Retinopathy of Prematurity

Updated: Feb 28, 2015
  • Author: KN Siva Subramanian, MD; Chief Editor: Ted Rosenkrantz, MD  more...
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Overview

Background

Retinopathy of prematurity (ROP) is a serious vasoproliferative disorder that affects extremely premature infants. Retinopathy of prematurity often regresses or heals but can lead to severe visual impairment or blindness. Significant retinopathy of prematurity can lead to lifelong disabilities for the smallest survivors of neonatal ICUs (NICUs). It remains a serious problem despite striking advances in neonatology.

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Pathophysiology

Retinopathy of prematurity primarily occurs in extremely low birth weight (ELBW) infants. Most research suggests that a low birth weight, a young gestational age (GA; see the Gestational Age from Estimated Date of Delivery calculator), and the severity of illness (eg, respiratory distress syndrome [RDS], bronchopulmonary dysplasia [BPD], sepsis) are associated factors. Recently, other associations have been described. However, the severity of the illness appears to be a major predictor of severe disease. The smallest, sickest, and most immature infants are at the highest risk for serious disease. Black infants appear to have less severe retinopathy of prematurity. [1, 2]

Retinal vasculature begins to develop around 16 weeks' gestation. It grows circumferentially and becomes fully mature at term. Premature birth results in the cessation of normal retinal vascular maturation. Exposure of newborn premature infants to hyperoxia downregulates retinal vascular endothelial growth factor (VEGF). Blood vessels constrict and can become obliterated, resulting in delays of normal retinal vascular development. This hyperoxia-vasocessation is known as stage I of retinopathy of prematurity. See the image below.

Stage I retinopathy of prematurity. Stage I retinopathy of prematurity.

Early on, oxygen and nutrients can be delivered to the retina by means of diffusion from the underlying choroid capillary bed. The retina continues to grow in thickness and eventually outgrows its vascular supply. Over time, retinal hypoxia occurs and results in an overgrowth of vessels; this hypoxia-vasoproliferation is stage II of retinopathy of prematurity. See the image below.

Stage II retinopathy of prematurity. Stage II retinopathy of prematurity.

This process is mediated, in part, by VEGF and is affected by insulinlike growth factor-1 (IGF-1) and other cytokines. These changes in the retina result in retinopathy of prematurity.

Dhaliwal et al found that retinopathy of prematurity occurred with significantly greater frequency and severity in small-for-GA (SGA) infants compared with appropriate-for-GA (AGA) infants. [3] In a review of 1413 infants with birth weight less than 1500 g and/or GA of 26-31 weeks, infants with a birth weight below the tenth percentile for GA were more likely to develop any stage of retinopathy of prematurity than their AGA peers (p< 0.01) and were more likely to develop severe retinopathy of prematurity (GA of 26-27 weeks, p< 0.01; GA of 28-31 weeks, p = 0.01).

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Epidemiology

Frequency

United States

The incidence varies with birth weight but is reported to be approximately 50-70% in infants whose weight is less than 1250 g at birth.

Hussain et al reviewed the incidence and the need for surgery in neonates with retinopathy of prematurity who were born at 22-36 weeks' gestation between July 1989 and June 30, 1997. [4] The incidences were 21.3% (202 of 950 patients) for retinopathy of prematurity of any stage and 4.6% (44 of 950 patients) for retinopathy of prematurity at stage III or worse. No retinopathy of prematurity was noted in infants born after 32 weeks' gestation. No infant born after 28 weeks' gestation needed retinal surgery in this study. Despite the increased survival of ELBW infants, they found a considerable reduction in the incidence and severity of retinopathy of prematurity compared with reports from an earlier period. However, infants born before 28 weeks' gestation and those with birth weights less than 1000 g were at risk to need retinal surgical treatment for retinopathy of prematurity.

Investigators from the Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOP-ROP) multicenter trial concluded that maintaining oxygen saturation in the high-90% range did not reduce the severity of the retinopathy when compared with the saturations in the low-90% range. [5] However, it did result in more adverse pulmonary events. In a subanalysis of infants who did not have plus disease (ie, tortuosity of vessels) at the time of study entry, the progression to threshold was significantly decreased when compared with the progression in infants with plus disease. Thus, a critical window for oxygen administration may be determined.

International

Retinopathy of prematurity is prevalent worldwide and several reports have detailed the incidence and risk factors associated with the disease.

A Korean study reported a 20.7% incidence (88 of 425 premature babies) and reported that a GA of 28 weeks or less and a birth weight of 1000 g or less were the most significant risk factors. [6] Another study from Singapore reported a 29.2% incidence (165 of 564 ELBW infants). [7] The median age of onset of retinopathy of prematurity was 35 weeks (range, 31-40 wk) postmenstrual age. The risk factors for development of threshold retinopathy of prematurity by regression analysis were maternal preeclampsia, birth weight, pulmonary hemorrhage, duration of ventilation, and duration of continuous positive airway pressure (CPAP).

An observational study from United Kingdom designed to compare the characteristics of infants with severe retinopathy of prematurity in countries with low, moderate, and high levels of development found that the mean birth weights of infants from highly developed countries was 737-763 g compared with 903-1527 g in less-developed countries. [8] Mean GAs of infants from highly developed countries were 25.3-25.6 weeks compared with 26.3-33.5 weeks in less-developed countries. Thus, larger and more mature infants seemed to be developing severe retinopathy of prematurity in less-developed nations. This suggests that individual countries need to develop their own screening programs with criteria suited to their local population.

Mortality/Morbidity

Long-term outcomes for serious disease include severe visual impairment and blindness. In addition, myopia, amblyopia, and strabismus may occur. Repka et al described the need for subsequent ophthalmic intervention in patients with retinopathy of prematurity. [9]

Race

Some reports indicate a decreased incidence of progression to threshold disease in black infants. Most evidence comes from the Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) study. [10] Further evidence that black infants are less likely to develop severe retinopathy of prematurity has been reported in studies of candidemia in ELBW infants. [11] The exact mechanism for the decreased incidence of progression to surgery in black infants has not been described. Bizzaro et al showed a strong genetic predisposition to retinopathy of prematurity when comparing monozygotic twins with dizygotic twins. [12]

Sex

Although some reports indicate a male predilection, the CRYO-ROP study revealed no differences based on sex. [10]

Age

Retinopathy of prematurity is a disease of the immature retina, and the occurrence of retinopathy of prematurity is inversely related to GA. The more premature the infant, the more likely retinopathy of prematurity is to develop.

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