Retinopathy of prematurity (ROP) is a vasoproliferative disorder of the premature retina that causes visual loss and blindness by the consequent effects of scarring and traction, creating macular displacement, macular distortion and retinal detachment.
ROP is the leading ocular cause of childhood blindness in developed nations and occurs predominantly in the very low birthweight infant (<1,250g).
The incidence of ROP blindness in infants is relatively low (1 in 820) due to high standard neonatal care, appropriate screening and effective treatments. Most infants (90%) develop mild self-limiting ROP which resolves without intervention, 50% of those under 24 weeks gestation develop severe ROP with visual impairment. The world-wide prevalence of blindness due to ROP is 50,000.
Retinal vascularisation commences at 18 weeks’ gestation at the disc and reaches the ora serrata at 40-44 weeks. Vascularisation is stimulated by vascular endothelial growth factor (VEGF) which is induced by normal physiologic intrauterine fetal hypoxia.
Following preterm birth, the post- natal environment doesn’t match the in-utero environment that supported retinal vascular development. Inevitable hyperoxia (to sustain life and reduce the incidence of cerebral palsy) downregulates VEGF, arresting vascularisation and, combined with loss of the benefits of the normal maternal-fetal interaction, retinal vaso-obliteration results. Neurogenesis proceeds despite arrested vascular development.
At 32 weeks, the retina becomes metabolically active and again becomes hypoxic, upregulating VEGF, leading to pathologic vascularisation.
ROP is classified according to site. Zone 1 being centred at the optic disc and extending with a radius of twice the disc to macula distance, Zone 2 an annulus outside Zone 1 extending to the nasal ora and Zone 3 the most peripheral crescent of the temporal retina.
‘Plus’ disease relates to vascular activity and is recognised by venous congestion and arterial tortuosity in the posterior retinal vasculature. ‘Pre-plus’ changes are less prominent.
Stages of ROP are defined by the appearance at the vascular/avascular junction. Stage 1 resembles a line, Stage 2 a ridge, Stage 3 extraretinal neovascularisation, Stage 4 partial retinal detachment (4a macula attached, 4b macula detached) and Stage 5 total retinal detachment.
In 1988 retinal ablation by cryotherapy was recommended for extensive Stage 3+ ROP with a 50% reduction in unfavourable anatomic outcome and improved visual results (CRYO-ROP) and in the 1990s transition to laser photoablation occurred; both modalities indirectly reducing VEGF and pathologic vascularisation and subsequent cicatrisation leading to Stages 4 and 5 ROP.
In 2003, earlier laser intervention was recommended to treat less extensive Stage 2+ and 3+ ROP and this became the standard of care (ET-ROP). Success rates of 90% are attainable for Zones 2 and 3 under these guidelines.
In the past two decades, advances in neonatal care has resulted in significant increased survival for very low birthweight infants and a greater incidence of more severe ROP-Aggressive Posterior ROP. Conventional laser treatment is only effective in 50-60% of these cases and causes undesirable loss of peripheral visual field and greater myopia.
In 2011, intravitreal bevacizumab was reported as significantly beneficial in the treatment of Stage 3+ ROP in Zones 1 and 2, with a particularly greater benefit in Zone 1, when compared to conventional laser ablation (BEAT-ROP). Bevacizumab has not been approved for intraocular use and also results in significant suppression of VEGF in the peripheral circulation for many weeks in the neonate, having implications for neurodevelopment and respiratory and renal systems.
Ranibizumab is a smaller molecule that targets VEGF-A and, importantly, has a minimal and relatively transient suppressive effect on systemic circulating VEGF in the neonate following intravitreal injection.
The RAINBOW trial comparing ranibizumab 0.1mg and ranibizumab 0.2mg with conventional laser for Zone 1 and Zone 2 showed significantly superior treatment success (80% ranibizumab, 66% laser) and fewer unfavourable structural outcomes and need for re-treatment with ranibizumab. Death, systemic and ocular adverse events were infrequent and evenly distributed among the treatment groups.
RAINBOW two-year outcomes, recently reported, have shown persistence of the superior structural outcomes, less high myopia (5% ranibizumab vs 20% laser) and better vision quality of life scores following ranibizumab 0.2mg. Ranibizumab did not appear to affect systemic nor neurologic development.
It is timely that the TGA has approved Lucentis (ranibizumab) for ROP, given an increasing population of at risk very low birthweight infants in whom laser outcomes are suboptimal and concern exists regarding systemic VEGF suppression with the use of other anti-VEGF drugs. A caveat with anti- VEGF therapy in ROP is late reactivation necessitating ongoing follow up.
ABOUT THE AUTHOR:
Name: Dr Jeremy Smith
Qualifications: FRANZCO, FRACS
Business/organisation: Royal Prince Alfred Hospital, Westmead Hospital, Children’s Hospital at Westmead
Position: Paediatric ophthalmologist
Location: Sydney
Years in profession: 30
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