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Review Retina The Role of Anti-vascular Endothelial Growth Factor Agents in the Management of Retinopathy of Prematurity Christopher D Conrady and M Elizabeth Hartnett Department of Ophthalmology and Visual Sciences, John A Moran Eye Center, University of Utah, Utah, US R etinopathy of prematurity is a vasoproliferative disease of preterm infants and has effects on infant vision and overall development. It is increasing worldwide with advances in perinatal care. In the following manuscript, we review the pathophysiology and possible treatments. We focused on anti-vascular endothelial growth factor (VEGF) agents and a few select other candidates. Keywords Retinopathy, prematurity, anti-VEGF, preterm, premature Disclosure: Christopher D Conrady has nothing to disclose in realtion to this article. M Elizabeth Hartnett consulted for SanBio in the last year but has nothing to disclose in relation to this article. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors. Acknowledgements: This work was supported in part by an unrestricted grant from Research to Prevent Blindness to the University of Utah’s Department of Ophthalmology and Visual Sciences and National Eye Institute R01 grants EY015130 and EY017011 to MEH. M. Elizabeth Hartnett has received NIH grant support as principal investigator for the following: R01EY015130, R01EY017011, T35EY026511. The authors would also like to thank Lane Bennion for the medical renderings. Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. Received: November 2, 2016 Accepted: January 2, 2017 Citation: US Ophthalmic Review, 2017;10(1): 57–63 Corresponding Author: M Elizabeth Hartnett, Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, 65 Mario Capecchi Dr., SLC, UT, 84108, US. E: Retinopathy of prematurity (ROP) is a vasoproliferative disease of preterm infants that continues to be a major cause of preventable blindness worldwide despite concerted efforts to reduce its frequency. 1 In developed countries, advances in perinatal care, a reduction in mortality rates of preterm infants, and increased surveillance for ROP has had unintended consequences and has resulted in nearly a 10-fold increase in ROP cases worldwide in the past 20 years. 2–4 In the United States, nearly 16% of premature infants hospitalized for more than 28 days develop ROP, and ROP is responsible for 6–20% of childhood blindness in the country. 1,5,6 As a result, the National Eye Institute estimates that approximately 14,000 neonates a year in the United States develop ROP, and of these approximately 400–600 become completely blind. 7 In 2010, a meta-analysis estimated 184,700 new cases of ROP worldwide of which 20,000 babies became blind, and an additional 12,300 developed mild to moderate visual impairment due to the disease. 8 Besides the obvious toll on patients and families, blindness acquired in infancy has a significant economic impact as well. In Peru, early treatment of ROP to prevent neonatal blindness resulted in nearly a $200,000 cost savings to the society (in US dollars). 9 The authors of the study further estimated that this would result in $516 million cost savings across a generation in Peru. 9 This finding has been reiterated in the developed world as well. 10 Consequently, ROP is a leading cause of childhood blindness worldwide with a significant economic impact. 11 Many attempts have been made to quell ROP due to its consequences both for the patient and community. Oxygen monitoring and regulation to reduce high oxygenation has had a noticeable effect on reducing the risk of developing ROP in preterm infants. 12 Furthermore, teleretinal imaging has shown promise in detecting ROP of any stage, with sensitivities of 76–97% and specificities of 89–100% in a meta-analysis. 13 While this will presumably make ROP classification more accessible to areas of the world lacking trained specialists, it is unclear what impact it will have on the disease treatment and outcomes. One burden is the concern that there are insufficient numbers of trained ophthalmologists to treat infants with severe ROP. 14 Despite these recent advances in surveillance and treatment, the disease remains an important cause of childhood blindness worldwide and likely will be for the foreseeable future. Role of vascular endothelial growth factor in angiogenesis Vascular endothelial growth factor (VEGF) is an important growth factor in angiogenesis and lymphangiogensis that promotes vessel sprouting, endothelial cell growth, survival, and homeostasis. 15,16 VEGF consists of a family of six subtypes that signal through activation of three distinct receptors that have been discussed extensively elsewhere (Figure 1). 17–19 Dysregulation of VEGF-A and its activation of VEGF receptor (VEGFR)-1 and -2 are believed to be an underlying mechanism in ROP, and for simplicity, VEGF-A will subsequently be referred to as VEGF throughout TOU CH MED ICA L MEDIA 57