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Advances in Retinopathy of Prematurity: New Treatments and Screening Strategies to Prevent Blindness in Preterm Infants

  • Definition and Epidemiology:

    • Retinopathy of Prematurity (ROP) is a multifactorial retinal vascular disorder affecting preterm infants, previously known as retrolental fibroplasia.

    • Incidence in the US increased from 14.70% to 19.88% between 2000 and 2012.

    • Globally, ROP causes ~50,000 cases of blindness in children annually.

    • Higher prevalence in male infants due to pathophysiological fragility and screening criteria.

  • Pathophysiology:

    • Two phases of ROP:

      • Vasoobliterative (ischemic) phase (<32 weeks gestation): Decreased VEGF and IGF-1 lead to vasoconstriction and arrested vessel growth.

      • Vasoproliferative phase (>32 weeks gestation): Hypoxia induces increased VEGF, IGF-1, and neovascularization, potentially causing retinal detachment.

    • Sequelae include inflammation, hemorrhage, fibrous bands, macular dragging, and blindness.

  • Screening Guidelines:

    • Systematic screening is critical to identify at-risk infants and those requiring treatment, with sensitivity up to 100% using specific methods.

    • International Classification of Retinopathy of Prematurity (ICROP) (updated 2021):

      • 5 stages: Demarcation line (1), elevated ridge (2), vascularized ridge (3), partial retinal detachment (4), complete retinal detachment (5).

      • 3 zones: Zone I (most posterior), Zone II, Zone III (peripheral).

      • Plus disease: Tortuosity and dilatation of retinal arteries; preplus indicates milder changes.

      • Aggressive ROP (AROP): Can occur in larger preterm infants and extend beyond posterior retina.

    • Type I ROP (treatment threshold): Zone I, any stage with plus disease; Zone I, stage 3 without plus disease; Zone II, stage 2 or 3 with plus disease.

  • Diagnosis:

    • Binocular indirect ophthalmoscopy remains the gold standard.

    • Emerging tools include artificial intelligence (AI) (e.g., convolutional neural networks) to reduce interobserver variability in diagnosing preplus/plus disease.

    • Telemedicine (e.g., SUNDROP program) uses portable wide-field fundus cameras (130-degree) for remote screening, with sensitivity up to 100% and specificity up to 99.8%.

    • Predictive biomarkers (metabolites, cytokines, noncoding RNAs, gut microbiota) are under investigation for earlier diagnosis.

  • Treatment Options:

    • Laser Photocoagulation:

      • Primary treatment for proliferative ROP, reducing hypoxia by ablating peripheral avascular retina.

      • Advantages over cryotherapy: Less pain, inflammation, and refractive errors (myopia, astigmatism, hyperopia).

      • Adverse effects: Corneal edema, intraocular hemorrhage, cataract, ocular ischemia, limited visual field.

    • Cryotherapy:

      • Historical treatment; reduced progression to retinal detachment by 50% but is time-consuming and proinflammatory.

    • Intravitreal Anti-VEGF Injections:

      • Agents: Bevacizumab (Avastin), Ranibizumab (Lucentis), Aflibercept (Eylea).

      • Bevacizumab (BEAT-ROP trial): 0.625 mg effective for Zone I ROP, lower retreatment rates, reduced myopia (1.7% vs. 36.4% with laser).

      • Ranibizumab (RAINBOW trial): 0.2 mg potentially superior to laser; does not decrease systemic VEGF levels.

      • Aflibercept (FIREFLEYE trial): 85% success rate.

      • Dosage concerns: Lower doses (e.g., 0.031 mg bevacizumab) effective but may increase retreatment rates; systemic VEGF suppression may affect neurodevelopment.

      • Anti-VEGF promotes normal intraretinal vascularization, unlike laser’s destructive approach.

    • Surgery:

      • Indicated for stages 4A, 4B, and 5 ROP.

      • Lens-sparing vitrectomy preferred over lensectomy to reduce complications like aphakia; success rates 84–100% for stage 4A, 14.3–45.5% for stage 5.

      • Anti-VEGF can be used pre-surgery to reduce vascularization.

  • Prevention and Future Directions:

    • Prophylactic measures: Minimize prolonged ventilation and uncontrolled oxygen supplementation.

    • Supplemental oxygen: Higher saturation (96–99%) in the vasoproliferative phase may reduce progression (STOP-ROP trial).

    • Pharmacological interventions:

      • Propranolol: Beta-blocker suppressing VEGF; under investigation for prethreshold ROP.

      • Antioxidants (e.g., D-Penicillamine): Limited evidence for VEGF suppression.

      • Vitamin A: Trend toward lower ROP incidence; no established guidelines.

      • Vitamin E: Inconsistent results; use discontinued due to morbidity risks.

      • Omega-3 fatty acids: Fish oil reduced ROP severity; lacks large-scale trials.

      • COX inhibitors (e.g., ketorolac): Mixed results in preventing threshold ROP.

  • Global Disparities:

    • High-income countries favor anti-VEGF as initial treatment; middle-income countries prefer laser for recurrent ROP.

    • Developing countries face gaps in screening and treatment due to resource limitations, contributing to an “epidemic” of ROP-related blindness.

Citation

Chaaya C, Hoyek S, Patel NA. Update on Management of Retinopathy of Prematurity: A Review. Int Ophthalmol Clin. 2025;65(1):81-90. doi:10.1097/IIO.0000000000000552