Imaging and Functional Correlates of Fibrosis in Neovascular Age-Related Macular Degeneration: A Systematic Review

Kimberly Spooner^1,2,3,4Samantha Fraser-Bell^2,5,6Dun Jack Fu⁴Livia Faes⁴Francesco Romano⁷Mariano Cozzi^7,8Andrew A Chang^2,6Sobha Sivaprasad^4*

• ¹The University of Sydney, Darlington, Australia
• ²The University of Sydney Save Sight Institute, Sydney, Australia
• ³University of Technology Sydney Graduate School of Health, Sydney, Australia
• ⁴Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom
• ⁵Royal North Shore Hospital, St Leonards, Australia
• ⁶Sydney Hospital and Sydney Eye Hospital, Sydney, Australia
• ⁷Ospedale Luigi Sacco-Polo Universitario, Milan, Italy
• ⁸UniversitatsSpital Zurich Augenklinik und Poliklinik, Zürich, Switzerland

Registration: PROSPERO CRD420231132016 Background: Despite intravitreal anti–vascular endothelial growth factor (VEGF) therapy being the standard of care for neovascular age-related macular degeneration (nAMD), long-term visual decline remains common, with subretinal fibrosis representing a major cause of irreversible vision loss. Objective: To systematically evaluate how imaging-defined fibrosis in nAMD is defined and quantified, its incidence under anti-VEGF therapy, associated baseline associations, and its impact on visual outcomes. Methods: We systematically searched MEDLINE, Embase, CENTRAL, and Scopus through September 2025 for studies reporting imaging-defined fibrosis in anti-VEGF–treated nAMD. Eligible studies included randomized controlled trial secondary analyses, prospective and retrospective cohorts, and registries. Two reviewers independently extracted data on fibrosis definitions, imaging modalities, associations, and functional outcomes. Random-effects meta-analyses pooled the best-corrected visual acuity (BCVA) difference (ETDRS letters) and the odds ratio for incident fibrosis. Risk of bias was assessed using the Quality in Prognosis Studies (QUIPS) tool, and the certainty of evidence was evaluated using the GRADE approach. Results: Fifty-eight studies were included (12 randomized trial secondary analyses, 18 prospective studies, and 28 retrospective studies). Across studies, subretinal fibrosis developed in approximately 10– 15% of eyes within 2 years and 40–50% by 5 years of anti-VEGF therapy, with a lower incidence under fixed or treat-and-extend regimens compared with pro re nata dosing. Eyes with fibrosis had consistently worse visual outcomes (pooled BCVA difference −29 ETDRS letters; 95% CI −47 to −12). Key associations included type 2 macular neovascularisation (OR 5.7), subretinal hyperreflective material (OR 2.7), intraretinal fluid (OR 3.6), and large haemorrhage (OR 2.3), while subretinal fluid appeared protective (OR 0.6). Definitions and