Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Comment
  • Published:

Prethreshold retinopathy of prematurity: VEGF inhibition without VEGF inhibitors

Abstract

The risk of developing treatment-warranted Type 1 retinopathy of prematurity (ROP) might be reduced in preterm infants by modifying certain systemic factors. There are steps that can be taken both early and late in the course of retinal vascular maturation that may potentially reduce an infant’s risk of developing Type 1 ROP. In prethreshold stage 2–3 ROP without plus disease, a combination of supplemental oxygen, correction of severe anemia, and light adaptation to reduce rod photoreceptor oxygen consumption helped us to reduce ROP severity, and encouraged a return to a more physiologic retinal vascular maturation pattern. Thus, it may be possible to reduce the risk of developing Type 1 ROP by making adjustments in certain systemic parameters aimed at reducing retinal hypoxia, thereby gently lowering pathologically elevated levels of vascular endothelial growth factor (VEGF) within the eye.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

References

  1. McNamara JA, Tasman W, Brown GC, Federman JL. Laser photocoagulation for stage 3+ retinopathy of prematurity. Ophthalmology. 1991;98:576–80.

    Article  CAS  PubMed  Google Scholar 

  2. VanderVeen DK, Melia M, Yang MB, Hutchinson AK, Wilson LB, Lambert SR. Anti-vascular endothelial growth factor therapy for primary treatment of type 1 retinopathy of prematurity: a report by the American Academy of Ophthalmology. Ophthalmology. 2017;124:619–33.

    Article  PubMed  Google Scholar 

  3. Sankar MJ, Sankar J, Chandra P. Anti-vascular endothelial growth factor (VEGF) drugs for treatment of retinopathy of prematurity. Cochrane Database Syst Rev. 2018;1:CD009734.

    PubMed  Google Scholar 

  4. Vogel RN, Strampe M, Fagbemi OE, Visotcky A, Tarima S, Carroll J, et al. Foveal development in infants treated with bevacizumab or laser photocoagulation for retinopathy of prematurity. Ophthalmology. 2018;125:444–52.

    Article  PubMed  Google Scholar 

  5. Toy BC, Schachar IH, Tan GS, Moshfeghi DM. Chronic vascular arrest as a predictor of bevacizumab treatment failure in retinopathy of prematurity. Ophthalmology. 2016;123:2166–75.

    Article  PubMed  Google Scholar 

  6. Lepore D, Quinn GE, Molle F, Orazi L, Baldascino A, Ji MH, et al. Follow-up to age 4 years of treatment of type 1 retinopathy of prematurity intravitreal bevacizumab injection versus laser: fluorescein angiographic findings. Ophthalmology. 2018;125:218–26.

    Article  PubMed  Google Scholar 

  7. Chuluunbat T, Chan RV, Wang NK, Lien R, Chen YP, Chao AN, et al. Nonresponse and recurrence of retinopathy of prematurity after intravitreal ranibizumab treatment. Ophthalmic Surg Lasers Imaging Retin. 2016;47:1095–105.

    Article  Google Scholar 

  8. Yonekawa Y, Thomas BJ, Thanos A, Todorich B, Drenser KA, Trese MT, et al. The cutting edge of retinopathy of prematurity care: expanding the boundaries of diagnosis and treatment. Retina. 2017;37:2208–25.

    Article  PubMed  Google Scholar 

  9. Yonekawa Y, Wu WC, Nitulescu CE, Chan RVP, Thanos A, Thomas BJ, et al. Progressive retinal detachment in infants with retinopathy of prematurity treated with intravitreal bevacizumab or ranibizumab. Retina. 2018;38:1079–83.

    Article  CAS  Google Scholar 

  10. Wu WC, Shih CP, Lien R, Wang NK, Chen YP, Chao AN, et al. Serum vascular endothelial growth factor after bevacizumab or ranibizumab treatment for retinopathy of prematurity. Retina. 2017;37:694–701.

    Article  CAS  PubMed  Google Scholar 

  11. Ells AL, Wesolosky JD, Ingram AD, Mitchell PC, Platt AS. Low-dose ranibizumab as primary treatment of posterior type I retinopathy of prematurity. Can J Ophthalmol. 2017;52:468–74.

    Article  PubMed  Google Scholar 

  12. Wallace DK, Kraker RT, Freedman SF, Crouch ER, Hutchinson AK, Bhatt AR, et al. Assessment of lower doses of intravitreous bevacizumab for retinopathy of prematurity: a phase 1 dosing study. JAMA Ophthalmol. 2017;135:654–6.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Araz-Ersan B, Kir N, Tuncer S, Aydinoglu-Candan O, Yildiz-Inec D, Akdogan B, et al. Preliminary anatomical and neurodevelopmental outcomes of intravitreal bevacizumab as adjunctive treatment for retinopathy of prematurity. Curr Eye Res. 2015;40:585–91.

    Article  CAS  PubMed  Google Scholar 

  14. Kennedy KA, Mintz-Hittner HA, BEAT-ROP Cooperative Group. Medical and developmental outcomes of bevacizumab versus laser for retinopathy of prematurity. J AAPOS. 2018;22:61–5 e1.

    Article  PubMed  Google Scholar 

  15. Lien R, Yu MH, Hsu KH, Liao PJ, Chen YP, Lai CC, et al. Neurodevelopmental outcomes in infants with retinopathy of prematurity and bevacizumab treatment. PLoS ONE. 2016;11:e0148019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Morin J, Luu TM, Superstein R, Ospina LH, Lefebvre F, Simard MN, et al. Neurodevelopmental outcomes following bevacizumab injections for retinopathy of prematurity. Pediatrics. 2016;137:e20153218.

    Article  PubMed  Google Scholar 

  17. Kamba T, Tam BY, Hashizume H, Haskell A, Sennino B, Mancuso MR, et al. VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature. Am J Physiol Heart Circ Physiol. 2006;290:H560–76.

    Article  CAS  PubMed  Google Scholar 

  18. Lutty GA, Hasegawa T, Baba T, Grebe R, Bhutto I, McLeod DS. Development of the human choriocapillaris. Eye. 2010;24:408–15.

    Article  CAS  PubMed  Google Scholar 

  19. Maharaj AS, Walshe TE, Saint-Geniez M, Venkatesha S, Maldonado AE, Himes NC, et al. VEGF and TGF-beta are required for the maintenance of the choroid plexus and ependyma. J Exp Med. 2008;205:491–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Melamed S, Ben-Sira I, Ben-Shaul Y. Ultrastructure of fenestrations in endothelial choriocapillaries of the rabbit—a freeze-fracturing study. Br J Ophthalmol. 1980;64:537–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rhee S, Chung JI, King DA, D’amato G, Paik DT, Duan A, et al. Endothelial deletion of Ino80 disrupts coronary angiogenesis and causes congenital heart disease. Nat Commun. 2018;9:368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hartnett ME, DeAngelis MM. The role of reactive oxygen species and oxidative signaling in retinopathy of prematurity. In: Stratton RD, Hauswirth WW, Gardner TW, editors. Studies on retinal and choroidal disorders. Humana Press, Springer Science; 2012. pp. 559–84 New York.

    Chapter  Google Scholar 

  23. Heidary G, Vanderveen D, Smith LE. Retinopathy of prematurity: current concepts in molecular pathogenesis. Semin Ophthalmol. 2009;24:77–81.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Hellstrom A, Ley D, Hallberg B, Lofqvist C, Hansen-Pupp I, Ramenghi LA, et al. IGF-1 as a drug for preterm infants: a step-wise clinical development. Curr Pharm Des. 2017;23:5964–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hellstrom A, Ley D, Hansen-Pupp I, Hallberg B, Ramenghi LA, Lofqvist C, et al. IGF-I in the clinics: use in retinopathy of prematurity. Growth Horm IGF Res. 2016;30:3175–80.

    Google Scholar 

  26. Gaynon MW. Rethinking STOP-ROP: is it worthwhile trying to modulate excessive VEGF levels in prethreshold ROP eyes by systemic intervention? A review of the role of oxygen, light adaptation state, and anemia in prethreshold ROP. Retina. 2006;26:S18–23.

    Article  PubMed  Google Scholar 

  27. Gaynon MW, Stevenson DK. What can we learn from STOP-ROP and earlier studies? Pediatrics. 2000;105:420–1.

    Article  CAS  PubMed  Google Scholar 

  28. Gaynon MW, Stevenson DK, Sunshine P, Fleisher BE. Supplemental oxygen and light for prethreshold retinopathy of prematurity. In: Shapiro MJ, Biglan AW, Miller MM, editors. Retinopathy of prematurity. Amsterdam/New York: Kugler Publications; 1995. pp. 137–8.

    Google Scholar 

  29. Gaynon MW, Stevenson DK, Sunshine P, Fleisher BE, Landers MB. Supplemental oxygen may decrease progression of prethreshold disease to threshold retinopathy of prematurity. J Perinatol. 1997;17:434–8.

    CAS  PubMed  Google Scholar 

  30. Support Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, Carlo WA, Finer NN, Walsh MC, Rich W, Gantz MG, et al. Target ranges of oxygen saturation in extremely preterm infants. N Engl J Med. 2010;362:1959–69.

    Article  PubMed Central  Google Scholar 

  31. Cayabyab R, Arora V, Wertheimer F, Durand M, Ramanathan R. Graded oxygen saturation targets and retinopathy of prematurity in extremely preterm infants. Pediatr Res. 2016;80:401–6.

    Article  CAS  PubMed  Google Scholar 

  32. Chen ML, Guo L, Smith LE, Dammann CE, Dammann O. High or low oxygen saturation and severe retinopathy of prematurity: a meta-analysis. Pediatrics. 2010;125:e1483–92.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Darlow BA, Binenbaum G. Oxygen, weight gain, IGF-1 and ROP: not a straight-forward equation. Acta Paediatr. 2018;107:732–3.

    Article  PubMed  Google Scholar 

  34. Lundgren P, Hard AL, Wilde A, Lofqvist C, Smith LEH, Hellstrom A. Implementing higher oxygen saturation targets reduced the impact of poor weight gain as a predictor for retinopathy of prematurity. Acta Paediatr. 2018;107:767–73.

    Article  CAS  PubMed  Google Scholar 

  35. STOP-ROP Manual of Procedures. Available from the Emmes Corp. 2000, pp. 31–2 http://pub.emmes.com/study/rop/stop-publications.html.

  36. The STOP-ROP Multicenter Study Group Supplemental therapeutic oxygen for prethreshold retinopathy of prematurity (STOP-ROP), a randomized, controlled trial. I: primary outcomes. Pediatrics. 2000;105:295–310.

  37. Colaizy TT, Longmuir S, Gertsch K, Abramoff MD, Klein JM. Use of a supplemental oxygen protocol to suppress progression of retinopathy of prematurity. Invest Ophthalmol Vis Sci. 2017;58:887–91.

    Article  PubMed  Google Scholar 

  38. Lundgren P, Athikarisamy SE, Patole S, Lam GC, Smith LE, Simmer K. Duration of anaemia during the first week of life is an independent risk factor for retinopathy of prematurity. Acta Paediatr. 2018;107:759–66.

    Article  PubMed  Google Scholar 

  39. Arden GB, Sidman RL, Arap W, Schlingemann RO. Spare the rod and spoil the eye. Br J Ophthalmol. 2005;89:764–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Cringle SJ, Yu DY, Yu PK, Su EN. Intraretinal oxygen consumption in the rat in vivo. Invest Ophthalmol Vis Sci. 2002;43:1922–7.

    PubMed  Google Scholar 

  41. Chan-Ling T, Barnett NL, Maccarone R, Provis J, Koina M, Hu P, et al. Dark-rearing (DR) precludes the initiating event in OIR and eliminates the pathology seen in the second phase of disease: rationale for novel non-invasive treatment for ROP. Invest Ophthalmol Vis Sci. 2016;57:37–50.

  42. Löfqvist CA, Najm S, Hellgren G, Engström E, Sävman K, Nilsson AK, et al. Association of retinopathy of prematurity with low levels of arachidonic acid: a secondary analysis of a randomized clinical trial. JAMA Ophthalmol. 2018;36:271–7.

    Article  Google Scholar 

  43. Hartnett ME. The prematurity of recommending particular polyunsaturated fatty acid supplements for retinopathy of prematurity. JAMA Ophthalmol. 2018;36:277–8.

    Article  Google Scholar 

  44. Ohlsson A, Aher SM. Early erythropoiesis-stimulating agents in preterm or low birth weight infants. Cochrane Database Syst Rev. 2017;11:CD004863.

    PubMed  Google Scholar 

  45. Aiello LP. Angiogenic pathways in diabetic retinopathy. N Engl J Med. 2005;353:839–41.

    Article  CAS  PubMed  Google Scholar 

  46. Manzoni P, Maestri A, Gomirato G, Takagi H, Watanabe D, Matsui S. Erythropoietin as a retinal angiogenic factor. N Engl J Med. 2005;353:2190–1.

    Article  CAS  PubMed  Google Scholar 

  47. Watanabe D, Suzuma K, Matsui S, Kurimoto M, Kiryu J, Kita M, et al. Erythropoietin as a retinal angiogenic factor in proliferative diabetic retinopathy. N Engl J Med. 2005;353:782–92.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michael W. Gaynon.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gaynon, M.W., Wong, R.J., Stevenson, D.K. et al. Prethreshold retinopathy of prematurity: VEGF inhibition without VEGF inhibitors. J Perinatol 38, 1295–1300 (2018). https://doi.org/10.1038/s41372-018-0177-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41372-018-0177-9

This article is cited by

Search

Quick links