablation of the peripheral retina for the management of moderate to severe retinopathy of prematurity (ROP). Approximately 7000 infants with birth weights <1251 g were screened at 26 centers over a 2-year period to achieve the sample size of 401 consented infants for the randomized trial. In order to minimize treatment of eyes with ROP that were likely to undergo spontaneous regression of the disease, a risk analysis model, RM-ROP2, was used to select for inclusion in the randomized trial only prethreshold eyes that had a high risk of an adverse outcome. The primary outcome measure was grating visual acuity measured by Teller acuity card testing conducted by masked testers in eyes randomized to earlier treatment vs. eyes randomized to conventional management when infants were 9 months post-term. Results were categorized into favorable (>or=1.85 cycles/degree) vs. unfavorable (<1.85 cycles/degree). The secondary outcome measure was retinal structure, assessed by ophthalmological examinations conducted at 6 and 9 months post-term. Here we describe a unique approach used in the ETROP study to select high-risk prethreshold ROP eyes for randomization and details about design of the study. Study results indicated that earlier intervention in selected high-risk prethreshold eyes results in improved vision in premature infants with ROP.

Risk analysis of prethreshold retinopathy of prematurity.

OBJECTIVE: To present a new multifactorial algorithm to integrate important risk factors for unfavorable retinal outcome in eyes that reached prethreshold retinopathy of prematurity (ROP) in the Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) study. A computerized risk model (RM-ROP2) was developed from this algorithm to identify high-risk prethreshold eyes for enrollment in the Early Treatment for Retinopathy of Prematurity randomized trial. METHODS: Data were analyzed from 613 eyes (1 eye per infant) in the natural history cohort of the Multicenter Trial for Cryotherapy for Retinopathy of Prematurity. These eyes were selected from infants in whom 1 or both eyes progressed to prethreshold ROP. Eyes that progressed to threshold ROP and were randomized to cryotherapy were excluded from this study, but control eyes that reached threshold ROP were included. The course of ROP for 1 prethreshold eye for each infant was tracked until the evaluation of its structural outcome at 3 months' postterm. Tables present structural outcome by selected risk characteristics. A multiple logistic risk model is used to summarize the combined effect of all of these known prognostic risk factors as they relate to structural outcome. RESULTS: Eyes were classified by predicted outcome into 10 risk categories, lowest to highest. Both the observed and predicted outcomes in each category showed an increasingly unfavorable outcome when viewed from lowest to highest risk. Prethreshold ROP eyes were then divided into 2 groups, high-risk, eyes (risk, 0.15-1.0) and low-risk eyes (risk, <0.15). High-risk eyes had an unfavorable outcome of 36% at 3 months' postterm; whereas, only 5% of the low-risk eyes had an unfavorable outcome. CONCLUSION: The model effectively identifies prethreshold ROP eyes that have a relatively high risk and eyes that have a lower risk of an unfavorable structural outcome at 3 months.