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 curing rates of 1.25 mg, 0.75 mg and 0.5 mg bevacizumab treatment also were 100% in the 2nd month after treatment. And the proportion of retinal complete vasculization respectively in 1.25mg , 0.75mg and 0.5mg group is 66.67%, 43.48% and 50% in the 3rd month after treatment. 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 0.625 mg bevacizumab was 90%, with 10% of the cases needed additional laser treatment . The above reports are similar to the experimental results of 0.5 mg and 0.75 mg 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 0.5 mg and 0.625 mg bevacizumab in the treatment of acute posterior pole retinopathy of prematurity (AP-ROP), in which the recurrence rate of the 0.5 mg group was higher, and half of the eyes needed further photocoagulation at the corrected gestational age of 47.6 ± 1.5 weeks . In the 0.5 mg group of our study, the cure rate was 100% and the retinal complete 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 lower 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 [18-19]. 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 IVB 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 fundus change of 0.5mg and 0.75mg group is significantly from the 4th day to the 2nd month after treatment. The proportion of retinal complete vasculization respectively in 1.25mg, 0.75mg and 0.5mg group is 66.67%, 43.48% and 50% in the 3rd month after treatment. The results also showed that the efficacy of bevacizumab in the 1.25 mg group was better than other two groups within 4 weeks after treatment, however we believe it should not be simply deducted that the efficacy of low-dose bevacizumab is not obvious, because the efficacy was similar in three groups from postoperative 2th to 3th month. 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 IVB is about 10 weeks later. Therefore, it is suggested that for the treatment of ROP with IVB, the follow-up time should be longer, so as to detect the recurrence of the disease [20-21]. 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 0.75 mg group, one patient was found to have a recurrence of ROP in the left eye 4 weeks after treatment, and laser treatment was given. The eye was excluded from the study from the 4th week to the 3rd month after treatment. 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: Retinal complete vascularization was slightly better in 1.25 mg group, but failed to reach a statistical significance. Based on results, the lowest dose 0.5 mg may be preferred since our final results were similar (p>0.05). 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 . More studies with larger samples are required to find the adequate dose in ROP management.