Retinopathy of prematurity (ROP) is a major cause of blindness in children in the Western World. Premature birth disturbs normal vascular development. Children with more avascular retina have higher risk of developing pathologic neovascularization (NV) and
severe ROP. The present standard of care has been laser or cryoablation of the peripheral avascular retina in order to control the
pathologic neovascularization. Despite the undeniable benefit of these primitive yet time tested interventions, there is incomplete effectiveness and significant morbidity. Molecular understanding of normal and abnormal vascular development has highlighted the
role of VEGF and suggested a role of anti-VEGF therapy.1 The effectiveness of anti-VEGF therapy in AMD and other neovascular diseases has generated excitement about application of ‘‘gentler’’ anti-VEGF therapies for ROP. The Bevacizumab Eliminates the
Angiogenic Threat of Retinopathy of Prematurity study gave us excitement, but also caution about delayed normal vascular development and NV formation.(2)

It is natural to think that in a developing organ, the exact level of VEGF inhibition will be important in order to control pathologic NV, while at the same time allowing normal vascular development to proceed. Lutty et al.3 has demonstrated this principle in a dog model of ROP using an agent that blocks simultaneously VEGF-A, VEGF-B, and placental growth factor. In this issue, McCloskey et al.4 show similar findings using VEGF blockade alone. In a well controlled study in rodents, they show that more anti-VEGF blockade is not better but worse, leading to increased avascular retina and delayed atypical NV formation with activation of compensatory angiogenic signals that may not respond to subsequent VEGF blockade. They also showed that anti- VEGF therapy was associated with reduced weight gain. Their study highlights the need for more systematic research regarding the appropriate dose and monitoring of anti-VEGF in ROP babies in order to have a safer and more effective therapy than the current primitive ablative approaches.