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Year : 2022  |  Volume : 10  |  Issue : 1  |  Page : 19-22

Factors associated with nonregression of retinopathy of prematurity after laser treatment in western India

Department of Vitreo-Retina Services, PBMA's H.V. Desai Eye Hospital, Pune, Maharashtra, India

Date of Submission01-May-2021
Date of Decision31-Jul-2021
Date of Acceptance16-Oct-2021
Date of Web Publication3-Feb-2022

Correspondence Address:
Ananya Sudhir Nibandhe
303 Sea Breeze, Plot No 14, Sector No -2, Near Charkop Police Station, Charkop, Kandivali (West), Mumbai - 400 067, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcor.jcor_65_21

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Background: To report the characteristics of preterm infants treated for retinopathy of prematurity (ROP) and to establish the factors associated with nonregression of ROP. Methods: This cross-sectional study where data were collected retrospectively was carried out at a tertiary eye care center in Pune, India, from December 1, 2017, to November 30, 2019. All infants who were treated for severe ROP (either laser therapy or combination of anti-vascular endothelial growth factor and laser) and had completed 3-month follow-up were included in the study. Nonregression was defined as a persistent plus disease/active new vessels, progression to tractional disease after 3 weeks of completion of treatment, or poor structural outcome (tractional retinal detachment) within 3 months of treatment. Data were assessed at 3 months to look for treatment outcome and reasons for nonregression. Association between risk factors and nonregression of ROP was analyzed using statistical tests. Results: Of the 210 eyes (105 infants) which were treated, 95 eyes (45.23%) had aggressive posterior ROP (APROP). Nonregression was documented in 12/210 (5.7%) eyes. At 3 months, ten eyes developed tractional retinal detachment whereas two eyes developed vitreous hemorrhage. Eleven of the 12 eyes had APROP (P = 0.0014). Ocular risk factors, systemic risk factors, and delayed institution of treatment were associated with nonregression in about a third of eyes (33.3%) each. Conclusion: Most nonregressing ROP cases are APROP in western India.

Keywords: Aggressive posterior retinopathy of prematurity, nonregression, retinopathy of prematurity, tractional retinal detachment

How to cite this article:
Kulkarni SR, Nibandhe AS, Kakade NA, Bhatt AG, Deshpande MD. Factors associated with nonregression of retinopathy of prematurity after laser treatment in western India. J Clin Ophthalmol Res 2022;10:19-22

How to cite this URL:
Kulkarni SR, Nibandhe AS, Kakade NA, Bhatt AG, Deshpande MD. Factors associated with nonregression of retinopathy of prematurity after laser treatment in western India. J Clin Ophthalmol Res [serial online] 2022 [cited 2022 Aug 11];10:19-22. Available from: https://www.jcor.in/text.asp?2022/10/1/19/337197

Retinopathy of prematurity (ROP) is a potentially blinding disease affecting preterm infants. Impact of this infantile blindness on the child as well as on family can be multidimensional and devastating.[1] Preterm infants are at risk for serious visual sequelae from ROP. Various risk factors have been associated with the development of ROP.[2],[3],[4] Majority of the cases which develop ROP regress spontaneously, whereas a minor proportion of cases require treatment.[5] Studies have reported favorable treatment outcomes in eyes with treatable ROP and the effectivity of laser photocoagulation which is the standard of care.[3],[6],[7],[8],[9],[10],[11] Some laser-treated cases can show initial regression but may develop vision-threatening complications such as retinal detachment, disc drag, macular drag, and narrowing of vascular arcades few months/years after laser.[12] Whereas other laser-treated cases do not show optimal regression despite adequate laser treatment. Such cases usually need frequent follow-up and close observation for weeks together adding to the burden on the health system as well as on the family. In a study from Pune, India, 26% of infants presenting with blindness due to ROP had received treatment for the same.[1]

Hence, it is important to identify factors responsible for nonregression of ROP after laser treatment and address them to further reduce failure rates of treatment. Few studies have identified some ocular factors such as presence of aggressive posterior ROP (APROP), preretinal hemorrhage prior to laser treatment, and clinically important vitreous organization responsible for immediate treatment failure.[9],[10] However, insufficient concrete information exists on factors responsible for nonregression and continued worsening of ROP despite laser treatment.

Thus, we conducted this study to assess the ocular, systemic, patient/provider-related factors associated with nonregression of ROP after laser treatment.

  Methods Top

This cross-sectional study where data were collected retrospectively was carried out at a tertiary eye care center in Pune, India, from December 1, 2017, to November 30, 2019. This study adhered to the Declaration of Helsinki and was approved by the institutional ethics committee. Records of preterm infants undergoing treatment for ROP were screened. The institute has been running a ROP screening program for 10 years. Retinal imaging is a primary mode of screening at the study institute. Digital wide-field camera (RetCam, Clarity MSA, USA) was used for this purpose. Two trained and experienced technicians performed screening under topical anesthesia after dilating pupils with commercially available but diluted tropicamide (0.4%) and phenylephrine (2.5%) solution. Three trained and experienced ROP specialists graded the disease as per classification by the International Committee for the Classification of ROP (ICROP).[13] All treatable ROP cases additionally underwent thorough examination with binocular indirect ophthalmoscope to confirm findings before treatment. For treatment, the Early Treatment for ROP Study Group's criteria were followed.[14] Written informed consent was obtained from parents before screening as well as before instituting any treatment. The primary treatment modality used was laser therapy. Green laser (Iridex Inc., USA) was delivered through indirect delivery mode in a near confluent manner to cover the entire avascular area of the retina. Intravitreal anti-vascular endothelial growth factor (VEGF) injection therapy was reserved for APROP in Zone 1 or infants presenting late with small pupils and neovascularization of iris.[15] Institute's protocol is to wait for up to 3 weeks after anti-VEGF injection and institute laser treatment if retinal vessels have not reached Zone III by then.

Cases included all the infants who were diagnosed with and treated for Type 1 ROP or APROP. The disease typically starts regressing within a week of laser and re-treatment can be considered if it does not regress within 2 weeks.[16] Late recurrence is a remote possibility after adequate laser treatment.[17] Nonregression was defined persistent “plus” disease or new vessels at 3 weeks after completion of laser treatment and/or poor structural outcome (tractional retinal detachment, disc drag/macular drag) within 3 months of treatment. Infants presenting with preexisting fibrous tractional component or tractional detachment, large skipped areas after laser treatment, unavailable fundus images, incomplete medical records, and those lost to follow-up after treatment were excluded.

Factors associated with nonregression were divided into three categories: (1) provider-related factors such as delayed treatment, (2) patient-related factors such as late presentation and noncompliance to follow-up protocols, and (3) disease-related factors such as APROP, any systemic risk factor which has direct implications on tissue oxygenation, and retinal blood vessel growth (such as prolonged oxygen supplementation, severe anemia requiring blood transfusion, and sepsis). Reason for nonregression was assessed in each of these cases by ruling out factors one by one. In infants with presence of multiple factors, a single factor which if controlled could have prevented negative outcome of treatment was identified as the reason for nonregression (for example: in infants with systemic risk factors such as respiratory distress and delayed presentation, latter was considered as a factor responsible for nonregression). This was done by arriving at a consensus between two trained and experienced ROP specialists.

Data on demographics and risk factors for ROP were collected as follows: gestational age (GA), birth weight (BW), oxygen supplementation (O2), respiratory distress syndrome, sepsis, anemia requiring blood transfusion, thrombocytopenia, etc. These data were collected from neonatal intensive care unit files or from discharge summaries.

Ocular characteristics

Data on zone, stage, the highest grade of the disease, presence of preexisting vitreous hemorrhage (VH)/active elevated vascular proliferation, and type of disease (Type 1 or APROP) according to revised ICROP guidelines[13] were collected. Anterior segment examination findings such as presence of tunica vasculosa lentis, engorged iris vessels, pupillary dilatation, and presence of neovascularization of iris were collected. To elicit whether treatment was successful or not and reasons for failure, the following data were collected: time gap between diagnosis and treatment, status of immediate treatment outcome (regression/nonregression, especially of the plus disease), and reason for treatment failure (provider/patient/disease factor).

Data were collected in Microsoft Excel, and analysis was done using IBM SPSS (Statistical Product and Service Solutions, Chicago, Illinois, United States). Descriptive statistics were calculated as mean ± standard deviation, frequencies, and percentage. Level of significance in the study was set at P < 0.05. Association between disease characteristics and reason for immediate treatment failure was analyzed using Fisher's exact test.

  Results Top

Of the total 147 preterm infants treated during the study period, a total of 105 (210 eyes) infants fulfilled inclusion criteria and were enrolled in the study. Among the 42 who were excluded, the distribution of exclusion criteria was lost to follow-up (23), tractional band at presentation (9), no photo documentation (7), and large skipped areas (3).

General characteristics of enrolled infants included mean BW of 1.3 ± 0.3 kg and mean GA of 29.9 ± 2.2 weeks. There was no significant difference between mean BW (1.25 kg ± 0.3 vs. 1.24 ± 0.3 kg) and mean GA (29.9 ± 2.3 vs. 29.9 ± 2.1 weeks) of infants with classical Type 1 ROP and APROP, respectively. Out of 105 infants, male infants accounted for 75 (71.4%) whereas female infants accounted for 30 (28.6%) cases.

Supplemental oxygen therapy (104/110, 94.5%), anemia requiring blood transfusion (40/110, 36.4%), thrombocytopenia (44/110, 40%), and sepsis (38/110, 34.5%) were the most frequently observed systemic risk factors. Stratification by type of ROP (classic/APROP) did not show any significant difference between occurrences of systemic risk factors. There were 2/110 (0.9%) infants without any systemic risk factors.

We hereby present the results of 210 eyes enrolled in the study. Of these, 95 (45.2%) eyes had APROP. Total 34/95 (35.8%) eyes with APROP received intravitreal injection anti-VEGF as primary therapy due to small pupil size and neovascularization of iris. This was followed by laser treatment within 3 weeks. None of the 115 eyes with classical ROP required anti-VEGF injection as primary therapy.

Nonregression assessed at 3 weeks after laser treatment was noted in 12 (5.7%) eyes. Four eyes (3, 24.9% APROP and 1, 8.3% classic ROP) presented with large preretinal hemorrhage. Most (11/12, 91.7%, P = 0.001) had APROP. Of the total 12 treated eyes, six (50%) eyes received a primary anti-VEGF injection. Within 3 months, 10 (83.3%) of the 12 eyes developed tractional detachment and 2 (16.7%) developed VH. No cases developed attributable adverse systemic effects at 3-month follow-up.

Five (41.6%) of the 12 infants had persistent systemic illnesses during the treatment period. Anemia was more common in nonregressing ROP group compared to regressed ROP group (33.3% vs. 18.2%, P = 0.2). Association between other systemic risk factors and nonregression of ROP too was insignificant (P = 0.15).

  Discussion Top

Severe ROP, if left untreated, can lead to progression of the disease, ultimately resulting in retinal detachment and blindness. Timely treatment is important to prevent blindness. Laser therapy is the gold standard of treatment,[14] and anti-VEGF injections are recommended in selective cases.[18],[19] However, there are no guidelines giving clear indications for the use of anti-VEGF in ROP. It is important to identify possible factors associated with failure of treatment. This could help select the treatment option to maximize success rate.

Over two-thirds of infants in this study were males. Gender inequalities in access to health care have been reported earlier.[20] Parents of male infants were more likely to have sought treatment. Mean BW and mean GA observed were consistent with findings from other studies in India.[10],[11],[21] Almost all infants in this study had at least one documented systemic risk factor. Their association with ROP is well established[22] and could adversely influence the natural history of the disease.

Data collected from existing medical records from our institute confirm the effectiveness of laser photocoagulation. The rate of success of treatment was 94.3% whereas that of nonregression of ROP after treatment was 5.7%. Other studies[3],[6],[7],[8],[9],[10],[11] addressed the long-term treatment outcome, whereas our study focused on immediate nonregression and short-term outcome of treatment. Our study revealed that APROP was the single most associated factor with nonregression. These results corresponded with the earlier studies[7],[10],[23] where poorer outcomes in APROP were reported. A high proportion of APROP cases have been possibly attributable to better survival of extremely low BW infants in our country and more importantly to unmonitored supplemental oxygen as well as wide variation in the quality of neonatal care.[24]

Four eyes presented with preretinal hemorrhage preventing adequate laser treatment. The presence of preexisting hemorrhage has been reported to be a poor prognostic ocular factor.[9] This may suggest delayed presentation. Parents of preterm infants might face several barriers such as lack of awareness, financial challenges, distance, and gender bias which need to be explored. Similarly, delayed referral by pediatricians may be due to lack of awareness of Indian screening guidelines, as has been reported earlier.[25] Awareness creation about ROP guidelines and of the Universal Health Coverage Scheme[26] could help tackle some barriers.

In the present study, supplemental oxygen therapy and anemia requiring blood transfusion were the most frequently observed risk factors. Although anemia was more common in nonregressing ROP group compared to regressed ROP group, none of the systemic risk factors showed any statistically significant association with nonregression. Some reports have shown that systemic risk factors influence the severity of ROP and response to laser therapy.[27]

All the eyes of nonregressing ROP developed either retinal detachment or VH despite laser photocoagulation. New-onset fibrovascular traction can limit outcome in APROP significantly, despite adequate laser treatment,[28] and such traction usually begins 1–3 weeks after laser treatment, with a rapid progression to retinal detachment.

In our study, laser treatment was performed as primary treatment whenever possible. Efficacy of anti-VEGF injections in APROP or Zone 1 disease has been established in few randomized controlled trials.[18],[19] Delivering adequate primary laser therapy in Zone I disease is difficult due to extensive avascular area including macula. Hence, shifting the standard of care to primary anti-VEGF therapy for APROP (followed by laser treatment) might offer better structural outcomes.

There are certain limitations to this study. Association between individual systemic risk factor and nonregression of ROP could not be established owing to small number of cases of treatment failure. Further studies with larger sample size are required to establish this. Risk factor data were collected from discharge summaries, hence undocumented risk factors at the time of data collection might have been missed/inaccurately reported. Findings from this study may not be generalized to severe ROP cases across India. Most cases enrolled in this study were from private sector facilities, hence these findings may not represent a population of infants in public sector.

  Conclusion Top

Diagnosis of APROP and preexisting retinal hemorrhages is associated with nonregression after therapy for ROP in western India. Primary treatment with anti-VEGF followed by laser might result in better outcomes.


  1. Dr. Ajit Vhatkar for assistance, contribution toward screening of preterm infants, maintaining clinical data, and its retrieval.
  2. Dr. Ashwini Sonawane for diagnosing treatable ROP infants and their adequate treatment.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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