|Year : 2023 | Volume
| Issue : 1 | Page : 15-20
Reactivation of retinopathy of prematurity after intravitreal bevacizumab monotherapy in aggressive posterior retinopathy of prematurity
Ritesh Verma1, Manisha Rathi2, Jitender Phogat2, Amita Sodhi3, Sakshi Lochab2
1 Department of Ophthalmology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
2 Department of Ophthalmology, PGIMS, Rohtak, Haryana, India
3 Department of Paediatrics, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
|Date of Submission||09-May-2022|
|Date of Decision||06-Dec-2022|
|Date of Acceptance||14-Jan-2023|
|Date of Web Publication||8-Feb-2023|
Dayanand Medical College and Hospital, Ludhiana, Punjab
Source of Support: None, Conflict of Interest: None
Aims: The aim of the study was to identify the risk factors and timing for the reactivation of retinopathy of prematurity (ROP) after intravitreal bevacizumab (IVB) in aggressive posterior retinopathy of prematurity (APROP). Materials and Methods: A retrospective study to analyze the outcome of 24 eyes of 12 infants treated with IVB monotherapy (0.625 mg) was done. Data were analyzed regarding the initial response to IVB, the incidence of ROP reactivation, timing, location, and stage of reactivation. Gestational age, postmenstrual age, and other neonatal comorbid risk factors were compared between the reactivation and those without reactivation after IVB. Results: The mean follow-up time was 50.2 ± 1.4 weeks after IVB. Reactivation was identified in 8 (33.3%) eyes. Reactivation in zone I was seen in only two eyes and zone II reactivation was present in six eyes. The mean postmenstrual age at the time of recurrence was 44.0 ± 1.15 weeks (range: 43–45). The mean time between initial treatment and treatment-requiring recurrence was 11.8 ± 0.9 weeks. Multiple pregnancy, low birth weight, sepsis, and necrotizing enterocolitis were significantly associated with ROP reactivation. None of our patients progressed to retinal detachment after laser treatment for reactivation. Conclusions: Although IVB treatment is effective in inducing the regression of APROP, the effect may be transient. The recurrence of ROP should be carefully watched in a long-term follow-up after IVB monotherapy, particularly in the first 12 weeks after IVB.
Keywords: Aggressive posterior retinopathy of prematurity, antivascular endothelial growth factor, bevacizumab, reactivation of retinopathy of prematurity
|How to cite this article:|
Verma R, Rathi M, Phogat J, Sodhi A, Lochab S. Reactivation of retinopathy of prematurity after intravitreal bevacizumab monotherapy in aggressive posterior retinopathy of prematurity. J Clin Ophthalmol Res 2023;11:15-20
|How to cite this URL:|
Verma R, Rathi M, Phogat J, Sodhi A, Lochab S. Reactivation of retinopathy of prematurity after intravitreal bevacizumab monotherapy in aggressive posterior retinopathy of prematurity. J Clin Ophthalmol Res [serial online] 2023 [cited 2023 Mar 23];11:15-20. Available from: https://www.jcor.in/text.asp?2023/11/1/15/369357
Retinopathy of prematurity (ROP) is one of the leading causes of blindness in children and is an ongoing epidemic in low- and middle-income countries., A discrepancy has been reported in the clinical profile of ROP between the developed and the developing nations with a significantly higher incidence of severe forms of ROP in the developing countries. Aggressive posterior retinopathy of prematurity (APROP) which has now been reclassified as aggressive ROP is defined in the international classification of ROP as a rapid development of pathologic neovascularization and severe plus disease without progression being observed through the typical stages of ROP that rapidly progresses to retinal detachment if not managed promptly. Multiple factors contribute to the etiopathogenesis of ROP, but vascular endothelial growth factor (VEGF) has been recognized as the main culprit in the oxygen-induced retinopathy models of angiogenesis., Unfavorable structural outcomes have been reported despite confluent laser photocoagulation in APROP.,
In recent years, intravitreal bevacizumab (IVB) is being preferred as an initial treatment modality in APROP as it promotes the rapid regression of neovascularization and plus disease., However, there have been concerns regarding the reactivation of ROP once the drug is washed out from the vitreous cavity.,,, Therefore, timely detection as well as management of recurrence has become a major concern in anti-VEGF therapy for ROP. Performing supplemental laser therapy immediately after anti-VEGF may cause more recurrences due to the breakdown of the blood–retinal barrier perhaps allowing more escape of drug from the vitreous. Due to the paucity of evidence, there are no strict guidelines regarding the follow-up, time of recurrence, and risk factors for recurrence post-IVB monotherapy in APROP.
In this study, we have analyzed the structural outcomes with IVB monotherapy in 24 eyes of 12 APROP infants. The risk factors and timing of ROP reactivation after IVB were studied and discussed. The management of reactivation has also been discussed.
| Materials and Methods|| |
This retrospective study was conducted, after approval from the institutional ethics committee, among the premature neonates from the neonatal intensive care unit (NICU) of our institute between April 2019 and March 2020.
All neonates with gestational age <34 weeks, birth weight <1750 g, and term babies with risk factors as identified by neonatologists were screened in the NICU as early as 2–3 weeks of postmenstrual age (PMA) to identify severe forms of ROP as per the institute's screening protocol. ROP was classified according to the revised ICROP guidelines. APROP was defined as extreme vessel dilation and tortuosity in four quadrants, direct arteriovenous shunting, flat neovascularization, and rapid evolution, without following Stage 1–3 progression.
Patients with APROP in both eyes were enrolled in the study after detailed informed and written consent from the parents. There were no exclusion criteria. Infants who developed conventional ROP stages were treated in accordance with the early treatment of ROP guidelines by laser photocoagulation.
All infants diagnosed with APROP underwent bilateral IVB in the operation theater in a single sitting within 48 h of the diagnosis. All injections were performed by a single surgeon. The pupils were dilated with a mixture of tropicamide 0.5% and phenylephrine 0.5% administered three times with punctual occlusion. Topical proparacaine hydrochloride 0.5% was administered once to achieve anesthesia 2 min before the procedure. The skin and adnexa were prepared in a sterile manner with 10% povidone-iodine. Each eye was prepared separately using 5% povidone-iodine drops instilled in the eye 5 min before injection and after applying the drape immediately before the injection. Infants' head was stabilized with the help of an assistant, and 0.025 ml of bevacizumab (0.625 mg) was injected 1.5 mm from the limbus in the superotemporal quadrant in both the eyes with a 30G needle. All the infants were kept under observation in the NICU postinjection for 24 h. Topical moxifloxacin 0.5% eye drops were administered four times daily for 1-week postinjection. The neonates were examined on days 1 and 3 and then weekly after the injection till the regression of APROP was confirmed.
The regression of tunica vasculosa lentis, decrease/complete regression of plus disease, and neovascularization were considered early signs of regression of APROP. Reactivation was defined as the recurrence of plus disease, progression of retinal neovascularization, and new preretinal hemorrhage.
Reactivation requiring treatment
Infants with the reactivation of ROP underwent laser photocoagulation with a portable 532 nm frequency-doubled Nd:YAG green laser (IRIS Medical Oculight GLX, IRIDEX, CA, USA) under topical anesthesia. Power settings varied between 100 and 200 mW with an exposure duration of 100 to 200 ms. The number of shots varied according to the zone of the retina subjected to laser therapy as near-confluent burns were applied to the avascular retina. Posttreatment all eyes received prednisolone 0.1% and tobramycin 0.3% eye drops, four times a day for 2 weeks. Patients were followed up weekly after treatment for initial 4 weeks. Skip areas (if found) were lasered at 1-week follow-up. Postlaser regression was defined as the absence of plus or preplus, no fresh preretinal hemorrhage, and regression of stage if any.
At the end of the study, data were entered into MS Excel spreadsheet, and analysis was done using the Statistical Package for the Social Sciences (SPSS) version 25.0. (IBM® SPSS® NY).
Categorical variables were presented in number and percentage (%) and continuous variables were presented as mean ± standard deviation (SD) and range. Normality of data was tested by the Kolmogorov–Smirnov test. If the normality was rejected, then nonparametric test was used.
Quantitative variables were compared using the paired t-test/Wilcoxon rank-sum test (when the data sets were not normally distributed) across follow-up. Univariate regression analysis was used to assess the association of a risk factor in APROP reactivation.
P < 0.05 was considered statistically significant.
| Results|| |
From April 2019 to March 2020, a total of 13 infants (26 eyes) underwent IVB as an initial treatment for bilateral APROP in zone I. Out of those 13, only 24 eyes of 12 patients were included in this study as one patient was lost to follow-up 5 weeks postinjection. The mean gestational age (±SD) of patients in our study was 29.5 ± 2.4 weeks (range: 28–36). The mean PMA at the time of IVB was 34.0 ± 2.6 weeks (range: 32–40). The demographic and clinical profile of the patients is described in [Table 1].
|Table 1: Demographic and clinical profile of the aggressive posterior retinopathy of prematurity patients in the study|
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All patients had a favorable outcome 1 week postinjection as there was obvious regression of plus disease and neovascularization. There were no ocular complications related to the intravitreal injection in any of our patients. None of our patients developed systemic complications or required additional NICU stay postinjection. The mean follow-up period was 50.2 ± 1.4 weeks post-IVB.
Treatment requiring reactivation occurred in bilateral eyes of 4 (33.33%) infants. The rest of the patients (66.67%) had a complete involution of ROP [Figure 1]a and [Figure 1]b and did not require additional treatment post-IVB, but the avascular retina persisted in all the infants with involution. The details of the patients with reactivation are shown in [Table 2]. The mean time of recurrence was 11.8 ± 0.9 weeks (range: 11–13) post-IVB. The mean PMA at the time of recurrence was 44.0 ± 1.15 weeks (range: 43–45). Zone I reactivation occurred in both eyes of one patient [Figure 2]a and [Figure 2]b; the rest of the three patients had zone II reactivation. Once the reactivation was diagnosed, laser photocoagulation of the avascular retina was done under topical anesthesia. All the patients had a good structural outcome at the end of the follow-up. None of our patients progressed to retinal detachment, and there was no disc dragging.
|Figure 1: Right (a) and left eyes (b), respectively, of APROP female infant, BW 1100 g, gestational age 28 weeks, 12 weeks post-IVB, PMA-44, showing the complete regression of plus disease and advancement of vessels to anterior zone 2. IVB: Intravitreal bevacizumab, APROP: Aggressive posterior retinopathy of prematurity|
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|Figure 2: Right (a) and left (b) eyes, respectively, of APROP male infant patient 2 in Table 2, BW 1070 g, gestational age 30 weeks, 13 weeks post-IVB, PMA-46, showing reactivation of ROP as appearance of arterial tortuosity and stage 2 in zone 1. Laser photocoagulation was done to the avascular retina with a good structural outcome in both eyes. IVB: Intravitreal bevacizumab, APROP: Aggressive posterior retinopathy of prematurity, ROP: Retinopathy of prematurity|
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|Table 2: Description of patients with reactivation after intravitreal bevacizumab monotherapy|
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A univariate logistic regression analysis was done to compare the ROP reactivation group and those with complete involution [Table 3]. The mean BW of the premature infants with reactivation after IVB was significantly lower than the group with involution (P < 0.05). Multiple pregnancy, neonatal sepsis, and necrotizing enterocolitis were the other factors significantly associated with ROP reactivation in our study.
|Table 3: Univariate logistic regression analysis between reactivation and regressed retinopathy of prematurity group|
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| Discussion|| |
In the past decade, IVB is being used increasingly for the management of zone I disease after a landmark BEAT-ROP trial. In our study, IVB had a favorable initial outcome as there was rapid regression of APROP without any adverse outcomes related to intravitreal injection in all 24 eyes. Few studies have reported devastating complications related to intravitreal injection for ROP in the recent past, but this was not the scenario in our study. Two-thirds of the patients in our study had a complete regression of APROP and subsequent vascularization in zone III. The reactivation of ROP after IVB in APROP infants has been reported in the previous studies which ranged from 6.3% to 41%.,, The reactivation of severe ROP after IVB in the BEAT-ROP trial was 31.6% as compared to 33% in our study. Although the response in all the patients in our study was bilaterally symmetrical, there have been reports of asymmetrical response to IVB in some studies. The mean time of reactivation was 11.8 ± 0.9 weeks (range: 11–13) post-IVB which is comparable to other studies, though there have been reports of late reactivation after IVB monotherapy up to 3 years.,
All the cases with reactivation were managed by frequency-doubled Nd: YAG green laser photocoagulation as its safety has been established in ROP treatment., All the patients had favorable structural outcome after laser photocoagulation. Some studies advocate supplemental laser therapy in all ROP cases treated with IVB to prevent late recurrences and adverse outcomes. However, the use of dual therapy may lead to more recurrences as it will lead to enhanced drug escape from the vitreous cavity. The mean number of laser spots used to treat the reactivation was 1943 ± 1483 with only one patient requiring more than 1500 spots in each eye. There was complete involution of APROP in most of our study patients, hence we advocate laser therapy once there is reactivation of disease activity.
Laser treatment as a primary therapy tended to be heavier in APROP eyes than non-APROP eyes. A mean of 2967 spots were applied in APROP eyes in a study by Gunn et al. IVB monotherapy promotes revascularization in most of the cases with a lesser number of spots required to ablate the remaining avascular retina. Moreover, there have been reports of the progression of APROP to unfavorable structural outcome despite confluent laser photocoagulation., Patients with APROP usually have small pupils and hazy media both of which are suboptimal conditions to perform a successful laser treatment. The incidence of high myopia postlaser therapy in zone I disease is well documented. Several studies have reported a better refractive outcome post-IVB monotherapy as compared to primary laser therapy.,
The mean gestational age (±SD) in our study was 29.5 ± 2.4 weeks (range: 28–36) and the mean birth weight was 1107.75 ± 200.0 (800–1550). Severe ROP in bigger babies has been reported only in earlier studies from India and middle-income countries., This GA and BW were significantly higher than in previous studies from developed countries. Lower birth weight was significantly associated with ROP reactivation in our study. The critical PMA for ROP treatment is usually between 35 and 40 weeks. There was no difference between the reactivation and regressed groups in terms of PMA. The analysis has also found the association of neonatal comorbidities such as sepsis, necrotizing enterocolitis, and multiple pregnancy to be significantly associated with the reactivation of ROP. This has not been documented in the previous studies and requires further investigation due to the small sample size of our study.
A major concern regarding the use of IVB in APROP is the risk of systemic absorption and its potential side effects. Systemic absorption of IVB has been reported in several studies.,, Since the VEGF is necessary for the development of lungs, kidneys, and brain, the reduction of serum VEGF levels can have deleterious effects on these organs.
Several studies have reported the association of severe ROP with nonvisual disabilities. Others have reported developmental impairments such as gross motor, cognitive, and severe hearing loss to be three to four times frequent in children who had severe ROP.,
The major limitation of our study is the retrospective nature of the study. The other limitation of our study is the small sample size and limited follow-up duration of a mean of 50 weeks. The refractive status of the patients has not been mentioned in this study. We had one dropout from our study. The patient was eventually counseled, and supplemental laser was done to the avascular retina to avoid any late reactivation. The rest of our patients are on regular follow-up and we have had promising functional outcomes in these patients. We routinely use IVB in APROP cases at our institute. These patients are being regularly monitored by the pediatrician for any systemic side effects of the drug.
| Conclusions|| |
IVB monotherapy provides a good initial regression in APROP cases and promotes retinal vascularization in most cases without any ocular side effects. Anti-VEGF therapy followed by laser treatment in reactivation cases should become standard of treatment in APROP cases in the coming years. There are chances of reactivation of ROP, so careful monitoring is required postoperatively. It should be avoided in cases where long-term follow-up is not possible. Further prospective studies are required to establish the long-term safety of the anti-VEGF drugs.
The study was approved by the institutional ethics committee and adhered with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]