In this large Malaysian multicentre study of VLBW neonates of gestation <32 wk, 90.5% of survivors were screened, 16.1% had ROP, and 2.9% had severe ROP. Screening rates varied widely among NICUs. The bigger and more mature neonates had higher rate of missed screening, like study elsewhere [13].

The incidences of all stage ROP and severe ROP in Malaysian NICUs were lower than those reported in Turkey (16.1% vs. 42.0% and 2.1% vs. 11.1%) [14], Sweden (16.1% vs. 41.1%, 2.1% vs. 20.3%) [15], and Taiwan (16,1% vs. 42.5%) [16]. However, severe ROP were much more common in EPT and ELBW neonates in Malaysian NICUs than those in Australian-New Zealand network (37.7% vs. 9.6%) [4].

Besides neonatal demographic characteristics, and duration of oxygen therapy, the role of sepsis, various treatment procedures, and clinical conditions commonly causing fluctuation of oxygenation as potential risk factors associated with ROP were investigated in the present study. This is because both prolonged duration of oxygen therapy and conditions causing fluctuation of oxygenation were found to be significant risk factors in animal studies [17,18,19]. These factors were found to promote initial compromised retinal physiologic vascularity and delayed development during the first few weeks of life, and subsequent vaso-proliferation. In the present study, the results of multiple regression analysis confirmed these findings.

Unlike study elsewhere [20], PDA was only of borderline significance. Like studies elsewhere, decreasing gestational age, decreasing birthweight [2,3,4], vaginal delivery [21], TPN [16], LOS [22], IVH [23], and BPD [17] were significant independent factors associated with increased risk of ROP in present cohort. Greater fluctuation of oxygenation could be a possible mechanism for increasing risk of ROP during vaginal delivery than during LSCS.

The present study is the first to report on the effect of oxygen therapy during resuscitation at birth on ROP, and found this brief exposure was associated with significantly lower risk. The risk of ROP was significantly higher only in those receiving prolonged oxygen therapy ≥4 wk in neonates with BPD, as reported previously [16]. Unlike a large Korean neonatal network study [24], which reported mechanical ventilation longer than 2 wk was significant risk factor associated with severe ROP, the present study found ROP risk increased significantly even with shorter duration of >5 d.

Although univariate analysis in this study showed neonates with ROP had higher rates of exposure to endotracheal intubation at birth, multiple logistic regression analysis did not show statistical significance. One possible explanation was shorter duration of fluctuation of oxygenation associated with endotracheal intubation did not pose significant risk.

Both animal and clinical studies reported sepsis-associated inflammation possibly played an important role in ROP [25]. In the present study only LOS, but not EOS, was a significant independent factor associated with increased risk. One possible explanation for this discrepancy could be the small number of neonates with EOS in the present cohort which was under-powered to detect its role on ROP.

Contrary to reports elsewhere [16], SGA was not a significant independent risk factor associated with ROP in the present cohort. The authors found Indian Malaysians had significantly higher risk, and Malaysians of other ethnicity had significantly lower risk of ROP than Chinese and Malay Malaysians. These differences could be due to genetic variants, as extremely preterm neonates with variants in the intronic region of the brain-derived neurotrophic factor (BDNF) had significantly higher risk associated with ROP and severe ROP [26, 27].

Studies elsewhere reported VLBW neonates of <32 wk gestation given fish-oil-rich lipids in TPN had significantly lower risk of ROP than those given soy-based lipid in TPN [28, 29]. In the present study, TPN was a significant independent factor associated with increased risk of ROP. As the MNNR database did not capture information on types of lipids used in TPN, the authors were unsure whether failure to use fish-oil based TPN was an explanation for TPN being a factor associated with increased risk of ROP in Malaysian neonates.

The following are the strengths of this study: it is a large sample-sized multicentre national study from a LMIC; a standardised format was used to collect the data prospectively; and >90% of VLBW/<32-wk-gestation livebirths in Malaysia were admitted to the 44 participating centres during this period.

The main limitations of this study were its inability to report on the roles of other potential risk associated with ROP (including total duration of oxygen therapy, neonatal anemia [30], blood transfusion), reasons for no screening in some neonates, and information on the zone status of ROP in the affected eyes. The MNNR did not include these variables in its database.

The principal new findings in this study are short duration of oxygen exposure at birth is associated with reduced risk, while prolonged duration of exposure to oxygen, invasive respiratory support and fluctuation of oxygenation are associated with increased risk of ROP.

Based on the findings of this study, the ROP screening rates of EPT and ELBW neonates in Malaysian NICUs need further improvement as these neonates have the highest incidence and risk of severe ROP. Avoidance of vaginal delivery, use of oxygen therapy for resuscitation at birth, reduction of duration of mechanical ventilation and HFV, use of fish-oil-based lipids in TPN, and prevention of LOS, IVH and BPD are strategies which may reduce the incidence and severity of ROP in these high-risk neonates.