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Review Article

Update on Anti-Vascular Endothelial Growth Factor Safety for Retinopathy of Prematurity

Enríquez, Ana Bety MD; Avery, Robert L. MD; Baumal, Caroline R. MD

Author Information
Asia-Pacific Journal of Ophthalmology: July-August 2020 - Volume 9 - Issue 4 - p 358-368
doi: 10.1097/APO.0000000000000302
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Retinopathy of prematurity (ROP) is a neovascular retinal disorder that occurs in infants born prematurely. Currently, it constitutes a leading cause of childhood blindness globally that is characterized by aberrant angiogenesis, retinal ischemia, fibrovascular proliferation, and progressive vitreoretinal traction.1–3 Although milder forms of ROP pathology may resolve spontaneously without sequelae, more severe forms require immediate treatment to prevent serious complications such as retinal detachment, vision impairment, and permanent blindness.4

Vascular endothelial growth factor (VEGF), a key regulator of angiogenesis in embryonic and fetal life, has been identified as a major mediator of the pathological angiogenesis observed in ROP.3,5 For decades, the standard of care has involved peripheral retinal ablation, by either cryotherapy or confluent laser photocoagulation.2,5 However, laser photocoagulation has been associated with poor structural outcomes in some of the preterm infants, particularly in those with zone 1 disease and aggressive-posterior ROP (AP-ROP).6,7 As well, the specialized equipment and trained physicians required to perform ablative therapy may not be readily available in developing nations and even in some regions of first world countries. For these reasons, investigators have focused on finding less destructive, easily accessible, and more efficient therapies.1,3,5,8

Recently, the intravitreal administration of anti-VEGF agents for ROP has increased worldwide and has been promoted as first-line therapy by some ophthalmologists.8 In multiple small uncontrolled retrospective and several larger prospective studies, these agents have demonstrated ROP regression by reducing neovascular activity and allowing continuous and controlled vessel growth into the peripheral retina.2,3,9–17 Nevertheless, the use of anti-VEGF agents for ROP remains off-label and the lack of information regarding the appropriate drug and optimal dose, the safety profile (ocular and systemic), and the possibility of unfavorable long-term outcomes causes the utmost concern.3,4,8–10 In the context of new clinical information from the multicenter, randomized ranibizumab versus laser therapy for the treatment of very low birth weight infants with retinopathy of prematurity (RAINBOW) study, which evaluated the use of ranibizumab versus laser for ROP, the evidence regarding systemic and ocular safety of anti-VEGF treatment for ROP, is reviewed.


A comprehensive search of PubMed and MEDLINE databases was conducted in October 2019, November 2019, and May 2020 for the terms “retinopathy of prematurity,” “retrolental fibroplasia,” “anti–vascular endothelial growth factor,” “bevacizumab,” “ranibizumab,” “aflibercept,” “VEGF trap-eye,” “pegaptanib,” “conbercept,” “brolucizumab,” and “safety” in various combinations. Only English-language publications in indexed journals were considered and references within articles were manually reviewed to identify additional relevant publications. No publication date or publication status restrictions were imposed; however, all articles were carefully reviewed to select those that addressed the safety on the use of anti-VEGF medications for ROP.



In 1942, Dr. T.L. Terry described a bilateral progressive disease exclusively seen in premature infants with low birth weight.18 This condition was thought to be secondary to mesodermal persistence or overgrowth, therefore the term “retrolental fibroplasia,” which was suggested by Dr. H.K. Messenger and depicted the fibrous tissue observed behind the lens, was accepted.18 However, this disease was so uncommon that interest in this pathology rose only when ophthalmologists and pediatricians recognized an increment in its incidence 1 decade later.14,18,19 With the improvement of neonatal care, survival outcomes of premature infants improved but paradoxically caused 3 distinct ROP epidemics. In the 1940s and early 1950s, the first ROP epidemic was observed in highly developed countries of Western Europe and the United States. It was a consequence of unrestricted oxygen administration combined with the absence of means of monitoring its use.14,20,21 The second epidemic, recorded in the late 1960s and 1970s, was observed in industrialized countries with well-developed neonatal units. This epidemic was a result of the improvement of survival rates of increasingly premature and extremely low-birth-weight babies.14,20,21 Finally, the third epidemic took place in middle-income countries, in the 1990s. The multiple reasons for this epidemic were the increase of rates of preterm births and risk factors, combined with the development of neonatal intensive care and its upsurge in access in those countries (which had substantial variations in the levels of care).14,20,21

Nowadays, ROP constitutes a leading cause of childhood blindness worldwide; however, its prevalence is highly dependent on socioeconomic factors.1,4,5 In high-income countries, <10% of blindness is from ROP. In contrast, in middle and low-income countries, the large proportion of preterm babies being born, coupled with the improvement of neonatal care, is resulting in an absolute increase in the number of surviving preterm infants which in turn leads to an increased number of ROP cases (that account for up to 40% of blindness).22–24 Also, as expertise in neonatal care develops in these regions, ROP may develop in patients with a lower risk of this condition (more mature and larger birth weight newborns).20

VEGF Role in Development and ROP

VEGF, also known as vascular permeability factor, was initially described in vitro as an endothelial cell-specific mitogen. It is produced by multiple cell types throughout the body and in vivo has been identified as the most indispensable angiogenic factor during embryonic vascular development.10,13,25 Moreover, VEGF is fundamental for the proliferation, migration, and survival of neural stem cells and neurons, the proliferation and migration of microglia, the proliferation of astrocytes, and the development and preservation of the integrity of the blood-brain barrier. VEGF also plays an important role in the development of the kidneys, lungs, skeletal, and hematopoietic systems.13,26

Normal retinal vascular development relies on a physiological hypoxic gradient that occurs at the developing vascular front. This hypoxia is responsible for the production, by Müller cells and astrocytes of the inner retina, of VEGF which leads to the development of blood vessels towards the avascular peripheral retina. As a result, the growth of vessels mitigates the hypoxia and the local expression of VEGF.13

ROP pathogenesis presents with 2 stages. In the first phase, the loss of the third-trimester growth factors previously provided by the mother combines with an increment in the newborn's oxygen pressure levels (as extrauterine atmosphere provides higher levels of oxygen than the intrauterine environment). These 2 conditions may be exacerbated by supplemental oxygen but are enough to lead to the suppression of VEGF and other growth factors, interrupting the physiological angiogenesis. This plight is observed clinically as a delay in the vascular maturation and central vaso-obliteration.2,25 As the retina continues to develop its metabolic activity increases; however, the vascular perfusion is insufficient to maintain the demand, worsening the hypoxic environment. These circumstances lead to the second phase of ROP in which the ischemic retina, in an effort to compensate for the metabolic imbalance, rapidly elevates the previously suppressed growth factors (particularly VEGF) which in turn guide an abnormal neovascular proliferation.10,25 If untreated or insufficiently treated, retinal neovascularization may progress to a cicatricial phase in which scar tissue formation will take place and may cause macular and disc dragging, vitreoretinal-lens adhesions, retinal detachment, and potential blindness.27

Treatment for ROP

Therapy for ROP is implemented when early proliferative or cicatricial changes are observed. Treatment of the proliferative phase is oriented to decrease the angiogenic activity of VEGF. This can be achieved either by destroying the peripheral avascular retina that incites VEGF production (ablation therapy) or by inactivating the VEGF produced at the retinal ischemic areas (anti-VEGF therapy).2,5,13

Cryotherapy was the first ablation treatment that was used to treat severe ROP.28 In the 1970s, it was the favored treatment option because of its availability and its ease of use in conjunction with binocular indirect ophthalmoscopy.13 In 1988, the results of the Cryotherapy for Retinopathy of Prematurity study demonstrated a significant reduction in unfavorable anatomical and functional outcomes in premature infants with threshold ROP treated with cryotherapy (when compared with control eyes).3,5,13,29 However, cryotherapy for ROP was associated with a moderate incidence of undesired outcomes including periocular inflammation, ablation of extensive areas of peripheral retina, high myopia, retinal dragging, and retinal folds with poor visual acuity.

Development of new less-invasive methods of retinal ablation, in particular the portable solid-state compact diode laser, drove the replacement of cryotherapy.19,28,29 In 2004, laser photocoagulation became the standard of care for type 1 ROP after the Early Treatment for Retinopathy of Prematurity study reported the efficacy of laser ablative therapy in high-risk eyes.5,9,30,31 Laser ablation has several advantages, including precise delivery, less traumatic procedural, reduced ocular morbidity, and improved long-term outcomes.5,12,13 In addition, when compared with anti-VEGF medications, laser photocoagulation does not cause specific systemic adverse events and has more predictable recurrences (in frequency and time of appearance).32

However, laser ablation has the disadvantages of being time-consuming and technically challenging procedurally, and requiring special equipment. These unfavorable factors may limit laser use in countries with restricted medical personnel. In addition, laser ablation may cause stress to the neonate, may require sedation or intubation of the infant, shows a delayed response, and has potential ocular adverse effects like high myopia and permanent peripheral visual field loss.3,9,33 Other adverse events reported after laser treatment, such as cataracts and vitreous hemorrhage, are rare but can occur even without treatment or as a consequence of other treatments, whereas corneal opacities, anterior segment ischemia, corneal and iris burns exudative detachments, and phthisis bulbi are also possible but uncommon.13 Also, a high prevalence of amblyopia and strabismus has been observed in long-term follow-up observations (possibly related to the refractive errors and the increase in macular thickness with flattened foveal contour induced after treatment).13 Moreover, despite adequate laser ablation up to 50% of cases with AP-ROP continue to progress and regardless of good anatomical success rates, visual outcomes are generally poor.3,13,16,24 Therefore, the search for simpler and more efficient strategies, which do not involve the destruction of the peripheral retina, led to the assessment of intravitreal anti-VEGF medications for ROP.1,3,5,8

Anti-VEGF Agents

Anti-VEGF agents have been an attractive therapeutic target for ROP due to their ability to inhibit pathologic neovascularization.3,12,13 In recent years, their intravitreal administration has largely increased as they have proven their efficacy in multiple studies.3,5,8,13 Also, anti-VEGF medications have shown better success rates in the treatment of eyes with severe ROP, such as zone 1 ROP and AP-ROP.8 Moreover, when compared with peripheral laser ablation, anti-VEGF therapy has a larger treatment window, is procedurally easier and faster, requires fewer resources (no special equipment and no sedation, eliminating the risks of general anesthesia), can be applied in presence of media opacities and in unstable infants unable to undergo laser procedure, is capable of inducing rapid anatomical responses (promoting faster vascular regression and allowing a better development of the fovea, posterior and anterior retina), preserves the visual field, and causes less refractive errors.8,9,32–34 Currently, the available drugs that inhibit VEGF and have been evaluated for ROP treatment including bevacizumab, ranibizumab, aflibercept, pegaptanib, and conbercept.


Bevacizumab is a full-length humanized murine IgG monoclonal antibody that has a molecular weight of 149 kD and binds to all VEGF isoforms.15,35,36 It has a long half-life in the vitreous (5.6 days in adults), a serum peak level of approximately 2 weeks post-injection, and a serum half-life of 21 days in preterm infants.4,13,16,37,38 Moreover, it has been widely employed as an intravitreal treatment for multiple retinal diseases and, to date, it has been the most frequently used and studied intravitreal anti-VEGF for ROP due to its widespread availability, low cost, and effectivity (with a low number of recurrences and low reported adverse events) (Table 1).3,8,35,36,37,39–41

Anti-VEGF Medications for ROP

It has been documented that after intravitreal bevacizumab injections, a decrease of VEGF serum levels in ROP patients may occur for as long as 8 weeks after its administration (with significant negative correlation)38,42–45; however, the clinical significance of this finding is uncertain given the scarcity of data on normal systemic VEGF levels of preterm newborn infants.38,42–46 Also, when comparing between VEGF serum levels of ROP patients treated with bevacizumab and ROP babies treated with laser or premature newborns without ROP, the systemic values of VEGF have shown controversial results (as some studies report a significative difference between the 2 groups, whereas others find no differences).4,37,47,48

In 2011, the Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity trial studied intravitreal bevacizumab as an alternative for ROP management, demonstrating the efficacy of bevacizumab for treatment of Zone 1 or posterior Zone 2 stage 3+ ROP.2 When compared with laser treatment, the rate of recurrence of ROP did not differ in patients with zone II posterior disease; however, zone I disease recurrence was significantly reduced with anti-VEGF treatment (Table 2).2 Since then, many additional investigators have evaluated anti-VEGF treatment for ROP, reporting their findings in >200 articles.2,3

Randomized Studies Evaluating Intravitreal Anti-VEGF for Treatment of Retinopathy of Prematurity


Ranibizumab is a humanized monoclonal antibody fragment of 48 kDa that, like bevacizumab, has affinity for all the isoforms of VEGF.15,35,36 However, when compared with bevacizumab, ranibizumab has 5- to 20-fold greater potency on a molar basis and increased affinity for VEGF, and the advantage of a shorter serum half-life (2 hours in adults) which may reduce its potential toxicity in premature infants (Table 1).4,10,15,35,36,39,41,49–51 Moreover, although a transient reduction in plasma VEGF levels has been documented after its intravitreal administration in premature infants, its systemic effect on VEGF has been proven to be less prolonged (7 days) and intense than bevacizumab.16,45,52–54 As a consequence of the previous theoretical advantages of ranibizumab over bevacizumab, the reports on ranibizumab use for ROP treatment have increased in recent years.15,45

The recent results of the Phase III RAINBOW study indicate that intravitreal use of ranibizumab is an efficacious and well-tolerated treatment for ROP.4 In this study, treatment success was achieved in 80% of patients treated with 0.2 mg ranibizumab (compared with 66% success in patients treated with laser) and better ocular anatomic outcomes were documented. Also, no clear evidence of suppression of systemic VEGF levels was found, and serum ranibizumab levels decreased slowly (detectable but reduced at day 29).4 Moreover, ranibizumab showed an acceptable short-term safety profile (with no systemic events related to its use) and ocular adverse events were compatible with the established profile for ranibizumab in adults (Table 2).4 The long-term evaluation on safety data and functional outcomes (to 5 years of age) will be included in the ongoing RAINBOW extension study.4


Aflibercept is a 115 kDa recombinant fusion protein that contains the Fc portion of human IgG1 combined with VEGF-binding portions from the extracellular domains of human VEGF receptors 1 and 2.5,55 These features allow aflibercept to have a high binding affinity, have an intraocular half-life of 4.8 days in adults, and shorter serum half-life than bevacizumab (11.4 days in adults). This medication is capable of inhibiting all isoforms of VEGF-A and placental growth factor and, after its intravitreal administration, has the ability to penetrate the retina and access the systemic circulation, reducing the systemic levels of VEGF for 12 weeks (Table 1).10,36,41,46,49 Although extensively used in adult retinal pathologies, the experience using aflibercept for ROP is minimal. Early effectiveness has been documented in small studies treating prethreshold ROP, threshold ROP, and AP-ROP.11,55,56

Other Anti-VEGF Agents

Pegaptanib was the first anti-VEGF drug licensed for the treatment of neovascular age-related macular degeneration in adults. It is a pegylated RNA aptamer with the ability to selectively suppress VEGF-165.10,32 Only a scarce number of studies have evaluated its efficacy in ROP and its use in combination with laser was effective in reducing the risk of retinal detachment in premature infants with type 1 ROP.10,32,57,58

Likewise, in China, conbercept has been approved to treat neovascular age-related macular degeneration.59 Conbercept is a recombinant fusion protein, composed of the Fc region of human IgG1, the second Ig domain of VEGFR1, and the third and fourth Ig domain of VEGFR2, that has the ability to bind to placental growth factor and all VEGF isoforms.60–62 When compared with ranibizumab and bevacizumab, conbercept has shown higher VEGF binding capacity and longer half-life in the vitreous. There is limited experience on its use for ROP treatment (due to its lack of availability in most countries) and concern regarding its safety (given that conbercept has been associated to lower serum VEGF levels possibly due to higher systemic absorption).60–62

Concerns Regarding Anti-VEGF Use for ROP

One of the most important concerns regarding anti-VEGF use for ROP is that the long-term systemic profile of the medications is yet to be determined.5,9 VEGF is a fundamental factor for angiogenesis regulation not only for the developing retina but also for the central nervous system, lung, kidney, bone, and hematopoietic system. Intravitreal anti-VEGF medications carry the possibility of systemic absorption and activity in preterm infants, which is supported by the presence of anti-VEGF agents in the systemic circulation with a decrease in serum VEGF concentrations after intravitreal anti-VEGF treatment in premature infants, and the rare case report of bilateral improvement after monocular anti-VEGF injection.3,16 Hence, there may be potential for untoward systemic adverse effects when altering anti-VEGF pathways, especially in preterm infants with often impaired immune functions and an immature blood-retinal barrier.5

Coupled with this, the intravitreal administration of anti-VEGF for ROP has the potential risk of ocular adverse effects and/or retinal abnormalities and requires a more rigorous, frequent and longer ocular follow-up to detect recurrences of the disease.4,9

Anti-VEGF Safety in Animal Models

To study the efficacy and safety of inhibition of VEGF, preclinical studies use animal models of oxygen-induced retinopathy (OIR), which are capable of generating hypoxia-induced intravitreal neovascularization.63 Although most of the animal models of OIR feature some of the characteristics of human ROP, the rat and mouse OIR models are typically utilized.1 However, the use of the canine models has been supported by multiple investigators, as it has proven to share multiple features with human ROP including equivalent eye size and vitreous volume, pathologic neovascularization that persists for a long time and does not spontaneously regress, and absence of astrocytes preceding the forming inner vasculature.64,65

The use of bevacizumab and ranibizumab in animal models is not optimal; therefore, specific neutralizing antibodies (such as VEGF164 rat neutralizing antibody or anti-VEGFR2 neutralizing antibody for canine models) or other anti-VEGF medications (such as aflibercept) must be employed in OIR models.1,63,65 Likewise, safety is difficult to assess but can be measured in terms of weight gain (total body weight and specific organ weight), serum VEGF, anatomic changes, neuroretinal function (measured by electroretinography changes), and by the presence of molecular signals (eg, caspase 3, mRNA of VEGF and VEGF-receptors).1,63

To date, several investigators have proven that suppression of the bioactivity of VEGF leads to restriction of intravitreal neovascularization in animals; nevertheless, the safety of VEGF inhibition is still being studied. McCloskey et al63 reported their findings on rodents treated with intravitreal anti-VEGFs. They detected a decrease in weight gain and a reduction of systemic VEGF, resulting in concerns about the systemic safety of anti-VEGF treatment for human preterm newborns.63 In contrast, Khalili et al66 did not observe differences in total body and organ weight in rats treated with intraperitoneal anti-VEGF and mortality was not proven to be affected. Still, VEGF mRNA expression in kidneys and lungs increased and the heart had anatomical changes consistent with pulmonary hypertension.66 Additionally, Tokunaga et al67 reported their long-term findings on retinal VEGF suppression in an OIR murine model. In their study, aflibercept was injected into the vitreous cavity of mice and, despite vascular growth recovery was reported, a decrease of B-wave amplitude in electroretinography was observed (which may indicate a reduction of neuroretinal function) and anatomic alterations were documented (reduction of retinal thickness, loss of bipolar and amacrine cells, and disruption of outer nuclear layer).67

On the contrary, OIR canine models have proven that the dosage of anti-VEGF drugs is of the utmost importance given that medications (such as anti-VEGFR2) are capable not only of inhibiting the formation of preretinal neovascularization but also suppressing the revascularization of the inner retina.65,68 This problem was assessed by Lutty et al who, by using low doses (5 μm) of aflibercept in OIR canine models, were able to inhibit and cause regression of preretinal neovascularization without affecting retinal revascularization.64,65

Overall, it can be affirmed that evidence regarding VEGF suppression in animal models has been shown to cause ocular and systemic adverse effects; however, their interpretation and adaptation to human ROP will always require caution.

Anti-VEGF Systemic Safety

As was previously stated, the increasing use of anti-VEGF treatment has raised concern on its safety profile and its potential effect on long-term development. Mounting evidence has shown differences in the growth and development of preterm patients, principally in low gestational age with morbidities, when compared with full-term healthy infants.67,69 Therefore, it is fundamental to deeply study and analyze the possible side effects of this promising ROP treatment, without forgetting that the ability of studies to discern between systemic disorders secondary to prematurity against anti-VEGF effects may be limited, particularly at very young ages.

To date, the potential systemic activity of intravitreal anti-VEGF treatments has been addressed by several investigators, given that pharmacological studies have shown that systemic absorption is possible. Most published studies have evaluated for neurological sequelae after anti-VEGF injections in preterm infants by measuring the neurodevelopmental function. To achieve this, most studies have used The Bayley Scales of Infant and Toddler Development, Third Edition (also known as the Bayley III scale). This instrument has the ability to measure the developmental functioning of infants and toddlers, from 1 to 42 months of age, with 5 distinct scales (the cognitive scale, the receptive language scale, the expressive language scale, the fine motor scale, and the gross motor scale).16,31,70–74 Other methods that have been also used to evaluate the development of ROP patients include the Ages and Stages Questionnaire, the absence or presence of cerebral palsy (and its severity), the existence of hearing loss, and the presence of visual impairment.31,72–74

In 2016, a retrospective study of 125 children with treated ROP indicated that patients who received intravitreal bevacizumab had lower motor scores and higher risk for severe neurodevelopment disability when compared with patients treated with laser ablation.73 That same year, Lien et al71 published a retrospective observational case series that aimed to compare the neurodevelopment of 61 premature patients treated with laser photocoagulation alone, bevacizumab alone, or bevacizumab with rescue laser treatment. At the age of 24 months, no differences were identified in the neurodevelopment of patients treated with bevacizumab or laser only; however, a statistically significant higher incidence of mental and psychomotor impairment was observed in patients who received both laser and bevacizumab.71 Likewise, Natarajan et al74 compared the neurodevelopmental outcomes of 181 extremely preterm infants that either received bevacizumab or underwent laser or cryotherapy for ROP. The authors concluded that patients who received bevacizumab had poorer early cognitive outcomes and higher mortality; nevertheless, those findings could be confounded by the differences between groups (patients in the bevacizumab group had significantly lower birth weight, longer duration of ventilation, and longer use of supplemental oxygen patients).74

In contrast, 2 retrospective analyses refuted the presence of outcome differences between infants who received intravitreal bevacizumab or laser treatment.31,70 This was further supported by Fan et al72 who prospectively observed that, even when bevacizumab treated ROP infants had lower gestational age (when compared with premature children without ROP or ROP patients without treatment), no significant differences were observed in the neurodevelopment assessment. Notwithstanding, although the risk for poor neurodevelopmental outcomes was not significantly different between groups, it must be highlighted that it is possible that the last studies were not powered to prove the absence of neurodevelopmental delay.72

In addition, other complications such as thromboembolic events, respiratory failure or infection, hepatic dysfunction, and nephropathy, have been reported.2,75–78 Nonetheless, information regarding these rare complications is limited and their association with anti-VEGF therapy has not been conclusively demonstrated.3

As a result of the conflicting findings between studies aimed to investigate the systemic safety of anti-VEGF medications, investigators have focused on identifying lower effective doses that may decrease the risk of neurodevelopmental adverse events or other maturation complications. Wallace et al performed a prospective study in which deescalation therapy with bevacizumab was applied to premature infants with type 1 ROP. A dose as low as 0.031 mg was able to improve disease12; however, upon longer follow-up, 5% of patients showed early treatment failure and 18% of patients presented late ROP recurrence with no relationship between recurrence and lower dose (Table 2).79 Similarly, in the Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity study, Stahl et al17 prospectively evaluated the effect of reduced doses of ranibizumab for ROP finding that 0.12 mg doses were effective in treating ROP without causing changes in plasma VEGF (Table 2). However, the RAINBOW study found that the higher 0.2 mg dose of ranibizumab was more effective with less unfavorable structural outcomes than 0.1 mg ranibizumab (Table 2).4 Additionally, Cheng et al61 assessed the effect of the reduction of conbercept in the treatment of ROP concluding that 0.15 mg of conbercept were adequate for treating Zone 2 Stage 2/3 plus ROP. Thus each agent must be considered individually to find the optimal lowest dose to give maximal effect, and lower doses of anti-VEGF may not necessarily confer more safety.

Anti-VEGF Ocular Safety

Most of the ocular risks of anti-VEGF therapy are related to the injection procedure and are fortunately uncommon. Endophthalmitis, intraocular inflammation, intraocular pressure elevation, corneal opacification, iatrogenic cataract, rhegmatogenous retinal detachment, and ocular hemorrhage are some of the adverse effects that have been reported in the literature.3,10,80 Additional uncommon adverse events include vascular sheathing, Retinal pigment epithelium rupture, choroidal ischemia, choroidal rupture, and optic atrophy.2,3,15,81 Moreover, when anti-VEGF is applied too late, contraction of membranes may occur causing retinal dragging and/or tractional retinal detachment.82 Also, a paradoxical response to anti-VEGF injection with subsequent fibrosis (requiring surgical treatment) has been described in severe cases of ROP up to 4 months after the administration of the medication.13

Some of the long-term ocular complications that have been reported consist of intraocular vascular abnormalities (such as abnormal vascular branching and shunt vessels)10,83 and refractive errors (such as myopia, high myopia, and astigmatism).14,84 Notwithstanding, solid evidence shows that, when compared with laser photocoagulation, these complications have a lower incidence after anti-VEGF therapy.14

Unfortunately, the technical difficulty of performing a complete evaluation in a child and the possible need for multiple examinations under anesthesia, the potential of a delayed or atypical presentation, the lack of clear clinical features, the difficulty in differentiating between other differential diagnoses with similar clinical characteristics, the likelihood of initial misdiagnosis, and the possibility of systemic involvement (eg, extraocular spread of endophthalmitis) make the diagnosis and treatment of these ocular complications very challenging.85 However, measures can easily be applied to minimize the risk of complications including careful selection of treatment in patients with advanced stages of ROP, use of adequate materials for injection (including shorter and thinner needles), and execution of a meticulous aseptic technique with an accurate injection technique (taking into consideration the anatomical differences of premature children).3

Anti-VEGF Therapy Combined With Laser Photocoagulation

The use of anti-VEGF medications combined with laser photocoagulation has been reported in multiple publications. These medications can be used in combination with laser as a rescue treatment for failed laser treatment or as primary treatment followed by laser if complete vascularization fails to occur.13 Other authors have reported the primary simultaneous use of both treatments, particularly in complicated cases.

In a prospective randomized trial by Autrata et al,57 the use of pegaptanib combined with laser therapy (for zone 1 and posterior zone 2, stage 3+ROP) showed no recurrence of the disease and a lower statistically significant final unfavorable outcome when compared with laser alone. Likewise, Kim et al86 reported no recurrence in eyes with zone 1 ROP treated with bevacizumab and laser. Nazari et al87 described no recurrence and absence of unfavorable outcomes in patients, with vitreous or retinal hemorrhages and severe ROP who were treated with laser ablation followed by bevacizumab. Wutthiworawong et al88 demonstrated no recurrence and favorable anatomic outcomes in patients with AP-ROP treated with laser and bevacizumab. However, Tanaka et al89 described recurrence of ROP after combined bevacizumab and laser treatment for AP-ROP; Altinsoy et al90 reported variable results (favorable and unfavorable) after bevacizumab and laser treatment for AP-ROP; and a case report by Jang et al91 described recurrence of the disease 4 months after treatment in a patient treated with laser and ranibizumab for zone 1, stage 3+ ROP.

It is important to highlight that laser has the capacity of breaking down of the blood-retinal barrier, potentially allowing anti-VEGF medications to escape the eye (which would increase the systemic exposition to the drug).92 Therefore, when considering the use of anti-VEGF agents combined with laser treatment great caution should be taken.

Recurrence of ROP

After the intravitreal administration of an anti-VEGF medication, the abnormal vascular development of ROP stops as a consequence of VEGF suppression. In some eyes, this drug administration seems to cause suppression of all angiogenic activity and may cause incomplete periphery retinal vascularization or long-term persistence of peripheral avascular retina.8,13 This complication seems to be related to gestational age at birth or genetic factors, may be dependent of the anti-VEGF medication dosage, has rates that vary from 3% to 80%, and may cause recurrence of the disease.2,33,60,62,64,65,67,85,93

Currently, there is no consensus on the definition of recurrence of ROP after intravitreal anti-VEGF treatment; however, multiple studies have employed the term recurrence to describe the evidence of progression of the disease that requires the application of additional treatment.3,8 This definition may include progression of disease despite previous treatment, and reappearance of neovascularization, fibrovascular proliferation, or plus disease after previous improvement.3 Even if progression is not observed, leakage at the peripheral vascular-avascular junction and persistent peripheral avascularity have been also considered as “treatment-requiring” (to prevent adverse events, such as retinal holes and retinal detachment).3,8,94 The locations prone to recurrent neovascularization are the advancing edge of retinal vascularization and the initial ridge and extraretinal fibrovascular proliferative complex.8,92 Additionally, the risk factors with the greatest significance for ROP recurrence are lower birth weight, extended duration of hospitalization, and presence of AP-ROP.92

ROP recurrence has been extensively documented. Most of the patients treated with laser photocoagulation show regression of the disease after 1 session.13 However, a small but significant percentage of patients (usually with severe ROP) may require additional treatment, generally within the first 9 weeks after treatment.3 In contrast, rates of ROP recurrence after intravitreal administration of anti-VEGF medications have been reported in a higher percentage of patients; however, rates vary depending on the type of medication used (being ranibizumab the medication with the higher frequency of recurrence).3 Also, the time between treatment and recurrence may be longer after anti-VEGF treatment.3 This late reactivation is a consequence of the delay on the normal vascular development produced by the medication and has been reported in up to 2 years after treatment.3,8

The Early Treatment for Retinopathy of Prematurity study reported that after laser therapy 13.9% of patients required additional treatment.30 Yetik et al95 described that 4.6% of patients with prethreshold, threshold, and AP-ROP disease treated with bevacizumab, required additional injections. The Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity study reported that recurrence was more common in patients who received laser versus bevacizumab (22 vs 4%); however, the time to recurrence was longer in the bevacizumab group (19.2 vs 6.4 weeks).2 In contrast, Hwang et al reported that in eyes with type 1 ROP the rate recurrence after laser was lower and presented earlier when compared with bevacizumab (3% recurrence 2.6 after laser vs 14% recurrence 9 weeks after bevacizumab).96 Mueller et al97 confirmed Huang's findings on type I ROP when they observed 0% recurrence with laser versus 12% recurrence in 12.7 weeks with bevacizumab. Likewise, Karkhaneh et al showed a similar trend in eyes with zone 2, stage 2–3+ ROP (1.4% recurrence 3 weeks after laser vs 10.5% recurrence 5 weeks after bevacizumab).98

Conversely, Zhang et al showed that intravitreal ranibizumab in eyes with zone 2, stage 2 or 3+ disease had higher rates of recurrence when compared with laser (52% after ranibizumab versus 4% after laser).99 Li et al100 reported 22% of recurrence in AP-ROP patients 2 to 8 weeks after ranibizumab treatment and Erol et al78 showed that type 1 ROP recurred in 27% of eyes treated with ranibizumab. Likewise, Lyu et al101 reported 64% recurrence in type 1 ROP, 7.9 weeks after ranibizumab treatment.

Undoubtedly, the follow-up period after managing acute ROP with anti-VEGF treatment should be prolonged, to effectively identify all cases of ROP recurrence, and the treatment of recurrent ROP should be based on the severity of the disease.3,8 Anti-VEGF agents can be repeated as it does not constitute a single-session therapy; however, the follow-up period should be extended as the risk of delayed and/or incomplete retinal vascularization exists (especially for zone 1 ROP).8 Laser and vitrectomy are other useful treatment choices that should be considered.8

Current Anti-VEGF Use

Nowadays, diode laser is the mainstay of treatment in developed economies; however, in developing countries, the lack of availability of lasers and the scarcity of well-trained ophthalmologists who can operate them made anti-VEGF treatment an appealing option.13 The wide availability and ease on accessibility (particularly for bevacizumab, a more a cost-effective option compared with other more expensive anti-VEGF agents), and the simplicity of administration by less experienced physicians, account for its increased use as a first-line therapy or as a rescue treatment in many middle-income and emerging economies.5,13,32

Nevertheless, the acceptance of anti-VEGF treatment has been limited due to the need for an extended follow-up period (that would require multiple examinations under anesthesia for older/larger patients), its potential late recurrence (that would require additional treatment), the possibility of adverse outcomes (such as persistent peripheral avascular retina after treatment, membrane contraction with retinal detachment, or delayed onset retinal detachment), and the requirement of expertise by the physician (as he/she should be able to perform an adequate examination that would allow a timely detection and treatment of adverse events and recurrences).13,14,92


Our review has several limitations. Given its qualitative nature, it is unavoidably susceptible to study selection bias. Likewise, it lacks strict inclusion criteria, which may increase the importance given to small, nonrandomized, and/or uncontrolled studies that may not be powered to prove the presence or absence of statistically significant differences but may provide the advantage of including clinically significant results.


In this new era, when more premature infants are surviving and there are still limited resources and trained personnel available to apply treatment to all ROP children, anti-VEGF therapy has demonstrated to be an efficacious option for treating this potentially blinding disease. Unfortunately, there is conflicting evidence in the literature in regard to the systemic and ocular safety of these agents and, to date, it is difficult to discriminate between neurological problems secondary to prematurity or due to the use of anti-VEGF treatments. Larger studies, especially prospective ones, may help answer these safety questions. Until safety concerns are clarified by further studies, reasonable options would be to recur to other treatments, such as laser photocoagulation, use lower doses of anti-VEGF agents to decrease the systemic exposure, and follow-up patients for longer periods, to detect recurrences or potentially treatable adverse events.


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anti-VEGF injection; intravitreal injection; retinopathy of prematurity; ROP; safety

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