This study showed that delayed laser photocoagulation after IVA had some benefits on development of immature neurovascular tissues over prompt laser photocoagulation. Especially Zone 1 and Zone 2p ROP were changed into Zone 2p and Zone 2a, respectively during the delayed period. Average period of the delay was about 7 ~ 8 weeks after IVA. We supposed that delayed laser photocoagulation after a single IVA can be another option for recurred ROP after IVA to minimize the potential systemic side effects caused by multiple IVAs and myopic shift after laser photocoagulation.
The current standard treatment for ROP is LP of the avascular peripheral retina. The ET-ROP trial reported that early LP for high-risk, pre-threshold disease resulted in better visual and structural results than did conventional LP for threshold disease, and recommended laser retinal ablation for type I ROP. However, LP complications should be considered. Destruction of the peripheral retina can cause myopic changes and visual field defects [6, 8, 12]. In previous studies, the mean refractive error at five or seven years after LP was reported to be − 2.3 to − 6.7 diopters (D) [15, 17–20]. Hwang et al. reported that the myopic change was more severe in Zone 1 ROP than in Zone 2 ROP, and the mean spherical equivalent values were − 10.1 ± 10.5 D and − 4.7 ± 4.6 D, respectively .
The myopic shift in ROP patients decreased in eyes who received IVA instead of laser photocoagulation. Hwang et al. reported that the mean spherical equivalent was 0.6 D in Zone 2 ROP with IVA treatment, which was significantly lower than that of − 4.7 D in the LP treatment group. In Zone 1 ROP, the mean spherical equivalents were − 3.7 D and − 10.1 D in the IVA and LP groups, respectively, but the difference was not statistically significant. Otherwise, Geloneck et al. showed that In addition, visual fields are better preserved with IVA compared to LP because IVA can lead to further growth of peripheral retinal vessels. IVA also better reduces the recurrence of ROP after treatment compared to LP. The Bevacizumab Eliminates the Angiogenic Threat of ROP (BEAT ROP) study reported that the rates of recurrence were 6% and 27% in the IVA and LP groups of Zone 1 ROP, respectively, and the difference was statistically significant .
Despite the low recurrence rate, there is a concern regarding the timing of recurrences and the follow-up period after IVA. The reported intervals between bevacizumab treatment and recurrence in the BEAT-ROP study were 19.2 (± 8.6) weeks and 14.4 (± 0.8) weeks in Zone 1 and Zone 2 ROP, respectively. There also exist several case reports to date describing ROP recurrence after IVA. Hoang et al. and Kong et al. reported that ROP recurred at two months and 11 months after initial IVA, respectively [10, 11]. The intervals from initial IVA treatment to recurrence are relatively long and variable, and are affected by multiple factors such as the systemic condition of the infant, population origin, and the type of anti-VEGF agent [10, 11]. Any unexpected recurrence of ROP after initial IVA during the follow-up period should be of concern to clinicians, even though there is a relatively low rate of such recurrence. Thus, infants receiving IVA treatment for ROP require careful follow-up until vascularization is complete . However, complete examination of the fundus to the peripheral retina is difficult to achieve in babies older than 50 to 60 weeks, and there is no definite protocol for follow-up after IVA treatment.
To avoid these problems, the combination treatment of either LP with IVA or IVA with LP may have advantages versus monotherapy [14, 21–23]. However, in previous studies, IVAs were used as adjuvant treatments and performed with LP simultaneously. According to our results, initial LP may interfere with further retinal vascularization. Thus, a combination of initial IVA followed by deferred LP may increase the chances for the continuation of retinal vessel development and prevent unexpected recurrences of ROP. It is certain that the achievement of complete ROP regression by only a single IVA is the best course of treatment. However, due to the variable intervals of recurrences, careful fundus examination of the peripheral retina is needed continually until full vascularization of the retina occurs. For some cases in which long-term follow-up is not possible, deferred, elective LP after initial IVA may be an option to minimize destruction of the peripheral retina, decrease myopic progression, and protect the visual fields versus initial LP, without the need for long-term follow-up with a concern for recurrences. The recommended interval is eight to 12 weeks according to our results and those of previous studies.
Only mild ocular adverse effects such as transient intraocular pressure elevation, subconjunctival hemorrhage, and retinal hemorrhage were observed. No systemic side effects associated with IVA were found during the observation period in the present study. Furthermore, these results of systemic effects were similar to findings in recent several reports about the systemic side effects of anti-VEGF injection treatment for ROP [24, 25].
This study has several limitations. First, it was retrospective in nature and had no randomized control group. The follow-up period was about six months, which is relatively short and therefore does not allow for any conclusions about the long-term effects of IVA and LP on ROP. The number of children included was also small. In addition, our study could not compare the detailed systemic effects between IVA and LP.