Retinopathy Of Prematurity & Anti-VEGF Therapy

Retinopathy Of Prematurity & Anti-VEGF Therapy

March 22, 2021

Retinopathy of prematurity (ROP) is a potentially blinding eye disorder that primarily affects premature infants weighing about 2¾ pounds (1250 grams) or less that are born before 31 weeks of gestation (a full-term pregnancy has a gestation of 38–42 weeks).

The smaller a baby is at birth, the more likely that baby is to develop ROP. This disorder — which usually develops in both eyes — is one of the most common causes of visual loss in childhood and can lead to lifelong vision impairment and blindness. ROP was first diagnosed in 1942.

The retinas are the light-sensitive linings of the insides of the eyes. In infants born prematurely, the blood vessels that supply the retinas are not yet completely developed.

Although blood vessel growth continues after birth, these vessels may develop in an abnormal, disorganized pattern, known as ROP. In some affected infants, the changes associated with ROP spontaneously subside.

However, in others, ROP may lead to bleeding, scarring of the retina, retinal detachment and visual loss.

Even in cases in which ROP changes cease or regress spontaneously, affected children may have an increased risk of certain eye (ocular) abnormalities, including nearsightedness, misalignment of the eyes (strabismus), and/or future retinal detachment.

The two major risk factors for ROP are a low birth weight and premature delivery.

Signs & Symptoms

Retinopathy of prematurity (ROP) is characterized by abnormal and uncontrolled development of blood vessels in the back of the eye (i.e., the retina) in premature infants.

The retina is the innermost tissue layer in which images are focused at the back of the eye; it contains light-responding nerve cells (rods and cones) that convert light images into nerve impulses, which are conveyed via the optic nerve to the brain.

During fetal development–at about 16 weeks’ gestation–blood vessels that supply the retina begin to bud from the center of the retina (i.e., near the optic nerve), gradually reaching the front edges (periphery) of the retina at about the time of normal delivery.

Thus, when infants are born prematurely, this process is incomplete. (Gestation is the period of time from fertilization to birth. Full term is the normal period of human gestation from about 38 to 42 weeks.)

ROP occurs when the blood vessel development is abnormal, with disorganized branching of retinal vessels and anomalous interconnections.

ROP is descriptively localized within the eye according to three anatomic “zones”, based on the specific areas of the retina that are malformed (i.e., posterior (rear-most), middle, and anterior (most forward in the eye) zones).



It is also classified into five sequential stages, based on the severity of the disease. In infants with early-stage ROP, the normal growth of blood vessels ends abruptly (stage 1), marked by a flat, whitish, “demarcation” line separating retinal regions that are and are not supplied with blood vessels (vascularized and avascular retina); multiple, abnormal, wide-branching blood vessels often lead into the line.

In some cases, this line may then grow into a “ridge” that is higher and wider, extends inward above the plane of the retina, and may change in color from white to pink (if the central core fills with blood) (stage 2).

Stages 1 and 2 may improve without treatment (spontaneous involution). In stage 3, the ridge increases in dimension, and new, abnormal blood vessels extend internally toward the vitreous humor gel that fills the large rear cavity of the eye between the retina and the lens., or on and along the retinal surface (stage 3).

Stage 3 often requires treatment intervention. (For information on treatment, see the Standard Therapies section below.)

The overgrowth of these abnormal blood vessels in the wrong locations may lead to development of scar tissue. The scars may then contract and tug on the retina, causing its separation from underlying, supporting tissue (retinal detachment).

Stage 4 is characterized by partial detachment of the retina, potentially resulting in loss of vision. This stage is further categorized into two phases, based on whether the macula (the center vision area) is or is not involved.

Macular detachment results in a marked deterioration of vision. Stage 5 indicates complete and total retinal detachment, sometimes leading to a white mass behind the pupil, cataract, and blindness. (Note: The term “retrolental fibroplasia” was used formerly as the name for ROP; however, it is used currently only to refer to advanced stages of ROP).

In some affected infants, unusual blood vessel appearance may suggest a rapidly progressive course of disease.

These cases have abnormal growth, widening (dilation), and twisting (tortuosity) of blood vessels near the optic nerve in the back of the eye and on the surface of the colored region surrounding the pupil of the eye (iris); rigidity of the pupil (meaning that it is difficult to dilate); and haziness of the vitreous humor.

This situation is labeled “Plus Disease”, and this is a marker of poor prognosis unless treatment is performed.

According to medical literature, the disease process ceases and returns to its original condition (involutes) spontaneously in approximately 90 percent of affected infants. In the birth weight category under 2 lb. 2 oz. (1250 g), fewer than 10 percent of cases progress to severe ROP, characterized by proliferation of blood vessels outside the retina, retinal detachment, and visual loss.

In those affected by end-stage disease, the eyes may be unusually small and sunken (phthisis bulbi), when the retina appears as a whitish mass pressing against the lens (leukokoria).


Some may also develop increased fluid pressure within the eye (glaucoma), loss of transparency of the lens of the eye (cataract), signs of inflammation, and/or other changes.

Even after the disease subsides, affected children may have an increased risk of certain eye (ocular) abnormalities.

In some instances, arrested or regressed ROP may leave demarcation lines or changes of the underlying pigment layer of the retina, retinal scarring and displacement of the macula, and may increase the risk of retinal detachment later in life.

Affected children also have an increased incidence of nearsightedness (myopia); decreased clearness of vision (visual acuity) due to lack of a clear image falling on the retina (amblyopia); misalignment of the eyes (strabismus); unequal focusing ability of the two eyes (anisometropia); and/or other abnormalities.

Advancements in antenatal care, along with the increased establishment of neonatal intensive care units, have resulted in improved survival of preterm and lowbirth-weight infants.

In consequence, the number of infants at risk for developing ROP is increasing and thus updated management approach is needed in this debilitating disease.


Vascular endothelial growth factor (VEGF) is an important angiogenic factor during embryonic vascular development.

It leads to the growth of retinal blood vessels toward the avascular peripheral retina. Phase 1 ROP occurs during 22 to 30 weeks of gestation, whereby relative hyperoxia causes low VEGF levels and cessation of blood vessels growth (vasoattenuation).

Subsequently, phase 2 ROP occurs during 31 to 41 weeks of gestation. The increased metabolic demand in peripheral avascular retina induces a hypoxic milieu, stimulating VEGF release and abnormal vessel proliferation (vasoproliferation).

Over the past 50 years, ROP treatment has limited treatment modalities such as cryotherapy and laser photocoagulation. More recently, there has been growing evidence to support the use of anti-VEGF agents for the treatment of ROP.

Figure 1 shows both regression of retinopathy of prematurity (ROP) after treatment by laser photocoagulation or intravitreal injection of anti-VEGF.

Currently, the use of anti-VEGFs is off label. However, there are increasing numbers of studies examining their efficacy and safety in treating ROP.


Bevacizumab – The most commonly used anti-VEGF agents is bevacizumab (Avastin; Genentech), a 148-kDa recombinant humanized antibody that binds to VEGF-A isoforms.

The Bevacizumab Eliminates the Angiogenic Threat for Retinopathy of Prematurity (BEAT-ROP) study was the first randomized clinical trial that compared the use of anti-VEGF (bevacizumab) with conventional laser therapy.

Bevacizumab reduced the risk of reactivation before 54 weeks of postmenstrual age (PMA) by 5 times as compared to conventional laser therapy for infants with zone I disease.

Also, the peripheral retina continued to vascularize after treatment with bevacizumab, whereas with conventional laser therapy, the peripheral retina would have been ablated. Anti-VEGF therapy was also useful for very aggressive posterior ROP.

However, the trial did not report on mortality or on local or systemic toxicity. There was also a risk of late reactivation up to approximately 16 weeks after bevacizumab injection.

There are other similar studies with smaller sample sizes which compared bevacizumab to laser photocoagulation. Results by Lepore et al6 revealed in his study that 2/11 (18%) laser-treated eyes had reactivation while 0/12 (0%) eyes recurred in bevacizumab-treated eyes.

Eyes treated with bevacizumab had abnormal features seen under fluorescein angiography, such as peripheral avascular areas, abnormal vessel branching, or absence of foveal avascular zone, but these were not seen in laser-treated eyes at 9 months of age.

The longterm implications of these angiographic abnormalities as patients develop into adulthood are still unknown.

RanibizumabRanibizumab (Lucentis; Genentech) is a smaller molecule than bevacizumab that is more rapidly eliminated from the bloodstream and thus has potentially less systemic toxicity.

Recently, the multicenter Ranibizumab Compared With Laser Therapy for the Treatment of Infants Born Prematurely With Retinopathy of Prematurity (RAINBOW) randomized clinical trial was performed to compare intravitreal ranibizumab with laser photocoagulation for treating ROP infants.

The authors found that treatment success was achieved in 80% of infants treated with a 0.2-mg dose of ranibizumab, 75% with the 0.1-mg dose, and only 66.2% following laser.

However, there are concerns that there is a higher reactivation of ROP with ranibizumab use. For instance, a recurrence rate as high as 83% within 6 weeks of injection was reported.

On the other hand, the Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity (CARE-ROP) study group revealed that 0.12 mg of ranibizumab was as effective as 0.20 mg in ROP treatment.

The optimal dose of ranibizumab has not been ascertained and therefore more clinical studies are warranted.

Aflibercept – Approved for the treatment of wet macular degeneration in 2011, aflibercept (Eylea; Regeneron) has been used for ROP treatment only for the past 5 years.

Due to high binding affinity and longer intraocular halflife, a longer duration of clinical action is theorized to occur after intravitreal injection of aflibercept.

Sukgen et al9 demonstrated that recurrence for aflibercept treatment was less frequent and much later than for ranibizumab, even though the 2 drugs showed comparable activities in the early period, such as prompt regression of ROP and continued peripheral retinal vascularization.

Largescale, clinical trials are currently ongoing to assess the efficacy and safety of aflibercept in ROP treatment.



The relative advantages of antiVEGF treatment over that of laser photocoagulation include that it is useful for patients with media opacity, tunica vasculosa lentis, and rigid pupil; it is readily applicable for patients with unstable systemic conditions; there is no need to intubate; there is increased success rate for zone I disease or aggressive posterior ROP; there is further vascularization of retinal vasculature toward the peripheral retina; it is less likely that myopia or high myopia will develop; there is better bare vision; and there is less foveal hypoplasia in the long run (Figure 2).

Desipte the advantanges, there are some concerns about this treatment. The injection technique is different from that for adult patients. It is usually performed at the site of pars plicata with the needle almost perpendicular to the injection surface.

The injected dose is half of an adult dose, and optimal dose for pediatric eyes is still unknown. Close follow-up after this treatment is needed to monitor treatment effects. It is important to look for signs of regression and reactivation following anti-VEGF for ROP patients.

Regression of the ROP lesion is characterized by gradual thinning and whitening of neovascular tissue and decrease of plus disease. Vascular changes in ROP reactivation include recurrent vascular dilation and/or tortuosity, similar to acute phase “pre-plus” or plus disease or reappearance of neovascularization.

Additional concerns for the use of anti-VEGF for ROP inlcude risks of ocular complications, such as cataract and endophthalmitis following injection; late reactivation; the need for long-term follow-up after injection; the risk of increased retinal traction (crunch syndrome); abnormal retinal vascularization after the acute phase; uncertainty of future neurodevelopmental outcomes; and persistent avascular retinal areas and other angiographic anomalies.


VEGF is an important neurodevelopmental growth factor in the early newborn period and is involved in organogenesis, especially that of the lungs and kidneys.

In our previous study, we found that intravitreal bevacizumab or aflibercept could suppress serum VEGF levels for up to 2 months after treatment.

On the other hand, serum VEGF suppression was only 1 week with ranibizumab. Among the 3 anti-VEGF agents, ranibizumab had the least systemic suppressive effect.

This difference is presumably due to the larger molecular size of bevacizumab resulting in slower retinal clearance and therefore prolonged diffusion into the systemic circulation. What about the impact of anti-VEGF on neurodevelopmental outcomes in these patients?

More recently, our group conducted a prospective study to evaluate infants with type 1 ROP who underwent treatment with bevacizumab. Bayley III scores were determined at 1 to 3 years of age.

Premature infants with a history of ROP treatment with bevacizumab had similar refractive, visual, and neurodevelopmental outcomes compared to premature patients with ROP who did not require treatment.

On the contrary, some studies report negative neurodevelopmental outcome following anti-VEGF use.

Although anti-VEGF may lead to better structural outcomes of eyes and less refractive errors, there is a lack of long-term studies, especially prospective randomized studies, to identify a lasting effect on systemic organs or neurodevelopment.

Developmental deficits in cognition, emotional and behavioral development, and social adaptive functioning may emerge at older ages. Thus, studies involving longer followup of these anti-VEGF-treated infants are needed to fully assess any potential systemic adverse events resulting from intravitreal anti-VEGF treatment.

Anti-VEGF agents are increasingly being adopted over laser photocoagulation and cryotherapy due to the ease of administration, quick treatment response, and no need to purchase a laser machine.

There are, however, concerns about anti-VEGF treatment for ROP, including possible ocular complications and long-term systemic effects. Further studies are needed on the optimal doses, longterm efficacy, and systemic effects using them in ROP treatment.

Laser photocoagulation remains the gold standard for the treatment of ROP. Retina specialists must use both treatments carefully for children to achieve the best outcome. Knowing each treatment’s strengths and limitations is vital before we apply them to this vulnerable group of patients.