Retinopathy of Prematurity

Retinopathy of prematurity (ROP) is a serious vasoproliferative disorder that affects the retina of extremely premature infants. Milder forms of ROP often regress or heal without intervention; however, more advanced stages can lead to severe visual impairment or blindness. ROP remains a serious problem despite striking advances in neonatology: it can lead to lifelong disabilities for the smallest survivors of neonatal intensive care units (NICUs).

Retinopathy of prematurity (ROP) primarily occurs in extremely low birth weight (ELBW) infants. Most research suggests that a low birth weight, a young gestational age (GA) (see the Gestational Age from Estimated Date of Delivery calculator), and the severity of illness (eg, respiratory distress syndrome [RDS], bronchopulmonary dysplasia [BPD], sepsis) are associated risk factors. Other associations have been described; however, the severity of systemic illness appears to be a major predictor of severe disease. The smallest, sickest, and most immature infants are at the highest risk for serious disease. Race is also a factor: Black infants appear to have less severe ROP.[1, 2]

In essence, an early stage of retinal microvascular degeneration is followed by neovascularization that has the potential for the development of retinal detachment and permanent loss of vision.[3] A review by Fevereiro-Martins et al indicates that key contributory factors during this early stage include oxidative and nitrosative stress, as well as inflammatory processes. Nitric oxide synthase and arginase contribute to ischemia/reperfusion-induced neurovascular degeneration, mediators of the hypoxia-inducible factor pathway (eg, vascular endothelial growth factor [VEGF], metabolic factors such as succinate) drive destructive neovascularization, and the extracellular matrix is involved in hypoxia-induced retinal revascularization. Revascularization of the avascular zone is prevented by vasorepulsive molecules (semaphorin 3A).[3]

Retinal vasculature begins to develop around 16 weeks' gestation. It extends from the optic nerve head centrifugally toward the periphery. Full vascular maturation of the retina typically occurs near term (40 weeks). Premature birth results in a disruption of normal retinal vascular maturation. Exposure of newborn premature infants to hyperoxia downregulates retinal VEGF. Blood vessels constrict and can become obliterated, resulting in delays of normal retinal vascular development. This hyperoxia-vasocessation results in avascular peripheral retina, and it is seen clinically as stage 0 or stage 1 of retinopathy of prematurity. See the image below.

Early on, oxygen and nutrients can be delivered to the retina by means of diffusion from the rich vascular bed beneath the retina known as the choroid. The retina continues to grow in thickness and eventually outgrows this vascular supply, and the inner retina must receive oxygen and nutrients from the retinal vessels. Prolonged retinal hypoxia leads to an upregulation of VEGF, and the growth of abnormal/extraretinal vessels. Stage 2 ROP represents the first appearance of this abnormal growth, and it is seen clinically as a ridge at the border of the vascular-avascular retina (see the image below).

In addition to VEGF, this process is mediated by insulinlike growth factor-1 (IGF-1) and other cytokines.

Further growth of the abnormal vasculature tends to occur out of the plane of the retina and into the vitreous (stage 3 ROP). This is known clinically as neovascularization, because the vessels are largely incompetent, leaking proteins and other cytokines into the vitreous where they can precipitate localized contraction of the gel. This contraction can lead to traction and, eventually, elevation (detachment) of the retina (stages 4 and 5 ROP).

"Plus disease" is the dilation and tortuosity of the normal retinal vessels in the posterior pole (most posterior part) of the retina.

Dhaliwal et al found that ROP occurred with significantly greater frequency and severity in small-for-GA (SGA) infants compared with appropriate-for-GA (AGA) infants.[4] In a review of 1413 infants with birth weight less than 1500 g and/or GA of 26-31 weeks, infants with a birth weight below the tenth percentile for GA were more likely to develop any stage of ROP than their AGA peers (P< 0.01), and they were more likely to develop severe ROP (GA of 26-27 weeks, P< 0.01; GA of 28-31 weeks, P = 0.01).

United States data

The incidence of retinopathy of prematurity (ROP) varies with birth weight, but it is reported to be approximately 50-70% in infants whose weight is less than 1250 g at birth.

in a retrospective review (1989-1997), Hussain et al analyzed the incidence and the need for surgery in neonates with ROP who were born at 22-36 weeks' gestation.[5] The incidences were 21.3% (202 of 950 patients) for ROP of any stage and 4.6% (44 of 950 patients) for ROP at stage III or worse. No ROP was noted in infants born after 32 weeks' gestation, and no infant born after 28 weeks' gestation needed retinal surgery in this study. Despite the increased survival of extremely low birth weight (ELBW) infants, they found a considerable reduction in the incidence and severity of ROP compared with reports from an earlier period.[5] However, infants born before 28 weeks' gestation and those with birth weights less than 1000 g were at risk to need retinal surgical treatment for ROP.

Investigators from the Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOP-ROP) multicenter trial concluded that maintaining oxygen saturation in the high-90% range did not reduce the severity of the retinopathy when compared with the saturations in the low-90% range.[6] However, it did result in more adverse pulmonary events. In a subanalysis of infants who did not have plus disease (ie, tortuosity of vessels) at the time of study entry, the progression to threshold was significantly decreased when compared with the progression in infants with plus disease.[6] Thus, a critical window for oxygen administration may be determined.

International data

ROP is prevalent worldwide, and several reports have detailed the incidence and risk factors associated with the disease.

A Korean study reported a 20.7% incidence of ROP (88 of 425 premature babies), with a gestational age of 28 weeks or less and a birth weight of 1000 g or less were the most significant risk factors.[7] A study from Singapore reported a 29.2% incidence of ROP (165 of 564 ELBW infants), with a median age of onset of 35 weeks (range, 31-40 wk) postmenstrual age.[8] The risk factors for development of threshold ROP by regression analysis were maternal preeclampsia, birth weight, pulmonary hemorrhage, duration of ventilation, and duration of continuous positive airway pressure (CPAP).[8]

An observational study from United Kingdom designed to compare the characteristics of infants with severe ROP in countries with low, moderate, and high levels of development found that the mean birth weights of affected infants from highly developed countries was 737-763 g compared with 903-1527 g in less-developed countries.[9] Mean gestational ages of affected infants from highly developed countries were 25.3-25.6 weeks compared with 26.3-33.5 weeks in less-developed countries. Thus, larger and more mature infants seemed to be developing severe ROP in less-developed nations. This suggests that individual countries need to develop their own screening programs with criteria suited to their local population.

Race-, sex-, and age-related demographics

Some reports indicate a decreased incidence of progression to threshold disease in Black infants. Most evidence comes from the Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) study.[10] Further evidence that Black infants are less likely to develop severe ROP has been reported in studies of candidemia in ELBW infants.[11] The exact mechanism for the decreased incidence of progression to surgery in Black infants has not been described. Bizzaro et al showed a strong genetic predisposition to ROP when comparing monozygotic twins with dizygotic twins.[12]

Although some reports indicate a male predilection, the CRYO-ROP study revealed no differences based on sex.[10]

ROP is a disease of the immature retina, and the occurrence of ROP is inversely related to gestational age. Generally, infants born at 32 weeks or greater have an extremely low risk of ROP. EBLW infants, especially those with a more unstable clinical course (more comorbidities), are more likely to develop and require treatment for ROP.

The prognosis of retinopathy of prematurity (ROP) is predicted by the disease stage.

Patients who did not progress beyond stage 1 or stage 2 have a good prognosis, as do most successfully treated babies with zone II/III disease.

Patients with posterior zone I disease or stage 4 have a guarded prognosis for their vision. Infants with stage 5 disease mostly have extremely poor vision.

Long-term outcomes for serious disease, especially those babies who received treatment for ROP, include severe visual impairment and blindness. Infants with advanced ROP may develop vision-threatening conditions such as myopia, amblyopia, and strabismus, and these infants require close follow-up after discharge from the neonatal intensive care unit. Repka et al described the need for subsequent ophthalmic intervention in patients with ROP.[13]

The structure of the retina, especially the macula, of infants with ROP does not closely correlate with the function (vision). Specialized testing (Teller Acuity Cards) may be necessary early on to fully appreciate the visual function of each eye. Significant differences in the acuity between the eyes can rapidly lead to amblyopia of the poorer-seeing eye.

Complications

Late complications of ROP include myopia, amblyopia, strabismus, nystagmus, cataracts, retinal breaks, and retinal detachment.

VanderVeen et al observed strabismus is often variable and may improve by age 9 months.[14]

Follow-up by an ophthalmologist is required on a long-term basis (see "Long Term Monitoring" in the Treatment section).

The peripheral retina of adults with regressed or treated ROP is not normal. The abnormal development of the peripheral retina can lead to thinning (lattice degeneration) of the peripheral retina, retinal holes, tears, and detachments later in life.[15] Young adults with treated or regressed ROP should be counselled about these risks and should have regular dilated funduscopic examinations by a retina specialist. Special attention should be paid to teenagers who engage in contact sports; they and their parents should be taught the signs and symptoms of retinal tears and detachments. More frequent examinations (eg, at the start and conclusion of their sport's season) may be prudent.

Infants at highest risk for retinopathy of prematurity (ROP) are those with the lowest birth weights and youngest gestational ages. See the Gestational Age from Estimated Date of Delivery calculator.

Prolonged exposure to supplemental oxygen is also a risk factor.

The severity of illness (including sepsis), blood transfusions, days receiving mechanical ventilation, a patent ductus arteriosus, and intraventricular hemorrhage are also associated with ROP.

The effect of blood transfusion on ROP is controversial. The smallest, sickest infants receive more transfusions than their healthy counterparts and may have more frequent or severe ROP. However, theoretical risks associated with factors such as volume and iron load may place infants who receive more transfusions at higher risk for the condition.

Studies by Hellstrom et al have shown that infants whose postnatal gain weight is less than expected are at increased risk.[16]

Screening

An ophthalmologist experienced in evaluating infants for retinopathy of prematurity (ROP) should perform a screening examination.

International classification

To standardize examinations, a group of physicians organized an international classification of ROP (ICROP) in 1984 and updated the classification in 1987 and 2005.[17, 18]

ROP is characterized by three parameters: stage, zone, and plus disease (ie, tortuosity of vessels).

Examination recommendations

The American Academy of Pediatrics (AAP) and the American Academy of Ophthalmology (AAO) have joint recommendations for infants who should be screened for ROP.[19]

Screening should include those infants with a birth weight of less than 1500 g or a gestational age (GA) of 31 weeks or less, as well as selected infants with a birth weight of 1500-2000 g or a GA of more than 31 weeks with an unstable clinical course, including those who require cardiorespiratory support and those who are believed to be at high risk by their attending pediatrician or neonatologist.

The retinal screening examinations should be performed by an experienced ophthalmologist after pupillary dilation using binocular indirect ophthalmoscopy to detect ROP.

The time of initiation of ROP screening should be based on the infant's age. The onset of serious ROP correlates better with postmenstrual age (GA at birth + chronologic age) than with postnatal age; this means that the youngest infants at birth take the longest time to develop serious ROP.

Screening guidelines have been the focus of relatively recent studies. The issue of cost-effectiveness versus missing cases is controversial. In addition, Subhani et al suggested that infants should be examined by age 4-6 weeks, contrary to the standard postmenstrual age criteria.[20] The AAP guidelines for ROP screening suggested a schedule for detecting prethreshold ROP (99% confidence), usually well before any required treatment. See the table below.

Table. Timing of First Eye Examination Based on Gestational Age at Birth (Open Table in a new window)

This guideline should be considered tentative rather than evidence-based for infants with a GA of 22-23 weeks because of the small number of survivors in these categories.

Follow-up examinations are based on initial examination findings. Most infants are screened every 2 weeks. More frequent (once a week or less) follow-up is recommended in stage 1 or 2 ROP in zone I and in stage 3 ROP in zone II. The presence of plus disease requires careful evaluation because, in these cases, peripheral ablation is more appropriate rather than observation alone.

Screening examinations are continued until the blood vessels reach the anterior edge of the retina (complete retinal vascularization around 40 weeks' gestation) or until postmenstrual age of 45 weeks with no prethreshold disease (defined as stage 3 ROP in zone II, any ROP in zone I) or no worse ROP is present.

The evaluation of premature infants at risk for retinopathy of prematurity (ROP) should be limited to practitioners who are facile with binocular indirect ophthalmoscopy and scleral depression, and who have significant experience with ROP.

Ocular ultrasonography is an important tool when there is a media opacity (eg, cataract, vitreous hemorrhage) that precludes a view of the retina.

Some center utilize fundus photography with remote image reading.[21] There have been encouraging results with this approach.

Ophthalmologic evaluation in retinopathy of prematurity (ROP)

Record the vascular maturity (how far out the vessels have grown), as indicated by zone, stage of disease, and the presence or absence of plus disease or preplus disease.

Quantify the extent of ROP on the basis of number and contiguity of clock hours (meridians) in which the disease is present in the retina.

The International Classification of Retinopathy of Prematurity (ICROP) describes five stages of ROP, as follows[17] :

• Stage I is characterized by a line of demarcation between the vascular and avascular retina. Branching or arborization can be seen growing at the leading edge of the retinal vasculature. (See the image below.)

• Retinopathy of Prematurity. Stage I retinopathy of prematurity.

• Stage II is characterized by an elevated ridge, rather than a flat demarcation line. Flat neovascularization may be present but is posterior to the ridge. (See the following image.)

• Retinopathy of Prematurity. Stage II retinopathy of prematurity.

• Stage 3 is extraretinal neovascularization, or vessels that grow off the ridge into the vitreous toward the examiner. (See the image below.)

• Retinopathy of Prematurity. Stage III retinopathy of prematurity.

• Stage IV refers to partial retinal detachment. Stage IV-A is outside the macula; stage IV-B involves the macula.

• Stage IV is total retinal detachment. (See the following image.)

• Retinopathy of Prematurity. A comparison between attached and detached retina.

 

Some ophthalmologists describe an immature or avascular retina as stage 0 ROP.

Plus disease is an important marker of disease activity/severity; plus refers to severe tortuosity of vessels in the posterior pole. Rapidly progressing plus disease is sometimes referred to as Rush disease. Preplus disease is defined as vascular abnormalities of the posterior pole characterized by more arterial tortuosity and more venous dilatation than normal but not severe enough to be classified as plus disease.

Zones of disease

Zone I is the innermost area of the retina surrounding the macula (see the image below).

 

Zone II is the middle third of the retina, nasally extending to the edge of the retina (see the following image).

 

Zone III is the most peripheral area of the retina on the temporal side (see the image below).

Types

As of the publication of the Early Treatment for Retinopathy of Prematurity (ETROP) study, more ophthalmologists are describing eyes with ROP into two types (see the image below):

Type 1 ROP requires treatment and includes the following:

• Eyes with zone I, stage III ROP without plus disease, or

• Eyes with zone II, stage II or stage III ROP with plus disease

Type 2 ROP requires observation and includes the following:

• Eyes with zone I, stage I or stage III ROP without plus disease, or

• Eyes with zone II, stage III ROP without plus disease

A proper examination of the fundus requires adequate pupillary dilation. Typically, the infant's nurse will instill a combination of 0.2% cyclopentolate hydrochloride (HCl)/1% phenylephrine HCl) (Cyclogyl) ophthalmic solution 2-3 times in the hour before the scheduled examination. Mydriatic agents can cause blanching of the skin of the lids and increased blood pressure,

Infants examined in the neonatal intensive care unit should be relatively medically stable. They should be swaddled, and the attending nurse should assist the examination by stabilizing the head and upper body of the baby.

Wire lid speculums are used to hold the lids open. Most examiners will instill a topical anesthetic to reduce the discomfort of the speculum and the scleral depression (gentle pressing on the sclera to bring the peripheral retina into better view).

The examination can cause bradycardia, apnea, and hypertension (in response to pain) and, rarely, seizures and arrhythmia. Examiners should be able to examine each eye in a few minutes to reduce the risk of these complications. Medications and equipment for cardiovascular support should be at hand.

The presence of a clear media (lens, cornea, and vitreous) is essential for the evaluation and treatment of retinopathy of prematurity (ROP). Very low birth weight (VLBW) infants may have corneal haze due to prematurity. Congenital cataracts are rare, but cataracts have developed as the result of laser and cryotherapy for ROP. Vitreous hemorrhage can be a feature of active ROP, but this condition can develop in relatively benign eyes in conjunction with systemic conditions, such as hematologic abnormalities, (eg, thrombocytopenia, sepsis, cardiopulmonary resuscitation).

Intravitreal aflibercept (Eylea), a vascular endothelial growth factor (VEGF) inhibitor, gained FDA approval in February 2023 as the first pharmacologic treatment for preterm infants with ROP.

Medical care of retinopathy of prematurity (ROP) consists of ophthalmologic screening of appropriate infants.

Patients who are medically monitored must undergo ophthalmologic examinations until the retinal vasculature is mature. Ensuring appropriate monitoring of infants is critical if they are discharged from the nursery before retinal vascular maturity is attained.

ROP is a disease that is most active in the neonatal intensive care unit (NICU): Retinal detachments commonly occur at 38-42 weeks' postmenstrual age. It is critical for examiners and the attending neonatologists to be familiar with and adhere to a rigid examination and reexamination schedule.

Vascular endothelial growth factor (VEGF) inhibitors

Intravitreal (IVT) aflibercept (AFL) (Eylea), a VEGF inhibitor, gained FDA approval in February 2023 as the first pharmacologic treatment for preterm infants with ROP, supported by data from two randomized global phase 3 trials—FIREFLEYE (N = 113) and BUTTERFLEYE (N=120).[22, 23] These trials investigated aflibercept intravitreal injection 0.4 mg versus laser photocoagulation (laser) in infants with ROP; in each study, approximately 80% of aflibercept-treated infants achieved an absence of both active ROP and unfavorable structural outcomes at age 52 weeks, outcomes that are better than would have been expected without treatment. However, noninferiority of IVT-AFL versus laser treatment could not be formally shown, because the observed laser success rate was higher than expected based on previously published data.[22, 23]

Extension trials are ongoing to observe efficacy and safety for 5 years (FIREFLEYE Next [NCT04015180]; BUTTERFLEYE Next [NCT04515524]).

Research examining the potential use of intravitreal injections of antineovascularization drugs was based on their successful use in patients with other forms of neovascularization, such as diabetic retinopathy.[24] Other treatments may involve restoring normal levels of insulinlike growth factor (IGF)-1 and omega-3-polyunsaturated fatty acids (PUFAs) in the developing retina, as proposed by Chen and Smith[25] and other investigators.[26, 27] In a study comprising 150 infants that compared treatment with laser therapy over intravitreal bevacizumab monotherapy, intravitreal bevacizumab showed better results for zone I but not zone II disease.[28] Laser therapy led to permanent destruction of the peripheral retina, whereas the peripheral retinal vessels continued to develop after treatment with bevacizumab.[28]

When Lorenz et al investigated the outcome in 17 prematurely born infants treated with intravitreal bevacizumab (0.312 mg in 0.025 mL per eye) because of acute ROP in posterior zone II or zone I (including aggressive posterior ROP), acute ROP regressed in 19 out of 27 analyzed eyes (70%), including 100% of posterior zone II eyes and 80% of zone I eyes.[29] However, acute ROP regressed in only 25% of aggressive posterior ROP eyes.[29]

Supplemental oxygen management

The Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOP-ROP) Trial assessed the effect of supplemental oxygen in reducing the probability of progression to threshold ROP as well as the need for peripheral retinal ablation in infants with prethreshold ROP.[6] There was no reduction in the infants who required ablative surgery. A post hoc subgroup analysis showed that infants without plus disease may be more responsive to supplemental oxygen therapy (46% progression in the conventional arm vs 32% progression in the supplemental arm) than infants with plus disease (52% progression in the conventional arm vs 57% in the supplemental arm).[29] Supplemental oxygen increased the risk of adverse pulmonary events (8.5% conventional arm vs 13.2% in the supplemental arm).

Dietary considerations

A study by Stoltz Sjöström et al indicated that in preterm infants born prior to 27 weeks’ gestation, low energy intake during the first 4 weeks following birth is an independent risk factor for severe ROP.[30] The study included 498 infants, 172 of whom had severe ROP. The investigators found a significant relationship between higher intakes of energy (including fat and carbohydrates, but not protein) and a decreased risk of severe retinopathy. Indeed, an increased energy intake of 10 kcal/kg/day correlated with a 24% reduction in the severe form of the disease.[30]

Ablative surgery

Ablative therapy, first by cryotherapy, and now by laser, has been an established efficacious treatment for retinopathy of prematurity (ROP) for decades. If threshold disease is present, ablative (laser) surgery should be performed within 72 hours. If the ROP in the two eyes is asymmetric, the worst eye is treated first in case the procedure needs to be aborted due to medical considerations. Most laser procedures can be done in the neonatal intensive care unit, either at the infant's bedside (with proper measures to isolate the baby and the treating team, usually behind a curtain), or in a designated room. Intravenous sedation and topical anesthesia are required, and equipment for resuscitation must be at hand.

The average gestational age (GA) at which surgery is necessary is usually 37-40 weeks.

If the ROP continues to progress, more than one treatment may be required.

Cryotherapy

Unless a laser is not available, cryotherapy should be avoided as it can cause significant inflammation and tissue destruction and has been associated with high myopia. Cryotherapy for Retinopathy of Prematurity (CRYO-ROP), a randomized prospective trial of cryotherapy for threshold ROP, showed a 50% reduction in unfavorable outcome for zone 2 and 3 disease.[10] The treatment benefit was observed in infants with threshold disease, defined as five contiguous clock hours of stage III disease with plus disease or as eight noncontiguous clock hours of stage III disease with plus disease. ROP in zone 1 had a poor outcome despite treatment. 

Laser surgery

Laser surgery is currently preferred to cryotherapy because it may be more effective in treating zone I disease and causes less inflammation.[31] Laser photocoagulation appears to be associated with outcomes in structure and function that are at least as good as those of cryotherapy 7 years after therapy.[32, 33] In addition, visual acuity and refractive error data suggest that laser surgery has an advantage over cryotherapy. Laser surgery is also easier to perform and better tolerated by infants. 

Binocular laser delivery systems, widely available since the mid-1990s, has become a standard tool for outpatient and intraoperative retinal care. Aiming of the laser beam is extremely precise, and the intensity of the burn easily titrated. There is much less risk of media opacity during laser than with cryotherapy and, in the majority of cases, the treatment can be completed in much less time.

Importantly, laser can be applied in the posterior pole (zone I). However, the outcomes for ablative treatment of zone 1 disease remains problematic. Many treating physicians have migrated to intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections for zone 1 and posterior zone 2 disease.

For the first multicenter analysis of severe ROP in Germany, nine centers entered data from 90 treated infants with ROP into a central database in the German ROP Registry.[34] Laser was the most commonly used form of therapy, with an increasing use of anti-VEGF therapy over relatively recent years. Recurrence rates were high, with approximately 19% of infants requiring retreatment (16% of laser-treated infants and 21% of anti-VEGF treated infants).[34]  

After laser treatment, the treating ophthalmologist should examine the infant in 7-10 days, and then every 1-2 weeks until the ROP has resolved.

Early treatment

The Early Treatment for Retinopathy of Prematurity (ET-ROP) Trial showed that early treatment of high-risk prethreshold ROP significantly reduced unfavorable ROP outcomes at age 9 months and at age 2 years.[14, 35] Patients in this study had one eye randomized to "early" retinal ablative therapy. Eyes treated had type 1 ROP, defined as zone 1 with plus disease and any stage ROP; zone 1 with stage III and no plus disease; or zone 2, stage II or III, and plus disease.

The investigators subsequently compared their results from this ET-ROP study with those of the CRYO-ROP study, with respect to incidence and early course of ROP.[35] The incidence, time of onset of any disease and prethreshold disease, and rate of progression have changed little since the mid 1980s. The ET-ROP had more cases of prethreshold disease (36.9% in ET-ROP and 27.1% in CRYO-ROP) and more zone I ROP.[35]

Anti-VEGF therapy

The use of intravitreal injections for ROP followed close on the heels of its use for adult retinal neovascular disease (macular degeneration, diabetic retinopathy). Since the efficacy of bevacizumab injections for ROP was reported by Mintz-Hittner et al in 2011,[28] its use has accelerated. It is an excellent choice for posterior (zone I) disease, in eyes with vitreous hemorrhage,[36] and in eyes with media opacities.

Intravitreal injection for ROP has important advantages over laser: Although the baby needs to be stabilized (swaddled), sedation is not used, and the procedure takes just a few minutes, minimizing the stress on the infant, the infant's nurse, and the treating ophthalmologist. In addition, the procedure can be repeated.

Precautions with intravitreal anti-VEGF agents

The use of intravitreal anti-VEGF agents comes with several important caveats, all of which should be part of the informed consent process, including the following:

1. Rigorous testing and approval: Unlike ablative treatment, intravitreal injection has not been subject to case-control studies. Furthermore, bevacizumab, although widely used in the adult population, has not been US Food and Drug Administration (FDA)-approved (however, ranibizumab, its sister drug, has approval for adult use).

2. Systemic absorption: Intravitreal bevacizumab is absorbed systemically, and its effect on organogenesis has not been fully elucidated.[37] The systemic absorption may be several-fold higher in infants than in adults given the volume of distribution.

3. Dosage: The appropriate dose of bevacizumab has not been established in infants. The starting point for most treatments has been half the adult dose (0.625 mg); studies have shown efficacy at lower doses[38, 39] which may reduce the risk of systemic side effects.

4. Unlike laser, intravitreal injection is an invasive procedure, carrying with it the unique risks of retinal tears and detachment, as well as endophthalmitis, a potentially devastating infection that can result in total loss of vision. Due to the risk of endophthalmitis after intravitreal injection, a slit lamp examination of the anterior chamber should be performed 48-72 hours after the injection.

5. It has been well established that there is a risk of late reactivation of ROP after intravitreal injection, thus, more frequent postprocedure monitoring is mandatory. This adds to the financial and care burden of the parents and treating physicians, and exposes the infant to more stressful encounters. Reactivation with poor outcomes and retinal detachment have been reported months and even years after treatment.[40, 41] Many pediatric retina specialists will treat these late reactivation cases with laser, rather than another course of intravitreal injection.

No protocol has been established for follow-up of infants treated with intravitreal injection for ROP, and the prolonged monitoring required spills into the postdischarge period, when timely follow-up cannot always be assured. Missed follow-up with poor outcomes has been the source of significant malpractice claims.[42]

Surgery for stages IV-V ROP

If laser and/or intravitreal injection fails to prevent the progression of ROP, a retinal detachment may develop. Invasive surgery (vitrectomy) is indicated in stage IV. Vitrectomy is known to affect the crystalline lens, and it may lead to aphakia (through the need to remove the lens intraoperatively) or premature cataract. The placement of silicone oil in the vitreous to stabilize the reattached retina will induce refractive changes, contribute to cataract formation, and require a second surgery to remove it when the retina is stable. Parents should be informed of the "multi-stage" approach to the surgical repair of ROP, as well as the guarded prognosis.

The visual outcome for the repair of true stage V ROP (total retinal detachment) is poor.

Infants can experience apnea, bradycardia, seizures, and cardiopulmonary arrest during laser surgery for retinopathy of prematurity (ROP). Care must be taken to optimize the infant's condition prior to the treatment, and to ensure that adequate sedation and monitoring take place during the treatment and in the immediate postoperative period. Intubation of a baby during and after treatment is not a rare occurrence.

Ablative treatment has been associated with retinal dystopia (macular dragging), myopia, strabismus, and amblyopia. To minimize the impact of refractive errors and strabismus, close follow-up with a pediatric ophthalmologist is mandatory.

Gunzenhauser et al reported a case of rhegmatogenous retinal detachment in an infant during treatment for ROP with treatment by laser and intravitreal injection.[43]

The only known deterrent measure for retinopathy of prematurity (ROP) is to prevent preterm birth. The more mature a neonate is at birth, the less likely ROP is to occur.

Studies regarding the effects of antenatal corticosteroids on ROP have revealed that this treatment has a protective effect against severe ROP.[44]

Studies have shown that maintaining oxygen saturation values by pulse oximeter (SpO2) at 83-93% decreases the incidence of threshold ROP.[45, 46]

A schedule for follow-up examinations for infants with retinopathy of prematurity (ROP) has been established jointly by the American Academy of Pediatrics (AAP), the American Academy of Ophthalmology (AAO), and the American Association for Pediatric Ophthalmology and Strabismus (AAPO).[19]

The long-term outcome for infants with ROP continues to be problematic. These infants are at significant risk for myopia. In addition, strabismus, amblyopia, and late retinal detachment also continue to be problems.

Posttreatment monitoring is essential to ensure the optimal outcome in babies treated for ROP. The resolution of the active disease may take only a few weeks, but late reactivation after intravitreal injection—and the prompt recognition and treatment of refractive errors and strabismus to prevent amblyopia—demand coordinated care after discharge. As mentioned earlier, the failure to ensure the proper follow-up can lead to blindness, and to malpractice claims.[42]

Patients require yearly ophthalmologic follow-up evaluations. More frequent evaluation may be necessary, depending on the severity of the disease. Long-term, regular follow-up of eyes with threshold ROP is warranted.

Most neonatal intensive care units (NICUs) will designate an ROP coordinator whose duties include making the postdischarge appointment with a pediatric ophthalmologist and, later, following up with the physician to ensure that the baby has been seen.

Premature infants, especially very low birth weight (VLBW) infants, are at risk for neurologic complications that may affect the visual outcome. As in the NICU, the care of these infants after discharge often involves multiple caregivers (eg, pediatricians, pulmonologists, neurologists, ophthalmologists). This may be daunting for the parents or caregivers, but it is critical to communicate to them (verbally and, crucially, in writing at the time of discharge) that to maximize their baby's visual performance, close and timely follow-up with their pediatric ophthalmologist is extremely important.

Long-term follow-up findings from the Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) Cooperative Group indicate that refractive errors in eyes with mild ROP are associated with the same risk of myopia as that in eyes without ROP.[10] In patients with moderate-to-severe ROP, the prevalence of severe myopia is increased. Fifteen year follow-up from the CRYO-ROP Trial shows that children remain at risk for new retinal detachments, even with eyes that have relatively good structural findings at age 10 years.

Retinopathy of Prematurity (ROP) Screening Examination Guidelines (2018)

Guidelines on the screening of preterm infants for ROP were released on November 26, 2018, by the American Academy of Pediatrics (AAP).[47, 48] These guidelines are summarized below.

Infants should be screened for ROP on the basis of birth weight (≤1500 g), gestational age (30 weeks or less), and risk for ROP (eg, infants with hypotension or those who received oxygen supplementation). Some at-risk infants with a birth weight from 1500 g to 2000 g should also be screened.

Retinal screening examinations using binocular indirect ophthalmoscopy after pupillary dilation should be used to detect ROP.

Remote photographic screening for ROP may initially be used instead of binocular indirect ophthalmoscope examinations before treatment is indicated.

Perform indirect ophthalmoscopy before treatment or termination of acute-phase screening for at-risk infants.

The presence of plus disease (two or more quadrants of the retina affected by abnormal dilatation and tortuosity of the posterior retinal blood vessels) indicates treatment instead of observation.

Intravitreal injection of anti–vascular endothelial growth factor (anti-VEGF) agents (eg, bevacizumab injection) may be used as a treatment for aggressive posterior ROP.

Longer follow-up should be employed after anti-VEGF treatment, as it is often associated with a later recurrence of ROP when relative to conventional laser peripheral retinal ablative treatment.

Specific unit criteria for the management of ROP should be established for each neonatal intensive care unit in agreement with both the neonatology and ophthalmology services.

Ophthalmologic follow-up and transition of care should be arranged before the infant is discharged, including the necessary follow-up eye-examinations and the schedule for these examinations.

Infants who are develop subthreshhold ROP are at higher risk of visual disorders (strabismus, amblyopia, high refractive errors, cataracts, and glaucoma). Follow-up with a pediatric ophthalmologists 4 to 6 months after discharge is necessary to assess visual function and to address any issues (see "Long Term Monitoring" in the Treatment section).

For more information, go to Retinopathy of Prematurity Ophthalmologic Approach.

Intravitreal aflibercept (Eylea), a VEGF inhibitor, gained FDA approval in February 2023 as the first pharmacologic treatment for preterm infants with retinopathy of prematurity (ROP).

If a patient has prethreshold ROP, some centers try to maintain normal serum levels of vitamin E. Vitamin E use was evaluated in a meta-analysis, and levels should be maintained within the reference range in patients at high risk for severe ROP.

Class Summary

Vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF) are members of the VEGF family of angiogenic factors that can act as mitogenic, chemotactic, and vascular permeability factors for endothelial cells.  

VEGF receptor 1 (VEGFR-1) and VEGFR-2, present on the surface of endothelial cells. PlGF binds only to VEGFR-1, which is also present on the surface of leukocytes. 

Activation of these receptors by VEGF-A can result in neovascularization and vascular permeability.

Aflibercept intravitreal (Eylea)

Aflibercept acts as a soluble decoy receptor that binds VEGF-A and PlGF, and thereby can inhibit the binding and activation of these related VEGF receptors. It is indicated for prematurity of retinopathy.