Vascular changes on fluorescein angiography of premature infants with low risk of retinopathy of prematurity after high oxygen exposure

Immature retinas are especially susceptible to damage during development. When compared to adults, choroidal flow is almost absent and retinal blood flow has a narrow flow range that must be strictly auto-regulated. Moreover, retinas in neonates are rich in mitochondria; capable of producing high amounts of reactive oxygen species, which cannot be counterbalanced by antioxidants in utero. Consequently, excessive supplemental oxygen, a high fluctuation of oxygen saturation in the retina (hypoxia-hyperoxia) and a strictly choroidal blood flow, have a crucial role in the pathogenesis of proliferative vascular diseases in premature newborns [12–17].

In our country most of the Neonatal Intensive Care Units do not count with blenders that allow continuing oxygen regulation when hospitalized or discharged for parental control of oxygen intake. Consequently, we do not have a record that states the level of oxygen received at any time during the day over the time-lapse that oxygen is administered. Recently, an important publication from our country stated that uncontrolled oxygen supplementation is the major risk for ROP requiring treatment for infants born 32 weeks of GA, and that its regulation diminished the frequency of treatment for ROP [18]. This is the importance of our paper, that positions that there are clear angiographic differences among those with low-risk for developing ROP from regular risk ROP patients; findings that support that there must be a different etiology for the development of the retinopathy, which is still needed to be confirmed with histology and molecular studies.

In middle-income countries, neonatal survival has been increasing in later years. Which brings as a consequence, an increase in neonatal care-related pathologies, including ROP [19]. Standard of care in neonatal intensive care units (oxygen not well regulated), surveillance guidelines and treatment can vary widely in these countries; which leads to increase in ROP-like disease events, even in heavier and more mature babies, not typically considered at risk for ROP in developed countries. Zepeda-Romero et al. reported a case of a newborn of 1280 g birth weight who presented arteriovenous shunts capillary loss and multiple areas of non-perfusion; similar to the cases described herein. In this case series, we describe the peripheral vascular abnormalities of 28 eye belonging to 14 neonates with no medical history of extreme prematurity or very low birth weight, but who have been exposed to unmonitored high concentration of oxygen for variable periods of time [20]. All eyes developed vascular abnormalities, similar to those described as typical ROP but with distinctive differences like venous beading, tortuosity and dilation of major retinal vessels and capillaries (“plus-like” disease), arteriovenous shunting, areas of capillary closure, abnormal capillary tufts, microaneurysms, patches (“islands”) of leaking vessels. An additional finding is the absence of avascular foveal zone which has been reported by Henaine et al. [21] in 50% of patients born at 36 weeks of gestational age or more.

In patients with ROP, newly formed vessels are not fully mature, resulting in areas of non-perfusion. Although this vascular abnormality is not usually seen in patients with more mature retinas, it is a key component of murine models of ROP known as OIR [13, 14, 16, 17].

The hallmark of ROP stage 1 is a visible flat demarcation line between vascular and avascular peripheral retina [22]. In our case series, patients classified as having vascular abnormalities belonging to group 1, also had a flat demarcation line. But, unlike ROP, a clear capillary-free area, posterior to the demarcation line, can also be observed. This capillary-free zone also shows arteriovenous shunting among primary vessels, not typically seen in ROP stage 1. Additionally, patients with ROP stage 1 show perivascular leakage of dye during FA; a characteristic not found in patient classified as group 1 in this case series. The authors speculate that this phenomenon could be explained because in neonates with ROP, the cellular junctions in immature retinal vessels are still developing and the vessels are still not fully supported by pericytes (Fig. 5). Therefore, leakage could be observed. On the contrary, neonates in group 1 had no clear history of extreme prematurity, which make highly probable that they had more developed retinas with more mature vessels, already fully supported by pericytes which do not allowed leakage. Obliteration of previously formed retinal vessels, resulting in extensive areas of capillary drop-out could also be observed in patients from group 1.

Stage 2 ROP is characterized by an elevated ridge at the demarcation line which subtly leaks fluorescein at the forming ridge. In our series, patients in group 1 who presented a ridge, also presented leakage but to a lesser degree, possibly indicating more mature vessels. Vascular abnormalities beyond the posterior limit of the ridge are not classically observed in stage 2 ROP [23]. To our knowledge, there is only one report of vascular tufts posterior to the ridge adjacent to retinal hypoperfusion areas. In our series, patients typically shown aneurysm or tufts in an “island” pattern within normal-looking retina, far posterior to the demarcation line and ridge. Conversely to ROP cases, patients within group 1 could also show a marked boundary, easily distinguishable between vascular and avascular areas of the retina and areas of capillary non-perfusion. The demarcation line had a “dentate” pattern (deep bays) within an irregular ridge.

In stage 3 ROP, neovascularization appears at the ridge. In our series, patients classified as group 2 or proliferative cases, also had neovascularization at the optic disc. This feature is very uncommon in ROP. Finally, the most aggressive cases in group 2 also shown a “4-lobe” vascular topography, similarly to cases with Aggressive posterior retinopathy of prematurity (APROP) [24].