Traditionally, cryotherapy1 and, later, laser photocoagulation2 have been the standard of treatment for retinopathy of prematurity (ROP). Since publication of the BEAT-ROP study in 2011, intravitreal injection of bevacizumab (Avastin; Genentech, South San Francisco, CA) has emerged as an additional treatment option for infants with ROP.3 Yet complications of intravitreal bevacizumab therapy — both systemic and ocular — for patients with ROP are still being evaluated.4–6 A few reports have described vitreous hemorrhage after bevacizumab injection, although the timing of presentation is either unreported or delayed several months after injection in these cases.7,8 To our knowledge, there are also no reports of bilateral vitreous hemorrhage. Herein, we report a case of bilateral vitreous hemorrhage occurring in an infant with ROP treated with bilateral intravitreal injections of bevacizumab.
A 24-week postmenstrual age, 685 g male was born by spontaneous vaginal delivery and required immediate intubation. His early hospital course was complicated by respiratory distress syndrome, bronchopulmonary dysplasia, persistent high oxygen needs, grade 3 intraventricular hemorrhage, chronic kidney disease, and adrenal insufficiency.
Initial ROP evaluation at 30 weeks' gestation revealed immature retina in zone 1. At 33 weeks, examination showed zone 1, stage 1 ROP with no plus disease. Findings remained stable until 37 weeks, at which time the patient progressed to stage 2 ROP with vessel tortuosity. He required cardiopulmonary resuscitation during this exam. At 38 weeks, examination revealed zone 1, stage 3 ROP with plus disease bilaterally. After informed parental consent, both eyes were treated with 0.5 mg in 0.02 cc of bevacizumab (injected with a 30-gauge half-inch needle approximately 0.5 mm to 0.75 mm from the limbus, directed posteriorly with 2 mm of the needle entering the eye).
Follow-up examination 3 days later revealed vitreous hemorrhages in both eyes with no view of the fundus in the right eye. B-scan ultrasonography of the right eye demonstrated choroidal thickening, elevated hyperreflectivity consistent with extraretinal fibrovascular tissue (EFP), and attached retina with possible slight elevation at the fibrovascular interface (Figure 1). Pre-retinal hemorrhage was also observed in the left eye, but there was partial view of the fundus that showed regression in plus disease and improvement in EFP. Examination at 2 weeks post-injection showed resolving vitreous hemorrhage bilaterally with ROP regression, zone II, and no plus disease in both eyes (Figure 2). By 52 weeks gestation, vitreous hemorrhage was resolved bilaterally, and ROP status remained regressed in zone II with no plus disease, but with areas of EFP posterior to the vascular-avascular junction. Due to concern for late reactivation after treatment with bevacizumab, prophylactic ROP treatment completion was performed at 60 weeks with an exam under anesthesia, fluorescein angiography, and peripheral panretinal photocoagulation (PRP) in both eyes (Figure 3).
B-scan ultrasonography of the right eye 3 days after bevacizumab injection demonstrating elevation of fibrovascular tissue and choroidal thickening.
RetCam fundus photographs of right and left eyes 2 weeks after bevacizumab injection showing resolving vitreous hemorrhage, zone II regressed retinopathy of prematurity, and no plus disease bilaterally.
RetCam late-frame fluorescein angiography photographs of right and left eyes at 60 weeks showing anterior leakage near the vascular termination and posteriorly presumably at the original stage 3 ridge. Persistent peripheral avascular retina is present in both eyes.
Only a few prior reports have described vitreous hemorrhage following intravitreal bevacizumab injection in infants with ROP. Wu et al. reported four eyes with pre-retinal or vitreous hemorrhage out of a case series of 49 eyes that received bevacizumab injection.7 In these cases, the time between injection and hemorrhage was not reported, but all self-resolved. Kuniyoshi et al. reported a case series of eight ROP eyes that received bevacizumab injection with one instance of intravitreal hemorrhage occurring 19 weeks after injection.8 A second injection of bevacizumab was performed with subsequent laser photocoagulation and vitrectomy.
In our case, bilateral vitreous hemorrhage occurred within 2 weeks of bilateral bevacizumab injections, likely due to contraction of extraretinal vessels. The left eye showed a good response to treatment with early signs of regression. The ultrasound of the right eye, initially concerning for retinal detachment, revealed fibrovascular tissue in the vitreous cavity rather that detached retina, so no vitrectomy was recommended. Very close monitoring was performed and, ultimately, both eyes demonstrated regression of retinopathy and the vitreous hemorrhages self-resolved without additional intervention. It is known that advanced ROP can cause vitreous hemorrhage as well,9 but the timing after injection and the bilaterality of the hemorrhages make it more likely related to regression after bevacizumab injections than to progression of the ROP.
Given our patient's poor general medical condition, initial treatment with bedside bevacizumab was deemed a good option. For patients with numerous comorbidities and fragile cardiovascular statuses, the risks of general anesthesia to perform PRP are quite high. In our case, even routine bedside ocular examinations led to severe desaturations at several occasions, including one instance where cardiopulmonary resuscitation was performed. In patients such as these, bedside intravitreal bevacizumab is likely a safer treatment option than laser photocoagulation with general anesthesia.
Due to concern for ROP reactivation, and due to previous reports of late-stage reactivation after bevacizumab treatments,10–13 this patient received supplemental laser in both eyes at 60 weeks gestational age. This protocol — to prophylactically complete ROP treatment with PRP — has been adopted in our institution to reduce the risk of late recurrence of ROP after bevacizumab injections.14,15
Overall, our case demonstrates that vitreous hemorrhages are possible following bevacizumab injections when treating ROP. Given the relatively small sample sizes of patients in most bevacizumab ROP studies, it remains difficult to evaluate the incidence of this complication. As demonstrated, these hemorrhages can self-resolve with ROP regression without the need for urgent intervention.
- No authors listed. Multicenter trial of cryotherapy for retinopathy of prematurity: preliminary results. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Arch Ophthalmol. 1988;106(4):471–479. doi:10.1001/archopht.1988.01060130517027 [CrossRef]
- Early Treatment for Retinopathy of Prematurity Cooperative Group. Revised indications for the treatment of retinopathy of prematurity: results of the Early Treatment for Retinopathy of Prematurity randomized trial. Arch Ophthalmol. 2003;121(12):1684–1694. doi:10.1001/archopht.121.12.1684 [CrossRef]
- Mintz-Hittner H, Kennedy KA, Chuang AZ. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med. 2011;364(7):603–615. doi:10.1056/NEJMoa1007374 [CrossRef]
- Hwang CK, Hubbard GB, Hutchinson AK, Lambert SR. Outcomes after Intravitreal bevacizumab versus laser photocoagulation for retinopathy of prematurity: A 5-year retrospective analysis. Ophthalmology. 2015;122(5):1008–1015. doi:10.1016/j.ophtha.2014.12.017 [CrossRef]
- Micieli JA, Surkont M, Smith AF. A systematic analysis of the off-label use of bevacizumab for severe retinopathy of prematurity. Am J Ophthalmol. 2009;148(4):536–543. doi:10.1016/j.ajo.2009.05.031 [CrossRef]
- Sato T, Wada K, Arahori H, et al. Serum concentrations of bevacizumab (avastin) and vascular endothelial growth factor in infants with retinopathy of prematurity. Am J Ophthalmol. 2012;153(2):327–333. doi:10.1016/j.ajo.2011.07.005 [CrossRef]
- Wu WC, Yeh PT, Chen SN, Yang CM, Lai CC, Kuo HK. Effects and complications of bevacizumab use in patients with retinopathy of prematurity: A multicenter study in Taiwan. Ophthalmology. 2011;118(1):176–183. doi:10.1016/j.ophtha.2010.04.018 [CrossRef]
- Kuniyoshi K, Sugioka K, Sakuramoto H, Kusaka S, Wada N, Shimomura Y. Intravitreal injection of bevacizumab for retinopathy of prematurity. Jpn J Ophthalmol. 2014;58(3):237–243. doi:10.1007/s10384-014-0310-z [CrossRef]
- Hutcheson KA, Nguyen ATQ, Preslan MW, Ellish NJ, Steidl SM. Vitreous hemorrhage in patients with high-risk retinopathy of prematurity. Am J Ophthalmol. 2003;136(2):258–263. doi:10.1016/S0002-9394(03)00190-9 [CrossRef]
- Hajrasouliha AR, Garcia-Gonzales JM, Shapiro MJ, Yoon H, Blair MP. Reactivation of retinopathy of prematurity three years after treatment with bevacizumab. Ophthalmic Surg Lasers Imaging Retina. 2017;48(3):255–259. doi:10.3928/23258160-20170301-10 [CrossRef]
- Ittiara S, Blair MP, Shapiro MJ, Lichtenstein SJ. Exudative retinopathy and detachment: A late reactivation of retinopathy of prematurity after intravitreal bevacizumab. J AAPOS. 2013;17(3):323–325. doi:10.1016/j.jaapos.2013.01.004 [CrossRef]
- Patel RD, Blair MP, Shapiro MJ, Lichtenstein SJ. Significant treatment failure with intravitreous bevacizumab for retinopathy of prematurity. Arch Ophthalmol. 2012;130(6):801–802. doi:10.1001/archophthalmol.2011.1802 [CrossRef]
- Snyder LL, Garcia-Gonzalez JM, Shapiro MJ, Blair MP. Very late reactivation of retinopathy of prematurity after monotherapy with intravitreal bevacizumab. Ophthalmic Surg Lasers Imaging Retina. 2016;47(3):280–283. doi:10.3928/23258160-20160229-12 [CrossRef]
- Garcia Gonzalez JM, Snyder L, Blair M, Rohr A, Shapiro M, Greenwald M. Prophylactic peripheral laser and fluorescein angiography after bevacizumab for retinopathy of prematurity. Retina. 2018;38(4):764–772.
- Hu J, Blair MP, Shapiro MJ, Lichtenstein SJ, Galasso JM, Kapur R. Reactivation of retinopathy of prematurity after bevacizumab injection. Arch Ophthalmol. 2012;130(8):1000–1006. doi:10.1001/archophthalmol.2012.592 [CrossRef]