Retinopathy of Prematurity

Author: daniela mastromauro
Date: 22/01/2013



Retinopathy of prematurity (ROP) is a retinal vasoproliferative disorder that affects premature infants. ROP usually develops in both eyes and represents a major cause of vision loss (blindness) and impairment in children worldwide. It was previously known as retrolental fibroplasia (RLF).

Epidemiology and risk factors

The incidence of ROP is estimated to be over 15-20% of all premature births and according to some reports there is a slight male prevalence. An increase in ROP is recently due to the neonatal care advances and the rising number of surviving premature infants.
Major risk factors are: decreased gestational age, low birth weight and high levels of supplemental oxygen. Associated risk factors include acidosis, apnea, high CO 2 levels, anemia, bradycardia.
In particular, gestational age of <28 weeks is reported to be more significant than birth weight, suggesting that maturity plays a more relevant role in the pathogenesis of ROP than intrauterine growth. (A co-twin study of the relative effect of birth weight and gestational age on retinopathy of prematurity. 2011 Nov)
(Retinopathy of prematurity)


Essentially, the development of retinopathy of prematurity occurs in two phases.
In the human fetus, retinal blood vessel development begins during the 4 th month of gestation.
Between the 16 th and 40 th week of gestation, the vessels grow in a centrifugal pattern from the optic disc to the ora serrata (the far peripheral retina) to fully vascularize the retina.
Consequently, at the time of a preterm delivery, the development of the retinal vasculature will be incomplete, with a peripheral avascular zone, the area of which depends on the gestational age.
The cessation of the normal retinal vascular growth that would occur in utero, represents phase I of ROP.
Any injury to the immature and developing retinal capillary bed, from oxygen or other etiological factors, can result in ROP. Once these capillaries are lost, the non-vascularized retina becomes increasingly metabolically active and hypoxic. Retinal neovascularization, which is hypoxia-induced, represents phase II of ROP.
Abnormal blood vessels may begin to regrow as a result of angiogenic factors (such as VEGF). Eventually, the new vessel growth can either complete physiological vascularization of the retina or lead to the pathological changes associated with ROP, such as extra-retinal neovascularization, hemorrhages, scar formation, traction retinal folds, and retinal detachments.
(Pathogenesis of retinopathy of prematurity. 2004 Jun)
(Retinopathy of prematurity: A clinical approach)

Role of hypoxia and VEGF

As the retinal vasculature develops, there is increased oxygen demand, which creates localized hypoxia. Vascular endothelial growth factor (VEGF) is a hypoxia-inducible cytokine and is a vascular endothelial cell mitogen. In fact, experiments with the mouse and other animal models demonstrate that VEGF is expressed in response to the retinal hypoxia, and it stimulates blood vessels growth.
As the hypoxia is relieved by oxygen from the newly formed vessels, VEGF mRNA expression is suppressed. Similarly, inhibition of VEGF decreases the neovascular response, indicating that VEGF is a critical factor in retinal neovascularization.
These results correspond to what is seen clinically. VEGF is elevated in the vitreous of patients with retinal neovascularization and was also found in the retina of a patient with ROP in a pattern consistent with mouse results.

Role of supplemental oxygen

It was seen that supplemental oxygen interferes with that normal development in the mouse and rat models of ROP. Effectively, ROP occurs principally in premature infants treated with high concentrations of oxygen in neonatal intensive care units.
Hyperoxia used in animal models causes cessation of normal vessel growth through suppression of VEGF mRNA. Furthermore, hyperoxia induces vaso-obliteration, which is caused by apoptosis of vascular endothelial cells and this can be at least partially prevented by administration of exogenous VEGF.
Although VEGF and oxygen play an important role in the development of retinal blood vessels, it is clear that other biochemical mediators also are involved in the pathogenesis. Inhibition of VEGF does not completely inhibit hypoxia-induced retinal neovascularization in phase II of ROP.
Despite controlled use of supplemental oxygen, the disease persists, suggesting that other factors are related to prematurity itself and that clinical ROP is multifactorial.

Role of GH and IGF-1

Both GH and IGF-1 are also critical to the disease process.
Proliferative retinopathy, phase II of ROP, is substantially reduced in transgenic mice expressing a
GH-receptor antagonist or in normal mice treated with a somatostatin analogue that decreases GH release.
Direct proof of the role of IGF-1 in the proliferative phase of ROP in mice was also established with an IGF-1 receptor antagonist, which suppresses retinal neovascularization without altering the vigorous VEGF response induced in the mouse ROP model.
Low levels of IGF-1 inhibit vessel growth despite the presence of VEGF. This suggests that IGF-1 serves a permissive function and VEGF alone may not be sufficient for promoting vigorous retinal angiogenesis. Therefore, IGF-1 is likely to be one of the non-hypoxia regulated factors critical to the development of ROP.
But IGF-1 is critical both in the first phase of ROP, and in the normal development of the retinal vessels. A lack of IGF-1 (normally provided by the placenta and the amniotic fluid) in the early neonatal period of premature infants is associated with poor vascular growth.
As the infant’s organs and systems then continue to mature, IGF-1 levels rise again, suddenly allowing the VEGF signal to produce abnormal blood vessels. This pathological neovascular proliferation then becomes ROP and can cause blindness.
These findings make clear that timing is critical to any intervention. Inhibition of either VEGF or IGF-1 early after birth can prevent normal blood vessel growth and precipitate the disease.
This evidence suggest the intriguing possibility that replacement of IGF-1 to uterine levels might prevent the disease by allowing normal retinal vascular development.
On the other hand, IGF-1 inhibition at the second proliferative phase might prevent destructive neovascularization.
(Pathogenesis of retinopathy of prematurity. 2004 Jun)


According to the International Classification of Retinopathy of Prematurity (1984, revised in 2005), ROP is classified in stages:
- Stage I: Mildly abnormal blood vessel growth; white demarcation line between vascularized and avascular retina.
- Stage II: Moderately abnormal growth of retinal blood vessels; characterized by an elevated ridge rather than a flat demarcation line; neovascularization may be present posterior to the ridge.
- Stage III: Severely abnormal retinal vessel growth; protrusion of the extraretinal vessels from the ridge into the vitreous; has a higher risk of long-term vision problems.
- Stage IV: Severely abnormal blood vessel growth and partial retinal detachment; may lead to long-term vision problems or blindness. At this stage, the retina may sometimes reattach spontaneously.
- Stage V: Total retinal detachment which is funnel-shaped and may be either open or closed at the anterior and posterior ends.
A "plus" sign is added to the above stages if any of the following findings is present: dilatation and tortuosity of the posterior vessels, dilatation of iris vessels, rigid and poorly dilating pupil, and vitreous haze.

The location of ROP is described in zones centered on the optic nerve.
The circumferential extent of the disease is based on the clock hours (1-12):
- Zone I is the posterior zone of the retina, the macular area. Any disease in zone I is critical.
- Zone II is the mid retinal area (the inner border is defined by zone I and the outer border is at the distance of the nasal ora serrata)
- Zone III is the peripheral area; the disease in this zone is usually inactive.


Proper screening and timely treatment are essential in improving anatomical and functional outcome. Guidelines for screening include:
- Infants born at 23-24 weeks should be examined within 3-4 weeks
- Infants born at or beyond 25-28 weeks should be examined by the 4th-5th week
- Infants born after 29 weeks should be examined prior to discharge from the hospital
Eye examinations every 6 months are recommended for all infants born <32 weeks or that weigh <1500 g. Screening can stop if the blood vessels in both retinas have completed normal development. Newborns who developed severe retinopathy must have life-long eye examinations at least once a year.
(Retinopathy of prematurity)


  • Drug therapy:
    • Anti-oxidant therapy with Vitamin E has been proposed to scavenge free radicals that are potentially damaging to developing retinal vessels, but several prospective studies have shown conflicting results. At the present time, the use of vitamin E for the management of ROP is not conclusively indicate.
    • Anti-VEGF therapy: uses intravitreal injections of Bevacizumab, a humanized recombinant antibody, that inhibits the biological activity of VEGF. Bevacizumab has been shown in a small case series to temporarily slow vasculogenesis and permanently halt angiogenesis, usually with a single intravitreal injection, when used for vision-threatening ROP stage 3.
      Another anti-VEGF drug researched is Pegaptanib sodium. According to the initial experience the medication is well tolerated, and helps to reduce the vascular activity in eyes with severe posterior disease. On the other hand it does not prevent the development of retinal detachment and it is still under study as an alternate anti-VEGF therapy.
  • Surgical management:
    • Cryotherapy: refers to applications of cold lesions to the avascular retina anterior to the region of active disease. The Multicenter Trial of Cryotherapy for ROP (Cryo-ROP) defines "threshold ROP" as eyes that reach Stage 3+ in zone 1 or 2 over at least 5 contiguous or 8 cumulative hours. These findings suggest that cryotherapy may be recommended for the treatment of a single eye in cases of bilateral threshold ROP.
    • Laser Photocoagulation: consists of applying a laser beam delivered through an indirect ophthalmoscope. The laser light is absorbed by tissue pigments and is converted into heat, which denatures cellular components and causes tissue coagulation. Preliminary results suggest that the effectiveness of laser therapy is comparable to that of cryotherapy in the treatment of ROP. Moreover, in laser photocoagulation, the retina is ablated by the laser beam directly. This is in contrast to cryotherapy which involves freezing the sclera, choroid, and retina. Consequently, fewer adverse effects are expected following the laser therapy.
    • Scleral Buckling and Vitrectomy partial retinal detachment in stage 4 ROP can sometimes be repaired with an encircling scleral buckle. Total retinal detachment in stage 5 ROP requires vitrectomy for repair.


The most common sequelae of regressed ROP include:
- Poor visual acuity (myopia)
- Higher incidence of strabismus (especially esotropia)
- Amblyopia
- Late retinal detachment
In contrast, progressive ROP can lead to:
- Legal blindness
- Closed-angle glaucoma
- Phthisis bulbi (shrunken globe)
- Entropion
(Retinopathy of prematurity: a clinical approach)
(Retinopathy of prematurity promising newer modalities of treatment. 2012 Feb)

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