Retinopathy of prematurity

INTRODUCTION

Retinopathy of prematurity (ROP) is a proliferative disorder of the developing retina that continues to be a major cause of blindness in children.

DISEASE PREVALENCE AND INFLUENCE

In the USA, it is among the most prominent causes of blindness in children under 3 years of age.1 It is estimated that 24% of LatinAmerican children with blindness have ROP.2

RISK FACTORS

The main recognized risk factors for developing ROP include birth weight of 1500 g or less (especially of 1250 g or less), gestational age of 32 weeks or less, and prolonged exposure to high concentrations of oxygen after birth.3

for normal peripheral retinal vascularization, which is commonly almost completed at term.

ABNORMAL RETINAL VASCULARIZATION IN ROP

When a newborn is born preterm, normal peripheral retinal vascularization is usually not yet completed. During increased oxygen exposure (such as when the newborn is under oxygen therapy), the nonvascularized retina becomes hyperoxic, which in turn decreases VEGF production, and normal peripheral retinal vascularization is arrested (stage 1 ROP). When returning to normal oxygen exposure, the nonvascularized retina becomes hypoxic. Hypoxia may then induce increased production of VEGF and degeneration of retinal astrocytes. At this point, a ridge, composed primarily of immature astrocytes, is formed (stage 2 ROP). Astroctye degeneration allows passage of VEGF to the vitreous humor. The abnormally increased levels of VEGF (which are maximally elevated in the border between vascular and avascular retina) promote new vessel formation (stage 3 ROP). These new vessels may bleed, causing vitreous hemorrhage, or may contract, causing partial (stage 4 ROP) or total (stage 5 ROP) retinal detachment. Increased VEGF levels may also induce dilatation or tortuosity in normal retinal vessels (“plus” disease).

ETIOLOGY/PATHOGENESIS

NORMAL RETINAL VASCULAR

DEVELOPMENT IN HUMANS

Retinal vascular development in humans occurs in two phases, mediated by two different mechanisms.4,5 The first phase depends on a mechanism known as vasculogenesis, and implies de novo blood vessel formation from endothelial precursor cells. It occurs at week 14–15 of gestational age and begins with the growth of spindle-shaped cells from the optic nerve. These spindle cells migrate towards the periphery, following the tracts of the future retinal vascular arcades, and form primitive vascular tubes. It is believed that the development of these primitive vascular tubes is independent of vascular endothelial growth factor (VEGF). It has also been suggested that alterations in vasculogenesis lead to zone I ROP, a more aggressive clinical course, and worse prognosis.6

The second phase of normal retinal vascular development relies on a process known as angiogenesis, which consists of the formation of new blood vessels that originate in previously existing blood vessels. It begins at week 17–18 of gestational age, and features new vessels and capillary networks that form in the perifoveal area and in the leading edge of peripheral retinal vascularization. This second phase is dependent on the production of VEGF by the nonvascularized retina (especially by Müller cells and astrocytes). In utero, the nonvascularized retina is in a state of relative hypoxia, which causes a delayed turnover of intracellular hypoxia-inducible factor-1, which in turn increases the transcription of VEGF mRNA, and increased VEGF production. These “physiologically increased” levels of VEGF are the main drive

ROLE OF GROWTH FACTORS IN ROP

The importance of increased levels of VEGF in the pathogenesis of retinal neovascularization has been corroborated in several animal models which simulate the fluctuating oxygen conditions present in patients with ROP.7–10

Increased levels of VEGF in the ocular fluids of human newborns with ROP have been found in two studies. The first study, by Sonmez et al.,11 measured vitreous levels of VEGF in patients with vascularly active (n = 12) and vascularly inactive (n = 10) stage 4 ROP that underwent vitrectomy, and compared the levels with vitreous samples (n = 5) obtained from controls (vitreous from patients that underwent surgery for congenital cataract), and found a median concentration of 3454 pg/ml (range, 774–8882 pg/ml), 316 pg/ml (range, 105–665 pg/ ml), and 59 pg/ml (range, 38–135 pg/ml), respectively (P < 0.001).

The second study, performed by our group,12 measured VEGF levels in the aqueous humor and subretinal fluid of patients with stage 5 ROP that underwent open-sky vitrectomy, and compared them with VEGF levels in the aqueous of controls that underwent surgery for congenital cataract. VEGF levels in the aqueous and subretinal fluid were 85.03 ± 61.42 pg/ml and 1600.63 ± 355.14 pg/ml respectively, while VEGF levels in the aqueous of controls were 15.15 ± 1.89 pg/ml (P < 0.005).

Insulin-like growth factor-1 (IGF-1) has also been implicated in the pathogenesis of ROP. IGF-1 is thought to play a permissive role for VEGF-induced normal peripheral retinal vascular development. Lack of IGF-1 in preterm infants has been shown to prevent normal retinal vascular growth in stage 1 ROP, despite the presence of VEGF. As newborns mature, increasing levels of IGF-1 in later stages of ROP allow VEGF-stimulated pathological neovascularization.13,14

Prolactin peptides have also been studied in patients with ROP.15 A 16-kDa fragment of prolactin (16K-PRL), which has antiangiogenic