Short-term Reactivation of Retinopathy of Prematurity after Primary Ranibizumab Treatment
November 2024
Current treatment options for Type 1 retinopathy of prematurity (ROP) includes laser ablation to the avascular retina and intravitreal anti-vascular endothelial growth factor (anti-VEGF). The Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEAT-ROP) trial was one of the earliest studies to show benefits of intravitreal anti-VEGF treatment in ROP and anti-VEGF injections are now being used increasingly as first-line therapy in these infants.1
Advantages of anti-VEGF over conventional laser include ease and access of treatment, rapid disease regression, lower rates of myopia and avoidance of laser associated compliations.2 Questions remain though regarding the optimal drug choice and dosage. The RAINBOW and FIREFLEYE studies, as well as others, have been performed to assess many of these questions and have greatly added to the knowledge base regarding anti-VEGF in ROP but with no clear consensus to date in ROP treatment guidelines.3-5
Reactivation of ROP and frequency of follow-up also is a great concern with anti-VEGF treated infants due to peripheral avascular retina. The BEAT-ROP trial found a mean time for recurrence of 16 weeks after intravitreal bevacizumab and the RAINBOW trial found a reactivation average of approximately 8 weeks after initial intravitreal ranibizumab (IVR).1,4
This article by Strawbridge et al. published in Retina in 2024 was a retrospective chart review of infants screened for ROP in the UCLA health care system between 2013 and 2023 who received IVR. The primary outcomes were rates and timing of “short-term ROP reactivation”. Short-term ROP reactivation was defined as worsening of ROP to stage 2 or 3 before 52 weeks postmenstrual age (PMA). The authors also looked at risk factors for reactivation, adverse events and rates of reactivation after a second/repeat intravitreal injection.
In this study, infants qualified for ROP screening when gestational age (GA) was less than 30 weeks, birth weight (BW) was less than 1,500 g, or infants were deemed to be high risk for ROP based on an unstable clinical course (such as prolonged supplemental oxygen, cardiopulmonary instability). The mean GA of the IVR treated infants was 24.7 weeks +/-1.71 weeks (range 22–32 weeks), with a mean BW of 672.6 g +/-189.1 g (range 410–1395 g).
Eighty-two eyes of 43 patients received IVR 0.25 mg/0.025cc for type 1 ROP. Thirteen patients (22 eyes) (30.2% of patients, 26.8% of eyes) developed short-term ROP reactivation. Reactivation occurred at an average of 7.2 weeks ± 1.7 weeks (range 5.0 –10.7 weeks) post-injection. These 13 patients received repeat IVR injections and five required laser treatment for a second reactivation following the repeat IVR treatment. The mean PMA at the time of the repeat IVR injection was 41.2 weeks +/- 2.1 weeks (range 38.0 – 45.6 weeks). Of the eyes that received laser treatment for a second reactivation, the mean PMA at time of laser was 47.3 weeks +/- 2.0 weeks (range 45.4 – 51.1 weeks). The five infants who were treated with laser following second reactivation were very premature (mean 23.5 weeks GA), had particularly low birthweight (435-601g) and all required supplemental oxygen.
The authors noted that increased reactivation risk was associated with zone I disease (odds ratio 6.23, 95% CI, 1.35-28.7, P = 0.019), lower PMA at first injection (odds ratio 1.64, 95% CI, 1.19-2.26; P = 0.003), and lower GA at birth (odds ratio 1.80, 95% CI, 1.04-3.13, P = 0.037). Regarding safety and complications, no eyes developed vascular occlusions, endophthalmitis, retinal tear/detachment or cataract.
In this study, all infants who received primary IVR underwent planned laser treatment to areas of persistent avascular retina at approximately 52 weeks PMA, unless they had already received laser for repeat reactivation. The rational for this was due to concern for ROP reactivation with the difficulty of reliable dilated retinal exams in larger infants and toddlers and possible loss-to-follow-up.
In conclusion, repeat injections may be required after primary IVR for type 1 ROP. This article will assist retinal specialists when counselling parents and highlights the importance of frequent monitoring in post-treatment eyes, especially within the first seven weeks in high-risk patients. The limitations of the study include its retrospective design and small sample size but it adds to the growing literature base for anti-VEGF in ROP treatment.
- Mintz-Hittner HA, Kennedy KA, Chuang AZ, BEAT-ROP Cooperative Group. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med 2011; 364:603–615.
- Strawbridge J, Cheng JY, Gundlach BS, Gillespie T, Karmouta R, Khitri M, Chu A, Tsui I. Short-term reactivation of retinopathy of prematurity after primary ranibizumab treatment. Retina. 2024 Nov 1;44(11):1945-1951.
- Wallace DK, Dean TW, Hartnett ME, et al. A Dosing Study of Bevacizumab for Retinopathy of Prematurity: Late Recurrences and Additional Treatments. Ophthalmology. 2018;125(12):1961-1966.
- Stahl A, Lepore D, Fielder A, et al. Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): an open-label randomised controlled trial. Lancet 2019;394:1551–1559
- Stahl A, Nakanishi H, Lepore D, et al. Intravitreal Aflibercept vs Laser Therapy for Retinopathy of Prematurity: Two-Year Efficacy and Safety Outcomes in the Nonrandomized Controlled Trial FIREFLEYE next. JAMA Netw Open. 2024;7(4):e248383
