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Treatment of Acute ROP

General Considerations: Each NICU and treating ophthalmology team should be comfortable delivering the full range of ROP services - surveillance, peripheral ablation and vitreoretinal surgery - either on site or within reach by referral. Examination under anesthesia is necessary on occasion to allow more thorough fundus evaluation and guide treatment. Adequate sedation and anesthesia are a necessity for application of any procedure.

Recchia FM, Capone A Jr. Contemporary understanding and management of retinopathy of prematurity. Retina. 2004 Apr;24(2):283-92.

Anesthesia and Sedation: Peripheral retinal ablation is performed either under general anesthesia or with sedation. Infants can be greatly stressed during treatment. Respiratory arrest and cardiac arrest have both been reported. There may be a decline in an infant’s systemic well being following treatment as well. It is important to maintain good communication with the neonatologist and anesthesiologist to enable prompt treatment. The expertise of a pediatric anesthesiologist with experience managing neonates is invaluable in maximizing the safety of anesthesia in fragile premature infants.

Peripheral Retinal Ablation: Based on the ETROP Study outcomes (see section on “ROP Clinical Trials”), peripheral retinal ablation is considered for any eye defined as having “Type I Prethreshold ROP” (note that plus disease is redefined as dilation and tortuosity of the posterior retinal blood vessels in at least two quadrants):

  • Zone I, any stage ROP with plus disease
  • Zone I, stage 3 ROP with or without plus disease
  • Zone II, stage 2 or 3 ROP with plus disease

Good WV; Early Treatment for Retinopathy of Prematurity Cooperative Group. Final results of the Early Treatment for Retinopathy of Prematurity (ETROP) randomized trial. Trans Am Ophthalmol Soc. 2004;102:233-48

Treatment Pattern and Complications of Peripheral Retinal Ablation: Progression of ROP despite treatment may occur despite well-applied laser, or as a consequence of incomplete peripheral retinal ablation. Conversely, complications of cryotherapy and laser appear to be related in part to the density of the treatment pattern. Therefore, a near confluent pattern laser (Figure 11A) without skip areas (Figure 11B, blue arrow) is desirable to maximize outcome and minimize serious complications such as cataract and anterior segment ischemia (Figure 11C).

Figure 11A
Figure 11B
Figure 11C

Banach MJ, Ferrone PJ, Trese MT. A comparison of dense versus less dense diode laser photocoagulation patterns for threshold retinopathy of prematurity. Ophthalmology 2000;107:324-328.

Ibarra MS, Capone A Jr. Retinopathy of prematurity and anterior segment complications. Ophthalmol Clin North Am. 2004 Dec;17(4):577-82, vii. Review.

Pharmacologic Treatment of ROP: The prospect of eradicating a blinding disease with a single injection is an attractive one. Targeted pharmacologic inhibition of VEGF for acute phase ROP (as an adjunct to laser or as monotherapy) is both popular and controversial.

The most widely studied agent to date is the monoclonal anti-VEGF antibody bevacizumab (Avastin, Genentech, South San Francisco, CA) given by intravitreal injection. Bevacizumab is a recombinant humanized monoclonal VEGF antibody that binds to all isoforms of VEGF, blocks VEGF-induced angiogenesis and was approved by the U.S. Food and Drug administration in 2004 for the treatment of metastatic colorectal cancer. The clinical literature speaking to the off-label use of bevacizumab (Avastin, Genentech, South San Francisco, CA) given by intravitreal injection for infants with advanced ROP consists of case reports/case series and one clinical trial. Both lines of evidence provide clinical information of interest to the management of ROP.

The case series and case report literature on anti-VEGF therapy for ROP is highly variable as to treatment indications, dosage, treatment timing, treatment frequency, outcome measures, follow-up and more. Three main indications for treatment have emerged:

  • treatment-naïve eyes with vascular congestion of the anterior segment precluding adequate visualization for laser treatment
  • previously treated eyes with persistent plus disease and/or exudation
  • primary monotherapy (without adjuvant retinal ablation) for eyes with posterior or aggressive disease

In the BEAT-ROP study,150 infants with bilateral Stage 3+ ROP in zone I or posterior zone II were randomized to receive either intravitreal bevacizumab monotherapy (0.625 mg in 0.025 cc) or laser photocoagulation in each eye. The primary outcome measure was recurrence of retinal neovascularization between 50 and 70 weeks post-conceptional age, ascertained in 143 surviving infants. In eyes with zone I ROP treated with bevacizumab, recurrence was significantly less than in eyes treated with standard laser photocoagulation (6% compared with 42%, p = 0.003). In eyes with posterior zone II ROP, recurrence was lower in eyes treated with bevacizumab (5% compared with 12%, p = 0.27), but not to a statistically significant degree. The timing of recurrence was much later in eyes treated with bevacizumab (16 weeks compared with 6 weeks). No systemic safety signals were raised, but no systemic adverse events were defined a priori as outcome measures.

Mintz-Hittner, et al. NEJM 2011 February 17; 364(7): 603–615.

The BEAT-ROP study provided proof, in the context of a clinical trial, of the prevailing concept that appropriately timed intraocular VEGF inhibition can eliminate most cases of acute ROP. Yet in many respects the BEAT-ROP study data are the source of more questions and controversies than answers:

  • Study outcomes may have been confounded by population bias: 10 of the 15 BEAT-ROP study centers were located in south and west Texas and more than half of enrolled infants were Hispanic.
  • The failure rate for ROP following laser in BEAT-ROP is unusually high compared to outcomes in previously published series of laser therapy for zone 1 ROP. If similar laser success rates had been achieved in BEAT-ROP, it is less likely that the results would be statistically significant for zone 1 disease (Figure 12).
  • The mean time of recurrence was 16 weeks post-treatment, which is well beyond the timeframe within which most infants are discharged.
  • The tendency to persistent broad areas of avascular peripheral retina (Figure 13) and late recurrence mandates extended follow-up. There are no data available to provide guidance as to whether such eyes are best observed or treated.
  • Intravitreal injection is not trivial, requires detailed understanding of the relevant anatomy and technique, and carries risk (endophthalmitis, retinal detachment, significant intraocular pressure elevation and cataract, to name a few).
  • BEAT-ROP was not powered for evaluation of safety. Of the infant deaths in this study, 71% (5 of 7) occurred in infants who received bevacizumab.
Figure 12
Figure 13

It is likely that there will be an important role for anti-VEGF therapy in the management of ROP. However, until the issues outlined above are addressed with the rigor of a randomized prospective controlled clinical trial, caution is advised in using anti-VEGF drugs, as is full informed consent. A sample consent is available at http://www.omic.com/rop-intravitreal-anti-vegf-injections/.

Mintz-Hittner, et al. NEJM 2011 February 17; 364(7): 603–615.

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Quiroz-Mercado H, Martinez-Castellanos MA, Hernandez-Rojas ML, Salazar-Teran N, Chan RV. Anti-angiogenic therapy with intravitreal bevacizumab for retinopathy of prematurity. Retina. 2008 Mar;28(3 Suppl):S19-25. Erratum in: Retina. 2009 Jan;29(1):127.

Dorta P, Kychenthal A. Treatment of type 1 retinopathy of prematurity with intravitreal bevacizumab (Avastin). Retina. 2010 Apr;30(4 Suppl):S24-31.

Wu WC, Yeh PT, Chen SN, Yang CM, Lai CC, Kuo HK. Effects and Complications of Bevacizumab Use in Patients with Retinopathy of Prematurity: A Multicenter Study in Taiwan. Ophthalmology. 2010 Jul 27.

Suk KK, Berrocal AM, Murray TG, Rich R, Major JC, Hess D, Johnson RA. Retinal detachment despite aggressive management of aggressive posterior retinopathy of prematurity. J Pediatr Ophthalmol Strabismus. 2010 Dec 22;47

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 Jul;246(7):1061-3.

Avery RL. Bevacizumab (Avastin) for retinopathy of prematurity: wrong dose, wrong drug, or both? J AAPOS, 2012;16(1):2-4.

Moshfeghi DM, Berrocal AM. Retinopathy of prematurity in the time of bevacizumab: incorporating the BEAT-ROP results into clinical practice. Ophthalmology, 2011;118(7):1227-1228.

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