Intravitreal bevacizumab injection for retinopathy of prematurity and pulmonary hypertension

INTRODUCTION

Retinopathy of prematurity (ROP) results from episodes of hyperoxia, insufficient vascularization of the developing retina, retinal hypoxia triggering increased expression of vascular endothelial growth factor (VEGF) in premature infants. The standard treatment for advanced ROP is laser ablation of the abnormal blood vessels [1–3]. Bevacizumab, a recombinant antibody against VEGF, is used as an alternative therapy for ROP [3]. Animal and human studies suggest there is systemic absorption of bevacizumab following intravitreal injection [4, 5]. Angiogenesis mediated by VEGF plays an important role in pulmonary vascular and alveolar development (Fig. 1). By inhibiting the effects of VEGF, bevacizumab may result in pulmonary hypertension (PH) [6]. In fact, PH following bevacizumab therapy has been described in adult cancer patients [7]. We evaluated the incidence of new-onset PH or exacerbation of PH after intravitreal bevacizumab for ROP.

Fig. 1. Illustration descripting the potential mechanism by which bevacizumab may exacerbate pulmonary hypertension.

Bevacizumab injected intravitreally for retinopathy of prematurity may be absorbed into the systemic circulation by extra-ocular leakage. Inhibition of VEGF action in the pulmonary endothelial cells may affect vasculogenesis and angiogenesis resulting in vascular growth arrest. Vascular and alveolar growth arrest may potentially lead to remodeling of pulmonary vasculature and pulmonary hypertension. VEGF vascular endothelial growth factor.

METHODS

After institutional review board approval at UC Davis Children’s Hospital, Sacramento, CA, we performed a retrospective study on preterm infants admitted in the NICU from August 2011 to July 2021, who received bevacizumab for ROP. Current procedural terminology codes (67028 intravitreal injections, J2779 and J9035 bevacizumab injections) were used to identify infants treated with bevacizumab in the NICU. Demographic data, type of ROP, echocardiographic findings within 2 weeks before and after ROP treatment, presence of bronchopulmonary dysplasia (BPD), respiratory support before and after treatment, and use of pulmonary vasodilators (inhaled nitric oxide, sildenafil, and bosentan) were collected. Echocardiographic findings including right ventricular (RV) hypertrophy, interventricular septal (IVS) flattening, elevated RV systolic pressures, and right-to-left and bidirectional shunting across the patent foramen ovale (PFO) and/or patent ductus arteriosus (PDA), were used to define PH. Finally, we also identified infants treated with laser ablation for ROP (codes 67228 and 67229) in the NICU.

RESULTS

A total of 15 patients received at least one dose of bevacizumab for ROP (Supplement Table 1). Eight infants (53.3%) had PH following bevacizumab therapy. Three infants had evidence of worsening PH on echocardiogram (Supplement Table 2). Five infants had new-onset PH with significant clinical deterioration and escalation of respiratory support. One infant required initiation of pulmonary vasodilator therapy (three other infants were already on pulmonary vasodilators). One of these infants required nasal continuous positive airway pressure (CPAP) for a week prior to weaning to high flow nasal cannula. Second infant required high frequency ventilation along with initiation of inhaled NO, sildenafil and bosentan. The third infant required 5 days of mechanical ventilation. In contrast, none of the infants treated with laser (n = 17) during the study period had new-onset PH, while three (17.6%) had exacerbation of PH. Seven infants (46.7%) required subsequent laser treatment following initial bevacizumab therapy.

DISCUSSION

Preterm infants with BPD and ROP are at risk for PH. Our findings suggest that therapy with intravitreal bevacizumab may be associated with exacerbation of PH, as described recently [8]. Elevated serum bevacizumab concentrations were previously observed among infants after intravitreal injections [5].

As VEGF is necessary for normal development of brain, lungs, bones, kidneys, and retina, there are potential safety concerns owing to adverse effects of decreased VEGF concentrations. Newborn rats treated with a VEGF receptor inhibitor had reduced pulmonary arterial density and alveolar counts, and higher RV weights and pulmonary arterial wall thickness, with effects persisting into adulthood [6]. In the BEAT-ROP trial, four out of the five infants who died in bevacizumab group had low oxygen or respiratory failure, and one had a do-not-resuscitate order [3].

In preterm infants, alveolar phase of lung development occurs over several weeks after birth, accompanied by rapid pulmonary vascular growth. It is possible that pulmonary vascular growth is disrupted by anti-VEGF agents. Reduced angiogenesis can be associated with PH (Fig. 1). VEGF stimulates endothelial nitric oxide synthase (eNOS) and releases nitric oxide (NO) which relaxes pulmonary vascular smooth muscle cells [9]. VEGF inhibition mimics structural and functional abnormalities of PH, and VEGF treatment improves PH through upregulation of NO production. Lung VEGF expression is markedly decreased in ovine models of PH. In preterm infants at risk of BPD with arrested vascular and alveolar growth, a decrease in NO release may contribute to worsening or new-onset PH [10].

Larger multicenter observational studies with over 115 infants each in bevacizumab and laser ablation groups matched by gestational age and postnatal age at intervention will be needed to assess whether there is a true effect of bevacizumab on PH. Until then, echocardiographic monitoring for PH may be beneficial in infants treated with bevacizumab.

DATA AVAILABILITY

The data presented in this study are available in this article.