Circulating VEGF-A Levels in Relation to Retinopathy of Prematurity and Treatment Effects: A Systematic Review and Meta-Analysis

Topic Retinopathy of prematurity (ROP) is a severe retinal vascular disorder affecting preterm infants, potentially leading to retinal detachment and blindness. This review aims to elucidate the relationship between systemic VEGF levels and ROP. Clinical Relevance This systematic review aims to consolidate evidence from available studies to guide future research and inform clinical practice. In particular, the role of circulating VEGF-A levels in predicting ROP onset and progression, and evaluating the impact of anti-VEGF therapy on these levels, is crucial in ensuring efficacy and safety in patient care. Methods Scopus and PubMed were searched to identify studies investigating circulating VEGF-gene products in ROP patients using immunologic assays. Two authors independently screened the literature and extracted data, employing a random-effects meta-analysis to compare VEGF levels as the ratio of means between ROP patients and controls before and after treatment, heterogeneity was reported by I2-statistics. Risks of bias and publication bias were assessed using Quality Assessment of Diagnostic Accuracy Studies-2 and funnel plots/Egger’s tests, respectively. Results Out of 941 papers, 54 were included, with 26 providing posttreatment data and 31 providing biomarker data. Findings show a significant decrease in VEGF-A levels in the first week after ROP treatment (ratio of means [95% confidence interval] 0.34 [0.25–0.45], I2 = 97%, 17 publications). Anti-VEGF therapy showed a significantly more pronounced decrease (0.31 [0.25–0.38], I2 = 40%, 7 publications) than laser treatment in the first week after treatment (0.77 [0.61–0.97], I2 = 42%, 2 publications, subgroup difference, P < 0.01), among studies with a low risk of bias. Serum samples demonstrated a more marked decrease in VEGF-A than plasma (subgroup difference P < 0.01). However, the use of blood VEGF-A concentration as a biomarker for ROP prediction has shown inconsistent trends. The risk of bias mainly stems from unclear patient selection and lack of sample timing or analytical method details. Conclusion While anti-VEGF treatment significantly reduced blood VEGF-A levels in the first week post-ROP treatment, blood VEGF-A levels did not consistently predict ROP development. Heterogeneity in the results underscores the need for optimized analytical methods and emphasizes the importance of considering individual variation in VEGF-A concentrations independent of ROP diagnosis. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.


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Ratio of means meta-analysis performed with meta.cont in RStudio for reported vascular endothelial growth factor (VEGF) concentrations after treatment of retinopathy of prematurity (ROP) with Laser, ratio of VEGF concentrations calculated against before treatment including a subgroup analysis comparing the sample system (serum vs. plasma).
Abbreviations: SD: standard deviation, CI: confidence interval Figure S20 The change of VEGF levels per sample system the first month after treatment with Laser Ratio of means meta-analysis performed with meta.cont in RStudio for reported vascular endothelial growth factor (VEGF) concentrations after treatment of retinopathy of prematurity (ROP) with Laser, ratio of VEGF concentrations calculated against before treatment including a subgroup analysis comparing the sample system (serum vs. plasma).
Abbreviations: SD: standard deviation, CI: confidence interval Figure S21 The change of VEGF levels per sample system the first week after treatment with Bevacizumab Ratio of means meta-analysis performed with meta.cont in RStudio for reported vascular endothelial growth factor (VEGF) concentrations after treatment of retinopathy of prematurity (ROP) with Bevazicumab, ratio of VEGF concentrations calculated against before treatment including a subgroup analysis comparing the sample system (serum vs. plasma).
Abbreviations: SD: standard deviation, CI: confidence interval Figure S22 The change of VEGF levels per sample system the first month after treatment with Bevacizumab Ratio of means meta-analysis performed with meta.cont in RStudio for reported vascular endothelial growth factor (VEGF) concentrations after treatment of retinopathy of prematurity (ROP) with Bevazicumab, ratio of VEGF concentrations calculated against before treatment including a subgroup analysis comparing the sample system (serum vs. plasma).
Abbreviations: SD: standard deviation, CI: confidence interval Figure S23 The change of VEGF levels per sample system the first week after treatment with Ranibizumab Ratio of means meta-analysis performed with meta.cont in RStudio for reported vascular endothelial growth factor (VEGF) concentrations after treatment of retinopathy of prematurity (ROP) with Ranibizumab, ratio of VEGF concentrations calculated against before treatment including a subgroup analysis comparing the sample system (serum vs. plasma).
Abbreviations: SD: standard deviation, CI: confidence interval Figure S24 The change of VEGF levels per sample system the first month after treatment with Ranibizumab Ratio of means meta-analysis performed with meta.cont in RStudio for reported vascular endothelial growth factor (VEGF) concentrations after treatment of retinopathy of prematurity (ROP) with Ranibizumab, ratio of VEGF concentrations calculated against before treatment including a subgroup analysis comparing the sample system (serum vs. plasma).
Figure S5 VEGF levels the first week after ROP treatment: laser, vs. anti-VEGF a) Ratio of means meta-analysis performed with meta.cont in RStudio for reported vascular endothelial growth factor (VEGF) concentrations the first week after treatment for retinopathy of prematurity (ROP), ratio of VEGF concentrations calculated against before treatment including a subgroup analysis comparing anti-VEGF with laser.b) Publications with a high risk of bias and the study by Cakir et.al.(2019) identified as an outlier excluded.

Figure
Figure S25 Funnel plots for publications investigating VEGF levels one week after treatment of ROP Ratio of means calculated against baseline levels before treatment and plotted against a) against standard error b) 1/√(effective study size) c) against standard error excluding publications with a high risk of bias and outliers d) 1/√(effective study size)

Table S1 .
Identified but excluded publications.