ROP is a VEGF-driven vasoproliferative disease. Although retinal photocoagulation is the mainstay of ROP treatment, some authors suggest anti-VEGF agents for treating some ROP cases, like ones with media opacity, meiotic pupils, or the APROP. It has several advantages over conventional laser therapy. It is easier and less expensive without any need for expensive equipment. Also, it does not induce visual field loss which frequently occurs with laser therapy.
To our knowledge, none of the previous investigations have provided evidence regarding risk factors for primary treatment failure in patients treated initially with anti-VEGF therapy alone. Thirty-five eyes from 865 eyes treated with intravitreal bevacizumab (4.04%) meet the criteria of primary failure. Our results demonstrated that infants with younger age and plus disease who have a history of phototherapy and oxygen therapy harbor a greater risk of treatment failure following injection of bevacizumab to treat type I ROP in zone I or II.
Nevertheless, ROP recurrence is a significant concern about anti-VEGF agents because it can devastate outcomes, like vitreoretinal traction and retinal detachment.13 Notably, it may recur after a more extended period compared with laser therapy.13 Off-label usage of Bevacizumab for regression of abnormal retinal vessels is acceptable. Its relatively large size and long half-life suggest that a single intravitreal injection may be adequate for the ROP treatment.5
In this study, we used intravitreal bevacizumab injection to treat ROP in zone 1 and zone 2. All of the 830 eyes that were treated successfully showed primary regression after receiving IVB, but ROP recurred in 33 eyes. Thereby, intravitreal bevacizumab treatment is an effective modality in inducing regression in treatment required type 1 ROP, but recurrence is an important factor.
The art of managing IVB-treated ROP patients is to differentiate treatment failure from recurrence, chiefly because the mainstream of treatment failures signifies a misdiagnosis.11 Currently, evidence on response patterns to IVB, primary failure rate, and risk factors are scarce. Chen and colleagues described a spectrum of regression, including full vascular maturity, vascular arrest alone, or vascular arrest with persistent tortuosity following injection of bevacizumab.14 They evaluated 92 eyes of 42 infants, of whom 16 eyes (18%) experienced reactivation. Areas of ischemia were greater in eyes with reactivation. They found younger age at IVB treatment was associated with vascular arrest accompanied by tortuosity; however, their results don't provide data about primary treatment failure.
On the other hand, recurrences need to be carefully assessed in order to avoid overtreatment. In the light of the importance of recurrence, Many studies reported the incidence of recurrences after initial treatment with intravitreal injections. The incidence of recurrence reported varies from 4 to 10%. On the other hand, IVB monotherapy led to persistent avascular retina12,15 and delayed recurrence of ROP (even three years after IVB).16–18 BEAT-ROP study demonstrated a 4 % risk of recurrence at a mean time of 16 ± 4.4 weeks post IVB injection.5 This is relatively similar to our results showing 3.9% recurrence at a mean of 18 weeks and 3 days. More recently, in a large cohort of IVB-treated ROP patients, they demonstrate, 2.5% (17 patients) failed treatment and a recurrence rate of 6.8% within the first 12 ± 4weeks.11 They found initial misdiagnosis as the main culprit for unresponsiveness. However, in our study, cases of misdiagnosis are not included, and the remaining infants with primary failure have been re-examined by two experts in the field to assure correct diagnosis. Another explanation for discrepancy could be the inclusion of patients with different baseline demographic factors such as GA and birth weight which were lower in our study (1450 ± 750g vs. 1121 ± 312 g; 30 ± 2 weeks vs. 28 ± 2 weeks; respectively), as long as different ethnic.
Additionally, a lack of widely accepted criteria for practice patterns after initial treatment with IVB may lead to different approaches in various centers, which some may attain a more aggressive and cautious approach. Furthermore, Experts in ROP describe plus disease differently, but they tend to be internally consistent.19 On the other hand, other studies on ranibizumab have demonstrated an earlier and higher risk of recurrence.13,20
Some authors propose laser photocoagulation for the treatment of such recurrences, while others advocate for repeat injections. In retreatment required patients, Based on our experience, we recommend laser photocoagulation. Repeat anti-VEGF was done in cases with recurrence of retinopathy of prematurity when the border of the vascular – avascular area was posterior (posterior zone 2).
In terms of primary failure, Our results demonstrated that younger age and plus disease, history of phototherapy, and oxygen therapy harbor a greater risk following injection of bevacizumab to treat type I ROP in zone I or II.
GA is the strongest risk factor for developing severe ROP. In cryotherapy for ROP study (CRYO-ROP), younger age was associated with the development of threshold ROP21. This finding has been replicated in other studies22–25. Lower GA was a common risk factor among various studies to be associated with recurrence after successful initial treatment12,26,27. Infants with lower GA are more ill, have a higher grade of retinopathy, and additionally lower capacity to produce anti-oxidant enzymes. Our result implies that GA under 32 weeks imposes a 4.4% increased possibility of primary treatment failure. Therefore it is crucial to maintain vigorous follow-up examination in the early phase after therapy to detect signs of treatment failure in these subsets of infants.
Our results demonstrate that plus disease, defined as vascular tortuosity and dilation, is associated with a 4% increase in the prevalence of treatment failure. Excessive signaling through VEGF-VEGFR2 is involved in the features of plus disease. Therefore, regulation of VEGFR2 signaling through anti-VEGF treatment combats this condition and prevents progressive neovascularization. On the other hand presence of plus disease indicates a more severe form of the disease2. Additionally, primary failure indicates an overabundance of VEGF, which is not completely controlled with single-dose treatment. So, it is rational that those infants suffering from a more severe form of the disease are prone to treatment failure and might require further therapy throughout the course of the disease. However, 99.5% of infants in our study had plus disease. This issue underscores the necessity for a standard grading scale of vascular abnormality in ROP. Recently, efforts have been made to apply vascular severity scores for patients with ROP28–30. These investigations showed variability in plus disease. In fact, eyes with higher severity scores may be prone to unresponsiveness to treatment or recurrence. This hypothesis requires further prospective studies to evaluate objective vascular scores to differentiate the severity of plus disease and its association with treatment response.
Based on our findings, oxygen therapy is associated with a 4.5% increase in the prevalence of primary treatment failure. A historical trial published in 1956 found that the incidence of ROP is higher in infants treated with >50% oxygen31. Additionally, the period of oxygen therapy, fluctuation in oxygen saturation, and mechanical ventilation are independent risk factors for the development of severe ROP32–34. Although lower oxygen saturation may decrease the incidence of severe ROP, an increase in mortality has been observed in BOOST II collaborative group study35. So the optimum root of oxygen delivery is still controversial, and due to the relatively small sample size for subgroup analysis of methods of oxygen therapy, our data do not have sufficient power to determine this detail.
Previous retrospective and observational studies define various risk factors for the prediction of recurrence of ROP after IVB-treatment. Previously reported risk factors for recurrent ROP after anti-VEGF therapy includes lower GA, lower BW, longer duration of hospitalization, extensive retinal neovascularization, supplemental oxygen requirement after treatment, and preretinal hemorrhage before treatment, as long as multiple bitrth.12,13,20,36. In the current study, we assessed the risk factors for recurrence of ROP after treatment with Bevacizumab. From 16 factors we assessed, lower birth weight, zone 1 pretreatment, history of intubation, anemia, and sepsis were associated with increasing recurrence chance in univariate analysis, while only intubation is significant in multivariable analysis.
Unlike the abovementioned studies, we did not find gestational age an independent risk factor of recurrence. Although, Earlier gestational age at initial treatment may show illness of these infants and had more severe retinopathy that required earlier treatment. Likely because 2 of 20 patients who suffered recurrence after IVB were in 34 weeks of gestational age. It implies that vigilant follow-up for IVB treated patients requires all treated patients independent of gestational age. Main ROP risk factors include low gestational age and birth weight;37,38 in our study, we mentioned that maybe birth weight is a more independent risk factor that implies prematurity than gestational age. Moreover, the history of ARDS was marginally an insignificant risk factor. Lyu et al. reported an 11-fold increased risk of ROP recurrence in patients with a history of oxygen therapy. 36
History of intubation and sepsis in infants implies more severe ocular hypoxia and higher oxygen requirements. Then, Systemic hypoxia during this period may exacerbate the retina's hypoxia and block retinal maturation, increasing the risk of recurrent neovascularization. Moreover, Zone 1 pretreatment implies a more aggressive nature of retinopathy which requires more vigilant follow-up.
Similar to previous studies on this subject, our study's limitations include its retrospective nature, data collection from a single institution as long as we did not perform fluorescein angiography in our recurrent cases. In order to accurately diagnose persistent disease or recurrence of ROP in IVB- treated ROP, the cautious approach is to done fluorescein angiography to confirm the extent of retinal vascularization. As a result, Our results cannot be generalized to all eyes with type 1 ROP, as only eyes with more aggressive forms of ROP whereby laser would be suboptimal or not possible were offered IVB in our series. On the other hand, a large sample size and being treated at the same hospital with standardized treatment protocols are significant strengths of the study.
Our results help incorporate risk factors into practice patterns and devise a plan for early detection of treatment failure and recurrence. Although over examination following treatment can prevent dreadful sequels of ROP, it is worthy of note that ROP examinations, despite their medical cost, can induce morbidity in neonates, including decreased oxygen saturation, increased heart rate, and apnea events.39 Attention to risk factors accompanied by special care to patterns of treatment failure, and recurrence, helps to achieve both objectives.
In Conclusion, intravitreal Bevacizumab is an effective treatment in inducing ROP regression, low rate of primary failure, but the effect may be transient in some cases. Post IVB treatment, recurrence can occur later in the course than with conventional laser therapy. The risk factor for predicting primary failure in our study is infants with younger age and plus disease who have a history of phototherapy and oxygen therapy. The risk factor predicting recurrence is a history of intubation. Future studies on the definition of primary failure, recurrence and screening criteria, treatment type recommendations, and time should be done.