Successful management of high-risk proliferative diabetic retinopathy during pregnancy with intravitreal faricimab

Abstract

Management of proliferative diabetic retinopathy during pregnancy requires balancing maternal vision preservation against uncertain fetal risks associated with intravitreal anti-vascular endothelial growth factor therapy. We report a 27-year-old woman with a chronic type 1 diabetes mellitus who presented at 28 weeks and 1 day of gestation with high-risk proliferative diabetic retinopathy and dense vitreous hemorrhage in the left eye, precluding panretinal photocoagulation. After multidisciplinary counseling regarding limited pregnancy safety data and treatment alternatives, a single intravitreal faricimab injection was administered at 29 weeks and 6 days of gestation. One month later, left eye visual acuity improved from counting fingers to 20/25 with substantial clearance of the vitreous hemorrhage. Cesarean delivery was performed 37 days after injection at 36 weeks and 1 day of gestation for nonreassuring fetal heart tracings. No treatment-attributable adverse event was identified. To our knowledge, this represents the first reported use of intravitreal faricimab during pregnancy.

Introduction

Diabetic retinopathy is a leading cause of vision impairment among working-age adults, and pregnancy is a recognized period of increased vulnerability for retinopathy progression in patients with preexisting diabetes mellitus [1]. Longer diabetes duration, baseline retinopathy severity, and suboptimal glycemic control are principal risk factors associated with worsening retinal disease during gestation [1]. In some patients, progression may be rapid and visually threatening, particularly when proliferative diabetic retinopathy (PDR) develops or worsens during pregnancy [1].

Treatment of PDR during pregnancy is clinically challenging. Panretinal photocoagulation (PRP) remains the preferred treatment strategy because it reduces ischemic drive and avoids systemic pharmacologic exposure [2]. However, PRP requires adequate visualization of the peripheral retina. Dense vitreous hemorrhage may prevent timely or safe laser treatment. In such cases, clinicians must weigh the risk of irreversible maternal visual loss against the uncertain fetal and obstetric implications of intravitreal pharmacotherapy.

Intravitreal anti-vascular endothelial growth factor (VEGF) agents have transformed the treatment of diabetic retinopathy, and retinal neovascular disease. During pregnancy, however, their use remains controversial because VEGF signaling contributes to placental vascular development, fetal growth, and maternal vascular homeostasis [3]. Existing human data are limited primarily to case reports involving bevacizumab, ranibizumab, and aflibercept [4, 5]. Faricimab is a bispecific antibody that inhibits both VEGF-A and angiopoietin-2 (Ang-2), targeting complementary pathways involved in angiogenesis and vascular permeability [6, 7]. To our knowledge, intravitreal faricimab use during pregnancy has not previously been reported. We describe a pregnant patient with high-risk PDR and dense vitreous hemorrhage in whom PRP could not be performed because of media opacity. After multidisciplinary counseling, a single intravitreal faricimab injection was administered during the third trimester, resulting in substantial visual and anatomic improvement without treatment-attributable maternal, fetal, or neonatal adverse event.

Case report

A 27-year-old pregnant woman at 28 weeks and 1 day of gestation presented with decreased vision in the left eye for 1 month. Her history included type 1 diabetes mellitus for 12 years. She had previously been diagnosed with moderate nonproliferative diabetic retinopathy in both eyes but was lost to follow-up.

At presentation, best-corrected visual acuity was 20/25 in the right eye and counting fingers at 3 feet in the left eye. Dilated fundus examination of the right eye demonstrated neovascularization elsewhere with preretinal hemorrhage. Examination of the left eye revealed dense vitreous hemorrhage with neovascularization and fibrotic proliferation involving the optic disc, consistent with high-risk PDR. Media opacity limited posterior segment visualization.

PRP was performed in the right eye; however dense vitreous hemorrhage precluded adequate visualization for PRP in the left eye. Intravitreal anti-VEGF therapy was initially deferred pending multidisciplinary discussion. At 2-week follow-up, corresponding to 29 weeks and 6 days of gestation, visual acuity was 20/30 in the right eye and counting fingers at 2 feet in the left eye. The left eye continued to demonstrate vitreous hemorrhage with neovascularization and fibrosis of the optic disc. The persistence of media opacity continued to prevent timely PRP of the left eye. After multidisciplinary counseling, she elected to receive a single off-label use of intravitreal faricimab injection (6 mg/0.05 mL) in the left eye.

One week after faricimab injection, the vitreous hemorrhage in the left eye had substantially cleared, permitting visualization of fundus details. Fundus examination demonstrated a fibrotic membrane with associated neovascularization of the disc extending along the superior arcade (Figure 1 A). One month after injection, at 35 weeks and 6 days of gestation, visual acuity was 20/40 in the right eye and 20/25 in the left eye with improved fundus visualization (Figure 1 B). Fundus autofluorescence image and Optical coherence tomography of the macula demonstrated preserved foveal contour without intraretinal or subretinal fluid (Figure 2 A,B). The central retinal thickness measured 229 μm. Dilated examination of the left eye demonstrated clearing of the vitreous hemorrhage. The right eye showed new preretinal hemorrhage along the superior arcade.

Figure 1.

Color fundus photograph of the left eye. (A) 1 week after intravitreal faricimab injection showing substantial clearance of vitreous hemorrhage, with visualization of a fibrotic membrane and neovascularization of the disc extending along the superior arcade. (B) 4 weeks after intravitreal faricimab injection showing clear media with persistent fibrovascular proliferation and neovascularization of the disc extending along the superior arcade.

Figure 2.

Left eye improvement after intravitreal faricimab injection. (A) Fundus autofluorescence image and (B) Optical coherence tomography of the macula showing mild residual vitreous opacities, preserved foveal contour, and no intraretinal or subretinal fluid. The central retinal thickness was 229 μm.

Pregnancy had been followed by high-risk obstetrics because of longstanding type 1 diabetes mellitus with uncontrolled hyperglycemia, prior preterm premature rupture of membranes, and prior spontaneous abortion. Thirty-seven days after intravitreal faricimab administration, at 36 weeks and 1 day of gestation, the patient was admitted for delivery because of nonreassuring fetal heart tracings detected during routine high-risk obstetric monitoring. She underwent uncomplicated low transverse cesarean delivery. No treatment-attributable maternal, fetal, or neonatal adverse event was identified in the available clinical record.

Discussion

This case illustrates a central clinical dilemma in the management of vision-threatening retinal disease during pregnancy: treatment may be necessary to prevent irreversible maternal visual loss, yet the fetal and obstetric implications of intravitreal anti-VEGF therapy remain incompletely defined. The use of faricimab in this case was considered biologically plausible but remains off-label. In the present case, the dense vitreous hemorrhage prevented adequate visualization for PRP, the usual preferred treatment modality in pregnancy [2, 8]. Observation alone in this setting may expose the patient to persistent hemorrhage, progressive neovascularization, fibrovascular proliferation, tractional retinal detachment and permanent vision loss. Hence, treatment could not be deferred due to high-risk PDR with dense vitreous hemorrhage and inability to perform PRP [2].

Multidisciplinary care was essential, involving retina and maternal-fetal teams. The patient was counseled regarding the limited safety data, and alternative treatment. Evidence for intravitreal anti-VEGF therapy during pregnancy remains limited to case reports or small series involving. Published reports have primarily described bevacizumab, ranibizumab, and aflibercept exposure, often in patients with complex systemic or obstetric comorbidities that confound interpretation of pregnancy outcomes [4, 5]. Although many reports have not demonstrated a clear causal relationship between intravitreal anti-VEGF exposure and adverse fetal outcomes [4], the available data are insufficient to establish safety. Systemic absorption after intravitreal injection and suppression of circulating VEGF levels have been described with several anti-VEGF agents, supporting the biologic plausibility of fetal or placental effects [5].

Gestational timing is an important consideration. VEGF signaling is essential during embryogenesis, placental vasculogenesis, and fetal vascular remodeling, with particular relevance during early pregnancy [3]. Theoretical risks include impaired placental angiogenesis, fetal growth restriction, hypertensive disorders of pregnancy, and pregnancy loss [3]. In this patient, faricimab was administered at approximately 30 weeks of gestation (3^rd trimester), after major organogenesis (1^st trimester), which represent a different theoretical risk period, although available evidence is insufficient to quantify that risk.

Faricimab is mechanistically distinct from earlier intravitreal agents because it inhibits both VEGF-A and Ang-2. [6, 7] Ang-2 is implicated in vascular destabilization, pericyte loss, blood-retinal barrier disruption, and potentiation of VEGF-mediated vascular leakage [7]. Dual-pathway inhibition may provide durable retinal vascular stabilization [7], but the systemic significance of Ang-2 blockade during pregnancy is not well characterized. This represents one of the most important unanswered questions raised by this case.

The choice of faricimab also reflects pharmacologic considerations relevant to pregnancy. The choice was not based on any proven superiority of faricimab over other anti-VEGF agents with respect to pregnancy safety. Rather, faricimab contains an engineered Fc region intended to reduce Fc receptor binding and systemic effector function [6]. Because placental immunoglobulin transfer depends in part on Fc receptor-mediated mechanisms, this molecular design may theoretically reduce placental transfer relative to agents with intact Fc-mediated interactions [9]. However, direct human placental transfer data for intravitreal faricimab during pregnancy are lacking. No placental assessment related to faricimab exposure was performed in this case. Future studies incorporating placental evaluation may provide additional insight into potential maternal-fetal exposure and safety considerations

Multidisciplinary care was essential. The patient's management involved retina specialists, maternal-fetal medicine specialists, and informed patient participation. This collaborative approach allowed careful discussion of the visual risks of deferring treatment, the limited pregnancy safety data, and alternative treatment pathways. Such a framework is advisable whenever intravitreal antiangiogenic therapy is considered during pregnancy.

No identifiable treatment-attributable maternal, fetal, or neonatal adverse effect was observed in this case. Nevertheless, this favorable outcome should be interpreted cautiously. The patient had multiple independent obstetric risk factors, including poorly controlled longstanding type 1 diabetes mellitus, although serial HbA1c measurements were unavailable, as well as a history of prior preterm premature rupture of membranes and prior spontaneous abortion. Additionally, the estimated vitreous half-life of faricimab is approximately 7.5 days, which is shorter than the reported vitreous half-lives of other intravitreal anti-VEGF agents, including bevacizumab (18.7 days), aflibercept (11.4 days), and ranibizumab (8.5 days) [10]. Therefore, by the time of delivery, more than five half lives had elapsed after injection, suggesting substantially reduced intraocular drug levels. The indication for delivery was unrelated to ophthalmic treatment but occurred in the setting of multiple independent obstetric risk factors.

This report contributes to the limited literature on intravitreal anti-VEGF therapy during pregnancy and may represent the first reported case of intravitreal faricimab use during gestation. The case supports the importance of reporting pregnancy exposures to pharmacovigilance systems and prospective registries. As faricimab adoption increases in retinal practice, systematic data collection will be necessary to define maternal, fetal, and neonatal outcomes more reliably.

In summary, Intravitreal faricimab administered during the third trimester was associated with substantial visual and anatomic improvement in a pregnant patient with high-risk PDR in whom dense vitreous hemorrhage precluded timely PRP. No treatment-attributable maternal, fetal, or neonatal adverse event was identified in this single case. However, safety cannot be inferred from an isolated observation. Longitudinal postpartum ophthalmic follow up is essential to evaluate long term retinal stability and potential delayed treatment related ocular outcomes after intravitreal faricimab exposure during pregnancy. Faricimab-specific pregnancy exposure data, prospective registries, and pharmacovigilance are needed to better guide safety.

Conflicts of interest

No conflicts of interest.

Funding

This study was not supported by any grant.

Ethical approval

Institutional review board approval was not required for this single deidentified case report in accordance with institutional policy.

Consent

Written informed consent for publication of this case report and accompanying clinical images was obtained from the patient.

Guarantor

Kakarla V. Chalam, MD, PhD is the guarantor.