Annually an estimated 14.8 million preterm infants are born worldwide. In a developing country like India, this situation becomes complex as 23.4% of the world’s premature births are from India, and severe forms of ROP are commonly reported even in larger babies. India accounts for 10% of the world’s ROP related blindness, possibly due to improved survival of the preterm infants coupled with a relative paucity of trained ophthalmologists for timely screening and treatment for ROP. To address these unique issues, the Indian Retinopathy of Prematurity (iROP) society, comprising of ophthalmologists from various sub-specialties, who are actively engaged in ROP screening and treatment in different parts of India, was established in 2016.
Laser photocoagulation of the avascular retina remains the standard of care for the management of severe ROP and has a documented anatomical success rate over 90% in Type 1 ROP. However, the ablation of the peripheral retina may influence the prevalence of refractive error or possible visual field loss in the long term. Anatomical outcomes following laser in aggressive posterior retinopathy of prematurity (APROP) are not as good as classical staged (Type 1) ROP.
Vascular endothelial growth factor (VEGF) plays a key role in the angiogenesis of immature retina as well as in the pathogenesis of ROP. Following encouraging results of BEAT-ROP and RAINBOW trials, anti-VEGF has been seen as a viable treatment option for severe ROP. Besides relative ease of administration, anti-VEGF not only halts the growth of pathological retinal vessels but may promote the growth of normal retinal vessels into the immature retina. Hypothetically, this may help to preserve more functional retina. However, the use of anti-VEGF has multiple inherent risks such as development of cataract, endophthalmitis, vitreous hemorrhage, and retinal detachment. Delayed recurrence of retinopathy has been documented with anti-VEGF in ROP, making a long-term follow-up essential. Suppression of systemic VEGF following intravitreal anti-VEGF injection may have a deleterious effect on the development of other organs including the nervous system of the preterm infant. Furthermore, there are no established national or international guidelines and protocols regarding use, dosage, or follow-up regimen after the use of anti-VEGF in ROP.
A survey of the initial 113 members of iROP society, conducted in 2017, showed that laser was still the preferred modality of treatment in 98% of the members and 86% were comfortable with it. Anti-VEGF agents had lower popularity and confidence among the members, with 41% having never used it for ROP treatment. This prompted the current survey, aiming to study and interpret the practice patterns of using anti-VEGF as a therapy for ROP by specialists in India.
Survey questionnaire was developed by reviewing previously conducted surveys among vitreoretinal surgeons and pediatric ophthalmologists and adapting them to the Indian scenario.
Survey population and design
A total of 226 iROP society members (at the time of the study) were contacted for the survey. The survey questionnaire was designed on Google forms® (https://www.google.com/forms/about/) in English and sent as a link to the registered mobile number of the members. Most of the questions had multiple options, with the single best answer to select from [Supplemental Table 1].
The study met the approval of the Institutional Review Board and did not involve any patient information or identifiers. The results were submitted anonymously through the provided web link that was active from 21st February 2019 to 31st March 2019. The participants submitted their responses through their smartphones.
Data management and analysis
The responses were collated on a spreadsheet using Microsoft Excel. The result of each question was analyzed based on the number of responses obtained, individually. Responses excluding the “not applicable” were analyzed. Categorical variables were summarized by counts and percentages. Continuous variables were analyzed by mean and standard deviations. Subgroup analysis of the responses was also done, based on age (age ≤ 40 and age > 40) and practice setting of the respondent, and these were compared with multiple variables. Pearson Chi-square test was used to know the association between variables. P value of less than 0.05 was considered statistically significant.
Demographics and general practice
Among the 226 members with whom the survey link was shared, 157 responded (69.4%). The mean age of the respondents was 38.3 ± 11.6 (range: 27–62) years and there was a male preponderance (109, 69.4%). The majority of the respondents were vitreoretinal surgeons (129, 82.1%) and were practicing in private institutes (66, 42%) with an average experience of 8.9 ± 8.9 (range: 0.5-25) years in ROP screening and treatment. Each respondent screened an average 77.1 ± 203.5 (median: 30, range: 2–2000) and treated 4.4 ± 5.3 infants (median: 3, range: 0–30) per month. One-hundred fifty respondents (95.5%) were registered members of the All India Ophthalmological Society (AIOS), 111 (70.7%) were members of Vitreoretinal Society of India (VRSI), and 11 (7%) were members of Strabismus and Pediatric Ophthalmological Society of India (SPOSI).
Anti-VEGF: Indications, agents, technique, and follow-up
The most common indication for using anti-VEGF was APROP/Hybrid ROP (78, 52.7%) (Hybrid ROP: presence of ridge tissue, characteristic of staged ROP along with flat neovascular syncytium, and characteristic of APROP in the same eye). The procedure was largely conducted in the operating room (OR) (102, 70.3%), under topical anesthesia (134, 86.4%) and in both eyes on the same day (97, 68%) [Fig. 1a-d]. Bevacizumab was the most commonly used agent (85, 54%). However, the majority of the respondents practicing in Government organizations preferred Ranibizumab. Irrespective of the agent of choice, most respondents used half the adult dose (113, 77.9%), which was obtained from a single-use vial (66, 47%) and injected 1–1.5 mm away from the limbus (133, 93%) in the inferotemporal quadrant (55, 38%). Follow-up schedules varied among the members, with 68 (46.5%) reviewing the infant weekly while 53 (36.3%) followed up on the basis of the severity and clinical findings rather than a fixed schedule [Fig. 2a-d].
Documentation and monitoring
Photo documentation was used before and after anti-VEGF therapy by 33 (23%) respondents and only 4 (2.8%) performed fundus fluorescein angiography (FFA) as part of their management protocol. Drug Controller General of India (DCGI) had issued a ban on the intraocular use of bevacizumab in adults and subsequently revoked the ban. Following this episode, there was a change in the practice pattern of the members in using the drug for ROP with 34 (27.6%) respondents switching over to ranibizumab. A specially drafted consent for anti-VEGF use was used by 89 (62%) respondents. One-hundred fifty one (96.2%) respondents felt the need for guidelines from the iROP society regarding the usage of anti-VEGF in ROP.
Anti-VEGF provides an effective and technically simpler alternative to the laser in ROP. In addition, it tends to preserve more functional retina and has been shown to have lesser myopia than laser. The major concerns about the use of anti-VEGF for ROP are recurrence of the disease and the possible effect on neurological development. The benefits of anti-VEGF in ROP should be weighed against these and other unknown possible risks. Due to wide variation in literature regarding the preferred drug, dosage, effectiveness, recurrence, and systemic adverse effect as well as lack of guidelines about the use of anti-VEFG in ROP, the decision for an ROP practitioner is challenging.
The Indian ROP society is the first, registered, professional body worldwide to enroll ROP specialists nationally. India has over 20,000 ophthalmologists, approximately 2000 vitreoretinal surgeons and just over 200 ROP specialists. This report is the hitherto largest survey result that details the practice patterns of using anti-VEGF therapy for ROP treatment.
Demographics, practice setting, indications, and agent
The age of the respondents or their duration of experience in ophthalmology or respective subspecialties, as well as experience in managing ROP, had no influence on the use of anti-VEGF and preference to a particular agent. However, respondents working in Government hospitals preferred ranibizumab over bevacizumab. This is possibly following the Government advisory on limiting the intraocular use of bevacizumab in adults, making it mandatory to use ranibizumab. In public hospitals, the cost including the pharmaceutical agent is either free or subsidized. Private hospitals, in contrast, have price-sensitive decisions to make for their patients since a majority in India are still not covered under insurance schemes.
The most common indication for the use of anti-VEGF was APROP or hybrid disease; this preference is supported by the relatively poor outcomes after laser monotherapy in APROP as compared to staged ROP. For non APROP disease requiring treatment (i.e., Type 1 ROP defined by ETROP), only 8 (5.3%) of the respondents are likely to use anti-VEGF as a primary modality, suggesting that laser therapy is still the gold standard.
In this survey, 137 (87.2%) used anti-VEGF for treating ROP. This is considerably higher than a previously conducted survey of 113 members in 2017, wherein 41% of members had never used anti-VEGF. This indicates the increasing popularity of anti-VEGF as a treatment modality but may also indicate the increase in the number of cases of APROP across the country, especially after the increase in the number of special newborn care units (SNCU) situated in district headquarters. Although ranibizumab is used by a significant proportion (61, 38.8%), the majority of specialists still preferred bevacizumab (85, 54.1%). This may be due to the ease of multiple usage vials, relatively lower cost, and relatively delayed recurrence with bevacizumab. Fouzdar Jain et al. in their survey of pediatric ophthalmologists reported that laser was the preferred modality of treatment and bevacizumab was the preferred anti-VEGF. In a survey from USA, 54% respondents preferred anti-VEGF as a primary modality for the treatment of zone 1 ROP with plus disease and bevacizumab was the preferred agent (78%).
Unlike retinal pathologies in adults which are US FDA approved, the use of anti-VEGF in ROP continues to be “off label” and not yet approved. Recently, ranibizumab 0.2 mg was approved by the European Commission for the management of severe ROP. Bevacizumab, the most frequently used anti-VEGF for ophthalmic conditions in adults as well as in infants with severe ROP, has never been approved for intraocular use and remains off label.
Following the ban on intraocular use of bevacizumab by DCGI, 27.6% of respondents switched to ranibizumab for the treatment of infants with ROP, while the majority of the others are still using bevacizumab. The ban was subsequently revoked by DCGI, and a specially drafted consent describing the off label indication and its use, ophthalmic indications and complications or adverse effect has been issued by All India Ophthalmological Society and Vitreo-retinal Society of India. This consent does not include ROP among the list of ophthalmic indications. Among the specialists, 85.3% of the respondents were aware of this fact and 25 (18.6%) respondents are still using the older consent for infants with ROP. Moreover, 56.7% of respondents used specially drafted consent, which describes the use of anti-VEGF as “off label” along with possible long-term risks in preterm infants including neurodevelopmental delay. Subgroup analysis revealed respondents of age more than 40 years of age were using general consent more commonly than those under 40 years (P = 0.02)
Photo documentation done prior, or on the day of the injection and during subsequent follow-up visits, will serve as an objective documentation to monitor clinical response and also safeguard against future litigation and medico-legal cases. In the current survey, only 21% of the respondents are photo-documenting their cases. This is possibly due to the unavailability of pediatric wide-field digital cameras with most of the respondents. However, with the availability of more affordable cameras that are portable, it is likely to improve the accessibility and utility in the future.
The relatively lower proportion of surgeons using retinal imaging in ROP screening is not unique to India. In a recent survey among the medical directors of level 3 neonatal intensive care units (NICUs) in the United States, retinal imaging was performed in 21% of centers only. Furthermore, only 4 (2.8%) respondents in our survey are using FFA after anti-VEGF injection, possibly due to limited availability of the pediatric wide-field cameras compatible with FFA (currently on the RetCam 3, Natus, California, USA, only).
Safety of intravitreal injection (IVI) for treating ROP in the NICU under topical anesthesia has been reported. The procedure if done in NICU helps in carrying out it under the supervision of neonatologist, with minimal risk of systemic instability like apnea, lowering of oxygen saturation, which might occur while shifting these preterm infants to OR. However, carrying out the procedure in NICU without operating a microscope or loop may increase the chances of injury to crystaline lens. A relatively compromised perioperative asepsis in NICU compared to the OR can increase the risk of intraocular infection as well. In the current survey, though the majority of the respondents (86.4%) performed the procedure under topical anesthesia, a majority (70.3%) still preferred the main OR for the procedure and not the office or the neonatal unit. This might reflect the VRSI or AIOS guidelines for injecting intravitreal bevacizumab (IVB) in adults, which do not recommend it as an office procedure. However, it must be noted that both national societies do not have guidelines for anti-VEGF injections for infants or children.
Eye to be treated
Though the safety of bilateral IVI in adults has been reported in retrospective studies involving thousands of procedures, VRSI and AIOS guidelines for IVB do not recommend a bilateral injection on the same day. ROP usually is bilaterally symmetrical in most cases and therefore injecting both eyes on the same day is logistically more convenient. Furthermore, these infants are often systemically brittle and scheduling and treating the fellow eye on the following day or a few days later may increase the systemic stress to the infant. In babies with both eyes having symmetrical disease, the delay in treating the delayed eye may influence the final outcome. It may thus be logistically justified to inject both eyes on the same day, but we recommend that this must be explained to the parents and mentioned in the special consent. In the current survey, more than two-thirds (67.8%) of the respondents injected IVI in both eyes in the same sitting.
Dose and site
A dose that causes suppression of VEGF to an extent just enough to halt or reverse the formation of abnormal retinal blood vessels without affecting physiological angiogenesis in the retina and other organ systems must be the most important consideration in deciding the appropriate dose of anti-VEGF in ROP. The lower dose has the risk of early recurrence while higher doses may unduly suppress systemic VEGF for a longer time. For IVB, the dosage has varied from 0.031 mg to 0.625 mg and success has been reported with all the lower doses as well. Similarly, for intravitreal ranibizumab (IVR), dosage used has varied from 0.1 mg to 0.25 mg. Two randomized clinical trials for IVR, RAINBOW and CARE-GROUP, recommended the use of 0.2 mg and 0.12 mg, respectively. However, most of the studies have used half the adult dose. In the current survey, 113 (77.9%) respondents used half the adult dose for the procedure, irrespective of the agent used, while 30 (20.7%) respondents used one-third or less of the adult dose. Even lower doses require fractioning or special types of equipment which are not accessible to most ROP specialists.
Infants have poorly differentiated pars plana zone of the ciliary body along with a relatively larger crystalline lens in proportion to the globe size. Thus in infants less than three months of age undergoing pars plana vitrectomy the sclerotomies are made at 1.5 mm from the limbus. However, various studies on IVI in infants with ROP have reported the safety of injection at 1 mm, 1.5 mm as well as 2 mm from the limbus. The current survey shows 51.1% of respondents injecting IVI at 1 mm from the limbus, and a nearly equal number (41.9%) injecting at 1.5 mm from the limbus.
After IVI of anti-VEGF, it is necessary to have these infants followed up to monitor the possible procedure-related adverse events, regression of the disease, status of vascularization of the immaturity retina, and recurrence of the disease. This follow-up period is likely to be prolonged as late recurrence is common feature in infants treated with anti-VEGF. Recurrence rates have been reported to be more than 50% in various studies for ROP. The recurrence rate is higher in type 1 ETROP with RBZ as compared to BVZ, and almost similar recurrence in APROP with either of the two drugs. The majority of the respondents of the current survey (46.5%) preferred weekly follow-up. However, around one-third (36.3%) of respondents decided their follow-up schedule based on the disease severity. The outer limit of follow-up for these infants was not uniform in the absence of guidelines.
Need for guidelines
With the increasing popularity for using anti-VEGF for ROP treatment and the increasing number of APROP cases, a rise in the use of anti-VEGF therapy is expected. However, due to a wide variability in the literature about the indication, drug, dosage, settings for their usage as well as lack of data on long-term systemic safety profile, the treating ROP specialist is unsure which protocol to follow. In our survey, 96% of the respondents expressed the need for guidelines for the use of anti-VEGF in ROP.
This survey has several strengths including a relatively high response rate, a pan-national coverage, a wide range of experience in subspecialty, and high number of cases being treated by the individual members. The limitations are the fact that the survey was restricted to practicing specialists from India only, who have been influenced by the national guidelines for the use of anti-VEGF for adults by the national society. The ROP screening program in India is similar to other middle-income countries, but different from the western nations making our results not generalizable. Furthermore, we did not enquire about the use of perioperative antibiotic, procedure-related adverse events, an interval of disease recurrence, use of laser as primary or combination therapy, and outcome at the end of follow-up.
Although this survey is not linked or compared with the disease outcome, it represents a strong database of the current practice patterns of various aspects of anti-VEGF used in ROP in India, which is currently the nation with the largest number of preterm infants and is summarized in Table 1. These are not guidelines, but in the absence of one, can help to develop one based on this data, along with expert consensus and outcome validation.
Financial support and sponsorship
No financial support to disclose.
Conflicts of interest
None of the above authors has any proprietary interests or conflicts of interest related to this submission.
Members of Indian Retinopathy of Prematurity Society for participation in the online survey.
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