Serum Levels of Vascular Endothelial Growth Factor and Related Factors After Intravitreous Bevacizumab Injection for Retinopathy of Prematurity

Abstract

(IVB) have been found to be effective for the treatment of retinopathy of prematurity (ROP). However, serum levels of vascular endothelial growth factor (VEGF) have been found to be suppressed for 2 weeks after IVB in patients with ROP. Changes in serum VEGF levels after IVB in patients with ROP may be important because VEGF also plays a role in the neurodevelopment of newborns. OBJECTIVE To investigate the correlation of levels of VEGF and related growth factors with bevacizumab levels in the systemic circulation after IVB in patients with type 1 ROP. DESIGN, SETTING, AND PARTICIPANTS We studied a prospective case series at an institutional referral center from December 1, 2011, through February 28, 2013. We enrolled patients with type 1 ROP who received IVB. We collected blood samples before and for as long as 8 weeks after IVB. The samples were tested for serum levels of bevacizumab and growth factors, including VEGF, VEGF receptor 1 (VEGFR1), VEGFR2, Tie2, erythropoietin, transforming growth factor β1, insulinlike growth factor type 1, angiopoietin 1, angiopoietin 2, angiopoietinlike 3, and angiopoietin 4. The serum concentrations of these factors were measured using enzyme-linked immunosorbent assays. MAIN OUTCOMES AND MEASURES Serum levels of VEGF, bevacizumab, and the other growth factors before and for as long as 8 weeks after IVB. RESULTS We enrolled 8 patients with type 1 ROP. Bevacizumab levels were elevated 1 day after IVB in the 3 patients for whom measurements were available (mean [SD], 1425 [1010 (95% CI, 0-3934)] ng/mL; P = .13) and remained detectable in the serum as long as 8 weeks after IVB (285 ng/mL for the 1 patient with a measurement available). Serum VEGF levels were suppressed for the same period (mean [SD] level at 1 day after IVB, 379 [226 (95% CI, 190-568)] pg/mL for the 3 patients with measurements available; at 8 weeks, 216 pg/mL for the 1 patient with a measurement available). We found a negative correlation between the serum levels of bevacizumab and VEGF in the patients with ROP who received IVB (r = −0.43 [95% CI, −0.67 to −0.10]; P = .01). No changes were identified in the serum levels of any of the other factors after IVB. Bevacizumab may interfere with the actual level of VEGF in the serum, and the total VEGF level in the serum cannot be determined when bevacizumab is present. Wide CIs were noted in the measurement of these factors, probably owing to the small number of patients enrolled in this study. CONCLUSIONS AND RELEVANCE Serum VEGF levels were suppressed for 2 months after IVB in patients with type 1 ROP owing to the leakage of bevacizumab into the systemic circulation.

Hypotension Associated With Intravitreal Bevacizumab Therapy for Retinopathy of Prematurity

“…4 In published reports on the effectiveness of bevacizumab, there are no systemic complications attributable to intravitreal bevacizumab, such as blood pressure fluctuation, cardiopulmonary distress, or infection, in the treatment of ROP. [10][11][12] However, the medication can leak through the compromised blood-retina barrier with ROP and be detected in serum 2 days after injection. 14 We report that only 1 preterm twin (twin B, but not twin A) suffered hypotension and desaturation after intravitreal bevacizumab therapy.…”

“…9 Neither systemic adverse events nor hypotension effects were reported in clinical trials after treatment with bevacizumab for ROP 4,10,11 ; however, the serum level of bevacizumab has been detected after intravitreous injection in preterm infants. 12 To provide more safety information for bevacizumab in preterm infants, we report a case of twin preterm infants treated abstract Intravitreal bevacizumab therapy in preterm infants for retinopathy of prematurity (ROP) can be associated with hypotension. We report twin preterm infants who developed hypotension within 1 day after intravitreal bevacizumab therapy for ROP.…”

Bevacizumab treatment for retinopathy of prematurity in South Africa

“…Underlining fears about systemic safety, bevacizumab has been detected in the serum of both infants and adults after intraocular injection, [7] leading to ongoing debate around appropriate dosage and the best anti-VEGF agent. The dose used by Kana et al [5] (0.625 mg) is the same as used by most authors in the current literature, although some have recommended a lower dose of 0.25 mg. [8,9] A lower dose would be expected to reduce systemic complications at the expense of a higher risk of recurrence.…”

Serial evaluation of retinal vascular changes in infants treated with intravitreal bevacizumab for aggressive posterior retinopathy of prematurity in zone I

“…Serum VEGF level is reportedly suppressed for 2 months after IVB (0.625 mg) in patients with type 1 ROP (as defined by the early treatment for ROP guidelines). 35 In the fetus, VEGF is expressed in most tissues and has a vital role in organogenesis and neurodevelopment. 36 This raises the concern that important normal physiological effects associated with VEGFs might get inhibited leading to abnormal organogenesis.…”

“…Anti-VEGF treatment may have the capacity to reduce their reserves even further. 35 Unfortunately, we do not have access to see the growing vasculature of the various developing organs as clearly and directly as retinal blood vessels in an infant. The retinal vasculature has many similarities with the CNS and renal blood vessels.…”