Approach Considerations
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
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]
Surgical Care
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:
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).
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.
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.
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.
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.
Complications
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]
Prevention
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]
Long-Term Monitoring
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.
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Retinopathy of Prematurity. Stage I retinopathy of prematurity.
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Retinopathy of Prematurity. Scheme of retina of right eye (RE) and left eye (LE) showing zone borders and clock hours used to describe location and extent of retinopathy of prematurity.
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Retinopathy of Prematurity. Zone I retinopathy of prematurity.
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Retinopathy of Prematurity. Zone II retinopathy of prematurity.
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Retinopathy of Prematurity. Zone III retinopathy of prematurity.
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Retinopathy of Prematurity. Stage II retinopathy of prematurity.
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Retinopathy of Prematurity. Stage III retinopathy of prematurity.
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Retinopathy of Prematurity. Mild extraretinal fibrovascular proliferation.
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Retinopathy of Prematurity. Moderate extraretinal fibrovascular proliferation.
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Retinopathy of Prematurity. Severe extraretinal fibrovascular proliferation.
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Retinopathy of Prematurity. A comparison between attached and detached retina.
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Retinopathy of Prematurity. Retinopathy of prematurity (ROP) threshold, according to the Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) Cooperative Group.
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Retinopathy of Prematurity. Treatment guidelines, according to the Early Treatment for Retinopathy of Prematurity (ET-ROP) study.
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Retinopathy of Prematurity. Laser photocoagulation. RPE = retinal pigment epithelium.
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Retinopathy of Prematurity. Cryotherapy probe application.
Tables
Gestational Age at Birth (wk) |
Chronologic Age (wk) |
Postmenstrual Age (wk) |
22* |
9 |
31 |
23* |
8 |
31 |
24 |
7 |
31 |
25 |
6 |
31 |
26 |
5 |
31 |
27 |
4 |
31 |
28 |
4 |
32 |
29 |
4 |
33 |
30 |
4 |
34 |
31 (if necessary) |
4 |
35 |
32 (if necessary) |
4 |
36 |
