Yuxin Zhang
Qian Chen1
Jianli Lv- 1Department of Neonatology, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, China
- 2Department of Pediatric Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
Background: Retinopathy of prematurity (ROP) remains a leading cause of childhood blindness worldwide. While anti-VEGF therapy has revolutionized ROP treatment, concerns regarding systemic absorption, potential neurodevelopmental impacts, and late reactivation have spurred the quest for alternative therapeutic approaches. This mini-review examines emerging therapeutic targets and novel biomarkers that may transform ROP management beyond the anti-VEGF era.
Methods: We conducted a comprehensive literature review of studies published between 2001 and 2025, focusing on novel therapeutic mechanisms, biomarker discovery, and translational research in ROP.
Results: Several promising therapeutic targets have emerged, including: (1) IGF-1 supplementation and IGF-1/IGFBP3 complex therapy; (2) Omega-3 polyunsaturated fatty acids, demonstrating anti-inflammatory and anti-angiogenic properties; (3) Antioxidant therapies targeting oxidative stress pathways; (4) HIF-stabilizing agents that promote physiological vascularization; (5) Cell-based therapies using mesenchymal stem cells and (6) Non-selective beta-adrenergic receptor blockers (propranolol), which target the sympathetic drive of pathological neovascularization. Novel biomarkers under investigation and advanced imaging biomarkers using OCT angiography. Combination approaches integrating multiple pathways show particular promise.
Conclusions: Emerging therapies targeting multiple pathogenic mechanisms, combined with novel biomarkers for risk stratification and treatment monitoring, show potential for more personalized and effective ROP management. Future research should focus on validating these biomarkers in diverse populations and optimizing combination therapy protocols to minimize treatment burden while maximizing visual outcomes and systemic safety.
1 Introduction
Retinopathy of prematurity (ROP) represents a significant global health challenge, affecting approximately 20,000 infants annually and remaining the leading cause of preventable childhood blindness in both developed and developing nations (1, 2). The pathophysiology of ROP involves a biphasic process: an initial phase of vessel growth cessation and vaso-obliteration triggered by relative hyperoxia, followed by a proliferative phase characterized by pathological neovascularization driven by hypoxia-induced factors, particularly vascular endothelial growth factor (VEGF) (3, 4).
The introduction of intravitreal anti-VEGF therapy has fundamentally transformed the treatment landscape for severe ROP. Bevacizumab, ranibizumab, and more recently aflibercept have demonstrated remarkable efficacy in inducing disease regression, often with a single injection (5, 6). The BEAT-ROP study established anti-VEGF therapy as a viable alternative to laser photocoagulation, particularly for zone I disease (7). However, accumulating evidence has raised important concerns about the systemic effects of anti-VEGF agents in premature infants.
Several critical limitations of anti-VEGF monotherapy have emerged. First, systemic absorption of intravitreal anti-VEGF agents leads to suppression of circulating VEGF levels for weeks to months, potentially affecting normal organ development during a critical period (8, 9). Recent studies have reported associations between anti-VEGF treatment and adverse neurodevelopmental outcomes, including lower cognitive scores and increased risk of severe neurodevelopmental impairment at 2 years corrected age (10, 11). Second, late reactivation of ROP following anti-VEGF therapy occurs in 8.3%–18% of cases, necessitating prolonged follow-up and potential retreatment (12, 13). Third, anti-VEGF therapy may delay physiological retinal vascularization, leading to persistent avascular peripheral retina (14).
These concerns have catalyzed intensive research into alternative therapeutic approaches that address ROP pathogenesis through non-VEGF dependent mechanisms. The complex pathophysiology of ROP involves multiple interconnected pathways beyond VEGF, including insulin-like growth factor-1 (IGF-1) deficiency, oxidative stress, inflammation, lipid metabolism dysfunction, and mitochondrial dysfunction (15, 16). This multifactorial nature suggests that targeting alternative or complementary pathways may offer therapeutic advantages while potentially avoiding the systemic risks associated with VEGF suppression.
Furthermore, the identification of reliable biomarkers for ROP risk stratification and treatment response monitoring has become a research priority. Current screening protocols rely primarily on clinical risk factors (gestational age, birth weight) and retinal examination findings, which have limited predictive value for individual patients (17). Novel biomarkers derived from serum proteomics, metabolomics, and molecular imaging techniques promise to enable more personalized approaches to ROP management (18, 19).
This review aims to comprehensively examine the emerging therapeutic landscape in ROP beyond anti-VEGF therapy. While many novel pathways are under investigation, significant research gaps remain, particularly in the large-scale clinical validation of these non-VEGF targets and the standardization of new biomarkers. We synthesize current evidence on novel therapeutic targets, evaluate promising biomarkers for disease prediction and monitoring, and discuss combination therapy approaches that may optimize outcomes while minimizing systemic risks. By highlighting these advances and their current evidentiary limitations, we aim to provide clinicians and researchers with a critical framework for understanding the future directions of ROP management in the era of precision medicine.
2 Methods
We conducted a comprehensive literature search using PubMed, MEDLINE, Cochrane Library, and ClinicalTrials.gov databases for articles published between 2001 and 2025. The final database search was performed on January 15, 2025. Search terms included combinations of “retinopathy of prematurity,” “ROP,” “anti-VEGF alternatives,” “novel therapy,” “biomarkers,” “IGF-1,” “omega-3,” “antioxidants,” “stem cells,” “combination therapy,” and “personalized medicine.” We prioritized peer-reviewed original research articles, systematic reviews, meta-analyses, and registered clinical trials investigating non-VEGF therapeutic approaches or novel biomarkers for ROP.
To select relevant studies from the search results, the following criteria were applied. Inclusion criteria encompassed: (1) studies investigating therapeutic mechanisms beyond VEGF inhibition; (2) biomarker discovery or validation studies; (3) clinical trials of novel therapeutic agents; and (4) preclinical studies with clear translational potential. We excluded case reports, conference abstracts without full-text availability, and studies focusing exclusively on anti-VEGF monotherapy. Two independent reviewers screened titles and abstracts, with discrepancies resolved through consensus discussion.
Data extraction focused on therapeutic mechanisms, clinical efficacy, safety profiles, biomarker performance characteristics, and stage of clinical development. For biomarker studies, we assessed sensitivity, specificity, and predictive values when available.
2.1 Evidence synthesis and limitations
Given the mini-review format, a formal systematic review or meta-analysis adhering to PRISMA guidelines was not performed. The primary objective was a narrative synthesis of emerging trends rather than an exhaustive quantitative analysis. Consequently, a formal quality assessment or risk of bias score (e.g., Cochrane risk-of-bias tool, QUADAS-2 for biomarkers) was not applied to the included studies. The evidence synthesis instead prioritizes describing the mechanism of action and current development status (e.g., preclinical, pilot study, Phase II RCT). This review acknowledges that many cited studies are preclinical or small-scale pilot trials, and these limitations on evidence strength are discussed within the relevant results sections.
3 Results
3.1 Literature search results
The literature search process and results are summarized in Figure 1. Initial database searches yielded 2150 potentially relevant citations. After removing duplicates (n = 570), 1,580 articles were screened based on titles and abstracts. Of these, 850 were excluded for not meeting inclusion criteria. The remaining 365 articles underwent full-text review, resulting in 255 articles being excluded for various reasons (focused exclusively on anti-VEGF monotherapy, not a novel therapeutic target or biomarker, preclinical study with no clear translational link, or being case reports with limited generalizability). Ultimately, 110 articles were included in this comprehensive review.
Figure 1. Flow diagram of literature search and selection process.
3.2 Emerging therapeutic targets
3.2.1 IGF-1 and the IGF-1/IGFBP3 complex
Insulin-like growth factor-1 (IGF-1) deficiency represents a fundamental pathogenic mechanism in ROP development. Premature birth interrupts the transplacental transfer of IGF-1, resulting in serum levels lower than in utero values (20). This deficiency impairs normal retinal vascular development during the first phase of ROP and exacerbates pathological neovascularization in the second phase (21).
The NIRTURE trial investigated rhIGF-1/rhIGFBP3 complex supplementation in extremely preterm infants. Phase II results demonstrated a 53% reduction in severe bronchopulmonary dysplasia and showed promising trends toward reduced severe ROP incidence (22). Importantly, the treatment appeared safe with no increase in adverse events. Mechanistically, IGF-1 supplementation promotes physiological vascularization through Akt pathway activation while suppressing pathological angiogenesis by modulating VEGF sensitivity (23).
Current research focuses on optimizing IGF-1 delivery and dosing strategies. Continuous intravenous infusion maintains more stable levels compared to subcutaneous administration, potentially improving efficacy (24). Additionally, combining IGF-1 supplementation with nutritional interventions that naturally boost IGF-1 levels, such as enhanced protein intake and breast milk fortification, represents a promising integrated approach (25).
3.2.2 Omega-3 polyunsaturated fatty acids
Long-chain polyunsaturated fatty acids (LC-PUFAs), particularly docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), exert multiple protective effects against ROP development. These include anti-inflammatory actions through specialized pro-resolving mediators (SPMs), direct anti-angiogenic effects, and promotion of neuronal and vascular maturation (26). Adequate levels of both Omega-3 and Omega-6 LCPUFA are crucial in protecting against retinal neurovascular dysfunction in a Phase I ROP model; however, supplementation should focus on optimizing the ratio while ensuring adequate Omega-6 levels are maintained. Activation of the APN pathway may further enhance the Omega-3 and Omega-6 LCPUFA's protection against ROP (27).
Recent mechanistic studies have elucidated how omega-3 fatty acids generate specialized pro-resolving mediators including resolvins, protectins, and maresins. These bioactive lipid mediators actively resolve inflammation and promote tissue repair without immunosuppression (28). In oxygen-induced retinopathy models, resolvin D1 and neuroprotectin D1 significantly reduced pathological neovascularization while promoting revascularization of avascular areas (29).
Parenteral lipid emulsions containing fish oil (SMOFlipid) vs. traditional soybean oil-based formulations have shown promise in reducing ROP incidence. A systematic review found that fish oil-containing emulsions significantly reduced severe ROP compared with conventional lipids (30). Current research investigates optimal omega-3:omega-6 ratios and the role of specialized pro-resolving mediator supplementation.
3.2.3 Antioxidant therapies
Oxidative stress plays a central role in ROP pathogenesis, as preterm infants have immature antioxidant systems and experience relative hyperoxia after birth. Multiple antioxidant strategies are under investigation:
N-acetylcysteine (NAC): Preclinical studies in animal models suggest that acetylcysteine can significantly reduce the formation of retinal neovascularization by continuously interfering with the nitration of tyrosine, and can also mediate its antioxidant anti-angiogenic effect by reducing the expression of insulin-like growth factor 1 at the RNA and protein levels (31).
Vitamin E supplementation: While early trials showed mixed results, recent studies using water-soluble formulations with improved bioavailability have renewed interest. The optimal dosing window appears critical, with supplementation most effective when initiated within 48 h of birth (32, 33).
Lutein and zeaxanthin: These macular carotenoids accumulate in the developing retina during the third trimester. Studies have shown reduced oxidative stress markers and trends toward lower ROP incidence, though larger trials are needed (34).
Melatonin: Beyond its antioxidant properties, melatonin modulates VEGF expression and promotes anti-inflammatory pathways. A pilot study of oral melatonin (0.5 mg/kg) showed reduced inflammatory cytokines and a trend toward lower ROP severity (35).
3.2.4 Hypoxia-inducible factor (HIF) stabilization
HIF-1α stabilization represents a paradigm shift from anti-angiogenic to pro-physiological vascularization strategies. During the first phase of ROP, relative hyperoxia destabilizes HIF-1α, halting normal vessel growth. Prolyl hydroxylase domain (PHD) inhibitors stabilize HIF-1α, promoting controlled vascular development (36).
Roxadustat, an oral PHD inhibitor approved for anemia treatment, has shown promise in preclinical ROP models. Low-dose treatment during the hyperoxic phase preserved normal vascular development and reduced subsequent neovascularization (37). However, these findings are from preclinical ROP models, and the translatability of this critical therapeutic window to human infants, as well as the long-term safety of systemic HIF stabilization, remains to be established.
Novel delivery approaches using nanoparticle formulations enable targeted retinal delivery while minimizing systemic effects. Proof-of-concept studies demonstrate that intravitreal PHD inhibitor-loaded nanoparticles promote revascularization of avascular retina without inducing pathological neovascularization (38).
3.2.5 Cell-based therapies
Mesenchymal stem cells (MSCs) offer unique advantages through paracrine effects, immunomodulation, and tissue regeneration capabilities. Multiple preclinical studies demonstrate that intravitreal MSC injection during early ROP reduces vaso-obliteration and subsequent neovascularization (39). While mechanistically compelling, significant hurdles in cell sourcing, standardization, dosing, and long-term safety (e.g., immunogenicity, tumorigenicity) must be addressed before this approach can be considered for human clinical trials.
Human umbilical cord-derived MSCs (hUC-MSCs) show particular promise due to their accessibility, low immunogenicity, and robust secretome. These cells secrete multiple protective factors including IGF-1, VEGF-A165 (physiological isoform), angiopoietin-1, and anti-inflammatory cytokines (40).
Exosomes derived from MSCs represent a cell-free alternative that maintains therapeutic efficacy while potentially reducing safety concerns. MSC-derived exosomes contain microRNAs, proteins, and lipids that modulate angiogenesis, reduce inflammation, and promote tissue repair (41). Preclinical studies show that intravitreal exosome injection achieves similar efficacy to whole-cell therapy with improved safety profile.
3.2.6 Beta-adrenergic receptor blockade
The adrenergic system has emerged as a crucial regulator of retinal angiogenesis. Preclinical studies using the oxygen-induced retinopathy (OIR) model have demonstrated that retinal hypoxia triggers a surge in norepinephrine release, which stimulates β2-and β3 adrenoreceptors (ARs). This stimulation subsequently upregulates pro-angiogenic factors, including VEGF and HIF-1α, driving pathological neovascularization (42, 43). Crucially, blockade of these receptors selectively inhibits pathological neovascularization without interfering with physiological retinal vascular development, offering a distinct safety advantage over direct VEGF inhibition (42).
Clinical translation of these findings has focused on propranolol, a non-selective beta-blocker. Several randomized controlled trials (RCTs) and prospective studies investigating oral propranolol (typically 1–2 mg/kg/day) have reported a reduction in ROP progression to advanced stages and a decreased need for rescue therapies (laser or anti-VEGF) (44). For instance, a multicenter RCT by Filippi et al. showed reduced progression to stage 3 ROP (45). Recent meta-analyses confirm that prophylactic oral propranolol significantly reduces the risk of severe ROP and the need for invasive treatment (46).
However, systemic safety remains a primary concern. Oral propranolol has been associated with adverse events such as bradycardia, hypotension, and apnea, particularly in unstable preterm infants with comorbidities (45). To mitigate these systemic risks, recent research has pivoted toward topical administration. While 0.1% drops were found to be well-tolerated but insufficiently effective, dose-optimization studies continue to refine this approach (47).A phase II trial of 0.2% propranolol eye micro-drops demonstrated a reduction in ROP progression with significantly lower plasma drug levels compared to oral administration, suggesting a safer therapeutic window (48) Table 1.
Table 1. Summary of emerging therapeutic targets for ROP (beyond anti-VEGF).
3.3 Novel biomarkers for ROP
3.3.1 Serum biomarkers
3.3.1.1 IGF-1 and IGFBP-3
Serum IGF-1 levels have emerged as one of the most validated biomarkers for ROP risk stratification. The WINROP (Weight, IGF-1, Neonatal ROP) algorithm combines longitudinal IGF-1 measurements with weight gain patterns to predict ROP development. Validation studies across multiple populations demonstrate sensitivity of 100% for detecting severe ROP, with the ability to reduce screening burden by 84% (49).
Recent refinements include the incorporation of IGFBP-3 levels, which stabilize IGF-1 and provide additional predictive value. The IGF-1/IGFBP-3 molar ratio at 34 weeks postmenstrual age shows stronger correlation with ROP severity than either biomarker alone (50). Machine learning algorithms integrating these biomarkers with clinical parameters achieve area under the curve (AUC) values exceeding 0.95 for predicting treatment-requiring ROP (51).
3.3.1.2 Inflammatory markers
Systemic inflammation plays a crucial role in ROP pathogenesis. A comprehensive proteomic analysis identified a panel of inflammatory biomarkers with predictive value:
• C-reactive protein (CRP): Elevated CRP levels during the three weeks of life correlate with ROP severity. Serial measurements showing persistent elevation predict progression to severe ROP (52).
Inflammatory cytokine spectrum: The dynamic changes in cytokine profiles offer predictive value for ROP.Multiple cytokines exhibit temporal trends: In preterm infants, elevated IL-6 levels and decreased IL-17/IL-18 levels at birth, or increased CRP and reduced NT-4 levels on day 3 postnatal; or elevated IL-18 with decreased TGF-β, BDNF, and RANTES levels during the first 1–3 weeks after birth. These patterns collectively indicate potential ROP development (52).
Soluble E-selectin (sE-selectin): This endothelial activation marker demonstrates superior performance to traditional inflammatory markers. Levels >43 ng/mL predict ROP with 83% sensitivity and 60% specificity (53).
3.3.2 Metabolomic profiling
Untargeted metabolomics has revealed novel biomarkers reflecting altered metabolism in ROP:
Amino acid signatures: Infants with severe retinopathy of the developing retina (ROP) present a specific metabolic pattern characterized by elevated levels of arginine, glutamate, citrulline, and tryptophan, and decreased levels of lysine and aspartate. Studies have found that the degree of elevated arginine and glutamine levels can predict the severity of ROP (54).
Lipid mediators: Lipidomic analysis identifies reduced levels of anti-inflammatory lipid mediators (resolvins, protectins) and elevated pro-inflammatory eicosanoids in infants developing ROP (55).
One-carbon metabolism: Altered folate and methionine metabolism, reflected by elevated homocysteine and reduced S-adenosylmethionine levels, correlates with ROP severity. These changes may reflect epigenetic dysregulation and oxidative stress (56).
3.3.3 MicroRNA signatures
Circulating microRNAs offer advantages as biomarkers due to their stability and tissue-specific expression patterns. Recent studies have identified several promising candidates:
miR-200b: This microRNA regulates angiogenesis through VEGF modulation. Serum levels show inverse correlation with ROP severity. Low miR-200b predicts progression to severe ROP (57).
miR-221: Over-expression of miR-221 inhibited the growth of endothelial cells in vitro by targeting the c-kit receptor. A study in zebra fish showed that miR-221 deficiency resulted in drastic developmental vascular defects which underscore an important function of miR-221 in angiogenesis. A rapid decline in miR-221 levels indicates increased ROP risk (58).
miR-126: This endothelial-enriched microRNA regulates vascular development. Combined measurement of miR-126 and its complementary strand miR-126* improves predictive accuracy, with the miR-126/miR-126* ratio showing strongest correlation with ROP outcomes (59).
MicroRNA panels: Machine learning approaches combining multiple microRNAs achieve superior performance. A seven-microRNA signature (miR-106a, miR-146, miR-181, miR-199a, miR-214, miR-424, miR-451) predicts treatment-requiring ROP (60).
3.3.4 Advanced imaging biomarkers
3.3.4.1 OCT and OCT-angiography
Optical coherence tomography (OCT) provides high-resolution imaging of retinal microstructure, revealing subclinical changes preceding visible ROP:
Foveal development: Delayed foveal maturation, evidenced by persistent inner retinal layers and shallow foveal depression, predicts ROP progression. Quantitative metrics including median central foveal thickness, median inner retinal layer thickness, and the median foveal-to-parafoveal thickness ratio at 31–36 weeks show strong correlation with final ROP severity (61).
Choroidal changes: Subfoveal choroidal thickness measurements reveal early vascular compromise. Progressive choroidal thinning indicates high risk for severe ROP development (62).
OCT-angiography: This non-invasive technique quantifies retinal vascular density and complexity. Reduced parafoveal vessel density and increased vascular tortuosity precede clinical ROP, offering opportunity for earlier intervention (63).
3.3.4.2 Artificial intelligence-enhanced screening
Deep learning algorithms analyzing retinal images have revolutionized ROP screening:
Automated severity grading: Convolutional neural networks achieve expert-level performance in detecting plus disease and stage classification. The i-ROP DL system demonstrates 93% sensitivity and 94% specificity for identifying treatment-requiring ROP (64).
Predictive modeling: AI systems integrating imaging features with clinical data predict ROP progression more accurately than either modality alone. Temporal analysis of vascular changes enables prediction of treatment need before conventional criteria (65).
Quantitative vascular analysis: Automated measurement of vascular tortuosity, diameter, and branching patterns provides objective metrics. The tortuosity index at posterior pole combined with peripheral vascular density was 95% accurate in predicting ROP (66).
3.3.5 Challenges in biomarker validation and implementation
While the biomarkers cataloged above show potential, their transition from research to routine clinical use faces significant hurdles. Many findings originate from single-center or small-scale pilot studies and lack large-scale, multi-center validation in diverse patient populations. Standardization of assays is a major challenge; for example, metabolomic and microRNA profiles can be highly sensitive to sample collection, processing, and analysis techniques, leading to poor reproducibility across different laboratories.
Furthermore, clinical feasibility and cost-effectiveness must be considered. Advanced imaging like OCT-A and deep learning systems require substantial capital investment and specialized training, limiting their accessibility in lower-resource settings. Serum-based algorithms like WINROP are more scalable, but the cost and rapid turnaround time required for serial IGF-1 measurements must be proven practical for routine NICU workflows. Future research must focus not only on discovery but also on rigorous validation, standardization, and health-economic analyses to prove clinical utility.
3.4 Combination therapy approaches
3.4.1 Rationale for combination treatment
The multifactorial pathogenesis of ROP suggests that targeting multiple pathways simultaneously may enhance efficacy while reducing individual drug doses and associated toxicity. Combination approaches aim to address both phases of ROP: preventing vaso-obliteration during phase I while controlling neovascularization in phase II (67).
3.4.2 Anti-VEGF plus Omega-3 supplementation
Combining anti-VEGF therapy with omega-3 fatty acids leverages complementary anti-inflammatory and anti-angiogenic mechanisms:
The PROP-ROP trial is investigating whether post-treatment omega-3 supplementation reduces ROP reactivation after anti-VEGF therapy. Preliminary results suggest 60% reduction in reactivation rates with combined treatment (68).
Mechanistically, omega-3-derived specialized pro-resolving mediators enhance resolution of inflammation following anti-VEGF treatment, promoting healing and reducing scarring. Resolvin E1 administration following anti-VEGF injection accelerates retinal vascular maturation in animal models (69).
3.4.3 Antioxidant cocktails
Recognizing that oxidative stress involves multiple pathways, combination antioxidant approaches show promise:
Coenzyme Q10 plus vitamin E: Current research found that the use of Q10/Vitamin E combination coenzyme provided faster retinal maturation with fewer treatments in infants with ROP. This appears compatible with the biological effects of the CQ10 and Vitamin E complex which is shown to support antioxidant defense systems and suppress toxic effects of the free oxygen radicals in premature infants and thereby reduce the incidence of ROP (70).
Lutein and zeaxanthin: Studies have reported that lutein and zeaxanthin supplementation during pregnancy can effectively reduce the incidence of retinopathy in preterm infants, mainly by reducing pathological hypoxia stimulation of vascular endothelial cells to control vascular loss in hypoxic stress environment, so as to protect and improve oxygen-induced retinopathy (71).
3.4.4 Sequential therapy protocols
Time-sensitive interventions targeting different disease phases represent an emerging strategy, For instance, two reviews suggested that sequential treatment regimens may help reduce the occurrence of severe ROP compared with standard treatment regimens (72, 73):
Phase I intervention (birth to 32 weeks PMA): using exogenous EPO, preventing hyperglycemia and supplementing with IGF-1, omega-3 fatty acids to promote physiological vascularization and reduce inflammation (72).
Transition phase (32–34 weeks PMA): Avoiding exogenous EPO in this phase may prevent further increase in retinal EPO. Omega-3 supplements suppress TNF-α and vitamin E suppresses oxidative stress (72).
Phase II intervention (>34 weeks PMA): In addition to targeting oxygen saturation, correcting anemia with PRBC transfusion and exposing infants to light may improve retinal hypoxia and decrease VEGF. Low-dose anti-VEGF if proliferative disease develops, with continuation of supportive therapies (72).
3.5 Practical implementation considerations for clinicians
The translation of novel therapeutic approaches into clinical practice requires careful consideration of several practical aspects:
Risk-benefit assessment: When considering alternative therapies, clinicians must weigh potential benefits against the established the immediate sight-saving benefits of anti-VEGF therapy may outweigh theoretical lo efficacy of conventional treatments. For infants with zone I or aggressive posterior ROP, ng-term concerns (74). Conversely, for less severe disease, approaches with better safety profiles may be preferable even if efficacy is comparable rather than superior.
Integration with existing protocols: Novel treatments should be integrated into established ROP screening and treatment protocols. For example, biomarker testing could be scheduled alongside routine blood sampling to minimize procedural burden, while IGF-1 supplementation might be incorporated into nutritional management protocols (75).
Resource stratification: Implementation strategies should be tailored to resource availability. High-resource settings might implement comprehensive approaches combining advanced biomarker testing with personalized treatment protocols, while resource-limited settings could prioritize cost-effective interventions like nutritional optimization and affordable antioxidant supplementation (76).
Multidisciplinary collaboration: Effective ROP management requires coordination between neonatologists, ophthalmologists, nutritionists, and pharmacy services. Establishing clear communication pathways and standardized protocols is essential, particularly for implementing combination therapy approaches (77).
3.6 Clinical translation and implementation challenges
3.6.1 Regulatory considerations
The translation of novel ROP therapies faces unique regulatory challenges:
Pediatric drug development: The small market size and ethical considerations of clinical trials in premature infants create barriers. The FDA's Pediatric Drug Development Program provides incentives, but ROP-specific guidance remains limited (78).
Combination therapy approval: Regulatory pathways for combination therapies are complex, particularly when combining approved drugs (anti-VEGF) with investigational agents. Adaptive trial designs may facilitate development (79).
Biomarker validation: Regulatory acceptance of biomarkers for patient selection or treatment monitoring requires extensive validation across diverse populations. The FDA's Biomarker Qualification Program provides a framework but requires substantial evidence (80).
3.6.2 Economic considerations
Cost-effectiveness analyses reveal important insights:
Biomarker screening: Implementation of WINROP or similar algorithms could reduce screening costs while maintaining safety. However, initial setup costs and training requirements present barriers (81).
Combination therapies: While potentially more expensive initially, reduced retreatment rates and improved outcomes may offer long-term cost savings. Economic modeling suggests break-even within 3 years when considering reduced visual disability (82).
3.6.3 Implementation barriers
Several challenges impede clinical adoption:
Infrastructure requirements: Advanced biomarker testing and specialized drug preparation may not be available in all neonatal units. Centralized testing models and point-of-care devices are under development (83).
Training needs: Implementation of new therapies requires extensive staff education. Telemedicine models for expert consultation show promise in addressing expertise gaps (84).
Global health disparities: Novel therapies may widen the gap between high and low-resource settings. Simplified protocols and affordable alternatives are crucial for global impact (85).
4 Future directions
4.1 Emerging technologies
Several cutting-edge approaches show promise for future ROP management:
Gene therapy: AAV-mediated delivery of protective factors (IGF-1, PEDF) offers potential for sustained therapeutic effect with single administration. Preclinical studies demonstrate long-term efficacy and safety (86).
Nanotechnology: Targeted nanoparticle delivery systems enable precise drug delivery to the retina while minimizing systemic exposure. Biodegradable nanoparticles loaded with multiple therapeutic agents achieve sustained release over weeks (87).
Tissue engineering: Bioengineered retinal vessels using induced pluripotent stem cells may eventually enable replacement of damaged vasculature. Proof-of-concept studies show integration of engineered vessels with host retina (88).
4.2 Personalized medicine approaches
The integration of multi-omic data promises truly personalized ROP management:
Risk stratification algorithms: Machine learning models integrating genomic, proteomic, metabolomic, and clinical data achieve unprecedented predictive accuracy. Cloud-based platforms enable real-time risk assessment.
Therapeutic selection: Pharmacogenomic markers may guide treatment selection. Variants in VEGF pathway genes influence anti-VEGF response, while IGF1 polymorphisms affect supplementation efficacy (89).
Outcome prediction: Long-term visual and neurodevelopmental outcomes can be predicted using early biomarkers, enabling targeted early intervention services.
5 Conclusions
The landscape of ROP management is rapidly evolving beyond exclusive reliance on anti-VEGF therapy. Novel therapeutic targets addressing fundamental pathogenic mechanisms show potential for more effective and safer treatments. IGF-1 supplementation, omega-3 fatty acids, antioxidants, HIF stabilizers, and cell-based therapies each show promise. However, significant evidence gaps must be addressed. The safety and efficacy of most non-VEGF therapies have not yet been confirmed in large-scale, Phase III randomized controlled trials. Combination approaches, while mechanistically appealing, require rigorous investigation to define optimal dosing and rule out antagonistic effects.
The development of robust biomarkers is crucial for enabling risk stratification and personalized treatment selection. From simple serum markers to sophisticated imaging analyses and multi-omic signatures, these tools have the potential to transform ROP screening and management. Crucially, most novel biomarkers require multi-center validation to confirm their predictive value, reproducibility, and clinical utility before they can be widely adopted.
Successful clinical translation requires addressing regulatory, economic, and implementation challenges. The ultimate goal—preventing blindness while optimizing overall outcomes for premature infants—may become more achievable through these innovative approaches. The next decade could witness a paradigm shift in ROP management, moving from reactive treatment of established disease to proactive, personalized interventions that promote healthy retinal development from birth. This transformation promises to significantly reduce the global burden of ROP-related visual impairment while serving as a model for precision medicine in neonatal care.
Author contributions
YZ: Writing – original draft, Writing – review & editing. QC: Writing – review & editing, Methodology, Supervision. JL: Writing – review & editing, Software, Conceptualization, Data curation.
Funding
The author(s) declared that financial support was not received for this work and/or its publication.
Acknowledgments
The authors thank the Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University and the Shandong Provincial Hospital Affiliated to Shandong First Medical University for their support. Thanks to the neonatology and ophthalmology colleagues and the literature room staff for their assistance.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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The author(s) declared that generative AI was not used in the creation of this manuscript.
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References
1. Blencowe H, Lawn JE, Vazquez T, Fielder A, Gilbert C. Preterm-associated visual impairment and estimates of retinopathy of prematurity at regional and global levels for 2010. Pediatr Res. (2013) 74 (Suppl 1):35–49. doi: 10.1038/pr.2013.205
2. Sabri K, Ells AL, Lee EY, Dutta S, Vinekar A. Retinopathy of prematurity: a global perspective and recent developments. Pediatrics. (2022) 150(3):e2021053924. doi: 10.1542/peds.2021-053924
3. Jasani B, Nanavati R, Kabra N. Mechanisms and management of retinopathy of prematurity. N Engl J Med. (2013) 368(12):1161–2. doi: 10.1056/NEJMc1301021
4. Sapieha P, Joyal JS, Rivera JC, Kermorvant-Duchemin E, Sennlaub F, Hardy P, et al. Retinopathy of prematurity: understanding ischemic retinal vasculopathies at an extreme of life. J Clin Invest. (2010) 120(9):3022–32. doi: 10.1172/JCI42142
5. Sankar MJ, Sankar J, Chandra P. Anti-vascular endothelial growth factor (VEGF) drugs for treatment of retinopathy of prematurity. Cochrane Database Syst Rev. (2018) 1(1):CD009734. doi: 10.1002/14651858.CD009734.pub3
6. Stahl A, Lepore D, Fielder A, Fleck B, Reynolds JD, Chiang MF, 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. Lancet. (2019) 394(10208):1551–9. doi: 10.1016/S0140-6736(19)31344-3
7. Mintz-Hittner HA, Kennedy KA, Chuang AZ, BEAT-ROP Cooperative Group. Efficacy of intravitreal bevacizumab for stage 3+retinopathy of prematurity. N Engl J Med. (2011) 364(7):603–15. doi: 10.1056/NEJMoa1007374
8. Sjöbom U, Hellqvist T, Humayun J, Nilsson AK, Gyllensten H, Hellström A, et al. Circulating VEGF-A levels in relation to retinopathy of prematurity and treatment effects: a systematic review and meta-analysis. Ophthalmol Sci. (2024) 4(6):100548. doi: 10.1016/j.xops.2024.100548
9. Tsai AS, Chou HD, Ling XC, Al-Khaled T, Valikodath N, Cole E, et al. Assessment and management of retinopathy of prematurity in the era of anti-vascular endothelial growth factor (VEGF). Prog Retin Eye Res. (2022) 88:101018. doi: 10.1016/j.preteyeres.2021.101018
10. Tsai CY, Yeh PT, Tsao PN, Chung YE, Chang YS, Lai TT. Neurodevelopmental outcomes after bevacizumab treatment for retinopathy of prematurity: a meta-analysis. Ophthalmology. (2021) 128(6):877–88. doi: 10.1016/j.ophtha.2020.11.012
11. Rodriguez SH, Blair MP, Shapiro MJ, Berrocal AM, Murray TG, Martinez-Castellanos MA, et al. Neurodevelopmental outcomes of preterm infants with retinopathy of prematurity by treatment. Pediatrics. (2020) 145(4):e20200056A. doi: 10.1542/peds.2020-0056A
12. Mintz-Hittner HA, Geloneck MM, Chuang AZ. Clinical management of recurrent retinopathy of prematurity after intravitreal bevacizumab monotherapy. Ophthalmology. (2016) 123(9):1845–55. doi: 10.1016/j.ophtha.2016.04.028
13. Wallace DK, Dean TW, Hartnett ME, Kong L, Smith LE, Hubbard GB, et al. A dosing study of bevacizumab for retinopathy of prematurity: late recurrences and additional treatments. Ophthalmology. (2018) 125(12):1961–6. doi: 10.1016/j.ophtha.2018.05.001
14. Sternfeld A, Rahmani S, Rossen JL, Zhang DL, Li YD, Quan VL, et al. Long-term retinal vasculature abnormalities following intravitreal bevacizumab for retinopathy of prematurity. Graefes Arch Clin Exp Ophthalmol. (2022) 260(6):1915–21. doi: 10.1007/s00417-021-05499-0
15. Hellström A, Ley D, Hansen-Pupp I, Hallberg B, Löfqvist C, van Marter L, et al. Insulin-like growth factor 1 has multisystem effects on foetal and preterm infant development. Acta Paediatr. (2016) 105(6):576–86. doi: 10.1111/apa.13350
16. Fu Z, Gong Y, Liegl R, Wang Z, Liu CH, Meng SS, et al. FGF21 Administration suppresses retinal and choroidal neovascularization in mice. Cell Rep. (2017) 18(7):1606–13. doi: 10.1016/j.celrep.2017.01.014
17. Pivodic A, Hård AL, Löfqvist C, Smith LEH, Wu C, Bründer MC, et al. Individual risk prediction for sight-threatening retinopathy of prematurity using birth characteristics. JAMA Ophthalmol. (2020) 138(1):21–9. doi: 10.1001/jamaophthalmol.2019.4502
18. Oruz O, Dervişoğulları MS, Öktem ME, İncekaş C. Predictive role of systemic immune-inflammation index and neutrophil/lymphocyte ratio values in infants with retinopathy of prematurity. Graefes Arch Clin Exp Ophthalmol. (2024) 262(10):3125–34. doi: 10.1007/s00417-024-06493-y
19. Almutairi M, Chechalk K, Deane E, Fox R, Janes A, Maguire-Henry T, et al. Biomarkers in retinopathy of prematurity: a systematic review and meta-analysis. Front Pediatr. (2024) 12:1371776. doi: 10.3389/fped.2024.1371776
20. Nagano N, Katayama D, Hara K, Akimoto T, Imaizumi T, Seimiya A, et al. Association of umbilical cord insulin-like growth factor 1 levels with severe retinopathy in extremely preterm infants. Pediatr Neonatol. (2023) 64(2):126–32. doi: 10.1016/j.pedneo.2022.05.015
21. Fu Y, Lei C, Qibo R, Huang X, Chen Y, Wang M, et al. Insulin-like growth factor-1 and retinopathy of prematurity: a systemic review and meta-analysis. Surv Ophthalmol. (2023) 68(6):1153–65. doi: 10.1016/j.survophthal.2023.06.010
22. Ley D, Hallberg B, Hansen-Pupp I, Dani C, Ramenghi LA, Marlow N, et al. rhIGF-1/rhIGFBP-3 in preterm infants: a phase 2 randomized controlled trial. J Pediatr. (2019) 206:56–65.e8. doi: 10.1016/j.jpeds.2018.10.033
23. Furuncuoglu U, Vural A, Kural A, Onur IU, Yigit FU. Serum vascular endothelial growth factor, insulin-like growth factor-1 and aflibercept levels in retinopathy of prematurity. Jpn J Ophthalmol. (2022) 66(2):151–8. doi: 10.1007/s10384-021-00895-9
24. Salamat-Miller N, Turner MA, Bandekar A, Dixit N, Jochim E, Mangum B, et al. Assessment of compatibility of rhIGF-1/rhIGFBP-3 with neonatal intravenous medications. World J Pediatr. (2023) 19(1):58–67. doi: 10.1007/s12519-022-00610-9
25. Cormack BE, Harding JE, Miller SP, Bloomfield FH. The influence of early nutrition on brain growth and neurodevelopment in extremely preterm babies: a narrative review. Nutrients. (2019) 11(9):2029. doi: 10.3390/nu11092029
26. Zeppieri M, Gagliano C, D'Esposito F, Musa M, Gattazzo I, Zanella MS, et al. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA): a targeted antioxidant strategy to counter oxidative stress in retinopathy. Antioxidants (Basel). 2(024) 14(1):6. doi: 10.3390/antiox14010006
27. Fu Z, Yan W, Chen CT, Nilsson AK, Bull E, Allen W, et al. Omega-3/Omega-6 long-chain fatty acid imbalance in phase I retinopathy of prematurity. Nutrients. (2022) 14(7):1333. doi: 10.3390/nu14071333
28. Serhan CN, Levy BD. Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators. J Clin Invest. (2018) 128(7):2657–69. doi: 10.1172/JCI97943
29. Connor KM, SanGiovanni JP, Lofqvist C, Aderman CM, Chen J, Higuchi A, et al. Increased dietary intake of omega-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis. Nat Med. (2007) 13(7):868–73. doi: 10.1038/nm1591
30. Vayalthrikkovil S, Bashir RA, Rabi Y, Amin H, Spence JM, Robertson HL, et al. Parenteral fish-oil lipid emulsions in the prevention of severe retinopathy of prematurity: a systematic review and meta-analysis. Am J Perinatol. (2017) 34(7):705–15. doi: 10.1055/s-0036-1597131
31. El-Hadidy AR, El-Mohandes EM, Asker SA, Ghonaim FM. A histological and immunohistochemical study of the effects of N-acetyl cysteine on retinopathy of prematurity by modifying insulin-like growth factor-1. Biotech Histochem. (2016) 91(6):401–11. doi: 10.1080/10520295.2016.1180428
32. Bell EF, Hansen NI, Brion LP, Ehrenkranz RA, Kennedy KA, Walsh MC, et al. Serum tocopherol levels in very preterm infants after a single dose of vitamin E at birth. *Pediatrics*. (2013) 132:e1626–33. doi: 10.1542/peds.2013-1684
33. Ogihara T, Mino M. Vitamin E and preterm infants. Free Radic Biol Med. (2022) 180:13–32. doi: 10.1016/j.freeradbiomed.2021.11.037
34. Manzoni P, Guardione R, Bonetti P, Priolo C, Maestri A, Mansoldo C, et al. Lutein and zeaxanthin supplementation in preterm very low-birth-weight neonates in neonatal intensive care units: a multicenter randomized controlled trial. Am J Perinatol. (2013) 30(1):25–32. doi: 10.1055/s-0032-1321494
35. Xu Y, Lu X, Hu Y, Yang B, Tsui CK, Yu S, et al. Melatonin attenuated retinal neovascularization and neuroglial dysfunction by inhibition of HIF-1α-VEGF pathway in oxygen-induced retinopathy mice. J Pineal Res. (2018) 64(4):e12473. doi: 10.1111/jpi.12473
36. Hoppe G, Yoon S, Gopalan B, Savage AR, Brown R, Case K, et al. Comparative systems pharmacology of HIF stabilization in the prevention of retinopathy of prematurity. Proc Natl Acad Sci U S A. (2016) 113(18):E2516–25. doi: 10.1073/pnas.1523005113
37. Hoppe G, Bolok Y, McCollum L, Zhang J, Sears JE. Rank order of small molecule induced hypoxiamimesis to prevent retinopathy of prematurity. Front Cell Dev Biol. (2020) 8:488. doi: 10.3389/fcell.2020.00488
38. Singh R, Batoki JC, Ali M, Bonilha VL, Anand-Apte B. Inhibition of choroidal neovascularization by systemic delivery of gold nanoparticles. Nanomedicine. (2020) 28:102205. doi: 10.1016/j.nano.2020.102205
39. Park SS, Moisseiev E, Bauer G, Anderson JD, Grant MB, Zam A, et al. Advances in bone marrow stem cell therapy for retinal dysfunction. Prog Retin Eye Res. (2017) 56:148–65. doi: 10.1016/j.preteyeres.2016.10.002
40. Ding SLS, Kumar S, Mok PL. Cellular reparative mechanisms of mesenchymal stem cells for retinal diseases. Int J Mol Sci. (2017) 18(8):1406. doi: 10.3390/ijms18081406
41. Mead B, Tomarev S. Extracellular vesicle therapy for retinal diseases. Prog Retin Eye Res. (2020) 79:100849. doi: 10.1016/j.preteyeres.2020.100849
42. Ristori C, Filippi L, Dal Monte M, Martini D, Cammalleri M, Fortunato P, et al. Role of the adrenergic system in a mouse model of oxygen-induced retinopathy: antiangiogenic effects of beta-adrenoreceptor blockade. Invest Ophthalmol Vis Sci. (2011) 52(1):155–70. doi: 10.1167/iovs.10-5536
43. Martini D, Monte MD, Ristori C, Cupisti E, Mei S, Fiorini P, et al. Antiangiogenic effects of β2 -adrenergic receptor blockade in a mouse model of oxygen-induced retinopathy. J Neurochem. (2011) 119(6):1317–29. doi: 10.1111/j.1471-4159.2011.07530.x
44. Kong HB, Zheng GY, He BM, Zhang Y, Zhou Q. Clinical efficacy and safety of propranolol in the prevention and treatment of retinopathy of prematurity: a meta-analysis of randomized controlled trials. Front Pediatr. (2021) 9:631673. doi: 10.3389/fped.2021.631673
45. Filippi L, Cavallaro G, Bagnoli P, Dal Monte M, Fiorini P, Donzelli G, et al. Oral propranolol for retinopathy of prematurity: risks, safety concerns, and perspectives. J Pediatr. (2013) 163(6):1570–7.e6. doi: 10.1016/j.jpeds.2013.07.049
46. Stritzke A, Kabra N, Kaur S, Robertson HL, Lodha A. Oral propranolol in prevention of severe retinopathy of prematurity: a systematic review and meta-analysis. J Perinatol. (2019) 39(12):1584–94. doi: 10.1038/s41372-019-0503-x
47. Filippi L, Cavallaro G, Bagnoli P, Dal Monte M, Fiorini P, Berti E, et al. Propranolol 0.1% eye micro-drops in newborns with retinopathy of prematurity: a pilot clinical trial. Pediatr Res. (2017) 81(2):307–14. doi: 10.1038/pr.2016.230
48. Filippi L, Cavallaro G, Berti E, Padrini L, Araimo G, Regiroli G, et al. Propranolol 0.2% eye micro-drops for retinopathy of prematurity: a prospective phase IIB study. Front Pediatr. (2019) 7:180. doi: 10.3389/fped.2019.00180
49. Löfqvist C, Andersson E, Sigurdsson J, Engström E, Hård AL, Niklasson A, et al. Longitudinal postnatal weight and insulin-like growth factor I measurements in the prediction of retinopathy of prematurity. Arch Ophthalmol. (2006) 124(12):1711–8. doi: 10.1001/archopht.124.12.1711
50. Ley D, Hansen-Pupp I, Niklasson A, Domellöf M, Friberg LE, Borg J, et al. Longitudinal infusion of a complex of insulin-like growth factor-I and IGF-binding protein-3 in five preterm infants: pharmacokinetics and short-term safety. Pediatr Res. (2013) 73(1):68–74. doi: 10.1038/pr.2012.146
51. Pivodic A, Holmström G, Smith LEH, Hård AL, Löfqvist C, Al-Hawasi A, et al. Prognostic value of parenteral nutrition duration on risk of retinopathy of prematurity: development and validation of the revised DIGIROP clinical decision support tool. JAMA Ophthalmol. (2023) 141(8):716–24. doi: 10.1001/jamaophthalmol.2023.2336
52. Sood BG, Madan A, Saha S, Schendel D, Thorsen P, Skogstrand K, et al. Perinatal systemic inflammatory response syndrome and retinopathy of prematurity. Pediatr Res. (2010) 67(4):394–400. doi: 10.1203/PDR.0b013e3181d01a36
53. Pieh C, Krüger M, Lagrèze WA, Gimpel C, Buschbeck C, Zirrgiebel U, et al. Plasma sE-selectin in premature infants: a possible surrogate marker of retinopathy of prematurity. Invest Ophthalmol Vis Sci. (2010) 51(7):3709–13. doi: 10.1167/iovs.09-4723
54. Ozcan Y, Huseyin G, Sonmez K. Evaluation of plasma amino acid levels in preterm infants and their potential correlation with retinopathy of prematurity. J Ophthalmol. (2020) 2020:8026547. doi: 10.1155/2020/8026547
55. Hardy P, Beauchamp M, Sennlaub F Jr, Gobeil F Jr, Mwaikambo B, Lachapelle P, et al. Inflammatory lipid mediators in ischemic retinopathy. Pharmacol Rep. (2005) 57(Supp l):169–90.16415498
56. Sonne SR, Bhalla VK, Barman SA, White RE, Zhu S, Newman TM, et al. Hyperhomocysteinemia is detrimental to pregnancy in mice and is associated with preterm birth. Biochim Biophys Acta. (2013) 1832(8):1149–58. doi: 10.1016/j.bbadis.2013.04.006
57. Metin T, Dinç E, Görür A, Erdoğan S, Ertekin S, Sarı AA, et al. Evaluation of the plasma microRNA levels in stage 3 premature retinopathy with plus disease: preliminary study. Eye (Lond). (2018) 32(2):415–20. doi: 10.1038/eye.2017.193
58. Agrawal S, Chaqour B. MicroRNA signature and function in retinal neovascularization. World J Biol Chem. (2014) 5(1):1–11. doi: 10.4331/wjbc.v5.i1.1
59. Fish JE, Santoro MM, Morton SU, Yu S, Yeh RF, Wythe JD, et al. miR-126 regulates angiogenic signaling and vascular integrity. Dev Cell. (2008) 15(2):272–84. doi: 10.1016/j.devcel.2008.07.008
60. Liu CH, Wang Z, Sun Y, Chen J. Animal models of ocular angiogenesis: from development to pathologies. FASEB J. (2017) 31(11):4665–81. doi: 10.1096/fj.201700336R
61. Maldonado RS, O'Connell R, Ascher SB, Sarin N, Freedman SF, Wallace DK, et al. Spectral-domain optical coherence tomographic assessment of severity of cystoid macular edema in retinopathy of prematurity. Arch Ophthalmol. (2012) 130(5):569–78. doi: 10.1001/archopthalmol.2011.1846
62. Erol MK, Coban DT, Ozdemir O, Dogan B, Tunay ZO, Bulut M. Choroidal thickness in infants with retinopathy of prematurity. Retina. (2016) 36(6):1191–8. doi: 10.1097/IAE.0000000000000866
63. Campbell JP, Zhang M, Hwang TS, Bailey ST, Wilson DJ, Jia Y, et al. Detailed vascular anatomy of the human retina by projection-resolved optical coherence tomography angiography. Sci Rep. (2017) 7:42201. doi: 10.1038/srep42201
64. Brown JM, Campbell JP, Beers A, Chang K, Ostmo S, Chan RVP, et al. Automated diagnosis of plus disease in retinopathy of prematurity using deep convolutional neural networks. JAMA Ophthalmol. (2018) 136(7):803–10. doi: 10.1001/jamaophthalmol.2018.1934
65. Li J, Huang K, Ju R, Chen Y, Li M, Yang S, et al. Evaluation of artificial intelligence-based quantitative analysis to identify clinically significant severe retinopathy of prematurity. Retina. (2022) 42(1):195–203. doi: 10.1097/IAE.0000000000003284
66. Campbell JP, Ataer-Cansizoglu E, Bolon-Canedo V, Bozkurt A, Erdogmus D, Kalpathy-Cramer J, et al. Expert diagnosis of plus disease in retinopathy of prematurity from computer-based image analysis. JAMA Ophthalmol. (2016) 134(6):651–7. doi: 10.1001/jamaophthalmol.2016.0611
67. Hartnett ME. Advances in understanding and management of retinopathy of prematurity. Surv Ophthalmol. (2017) 62(3):257–76. doi: 10.1016/j.survophthal.2016.12.004
68. Beharry KD, Valencia GB, Lazzaro DR, Aranda JV. Pharmacologic interventions for the prevention and treatment of retinopathy of prematurity. Semin Perinatol. (2016) 40(3):189–202. doi: 10.1053/j.semperi.2015.12.006
69. Sapieha P, Stahl A, Chen J, Seaward MR, Willett KL, Krah NM, et al. 5-Lipoxygenase metabolite 4-HDHA is a mediator of the antiangiogenic effect of ω-3 polyunsaturated fatty acids. Sci Transl Med. (2011) 3(69):69ra12. doi: 10.1126/scitranslmed.3001571
70. Akdogan M, Polat O. Clinical efficacy of topical CoQ10 and vitamin-E eye-drop in retinopathy of prematurity. Med Hypothesis Discov Innov Ophthalmol. (2019) 8(4):291–7.31788491
71. Arunkumar R, Li B, Addo EK, Hartnett ME, Bernstein PS. Prenatal carotenoid supplementation with lutein or zeaxanthin ameliorates oxygen-induced retinopathy (OIR) in Bco2-/- macular pigment mice. Invest Ophthalmol Vis Sci. (2023) 64(4):9. doi: 10.1167/iovs.64.4.9
72. Raghuveer TS, Bloom BT. A paradigm shift in the prevention of retinopathy of prematurity. Neonatology. (2011) 100(2):116–29. doi: 10.1159/000322848
73. Cayabyab R, Ramanathan R. Retinopathy of prematurity: therapeutic strategies based on pathophysiology. Neonatology. (2016) 109(4):369–76. doi: 10.1159/000444901
74. Nowroozzadeh MH, Sadeghi E, Shahriari-Garaee H, Badie MR, Banihashemi J, Garg SJ. An update on anti-vascular endothelial growth factor treatment for retinopathy of prematurity. J Curr Ophthalmol. (2023) 35(2):125–34. doi: 10.4103/joco.joco_38_23
75. Hellström A, Kermorvant-Duchemin E, Johnson M, Sáenz de Pipaón M, Smith LE, Hård AL. Nutritional interventions to prevent retinopathy of prematurity. Pediatr Res. (2024) 96(4):905–11. doi: 10.1038/s41390-024-03208-1
76. Kaur K, Mikes BA. Retinopathy of prematurity. In: StatPearls. Treasure Island, FL: StatPearls Publishing (2025).
77. Visser L, Singh R, Young M, Lewis H, McKerrow N. Guideline for the prevention, screening and treatment of retinopathy of prematurity (ROP). S Afr Med J. (2012) 103(2):116–25. doi: 10.7196/samj.6305
78. Davis JM, Connor EM, Wood AJ. The need for rigorous evidence on medication use in preterm infants: is it time for a neonatal rule? JAMA. (2012) 308(14):1435–6. doi: 10.1001/jama.2012.12883
79. Laughon MM, Benjamin DK Jr, Capparelli EV, Kearns GL, Berezny K, Paul IM, et al. Innovative clinical trial design for pediatric therapeutics. Expert Rev Clin Pharmacol. 2011 4(5):643–52. doi: 10.1586/ecp.11.43
80. FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and Other Tools) Resource. Silver Spring, MD: Food and Drug Administration (US) (2016).
81. Binenbaum G. Algorithms for the prediction of retinopathy of prematurity based on postnatal weight gain. Clin Perinatol. (2013) 40(2):261–70. doi: 10.1016/j.clp.2013.02.004
82. Dunbar JA, Hsu V, Christensen M, Black B, Williams P, Beauchamp G. Cost-utility analysis of screening and laser treatment of retinopathy of prematurity. J AAPOS. (2009) 13(2):186–90. doi: 10.1016/j.jaapos.2008.10.014
83. Kovács G, Somogyvári Z, Maka E, Nagyjánosi L. Bedside ROP screening and telemedicine interpretation integrated to a neonatal transport system: economic aspects and return on investment analysis. Early Hum Dev. (2017) 106-107:1–5. doi: 10.1016/j.earlhumdev.2017.01.007
84. Quinn GE, Ying GS, Daniel E, Hildebrand PL, Ells A, Baumritter A, et al. Validity of a telemedicine system for the evaluation of acute-phase retinopathy of prematurity. JAMA Ophthalmol. (2014) 132(10):1178–84. doi: 10.1001/jamaophthalmol.2014.1604
85. Gilbert C, Fielder A, Gordillo L, Quinn G, Semiglia R, Visintin P, et al. Characteristics of infants with severe retinopathy of prematurity in countries with low, moderate, and high levels of development: implications for screening programs. Pediatrics. (2005) 115(5):e518–25. doi: 10.1542/peds.2004-1180
86. Bainbridge JW, Mehat MS, Sundaram V, Robbie SJ, Barker SE, Ripamonti C, et al. Long-term effect of gene therapy on leber’s congenital amaurosis. N Engl J Med. (2015) 372(20):1887–97. doi: 10.1056/NEJMoa1414221
87. Wu KY, Wang XC, Anderson M, Tran SD. Innovative use of nanomaterials in treating retinopathy of prematurity. Pharmaceuticals (Basel). (2024) 17(10):1377. doi: 10.3390/ph17101377
88. Park TS, Bhutto I, Zimmerlin L, Huo JS, Nagaria P, Miller D, et al. Vascular progenitors from cord blood-derived induced pluripotent stem cells possess augmented capacity for regenerating ischemic retinal vasculature. Circulation. (2014) 129(3):359–72. doi: 10.1161/CIRCULATIONAHA.113.003000
Keywords: anti-VEGF alternatives, biomarkers, combination therapy, IGF-1, oxidative stress, personalized medicine, retinopathy of prematurity
Citation: Zhang Y, Chen Q and Lv J (2026) Beyond anti-VEGF: expanding the therapeutic horizon and biomarker landscape in retinopathy of prematurity. Front. Pediatr. 13:1713783. doi: 10.3389/fped.2025.1713783
Received: 26 September 2025; Revised: 11 December 2025;
Accepted: 12 December 2025;
Published: 30 January 2026.
Edited by:
Paola Bagnoli, University of Pisa, ItalyReviewed by:
Luca Filippi, University of Pisa, ItalyCeline Chaaya, Massachusetts Eye and Ear Infirmary, Boston, United States
Copyright: © 2026 Zhang, Chen and Lv. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Jianli Lv, ZHJqbGx2QGdtYWlsLmNvbQ==