ROP is a bimodal disease that has been linked to excessive oxygen exposure since the early 1950s [1]. An initial phase of vessel loss (vasoobliteration) is followed by a second phase of abnormal new vessel proliferation [2]. Initially discovered as a permeability factor, VEGF was later shown to induce endothelial cell mitosis [3]. VEGF mRNA has been shown to increase with hypoxia and pathologic retinal neovascularization [3–6]. It is now understood that hyperoxia stops normal angiogenesis, leaving an ischemic peripheral retina, which releases supranormal levels of VEGF and IGF-1, the stimuli for extraretinal and sometimes intra-retinal neovascularization [5, 7]. With this overview, the pathophysiology of the two phases of ROP can be understood.

Normal vascularization of the retina begins from the optic disk at 16 weeks gestation and radiates progressively towards the periphery (ora seratta) at 40 weeks post-conception [8]. With premature birth, the normal development of retinal vessels taking place in utero abruptly halts in the setting of relative hyperoxia. The supplemental oxygen given to premature infants leads to a decrease in VEGF levels through a negative feedback loop. The arrest of angiogenesis corresponds to a bump in oxygen saturation from 70% in utero to approximately 99% with respiration of room air. This corresponds to a rise in PaO₂ from 30 mmHg to a range between 60 and 100 mmHg. The primitive vascular bed, in response to the rise in oxygen levels, constricts in an effort to auto-regulate the oxygen. When this constriction persists for four hours or more, it may result in irreversible vasoobliteration.

Phase I ROP takes place from birth to 30 to 32 weeks post conception. As the infant matures, there is an increase in metabolic demands of the retina. High ambient oxygen and consequent vasoobliteration leave the peripheral retina devoid of adequate circulation. This peripheral non-perfused retina becomes hypoxic [2]. With increasing oxygen demand in retinal tissue devoid of circulation, a situation of ‘pathologic hypoxia’ ensues [1].

Following Phase I vessel loss, pathological neovascularization of the ischemic retina is caused by supranormal quantities of VEGF [1]. Intravitreal injection of anti-VEGF agents has been shown to significantly decrease the neovascular response [9, 10]. Within 24 h of intravitreal injection of 0.625 mg bevacizumab in ROP stage 3 plus, a reliably marked decrease in retinal neovascularization, plus disease, and vessel leakage is demonstrated on fluorescein angiography.

Phase II ROP takes place between 32 and 34 weeks post conception, driven by persistent hypoxia leading to neovascularization. To compensate for ischemia, rapid growth of new vessels occurs at the junction between the vascularized and avascular retina (see Figs. 8.4 and 8.5). Retinal hypoxia is partially compensated by these new vessels, and decreases intrinsic retinal vascular growth through negative feedback [1]. These pathological vessels eventually transform to a fibrovascular cicatrix, which extends from the retina to the vitreous gel and lens. Cicatricial contraction can separate the retina from its pigment epithelium, with ensuing retinal detachment and loss of vision [2].

Standard or Typical ROP is the most prevalent form of ROP. It typically affects small- to medium-sized preemies under 31 weeks gestation or 1250 g birth weight. Standard ROP follows the typical paradigm of the International Classification of ROP proposed by CRYO-ROP. The timing and progression from stages I to V are predictable, as is the response to ablative treatment.

Type 1 ROP or AP-ROP, is a disease of micro-preemies, who are typically born between 22 and 25 weeks gestation, or very ill older babies. Infants who experience sepsis, acidosis, and unregulated or high fluctuations in O₂ saturations have a greater risk of developing this disease. This is increasing in prevalence as neonatologists with modernized NICUs and O₂ monitoring are sustaining very low birth weight micro-preemies. However, there is also an increase in prevalence in countries that do not have sophisticated NICUs and O₂ monitoring. These populations sustain slightly larger babies that sometimes have unregulated and highly fluctuating O₂ levels that create a form of retinal toxicity. This form of ROP is unfortunately the least understood and is also potentially the most devastating.

AP-ROP is often sinister, moving unpredictably from flat neovascularization to retinal detachment in a matter of days. In the Cryo-ROP study, the majority of retinas with features of AP-ROP progressed to unfavorable structural outcomes, including: retinal detachment, macular folds, and retrolental fibroplasia. The ET-ROP and BEAT-ROP studies were a concerted effort to improve outcomes in cases of AP-ROP [11]. Figure 8.6 is an example of AP-ROP.

Characteristics of AP-ROP include

Typical ROP is a mono-phasic vasculopathy in which threshold for laser ablation occurs in some eyes reliably between 33 and 38 weeks post-conception, and the minority that progress to retinal detachment usually do so within a few weeks after the due date. Traditionally, a child who reaches 45 weeks post-conception without developing pre-threshold features is considered to be at low or no risk for retinopathy of prematurity associated retinal detachment. This concept was first proposed in the Cryo-ROP study.

Cases of ROP progressing to retinal detachment without developing plus disease or pre-threshold characteristics have been observed to occur in the past decade. These eyes have aborted vascular development and are stuck in a state of perpetual non-perfusion and retinal ischemia, otherwise known as Smoldering ROP. Retinal vascular maturation fails to develop, but there is no sufficient VEGF production to create an active shunt and major neovascular proliferation. These eyes are in a non-ending ischemic state and are at risk for developing macular dragging and late retinal detachment, much later than 50 weeks post-conception. In fact, there have been cases of teenagers developing spontaneous tractional detachments after having neonatal ROP that regressed without ablative treatment.

Some of the common characteristics of Smoldering ROP include:

Prior to the anti-VEGF era this condition was recognized; however its incidence was infrequent. It occurs more often in children with intracranial pathology such as intra-ventricular hemorrhage, microcephaly, periventricular leukomalacia, sepsis, necrotizing enterocolitis, acidosis, high output congenital heart disease, thrombocytopenia, hypoxia, and respiratory distress. Definitive treatment requires semi-confluent ablative laser to the non-perfused zones. This can be guided by fluorescein angiography.

In the anti-VEGF era, Smoldering ROP is being seen with increased frequency in cases that have received anti-VEGF treatment with regression of neovascularization and simultaneous loss of the metabolic drive for vascular development. Cases of late onset retinal detachment after anti-VEGF therapy are largely cases of Smoldering ROP with predominately fibrous proliferation. It is important to recognize this condition and perform ablative treatment when it is clear that intrinsic retinal development has failed. In our practice, a “line is drawn in the sand” at the first birthday, which usually corresponds to approximately 75 weeks post-conceptional age. By this time, if the leading edge of vessel development has not reached the ora serrata, in our experience it is unlikely to ever do so. These eyes will remain at risk for fibrous traction/smoldering ROP, potentially for the life of the patient. This risk can be eliminated by semi-confluent laser ablation of the avascular retina, which is best performed using guidance with fluorescein angiography to define zones of non-perfusion.

In 1948, Michaelson hypothesized that a diffusible angiogenic ‘factor X’ induced by hypoxia was responsible for iris and retinal neovascularization associated with ischemic retinopathies [12]. This factor was later found to be a glycoprotein vascular permeability factor (VPF) [12]. Independently, in 1989 Leung et al. isolated this same glycoprotein from pituitary follicular cells with characteristics of an endothelial mitogen, labeled vascular endothelial growth factor (VEGF) [12]. Simultaneously, Keck et al. also discovered a tumor-derived factor inducing vascular permeability, and officially named it ‘Vascular Permeability Factor’ [12]. It was proven subsequently that these factors were in fact all the same ‘factor X’ originally described by Michaelson [12].

Additional support for the ‘factor X’ concept comes from studies of primate retinas that developed neovascularization in response to laser photocoagulation [12]. A diffusible VEGF MRNA was implicated as the instigating agent [12]. Furthermore, patients with active pathologic neovascularization consistently have elevated levels of VEGF Mrna comparison to controls [12].

The CRYO-ROP study is still one of the largest ROP studies to have been done, even 30 years later. Although cryotherapy has now been replaced by newer interventions, the landmark study helped establish the framework for ROP treatment strategies and clinical studies employed today. The International Classification Staging System for ROP was used in the CRYO-ROP study as a means to classify the different stages of ROP [13].

In CRYO-ROP, 291 premature infants weighing less than 1251 g with threshold ROP, stage III+ in five contiguous or eight cumulative clock hours, were enrolled. Of these 291 infants, 254 survived [14]. At 15 years of age, unfavorable ocular structural outcomes defined as posterior retinal folding or worse were judged by study-certified ophthalmologists [14].

The fifteen year outcomes were favorable for typical ROP. In contrast, zone I disease had unfavorable outcomes in approximately 50%. This has led to alternative treatment paradigms as the Multicenter Trial of Cryotherapy of ROP reported statistically significant evidence that ablation of the peripheral nonvascularized retina of premature infants affected with ‘threshold’ ROP was safe and effective [14]. The question of stability of treatment benefit was answered by the 15-year outcome data of the CRYO-ROP study. Complications of stage III ROP occur decades after treatment, and include: retinal detachment, retinal degeneration, pigment atrophy or migration, cataract, glaucoma, band keratopathy, and hypotony. CRYO-ROP found 30% of treated eyes and 51.9% of control eyes (p < 0.001) had unfavorable structural outcomes [14]. Between 10 and 15 years of age, new retinal folds, retinal detachments, or obscuration of the view of the posterior pole occurred in 4.5% of treated and 7.7% of control eyes [14]. Unfavorable visual acuity outcomes were found in 44.7% of treated and 4.3% of control eyes (P < 0.001) [14]. CRYO-ROP concluded that near confluent cryo-obliteration may reduce progression of zone 2 threshold ROP to unfavorable structural outcomes. The near confluent treatment may also reduce the need for re-treatment [14].

ET-ROP explored the possibility of obtaining better structural outcomes by treating high-risk ‘pre-threshold’ cases of ROP as opposed to waiting until threshold, as done in CRYO-ROP. From the CRYO-ROP experience, the study criteria was developed to identify high-risk cases for early treatment with ablation. High-risk ‘pre-threshold’ cases were defined as

Based on patient data from the CRYO-ROP, the ET-ROP study defined high risk as having a ≥15% chance of an unfavorable outcome [11]. One eye was kept as a control, it was treated with ablation if threshold was reached.

The 2005 review by the original investigators demonstrated three specific advantages with the early treatment of high-risk pre-threshold ROP cases. The major finding was the reduction in unfavorable visual outcomes occured in the treatment group by 5.5% (p < 0.005) [11]. The control eyes of bilateral cases provided additional support as discordant outcomes in two eyes out of 33 infants with bilateral disease; this provided stronger evidence of the beneficial effect of treatment for at high-risk pre-threshold ROP (P < 0.005) [11]. Structural outcomes at 9 months provided additional data to support earlier treatment. The treatment group had reduced unfavorable structural outcomes from the 15.6% of conventional treatment group to 9.0%, a 6.6% difference across the groups (p < 0.001) [11].

The latest findings published in 2011 showed no statistically significant overall benefit when combining Type I and II cases (18.1 and 22.8% p = 0.08) [15]. However, high-risk Type I cases showed a benefit in early treatment compared to control (16.4 vs. 25.2% respectively, p = 0.004), and an outcome of 21.3 versus 15.9%, p = 0.29 for type II cases [15]. The latest review by the ET-ROP Cooperative Study Group recommends early treatment of Type I eyes, and Type II eyes should be followed closely and without treatment [15].

The pre-threshold types defined by ET-ROP predictably occur between 35 and 37 weeks post-conception. The neovascularization is typically extravascular and responds predictably to standard laser ablation of the avascular retina with a success rate of around 99% when timed appropriately.

The reasoning behind this aggressive stance is that it is difficult to predict which of these cases will have a fulminant course. Although following ET-ROP recommendations may lead to treating significantly more babies than actually necessary, the benefit of reducing unfavorable outcomes requires treating some patients that would have matured well without treatment. ROP is unforgiving in terms of timing, making it difficult to know which cases require treatment. Once ROP accelerates to massive fibrovascular proliferation and cicatricial contraction, the prognosis deteriorates rapidly. ET-ROP advocates ‘over treat’ some cases in order to prevent any child from losing vision. Systemic complications of early treatment in high-risk pre-threshold cases were greater than conventional including: apnea, bradycardia, and reintubation. One must also consider the ocular implications of treatment and potential secondary effects, which include