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Indications for treatment of ROP

The history and evidence underpinning the different treatments for ROP and when they should be applied.
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The screening examination for retinopathy of prematurity leads to a clear detection of the stage of ROP in one or both of a baby’s eyes. The expert ophthalmologist or trained grader then uses this result to make
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one of three key management decisions: Treat immediately, plan to rescreen to see if progression to sight-threatening ROP takes place, or discharge if the baby is no longer at risk of sight-threatening ROP. Timely decision making on ROP treatment is needed to prevent severe vision loss.
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In ROP, the avascular retina produces vascular endothelial growth factors (VEGF) which lead to excessive and abnormal growth of retinal vessels and, in some cases, ROP progression and retinal detachment, with a poor visual outcome. The basic principle of ROP treatment is the complete ablation (a form of destruction) of the avascular retina.
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Timing of the treatment is important so that it is early enough to reduce ROP progression and retinal detachment. Completion and follow up of treatment is equally important to avoid retinal detachment. Scientific evidence has led to significant changes in ROP treatment options over the last several decades.
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Three main treatment types have been considered: Cryotherapy, Transpupillary laser, and anti-VEGF injection.
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Cryotherapy: An important, multi-centre randomised controlled trial called CRYO-ROP tested cryotherapy for ROP in late 1980s. Cryotherapy for ROP uses a probe through the sclera to deliver freezing temperatures which destroy (or ablate) the avascular fringe retina. In the CRYO-ROP trial, cryotherapy was allocated to one eye with the fellow eye as control with no treatment. The findings showed an overwhelming effectiveness of cryotherapy on eyes with ROP that had five contiguous or eight non-contiguous clock hours of stage 3 with plus disease. This was referred to as threshold disease and an indication to apply cryotherapy.
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However, a 15 year follow up study of the babies from the CRYO-ROP trial showed some unfavourable structural outcomes in 27% of the treated eyes and a visual acuity outcome of 20/200 or worse (severe visual impairment) in about 44% of the treated eyes.
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Transpupillary laser: At present, based on clinical studies, the choice of treatment has shifted from cryotherapy to transpupillary laser treatment. This can target treatment precisely to the affected areas of the retina. It is usually carried out by a diode or green laser under sedation and with pain relief. A laser is portable and can be used on other retinopathies so it can be a worthwhile investment for an ophthalmic unit.
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The green laser has some reported advantages over diode: Less pain for the baby due to less penetration as the green laser uses a shorter wavelength. It is easier to see spots on the retina as they are whiter. Less power is required and the scars are less dense. In addition, most retina specialists have a green laser for diabetic retinopathy so there can be multiple uses in resource limited clinics. In 2003, the Early Treatment for ROP (ETROP) Cooperative Group undertook a randomised controlled trial to determine the best timing for laser treatment.
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The study compared laser treatment of eyes reaching threshold disease where the risk of progression to retinal detachment was 50% - as recommended by the CRYO-ROP study - with ‘pre-threshold’ disease, that is Zone I ROP of any stage short of threshold, which has a risk of progression to retinal detachment of 15%.
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The findings from the ETROP trial have led to the indications for initiating laser treatment that are in current use for type 1 ROP,
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or sight-threatening ROP, that is: Zone I stage 3 without plus disease, or Zone I any stage with plus disease, or Zone II, stage 2 or 3 with plus disease. In cases of aggressive posterior ROP, aggressive laser treatment needs to be closely followed up for recurrence with retreatment undertaken as necessary. Crucially, treatment must be carried out as soon as possible, within 24 to 48 hours, before any vitreoretinal traction begins. This timing may be a challenge in some areas, particularly where transfer for treatment is needed. An upper limit of 72 hours is set by when treatment must have taken place. All infants treated with laser need to be followed up to ensure that the ROP has completely regressed.
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If the signs persist, or return, further laser treatment or anti-VEGF injections can be given. Failure of the signs to regress is much more common in aggressive posterior ROP and close follow up is essential. Crucially, treatment must be carried out as soon as possible, within 24 to 48 hours.
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Stages 4 and 5 of ROP are complications (retinal detachment) and screening programmes should strive to ensure that no baby progresses to these stages. Treatment before stage 4 can produce good results which is why timing is crucial. Complex vitreoretinal surgery is required for stages 4 and 5. The visual results can be good for stage 4 ROP but are usually very poor after surgery for stage 5. A milder disease called type 2 ROP - zone I stage 1 or 2 without plus disease, or zone II stage 3 without plus disease - should be observed closely. Myopia is a long-term complication of laser but about two thirds of treated eyes achieve a vision of 20/40 or better.
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Preterm babies must be followed up as they have a higher prevalence of refractive error.
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Anti-VEGF injection: In ROP, the growth of abnormal new vessels is largely due to VEGF and new approaches to treatment include intravitreal injection of anti-VEGF drugs. Four types of anti-VEGF drugs have been used for acute ROP and their continued use is guided by the evidence. Anti-VEGF treatment can be administered quickly in two to three minutes per eye compared to 40 minutes per eye in laser and does not require specialised equipment. However, it must be used cautiously in premature babies because VEGF has a key role in the normal development of many organs including the brain, kidneys and lungs.
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In addition, anti-VEGF ROP treatment trials to-date have not recruited enough babies or followed them up for long enough to provide conclusive evidence that these agents are safe and do not cause long term harm, such as neurodevelopmental delay.
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The BEAT-ROP randomised controlled trial showed that the anti-VEGF injection bevacizumab was effective in successful regression of zone I or zone II posterior ROP. In this trial intravitereal injection of 0.625 milligrams of bevacizumab was compared with laser treatment as the control. There have been several concerns raised about the design of the study. Other trials have documented late recurrence of ROP after anti-VEGF treatment. Therefore, at present, anti-VEGF treatment should be reserved for a certain subgroup of sight-threatening ROP cases where laser is impossible or has failed. Further studies are taking place to establish an understanding of the ideal dosage of anti-VEGF to minimise any systemic side effects for preterm babies.
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Lens sparing vitrectomy can be undertaken in cases of retinal detachment in ROP when visual outcome is usually poor but, ideally, all efforts are directed toward the early detection and management of ROP.
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In conclusion: Following screening and early detection, laser treatment remains the gold standard for treatment of sight-threatening ROP. Anti-VEGF agents still need to be approached with caution because of the risk of late recurrence of abnormal vascularisation and uncertainty about dosage and systemic side effects.

Retinopathy of prematurity (ROP) was first described in 1942 but it took more than four decades before an effective treatment, ablative cryotherapy, was identified. Treatment approaches continue to evolve.

Cryotherapy uses a probe through the sclera to deliver freezing temperatures which destroy (ablate) the avascular peripheral retina. Originally used for proliferative diabetic retinopathy, cryotherapy became the treatment of choice for ROP but poor outcomes were a cause for concern. At present, based on clinical studies, the choice of treatment has shifted from cryotherapy to transpupillary laser. New approaches to treatment include anti-VEGF medication although there are doubts about long-term safety and the evidence so far is inconclusive.

Over the years our understanding of ROP has grown in terms of risk factors, natural history, and indications for treatment and their outcomes. A key landmark was the International Classification of ROP which allowed comparison between studies and over time, and agreement on the constellation of signs at which treatment is recommended. The Classification was revised in 1995, and is currently undergoing a further revision.

Evidence timeline for ROP disease and treatment

Adapted from Sternberg & Durrani 2017
  • 1942: First observation of retrolental fibroplasia (original name for ROP).
  • 1952 – 1953: First description of the role of oxygen in ROP.
  • 1984: Publication of the first International Classification of Retinopathy of Prematurity. This was important, as earlier reports on treatment were difficult to interpret because there was no uniform grading system to report changes in the retina.
  • 1988: Publication of findings from the Cryotherapy for ROP trial (CRYO-ROP study) for threshold ROP.
  • 1994: Meta-analysis by the Laser ROP Study Group concludes that laser is as effective as cryotherapy.
  • 2003: The ETROP trial findings led to the recommendation that treatment be given before threshold disease develops, when Type 1, pre-threshold disease is present. This means that more infants now require treatment.
  • 2011: The BEAT-ROP trial studied the efficacy of intravitreal Bevacizumab (anti-VEGF injection).
  • More recent studies are addressing the optimal dose and anti-VEGF agent to use, to plan trials to explore their effectiveness and long-term ocular and systemic complications.

In the video on this step we show how the evidence on ROP treatment has changed over time, from cryotherapy to laser and anti-VEGF medication. As you watch, consider what this changing evidence means for your setting in terms of resources and infrastructure requirements.

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Retinopathy of Prematurity: Practical Approaches to Prevent Blindness

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