Abstract
Persistent avascular retina (PAR) in prematurely born individuals may be a risk factor for late sequelae of retinopathy of prematurity (ROP), including retinal detachment in older childhood and adulthood. Although PAR has been associated with use of vascular endothelial growth factor antagonist therapy for treatment-requiring ROP, the prevalence of this finding in patients without prior ROP treatment is unknown. We performed a cross-sectional study to determine the prevalence of PAR in a cohort of patients 4–8 years of age who were screened for ROP in the neonatal intensive care unit and did not receive treatment. Patients were recruited from an existing population-based cohort and underwent ultra-widefield fluorescein angiography (UWFFA). UWFFA images of 43 eyes of 23 patients were evaluated. Average age at time of evaluation was 6.2 years. PAR was observed in 21 patients (91%). Thirteen eyes (30%) had PAR in zone II; 23 (53%), in zone III. Six eyes (14%) had abnormal vessels without clear PAR. These findings indicate a high prevalence of PAR in patients with a history of ROP screening without treatment.
Persistent avascular retina (PAR) has previously been reported as a consequence or complication of vascular endothelial growth factor antagonist (anti-VEGF) therapy for retinopathy of prematurity (ROP) and is now formally included within the International Classification for ROP (ICROP).1,2 Although abnormal ophthalmoscopic findings, such as macular dragging and pigmentary changes, have long been reported in eyes with a history of untreated ROP, the prevalence of PAR in eyes with an apparently benign ophthalmoscopic examination is unknown.3–5 As an increasing number of extremely preterm babies are surviving into adulthood, of whom the vast majority required no treatment for ROP, knowledge of the prevalence of PAR in this population may be increasingly clinically relevant.6 In this study, we evaluated the prevalence of PAR in a cohort of patients with a history of premature birth meeting ROP screening criteria using ultra-widefield fluorescein angiography (UWFFA).
Subjects and Methods
This cross-sectional study, conducted at Oregon Health & Science University (OHSU), complied with the Health Insurance Portability and Accountability Act (HIPAA) of 1996 and with the tenets of the Declaration of Helsinki. Institutional Review Board/Ethics Committee approval was obtained.
Patients were recruited from an existing cohort of ROP patients from the ongoing Imaging & Informatics in ROP (i-ROP) study (July 2011-present). Inclusion criteria included age 4–8 years and a history of ROP screening, with or without a clinical diagnosis of ROP. Eyes previously treated for ROP were excluded. Electronic medical records were reviewed for gestational age, birthweight, sex, and peak ROP category before disease regression as follows: “none” (immature vessels without stage 1 disease), “mild” (less than type 2), and “type 2 or preplus.” Wide-angle retinal images obtained in the neonatal period via Retcam (Natus Medical Incorporated, Pleasanton, CA) were available for all patients.
Patients were recruited from the i-ROP cohort at OHSU. Those who met inclusion criteria, were reachable, and were willing to participate were scheduled to return for outpatient evaluation between September 2019 and April 2021. Written, informed consent and HIPAA authorization were obtained for all participating subjects. Outpatient clinical evaluations included dilated ophthalmic examinations and oral UWFFA (California; Optos Inc, Marlborough, MA). UWFFA images were reviewed by two masked vitreoretinal surgery fellows (RHG, BAS) for the presence of PAR, and differences were adjudicated by a pediatric retina specialist (JPC). Eyes were additionally subcategorized as follows: no abnormalities visualized on available images, abnormal vessels without PAR or leakage, PAR in zone III and PAR in zone II.
Results
A total of 23 patients (43 eyes; 10 females) were included. Two eyes that were previously treated with laser photocoagulation therapy were excluded from review. One patient was monocular due to anophthalmos. Average (with standard deviation [SD]) gestational age and weight at birth were 27 ± 2 weeks (range, 24–32) and 0.85 ± 0.25 kg (range, 0.52–1.49 kg), respectively. Of the 43 eyes, peak ROP severity was “none” in 13, “mild” in 22, and “type 2 or pre-plus” in 8 (Table 1).
Table 1.
Number of eyes by peak ROP severity and peripheral vascular abnormality grading
| Peak severity | None | Mild | Type 2 or pre-plus | Grade total |
|---|---|---|---|---|
| Normal peripheral retina as visualized | 1 | — | — | 1 |
| Abnormal peripheral vessels without visible PAR | 3 | 1 | 2 | 6 |
| PAR in zone 3 | 8 | 13 | 2 | 23 |
| PAR in zone 2 | 1 | 8 | 4 | 13 |
| Severity total | 13 | 22 | 8 | 43 |
PAR, persistent avascular retina; ROP, retinopathy of prematurity.
Average age at follow-up was 6.2 ± 1.3 years (range, 3.9–8.1). Average logMAR visual acuity was 0.2 ± 0.22 (Snellen equivalent, 20/32). Of the 23 patients, 21 (91%), or 36 of 43 eyes (84%) demonstrated regions of PAR on UWFFA (Figure 1). Of the 43 eyes, only 1 appeared to have normal peripheral retinal vasculature. Thirteen eyes (30%) demonstrated PAR in zone II; 23 (53%), in zone III. The remaining 6 eyes (14%) demonstrated abnormal vessels without clear PAR. Other peripheral retinal findings ranged from persistent vascular tortuosity to progressive straightening and leakage (Figure 2).
FIG 1.
Acute-phase and follow-up imaging. Acute-phase ROP fundus photographs (A, C) with respective follow-up UWFFA imaging (B, D) of 2 patients (A+B, C+D). Each patient was documented to have a peak ROP severity of “type 2 or pre-plus.” Both UWFFA images were obtained at 7.3 years of age and demonstrate clear regions of nonperfusion in zone II.
FIG 2.
Representative vascular findings from UWFFA imaging. A, Persistent vascular tortuosity. B, Progressive vessel straightening. C, Telangiectatic vessels at the border of avascular retina. D, Peripheral vessel leakage.
Four of 8 eyes documented to have a peak ROP severity of type 2 or pre-plus demonstrated PAR in zone II with or without leakage. This finding was additionally noted in 8 of 22 eyes with mild peak ROP severity and 1 of 13 eyes with peak ROP severity of none (Table 1).
Discussion
This study evaluated the prevalence of PAR in a cohort of patients with a history of ROP screening without treatment. We found evidence of PAR in 91% of patients, with approximately one-third of eyes exhibiting PAR in zone II. It has long been recognized that patients may have significant vitreoretinal pathology associated with a history of ROP, with or without treatment, and that a minority may develop late-onset tractional and/or exudative disease that is refractory to treatment.6,7 There is a growing awareness that untreated PAR may be a risk factor for late-onset tractional and/or exudative vitreoretinal pathology associated with a history of ROP with or without treatment.2,6 These findings therefore indicate a potentially large population at risk, because up to 90% of babies who develop ROP may demonstrate spontaneous disease regression without treatment.8 As survival in extreme prematurity increases, so may the incidence of late-onset retinal detachment in late childhood and early adulthood.2,6,7
There are no clinical trials to guide management of PAR, whether due to spontaneous regression or after anti-VEGF. With these data demonstrating that almost all patients who are born extremely premature have PAR on UWFFA, more research is needed to determine the optimal screening intervals and management of these patients. Presumably, many of these patients will be asymptomatic throughout life; however, a minority may develop vision-threatening complications. Management options include close observation or laser photocoagulation to areas of PAR in older children; however, the number needed to treat to avoid one case of late-onset blindness remains unknown. In the absence of a clinical trial, at the very least patient and parental education seems important, and close follow-up for the development of peripheral retinal pathology seems warranted.9,10
The primary limitation of this study stems from the relatively small size of the cohort. We hope that future studies looking at larger population-based cohorts explore the incidence and risk factors of late complications of ROP. Additionally, there was no control group included in the grading of the UWFFA eyes, although the masked graders were well experienced in evaluating normal versus abnormal findings. Incorporation of controls may reinforce the observation of reported abnormal findings in future studies.
These findings should raise awareness among eye care providers for the high prevalence of PAR in patients with a history of extreme prematurity, with or without a history of ROP treatment. Given the association of PAR with late vitreoretinal complications, close follow-up with patient education and monitoring for development of other retinal pathology is essential in this high-risk population.9,10
Acknowledgments
Financial support: This work was supported by grants R01EY19474, R01 EY031331, R21 EY031883, and P30 EY10572 from the National Institutes of Health (Bethesda, MD), an investigator-initiated grant from Genentech (San Francisco, CA), and by unrestricted departmental funding and a Career Development Award (JPC) from Research to Prevent Blindness (New York, NY). The sponsors or funding organizations had no role in the design or conduct of this research.
Declarations of interest: JPC received financial support (grant) from Genentech (San Francisco, CA) and is a consultant to Boston AI labs. MFC was previously a consultant for Novartis (Basel, Switzerland) and is an equity owner in InTeleretina, LLC (Honolulu, HI).
Footnotes
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References
- 1.Harper CA 3rd, Wright LM, Young RC, Read SP, Chang EY. Fluorescein angiographic evaluation of peripheral retinal vasculature after primary intravitreal ranibizumab for retinopathy of prematurity. Retina 2019;39:700–705. [DOI] [PubMed] [Google Scholar]
- 2.Chiang MF, Quinn GE, Fielder AR, et al. International Classification of Retinopathy of Prematurity, Third Edition. Ophthalmology 2021;128:e51–e68. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Kushner BJ. Long-term follow-up of regressed retinopathy of prematurity. Birth Defects Orig Artic Ser 1988;24:193–9. [PubMed] [Google Scholar]
- 4.Machemer R Late traction detachment in retinopathy of prematurity or ROP-like cases. Graefes Arch Clin Exp Ophthalmol 1993;231:389–94. [DOI] [PubMed] [Google Scholar]
- 5.Tufail A, Singh AJ, Haynes RJ, Dodd CR, McLeod D, Charteris DG. Late onset vitreoretinal complications of regressed retinopathy of prematurity. Br J Ophthalmol 2004;88:243–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Hamad AE, Moinuddin O, Blair MP, et al. Late-onset retinal findings and complications in untreated retinopathy of prematurity. Ophthalmol Retina 2020;4:602–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Uner OE, Rao P, Hubbard GB 3rd. Reactivation of retinopathy of prematurity in adults and adolescents. Ophthalmol Retina 2020;4:720–27. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Ju R-H, Zhang J-Q, Ke X-Y, Lu X-H, Liang L-F, Wang W-J. Spontaneous regression of retinopathy of prematurity: incidence and predictive factors. Int J Ophthalmol 2013;6:475–80. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Kaiser RS, Trese MT, Williams GA, Cox MS Jr. Adult retinopathy of prematurity: outcomes of rhegmatogenous retinal detachments and retinal tears. Ophthalmology 2001;108:1647–53. [DOI] [PubMed] [Google Scholar]
- 10.Ho LY, Ho V, Aggarwal H, et al. Management of avascular peripheral retina in older prematurely born infants. Retina 2011;31:1248–54. [DOI] [PubMed] [Google Scholar]