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Multicenter Trial of Cryotherapy for Retinopathy of Prematurity
Natural History ROP: Ocular Outcome at 5 Years in Premature Infants With Birth Weights Less Than 1251 g
Editorial Committee; for Cryotherapy for Retinopathy of Prematurity
Cooperative Group
Arch Ophthalmol. 2002;120:595-599.
ABSTRACT
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Objective To present ophthalmological outcome data at 5 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.
INTRODUCTION
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.
PATIENTS AND METHODS
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 5-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).
ACUTE-PHASE ROP DIAGNOSIS
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.
EXAMINATION AT AGE 5 YEARS
Ocular Structure
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.
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Table 1. Retinal Outcome Categories
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Refractive Error
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.
VISUAL ACUITY
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 5-year examination have
been published.17
VISUAL ACUITY OUTCOME
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.
ANALYSIS
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.
RESULTS
POPULATION
Nine enrolled patients at these 5 centers died between the 1-year and
the 5-year examinations. Of the remaining 1199 natural history patients,
1068 (89.1%) completed the 5-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 5-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.
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Table 2. Baseline Characteristics for Patients Followed at 1 Year and
5 Years*
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EXAMINATION OUTCOMES
Ocular Structure
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).
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Table 3. Retinal Outcome by Retinopathy of Prematurity (ROP) Category
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Refraction
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).
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Distribution of 5-year refractive error by category of early
acute retinopathy of prematurity (ROP) severity. Circle indicates median;
vertical line, range; and box, 90% of eyes in that category. Each eye is included
in only 1 category, determined by the lowest zone and the highest stage ever
observed.
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Fixation Behavior
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.
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Table 4. Fixation Behavior by Retinopathy of Prematurity (ROP) Category*
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Visual Acuity
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.
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Table 5. Relationship Between Observed Fixation Behavior and Measurement
of Snellen Visual Acuity*
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Table 6. Snellen Visual Acuity Outcome by Retinopathy of Prematurity
(ROP) Category
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COMMENT
This article provides 5-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
AUTHOR INFORMATION
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{at}ohsu.edu).
The Editorial Committee members are Earl A. Palmer, MD; Robert H. Hardy,
MD; Velma Dobson, PhD; Dale L. Phelps, MD; Graham E. Quinn, MD; C. Gail Summers,
MD; and Betty Tung, MS. The authors have no commercial, proprietary, or financial
interest in the products or companies described in this article. A complete
listing of the participants in the Cryotherapy for Retinopathy of Prematurity
Cooperative Group during the 5-year examination period was published
previously (Arch Ophthalmol. 1996;114:417-424).
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