International Classification of Retinopathy of Prematurity, Third Edition.

PURPOSE: The International Classification of Retinopathy of Prematurity is a consensus statement that creates a standard nomenclature for classification of retinopathy of prematurity (ROP). It was initially published in 1984, expanded in 1987, and revisited in 2005. This article presents a third revision, the International Classification of Retinopathy of Prematurity, Third Edition (ICROP3), which is now required because of challenges such as: (1) concerns about subjectivity in critical elements of disease classification; (2) innovations in ophthalmic imaging; (3) novel pharmacologic therapies (e.g., anti-vascular endothelial growth factor agents) with unique regression and reactivation features after treatment compared with ablative therapies; and (4) recognition that patterns of ROP in some regions of the world do not fit neatly into the current classification system. DESIGN: Review of evidence-based literature, along with expert consensus opinion. PARTICIPANTS: International ROP expert committee assembled in March 2019 representing 17 countries and comprising 14 pediatric ophthalmologists and 20 retinal specialists, as well as 12 women and 22 men. METHODS: The committee was initially divided into 3 subcommittees-acute phase, regression or reactivation, and imaging-each of which used iterative videoconferences and an online message board to identify key challenges and approaches. Subsequently, the entire committee used iterative videoconferences, 2 in-person multiday meetings, and an online message board to develop consensus on classification. MAIN OUTCOME MEASURES: Consensus statement. RESULTS: The ICROP3 retains current definitions such as zone (location of disease), stage (appearance of disease at the avascular-vascular junction), and circumferential extent of disease. Major updates in the ICROP3 include refined classification metrics (e.g., posterior zone II, notch, subcategorization of stage 5, and recognition that a continuous spectrum of vascular abnormality exists from normal to plus disease). Updates also include the definition of aggressive ROP to replace aggressive-posterior ROP because of increasing recognition that aggressive disease may occur in larger preterm infants and beyond the posterior retina, particularly in regions of the world with limited resources. ROP regression and reactivation are described in detail, with additional description of long-term sequelae. CONCLUSIONS: These principles may improve the quality and standardization of ROP care worldwide and may provide a foundation to improve research and clinical care.

Outcomes of Two Trials of Oxygen-Saturation Targets in Preterm Infants.

BACKGROUND: The safest ranges of oxygen saturation in preterm infants have been the subject of debate. METHODS: In two trials, conducted in Australia and the United Kingdom, infants born before 28 weeks' gestation were randomly assigned to either a lower (85 to 89%) or a higher (91 to 95%) oxygen-saturation range. During enrollment, the oximeters were revised to correct a calibration-algorithm artifact. The primary outcome was death or disability at a corrected gestational age of 2 years; this outcome was evaluated among infants whose oxygen saturation was measured with any study oximeter in the Australian trial and those whose oxygen saturation was measured with a revised oximeter in the U.K. trial. RESULTS: After 1135 infants in Australia and 973 infants in the United Kingdom had been enrolled in the trial, an interim analysis showed increased mortality at a corrected gestational age of 36 weeks, and enrollment was stopped. Death or disability in the Australian trial (with all oximeters included) occurred in 247 of 549 infants (45.0%) in the lower-target group versus 217 of 545 infants (39.8%) in the higher-target group (adjusted relative risk, 1.12; 95% confidence interval [CI], 0.98 to 1.27; P=0.10); death or disability in the U.K. trial (with only revised oximeters included) occurred in 185 of 366 infants (50.5%) in the lower-target group versus 164 of 357 infants (45.9%) in the higher-target group (adjusted relative risk, 1.10; 95% CI, 0.97 to 1.24; P=0.15). In post hoc combined, unadjusted analyses that included all oximeters, death or disability occurred in 492 of 1022 infants (48.1%) in the lower-target group versus 437 of 1013 infants (43.1%) in the higher-target group (relative risk, 1.11; 95% CI, 1.01 to 1.23; P=0.02), and death occurred in 222 of 1045 infants (21.2%) in the lower-target group versus 185 of 1045 infants (17.7%) in the higher-target group (relative risk, 1.20; 95% CI, 1.01 to 1.43; P=0.04). In the group in which revised oximeters were used, death or disability occurred in 287 of 580 infants (49.5%) in the lower-target group versus 248 of 563 infants (44.0%) in the higher-target group (relative risk, 1.12; 95% CI, 0.99 to 1.27; P=0.07), and death occurred in 144 of 587 infants (24.5%) versus 99 of 586 infants (16.9%) (relative risk, 1.45; 95% CI, 1.16 to 1.82; P=0.001). CONCLUSIONS: Use of an oxygen-saturation target range of 85 to 89% versus 91 to 95% resulted in nonsignificantly higher rates of death or disability at 2 years in each trial but in significantly increased risks of this combined outcome and of death alone in post hoc combined analyses. (Funded by the Australian National Health and Medical Research Council and others; BOOST-II Current Controlled Trials number, ISRCTN00842661, and Australian New Zealand Clinical Trials Registry number, ACTRN12605000055606.).

Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): five-year outcomes of a randomised trial.

Background: Concerns remain over the long-term safety of vascular endothelial growth factor (VEGF) inhibitors to treat retinopathy of prematurity (ROP). RAINBOW is an open label randomised trial comparing intravitreal ranibizumab (in 0.2 mg and 0.1 mg doses) with laser therapy in very low birthweight infants (<1500 g) with ROP. Methods: Of 201 infants completing RAINBOW, 180 were enrolled in the RAINBOW Extension Study. At 5 years, children underwent ophthalmic, development and health assessments. The primary outcome was visual acuity in the better-seeing eye. The study is registered with ClinicalTrial.gov, NCT02640664. Findings: Between 16-6-2016 and 21-4-2022, 156 children (87%) were evaluated at 5 years. Of 32 children with no acuity test result, 25 had a preferential looking test, for 4 children investigators reported low vision for each eye, and in 3 further children no vision measurement was obtained. 124 children completed the acuity assessment, the least square mean (95% CI) letter score in the better seeing eye was similar in the three trial arms-66.8 (62.9-70.7) following ranibizumab 0.2 mg, 64.6 (60.6-68.5) following ranibizumab 0.1 mg and 62.1 (57.8-66.4) following laser therapy; differences in means: ranibizumab 0.2 mg v laser: 4.7 (95% CI: -1.1, 10.5); 0.1 mg v laser: 2.5 (-3.4, 8.3); 0.2 mg v 0.1 mg: 2.2 (-3.3, 7.8). High myopia (worse than -5 dioptres) in at least one eye occurred in 4/52 (8%) children following ranibizumab 0.2 mg, 8/55 (15%) following ranibizumab 0.1 mg and 11/45 (24%) following laser therapy (0.2 mg versus laser: odds ratio: 3.99 (1.16-13.72)). Ocular and systemic secondary outcomes and adverse events were distributed similarly in each trial arm. Interpretation: 5-year outcomes confirm the findings of the original RAINBOW trial and a planned interim analysis at 2 years, including a reduced frequency of high myopia following ranibizumab treatment. No effects of treatment on non-ocular outcomes were detected. Funding: Novartis Pharma AG.

Time Course of Retinopathy of Prematurity Regression and Reactivation After Treatment with Ranibizumab or Laser in the RAINBOW Trial.

PURPOSE: To study the time course of retinopathy of prematurity (ROP) regression and reactivation after treatment with intravitreal ranibizumab or laser in the ranibizumab compared with laser therapy for the treatment of infants born prematurely with ROP trial. DESIGN: Post hoc analysis of a randomized, clinical trial. SUBJECTS: A total of 225 infants (448 eyes) were randomized to ranibizumab 0.2 mg (n = 74, 148 eyes), ranibizumab 0.1 mg (n = 77, 152 eyes), and laser (n = 74, 148 eyes). METHODS: Features of disease regression were measured using time-to-event analysis per eye, corrected for within-subject association. Analyses of disease reactivation and additional treatments were descriptive. MAIN OUTCOME MEASURES: Median time to regression of plus disease, stage 3 ROP, aggressive posterior (AP)-ROP to 24-week follow-up and disease reactivation and first additional treatment to 2-year follow-up. RESULTS: The median times to regression after ranibizumab 0.2 mg vs. laser were as follows: plus disease, 4 vs. 16 days (P < 0.001); stage 3 ROP, 8 vs. 16 days (P = 0.004); and AP-ROP, 7.3 vs. 22 days (P = 0.03). Results for ranibizumab 0.1 mg were similar to those for 0.2 mg, with a median of 4, 9, and 8 days, respectively. Additional treatments were given in 34 (25%) of 138 eyes after laser and 40 (27%) of 146 and 42 (28%) of 152 eyes after 0.2 mg and 0.1 mg ranibizumab, respectively. Incomplete disease regression requiring additional treatment occurred in 30 (22%) of 138 eyes after laser after a median interval of 15 days compared with 11 (8%) of 146 and 9 (6%) of 152 after 0.2 mg and 0.1 mg ranibizumab after a median interval of 21 and 13 days, respectively. Retinopathy of prematurity reactivation requiring additional treatment occurred in 3 (2%) of 138 eyes after laser after a median interval of 43 days compared with 22 (15%) of 146 and 26 (17%) of 152 after 0.2 and 0.1 mg ranibizumab after a median interval of 53.5 (maximum, 105) and 54.5 days (maximum, 128), respectively. CONCLUSIONS: Intravitreal 0.2 or 0.1 mg ranibizumab induced a faster regression of plus disease, stage 3 ROP, and AP-ROP than laser did. Ranibizumab was associated with fewer additional treatments for incomplete disease regression but more for disease reactivation.

Ranibizumab Population Pharmacokinetics and Free VEGF Pharmacodynamics in Preterm Infants With Retinopathy of Prematurity in the RAINBOW Trial.

Purpose: To develop a population pharmacokinetic (PK) model for intravitreal ranibizumab in infants with retinopathy of prematurity (ROP) and assess plasma free vascular endothelial growth factor (VEGF) pharmacodynamics (PD). Methods: The RAnibizumab compared with laser therapy for the treatment of INfants BOrn prematurely With retinopathy of prematurity (RAINBOW) trial enrolled 225 infants to receive a bilateral intravitreal injection of ranibizumab 0.1 mg, ranibizumab 0.2 mg, or laser in a 1:1:1 ratio and included sparse sampling of blood for population PK and PD analysis. An adult PK model using infant body weight as a fixed allometric covariate was re-estimated using the ranibizumab concentrations in the preterm population. Different variability, assumptions, and covariate relationships were explored. Model-based individual predicted concentrations of ranibizumab were plotted against observed free VEGF concentrations. Results: Elimination of ranibizumab had a median half-life of 5.6 days from the eye and 0.3 days from serum, resulting in an apparent serum half-life of 5.6 days. Time to reach maximum concentration was rapid (median: 1.3 days). Maximum concentration (median 24.3 ng/mL with ranibizumab 0.2 mg) was higher than that reported in adults. No differences in plasma free VEGF concentrations were apparent between the groups or over time. Plotted individual predicted concentrations of ranibizumab against observed free VEGF concentrations showed no relationship. Conclusions: In preterm infants with ROP, elimination of ranibizumab from the eye was the rate-limiting step and was faster compared with adults. No reduction in plasma free VEGF was observed. The five-year clinical safety follow-up from RAINBOW is ongoing. Translational Relevance: Our population PK and VEGF PD findings suggest a favorable ocular efficacy: systemic safety profile for ranibizumab in preterm infants.

The optical treatment of amblyopia.

The role of refractive correction has been underestimated as a distinct component of amblyopia therapy. Until relatively recently, the extent to which it could ameliorate the amblyopic acuity deficit remained unquantified and the time course of its effect unknown. Improvement of vision after refractive correction appears to occur in all the major types of amblyopia, including, somewhat surprisingly, in the presence of strabismus. Although the neurophysiological basis of the remediative effect of such "optical treatment" is unknown, some insight is now available from animal models and psychophysical investigations in humans. An appreciation of the role that refractive correction can play in the overall management of amblyopia has led to the formulation of new treatment guidelines, whereby a defined period of spectacle or contact lens wear always precedes traditional therapies, such as occlusion or penalization.

Long term ophthalmic sequelae of prematurity.

There are numerous reports of an increase in refractive errors and amblyogenic factors in the low birth weight population relative to children born at full term. This raises the question of whether additional long term ophthalmic screening is required. The current provision of follow up care for preterm infants in the UK is haphazard and varies in terms of its availability, the type of assessment, age at assessment and age at discharge. This issue needs to be addressed to provide the best care for these children however there are different possible methodologies. One key aspect of a screening programme is the age at testing as this dictates the possible tests used which impacts on the efficacy. However, although the prevalence of strabismus and refractive errors is well documented the development of these conditions is poorly understood so for this and other reasons it is difficult to devise the most effective screening programme.

Modeling dose-response in amblyopia: toward a child-specific treatment plan.

PURPOSE: This article describes an empirically derived mathematical model of the treatment dose-response of occlusion therapy for amblyopia based on outcome data obtained from the Monitored Occlusion Treatment for Amblyopia Study (MOTAS). METHODS: The MOTAS protocol comprised three discrete phases: baseline, refractive adaptation, and occlusion. Only data from the occlusion phase were used in this dose-response model. Seventy-two participants, 3 to 8 years of age, mean +/- SD age 5.2 +/- 1.4 years (anisometropia [n = 18]); strabismus [n = 22]); both anisometropia and strabismus [n = 32]) completed the occlusion phase. All participants were prescribed 6-h/d patching, which was objectively monitored by an occlusion dose monitor (ODM). RESULTS: Simple normal linear regression modeling of the data on an interval-by-interval basis (interval between clinic visits) indicates that increasing cumulative dose within interval (hours) yields an increase in visual acuity (R2 = 0.918; 684 data points). Most of the children achieved their best visual acuity with 150 to 250 hours' cumulative dose. Specific patient characteristics (especially age) modify the steepness of this function. For example, a 0.20-logMAR (2-line logarithm of the minimum angle of resolution) gain in visual acuity requires a cumulative dose of 170 hours for children at age 48 months and 236 hours at age 72 months. CONCLUSIONS: Mathematical modeling of amblyopia therapy is a novel approach that elucidates the kinetics of the therapeutic response in humans. This response is age-influenced so that older children require a greater dose to achieve the same outcome--evidence of altered plasticity of the visual system. Fine-tuning the dose-response in amblyopia therapy will facilitate the development of child-specific, evidence-based treatment plans.

Visual outcomes and perinatal adversity.

Preterm birth per se, the neonatal environment, retinopathy of prematurity (ROP) and neurological damage are all causes of visual impairment and the impact of these factors is discussed in relation to the resultant ophthalmic deficits. Visual acuity impairments range from blindness, due to ROP or cortical visual impairment, which can be identified at an early age, to subtle deficits related to preterm birth only identified at a later age. Visual function deficits are not limited to visual acuity but can affect contrast sensitivity, field of vision and colour vision. Strabismus and refractive errors are also very common in children following perinatal adversity. Although more is now known about the types of deficits affecting these children, there is still a poor understanding of how these deficits impact on a child's functional ability. The impact of these ophthalmic deficits on the long term ophthalmic care required, and the role of perinatal factors, is discussed.

Occlusion dose monitoring in amblyopia therapy: status, insights, and future directions.

Occlusion therapy remains the mainstay treatment of amblyopia, but its outcome is not assured or universally excellent. Many factors are known to influence treatment outcome, among which compliance is foremost. The occlusion dose monitor (ODM) removes one variable from the treatment equation, because it records the occlusion actually received by-rather than prescribed for-the child. Improvement observed can thus be quantitatively related to the patching received. This review summarizes the insights the ODM has provided to date particularly in elucidating the dose-response relationship. We are entering the era of personalized ophthalmology in which treatments will be tailored to the needs of the individual child and facilitated by the use of wearable monitors.

Optic disk size and optic disk-to-fovea distance in preterm and full-term infants.

PURPOSE: Few studies have assessed optic disk and retinal morphology in infants. Here the optic disk and optic disk-to-fovea distance were measured in preterm and full-term infants in vivo. METHODS: Optic disk (OD) dimensions and the center-to-center distance between the OD and the macula were measured using digital imaging in infants undergoing routine ophthalmic examinations. Postmenstrual age of the mother at the time of examination ranged from 32 to 50 weeks. From each image, the OD-to-fovea distance (ODF) and the OD height (ODH) and OD width (ODW) were measured. RESULTS: In 51 retinal images from 51 infants, mean +/- SD values obtained were 4.4 +/- 0.4 mm (ODF), 1.41 +/- 0.1 9 mm (ODH), and 1.05 +/- 0.13 mm (ODW). These dimensions did not change significantly over the age range studied. The mean value for the ratio between ODF and mean OD diameter (ODF/DD) was 3.76. CONCLUSIONS: Results of this in vivo study suggest that though the optic nerve head diameter increases by more than 50%, only limited growth occurs at the highly organized area of the posterior pole from birth to adulthood. This study discusses the finding of a large-angle kappa in infants and the use of a disk macula/disk diameter ratio in the diagnosis of optic nerve hypoplasia.

Treatment of Amblyopia Using Personalized Dosing Strategies: Statistical Modelling and Clinical Implementation.

PURPOSE: To generate a statistical model for personalizing a patient's occlusion therapy regimen. METHODS: Statistical modelling was undertaken on a combined data set of the Monitored Occlusion Treatment of Amblyopia Study (MOTAS) and the Randomized Occlusion Treatment of Amblyopia Study (ROTAS). This exercise permits the calculation of future patients' total effective dose (TED)-that predicted to achieve their best attainable visual acuity. Daily patching regimens (hours/day) can be calculated from the TED. RESULTS: Occlusion data for 149 study participants with amblyopia (anisometropic in 50, strabismic in 43, and mixed in 56) were analyzed. Median time to best observed visual acuity was 63 days (25% and 75% quartiles; 28 and 91 days). Median visual acuity in the amblyopic eye at start of occlusion was 0.40 logMAR (quartiles 0.22 and 0.68 logMAR) and at end of occlusion was 0.12 (quartiles 0.025 and 0.32 logMAR). Median lower and upper estimates of TED were 120 hours (quartiles 34 and 242 hours), and 176 hours (quartiles 84 and 316 hours). The data suggest a piecewise linear relationship (P = 0.008) between patching dose-rate (hours/day) and TED with a single breakpoint estimated at 2.16 (standard error 0.51) hours/day, suggesting doses below 2.16 hours/day are less effective. CONCLUSION: We introduce the concept of TED of occlusion. Predictors for TED are visual acuity deficit, amblyopia type, and age at start of occlusion therapy. Dose-rates prescribed within the model range from 2.5 to 12 hours/day and can be revised dynamically throughout treatment in response to recorded patient compliance: a personalized dosing strategy.

Treatment of unilateral amblyopia: factors influencing visual outcome.

PURPOSE: To identify factors that influence the outcome of treatment for unilateral amblyopia, as a part of the Monitored Occlusion Treatment of Amblyopia Study (MOTAS). METHODS: This was an intervention study consisting of three nonoverlapping phases: "Baseline", "refractive adaptation" (18 weeks of full-time spectacle wear), and "occlusion" (6 hours of patching per day, objectively monitored). Condition factors: type of amblyopia, age of participant, initial severity of amblyopia, fixation, and binocular vision status; treatment factors: refractive adaptation and occlusion (total dose [hours] and dose rate [hours per day]) were assessed for their influence on visual outcome. Visual outcome was expressed in three ways: logMAR (logarithm of the minimum angle of resolution) change, residual amblyopia, and proportion of the deficit corrected. RESULTS: The study included 85 participants (mean age, 5.1 +/- 1.4 years) with amblyopia associated with strabismus (n = 32) or anisometropia (n = 20) or associated with both anisometropia and strabismus (n = 33). Treatment factors: cumulative occlusion dose exceeding 50 hours, and dose rates > or =1 hour per day resulted in (P < or = 0.01) lower residual amblyopia and a greater proportion of the deficit corrected. Condition factors associated with poor outcome (high residual amblyopia) were presence of eccentric fixation, severe initial amblyopia, and no binocular vision. CONCLUSIONS: Factors influencing outcome with treatment for amblyopia are occlusion dose (the rate of delivery and cumulative dose worn), the initial severity of the amblyopia, binocular vision status, fixation of the amblyopic eye, and the age of the subject at the start of treatment.

Personalized versus standardized dosing strategies for the treatment of childhood amblyopia: study protocol for a randomized controlled trial.

BACKGROUND: Amblyopia is the commonest visual disorder of childhood in Western societies, affecting, predominantly, spatial visual function. Treatment typically requires a period of refractive correction ('optical treatment') followed by occlusion: covering the nonamblyopic eye with a fabric patch for varying daily durations. Recent studies have provided insight into the optimal amount of patching ('dose'), leading to the adoption of standardized dosing strategies, which, though an advance on previous ad-hoc regimens, take little account of individual patient characteristics. This trial compares the effectiveness of a standardized dosing strategy (that is, a fixed daily occlusion dose based on disease severity) with a personalized dosing strategy (derived from known treatment dose-response functions), in which an initially prescribed occlusion dose is modulated, in a systematic manner, dependent on treatment compliance. METHODS/DESIGN: A total of 120 children aged between 3 and 8 years of age diagnosed with amblyopia in association with either anisometropia or strabismus, or both, will be randomized to receive either a standardized or a personalized occlusion dose regimen. To avoid confounding by the known benefits of refractive correction, participants will not be randomized until they have completed an optical treatment phase. The primary study objective is to determine whether, at trial endpoint, participants receiving a personalized dosing strategy require fewer hours of occlusion than those in receipt of a standardized dosing strategy. Secondary objectives are to quantify the relationship between observed changes in visual acuity (logMAR, logarithm of the Minimum Angle of Resolution) with age, amblyopia type, and severity of amblyopic visual acuity deficit. DISCUSSION: This is the first randomized controlled trial of occlusion therapy for amblyopia to compare a treatment arm representative of current best practice with an arm representative of an entirely novel treatment regimen based on statistical modelling of previous trial outcome data. Should the personalized dosing strategy demonstrate superiority over the standardized dosing strategy, then its adoption into routine practice could bring practical benefits in reducing the duration of treatment needed to achieve an optimal outcome. TRIAL REGISTRATION: ISRCTN ISRCTN12292232.

Treatment dose-response in amblyopia therapy: the Monitored Occlusion Treatment of Amblyopia Study (MOTAS).

PURPOSE: Amblyopia is the commonest visual disorder of childhood. Yet the contributions of the two principal treatments (spectacle wear and occlusion) to outcome are unknown. This study was undertaken to investigate the dose-response relationship of amblyopia therapy. METHODS: The study comprised three distinct phases: baseline, in which repeat measures of visual function were undertaken to confirm the initial visual deficit; refractive adaptation: an 18-week period of spectacle wear with six weekly measurements of logarithm of the minimum angle of resolution (logMAR) visual acuity; occlusion: in which participants were prescribed 6 hours of "patching" per day. In the latter phase, occlusion was objectively monitored and logMAR visual acuity recorded at 2-week intervals until any observed gains had ceased. RESULTS: Data were obtained from 94 participants (mean age, 5.1 +/- 1.4 years) with amblyopia associated with strabismus (n = 34), anisometropia (n = 23), and both anisometropia and strabismus (n = 37). Eighty-six underwent refractive adaptation. Average concordance with patching was 48%. The relationship between logMAR visual acuity gain and total occlusion dose was monotonic and linear. Increasing dose rate beyond 2 h/d hastened the response but did not improve outcome. More than 80% of the improvement during occlusion occurred within 6 weeks. Treatment outcome was significantly better for children younger than 4 years (n = 17) than in those older than 6 years (n = 24; P = 0.0014). CONCLUSIONS: Continuous objective monitoring of the amount of patching therapy received has provided insight into the dose-response relationship of occlusion therapy for amblyopia. Patching is most effective within the first few weeks of treatment, even for those in receipt of a relatively small dose. Further studies are needed to elucidate the neural basis for the dose-response functions.

Nasotemporal asymmetry of retinopathy of prematurity.

OBJECTIVE: To quantify an apparent nasotemporal asymmetry in the location of retinopathy of prematurity with respect to the optic disc. METHODS: Twenty-four-bit color images were captured using a contact digital fundus camera during routine screening. Semiautomated measurements were undertaken to determine the distance between the optic disc and retinopathy located in the nasal and temporal regions of the retina. RESULTS: Forty-nine image pairs (17 right eye, 32 left eye) were captured from 10 infants during a period of 32 to 40 weeks postmenstrual age. For right eyes, averaged across age, the mean (SD) distance between the optic disc and temporal retinopathy was 426 (26) pixels and that between the optic disc and nasal retinopathy was 330 (26) pixels. Corresponding measurements for the left eye were 428 (30) and 332 (24) pixels. This observed asymmetry was found to be statistically significant in both left and right eyes (Mann-Whitney U test, P<.01). While the distance between the optic disc and retinopathy increased with age by 10 to 17 pixels per week, the extent of the asymmetry did not vary systematically with age. CONCLUSION: The location of retinopathy of prematurity is asymmetric along the horizontal meridian with respect to the optic disc-an observation germane to retinal vascular development, the pathogenesis of retinopathy of prematurity, and current disease classification by circular (symmetric) zones.