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 Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 107  |  Issue : 3  |  Page : 173-180

Outcomes of intravitreal bevacizumab injection versus conventional laser as first-line treatment in stage III retinopathy of prematurity


Department of Ophthalmology, Faculty of Medicine, Mansoura University, Mansoura, Egypt

Date of Submission19-Apr-2014
Date of Acceptance30-Jul-2014
Date of Web Publication30-Dec-2014

Correspondence Address:
Abeer M. S. Khattab
Ophthalmology Department, Faculty of Medicine, Mansoura University, Mansoura
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2090-0686.148135

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  Abstract 

Purpose
The aim of the study was to evaluate the outcomes of intravitreal bevacizumab (IVB) monotherapy compared with conventional laser therapy in preterm infants with stage III and plus disease retinopathy of prematurity (ROP) who had zone I or II posterior disease.
Patients and methods
This was a prospective randomized comparative interventional pilot study. Twenty-four eyes of 12 preterm infants suffering from ROP were included. All eyes had bilateral stage III ROP with 'plus disease' affecting zone I or zone II posterior. Infants were assigned to receive conventional laser therapy in their right eyes and IVB in their left eyes. Follow-up period was 6 months following treatment.
Results
The study included five female infants and seven male infants. The gestational ages ranged from 26 to 33 weeks (mean 29 weeks), and the birth weights ranged from 750 to 1390 g (mean 1005 g). The postmenstrual age at which threshold ROP was detected ranged between 34 and 41 weeks (mean 36.75 weeks). All 24 eyes had stage III ROP with plus disease; 10 eyes had zone I, whereas the other 14 eyes had zone II posterior. Regression of neovascularization occurred in all 24 eyes following both treatment modalities and remained stable during follow-up. No local or systemic side effects of bevacizumab were observed, and no further treatment was necessary.
Conclusion
IVB injection seems to be as effective as conventional laser in treating stage III ROP. It provides the advantages of preservation of peripheral visual field and complete peripheral retinal vascularization.

Keywords: intravitreal bevacizumab, laser, plus disease, retinopathy of prematurity, stage III


How to cite this article:
Khattab AM, Torky MA. Outcomes of intravitreal bevacizumab injection versus conventional laser as first-line treatment in stage III retinopathy of prematurity. J Egypt Ophthalmol Soc 2014;107:173-80

How to cite this URL:
Khattab AM, Torky MA. Outcomes of intravitreal bevacizumab injection versus conventional laser as first-line treatment in stage III retinopathy of prematurity. J Egypt Ophthalmol Soc [serial online] 2014 [cited 2019 Aug 19];107:173-80. Available from: http://www.jeos.eg.net/text.asp?2014/107/3/173/148135


  Introduction Top


Retinopathy of prematurity (ROP) is a neovascular retinal disorder of childhood that causes loss of vision by means of macular dragging and retinal detachment [1-3]. The first known description of the condition was in the 1940s [4]. It is a leading cause of childhood blindness in the developed nations, occurring primarily in infants of low birth weight (≤1250 g) or gestational age of 30 weeks or less [1-3].

The hallmark of ROP is abnormal retinal vasculature [5]. The International Classification of Retinopathy of Prematurity (ICROP), published in 1984, defined ROP in terms of location (zones I-III), severity (stages I-V), extent (clock hours 1-12), and vascular dilatation and tortuosity (plus disease). It is important to note that staging is crucial in deciding the timing of treatment [6-8]. ROP in zone I is the most difficult to treat and has a high incidence of recurrence warranting additional treatment. Stage III, in which a ridge with neovascularization extends into the vitreous gel, is the ideal time for treatment [1]. Dilatation and tortuosity of the retinal vessels at the posterior pole in two or more quadrants, termed plus disease, emerged as a sign of high-risk prethreshold ROP that benefits from early laser ablation of the peripheral avascular retina [5].

The pathogenesis of ROP involves two discrete phases. Phase 1 involves relative hyperoxia and decreased vascular endothelial growth factor (VEGF) levels [1]; hyperoxia suppresses VEGF expression and results in vaso-obliteration. Meanwhile, in phase 2, VEGF expression is increased due to peripheral retinal hypoxia, leading to neovascularization [6].

Earlier treatment is administered to the avascular retina when an eye reaches high-risk 'prethreshold' ROP. However, 'classic threshold' ROP is defined as stage III ROP in zone I or II involving at least five contiguous or eight cumulative clock hours with plus disease. The mainstay of treatment for threshold ROP is ablation of peripheral avascular retina through cryotherapy or laser. Laser photocoagulation remains the standard of care in the treatment of advanced ROP; however, regression is not seen in all cases (especially in aggressive posterior disease) following laser alone. As ablative treatments are destructive and treatment often requires intubation and anesthesia in preterm neonates with comorbid conditions, there has been interest in alternative treatments [2, 6, 9].

Off-label use of intravitreal bevacizumab (IVB) therapy for ophthalmologic neovascular disorders began shortly after its approval by the Food and Drug Administration (FDA) in 2004 for nonophthalmic purposes. Cases of stage III, IV, and V ROP with plus disease had been treated with IVB, both as monotherapy and in combination with conventional laser therapy or vitrectomy or both [9-12].

In this prospective, randomized comparative interventional pilot study, IVB monotherapy was compared with conventional laser therapy in preterm infants who had stage III ROP with plus disease in zone I or zone II posterior disease.


  Patients and methods Top


This study included 24 eyes of 12 preterm infants suffering from ROP, and they were recruited through the screening protocol, which included all babies less than 1500 g birth weight or younger than 32 weeks' gestational age who are at risk of developing ROP. All cases underwent treatment in Alhayah Private Eye Hospital in Mansoura City from February 2012 to April 2013. The study was approved by the Hospital Trust Ethics Committee and was carried out in accordance with the Declaration of Helsinki (1989) of the world medical association.

Inclusion criteria were preterm infants 32 weeks of gestation age or less and/or birth weight of 1500 g or less and having bilateral ROP stage III with plus disease affecting zone I and zone II posterior. The ROP stage and plus disease were defined on the basis of the international classification scheme (ICROP) [13]. The detection of peripheral neovascular activity during the preoperative examinations and follow-up was performed using indirect ophthalmoscope. Tortuosity and dilatation of retinal vessels were evaluated by two different fundus examinations. Exclusion criteria were eyes with any stage of retinal detachment or congenital ocular anomaly.

Data were collected for each baby regarding date of birth, sex, single or multiple pregnancy, gestational age at birth, birth weight, age at which ROP was detected, the stage of ROP, the affected zone, and presence or absence of plus disease. Other data included oxygen and surfactant given or not, presence of common problems of prematurity, presence of intrauterine growth retardation, and duration of stay of infant in the Intensive Care Unit of the Neonatology Department.

Infants were assigned to receive conventional laser therapy in their right eyes and IVB in their left eyes. Before drug administration, the parents were fully informed about the experimental character of the therapy, the off-label use of bevacizumab, its possible short-term and long-term complications, alternative treatment options, possible treatment outcomes, and detailed explanation of the procedure. In all cases, a written informed consent form was obtained from the guardians before the treatment whether laser or injections were administered. The treatment was carried out with no delay beyond 48 h after detection of the threshold ROP.

The treatment was performed utilizing a continuous cardiorespiratory monitor with infants, as they were not intubated and local proparacaine hydrochloride (0.5%) ophthalmic solution for topical anesthesia was applied for both eyes as well as topical mydriatic drops (1% tropicamide and 2.5% phenylephrine) instilled twice, 10 min apart, at least 30 min before the treatment.

Indirect laser photocoagulation was applied to the right eye of the 12 infants. It was applied to the 360° avascular retina, extending to the ora serrata with confluent spots with less than half burn width apart. This was performed using 810-nm infrared diode laser (IRIS Medical Oculight SL, 810-nm infrared laser; Iris Medical Inc., Mountain View, CA, USA). This laser is mounted on indirect ophthalmoscope (Heine, Germany). The procedure usually lasts from 45 to 90 min depending on the extent of treatment required and the zone of the disease. In some occasions, corneal edema occurred and this was secondary to excessive pressure on the globe, from using balanced salt solution (BSS) for irrigation or due to hyphema from dilated iris vessels and sometimes due to intraoperative vitreous hemorrhage. The corneal edema cleared a few minutes after removal of the eyelid speculum most of the times. If this did not happen, laser was performed on the following day or within few days after clearance of the media, and this was considered continuation of the first session rather than a second one. The initial settings on the laser console depend on the fundus pigmentation and area to be treated, initiating with 250 mW for 150 ms with the repeat mode set at 300 ms. The treatment was not faster as this can result in inadequate burns. The intensity of burns was grayish white rather than white and placement of spots was nearly confluent.

Bevacizumab was obtained from the commercially available Avastin (Genentech/Roche Inc., South San Francisco, California, USA). The medication was supplied in sterile unit doses of 0.625 mg (0.025 ml) in single-use 0.3-ml syringes with a 0.5-inch 30-G needle attached. Sterile gloves, speculum, and forceps were utilized while administering the injections. Sterilization of skin was performed using povidone-iodine 10%. A speculum for premature infants was placed between the lids. A drop of povidone-iodine (5%) ophthalmic solution was placed into the conjunctival sac for 1 min with the excess removed by a sterile cotton tip applicator from the temporal lid margin. The eye was stabilized with a toothed forceps while the dose of bevacizumab 0.025 ml (0.625 mg) was injected in the superior nasal quadrant behind the lens. The needle, aimed posteriorly (toward the optic nerve), entered the sclera through the conjunctiva 1.5 mm behind the limbus and was advanced approximately two-third of the length of the needle (not to the hub), and the syringe was emptied completely into the central vitreous. After the injection, povidone-iodine was again placed into the conjunctival sac for 1 min with the excess removed by a sterile cotton tip applicator from the temporal lid margin. Indirect ophthalmoscope was utilized to look for any injury to the lens, to determine the presence of adequate blood flow through the central retinal artery, and to identify any retinal tears or vitreous hemorrhage immediately after the injection. With the lid closed, tactile pressure was determined. None of the above-mentioned complications was encountered in any of the eyes.

Topical steroids FML (fluorometholone 0.1%; Allergan) are prescribed four times per day to reduce any inflammation and to decrease the risk for postlaser posterior synechiae. In addition, the ophthalmic antibiotic drops Zymar (gatifloxacin ophthalmic solution; Allergan, Irvine CA, USA) 0.3% were prescribed for both eyes to begin immediately and to be continued every 6 h for 7 days.

The follow-up period continued for 6 months following treatment. The babies were examined using indirect ophthalmoscope on the following day to specifically look for any sign of vitreous infection and signs of ROP progression or regression. The second examination post-treatment should take place 5-7 days after treatment and should be continued at least weekly for signs of decreasing activity and regression. The following characteristics of regression should be seen on at least two successive examinations:

(1) Lack of increase in severity.

(2) Partial resolution progressing toward complete resolution.

(3) Change in color in the ridge from salmon pink to white.

(4) Transgression of vessels through the demarcation line.

(5) Commencement of the process of replacement of active ROP lesions by scar tissue. The primary ocular outcome was progression or recurrence of ROP requiring retreatment before end of follow-up period. The postmenstrual age (PMA) at which total regression of retinal neovascularization of both groups was recorded as well as the PMA at which complete peripheral retinal vascularization occurred after IVB injection were also recorded ([Table 1]). After the acute phase, treated eyes should be monitored at a frequency dictated by the clinical condition to determine the risk of sequelae. In addition, at the end of the 6-month follow-up examinations, refraction was performed not to skip any possible refractive error.
Table 1 Follow-up of the studied groups


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  Results Top


The patient characteristics are shown in [Table 2]. The study included five female infants and seven male infants. The gestational age ranged from 26 to 33 weeks (mean 29 weeks), and the birth weights ranged from 750 to 1390 g (mean 1005 g). The first, second, and third babies were triplet brothers. The PMA at which threshold ROP was detected ranged between 34 and 41 weeks (mean 36.75 weeks). All 24 eyes had stage III ROP with plus disease; 10 eyes had zone I, whereas the other 14 eyes had zone II posterior.
Table 2 Patients characteristics


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After both types of treatment, regressed neovascular activity was observed in all 24 eyes, and they remained stable during follow-up. PMA of complete regression of retinal neovascularization ranged between 36 and 43 weeks (mean 39.29 weeks) ([Table 1]). In the LASER group, it ranged from 37 to 43 weeks (mean 39.67 weeks), whereas in the bevacizumab group it ranged from 36 to 42 weeks (mean 38.91 weeks).

Conventional laser therapy resulted in permanent destruction of the vessels in the peripheral retina beyond the affected zone, whereas IVB allowed for continued but slow vessel growth into the peripheral retina toward the temporal ora serrata. PMA of complete retinal vascularization toward the retinal periphery (temporal ora serrata) in the IVB group ranged between 44 and 57 weeks (mean 50.83 weeks) ([Table 1]). Neither ocular nor systemic side effects of bevacizumab were observed, and no further treatment was necessary in any of the treated eyes.


  Discussion Top


Randomized, controlled trials played a role in the evolution of treatment in ROP. The study group CRYO-ROP, published in 1988, established the benefit of peripheral retinal ablation for threshold ROP [6]. At 15 years, there was a decrease of more than 40% in unfavorable structural outcomes and a decrease of 30% in unfavorable visual acuity in treated eyes compared with observed eyes [14,15]. Despite the impressive findings and benefits shown by CRYO-ROP, the reality was that 44% of children with threshold ROP treated with cryotherapy had vision less than 20/200 at 10 years. Hence, the Early Treatment of Retinopathy of Prematurity (ET-ROP) trials were conducted in the early 2000s and demonstrated the benefit of earlier treatment with laser of high-risk prethreshold ROP [6].

Despite the success of retinal ablation in treating ROP, there are inherent disadvantages to laser therapy in a newborn. These include cataract formation, anterior segment and vitreous hemorrhage, anterior segment ischemia, iris adhesions to the lens, and fluctuating intraocular pressures. In the long term, ablative therapy can lead to loss of peripheral vision, strabismus, and marked myopia. In addition, some but not all clinicians prefer to intubate the babies for laser treatment. In other countries, there is no availability of a laser, cryotherapy, or trained surgeons for treatment, letting these infants go blind. Therefore, a quicker, less painful treatment for ROP could potentially revolutionize the management of this disease (especially in countries where laser is a luxury), and that is where anti-VEGF agents have come onto the scene [6].

In this study, the results of IVB injection in stage III with plus ROP were encouraging and similar to those obtained with laser therapy. There was regression of retinal neovascularization and plus disease; in addition, there was complete vascularization of retinal periphery within 6 months of treatment without any recurrences. Our findings are in agreement with other reports of IVB injection in ROP. Mintz-Hittner et al. [9] reported a case series of stage III ROP in zone I or posterior zone II treated by bilateral IVB. The study included 11 infants with the mean weight of 706.4 g and mean gestational ages of 24.3 weeks who received IVB at 9-15 weeks of age and never underwent laser therapy. The mean follow-up period was 48.5 weeks. All 22 eyes were treated successfully (no retinal detachment, macular ectopia, high myopia, anisometropia, or other ocular abnormalities) with only one injection. No complications were encountered.

Travassos A et al. [10] described the anatomic response to IVB injection in three patients with aggressive posterior retinopathy of prematurity (AP-ROP). In 24 h, all injected eyes showed regression of the tunica vasculosa lentis and iris vessel engorgement and disappearance of iris rigidity. In addition, plus disease and retinal proliferation began to regress. None of the eyes required additional treatment up to 10 months follow-up. Dorta et al. [11] conducted study on 12 consecutive eyes of seven premature infants who were treated with only one IVB. Nine eyes had zone I and three eyes had zone II ROP. The mean weight of infants was 846.57 g. The mean gestational age was 25.57 weeks. All eyes showed regression of the disease with no additional treatment needed.

In 2011, Mintz-Hittner et al. [1] conducted the BEAT-ROP (Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity), a prospective multicenter trial to assess IVB monotherapy for zone I or zone II posterior stage III with plus disease ROP. Infants were randomly assigned to receive IVB or conventional laser therapy, bilaterally. The primary ocular outcome was recurrence of ROP in one or both eyes requiring retreatment before 54 weeks' PMA. ROP recurred in four infants in the bevacizumab group [6/140 (4%) eyes] and 19 infants in the laser-therapy group [32/146 (22%) eyes, P = 0.002]. A significant treatment effect was found for zone I ROP but not for zone II disease. They concluded that IVB monotherapy, as compared with conventional laser therapy, in infants with stage III with plus disease ROP showed a significant benefit for zone I but not for zone II disease. In another multicenter study in 2011, 27 (49 eyes) patients received IVB for the treatment of ROP with a follow-up of at least 6 months. The mean gestational age and birth weight were 26.0 ± 2.4 weeks and 971.6 ± 589.6 g, respectively. There were 41 eyes (23 patients) with stage III ROP, six eyes (three patients) with stage IV-A ROP, and two eyes (one patient) with stage V ROP. A total of 37 of 41 (90%) eyes with stage III ROP regressed after IVB injection only. Four (10%) eyes required additional laser treatment to regress the ROP. Of six eyes (three patients) with stage IV-A ROP, two eyes (one patient, 33%) regressed after IVB injection and four eyes (67%) regressed after IVB injection and subsequent vitrectomy. Major complications included vitreous or preretinal hemorrhage in four (8%) eyes and transient vascular sheathing in two (4%) eyes [12].

Spandau et al. [15] discussed treatment modalities for AP-ROP. Eight infants (16 eyes) with a mean gestational age of 23.8 weeks and a mean birth weight of 592 g were treated with laser and/or IVB. All infants had AP-ROP in zone I. Two eyes (one infant) were only treated with laser, and six eyes (three infants) were treated with laser therapy or cryopexy because of lack of regression, with bevacizumab as salvage therapy. Eight eyes (four infants) were treated with a first-line IVB and four of these eyes (two infants) with additional laser ablation for continued disease progression in zone II. Macular dragging occurred in one eye of one infant primarily treated with laser. They concluded that, due to the high complication rate of the extensive laser treatment for zone I ROP, it is worth considering anti-VEGF treatment as an alternative therapy.

In addition to its use as monotherapy, there are multiple reports on the use of IVB as adjunctive therapy in different stages of ROP. Axer-Siegel et al. [16] investigated the benefit of IVB as supplemental or primary treatment for ROP. The files of nine consecutive infants treated with IVB for bilateral AP-ROP were reviewed. Indications for treatment were ROP progression from stage III to IV-A or from II to III with extraretinal neovascularization, despite laser treatment; active neovascular stage IV-A disease after laser and cryotreatment; anterior segment neovascularization and bleeding after laser treatment; and aggressive posterior disease with tunica vasculosa lentis and vitreous haze, which prevented laser treatment. One patient (two eyes) underwent lens-sparing vitrectomy after bevacizumab treatment; one eye acquired macular fold. One patient underwent bilateral scleral buckle. Bevacizumab treatment was associated with subsidence of the active vascular component in all eyes. Anatomical results were favorable in 17 eyes. There were no local or systemic complications. They concluded that IVB may serve as a supplemental therapeutic agent for severe laser-refractory ROP or as monotherapy when media opacities preclude diode laser photocoagulation or the patient is too sick for lengthy laser treatment.

Mititelu et al. [17] made a report on the quality and depth of new evidence published from 2009 to 2011 concerning the treatment of ROP with bevacizumab as either primary or adjunctive treatment for ROP. They found that there is significant variability in the evidence, quality, and design of the studies available in the literature. There has been a trend in the scientific literature of the past 2 years toward larger multicenter randomized studies investigating the role of bevacizumab in the treatment of ROP.

More recent evidence suggests that monotherapy with IVB may be a viable first-line treatment for selected cases of zone I ROP and possibly for posterior zone II disease. Adjunctive treatment with bevacizumab may enhance outcomes in patients treated with laser photocoagulation or pars plana vitrectomy.

Intravitreal medical therapy for ROP as compared with laser therapy has the following advantages:

(1) The possibility of performing the therapy under local anesthesia instead of general anesthesia;

(2) The possibility of not destroying the peripheral retina by coagulation; and

(3) Potentially a lower degree of myopization [18].

One of the limitations of our study is the absence of evaluation of the refractive outcome. However, this was previously studied by Harder et al. [18] who compared children who had been treated with an IVB with a control group that had previously undergone retinal argon laser therapy of ROP in the same center and was matched with the study group for birth weight, gestational age, and length of follow-up. They found that children receiving IVB therapy as compared with children undergoing retinal laser coagulation were significantly less myopic at 1 year of follow-up.

Another advantage that was observed in this study is that conventional laser therapy resulted in permanent destruction of the vessels in the peripheral retina, whereas IVB allowed for continued but slow vessel growth into the peripheral retina until the temporal ora serrata, a finding that is consistent with previous studies [1, 11, 12].

In this study, no complications were encountered regarding either techniques. However, there were different reports regarding the complications of bevacizumab use in the treatment ROP. In the study by Wu et al. [19], 14 (9%) eyes required additional laser treatment for ROP regression after the absence of a positive response to the IVB injections. Two (1%) eyes received one additional IVB injection to decrease persistent plus disease. The major ocular complications that were associated with IVB injections included vitreous or preretinal hemorrhage in two (1%) eyes, cataract in one (1%) eye, and exotropia in one (1%) eye. No notable systemic complications related to the IVB injections were observed.

Lee et al. [20] reported that, after the regression of ROP, atypical fibrous traction membrane had arisen along the major vascular arcades, which progressed into tractional retinal detachment in three of five eyes. They concluded that, in active stage III ROP, fibrous tractional membrane and subsequent tractional retinal detachment along the major vascular arcades were developed unpredictably after the regression of neovascular activity following IVB as an initial treatment. Therefore, ROP patients who received bevacizumab treatment without previous retinal photocoagulation should be closely followed for more than 4 months after the treatments, although the disease seems to have regressed.

In this study, no recurrences were observed with either type of treatment and no additional treatment was needed up to the end of follow-up period. The time and the pattern of recurrence represent a major concern after IVB monotherapy. Hu et al. [21] reported late reactivation and progression of ROP after IVB monotherapy. They found that the mean age at treatment-requiring recurrence was 49.3 weeks PMA. The mean time between initial treatment and treatment-requiring recurrence was 14.4 weeks, with a minimum of four and maximum of 35 weeks. Five eyes progressed to retinal detachment. No eye that received laser treatment for recurrence progressed to retinal detachment. They concluded that, although IVB treatment is effective in inducing regression of ROP, the effect may be transient. Recurrence can occur later in the course than with conventional laser therapy.

Late retinal detachment can occur despite early regression. Long-term favorable structural outcome may require extended observation and retreatment. The observation about the time of recurrence after bevacizumab treatment was performed by Patel et al. [22] who commented on The BEAT-ROP study, which demonstrated a significant benefit of bevacizumab over laser in reducing treatment-requiring recurrence by 54 weeks. Thus, late recurrences may not have been detected by the BEAT-ROP study and they reported a case of significant treatment failure after bevacizumab monotherapy. They concluded that, despite its promising results as monotherapy, caution must be taken during its use. Clearly, the progression of ROP is altered with initial regression but possible recurrences such as the effect decline over time. Unfortunately, the timing and the rapidity of onset are not well characterized. Moreover, the location and the pattern of recurrence may also be altered. Their patient displayed a posterior rather than anterior recurrence that progressed rapidly to retinal detachment [23].

A concern about the correct technique of intravitreal injection in premature infants was raised by Raizada et al. [24] and Darlow et al. [25]. The pars plana first develops during the second trimester of gestation. A rapid growth phase occurs between 26 and 35 weeks after conception. In the neonatal eye, the pars plana region is incompletely developed, and the anterior retina lies just behind the pars plicata. Hence, utmost care is needed in administering an injection, because it may cause inadvertent lens touching, traction on the vitreous base, and retinal damage, especially if the intravitreal injection is given in a condition of topical anesthesia, when the infant may move suddenly. However, it is believed that, by following the correct technique with a pars plana injection not greater than 1.5 mm posterior to the limbus, no complications will be encountered.

Safety is the primary reason for exercising caution when considering the use of IVB in the treatment of preterm infants [1]. The pharmacokinetics and pharmacodynamics of bevacizumab had not been extensively studied in preterm neonates, and, 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 this age group. VEGF is essential for organogenesis and skeletogenesis. The systemic adverse effects of bevacizumab include hypertension, proteinuria, hemorrhage, and thromboembolic events [24-27]. However, Sato et al. [28] determined the serum concentrations of bevacizumab and VEGF in infants with ROP who received IVB and whether the changes in the serum concentration of bevacizumab were significantly correlated with the serum concentration of VEGF after IVB. Their results indicated that bevacizumab can escape from the eye into the systemic circulation and reduce the serum level of VEGF in infants with ROP. Continued extensive evaluations of infants are warranted for possible effects after IVB in ROP patients.

In contrast, in 2012 with a long follow-up period, Martνnez-Castellanos et al. [29] evaluated ocular function and systemic development in premature infants treated with IVB injections for ROP over a period of 5 years. Eighteen eyes of 13 consecutive patients were divided into three groups: group 1, stage IV unresponsive to previous conventional treatment (n = 4); group 2, in which conventional treatment was difficult or impossible because of inadequate visualization of the retina (n = 5); and group 3, newly diagnosed high-risk prethreshold or threshold ROP (n = 9). All patients showed initial regression of neovascularization. One patient was diagnosed with recurrence of neovascularization and was treated with IVB. Visual acuity was preserved, and median vision was 20/25. Twelve eyes developed mainly low myopia over the years, with an overall mean value of 3.2 D. Electroretinograph was normal in four eyes that had no previous detachment. One patient showed delay in growth and neurodevelopment, whereas all others were within the normal range. They concluded that 5 years of follow-up in this small series suggested that IVB for ROP results in apparently preserved ocular function and systemic development.


  Conclusion Top


IVB injection seems to be as effective as conventional laser in treating stage III ROP. It provides the advantages of preservation of peripheral visual field and complete peripheral retinal vascularization. However, our understanding of the short-term and long-term effects of VEGF inhibition in newborns is extremely limited, and research is still in its infancy. The implications of VEGF blockade in an infant in whom physiologic VEGF is required for normal organogenesis are not known. Although no short-term systemic side effects of intravitreal Avastin for ROP had been reported, the long-term safety in infants is unknown. All these items should be carefully studied before approving anti-VEGF as first-line therapy in ROP. A study with longer follow-up and larger number of included premature infants has been planned to enable us for a better and more comprehensive evaluation of local and systemic effects of bevacizumab.


  Acknowledgements Top


 
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