Abstract
Background
This study aimed to evaluate the prevalence and risk factors of retinopathy of prematurity (ROP) in preterm infants with a birth weight (BW)>1500 g or gestational age (GA) >32 weeks in Turkiye.
Methods
A prospective cohort study (TR-ROP 2) was conducted in 80 neonatal intensive care units between 30 September 2023 and 1 November 2024. Infants with a BW >1500 g or GA >32 weeks who had an unstable clinical course or were deemed at risk for ROP were included. The effect of medicolegal concerns on the decision to screen was also evaluated.
Results
The study included 4140 infants at risk for ROP development; 242 (5.8%) developed any stage of ROP, and 17 (0.4%) developed severe ROP requiring treatment. Risk factors independently associated with ROP included lower GA and BW, being small for GA, red blood cell transfusion, oxygen therapy >5 days, mechanical ventilation >1 day, early neonatal sepsis (ENS) with comorbidities or presence of ≥3 comorbidities (excluding ENS). Of those with BW ≥2000 g, 31.4% were screened for medicolegal reasons; 2.2% developed ROP, but none had severe ROP.
Conclusions
ROP in mature infants is rare but can occur in the presence of multiple risk factors. Medicolegal concerns may contribute to overscreening. Developing evidence-based, risk-adapted screening guidelines is essential to ensure appropriate care without unnecessary interventions.
Keywords: Retina, Epidemiology, Neovascularisation, Angiogenesis, Retinopathy of Prematurity
WHAT IS ALREADY KNOWN ON THIS TOPIC
Severe retinopathy of prematurity (ROP) can occasionally occur in more mature and larger preterm infants.
WHAT THIS STUDY ADDS
Being small for gestational age and the presence of multiple systemic comorbidities play an important role in ROP development in infants with greater gestational age.
Medicolegal concerns drive expanded screening beyond evidence-based indications.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Revisiting and refining existing ROP screening guidelines to incorporate population specific systemic risk factor stratification could reduce unnecessary screening, improve resource utilisation and maintain patient safety.
Introduction
Retinopathy of prematurity (ROP) is a leading cause of preventable vision loss and blindness in children worldwide.1 The global prevalence of ROP varies, with lower rates observed in high-income countries where strict oxygen monitoring and advanced neonatal care are implemented.2
The TR-ROP study, published in 2018, reported that the incidence of treatment-requiring ROP in Turkiye was 26% among extremely low birth weight (BW) and 11% among very low BW infants (VLBW), comparable to those from other middle-income countries.3 Subsequently, the national guideline was revised to offer ROP screening for preterm infants born before 34 weeks of gestation or with a BW under 1700 g, as well as for any preterm infants with existing risk factors. As gestational age (GA) remains the strongest risk factor for ROP, both our earlier cohort and international data confirm that ROP predominantly affects extremely preterm infants. However, larger preterm infants have also been reported to develop ROP requiring treatment.4–6 Still, specific risk factors for ROP in this more mature population remain undefined. As an upper-middle-income country, Turkiye continues to enhance ROP screening criteria while addressing the specific needs of its healthcare system.
In this multicentre study, we aimed to assess the prevalence and risk factors associated with the development of ROP in preterm infants with a BW >1500 g or a GA >32 weeks. Additionally, we investigated the effect of medicolegal concerns on the decision to screen. By providing context-specific data, we hope this study will support the refinement of screening guidelines in middle-income settings while contributing to the global discussion on ROP prevention.
Methods
The TR-ROP 2 study was initiated by the Turkish Neonatal Society and included preterm infants screened for ROP between 1 September 2023 and 1 November 2024, across 80 level 3 neonatal intensive care units (NICUs).
Study population
This prospective cohort study examined ROP incidence, risk factors, severity and treatment in preterm infants >1500 g BW or >32 weeks gestation. At-risk infants identified by clinicians were included, excluding those with major congenital anomalies, chromosomal abnormalities or early death before the first eye exam.
Then the medical records of retinal examinations of preterm infants who met the screening criteria were evaluated. Examinations took place in the NICU or outpatient facility (for discharged infants). Eligible infants who were discharged before the first screening and missed or did not complete all screening sessions were excluded from the study. The data are restricted to all babies who underwent all the screening sessions.
Data collection
Neonatologists participating in the study submitted data on ROP cases in their NICUs. For each patient, a case report form was completed using an online system via the ‘Trials-Network’. All questions had to be answered; the system blocked submission if any were left blank. Data were entered anonymously into a password-protected database. To ensure data completeness and consistency, the coordinating investigators maintained regular communication with local investigators and randomly verified the submitted data against NICU admission and ophthalmology screening records before analysis. In total, records from 80 NICUs were collected and analysed at the conclusion of the study to ensure comprehensive results.
Clinical characteristics
Antenatal, perinatal and postnatal characteristics of included infants were evaluated, including:
Antenatal characteristics: Corticosteroid administration (complete; two doses), pre-eclampsia/eclampsia, oligohydramnios, chorioamnionitis and maternal diabetes.
Perinatal characteristics: Assisted reproduction, multiple births, mode of delivery, GA, BW and sex.
Postnatal characteristics: Small for GA (SGA, <10 th percentile),7 delivery room resuscitation, respiratory distress syndrome, red blood cell (RBC) transfusions, delayed weight regain (> 14 days to regain weight), and early morbidities and respiratory treatment characteristics both were evaluated within the first month of life. The early morbidities included intraventricular haemorrhage (Papile’s classification),8 9 patent ductus arteriosus required treatment for ductal closure, clinical or culture positive early neonatal sepsis (ENS) and late neonatal sepsis, necrotising enterocolitis (≥stage II, per Bell’s criteria).10 Respiratory treatment characteristics were recorded; initial respiratory support, duration of oxygen, mechanical ventilation (MV) and positive pressure ventilation (PPV; last day of positive pressure), any oxygen or PPV treatment and fractional inspired oxygen requirement on 28th postnatal day.
To assess medicolegal influences on ROP screening, participants were asked the reason to perform ROP screening if the infant with a BW ≥2000 g underwent retinal examination. The multiple-choice options were: (a) clinical indication, (b) medicolegal indication or (c) both.
Retinal examinations
The International Classification of Retinopathy of Prematurity, Third Edition, was used to classify ROP based on disease location (zone), stage (appearance at the avascular-vascular junction) and the presence of plus disease.11 Screening continued until full or near-complete retinal vascularisation was achieved, and the maximum stage of ROP was documented. Severe ROP was defined as requiring treatment per the Early Treatment for Retinopathy of Prematurity guidelines.12 Treatment modalities, including laser photocoagulation and intravitreal bevacizumab, were also recorded.
Statistical analysis
Statistical analyses were conducted using SPSS statistical software for Windows, V.25.0 (SPSS). The results are presented as numbers (n), frequencies (%), means with the respective SDs, and medians with their IQRs. Parametric or non-parametric tests were used to analyse variables based on the normality of their distribution. The χ2 test was used to compare categorical variables. A two-tailed value of p≤0.05 was considered statistically significant. Two consecutive multivariate logistic regression analyses were performed. In the initial model, all variables that were significantly different between infants with and without ROP in the univariate analysis were entered to identify independent predictors of any ROP. In the final model, variables were recategorised based on their clinical relevance and collinearity assessment to refine the analysis and better represent the combined effects of early morbidities and respiratory support characteristics. The Hosmer-Lemeshow goodness-of-fit statistic was used to assess model fit. A p≤0.05 was considered statistically significant. The ORs and 95% CIs for each risk factor were determined.
Results
During the study period, 20 943 preterm infants with a BW >1500 g or a GA >32 weeks were admitted to 80 centres. Of these, 369 were excluded due to major congenital anomalies or death before the first retinal examination. The study population included 4140 patients (20.1% of total), who were considered at risk for ROP by their attending clinicians. Among the screened infants, the incidence of any ROP was 5.8%, while severe ROP was diagnosed in 17 infants (0.4%). The study included 46 university hospitals (2208 infants), 28 state hospitals (1521 infants) and 6 private hospitals (411 infants). The incidence of any ROP was 5.7%, 6.0% and 6.1% (p=0.918) and severe ROP was 0.4%, 0.3% and 1.0% (p=0.169) across these hospital types, with no significant differences.
The mean BW and GA for the total cohort were 2141±465 g (range: 850–4300 g) and 34±1 weeks (range: 28–36 weeks, respectively). Of the cohort, 632 infants (15.3%) had a GA ≤32 weeks. Most were late preterm infants (n=2490; 60.1%) and had a BW ≥ 2000 g (n=2386; 57.6%). Table 1 presents the incidences of any ROP and severe ROP in relation to GA and BW. The mean postnatal day and postmenstrual age at initial ROP diagnosis were 34±12 days and 38±3 weeks, respectively. At the time of maximum ROP severity, these were 38±16 days and 38±3 weeks.
Table 1. Incidence of any ROP and severe ROP in relation to gestational age and birth weight.
| Included infants n=4140 |
Any ROP n=242 (5.8%) |
Severe ROP n=17 (0.4%) |
|---|---|---|
| Gestational age; weeks | ||
| ≤ 32 weeks (n=632) | 66 (10.4) | 8 (1.3) |
| 280/7–6/7 weeks (n=2) | 0 (-) | 0 (-) |
| 290/7–6/7 weeks (n=7) | 3 (42.9) | 1 (14.3) |
| 300/7–6/7 weeks (n=81) | 17 (21.0) | 2 (2.5) |
| 310/7–6/7 weeks (n=142) | 17 (12.0) | 3 (2.1) |
| 320/7–6/7 weeks (n=400) | 29 (7.2) | 2 (0.5) |
| 33–36 weeks (3508) | 176 (5.0) | 9 (0.3) |
| 330/7–6/7 weeks (n=1002) | 75 (7.5) | 6 (0.6) |
| 340/7–6/7 weeks (n=1210) | 65 (5.4) | 2 (0.2) |
| 350/7–6/7 weeks (n=798) | 28 (3.5) | 1 (0.1) |
| 360/7–6/7 weeks (n=498) | 8 (1.6) | 0 (0.0) |
| Birth weight; grams | ||
| <1500 g (n=176) | 26 (14.8) | 3 (1.7) |
| 1500–1999 g (n=1578) | 106 (6.7) | 10 (0.6) |
| >2000 g (n=2386) | 110 (4.6) | 4 (0.2) |
Data are presented as n (%).
ROP, retinopathy of prematurity.
Infants who developed ROP were more frequently SGA, required delivery room resuscitation and had higher rates of RBC transfusion, delayed postnatal weight gain and early neonatal morbidities. They were also more likely to receive initial MV and had prolonged durations of respiratory support. A detailed comparison of clinical characteristics between infants with and without ROP is presented in table 2.
Table 2. Characteristic of infants without ROP and with any ROP.
| No ROP (n=3898) | Any ROP (n=242) | P value | |
|---|---|---|---|
| Infant and maternal characteristics | |||
| Gestational age (weeks), mean±SD, | 34±1 | 33±2 | <0.001 |
| <32 weeks, n (%) | 566 (14.4) | 66 (27.3) | <0.001 |
| 330/7–366/7 weeks, n (%) | 3332 (85.5) | 176 (72.2) | |
| Birth weight (g), mean±SD, | 2154±463 | 1900±447 | <0.001 |
| <1500 g, n (%) | 150 (3.8) | 26 (10.7) | <0.001 |
| 1500–1999 g, n (%) | 1472 (37.8) | 106 (43.8) | |
| >2000 g, n (%) | 2276 (58.4) | 110 (45.5) | |
| Maternal age (years), mean±SD | 30±6 | 30±6 | 0.314 |
| In vitro fertilisation, n (%) | 448 (11.5) | 28 (11.6) | 0.971 |
| Multiple births, n (%) | 1009 (25.9) | 61 (25.2) | 0.441 |
| Antenatal steroid, two doses, n (%) | 1186 (33.7) | 60 (29.6) | 0.024 |
| Chorioamnionitis, n (%) | 70 (1.8) | 2 (0.8) | 0.263 |
| Oligohydramnios, n (%) | 268 (6.9) | 21 (8.7) | 0.286 |
| Pre-eclampsia, n (%) | 530 (14.2) | 30 (13.1) | 0.653 |
| Gestational diabetes, n (%) | 373 (10.2) | 21 (9.4) | 0.679 |
| Small for gestational age, n (%) | 285 (7.3) | 28 (11.6) | 0.047 |
| Male gender, n (%) | 2088 (53.6) | 135 (55.8) | 0.502 |
| Caesarean section, n (%) | 3370 (86.5) | 209 (86.4) | 0.968 |
| Resuscitation at birth, n (%) | 1141 (29.3) | 113 (46.7) | <0.001 |
| Any RBC transfusion, n (%) | 306 (7.9) | 61 (25.2) | <0.001 |
| Delayed time to regain birth weight, n (%) | 710 (18.2) | 70 (28.9) | <0.001 |
| Early morbidities** | |||
| Respiratory distress syndrome, n (%) | 1104 (28.3) | 119 (49.2) | <0.001 |
| Patent ductus arteriosus treatment, n (%) | 139 (3.6) | 24 (9.9) | <0.001 |
| Intracranial haemorrhage (>grade II), n (%) | 194 (5.0) | 34 (14.0) | <0.001 |
| Early neonatal sepsis, n (%) | 843 (21.6) | 102 (42.1) | <0.001 |
| Culture-proven sepsis, n (%) | 42 (1.1) | 4 (1.7) | <0.001 |
| Late neonatal sepsis, n (%) | 538 (13.8) | 63 (26.0) | <0.001 |
| Culture-proven sepsis, n (%) | 172 (4.4) | 28 (11.6) | <0.001 |
| Necrotising enterocolitis (≥stage II), n (%) | 44 (1.1) | 12 (5.0) | <0.001 |
| Respiratory treatment characteristics | |||
| Initial respiratory support | <0.001 | ||
| None/oxygen, n (%) | 928 (23.8) | 21 (8.7) | |
| Non-invasive ventilation, n (%) | 1795 (46.0) | 89 (36.8) | |
| Mechanical ventilation, n (%) | 1175 (30.2) | 132 (54.5) | |
| Duration of oxygen;* (days), median (25p–75p) | 5 (1–9) | 10 (4–19) | <0.001† |
| Duration of positive pressure;* ‡ (days), median (25p–75p) | 4 (1–6) | 6 (3–11) | <0.001† |
| Duration of mechanical ventilation;* (days), median (25p–75p) | 0 (0–1) | 1 (0–6) | <0.001† |
| Any positive pressure on day 28, n (%) | 77 (2) | 12 (5.0) | 0.002 |
| Any oxygen treatment on day 28, n (%) | 168 (4.3) | 32 (13.2) | <0.001 |
| FiO2 on day 28, all infants | 21 (21–21) | 21 (21–21) | 0.164† |
The values are presented as mean±SD, median (25p–75p) and n (%) where appropriate.
All infants, until first examination.
Mann-Whitney U test.
The last postnatal day on which the infant received any positive pressure support, either via mechanical or non-invasive ventilation.
FiO2, fractional inspired oxygen; RBC, red blood cell; ROP, retinopathy of prematurity.
Variables that were significantly different between infants without ROP and with any ROP in the univariate analysis were included in the multivariate regression model. Higher GA and BW, and antenatal steroid exposure were associated with a decreased risk of ROP development. In contrast, being SGA (OR 2.055, 95% CI 1.095 to 3.854, p=0.025), any RBC transfusion (OR 1.923, 95% CI 1.248 to 2.964, p=0.003), MV as initial respiratory support (OR 2.360, 95% CI 1.236 to 4.507, p=0.009), prolonged oxygen therapy (OR 1.045, 95% CI 1.015 to 1.075, p=0.003) and ENS (OR 1.699, 95% CI 1.231 to 2.346, p=0.001) were identified as independent predictors for ROP.
Final multivariate regression analysis for the development of any ROP in study infants is shown in table 3. Since only ENS remained statistically significant among early morbidities, the final regression model categorised early morbidities according to the presence of ENS and its coexistence with other morbidities. Variables were categorised for regression model as follows: early morbidities; (1) ENS only, (2) ENS+1 morbidity, (3) ENS + ≥2 morbidities (4) ≤2 morbidities without ENS and (5) ≥3 morbidities without ENS. The distribution of these morbidities significantly differed between groups. (Any ROP vs no ROP; %: (1): 12.8 vs 9.6; (2): 15.3 vs 8.4; (3): 14.0 vs 3.6; (4): 28.5 vs 26.7 and (5): 4.1 vs 0.9; p<0.001). The duration of respiratory treatments was categorised based on the median duration for infants without ROP (any ROP vs no ROP; %): (1) MV >1 day (76.5 vs 23.5), (2) PPV >4 days (67.3 vs 32.7) and (3) oxygen >5 days (62.6 vs 37.4) (p<0.001 for all comparisons). ENS combined with any comorbidity or the presence of at least three comorbidities (excluding ENS), prolonged oxygen therapy for more than 5 days and MV for more than 1 day were found to be associated with an increased risk of ROP.
Table 3. Multivariate regression analysis for development of any retinopathy of prematurity in study infants.
| Covariates | OR | 95% CI | P value |
|---|---|---|---|
| Gestational age; week | 0.795 | 0.694 to 0.910 | <0.001 |
| Birth weight; 100 g | 0.591 | 0.352 to 0.992 | 0.047 |
| Small for gestational age | 2.043 | 1.092 to 3.827 | 0.025 |
| Resuscitation at birth | 1.021 | 0.739 to 1.410 | 0.902 |
| Antenatal steroid | 0.602 | 0.431 to 0.841 | 0.003 |
| Any RBC transfusion | 1.914 | 1.278 to 2.866 | 0.002 |
| Delayed weight regain | 1.169 | 0.825 to 1.656 | 0.380 |
| Early morbidities (Reference: No morbidity) | 0.028 | ||
| ENS | 1.633 | 0.939 to 2.839 | 0.082 |
| ENS + 1 morbidity | 1.939 | 1.150 to 3.270 | 0.013 |
| ENS + ≥ 2 morbidities | 2.263 | 1.215 to 4.214 | 0.010 |
| ≤ 2 morbidities, no ENS | 1.230 | 0.800 to 1.891 | 0.345 |
| ≥ 3 morbidities, no ENS | 2.684 | 1.074 to 6.461 | 0.034 |
| Mechanical ventilation > 1 day | 1.590 | 1.024 to 2.467 | 0.039 |
| Positive pressure > 4 days | 0.824 | 0.493 to 1.376 | 0.459 |
| Oxygen > 5 days | 2.285 | 1.443 to 3.369 | <0.001 |
| Positive pressure on day 28 | 0.507 | 0.217 to 1.184 | 0.117 |
| Oxygen on day 28 | 1.535 | 0.844 to 2.792 | 0.161 |
p<0.05 represents statistical significance.
Early morbidities include: ENS, RDS, PDA, IVH, LNS, NEC
ENS, early neonatal sepsis; IVH, intraventricular haemorrage; MV, mechanical ventilation; RBC, red blood cell; SGA, small for gestational age.
Among all infants screened for ROP, 17 (0.4%) required treatment. Laser photocoagulation was performed in nine patients, anti-VEGF in ten, and two received both. Sixteen infants received treatment for both eyes; no infants required vitreoretinal surgery. The maximum BW and GA among these infants were 2.400 g and 35 weeks, respectively.
Figure 1 illustrates the plot graph of infants with severe ROP in relation to BW and GA. The mean BW (1731±392 g) and mean GA (32±2 weeks) were significantly lower than those of infants without ROP (p=0.03 and p=0.01, respectively). Table 4 presents the individual characteristics of infants with severe ROP.
Figure 1. Plot graph of infants with severe ROP in relation to BW and GA. BW, birth weight; GA, gestational age; ROP, retinopathy of prematurity.
Table 4. Characteristics of infants with severe ROP.
| BW; grams GA; weeks |
Retinal examination Treatment |
Existing risk factors * calculated risk factors - Other infant characteristics |
|---|---|---|
| 930 g 333/7 wks |
Zone 1 stage 3, plus, A-ROP LP, IVB |
* SGA, RBC transfusion, ENS + ≥ 2 morbidities (LNS, NEC, IVH) - Resuscitation at birth, initial support: NIV |
| 1200 g 331/7 wks |
Zone 2 stage 3, plus LP |
* SGA, MV > 1 day, Oxygen > 5 days, No ANS - Initial support: MV, positive pressure > 4 days, RDS, PDA |
| 1250 g 332/7 wks |
Zone 2 stage 3, plus LP |
* SGA, Oxygen > 5 days, No ANS - Initial support: NIV, positive pressure > 4 days |
| 1505 g 291/7 wks |
Zone 1 stage 1, plus LP |
* MV > 1 day, Oxygen > 5 days, RBC transfusion, ENS + ≥ 2 morbidities (RDS, LNS, NEC), No ANS - Resuscitation at birth, delayed weight regain, initial support: MV, positive pressure > 4 days, oxygen and positive pressure on day 28. |
| 1520 g 313/7 wks |
Zone 2 stage 2, plus IVB |
* Oxygen > 5 days - Delayed weight regain, initial support: NIV, oxygen on day 28. |
| 1585 g 302/7 wks |
Zone 2 stage 2, plus IVB |
* RBC transfusion, ENS + ≥ 2 morbidities (RDS, PDA, IVH, NEC), No ANS, MV > 1 day, Oxygen > 5 days - Delayed weight regain, initial support: MV, positive pressure > 4 days, oxygen on day 28. |
| 1600 g 301/7 wks |
Zone 1 stage 1, plus IVB |
* MV > 1 day, Oxygen > 5 days, ENS +1 morbidity (RDS), No ANS - Resuscitation at birth, initial support: MV, positive pressure > 4 days, delayed weight regain |
| 1705 g 316/7 wks |
Zone 2 stage 3, plus LP |
* MV > 1 day, Oxygen > 5 days, No ANS - Initial support: MV, positive pressure > 4 days, resuscitation at birth, PDA |
| 1700 g 316/7 wks |
Zone 2 stage 3, plus LP |
* MV > 1 day, Oxygen > 5 days, No ANS - Initial support: MV, positive pressure > 4 days, RDS, PDA |
| 1800 g 331/7 wks |
Zone 2 stage 2, plus IVB |
* MV > 1 day, Oxygen > 5 days - Initial support: MV, positive pressure > 4 days, RDS, PDA |
| 1815 g 331/7 wks |
Zone 2 stage 3 LP |
* Oxygen > 5 days - Initial support: NIV, positive pressure > 4 days |
| 1900 g 343/7 wks |
Zone 2 stage 3, plus, A-ROP IVB |
* Oxygen > 5 days, No ANS - Resuscitation at birth, initial support: NIV |
| 1970 gr 324/7 wks |
Zone 2 stage 3, plus LP |
* MV > 1 day, Oxygen > 5 days, No ANS - Resuscitation at birth, initial support: MV, positive pressure > 4 days, RDS, LNS |
| 2140 g 332/7 wks |
Zone 2 stage 3, plus, A-ROP IVB |
* MV > 1 day, Oxygen > 5 days, RBC transfusion, No ANS - Resuscitation at birth, delayed weight regain, initial support: MV, positive pressure > 4 days, ENS, oxygen on day 28. |
| 2200 g 351/7 wks |
Zone 2 stage 3, plus LP, IVB |
* MV > 1 day, Oxygen > 5 days, No ANS - Initial support: MV, positive pressure > 4 days, RDS, LNS |
| 2210 gr 322/7 wks |
Zone 3 stage 1, plus IVB |
* Oxygen > 5 days, No ANS - Delayed weight regain, initial support: NIV, positive pressure > 4 days, LNS |
| 2400 g 341/7 wks |
Zone 2 stage 3, plus, A-ROP IVB |
* MV >1 day, Oxygen > 5 days, RBC transfusion, No ANS - Resuscitation at birth, delayed weight regain, initial support: MV, positive pressure > 4 days, PDA, oxygen and positive pressure and on day 28. |
* calculated risk factors, - Other infant characteristics
A-ROP, aggressive posterior retinopathy of prematurity; ENS, early neonatal sepsis; IVB, intravitreal bevacizumab; IVH, intraventricular haemorrage; LNS, late neonatal sepsis; LP, laser photocoagulation; MV, mechanical ventilation; NEC, necrotising enterocolitis; NIV, non-invasive ventilation; PDA, patent ductus arteriosus; RBC, red blood cell; RDS, respiratory distress syndrome; SGA, small for gestational age; wks, weeks.
Among infants with a BW ≥ 2000 g, the decision to perform ROP screening was based on medicolegal concerns in 37.8% (n=901), clinician discretion in 40.4% (n=964), and a combination of both in 21.8% (n=521). The incidence of any ROP within these groups was 2.2%, 7.3% and 3.8%, respectively. Notably, four infants developed severe ROP, none of whom were screened solely due to medicolegal concerns.
Discussion
In middle-income countries, ROP can be diagnosed among more mature preterm infants born at 32 weeks of gestation and beyond.6 13 14 We found that ROP in these more mature infants was rare, with an incidence of 5.8% for any ROP and 0.4% for severe ROP, which occurred only in the presence of multiple risk factors. It is noteworthy that if the current Turkish national guideline thresholds (<34 weeks or <1700 g) were applied without consideration of additional risk factors, three infants with severe ROP would have been missed, reflecting the appropriateness of the Turkish national guideline recommending screening above these thresholds when risk factors are present. This observation reinforces the importance of integrating risk assessment into screening decisions and supports the view that selected larger or more mature preterm infants who manifest such risk factors benefit from ophthalmologic screening. Nevertheless, our findings also indicate that screening has often been extended beyond these evidence-based limits, mainly driven by medicolegal concerns, which may contribute to an increased clinical workload.
Our results align with previous evidence identifying low GA and low BW as the strongest predictors of ROP. Prematurity-related morbidities, including neonatal sepsis, being SGA, prolonged oxygen exposure, MV and RBC transfusions, were also associated with increased ROP risk, consistent with prior studies.15–19 Moreover, oxygen therapy beyond 5 days and MV for over 1 day emerged as independent risk factors in our study, reflecting the well-established association between prolonged hyperoxia and ROP development.17 It was also shown in our results that antenatal steroid administration was protective against ROP, supporting findings from meta-analyses and likely attributable to a proposed retinal protective effect in addition to established respiratory benefits.20 21 The regression model highlights the cumulative impact of these factors.
The finding on the significance of a composite measure of morbidities and the progressive increase in OR with a higher number of morbidities emphasises the multifactorial nature of ROP. The central role of sepsis among these morbidities highlights the relevance of inflammation-induced oxidative stress, VEGF expression, microglial activation and retinal ganglion cell death in the early postnatal period.15 Based on these insights, we propose a more individualised, risk-based approach for infants exceeding standard GA and BW thresholds; recommending screening only in the presence of risk factors such as MV >1 day, oxygen therapy >5 days, being SGA transfusions, ENS accompanied by any morbidity, or any three prematurity-related morbidities. Further prospective, multicentre studies are warranted to validate this approach and to support optimal resource utilisation without compromising patient safety.
Several risk-based algorithms have been developed to optimise ROP screening practices while ensuring patient safety. Among these, WINROP, G-ROP, CO-ROP, Alex-ROP, ROPScore, CHOP-ROP, DIGIROP and the PINT model use postnatal weight gain as a central predictor of treatment-requiring ROP and also incorporate clinical parameters such as hydrocephalus, ventilation and/or oxygen exposure, blood transfusions and sepsis. Although these algorithms have demonstrated high sensitivity for detecting treatment-requiring ROP, their relatively low specificity in middle-income countries limits their generalisability.22–24
A striking finding was that nearly one-third of infants with a BW ≥ 2000 g underwent retinal examinations due to medicolegal concerns, yet none had severe ROP. This suggests that medicolegal fears may lead to overscreening. In our country, significant legal fines are imposed on paediatricians or neonatologists who fail to perform ROP screening resulting in blindness, with compensation to the patient’s family ranging from 300 000 to 500 000 dollars. This threat of substantial legal penalties has driven defensive medical practices, contributing to unnecessary examinations. While the national guideline recommends screening for all infants with BW≤1700 g or GA<34 weeks and selected more mature or heavier preterm infants requiring cardiorespiratory support, our findings support that infants above these thresholds without additional risk factors are at extremely low risk for severe ROP.3
The strength of the TR-ROP 2 study lies in its large-scale, multicentre, prospective design, allowing the collection of robust, real-world data across 80 NICUs. This comprehensive methodology provides valuable insight into actual ROP screening practices in more mature preterm infants and highlights individual risk factors. However, the lack of data on nutritional status and growth outcomes is a notable limitation.
In conclusion, while prematurity and inappropriate oxygen therapy remain key risk factors for ROP, numerous additional factors have been reported. Notably, the exact impact of various risk factors in more mature preterm infants remains unclear, leading to increased medicolegal concerns and, in some cases, potentially excessive screening practices. Developing risk factor assessment tools and determining the relative contribution of each risk factor would be valuable in refining screening criteria and ensuring that infants at genuine risk receive appropriate evaluation. Given that these more mature infants differ from VLBW infants in how clinical factors influence ROP development, tailored screening strategies specific to this population are essential.
Footnotes
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Data availability free text: The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.
Patient consent for publication: Not applicable.
Ethics approval: This study involves human participants and received approval from the Gazi University Ethics Committee (E-66429, dated 23 May 2023). Participants gave informed consent to participate in the study before taking part.
Provenance and peer review: Not commissioned; externally peer reviewed.
Collaborators: TR-ROP 2 Study Group Collaborators - Neonatology section: Zehra Arslan, Ankara Etlik City Hospital, Ankara, Turkiye; Semra Gundogdu, Istanbul Medipol University, Istanbul, Turkiye; Fatma Iyigun, Umraniye Training and Research Hospital, Istanbul, Turkiye; Yusuf Kale, Private Batman Medicalpoint Hospital, Batman, Turkiye; Sema Tanrıverdi, Manisa Celal Bayar University, Manisa, Turkiye; Birgul Mutlu, Bursa Private Doruk Yildirim Hospital, Turkiye; Aslihan Abbasoglu, Izmir City Hospital, Izmir, Turkiye; Meltem Karabay, Sakarya University, Sakarya, Turkiye; Salih Cagri Cakir, Bursa Uludag University, Bursa, Turkiye; Tülin Gokmen Yildirim, University of Health Sciences Izmir Faculty of Medicine Dr. Behcet Uz Children’s Diseases and Surgery Training and Research Hospital, Izmir, Turkiye; Mehmet Buyuktiryaki, Istanbul Medipol University Bahcelievler Hospital, Istanbul, Turkiye; Chousein Amet, Biruni University, Istanbul, Turkiye; Ozge Serce Pehlevan, Kocaeli University, Istanbul, Turkiye; Guner Karatekin, University of Health Sciences, Zeynep Kamil Maternity and Children Training and Research Hospital, Istanbul, Turkiye; Saime Sundus Uygun, Konya Selcuk University, Konya, Turkiye; Sinan Tufekci, Tekirdag Namik Kemal University, Tekirdag, Turkiye; Ipek Guney Varal, Bursa Yuksek Ihtisas Training and Research Hospital, Bursa, Turkiye; Ilkay Er, Recep Tayyip Erdogan University, Rize, Turkiye; Hasan Kahveci, Erzurum City Hospital, Erzurum, Turkiye; Didem Armangil, Ankara Koru Hospital, Ankara, Turkiye; Nilay Hakan, Mugla Sitki Kocman University, Mugla, Turkiye; Eyyüp Yurekturk, Van Yuzuncu Yil University, Van, Turkiye; Fatma Narter, Kartal Dr Lutfi Kirdar City Hospital, Istanbul, Turkiye; Sema Arayici, Akdeniz University, Antalya, Turkiye; Berna Saygin Hekimoglu, Trabzon Kanuni Training and Research Hospital, Trabzon, Turkiye; Nurdan Ozturk Tasar, Afyonkarahisar Health Sciences University, Afyonkarahisar, Turkiye; Hasan Avsar, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkiye; Deniz Anuk Ince, Ankara Baskent University, Ankara, Turkiye; Huseyin Simsek, Mersin Training and Research Hospital, Mersin, Turkiye; Didem Arman, Istanbul Training and Research Hospital, Istanbul, Turkiye; Meltem Bor, Istanbul University, Istanbul, Turkiye; Bilin Cetinkaya, Baskent University Adana Hospital, Adana, Turkiye; Irem İyigün, Ordu University, Ordu, Turkiye; Bayram Ali Dorum, Bursa City Hospital, Turkiye; Murat Ekinci, Istanbul Kanuni Training and Research Hospital, Istanbul, Turkiye; Funda Eroglu, Ankara Guven Hospital, Ankara, Turkiye; Ramazan Ozdemir, Malatya Inonu University, Malatya, Turkiye; Serdar Beken, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkiye; Omer Ertekin, Bilkent City Hospital, Ankara, Turkiye; Zeynep Alp Unkar, Istanbul University-Cerrahpasa, Istanbul, Turkiye; Sadık Yurttutan, Kahramanmaras Sutcu Imam University, Kahramanmaraş, Turkiye; Fatih Isleyen, Sanliurfa Training and Research Hospital, Sanliurfa, Turkiye; Makbule Ercan, Zonguldak Bülent Ecevit University, Zonguldak, Turkiye; Filiz Akturk Acar, Karadeniz Technical University, Trabzon, Turkiye; Ebru Yücesoy Bagdiken, Harran University, Turkiye; Abdullah Baris Akcan, Aydin Adnan Menderes University, Aydin, Turkiye; Selvi Gulasi, Adana City Hospital, Adana, Turkiye; Sait İlker Uslu, Istinye University, Istanbul, Turkiye; Huseyin Altunhan, Necmettin Erbakan University, Konya, Turkiye; Selma Aktas, Acibadem Mehmet Ali Aydınlar University/Acibadem Maslak Hospital, Istanbul, Turkiye; Belma Saygılı Karagol, University of Health Sciences, Gulhane Training and Research Hospital, Ankara, Turkiye; Sinem Gulcan Kersin, Marmara University Pendik Training and Research Hospital, Istanbul, Turkiye; Emel Okulu, Ankara University, Ankara, Turkiye; Sahin Takci, Ondokuz Mayıs University, Samsun, Turkiye; Umit Ayse Tandircioglu, Kirikkale University, Kirikkale, Turkiye; Ozmert M.A Ozdemir, Pamukkale University, Denizli, Turkiye; Kadir Serafettin Tekgunduz, Erzurum Ataturk University, Erzurum, Turkiye; Ozge Aydemir, Eskisehir Osmangazi University, Eskisehir, Turkiye; Ahmet Ozdemir, Kayseri City Hospital, Kayseri, Turkiye; Mine Ozdil, University of Health Sciences, Balikesir Ataturk City Hospital, Balikesir, Turkiye; Tugrul Donmez, Kocaeli Health and Technology University, European Vocational School, Kocaeli, Turkiye; Dilek Sarici, Ankara Ataturk Sanatoryum Training and Research Hospital, Ankara, Turkiye; Merih Cetinkaya, Basakşehir Cam and Sakura City Hospital, Istanbul, Turkiye; Birgul Livaoglu Say, Alanya University Training and Research Hospital, Alanya, Turkiye; Hakan Aylanc, Canakkale Onsekiz Mart University, Canakkale, Turkiye; Sadrettin Ekmen, Karabuk University, Karabuk, Turkiye; Istemi Han Celik, Etlik Zubeyde Hanım Women’s Health Care, Training and Research Hospital, Ankara, Turkiye; Safiye Elif Uzlu, Giresun Maternity and Children Health Training and Research Hospital, Giresun, Turkiye; Erdal Taskin, Elazig Fırat University, Elazig, Turkiye; Gozdem Kayki, Hacettepe University, Ankara, Turkiye; Melda Tas, Ankara Training and Research Hospital, Ankara, Turkiye; Tugba Gursoy, Koc University, Istanbul, Turkiye; Mehmet Fatih Deveci, Sanliurfa Mehmet Akif Inan Training and Research Hospital, Sanliurfa, Turkiye; Ridvan Duran, Trakya University, Edirne, Turkiye; Nihat Demir, Private Esencan Hospital, Istanbul, Turkiye; Mehtap Durukan Tosun, Mardin Training and Research Hospital, Mardin, Turkiye; Sahin Hamilcikan, Istanbul Bagcilar Training and Research Hospital, Istanbul, Turkiye; Lachin Cumshudov, Gazi University, Ankara, Turkiye; Selahattin Akar, Adiyaman Training and Research Hospital, Adiyaman, Turkiye; Aslan Yilmaz, Batman Training and Research Hospital, Batman, Turkiye. TR-ROP 2 Study Group Collaborators - Ophthalmology section: Caner Kara, Etlik City Hospital, Ankara, Turkiye; Sevil Karaman Erdur, Istanbul Medipol University, Istanbul, Turkiye; Aslihan Dogan Dursun, Umraniye Training and Research Hospital, Istanbul, Turkiye; Yakup Gunes, Private Batman Medicalpoint Hospital, Batman, Turkiye; Huseyin Mayali, Manisa Celal Bayar University, Manisa, Turkiye; Ayhan Yilmaz, Bursa Private Doruk Yildirim Hospital, Turkiye; Emine Kaya Güner, Izmir City Hospital, Izmir, Turkiye; Burcin Cakir, Sakarya University, Sakarya, Turkiye; Meral Yildiz, Bursa Uludag University, Bursa, Turkiye; Ali Devebacak, University of Health Sciences Izmir Faculty of Medicine Dr. Behcet Uz Children’s Diseases and Surgery Training and Research Hospital, Izmir, Turkiye; Tülin Ogreden, Istanbul Medipol University Bahcelievler Hospital, Istanbul, Turkiye; Mehmet Giray Ersoz, Biruni University, Istanbul, Turkiye; Dilara Pirhan, Kocaeli University, Istanbul, Turkiye; Gokhan Celik, Zeynep Kamil Maternity and Children Training and Research Hospital, Istanbul, Turkiye; Ugur Acar, Konya Selcuk University, Konya, Turkiye; Ozge Pinar Acar, Tekirdag Namik Kemal University, Tekirdag, Turkiye; Asiye Ekinci, Bursa Yuksek Ihtisas Training and Research Hospital, Bursa, Turkiye; Fatma Sumer, Recep Tayyip Erdogan University, Rize, Turkiye; Metin Ucar, Erzurum City Hospital, Erzurum, Turkiye; Nazife Asikgarip, Ankara Koru Hospital, Ankara, Turkiye; Goksu Alacamli, Mugla Sitki Kocman University, Mugla, Turkiye; Erbil Seven, Van Yuzuncu Yil University, Van, Turkiye; Nilufer Zorlutuna Kaymak, Kartal Dr Lutfi Kirdar City Hospital, Istanbul, Turkiye; Mehmet Erkan Doğan, Akdeniz University, Antalya, Turkiye; Cenap Mahmut Esenulku, Trabzon Kanuni Training and Research Hospital, Trabzon, Turkiye; Müberra Akdogan, Afyonkarahisar Health Sciences University, Afyonkarahisar, Turkiye; Mehmet Egemen Karatas, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkiye; Hatice Bilge Araz Ersan, Istanbul Kanuni Research and Training Hospital, Istanbul, Turkiye; Imren Akkoyun, Ankara Baskent University, Ankara, Turkiye; Fatma Merve Bektas, Mersin Training and Research Hospital, Mersin, Turkiye; Zeynep Seymen, Istanbul Training and Research Hospital, Istanbul, Turkiye; Nihan Aksu Ceylan, Istanbul University, Istanbul, Turkiye; Oguzhan Oruz, Baskent University Adana Hospital, Adana, Turkiye; Aslihan Uzun, Ordu University, Ordu, Turkiye; Mustafa Yasar, Bursa City Hospital, Turkiye; Sadik Etka Bayramoglu, Istanbul Kanuni Training and Research Hospital, Istanbul, Turkiye; Cengaver Tamer, Ankara Guven Hospital, Ankara, Turkiye; Serpil Yazgan, Malatya Inonu University, Malatya, Turkiye; Ali Riza Cenk Celebi, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkiye; Ozdemir Ozdemir, Bilkent City Hospital, Ankara, Turkiye; Bilge Batu Oto, Istanbul University-Cerrahpasa, Istanbul, Turkiye; Aysegul Comez, Kahramanmaras Sutcu Imam University, Kahramanmaraş, Turkiye; Abdulmutalip Yildirim, Sanliurfa Training and Research Hospital, Sanliurfa, Turkiye; Numan Kucuk, Zonguldak Bülent Ecevit University, Zonguldak, Turkiye; Murat Gunay, Karadeniz Technical University, Trabzon, Turkiye; Cagri Mutaf, Harran University, Turkiye; Ayse Ipek Akyuz Unsal, Aydin Adnan Menderes University, Aydin, Turkiye; Zeynep Buket Cansever, Adana City Hospital, Adana, Turkiye; Suleyman Mesut Karaatlı, Istinye University, Istanbul, Turkiye; Gunhal Satirtav Akdeniz, Necmettin Erbakan University, Konya, Turkiye; Dilek Guven, Acibadem Mehmet Ali Aydınlar University/Acibadem Maslak Hospital, Istanbul, Turkiye; Osman Melih Ceylan, University of Health Sciences, Gulhane Training and Research Hospital, Ankara, Turkiye; Ozlem Sahin, Marmara University Pendik Training and Research Hospital, Istanbul, Turkiye; Huban Atilla, Ankara University, Ankara, Turkiye; Ozlem Eksi Yucel, Ondokuz Mayıs University, Samsun, Turkiye; Zafer Onaran, Kırıkkale University, Kırıkkale, Turkiye; Osman Parca, Pamukkale University, Denizli, Turkiye; Mustafa Yildirim, Erzurum Ataturk University, Erzurum, Turkiye; Haluk Huseyin Gursoy, Eskisehir Osmangazi University, Eskisehir, Turkiye; Semra Koca, Kayseri City Hospital, Kayseri, Turkiye; Meydan Turan, University of Health Sciences, Balikesir Ataturk City Hospital, Balikesir, Turkiye; Ufuk Urdem, Kocaeli Health and Technology University, European Vocational School, Kocaeli, Turkiye; Zeliha Colluoglu Hamurcu, Ankara Ataturk Sanatoryum Training and Research Hospital, Ankara, Turkiye; Nedime Sahinoglu Keskek, Alanya University Training and Research Hospital, Alanya, Turkiye; Caglar Bektas, Canakkale Onsekiz Mart University, Canakkale, Turkiye; Ahmet Ekizoglu, Karabuk University, Karabuk, Turkiye; Esay Kiray Yenice, Etlik Zubeyde Hanım Women’s Health Care, Training and Research Hospital, Ankara, Turkiye; Safak Korkmaz, Giresun University, Giresun, Turkiye; Sabiha Kobat, Elazig Fırat University, Elazig, Turkiye; Sibel Kadayifcilar, Hacettepe University, Ankara, Turkiye; Ozlem Candan, Ankara Training and Research Hospital, Ankara, Turkiye; Cem Kesim, Koc University, Istanbul, Turkiye; Furkan Sen, Sanliurfa Mehmet Akif Inan Training and Research Hospital, Sanliurfa, Turkiye; Ayca Kupeli Cinar, Trakya University, Edirne, Turkiye; Tamer Tatar, Private Esencan Hospital, Istanbul, Turkiye; Yakup Acet, Mardin Training and Research Hospital, Mardin, Turkiye; Hatice Erolur, Istanbul Bagcilar Training and Research Hospital, Istanbul, Turkiye; Sengul Ozdek, Gazi University, Ankara, Turkiye; Abdurrahman Bilen, Adiyaman Training and Research Hospital, Adiyaman, Turkiye; Umit Karaalp, Batman Training and Research Hospital, Batman, Turkiye.
Contributor Information
TR-ROP 2 Study Group:
Zehra Arslan, Semra Gundogdu, Fatma Iyigun, Yusuf Kale, Sema Tanrıverdi, Birgul Mutlu, Aslihan Abbasoglu, Meltem Karabay, Salih Cagri Cakir, Tulin Gokmen Yildirim, Mehmet Buyuktiryaki, Chousein Amet, Ozge Serce Pehlevan, Guner Karatekin, Saime Sundus Uygun, Sinan Tufekci, Ipek Guney Varal, Ilkay Er, Hasan Kahveci, Didem Armangil, Nilay Hakan, Eyyup Yurekturk, Fatma Narter, Sema Arayici, Berna Saygin Hekimoglu, Nurdan Ozturk Tasar, Hasan Avsar, Deniz Anuk Ince, Huseyin Simsek, Didem Arman, Meltem Bor, Bilin Cetinkaya, Irem Iyigun, Bayram Ali Dorum, Murat Ekinci, Funda Eroglu, Ramazan Ozdemir, Serdar Beken, Omer Ertekin, Zeynep Alp Unkar, Sadık Yurttutan, Fatih Isleyen, Makbule Ercan, Filiz Akturk Acar, Ebru Yucesoy Bagdiken, Abdullah Baris Akcan, Selvi Gulasi, Sait Ilker Uslu, Huseyin Altunhan, Selma Aktas, Belma Saygili Karagol, Sinem Gulcan Kersin, Emel Okulu, Sahin Takci, Umit Ayse Tandircioglu, Ozmert M A Ozdemir, Kadir Serafettin Tekgunduz, Ozge Aydemir, Ahmet Ozdemir, Mine Ozdil, Tugrul Donmez, Dilek Sarici, Merih Cetinkaya, Birgul Livaoglu Say, Hakan Aylanc, Sadrettin Ekmen, Istemi Han Celik, Safiye Elif Uzlu, Erdal Taskin, Gozdem Kayki, Melda Tas, Tugba Gursoy, Mehmet Fatih Deveci, Ridvan Duran, Nihat Demir, Mehtap Durukan Tosun, Sahin Hamilcikan, Lachin Cumshudov, Selahattin Akar, Aslan Yilmaz, Sevil Karaman Erdur, Caner Kara, Aslihan Dogan Dursun, Yakup Gunes, Huseyin Mayali, Ayhan Yilmaz, Emine Kaya-Güner, Burcin Cakir, Meral Yildiz, Ali Devebacak, Tulin Ogreden, Mehmet Giray Ersoz, Dilara Pirhan, Gokhan Celik, Ugur Acar, Ozge Pinar Acar, Asiye Ekinci, Fatma Sumer, Metin Ucar, Nazife Asikgarip, Goksu Alacamlı, Erbil Seven, Nilufer Zorlutuna-Kaymak, Mehmet Erkan Doğan, Cenap Mahmut Esenulku, Müberra Akdogan, Mehmet Egemen Karatas, Hatice Bilge Araz Ersan, Imren Akkoyun, Fatma Merve Bektas, Zeynep Seymen, Nihan Aksu Ceylan, Oguzhan Oruz, Aslihan Uzun, Mustafa Yasar, Sadik Etka Bayramoglu, Cengaver Tamer, Serpil Yazgan, Ali Riza Cenk Celebi, Ozdemir Ozdemir, Bilge Batu Oto, Aysegul Comez, Abdulmutalip Yildirim, Numan Kucuk, Murat Gunay, Cagri Mutaf, Ayse İpek Akyuz Unsal, Zeynep Buket Cansever, Suleyman Mesut Karaatlı, Gunhal Satirtav Akdeniz, Dilek Guven, Osman Melih Ceylan, Ozlem Sahin, Huban Atilla, Ozlem Eksi Yucel, Zafer Onaran, Osman Parca, Mustafa Yildirim, Haluk Huseyin Gursoy, Semra Koca, Meydan Turan, Ufuk Urdem, Zeliha Colluoglu Hamurcu, Nedime Sahinoglu-Keskek, Caglar Bektas, Ahmet Ekizoglu, Esay Kiran Yenice, Safak Korkmaz, Sabiha Kobat, Sibel Kadayifcilar, Ozlem Candan, Cem Kesim, Furkan Sen, Ayca Kupeli Cinar, Tamer Tatar, Yakup Acet, Hatice Erolur, Sengul Ozdek, Abdurrahman Bilen, and Umit Karaalp
Data availability statement
Data are available on reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data are available on reasonable request.