Journal of Pediatric Ophthalmology and Strabismus

Review Article 

Update on the Use of Anti-VEGF Drugs in the Treatment of Retinopathy of Prematurity

Christopher W. Seery, MD; Saul Betesh, BS; Suqin Guo, MD; Marco A. Zarbin, MD, PhD; Neelakshi Bhagat, MD; Rudolph S. Wagner, MD

Abstract

Retinopathy of prematurity (ROP) is one of the many significant consequences of premature birth and remains one of the leading causes of visual impairment in infants. Originally, cryotherapy was used to prevent the complications of vitreous hemorrhage and retinal detachment. Subsequently, laser photocoagulation, which is at least as effective and possibly safer than cryoretinopexy, was adopted as the primary treatment for type 1 ROP (stage 2 or 3 disease in zone II with plus disease or any stage disease in zone I with plus disease or stage 3 disease in zone I without plus disease). Laser therapy has been proven effective, and has a degree of permanence that is yet to be matched by alternative treatments, but can be associated with significant ocular side effects such as myopia. Treatment of type 1 ROP with anti-vascular endothelial growth factor (VEGF) agents seems to have fewer ocular side effects than laser ablation of the retina, particularly if used to treat type 1 ROP in zone I. However, ROP recurrence is a real threat after anti-VEGF therapy and long-term systemic side effects of this therapy remain under evaluation. This review focuses on the ophthalmic and systemic benefits and risks of anti-VEGF therapies for ROP as compared to retinal photocoagulation. Anti-VEGF therapies have dramatically altered the management of ROP and have also been shown to be beneficial with regard to the visual prognosis of patients with ROP, but patients so treated require frequent short- and long-term follow-up to detect and manage potential complications associated with this form of treatment. Such information also will allow clinicians to characterize the efficacy, side effect profile, and utility of intravitreal anti-VEGF agents for this condition. Prospective studies are needed to identify the optimum anti-VEGF drug and dose. [J Pediatr Ophthalmol Strabismus. 2020;57(6):351–362.]

Abstract

Retinopathy of prematurity (ROP) is one of the many significant consequences of premature birth and remains one of the leading causes of visual impairment in infants. Originally, cryotherapy was used to prevent the complications of vitreous hemorrhage and retinal detachment. Subsequently, laser photocoagulation, which is at least as effective and possibly safer than cryoretinopexy, was adopted as the primary treatment for type 1 ROP (stage 2 or 3 disease in zone II with plus disease or any stage disease in zone I with plus disease or stage 3 disease in zone I without plus disease). Laser therapy has been proven effective, and has a degree of permanence that is yet to be matched by alternative treatments, but can be associated with significant ocular side effects such as myopia. Treatment of type 1 ROP with anti-vascular endothelial growth factor (VEGF) agents seems to have fewer ocular side effects than laser ablation of the retina, particularly if used to treat type 1 ROP in zone I. However, ROP recurrence is a real threat after anti-VEGF therapy and long-term systemic side effects of this therapy remain under evaluation. This review focuses on the ophthalmic and systemic benefits and risks of anti-VEGF therapies for ROP as compared to retinal photocoagulation. Anti-VEGF therapies have dramatically altered the management of ROP and have also been shown to be beneficial with regard to the visual prognosis of patients with ROP, but patients so treated require frequent short- and long-term follow-up to detect and manage potential complications associated with this form of treatment. Such information also will allow clinicians to characterize the efficacy, side effect profile, and utility of intravitreal anti-VEGF agents for this condition. Prospective studies are needed to identify the optimum anti-VEGF drug and dose. [J Pediatr Ophthalmol Strabismus. 2020;57(6):351–362.]

Introduction

Retinopathy of prematurity (ROP) is increasingly a disease that ophthalmologists are accustomed to seeing in both the acute stage and its sequelae as innovations in prenatal, antenatal, and obstetrical care enhance the survival into adulthood of neonates with abbreviated gestational periods. Since 1990, the overall proportion of preterm births has increased by 21%, leading to a larger population predisposed to developing ROP.1 ROP is a biphasic disease characterized by an initial phase of retarded retinal vascularization (typically from birth to a postmenstrual age of 0 to 32 weeks) followed by a phase of retinal vascular proliferation. Increased metabolic activity of the poorly vascularized retina drives the hypoxia-induced second phase of retinal neovascularization (typically starting at 32 to 34 weeks of postmenstrual age). Vascular endothelial growth factor (VEGF) is prominent among these hypoxia-stimulated, pro-angiogenic substances.2–4

Great advances have been made in the treatment of ROP, initially with the application of retinal cryopexy once threshold criteria were met (ie, presence of plus disease and 5 contiguous or 8 total clock hours of stage 3 ROP in zones I or II), as shown in the Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) trial,5 and subsequently with application of indirect laser photocoagulation using more aggressive treatment criteria (ie, type 1 ROP: presence of stage 2 disease in zones I or II with plus disease or presence of stage 3 disease in zone I with or without plus disease or presence of any stage disease in zone I with plus disease) in the Early Treatment for Retinopathy of Prematurity (ETROP) trial.6

Because there was ample evidence from pre-clinical models that retinal neovascularization in ROP is strongly driven by increased VEGF production,4 it was logical to conclude that intravitreal anti-VEGF therapy might be effective in preventing retinal neovascularization in infants with ROP. The Bevacizumab Eliminates the Angiogenic Threat for ROP (BEAT-ROP), a multi-center randomized laser-controlled trial, demonstrated that intravitreal bevacizumab (IVB) injections were at least as effective as indirect laser photocoagulation in treating type 1 ROP.7 There were some concerns with this study, however, such as the relatively high recurrence rate in the laser treatment cohort and the relatively high death rate in the bevacizumab cohort.8,9

Intravitreal injections may be easier to administer than panretinal photocoagulation (particularly if the media are hazy due to persistence of the anterior tunica vasculosa lentis or vitreous hemorrhage), and they can be administered under topical anesthesia in contrast to indirect laser photocoagulation, which usually requires sedation and, in some cases, intubation. There is an appropriate concern about the systemic side effects of intravitreal anti-VEGF agents in the neonatal population, because their bodies are still undergoing neurologic and organ development and maturation, and anti-VEGF drugs are transported from the eye to the systemic circulation in significant quantities and thus lower systemic VEGF levels.9

The purpose of this article is to provide an update on the pertinent data regarding the risks and benefits of the application of anti-VEGF therapies in the treatment of ROP since this journal last published a review on this topic.10

Ocular Benefits of Anti-VEGF Therapy

Anti-VEGF agents have proved to be most advantageous in treating patients with aggressive posterior ROP (APROP), a condition characterized by: (1) posterior disease location in zone I or at the zone I and zone II interface; (2) prominence of plus disease; (3) ill-defined retinal neovascularization (flat, featureless vascular–avascular junction, and vessel-to-vessel shunting); and (4) rapid progression, often without progression through traditional stages 1 to 3. In these cases, presumably the VEGF concentration is highest due to the higher ratio of ischemic retina to vascularized retina.11 In a retrospective study, Blair et al12 found that in patients with APROP, 4.5% (1 of 22) of patients who were initially treated with IVB underwent surgery for detachment versus 36% (5 of 14) of patients who initially received laser treatment (P = .002). In a study comparing IVB and retinal photocoagulation in patients with stage 3+ disease, Mintz-Hittner et al7 reported only a 4% recurrence of disease for patients receiving IVB as compared to a 22% recurrence in the retinal photocoagulation treatment group (P = .002). This decrease in pathologic recurrence in the IVB group was statistically significant only for infants with zone I disease. IVB and laser had recurrence rates of 3.2% and 35%, respectively, for zone I disease and 5.1% versus 11.2%, respectively, for posterior zone II disease. In a retrospective study comparing IVB and laser in patients with type 1 ROP, Roohipoor et al13 showed that persistent or recurrent retinopathy requiring re-treatment occurred in 12% (69 of 558) of patients given IVB, and in 7.9% (20 of 251) of patients treated with laser for zone II ROP (P = .017). Statistically significant differences in disease recurrence were only seen in patients with zone II disease.

The authors of the BEAT-ROP study also noted that vascularization of the peripheral retina was observed clinically even after treatment with IVB. This may be a major benefit of the anti-VEGF treatment approach because after indirect laser photocoagulation, the retina anterior to the ridge separating perfused and non-perfused retina is permanently obliterated. This feature of treatment may underlie the lower incidence of myopia with anti-VEGF therapy versus laser treatment for ROP.14,15 It may also support greater peripheral visual field function. Indirect laser photocoagulation treatment has been associated with decreased visual acuity, most marked in patients receiving treatment for zone I disease.16 As indicated above, some patients with type 1 ROP are not amenable to treatment with indirect laser photocoagulation due to the presence of vitreous hemorrhage, poor media clarity due to miotic pupil and/or persistence of the anterior tunica vasculosa lentis, or inability to undergo general anesthesia. These patients often can be treated with topical anesthesia with intravitreal injection of an anti-VEGF agent. In some cases, panretinal cryopexy or even vitrectomy could also be considered as an alternative treatment.

The incidence of high myopia seems to be much lower after intravitreal anti-VEGF injection for type 1 ROP than after indirect laser photocoagulation.15 The BEAT-ROP study reported an average refractive error of −1.51 diopters (D) in 52 eyes with zone I disease treated with IVB compared to −8.44 D (P < .001) in 35 eyes with the same severity of disease treated with retinal photocoagulation.7 In 109 infants (211 eyes) comprising those with zone I or zone II stage 3+ or APROP, there was a significant difference in the degree of myopia. The eyes with zone II disease showed a similar trend for the difference in refractive error of the IVB- and laser-treated groups, −0.58 D (58 eyes) and −5.83 D (66 eyes), respectively (P < .001).17 The presence of very high myopia (defined as −8.00 D or greater) in patients treated for zone I or zone II disease was also significantly increased (P < .001) in the patients treated with laser photocoagulation versus those treated with IVB and with the same disease severity.18

Hwang et al18 also reported that the degree of myopia was less in an ROP cohort treated with IVB as compared to retinal photocoagulation. Their study comprised 54 eyes of 28 patients. Twenty-two eyes (11 patients) received IVB; 16 of these had zone I disease and 6 had posterior zone II disease. The remaining 32 eyes received indirect laser photocoagulation: 5 with zone I disease and 27 with zone II disease. The mean spherical equivalents at last follow-up for those treated with IVB and retinal photocoagulation were −2.40 and −5.30 D, respectively. A significant difference in the degree of myopia was evident only in patients with zone II disease where IVB and retinal photocoagulation showed spherical equivalents of 0.60 and −4.70 D (P = .002), respectively. These investigators also reported the well-known increased risk of developing retinal detachment and macular ectopia in neonates with high myopia, as well as the visual impairments mentioned above, that are side effects associated with retinal photocoagulation. These complications did not occur in eyes treated with IVB. One eye developed a retinal detachment and 5 eyes developed macular ectopia in the cohort treated with retinal photocoagulation.18 Similar findings were reported in a recent retrospective case series. Roohipoor et al13 reported significantly higher degrees of myopia (spherical equivalent) in patients treated with laser (−2.84 ± 2.77 D) than in patients treated with IVB (−1.26 ± −3.21 D) (P = .007).

Ocular Side Effects of Anti-VEGF Therapy

Peripheral retinal and posterior pole abnormalities become apparent over time in some eyes that receive intravitreal anti-VEGF injections. Lepore et al19 reported that all 12 eyes treated with 0.5 mg of IVB had peripheral avascular areas with shunt vessels or abnormal branching. Posterior pole abnormalities included hyperfluorescent lesions and absence of a foveal avascular zone. Although the age at treatment was not recorded, the gestational age at birth ranged from 23 to 29 weeks, and the grading of ROP at the time of injection was either zone I with plus disease or zone I without plus disease. None of the above examination findings were present in the comparison group treated with retinal photocoagulation, and no visual acuity data were reported.17 As the authors indicated, the anatomic abnormalities in the IVB cohort require further follow-up to determine their clinical significance. Such retinal abnormalities in the posterior pole have not been reported with laser photocoagulation, although foveal development in ROP may not proceed normally.20

In a retrospective study, Mansukhani et al21 reported similar fluorescein angiography (FA) findings in patients who had spontaneous regression of untreated ROP and patients treated with IVB. On FA, both groups exhibited non-occult and occult neovascularization. Peripherally, eyes from both groups had anomalous branching patterns, vessel blunting, abnormal capillary beds, and vascular shunts. At the posterior pole, both groups exhibited vessel tortuosity and vessels encroaching or crossing the fovea. Of all patterns discovered on FA, statistically significant variance between both groups was only seen in vessels encroaching the fovea, as seen in 65% (26 of 40) and 25% (4 of 16) of eyes in the IVB and untreated groups, respectively, (P = .009).21 These findings suggest that abnormal FA patterns in patients with IVB may be the result of the natural history of ROP and are not necessarily secondary to IVB. Further FA studies should be done to ascertain the clinical significance of these findings.

Several investigators have reported development of retinal detachment after intravitreal anti-VEGF therapy, often secondary to the development of vitreoretinal traction bands that constrict and lead to traction retinal detachment (TRD).22–25 One case report described a patient born at 23 weeks of gestation who developed zone I, stage 3 ROP with plus disease. The patient progressed to stage 4a with a partial TRD following retinal photocoagulation that was performed 10 weeks after birth. The patient received 0.4 mg of IVB at week 14 after birth. One week after the injection, the patient developed a funnel-like TRD associated with regression of the vascular component of the fibrovascular membrane.22 Another case involved a patient with zone I, stage 3 disease that was initially treated successfully with 0.625 mg of IVB, but later recurred as fine vascularity 16 weeks after the injection, which rapidly progressed to retinal detachment (stage 4a) by 18 weeks after the injection.23 All of the cases mentioned here and elsewhere24 displayed a brief period of ROP regression.

To further characterize those patients with ROP who received anti-VEGF and later developed retinal detachments, one retrospective, international, multicentered study reviewed 35 such eyes of 23 infants (29 receiving 0.625 mg of bevacizumab and 6 receiving 0.25 mg of ranibizumab). Twenty-five (71%) eyes received anti-VEGF injections alone, 7 (20%) received laser photocoagulation prior to injections, and 3 (9%) were treated with laser photocoagulation concomitantly. Of the 25 eyes that only received anti-VEGF injection as the initial treatment, 15 (60%) underwent subsequent laser photocoagulation. Retinal detachment was noted in 4 eyes (11%) 1 week after injection, 8 eyes (23%) within 2 weeks, and 17 eyes (49%) within 4 weeks with a mean time of progression to retinal detachment of 70 days (median: 34 days, range: 4 to 335 days). The time to clinical detection of retinal detachment was negatively correlated with the post-menstrual age at the time of injection. This retrospective review also noted that there are three types of retinal detachments: conventional detachments and two types of anti-VEGF–related detachments. The “conventional” detachments include two different configurations: an elevated peripheral ridge with focal detachment or a typical stage 5 detachment with a “volcano” configuration posteriorly and peak retinal elevation in the anterior periphery. Detachments unique to eyes with ROP treated with anti-VEGF have two configurations: one is relatively peripheral with circumferential hyaloidal contraction creating a circular detachment (associated with more anterior retinal vascularization before the development of acute ROP), and the other is posterior with prepapillary contraction that pulls the retina toward the optic nerve head (associated with more posterior disease than the former type of detachment). All configurations were amenable to surgical repair (with slight technical differences), with 86% of those who did undergo vitrectomy achieving full or partial reattachment.25 If some fibrosis or, particularly, TRD has developed, it is probably best to avoid intravitreal anti-VEGF therapy because it may exacerbate the progression of TRD. Intravitreal anti-VEGF therapy can also precipitate the development of progressive TRD in patients with proliferative diabetic retinopathy.26

Follow-up of patients with ROP treated with intravitreal anti-VEGF therapy must be longer and more frequent due to the greater potential for a later recurrence than with retinal photocoagulation. Typically, the follow-up period for patients treated with retinal photocoagulation is every 2 to 4 weeks until the retina is fully vascularized, as documented on two separate visits approximately 4 to 6 weeks apart, which is typically approximately 3 months after treatment. As seen in the case reports above, however, severe recurrences can occur between 6 and 8 months after intravitreal anti-VEGF therapy. Thus, patients with ROP treated with anti-VEGF therapy require a follow-up period well beyond the 3-month time frame. This boundary condition can create difficulties for the family, particularly if they have been referred from a long distance to the treatment center, and yet the consequences for failure to maintain routine follow-up may be devastating. For example, one patient with ROP lost to follow-up for 5 weeks progressed from stage 4a (partial, extramacular TRD), which may have had some potential for treatment with vitrectomy, to total retinal detachment with fibrous membranes extending to the posterior surface of the lens.24

Huang et al27 noted that even in the same individual, the response to anti-VEGF therapy (specifically, ranibizumab in their study) can vary. In their report of 84 patients, 9 (10.7%) showed an asymmetric response. There was a significant difference in birth weights between the groups that had asymmetric outcomes (1222.2 ± 216.6 g) versus symmetric outcomes (1412.2 ± 335.6 g, P = .001). These data highlight the need for vigilant follow-up of patients with ROP after intravitreal anti-VEGF treatment for type 1 ROP and APROP.

A retrospective review of 471 eyes with ROP that received IVB showed that ROP recurred in 34 eyes (7.2%). Features associated with recurrence were: (1) neovascularization (P = .006); (2) extended duration of hospitalization (P = .01); and (3) lower birth weight (P = .024), which indicates that the sickest and most severe cases were the ones most likely to recur. The recurrence risk period was between 45 and 55 weeks of adjusted age, with a mean of 51.2 weeks, and 16.2 weeks after treatment.19 In a retrospective study, Chen et al28 analyzed the patterns of disease regression after IVB in patients with type 1 ROP or APROP. In 92 eyes of 46 infants examined at 60 weeks of age, the patterns observed included vascular maturity (3.3%), vascular arrest (44%), persistent vascular tortuosity in addition to vascular arrest (38%), and reactivation of disease (18%). Patients with reactivation were more likely to be Asian (50%, P = .008), have zone I, stage 2 plus disease (50%, P = .002), or have APROP (75%, P = .004). The study also examined the areas of ischemia on FA in the peripheral retina after IVB treatment. The eyes with reactivation were found to have the greatest area of ischemia (112.2 mm2) followed by eyes showing vascular arrest with (72.5 mm2) or without (56.6 mm2) tortuosity (P = .007).28 Therefore, Chen et al28 suggested that the presence of vessel tortuosity with vascular arrest is an indicator for an increased ischemia burden and elevated levels of VEGF. Garcia Gonzalez et al29 retrospectively studied reactivation rates and peripheral vascularization in patients initially treated with 0.625 mg of IVB for APROP or type 1 ROP; 21% (10 of 48) of eyes with type 1 ROP had zone I disease compared to 88% (14 of 16) eyes with APROP (P = .0001). Recurrence rates after IVB were 50% (8 of 16) and 4% (2 of 48) in the APROP and type 1 ROP groups, respectively (P < .0001).29 In patients who presented with zone I APROP or zone I type 1 ROP, recurrence rates were 57% (8 of 14) and 0% (0 of 10), respectively (P = .007).29 At a mean of 73 weeks, 14% (7 of 49) of eyes had normal peripheral vascularization to 1.5 disk diameters temporally and 0.5 disk diameters nasally. Patients with APROP had significantly more areas of avascular retina than patients with type 1 ROP (P = .0004).29

A meta-analysis that included applicable articles already in publication between December 27, 2014 and January 8, 2015 used data from 24 original studies, consisting of 1 randomized control study, 2 case-control studies, and 21 observational studies that characterized the complications following anti-VEGF therapy for ROP. The 24 studies comprised 882 eyes that had sufficient data for analysis of ocular complications. The overall complication rate requiring re-treatment was 2.8%. The causes of re-treatment were recurrent neovascularization (58.2%), retinal hemorrhages (18.2%), retinal detachment (16.4%), partial retinal detachment (1.8%), macular dragging (3.6%), and persistent plus disease (1.8%).14 In contrast, the need for retreatment occurred in 11% to 14% of patients in the ETROP study. The need for re-treatment after laser photocoagulation is probably higher in cases with APROP.30

In addition to retinal complications associated with anti-VEGF therapy, anterior segment complications have been reported. Khokhar et al31 reported a case of total cataract forming bilaterally after IVB for APROP, despite the lack of evidence for lens touch with intravitreal injections.

Systemic Side Effects of Anti-VEGF Therapy

Promising data support the effectiveness of intravitreal anti-VEGF therapy as treatment for type 1 ROP. The ocular limitations/side effects of this approach have been considered above, but one must also consider the risk of significant systemic off-target effects. Studies have shown the presence of anti-VEGF drugs in the systemic circulation after intravitreal injections of these agents.9,32–36 Bakri et al33 compared the systemic levels of serum VEGF and insulin-like growth factor-1 (IGF-1) in infants treated with 0.625 mg of IVB, 0.25 mg of IVB, and retinal photocoagulation. In all three of these treatment groups, there was a decrease in serum free VEGF 2 days after treatment. However, there was a significantly lower amount present in the two bevacizumab-treated groups. These two groups also had significantly lower serum levels of IGF-1 after IVB injection.

Regarding systemic off-target effects, neonates are in a critical period of organogenesis (eg, lung) and neurogenesis. These changes are highly dependent on adequate vascular supply to sustain rapid growth and development, a situation that might be altered adversely as a result of anti-VEGF therapy. In one study that analyzed data from the Canadian Neonatal Network and the Canadian Neonatal Follow-Up Network, neurodevelopment of an age-corrected 18-month-old population who had received either IVB or retinal photocoagulation for ROP showed some interesting differences. Of the 125 infants treated for ROP, 27 had received IVB and 98 had received retinal photocoagulation. Although no difference was seen in language composite score, cognitive scores, or Bayley Scales of Infant and Toddler Development (BSITD-III) scores, the motor score was decreased in those who had received IVB (P = .02). The odds of developing a severe neurodevelopmental disability (defined as cerebral palsy, requirement for hearing aids or cochlear implants, bilateral visual impairment, or severe developmental delay) after adjusting for confounding variables was 3.1 times higher in the IVB cohort (95% CI = 1.2 to 8.4).36 However, additional research has not detected the presence of systemic side effects of IVB.

Rodriguez et al37 reported that among 40 infants treated with indirect laser and 46 infants treated with IVB there was no significant difference in outcomes, such as death, cerebral palsy, hearing loss, or BSITD-III scores between treatment groups. In a prospective case-control study of 148 patients, Fan et al38 reported that at 1.49 ± 0.59 years of age, there was no significant difference among patients without ROP, with ROP receiving no treatment, and with ROP receiving IVB when assessing neurodevelopmental outcomes using the BSITD-III scores after adjusting for birth weight, gestational age, sepsis, Appearance, Pulse, Grimace, Activity, and Respiration (APGAR) score, and intraventricular hemorrhage. However, the small sample size in each study certainly limits the ability to detect significant differences in scores between treatment groups.

Bevacizumab Versus Ranibizumab

Bevacizumab was used in most of the earliest studies of intravitreal anti-VEGF therapy for ROP, probably due to its relatively low cost and widespread availability. However, other anti-VEGF therapies, such as ranibizumab, might provide a more favorable side effect profile based on a smaller molecular size and absent Fc component. The lack of an Fc component leads to less recirculation of ranibizumab in the bloodstream after diffusing from the eye to the systemic circulation with a corresponding short systemic half-life of approximately 2 to 4 hours versus bevacizumab, which has an Fc component and has a systemic half-life on the order of 20 days. Differences in the pharmacokinetics between these two anti-VEGF agents and aflibercept, which also has an Fc component, have been well documented in adult humans receiving clinically relevant doses of intravitreal anti-VEGF therapy.39,40

Although clinically relevant drug levels are present in the serum of adults for as long as 30 days after intravitreal injection of bevacizumab and aflibercept (and, in contrast, systemic levels of ranibizumab are extremely low at this time) and although corresponding reductions in free plasma VEGF have been correlated with these persistently elevated drug levels,9,39,40 the evidence that there is a greater risk of systemic side effects with one anti-VEGF agent versus another has been inconsistent.41–43

Although the focus of the comparison between the anti-VEGF options has been on the systemic effects, Chen et al44 also found a difference in ocular side effects. These authors noted that the incidence of high myopia was greater among patients treated with IVB versus intravitreal ranibizumab (IVR) (P = .03). However, no other differences in the ocular profiles were reported. Huang et al27 reported 168 eyes from 84 patients treated with 0.25 mg of IVR and found that the ROP recurrence rate was approximately 40%, much higher than what has been reported elsewhere. These investigators hypothesized that this result may be due to ranibizumab's relatively short systemic half-life, resulting in incomplete treatment (ie, less prolonged VEGF suppression).

Kimyon and Mete45 reported similar effectiveness of IVB and IVR for type 1 zone I ROP; 68 eyes of 37 infants received either 0.625 mg of bevacizumab (40 of 68) or 0.25 mg of ranibizumab (28 of 68) intravitreally. No significant difference was seen between the number of eyes having reactivation of ROP or incomplete vascularization. However, axial length and spherical equivalents measured at age 1 year were significantly different between the two groups. Mean axial length in patients receiving IVB was 20.50 ± 0.99 versus 19.30 ± 0.48 mm in the IVR group (P < .001). Mean spherical equivalent was −1.49 ± 2.38 D in the IVB group versus 0.98 ± 2.18 D in the IVR group (P < .001).45 These findings underscore the fact that additional data about IVR should continue to be collected.

Harper et al46 examined FA findings at 60 weeks in 30 eyes of 16 infants treated for type 1 ROP or APROP with IVR. One infant had bilateral vascularization to within 1 disk diameter of the ora serrata; 50% of eyes had vascularization to zone III. Other FA findings included vascular leakage, vascular dilatation or blunting, and capillary dropout found in 40%, 90%, and 93% of eyes, respectively. Cheng et al47 examined FA findings in 34 eyes of 17 infants with avascular portions of the retina after IVR treatment. Findings included finger-shaped vessels and arteriovenous shunts (100% of eyes), popcorn abnormalities (94% of eyes), and leakage at the vascular–avascular junction (24% of eyes). Damage in the retinal capillary bed and retinal pigment epithelial atrophy occurred in 2 (5.9%) and 3 (8.8%) eyes, respectively. These vascular changes should be studied further to assess their significance in disease progression and clinical management.

Arámbulo et al48 retrospectively examined the use of IVR in patients with type 1 ROP or APROP and reported that all 85 eyes of 43 infants who received 0.25 IVR had plus disease regression within 1 week of treatment; 22 infants (54%) required laser treatment due to reactivation of plus disease in zone II or III at a mean of 7.1 ± 3 weeks. At 6 months of follow-up, 12 (29%) infants had clinically complete vascularization in zones II and III.48 Tong et al49 studied the use of 0.3 mg of IVR in patients with APROP; 43 of 160 (27%) of eyes had stable disease regression after initial IVR, 82 of 160 (51%) eyes regressed with re-treatment, and 35 of 160 (21.9%) eyes developed TRD. Kang et al50 compared the use of IVR and laser as primary treatment in 153 and 161 eyes, respectively. Disease recurrence occurred in 22 (14%) and 15 (9.8%) eyes in the laser and IVR treatment groups, respectively; 8 (5.0%) eyes treated with laser and only 1 (0.7%) of the patients receiving IVR developed a retinal detachment.

In addition to IVB and IVR, the use of anti-VEGF agents such as aflibercept and conbercept has been reported. Vedantham51 studied the use of intravitreal aflibercept (IVA) in patients with high-risk prethreshold ROP, threshold ROP, and APROP. All 46 eyes of 23 infants injected exhibited disease regression after 1 week; 15 of 46 (33%) eyes had complete retinal vascularization with no disease recurrence by 64 weeks of postconceptual age. Of the 22 eyes that had disease recurrence with zone I ROP initially, 82% (18 of 22) demonstrated continuing retinal vascular development prior to disease recurrence.51

Sukgen and Koçluk 52 compared the use of IVA and IVR in patients with type 1 ROP (excluding stages 4 and 5) or APROP. There were no significant differences in baseline clinical presentations or demographic data between the two groups. Both treatment groups demonstrated continued peripheral vascularization in addition to complete disease regression. Complete peripheral vascularization occurred at 59.68 ± −9.91 and 68.36 ± 7.02 weeks of postmenstrual age in the IVR and IVA groups, respectively (P < .001). Disease recurrence occurred in 26 of 54 (48%) eyes of the IVR group and in 10 of 72 (14%) eyes of the IVA group (P = .001). The mean recurrence times of the IVR and IVA cohorts were 8.20 ± 0.92 and 14.2 ± 1.03 weeks, respectively; P < .001).52 Previous studies have suggested that the half-lives of IVA and IVR in adult human eyes with age-related macular degeneration are 7.13 and 4.75 days, respectively.53

Vural et al54 retrospectively studied the effect of IVA in patients with either type 1 ROP or APROP. Of the 36 eyes in 18 infants who received 1 mg of IVA, 34 (94%) had disease regression after 1 week. The 2 eyes that had disease persistence at 1 week were both successfully treated with IVA reinjection. Late recurrences of disease occurred in 19% of eyes, and all subsequently regressed without the need for re-treatment; 83% of eyes at 19 weeks had vascularization within 2 disk diameters of the ora serrata.54

Bai et al55 showed that intravitreal conbercept (IVC) is an effective treatment for APROP and type 1 ROP; 48 eyes of 24 patients were given 0.25 mg of IVC and 40 of 48 eyes (84%) showed disease regression with no recurrence at 6 months of follow-up. ROP recurred in 8 eyes (16%) at 5.6 ± 0.5 weeks. The remaining eyes with recurrence were treated successfully with either repeat IVC (4 of 8 eyes) or laser (4 of 8 eyes); 12 of 48 (25%) eyes had full retinal vascularization at the end of the 6-month follow-up55 and 0.15 mg of IVC was found to be effective.56

In a retrospective study, Jin et al57 compared outcomes of 0.25 mg of IVC and 0.25 mg of IVR treatment in patients with either type 1 ROP and APROP; 17 of 20 (85%) eyes in the IVC treatment group and 13 of 28 (46%) eyes in the IVR treatment group exhibited regression of plus disease after one injection by 4.3 ± 2.08 and 2.62 ± 1.80 weeks, respectively. No recurrence was observed by 6 months of follow-up in the IVC group compared to 11 of 28 (39%) in the IVR group. Recurrence was treated with additional IVR, and all patients had regression of plus disease within 2 weeks. Retinal complications such as retinal detachment or vitreous hemorrhage were not observed in either treatment group. In addition, 4 of 20 (20%) of eyes in the IVC cohort and 8 of 28 (29%) of eyes in the IVR cohort had full vascularization after only one injection.

Effect of Decreased Dosage of Anti-VEGF Therapy

At this time, it is not clear what the lowest effective dose of intravitreal anti-VEGF therapy is for ROP treatment. By decreasing the intravitreal dose of the anti-VEGF agent, one hopes to reduce the systemic anti-VEGF concentration and thus the risk of systemic side effects. The current standard for dosing for IVB in infants with type 1 ROP is 0.625 mg/0.025 mL. The Pediatric Eye Disease Investigator Group (PEDIG) assessed efficacy in treating type 1 ROP, including zone I ROP, using 0.25, 0.125, 0.063, or 0.031 mg of IVB in one eye only. Success was defined as improvement in pre-injection plus disease or zone I, stage 3 ROP by 5 days after injection and no recurrence of type 1 ROP or severe neovascularization requiring additional treatment within 4 weeks. Of the 58 study eyes involved in the study, 32 (55%) had zone II disease and 26 (45%) had zone I disease. In total, 11 eyes received the 0.25 mg dose, 14 received the 0.125 mg dose, 24 received the 0.063 mg dose, and 9 received the 0.031 mg dose. Success was achieved in 11 (100%), 14 (100%), 21 (88%), and 9 (100%) eyes, respectively. There was no statistically significant difference in the success rates among all of the doses.58

Hillier et al59 published a case series of 29 eyes (15 patients) using 0.16 mg of IVB in 0.025 mL and found that 79% of eyes showed complete regression of retinopathy and neovascularization into zone III after just one treatment; 93% of eyes treated with this formulation showed complete regression after either two intravitreal injections or one intravitreal injection and one diode laser retinal photocoagulation treatment.59 Akdogan et al60 studied the use of 0.16 mg of IVB in 43 infants with ROP requiring treatment and the need for re-treatment with laser photocoagulation. Disease persistence was observed in 3 of 43 (7%) patients after IVB only; 21 of 43 (44%) infants received laser in avascular areas at 70 weeks of gestational age to prevent disease recurrence with no complications reported. Results from these small studies are consistent with the notion that lower doses of IVB can be effective in treating ROP. Just as important as the success of the treatment with lower doses is the lack of any adverse systemic side effects noted to date.59

Andreas et al61 investigated lower doses of IVR in a randomized, multicenter, double-blinded, investigator-initiated trial at 9 academic medical centers in Germany. The investigators compared IVR doses of 0.12 versus 0.20 mg in infants with bilateral APROP; ROP stage 1 with plus disease, stage 2 with plus disease, or stage 3 with or without plus disease in zone I; or ROP stage 3 with plus disease in posterior zone II. All infants received one baseline IVR injection per eye. Reinjections were allowed in cases of ROP recurrence after at least 28 days; 19 infants with ROP were enrolled (9 [47%] female; median [range] postmenstrual age at first treatment, 36.4 [range: 34.7 to 39.7] weeks), 3 of whom died during the study (1 in the 0.12-mg group and 2 in the 0.20-mg group). Of the surviving infants, 8 (89%) (17 eyes [94%]) in the 0.12-mg group and 6 (86%) (13 eyes [93%]) in the 0.20-mg group did not require rescue therapy. Both ranibizumab doses were equally successful in controlling acute ROP (Cochran-Mantel-Haenszel analysis; odds ratio [OR] = 1.88; 95% CI = 0.26 to 13.49; P = .53), and physiologic intraretinal vascularization was superior in the 0.12-mg group. The VEGF plasma levels were not systematically altered in either group.61

This pilot study demonstrated that IVR is effective in controlling acute ROP and that 24% of the standard intravitreal adult dose (0.12 mg) appears to be as effective as 40% of the standard adult dose (0.20 mg). Superior vascularization of the peripheral retina with 0.12 mg of IVR indicates that the lower dose may be favorable. Unchanged plasma VEGF levels point toward a limited systemic drug exposure after IVR.61

Results from these trials are consistent with the notion that lower doses of anti-VEGF agents, such as bevacizumab or ranibizumab, are at least as effective in treating ROP as standard doses. Perhaps as important as the success of the treatment with lower doses is the decrease in systemic exposure to anti-VEGF signaling blockade. The RAnibizumab Compared With Laser Therapy for the Treatment of INfants BOrn Prematurely With Retinopathy of Prematurity (RAINBOW) study ( ClinicalTrials.gov Identifier: NCT02375971), a randomized, open label, superiority trial that compared ranibizumab 0.2 mg (n = 74), ranibizumab 0.1 mg (n = 77), and laser photocoagulation (n = 74), reported an odds ratio in favor of 0.2 mg of IVR compared to laser therapy (odds ratio = 2.32; 95% CI = 1.04 to 5.16), with no significant difference in the risk of death/serious or non-serious systemic adverse events/serious or non-serious ocular adverse events, although unique to IVR were one cataract thought to be secondary to injection trauma and one case of endophthalmitis and orbital infection in an infant who was injected after treatment of conjunctivitis. Additional treatments were more frequent in both injection groups compared to laser, and when comparing retinal vascularization assessed by indirect ophthalmoscopy between the 0.1 mg of IVR and 0.2 mg of IVR groups, full retinal vascularization at day 169 was observed in 27% and 38%, respectively. Overall, the use of a lower 0.1 mg of IVR did not show any benefit over 0.2 mg, and may actually be associated with more unfavorable structural outcomes. The 5-year data will reveal whether any additional differences between these treatment groups develop. The RAINBOW study also showed that there was no significant change in systemic VEGF concentrations between the two injection groups or compared to laser (confirming the findings of the CARE-ROP trial).61,62

Anti-VEGF and Laser Combination Therapy

Recent studies have attempted treatment and prevention of disease recurrence with various forms of anti-VEGF and laser combination therapies. In a retrospective study, Seo and Lee63 compared outcomes of temporal zone II–sparing laser combined with IVB (32 of 74 eyes) versus conventional laser alone (42 of 74 eyes) in 74 eyes of 37 patients with type 1 ROP in zone I. Seo and Lee63 reported a more rapid disease regression (12.1 ± 6.2 vs 25.6 ± 21.3 days, P = .011) in patients treated initially with laser and IVB. Additionally, patients given combination therapy required re-treatment less often (0% vs 24%, P = .004). The use of zone II–sparing laser therapy allows for minimized visual field loss. Retinal/preretinal hemorrhage occurred more frequently in the laser alone treatment group (43% vs 9.4%, P = .002).63

In the study by Chen et al28 mentioned previously, all patients with avascular areas in the retinal periphery at 60 weeks after IVB treatment received photocoagulation therapy in those avascular regions. Although results of this method have not yet been reported, the authors did not create a control group that did not receive secondary laser treatment. Similarly, Harper et al46 reported the use of secondary laser treatment for avascular retinal regions at 60 weeks after treatment with IVR. However, outcomes have not yet been reported. Garcia Gonzalez et al29 examined the effect of prophylactic laser treatment for avascular retina at 60 weeks of gestational age. Of 41 eyes treated with prophylactic laser, none had poor structural outcome after a mean follow-up time of 125 weeks of gestational age.

Current Clinical Trials for ROP

The need for further investigation into optimizing the visual potential while minimizing side effect profiles of treatment options for patients with ROP is growing. Results as mentioned above have now been reported in the RAINBOW study, which is comparing 0.1 versus 0.2 mg of IVR versus panretinal photocoagulation, which still leaves long-term data wanting and may open the door to more dosing trials in the future ( ClinicalTrials.gov Identifier: NCT02375971). The BLOCK-ROP study is comparing bevacizumab doses of 0.625 and 0.75 mg with panretinal photocoagulation ( ClinicalTrials.gov Identifier: NCT01232777). The PEDIG study also is exploring the minimum concentration of bevacizumab needed to treat type 1 ROP (ClinicalTrials. gov Identifier: NCT02390531). Propranolol, as it has been applied safely to other neovascular diseases of infancy (eg, capillary hemangioma64), also has theoretical potential to aid in the management of ROP, and investigators involved in the prophylactic propranolol for prevention of ROP trial (PreROP) and the Oral Propranolol for Prevention of Threshold Retinopathy of Prematurity trial seek to determine whether oral use of this drug has any impact on preventing the disease, which to date has shown a statistically insignificant decreasing trend in the incidence of ROP (57% for treatment vs 69% for controls; P = .39)65–67 ( ClinicalTrials.gov Identifier: NCT03083431). Finally, although the outcome that one group has reported does not appear to be clinically significant, IGF-1/IGFBP3 is being investigated for safety and prevention of ROP and other diseases of prematurity.68

Brown et al69 developed a deep learning algorithm (i-ROP DL) to detect the presence of normal, pre-plus disease, and plus disease using fundus photographs. When comparing 100 fundus photographs to a reference standard diagnosis containing 5,511 images, the algorithm was found to achieve a sensitivity of 93% and specificity of 94% when detecting the presence of plus disease. For pre-plus or plus disease, the algorithm had a sensitivity of 100% and specificity of 94%. Redd et al70 further applied the i-ROP DL algorithm to incorporate probabilities of normal and pre-plus and plus disease and produced a vascular severity score of 1 to 9. Gupta et al71 applied the i-ROP DL algorithm to monitor disease regression after treatment with either IVB or laser photocoagulation. They found that patients receiving IVB had a significantly increased mean change in ROP severity score (−3.28) when compared with patients treated with laser photocoagulation (−1.91) at 1 week after therapy (P = .04). The technology of deep learning algorithms such as i-ROP DL can be used to consistently assess disease severity, which will assist in obtaining accurate data for further ROP research.

Conclusions

The debilitating consequences of ROP, treated or untreated, as well as the need for lifelong follow-up are indisputable. However, the role of anti-VEGF therapy in the treatment of type 1 ROP is highly debated,72–74 despite its documented beneficial effects. Thus, there remains a need for large, multicenter active control studies with long-term follow-up of patients who have received anti-VEGF therapy for type 1 ROP and also for studies that address the efficacy and safety of various anti-VEGF agents. At this time, anti-VEGF therapy plays an important role in type 1 ROP treatment. However, until safety concerns are further addressed and longer-term consequences of therapy are better understood, anti-VEGF therapy has not supplanted laser treatment.75,76 Instead, these treatments are likely to be used in different scenarios (eg, anti-VEGF therapy for APROP, laser photocoagulation for zone II type 1 ROP) and possibly in combination (eg, laser treatment as “consolidation therapy” following successful administration of intravitreal anti-VEGF therapy for APROP), at least until the optimal treatment regimen of anti-VEGF has been determined and the subject can be revisited.

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Authors

From the Department of Ophthalmology, The Institute of Ophthalmology and Visual Sciences, Rutgers – New Jersey Medical School, Newark, New Jersey.

The authors have no financial or proprietary interest in the materials presented herein.

Dr. Wagner did not participate in the editorial review of this manuscript.

Correspondence: Rudolph S. Wagner, MD, The Institute of Ophthalmology and Visual Sciences, New Jersey Medical School, Doctors Office Center, Suite 6100, P.O. Box 1709, Newark, NJ 07101-1709. Email: r.s.wagner@njms.rutgers.edu

Received: August 11, 2019
Accepted: April 30, 2020

10.3928/01913913-20200824-02

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