Systemic Effects of Intravitreal Anti-VEGF Therapy: A Review of Safety across Organ Systems

Abstract

Intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapies have transformed the management of retinal diseases such as diabetic macular edema and neovascular age-related macular degeneration. However, concerns about their systemic absorption and potential adverse effects on overall health remain. In this review, we systematically aggregate existing literature on the systemic impact of anti-VEGF therapy, with a detailed analysis of the pharmacodynamics and pharmacokinetics of individual drugs. By examining their metabolism, clearance, and systemic exposure, we aim to clarify the extent of their effects beyond the eye. We further explore their influence on renal and cardiovascular health, with evidence suggesting a generally safe profile in the short term but potential risks in high-risk patients, particularly those with preexisting kidney or heart conditions. Additionally, this review addresses the critical concerns surrounding anti-VEGF use in special populations, including pregnant and lactating women and neonates with retinopathy of prematurity (ROP). We discuss the potential risks, the safest options available, and precautionary measures that should be taken when administering these therapies in these groups. While anti-VEGFs remain an essential tool in ophthalmology, careful patient selection, monitoring, and individualized treatment approaches are necessary to mitigate potential systemic risks. Further research is needed to refine our understanding of long-term safety.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40123-025-01157-4.

Plain Language Summary

Anti-vascular endothelial growth factor (anti-VEGF) injections are widely used to treat eye diseases such as diabetic macular edema and age-related macular degeneration by blocking abnormal blood vessel growth in the retina. Although these drugs are injected into the eye, small amounts can enter the bloodstream, raising concerns about their effects on other organs, especially the kidneys, heart, and brain. This review explores whether anti-VEGF therapy affects kidney function, increases the risk of heart disease, or impacts the nervous system. Most studies suggest that these drugs are generally safe for the kidneys, but some research indicates a possible risk of kidney damage in patients with preexisting conditions. Similarly, while there is no strong evidence that anti-VEGFs cause heart problems, certain patients—such as those with a history of heart disease—may be at higher risk of complications such as stroke or heart attacks. There are also concerns about potential effects on brain health, with some studies linking anti-VEGFs to an increased risk of stroke and cognitive decline. Special precautions are needed for pregnant and breastfeeding women, as well as premature infants receiving these treatments for retinopathy of prematurity. Overall, anti-VEGF therapy remains a crucial treatment for vision-threatening diseases, but doctors should monitor patients carefully, especially those with underlying health conditions.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40123-025-01157-4.

Key Summary Points

While short-term use of anti-vascular endothelial growth factor (anti-VEGF) agents appears safe for most patients, those with preexisting kidney disease may be at higher risk of kidney dysfunction, particularly with prolonged treatment.

There is no definitive evidence linking anti-VEGF therapy to major heart problems, but patients with prior cardiovascular disease may face a slightly increased risk of stroke or heart attacks, necessitating close monitoring.

Pregnant women, breastfeeding mothers, and neonates with retinopathy of prematurity require careful evaluation before receiving anti-VEGF therapy, as its systemic effects may impact fetal and infant development.

By synthesizing available literature, our review not only discusses potential systemic risks but also offers practical recommendations on patient selection, monitoring protocols, and risk mitigation strategies. This adds a real-world clinical perspective, helping ophthalmologists and other specialists make informed treatment decisions.

Introduction

Intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections have transformed the treatment of retinal diseases such as diabetic macular edema and neovascular age-related macular degeneration by targeting VEGF, a key mediator of pathological angiogenesis and vascular permeability. However, many elderly patients and those with diabetes receiving these therapies have systemic comorbidities, including cardiovascular and renal diseases, raising concerns about potential systemic effects. While some studies suggest minimal risk, others indicate possible adverse outcomes, highlighting the need for further research. Despite low intravitreal doses, systemic absorption and fellow eye effects suggest a plausible risk, warranting closer investigation.

In this review article, we provide a comprehensive assessment of the pharmacokinetics and pharmacodynamics of these drugs to better understand their safety profile. Additionally, we review existing literature to summarize known systemic effects and potential risks. We also discuss their use in special populations, including pregnant women, breastfeeding mothers, and neonates.

Methods

This comprehensive review describes the pharmacokinetics, pharmacodynamics, and reported systemic side effects of intravitreal anti-VEGF administration with special emphasis on renal, cardiovascular, and neuronal health. A systematic literature search was conducted using the MEDLINE database accessed through the PubMed search engine. The search strategy included the terms “pharmacodynamics”, “pharmacokinetics”, “renal effects”, “cardiovascular effects”, “central nervous system effects” of individual anti-VEGF agents available on the market at present, “anti-VEGF” and “pregnancy” or “breastfeeding” or “lactation” or “fetal development” or “Retinopathy of prematurity”. The review focused on articles published in English up until January 2025. A total of approximately 105 articles were identified initially; however, 22 articles were removed owing to de-duplication, commentaries, animal studies not relevant to systemic safety concerns, and non-English articles (Supplementary Material).

Abstracts of all relevant articles were initially screened by two authors (M.B. and S.K.P.), and the full texts of the articles were carefully examined for further synthesis. Non‑English articles and conference papers were excluded from the analysis. The review process followed the guidelines recommended by the Enhancing Transparency in Reporting the Synthesis of Qualitative Research (ENTREQ) checklist for qualitative studies, ensuring a systematic and rigorous approach to data synthesis. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Pharmacokinetics and Pharmacodynamics of Individual Anti-VEGFs

Pharmacokinetics is defined as the study of the time course of drug absorption, distribution, metabolism, and excretion. In other words, it describes what the body does to the drug administered [26]. Pharmacodynamics explores the relationship between the concentration of a drug at its site of action and the resulting effects. It explains how the drug influences the body, providing insights into its mechanism of action, therapeutic efficiency, and potential toxicity. The pharmacodynamic and pharmacokinetic parameters of anti-VEGF agents are summarized in Table 1.

Table 1.

Pharmacokinetic and pharmacodynamic parameters of intravitreal anti–vascular endothelial growth factor agents

Distribution	Primarily confined to the vitreous cavity, with minimal distribution to other ocular structures (lens, retina, ciliary body, and iris) due to high molecular weight, steric hindrance, and hydrophilic properties [24, 25].
Vitreal clearance	Cleared from the vitreous mainly via passive diffusion into surrounding ocular tissues and aqueous humor outflow. Intravitreal biologics are predominantly eliminated through the anterior route. Minimal intraocular metabolism or degradation occurs [26].
Metabolism	Proteolytic degradation of the macromolecular structure into smaller peptides and amino acids [26].
Excretion	Metabolites are excreted primarily through the renal system. Larger molecules (e.g., bevacizumab) are mainly excreted via the hepatobiliary route.

The pharmacokinetic model for intravitreal anti-VEGFS is illustrated in the flowchart in Fig. 1 [27]. The structural, pharmacodynamic, and pharmacokinetic parameters of the routinely used antiangiogenic drugs are presented in Table 2 [28–31].

Fig. 1.

Systemic pharmacokinetics of anti-VEGF agents following intravitreal injection. The diagram illustrates the differential transport and clearance mechanisms of full-length monoclonal antibodies (Fc-derived drugs) versus antibody fragments lacking the Fc region (Fab-only drugs). Fc-derived drugs undergo Fc receptor (FcRn)-mediated transport across the blood–retina barrier into systemic circulation, where their large molecular size prevents renal excretion. They are recycled via endothelial FcRn receptors, prolonging their half-life in blood. In contrast, Fab-only drugs enter systemic circulation through Fc-independent mechanisms, are subject to proteolytic degradation, and are cleared via renal excretion, resulting in a shorter systemic half-life. VEGF vascular endothelial growth factor, Fc fragment crystallizable, Fab fragment antigen-binding, FcRn neonatal Fc receptor

Table 2.

Structural, pharmacodynamic, and pharmacokinetic properties of commonly used antiangiogenic drugs

Agent	Structure	Target (s)	Mol. weight (kDa)	Fc portion	Affinity (Kd, pM)	Potency (IC50, pM)	t1/2 (vitreous, days)	t1/2 (plasma, days)	Dose
Bevacizumab	Humanized monoclonal full-length antibody	VEGF-A	149	Yes	58–4456	500–1476	6/7–10	21	1.25 mg (0.05 mL)
Ranibizumab	Humanized recombinant Fab	VEGF-A	48	No	9.2–179	88–1140	7.1	0.25	0.5 mg (0.05 mL)
Aflibercept	Recombinant fusion protein	VEGF-A, VEGF-B, PlGF	115	Yes	0.49–9263	16–90	4.5–4.7 (rabbits)	18	2 mg (0.05 mL)
Brolucizumab	Humanized single-chain antibody fragment	VEGF-A	26	No	28.4 (for VEGF₁₆₅)	860	4.4–5.6	6	6 mg (0.05 mL)
Faricimab	Bispecific monoclonal antibody	VEGF-A, Ang-2	150	Modified Fc region to reduce FcγR and FcRn binding	46–60 (VEGF-A), 22–30 (Ang-2)	490 (VEGF-A), 240 (Ang-2)	6.7–12	12	6 mg (0.05 mL)

Abbreviations: VEGF Vascular endothelial growth factor, PlGF placental growth factor, Ang-2 Angiopoietin-2, Fab fragment antigen-binding, Fc fragment crystallisable, FcγR Fc gamma receptor, FcRn neonatal Fc receptor, Kd dissociation constant (affinity), IC₅₀ half maximal inhibitory concentration (potency), t_1/2 half-life

Role of VEGF in Renal and Cardiovascular System

VEGF and Renal System

VEGF plays a pivotal role in the renal system by stimulating endothelial cell proliferation and differentiation, facilitating endothelium-dependent vasodilatation, inducing microvascular hyperpermeability, and contributing to interstitial matrix remodeling [1].

Distribution of VEGF and Its Receptors in the Kidney

VEGF is expressed most prominently in the glomerular podocytes and tubular epithelial cells [1]. In the tubules of the normal human kidney, VEGF expression has been observed to be confined to the distal and collecting duct epithelium [2]. The expression of the VEGF in the distal tubule was found to be weaker than in the glomerulus [3]. VEGF receptors VEGFR-1 and VEGFR-2 are found on preglomerular, glomerular, and peritubular endothelial cells [2, 4, 5].

Functional role of VEGF in the Kidney

• I.Renal development

  VEGF is responsible for renal vasculogenesis, glomerulogenesis, and tubulogenesis. It guides endothelial cell proliferation and migration during kidney morphogenesis [6].

• II.Glomerular function

  VEGF secreted by the podocytes is postulated to be involved in the induction and maintenance of the fenestrae in the glomerular capillary endothelial cells [7]. Thus, it facilitates high rate of glomerular ultrafiltration, maintaining the selective permeability of the glomerular capillaries, preventing leakage of protein in the urine. Caveolae, the plausible structures responsible for the increase in the endothelial permeability, are seen to organize into elongated cell-spanning structures in vitro after exposure to VEGF [8]. VEGF is necessary for glomerular and tubular hypertrophy and proliferation in response to reduction in nephrons [1].

• III.Hypoxia and ischemic response

  VEGF expression is upregulated by hypoxia, leading to an angiogenic response [9]. This helps in tissue recovery after ischemic injury. This is crucial in acute kidney injury, where VEGF upregulation prevents endothelial cell apoptosis and supports vascular repair.

Role of VEGF in Diabetic Nephropathy

In diabetes, overexpression of VEGF-A has been noted, which triggers the activation of transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF). This promotes mesangial and endothelial cell proliferation, foot process effacement, and thickening of the glomerular basement membrane, ultimately resulting in renal fibrosis [10–12].

VEGF maintains vascular integrity through a nitric oxide (NO)-dependent pathway but contributes to vascular injury, endothelial overactivation, vascular smooth muscle cell proliferation, and macrophage activation via an NO-independent pathway. In diabetes, reduced endothelial NO bioavailability amplifies the harmful effects of VEGF through the NO-independent pathway, exacerbating diabetic nephropathy [13].

In summary, the pathological changes in diabetic nephropathy caused by overexpressed VEGF-A include increased vascular permeability leading to proteinuria, glomerular hypertrophy, basement membrane thickening, podocyte injury, and capillary rarefaction.

VEGF and Cardiovascular System

VEGF plays a crucial role in the human heart by regulating angiogenesis, vascular permeability, inflammation, lipid metabolism, and resisting oxidative stress.

Distribution of VEGF and Its Receptors in the Heart

VEGF-A is expressed in the pericytes, endothelial cells, and angioblasts of the cardiovascular system [14]. In patients with congestive heart disease, the myocardium secretes VEGF in response to local inflammation, mechanical stress, and cytokines. This leads to myocardial deformation, impaired contraction, and hindered recovery [15]. VEGF-B is expressed in myocardium, coronary artery smooth muscle cells, and endothelial cells [16]. VEGF-C and VEGF-D are also reported to be expressed in the heart [17].

VEGFR-1 and VEGFR-2 are expressed in endothelial cells, inflammatory cells, vascular smooth muscle cells, and cardiac fibroblasts. VEGFR-1 is a member of the receptor tyrosine kinase family with high affinity for VEGF-A, but weaker kinase activity compared with VEGFR-2. The combination of VEGF-A and VEGFR-1 and VEGFR-2 controls angiogenesis, vascular permeability, and inflammation.

Functional Role of VEGF in Human Heart

• I.Angiogenesis

  VEGF-A stimulates the proliferation, migration, and invasion of endothelial cells into surrounding tissues, facilitating the formation of lumen structures and neovascularization, which ensures an adequate blood supply to cardiac tissues.

  After myocardial infarction (MI), VEGF contributes to repairing damaged heart tissue by stimulating angiogenesis, which restores blood flow to ischemic areas.

• II.Vascular permeability

  VEGF-165 promotes synthesis of endogenous endothelial platelet activating factor and nitric oxide, leading to vascular permeability [18]. This ensures proper oxygen and nutrient delivery to the cardiac tissues.

• III.Inflammation

  VEGF facilitates the recruitment of inflammatory cells, primarily neutrophils and macrophages, and is a marker of local inflammatory response [19].

• IV.Antioxidant

  Oxidative stress is a significant risk factor for developing congestive heart disease. VEGF-B has been shown to exert antioxidant effects by binding to VEGFR-1 and upregulating various antioxidant genes, such as Gpx1 [20].

• V.Anti-apoptosis

  VEGF-B and VEGF-C play an anti-apoptotic effect on the myocardial cells after myocardial infarction (MI). VEGF-B induces specific gene expression profiles of compensatory hypertrophy, preventing the loss of myocardial mass and maintaining myocardial contractility [21].

• VI.Fibrinogenesis

  VEGF-C/VEGFR-3 promotes proliferation, migration, and collagen synthesis of cardiac fibroblasts, promoting myocardial fibrosis after MI [22].

• VII.Lymphangiogenesis

  Lymphangiogenesis is the cardinal biological effect of VEGF-C and VEGF-D. They bind to VEGFR-3 expressed on lymphatic endothelial cells, promoting their proliferation, migration, and differentiation. After acute MI, the cardiac lymphatic vessels transport immune cells to the mediastinal lymph nodes, promoting the clearance of the acute inflammatory response and aids in cardiac repair. It also enhances fluid drainage from the interstitial space, reducing myocardial edema and restoring tissue fluid balance [23].

In summary, VEGF-induced angiogenesis compensates for hypoxia and ischemia by restoring blood supply, while lymphangiogenesis helps reduce inflammation by providing an exit pathway for accumulated inflammatory cytokines. Its anti-apoptotic effects protect the myocardium from damage following MI, and its role in fibrinogenesis contributes to myocardial fibrosis after MI.

Renal Effects of Anti-VEGF

The effect of intravitreal anti-VEGF agents on the renal system is an area of growing interest owing to their systemic absorption and potential off-target effects.

The 50% inhibitory concentration required to “maximally inhibit systemic VEGF,” known as the IC₅₀, helps to determine the systemically measured serum drug levels after the injection of standard doses.

The average systemic level after intravitreal injection of aflibercept was found to be much higher than the IC₅₀ of aflibercept for weeks (up to 30 days), while that of bevacizumab closely approximated the IC₅₀ and decreased below that level 2 weeks post injection [32, 33]. Ranibizumab had initial post injection levels near the IC₅₀, but it decreases quickly within days and is eliminated more rapidly from the serum than other agents [32, 33]. These pieces of evidence have raised concerns regarding the systemic safety of these drugs.

VEGF secreted by podocytes is believed to regulate the proliferation, migration, and survival of glomerular endothelial, mesangial, and peritubular capillary cells through paracrine signaling [34, 35]. Depletion of VEGF due to anti-VEGF therapy can harm these cells, resulting in renal vascular and parenchymal damage. This damage may lead to impaired kidney filtration, proteinuria, hypertension, and thrombotic microangiopathy [36].

The cumulative evidence on the renal effects of multiple doses of different anti-VEGF agents is summarized in Table 3 on the basis of a total of 12 studies. Table 4 highlights recent case reports on the renal effects of anti-VEGF therapy.

Table 3.

Summary of studies assessing renal safety of intravitreal anti-VEGF agents

Author, year	Study type	Anti-VEGF agent(s)	Key results	Inference
Bagheri et al. 2018 [37]	Prospective observational study of 40 patients with diabetic nephropathy and PDR and/or significant DME	Bevacizumab	↑ Diastolic BP at 1 month (p = 0.002); no significant change in ACR, serum creatinine, or eGFR at 1 month	Bevacizumab not associated with renal dysfunction or proteinuria in diabetic nephropathy patients
Glassman et al. 2018 [38]	Secondary analysis of Protocol T (DRCR.net), 660 DME patients	Bevacizumab, ranibizumab, aflibercept	No significant changes in mean arterial pressure or UACR among groups at 1–2 years	No difference in renal impact between agents
Neill et al. 2019 [39]	Retrospective review over 2.6 years, assessing eGFR and ACR trends in patients with DME receiving multiple injections	Ranibizumab, aflibercept	Mean of 26.8 injections per patient; no association between injection frequency and eGFR/ACR change	Long-term VEGF inhibition not associated with progressive renal impairment
Yang et al. 2022 [40]	Retrospective review (2000–2017); anti-VEGF versus non-injection group with same retinal diagnoses	Ranibizumab, aflibercept	↑ Dialysis risk in anti-VEGF users, especially those treated for DME	Anti-VEGF may increase dialysis risk, particularly in DME
Chen et al. 2023 [41]	Retrospective review: patients > 20 years receiving versus not receiving injections	Ranibizumab	↑ Risk of CKD in patients receiving Ranibizumab	Ranibizumab exposure is an independent CKD risk factor
Cai et al. 2024 [42]	Retrospective cohort of patients ≥ 18 years receiving 3 monthly anti-VEGF injections	Bevacizumab, ranibizumab, aflibercept	Kidney failure incidence: 742/100,000 person-years; no significant differences in hazard ratio between agents	Risk of kidney failure present; no preference among agents based on current evidence
Bunge et al. 2024 [43]	Retrospective study of patients with PDR or DME receiving anti-VEGF versus controls	Bevacizumab, ranibizumab, aflibercept	No overall ↑ kidney risk; ↑ risk in patients with baseline eGFR > 30 mL/min/1.73 m [2] (HR: 1.86); > 12 injections not associated with decline	Anti-VEGF generally safe for kidney function, though caution advised in some subgroups

Abbreviations: VEGF vascular endothelial growth factor, DME diabetic macular edema, PDR proliferative diabetic retinopathy, BP blood pressure, eGFR estimated glomerular filtration rate, ACR albumin–creatinine ratio, UACR urine albumin–creatinine ratio, CKD chronic kidney disease, HRhazard ratio, CI confidence interval

Table 4.

Case reports highlighting renal effects of intravitreal anti-VEGF therapy

Author, year	Age/gender	Retinal disease	Anti-VEGF agent(s)	Renal symptoms	Renal diagnosis	Management
Shye et al. 2020 [44]	59 years/M 58 years/M 46 years/M	DR with DME (all cases)	Bevacizumab and ranibizumab	Proteinuria, hypertension, worsening renal function	Collapsing FSGS, diabetic glomerulosclerosis, interstitial nephritis	Dialysis
Hanna et al. 2020 [45]	37 years/F	DR with DME	Bevacizumab	Proteinuria, hypertension	Not specified	Renal replacement therapy
Morales et al. 2021 [46]	56 years/M	DR with DME	Ranibizumab	Proteinuria, worsening renal function	Not specified	Renal replacement therapy
Ahmed et al. 2021 [47]	41 years/M	DR with DME	Bevacizumab	Proteinuria, hypertension, worsening renal function	Diabetic nephropathy	Not specified
Gan et al. 2022 [48]	57 years/M	CRVO	Ranibizumab	Proteinuria, hypertension, worsening renal function	Membranoproliferative GN with nephroangiosclerosis	Discontinuation of injections

Abbreviations: DR diabetic retinopathy, DME diabetic macular edema, CRVO central retinal vein occlusion, FSGS focal segmental glomerulosclerosis, GN glomerulonephritis, y years, M/F male/female, VEGF vascular endothelial growth factor

Current evidence supports the short- to medium-term renal safety of intravitreal anti-VEGF agents, even in patients with diabetes and chronic kidney disease (CKD). However, data on long-term cumulative effects and subtle renal changes remain limited, warranting cautious optimism. Until larger, more comprehensive studies provide further clarity, clinicians should carefully assess individual patient risks and monitor renal function, particularly in high-risk groups receiving anti-VEGF therapy.

While no definitive evidence links anti-VEGF therapy to significant renal deterioration, patients with preexisting borderline kidney dysfunction may have a higher risk of renal adverse effects following injections. According to existing literature, anti-VEGF agents can be used safely even in patients with CKD [37–39]. However, in cases where baseline renal function is significantly compromised (e.g., eGFR < 30 mL/min/1.73m²), additional caution is advised, with close monitoring to detect any potential renal impact [43].

Cardiovascular Effects of Anti VEGFs

Intravitreal anti-VEGF therapy has been widely used for retinal diseases in recent times, which has raised concerns about its systemic effects, particularly on the heart. Systemic absorption of anti-VEGFs has been reported to be associated with arterial thromboembolic events (ATEs), hypertension, heart failure, and arrhythmias [49].

The cumulative evidence on the cardiovascular effects of repeated doses of various anti-VEGF agents is reviewed in Table 5 to understand the potential impact of intravitreal anti-VEGF therapy on the heart.

Table 5.

Cardiovascular effects of repeated intravitreal anti-VEGF therapy

Author, year	Type of study	Anti-VEGF agent(s)	Results	Inference
Kwon et al. 2018 [50]	Retrospective study investigating MI within 2 months of anti-VEGF injections	Bevacizumab	No difference in MI prevalence by retinal disease; MI associated with prior MI/CVA	Caution advised before administering anti-VEGF in patients with MI risk factors
Dalvin et al. 2019 [51]	Population-based cohort study of patients with exudative ARMD (2004–2013)	Pegaptanib, bevacizumab, ranibizumab, aflibercept	Anti-VEGF therapy was not associated with increased MI risk versus controls	Cardiac events not attributable to anti-VEGF therapy in exudative ARMD
Chen et al. 2021 [52]	Retrospective population-based study comparing IVI versus non-IVI groups in patients with prior MI/stroke	Not specified	IVI group had significantly higher mortality, especially when injections occurred within 1 year of prior MI/stroke	Increased mortality risk associated with anti-VEGF in post-MI/stroke patients
Chou et al. 2023 [49]	Nationwide population-based cohort study analyzing ATE risk	Ranibizumab, aflibercept	38 ATEs in 6 months post-injection; IVR had lower ATE risk than IVA; higher ATE risk in patients with recent MI/IS or CAD	IVR may be safer than IVA in patients with recent cardiovascular events; caution recommended
Lai et al.. 2024 [53]	Retrospective study of diabetic patients without prior CVD; compared anti-VEGF versus laser/steroid cohort	Bevacizumab, ranibizumab, aflibercept, faricimab, brolucizumab	No acute MI events at 1 month; similar MI incidence at 6 and 12 months across groups	Anti-VEGF therapy appears safe in diabetic patients without baseline CVD
Sui et al. 2024 [54]	Case report of elderly patient with 10 years of anti-VEGF therapy	Ranibizumab, conbercept, aflibercept	Unexpected cardiac dysfunction observed; improvement after discontinuation of anti-VEGF	Suggests importance of cardiac monitoring in elderly and long-term anti-VEGF users

Abbreviations: MI myocardial infarction, CVA cerebrovascular accident, ARMD age-related macular degeneration, IVI intravitreal injection, ATE arterial thromboembolic events, CAD coronary artery disease, IS ischemic stroke, IVR intravitreal ranibizumab, IVA intravitreal aflibercept, CVD cardiovascular disease, VEGF vascular endothelial growth factor

Systematic reviews and meta-analyses of intravitreal anti-VEGF agents, including bevacizumab, ranibizumab, and aflibercept, have found no significant increase in the risk of major adverse cardiovascular events (MACEs) such as myocardial infarction (MI), stroke, or cardiovascular death compared with controls [55]. Similarly, overall mortality was not significantly elevated; however, subgroup analysis indicated a potential concern in patients with diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR), where mortality risk appeared higher. Notably, no increased risk was observed for nonocular hemorrhages, venous thromboembolism, arterial hypertension, or heart failure across studies. Sensitivity analyses confirmed the robustness of these findings, with low heterogeneity, though slight asymmetry in funnel plots suggested minor publication bias, which was not statistically significant.

A systematic review and meta-analysis by Lees et al. found that the incidence of hypertension and new or worsening heart failure was comparable between patients receiving intravitreal anti-VEGF therapy and control groups [56].

A pharmacovigilance study using the VigiBase database analyzed 23,129 adverse drug reactions (ADRs) associated with intravitreal anti-VEGF therapy and found a significantly higher reporting rate of cardiovascular and cerebrovascular ADRs compared with the full database [57]. Reported cardiovascular ADRs included myocardial infarction, angina pectoris, arrhythmias (such as atrial fibrillation, atrial flutter, and ventricular fibrillation), hypertension, and hypertensive crisis. Interdrug comparisons showed that aflibercept had lower reporting odds ratios for myocardial infarction, atrial fibrillation, and cerebrovascular accidents compared with ranibizumab. These findings emphasize the increased reporting of cardiovascular and cerebrovascular ADRs following anti-VEGF therapy, with ranibizumab exhibiting a higher reporting rate relative to bevacizumab and aflibercept. This underscores the importance of careful monitoring, especially in patients at higher risk for systemic adverse events.

The apparent discrepancy between these studies could stem from differences in methodology. Systematic reviews and meta-analyses synthesize controlled trial data, whereas pharmacovigilance studies reflect real-world reporting, which may include biases and confounders. Nonetheless, the increased reporting in pharmacovigilance data emphasizes the need for heightened vigilance, especially for high-risk groups such as those with preexisting cardiovascular or cerebrovascular conditions.

These conclusions advocate for personalized treatment approaches, careful patient selection, and post-marketing surveillance to mitigate systemic risks while ensuring the therapeutic benefits of anti-VEGF therapies in retinal diseases. Further research is needed to explore the biological and pharmacokinetic mechanisms underlying these observed ADRs and their variation across different anti-VEGF agents. While intravitreal anti-VEGF therapies are generally safe, systemic risks, particularly cardiovascular and cerebrovascular ADRs, should not be overlooked in high-risk populations. The choice of anti-VEGF agent should be personalized, with heightened vigilance for patients with diabetes or preexisting cardiovascular conditions. Bridging the gap between controlled trials and real-world data remains essential to optimize patient safety.

To summarize, while concerns exist regarding systemic absorption of anti-VEGF agents following intravitreal administration, current evidence from the literature generally indicates no significant adverse effects on the heart. Our research findings suggest that the proximity of a prior stroke or MI, particularly within 6–12 months, is a stronger predictor of increased cardiovascular risk than prolonged q4 injections. While long-term frequent injections (e.g., over 10 years) may contribute to gradual cardiac dysfunction, the immediate post-stroke/MI period presents the highest risk.

From an extensive review of the nine documented studies, we summarize that a thorough cardiac evaluation before and after injections is essential for patients with cardiovascular risk factors.

Central Nervous System (CNS) Effects of Anti-VEGFs

The systemic absorption of intravitreal anti-VEGF agents raises concerns about their potential impact on the nervous system. The blood–brain barrier (BBB) is a highly selective barrier that typically prevents anti-VEGF molecules from crossing under normal conditions. However, in pathological states such as stroke, neuroinflammatory disease, or tumors, a compromised BBB may allow small amounts of these agents to enter the CNS. Additionally, minimal levels may reach the CNS through systemic circulation.

The BHAM study highlighted that neuronal health and cognitive function in the central nervous system are linked to the maintenance of normal physiological VEGF expression levels [58].

The cumulative evidence on the nervous system effects of repeated doses of various anti-VEGF agents is reviewed in Table 6 on the basis of an extensive analysis of eight recent studies, to understand the potential impact of intravitreal anti-VEGF therapy on the CNS.

Table 6.

Neurological and cerebrovascular effects of repeated intravitreal anti-VEGF therapy

Author, year	Type of study	Anti-VEGF agent(s)	Results	Inference
Starr et al. 2019 [59]	Retrospective study with 2-year follow-up; control group with no anti-VEGF injections	Not specified	5.8% had stroke post anti-VEGF; 71.1% ischemic, 15.8% embolic, 13.2% hemorrhagic; stroke types similar to control group	No increased stroke subtype risk due to anti-VEGF; no predilection toward infarcts or hemorrhages
Dalvin et al. 2019 [60]	Population-based retrospective cohort study (2004–2013) in exudative ARMD patients	Pegaptanib, bevacizumab, ranibizumab, aflibercept	No increased stroke risk in anti-VEGF group versus controls	Intravitreal anti-VEGF not linked to increased stroke risk in ARMD
Sultana et al. 2020 [61]	Retrospective review of individual case safety records (ICSRs) for anti-VEGF drugs (2010–2016)	Bevacizumab, ranibizumab, pegaptanib, aflibercept	59.88% of ICSRs from > 65 y/o; potential signal linking intravitreal ranibizumab with Parkinson’s disease	VEGF inhibition might impair neural signalling and plasticity, potentially contributing to Parkinson’s disease
Chen et al. 2021 [51]	Population-based retrospective study comparing patients with stroke/MI who received versus did not receive anti-VEGF	Not specified	Higher mortality in IVI group, especially if injections given within 1 year of MI/stroke	Increased mortality risk with anti-VEGF in patients with recent stroke/MI
Yoshimoto et al. 2021 [62]	Case report of 70-year-old male with DME	Aflibercept	Hypertensive cerebral hemorrhage 1-month post-bilateral injections; plasma VEGF dropped below detection and remained low for 2 months; recovered to 41 pg/ml after 2 months	Persistent VEGF suppression can trigger hypertension and cerebral hemorrhage; caution in elderly with comorbidities
Ray et al. 2021 [57]	Prospective study of ARMD patients (age 65–85); used iPad-based brain health test versus injection number	Not specified	> 20 injections linked with increased risk of mild cognitive impairment	Possible cumulative effect of anti-VEGF on cognitive function; brain health monitoring may be warranted
Fugara et al. 2022 [63]	Prospective study of diabetic patients: laser/conservative (Ggroup 1) versus anti-VEGF (group 2)	Bevacizumab	Non-arteritic ischemic optic neuropathy (NAION) more common in group 2, especially with ≥ 3 injections	Repeated bevacizumab may increase NAION risk in diabetic eyes
Yang et al. 2025 [57]	Pharmacovigilance study using VigiBase for cardiovascular/cerebrovascular ADRs with anti-VEGF	Ranibizumab, bevacizumab, aflibercept	Higher reporting of cerebral infarction, carotid stenosis, cerebral and subarachnoid hemorrhage; underreporting with aflibercept; higher rates with ranibizumab	Intravitreal anti-VEGF associated with cerebrovascular ADRs; ranibizumab showed higher cerebrovascular ADR reports than other agents

IVI intravitreal injection, DME diabetic macular edema, ARMD age-related macular degeneration, ICSR individual case safety record, ADRs adverse drug reactions, NAION non-arteritic ischemic optic neuropathy, VEGF vascular endothelial growth factor, MI myocardial infarction

The impact of anti-VEGF therapy on CNS health remains a subject of ongoing debate. While some studies suggest a decline in neuronal health with repeated injections and an increased risk of cerebrovascular adverse events, many others have demonstrated a favorable safety profile compared with controls. However, there is a broad consensus on exercising caution when administering anti-VEGF injections in patients with a recent history of stroke, as repeated injections may elevate the risk of stroke. Further research is needed to clarify these concerns, but until then, patient management should be approached on a case-by-case basis.

Safety Concerns of Anti-VEGFs in Special Situations

Pregnancy

The administration of intravitreal anti-VEGFs in sight-threatening conditions during pregnancy raises significant concerns. This is primarily due to the systemic absorption of these drugs and the potential risk of placental transmission, which raises questions about possible teratogenic effects on the fetus. In this context, it is essential to examine the concerns, review the available evidence, and explore the major consensus on the use of anti-VEGFs during pregnancy.

Concerns about Intravitreal Anti-VEGF Use during Pregnancy

Anti-VEGF drugs are classified as category C medications and are generally not recommended for use in pregnant women [64]. However, pregnancy can trigger or worsen retinal conditions that may necessitate treatment with these agents. Therefore, a thorough evaluation of their safety is crucial for making an informed clinical decision. Since VEGF plays a vital role in maintaining fetal and placental vasculature, the antiangiogenic effects of these drugs raise significant concerns [65, 66].

Evidence on the Safety Concerns of Anti-VEGF Use in Pregnancy

Table 7 presents the latest evidence on the safety of intravitreal anti-VEGF use during pregnancy.

Table 7.

Latest evidence on the safety of intravitreal anti-VEGF use during pregnancy

Study	Study design	Anti-VEGF agent(s)	Patient details and results	Inference
Polizzi et al. 2015 [67]	Case series (n = 3)	Bevacizumab	All injections in second or third trimester No drug-related adverse events Healthy full-term infants One patient had miscarriage risk factors	Anti-VEGF may be used in later trimesters when benefit outweighs fetal risk Exercise caution, especially in the first trimester
Fossum et al. 2018 [68]	Case series (n = 3)	Ranibizumab	Injections at 8, 10, and 21 weeks post-LMP All delivered healthy babies No developmental malformations	Ranibizumab did not show adverse effects, even in early pregnancy exposure
Ong et al. 2022 [69]	Retrospective study (n = 42 pregnancies)	Ranibizumab, aflibercept	40% (16/41) unaware of pregnancy during injection 81% live births (34/42) 12% miscarriages (5/42), 7% stillbirths (3/42), mostly in high-risk pregnancies	Anti-VEGF may not significantly affect obstetric outcomes Recommend routine pregnancy screening before injections in women of child-bearing age

n number of subjects or patients in the study, VEGF vascular endothelial growth factor, LMP last menstrual period

Isolated case reports have documented instances of spontaneous abortion occurring within days of intravitreal bevacizumab administration, particularly in high-risk patients [70, 71]. Additionally, Sullivan et al. reported a case of preeclampsia following intravitreal bevacizumab treatment [72] .

Major Consensus till Date Based on Available Evidence

Among anti-VEGF agents, bevacizumab has been linked to the highest systemic exposure, while ranibizumab exhibits the least. Furthermore, no drug accumulation has been observed between the first and third doses of ranibizumab, in contrast to the persistent accumulation seen with bevacizumab and aflibercept. On the basis of this evidence, ranibizumab may be considered a potentially safer intravitreal option for pregnant patients [73]. Given the inherently high risk of spontaneous miscarriage in the first trimester, establishing a direct causal relationship between early pregnancy loss and anti-VEGF injections is challenging. However, the short interval between injection administration and abortion raises concern. Therefore, it is advisable to avoid intravitreal anti-VEGF treatment during the first trimester, particularly in high-risk cases [73].

The transplacental passage rate of ranibizumab is lower than bevacizumab owing to the inability of the Fab fragment to cross the placenta [68]. So, ranibizumab seems to be a safer option than other anti-VEGFs in pregnancy. Many patients are unaware of their pregnancy when injected with anti-VEGFs. Conducting a routine urinary pregnancy test in the child-bearing age group can be considered before treatment to prevent unwanted complications [69]. To conclude, intravitreal anti-VEGFs can be given during pregnancy only when the potential benefit to the woman justifies the potential risks to the fetus.

Lactating Women

The systemic absorption of anti-VEGF agents and their potential secretion into breast milk during the postpartum period have raised concerns regarding their safety.

Concerns about Intravitreal Anti-VEGF Use during Breastfeeding

VEGF-A regulates local mammary gland development in the lactating mother and is an essential growth factor in infancy. It is present in high concentration in breast milk [74]. VEGF-A also plays an important role in the development of the digestive system, neurogenesis, renal medullary microcirculation expansion, and lung angiogenesis and alveolarization in infants [74].

Intravitreal anti-VEGF administration has been reported to be associated with a reduction in VEGF-A levels in breast milk [74]. This raises concern about the safety of these drugs.

Evidence on Safety Concerns of Anti-VEGF Use during Breastfeeding

There are very limited data on breastfeeding in the context of intravitreal anti-VEGFs. McFarland et al. [75] reported a reduction of 35% in VEGF-A levels in breast milk 2 weeks following bevacizumab injection. A transient drop in VEGF-A levels in breast milk has been reported within 6–12 h (about 20–30% lower), after an intravitreal ranibizumab injection, and increasing to pre-injection levels by 24 h after injection [76]. It has been observed that discontinuation of breast feeding after injection can lead to accumulation of the drug in breast milk.

Table 7 illustrates the effects of anti-VEGF therapy on pregnancy on the basis of findings from three recent comprehensive studies.

Major Consensus till Date Based on Available Evidence

Considering the small number of cases in the literature, it is challenging to draw definite conclusions regarding the clinical impact of anti-VEGF injections during breastfeeding. On the basis of available data, ranibizumab appears to be a safer option than aflibercept for breastfeeding women, as aflibercept has been associated with a greater reduction in plasma VEGF levels compared with ranibizumab [77].

Basilious et al. recommended a 3-day “pump and dump” breastfeeding strategy for lactating mothers after an intravitreal injection [64]. In this approach, nursing mothers pump and discard their breast milk for 3 days following the injection, then resume breastfeeding on demand after the third day. Preliminary results from this study suggest that this strategy effectively minimizes the infant’s exposure to the drug. This approach resulted in undetectable levels of ranibizumab in the infant’s serum, with plasma VEGF-A levels remaining comparable to those observed in control infants.

Retinopathy of Prematurity (ROP)

The use of anti-VEGF treatment has revolutionized the management of ROP by promoting progressive vascularization of the avascular retina, offering the potential for a broader visual field development. However, this has raised concerns about its safety in newborns.

Concerns about Intravitreal Anti-VEGF Use in ROP

Inhibiting VEGF bioactivity in preterm neonates may disrupt normal growth and development in multiple organs. VEGF is crucial for neuronal and endothelial cell survival, with neuroprotective and neurotrophic properties in the brain. It also supports blood–brain barrier maintenance, lung alveolar development, surfactant synthesis, and kidney glomerular development, while playing a role in skeletal growth. Blocking VEGF could therefore impact various developing organs in neonates [78, 79].

Evidence on the Safety Concerns of Anti-VEGF Use in ROP

Table 8 presents the safety concerns of anti-VEGF use in ROP on the basis of an evaluation of four recent studies.

Table 8.

Evidence on the safety concerns of anti-VEGF use in retinopathy of prematurity (ROP)

Author, year	Study design	Anti-VEGF	Results	Inference
Arima et al. 2020 [80]	Retrospective study	Bevacizumab (IVB)	Significant association between IVB and neurodevelopmental delay in language-social scores, even after adjusting for GA and BW	IVB may affect the development of verbal/social skills in ROP infants
Zayek et al. 2020 [81]	Retrospective study	Bevacizumab (IVB)	No significant association between IVB and neurodevelopmental delay	IVB was not associated with adverse neurodevelopment
Abrishami et al. 2021 [82]	Retrospective study	Bevacizumab	No significant difference between treatment groups in developmental milestones (motor, personal–social, etc.) at 18 months	No growth or neurodevelopmental differences between treatment-naïve infants and those receiving bevacizumab for ROP
Chen et al. 2023 [83]	Retrospective study	Ranibizumab (IVR), Aflibercept (IVA)	BW gain for the first week after treatment was significantly lower than pre-treatment week (P < 0.05). No decrease in BW gain in the second week	IVR and IVA could have a short-term inhibitive effect on body weight gain in infants after ROP treatment

IVB intravitreal bevacizumab, IVR intravitreal ranibizumab, IVA intravitreal aflibercept, GA gestational age, BW birth weight, VGEF vascular endothelial growth factor

Major Consensus till Date Based on Available Evidence

Infants treated with intravitreal injections are often significantly more premature and have lower birth weights compared with those treated with laser. Therefore, it is challenging to establish a direct causal association between anti-VEGF treatment and potential adverse effects.

Most of the literature does not report significant long-term systemic side effects or neurological impairment associated with anti-VEGF use in ROP. Thus, to conclude, anti-VEGF therapy can be considered for vision-threatening ROP cases after carefully weighing the potential risks and benefits [84].

Table 9 summarizes the key clinical guidelines for anti-VEGF use across different systems.

Table 9.

Clinical guidelines for anti-VEGF use across different systems

System	Guidelines
Renal	Exercise caution in patients with significantly compromised renal function (eGFR < 30 mL/min/1.73m2)
	Close monitoring is advised to detect potential renal impact
Cardiovascular (CVS)	Prior stroke or MI within 6–12 months is a stronger predictor of cardiovascular risk than prolonged q4 injections
	Long-term frequent injections (> 10 years) may contribute to gradual cardiac dysfunction
	—
Central nervous system (CNS)	Most of the literature does not report significant long-term systemic side effects or neurological impairment associated with anti-VEGF use
	Caution is advised when administering anti-VEGFs to patients with a recent history of stroke, as repeated injections may elevate stroke risk
Pregnancy	Anti-VEGFs should be used only when the potential benefit to the woman justifies the potential fetal risks
	A routine urinary pregnancy test can be considered before treatment in women of childbearing age
	Ranibizumab appears safer than other anti-VEGFs in pregnancy
	Avoid intravitreal anti-VEGF treatment during the first trimester, particularly in high-risk cases
Breastfeeding	Ranibizumab appears to be a safer option than aflibercept for breastfeeding women
	A 3-day “pump and dump” strategy is recommended after intravitreal injections
Retinopathy of prematurity (ROP)	Anti-VEGF therapy can be considered for vision-threatening ROP cases after carefully weighing risks and benefits

VEGF vascular endothelial growth factor, eGFR estimated glomerular filtration rate, MI myocardial infarction

Conclusions

While intravitreal anti-VEGF therapies have revolutionized the treatment of various retinal conditions, understanding their systemic side effects is crucial for optimizing patient care. Current evidence supports the renal safety of anti-VEGF agents in the short to medium term, with cautious monitoring advised for patients with preexisting renal dysfunction, particularly those with significantly impaired kidney function. Cardiovascular and cerebrovascular risks, though not conclusively linked to anti-VEGF therapy, warrant vigilance, especially in high-risk patients, as some studies suggest a slight increase in adverse events such as myocardial infarction, stroke, and arrhythmias. As further studies are conducted, a more refined understanding of the long-term and subtle systemic impacts of anti-VEGF therapy will be essential. Clinicians must continue to assess individual risks, monitor patients closely, and provide personalized care to ensure the safe use of these therapies.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Mousumi Banerjee conducted the literature search and drafted the manuscript. Sikshya Moharana contributed to drafting the section on pregnancy and anti-VEGF. Srikanta Kumar Padhy assisted with conceptualization, study design, and manuscript editing. All authors reviewed and approved the final version of the manuscript.

Funding

No funding or sponsorship was received for this study or publication of this article.

Declarations

Conflict of Interest

Srikanta Kumar Padhy, Sikshya Moharana, and Mousumi Banerjee have nothing to disclose.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.