Retinopathy of Prematurity

Introduction

Retinopathy of prematurity (ROP) is a disease affecting the retina of premature infants. It is a very common cause of reduced vision in the developed world. ROP is characterized by neovascularization of the immature infant retina. The spectrum of ROP outcomes varies from the most minimal sequelae without affecting vision to bilateral, irreversible, total blindness. Improving neonatal care has resulted in improved survival rates of the smallest premature infants, who are at the greatest risk for ROP. ROP was first identified by Terry in 1942. He termed the condition retrolental fibroplasia. Serial examination of premature infants led to the revelation that the condition develops after birth. The term ROP was coined by Heath in 1951. ROP soon became the largest cause of childhood blindness in the developed world and exceeded all other causes of childhood blindness in the United States.

The incidence varies with birth weight but is reported in approximately 50% to 70% of infants whose weight is less than 1250 g at birth. Fielder studied infants weighing less than 1700 g and noted development of ROP in 51%. In general, more than 50% of premature infants weighing less than 1250 g at birth show evidence of ROP, and about 10% of the infants develop stage 3 ROP. Significant ROP rarely develops after 30 weeks’ postmenstrual age.

The median age of onset of ROP is at 35 weeks’ (range, 31–40 weeks’) postmenstrual age. Risk factors for development of threshold ROP include preeclampsia, birth weight, pulmonary hemorrhage, duration of ventilation, and duration of continuous positive airway pressure.

An observational study compared the characteristics of infants with severe ROP in countries with low, moderate, and high levels of development and found that the mean birth weight of infants from highly developed countries was 737 to 763 g compared with 903 to 1527 g in less-developed countries. The mean gestational ages of infants from highly developed countries were 25.3 to 25.6 weeks compared with 26.3 to 33.5 weeks in less-developed countries. Thus larger and more mature infants develop severe ROP in less-developed nations. This suggests that individual countries need to develop their own screening programs with criteria suited to their local population.

As early as the 1950s, high oxygen saturation was identified as the cause for development of ROP. However, as the natural history of the disease was better understood, other factors including low birth weight, gestational age, sepsis, necrotizing enterocolitis, intraventricular hemorrhage, sepsis, bronchopulmonary dysplasia, respiratory distress, and hypotension were recognized to have a role too.

Pathophysiology

Retinal blood vessels develop through vasculogenesis at the optic nerve opening in the sclera. Beginning at approximately 15 weeks’ gestation and continuing through 22 weeks’ gestation, these precursor cells become angioblasts and form a vascular network in the inner retina extending from the optic nerve. After 22 weeks’ gestation, additional development of the retinal vasculature occurs through budding angiogenesis. Astrocytes sense physiologic hypoxia and up-regulate vascular endothelial growth factor (VEGF). Endothelial cells proliferate and migrate along the gradient of VEGF and thereby extend the inner vascular plexus toward the peripheral retina. Besides astrocytes, glial cells, Müller cells, and neurons such as ganglion cells are also important. Of the many factors involved in retinal vascular development, VEGF is essential.

Normal retinal blood vessel development in humans commences at the optic nerve at approximately 15 to 16 weeks’ gestation, proceeding in a centripetal manner at about 0.1 mm/day. The nasal retina is completely vascularized by about 36 weeks’ postmenstrual age, whereas the temporal retina is completed near term.

The development of ROP has two phases, obliterative and vasoproliferative ( Fig. 62.1 ). The first phase of ROP (obliterative) occurs from birth to a postmenstrual age of approximately 30 to 32 weeks. During this phase retinal vascular growth slows, along with some regression of retinal vessels. The relative hyperoxia of the extrauterine environment and supplemental oxygen are thought to be responsible for this process. Normally in utero, the blood is only approximately 70% saturated compared with 100% in full-term infants on room air. Pa o ₂ in utero is 30 mm Hg, whereas a normal infant breathing room air will have a Pa o ₂ of 60 to 100 mm Hg. The relative hyperoxia results in down-regulation of VEGF and other factors, leading to cessation or regression of vasculogenesis. The inner retinal blood vessels are vulnerable to injury and may be obliterated by stressors including excessive oxygen supply, decreased VEGF, and the scarcity in cytoprotective factors, notably insulinlike growth factor (IGF).

As the child ages the relatively avascular retina becomes increasingly hypoxic due to an increased metabolic demand of the developing retina. This sets the stage for the second phase (vasoproliferative) of ROP. This phase begins ophthalmoscopically at approximately 32 to 34 weeks’ postmenstrual age. The relative hypoxia increases expression of VEGF and blood vessel growth. New but abnormal vessels form at the junction between the vascularized retina and the avascular zone of the retina. These vessels may, weeks later, produce a fibrous scar on the surface of the retina. Contraction of the scar tissue can in some cases produce a retinal detachment and blindness, while in others it can involute.

Role of Growth Hormone and IGF-1 in ROP

Biochemical mediators in addition to VEGF are likely involved in ROP. Inhibition of VEGF does not completely halt development of hypoxia-induced retinal neovascularization. Even with much improved management of supplemental oxygen, the disease persists.

IGF-1 is important to normal development of retinal vessels. Reduced IGF-1 is associated with lack of vascular growth and subsequent proliferative ROP. IGF-1 controls maximum VEGF activation of an endothelial cell survival pathway. Low postnatal serum levels of IGF-1 are directly correlated with the severity of clinical ROP.

A hypothesis for retinal vessel development and ROP has emerged. Retinal vessel growth requires both IGF-1 and VEGF. In premature infants, IGF-1, which is normally supplied by the placenta and the amniotic fluid, is at very low levels after birth because the infant cannot replace the loss. Retinal vessel growth slows or stops because IGF-1 is required for VEGF to promote vascular endothelial growth. When supplemental oxygen is provided after birth, VEGF is also suppressed. Thus prematurity and oxygen administration contribute to the suppression of vessel growth and vessel loss. As the infant grows and the retina begins to mature without an adequate supply of oxygen, hypoxia develops, which induces increased expression of VEGF. In addition, the infant’s liver begins to produce IGF-1, allowing the elevated levels of VEGF to stimulate blood vessel growth.

Other Factors With Possible Roles in Pathogenesis of ROP