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Year : 2012  |  Volume : 2  |  Issue : 4  |  Page : 115-116

Anti-vascular endothelium growth factor therapy for retinopathy of prematurity: A continuing debate

Associate Professor, Department of Ophthalmology, National University Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan

Date of Web Publication7-Dec-2012

Correspondence Address:
Chang-Hao Yang
Associate Professor, Department of Ophthalmology, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 100
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Source of Support: None, Conflict of Interest: None

DOI: 10.1016/j.tjo.2012.11.002

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How to cite this article:
Yang CH. Anti-vascular endothelium growth factor therapy for retinopathy of prematurity: A continuing debate. Taiwan J Ophthalmol 2012;2:115-6

How to cite this URL:
Yang CH. Anti-vascular endothelium growth factor therapy for retinopathy of prematurity: A continuing debate. Taiwan J Ophthalmol [serial online] 2012 [cited 2022 Nov 29];2:115-6. Available from: https://www.e-tjo.org/text.asp?2012/2/4/115/203728

Retinopathy of prematurity (ROP) occurs in the incompletely vascularized retina of premature babies and is an important cause of blindness in children in both developed and developing countries. With the progress of neonatal intensive care in the past decades, more extremely low birth weight premature infants survive, and subsequently, the incidence of ROP increases.[1] The treatment of ROP has evolved in the past 30-40 years. Retinal cryo-therapy and laser photocoagulation have both proven to be effective methods of treating active ROP.[2],[3] They are used to ablate the avascular retina anterior to the fibrovascular ridge. However, both procedures should be done under general anesthesia with or without intubation. Furthermore, ablation of the peripheral retina leads to inflammation, scar formation and induces high refractive errors or astigmatism. Recently, application of anti-vascular endo-thelium growth factor (VEGF) therapy for the treatment ROP has been reported. Anti-VEGF agents, including pegaptanib,[4] ranibizumab,[5] and bevacizumab,[6] have been used clinically for the treatment of ROP. In contrast to cryotherapy and laser photocoagulation, intravitreal injection of anti-VEGF agents can be done under local anesthesia at the bedside in the neonatal intensive care unit and a cryo or laser machine is not necessary. Most reports so far describe the effectiveness of bevacizumab in ROP treatment, whereas ranibizumab has rarely been used. In this issue of Taiwan Journal of Ophthalmology, Lin and associates describe their preliminary results of ranibizumab for the treatment of very low birth weight infants with Stage 3 ROP.[7] They concluded that intravitreal ranibizumab injections seem to be effective and well tolerated in these patients. Since the increasing use of anti-VEGF therapy for the treatment of ROP, several issues should be considered and answered before it is widely applied.

There is evidence showing that increased levels of VEGF can be detected in the vitreous of ROP. Therefore, application of anti-VEGF therapy could suppress VEGF-mediated angiogenesis. However, VEGF serves as a double-edged sword. VEGF is not only a potent angiogenic factor, but also a critical neural survival factor, and its equilibrium in the eye should be carefully regulated.[8] In the eye, VEGF is required for normal neural retinal development, independent of angiogenesis. Any disturbance of normal VEGF expression patterns might interfere with the normal retinal function. Anti-VEGF therapy could inhibit VEGF and thus suppress the neovascularization in the retina of ROP eyes. However, it might also deplete the factor which the neurons in the immature retina mostly need to survive.

There are reports suggesting that intravitreal anti-VEGF can lead to a worsening of tractional retinal detachment in Stage 4 ROP.[9] After injection of anti-VEGF, the vascular component of the fibrovascular membrane regresses, but acute fibrosis occurs, leading to a deterioration of the tractional retinal detachment.

Studies of eyes with ROP have demonstrated vascular leakage and breakdown of the blood ocular barrier. Therefore, anti-VEGF agents might escape from the vitreous into the systemic circulation and reduce serum VEGF concentration, which warrants extensive evaluation of the patient. Because VEGF is involved in a wide variety of physiologic processes, the ocular and systemic safety of anti-VEGF agents is of prime concern in patients of this age group.[10] Preterm infants are still undergoing organogen-esis at the time of ROP treatment late in their third trimester. VEGF has actions beyond vasculogenesis. In the brain, it is neurotropic and neuroprotective and helps maintain the blood-brain barrier. In the lungs, VEGF has important roles in alveolar development and surfactant synthesis. VEGF is also critical for glomerulogenesis in kidney and skeletal growth. Sato et al[11] found that the serum bevacizumab levels continue to increase from 1 day to 1 week to 2 weeks after intravitreal injection and the serum VEGF levels drops below normal range 2 weeks after injection. Intravitreal injection of ranibizumab suppresses serum VEGF as well. Hoerster et al[12] reported that after injection of 0.2 mg ranibizumab, the systemic VEGF dropped to levels below detection limit for 2 weeks and returned to normal levels 4 weeks after injection. Therefore, consideration should be given to decreasing the systemic exposure by injecting a lower effective dose of anti-VEGF agents and/or changing to drugs that have more rapid systemic clearance.

In summary, although increasing evidence shows that anti-VEGF therapy is a treatment of ROP due to its ease of use, lower cost and high success rate, serious consideration is needed before it can be applied as the preferred therapeutic method for ROP. The patho-physiology of ROP and the pharmacokinetics of anti-VEGF agents after intravitreal injection are still not fully understood. In addition, when anti-VEFG therapy is recommended by ophthalmologists, parents should be fully informed that such treatment remains experimental and that the long-term outcomes are unknown. Currently, a randomized, controlled trial with adequate long-term follow-up might necessary to answer the above-mentioned issues. We look forward to reading these results in the near future.

  References Top

Tasman W. Retinopathy of prematurity: do we still have a problem? The Charles L. Schepens lecture. Arch Ophthalmol 2011;129:1083-6.  Back to cited text no. 1
Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity: preliminary results. Arch Ophthalmol 1988;106:471-9.  Back to cited text no. 2
Early Treatment for Retinopathy of Prematurity Cooperative Group. Revised indications for the treatment ofretinopathy ofprematurity: results ofthe early treatment for retinopathy of prematurity randomized trial. Arch Ophthalmol 2003;121:1684-94.  Back to cited text no. 3
Mintz-Hittner HA. Intravitreal pegaptanib as adjunctive treatment for stage 3+ ROP shown to be effective in a prospective, randomized, controlled multicenter clinical trial. Eur J Ophthalmol 2012;22:685-6.  Back to cited text no. 4
Mota A, Carneiro A, Breda J, Rosas V, Magalhães A, Silva R, et al. Combination of intravitreal ranibizumab and laser photocoagulation for aggressive posterior retinopathy of prematurity. Case Report Ophthalmol 2012;3:136-41.  Back to cited text no. 5
Mintz-Hittner HA, Kennedy KA, Chuang AZ. BEAT-ROP cooperative group. efficacy of intravitreal bevacizumab for stage 3 retinopathy of prematurity. N Engl J Med 2011;364:603-15.  Back to cited text no. 6
Lin C-J, Chen S-N, Tseng C-C, Chang Y-C, Hwang J-F. Effects of ranibizumab on very low birth weight infants with stage 3 retinopathy of prematurity: A preliminary report. Taiwan J Opthalmol 2012;2:136-9.  Back to cited text no. 7
Haigh JJ. Role of VEGF in organogenesis. Organogenesis 2008;4:247-56.  Back to cited text no. 8
Honda S, Hirabayashi H, Tsukahara Y, Negi A. Acute contraction of the proliferative membrane after an intravitreal injection of bevacizumab for advanced retinopathy of prematurity. Graefes Arch Clin Exp Ophthalmol 2008;246:1061-3.  Back to cited text no. 9
Tolentino M. Systemic and ocular safety of intravitreal anti-VEGF therapies for ocular neovascular disease. Surv Ophthalmol 2011;56:95-113.  Back to cited text no. 10
Sato T, Wada K, Arahori H, Kuno N, Imoto K, Iwahashi-Shima C, et al. Serum concentrations of bevacizumab (avastin) and vascular endothelial growth factor in infants with retinopathy of prematurity. Am J Ophthalmol 2012;153:327-33.  Back to cited text no. 11
Hoerster R, Muether P, Dahlke C, Mehler K, Oberthür A, Kirchhof B, et al. Serum concentrations of vascular endothelial growth factor in a infant treated with ranibizumab for retinopathy of prematurity. Acta Ophthalmol 2012 Jun 6. http://dx.doi.org/10.1111/j.1755-3768.2012.02469.x [Epub ahead of print].  Back to cited text no. 12

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