The biology of retinopathy of prematurity: how knowledge of pathogenesis guides treatment

Abstract

Retinopathy of prematurity occurs because the retina of a preterm infant at birth is incompletely vascularized, and if the postnatal environment does not match the in utero environment that supported retinal development, the vessels and neural retina will not grow normally. Risk factors determined from many clinical studies and animal studies fall into 2 categories: prenatal factors and postnatal factors.

Figure 1. Treatment of ROP is based on understanding pathogenesis

1. Laser photocoagulation of ROP: Hypoxic retina anterior to neovascularization in phase II of ROP which produces VEGF and Epo is destroyed to decrease pathological blood vessel formation (promoting C to D) 2. Anti-VEGF therapy: Direct suppression of neovascularization with suppression of VEGF (promoting C to D) 3. Increasing IGF-1 to in utero levels after birth: prevents vessel loss (phase I) (preventing A to B) to prevent phase II (C) 4. Control of oxygen after preterm birth: Prevents hyperoxia induced suppression of Hif regulated factors VEGF and Erythropoietin that are necessary for normal retinal vascular development thus preventing vessel loss (preventing A to B) 5. Maintaining adequate intake of the essential fatty acid DHA after preterm birth: Promotes normal vascularization and directly inhibits neovascularization (promote B to D and C to D) 6. Monitoring postnatal growth which is based on rate of increase of postnatal IGF-1 levels: Predicts the future development of neovascular ROP (C)

Figure 2. Mouse model of oxygen-induced retinopathy

Neonatal mice are exposed to 75% oxygen from postnatal day 7 (P7) until P12 causing vessel loss and cessation of vascular growth to simulate Phase I of ROP. The central retinal microvessels are obliterated and radial vascular growth ceases. When the mice are returned to room air with incompletely vascularized retina, retinal neovascularization is seen, similar to phase II of ROP. Vessel proliferation is maximum at P17 then regresses, which also occurs in human ROP. These changes can be quantified in retinal flat mounts.