Nowadays, the efficacy of anti-VEGF treatment on ROP has been confirmed in many aspects. Bevacizumab and ranibizumab are the most commonly used anti-VEGF drugs in clinic. The latter may have less systemic effects than the former, because it has a shorter half-life in the blood. It was found that after intravitreal injection of ranibizumab, plasma VEGF levels decreased the next day, but returned to normal after one week . In another study, it was found that the recurrence rate of ROP patients treated with the first injection of ranibizumab may be higher, because it could vanish from the ocular local more quickly . A large study  showed that 127 eyes (45%) of 283 eyes relapsed after intravitreal injection of ranibizumab. For these reasons, we chose bevacizumab, which is also the most commonly used anti-VEGF drug for ROP in the world.
Results in our study showed that the cure rates of 1.25 mg, 0.5 mg and 0.75 mg bevacizumab treatment were 100%, 100% and 95.83% respectively in the 2nd month after treatment. And the normal retinal vascularization rate of the three groups was only 41.67% − 66.67%. In comparison, Henaine-Berra A. et al. studied 47 eyes of 26 patients with threshold or pre-threshold ROP treated with 0.75 mg bevacizumab, with regular fundus fluorescein photography and Retcam examination, and found that the cure rate was 92%, with 45% of the patients did not complete normal retinal vascularization. However, Wu W.C. et al. conducted a multicenter study in Taiwan, and found that the cure rate of patients with stage 3 ROP treated with once 0.625mg bevacizumab was 90%, with 10% of the cases needed additional laser treatment . The above reports are similar to the experimental results of 0.5mg and 0.75mg groups in our study, suggesting that regular review is still needed after bevacizumab treatment to prevent recurrence.
Considering the potential effects of anti-VEGF drugs on the organs of the whole body, experts have been trying to use low-dose bevacizumab to treat ROP. Wallace et al.  used intravitreal injection of 0.25 mg, 0.125 mg, 0.063 mg or 0.031 mg bevacizumab in 61 eyes with type I ROP in a single-blinded multicenter study. They found that low-dose bevacizumab treatment has positive effects, but many eyes needed additional treatment. Dikci S. et al. Also confirmed the above results in a clinical study of 0.5mg and 0.625mg bevacizumab in the treatment of acute posterior pole retinopathy of prematurity (AP-ROP), in which the recurrence rate of the 0.5mg group was higher, and half of the eyes needed further photocoagulation at the corrected gestational age of 47.6 ± 1.5 weeks . In the 0.5mg group of our study, the cure rate was 100% and the retinal vascularization rate was 50% on 3 months after treatment (corrected gestational age 49–50 weeks), with no recurrent cases. Considering the limited number of cases and insufficient follow-up time, further study is still needed. However, based on the current literature reports, we believe that ROP treated with ultra-low dose bevacizumab is more likely to recur.
For the postoperative evaluation of bevacizumab-treated ROP, fundus examination should be carried out regularly. The wide-angle digital fundus photography system (RetCam) and fluorescein angiography can be used to evaluate and analyze [15–16]. Because the latter requires intravenous injection of fluorescein sodium contrast agent, there is a certain risk for the infants, so it is not recommended to be used repeatedly. Therefore, at present, we mainly use fundus photography equipment such as RetCam for examination. Our study showed that the curative efficacy of bevacizumab treatment was different under different doses or under different periods. On the 4th day and 2nd week after treatment, the curative efficacy of 1.25 mg group was better, and there was no difference among the three groups after 4 weeks. The efficacy of 0.5 mg and 0.75 mg groups changed significantly from the 4th day to 2nd month after treatment, with normal retinal vascularization rate of the three groups being only 41.67% − 66.67%. The results also showed that the efficacy of bevacizumab in the ultra-routine dose group was better than that in the routine dose group within 2 weeks after treatment, and the efficacy was similar to that in the routine dose group and the low-dose group within 1 month after treatment, whereas the efficacy of bevacizumab in the latter two groups became gradually obvious with the extension of postoperative time (within 3 months). We believe it should not be simply deducted that the efficacy of low-dose bevacizumab is not obvious, since the degradation degree of different groups variated significantly in the first two weeks after treatment. Long-term postoperative fundus review and dynamic observation are needed. As long as the no deterioration of retinopathy was observed after treatment, additional therapy is not necessary. Up till now, there is no related research report.
In terms of disease recurrence, multiple studies have found that comparing with photocoagulation, the average recurrence time of retinopathy treated with intravitreal injection of bevacizumab is about 10 weeks later. Therefore, it is suggested that for the treatment of ROP with intravitreal bevacizumab, the follow-up time should be longer, so as to detect the recurrence of the disease [17–18]. The three groups of patients in this study were all nonlocal and could not adhere to the long-term follow-up, so they only followed up to the 3rd month after treatment, and then followed up in the local hospital. In the 0.75mg group, one patient was found to have a recurrence of ROP in the left eye 4 weeks after treatment, and laser treatment was given. No recurrence was found in other cases. Because the pharmacokinetic duration of bevacizumab in newborns may be longer than that in adults, the efficacy, recurrence rate and safety of bevacizumab may be different. At the same time, the blood-retinal barrier of ROP infants is not fully developed. Therefore, the results of bevacizumab injection in preterm infants are different from that of adults. Intraocular injection of bevacizumab in preterm infants had been proven to reduce serum VEGF level . whereas, many organs of ROP infants are not fully developed. The decrease of VEGF concentration in blood may affect the develop of nervous system, kidney, lung and other related organs. Arima M. et al.  conducted a 10-year retrospective study, and used the Kyoto Scale of Psychological Development (KSPD) to evaluate the neurodevelopment of type I ROP patients treated with early use of 0.625mg bevacizumab injection at the age of 18 months. The results showed that the treatment may lead to the impairment of interpersonal relationship, social communication and / or speech ability development in premature infants. Therefore, we suggest that low-dose bevacizumab should be used in the treatment of ROP.
Summary: ① Comparing the three doses of bevacizumab treatment, the efficacy of 1.25mg group is the best on the 4th day and the 2nd week after treatment, and there is no difference among the three groups after 4 weeks. The efficacy of 0.5mg and 0.75mg group changes significantly from the 4th day to the 2nd month after treatment, which needs to be followed up regularly and timely to assess the situation of fundus after treatment. ② The proportion of normal retinal vessels of the three groups is 41.67% − 66. 67% in the 3rd month after treatment. Long-term follow-up of fundus changes is still needed to avoid recurrence of ROP whatever the dose of bevacizumab is uesed for treatment of ROP .③ This study is limited in the number of subjects and follow-up length, also in lack of multi center data, which requires further study.