Current evidence and outcomes for retinopathy of prematurity prevention: insight into novel maternal and placental contributions

Abstract

Retinopathy of prematurity (ROP) is a blinding morbidity of preterm infants, which represents a significant clinical problem, accounting for up to 40% of all childhood blindness. ROP displays a range of severity, though even mild disease may result in life-long visual impairment. This is complicated by the fact that our current treatments have significant ocular and potentially systemic effects. Therefore, disease prevention is desperately needed to mitigate the life-long deleterious effects of ROP for preterm infants. Although ROP demonstrates a delayed onset of retinal disease following preterm birth, representing a potential window for prevention, we have been unable to sufficiently alter the natural disease course and meaningfully prevent ROP. Prevention therapeutics requires knowledge of early ROP molecular changes and risk, occurring prior to clinical retinal disease. While we still have an incomplete understanding of these disease mechanisms, emerging data integrating contributions of maternal/placental pathobiology with ROP are poised to inform novel approaches to prevention. Herein, we review the molecular basis for current prevention strategies and the clinical outcomes of these interventions. We also discuss how insights into early ROP pathophysiology may be gained by a better understanding of maternal and placental factors playing a role in preterm birth.

Clinical spectrum of blunted foveal contour

“…ROP is a disorder that affects the maturation of the retinal vasculature causing delayed and anomalous vascularization in premature infants. 36 – 38 Higher incidences of strabismus, cataracts, glaucoma, retinal detachment, macular ectopia, and decreased VA have been described. 9 , 36 – 38 Patients with a history of prematurity, with or without a diagnosis of ROP, and with or without macular ectopia, may show a characteristic blunting of the foveal contour.…”

“… 36 – 38 Higher incidences of strabismus, cataracts, glaucoma, retinal detachment, macular ectopia, and decreased VA have been described. 9 , 36 – 38 Patients with a history of prematurity, with or without a diagnosis of ROP, and with or without macular ectopia, may show a characteristic blunting of the foveal contour. Patients born prematurely may have retention of the inner retinal layers at the foveal center with ONL widening and photoreceptor elongation, which is typically asymptomatic with normal or near-normal VA. 9 , 18 , 19 , 39 Clinical examples are shown in Figures 6 and 7 .…”

PFKFB3: A Potential Key to Ocular Angiogenesis

“…Considering the fundamental role of VEGF in angiogenesis, anti-VEGF therapy has become increasingly popular in the treatment of ocular angiogenesis. In fact, anti-VEGF therapy has been widely used in current clinical applications, including ROP, wet AMD and PDR ( Alon et al, 1995 ; Mintz-Hittner and Kuffel, 2008 ; Penn et al, 2008 ; Mintz-Hittner et al, 2011 ; Carroll and Owen, 2020 ). However, concerns still exist on the potential local and systemic side effects of intraocular anti-VEGF therapy ( Geloneck et al, 2014 ; Wu and Wu, 2018 ; Natarajan et al, 2019 ; Raghuram et al, 2019 ).…”

“…Intraocular injection of an inhibitor of VEGF may interrupt ocular development and vasculature reconstruction. Furthermore, the potential leakage of anti-VEGF drugs into the circulation may produce systemic side effects ( Carroll and Owen, 2020 ).…”

The Serine Protease HTRA-1 Is a Biomarker for ROP and Mediates Retinal Neovascularization

“…While post-natal oxygen is the most modifiable risk, limiting post-natal oxygen may confer higher mortality (Carlo et al, 2010 ; Stenson et al, 2013 ; Owen and Hartnett, 2014 ). Beyond addressing these risk factors directly, numerous therapeutic interventions have been evaluated for efficacy in ROP prevention, though none have shown significant benefit as reviewed by Carroll and Owen (Carroll and Owen, 2020 ). As a result, current interventions are unable to modify risk and instead target ROP once the retinal disease is present and we are unable to restore normal retinal architecture and visual function.…”