Clinical Management of Recurrent Retinopathy of Prematurity after Intravitreal Bevacizumab Monotherapy

doi:10.1016/j.ophtha.2016.04.028

Ophthalmology

Volume 123, Issue 9, September 2016, Pages 1845-1855

Presented at: Third Congress of the World Society of Pediatric Ophthalmology and Strabismus, September 2015, Barcelona, Spain.

https://doi.org/10.1016/j.ophtha.2016.04.028 Get rights and content

Purpose

To determine incidence, risk factors, risk period, and characteristics of recurrent retinopathy of prematurity (ROP) treated by intravitreal bevacizumab (IVB) monotherapy.

Design

Retrospective case series.

Participants

Premature infants with type 1 ROP (subdivided into stage 3+ ROP and aggressive posterior ROP [APROP]) in zone I or zone II posterior who received IVB monotherapy and were followed up for at least 65 weeks adjusted age (AA).

Methods

Retrospective review of infants who demonstrated recurrence of type 1 ROP after IVB monotherapy, including examination of RetCam fundus photographs and fluorescein angiograms.

Main Outcomes Measures

Incidence, risk factors, risk period, and characteristics of recurrent ROP.

Results

Intravitreal bevacizumab monotherapy in 241 infants (471 eyes) was reviewed. Recurrence incidence was 8.3% (20/241) for infants and 7.2% (34/471) for eyes. Recurrence risk factors of greatest significance were appearance of neovascularization as APROP (P = 0.006), extended duration of hospitalization (P = 0.01), and lower birth weight (P = 0.024). Recurrence risk period was between approximately 45 and 55 weeks AA (90.0% [18/20] for infants and 94.1% [32/34] for eyes), with mean recurrence of 51.2 weeks AA (±4.6 weeks; range, 45.7–64.9 weeks) and mean interval of 16.2 weeks (±4.4 weeks) between treatments. Recurrence characteristics included plus disease (20/20 infants [100%]) and neovascularization, which appeared at the following sites: stage 3+ ROP with confluent neovascularization recurred both at the advancing edge and at the initial ridge and extraretinal fibrovascular proliferative complex (12/14 infants [85.7%]). However, APROP (6/6 infants [100%]) and stage 3+ ROP with nonconfluent neovascularization (2/14 infants [14.3%]) recurred only at the advancing edge. Also, the anterior extent of retinal vascularization was decreased (mean, 1.76 disc diameters [DD] vs. 4.48 DD), and the rate of retinal vascularization was delayed (mean, 0.11 DD/week vs. 0.23 DD/week) in those with versus without recurrence, respectively. After retreatment with IVB, retinal vascularization proceeded minimally and slowly.

Conclusions

Premature children with severe ROP are being treated successfully with IVB monotherapy. However, recurrence is not uncommon, so vigilant follow-up is necessary to ensure timely re-treatment. Knowledge of recurrence incidence, risk factors, risk period, and characteristics allows for tailored clinical management.

Section snippets

Methods

Two cohorts were reviewed in this large retrospective case series: 75 infants treated with IVB in the BEAT-ROP clinical trial (Clinicaltrials.gov trial identifier, NCT00622726) from March 13, 2008, through August 4, 2010,¹² and 218 infants treated consecutively with IVB (by H.M.H.) after the BEAT-ROP clinical trial who were treated and followed up at the Memorial Hermann Hospital System, Houston, Texas, and at the hospitals in Webster, Corpus Christi, and El Paso, Texas, from August 5, 2010,

Results

A total of 241 infants (471 eyes, i.e., 11 unilateral cases) treated with IVB monotherapy for ROP in zones I or II posterior were eligible for review in this study (55 infants from the BEAT-ROP clinical trial and 186 infants treated after the BEAT-ROP clinical trial). Thirty-one infants without follow-up examinations extending to 65 weeks were excluded from analysis, as well as 21 infants who had died before 65 weeks.

The demographics, infant characteristics, and initial treatment information

Discussion

There have been several case reports of late recurrence after treatment of stage 3+ ROP or APROP with IVB monotherapy27, 28 and after combined treatment using laser therapy with intravitreal ranibizumab²⁹ or with IVB.27, 30, 31, 32 In each of these reports, close follow-up (every 1 or 3 weeks) was not performed beyond 55 weeks AA; however, standard follow-up recommendations have not been established by ophthalmologic studies reviewing prospective data. Also, not surprisingly, there are reports

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Cited by (138)

Comparing reactivation and retreatment for three doses of bevacizumab in type 1 retinopathy of prematurity
2024, Journal of AAPOS
To determine timing and rates of reactivation and retreatment of type 1 retinopathy of prematurity (ROP) after treatment with either 0.125 mg, 0.250 mg, or 0.500 mg of intravitreal bevacizumab (IVB).
Retrospective data, including demographic information, past medical history, and ROP characteristics were analyzed for babies with type 1 ROP treated with IVB at Riley Hospital for Children for the perioed 2014-2021.
A total of 84 patients met inclusion criteria: 29 patients received 0.125 mg of IVB; 39, 0.250 mg; and 16, 0.500 mg. Of the 84, 67 (80%) had additional laser treatment because of late reactivation (n = 52) or persistent avascular retina (PAR) (n = 15). Subsequent laser treatment was more common with lower doses: 0.125 mg (n = 27 [93%]); 0.250 mg (n = 31 [80%]); 0.500 mg (n = 9 [57%]) (P = 0.012). There was no difference between groups with regard to reason for subsequent laser treatment (reactivation vs PAR). The 0.125 mg group required retreatment because of reactivation 3.8 weeks sooner than the other dosing groups (P = 0.047).
The outcomes comparing three doses of IVB for severe ROP showed a difference in the timing of secondary treatment, with the lower dosing group requiring laser for reactivation earlier.
Treated Cases of Retinopathy of Prematurity in Germany: 10-Year Data from the Retina.net Retinopathy of Prematurity Registry
2024, Ophthalmology Retina
To analyze changes in demographic parameters and retreatment patterns over a 10-year period in a clinical routine setting of infants with retinopathy of prematurity (ROP) requiring treatment documented in the German Retina.net ROP registry.
Multicenter, noninterventional, observational registry study recruiting patients treated for ROP.
A total of 692 eyes of 353 infants treated for ROP were documented in the Retina.net ROP registry over a 10-year period between 2011 and 2020. These cases cover about 15% of all infants treated for ROP in Germany.
The Retina.net ROP registry was established in 2012 to jointly collect information on infants treated for ROP. The database collects information on demographic parameters (gestational age [GA], birth weight, neonatal comorbidities) as well as treatment parameters (type of treatment, weight and age at treatment, and stage of ROP). A total of 19 centers contributed to the analysis. This is the 10-year analysis of data from 2011 to 2020, in which we focus on changes over time regarding the respective parameters.
Changes over time in demographic parameters and treatment patterns for ROP in Germany.
The overall incidence of treatment requiring ROP was 3.5% of all infants screened for ROP at participating centers. Gestational age, weight at birth, and weight at treatment remained stable over the 10-year period, whereas postmenstrual and postnatal age at treatment increased moderately but statistically significantly over the years. The most prevalent ROP severity stage at treatment was stage 3+ in zone II (76.6% of all treated eyes). Treatment patterns changed considerably from predominantly laser treatments in 2011 (75% of all treated eyes) to predominantly ranibizumab treatments in 2020 (60.9% of all treated eyes). The overall retreatment rate was 15.6%. Retreatment rates differed between initial treatment modalities (14.1% after laser coagulation, 12% after bevacizumab and 24.5% after ranibizumab). Treatment-associated systemic or ophthalmic complications were rare.
This data analysis represents one of the largest documented cohorts of infants treated for ROP. The data on demographic parameters and treatment patterns provide useful information for further improvement of ROP management.
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Comparison of different agents and doses of anti-vascular endothelial growth factors (aflibercept, bevacizumab, conbercept, ranibizumab) versus laser for retinopathy of prematurity: A network meta-analysis
2024, Survey of Ophthalmology
Laser photocoagulation (LPC) and/or intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections constitute the current standard treatment for retinopathy of prematurity (ROP). This network meta-analysis focus on whether a ranking of interventions may be established for different dose levels of intravitreal injection of anti-VEGF agents (aflibercept, bevacizumab, conbercept, ranibizumab) as primary treatments for ROP versus laser in terms of retreatment rate as primary outcome, and time to retreatment and refractive error as secondary endpoints, since best anti-VEGF dosage remains under debate. Sixty-eight studies (15 randomized control trials and 53 nonrandomized studies) of 12,356 eyes of 6445 infants were retrieved from databases (2005 Jan. – 2023 June). Studies were evaluated for model fit, risk of bias and confidence of evidence in Network Meta-Analysis (CINeMA). Bayesian NMA showed that anti-VEGF drugs were not inferior to laser in terms of retreatment rate. For intravitreal bevacizumab (IVB), doses half of the conventional infant dose showed a low risk of retreatment rate (risk ratio (RR) of 1.43; 95% credible interval (CrI): 0.508, 4.03). On probability ranking as surface under the cumulative ranking curve (SUCRA) plot, half dose of bevacizumab had a better position than conventional and augmented (1.2–2 times the regular dose) doses. A similar probability trend was observed for half vs. conventional doses of aflibercept and ranibizumab. Conventional infant dose of conbercept showed the lowest risk for retreatment (RR 0.846; 95% CrI: 0.245, 2.91). For secondary endpoints, lower doses of anti-VEGF agents were associated with shorter times to retreatment. The largest changes were noted for the augmented doses of bevacizumab and ranibizumab (0.3 mg) with means of 14.1 weeks (95% CrI: 6.65, 21.6) and 12.8 weeks (95% CrI: 3.19, 20.9), respectively. Finally, NMA demonstrated better refractive profile for anti-VEGF than laser therapy, especially for the conventional infant doses of bevacizumab and ranibizumab which exhibited a significantly better refractive profile than LPC, with mean differences of 1.67 (spherical equivalent - diopters) (95% CrI: 0.705, 2.67) and 2.19 (95% CrI: 0.782, 3.59), respectively. In the SUCRA plots, LPC had a markedly different position with a higher probability for myopia. Further clinical trials comparing different intravitreal doses of anti-VEGF agents are needed, but our findings suggest that low doses of these drugs retain efficacy and may reduce ocular and systemic undesired events.
Fundus fluorescein angiography imaging of retinopathy of prematurity in infants: A review
2023, Survey of Ophthalmology
Fluorescein angiography in retinopathy of prematurity is increasingly utilized over the past decade. The development of ultra-wide-field imaging combined with fluorescein angiography has allowed improved visualization of the peripheral retinal vasculature. Patient cooperation in the pediatric population is particularly challenging, but hand-held digital retinal photography has shown promise and can visualize the infant retina without the need for anesthesia and intravenous access. Many features of retinopathy of prematurity and its response to laser and anti-VEGF treatment can be either exclusively or better visualized on fluorescein angiography compared to indirect ophthalmoscopy or color fundus photography. Disease treatment is gradually shifting from laser photocoagulation to intravitreal anti-VEGF agents, the latter being associated with late-onset vision-threatening sequelae. The role of fluorescein angiography in retinopathy of prematurity monitoring will continue to increase with the longer follow-up required and different clinical behavior seen with anti-VEGF treatment. We highlight the utility, safety, and importance of fluorescein angiography in the diagnosis, treatment, and follow-up of retinopathy of prematurity.
Retinopathy of prematurity: A review of pathophysiology and signaling pathways
2023, Survey of Ophthalmology
Citation Excerpt :
It was approved for cancer therapy but is used off-label for eye diseases.403 Although it has shown an advantage over laser therapy for ROP stage 3 with plus disease in zone I but not in zone II, recurrence of ROP is not uncommon.167,255,256 In addition, bevacizumab has been associated with several serious adverse outcomes in clinical studies.15,96
Retinopathy of prematurity (ROP) is a vasoproliferative disorder of the retina and a leading cause of visual impairment and childhood blindness worldwide. The disease is characterized by an early stage of retinal microvascular degeneration, followed by neovascularization that can lead to subsequent retinal detachment and permanent visual loss. Several factors play a key role during the different pathological stages of the disease. Oxidative and nitrosative stress and inflammatory processes are important contributors to the early stage of ROP. Nitric oxide synthase and arginase play important roles in ischemia/reperfusion-induced neurovascular degeneration. Destructive neovascularization is driven by mediators of the hypoxia-inducible factor pathway, such as vascular endothelial growth factor and metabolic factors (succinate). The extracellular matrix is involved in hypoxia-induced retinal neovascularization. Vasorepulsive molecules (semaphorin 3A) intervene preventing the revascularization of the avascular zone. This review focuses on current concepts about signaling pathways and their mediators, involved in the pathogenesis of ROP, highlighting new potentially preventive and therapeutic modalities. A better understanding of the intricate molecular mechanisms underlying the pathogenesis of ROP should allow the development of more effective and targeted therapeutic agents to reduce aberrant vasoproliferation and facilitate physiological retinal vascular development.
Computed Analysis of Retinal Vascular Growth After Bevacizumab Treatment of Retinopathy of Prematurity Until Age 3 Years
2023, Clinical Therapeutics
Premature infants, after anti–vascular endothelial growth factor injections for retinopathy of prematurity, have persistent peripheral avascular retina (PAR). PAR is ablated with laser; however, physiologic growth of the retinal vasculature in the long term has not been measured. The purposes of this study were to measure retinal vessel growth after treatment with intravitreal bevacizumab (IVB) for retinopathy of prematurity, using serial fluorescein angiography (FA), until age 3 years, and to assess the timing for providing laser ablation in PAR.
Data from an observational, longitudinal clinical study were collected. Angiographic images of eyes treated with IVB were included; imaging data from laser photocoagulation were excluded. All eyes underwent initial examination under general anesthesia with FA and photographic imaging. The retinal vessel length was measured from the temporal margin of the optic disc passing through the foveal center, and the lengths at subsequent FA were compared. To compare the changes in retinal vessel length over time in individual eyes, a paired-sample t test was performed.
FA images from 70 eyes (35 infants) treated with IVB were available. A total of 150 FA images were available for review; data from 125 images of good quality were used for analysis. The mean postmenstrual ages (PMAs) at first, second, third, and fourth FA were 66.2, 100.9, 135.1, and 180.7 weeks, respectively. The mean retinal vessel length was 14.177 mm at first FA and 13.199 mm at fourth FA (PMA range, 42...234 weeks). Retinal vascular lengths of individual eyes compared over time showed no statistically significant growth from the first FA to age 3 years. The changes in retinal vessel length from first to second FA were –0.117 ± 0.79 mm (p = 0.42; n = 30); from first to third FA, +0.060 ± 0.85 mm (p = 0.79; n = 15); and first to fourth FA, –0.404 ± 1.32 mm (p = 0.45; n = 7).
Beyond 65 weeks' PMA, no meaningful retinal vascular growth occurred after IVB up to age 3 years, guiding the timing for physicians if laser photocoagulation is being considered. Future studies are needed to address retinal growth changes in the growing eyes of infants.

View all citing articles on Scopus

: See Editorial on page 1843.

: Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

: Supported by the National Eye Institute, National Institutes of Health, Bethesda, Maryland (grant no.: P30EY010608; Research to Prevent Blindness, Inc, New York, New York (Challenge Grant to The University of Texas Health Science Center at Houston McGovern Medical School); the National Center for Research Resources, National Institutes of Health, Bethesda, Maryland (grant no.: UL1 RR024148); Alfred W. Lasher III Research Funds to The University of Texas Health Science Center at Houston McGovern Medical School, Houston, Texas; and the Hermann Eye Fund, Houston, Texas. The funding organizations had no role in the design or conduct of this research.

: Author Contributions:

: Conception and design: Mintz-Hittner, Chuang

: Analysis and interpretation: Mintz-Hittner, Geloneck

: Data collection: Mintz-Hittner, Geloneck

: Obtained funding: none

: Overall responsibility: Mintz-Hittner, Geloneck, Chuang

View full text

Original articleClinical Management of Recurrent Retinopathy of Prematurity after Intravitreal Bevacizumab Monotherapy

Purpose

Design

Participants

Methods

Main Outcomes Measures

Results

Conclusions

Section snippets

Methods

Results

Discussion

Preterm-associated visual impairment and estimates of retinopathy of prematurity at regional and global levels for 2010

Pediatr Res

Multicenter trial of cryotherapy for retinopathy of prematurity: preliminary results

Arch Ophthalmol

Revised indications for the treatment of retinopathy of prematurity

Arch Ophthalmol

Ocular neovascularization. The Krill Memorial Lecture

Am J Ophthalmol

The demonstration of angiogenic activity from ocular tissues. Preliminary report

Ophthalmology

Vitamin E protects against retinopathy of prematurity through action on spindle cells

Nature

Vascular endothelial growth factor is a secreted angiogenic mitogen

Science

Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders

N Engl J Med

Neutralizing antibody to VEGF reduces intravitreous neovascularization and may not interfere with ongoing intraretinal vascularization in a rat model of retinopathy of prematurity

Mol Vis

Quantitative analyses of retinal vascular area and density after different methods to reduce VEGF in a rat model of retinopathy of prematurity

Invest Ophthalmol Vis Sci

Intravitreal bevacizumab (Avastin) for post laser anterior segment ischemia in aggressive posterior retinopathy of prematurity

Indian J Ophthalmol

Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity: preliminary results of the BEAT-ROP clinical trial

N Engl J Med

Visual field extent at 6 years of age in children who had high-risk prethreshold retinopathy of prematurity

Arch Ophthalmol

Progression of myopia and high myopia in the early treatment for retinopathy of prematurity study: findings at 4 to 6 years of age

J AAPOS

Anterior segment abnormalities in cicatricial retinopathy of prematurity

Ophthalmology

Case series of angle-closure glaucoma after laser treatment for retinopathy of prematurity

J AAPOS

Intravitreal bevacizumab for retinopathy of prematurity: refractive error results

Am J Ophthalmol

Refractive outcomes following bevacizumab monotherapy compared with conventional laser treatment: a randomized clinical trial

JAMA Ophthalmol

Refractive errors after the use of bevacizumab for the treatment of retinopathy of prematurity: 2-year outcomes

Eye

Original article
Clinical Management of Recurrent Retinopathy of Prematurity after Intravitreal Bevacizumab Monotherapy