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Retinopathy of prematurity in preterm infants: A prospective study of prevalence and predictors in Northern India

Open AccessPublished:January 19, 2023DOI:https://doi.org/10.1016/j.cegh.2023.101230

      Abstract

      Objectives

      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.

      Keywords

      Abbreviations

      ROP
      Retinopathy of Prematurity
      NEC
      Necrotizing Enterocolitis
      IVH
      Intra Ventricular Haemorrhage
      WHO
      World Health Organization
      CPAP
      continuous positive airway pressure
      RDS
      respiratory distress syndrome
      PDA
      Patent Ductus Arteriosus
      HDN
      Haemorrhagic Disease of Newborns
      SPO2
      oxygen saturation
      FiO2
      fraction of inspired oxygen
      PIH
      Pregnancy Induced Hypertension
      APH
      antepartum haemorrhage
      MSAF
      meconium stained amniotic fluid
      ACS
      antenatal corticosteroid administration
      AAP
      American Academy of Pediatrics
      NNF
      National Neonatology Forum
      ICROP
      International Classification of ROP
      ETROP
      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.

      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.

      The incidence of ROP increases with decreasing gestation and birth weight; however, not all preterm newborns develop it.

      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.

      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.
      • Vanderveen D.K.
      • Zupancic J.A.F.
      Retinopathy of prematurity.
      ,
      • Singh M.
      Miscellaneous conditions: retinopathy of prematurity.
      The World Health Organization (WHO) program of Vision 2020 emphasizes the importance of early screening and referral in reducing the incidence of ROP.
      • Gilbert C.
      • Foster A.
      Childhood blindness in the context of vision 2020- the right to sight.
      The world is facing the third epidemic of ROP, emerging as a significant public health concern in low and middle-income countries.
      • Gilbert C.
      • Rahi J.
      • Eckstein M.
      • O'Sullivan J.
      • Foster A.
      Retinopathy of prematurity in middle-income countries.
      Among them, India contributes to nearly 10% of the worldwide estimate of blindness and visual impairment due to ROP.
      • Gilbert C.
      • Rahi J.
      • Eckstein M.
      • O'Sullivan J.
      • Foster A.
      Retinopathy of prematurity in middle-income countries.
      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.
      • Ballard J.L.
      • Khoury J.C.
      • Wedig K.L.
      • Wang L.
      • Eilers-Walsman B.L.
      • Lipp R.
      New Ballard Score, expanded to include extremely premature infants.
      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.
      • Sivanandan S.
      • Chandra P.
      • Deorari A.K.
      • Agarwal R.
      Retinopathy of prematurity: AIIMS, New Delhi experience.
      Perinatal asphyxia was defined as an Apgar score at 1 min<6.
      • Sivanandan S.
      • Chandra P.
      • Deorari A.K.
      • Agarwal R.
      Retinopathy of prematurity: AIIMS, New Delhi experience.
      Apnoea was identified as cessation of respiration for >20 s/any duration if accompanied by bradycardia or cyanosis.
      • Stark A.R.
      Apnea.
      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.
      • Puopolo K.M.
      Bacterial and fungal infections.
      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.
      • Christou H.A.
      Anemia.
      Standard guidelines were followed for blood and exchange transfusion.
      Maternal factors like GA, parity, type of delivery, multiple pregnancy, pregnancy induced hypertension (PIH), antepartum haemorrhage (APH), chorioamnionitis, meconium stained amniotic fluid (MSAF) and antenatal corticosteroid administration (ACS) were recorded.
      All enrolled preterm newborns were screened for ROP as per the American Academy of Pediatrics (AAP) and National Neonatology Forum (NNF) guidelines.
      • Fierson W.M.
      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.
      ,

      National neonatology forum, Screening and Management of Retinopathy of Prematurity 2020, p231-p236.

      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.
      Committee for the classification of retinopathy of prematurity: an international classification of retinopathy of prematurity.
      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.
      • Ahuja A.A.
      • Reddy Y.C.
      • Adenuga O.O.
      • Kewlani D.
      • Ravindran M.
      • Ramakrishnan R.
      Risk factors for retinopathy of prematurity in a district in South India: a prospective cohort study.
      ,
      • Rao K.A.
      • Purkayastha J.
      • Hazarika M.
      • Chaitra R.
      • Adith K.M.
      Analysis of prenatal and postnatal risk factors of retinopathy of prematurity in a tertiary care hospital in South India.
      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.
      ParametersROP Group (n = 63)Non-ROP Group (n = 277)p-value
      Gender, Male41 (65.0%)144 (51.9%)0.06
      Birth Weight (mean ± SD), grams1396.03 ± 260.961592.02 ± 196.52<0.001
      Gestation (mean ± SD), weeks30.1 ± 2.132.4 ± 0.8<0.001
      Postnatal weight gain proportion (mean ± SD)
      • 1
        Weight gain proportion at 4-week
      12.45 ± 5.4515.35 ± 3.33<0.001
      • 2
        Weight gain proportion at 5-week
      23.30 ± 12.4029.17 ± 7.87<0.001
      • 3
        Weight gain proportion at 6-week
      33.35 ± 10.2438.75 ± 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 administration41 (65.1%)65 (23.5%)<0.001
      Duration of oxygen (hours)51.2 ± 50.912.7 ± 28.5<0.001
      Days of establishment of full enteral feed (days) (mean ± SD)5.36 ± 2.623.17 ± 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.
      ParametersROPSevere ROP
      VariablesOR (95%CI)p-valueOR (95%CI)p-value
      Birth weight <1250 g12.6 (2.1–73.8)0.01102 (4.1–2521)0.01
      Gestation <30 weeks44.10 (13.8–140.5)<0.00155.2 (28.8–87.8)0.99
      Weight gain proportion at 4 weeks ≥ 141.10 (1.0–1.7)0.020.14 (0.0–1.2)0.08
      Weight gain proportion at 5 weeks ≥ 242.49 (1.1–5.7)0.012.26 (0.2–19.8)0.46
      Weight gain proportion at 6 weeks ≥ 356.73 (1.3–33.4)0.021.89 (0.2–16.2)0.56
      Chorioamnionitis0.99 (0.1–7.9)0.992.2 (0.5–18.9)0.99
      Respiratory distress syndrome25.56 (1.28–65.81)0.0412.5 (2.4–67.9)0.99
      Blood transfusion1.1 (0.2–23.5)0.540.18 (0.0–1.1)0.06
      Apnea2.1 (0.1–26.5)0.243.3 (1.4–7.8)0.01
      Surfactant administration0.20 (0.1–0.8)0.020.05 (0.0–0.6)0.01
      Perinatal asphyxia0.89 (0.2–3.5)0.880.25 (0.0–2.0)0.19
      Sepsis4.44 (0.5–38.2)0.177.6 (0.9–84.7)0.99
      Oxygen needed31.77 (1.8–561.9)0.0216.7 (2.1–88.2)0.99
      Oxygen duration ≥80 h0.23 (0.1–1.0)0.054.7 (2.1–16.3)0.01
      Day to full enteral feed ≥4 days2.78 (0.7–10.5)0.131.95 (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. 2
      Fig. 2ROC curve for postnatal weight gain at 6 weeks and development of ROP.

      4. Discussion

      ROP has been reported in India for 21.7%–51.9% of low birth weight infants.
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      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.
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      • Paul V.K.
      Incidence and risk factors of retinopathy of prematurity in a tertiary care new born unit in New Delhi.
      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.
      • Lee S.
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      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.
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      Incidence and risk factors of retinopathy of prematurity in a tertiary care new born unit in New Delhi.
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      Retinopathy of prematurity.
      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.
      • Higgins R.D.
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      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 V.P.
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      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.
      • Gupta V.P.
      • Dhaliwal U.
      • Sharma R.
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      Retinopathy of prematurity – risk factors.
      Both, maternal chorioamnionitis and neonatal sepsis have been reported as a risk factor for ROP in other study.
      • Dammann O.
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      • et al.
      Immaturity, perinatal inflammation, and retinopathy of prematurity: a multi-hit hypothesis.
      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.
      • Higgins R.D.
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      • Hendricks-Munoz K.D.
      Antenatal dexamethasone and decreased severity of ROP.
      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.
      • Shah V.A.
      • Yeo C.L.
      • Ling Y.L.F.
      • Ho L.Y.
      Incidence, risk factors of retinopathy of prematurity among very low birth weight infants in Singapore.
      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.
      • Gupta V.P.
      • Dhaliwal U.
      • Sharma R.
      • Gupta P.
      • Rohatgi J.
      Retinopathy of prematurity – risk factors.
      In our study, 61.9% of babies in the ROP group had RDS, which is comparable to existing literature.
      • Ahuja A.A.
      • Reddy Y.C.
      • Adenuga O.O.
      • Kewlani D.
      • Ravindran M.
      • Ramakrishnan R.
      Risk factors for retinopathy of prematurity in a district in South India: a prospective cohort study.
      ,
      • Rao K.A.
      • Purkayastha J.
      • Hazarika M.
      • Chaitra R.
      • Adith K.M.
      Analysis of prenatal and postnatal risk factors of retinopathy of prematurity in a tertiary care hospital in South India.
      Surfactant administration has also been shown to be protective for ROP, and we observed the same in the present study(p = 0.01).
      • Ahuja A.A.
      • Reddy Y.C.
      • Adenuga O.O.
      • Kewlani D.
      • Ravindran M.
      • Ramakrishnan R.
      Risk factors for retinopathy of prematurity in a district in South India: a prospective cohort study.
      ,
      • Rao K.A.
      • Purkayastha J.
      • Hazarika M.
      • Chaitra R.
      • Adith K.M.
      Analysis of prenatal and postnatal risk factors of retinopathy of prematurity in a tertiary care hospital in South India.
      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.
      • Pierce E.A.
      • Foley E.D.
      • Smith L.E.
      Regulation of vascular endothelial growth factor by oxygen in a model of retinopathy of prematurity.
      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.
      • Shohat M.
      • Reisner S.H.
      • Krikler R.
      • Nissenkorn I.
      • Yassur Y.
      • Ben-Sira I.
      Retinopathy of prematurity: incidence and risk factors.
      Prolonged parenteral nutrition is a risk factor for ROP, as concluded in the study by Porcelli et al.
      • Porcelli P.J.
      • Weaver Jr., R.G.
      The influence of early postnatal nutrition on retinopathy of prematurity in extremely low birth weight infants.
      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.
      • Sathar A.
      • Shanavas A.
      • Girijadevi P.S.
      • Jasmin L.B.
      • Kumar S.S.
      • Pillai R.K.
      Risk factors of retinopathy of prematurity in a tertiary care hospital in South India.
      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.
      • Di Fiore J.M.
      • Bloom J.N.
      • Orge F.
      • Schutt A.
      • Schluchter M.
      • Cheruvu V.K.
      A higher incidence of intermittent hypoxemic episodes is associated with severe retinopathy of prematurity.
      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.
      • Kamath K.M.
      • Asha M.N.
      • Vinay V.
      Correlation between postnatal weight gain and development of retinopathy of prematurity: an experience in rural tertiary care centre.
      ; Binenbaum et al.
      • Binenbaum G.
      • Ying G.S.
      • Quinn G.E.
      • Dreiseitl S.
      • Karp K.
      • Roberts R.S.
      A clinical prediction model to stratify retinopathy of prematurity risk using postnatal weight gain.
      ). 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.

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