Spontaneous appearance and resolution of vitreous hemorrhage after bevacizumab injection in retinopathy of prematurity

Retinopathy of prematurity (ROP) is now the leading cause of childhood blindness in premature infants because of the advanced Neonatal intensive care unit (NICUs) leading to the survival of these premature babies.1 Now, we have multiple treatment options for these babies and it depends on the staging and severity of the disease. According to the BEAT-ROP trial, intravitreal bevacizumab was effective over laser photocoagulation in the treatment of zone 1 stage 3 ROP but had no significant favorable outcome with zone 2 ROP.2 Here, we present a case showing the nature and outcome of vitreous hemorrhage after intravitreal bevacizumab in a preterm baby having posterior zone 2 stage 3 ROP over the course of time. A preterm baby born at the gestational age of 27 weeks and birth weight of 650 g was first screened for ROP at PCA of 33 weeks. The child was delivered by cesarean section, had respiratory distress, and was on a ventilator for 5 days and then on oxygen support for 17 days. On examination, anterior segment showed extensive neovascularization of the iris (NVI) and rigid pupil Figure 1a and b. Fundus examination showed both eyes posterior zone 2 stage 3 ROP with extensive fibrovascular proliferation in 12 clock hours with plus disease Figure 1c and d. Due to extensive iris neovascularization, rigid pupil, and posterior location of the disease, the child was advised of anti-vascular endothelial growth factor (VEGF) injection. Informed written consent was obtained from the parents. Sterile gloves, speculum, and forceps were utilized while administering the injections. A speculum for premature infants was placed between the lids. A drop of povidone-iodine (5%) ophthalmic solution was placed into the conjunctival sac for 1 min with the excess removed by a sterile cotton tip applicator from the temporal lid margin. Intravitreal bevacizumab (0.025 mL) was given under aseptic precaution under topical anesthesia using a 30 gauge needle. On day 1 post-bevacizumab, the right eye showed NVI grossly reduced with pupils dilating well with regressing plus disease. The left eye showed total vitreous hemorrhage with no view of the fundus Figure 2a. A B-scan examination of the left eye showed dispersed vitreous hemorrhage with no anteroposterior traction. The child was kept on close follow-ups and serial ultrasound was done for the left eye each visit. Two weeks postinjection, in the right eye, fibrovascular proliferation was regressing and the left eye, although the posterior pole was not visible, the mid periphery was visible with vessels going beyond the vitreous hemorrhage and the retina was flat Figure 2b. Left eye vitreous hemorrhage regressed completely 6 weeks post-bevacizumab and there was an epiretinal membrane inferior to fovea which also showed spontaneous retraction on follow-up visits Figure 2c and d. Vessels reached maturity 4 months post-bevacizumab with complete regression of the disease in both eyes. Eighth-month follow-up visit, the child showed no resistance to occlusion to either of the eyes and developed myopia of -5.5 diopters in both eyes for which glasses were prescribed.Figure 1: (a and b) Anterior segment shows extensive neovascularization of the iris and rigid pupil (black arrows). (c and d) Fundus examination shows both eyes posterior zone 2 stage 3 retinopathy of prematurity with extensive fibrovascular proliferation in 12 clock hours (white arrows) with plus diseaseFigure 2: (a) Left eye shows vitreous hemorrhage. (b) Two weeks postinjection, Left eye although the posterior pole was not visible, the mid periphery was visible with vessels going beyond the vitreous hemorrhage (white arrow). (c and d) Left eye vitreous hemorrhage regressed completely 6 weeks post bevacizumab and there was an epi-retinal membrane (black arrow) inferior to the fovea which also showed spontaneous retraction on follow-up visitsThe concern of contracture of fibrovascular proliferation post and anti-VEGF gives a dilemma in treating zone 1 and posterior zone 2 ROP with extensive fibrovascular proliferation. This baby developed a massive vitreous hemorrhage in only the left eye immediately postinjection, which was initially thought due to contracture of fibrovascular proliferation. But because of these resolving proliferations in the right eye and the absence of progressive anteroposterior traction in the left eye on serial ultrasounds, we took a conservative approach. Complications post-bevacizumab such as ocular hemorrhages are reported.3 The presence of vessels in the mid periphery on follow-up visits showed the vitreous hemorrhage which occurred immediately postinjection might be due to minimal induction of posterior vitreous detachment. Acute contracture of fibrovascular proliferation post-bevacizumab injection in a baby with stage 4A ROP was shown by Honda et al.4 The adjuvant effect of intravitreal bevacizumab before vitrectomy is shown by many studies where vascularity is reduced despite of contracture of proliferative membrane and early timing for surgery.5 In all the mentioned studies, anti-VEGF was given in the presence of anteroposterior traction in tractional detachment phase of ROP where TGFβ is high leading to the progression of fibrosis and contracture resulting and worsening of ROP.6 Although our case presented with fibrosis, it was still presumed to be in the vasoproliferative phase (Phase-2), with no clinical evidence of anteroposterior traction. Here, the vascular component predominates fibrosis, and when treated with anti-VEGF no contracture occurs and new vessels shrink and disappear. Vitreous hemorrhage in our case was attributed to the intravitreal injection procedure and not due to contracture and both resolved over the period without the need of vitrectomy. To conclude, intravitreal bevacizumab injection is an effective method for the management of patients with ROP requiring treatment. Close monitoring for recurrence or progression is necessary. The unpredictable postinjection course and the unknown systemic side effect profile in premature infants have created significant controversy and limited its widespread acceptance. The case report describes a successful response to anti-VEGF monotherapy with no further complications such as disease reactivation or progression to retinal detachment. Financial support and sponsorship Nil Conflicts of interest There are no conflicts of interest.