In our study we found a high incidence of type 1 ROP and a significant disparity between local and international screening criteria for ROP as well as key associations between screening practices, zones of ROP and treatment modalities utilized. Unblended oxygen is common in resource-limited settings like Pakistan, all babies were receivers of unblended oxygen in this study which may have lead to vessel die-back and AROP in older and heavier babies [14, 15]. Unblended oxygen causes fluctuations in oxygen levels, abnormal vessel growth occurs under low oxygen, but excess oxygen can cause vessel die-back or regression. We found that 25% of screened babies had retinopathy of prematurity, aligning with findings from Hamid Latif Hospital (28% ), [16] and Ganga Ram Hospital, Lahore (43/160) [4]/ In contrast, a 2016 study at Mayo Hospital reported a significantly lower ROP incidence of 15% [3]. This variation can be attributed to advancements in neonatal intensive care, which have led to improved survival rates among preterm infants, as well as the implementation of enhanced screening protocols and diagnostic tools that have facilitated earlier detection of retinopathy of prematurity Shifa Hospital and Aga Khan University reported lower ROP incidences of 3.2% and 11.2%, respectively [17, 18], reflecting advancements in neonatal care, better NICU practices, and controlled oxygen therapy [19].

Comparative international data suggests that the incidence of retinopathy of prematurity varies significantly between developed and developing regions. Studies from Iran (23.5%) and North India (18.18%) align with our findings, whereas a Chinese study found 13.99% incidence of ROP requiring treatment [20,21,22]. Developed countries like Poland (6.1%) and North America (6%), [23, 24] reported lower rates, likely due to advanced neonatal care and improved screening and treatment modalities which contribute to better management and prevention of ROP.

Regarding screening practices, we found that 29.2% of infants with Type 1 ROP would have been missed if only international screening criteria (group 1) underscoring the need for region-specific guidelines. Supporting this, a 2017–2019 study at our centre reported that international criteria would have missed 4 (7.8%) of ROP-blind children [6], while a 2019 study in Lahore found that international criteria would have missed 4 (19%) infants based on GA and 2 (9%) based on BW [16]. Similarly, a 2016 study at our centre identified 4 infants > 32 weeks and 1 infant > 1500 g [3]. In contrast, a Karachi study (2010–2012) reported no cases falling outside UK screening guidelines established in 2008 [2]. These studies combined with our results indicate a concerning trend of bigger and more mature babies in Pakistan developing sight-threatening ROP.

The global third ROP epidemic disproportionately affects lower and lower-middle-income countries like Pakistan due to increasing preterm survival, unregulated oxygen use, lack of ROP awareness, and poor follow-up [25]. The number of infants missed by international screening criteria is concerning. In these conditions, the need for an ROP screening guideline is paramount. While screening thresholds are being lowered globally (e.g., US: 30 weeks/1500 g in 2013, UK: 32 weeks in 2022 from 32 weeks/1500 g), our findings support broadening these parameters in our region [26]. Regional variation in criteria has been recommended, as low-income regions often find ROP in older, heavier babies. Sub optimal neonatal care services may be responsible for this disparity, as it has been consistently noted that countries lower on the human development index require guidelines more extensive than the standard 32 weeks and 1500 g and require extensive studies and data to fine tune these guidelines to suit their populations needs [27]. This is why the Ophthalmological Society of Pakistan (OSP, December 2019) recommends screening at ≤ 35 weeks or ≤ 2000 g, which our findings support [6].

We found zones of ROP to be significantly associated with GA, BW and treatment modalities. Larger and heavier infants (> 2000 g, > 35 weeks) commonly presented with zone 2 ROP, requiring laser therapy, while smaller, younger infants (< 32 weeks, < 15000 g or 1500-2000 g) were more likely to have zone 1 disease, treated initially with anti-VEGF. Other studies also found higher birth weight and age leading to zone 2 ROP and laser therapy and zone 1 disease got anti-VEGF [22, 23]. Real world data reports that Anti-VEGF is preferred for zone 1 ROP and zone 2 posterior disease, while laser is better for zone 2 ROP [28]. Although studies such as the BEAT-ROP have found anti-VEGF treatment to be more effective in zone 1 than zone 2 ROP, we found no significant difference in disease regression after initial anti-VEGF in both zones [9]. Two-thirds of zone 1 ROP and three-fourth of zone 2 ROP babies initially treated with anti-VEGF failed to achieve disease regression and required laser treatment on follow up. No significant difference between the two groups was noted.

Importantly, 68.6% of babies treated initially with anti-VEGF required additional laser therapy, while all babies treated with laser alone achieved disease regression. This mirrors findings from other studies [29] and underscores the necessity of robust follow-up programs for anti-VEGF-treated ROP.

Overall, it is very encouraging that all of the babies treated for type 1 ROP in our centre managed to achieve disease regression. The main strength of this study is that we studied a large population compared to previous studies, offering important insights into ROP incidence and evaluation of screening practices.

Our study has several limitations, Firstly, the relatively small sample size of 89 participants limits the generalizability of our findings. The single-centre design introduces potential selection bias, restricting the applicability of our findings to other settings with different neonatal care practices and screening protocols. The short follow up duration may have been insufficient to fully evaluate the long-term implications and sustainability of the treatment modalities examined. We observed a low regression rate with anti-VEGF injections. It is important to note that we used ranibizumab in our study, which, according to network meta-analyses, has lower single-treatment effectiveness compared to other anti-VEGF agents [30]. Other factors, such as unblended oxygen causing more severe and atypical A-ROP strains that standard anti-VEGF doses cannot manage, may also contribute [28]. Further research is needed to explore the causes of these low regression rates in our population.