Retinopathy of prematurity (ROP), previously called retrolental fibroplasia, is a vaso-proliferative retinopathy which affects premature infants exposed to high concentration of oxygen. Retinopathy of prematurity often regresses but has the potential of causing visual impairment or blindness. ROP causes disorganised growth of retinal blood vessels which may lead to retinal scarring or even detachment of retina.
Retina has no blood vessels until fourth month of gestation. Thereafter, vessels emanate from hyaloid vessels at the optic disc and progress towards periphery. These vessels reach nasal periphery after eight months of gestation, but do not reach temporal periphery until about one month after delivery. Incompletely vascularised temporal part of retina is particularly susceptible to damage with oxygen therapy, particularly in premature infants. Pre-term birth affects normal retinal vascular maturation. Exposure to oxygen down-regulate retinal vascular endothelial growth factor (VEGF), resulting in constriction/obliteration of blood vessels and delays normal retinal vascular development.
Significant ROP can lead to lifelong disability, especially in smallest survivors of neonatal intensive care units (NICUs).
Kanski,Jack J. Clinical Ophthalmology, A Systematic Approach .Third Edition.UK. Butterworth Heinemann, 1994.
Retinopathy of prematurity occurs in pre-term infants born before the normal growth of retinal blood vessels. Like other retinopathies, local ischaemia of retina plays a role in ROP.
Excessive oxygen exposure causes obliteration of blood vessels in immature retina. Oxygen saturation maintained at lower level from birth can reduce the rate of advancement of ROP.
Risk factors for ROP:
- Gestational age (32 weeks or less).
- Low birth weight (Less than 1500 grams).
- Extended use of supplemental oxygen.
Foetus in uterus is in hypoxic state as compared to life after birth. In pre-term infants, growth of retinal vessels is stimulated by vascular endothelial growth factor (VEGF). However, on exposure of immature retina to oxygen, the blood vessel constricts and can become obliterated resulting in delay of normal retinal vascular growth. This is the stage of hyperoxia-vasocessation.
Initially, the retina derives oxygen by diffusion from the underlying capillary bed of choroidal layer. The retina continues to grow in thickness and outgrows its vascular supply. But over the time, avascular retina becomes ischaemic and stimulates VEGF leading to hypoxia-vasoproliferation stage and manifest as arterio-venous shunts and neovascularisation.
Infants at risk are screened with appropriate timing of examination and follow up.
Diagnosis depends on the history of development and the clinical features.
Infants with lowest birth weights and youngest gestational ages are at increased risk of ROP.
Prolonged exposure to supplemental oxygen is a risk factor contributing to ROP.
Other predispositions with ROP are use of mechanical ventilation, patent ductus arteriosus, severity of associated illness (respiratory distress syndrome, sepsis or bronchopulmonary dysplasia).
The severity of active ROP is assessed according to location, extent, stage and ‘plus’ disease.
Location: Location of ROP is determined based on three zones with optic disc being at the center.
- Zone 1: It includes a circular area bounded by an imaginary circle, radius which is twice the distance from optic disc to macula.
- Zone 2: It includes an area extending from edge of zone 1 to a point tangential to Ora serrata (anterior limit of retina) and round to an area near equatorial temporal retina.
- Zone 3: This is the area consisting of residual temporal crescent lying anterior to zone 2.
Extent: This refers to the number of clock hours affected.
Stages: It refers to the clinical features according to the severity of ROP.
- Stage 1 (Demarcation line): The earliest sign of ROP is formation of a thin, tortuous, grey-white line running almost parallel to Ora serrata. This line is more prominent in peripheral part of temporal retina. It separates vascular posterior retina from avascular immature peripheral retina. Abnormal and branching blood vessels may form reaching up to the demarcation line.
- Stage 2 (Ridge formation): Demarcation line develops into a raised ridge of tissue which represents shunt joining veins with arteries. Isolated neovascular tufts may be seen posterior to it.
- Stage 3 (Ridge with extraretinal fibrovascular proliferation): There is fibrovascular proliferation over retina and into vitreous. The ridge becomes pink in colour.There is dilatation and tortuosity of the retinal blood vessels posterior to the equator. There may be retinal or vitreous haemorrhage.
- Stage 4 (Partial retinal detachment): The contraction of fibrovascular tissue leads to tractional retinal detachment which starts in extreme periphery and spreads towards the center.
- Stage 5 (Total retinal detachment): There is total detachment of retina.
‘Plus disease’: There is venous dilatation and tortuosity of arterioles in the posterior fundus (interior of the eyeball). When these vascular changes are present, a ‘Plus’ sign is added to the stage of disease.
Screening for ROP:
All infants born at less than 36 weeks or weighing less than 1500 grams, who have received oxygen therapy, should be screened for ROP.
The most useful time for screening is between post-conceptual ages of 32 to 36 weeks. This is because retinal detachment seldom develops before that and ROP rarely appears for the first time after 36 weeks. Before post-conceptual age of 31 weeks, screening is of limited value, because it is difficult to dilate pupils and there is vitreous haze due to the presence of tunica vasculosa lentis (capillary vasculature on posterior surface of lens which disappears after birth).
Few patients with active ROP develop cicatricial complications. More advanced proliferative disease leads to more serious cicatricial sequlae. Various stages are:-
- Stage 1: This shows myopia with associated retinal pigmentary disturbance and haze at the base of vitreous.
- Stage 2: There is temporal vitreoretinal fibrosis with dragging of posterior retina.
- Stage 3: There is more severe peripheral fibrosis with contracture and falciform (sickle shaped) retinal fold.
- Stage 4: This shows partial ring of retrolental-fibrovascular tissue with partial retinal detachment.
- Stage 5: There is complete ring of retrolental fibrovascular tissue with total retinal detachment. Total retinal detachment may lead to secondary angle-closure glaucoma.
ROP should be differentiated from:-
- Familial exudative vitreoretinopathy: Familial exudative vitreoretinopathy is a genetic disorder which occurs in full term infants.
- Persistent foetal vasculature: Persistent foetal vasculature, previously called persistent hyper-plastic primary vitreous (PHPV) is typically unilateral and is not related to prematurity. It can cause tractional retinal detachment.
The infant should be managed under medical supervision.
Ablative surgery is the mainstay of treatment. It is recommended for:-
- Zone 1 ROP: Any of the stage with ‘Plus’ disease.
- Zone 1 ROP: Stage 3 with no ‘Plus’ disease.
- Zone 2 ROP: Stage 2 or 3 with ‘Plus’ disease.
Ablation of avascular immature retina:
- Cryotherapy (use of low temperatures): Cryotherapy produces a reduction in unfavourable outcomes in threshold disease. Threshold disease is defined as five contiguous clock hours or eight non-contiguous clock hours of extra-retinal neovascularisation i.e. stage 3 disease in zone 1 or zone 2, associated with ‘Plus’ disease. It reduces the incidence of retinal detachment in many patients but some progress to retinal detachment in spite of treatment.
- Laser photocoagulation: Argon or Diode laser may be used to photocoagulate avascular areas of retina to reduce the incidence of complications. In spite of treatment, some patients still progress to develop complications like posterior pole macular fold or retinal detachment.
Patients not responding to cryotherapy or laser photocoagulation may require vitreoretinal surgery to treat complications like retinal detachment.
Scleral buckling with or without pars plana vitrectomy may be done for cases with tractional retinal detachment. Visual outcome is usually not very good.
Role of vitamin E as antioxidant is controversial. Administration of vitamin E may produce undesirable side effects.
Yearly ophthalmologic follow-up evaluation is required. Depending upon the severity of disease, more frequent evaluations may be done.
Visual prognosis is not good in infants developing retinal detachment. Retinal detachments commonly occur at 38-42 weeks postmenstrual age, in untreated patients.
Treatment of ROP reduces the risk and incidence of unfavourable outcome.
Retinopathy of prematurity may lead to complications like:-
- Retinal detachment.
- Retinal breaks.
- Macular fold.
Preventive considerations may be:-
ROP is less likely to develop if neonate is more mature at birth.
Maintaining oxygen saturation value at 83-93% by pulse oximeter in low birth weight premature infant, decreases the incidence of threshold ROP (http://reference.medscape.com/medline/abstract/17471328).