|Year : 2018 | Volume
| Issue : 3 | Page : 205-210
Retinopathy of prematurity: screening and management
Hani A Albialy1, Anwar A Rass2
1 Department of Ophthalmology, Zagazig University, Zagazig, Egypt
2 Department of Pediatrics, Zagazig University, Zagazig, Egypt
|Date of Submission||12-Jan-2018|
|Date of Acceptance||22-Mar-2018|
|Date of Web Publication||24-Sep-2018|
Hani A Albialy
Ophthalmology Department, Zagazig University, Zagazig 44519
Source of Support: None, Conflict of Interest: None
Purpose To screen neonates for retinopathy of prematurity (ROP) and to evaluate the use of antivascular endothelial growth factor in its treatment.
Patients and methods This prospective study included 128 preterm infants with a birth weight (BW) less than 2000 g or estimated gestational age (GA) less than 32 weeks who were subjected to ophthalmological screening. Screening was done by fundus examination once the preemie completed his/her fourth week after birth or reached a GA of 32 weeks. The presence or absence of ROP and the staging and grading of the disease were noted. Severe cases that were selected as high-risk cases especially those with pre-plus or plus disease were subjected to intravitreal bevacizumab (IVB) injection.
Results One hundred and twenty-eight premature infants were enrolled in the study. Thirty-six infants were identified to have ROP in different stages (28.1%); 26 (72.2%) were with mild ROP and 10 (27.7%) with severe ROP, who were treated with IVB injection. Regarding the preterm babies with no ROP, there was a significant difference between their mean BW and GA in comparison with those with ROP. Stages of ROP were directly related to GA as most of the ROP cases were younger than 31 (83.3%) weeks of age, with a significant correlation with total screening cases. A highly significant correlation of different stages of ROP with BW was observed as all cases were under 1800 g. The results of ROP treated cases with IVB injection revealed highly significant success in stage III and IV ROP with regression of neovascularization and no reported significant complications.
Conclusion Screening of the neonates for ROP should be performed as early as possible. Antivascular endothelial growth factor therapy is a safe and effective primary treatment option for ROP.
Keywords: antivascular endothelial growth factor, bevacizumab, intravitreal, pediatric, retinopathy of prematurity
|How to cite this article:|
Albialy HA, Rass AA. Retinopathy of prematurity: screening and management. Delta J Ophthalmol 2018;19:205-10
| Introduction|| |
Retinopathy of prematurity (ROP) is an ocular disorder involving the vascular proliferation of the developing peripheral retinal blood vessels of the preterm infants that may lead to poor visual acuity or blindness . It progresses into two phases: phase I, which begins with increased oxygen in the retina causing a decrease of vascular endothelial growth factor (VEGF), and phase II, in which decreased oxygen causes increased production of VEGF with subsequent neovascularization. So, oxygen therapy plays an important role in retinal vascular development . Another factor that contributes to the development and increased incidence of ROP is the increased survival rate of the low-birth-weight (BW) infants and lowered gestational age (GA) of preemies survival .
Cryotherapy was the standard treatment for the acute-phase ROP in the 1980s, following the publication of the results of cryotherapy for ROP (Cooperative Group CRYO ROPCG) trial. The study showed a significant decline in the progression of threshold ROP, at which stage the risk of blindness, if untreated, was 50% . It also reduced the unfavorable structural outcome of threshold ROP to 49.3% at 3 months and 45.8% at 12 months . Conjunctival dissection was needed in posterior disease to enable access for the cryoprobe. Other hazards included postoperative pain, lid edema, laceration, and hemorrhage ,.
Laser photocoagulation of the avascular retina reduces the risk of severe visual loss, presumably by decreasing VEGF production, but the loss of the peripheral retinal function is a potential hazard. The complications reported with laser are burns of the cornea, iris, and lens; hyphema; retinal hemorrhages; and choroidal rupture . Despite treatment by either laser or cryotherapy, the functional outcomes are still not satisfying, and some patients progress to retinal detachment especially in the late stages of ROP with poor visual outcome even after vitrectomy or scleral buckling ,.
An overexpression of VEGF appears to be important in the pathogenesis of ROP, as it was found to be highly elevated in advanced ROP; thus, it may play a vital role as the driving force for neovascularization ,. Blocking VEGF with anti-VEGF agents such as bevacizumab seems to be a reasonable approach in ROP management as a primary treatment or as an adjunct to photocoagulation ,.
Bevacizumab has been reported to be used in the treatment of diabetic pre-retinal and vitreous hemorrhage, and beside laser therapy, it evolved as the primary modality of treatment in 1990s, with less complications, and can prevent blindness as effectively as cryotherapy. Bevacizumab is a recombinant antibody against VEGF and was approved to be effective for inducing regression of new vessels. The rational for the use of bevacizumab in stage IV or V ROP is to reduce the plus sign, thus reducing hemorrhages during the subsequent vitrectomy. Some authors reported cases of resolution of stage IV ROP after bevacizumab injection .
The aim of this study was to screen neonates for ROP and to evaluate intravitreal bevacizumab (IVB) as a newer modality treatment which requires less skills and equipments.
| Patients and methods|| |
This prospective study was done at the neonatal ICU (NICU) at Zagazig University Hospitals in the period between May 2015 and April 2016. A total of 128 preterm babies with a BW less than 2000 g or estimated GA less than 32 weeks were included in the present study. All patients’ legal guardians provided an informed consent, and the study was approved by the Institutional Review Board and was conducted in accordance with the Declaration of Helsinki and the principles of Good Clinical Practice.
All the admitted babies with these criteria were screened including the following variables: sex, BW, GA, single or multiple pregnancies, weight gain from birth till the sixth week of life, total duration of exposure to oxygen, mechanical ventilation, jaundice, hypoglycemia or hyperglycemia, thrombocytopenia, septicemia, light exposure, the need of dopamine or surfactant therapy, hyaline membrane disease, time and frequency of blood transfusion, APGAR score, presence of patent ductus arteriosus, and duration of NICU stay.
Exclusion criteria were any fatal systemic anomaly, unilateral or bilateral choroidal disease (other than ROP), and media opacity precluding fundus visualization such as cataract or refusal of initial consent.
ROP was screened in accordance with the screening criteria proposed by the American Academy of Ophthalmology and the American Academy of Pediatrics. Screening was done once the preemie completed his/her fourth week after birth or reached 32 weeks as his/her corrected GA.
Examination was done by binocular indirect ophthalmoscopy one hour after dilating the pupils using one drop of 0.5% cyclopentolate three times, 10 min apart. Follow-up was based on the initial findings. Presence or absence of ROP was noted. If present, the staging and grading of the disease was noted, and the presence or absence of plus disease was also documented.
The findings were classified according to the International classification of ROP and the early treatment of ROP study .
For the purpose of the present study, mild ROP was defined as stage I, II, or III, and severe ROP as high-risk cases was stages IV and V ([Table 1]) .
Pre-plus disease was defined as more vascular tortuosity than normal but insufficient for the diagnosis of plus disease, whereas plus disease was defined as vascular dilatation and tortuosity of at least two quadrants of the eye.
The severe cases that were selected as high-risk cases especially those with pre-plus or plus disease were given IVB injection after having a written consent from the parents and after being told about the nature of the procedure and that the injection is only a step in the treatment and laser photocoagulation may follow the injection. General anesthesia was given to all infants using halothane inhalation anesthesia. The dose given was the recommended dose of 0.025 ml (0.625 or ≤0.75 mg) after adjusting the dose of sterile undiluted commercially available bevacizumab (Avastin 100 mg/4 ml intravenously: Roche, Basel, Switzerland) .
Intravitreal injection was done in a sterile operating room under complete aseptic conditions. A 30-G needle was introduced at a 60° angle to the iris and 1.5 mm from limbus. The needle was advanced 5 mm through the pars plana to avoid touching the lens or the retina and then the injection was done. A paracentesis was done if the intraocular pressure was elevated.
Follow-up by regression of neovascularization was noted during the follow-up period by weekly examination using indirect ophthalmoscopy after papillary dilation using cyclopentolate 0.5%.
All the statistical analyses were performed with SPSS version 10 (SPSS Inc., Chicago, Illinois, USA), using the one-way analysis of variance to analyze the continuous variables. P value of 0.05 or less was considered statistically significant.
| Results|| |
A total of 128 premature infants were enrolled in the study. They included 72 male and 56 female preemies. During the period of the study, 36 (28.1%) infants were identified to have ROP in different stages including 26 (72.2%) with mild ROP and 10 (27.7%) with severe ROP who were treated by IVB.
In the 36 infants with ROP, the mean BW was 1050.97±401.23 g, and the average GA was 29.9±1.67 weeks. Ten of them had ROP requiring treatment (stages III–V) with a mean BW of 980±297.36 g and average GA of 28.2±2.3 weeks.
Regarding the preterm babies with no ROP, there was a significant difference between their mean BW and GA in comparison with the ROP group. In the no ROP group, the mean BW was 1464±0.279 g and the mean GA was 31.2±1.9 weeks ([Table 2]). Other risk factors that showed statistically significant relationship were consanguinity, days of mechanical ventilation, neonatal sepsis, oxygen therapy and saturation, hypoglycemia, anemia, and low APGAR score.
Regarding the correlation of ROP stages with the GA, most of the ROP cases were younger than 31 weeks (30 of 36 infants=83.3%), with a significant correlation in comparison with all screened cases (P<0.05) ([Table 3]). In addition, a highly significant correlation of the different stages of ROP with BW was noted, as all cases were less than 1800 g ([Table 4]).
|Table 3 Correlation of different retinopathy of prematurity stages to gestational age in weeks|
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|Table 4 Correlations of retinopathy of prematurity stages according to the birth weight|
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The results of ROP treated cases using intravitreal injection of bevacizumab revealed a highly significant success in stages III and IV ROP (P<0.001 and <0.01, respectively) ([Table 5]). No significant complications occurred with the exception of mild subconjunctival hemorrhage in three cases that resolved spontaneously within 5–7 days. Failure occurred in two cases that required vitrectomy with silicone oil tamponade to reattach the detached retina of whom one eye ended in atrophia bulbi.
|Table 5 Success rate of bevacizumab in treating severe retinopathy of prematurity|
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| Discussion|| |
ROP is considered a leading cause of visual impairment in premature infants ,. It is a proliferative disease that affects infants of low BW and young GA . Data regarding ROP in developing countries are limited, and there are no national guidelines to screen infants at high risk for ROP in this region . Most of the studies recommended screening all infants less than 1500 g at birth. However, these guidelines may not be suitable for other parts of the world as local ROP experience may necessitate different guidelines. So, we conducted this study aiming to identify the screening guidelines for ROP in this area.
Both CRYO-ROP and early-treatment ROP studies demonstrated improvement in structural and functional outcomes with peripheral ablation therapy . The role of VEGF in the pathogenesis of ROP has been described . Many reports of anti-VEGF use in ROP showed that it can be a safe and effective treatment ,,. However, there is a concern about the choice of the drug, dose and time of injection as well as about the local and systemic potential complications .
The results of the present study were consistent with Gharaibeh et al. , who found an incidence of ROP of 28.6% with average GA of 28.9 weeks and a BW of 1250 g and a higher incidence of ROP in infants less than 1000 g. However, Al-Bodoor et al.  found a higher incidence of ROP (44%) which reflects a difference in the protocol of management in NICU between various studies that include oxygen exposure and genetic factors that should be taken into consideration. On the contrary, Li et al.  found an ROP rate of 10.7% only when the GA was less than 34 weeks and the BW was less than 2000 g. This low incidence can be attributed to population-based discrepancies.
Multiple pregnancies, in the current study, showed a lower rate of ROP than singleton (28.2 vs. 11%), in comparison with the findings of Friling et al.  who reported a higher ROP incidence and severity in singleton, but Li et al.  reported the reverse, and they attributed it to the low GA and BW in multiple pregnancies.
Other risk factors especially neonatal sepsis and oxygen therapy showed comparable results to Chen et al. , who found that sepsis and oxygen exposure were independent risk factors associated with high risk of ROP (P=0.003 and 0.0347), respectively, in that study.
The treatment of ROP at risk cases using bevacizumab intravitreal injection, in the present study, showed high efficacy in stage III ROP (100%) in which progression to stage IV and V did not occur. In addition, this drug injection had also a value in decreasing neovascularization and hemorrhage in stage IV and V if subsequent vitrectomy was needed. The results of the previous studies that use bevacizumab in ROP were comparable to the current study results ,. Nonobe et al.  reported marked decrease in VEGF concentration in aqueous humor after intravitreal injection of bevacizumab in stage IV and V ROP. Mintz-Hittner et al. , in their prospective study, compared between IVB and conventional laser therapy in the treatment of stage III ROP (zones I and II). They concluded that there was a significantly lower recurrence rate of ROP with IVB treatment compared with laser therapy as laser therapy led to permanent destruction of the peripheral retina. Nicoară et al. , in their retrospective case series study, evaluated the regression of ROP after one IVB. They found that the regression occurred in 85.13% of cases with zone I stage III ROP, which is comparable with the results of this study. In addition, Kuniyoshi et al.  concluded that IVB was effective in eyes with ROP in zone II with no additional treatment required. They detected certain complications such as vitreous hemorrhage and cataract after one IVB injection. In the current study, we did not encounter any complications related the injection procedure.
AbdelHadi  evaluated the efficacy of intravitreal injection of ranibizumab and conventional laser photocoagulation for the treatment of prethreshold type ROP. He concluded that both of them were effective in the treatment of prethreshold type 1 ROP.
| Conclusion|| |
Screening and treatment of ROP should be done as early as possible. This could be achieved through raising the awareness of the general physician and pediatrician to its risk factors predominantly the BW and GA while not missing the other risk factors. Ophthalmologists should also actively participate in screening treatment programs of ROP as the bevacizumab injection therapy was highly effective in preventing early disease progression especially before development of retinal detachment. However, larger studies are needed to establish the anti-VEGF therapy as a safe primary treatment option before general clinical use can be suggested.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]