Retinopathy of Prematurity in Neonatal Intensive Care Unit at King Fahd University Hospital, Eastern Province: Prevalence, Risk Factors, and pattern of severity Seven years’ experience.

Introduction

One of the most significant and curable causes of childhood blindness is retinopathy of prematurity (ROP), a proliferative retinopathy that damages retinal blood vessels in preterm and low-birth-weight infants.¹ Retinal detachment, which results from scarring of aberrant retinal blood vessels, is the primary cause of visual impairment and blindness in patients with ROP.² Initially, it was speculated that ROP development was related to the complex and unreported use of oxygen supplementation in the care of premature infants placed in closed incubators for the treatment of respiratory distress. Patz et al. first described this relationship in 1952.³ Numerous studies have indicated that this illness is multifaceted and linked to risk factors, such as low birth weight, early intrauterine age, oxygen therapy while receiving medical care in a newborn critical care unit, respiratory issues, sepsis, and multiple parity. However, because some studies believe that this condition is dependent on geographic and medical facilities, the causal association between these elements has not been definitively proven.¹ The immature vasculature develops in two stages. First, ischemia and a hyperoxic phase restrict the blood vessels in the retina. Second, this ischemia may cause mesenchymal spindle cells to produce angiogenic factors, which may then cause the development of new immature vasculature. The International Classification for ROP (ICROP) was established in 1984. According to the zones of the retina affected by the illness (1, 2, and 3), the extent of the disease as measured by clock hours (1-12), and the severity of the disease as measured by different stages (0–5), the ROP is categorized.⁴ Moreover, a demarcation line, ridge with height and width, proliferation of fibrovascular cells in extra retinal tissue, partial retinal detachment, and total retinal detachment are the five phases of ROP.^2,4 This study aimed to determine the prevalence of ROP in the NICU at KFUH and to investigate the risk factors that influence its presence. The results of this study will provide local studies with a useful update and aid in enhancing the knowledge of how common the ROP is in our region.

In addition, Demirel et al. in 69 neonatal intensive care units (NICUs), A prospective cohort study was conducted between 2016 and 2017 in 69 neonatal intensive care units. The study included infants with a birth weight (BW) or gestational age (GA) of 1500 g or less, BW or GA of more than 1500 g, and an unstable clinical course. With a GA of 32 weeks or less, 964 (81%), and more than 32 weeks, 1151 (19%). Overall, 27% of the patients had ROP in some stages and 6.7% had severe ROP. In newborns with a BW of 1500 g, a lower BW, smaller GA, total number of days spent on oxygen, late-onset sepsis, frequency of red blood cell transfusions, and relative weight growth were found to be independent risk factors for severe ROP. Hence, suggestions for infants with a GA of 34 weeks or a BW of 1700 g should be screened in Turkey. To enhance newborn outcomes in Turkish NICUs, monitoring neonatal care standards, and carrying out quality improvement programs nationwide.⁵ In addition, Dwivedi et al. A five-year retrospective review was conducted at the Special Newborn Care Unit in a government Medical College located in eastern Madhya Pradesh. Thirty% of the 763 infants who underwent screening for ROP had this condition. Severe ROP prevalence was 14.2% (109) in 60 (55.5%) typical cases and 30 (27.7%) aggressive posterior ROP (APROP) cases. Stage IV and V ROP were detected in 18 patients (16.6%), making it a severe ROP. The mean gestational age (GA) and birth weight (BW) were 31.05 weeks and 1.34 kg, respectively, and both variables were negatively correlated with severe ROP. However, among late preterm infants, defined as those born at >34 weeks of age, 10% had severe ROP. The primary screening-related factor for stage IV and V ROP was late presentation. Severe ROP was quite common in this study. The main contributing factor to ROP-related blindness is late screening presentation.⁶ On the other hand, Fekri, et al. A 2021 case series study was conducted in Alavi Hospital between 2018 and 2019, including 400 infants with gestational age less than 34 weeks or birth weight of 2000 g or less. A total of 107 (26.8%) of the 400 preterm newborns investigated (57.2% male and 42.8% female) had ROP and 23 (21.5%) required therapy (5.8% of all infants studied required treatment). Zones I, II, and III were found in four (3.7%), 29 (27.1%), and 74 (69.2%) infants, respectively. Stages I, II, and III were present in 91 (85%), 11 (10.3%), and five (4.7%) babies, respectively. Parental consanguinity is linked to an increased risk of ROP.¹ Similarly, Nugud, et al. done a retrospective cohort research in Dubai hospital and it was carried out between 2012 to 2014; 611 neonates were admitted to the NICU throughout the research period, out of 163 individuals who were enrolled in the study, 44 (27%) experienced ROP, whereas 119 (73%) did not have ROP at any of the subsequent ophthalmological screening assessment. Eight patients (4.9%) had stage I ROP, 27 patients Page 4 of 5 (16%) had stage II ROP, and 9 patients (5.5%) had stage III disease. Stage IV and V illnesses were not present in any of the patients. Infants with ROP were born at a gestational age of 27 weeks; 55 patients (33.7%) experienced intracranial hemorrhage, and 14.1% developed ROP.³ In Saudi Arabia This retrospective study was conducted at King Abdulaziz University Hospital (KAUH) in Jeddah between January 2010 and January 2021. The study included 37 infants with ROP. The study showed a 51.4% female predominance, a mean gestational age of 27 weeks, a mean birth weight of 800 g, birth weight, and the development of ROP in the right eye were significantly correlated, as were gestational age and the development of ROP in the same eye, and 66.7% of infants who developed ROP were delivered by cesarean section.⁷

Lastly, a cohort review was conducted in King Abdulaziz Medical City, Riyadh, Saudi Arabia, from 2010 to 2014, with a total of 581 newly enrolled patients. A total of 224 newborns (38.6%) had ROP, and 22 (10.4%) had stage 3 ROP. Infants with ROP had a mean BW of 938 g and mean GA of 27 weeks at delivery. Small GA at birth, low BW, low APGAR score at one minute, and prolonged oxygen (O2) therapy duration were all significant predictors of ROP.⁴

Methods

Results

(Table 1) This study included 201 patients. The female/male ratio was similar to that in 50.2% of males. Nearly half of the mothers (49.8%) were 30 years old. More than three-quarters (77.6%) of the participants had singletons. The gestational age was 32 weeks or less (73.6%). Approximately 63.2% of the patients delivered by cesarean section. Newborns who received surfactant were approximately 60.7%, mostly one dose (72.1%). In addition, 55.7% had a duration of O₂ therapy of less than 28 days. The prevalence of patients who were diagnosed with ROP was 37.3%, mainly stage 1 (46%), unilateral (73.3%), and Zone 2 (25.3%). A total of 48.3% of premature patients received a blood transfusion, mainly two units (37.1%). Stressing the importance of follow-up screening, 30.8% only continued to follow up. The mean birth weight was 1203.9 (SD 365.7) g. In addition, the mean APGAR scores at 1, 5, and 10 minutes were 5.59, 7.67, and 7.26, respectively.

As shown in Table 2, the top five most common risk factors for ROP included respiratory distress syndrome (88.1%), septicemia (87.1%), jaundice (62.7%), multiple pregnancies (51.7%), and consanguinity (49.8%). None of the patients had congenital diaphragmatic hernias or hypothyroidism.

As shown in Table 3, the prevalence of ROP was significantly more common among those who had a gestational age of 32 weeks or less and who received surfactant, as well as duration of O2 therapy for more than 28 days. Patients who received blood transfusion, continued to follow-up, and had risk factors such as respiratory distress syndrome, Septicemia, Jaundice, consanguinity, intraventricular hemorrhage, congenital heart disease, and bronchopulmonary dysplasia showed statistically significant results compared to other risk factors. In addition, low birth weight was associated with an increased risk of ROP (p<0.001), while APGAR 1 min (p<0.001) and APGAR 5 minutes (p<0.001) were significantly lower in patients with ROP. Conversely, the difference was less significant among those with maternal diabetes (p=0.011).

In a univariate regression model (Table 4), it was found that patients who used Surfactant were 12.9 times higher to be associated with an increased risk of ROP (OR=12.952; 95% CI=5.512 – 30.433; p<0.001). Patients who had more than 28 days of O₂ therapy use were 9.3 times more likely to have an increased risk for ROP than those who had less than 28 days of O₂ therapy (OR=9.302; 95% CI=4.786 – 18.081; p<0.001). The number of patients at follow-up was 46.7-fold higher at an increased risk of ROP (OR=46.750; 95% CI=18.665 – 117.091; p<0.001). Patients with risk factors were at increased risk for ROP, such as Septicemia (OR=8.588; 95% CI=1.968 – 37.482; p=0.004), jaundice (OR=4.089; 95% CI=2.076 – 8.054; p<0.001), consanguinity (OR=12.628; 95% CI=6.106 – 26.118; p<0.001), intraventricular hemorrhage (OR=4.900; 95% CI=2.649 – 9.063; p<0.001), congenital heart disease (OR=4.406; 95% CI=2.390 – 8.124; p<0.001), and bronchopulmonary (OR=7.827; CI=3.313 – 18.488; p<0.001), whereas maternal diabetes was likely at decreased risk for ROP (OR=0.176; 95% CI=0.039 – 0.783; p=0.023). Gestational age > 32 weeks was associated with a decreased risk of ROP compared to those ≤32 weeks (OR=0.146; 95% CI=0.059 – 0.363; p<0.001). In addition, decreased birth weight was marginally associated with an increased risk of ROP (OR=1.004; 95% CI=1.003 – 1.005; p<0.001), APGAR 1 min (OR=1.476; 95% CI=1.244 – 1.752; p<0.001), and APGAR 5 min (OR=1.474; 95% CI=1.192 – 1.823; p<0.001).

Discussion

For retinopathy of prematurity (ROP) screening, We adhered to the Ministry of Health Guidelines for retinopathy of premature screening. They applied recommendations to identify premature infants with a GA of less than 32 weeks and a BW of less than 1500 g as possible ROP risk individuals. The reported prevalence of ROP among at-risk newborns varies widely, ranging between 29% and 68%.⁴ The prevalence of patients diagnosed with ROP was 37.3%, which is relatively similar to that reported by Al-Qahtani et al. in 2019 but substantially lower than the proportion discovered in the 2008 study by Binkhathlan et al.^4,8 Bokhary O. et al. Research conducted by an expert ophthalmologist separately staged ROP for each eye. According to the ICROP, stages 1, 2, and 3 are the demarcation line, ridge, and extraretinal, respectively. Both preterm eyes had a stage 1 predominance, with 18 in the right eye and 21 in the left eye, respectively.⁷ We found similar results in our study: the prevalence was stage 1 (46. %), and a unilateral eye affection by (73.3%). In addition, the most involved site was zone II (25.3%), which is in contrast to a study conducted in Tabuk city, Saudi Arabia, where they found that the majority of the implicated sites (69.4%) were in zone III, with zones II and I accounting for 27.8% and 2.7%, respectively.²

The proportion of males and females with ROP during the study period varied among the sample populations, but the variation was statistically insignificant. This is concordant with a study conducted in a tertiary hospital in Riyadh, Saudi Arabia that concluded the insignificant result of male and female ratio.⁴ The are well-known primary risk factors for the development of ROP; GA, BW, and oxygen therapy.⁶ A low BW and APGAR score, short GA with total number of days on oxygen were discovered to be independent risk factors for ROP in newborns. A gestational age of more than 32 weeks was at a decreased risk for ROP compared to those with 32 weeks or less. Additionally, decreased birth weight was marginally associated with an increased risk of ROP. Likewise, other studies have found the same occurrence of these risk factors.^1,4,6,8

This study demonstrated that packed red blood cell transfusions have a significant impact on the emergence of ROP. This is due to the decreased oxygen affinity of adult hemoglobin in packed red cells, and transfusions may enhance oxygen transport to the retina. Repeated transfusions may also lead to free iron buildup, which, as determined by the Fenton reaction, may lead to an increase in the formation of free hydroxyl radicals that could harm the retina.⁹ Numerous reports have claimed that receiving blood transfusions may increase the risk of developing ROP, although according to various studies, a transfusion restriction strategy did not lower the incidence of ROP.^10,11 According to our research, limiting blood transfusions based on recommended threshold hemoglobin values may help lower the prevalence of ROP.

Respiratory distress syndrome (RDS) is prevalent in premature newborns. RDS affects 60% of infants weighing less than 1500 g and 80% of infants weighing less than 1000 g at birth.¹² Low O₂ and high CO₂ levels and pulmonary and metabolic acidosis are common in this population. Each of these factors is strongly correlated with the emergence of acute ROP. A study in 1992 demonstrated that surfactant therapy administered within the first 48 h of life significantly increased the survival rate of critically ill neonates. Surfactant therapy can initially increase oxygenation to 20–30 kPa, which is continuously monitored by pulse oximetry to optimize tissue oxygenation and limit the risk of hyperoxemia. Hence, we concluded that surfactant therapy is not associated with an increased incidence or severity of severe ROP in the preterm population.¹³ The analysis of a study in 1994 concluded that surfactants do not contribute to more severe forms of ROP, but rather raise the risk of acquiring ROP.¹⁴ This study showed a statistically significant association between ROP, surfactant use, and RDS in this population.

Scheduling the first examination should be based on postmenstrual age (GA plus chronological age) rather than postnatal age because ROP takes a period of time to develop in very young infants. Stage 3 ROP did not develop until 31 weeks of postmenstrual age, according to prospective studies that involved infants aged 22–25 weeks GA.¹⁵ Furthermore, the most significant factor contributing to advanced ROP was the lack of timely screening, and false results were also a significant prothem.¹⁶ Our study showed that patients at follow-up were 46.7-fold higher at an increased risk of ROP. An ophthalmologist conducting an initial assessment should suggest subsequent screening examinations. Neonatal sepsis has been linked to the development in numerous studies.^17,18 In the present study, ROP in low birthweight newborns was independently associated with late-onset sepsis. Cytokines and endotoxins, which directly affect retinal angiogenesis, may play a role in sepsis. Hypotension is frequently present throughout this phase and can impede tissue perfusion and result in retinal ischemia.

Consanguineous marriage was an intriguing finding in the current study and was a significant independent factor related to retinopathy in preterm infants. This is similar to Fekri Y. study which found that consanguineous marriages had a considerably greater prevalence of preterm infant retinopathy (42% vs. 22.9%) as well as linked to a 3.2-fold increase in the incidence of retinopathy in preterm infants.¹ Considering the retrospective design of the study, the sample size was relatively small, it was carried out at a single hospital, and generalization cannot be guaranteed. Multicentric prospective and longitudinal studies with adequate sample sizes are strongly advised to evaluate additional variables that affect ROP. In addition, ophthalmologists participated in a standardized process for ROP grading and follow-up plans as outpatients.

Conclusion

In conclusion, retinopathy of prematurity is one of the major disorders affecting premature newborns. The incidence of ROP in our study was within the range of disease incidence in developing countries and comparable to other local investigations. The important risk factors for ROP were low BW and low GA, although the ROP screening criteria should be expanded to encompass newborns with GAs between 32 and 35 weeks. Independent risk factors that influence ROP include the use of surfactants, septicemia, consanguinity, blood transfusion, and the pattern of follow-up. It is also advised to limit the quantity and duration of O2 therapy to the absolute minimum required. To enhance newborn outcomes, it is crucial to track neonatal care standards and implement quality improvement initiatives across the country.