Historical Aspects and Risk Factors: Retinopathy of Prematurity (ROP), formerly known as Retrolental Fibroplasia (RLF), was first described in 1942. (1) It is a disease of preterm infants with the most premature being at the highest risk of disease occurrence. Campbell in 19512first suggested that oxygen might play a role in the development of ROP and subsequent studies throughout the 1950’s 3, 4, 5 confirmed the adverse effects of oxygen therapy on the developing retinal vessels of premature infants. As it is believed that a fully vascularized retina is not prone to the harmful effects of increased oxygen concentrations to which an infant is exposed, it is rare for a full term newborn(> 37 weeks gestation) to be diagnosed with ROP.
In 2005, one study cited the incidence of ROP by gestational age as follows: < 27 weeks 89%; 27-32 weeks 52%; > 32 weeks 14%.
Risks and Associations
The two most identifiable risk factors for the development of ROP are prematurity and increased exposure to >21% oxygen. However, there have been no safe amounts of external oxygen use (FiO2) or levels of oxygen carried in the blood(PaO2) established. ROP has occurred in preterm babies who have never received supplemental oxygen and also in babies with cyanotic congenital heart disease who have physiologically low PaO2’s. 6 Higher levels of delivered oxygen(increased FiO2) are frequently needed in premature infants to support vital functions in other parts of the body even though these higher levels of delivered oxygen can be damaging to the eyes.
Other associations made with ROP include prolonged time on a ventilator, acidosis, shock, infection, apnea of prematurity, anemia, small for gestational age infant(SGA), patent ductus arteriosis(PDA), vitamin E deficiency, and possibly low levels of other antioxidants present in preterm babies.
ROP can effect one eye or both eyes; if both eyes are affected, one eye may be worse than the other.
Pathophysiology
ROP is due to the incomplete vascularization (blood vessel formation) of the retina. The development of the vascular part of the eye(the retina) starts in the posterior part of the eye at about the 16th week of gestation and steadily progresses toward the anterior part of the eye as the infant progresses to term. Preterm birth interrupts the normal vascular development of the retina which is supposed to take place in utero in a relatively low oxygen environment and in complete darkness; ROP is the result of this interruption. The more premature the birth, the earlier the insult to the retina, and the more severe the disease can be.
ROP occurs in 2 phases:
Phase1 is called the vaso-obliterative phase (or incomplete vasculogenesis). Once the baby is born, IGF-1 (insulin-like growth factor – a hormone) from the placenta is decreased. By virtue of being born, the normal fetal low-oxygen state is replaced by a relatively hyperoxic state, which leads to a decrease in VEGF (vascular endothelial growth factor) production. This decrease in VEGF leads to decreased development of blood vessels in the retina. The baby’s body eventually realizes that that the eye needs these retinal blood vessels to develop and grow and the VEGF levels start to increase at about 32- 34 weeks postconceptual age. The VEGF levels now become abnormally high and lead to phase 2 of ROP.
Phase2 is called the vasoproliferative phase. Again this starts to develop at about 32-34 weeks postconceptual age. This phase is characterized by neovascularization which is abnormal vessel growth and abnormal function of the abnormally grown vessels. This abnormal growth can be seen on ophthalmologic exam by an ophthalmologist skilled in examining infants.
The two phases of the disease are gestationally dependent. The earlier in gestation that the baby is born the more likely the retinal vessels were arrested in the more posterior zones of the eye(zones 1 and 2) and this potentially leads to worse disease. If the baby is born before 30 weeks gestation the vasculature may not have progessed out of zone 1. If the baby is born after 30 weeks gestation the vasculature has most likely progressed into zone 2 and possibly even into zone 3 and the potential for severe disease is lessened.
Classification of Disease
The International Classification of ROP describes the disease by zone (where it is in the retina) and by stage (how bad it is).
There are 3 zones:
- Zone 1 is the most posterior part of the eye (this is where vascularization begins)
- Zone 2 is the middle part of the retina moving anteriorly
- Zone 3 is the most anterior part of the retina (and the last part of the retina to vascularize).
** the lower the number, the worse the prognosis **
There are 5 stages to ROP
- Stage 1 Demarcation Line : a just perceptible line that divides the vascular posterior retina from the avascular anterior retina. This line is flat to the retina.
- Stage 2 Ridge: The demarcation line now has a ridge. It has height as well as width. It elevates above the plane of the retina.
- Stage 3 : Extraretinal Fibrovascular Proliferation (aka neovascularization) New blood vessels eminating from the ridge of stage 2 into the eye itself.
- Stage 4: Partial Retinal Detachment
- Stage 5: Complete Retinal Detachment
** the lower the number, the worse the prognosis **
With the abnormally developing retinal vessels other criteria for severity of disease have been established.
Plus Disease is defined by increased venous dilatation , increased arterial tortuosity, and poor pupillary dilation. This venous dilatation and arterial tortuosity is based on a standard photograph available to the pediatric ophthalmologist. Plus disease may be present at any stage.
Pre-plus disease describes abnormal venous dilatation and increased arterial tortuosity but does not yet meet the requirements of plus disease based on the standard photograph of plus disease.
Aggressive posterior ROP (or AP-ROP) describes a rapidly progressive severe form of ROP. It has also been known as ‘Rush Disease’. 7
Treatment decisions are no longer based on the older Threshold and Pre-Threshold classifications.
Screening
Who to screen: Consensus recommendations regarding who and when to screen are published by the American Academy of Pediatrics in conjunction with the American Academy of Ophthalmology. They include:
- all infants less than 1500 grams at birth
- all infants less than 30 weeks gestation at birth
- infants 1500-2000grams at birth who have unstable courses and are believed to be at high risk
- infants born at greater than 30 weeks gestation who have unstable courses and are believed to be at high risk
When to screen: Because the emergence of the vasoproliferative phase of the disease appears at about 32 – 34wks PCA, timing of the baby’s first exam is based on a combination of chronologic and post-conceptual age.
| If Born At Age of 1st exam |
| 23 wks 8 wks |
| 24 wks 7 wks |
| 25 wks 6 wks |
| 26 wks 5 wks |
| > 27 wks 4 wks |
The next ROP exam will be scheduled by the eye doctor based on the findings of the first eye exam i.e. based on the zone and the stage of the ROP in the infant on the initial exam.
Examinations can be discontinued when the retina is fully vascularized, when the vascularization progresses into zone 3 (the anterior zone of the eye) without prior ROP in zones 1 or 2 or at 45-50 wks PCA at the discretion of the eye doctor assuring that there is no abnormal tissue capable of reactivation or progression.8
Treatment
ROP should be treated when the baby has:
- zone I, any stage with plus disease
- zone I ,stage 3, without plus disease
- zone II , stage 2 or 3 with plus disease
- zone III ,stage 3 with plus disease
- all retinal detachments need treatment regardless of zone
Treatment should take place within 72 hours of the decision to treat.
Treatment may entail transferring the bay to a larger academic or university setting to have access to a pediatric ophthalmologist.
If surgery is required it is usually occurs between 35-40 wks PCA.
Treatment is done to prevent retinal detachment and vision loss.
Standard ROP treatment is with laser therapy to the avascular retina. Cryotherapy (or freezing of the retina) is rarely used any longer because of its undesirable side effects, but there are certain instances when it may be the therapy of choice. Other types of surgeries may be required if retinal detachment has occurred.
New therapies on the horizon and still in the experimental phases include:
- Intravitreal anti VEGF
- Intravenous Insulin-like Growth factor 1
- Polyunsaturated fatty acids in the diet of the infants
- Propranolol IV or PO
- Anti-Oxidants (e.g vitamin E or d-penicillamine)
After surgery,the ophthalmologist will perform follow-up examination every 1-2 weeks to determine if more surgery is required. Once the ophthalmologist deems that the ROP is no longer progressing, these examinations will be spread out over time to at least once yearly or more depending on the severity of the disease. Patients with ROP are at increased risk for myopia, strabismus, nystagmus, cataracts, amblyopia, and late retinal detachment; therefore long term follow-up is imperative.
Prognosis
ROP can advance until 40-50 wks PCA, but it resolves spontaneously in the majority of cases. In one study, treatment for severe disease in infants born less than 1250 gm was only needed in 6% of patients. A, B
The prognosis is predicted by zone and stage of disease. Those who had mild disease i.e. those whose disease was more anteriorly located and did not progress beyond stage 1 or stage 2, have a good prognosis. Those who had more severe disease i.e. those with disease in the more posterior zones(zones 1 and 2) those with more advanced stages of disease (stages 2 and 3) , those with plus disease, and all retinal detachments (stages 4 and 5) have a guarded prognosis for vision.
The only known deterrent of ROP is prevention of preterm birth.