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Before considering anti-vascular endothelial growth factor (VEGF) agents in preterm infants, more studies are needed to determine long-term effects on safety, proper doses, or even the type of anti-VEGF agent or other drug.
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Retinopathy of prematurity phenotypes may vary throughout the world based on environmental factors and potential differences in genetic variants. These considerations are important when comparing outcomes from clinical reports after anti-VEGF therapy.
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Although there is promise
Vascular Endothelial Growth Factor Antagonist Therapy for Retinopathy of Prematurity
Section snippets
Key points
The problem: retinopathy of prematurity is increasing worldwide and has different phenotypes
With increases in preterm births, ROP has become one of the leading causes of childhood blindness worldwide.17 In the United States, ∼14% of childhood blindness is attributed to ROP and in some developing nations estimates are greater than 20%.18 In addition, some countries have developed the ability to save preterm infants but lack resources to regulate oxygen and are experiencing not only cases of ROP from extreme prematurity but also additional cases of ROP in larger and older infants from
Current treatment for retinopathy of prematurity and reasons for better therapies
When ROP was first diagnosed as retrolental fibroplasia in the 1940s in the United States, studies in animal models were performed that revealed that high oxygen at birth was a cause.21 Oxygen damaged newly formed retinal capillaries and led to broad areas of avascular retina.21, 22 When the infant was moved from high oxygen to a relatively hypoxic environment, cells within the avascular retina were stimulated by hypoxia and thought to increase the expression of angiogenic growth factors.23 Now
Toward a treatment solution
It is important to review new evidence regarding the pathophysiology of ROP that has been realized since early studies by Ashton and colleagues,48 Patz,21 and preclinical studies before the FDA approval of anti-VEGF agents in adult diseases. Because it is not possible to safely obtain tissue or vitreous samples from the preterm infant eye to study ROP without risks of bleeding, cataract, or inoperable retinal detachment,42 animal models of OIR have been used. It is important to know strengths
The bevacizumab eliminates the angiogenic threat of retinopathy of prematurity study
Although several clinical series had been reported previously, the Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEAT-ROP) was the first published clinical trial that tested intravitreal anti-VEGF antibody, bevacizumab (0.625 mg in 0.025 mL), compared with laser treatment in 150 infants.59 Infants rather than eyes were enrolled to reduce confounding from crossover effects of the antibody. A benefit for infants with zone I/posterior zone II, stage 3+ ROP was
Pro: Evidence That Inhibiting Vascular Endothelial Growth Factor Inhibits Intravitreal Angiogenesis in Severe Retinopathy of Prematurity
ROP has been characterized by 2 phases based on clinical observations and animal models.48, 61, 62 Human ROP also has a third, fibrovascular phase, in which retinal detachment occurs. Few animal models reflect this. The first “epidemic” of ROP occurred in the United States and the United Kingdom in the 1950s. Using a model in kittens, Ashton described phase 1 as high oxygen-induced vaso-obliteration and phase 2 as later hypoxia-induced vasoproliferation.48 Since then, with changes in neonatal
Considerations regarding adult/preterm infant size and dose considerations
No anti-VEGF agent has been FDA-approved for treatment of ROP. Ranibizumab (Genentech) or aflibercept (Regeneron) are the FDA-approved agents for adult eye diseases. The BEAT-ROP clinical trial used bevacizumab, which has not been FDA-approved for any eye disease, but has been tested head-to-head with ranibizumab in a clinical trial for adult AMD and shown to be noninferior.77 Bevacizumab is a humanized monoclonal antibody to VEGF that was tested as an anticancer agent but was not formally
Guidelines if considering anti-vascular endothelial growth factor treatment
Bevacizumab is not FDA-approved. However, there are more studies reported on bevacizumab than on ranibizumab, for which there is no clinical trial for ROP reported to date (Table 7). However, there have been opinions as to which anti-VEGF agent is optimal. Bevacizumab causes longer-term reduction in systemic VEGF levels in adults compared with ranibizumab and, therefore, may be more damaging to the preterm infant. However, in preterm infants, ranibizumab also reduced serum VEGF. Ranibizumab
Future
Studies are ongoing to determine pharmacologic approaches that target signaling downstream of VEGF receptors to safely and effectively inhibit pathologic angiogenesis without interfering with ongoing retinal vascular development. More clinical studies are needed to determine potential safe doses of anti-VEGF agents, and dose escalation studies are being considered. In addition, studies to promote normal retinal vascular development may be considered through the use of nutrients, such as
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Disclosure: NIH grants: NEI R01EY017011, NEI R01EY015130. March of Dimes grant: FY-13-75.