Retinopathy of prematurity (ROP) is an enigmatic, potentially blinding disease of the developing retinal vasculature of prematurely born infants. First described by Theodore Terry in 1942 and 1943, Dr. Messenger was the first to name this condition retrolental fibroplasia.1,2
As we gained more knowledge of the pathophysiology and natural history, it was renamed ROP.
History of retinopathy of prematurity
A large number of published articles exist, but our understanding of ROP is primarily based on a handful of multicenter clinical trials. The first such trial, the National Cooperative Study, made a critical discovery in the mid-1950s that supplemental oxygen delivered by incubators correlated with the incidence of ROP.3
The reaction to this clinical trial was immediate and dramatic. Nursery caregivers turned down the supplemental oxygen levels, and while this had the desired effect of reducing ROP and blindness, the unintended consequences were a decade of increased non-ocular morbidity and mortality.4
Progress after this was slow until the publication of the International Classification of Retinopathy of Prematurity. This and subsequent editions provided practitioners and researchers with a common language.
This led to the now-famous CRYO-ROP clinical trial in the mid-1980s that had two major consequences:
- Firstly, it was proven that peripheral avascular retinal ablation with cryotherapy can reduce the risk of retinal detachment and blindness.6
- Secondly, it provided a natural history control that has been the basis for much of our understanding of the pathophysiology of ROP.7
Subsequent clinical trials such as STOP-ROP, LIGHT-ROP, and ET-ROP provided more treatment refinement, allowing for earlier intervention, further reductions in blindness, and the substitution of laser photocoagulation for cryotherapy for peripheral retinal ablation.8,9,10 Unfortunately, STOP-ROP could not determine an optimal oxygenation level, and LIGHT-ROP showed that ambient nursery lighting was not a risk factor.
📝
Diagnosis and Management of ROP Quiz
Take this quiz designed for ophthalmology residents and fellows to test your knowledge of key topics from this article!
Classification of ROP
The current gold standard for ROP diagnosis remains the clinical exam using pupillary dilation and indirect ophthalmoscopy. Assessment of imaging technology can be helpful, but manual examination remains the standard.
The classification of ROP, most recently described in the latest edition of the International Classification, defines ROP in terms of severity stages, retinal location, and the presence or absence of plus disease.11
The ROP stages are as follows:11
- Stage 1: A visible demarcation line at the border of vascularized and non-vascularized retina in a circumferential pattern.
- Stage 2: An extra retinal ridge
- Stage 3: A neovascular extraretinal ridge
- Stage 4: Partial retinal detachment
- Stage 5: Total retinal detachment with open or closed funnel
Location within the retina is divided into concentric circular zones:
- Zone I: Concentric circle centered on the optic nerve with a radius of two times the nerve-fovea distance.
- Zone II: A concentric annular area arising from the outer border of zone I and ending at the nasal ora.
- Zone III: A large temporal crescent.
The third and perhaps most critical element of classification is plus disease, described as a photographically defined level of venous dilation and arterial tortuosity of the posterior pole vessels. This is a subjective determination and can be challenging without experience.
The classification also includes more minor items such as pre-plus, pre-threshold ROP, threshold ROP, aggressive posterior ROP, and others. Treatment depends on determining the level of severity within this classification system.
Figure 1: Fundus image of stage 1 ROP.
Figure 1: ROP fundus images© Xinyu Zhao, et al. Image cropped and used under CC BY 4.0.
Figure 2: Fundus image of stage 2 ROP.
Figure 2: ROP fundus images© Xinyu Zhao, et al. Image cropped and used under CC BY 4.0.
Figure 3: Fundus image of stage 3 ROP.
Figure 3: ROP fundus images© Xinyu Zhao, et al. Image cropped and used under CC BY 4.0.
Figure 4: Fundus image of stage 4 ROP.
Figure 4: ROP fundus image© Andrea Molinari, et al. Image used under CC BY-NC 4.0.
Screening for retinopathy of prematurity
Utilizing the International Classification, the optimal screening exam schedule and recommended intervention points were determined by the natural history arm of CRYO-ROP, LIGHT-ROP, and ET-ROP.12 US experts devised a consensus guide which includes recommended birth weights, gestational ages, and exam timing, including initiation, frequency, and conclusion of screening.
This screening protocol has stood the test of time since 2002.13 ET-ROP still defines the disease severity intervention points. Although the consensus guidelines incorporate other information, the crux of the guidelines are those two references.
Pathophysiology of ROP
Before discussing treatment, it is essential to have a rudimentary understanding of ROP pathophysiology. After premature birth, the infant is exposed to supplemental oxygen. The initial retinal response is the constriction of retinal vessels and a cessation of new vessel growth. This initial state of the retina is one of relative hyperoxia.
This excess of oxygen is due to the supplemental inspired oxygen, but also, significantly, to the reduced retinal oxygen consumption. The retinal photoreceptors come online at about 28 weeks of gestation. These cells have among the highest metabolic rates in the body, and oxygen demand skyrockets almost overnight. This dramatic demand, along with chronic lung changes, produces a relative retinal hypoxia.
This relative hypoxia elicits the increased production of vascular endothelial growth factors (VEGF). This upregulated VEGF stimulates new vessel growth, as expected. However, for reasons that are unclear, normal vessel growth may be replaced by abnormal vessel growth, such as extraretinal neovascularization (stage 3 ROP).
The result of this stereotyped retinal embryology means that the development of ROP is not determined by the length of time of exposure to iatrogenic supplemental oxygen. Rather, it is determined by the relative retinal hypoxia that is a direct consequence of the rigid timeline of photoreceptor development and metabolism.
Treatment for ROP
As mentioned, the first recognized effective treatment for ROP was the result of the CRYO-ROP trial. Peripheral avascular retinal ablation, first with cryotherapy and then laser photocoagulation, became the gold standard. ET-ROP defined the currently accepted severity of disease interdiction points.10
The current intervention is recommended for high-risk disease defined as:
- Stage 3, Zone II, plus
- Stage 3, Zone I, no plus
- Stage 3, Zone I, plus
Notably, plus disease is the dominant finding in this scheme, but Zone I is also at extremely high risk.
Laser photocoagulation, with cryo as a rarely used back-up, became the gold standard for many years following the publication of ET-ROP. This lasted until the publication of the BEAT-ROP trial, which established an entirely new approach to ROP treatment.14
Figure 5: Fundus image of ROP directly after laser treatment with fresh scars.
Figure 5: ROP fundus images© Xinyu Zhao, et al. Image cropped and used under CC BY 4.0.
Figure 6: Fundus image of ROP after laser treatment with stable scars.
Figure 6: ROP fundus images© Xinyu Zhao, et al. Image cropped and used under CC BY 4.0.
Managing ROP with anti-VEGF agents
This innovation followed the discovery of the actual VEGF cytokines and the application of anti-VEGF monoclonal antibodies for age-related macular degeneration (AMD). This revolutionized retinal care for AMD. And since wet AMD has pathologic similarities to ROP, it was reasonable to try anti-VEGF for ROP.
Bevacizumab was first used to attack tumor vascularity. This was extended to AMD and then to ROP by Hittner’s BEAT-ROP trial. That trial proved the efficacy of anti-VEGF treatment for ROP, although it did not prove its systemic effects, such as on brain development and safety.
However, it was so promising that an accompanying New England Journal of Medicine editorial by Reynolds suggested that “intravitreal bevacizumab will prove to be at least equal to laser therapy … for most forms of ROP.”15
Subsequent reports confirmed the efficacy of ROP. Peripheral retinal ablation with laser photocoagulation was associated with some significant side effects and logistical issues. Laser was time-consuming, required anesthesia in some form, diminished the peripheral visual field, and, most significantly, was associated with myopia and high myopia.
Intravitreal bevacizumab injections seemed to avoid these. It was quick and easy to perform, required no anesthesia, was much less expensive, needed minimal equipment and training, and was immediately effective (within 24 to 48 hours vs. 1 to 2 weeks for laser). Most importantly, it preserved more of the peripheral visual field and produced less myopia.
The impact of anti-VEGF on brain development in ROP patients
But systemic safety remained a concern. The systemic safety issue centered on brain development. Doctors worried that circulating bevacizumab following intravitreal escape could lead to cognitive and motor development issues. Anti-VEGF treatment slowly increased but could not be accepted as standard due to the systemic safety issues.
Other anti-VEGF agents were being developed for AMD and tried in ROP. A promising antibody arrived as ranibizumab. This was a smaller antibody that was more easily cleared from the plasma. Its safety profile might be better, but that requires a clinical trial.
Enter the RAINBOW trial
The RAINBOW international multicenter trial was intended to answer the question of ranibizumab efficacy, as well as long-term safety issues. Phase one was determining efficacy compared to laser and included 201 infants. Phase two was determining safety, and 156 children completed this 5-year follow-up. Beginning in 2019, the RAINBOW trial published a series of five papers over a 6-year period.
The first paper concluded that a 0.2mg intravitreal injection of ranibizumab was at least as effective as laser, but “might be superior” (p = 0.055).16 The second paper was a pharmacokinetic study based on subject blood samples and concluded that "adequate ocular retention followed by rapid systemic excretion may provide a particularly satisfactory ocular efficacy: systemic safety profile."17
The third paper was the 2-year follow-up study that proved the continuing efficacy with no new structural abnormalities, but also showed lower myopia than laser, and suggested no developmental effect. The fourth paper was a timing study, which showed that intravitreal ranibizumab produced faster disease regression but had more disease reactivation as the ranibizumab concentration decreased.18
However, the initial laser treatment showed incomplete regression, requiring re-treatment. So, re-treatment rates were equal between ranibizumab and laser, however, the reasons for re-treatment were different.19
The fifth and final paper was the 5-year follow-up study, which demonstrated that efficacy remained excellent, but the longer follow-up showed no difference in developmental scores, growth attainment, or vision-related quality of life.20
Together, this series of papers reporting the results of the RAINBOW trial demonstrated that compared to laser, intravitreal 0.2mg of ranibizumab:
- Was at least equal in efficacy to laser and might be superior
- Structural efficacy remained constant
- Visual acuity was equal in each group
- There was no difference in systemic development
- Fewer side effects were reported with ranibizumab, especially myopia
6 pearls for managing ROP
Practical tips from Dr. Reynolds for managing ROP include:
- Dilate pupils with Cyclomydril (cyclopentolate hydrochloride, phenylephrine hydrochloride ophthalmic solution, Alcon) because it combines cyclopentolate and neosynephrine, but at a lower dosage, which minimizes cardiopulmonary side effects.
- Use a lid speculum that has good spring/compressibility so one can insert easily in a small eye, but also has blades long enough to support sufficient lid surface contact, which ensures good separation.
- Use a scleral depressor that is not only effective at scleral depression but also can be used simultaneously to position the eye properly.
- Stop the procedure and remove instruments if bradycardia or cyanosis occurs. This usually resolves within 30 seconds, and the exam may then continue.
- Perhaps most importantly, when one’s examination findings are atypical compared with the natural history of ROP, e.g., zone III vascularization at only 28 weeks' gestational age, consider examiner error and re-examine or even consider a second examiner.
- Finally, establish a rigorous and robust screening system that is multidisciplinary and ensures that every at-risk baby receives timely examination as both an inpatient and an outpatient. No infant should “fall through the cracks.”
Conclusion
We have explored the history, classification, screening guidelines, pathophysiology, and the most current treatments of acute ROP. This update did not discuss chronic ROP, associated conditions like amblyopia, or the relatively heroic treatment of
when acute treatment fails.
The key takeaways for ROP management include:
- Utilize the International Classification.
- Follow the national screening guidelines.
- Follow the ET-ROP intervention guidelines (also in the national screening guidelines).
- Treat promptly when indicated.
- Treat with either laser or intravitreal anti-VEGF.
- Strongly consider the advantages and safety of intravitreal ranibizumab.
- Finally, recognize ROP as a predictable disease within the population, but unpredictable within the individual. Do not hesitate to re-examine or reconsider.
