International Ophthalmology

, Volume 39, Issue 10, pp 2161–2169 | Cite as

Efficacy of intravitreal aflibercept monotherapy in retinopathy of prematurity evaluated by periodic fluorescence angiography and optical coherence tomography

  • Aslı VuralEmail author
  • İrfan Perente
  • İsmail Umut Onur
  • Erdem Eriş
  • Zeynep Seymen
  • Gülsüm Oya Hergünsel
  • Özgül Salihoğlu
  • Fadime Ulviye Yiğit
Original Paper



To evaluate the efficacy of intravitreal aflibercept (IVA) in vascular and macular maturation in neonates with type 1 retinopathy of prematurity (ROP) and aggressive posterior retinopathy of prematurity (APROP).

Materials and methods

Thirty-six eyes of 18 patients with type 1 ROP or APROP in zone I or posterior zone II were enrolled in our study. At baseline, only fluorescein angiography (FA) was performed. After IVA injection, both FA and optical coherence tomography (OCT) were performed after 6.8 ± 0.8 (range 6–8) and 19 ± 0.9 (range 18–20) weeks to follow vascular and macular changes.


Both diffuse flat neovascularization with leakage and abnormal vascular branching at the small arteriolar level were detected in all eyes (100%) at baseline FA. Regression of the disease was observed in 34 eyes (94.4%) in the first week with binocular indirect ophthalmoscopy. Early unresponsiveness in remaining two eyes of an infant required an IVA re-treatment. Late reactivation was detected only in 19.4% of eyes, none of which required treatment during 12 months of follow-up. The most common feature after IVA injection was abnormal branching at capillary level, which was noted in 100% in the first post-injection FA and 50.0% of all eyes in the second FA. Meanwhile, the end limit of vascularization was observed in zone III in 83.3% of eyes. No vascular abnormality was also detected in 27.3% of eyes. The OCT examination at a mean postmenstrual age of 43.4 weeks revealed cystoid macular changes in four eyes of two infants (11.1%), normal foveal contour in 30 eyes of 15 infants (83.3%) and matured ellipsoid zone at the foveal center in 28 eyes of 14 infants (77.8%). Macular maturation was complete in all eyes in the last OCT analyses.


Intravitreal aflibercept monotherapy has been an effective treatment in type I ROP and APROP with much lower early and late re-treatment rates because of early unresponsiveness and late reactivation, respectively. In most of the eyes, rapid vascular outgrowth beyond zone III together with normal macular maturation was observed more precisely by periodic FA and OCT.


Aflibercept Fluorescein angiography Optical coherence tomography Retinopathy of prematurity 


Compliance with ethical standards

Conflict of interest

The authors report no conflicts of interest.


  1. 1.
    Stenkuller PG, Du L, Gilbert C, Foster A, Colins ML, Coats DK (1999) Childhood blindness. J AAPOS 3:26–32CrossRefGoogle Scholar
  2. 2.
    Kwinta P, Bik-Multanowski M, Mitkowska Z, Tomasik T, Pietrzyk JJ (2008) The clinical role of vascular endothelial growth factor (VEGF) system in the pathogenesis of retinopathy of prematurity. Graefes Arch Clin Exp Ophthalmol 246:1467–1475CrossRefGoogle Scholar
  3. 3.
    Wang H, Yang Z, Jiang Y, Flannery J, Hammond S, Kafri T, Vemuri SK, Jones B, Hartnett ME (2014) Quantitative analyses of retinal vascular area and density after different methods to reduce VEGF in a rat model of retinopathy of prematurity. Invest Ophthalmol Vis Sci 55:737–744CrossRefGoogle Scholar
  4. 4.
    Geisen P, Peterson LJ, Mariniuk D (2008) Neutralizing anti-body to VEGF reduces intravitreous neovascularization and may not interfere with ongoing intraretinal vascularization in a rat model of retinopathy of prematurity. Mol Vis 14:34557Google Scholar
  5. 5.
    Kong L, Mintz-Hittner HA, Penland Kretzer FL, Chevez-Barrios P (2008) Intravitreous bevacizumab as anti-vascular endothelial growth factor therapy for retinopathy of prematurity: a morphologic study. Arch Ophthalmol 126:1161–1163CrossRefGoogle Scholar
  6. 6.
    Lalwani GA, Berrocal AM, Murray TG, Buch M, Cardone S, Hess D, Johnson RA, Puliafito CA (2008) Off-label use of intravitreal bevacizumab (Avastin) for salvage treatment in progressive threshold retinopathy of prematurity. Retina 28:13–18CrossRefGoogle Scholar
  7. 7.
    Mintz-Hittner HA, Kuffel RR Jr (2008) Intravitreal injection of bevacizumab (Avastin) for treatment of stage 3 retinopathy of prematurity in zone I or posterior zone II. Retina 28:831–838CrossRefGoogle Scholar
  8. 8.
    Kusaka S, Shima C, Wada K, Arahori H, Shimojyo H, Sato T, Fujikado T (2008) Efficacy of intravitreal injection of bevacizumab for severe retinopathy of prematurity: a pilot study. Br J Ophthalmol 92:1450–1455CrossRefGoogle Scholar
  9. 9.
    Martinez-Castellanos MA, Schwartz S, Hernandez-Rojas ML, Kon-Jara VA, Garcia-Aguirre G, Guerrero-Naranjo JL, Chan RV, Quiroz-Meracado H (2013) Longterm effect of antiangiogenic therapy for retinopathy of prematurity up to 5 years of follow-up. Retina 33:329–338CrossRefGoogle Scholar
  10. 10.
    Castellanos MA, Schwartz S, García-Aguirre G, Quiroz-Mercado H (2013) Short-term outcome after intravitreal ranibizumab injections for the treatment of retinopathy of prematurity. Br J Ophthalmol 97:816–819CrossRefGoogle Scholar
  11. 11.
    Mintz-Hittner HA, Kennedy KA, Chuang AZ, the BEAT-ROP Cooperative Group (2011) Efficacy of intravitreal bevacizumab for stage 3 retinopathy of prematurity: preliminary results of the BEAT-ROP clinical trial. N Engl J Med 364:603–615CrossRefGoogle Scholar
  12. 12.
    Orozco-Gómez LP, Hernández-Salazar L, Moguel-Ancheita S, Ramírez-Moreno MA, Morales-Cruz MV (2011) Laser-ranibizumab treatment for retinopathy of prematurity in umbral-preumbral disease. Three years of experience. Cardiology 79:207–214, 225–232Google Scholar
  13. 13.
    Autrata R, Krejcírová I, Senková K, Holosova M, Dolezel Z, Borek I (2012) Intravitreal pegaptanib combined with diode laser therapy for stage 3+ retinopathy of prematurity in zone I and posterior zone II. Eur J Ophthalmol 22:687–694CrossRefGoogle Scholar
  14. 14.
    Papadopoulos N, Martin J, Ruan Q, Rafique A, Rosconi MP, Shi E, Pyles EA, Yancopoulos GD, Stahl N et al (2011) Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis 15:171–185CrossRefGoogle Scholar
  15. 15.
    Salman AG, Said AM (2015) Structural, visual and refractive outcomes of intravitreal aflibercept injection in high-risk prethreshold type 1 retinopathy of prematurity. Opthalmic Res 53(1):15–20CrossRefGoogle Scholar
  16. 16.
    Sukgen EA, Söker G, Koçluk Y, Gülek B (2017) Effect of intravitreal aflibercept on central retinal arterial blood flow in type 1 retinopathy of prematurity. Eur J Ophthalmol 27(6):751–755CrossRefGoogle Scholar
  17. 17.
    Fierson WM (2013) Screening examination of premature infants for retinopathy of prematurity. American Academy of Pediatrics Section on Ophthalmology; American Academy of Ophthalmology; American Association for Pediatric Ophthalmology and Strabismus; American Association of Certified Orthoptists. Pediatrics 131(1):189–195CrossRefGoogle Scholar
  18. 18.
    Early Treatment For Retinopathy Of Prematurity Cooperative Group (2003) Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial. Arch Ophthalmol 121(12):1684–1694CrossRefGoogle Scholar
  19. 19.
    Lepore D, Molle F, Pagliara MM, Baldascino A, Angora C, Sammartino M, Quinn GE (2011) Atlas of fluorescein angiographic findings in eyes undergoing laser for retinopathy of prematurity. Ophthalmology 118(1):168–175CrossRefGoogle Scholar
  20. 20.
    Lorenz B, Stieger K, Jäger M, Mais C, Stieger S, Adrassi- Dardida M (2017) Retinal vascular development with 0.312 mg intravitreal bevacizumab to treat severe posterior retinopathy of prematurity: a longitudinal fluorescein angiographic study. Retina 37(1):97–111CrossRefGoogle Scholar
  21. 21.
    Maldonado RS, Izatt J, Sarin N, Wallace DK, Freedman S, Cotten CM, Toth CA (2010) Optimizing hand-held spectral domain optical coherence tomography imaging for neonates, infants, and children. Invest Ophthalmol Vis Sci 51:2678–2685CrossRefGoogle Scholar
  22. 22.
    Blair MP, Shapiro MJ, Hartnett ME (2012) Fluorescein angiography to estimate normal peripheral retinal nonperfusion in children. J AAPOS 16:234–237CrossRefGoogle Scholar
  23. 23.
    Henaine-Berra A, Garcia-Aguirre G, Quiroz-Mercado H, Martinez-Castellanos MA (2014) Retinal fluorescein angiographic changes following intravitreal anti-VEGF therapy. J AAPOS 18(2):120–123CrossRefGoogle Scholar
  24. 24.
    Tahija SG, HersetyatiR Lam GC, Kusaka S, Mc Melamine PG (2014) Fluorescein angiographic observations of peripheral retinal vessel growth in infants after intravitreal injection of bevacizumab as sole therapy for zone I and posterior zone II retinopathy of prematurity. Br J Ophthalmol 98:507–512CrossRefGoogle Scholar
  25. 25.
    Garcia Gonzalez JM, Snyder L, Blair M, Rohr A, Shapiro M, Greenwald M (2017) Prophylactic peripheral laser and fluorescein angiography after bevacizumab for retinopathy of prematurity. Retina 38(4):764–772CrossRefGoogle Scholar
  26. 26.
    Huang Q, Zhang Q, Fei P, Xu Y, Lyu J, Ji X, Peng J, Li YA, Zhao P (2017) Ranibizumab injection as primary treatment in patients with retinopathy of prematurity: anatomic outcomes and influencing factors. Ophthalmology 161–6420(16):31697–31699Google Scholar
  27. 27.
    Stewart MW, Rosenfeld PJ, Penha FM, Wang F, Yehoshua Z, Buenu-Lopez E, Lopez PF (2012) Pharmacokinetic rationale for dosing every 2 weeks versus 4 weeks with intravitreal ranibizumab, bevacizumab, and aflibercept (vascular endothelial growth factor Trap eye). Retina 32:434–457PubMedGoogle Scholar
  28. 28.
    Yetik H, Gunay M, Sirop S, Salihoglu Z (2015) Intravitreal bevacizumab monotherapy for type-1 prethreshold, threshold, and aggressive posterior retinopathy: 27 month follow-up results from Turkey. Graefes Arch Clin Exp Ophthalmol 253:1677–1683CrossRefGoogle Scholar
  29. 29.
    Padhi TR, Das T, Rath S, Pradhan L, Sutar S, Panda KG, Modi R, Jalalli S (2016) Serial retinal evaluation of vascular changes in infants treated with intravitreal bevacizumab for aggressive posterior retinopathy of prematurity in zone I. Eye (Lond) 30:392–399CrossRefGoogle Scholar
  30. 30.
    Michaelson IC, Benezra D, Berson D (1982) Possible metabolic mechanism modulating blood vessel development in the inner eye and their significance for vascular pathology in the definitive eye. Metab Pediatr Syst Ophthalmol 6:1–10PubMedGoogle Scholar

Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  1. 1.Ophthalmology ClinicsSBU Bakirkoy Dr. Sadi Konuk Training and Research HospitalBakirkoyTurkey
  2. 2.Ophthalmology ClinicsSBU Beyoglu Eye Training and Research HospitalBeyoğluTurkey
  3. 3.Anesthesiology ClinicsSBU Bakirkoy Dr. Sadi Konuk Training and Research HospitalBakirkoyTurkey
  4. 4.Neonatology ClinicsSBU Bakirkoy Dr. Sadi Konuk Training and Research HospitalBakirkoyTurkey

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