title: Serum levels of vascular endothelial growth factor and related factors after intravitreous bevacizumab injection for retinopathy of prematurity.
abstract: OBJECTIVE
  Intravitreous injections of bevacizumab (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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
authors.affiliation: Department of Ophthalmology, Chang Gung Memorial Hospital, Guishan, Taoyuan, Taiwan2Department of Medicine, Chang Gung University, College of Medicine, Taoyuan, Taiwan.
authors.forename: Wei-Chi
authors.initials: WC
authors.lastname: Wu
authors.affiliation: Department of Medicine, Chang Gung University, College of Medicine, Taoyuan, Taiwan3Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Reyin
authors.initials: R
authors.lastname: Lien
authors.affiliation: Department of Health Care Administration, Oriental Institute of Technology, New Taipei City, Taiwan5Department of Business Administration, National Taiwan University, Taipei, Taiwan.
authors.forename: Pei-Ju
authors.initials: PJ
authors.lastname: Liao
authors.affiliation: Department of Ophthalmology, Chang Gung Memorial Hospital, Guishan, Taoyuan, Taiwan2Department of Medicine, Chang Gung University, College of Medicine, Taoyuan, Taiwan.
authors.forename: Nan-Kai
authors.initials: NK
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology, Chang Gung Memorial Hospital, Guishan, Taoyuan, Taiwan2Department of Medicine, Chang Gung University, College of Medicine, Taoyuan, Taiwan.
authors.forename: Yen-Po
authors.initials: YP
authors.lastname: Chen
authors.affiliation: Department of Ophthalmology, Chang Gung Memorial Hospital, Guishan, Taoyuan, Taiwan2Department of Medicine, Chang Gung University, College of Medicine, Taoyuan, Taiwan.
authors.forename: An-Ning
authors.initials: AN
authors.lastname: Chao
authors.affiliation: Department of Ophthalmology, Chang Gung Memorial Hospital, Guishan, Taoyuan, Taiwan2Department of Medicine, Chang Gung University, College of Medicine, Taoyuan, Taiwan.
authors.forename: Kuan-Jen
authors.initials: KJ
authors.lastname: Chen
authors.affiliation: Department of Ophthalmology, Chang Gung Memorial Hospital, Guishan, Taoyuan, Taiwan2Department of Medicine, Chang Gung University, College of Medicine, Taoyuan, Taiwan.
authors.forename: Tun-Lu
authors.initials: TL
authors.lastname: Chen
authors.affiliation: Department of Ophthalmology, Chang Gung Memorial Hospital, Guishan, Taoyuan, Taiwan2Department of Medicine, Chang Gung University, College of Medicine, Taoyuan, Taiwan.
authors.forename: Yih-Shiou
authors.initials: YS
authors.lastname: Hwang
authors.affiliation: Department of Ophthalmology, Chang Gung Memorial Hospital, Guishan, Taoyuan, Taiwan2Department of Medicine, Chang Gung University, College of Medicine, Taoyuan, Taiwan.
authors.forename: Chi-Chun
authors.initials: CC
authors.lastname: Lai
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D042501:Angiogenic Proteins / Q000097:blood; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000627:therapeutic use*; D000068258:Bevacizumab; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D019102:Infant, Very Low Birth Weight; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood*; D058449:Intravitreal Injections; D008297:Male; D011446:Prospective Studies; D020794:Receptor Protein-Tyrosine Kinases / Q000097:blood; D012178:Retinopathy of Prematurity / Q000097:blood / Q000188:drug therapy*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000097:blood*
chemical_list: D020533:Angiogenesis Inhibitors; D042501:Angiogenic Proteins; D061067:Antibodies, Monoclonal, Humanized; D036341:Intercellular Signaling Peptides and Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D020794:Receptor Protein-Tyrosine Kinases