Date of most recent amendment: 25/05/1999
Date of most recent substantive amendment: 10/05/1999
Date next stage expected: 10/05/2000
Contact
Dr Chad Andersen
Department of Pediatrics
Mercy Hospital for Women
Clarendon Street
East Melbourne
AUSTRALIA
3002
E-mail: candersen@mercy.com.au
Sources of support for the review
Acknowledgements
The authors thank Dr. B. Lemyre and Dr. P. Hamr for assistance with
the translation of foreign language articles and Scott Shutts and Audra
Boyer for extraction, copying and management of the numerous references.
This work was supported in part by the NIH, National Eye Institute (DLP).
Potential conflict of interest
None
It is clear that the incidence and severity of retinopathy is inversely related to gestational age. Whilst the majority of infants less than 30 weeks gestational age will develop some form of retinopathy, in most cases it will regress spontaneously. Some infants, however, will develop progressive retinopathy which threatens vision.
Following a series of consensus meetings in 1984, ROP was newly classified according to the location (zone), extent (clock hours of disease), severity (stage) and presence or absence of plus disease, which represents vascular decompensation manifest as vessel dilatation and tortuosity (ICCROP 1984). This included the description of 'threshold' ROP, a prognostically relevant level of disease severity at which the risk of blindness in untreated eyes is greater than 47% (CRYO- ROP 1988).
Treatment of established 'threshold' ROP was introduced in order to prevent the high risk of blindness in affected eyes. This involves ablation of the peripheral avascular retina, thus preserving central macula vision. Initially transscleral cryoablation was used, as it was technically easier in infants with hazy vitreous. Subsequently, both photocoagulation and cryoablation have been used to destroy the avascular immature retina thought to be responsible for the angiogenic growth factors that drive the neovascularisation of the ROP.
The purpose of this review is to systematically evaluate the effect
of peripheral avascular retinal ablation, by any means, on the incidence
of adverse ophthalmic outcome in premature infants with threshold ROP.
Valid: In addition to relevant:
Randomised assignment
Concealment of group assignment prior to randomisation
Independent outcome assessment with masking of treatment allocation
where possible.
Follow up rate > 80%.
Types of participants
Human preterm infants with "Threshold ROP".
Types of intervention
Ablation of the peripheral avascular retina by any means including
cryotherapy, laser diode, laser argon, xenon arc photocoagulation. Reports
using treatment to the proliferating ridge were not included.
Types of outcome measures
1. Early unfavorable retinal structure, assessed at less than 12 months,
defined as:
(1) a posterior retinal fold (usually involving the macula) or
(2) a retinal detachment involving zone 1 of the posterior pole or
(3) retrolental tissue or mass obscuring the view of the posterior
pole.
2. Early childhood unfavorable retinal structure, assessed at 4 to 6
years, defined as:
(1) ROP stage 4B or greater,
(2) obstructed view of macula from
(a) partial or complete cataract,
(b) partial retrolental membrane or
(c) partial or complete corneal opacity (owing to ROP),
(3) enucleation from all causes.
3. Early childhood unfavorable visual acuity, assessed at 4 to 6 years, defined as absence of vision or Snellen visual acuity of 20/200 or worse.
Databases searched included the Cochrane Neonatal Review Group Register of Clinical Trials, MEDLINE, EMBASE and the Oxford Database of Perinatal Trials. In addition to the databases, review articles, abstracts from pediatric and ophthalmologic meetings through 1998, letters and expert informants were used.
The initial comprehensive search yielded approximately 500 articles.
These articles were screened independently by both authors by title and
abstract into two groups, not relevant (by selection criteria) and possibly
relevant (112). There was very strong agreement between the authors.
Photocopies of the possibly relevant articles were provided to two
independent reviewers in order to determine the true relevance of the article
and the methodology used in the study. Fifteen articles were considered
relevant; twenty-six others were editorials, letters (without data), retrospective
reviews and case series without controls; sixty were not relevant and six
required further assessment (foreign language).
Four relevant studies contained in twenty citations were identified.
Photocopies of the citations were provided to both reviewers who independently
determined the methods used in the study. Methods were evaluated for concealment
of randomisation and intervention, masking of outcome assessment where
possible and completeness of follow up. Two studies were excluded; one
did not use random allocation and the other used ablation to the peripheral
avascular retina as well as the demarcation line, which is no longer recommended
therapy (Harris 1976).
For the two remaining randomised studies, both reviewers independently
extracted the data. As the unit of randomisation is the eye and not the
infant, data extraction was based on results in eyes rather than in infants.
Relative risk and absolute risk reduction were examined for each study and for pooled data.
2. Tasman, et al 1985: Included
In this study, 28 infants with bilateral threshold ROP (stage III ROP
and plus disease) were randomised to cryotherapy or control (no therapy).
One eye was randomised to treatment or control and the fellow eye received
the alternate therapy. Treatment occurred within 48 hours of randomisation.
Infants with unilateral disease were excluded. Outcome assessment was determined
within 14 days of therapy as satisfactory or unsatisfactory defined as
persistence of plus disease and continued development of extraretinal fibrovascular
proliferation leading to Stage 4 ROP. It is not clear if treatment allocation
was masked or if outcome assessment was independent.
3. Harris, 1976: Excluded from analysis
In this study 10 premature infants with bilateral ROP were randomised
to either retinal ablation or control. One eye was randomised using a coin
toss and the fellow eye received the alternate therapy. Treatment consisted
of either "direct xenon photocoagulation to the advancing fibrovascular
margin, transscleral cryocoagulation of this margin, transscleral cryocoagulation
of the margin plus cryocoagulation of the anterior avascular retina or
delimiting photocoagulation of the normal retina immediately behind the
vascularised ridge". Outcomes were not individually reported for the twenty
eyes as the authors intended to report only long term outcomes many years
later. The report concluded that treatment of the fibrovascular margin
often resulted in haemorrhage, and for this reason, it is no longer recommended
practice.
4. Mousel et al 1985: Excluded from analysis
Six eyes of six infants with bilateral ROP were treated with cryotherapy
at two centres. One eye was assigned to cryoablation and the fellow eye
received no therapy. In five of the six cases, treatment allocation was
non-random. The authors performed all the eye examinations and outcome
assessments.
Tasman et al 1985
Concealment of randomisation - cannot tell, probably not
Masked intervention - not possible
Complete follow up - yes (although excluded infants not described)
Masked outcome assessment - cannot tell, probably not
For outcomes in early childhood (5½ years) only data from the CRYO-ROP study were used. At 5½ years, cryotherapy reduced the incidence of unfavorable retinal structure from 44.3% to 26.3% (absolute risk reduction 18% [95% CI 27.0 - 9.1%]), RRR of 41%, and unfavorable visual acuity from 63% to 50.6% (absolute risk reduction of 12.2% [95% CI 21.2 - 3.1]), RRR of 19%. Therefore the number of eyes with threshold ROP needed to treat to prevent one early childhood unfavorable retinal structural event (NNT) is 5.5 . Similarly, the number needed to treat to prevent one unfavorable visual acuity event (NNT) in early childhood is 8. Visual field data from 78 infants at 5 of the 23 centres in the CRYO-ROP cohort and from 14 of 28 infants in Tasman's study was combined to provide information on visual field outcome in premature infants with ROP treated with cryotherapy. In the CRYO-ROP cohort the white sphere used for testing fields was 6 degrees in diameter whereas the Goldmann stimulus used in Tasman's cohort was approximately 3 degrees (25mm2 ). Analysis of the combined data show that cryotherapy reduced the visual field in sighted eyes from 58.2°± 14.5° in controls with ROP to 51.3° ± 11.8° in the treated group with ROP.
Interpretation of the data on visual fields is a little more complex.
Although the studies tested visual fields differently, both are kinetic
perimetry procedures and as such they are similar in methodology. In addition,
although only a quarter of the inception cohort from the CRYO-ROP randomised
study are reported, the cohort includes infants from five of twenty-three
participating centres. Clearly, it is difficult to make generalisations
from these data particularly as they do not include all of the original
cohort. However, these data were included in the review to provide
an insight into a possible adverse risk in the sighted eyes of infants
treated with cryotherapy for threshold ROP. Further data from the whole
cohort will be required before the significance of visual field reduction
after peripheral retinal ablation is known. It is important to note that,
compared to normal, eyes with ROP that spontaneously recovered also had
a reduction in visual field.
Study: Tasman 1985
Method: Controlled trial of treatment to one eye, allocation
uncertain
Participants: 28 infants with bilateral stage 3 ROP with plus
disease in Zone I or II.
Interventions: Cryotherapy to the avascular retina in one eye.
Outcomes: Regression of ROP vs retinal detachment.
Notes: Allocation of eyes was apparently not random. However,
treatment was not clearly based on the relative severity of the ROP.
Study Identifier: Bert 1981
Reason for exclusion: Case series, no controls.
Study Identifier: Davis 1990
Reason for exclusion: Narrative review.
Study Identifier: Fritch 1983
Reason for exclusion: Case series, no controls.
Study Identifier: Gerhard 1986
Reason for exclusion: Narrative review.
Study Identifier: Goggin 1993
Reason for exclusion: Laser compared to cryotherapy, no untreated
controls.
Study Identifier: Guilbert 1986
Reason for exclusion: Observational study, no control group.
Study Identifier: Harris 1976
Reason for exclusion: Treatment was not limited to the avascular
retina. Unable to assess outcomes from report.
Study Identifier: Hindle 1990
Reason for exclusion: Letter, no new data reported.
Study Identifier: Holmstrom 1993
Reason for exclusion: Narrative review.
Study Identifier: Iverson 1991
Reason for exclusion: Laser vs cryotherapy, no untreated controls.
Study Identifier: Kalina 1990
Reason for exclusion: Commentary, no data.
Study Identifier: Keith 1989
Reason for exclusion: Letter, contains case series data, no
controls.
Study Identifier: L'Esperance 1969
Reason for exclusion: Review of techniques, single case described,
no controls.
Study Identifier: Landers 1990
Reason for exclusion: Case series, no controls.
Study Identifier: Laser Group 1994
Reason for exclusion: No control group. Meta-analysis of laser
vs cryotherapy with original data.
Study Identifier: Mousel 1985
Reason for exclusion: Six infants with bilateral ROP. One eye
treated with cryotherapy; however, selection was based on severity.
Treatment was applied to both the avascular retina and the line of demarcation.
Ablation of the vessels at the transition is no longer recommended.
Study Identifier: Nagata 1988
Reason for exclusion: Natural history study, all severe ROP
treated with photocoagulation or cyrotherapy. No controls.
Study Identifier: NH Cryo 1986
Reason for exclusion: No randomized subjects, no control group.
Study Identifier: Nissenkorn 1984
Reason for exclusion: Case report, no controls.
Study Identifier: Patz 1971
Reason for exclusion: Narrative review.
Study Identifier: Schechter 1993
Reason for exclusion: Letter, no data.
Study Identifier: Silverman 1986
Reason for exclusion: Narrative review.
Study Identifier: Stefansson 1983
Reason for exclusion: Narrative review
Study Identifier: Topilow 1990
Reason for exclusion: No control group.
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. Multicenter 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. Multicenter trial of cryotherapy for retinopathy of prematurity. 3 1/2-year outcome--structure and function. Arch Ophthalmol 1993;111:339-344.
Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity. Snellen visual acuity and structural outcome at 5 1/2 years after randomization. Arch Ophthalmol 1996;114:417-424.
Dobson V, Quinn GE, Abramov I, Hardy RJ, Tung B, Siatkowski RM, Phelps DL. Color vision measured with pseudoisochromatic plates at five-and-a-half years in eyes of children from the CRYO-ROP study. Investigative Ophthalmology & Visual Science 1996;37:2467-2474.
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Palmer EA. Results of U.S. randomized clinical trial of cryotherapy for ROP (CRYO-ROP). Documenta Ophthalmologica 1990;74:245-251.
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Quinn GE, Miller DL, Evans JA, Tasman WE, McNamara JA, Schaffer DB. Measurement of Goldmann visual fields in older children who received cryotherapy as infants for threshold retinopathy of prematurity. Arch Ophthalmol 1996;114:425-428.
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01.01.00 Early unfavorable retinal structure (<12 mo) (RR)
01.01.00 Early unfavorable retinal structure (<12 mo) (RD)
01.02.00 Early childhood retinal outcomes (5.5 yr) (RR)
01.02.00 Early childhood retinal outcomes (5.5 yr) (RD)
01.02.01 Unfavorable retinal structure
01.02.02 Unfavorable visual acuity
01.03.00 Extent of visual fields (degrees)