KEY POINTS
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Retinopathy of prematurity (ROP) is a disease characterized by altered vascularization of the immature retina of premature infants and is common cause of reduced vision in the developed world.
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The first, obliterative phase of ROP occurs from birth to a postmenstrual age of about 30 to 32 weeks and is characterized by suppressed growth/obliteration of retinal vessels due to relative hyperoxia.
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The second, vasoproliferative phase of ROP begins at approximately 32 to 34 weeks’ postmenstrual age with altered blood vessel growth at the junction of the vascularized and the avascular zones of the retina.
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The International Classification of Retinopathy of Prematurity (ICROP) is a standard way to describe ROP based on extent and severity.
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The management of ROP is focused on three components: prevention, interdiction, and correction. Each component is a subject of intense preclinical, translational, and clinical study.
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Current management of ROP is based on the ablation of the avascular zones by cryotherapy or laser photocoagulation. Ongoing studies are evaluating the use of antibodies to suppress the effects of biologic mediators such as vascular endothelial growth factors (VEGF). Once ROP has progressed to stage 4 or beyond, vitreoretinal surgery is the only option.
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
Hypoxia-Induced Factor 1
During fetal development, low oxygen concentrations increase local hypoxia-induced factor (HIF)–1α and VEGF levels, which promote normal vascularization. Exposure to relative hyperoxia after premature birth suppresses HIF‐1α levels, thus reducing VEGF expression and reducing the number of retinal capillaries. As HIF‐1 increases, vasoproliferation ensues.
Erythropoeitin
The administration of erythropoeitin prevents the loss of retinal vasculature in the obliterative stage. In contrast, treatment during the vasoproliferative stage might exacerbate the disease by promoting endothelial cell proliferation.
Genetics
Although ROP has the same incidence rates in White and African American populations, the progression to severe stages is more common in White than in African American infants and in males than in females. There is an increased frequency of polymorphisms of β‐adrenoreceptors (β‐ARs) in Black compared with Caucasian infants. Several gene variants such as those of the Wnt pathway (frizzled 4, lipoprotein-related receptor-related protein 5, and Norrie disease protein) have been implicated.
Oxidative Stress
The premature retina is relatively deficient in antioxidants. Consequently, oxidative stress may induce peroxidation, damaging the retinal microvasculature and leading to vaso-obliteration.
Adrenergic Receptors
Angiogenesis is controlled by the adrenergic system through its regulation of proangiogenic factors. β‐ARs are widely expressed in vascular endothelial cells, and β‐adrenoreceptors (β‐ARs) can regulate angiogenesis in response to ischemia. β‐AR up‐regulates VEGF, thereby promoting the vasoproliferative phase of ROP. β‐blockers might represent useful drugs in the treatment of ROP.
Adenosine and Apelin
These agents have been found to regulate vasculogenesis of the developing retina. In animal models, these chemicals are found in low concentrations in the vaso-obliterative phase and are increased in the proliferative phase of ROP.
Omega 3 Lipids
Notably, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have been found to exert a number of beneficial biologic properties such as cytoprotection of neural tissue, decreased oxidant stress, and decreased inflammation. , Premature newborns are relatively deficient in omega-3 lipids, and supplementation with DHA and EPA has been found to improve visual acuity.
Clinical Features of ROP
The International Classification of Retinopathy of Prematurity (ICROP) is a standardized way to describe ROP. , The key aspects of the classification include (1) the location of retinal involvement by zone, (2) the extent of retinal involvement by clock hour, (3) the stage of retinopathy at the junction of the vascularized and avascular retina, and (4) the presence or absence of dilated and tortuous posterior pole vessels, termed plus disease ( Fig. 62.2 ).
Stages
There are five stages of acute ROP. The stage of disease represents the changes seen at the vascular-avascular junction in the retina. In an eye, the stage often differs in different portions of the retina. The retina is subdivided into zones and clock hours (discussed below). The patient is described by the most advanced stage that occurs in at least one clock hour of the retina.
Stage 0
No active disease is seen; the vascularized retina blends seamlessly into the avascular retina. Some vascular changes can be apparent prior to the development of ROP, such as dilatation of the vessels or vessels positioned in a circumferential pattern.
Stage 1: Demarcation Line
A whitish line is observed separating the vascular from the avascular retina. Abnormal branching of vessels can be seen leading up to the demarcation line, which is flat.
Stage 2: Ridge
The ridge has volume (height and width). It may be white or pink. Associated vascular abnormalities include isolated, vascular tufts at the retinal plane lying posterior to the ridge, called popcorn vessels.
Stage 3: Extraretinal Neovascularization
Neovascularization extends from the ridge on the surface of the retina into the vitreous. Typically, it has a pink color.
Stage 4: Partial Retinal Detachment
After the development of neovascularization, the vascular change can involute or develop fibrosis. The scarring causes traction on the retina toward the center of the base at the area of fibrosis. Stage 4 is subdivided into the following:
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Stage 4A: partial retinal detachment not involving the macula.
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Stage 4B: partial retinal detachment involving the macula.
Stage 5: Total Retinal Detachment
The detachment is most commonly tractional but can be exudative in nature too. It is usually funnel shaped. The most common is the open funnel, which is open both anteriorly as well as posteriorly.
When more than one ROP stage is present in an eye, staging for the eye as a whole is determined by the most severe stage identified. For purposes of recording the examination, ROP is drawn with the extent of each stage in clock hours on a drawing.
Zone
The retina is divided into three concentric zones centered on the optic disc. Zone 1 (the innermost zone) consists of the most posterior retina limited by a circle. The radius of the circle extends from the center of the optic disc to twice the estimated distance from the optic disc to the macula. This is closely approximated by the field of view using a 28 D indirect ophthalmoscopy lens. Zone 2 extends from the edge of zone 1 nasally to the ora serrata. Zone 3 is the crescent of the temporal retina anterior to zone 2. Zones 2 and 3 are mutually exclusive. By convention, ROP should be considered to be in zone 2 until it is determined that the nasal-most two clock hours are vascularized to the ora serrata. ,
Extent of Disease: Clock Hours
The extent of each stage of disease is recorded for a total of 12 clock hours (or as 30° sectors). These can be contiguous or not contiguous. For instance, when the disease is not contiguous, the hours of stage 3 may be added together, with the total termed “cumulative” (e.g., four cumulative clock hours of stage 3). In general, for the same number of clock hours, contiguous disease is considered more severe than noncontiguous disease.
Plus Disease
Plus disease describes venous dilation and arteriolar tortuosity of the posterior retinal vessels in at least two quadrants. A + symbol is added to the ROP stage to designate plus disease. For example, stage 2 ROP with plus would be written as stage 2+ ROP.
Preplus Disease
A recent version of the ICROP defined preplus disease as vascular abnormalities of the posterior pole insufficient for the diagnosis of plus disease but having more arterial tortuosity and venous dilatation than normal. Preplus disease may progress to plus disease or regress.
Aggressive-Posterior ROP
Aggressive-posterior ROP (AP-ROP) is an uncommon, rapidly progressing form of ROP that is posterior with prominent plus and poorly defined disease. This rapidly progressing retinopathy has been referred to previously as “Rush disease.” AP-ROP is observed most commonly in zone 1 but may occur in posterior zone 2. AP-ROP does not progress through the classic stages 1 to 3, instead reaching stage 3 very rapidly.
Regression of ROP
Most ROP regresses or involutes spontaneously. However, this is determined retrospectively. One of the first signs of involution of acute-phase ROP is failure to progress to the next stage during serial visits or a change to a more peripheral zone. In some cases the regression is accompanied by fibrosis of the areas of preretinal neovascularization. This scar may produce traction on the retina, varying from minor distortions of foveal architecture to dragging the retina peripherally, usually temporally, producing macular ectopia and pulling the superior and inferior retinal vascular arcades toward the horizontal meridian. This often causes some visual loss. Finally, axial traction on the retina can produce a traction or rhegmatogenous retinal detachment.
Management
Management of ROP includes three components: (1) prevention, (2) interdiction, and (3) correction. Prevention of ROP is the most effective, and the best preventive measure is to reduce preterm births through comprehensive prenatal and obstetric care. Additional methods aimed at the prevention of ROP include vitamin E supplementation, ambient light reduction, oxygen supplementation, and inositol supplementation. It was hoped that vitamin E supplementation would mitigate the effects of free-radical damage caused by hyperoxia. However, studies had contradictory results, and supplementation is standard. , Excessive visible light is also associated with free-radical generation and possibly increases the chances of ROP. However, the LIGHT-ROP study, a randomized, multicenter trial of light reduction with goggles worn by very low birth weight premature infants, did not demonstrate any effect of light reduction on the incidence of ROP.
STOP-ROP was a multicenter trial conducted to determine whether supplemental oxygen would decrease the progression to threshold ROP when administered to infants with prethreshold ROP, reducing the hypoxic drive for neovascularization. Infants with prethreshold ROP were randomized to a conventional oxygen arm with pulse oximetry targeted at 89% to 94% saturation or an oxygen supplemental arm with pulse oximetry targeted at 96% to 99% saturation. The study found no benefit to increasing the oxygen. In fact, supplemental oxygen increased the risk of adverse pulmonary events including pneumonia and/or exacerbations of chronic lung disease and the need for oxygen, diuretics, and hospitalization at 3 months’ corrected age.
A randomized controlled trial was conducted to determine the efficacy and safety of myo-inositol to reduce type 1 ROP among infants younger than 28 weeks’ gestational age. Treatment with myo-inositol for up to 10 weeks did not reduce the risk of type 1 ROP or death compared with placebo.
For the past 10 years there has been interest in reducing the oxygen levels of babies to reduce the rate of ROP while not increasing the mortality rate. The SUPPORT Study Group conducted a trial for children requiring supplemental oxygen to determine if a more hypoxic target range of 85% to 89% was better than the commonly used 91% to 95%. The primary outcome, a composite of death and ROP, was not different; however, the lower range was associated with greater mortality and less severe ROP, whereas the higher range showed the opposite.
Screening for ROP
ROP screening programs are established to identify infants who need treatment and to ensure follow-up upon neonatal intensive care unit discharge/transfer. Because undiagnosed or treatment-delayed ROP may lead to blindness, it is important that all infants at risk be screened. Current consensus guidelines recommend that timing be scheduled based on the gestational age of the infant and that the follow-up be determined by the severity of the ROP. The American Academy of Pediatrics guidelines recommend ROP screening for
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all infants with a birth weight of ≤1500 g or a gestational age of 30 weeks or less (as defined by the attending neonatologist) and
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infants with a birth weight between 1500 and 2000 g or a gestational age >30 weeks who are believed to be at risk for ROP (such as infants with hypotension requiring inotropic support, infants who received oxygen supplementation for more than a few days, or infants who received oxygen without saturation monitoring).
The screening should be performed by a trained ophthalmologist with pupillary dilation of the infant using binocular indirect ophthalmoscopy and scleral depression. Pupillary dilatation can be achieved with 1.0% phenylephrine hydrochloride and 0.5% cyclopentolate or tropicamide 1.0%, instilled twice after a gap of 5 to 15 minutes, taking care to wipe off the excess drops from the medial canthi to decrease the systemic absorption of these drugs. Multiple doses can adversely affect the cardiorespiratory and gastrointestinal status of the infant. Sterile instruments should be used to examine each infant.
The use of wide-angle retinal photography in the nursery, which captures images that can be transmitted electronically and read remotely, may improve the availability of screening in the community and may be used for improved documentation. , Digital retinal photography, when quality images can be obtained, has high accuracy for detection of clinically significant ROP. Remote grading has excellent inter- and intragrader agreement and would be one objective way to standardize ROP protocols, guidelines, and care delivery. ,
The results of the examinations and imaging should be available for the nursery team and, as appropriate, communicated with the parents of the infant.
Timing of Screening
The initial screening should be performed based on postmenstrual age, rather than postnatal age. This reduces the examinations for the youngest babies during a period when there is no risk of serious ROP. Table 62.1 follows current consensus screening guidelines.
