Abstract
Background
Data on long-term outcomes of antivascular endothelial growth factor therapy in retinopathy of prematurity (ROP) are still rare. We present 5-year post-treatment ophthalmological and paediatric outcomes of the prospective, multicentre, randomised, double-blinded, controlled pilot study CARE-ROP (Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity).
Methods
14 patients (28 eyes) completed the ophthalmologic and 5 patients completed the paediatric 5-year follow-up assessment. The ophthalmological assessment included best-corrected visual acuity (BCVA), orthoptic status, slit lamp examination, intraocular pressure and funduscopy. The paediatric examination followed the German Neonatal Network protocol and covered cognitive, motor and sensory development.
Results
17 of 28 eyes exhibited at least one ocular abnormality, such as optic disc pallor or atrophy of the optic nerve head, retinal pigment epithelium (RPE) pigment changes, persistent tortuosity or macular hypoplasia. Despite this, 19 of 26 eyes demonstrated a logarithm of the Minimum Angle of Resolution (logMAR) BCVA of 0.3 or better. Mean refractive error was −0.9 D (±3.4 D) with only two eyes of one infant having high myopia of < −5 D. The neurodevelopmental results were within the expected range for a population of preterm infants with treatment-warranting ROP but need to be interpreted with caution due to the low number of five patients.
Conclusion
The 5-year ophthalmologic and paediatric outcomes of the CARE-ROP study confirm the previous results and add important additional information on long-term safety of 0.12 and 0.20 mg ranibizumab for the treatment of ROP. The ophthalmologic functional outcome regarding BCVA and refraction is promising. These exploratory long-term data, however, need to be interpreted with caution due to the low patient number both in the ophthalmologic and paediatric assessment.
Keywords: Retina, Child health (paediatrics)
WHAT IS ALREADY KNOWN ON THIS TOPIC
Ranibizumab has become an approved therapy for retinopathy of prematurity (ROP) in many countries. However, long-term data remain scarce. The CARE-ROP trial (Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity) was the first randomised controlled trial comparing two doses of ranibizumab (0.2 mg and 0.1 mg) and can add valuable long-term data on the use of antivascular endothelial growth factor agents in ROP.
WHAT THIS STUDY ADDS
This study adds important data regarding long-term efficacy and safety on two dosages of ranibizumab in ROP. The observed structural ocular abnormalities were in line with expected changes seen in premature eyes with ROP. Overall, the functional results for best-corrected visual acuity and refraction were reassuring. The neurodevelopmental results were also reassuring but need to be interpreted with caution due to the low patient number.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
The reassuring long-term results from the CARE-ROP trial add confidence in the use of ranibizumab for ROP.
Introduction
Over the last decades, the management of retinopathy of prematurity (ROP) has changed tremendously since antivascular endothelial growth factor (anti-VEGF) treatment was shown to be comparably effective as the established laser treatment.1,3 With ranibizumab and aflibercept, two anti-VEGF agents became approved for ROP treatment in Europe and many other parts of the world.4 5 However, long-term data on anti-VEGF treatment in ROP still remain scarce. The BEAT-ROP Study (Bevacizumab Eliminates the Angiogenic Threat for Retinopathy of Prematurity) did not publish results on infants older than 22 months.6 The FIREFLEYE Study (Aflibercept for Retinopathy of Prematurity - Intravitreal Injection Versus Laser Therapy), investigating aflibercept and laser published data from their 2-year follow-up7 and only the RAINBOW Study (RAnibizumab Compared With Laser Therapy for the Treatment of INfants BOrn Prematurely With Retinopathy of Prematurity), comparing two doses of ranibizumab (0.2 mg and 0.1 mg) with laser published a longer follow-up of 5 years.8 No other data from controlled, prospective clinical trials exist that have more than 2 years of follow-up.
In this paper, we present the 5-year follow-up data from the CARE-ROP Study (Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity), which was conducted as a pilot study between 2014 and 2016 and enrolled 19 patients with treatment-warranting ROP. It was the first trial to investigate two different doses of ranibizumab (0.12 mg and 0.20 mg, corresponding to 24% and 40% of the adult standard dose) in ROP in a controlled clinical trial setting.9 The CARE-ROP core study demonstrated that both investigated doses are effective and safe for the treatment of ROP.9 The results from the 1-year and 2-year follow-up assessments did not indicate any negative long-term impact regarding neurological and ocular functional development. However, one patient had been found to have progressed to stage 5 ROP bilaterally in the 1-year ophthalmic follow-up examination following reactivation of the disease after the end of the core study.10 Such cases emphasise the importance of a vigorous long-term follow-up after anti-VEGF treatment. We consider it, therefore, important to communicate with this study the ophthalmological and paediatric 5-year results from the CARE-ROP trial.
Materials and methods
Study design
After the core part of the CARE-ROP study, infants were seen in three follow-up visits: at 1 year (±2 months), 2 years (±3 months)10 and 5 years (±6 months) post first injection of ranibizumab—the analysis presented here reports the results from the 5-year follow-up. Patients were not involved in the design, or conduct, or reporting or dissemination plans of our research.
Patient allocation and assessments
See figure 1 for patient enrolment and discontinuations in both the core study and the follow-up period. The 5-year follow-up visit consisted of an ophthalmological assessment (performed by 14 patients, 8 in the 0.12 mg group, 6 in the 0.20 mg group) and a paediatric assessment (performed by 5 patients, 3 in the 0.12 mg group, 2 in the 0.20 mg group). The ophthalmological assessment included visual acuity, orthoptic status (fixation, objection to occlusion, strabismus, eye motility, nystagmus), cycloplegic retinoscopy, slit lamp examination, intraocular pressure, funduscopy, optical coherence tomography (OCT) (optional) and fundus photography (optional). Visual acuity was assessed according to the established method used routinely at each site. During the ophthalmological assessment, late reactivations and treatments of ROP between the 2-year and the 5-year follow-ups were also documented. The paediatric 5-year follow-up assessment followed the highly standardised protocol of the German Neonatal Network (GNN), which is the largest German data collection on infants with very low birth weight (<1500 g) with currently more than 20 000 infants.11 Assessments included cognitive, motor and sensory development, as well as weight and height. Additionally, the exam contained structured interviews asking parents for the presence of certain diseases, such as asthma, cerebral palsy and diabetes. The history of febrile convulsions, seizures and other typical childhood diseases was documented if present. For detailed information on the tests conducted during the GNN assessment, see Dammann et al.12 Unfortunately, the COVID-19 pandemic had one of its peaks at the time when the CARE-ROP 5-year assessments were scheduled. Due to lockdowns and travel restrictions, assessments of six infants could not be conducted within the appropriate time window. Therefore, the paediatric assessment was only completed by five infants (three in the 0.12 mg group and two in the 0.20 mg group) (see figure 1).
Figure 1. Enrolment, allocation into the two study arms during the CARE-ROP core study (Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity study), the follow-up at 1 year (±2 months), 2 years (±3 months) and 5 years (±6 months) post initial treatment. *After initial regression of the disease, a regular reinjection of the same dose without unblinding of investigators was allowed per protocol after at least 28 days. #A rescue treatment was defined as treatment with laser coagulation or the higher ranibizumab dose after unblinding and was allowed at all timepoints. ∼Patients not present at the 5-year ophthalmological visit were contacted multiple times but parents did not want to participate in this examination. §Pediatric examinations for further six infants (three in each treatment arm) were planned to take place in December 2021, but needed to be cancelled due to the COVID-19 pandemic. ROP, retinopathy of prematurity.
Safety assessment
Adverse events (AEs) and serious adverse events (SAEs) were reported as part of the CARE-ROP trial and coded to system organ class and preferred term using the Medical Dictionary for Regulatory Activities, V.24.1.
Statistical analysis
The data obtained were mainly analysed by descriptive statistical methods. For numerical data, the number of observations (n), mean/median, SD/IQR, minimum and maximum values were analysed. Categorical variables are presented by frequency tables. For comparisons between groups, the appropriate statistical tests were used according to distribution of data and respective variances (see Results). For spherical equivalent, astigmatism, intraocular pressure and best-corrected visual acuity (BCVA) in logMAR, the mean of right and left eye was used when computing p values. All data relevant to the study are included in the article or uploaded as online supplemental information.
Results
Baseline characteristics
Mean gestational age (GA) of infants in the ophthalmological 5-year assessment was 24.9 (±1.8). Nine infants (64.3%) were born with GA up to 25 weeks, seven infants were girls (50%). Mean birth weight was 555 g (±148), body length at birth was 29.9 cm (±2.7) (n=12) and head circumference at birth was 21.4 cm (±2.0) (n=13). Apgar scores increased from 4 (±2.5) at 1 min to 5.9 (±2.0) at 5 min and 7.1 (±1.9) at 10 min. No statistically significant differences between groups were observed for any of these parameters (see online supplemental table S1).
Ophthalmological results
Late reactivations and vascularisation to the ora serrata
There was no late reactivation or progression to stage 4 or 5 ROP other than the one that had already occurred by 40 weeks post baseline in the 0.20 mg ranibizumab group and which had already been reported with the 2-year results.10
The extent of peripheral vascularisation was reported for 78% of eyes in the 0.12 mg arm and 86% in the 0.20 mg arm. Among these, all but one eye had complete vascularisation.
Detailed retinal and anterior segment examination
An overview of all abnormalities observed on slit lamp and retinal examination is given in online supplemental table S3. In more than half of the eyes (eight eyes (50%) in the 0.12 mg group and nine eyes (75%) in the 0.20 mg group), at least one abnormality was identified (see online supplemental table S2). Figure 2 shows examples of persistent posterior pole vascular tortuosity, optic disc pallor, persistent avascular retina13 and visible remnants of the previous ridge.
Figure 2. Examples of persistent posterior pole vascular tortuosity (A), optic disc pallor (B), persistent avascular retina (C) and persistent visible remnants of the previous ridge (D) at the 5-year assessment. Visual acuity is given for the respective eye in logMAR or decimals. Note that different from (C), the retinal vessels in (D) proceed beyond the previous ridge into the periphery.
A slit lamp examination was performed in 26 of 28 eyes and 86% of these were documented to be without abnormalities (see online supplemental table S2). Two eyes (13%; 0.12 mg group) were documented to have some abnormality on slit lamp examination: central thin corneal scar in one eye of one infant, and an internal hordeolum in another infant, both considered unrelated to the study treatment by the investigators.
Optical coherence tomography (OCT)
Figure 3 shows one OCT image per infant and eye as provided by the investigators arranged from close to normal foveal curvature (top left) to loss of foveal depression (bottom right). Visual acuity values were overall very good, but tended to be better in eyes with (near) normal foveal configuration.
Figure 3. Optical coherence tomography (OCT) images provided by the investigators for the 5-year follow-up. Images are arranged from close to normal foveal curvature (top left) to loss of foveal depression (bottom right). Visual acuity values were overall very good, but tended to be slightly better in eyes with (near) normal foveal configuration. Best-corrected visual acuity values given in logMAR are displayed for each eye next to the OCT scan embedded in the figure.
Orthoptic parameters
Equal fixation (n=14 infants) in both eyes was observed in 75% (six of eight infants) in the 0.12 mg group and in 67% (four of six infants) in the 0.20 mg group (see online supplemental table S4). A test for objection to occlusion was not done in the majority of the infants (six and five infants in the two arms). In all infants tested (n=3), no difference between the eyes was observed. Four infants (50%) in the 0.12 mg group and two infants (33%) in the 0.20 mg group had no strabismus. Three (38%; 0.12 mg) and two (33%; 0.20 mg) infants showed esotropia; one (13%; 0.12 mg) and two (33%; 0.20 mg) infants had other types of strabismus. Ocular motility was restricted in one infant (0.12 mg group) bilaterally, while all other infants assessed regarding motility (n=13) were able to fix and follow objects without problems with both eyes. Nystagmus (n=14 infants) was documented in four infants in the 0.12 mg group (50%) and in one infant in the 0.20 mg group (17%). For more detailed information on strabismus, see online supplemental table S5; on nystagmus, see online supplemental table S6.
Spherical equivalent, astigmatism, intraocular pressure and BCVA
In none of the parameters—spherical equivalent, astigmatism, intraocular pressure and BCVA—a statistically significant difference was observed between the two groups (figure 4). Median spherical equivalent was 0.13 D in the 0.12 mg group and 0.25 D in the 0.20 mg group (n=27 eyes; 14 patients) (figure 4A). Distribution of spherical equivalent by treatment modality and by need for retreatment is displayed in figure 5A. Overall, most eyes (n=16) were emmetropic (< −1 to +1 D) (9 patients). Four eyes (two patients) in the 0.20 mg group and two eyes (two patients) in the 0.12 mg group had mild to moderate myopia (< −5 to −1 D). In the 0.12 mg group, there were two eyes (one child) with very high myopia (> −8 D). This child had developed a stage 4 ROP in the right eye during the core part of the study, which was treated with laser coagulation and ranibizumab as rescue treatment. In the 0.20 mg group, there was one eye with high hyperopia (>4 D). The distribution of spherical equivalents at year 1 and year 5 is displayed in figure 5B, showing a trend towards more emmetropic eyes by year 5 compared with year 1. Mean astigmatism was 1.05 D in the 0.12 mg group and 0.89 D in the 0.20 mg group (figure 4B). Median intraocular pressure was 13 mm Hg in both groups (figure 4C). BCVA was 0.3 logMAR (0.5 decimal) or better in 19 of 26 eyes. Six eyes (four in the 0.12 mg group; two in the 0.20 mg group) had a moderate visual impairment according to WHO criteria.14 No eyes were observed with severe impairment or blindness at the 5-year follow-up assessment. Median BCVA was 0.20 logMAR (0.63 decimal) in the 0.12 mg group and 0.05 logMAR (≥0.8 decimal) (in the 0.20 mg group) (figure 4D). One infant, who did not attend the 5-year follow-up, however, had been diagnosed with bilateral retinal detachment at the 2-year follow-up.
Figure 4. Distribution of spherical equivalent, astigmatism, intraocular pressure (IOP) and visual acuity by treatment arm at year 5. Values of the two study arms were compared using the Mann-Whitney U test in case of spherical equivalent, IOP and visual acuity due to non-normal distribution of data. An unpaired t-test was used in case of astigmatism. Figure displays all eyes; for statistical comparisons between groups, the mean of the right and left eyes of each patient was used. In (A, C and D), line and whiskers represent median and IQR; in (B), line and whiskers represent mean with SD.
Figure 5. (A) Distribution of refractive error (spherical equivalent) by treatment modality (at year 5). (B) Comparison of refractive error (spherical equivalent) between the 1-year and 5-year follow-up. rbz, ranibizumab; wo, without.
Paediatric development
Although the numbers are very small, we still would like to report the results from the five infants who participated in the paediatric 5-year follow-up. See online supplemental table S7 for an overview of blood pressure and body measures. All five infants had received physical therapy during the first 2 years of life, four infants until 4 years of life and three infants even until the age of 5. Speech therapy had been attended by four of the five infants and occupational therapy by three. For four children, the hearing test was without pathologic findings. In one child, no hearing test was done. One infant (0.20 mg arm) had a history of seizures. Chronic diseases (chronic obstipation, overall developmental delay) were documented in two infants in the 0.12 mg group and a factor V Leiden mutation in one infant in the 0.20 mg group. No cerebral palsy was reported. A comparison of infants for whom we have paediatric results available with those for whom we do not have paediatric results available did not reveal any statistically significant difference regarding baseline demographic parameters such as birth weight, GA, body length, head circumference or APGAR scores at 1, 5 and 10 min.
Safety assessments
During the follow-up part of the CARE-ROP study, non-serious, non-ocular AEs were reported in two patients in the 0.12 mg group (moderate androgen insensitivity syndrome; moderate chronic bronchitis) and in one patient in the 0.20 mg group (moderate coeliac disease). Non-ocular SAEs were reported in one patient in each study arm (0.12 mg group: moderate bronchitis; 0.20 mg group: severe encephalitis and brain abscess). None of the ocular or non-ocular AEs or SAEs were suspected to be related to the study treatment and no accumulation of AEs or SAEs was observed in either treatment arm. No death was reported during the follow-up phase of the study.
Discussion
Based on the RAINBOW Study results, ranibizumab 0.20 mg received its approval for ROP treatment in the European Union (EU) and many other countries globally. Since its approval, the use of ranibizumab for ROP has increased significantly.15 16 Long-term data on safety and efficacy, however, are still rare.
The most important findings of our 5-year analysis were: (1) no late recurrence of ROP occurred after 40 weeks post baseline injection; (2) many eyes retained a certain degree of retinal structural abnormality such as persistent vessel tortuosity; (3) functional results were reassuring, with BCVA of 0.3 logMAR or better in 19 of 26 eyes (0.5 decimal or better); (4) most eyes were emmetropic, with only one infant having bilateral high myopia; and (5) the available paediatric results did not indicate negative effects of the study treatment. All findings, unfortunately, are limited by low patient numbers and must be seen as exploratory long-term data requiring validation in bigger study groups.
One of the biggest challenges with anti-VEGF treatment for ROP is the risk of late reactivations. It must be ensured that all treatment-warranting reactivations are identified in a timely manner through implementation of a vigorous follow-up protocol.17 18 The older the infant, the more difficult it is to identify reactivation of ROP. Similarly, it becomes more difficult to assess full retinal vascularisation, especially without fluorescein angiograms and/or examination under anaesthesia as was the case in this study. This might be the reason why in this study, the status of peripheral retinal vascularisation was not documented for all infants.
Late structural anomalies after treatment with anti-VEGF are another concern.13 19 Detailed retinal examination in our study revealed that a majority (61%) of treated ROP eyes retained some kind of retinal anomaly, such as optic disc pallor, excavations or atrophy of the optic nerve head, retinal pigment ephithelium (RPE) pigment changes, persisting dilatation and tortuosity or abnormal angles of retinal vessels. The difference between the two groups appears to be quite large (50% in the 0.12 mg group vs 75% in the 0.20 mg group). However, we assume that this might be a random finding based on the small group size. The statistical comparison (Fisher’s exact test) was not statistically significant (p=0.2530). Investigations using fluorescence angiography may show even more structural abnormalities.19
Visual acuity in our study tended to be better in eyes with (near) normal foveal configuration compared with eyes with loss of foveal depression as observed in macular OCT assessments. Loss of foveal depression is known to appear in ROP eyes also without anti-VEGF treatment.20,22 Severe unfavourable structural outcomes such as retinal tractions, retinal folds or macular dragging2 3 21 were not observed in our cohort.
It is well established that preterm infants in general are more prone to high myopia or strabismus than term-born infants.23 The rate of high myopia, however, is lower after anti-VEGF treatment compared with laser coagulation.824,27 In our cohort, there were two eyes from one patient with very high myopia (> −8 D) (2 of 27 eyes; 7%). In one of these eyes, a rescue treatment with laser and ranibizumab had been conducted during the core study due to stage 4 ROP. One eye was identified with high hyperopia of more than 4 D.
Significant astigmatism (≥ 1 D) was present in about 57% of all eyes in our cohort, while high astigmatism (≥ 2 D) was only present in two eyes (8%).28 This is not surprising, as astigmatism is a known feature of premature infants with and without ROP.29 30 Similarly, strabismus, nystagmus, fixation preferences or ocular motility are ophthalmological morbidities that are relatively frequently observed in preterm infants with and without ROP treatment.23
A major concern with anti-VEGF treatment for ROP has always been its potential effect on neurodevelopment. In contrast to bevacizumab or aflibercept, which can be measured in the systemic circulation for a relatively long time after intravitreal injection, ranibizumab is eliminated within a few hours from the systemic circulation, thus reducing potential effects on other organs.31,34 Neither in the CARE-ROP core study nor in the larger RAINBOW trial was an effect of ranibizumab injection on systemic VEGF levels observed.2 9 Also, the available long-term data for these two studies (2 years for CARE-ROP and 2 and 5 years for RAINBOW) did not indicate negative effects of intravitreal ranibizumab on neurodevelopmental development in ROP infants.8 10 27 Unfortunately, the COVID-19 pandemic prevented us from obtaining paediatric development data on some infants in our 5-year cohort. Our available paediatric results, however, did not indicate any major concerns. There was no accumulation of paediatric diagnoses or (serious) AEs in either treatment arm. While this is reassuring, low patient number remains a limiting factor and results must be validated in larger patient populations, either from prospective trials or real-life registries. The European registry on treated ROP (www.eu-rop.org) was established in 2021 in order to collect such real-life data and increase our understanding of ROP treatment patterns and outcomes.35
Supplementary material
Footnotes
Funding: Novartis Pharma GmbH, Germany, provided financial support and study medication. Novartis Pharma GmbH was not involved in the design and conduct of the study or collection, management, analysis and interpretation of the data; Novartis Pharma GmbH was able to review the manuscript prior to submission but was not involved in preparation or approval of the manuscript or the decision to submit the manuscript for publication.
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Not applicable.
Ethics approval: This study involves human participants and was approved by the ethic's commission at the Albert-Ludwigs university Freiburg (527/13). The study was conducted in line with ICH GCP and the Declaration of Helsinki. Parents or legal representatives gave informed consent to participate in the study before taking part.
Collaborators: The CARE-ROP Study Group members are as follows: Anima Buehler, Moritz Daniel, Susanne Felzmann, Nikolai Gross, Stefanie Horn, Wolf Lagreze, Fanni Molnar, Claudia Mueller, Sabine Reichl, Charlotte Reiff, Olga Richter, Andreas Stahl, Milena Stech, (University of Freiburg, Ophthalmology); Roland Hentschel, Dimitra Stavropoulou, Juliane Tautz, (University of Freiburg, Neonatology); Kerstin Bartsch, Jennifer Braunstein, Ralf Brinken, Christian K Brinkmann, Joanna Czauderna, Wiebke Dralle, Martin Gliem, Arno Goebel, Philipp Heymer, Martina Hofmann, Frank G Holz, Tim U Krohne, David Kupitz, Philipp Mueller, Michael Petrak, Eva J Schmitz, Steffen Schmitz-Valckenberg, Moritz Schroeder, Julia Steinberg, Julia Supe (University of Bonn, Ophthalmology); Evelyn Kant, Diana Kunze, Andreas Mueller, (University of Bonn, Neonatology); Adeline Adorf, Anne Alex, Florian Alten, Christoph R Clemens, Nicole Eter, Silvia Falkenau, Caroline Friedhoff, Desiree Sandra Loos, Natasa Mihailovic, Julia Termuehlen, Constantin Uhlig, (University of Muenster, Ophthalmology); Isabell Hoernig-Franz, Esther Rieger-Fackeldey, Maria Tekaat, Claudius Werner (University of Muenster, Neonatology); Mathias Altmann, Teresa Barth, Christiane Blecha, Sabine Brandl, Horst Helbig, Karsten Hufendiek, Herbert Jaegle, Julia Konrad, Eva Kopetzky, Fabian Lehmann, Isabel Oberacher-Velten, (University of Regensburg, Ophthalmology); Annette Keller-Wackerbauer, Jochen Kittel, Hugo Segerer, (Barmherzige Brueder Hospital Regensburg, Neonatology); Phillip Ackermann, Jemina Benga, Rainer Guthoff, Tanja Guthoff, Elena Kleinert, Ertan Mayatepek, Stefan Schrader, Magdalena Voelker, (University of Duesseldorf, Ophthalmology); Thomas Hoehn, Klaus Lohmeier, Hemmen Sabir, Ertan Mayatepek, (University of Duesseldorf, Neonatology); Francisco Brevis, Tina Moenig, Simone Schwarz, (University of Duisburg, Neonatology); Angela Ehmer, Synke Meltendorf, Claudia Schuart, (University of Magdeburg, Ophthalmology); Stefan Avenarius, Ralf Boettger, (University of Magdeburg, Neonatology); Christoph Apel, Anne Bergmann, Karsten Herrmann, Franziska Ockert-Schoen, Sabine Wegener (University of Magdeburg, Pharmacy); Oliver Ehrt, Martin Nentwich, Angelika Pressler, Guenther Rudolph, (Ludwigs-Maximilian University Munich, Ophthalmology); Orsolya Genzel-Boroviczeny, Susanne Schmidt, (Ludwigs-Maximilian University Munich, Neonatology); Hans-Georg Muench, Claude Thilmany, (Hauner’sches Kinderspital Munich, Neonatology); Sabine Aisenbrey, Anna Bruckmann, Spyridon Dimopoulos, Ulrike Hagemann, Werner Inhoffen, Michael Partsch, Merle Schrader, Daniela Suesskind, Michael Voelker, (University of Tuebingen, Ophthalmology); Anja Bialkowski, Ingo Mueller-Hansen, (University of Tuebingen, Neonatology); Andrea Gerberth, Heike Christine Hasselbach, Solveig Lindemann, Konstantine Purtskhvanidze, Yvonne Raffel, Johann Roider (University of Kiel, Ophthalmology); Heinrich Gerding, Claudia Jandeck, Lois Smith (Data Safety Monitoring Board (DSMB)).
Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Contributor Information
on behalf of the CARE-ROP Study Group:
Anima Bühler, Moritz Daniel, Susanne Felzmann, Nikolai Gross, Stefanie Horn, Wolf Lagrèze, Fanni Molnár, Claudia Müller, Sabine Reichl, Charlotte Reiff, Olga Richter, Andreas Stahl, Milena Grundel, Roland Hentschel, Dimitra Stavropoulou, Juliane Tautz, Kerstin Bartsch, Jennifer Braunstein, Ralf Brinken, Christian K Brinkmann, Joanna Czauderna, Wiebke Dralle, Martin Gliem, Arno Goebel, Philipp Heymer, Martina Hofmann, Frank G Holz, Tim U Krohne, David Kupitz, Philipp Müller, Michael Petrak, Eva J Schmitz, Steffen Schmitz-Valckenberg, Moritz Schröder, Julia Steinberg, Julia Supé, Evelyn Kant, Diana Kunze, Andreas Müller, Adeline Adorf, Anne Alex, Florian Alten, Christoph R Clemens, Nicole Eter, Silvia Falkenau, Caroline Friedhoff, Desiree Sandra Loos, Natasa Mihailovic, Julia Termühlen, Constantin Uhlig, Isabell Hörnig-Franz, Esther Rieger-Fackeldey, Maria Tekaat, Claudius Werner, Mathias Altmann, Teresa Barth, Christiane Blecha, Sabine Brandl, Horst Helbig, Karsten Hufendiek, Herbert Jägle, Julia Konrad, Eva Kopetzky, Fabian Lehmann, Isabel Oberacher-Kohlhäufl, Annette Keller-Wackerbauer, Jochen Kittel, Hugo Segerer, Phillip Ackermann, Jemina Benga, Rainer Guthoff, Tanja Guthoff, Elena Kleinert, Ertan Mayatepek, Stefan Schrader, Magdalena Völker, Thomas Höhn, Klaus Lohmeier, Hemmen Sabir, Ertan Mayatepek, Francisco Brevis, Tina Mönig, Simone Schwarz, Angela Ehmer, Synke Meltendorf, Claudia Schuart, Stefan Avenarius, Ralf Böttger, Christoph Apel, Anne Bergmann, Karsten Herrmann, Franziska Ockert-Schön, Sabine Wegener, Oliver Ehrt, Martin Nentwich, Angelika Pressler, Günther Rudolph, Orsolya Genzel-Boroviczeny, Susanne Schmidt, Hans-Georg Münch, Claude Thilmany, Sabine Aisenbrey, Anna Bruckmann, Spyridon Dimopoulos, Ulrike Hagemann, Werner Inhoffen, Michael Partsch, Merle Schrader, Daniela Süsskind, Michael Völker, Anja Bialkowski, Ingo Müller-Hansen, Andrea Gerberth, Heike Christine Hasselbach, Solveig Lindemann, Konstantine Purtskhvanidze, Yvonne Raffel, Johann Roider, Heinrich Gerding, Claudia Jandeck, and Lois Smith
Data availability statement
All data relevant to the study are included in the article or uploaded as online supplemental information.
References
- 1.Mintz-Hittner HA, Kennedy KA, Chuang AZ, et al. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med. 2011;364:603–15. doi: 10.1056/NEJMoa1007374. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Stahl A, Lepore D, Fielder A, et al. Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): an open-label randomised controlled trial. The Lancet. 2019;394:1551–9. doi: 10.1016/S0140-6736(19)31344-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Stahl A, Sukgen EA, Wu W-C, et al. Effect of Intravitreal Aflibercept vs Laser Photocoagulation on Treatment Success of Retinopathy of Prematurity: The FIREFLEYE Randomized Clinical Trial. JAMA. 2022;328:348–59. doi: 10.1001/jama.2022.10564. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.EMA . Europa.eu; 2020. Lucentis 10 mg/ml solution for injection SmPC. [Google Scholar]
- 5.EMA . Europa.eu; 2022. Eylea 40 mg/ml solution for injection in pre-filled syringe SmpC. [Google Scholar]
- 6.Kennedy KA, Mintz-Hittner HA, BEAT-ROP Cooperative Group Medical and developmental outcomes of bevacizumab versus laser for retinopathy of prematurity. J AAPOS. 2018;22:61–5. doi: 10.1016/j.jaapos.2017.10.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Stahl A, Nakanishi H, Lepore D, et al. Intravitreal Aflibercept vs Laser Therapy for Retinopathy of Prematurity: Two-Year Efficacy and Safety Outcomes in the Nonrandomized Controlled Trial FIREFLEYE next. JAMA Netw Open . 2024;7:e248383. doi: 10.1001/jamanetworkopen.2024.8383. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Marlow N, Reynolds JD, Lepore D, et al. Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): five-year outcomes of a randomised trial. EClinicalMedicine. 2024;71:102567. doi: 10.1016/j.eclinm.2024.102567. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Stahl A, Krohne TU, Eter N, et al. Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity: A Randomized Clinical Trial. JAMA Pediatr . 2018;172:278–86. doi: 10.1001/jamapediatrics.2017.4838. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Stahl A, Bründer M, Lagrèze WA, et al. Ranibizumab in retinopathy of prematurity – one‐year follow‐up of ophthalmic outcomes and two‐year follow‐up of neurodevelopmental outcomes from the CARE‐ROP study. Acta Ophthalmol (Copenh) 2022;100 doi: 10.1111/aos.14852. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Glaser K, Härtel C, Dammann O, et al. Erythrocyte transfusions are associated with retinopathy of prematurity in extremely low gestational age newborns. Acta Paediatr. 2023;112:2507–15. doi: 10.1111/apa.16965. [DOI] [PubMed] [Google Scholar]
- 12.Dammann M-T, Kraft H, Stichtenoth G, et al. Influenza Immunization in Very-Low-Birth-Weight Infants: Epidemiology and Long-Term Outcomes. Vaccines (Basel) 2025;13:42. doi: 10.3390/vaccines13010042. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Chiang MF, Quinn GE, Fielder AR, et al. International Classification of Retinopathy of Prematurity, Third Edition. Ophthalmology. 2021;128:e51–68. doi: 10.1016/j.ophtha.2021.05.031. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Bach M. Visual acuity “cheat sheet” for high and low vision. 2025
- 15.Pfeil JM, Barth T, Lagrèze WA, et al. Treated Cases of Retinopathy of Prematurity in Germany: 10-Year Data from the Retina.net Retinopathy of Prematurity Registry. Ophthalmol Retina. 2024;8:579–89. doi: 10.1016/j.oret.2023.12.002. [DOI] [PubMed] [Google Scholar]
- 16.Winter K, Pfeil JM, Engmann H, et al. Comparability of input parameters in the German Retina.net ROP registry and the EU‐ROP registry – An exemplary comparison between 2011 and 2021. Acta Ophthalmol (Copenh) 2024;102 doi: 10.1111/aos.15753. [DOI] [PubMed] [Google Scholar]
- 17.Maier RF, Hummler H, Kellner U, et al. Augenärztliche screening-untersuchung bei frühgeborenen awmf-leitlinien-register Nr. 024/010. 2020 doi: 10.1055/a-1248-0649. [DOI] [PubMed]
- 18.The royal college of ophthalmologists Treating retinopathy of prematurity in the UK. 2022
- 19.Lepore D, Ji MH, Quinn GE, et al. Functional and Morphologic Findings at Four Years After Intravitreal Bevacizumab or Laser for Type 1 ROP. Ophthalmic Surg Lasers Imaging Retina. 2020;51:180–6. doi: 10.3928/23258160-20200228-07. [DOI] [PubMed] [Google Scholar]
- 20.Cryotherapy for Retinopathy of Prematurity Cooperative Group Multicenter trial of cryotherapy for retinopathy of prematurity. Snellen visual acuity and structural outcome at 5 1/2 years after randomization. Arch Ophthalmol. 1996;114:417–24. doi: 10.1001/archopht.1996.01100130413008. [DOI] [PubMed] [Google Scholar]
- 21.Fielder A, Blencowe H, O’Connor A, et al. Impact of retinopathy of prematurity on ocular structures and visual functions. Arch Dis Child Fetal Neonatal Ed. 2015;100:F179–84. doi: 10.1136/archdischild-2014-306207. [DOI] [PubMed] [Google Scholar]
- 22.Hoppe C, Holt DG, Arnold BF, et al. Structural and refractive outcomes of intravitreal ranibizumab followed by laser photocoagulation for type 1 retinopathy of prematurity. J AAPOS. 2022;26:305. doi: 10.1016/j.jaapos.2022.08.524. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.O’Connor AR, Stephenson T, Johnson A, et al. Long-term ophthalmic outcome of low birth weight children with and without retinopathy of prematurity. Pediatrics. 2002;109:12–8. doi: 10.1542/peds.109.1.12. [DOI] [PubMed] [Google Scholar]
- 24.Geloneck MM, Chuang AZ, Clark WL, et al. Refractive outcomes following bevacizumab monotherapy compared with conventional laser treatment: a randomized clinical trial. JAMA Ophthalmol. 2014;132:1327–33. doi: 10.1001/jamaophthalmol.2014.2772. [DOI] [PubMed] [Google Scholar]
- 25.Hwang CK, Hubbard GB, Hutchinson AK, et al. Outcomes after Intravitreal Bevacizumab versus Laser Photocoagulation for Retinopathy of Prematurity: A 5-Year Retrospective Analysis. Ophthalmology. 2015;122:1008–15. doi: 10.1016/j.ophtha.2014.12.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Kong Q, Ming W-K, Mi X-S. Refractive outcomes after intravitreal injection of antivascular endothelial growth factor versus laser photocoagulation for retinopathy of prematurity: a meta-analysis. BMJ Open. 2021;11:e042384. doi: 10.1136/bmjopen-2020-042384. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Marlow N, Stahl A, Lepore D, et al. 2-year outcomes of ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW extension study): prospective follow-up of an open label, randomised controlled trial. Lancet Child Adolesc Health. 2021;5:698–707. doi: 10.1016/S2352-4642(21)00195-4. [DOI] [PubMed] [Google Scholar]
- 28.Holmström M, el Azazi M, Kugelberg U. Ophthalmological long-term follow up of preterm infants: a population based, prospective study of the refraction and its development. Br J Ophthalmol. 1998;82:1265–71. doi: 10.1136/bjo.82.11.1265. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Ouyang L-J, Yin Z-Q, Ke N, et al. Refractive status and optical components of premature babies with or without retinopathy of prematurity at 3-4 years old. Int J Clin Exp Med. 2015;8:11854–61. [PMC free article] [PubMed] [Google Scholar]
- 30.Tolia VN, Ahmad KA, Jacob J, et al. Two-Year Outcomes of Infants with Stage 2 or Higher Retinopathy of Prematurity: Results from a Large Multicenter Registry. Am J Perinatol. 2020;37:196–203. doi: 10.1055/s-0039-1694983. [DOI] [PubMed] [Google Scholar]
- 31.Krohne TU, Aisenbrey S, Holz FG. Aktuelle Therapieoptionen bei Frühgeborenenretinopathie. Ophthalmologe . 2012;109:1189–97. doi: 10.1007/s00347-012-2618-8. [DOI] [PubMed] [Google Scholar]
- 32.Sato T, Wada K, Arahori H, et al. Serum concentrations of bevacizumab (avastin) and vascular endothelial growth factor in infants with retinopathy of prematurity. Am J Ophthalmol. 2012;153:327–33. doi: 10.1016/j.ajo.2011.07.005. [DOI] [PubMed] [Google Scholar]
- 33.Wu W-C, Lien R, Liao P-J, et al. Serum levels of vascular endothelial growth factor and related factors after intravitreous bevacizumab injection for retinopathy of prematurity. JAMA Ophthalmol. 2015;133:391–7. doi: 10.1001/jamaophthalmol.2014.5373. [DOI] [PubMed] [Google Scholar]
- 34.Wu W-C, Shih C-P, Lien R, et al. SERUM VASCULAR ENDOTHELIAL GROWTH FACTOR AFTER BEVACIZUMAB OR RANIBIZUMAB TREATMENT FOR RETINOPATHY OF PREMATURITY. Retina (Philadelphia, Pa) 2017;37:694–701. doi: 10.1097/IAE.0000000000001209. [DOI] [PubMed] [Google Scholar]
- 35.Catt C, Pfeil JM, Barthelmes D, et al. Development of a joint set of database parameters for the EU-ROP and Fight Childhood Blindness! ROP Registries. Br J Ophthalmol. 2024;108:1030–7. doi: 10.1136/bjo-2023-323915. [DOI] [PubMed] [Google Scholar]
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Data Availability Statement
All data relevant to the study are included in the article or uploaded as online supplemental information.