Nikisha A. Kothari, MD and Audina M. Berrocal, MD

Retinopathy of prematurity (ROP), a disease of very low birth-weight premature infants, is characterized by abnormal vascularization and angiogenesis of the retina. ROP is a leading cause of vision loss and blindness evoked by retinal detachment and temporal dragging of the macula.¹ The prevalence of blindness from ROP is estimated to be 50,000 worldwide. Because of the survival of more low birth-weight infants, the absolute number of infants with ROP has consequently increased.¹

Retinal vascularization begins at 16 weeks gestation from the optic nerve and completes temporally at 40 weeks gestation. Infants born prior to 40 weeks may have abnormal avascular peripheral retina or ROP. The location of retinal vascularization defines the zone; zone 1 is a circle twice the distance from the center of the disc and center of the macula extending from the disc; zone 2 encircles zone 1 extending to the nasal ora; and zone 3 is the remaining crescent shaped temporal retina. The severity of disease, or staging, is determined by the appearance of the vasculature at the interface between the avascular and vascular retina. The interface is a line in stage 1, a ridge in stage 2, and a ridge with extraretinal neovascularization in stage 3. Furthermore, partial retinal detachment is classified as stage 4 disease and complete retinal detachment as stage 5.² Plus disease is the presence of 2 or more quadrants with dilated and tortuous vessels, which current guidelines emphasize when determining the threshold to treat.^2,3 Aggressive posterior ROP (AP-ROP) is defined as tortuous blood vessels in all 4 quadrants out of proportion to the extent of peripheral retinopathy and implies a poorer prognosis.² This classification of ROP is important to understand as it gives us a common language and guides management and the threshold to treat.

Treatment

Based on the Early Treatment of ROP study, treatment should be initiated in eyes with zone 1 ROP, any stage, with plus disease, zone 1 ROP that is stage 3 without plus disease, and zone 2 ROP that is stage 2 or 3 with plus disease.3 Conventional treatment is peripheral retinal ablation by laser therapy, which has largely replaced cryotherapy over the years. Laser photocoagulation results in reduced rates of retinal detachment and improvement in visual acuity outcomes.⁴ However, photocoagulation therapy has limitations, particularly in zone 1 and AP-ROP cases that require treatment adjacent to the macula and progress rapidly.⁵ Because of limitations of conventional therapy, anti-vascular endothelial growth factor (VEGF) agents have been proposed as an alternative therapy with early, promising results.⁵

In normal retinal development, VEGF is released in response to increased oxygen demand in order to facilitate vascularization of the peripheral retina. In ROP, the imbalance of VEGF levels divided into 2 phases is the cause of disease development and progression. In the vaso-obliterative phase, 22 to 30 weeks postmenstrual stage, hyperoxia caused by increased postnatal arterial oxygen levels and supplemental oxygen results in failure of the peripheral retinal vasculature to develop. In the vaso-proliferative phase, 31 to 40 weeks postmenstrual stage, ischemia in the avascular retina results in angiogenesis and the production of VEGF.⁶ While abnormal vasculature in ROP often spontaneously regresses without intervention, it can progress to traction and retinal detachment. Extremely high levels of VEGF are found in the vitreous of eyes with stage 4 disease, confirming the upregulation of VEGF as a marker of disease progression and severity.⁷ Thus, treatment is aimed at reducing VEGF levels either by ablating the peripheral avascular retina producing VEGF or pharmacologically inhibiting VEGF. As anti-VEGF agents have become more widely used in other retinal neovascular processes such as neovascular age-related macular degeneration, their use in ROP was explored. Multiple case reports and consecutive case series have been published; however, very limited data come from randomized, controlled clinical trials.

Anti-Vascular Endothelial Growth Factor Therapy

The Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEAT-ROP) study was the first multicenter randomized unmasked study that compared monotherapy with intravitreal bevacizumab to conventional diode laser photocoagulation. Study criteria included a birth weight of 1500 grams or less and 30 weeks gestational age or less with stage 3+ disease in zone 1 or 2. Bevacizumab (0.625 mg in 0.025 mL) was injected in the vitreous 2.5 mm posterior to the limbus with a 31-gauge needle. Infants, not eyes, were randomly assigned to injection or laser to avoid the potential risk of amblyopia from possible poor visual acuity in the eye treated with laser photocoagulation. The primary outcome of the study was recurrence of retinal neovascularization requiring treatment by 54 weeks. Eyes treated with intravitreal bevacizumab had lower rates of recurrence compared to those treated with conventional laser (6% vs 26%, respectively). However, this finding was statistically significant only in the eyes with zone 1 disease treated with bevacizumab, not zone 2 disease. An important consideration regarding the primary outcome in this study is that recurrence is typically later with anti-VEGF therapy compared to laser (19.2 weeks + 8.6 weeks vs 6.4 weeks + 6.7 weeks, respectively).⁵ Moreover, recurrence after the 54-week follow-up period after treatment with intravitreal bevacizumab is not uncommon.⁸ A similar randomized, controlled trial performed in Europe compared conventional laser therapy with and without adjuvant intravitreal pegaptanib (0.3 mg in 0.02 mL). The rate of recurrence was significantly higher in the conventional laser therapy group compared to the combination intravitreal pegaptanib and conventional laser therapy group (38% vs 11.7%, respectively).9

Another clinical trial, RAnibizumab Compared with Laser Therapy for the Treatment of INfants BOrn Prematurely with Retinopathy of Prematurity (RAINBOW), is currently underway to determine if intravitreal ranibizumab is superior to laser ablation therapy for the treatment of ROP. Primary outcome measures include the absence of active ROP and unfavorable structural outcome 24 weeks starting after study treatment. Secondary outcome measures include recurrence of ROP and requirement and timing for intervention with a second modality. It will also examine the systemic levels of ranibizumab and VEGF (NCT02375971).

Advantages Over Ablative Therapy

A potential pitfall of conventional laser therapy is the increased risk of high myopia, particularly very high myopia as demonstrated by the BEAT-ROP study group.¹⁰ Both the presence and severity of ROP are independent risk factors for the development of high myopia.^3,4 Interestingly, the difference in cycloplegic refraction was not statistically significant between zone 1 and zone 2 eyes in the BEAT-ROP study. Therefore, the authors concluded that laser therapy, not the severity of disease, was the primary etiology for myopia. Thus, treatment with anti-VEGF and possible avoidance of any laser therapy may reduce the incidence of laser-associated myopia.

Another major consequence of ablative therapy is the reduction of peripheral vision.⁵ Particularly in zone 1-treated eyes, the application of laser photocoagulation adjacent to the macula is technically challenging and causes constricted visual fields. In the Early Treatment of ROP study, zone 1 eyes had a 55.2% unfavorable outcome rate, representing a subset that has the capacity to greatly improve outcomes. An advantage of anti-VEGF monotherapy is the potential for normal retinal revascularization to develop in the periphery where it was previously avascular (Figure 13-1) and preservation of the peripheral field.

Anti-VEGF therapy is typically administered under local anesthesia at the bedside, compared to laser treatment, which often requires general anesthesia.⁵ Both administration of anti-VEGF and application of laser therapy require proper training and mentoring, although anti-VEGF treatment may arguably be easier for most clinicians than conventional laser. Intravitreal injections do carry other risks including endophthalmitis, cataract, and postinjection intraocular inflammation, rare in the neonate population.

Concerns

One consideration is the potential systemic effect and safety profile of anti-VEGF agents in infants. The authors of the BEAT-ROP study argue that minimal bevacizumab enters the systemic circulation because of its large molecular size. However, Sato et al¹¹ found serum levels of bevacizumab were higher and levels of VEGF were lower one week after injection with anti-VEGF. Also, while the BEAT-ROP study used half the adult dose of bevacizumab, there is a lack of understanding regarding the appropriate dosing in infants. Systemic anti-VEGF may affect organogenesis such as pulmonary, renal, neuronal, and skeletal development. In the BEAT-ROP study, 7 infants died, 5 of whom were in the bevacizumab group, though the difference between the groups was not statistically significant. All deaths in the bevacizumab group were secondary to respiratory arrest. The study concluded that a larger sample size would be needed to make an assessment regarding morbidity, mortality, and systemic or local toxicity. In general, when administering anti-VEGF agents in infants, one should err on the side of caution with lack of definitive evidence regarding their safety.

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