Ranibizumab was the first anti-VEGF approved to treat ROP by the European Medicines Agency [18]. Our research prospectively reported the outcomes of 37 eyes of 30 infants, who received IVR. A-ROP group included 18 eyes and type 1 ROP group included 19 eyes. Once insufficient regression or ROP recurrence requiring treatment was determined, IVR was reinjected.
Feng et al [19] reported retrospectively the outcomes of 629 eyes with APROP (105 eyes), threshold ROP (411 eyes), and type 1 prethreshold ROP (113 eyes) treated with IVR (0.25 mg). Recurrence was seen in 67% of eyes with APROP, 38% of eyes with threshold ROP, 16% of eyes with type 1 prethreshold ROP. It showed statistically significant increase with increasing stage and more posterior zone.
In partial agreement with our study, the recurrence rate was significantly higher in A-ROP eyes compared to type 1 ROP. Also, recurrence rate with zone I ROP (13.51%) was significantly higher than post zone II ROP (2.7%). The relatively higher rates of recurrence, additional treatments, according to Feng et al, were mostly due to large study population and that the authors included threshold ROP infants as well. Zone II disease is not further classified into ant zone II, mid zone II, and post zone II. All infants were of Chinese ethnicity.
Aldebasi T et al. [20] studied 74 eyes with ROP. Those eyes were categorized into stage III with plus disease in zone I (6 eyes), posterior zone II (10 eyes), mid and ant zone II (54 eyes) and AP- ROP (4 eyes). They received a single injection of 0.3 mg IVR. All eyes showed a favorable response in terms of regression of plus disease from the first day after treatment, followed by regression of stage III retinopathy.
Unlike the current study, insufficient regression occurred in 16.7% of eyes in A-ROP group. This can be explained by the higher dose of ranibizumab used by Aldebasi et al. Also, only 4 eyes of A-ROP were included in their study.
According to Menke et al [21] 6 eyes of 4 premature infants with threshold ROP stage III with plus disease in zone II were treated with 0.3 mg IVR. They reported complete resolution of threshold ROP with no recurrence. All patients developed complete vascularization over variable periods of time. All patients were of zone II disease and the study had small sample size.
In partial agreement with the previous study, we reported no recurrence and complete retinal vascularization in type 1 ROP group. Still Menke et al used a larger dose of IVR. Despite the relatively smaller dose in our study, many previous reports have shown almost 100% positive outcomes in terms of initial regression like ours [22–24].
Huang et al [25] carried out a retrospective review of 283 eyes with type 1 ROP who were treated with IVR (0.25 mg). 94% of eyes had a positive response. The recurrence rate was 47% in APROP, 58% in zone I, and 35% in zone II. In the positive response group, 84.2% of eyes were type 1 ROP, and 15.8% of eyes were AP-ROP.
Like the current study, 92% of eyes had initial regression and the recurrence rate was significantly higher in A-ROP eyes compared to type 1 ROP. The higher recurrence rate according to Huang et al [25] than our study may be explained with the smaller GA and BW. The ratio of zone I ROP was relatively smaller in our infants. It was a single-center study limited to Asian populations. Also, earlier PMA at initial injection than our study type 1 ROP infants, indicates that these infants may have been more ill and had more serious retinopathy that required earlier treatment [26].
In a study by Sukgen et al [27] for 26 eyes with AP-ROP treated with IVR. They noticed reactivation in 7 patients (53.8%) where 2 needed retreatment and other 5 regressed spontaneously. The higher rate of reactivation is either due to the smaller mean GA and BW than A-ROP group in the current study. Also, the zone I disease was much higher (76.9% versus 33.3%) and 8 patients had rubeosis iridis.
Xiu-Juan et al [28] revealed 21.88% recurrence in patients with AP-ROP (zone I in 22 eyes and posterior zone II in 10 eyes). Among them, 78.13% of eyes achieved primary success after the use of IVR injection only once in each eye. The location of recurrent cases was all in zone I.
Unlike the current study, in A-ROP group treatment success was achieved in 61.1%. The higher primary success according to Xiu-Juan et al is mostly due to higher dose of ranibizumab used (0.3 mg). The recurrence rate in A-ROP eyes is nearly like ours (22.22%). The location of the recurrent cases was in zone I only in 75% of cases.
According to our results, initial regression of neovascularization and plus disease was found within 1 week in 11/18 eyes (61.1%) compared to 9/19 eyes (47.4%) in type 1 ROP group. Therefore, for type 1 ROP cases, disease regression seems to be the primary problem, but for the A-ROP cases in the early stages of the disease, regression may be easier than type 1, but initial regression cannot
guarantee full maturation without additional treatment.
That agreed with Yetik et al [29] who reported that the indications for third injections of IVB were inadequate regression in the threshold (2/2; 100%) group and recurrence in the APROP (2/2; 100%) group. Also, Çömez A et al [30] described retrospectively that all findings for ROP and plus disease had regressed in 247 (96.1%) eyes within 48–72h after IVB. Ten eyes (3.9%) had insufficient regression and progression after initial injection (two eyes, Type 1 ROP; eight eyes, APROP).
Tong et al [31] collected the data of 160 eyes with AP-ROP treated with IVR (0.3 mg). Recurrence requiring retreatment occurred in 51% of eyes. Higher recurrence rate may be explained by smaller mean GA, younger mean BW than the current study. The retrospective nature of this study and the lack of a control group warrant further research.
The data of 340 eyes of type 1 ROP were recorded retrospectively by Ling et al [32] 61 eyes received laser treatment, 231 eyes received IVB, and 48 eyes received IVR. The recurrence rate of the IVR group (20.8%). The mean interval of recurrence from initial treatment in 8.3 ± 1.6 weeks.
Higher recurrence rate than type 1 ROP group in our study could be due to smaller BW, younger GA, higher zone 1 affection, higher stage 3 incidence and younger PMA at initial treatment in our study. The study was carried out in Taiwan. These differences could be due to ethnic composition and demographic variations [33–36].
Zhang et al [37] analyzed prospectively the outcomes of 50 eyes with bilateral type 1 ROP in zone II. They received either IVR or diode laser photocoagulation. In the ranibizumab group, higher recurrence rate (50%) than type 1 ROP group in our study could be due to smaller BW, younger GA. Later interval (12.6 ± 7.9 weeks) may be due to the higher dose of IVR (0.3mg in 0.03 ml). Moreover, anterior, and posterior Zone II treatment requiring ROPs have a striking difference in their behaviors and presumably also in their treatment responses; however, Zhang et.al did not stratify them in the first instance. All patients were of zone II disease and were Han Chinese.
According to Alymac et al [38] 65.2% of eyes completed vascularization in ranibizumab group at 56.30 ± 4.30 weeks’ PMA. In IVR group, 46 eyes of type 1 ROP, 11 patients of zone I and 12 patients of zone II disease. All type 1 ROP infants in our study are of zone II. Zone I ROP needs more time to achieve complete vascularization. The 4 weeks' difference from our study may be because total retinal vascularization was defined as perfusion within 2 DD from the ora serrata. However, according to Alymac et al, it was defined as retinal vessels reaching the ora serrata.
Aldebasi T et al [20] emphasized that complete retinal vascularization was achieved within 4–10 weeks of treatment. Earlier mean time of complete vascularization than our study may be due to more cases of A-ROP (48.6% versus 8.5%) and higher number of mid and ant zone II disease in type 1 ROP group (15.8% versus 77.1%).
According to Huang et al [25] 3% of eyes had incomplete vascularization after IVR. There were high proportions of zone I ROP 22.0% and APROP 17.1%. Zone I ROP and APROP require more time to achieve full vascularization.
All our patients were treated prospectively. This greatly minimized the missing data or incomplete examinations. All cases were evaluated before and after treatment, so that even minute changes are detected and analyzed using clinical examinations by BIO and colored RetCam-saved photos.
The efficacy of reinjection of ranibizumab in reactivated cases of type 1 ROP and aggressive ROP was reported. We believe this could be a better alternative to rescue laser photocoagulation for reactivated ROP, allows better growth of the normal retinal vessels to the periphery and better refractive outcome. Most previous studies evaluated the efficacy of ranibizumab in treatment-requiring ROP but few if any compared the efficacy of the drug in A-ROP and type 1 ROP.
Our study had a relatively small sample size. The follow-up period was enough to document ocular efficacy of IVR, but relatively short to document systemic safety. FFA is a useful tool in observing retinal vascular morphology and development. Still, it was not used routinely in our study. Our study infants were of higher BW and older GA. That was different compared with the previous publications.