Retinopathy of prematurity (ROP) is a prevalent complication in premature infants. The high incidence of cases1 leading to blindness or severe visual impairment is distressing, prompting experts to constantly seek improved methods for timely and effective intervention. At the recently held 5th World Congress of Pediatric Ophthalmology & Strabismus (WCPOS V 2024) in Kuala Lumpur, Malaysia, experts in the field shared their insights into the latest advancements in ROP treatment.
ROP treatment simulation
Each premature infant can have a different progression of ROP, depending on various factors such as birth weight, gestational age and overall health. Simulation models help tailor treatment plans to the specific needs of each patient, increasing the likelihood of successful outcomes. During her presentation, Dr. Eva Gajdosova (United Kingdom) discussed three different ROP treatment simulation models — Open Sky, Closed Sky and Closed Sky Anterior.
According to Dr. Gajdosova, the Open Sky model is the simplest to construct, simulating laser treatment up to posterior ROP (zone II) and allowing for direct trainer supervision. The Closed Sky model adds realism and technical difficulty, also simulating laser treatment up to posterior ROP (zone II). The Closed Sky Anterior model, on the other hand, enables the simulation of anterior ROP treatment, training practitioners in indentation skills.
Dr. Gajdosova emphasized that by integrating these simulations into clinical practice, healthcare providers can enhance their skills and optimize outcomes for young patients affected by this challenging condition.
Diagnosis and management of aggressive posterior ROP
Aggressive posterior ROP (APROP) is a severe and rapidly progressive form of ROP, typically located in zone I or posterior zone II. According to Dr. Sunder Ramasamy from Malaysia, this disease is now also occurring in larger preterm infants and beyond the posterior retina.
Dr. Ramasamy explained that the hallmarks of APROP include thin vessels within zone I early in the course of the disease, rapid development of severe plus disease, and capillary abnormalities such as arterio-venous shunting resembling dilated vascular loops and ‘flat’ neovascularization.
Laser photocoagulation monotherapy, initially used to treat APROP, has poor outcomes despite optimal screening and timely confluent laser photocoagulation. Prognosis worsens with retinal and vitreous hemorrhages due to poor visibility. “Laser works in some cases, but in the majority, it was not very good,” he said.
In response, anti-vascular endothelial growth factor (anti-VEGF) therapy has been introduced. Anti-VEGF therapy works by inhibiting the vascular endothelial growth factor (VEGF), which plays a crucial role in the abnormal blood vessel proliferation characteristic of ROP.
Dr. Ramasamy noted that anti-VEGF has been effective in treating ROP, as demonstrated by the RAINBOW trials, completed a few years ago. Nevertheless, there are three phases of vascular changes following intravitreal anti-VEGF injection in eyes with AP-ROP: rapid regression of plus disease, slow vascular development and complete regression on follow-up or progression to rebound/recurrent ROP.
The good news is, a combination therapy—treatment of AP-ROP eyes with anti-VEGF (ranibizumab) followed by laser treatment—has shown increased evidence of good anatomical outcomes. Treated eyes showed prompt regression of neovascular pathology and plus disease and generally without recurrence. “Combination therapy with intravitreal anti-VEGF and zone I sparing laser ablation appears to be an effective treatment approach in eyes with APROP,” said Dr. Ramasamy.
Long-term safety of anti-VEGF in ROP
Next, Dr. Wei-Chi Wu (Taiwan) looked into the effects of anti-VEGF therapy on the neurodevelopment and pulmonary function of ROP patients. He noted that anti-VEGF injections into the vitreous can enter the systemic circulation and cause systemic VEGF serum suppression, a concern because VEGF is an important growth factor for neurodevelopment.
Fortunately, from studies conducted by Dr. Wu and his colleagues,2,3 they did not find any serious deterioration in neurodevelopmental outcomes in ROP cases treated with bevacizumab. In fact, he mentioned, “In the recent publication, we found that the laser-treated group had slightly worse cognitive function in the 10-scale neurodevelopmental score at 24 months old compared to the bevacizumab-treated group.” However, he emphasized that this data needs further evaluation in a larger cohort.
Regarding pulmonary function, Dr. Wu explained that the lungs have the highest level of VEGF transcripts among all organs, raising concerns about whether VEGF suppression might impair lung function. An animal study had shown that VEGF blockage impaired lung function.4
Dr. Wu and his colleagues investigated respiratory outcomes in preterm infants with a gestational age of less than 34 weeks or a birth weight of less than 1500 grams, who had bilateral type 1 ROP and were treated with intravitreal bevacizumab (IVB). They compared these infants with matched treatment-naive controls and found that IVB did not compromise respiratory outcomes during the 28-day post-IVB period and at discharge.5
“In conclusion both neurodevelopment and pulmonary outcomes were similar between ROP patients with IVB and preterm individuals without IVB,” he said.
Strategies for ROP screening
According to Dr. Florence Manurung (Indonesia), 15 million children are born preterm worldwide, with 53,000 developing sight-threatening ROP requiring treatment and 20,000 suffering blindness or severe visual impairment. New research has identified potential risk factors of ROP, which include low IGF-1 values at birth, proteinuria and blood transfusion, she noted.
Dr. Manurung emphasized the critical importance of early detection and intervention in managing ROP. “Effective screening programs are essential for promptly identifying ROP and initiating treatment. ROP screening should be done before day 30 of the life of any premature baby, and before 20 days for those born at less than 30 weeks,” she said.
Screening methods usually involve indirect ophthalmoscope (first choice) and retina camera (RetCam). Other technologies include: smartphone-based fundus imaging, spectral-domain optical coherence tomography, and AI-based screening tools.
“When selecting the technologies for ROP screening, it is crucial to choose accessible technologies that suit your resources and capabilities. Always prioritize screening the patient over the technology used,” she emphasized.
Avastin use in Vietnam
Dr. Nguyen Xuan Tinh (Vietnam) noted that while laser is a standard treatment for ROP, it becomes particularly challenging when the disease affects zone I of the retina or when dealing with aggressive posterior ROP (AROP).
“Since the 2000s, anti-VEGF has been accepted worldwide as a new therapy modality for ROP. The BEAT-ROP study showed Avastin (bevacizumab) as better treatment for zone I ROP than lasers. In Vietnam, we started using Avastin in Hanoi in 2009. Most studies found that the success rate was 95-100%,” he said.
He noted that in Ho Chi Minh City, the use of Avastin for ROP has been increasing while laser treatment has been decreasing over the years. This preference is attributed to several reasons, including better outcomes, simpler technique, the ability to treat patients in the ICU or incubator, and without the need for an anesthesiologist.
Nevertheless, there are some concerns regarding this anti-VEGF agent. “It can slow/stop peripheral vessel vascularisation, needs longer follow-up, and may cause later retinal detachment. In terms of long term systemic side effects, it may cause neurodevelopmental delay although there is no clear evidence. Long-term systemic side effects are a major concern that needs further study,” said Dr. Nguyen.
References
- Hong EH, Shin YU, Cho H. Retinopathy of prematurity: a review of epidemiology and current treatment strategies. Clin Exp Pediatr. 2022;65(3):115-126.
- Chou HD, Shih CP, Huang YS, et al. Cognitive Outcomes Following Intravitreal Bevacizumab for Retinopathy of Prematurity: 4- to 6-Year Outcomes in a Prospective Cohort. Am J Ophthalmol. 2022;234:59-70.
- Chiang MC, Chen YT, Kang EY, et al. Neurodevelopmental Outcomes for Retinopathy of Prematurity: A Taiwan Premature Infant Follow-up Network Database Study. Am J Ophthalmol. 2023;247:170-180.
- Monacci WT, Merrill MJ, Oldfield EH. Expression of vascular permeability factor/vascular endothelial growth factor in normal rat tissues. Am J Physiol. 1993;264(4 Pt 1):C995-C1002.
- Huang YC, Hsu KH, Chu SM, et al. Respiratory outcomes in preterm infants following intravitreal bevacizumab for retinopathy of prematurity-a 10-year matched case study. Eye (Lond). 2023;37(17):3675-3681.
Editor’s Note: Reporting for this article occurred at the 5th World Congress of Paediatric Ophthalmology & Strabismus (WCPOS V 2024) from 11-13 July in Kuala Lumpur, Malaysia.
