Profiling of Retinopathy of Prematurity (ROP) Patterns at Various Gestational Ages in a Tertiary Care Institute in North India: A Retrospective Study

1. INTRODUCTION

Retinopathy of prematurity (ROP) is a potentially vision-threatening but treatable eye illness that primarily affects premature newborns weighing 1500 grams or less and/or those delivered before 34 weeks of gestation. This is one of the most prevalent causes of childhood vision loss, and if left untreated, it can lead to lifelong vision impairment and blindness. The prevalence of ROP ranges from 38% to 47% in various regions of India. The incidence of ROP is increasing due to a variety of factors, including an increase in the number of neonatal intensive care units, resulting in higher survival rates in preterm children. However, without controlled oxygen delivery, the incidence of ROP is high, particularly in rural regions. Furthermore, there is an increasing tendency to use artificial means of conception, such as IVF (in vitro fertilization), which results in numerous pregnancies and low birth weight and is another major risk factor for ROP [1-5].

ROP has been associated with several risk factors. It occurs only in premature children who delivered before 34 weeks and/or who weighed less than 1,500 grams at birth. Early exposure to high oxygen concentrations, multiple episodes of bradycardia, heart abnormalities, low vitamin E levels in the serum, uncontrolled convulsions, anemia, and blood transfusions are associated with other significant conditions, including genetic variation, among others [6, 7].

In general, evidence suggests that the lower the infant's birth weight, the greater the incidence of medical complications and the greater the likelihood of developing ROP because most of these medical conditions necessitate additional oxygen support for the infant, who is already premature and whose lungs and other organs are not fully functional [8]. India has the world's highest overall incidence of preterm babies. Although neonatal mortality remains high, it is steadily decreasing. The number of neonatal intensive care units (NICUs) in India is rapidly expanding, and NICUs are now accessible to people living in rural areas, resulting in a greater survival rate for preterm infants [1].

The main pathology is retinal blood vessel development in humans beginning at approximately 16 weeks of gestation, during which the vessel progresses from the optic disc to the periphery of the retina. The nasal retina is vascularized at up to 36 weeks of gestation, but the temporal retina takes approximately 40 weeks to complete vascularization because the distance between the optic disc and the orra serrata was greater on the temporal side of the eye than on the nasal side. As a result, it will take approximately 4 weeks for vessels to reach the Distal section of the temporal retina. Any impediment to this growth, such as an unregulated oxygen supply, will stop the vessel growth, leaving the retina avascular. This avascular retina becomes hypoxic, causing angiogenic factor (VEGF) to be released, resulting in the formation of aberrant and anarchic arteries throughout the retina [2, 3, 9].

ROP development is divided into two stages. After premature birth, vessel growth stops in the first phase. During this time, the vessels may be destroyed by a variety of factors, including lack of oxygen. Premature newborns exposed to greater oxygen tension after delivery had a decrease in the main hypoxia-triggered VEGF, leading to the development of retinal capillaries. This was one of the first occurrences in the history of ROP [10].

Owing to increasing oxygen demand, the peripheral retina, which is largely avascular or hypovascularized, becomes hypoxic in the second phase. As a result, abnormal development of retinal vessels occurred at that location. During this phase, excess hormones and growth factors are produced to provide adequate perfusion to increasingly hypoxic retinas. Specifically, VEGF and growth hormones such as IGF-1 are produced. These substances cause extracellular matrix proteins such as vitronectin, fibronectin, and fibrinogen to deposit sticky fibrils and drive endothelial cell proliferation, differentiation, and migration. These new vessels are chaotic and excessive, resulting in vitreous invasion, retinal traction, and hemorrhage. This key period of ROP most frequently occurs between 33 and 34 weeks after pregnancy. Traction on the retina results in tractional retinal detachment, which leads to blindness. In addition, there are genetic links. In a study of monozygotic and dizygotic preterm twins, secondary heritable variables were found to account for 70% of the variance in ROP incidence. Numerous gene variants, including those in the Wnt signaling pathway (FZD4, LRP5, and NDP), were discovered in small candidate gene investigations [2, 3, 10, 11].

There are many demographic profiles and ROP patterns available from North and South India, as well as internationally, but none of the data describe the pattern of ROP at different gestational stages. In light of this, the study's objective was to profile the retinopathy of prematurity (ROP) pattern at various gestational ages, ranging from 26 to 36 weeks, in a tertiary care hospital in North India. The newborn intensive care unit at the PGICH NOIDA is properly furnished. The Department of Ophthalmology receives a sizable number of preterm infants for ROP screening. Additionally, the department receives referrals from other sections of the Delhi NCR as well as from different regions of the state.

2. METHODS

3. RESULTS

Throughout the study period, 700 neonates were screened. Of these, 35 patients were excluded due to incomplete information, 9 were excluded because primary treatment was received elsewhere, and 13 were excluded due to a lack of follow-up. Ultimately, the data of 643 infants were analyzed. The screened infants had a mean birth weight (BW) of 1353 g and a standard deviation (SD) of 430.48 g (range: 700 to 3200 g) (Table 1).

The range of gestation was 26 to 36 weeks, with a mean gestational age of 28.66 weeks and a standard deviation of 1.12 (Table 2).

The first week after NICU admission was the first follow-up week, called ROP stage I, and the second to third weeks, called ROP stages II and III, depending on the clinical findings and severity of the patients. All patients were followed up until the age of five years.

The data were further examined over a gestational period of 26–36 weeks. The findings were divided into nine categories: nil/ no ROP, peripheral Avascular, zone 2 stage 1, zone 2 stage 3, zone 3 stage 1, zone 3 stage 2, zone 3 stage 1, and retinal maturation.

3.2. 27 Gestational Weeks

The 27 GW data showed that 42.8% of peripheral avascularity (stage 0), 17.85% of zone 2 stage 2, 14.28% of zone 3 stage 1, and 7.14% of no ROP, zone 2 stage 1, zone 2 stage 3, and 3.5% of zone 3 stage 2 cases were detected in the 1st ROP checkup. In the 2nd ROP checkup, the percentage of patients with no ROP increased to 46.4%, followed by 17% for zone 2 stage 1 and zone 2 stage 3 patients, 14% for zone 3 stage 1, and 10% for zone 2 stage 2 patients. Similarly, at the 3rd ROP checkup, 60.71% of the ROP patients had a mature retina, and 28.5% of the patients were diagnosed with zone 2 stage 3 ROP.

Of the 60.71% retina-matured ROP patients, 64.28% had matured without any intervention, 25% had been treated with intravitreal anti-VEGF injections + LASER,

and 10.7% had undergone LASER treatment (Fig. 2 and Table S2).

3.4. 29 Gestational Weeks

The 29 GW data showed that 37.68% of zone 3 stage 1 patients had 21.73% peripheral avascular tissue (stage 0), 13.04% of zone 2 stage 1 patients, 10.14% of zone 3 stage 2 patients, and 8.69% of patients with no ROP were detected at the 1st ROP checkup. In the 2nd ROP checkup, 21.73% of the no ROP patients had ROP, 46.37% had stage 1, and 11% had stage 3. Similarly, at the 3rd ROP checkup, 71.01% of the ROP patients had a mature retina, and 10.14% of the patients were diagnosed with zone 3 stage 1 ROP.

Of the 71.01% of the retina-matured ROP patients, 82.6% had matured without any intervention, 10% were treated with intra-vitreal anti-VEGF injections + LASER, 4% were treated with LASER, and 2% were treated with LASER alone (Fig. 4 and Table S4).

3.6. 31 Gestational Weeks

The 31 GW data showed that 73.63% of the patients had no ROP and 16.51% of the patients had zone 3 stage 1 ROP according to the 1st ROP checkup. In the 2nd ROP checkup, 62.72% of the patients did not have ROP, followed by 28.18% of the patients in zone 3 stage 1. Similarly, in the 3rd ROP checkup, 91.81% of the ROP patients were retinal mature, and 2.7% of the patients were diagnosed with zone 3 stage 2 or zone 3 stage 3.

Among 91.81% of retina-matured ROP patients, 92.72% had matured without any intervention, 2% had been treated with intravitreal anti-VEGF injections + LASER, 1% had been treated with AVGEF, and 2% had been treated with only LASER injections + LASER, 1% had been treated with AVGEF, and 2% had been treated with only LASER (Fig. 6 and Table S6).

3.7. 32 Gestational Weeks

The 32 GW data showed that 76.74% of the patients had no ROP and 16.27% of the patients had Zone 3 Stage 1 ROP according to the 1st ROP checkup. In the 2nd ROP checkup, 72.09% of the patients were not ROP and 24.41% were zone 3 stage 1. Similarly, at the 3rd ROP checkup in 95 patients, 34% of the ROP patients had retinal maturation, 2.0% had zone 3 stage 2, and 2.0% had zone 3 stage 3.

Of the 91.81% of retina-matured ROP cases, 97.67% of cases were matured without any intervention, whereas 1% of cases were treated with intravitreal anti-VEGF injections, and only 1% were treated with only LASER treatment (Fig. 7 and Table S7).

3.10. 35 Gestational Weeks

The 35 GW data showed that 87.5% of the patients had no ROP and 12.5% of the patients had zone 3 stage 1 ROP according to the 1st ROP checkup. In the 2nd ROP checkup, 87.5% of the patients had no ROP, 12.5% had zone 3 stage 1, and 2 had zone 3 stage 2. Similarly, at the 3rd ROP checkup, 87.5% of the ROP patients had a mature retina and 12.5% had zone 3 stage 1 ROP.

Of the 87.5% of retina-matured ROP patients, 100% had matured without any intervention, and of 87.5% of the retina-matured ROP patients, 100% had matured without any intervention (Fig. 10 and Table S10).

3.11. 36 Gestational Weeks

The 36 GW data showed that 100% of zone 3 stage 1 was detected during the 1st ROP checkup. As for the 2nd ROP checkup, 100% of the patients had zone 3 stage 1 ROP. Similarly, at the 3rd ROP checkup, 100% of the ROP patients had mature retinas, and all 100% of the patients had matured without any intervention (Fig. 11 and Table S11).

The regression data revealed a strong positive correlation between ROP regressed/not ROP and intravitreal anti-VEGF injections + LASER cases (r = 0.98, p > 8.75E-08, and r square = 0.96) and that the overall variation between predicted ROP regressed/not ROP and intravitreal anti-VEGF injections + LASER cases was very high (96%) (Table S12a-c). We further analyzed the ROP regressed/no ROP data with the predicted ROP regressed/no ROP for intravitreal anti-VEGF injections + LASER cases and found that the variation was very low throughout the gestation period (Table 3; Fig. S1).

The regression data revealed a strong positive correlation between ROP regressed/not ROP and intravitreal anti-VEGF injection (r = 0.94, p > 1.53E-05, and r square = 0.88) and that the overall variation between predicted ROP regressed/not ROP and intravitreal anti-VEGF injection was very high (88%) (Table S13a-c). We further analyzed the ROP regressed/no ROP data and the predicted ROP regressed/no ROP data for patients receiving intravitreal anti-VEGF injections and found that the variation was very low throughout the gestation period (Table 4; Fig. S2).

The regression data revealed that there was a low positive correlation between ROP regressed/no ROP and LASER cases (r = 0.43, p > 4.18E-08, and r square = 0.18) and that the overall variation between the predicted ROP regressed/NO ROP and LASER cases was very low (18%) (Table S14a-c). We further analyzed the ROP regressed/no ROP data with the predicted ROP regressed/no ROP data for patients with LASER and found that the variation was very large throughout the gestation period (Table 5 and Fig. S3).

4. DISCUSSION

The study was conducted at a single tertiary care institute in North India over a four-year period between 2019 and 2023. Throughout the study period, 700 preterm newborns were screened. A total of 643 preterm babies underwent analysis, although there was covid pandemic during this period. The infants who were screened had a mean birth weight (BW) of 1353 g and an average birth weight (SD) of 430.48 (ranging from 700–3200 g). With an SD of 1.12, the mean gestational duration was 28.66 weeks, with a range of 26 to 36 weeks. Similar statistics have been reported by Tekchandani et al. [12] when analysis of data from 2595 of the 3697 infants revealed a 32.3% overall incidence of ROP. The mean BW of children with ROP in the present study was 1353 g, which is greater than the 1277 g found in a 2021 study from India [12] as well as studies from Hong Kong [13], Taiwan [14], and Brazil [15]. Similarly, at 28.66 weeks, the mean gestational age in the present study was greater than that worldwide [12-15]. Hence, according to a previous Western study, ROP is more prevalent in newborns with higher birth weights and longer average gestation weeks than in neonates with lower birth weights.

The majority of ROP disease presentations occurred in Peripheral Avascular and zone 3 stage 1, which was comparable to the findings of other studies, such as Tekchandani et al., 2021, in which only zone 2 cases were found [12]; Hungi et al., 2012, in which aggressive posterior ROP was discovered in zone 1 [16]; and Charan et al., 1995, in which stage 1 and stage 2 cases were both discovered [17]. Yehiam et al. (2023) reported both Group 1 and Group 2 instances in New Zealand from January 2013 to December 2017 [18]. Rutnin and Schepens et al. studied incomplete peripheral retinal vascularization in both adults and children [19, 20]. Ho et al. reported two cases of zone 3 stage 2 ROP [21]. Hence, these studies indicate that the prevalence of ROP in this region of the world is predominantly peripheral Avascular and zone 3, with the majority occurring at 28.66 weeks of gestation.

Further analysis of the data from the range of 26 to 36 weeks of gestation revealed that 14.28% of the patients had ROP at 26 weeks of gestation, 35.7% had ROP at 27 weeks of gestation, 39.5% had ROP at 28 weeks of gestation, 16% had ROP at 29 weeks of gestation, 10% had ROP at 30 weeks of gestation, 5% had ROP at 31 weeks of gestation, 2% had ROP at 32 weeks of gestation, and 3% had ROP at 33 and 34 weeks of gestation; interestingly, all the ROP were mature without intervention at 35 and 36 weeks of gestation. The incidence of ROP varies by location in India, ranging from 38% to 47% in other parts of the country [12, 16, 17], and similar trends have been observed in other parts of the world, including 16% in Hong Kong [13], 37% in Taiwan [14], and 25.5% in Brazil [15]. These data indicate that the prevalence of ROP is greater during birth at 28th weeks of gestation and that the number of ROP cases decreases with increasing gestational age. A similar trend was observed by Ugurlu et al. in 2021, who concluded that newborns with a gestational age of 28 weeks accounted for 3.3% of all births and that the ROP rate was substantially greater than that of infants with older gestational ages (P 0.001) [22]. This could be related to the necessity for higher oxygen delivery during the 27th and 28th weeks of gestation, as opposed to the 35th and 36th weeks of gestation, implying that an uncontrolled oxygen supply in newborn critical care units may increase the incidence of ROP. However, there is an increasing trend toward artificial methods of conception, such as IVF, which could be another reason for the high prevalence of ROP [1].

Furthermore, detailed analysis revealed that compared to those with stage I ROP, 71.42%, 64.28%, 60.29%, 82.6%, 91%, 92.72%, 97.67%, 97.95%, 96.38%, and 100% of ROP patients at 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, and 36 gestational weeks, respectively, matured without any intervention in stage III ROP. These data indicate that as gestational age increases from 31 to 36 weeks, ROP regresses without any intervention, indicating that premature birth at 26 to 30 weeks is more susceptible to ROP than gestation at 33 to 36 weeks. However, studies report that babies with a gestational age ≤35 weeks and a gestational weight of 2000 grams are at a greater risk of developing ROP [22, 23]. Preterm birth under 28 weeks is the main cause of ROP in developed nations, although severe ROP can occur up to 34 weeks in developing countries [24-27].

These findings indicate that children between 26 and 30 weeks of gestation may develop advanced ROP that requires therapy. In contrast, Bas et al. (2024) found that newborns with higher gestational ages and weights may develop advanced ROP that requires treatment [28].

Similar trends were observed in the intravitreal anti-VEGF agent + LASER treatment group, in which 14.28%, 25%, 22%, 10%, 7%, 2%, 2% and 2% of the ROP patients were at 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 33 weeks and 34 weeks, respectively, needed AVEGF + LASER treatment. However, 14.28%, 10.7%, and 5.88% of ROP patients at 26, 27, and 28 weeks of gestation, respectively, and 1-2% of those at 29, 30, 31, 32, and 33 weeks of gestation needed LASER, respectively. These findings suggest that intravitreal anti-VEGF injections combined with laser treatment are more effective than laser treatment alone. Studies have reported that the combination of intravitreal anti-VEGF agents and minimally invasive laser therapy improves visual acuity (VA), relieves diabetic macular edema (DME) and may reduce the number of anti-VEGF agent injections required [29]. However, in ROP patients, anti-VEGF drugs are as effective as laser treatment and are safer than laser therapy for type 1 ROP [30]; however, Bezman et al., in 2023, reported that anti-VEGF agents are increasingly used in the treatment of ROP patients in recent time [31].

The ROP REGRESSED/NO ROP data were statistically analyzed in comparison to the predicted ROP REGRESSED/NO ROP data for patients treated with intravitreal anti-VEGF injections + LASER or intravitreal anti-VEGF injections, and the variation was found to be very low in all gestation period patients, indicating that intravitreal anti-VEGF injections + LASER and intravitreal anti-VEGF injection treatment was more suitable than LASER alone. Sen et al. (2021) endorsed the study and reported that combination therapy is an effective and safe treatment method for Type I ROP and Aggressive Posterior ROP [32]. However, Lingue et al., (2022) reported, in contrast to laser therapy, anti-VEGF drugs as primary therapies provide prospective benefits for eyes with zone I type 1 ROP [30]. Laser photocoagulation and anti-VEGF agent therapy were equally effective for treating eyes with zone II type 1 ROP; however, the rate of reactivation with laser therapy was much lower than that with anti-VEGF medications. Compared to anti-VEGF medication, laser treatment increases the tendency toward myopia [30]. According to Tran et al., anti-vascular endothelial growth factor (anti-VEGF) medication is increasingly being used off-label to treat ROP, but laser photocoagulation remains the gold standard for treating threshold and pre-threshold type 1 ROP [33].

CONCLUSION

These findings also suggest that the incidence of ROP is greater at the 27th and 28th weeks of gestation and that the number of ROP patients decreases with increasing gestational age. These findings suggest that as gestational age increases from 31 to 36 weeks, ROP regresses without intervention, indicating that premature births between 26 and 30 weeks are more prone to ROP than pregnancies between 33 and 36 weeks. These data imply that intravitreal anti-VEGF injections in conjunction with laser treatment are more effective than LASER treatment or intravitreal anti-VEGF injections alone.

REFERENCES