Retinopathy of Prematurity 

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



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.


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).



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.


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.


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]


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]


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


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.




Infants at highest risk for retinopathy of prematurity (ROP) are those with the lowest birth weights and youngest gestational ages (GAs). See the Gestational Age from Estimated Date of Delivery calculator.

Prolonged exposure to supplemental oxygen is also a risk factor.

The severity of illness (including sepsis), blood transfusions, days receiving mechanical ventilation, a patent ductus arteriosus, and intraventricular hemorrhage are also associated with retinopathy of prematurity.

The effect of blood transfusion on retinopathy of prematurity is controversial. The smallest, sickest infants receive more transfusions than their healthy counterparts and may have more frequent or severe retinopathy of prematurity. However, theoretical risks associated with factors such as volume and iron load may place infants who receive more transfusions at higher risk for retinopathy of prematurity.

Recent studies by Lofqvist et al have shown that infants whose postnatal gain weight is less than expected are at increased risk.[13]



An ophthalmologist experienced in evaluating infants for retinopathy of prematurity should perform a screening examination.

International classification

To standardize examinations, a group of physicians organized an international classification of ROP (ICROP) in 1984 and updated the classification in 1987 and again in 2005.[14]

ROP is characterized by 3 parameters: stage, zone, and plus disease (ie, tortuosity of vessels).

Examination recommendations

The American Academy of Pediatrics (AAP) and the American Academy of Ophthalmology have joint recommendations for infants who should be screened for retinopathy of prematurity.[15]

Screening should include those infants with a birth weight of less than 1500 g or a GA of 31 weeks or less and selected infants with a birth weight of 1500-2000 g or a GA of more than 31 weeks with an unstable clinical course, including those who require cardiorespiratory support and those who are believed by their attending pediatrician or neonatologist to be at high risk.

The retinal screening examinations should be performed by an experienced ophthalmologist after pupillary dilation using binocular indirect ophthalmoscopy to detect retinopathy of prematurity.

The time of initiation of retinopathy of prematurity screening should be based on the infant's age. The onset of serious retinopathy of prematurity correlates better with postmenstrual age (gestational age at birth plus chronologic age) than with postnatal age; this means that the youngest infants at birth take the longest time to develop serious retinopathy of prematurity.

Screening guidelines have been the focus of recent studies. The issue of cost-effectiveness versus missing cases is controversial. In addition, Subhani et al suggested that infants should be examined by age 4-6 weeks, contrary to the standard postmenstrual age criteria.[16] The AAP guidelines for retinopathy of prematurity screening suggested a schedule for detecting prethreshold retinopathy of prematurity (99% confidence), usually well before any required treatment. See the table below.

Table. Timing of First Eye Examination Based on Gestational Age at Birth (Open Table in a new window)

Gestational Age at Birth (wk)

Chronologic Age (wk)

Postmenstrual Age (wk)

22 *



23 *
























31 (if necessary)



32 (if necessary)




This guideline should be considered tentative rather than evidence-based for infants with a GA of 22-23 weeks because of the small number of survivors in these categories.

Follow-up examinations are based on initial examination findings. Most infants are screened every 2 weeks. More frequent (once a week or less) follow-up is recommended in stage I or II retinopathy of prematurity in zone I and in stage III retinopathy of prematurity in zone II. The presence of plus disease requires careful evaluation because, in these cases, peripheral ablation is more appropriate rather that observation alone.

Screening examinations are continued until the blood vessels reach the anterior edge of the retina (complete retinal vascularization around 40 weeks' gestation) or until postmenstrual age of 45 weeks with no prethreshold disease (defined as stage III retinopathy of prematurity in zone II, any retinopathy of prematurity in zone I) or no worse retinopathy of prematurity is present.



Differential Diagnoses

  • Familial exudative vitreoretinopathy



Other Tests

Ophthalmologic evaluation in retinopathy of prematurity (ROP)

Record the vascular maturity (how far out the vessels have grown), as indicated by zone, stage of disease, and the presence or absence of plus disease or preplus disease.

Quantify the extent of retinopathy of prematurity on the basis of number and contiguity of clock hours in which the disease is present in the retina.

Some centers are also experimenting by taking retinal fundus photographs and having an off-site ophthalmologist evaluate the photos.


The international classification of retinopathy of prematurity (ICROP) describes 5 stages of retinopathy of prematurity, as follows:[14]

  • Stage I is characterized by a line of demarcation. Extra vessels can be seen growing at the leading edge of the retinal vasculature. The line of demarcation separates the vascularized portion of the retina from the anteriorly positioned avascular retina.

  • Stage II is characterized by an elevated ridge, rather than a flat demarcation line. Neovascularization may be present but is posterior to the ridge.

  • Stage III refers to extraretinal neovascularization or vessels that grow onto the ridge and then into the vitreous toward the examiner.

  • Stage IV refers to partial retinal detachment.

  • Stage V is total retinal detachment.

  • Some ophthalmologists describe an immature or avascular retina as Stage 0 retinopathy of prematurity.

Plus disease refers to severe tortuosity of vessels. Preplus disease is defined as vascular abnormalities of the posterior pole characterized by more arterial tortuosity and more venous dilatation than normal but not severe enough to be classified as plus disease. Rapidly progressing plus disease is sometimes referred to as Rush disease.

Zones of disease

Zone I is the innermost area of the retina surrounding the macula (see the image below).

Zone I retinopathy of prematurity. Zone I retinopathy of prematurity.

Zone II is the middle third of the retina, nasally extending to the edge of the retina (see the image below).

Zone II retinopathy of prematurity. Zone II retinopathy of prematurity.

Zone III is the most peripheral area of the retina on the temporal side (see the image below).

Zone III retinopathy of prematurity. Zone III retinopathy of prematurity.


As of the publication of the Early Treatment for Retinopathy of Prematurity (ETROP) study, more ophthalmologist are describing eyes with retinopathy of prematurity into 2 types (see the image below):

Treatment guidelines, according to the Early Treat Treatment guidelines, according to the Early Treatment for Retinopathy of Prematurity (ET-ROP) study.

Type 1 requires treatment and includes the following:

  • Eyes with zone I, stage III retinopathy of prematurity without plus disease or

  • Eyes with zone II, stage II or stage III retinopathy of prematurity with plus disease

Type 2 requires observation and includes the following:

  • Eyes with zone I, stage I or stage III retinopathy of prematurity without plus disease or

  • Eyes with zone II, stage III retinopathy of prematurity without plus disease



Medical Care

Medical care of retinopathy of prematurity (ROP) consists of ophthalmologic screening of appropriate infants. No standard medical therapies are available at this time.

Ongoing research is examining the potential use of intravitreally injected antineovascularization drugs, such as bevacizumab (Avastin).[17] These drugs have been successfully used in patients with other forms of neovascularization, such as diabetic retinopathy. Other treatments may involve restoring normal levels of insulinlike growth factor (IGF)-1 and omega-3-polyunsaturated fatty acids (PUFAs) in the developing retina, as proposed by Chen and Smith.[18, 19, 20] One small study compared treatment with laser therapy over intravitreal bevacizumab monotherapy. Intravitreal bevacizumab showed better results for zone I but not zone II disease. Laser therapy led to permanent destruction of the peripheral retina, wheras the peripheral retinal vessels continued to develop after treatment with bevacizumab.[21]

The Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOP-ROP) Trial assessed the effect of supplemental oxygen in reducing the probability of progression to threshold retinopathy of prematurity and the need for peripheral retinal ablation in infants with prethreshold retinopathy of prematurity.[5] The results of the trial showed no reduction in the infants who required ablative surgery. A post hoc subgroup analysis showed that infants without plus disease may be more responsive to supplemental oxygen therapy (46% progression in the conventional arm vs 32% progression in the supplemental arm) than infants with plus disease (52% progression in the conventional arm vs 57% in the supplemental arm). Supplemental oxygen increased the risk of adverse pulmonary events (8.5% conventional arm vs 13.2% in the supplemental arm).

A study by Sjöström et al indicated that in preterm infants born prior to 27 weeks’ gestation, low energy intake during the first 4 weeks following birth is an independent risk factor for severe retinopathy of prematurity. The study included 498 infants, 172 of whom had severe retinopathy of prematurity. The investigators found a significant relationship between higher intakes of energy (including fat and carbohydrates, but not protein) and a decreased risk of severe retinopathy. Indeed, an increased energy intake of 10 kcal/kg/day correlated with a 24% reduction in the severe form of the disease.[22]

Surgical Care

Ablative surgery

If threshold disease is present, perform ablative surgery.

Ablative therapy currently consists of cryotherapy or laser surgery to destroy the avascular areas of the retina.

The average gestational age (GA) at which surgery is necessary is usually 37-40 weeks.

If the retinopathy of prematurity continues to progress, more than one treatment may be required.


A randomized prospective trial of cryotherapy showed a 50% reduction in retinal detachment in treated eyes versus nontreated eyes.

Beneficial effects were observed in infants with threshold disease, defined as 5 contiguous clock hours of stage III disease with plus disease or 8 noncontiguous clock hours of stage III disease with plus disease.

Laser surgery

Currently, laser surgery is preferred to cryotherapy because it may be more effective in treating zone I disease and causes less inflammation. Laser photocoagulation appears to be associated with outcomes in structure and function that are at least as good as those of cryotherapy 7 years after therapy.[23, 24] In addition, visual acuity and refractive error data suggest that laser surgery may have an advantage over cryotherapy, and evidence suggests that laser surgery is easier to perform and better tolerated by the infants. Cryotherapy is still the preferred treatment option when the view of the retina is limited by media opacities.

Laser surgery has been used more recently than cryotherapy, and whether the slightly improved outcomes with laser surgery are attributable to changes in the care of high-risk neonates (eg, antenatal glucocorticoid therapy, surfactant use) is unclear. However, cryotherapy has been rigorously evaluated in a multicenter prospective randomized fashion, and the 10-year follow-up data show long-term value in preserving visual acuity in eyes with threshold retinopathy of prematurity.[10]

Early treatment

The Early Treatment for Retinopathy of Prematurity (ET-ROP) Trial showed that early treatment of high-risk prethreshold retinopathy of prematurity significantly reduced unfavorable retinopathy of prematurity outcomes at age 9 months and at age 2 years.[25, 26] Patients in this study had one eye randomized to "early" retinal ablative therapy. Eyes treated had type 1 retinopathy of prematurity, defined as zone I with plus disease and any stage retinopathy of prematurity; zone I with stage III and no plus disease; or zone II, stage II or III, and plus disease.

The investigators subsequently compared their results from this ET-ROP study with those of the Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) study, with respect to incidence and early course of retinopathy of prematurity. The incidence, time of onset of any disease and prethreshold disease, and rate of progression have changed little since the mid 1980s. The ET-ROP had more cases of prethreshold disease (36.9% in ET-ROP and 27.1% in CRYO-ROP) and more zone I retinopathy of prematurity.



Medication Summary

If a patient has prethreshold retinopathy of prematurity (ROP), some centers try to maintain normal serum levels of vitamin E.

Vitamin E use was evaluated in a meta-analysis, and levels should be maintained within the reference range in patients at high risk for severe retinopathy of prematurity.



Further Outpatient Care

Patients require yearly ophthalmologic follow-up evaluations. More frequent evaluation may be necessary, depending on the severity of the disease.

The long-term outcome for infants with retinopathy of prematurity continues to be problematic. Patients with retinopathy of prematurity are at significant risk for myopia. In addition, strabismus, amblyopia, and late retinal detachment continue to be problems for these infants.

Long-term follow-up findings from the Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) cooperative group indicate that refractive errors in eyes with mild retinopathy of prematurity are associated with the same risk of myopia as that in eyes without retinopathy of prematurity.[10] In patients with moderate-to-severe retinopathy of prematurity, the prevalence of severe myopia is increased. Fifteen year follow-up from the CRYO-ROP Trial shows that children remain at risk for new retinal detachments, even with eyes that have relatively good structural findings at age 10 years.

Long-term, regular follow-up of eyes with threshold retinopathy of prematurity is warranted.

As stated above, laser surgery offers some advantage over cryotherapy in treating zone I disease.

Further Inpatient Care

Base follow-up examinations in patients with retinopathy of prematurity (ROP) on previous examination results. The more immature the retinal vasculature or the more serious the disease, the shorter the follow-up interval must be to enable the detection of disease. These examinations allow treatment to be offered if threshold disease develops in the eye.

After surgical intervention, an ophthalmologist should perform an examination every 1-2 weeks to determine if additional surgery is indicated.

Patients who are medically monitored must undergo examinations until the retinal vasculature is mature. Ensuring appropriate monitoring of infants is critical if they are discharged from the nursery before retinal vascular maturity is attained.

Numerous patients have lost sight due to inappropriate, untimely monitoring. In untreated patients, retinal detachments commonly occur at 38-42 weeks' postmenstrual age.


The only known deterrent measure is to prevent preterm birth. The more mature a neonate is at birth, the less likely retinopathy of prematurity is to occur.

Studies regarding the effects of antenatal corticosteroids on retinopathy of prematurity revealed that this treatment has a protective effect against severe retinopathy of prematurity.[27]

Recent studies have shown that maintaining oxygen saturation values by pulse oximeter (SpO2) at 83-93% decreases the incidence of threshold retinopathy of prematurity.[28, 29]


Late complications include myopia, amblyopia, strabismus, nystagmus, cataracts, retinal breaks, and retinal detachment.

Vanderveen et al observed strabismus is often variable and may improve by age 9 months.[25]

Follow-up by an ophthalmologist is required on a long-term basis.


The prognosis is predicted by the stage of retinopathy of prematurity.

Patients who did not progress beyond stage I or stage II have a good prognosis.

Patients with posterior zone I disease or stage III, IV, or V have a guarded prognosis for their vision.

Patient Education

Ophthalmic Mutual Insurance Company has useful sample forms available online for doctors and families.