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To determine the prevalence and predictors of Retinopathy of prematurity (ROP) and severe ROP.
Methods
A prospective observational study (April 2019–May 2020) was conducted at a tertiary care center in preterm newborns with; 1) birth-weight <2000 g or gestation <34 weeks and 2) gestation 34–36 weeks with risk factors that predispose to ROP.
Results
A total of 340 preterm newborns were screened. ROP was diagnosed in 63 (18.5%), of which 8 (2.4%) had severe ROP. 30.2%, 63.5%, and 9.5% babies had stage 1, 2, and 3 ROP, respectively. Perinatal risk factors for ROP were assessed using univariate analysis. In the binary logistic regression analysis, birth-weight<1250 g, gestation<30 weeks, weight-gain proportion at 4, 5 and 6 weeks, respiratory distress syndrome (RDS), surfactant administration, need for oxygen were significantly associated with ROP while birth-weight<1250 g, apnea, surfactant administration and oxygen duration≥80 h were associated with severe ROP (p < 0.005). Infants with poor postnatal weight-gain were found to be at risk for ROP. ROC plot depicted an absolute weight gain of 535 g at 6-weeks of age had a sensitivity of 58.7% and specificity of 32.9% for predicting ROP.
Conclusion
The prevalence of ROP was 18.5%. Birth-weight<1250 g, gestation <30 weeks, weight-gain proportion at 4, 5 and 6 weeks, RDS, surfactant administration, need for oxygen were independent predictors for ROP, however birth-weight<1250 g, apnea, surfactant administration and oxygen duration ≥80 h were independent predictors for severe ROP. Preterm newborns with poor postnatal weight-gain are at risk for ROP.
Early Treatment for Retinopathy of Prematurity Randomized Trial
ROC
Receiver operating characteristic
BW
Birth Weight
GA
Gestation Age
OR
Odds Ratio
PA
Perinatal Asphyxia
VEGF
Vascular endothelial growth factor
NNH
Neonatal Hyperbilirubinemia
SA
Surfactant administration
ET
Exchange Transfusion
1. Introduction
Retinopathy of prematurity (ROP) is a vaso-proliferative disorder of the retina that can produce significant vision impairment in infants and remains one of the leading causes of preventable blindness.
Hence, there ought to be other possible prenatal and postnatal risk factors responsible such as hypoxia, hyperoxia, sepsis, shock, necrotizing enterocolitis (NEC), intraventricular haemorrhage (IVH), prolonged exposure to oxygen (O2), severity of neonatal illnesses, mechanical ventilation, prolonged ventilatory support, anemia, blood transfusion, acidosis, high ambient light, and vitamin E deficiency, etc.
Great disparities in the quality of neonatal care among peripheral and tertiary care centers, along with increased survival of preterm neonates, are significant reasons. This coupled with low coverage of screening and management services due to a lack of awareness of ROP among healthcare workers, parents, and counselors along with the scarcity of trained ophthalmologists and neonatologists in the community, intensifies the problem. It has been observed that the majority of babies in these countries present with stage five disease and are heavy and more mature. Thus, it seems logical that the screening guidelines for ROP in developing countries should include simple, easily identifiable risk factors which could help in the early identification of at-risk newborns and possibly prevent sight-threatening ROP. Hence, we conceived this study to determine the prevalence of ROP and severe ROP and analyze the predictors for its development.
2. Patients and methods
This prospective observational study was conducted at a tertiary care center in Northern India comprising of both inborn and outborn newborns between April 2019 and May 2020. The study was approved by Institutional ethical committee. All admitted newborns were screened for the study. The inclusion criteria's were: 1) preterm newborns with birth weight <2000 gm or gestational age <34 weeks; 2) selected preterm newborns between 34 and 36 weeks gestational age with any of the following: continuous positive airway pressure (CPAP) or ventilation for any duration, oxygen therapy for ≥24 h, vasopressors support, blood transfusion and culture positive sepsis. Exclusion criteria's were: preterm newborns with major congenital anomalies and where parents declined enrolment and follow-up. The eligible preterm newborns were recruited after written consent from either of the parents. All neonatal and maternal details were recorded in a predesigned proforma.
Neonatal details like gestational age (GA), birth weight (BW), gender, apneic episodes, type of oxygen supplementation and duration, blood transfusion, hyperbilirubinemia, exchange transfusion, hypothermia, sepsis, shock, perinatal asphyxia, seizures, surfactant administration, respiratory distress syndrome (RDS), patent ductus arteriosus (PDA), intraventricular haemorrhage (IVH), necrotising enterocolitis (NEC) and haemorrhagic disease of newborns (HDN) were recorded. GA was determined by antenatal ultrasound in the first trimester or calendar method and confirmed by the New Ballard Score after delivery.
Electronic infant weighing scale was used to measure the BW. Postnatal weight gain proportion (%) in the first six weeks of life (4, 5 and 6 weeks) was calculated by: Postnatal weight gain proportion (%) = {[Weight at (x) weeks–BW] ÷ BW} × 100.
The duration of oxygen administration was recorded and extreme caution was taken to maintain oxygen saturation (SpO2) between 90 and 94% by titrating the fraction of inspired oxygen (FiO2) between 30 and 100%. Preterm newborns with mild to moderate respiratory distress were managed with CPAP and surfactant was administered if symptoms, signs and radiological features were compatible with RDS. Babies failing CPAP were managed with mechanical ventilation. Lung protective strategies were followed and ventilator parameters including FiO2 were noted.
Neonatal sepsis was diagnosed based on clinical suspicion, sepsis screen and microbiological confirmation.
Shock was considered by evidence of poor perfusion with tachycardia, cold extremities and capillary refill time >3 s or blood pressure below 5th percentile for GA. Cranial ultrasound was carried out in the first and fourth week as per unit protocol. Echocardiogram was done if the neonate was found to have significant murmur or clinical suspicion for PDA. Anemia was defined as haematocrit or haemoglobin level >2 standard deviations below the mean value for the age.
American Academy of Pediatrics Section on Ophthalmology; American academy of ophthalmology; American association for pediatric ophthalmology and strabismus; American association of certified orthoptists. Screening Examination of Premature Infants for Retinopathy of Prematurity [published correction appears in Pediatrics.
Screening of ROP was performed by an ophthalmologist using Retcam Shuttle (Clarity MSI, USA). Pre-treatment of the eyes with a topical Proparacaine was done to minimize discomfort to the babies followed by pupillary dilatation with phenylephrine 2.5% and Tropicamide 0.5%. The universally accepted Revised International Classification of ROP (ICROP) guidelines were adopted to define the location and extent of disease within the retina.
The cases were classified on the basis of vascularisation of retina and characterized by its position (zone), severity (stage), and extent (clock hours).
First ROP screening was done at 4 weeks after birth. However, for those <28 weeks GA or BW < 1200 g, screening was done at 2 weeks after birth. Thereafter, they were screened every 2 weeks/earlier until complete vascularisation of retina. The occurrence of ROP changes in either eye was recorded according to ICROP. The preterm newborns were then divided into two groups based on the presence or absence of ROP, Group 1: ROP and Group 2: Non- ROP group. The ROP group was further subdivided into Non-severe ROP (not requiring treatment, comprising of stages 1, 2, and 3 < threshold disease) and severe ROP group (requiring treatment, comprising of threshold ROP, stages 4 and 5). Threshold ROP included ROP of more than five contiguous or eight cumulative clock hours of stage 3 with plus in zone 1 or zone 2. The decision for the treatment of ROP was based on the type of ROP as per Early Treatment for Retinopathy of Prematurity Randomized Trial (ETROP).
Early Treatment for Retinopathy of Prematurity Cooperative Group Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial.
Babies with threshold ROP were treated with laser photocoagulation within 72 h of diagnosis. Additionally, all enrolled preterm newborns were followed at 4, 5, and 6 weeks to observe their weight gain and its impact on the development of ROP. The primary outcome measured was the prevalence of ROP and severe ROP. Secondary outcomes measured were the predictors and outcomes of ROP.
2.1 Statistical analysis
The incidence of ROP in the preterm population was found to be 32.6% and 21.6% in the studies done by Ahuja and Rao et al., respectively.
Considering the incidence of ROP as 30% with an absolute precision of 5% and confidence level (1-α) 95%, a total of 323 neonates were needed for screening. Continuous variables were analyzed by student t-test (normally distributed) and Mann-Whitney U test (non-normally distributed). Categorical variables were analyzed by Chi -square or Fischer -Exact test. A univariate and binary logistic regression analysis was performed to determine the predictors for ROP and severe ROP. The receiver operating characteristic (ROC) curve was plotted to determine the discriminative cut-off values of postnatal weight gain proportion. Analysis was done using SPSS software 23-version, and a p-value of <0.05 was taken as significant.
3. Results
Of the total 2367 admissions to Neonatal Unit, 412 preterm newborns (17.4%) fulfilled the inclusion criteria. A total of 340 preterm newborns (male, n = 185) were analyzed. ROP (any stage/zone) was detected in (n = 63, 18.5%), and the rest (n = 277) did not have ROP (non-ROP group). Among the ROP group, 55 had non-severe, and 8 had severe ROP; their baseline comparison is shown in Table 1. The mean BW of the ROP and the non-ROP group was 1396.03 ± 260.96 g and 1592.02 ± 196.52 g, respectively, and the mean GA was 30.1 ± 2.1 weeks and 32.4 ± 0.8 weeks respectively, both being significantly less in ROP group (p < 0.001).
Table 1Baseline comparisons of parameters among ROP and non-ROP group.
Parameters
ROP Group (n = 63)
Non-ROP Group (n = 277)
p-value
Gender, Male
41 (65.0%)
144 (51.9%)
0.06
Birth Weight (mean ± SD), grams
1396.03 ± 260.96
1592.02 ± 196.52
<0.001
Gestation (mean ± SD), weeks
30.1 ± 2.1
32.4 ± 0.8
<0.001
Postnatal weight gain proportion (mean ± SD)
1
Weight gain proportion at 4-week
12.45 ± 5.45
15.35 ± 3.33
<0.001
2
Weight gain proportion at 5-week
23.30 ± 12.40
29.17 ± 7.87
<0.001
3
Weight gain proportion at 6-week
33.35 ± 10.24
38.75 ± 6.63
<0.001
Birth weight (grams)
1
.<1000
5 (7.9%)
0 (0%)
0.05
2.
1000-1249
16 (25.4%)
8 (2.9%)
0.18
3.
1250-1499
22 (34.9%)
108 (38.9%)
<0.001
4.
≥1500
20 (31.8%)
159 (58.2%)
<0.001
Maternal risk factors
1
Pregnancy induced hypertension
11 (17.5%)
61 (22.0%)
0.42
2
Antepartum haemorrhage
4 (6.3%)
42 (15.2%)
0.07
3
Antenatal corticosteroid administration
9 (14.3%)
43 (15.5%)
0.80
4
Meconium stained liquor
12 (19.0%)
55 (19.6%)
0.88
5
Chorioamnionitis
46 (73.0%)
117 (42.2%)
<0.001
Neonatal risk factors
1
Respiratory distress syndrome
39 (61.9%)
65 (23.5%)
<0.001
2
Clinical sepsis
46 (73.0%)
117 (42.2%)
<0.001
3
Culture positive sepsis
25 (39.7%)
84 (30.3%)
0.15
4
Perinatal Asphyxia
18 (28.6%)
26 (9.4%)
<0.001
5.
Hypotension
9 (14.3%)
34 (12.2%)
0.66
6.
Apnea
13 (20.6%)
161 (58.1%)
0.15
7.
Blood transfusion
20 (31.7%)
70 (25.2%)
0.29
8.
Neonatal hyperbilirubinemia
39 (61.9%)
144 (51.9%)
0.15
9.
Surfactant Administration
9 (14.1%)
75 (27%)
0.01
10.
Patent ductus arteriosus
5 (7.9%)
14 (5.1%)
0.36
11.
Intraventricular haemorrhage
5 (7.9%)
20 (7.2%)
0.84
12.
Necrotising enterocolitis
0 (0%)
11 (3.9%)
0.11
13.
Haemorrhagic disease of newborn
3 (4.8%)
21 (7.6%)
0.43
14.
Exchange transfusion
3 (4.8%)
6 (2.2%)
0.25
Need for oxygen administration
41 (65.1%)
65 (23.5%)
<0.001
Duration of oxygen (hours)
51.2 ± 50.9
12.7 ± 28.5
<0.001
Days of establishment of full enteral feed (days) (mean ± SD)
5.36 ± 2.62
3.17 ± 1.33
<0.001
Values are expressed in number (percentage), and mean (standard deviation).
ROP: Retinopathy of Prematurity, SD: standard deviation.
A zone and stage-wise distribution of ROP is shown in Fig. 1. Zone I was detected among the infants with ROP in 4.5% (3/63), zone II in 50.8% (32/63), and zone III in 47.6% (30/63). Infants with ROP were: stage 1 in 30% (19/63), stage 2 in 63.5% (40/63), and stage 3 in 9.5% (6/63). The majority of our patients had Zone II involvement and 4.76% developed severe ROP. None of the preterm infants developed stage 4/5.
Table 1 shows the baseline analysis of prenatal and postnatal risk factors between the ROP and non-ROP groups. The prevalence of ROP was higher with a decrease in BW and GA. Apart from these, maternal chorioamnionitis, RDS, clinical sepsis, perinatal asphyxia, surfactant administration, need for oxygen and longer oxygen duration and delayed achievement to full enteral feed were significantly higher in the ROP group. The association of postnatal weight gain proportion in neonates among ROP and the non-ROP group was analyzed at 4, 5, and 6 weeks and was significantly less in the ROP group (p < 0.001). Full enteral feeding was established earlier in the non-ROP group (3 days vs. 5 days, p < 0.001). The oxygen administration [by any mode: hood, nasal prongs, bubble CPAP, or mechanical ventilation] was more often in preterm newborns with ROP (65% vs. 23%; p < 0.001). Similarly, the duration of oxygen administration was longer among ROP (51.2 ± 50.9 vs. 12.7 ± 28.5 h, p < 0.001).
To predict the risk factors for the development of ROP and severe ROP in the preterm newborns, we used variables one by one in univariate analysis and found 11 factors (BW, GA, weight gain proportion at 4, 5, 6 weeks, need for oxygen and longer oxygen duration, RDS, surfactant administration, clinical sepsis, perinatal asphyxia, delayed achievement to full enteral feed, history of chorioamnionitis in mother) to be significantly associated with ROP; however only seven risk factors were significantly associated with the development of severe ROP (BW, GA, perinatal asphyxia, RDS, apnea, need of surfactant and prolonged use of oxygen).
The factors found to be significant in univariate analysis were applied to binary logistic regression analysis (Table 2). Five independent risk factors (BW < 1250 g, GA<30 weeks, weight gain proportion at 4, 5, 6 weeks, RDS, surfactant administration, and need for oxygen.) were found for the development of ROP, while only four (BW < 1250 g, apnea, surfactant administration and oxygen duration ≥80 h) independent risk factors for severe ROP (Table 2).
Table 2Binary logistic regression analysis to determine independent predictors for development of ROP and severe ROP.
Parameters
ROP
Severe ROP
Variables
OR (95%CI)
p-value
OR (95%CI)
p-value
Birth weight <1250 g
12.6 (2.1–73.8)
0.01
102 (4.1–2521)
0.01
Gestation <30 weeks
44.10 (13.8–140.5)
<0.001
55.2 (28.8–87.8)
0.99
Weight gain proportion at 4 weeks ≥ 14
1.10 (1.0–1.7)
0.02
0.14 (0.0–1.2)
0.08
Weight gain proportion at 5 weeks ≥ 24
2.49 (1.1–5.7)
0.01
2.26 (0.2–19.8)
0.46
Weight gain proportion at 6 weeks ≥ 35
6.73 (1.3–33.4)
0.02
1.89 (0.2–16.2)
0.56
Chorioamnionitis
0.99 (0.1–7.9)
0.99
2.2 (0.5–18.9)
0.99
Respiratory distress syndrome
25.56 (1.28–65.81)
0.04
12.5 (2.4–67.9)
0.99
Blood transfusion
1.1 (0.2–23.5)
0.54
0.18 (0.0–1.1)
0.06
Apnea
2.1 (0.1–26.5)
0.24
3.3 (1.4–7.8)
0.01
Surfactant administration
0.20 (0.1–0.8)
0.02
0.05 (0.0–0.6)
0.01
Perinatal asphyxia
0.89 (0.2–3.5)
0.88
0.25 (0.0–2.0)
0.19
Sepsis
4.44 (0.5–38.2)
0.17
7.6 (0.9–84.7)
0.99
Oxygen needed
31.77 (1.8–561.9)
0.02
16.7 (2.1–88.2)
0.99
Oxygen duration ≥80 h
0.23 (0.1–1.0)
0.05
4.7 (2.1–16.3)
0.01
Day to full enteral feed ≥4 days
2.78 (0.7–10.5)
0.13
1.95 (0.3–13.9)
0.50
ROP: Retinopathy of Prematurity, OR: Odds Ratio, CI: Confidence interval.
The present study showed that early postnatal weight gain in preterm neonates has been protective for ROP; hence we analyzed the predictive power of weight gain proportion at 6 weeks for ROP by plotting the ROC (Fig. 2). The area under the curve was only 0.6944 (95% CI: 0.61 to 0.77). The discriminatory power was modest. The absolute weight gain of 535 gms from birth to 6 weeks of age had a sensitivity of 58.7% and specificity of 32.9% for predicting ROP. The severe ROP cohort (n = 8) was treated with laser ablation (n = 5) and anti-vascular endothelial growth factor (VEGF) (n = 3). All of them had regression following treatment.
Fig. 2ROC curve for postnatal weight gain at 6 weeks and development of ROP.
In our study, the prevalence of ROP and severe ROP was 19.1% and 2.47%, respectively. This was similar to studies done by Rao et al. [16] and Maheshwari et al.
with the inclusion of neonates with GA ≤35 weeks and BW ≤ 1500 g, which was 20%. The slight differences among the incidences of ROP in various studies may be related to different cut-offs of BW and GA, genetics profile, level of neonatal care, and methodology of research.
In our study, univariate analysis showed a significant relationship between the incidence of ROP (Any ROP and severe ROP) and lower BW and GA. Both have been identified as the main risk factors for the incidence of ROP by numerous studies.
BW ≤ 1250 g and GA≤30 weeks were also found to be an independent risk factors for development of ROP.
Among the prenatal risk factors, APH, PIH, ACS, MSAF, and chorioamnionitis have been found to be significantly associated with ROP; though we only found chorioamnionitis as a risk factor here.
Neonatal clinical sepsis was also found to be a risk factor on univariate analysis, and 73% of the ROP group had clinical sepsis (p < 0.001), which corroborates with findings of other studies.
Gupta et al. reported 52% sepsis among babies with ROP and observed that the risk of ROP was independently proportional to the presence of bacterial and fungal sepsis only in ELBW babies and those with threshold ROP.
The probable explanation for both seems to be hemodynamic instability caused by sepsis leading to hypotension and fluctuation of oxygen saturation which in turn causes alteration in retinal perfusion resulting in retinal ischemia and poor perfusion. Another possible elucidation could be that the increased systemic pro-inflammatory cytokines exert a direct effect on retinal neovascularization via VEGF production. Thus, it can be assumed that early prevention and treatment of sepsis may help in reducing the risk of ROP. A study by Rosemary et al. also showed a protective effect of maternal antenatal steroid administration on the development of ROP in neonates, which was not seen in the present study.
We also observed that perinatal asphyxia was an essential determinant for ROP; akin to Shah et al., who observed a higher risk of ROP in preterm babies with lower APGARs at 1 min.
RDS was also found to be a significant risk factor in the present study and an independent risk factor on binary logistic regression analysis for the development of ROP, similar to the study done by Gupta et al., who observed ROP in 33.3% with RDS.
A valid rationale is that these neonates eventually had lesser oxygen requirement and exposure. The preterm lungs are immature and are usually exposed to prolonged oxygen, often at high concentrations. Animal studies have demonstrated that immature retina is susceptible to such high concentrations of oxygen, which leads to vasoconstriction of these immature vessels. This vasoconstriction initiates continuous retinal tissue hypoxia even after discontinuation of oxygen, leading to the up regulation of VEGF.
VEGF, in turn, can stimulate retinal angiogenesis and plays a vital role in the pathogenesis of ROP. Moreover, some studies have reported that significant changes in blood oxygen saturation resulting from apnea and oxygen therapy can also predispose to ROP through the above mechanism.
Likewise, in our study ROP group had a late establishment of enteral feeds compared to non-ROP; however it was not found to be an independent risk factor for ROP. The need for oxygen and delayed achievement to full enteral was significantly associated with ROP compared to the non-ROP group. These findings were in accordance with Sathar et al.
In our study, parameters like BW < 1250 gms, apnea, surfactant not used, and longer oxygen duration ≥80 h were found to be independent predictors for the development of severe ROP. This reflects that patients requiring oxygen are more prone to severe respiratory disease, thus, are more likely to have fluctuations in oxygen concentration and episodes of hypoxia and hyperoxia that might exaggerate the risk of developing ROP.
We also observed that the weight gain proportion at 4, 5, and 6 weeks was significantly less in the ROP group as compared to the non-ROP group. It suggests that poor postnatal weight gain is associated with a higher incidence of ROP. This has been demonstrated as a risk factor in a few studies (Kamath et al.
). It may be a direct consequence of the early establishment of feeding and can play an important role in preventing/predicting ROP. This observation can be largely applied to community ROP screening programs in developing countries where the importance of early initiation of feeding is essentially ignored.
The present study highlights the magnitude of the problem due to ROP in our preterm population. The incidence is likely to increase as smaller babies survive unless a parallel reduction in other risk factors occurs.
We have looked for an association between weight gain proportion and ROP, which is a novel concept. Further cut-off values can be estimated, which can help better identify newborns at risk and early referral. The use of simple observations like weight gain proportion and time to establish full enteral feeds, which can be easily picked up at the community level, may be incorporated in the National guidelines of developing countries to facilitate early referrals of preterm neonates at risk of ROP.
Our study was powered by its prospective nature and rigorous protocols. We considered many maternal and neonatal risk factors for predicting ROP; however, there are a few limitations, like being a single-center study with a small sample size and fewer patients in the severe ROP group. Also, factors such as fluctuations in oxygen saturation were not measured which plays an important role in pathogenesis of ROP. Our study was conducted at a tertiary care referral center where sick babies are in the majority, so our results cannot be generalized for all preterm infants.
5. Conclusion
Low birth weight and prematurity were the most important predictors for developing any ROP. At the same time, respiratory distress syndrome, surfactant administration, and the need for oxygen were independent predictors for any ROP. Birth weight<1250 gm, apnea, surfactant administration, and oxygen duration≥80 h were independent predictors for severe ROP. Poor postnatal weight gain at 4, 5, and 6 was independently associated with developing ROP.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Ethics statement
The study was conducted after taking approval from the institutional human ethics committee. Informed written consent was taken from the study participants.
Declaration of competing interest
The author(s) declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Acknowledgment
None.
References
Isenberg SJ, Eye disorders, MacDonald MG, Mullet MD, Seshia MMK, Avery's Neonatology-Pathophysiology and Management of the Newborn. sixth ed, Philadelphia, PA, Lippincott Williams and Wilkins, 1469-1484.
American Academy of Pediatrics Section on Ophthalmology; American academy of ophthalmology; American association for pediatric ophthalmology and strabismus; American association of certified orthoptists. Screening Examination of Premature Infants for Retinopathy of Prematurity [published correction appears in Pediatrics.
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