Compared with other anti-VEGF agents, ranibizumab is a monoclonal antibody Fab fragment lacking the Fc region. A short half-life and rapid clearing from the vitreous and the absence of a Fc region theoretically makes it a better option for ROP treatment, because of its lower systemic side effects to premature infants during neurodevelopment [10-11]. However, IVR treatment for ROP may be associated with a higher incidence of recurrence, when compared with other anti-VEGF agents [12-16]. Recurrence rates after IVR monotherapy varied greatly in previous retrospective studies, which ranged from 0%−83% with different recurrence definitions, inclusion criteria, IVR dosages, and follow-up schedules [14, 15, 18, 27, 28]. Moreover, the risk factors for ROP recurrence in patients with IVR after long-term follow-up are scarce.
In the present study, zone Ⅰ disease and gestational diabetes mellitus were found to be independent risk factors for recurrence after IVR monotherapy. In our experience, IVR was effective in curing type 1 ROP for extended periods of time; however, successful treatment could not be achieved in all eyes with a single injection. The overall recurrence after IVR monotherapy was 36.4%, and recurrences occurred before 50.1 weeks at PMA (11.3 weeks following the initial IVR treatment). Two eyes of one patient had a second recurrence 54.1 weeks at PMA (11.6 weeks after recurrence). A previous study also reported that follow-up in the first 12 weeks after IVR treatment was important for timely identification of ROP recurrences [18]. Several late recurrence cases (even 2.5 years later) have shown the need for long-term examinations after anti-VEGF agent monotherpy for ROP [29-31]. Thus, after the initial IVR treatment, it is important to conduct follow-ups in the first 12 weeks for timely identification of ROP recurrences.
Zone I consists of a circle, the radius of which extends from the center of the optic disc to twice the distance from the center of the optic disc to the center of the macula [22]. It has been an important predictor for prognosis of ROP, and is associated with a high risk of adverse anatomic outcomes [32-34]. Aggressive posterior ROP has been most commonly observed in zone I [22], and has been identified as a risk factor for recurrence after IVB treatment [12], which is consistent with our results. Lyu et al. [18] reported that zone I did not correlate with ROP recurrence. One of the reasons for the discrepancy may be that they enrolled only patients with severe forms of type 1 ROP and poor systemic conditions.
Another independent factor for ROP recurrence in our study was gestational diabetes mellitus. Based on the pathogenesis, ROP and diabetic retinopathy are both retinal vascular diseases, in which there is leakage and/or neovascularization from damaged retinal vessels, based on retinal ischemia. Moreover, Opara et al. [35] have suggested that maternal diabetes is associated with ROP, with the strength of association increasing with increasing severity of ROP. Ling et al. [15], however, reported that gestational diabetes did not correlate with ROP recurrences after IVR treatments. The mean GA (26.2 ± 1.6 weeks) and mean BW (827.9 ± 187.3 g) in their study were lower, whereas our study patients had an older GA of 28.0 (26.1, 28.1) weeks and higher BW 993.0 (926.0, 1,114.0) g. These infants with lower GA and BW may have been more ill and with more advanced ROP.
Most retinal vessels of patients progressed anteriorly within the retina after IVR treatments. As an additional word of caution, two eyes of one patient had second recurrences 54.1 weeks at PMA, leaving the partially stopped vascularization retina. We recommend that follow-up examinations need to continue for several months after each injection, because of the lack of standard follow-up recommendations, especially for those patients with initial zone Ⅰ disease and/or mothers with gestational diabetes mellitus.
After the anti-VEGF agent treatment for ROP, persistent avascular areas in the peripheral retina were common. How to deal with the avascular area is still debatable. Although it was associated with shallower anterior chamber depths and more refractive errors [6], some studies have used laser ablation, to inhibit late recurrence [18, 36, 37]. However, we did not find recurrence after 54.1 weeks at PMA for even 5 years when only using anti-VEGF therapy.
Our study reported visual outcomes of a subgroup of eight patients, which made statistical comparisons difficult. Visual rehabilitation is the final objective of ROP treatment. Although depth increases with age, amblyopia remains treatable until 60 months, with a decline in treatment effectiveness after an age of 5 years [38]. Eyewear corrections are often needed for associated refractive errors and strabismus or amblyopia. During this study, amblyopia trainings was already conducted by a local ophthalmologist for one child. At the end of the study, one child was ready for strabismus surgery.
Hu et al. [17] reported that preretinal hemorrhage before treatment was an important risk factor that was associated with the recurrence of ROP, but hemorrhages before treatment were not associated with the recurrence of ROP in our study. The study by Hu et al. [17] excluded Zone I disease. Other possible reasons for the discrepancy may be that ROP specialists defined plus disease differently, but they tended to be internally consistent [39], thus resulting in different treatment criteria for ROP and clinical diagnoses of ROP recurrence.
There were several limitations to this study. First, it was a retrospective study with a small sample size. Second, some variables that may be related to ROP recurrence were not included, such as oxygen requirement, necrotizing enterocolitis, and hospital duration. Fluorescein angiography was not performed for all patients. Additionally, the possibility that screening and treatment of our population consisted of Chinese patients with older GAs and higher BWs than most other clinical trials may have influenced the clinical findings.