Abstract
OBJECTIVE:
The objective of the study was to determine the incidence, patterns, and risk factors for the development of retinopathy of prematurity (ROP) in infants weighing >1500 g at birth.
MATERIALS AND METHODS:
A retrospective analysis was done of the ROP screening records between April 2019 and March 2022. All the infants with birth weight >1500 g who underwent ROP screening were included. Data collected included demographic details, details of the risk factors (respiratory distress syndrome [RDS], hypoxia, anemia, septicemia, patent ductus arteriosus, congenital heart disease [CHD], i.e., atrial septal defects or ventricular septal defects, and multiple gestations), and ocular examination findings. Statistical analyses included calculation of mean, range, Chi-square test, and bivariate logistic regression for associations of risk factors with ROP.
RESULTS:
ROP was noted in 16.6% of the 336 eyes of 168 infants. The mean birth weight and mean gestational age (GA) of the infants were 1850 ± 33 g and 33.33 weeks ± 1.71 weeks, respectively. Eighteen eyes (32.1%) had Stage I, 17 eyes (30.35%) had Stage II, and 11 eyes (19.64%) had Stage III ROP in Zone II. Aggressive ROP was seen in 8 eyes (14.28%) and stage 5 ROP in two eyes (0.59%). Male gender, GA, CHD, and RDS showed a statistically significant association with the development of ROP in these infants.
CONCLUSION:
ROP was seen in 16.66% of our subjects. Treatment was required in 6.25% of infants. Risk factors for the development of ROP were low gestational age, male gender, the presence of RDS, and congenital heart disease.
Keywords: Birth weight, retinopathy of prematurity, risk factors
Introduction
Retinopathy of prematurity (ROP), first described in the 1940s and 1950s as retrolental fibroplasia, is a proliferative retinal vasculopathy, affecting preterm low birth weight infants.[1] The developing countries are currently experiencing an increase in ROP due to improved neonatal survival and unmonitored oxygen supplementation. Timely ROP screening helps to identify and treat the disease, thus helping to prevent blindness. The ROP screening guidelines vary in different parts of the world. The Western guidelines advise screening of all infants with gestational age (GA) <30 weeks and birth weight <1500 g.[2] In India, the current guidelines advocate screening all infants with birth weight <2000 g and GA <34 weeks.[3] Infants outside this guideline are to be included if the infant has a stormy neonatal period. Indian guidelines include bigger infants for screening compared to their Western counterparts, where infants with birth weight <1500 g are included. Our study aims to ascertain the incidence and patterns of development of ROP in infants who weighed >1500 g at birth, in a tertiary care hospital in South India. We aim to study the risk factors which are associated with the development of ROP in this cohort of infants.
Materials and Methods
This was a retrospective observational hospital-based study. Institutional ethics committee clearance was taken and the study adhered to the tenets of the Declaration of Helsinki. A retrospective data analysis of all the infants screened for ROP from April 2019 to March 2022 who weighed >1500 g at birth was done. Infants had undergone screening for ROP (with a binocular indirect ophthalmoscope) and treatment, if necessary, as per the prevailing guidelines.[3,4,5] The various data collected included name, GA, sex, hospital identification number, and birth weight. The systemic risk factors noted were respiratory distress syndrome (RDS), hypoxia, anemia, septicemia, packed cell transfusion, apnea, mechanical ventilation, multiple gestations, intraventricular hemorrhage, hypotension, and congenital heart disease (CHD) such as atrial septal defect (ASD) or ventricular septal defect (VSD) confirmed by echocardiogram. Anterior segment examination findings and fundus examination findings were collected. The presence of two or more risk factors was considered the presence of multiple risk factors. The pattern of ROP was described in terms of zone, stage, plus disease, and clock hours of ROP as per International Classification of ROP guidelines.[6] Data thus obtained were entered into the Microsoft Excel spreadsheet. The Statistical Package for the Social Sciences version 20.0 (IBM Inc, Ca, USA) was used to perform the statistical analysis. Descriptive statistics of the explanatory and outcome variables were calculated by mean and standard deviation for quantitative variables. Frequency and proportions were calculated for qualitative variables. The Chi-square test and Fisher’s exact test were applied to test the statistical association between ROP and risk factors (qualitative variables). Bivariate logistic regression was performed with ROP as dependent variable, and risk factors (gender, apnea, CHD, respiratory distress, and multiple risk factors) as independent variables. The level of significance was set at 5%.
Results
During the study period, 451 infants were screened for ROP. Of these, 168 infants (336 eyes) satisfied the inclusion criteria and were included in this study. Of the 168 infants, 96 (57.1%) were males and 72 (42.9%) were females. The mean birth weight of the subjects was 1850 ± 330 g. The birth weight of 123 (73.2%) infants was between 1501 and 2000 g, 38 (22.6%) was between 2001 and 2500 g, and 7 (4.2%) was >2500 g. When the GA was analyzed, 1 infant (0.6%) was <28 weeks of GA, 32 (19%) infants were 28–32 weeks of GA, 88 (52.4%) were 32–34 weeks of GA, and 47 (28%) were >34 weeks of GA. The mean GA was 33.33 weeks ± 1.71 weeks. Among the associated systemic risk factors studied, RDS was the most common risk factor, seen in 69 infants (41.7%). Other risk factors observed were septicemia in 61 infants (36.3%), multiple gestations in 45 infants (26.8%), apnea in 30 infants (17.9%), packed cell transfusion in 17 infants (10.1%), mechanical ventilation in 16 infants (9.5%), CHD (ASD or VSD) in 10 (5.9%), intraventricular hemorrhage in 7 infants (4.2%), anemia in 6 (3.6%), hypoxia in 4 infants (2.4%), and hypotension in two infants (1.2%). Multiple risk factors (two or more risk factors) were seen in 70 (41.7%) infants. On fundus examination, 56 eyes of 28 infants (16.66%) had ROP. Out of these, 18 eyes (32.1%) had Stage I ROP in Zone II, 17 eyes (30.35%) had Stage II ROP in Zone II, and 11 eyes (19.64%) had Stage III ROP in Zone II. Eight eyes (14.28%) showed tortuous vessels in Zone I and posterior Zone II with flat neovascularization, looping, and shunting of vessels with plus disease suggestive of aggressive ROP (AROP). None of the eyes had Stage IV ROP. Stage V disease was seen in both eyes (3.5%) of one infant who presented after 5 months of birth for ROP screening. The association of various risk factors with the development of ROP in the subjects was studied. Of the risk factors, GA, male gender, apnea, RDS, CHD (ASD or VSD), and the presence of multiple risk factors were found to be statistically significant. The association of gestation age with the development of ROP is shown in Table 1. The details of associations of risk factors with the development of ROP are shown in Table 2. On bivariate logistic regression, male gender, GA, CHD, and RDS showed a statistically significant association with the development of ROP in the study subjects. Details of bivariate logistic regression analysis done are shown in Table 3. Twenty-one eyes of 11 infants (6.25%) needed treatment. The average GA of infants who needed treatment was 31.27 weeks and the average birth weight was 1790 g (range of 1550–2300 g). Risk factors observed in infants who required treatment were RDS, septicemia, CHD, and apnea. Eight of the infants who needed treatment had multiple risk factors.
Table 1.
Association of gestational age with development of retinopathy of prematurity in infants with birth weight >1500 g
| Variable | ROP | n* | Mean (weeks)±SD | Mean difference (weeks) | P ⴕ |
|---|---|---|---|---|---|
| GA | Present | 28 | 32.26±1.63 | −1.28 | 0.00 |
| Absent | 140 | 33.54±1.65 | |||
| Total | 168 | 33.33±1.71 |
*Number of subjects, ⴕIndependent t-test value. SD: Standard deviation, ROP: Retinopathy of prematurity, GA: Gestational age
Table 2.
Association of various risk factors with development of ROP in infants with birth weight >1500 g
| Risk factor (variables) | ROP (%) | P (Chi-square test) | |
|---|---|---|---|
|
| |||
| Present (percentage within group with ROP, n=28*) | Absent (percentage within group without ROP, n=140*) | ||
| Male gender | 22 (78.6) | 74 (52.9) | 0.012 |
| RDS | 18 (64.3) | 51 (36.4) | 0.006 |
| CHD (ASD/VSD) | 6 (21.4) | 4 (2.9) | 0.00015 |
| Blood transfusion | 4 (14.3) | 13 (9.3) | 0.42 |
| Apnea | 9 (32.1) | 21 (15.0) | 0.03 |
| Mechanical ventilation | 5 (17.9) | 11 (7.9) | 0.09 |
| Septicemia | 11 (39.3) | 50 (35.7) | 0.71 |
| Hypoxia | 1 (3.6) | 3 (2.1) | 0.521 |
| Anemia | 1 (3.6) | 5 (3.6) | 1 |
| Multiple gestations | 5 (17.9) | 40 (28.6) | 0.24 |
| Hypotension | 1 (0.7) | 1 (3.6) | 0.3 |
| Multiple risks (presence of two or more risk factors) | 18 (64.3) | 52 (37.1) | 0.007 |
| Patent ductus arteriosus | 0 | 3 (2.1) | NAⴕ |
| Intraventricular hemorrhage | 7 (5.0) | 0 | NAⴕ |
*Number of subjects, ⴕNA: Not applicable, ASD: Atrial septal defect, VSD: Ventricular septal defect, ROP: Retinopathy of prematurity, CHD: Congenital heart disease, RDS: Respiratory distress syndrome
Table 3.
Details of bivariate logistic regression analysis done with retinopathy of prematurity as dependent variable and risk factors as independent variables
| Variables | Degree of freedom | P | OR | 95% CI for OR | |
|---|---|---|---|---|---|
|
| |||||
| Lower | Upper | ||||
| Male gender | 1 | 0.011 | 0.255 | 0.088 | 0.732 |
| Apnea | 1 | 0.197 | 0.498 | 0.172 | 1.437 |
| RDS | 1 | 0.020 | 0.309 | 0.116 | 0.828 |
| CHD | 1 | 0.007 | 0.117 | 0.025 | 0.553 |
| Multiple risks | 1 | 0.364 | 0.620 | 0.221 | 1.738 |
| Constant | 1 | 0.017 | 8.517 | ||
CHD: Congenital heart disease, RDS: Respiratory distress syndrome, OR: Odds ratio, CI: Confidence interval
Discussion
ROP is a worldwide disease seen in both developed and developing nations. However, the infants developing ROP in the developing world are older and weigh more compared to their Western counterparts.[7] Our study describes the incidence, patterns, and risk factors of ROP in infants with birth weight >1500 g from a single tertiary care center catering to the rural and suburban population of Southern India.
The majority of infants (123 infants, 73.2%) in our study weighed between 1500 and 2000 g at birth. A similar distribution was also observed by other authors who studied ROP in bigger infants in Turkey and Taiwan.[8,9] The mean GA of our subjects was 33.33 weeks. Infants who are born between 32 and 34 weeks of gestation age are likely to weigh more than those born before 32 weeks of gestation age and form the major part (52.4%) of our study subjects. A similar GA pattern has been observed by other authors who have studied ROP in infants weighing > 1500 g at birth.[8,9]
The incidence of ROP in our study was 16.6%. A similar study done by Al-Essa et al. in Kuwait showed an incidence of ROP in bigger infants of 19.1%.[10] Ongun et al. reported the incidence of ROP in their Turkish subjects as 7.6%.[8] Varying rates have been reported from Mexico and Oklahoma (4.2%).[11,12] The incidence of ROP varies between different countries and also between different centers located in the same region. Our hospital, being a referral center, caters to complicated cases, including complicated preterm deliveries. This could be one factor contributing to a higher incidence of ROP in our center which caters to babies who have many coexisting systemic problems. The incidence of treatable ROP in our study was 6.25% with an average birth weight of 1790 g in these infants. Treatment was warranted in 1.5% of the subjects in the Turkish study reported by Ongun et al.[8] In the Taiwanese study reported by Chen et al., the incidence of treatable ROP was 10% among all ROP infants.[9] When we searched literature from the Western world, we found that severe ROP was seen predominantly in infants with birth weight <1000 g and GA <28 weeks.[13,14] We observed AROP in 14.28% of our infants with ROP. Shah et al. and Sanghi et al. have also described AROP in bigger Indian babies.[15,16] This difference in the incidence and birth weight distribution of infants with severe ROP, especially AROP, observed between the developed and developing countries points toward the need for better neonatal care in the developing world. Protocols for neonatal management need standardization and application of the same at all neonatal intensive care units irrespective of urban, rural, or suburban location.
Bivariate logistic regression analysis showed GA, respiratory distress, the presence of CHD, and male gender to be significantly associated with the development of ROP. There was a mean difference of 1.28 weeks between infants with and without ROP. This can be explained by the immaturity of retinal vasculature at lower GA which increases the risk of developing ROP, independent of birth weight. Another important observation from our study is the association of CHD such as ASD or VSD with the development of ROP in infants with birth weight >1500 g. Of the 28 infants who showed ROP, 6 infants (21.4%) had the presence of CHD, which was found to be statistically significant. This has not been highlighted in previous studies. We need to screen bigger infants, including those outside of the screening guidelines, in the presence of CHD. In a study done in rural Southern India, Hungi et al. identified sepsis, neonatal jaundice, RDS, and oxygen therapy as risk factors in developing severe ROP in more mature infants.[17] In our study, the presence of septicemia was noted in 39.3% of infants with ROP but was not found to be statistically significant. This was due to the high prevalence of septicemia in infants with and without ROP in our NICU. Other studies also have identified similar risk factors for the development of ROP in more mature infants who weigh more.[18,19] Unmonitored supplemental oxygen therapy in the perinatal period has been shown to play an important role in this process. Each day of oxygen supplementation was found to increase the risk of retinopathy in infants with birth weight >1500 g.[20,21] Oxygen supplementation details which were not available in our study due to lack of proper documentation, indicate a need for monitored oxygen delivery in these infants. In infants with <1500 g birth weight, studies have shown an association of the development of ROP with low birth weight, low GA, RDS, oxygen supplementation, neonatal jaundice, patent ductus arteriosus, septicemia, anemia, apnea, hypoxia, etc.[20,21,22,23,24] The presence of multiple risk factors and poor NICU protocols lead to the development of ROP, especially AROP, in bigger infants. In the developing world, we have to emphasize the importance of including these infants in the screening programs. An effort needs to be done to improve NICU care and to optimize the oxygen supplementation to these at-risk infants. Blenders can be used to administer oxygen and oxygen levels have to be aimed at 83%–93%.[25] These measures may help to bring down the rate of ROP in at-risk infants in the developing world.
The strength of our study is the identification of patterns and risk factors for ROP in infants with birth weight > 1500 g in Southern India. This has emphasized the need to include these infants with coexisting risk factors, especially CHD and RDS, for ROP screening. The drawbacks of the study are its retrospective nature, lack of availability of details of oxygen administration, and antenatal/maternal risk factors. The lack of a control arm for infants with birth weight <1500 g has been addressed by considering other studies for comparison. This study has further highlighted the need for monitored oxygen delivery and the development of uniform practice protocols in neonatal care units in developing nations. Future studies can be planned to study the predictive value of the risk factors identified in our study.
Conclusion
ROP is seen in 16.6% of infants with birth weight >1500 g in our hospital. Treatment requiring ROP was seen in 6.5% of the infants. The presence of systemic risk factors, especially male gender, low GA, the presence of CHD, and RDS was associated with the development of ROP in our study subjects.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Acknowledgments
Dr Anupama S Desai, Professor and Head of the Department, Department of Ophthalmology, SDM College of Medical Sciences and Hospital, Shri Dharmasthala Manjunatheshwara University, Dharwad
Dr Vijay Kulkarni, Professor and Head of the Department, Department of Paediatrics, SDM College of Medical Sciences and Hospital, Shri Dharmasthala Manjunatheshwara University, Dharwad.
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