Prevalence and Risk Factors of Retinopathy of Prematurity in Iran

Abstract Purpose The present study aimed to evaluate the frequency and risk factors of retinopathy of prematurity (ROP) among Iranian infants. Methods A retrospective cohort study was conducted on infants who had undergone screening for ROP at Farabi Eye Hospital, between March 2016 and March 2017. Data were analyzed based on the presence of extreme prematurity (gestational age ≤ 28 weeks), extremely low-birth-weight (≤ 1000 g), and multiple-gestation (MG) infants. Results The prevalence of ROP was 27.28% (n = 543) among all screened infants, 74.4% for extremely preterm (EP) infants, 77.5% for extremely low birth weight (ELBW) babies, and 27.25% for infants from MG pregnancies. On multivariate analysis, gestational age, birth weight, and history of transfusion (P < 0.0001, P < 0.0001, and P = 0.04, respectively) were found to be significantly associated with ROP. More advanced stages of ROP (P < 0.0001) were observed in EP and ELBW infants. Birth weight (P = 0.088), history of transfusion (P = 0.066), and intubation (P = 0.053) were not associated with increased risk of ROP in EP infants, while gestational age (P = 0.037) and history of transfusion (P = 0.040) were significant risk factors for ROP in ELBW infants. Gestational age (P < 0.001) and birth weight (P = 0.001) were significantly associated with ROP in infants from MG pregnancies in multivariate analysis. Conclusion ROP remains a commonly encountered disease, especially in ELBW and EP infants. The history of transfusion may have a role in stratifying the risk for ROP and guiding future screening guidelines.


INTRODUCTION
Retinopathy of prematurity (ROP) is the leading cause of visual impairment in premature infants and is characterized by abnormal peripheral retinal vascularization. [1] The incidence of ROP is influenced by several factors including gestational age, birth weight, genetics, ethnicity, and level of neonatal care. Gestational age is defined as the length of time of growth of the fetus in the uterus. Screening programs should be regionally tailored to account for these differences. Advances in prenatal and neonatal care have resulted in increasing rates of ROP in the developing world. [2][3][4] Gestational age and birth weight are the two most well-established risk factors for ROP, with other factors such as oxygen therapy, history of transfusion, sepsis, and anemia being less significantly associated with ROP. [5] ROP is diagnosed only in a minority of premature infants, with a smaller subset requiring intervention. As a result, better understanding of risk factors of progression to ROP, especially in those cases requiring treatment, would allow for more effective screening programs. [5,6] The purpose of this study is to evaluate the prevalence of ROP and associated risk factors in a tertiary eye center in Tehran. Additional subgroup analysis was done for patients in three high risk categories: extremely low birth weight (≤ 1,000 g, ELBW), extremely preterm (≤ 28 weeks, EP), and multiple gestational (MG) infants.

METHODS
The current retrospective cohort study was performed at Farabi Eye Hospital from March 2016 until March 2017 after obtaining approval from the Institutional Review Board (IRB) of Tehran University of Medical Sciences. The tenets of the Declaration of Helsinki were followed. The medical records of all patients referred to the ROP clinic were assessed. All infants with gestational age ≤ 37 weeks were included in this study. Patients with incomplete medical records were excluded from the analysis. Demographic data (gestational age, birth weight, and gender) and ophthalmic findings (ROP stage, zone, and laterality) were collected and categorized for each patient. Stages of ROP were diagnosed based on the international classification of ROP as follows: Pre-threshold disease is characterized by all zone I and II changes, except zone II stage 1 and zone II stage 2 without plus disease that do not include the criteria of threshold disease, and is divided into two types: Type 1: Zone I, any stage ROP with plus disease, Zone I, stage 3 ROP without plus disease, or Zone III, stage 2 or 3 ROP with plus disease Type 2: Zone I, stage 1 or 2 ROP without plus disease and Zone II, stage 3 ROP without plus disease For the purpose of analysis, the stage of ROP in patients with bilateral disease was categorized based on the eye with the highest stage and lowest zone. Additionally, the history of sepsis, transfusion, acute respiratory distress syndrome (ARDS), oxygen therapy, intubation, intraventricular hemorrhage (IVH), and phototherapy were analyzed as risk factors for ROP. Follow-up visits, indications for treatment, types of treatment, and final ROP status at the last examination were also collected for each patient.
Data was analyzed using IBM SPSS version 19 (Armonk, NY: IBM Corp). Mean ± standard deviation was used to report data. After confirmation of the normal distribution of data by Shapiro-Wilk test, the comparison between birth weight and gestational age of patients with and without ROP was performed using student -test. Univariate logistic regression was performed to determine the significance of different potential predictive risk factors (gestational age, birth weight, transfusion, sepsis, ARDS, oxygen therapy, intubation, IVH, and phototherapy) in the development of ROP (dependent variable). Subsequently, the resultant significant risk factors were evaluated using multivariate logistic regression to discern the confounding factors. -value < 0.05 in the -test and logistic regression was considered statistically significant.

Subjects
A total of 1,990 patients met the inclusion criteria. Mean gestational age was 32.29 ± 2.75 weeks (range: 24 ± 37 weeks) and mean birth weight was 1,757.99 ± 563.51 g. The cohort comprised of 51.5% (1024) male infants.

Risk Factors
Univariate and multivariate logistic regression analyses were performed to examine the relationship between the different risk factors and development of ROP. Gestational age, birth weight, transfusion, ARDS, oxygen therapy, sepsis, intubation, and IVH were significant risk factors on univariate analysis; however, only gestational age, birth weight, and transfusion remained significant on multivariate analysis. [Tables 2 and 3]. Gestational age ( = 0.010), birth weight ( < 0.0001), and IVH ( = 0.028) were significant risk factors for ROP that required treatment.

Treatment
One hundred and eighty patients underwent treatment, which included intravitreal injection of bevacizumab [IVB, (155 eyes, 86% of patients)], laser (98 eyes, 54%), scleral buckle (5 eyes, 0.05%), vitrectomy (7 eyes, 4%), combination of IVB and scleral buckle (2 eyes, 1%), and combination of IVB and vitrectomy (1 eye, 0.5%). Twenty-nine patients (47 eyes) required retreatment, including 18 eyes with laser (previous treatment included IVB in 16 eyes and laser in 2 eyes), 17 eyes with IVB (previous treatment included IVB in all), 8 eyes with vitrectomy (previous treatment included laser in 4 eyes and IVB in 4 eyes), and 4 eyes with scleral buckle (previous treatment included laser in 2 eyes and IVB in 2 eyes). Seven eyes required a third treatment: vitrectomy in five eyes (all were primarily treated with IVB, followed by laser), and sclera buckle in two eyes (both received IVB followed by vitrectomy).

DISCUSSION
In this series, the rate of ROP was 27.28% on initial evaluation, with 1.6% developing ROP on subsequent follow-up. The rate of ROP reported in the literature ranges from 11.4 to 44% due to the differences in economic status, ethnicity, genetics, practice setting, screening programs, and level of perinatal care at the respective institutions. [6][7][8][9][10][11][12][13][14] A previous report from Iran found an 8.5% prevalence of ROP among premature infants. [15] The increased rate observed in the current study may be due to improved perinatal care, which has resulted in longer survival of high-risk infants. There is a considerable debate regarding the risk factors for ROP. In the present cohort, low gestational age and birth weight, history of transfusion, ARDS, oxygen therapy, sepsis, intubation, and IVH were significant risk factors for ROP on univariate analysis; however, on multivariate analysis only gestational age, birth weight, and history of transfusion were found to be statistically significant. Gestational age, birth weight, and IVH were significantly associated with the treatment for ROP among all infants on multivariate analysis ( = 0.010, < 0.001 and 0.028, respectively). Table 4 provides a summary of the rates of ROP and risk factors across several studies. Multiple studies have identified lower gestational age and birth weight, higher number of days of oxygen therapy, mechanical ventilation, hyperglycemia, sepsis, transfusion, inadequate weight gain during the first two weeks, and IVH as risk factors for ROP, with low gestational age and birth weight being the most consistently demonstrated risk factors. [6,8,11,12,[16][17][18] Khalesi et al. [19] observed gestational age, apnea score in the first minute, oxygen therapy, and phototherapy as significant risk factors, whereas Dai et al. [5] suggested that maternal iron deficiency may be another significant risk factor in the development of ROP. Increased oxygen demand during sepsis as well as toxic effects of high oxygen production during transfusion might result in increased susceptibility to ROP. [20] Similarly, Yau et al. [21] observed that the incidence of ROP in patients with a mean gestational age of 26.4 weeks was 60.7%. Lower birth weight, transfusion, and intubation approached statistical significance as risk factors for ROP in the present cohort of EP patients ( = 0.088, 0.066 and 0.053, respectively). Yau et al [21] retrospectively reviewed EP infants and reported that low gestational age, lighter birth weight, invasive ventilation were significant risk factors for the development of ROP on univariate analysis.
ROP was common in patients with ELBW (77.5%, = 124), which is consistent with the findings reported by Celebi et al (75.5%). [25] A wide spectrum exists in studies examining the rate of occurrence of ROP (32.8 ± 82.5%) and the rate of treatment for ROP (12.7 ± 48.9%) in ELBW infants. [4,[22][23][24] In multivariate analysis, we observed that lower gestational age ( = 0.037) and history of transfusion ( = 0.040) were significant risk factors for the development of ROP in ELBW infants. Celebi et al reported that gestational age, birth weight, history of transfusion, and sepsis were significant factors associated with severe ROP requiring treatment in all infants, while only gestational age was statistically significantly associated with ROP requiring treatment in ELBW infants. [25] Among patients born of MG pregnancies, lower gestational age and birth weight were significant risk factors for ROP ( < 0.001 and 0.001, respectively), and no significant difference existed in the severity of ROP and rate of treatment between MG patients and those born of a single gestation. Twin-twin transfusion syndrome has been found to increase the risk for ROP compared to MG alone ( < 0.01). [26] Yau et al [27] assessed the risk of