The choice of treatment for ROP has shifted from cryotherapy to diode laser photocoagulation after clinical studies showing the superiority of laser therapy to cryotherapy 
. Laser therapy can be applied both transpupillary or trans-sclerally. Indications of laser therapy for ROP have been described 
. Over time, the timing of treatment has moved to an earlier stage of the disease, as documented by the Early Treatment for Retinopathy of Prematurity (ETROP) study 
. Although ablation of the peripheral retina with laser reduced the progression and incidence of the disease in the ETROP study, patients still had poor visual outcomes after treatment, especially for zone I ROP. Despite the advances, progression to retinal detachment occurred in 12% of eyes in the ETROP study with adequate peripheral ablation. This may be related with either the individual skills of the surgeon who applies laser treatment, or vitreal VEGF levels which cannot be reduced by retinal laser photocoagulation. Although VEGF is mainly secreted in the avascular retina, vitreal macrophages as a second source of VEGF may be responsible for the lack of the effectiveness of laser therapy for ROP 
Additionally, laser therapy has some disadvantages including corneal edema, anterior chamber reaction, intraocular hemorrhage, cataract formation, intraocular pressure changes. Significant decrease in peripheral vision due to ablation of peripheral retina, strabismus, glaucoma, severe myopia and retinal detachment are some of the long-term side effects probably related to disease severity rather than laser therapy itself. However, the only evidence-based therapy for ROP is still laser photocoagulation, depending on the severity, in combination with vitreoretinal surgery.
Antivascular Endothelial Growth Factor Therapy
VEGF is a potent mitogen for vascular endothelial cells and necessary for the physiological angiogenesis and it is regulated by tissue hypoxia 
. It also promotes pathologic angiogenesis. Blocking the action of VEGF might be expected to reduce the vascular activity associated with ROP 
. Current treatment for ROP is retinal ablation either with cryo or laser photocoagulation that indirectly reduces VEGF levels by completely ablating the peripheral avascular retina that produces the VEGF 
. In contrast, anti-VEGF drugs offer the major advantage of limiting tissue destruction by decreasing VEGF levels both in the retina and vitreous 
. Available drugs include pegaptanib sodium (Macugen®
) for partial blockage of VEGF-A or drugs such as ranibizumab (Lucentis®
), bevacizumab (Avastin®
) and aflibercept (Eylea®
) for pan-VEGF-A blockage. Three anti-VEGF drugs (pegaptanib sodium, ranibizumab and aflibercept) are approved by the US Food and Drug Administration (FDA) for intraocular use in the treatment of some ocular neovascular diseases in adults. In contrast, bevacizumab is approved by the FDA for only intravenous use in the treatment of colorectal, breast, lung and renal cell cancers.
Pegaptanib sodium was the first anti-VEGF drug licensed for the treatment of age related macular degeneration. It may be a safer option with respect to normal development in premature newborns as it is a selective VEGF-165 inhibitor without blocking all VEGF isoforms. There are a few reports describing the use of intravitreal pegaptanib in the management of ROP and Autrata et al
recently reported promising results with the administration of intravitreal pegaptanib in the management of stage 3+ ROP without any systemic or ocular complications during 19.3 months. Ranibizumab has a shorter serum half-life than bevacizumab which may theoretically reduce the risk of systemic complications in premature infants 
. Aflibercept, a fusion protein that inhibits all isoforms of VEGF-A, has high binding affinity and longer intraocular half-life which may result in a longer duration of clinical action intraocularly than either ranibizumab or bevacizumab 
. However, no randomized clinical tials regarding the effects of intravitreal ranibizumab and aflibercept injections yet exist. Even though bevacizumab is associated with an increased risk of hemorrhagic and thromboembolic events in adults with intravenous therapy 
, clinical experiences with intravitreal bevacizumab have shown that this agent is well tolerated and widely off-label used in the treatment of intraocular neovascularizations 
. Lower doses of bevacizumab are used for the treatment of ocular conditions, however, use of anti-VEGF therapy in premature newborns is still controversial regarding safety 
Bevacizumab, a humanized recombinant antibody, binds all isoforms of VEGF-A 
. This could potentially be disadvantageous because physiologic vascular development could be suppressed. However, its large molecular weight and being a full antibody combined with its half-life and the thick preterm vitreous allow a longer period of effectiveness. Penetration of bevacizumab through the monkey retina after the intravitreal injection has been reported 
, and Sato et al
have recently reported high serum bevacizumab concentrations after intravitreal bevacizumab injection in infants with ROP. However, its low cost and promising results have led to a widespread off-label use of bevacizumab in the treatment of ROP in the last decade. While ablative therapy requires training, special equipment and facilities, the drug is inexpensive and can be administered at the bedside, if necessary, by an ophthalmologist trained for the treatment of ROP 
. But, bevacizumab is a cancer drug for intravenous use and has neither been approved for use in eyes nor in infants yet.
Bevacizumab and the other anti-VEGF drugs have already been in use for some ocular neovascular diseases in adults. So far, there have been various case reports or small case series of bevacizumab use in ROP 
. Currently, there are two ongoing and planned studies which are evaluating efficacy of bevacizumab by comparing with standard laser therapy: Pan-VEGF Blockade for the Treatment of ROP (BLOCK-ROP) study (clinicaltrials.gov Identifier: NCT01232777; unfunded and not yet open for participant recruiment) and Bevacizumab Eliminates the Angiogenic Threat of ROP (BEAT-ROP) study (clinicaltrials.gov Identifier: NCT00622726). Recently, Mintz-Hittner et al
(BEAT-ROP group) have reported on the study investigating the efficacy of intravitreal bevacizumab for stage 3+ ROP in zone I. The study consisted of a prospective, controlled, randomized, multicenter trial to assess intravitreal injection of bevacizumab for zone I or zone II posterior stage 3+ (i.e.
, stage 3 with plus disease) ROP. Infants were randomly assigned to receive intravitreal bevacizumab (0.625mg) or conventional laser therapy, bilaterally. The primary ocular outcome was recurrence of ROP in one eye or both eyes requiring retreatment before 54 weeks' gestational age. The results showed a strong benefit from intravitreal injection of bevacizumab as compared with conventional laser therapy in infants with stage 3+ ROP. Bevacizumab injection had a recurrence rate of 6% in combined retinal zones I and II compared with a 26% recurrence rate in laser treatment. The rate of recurrence with zone I disease alone was significantly higher with conventional laser therapy than that with intravitreal bevacizumab (42% vs
6%). However, the rate of recurrence with zone II posterior disease alone did not differ significantly between the laser-therapy group and the bevacizumab group (12% vs
5%). So, a significant treatment effect was reported for zone I ROP (P
=0.003) but not for zone II disease (P
=0.27). The authors also reported 6 cases of ROP with recurrence after intravitreal bevacizumab monotherapy. These findings suggest the importance of careful follow-up and choice of combined treatment (laser+intravitreal bevacizumab). There are various reports using bevacizumab for ROP simultaneously with laser therapy or separately, but these reports do not include evidence-based data 
. Correct injection timing of the bevacizumab is important. Trese 
reported that due to the interaction of an anti-VEGF drug and retinal vascular development, the timing of anti-VEGF therapy should be later than 30 weeks of postconceptional age. There are some other cytokines that have various roles for retinal development 
. Transforming growth factor-beta (TGF-β), a natural antagonist of VEGF, which plays an important role in wound healing and scarring, rises in concentration during retinal development, between 36 and 40 weeks of postmenstrual age 
. TGF-β becomes unopposed when VEGF is blocked through treatment and this may end up exacerbating proliferative tissues and cause tractional changes 
. If anti-VEGF drugs are given late in the course or in cases with retinal detachment, increased concentrations of TGF-β may contribute to a tractional retinal detachment. The use of anti-VEGF therapy in stages 4 or 5 may accelerate retinal detachment due to a rapid neovascular involution with accelerated fibrosis and contraction of fibrous membranes in response to decreased levels of VEGF. Bevacizumab seems to be useful in ROP stage 3 cases with especially rigid pupils due to iris neovascularization, with intravitreal hemorrhage or zone I disease 
. The use of anti-VEGF therapy seems as an efficacious treatment for severe ROP, but correct injection timing of the bevacizumab might be an important limitation for its use.
Another important consideration in the use of bevacizumab for ROP is the potential risk of local and systemic complications. Serious systemic complications may occur when bevacizumab is administered intravenously with high doses 
. Bevacizumab is originally an anticancer drug for intravenous use; it has no regulatory approval for use in eyes or in infants. However off-label use of intravitreal bevacizumab for ROP increases despite the lack of studies on safety and dosage in growing babies. Systemic absorption has been considered negligible in adults; however, serum levels following intravitreal bevacizumab injection have not yet been determined in premature infants. Intravitreal bevacizumab enters the general circulation, suppresses plasma VEGF levels and remains in the blood for more than 8 weeks in primates 
. There is no study reporting serious local and systemic complications of intravitreal bevacizumab injection 
. However, there are various reports describing the role of VEGF in the normal development of human kidney, brain and lung 
. Recently, Sato et al
reported that bevacizumab can escape from the vitreous into the systemic circulation and reduces the VEGF concentrations in infants with ROP following intravitreal bevacizumab injection to either one or both eyes. All of the 11 infants in that study received laser photocoagulation to the peripheral avascular retina before bevacizumab injection, and serum bevacizumab level one week after the injection was significantly higher than that before the intravitreal injection. So, possible adverse effects on VEGF dependent development should be considered. However, the BEAT-ROP study did not make any comment about the safety of the drug as the sample size of the trial was too small to assess the safety of the drug 
. Infants of the BEAT-ROP study randomly received either intravitreal bevacizumab injection or conventional laser therapy, bilaterally. Study designs and dosage of intravitreal bevacizumab injections are not similar in these studies 
. After publication of the BEAT-ROP study, some reviews, editorials and commentaries raised questions about the efficacy and safety of bevacizumab 
. Thus, efficacy and safety of bevacizumab are still important issues to be solved, and should be validated by evidence-based data.
Most recently, the American Academy of Pediatrics (AAP), the American Academy of Ophthalmology (AAO), the American Association for Pediatric Ophthalmology and Strabismus (AAPOS) and the American Association of Certified Orthoptists (AACO) revised the previous statement for screening of premature neonates for ROP which was published in 2006 and advised to consider intravitreal injection of bevacizumab for the treatment of infants with zone I, stage 3+ ROP even though bevacizumab is not currently approved by the US FDA for the treatment of ROP 
. Also they strictly advise to use bevacizumab only after obtaining a detailed informed consent, and long-term follow-up for the potential problems of the drug.
As a conclusion, further controlled studies with long-term follow-up and adequate sample size are needed for such potentially dangerous growth factor inhibitors, anti-VEGF agents, which may be considered as “a miracle rescue” for the treatment of ROP in immature infants.
Propranolol has been used for the treatment of infantile hemangiomas, and the effect of the propranolol was hypothesized to be the reduction of VEGF levels depending on systemic propranolol application 
. There are a few reports describing the effect of this β-adrenergic receptor blocker in regulation of retinal angiogenesis. Recently, systemic administration of propranolol has been reported to reduce retinal VEGF and IGF-1 expression, retinal neovascularization, and vascular leakage in a mouse model of oxygen-induced retinopathy 
. A pilot study, the Safety and Efficacy of Propranolol in Newborns with ROP (PROP-ROP) 
, was planned to compare safety and efficacy of propranolol with conventional laser treatment alone for stage 2 ROP in zone II or III without plus disease in premature infants. The study group hypothesized that VEGF overexpression in ROP might be induced by beta2-adrenoreceptor stimulation, and propranolol as a non-selective beta-adrenoreceptor blocker administered in preterm newborns could reduce the progression of ROP. However, this study was halted because of increased mortality in the treatment arm. Although the use of prophylactic propranolol for oxygen-induced retinopathy in mice model reported promising results, Chen et al
recently reported that propranolol treatment with a dose up to 30 times the standard human dose failed to suppress retinopathy development in mice. This recent finding raised the question about the effect of propranolol as an appropriate therapeutic approach for treating ROP. Propranolol has also serious side effects such as bradycardia, heart block, hypotension, bronchospasm, hypoglycemia and dyslipidemia 
. The efficacy of this drug may be quite disappointing in a vulnerable preterm infant. The relevance of all these results, benefits and safety of propranolol to the developing preterm infant is uncertain, and further animal and prospective clinical trials should be conducted.