Delhi Journal of Ophthalmology

Retinopathy of Prematurity

Neha Rathie, Birbala Okram, Lavi Mangla, Pragya Saini
Guru Nanak Eye Centre, Maulana Azad Medical College, New Delhi, India

Corresponding Author:

Neha Rathie
Senior Resident, Guru Nanak Eye Centre, Maulana Azad Medical College, New Delhi, India

Received: 13-AUG-2016

Accepted: 23-AUG-2016

Published Online: 09-SEP-2016


Retinopathy of prematurity is a vasoproliferative disease affecting the retina of premature infants. The manifestations of the disease can range from mild with no visual defects to severe with new vessel formation (neovascularisation) and progress to retinal detachment and blindness.

There are various risk factors for the disease, the most important ones being prematurity and low birth weight. Proper screening of babies is important for early detection and prompt management. There are various treatment options available depending on the stage and extent of disease. Laser photocoagulation and cryotherapy have been the accepted modalities for uncomplicated disease. Intravitreal bevacizumab and its effect on retinopathy of prematurity has been evaluated in few studies but no conclusive results have been found. This article aims to provide a comprehensive information about the disease to aid in timely screening, early detection and management.

Keywords :ROP, bevacizumab, prematurity

Retinopathy of prematurity is a vasoproliferative disease affecting the retina of premature infants. The manifestations of the disease can range from mild with no visual defects to severe with new vessel formation (neovascularisation) and progress to retinal detachment and blindness.[1]

ROP was first described by Terry in early 1942[2] as retrolental fibroplasia and a few years later was recognized as one of the leading causes of infant blindness.[3]

Risk Factors

•    Birth weight and gestational age

Prematurity is the single most important risk factor responsible for retinopathy of prematurity. Incidence of ROP increases with decreasing gestation and birth weight. In general more than 50% of preterm infants weighing less than 1250 g at birth show evidence of ROP and about 10% of the infants develop severe ROP.[4] However, retinal detachment occurs and leads to visual loss in only a few percent of infants with severe ROP, and in most cases, ROP regresses spontaneously.

•    Oxygen Use

Recent evidence suggests that repeated hypoxic and hyperoxic episodes may be an important factor in the pathogenesis of ROP.5 Strict management of oxygen delivery without fluctuations and monitoring may be associated with decreased occurrence of ROP. Although the exact relationship between oxygen therapy and ROP is currently not well established, oxygen therapy seemed to play an important role in the pathogenesis of ROP.

•    Other Factors

Apnea treated by mask-and-bag ventilation; prolonged parenteral nutrition; repeated blood transfusions; episodes of hypoxemia; hypercarbia; and hypocarbia.


The currently followed International Classification of Retinopathy of Prematurity ICROP[6] describes vascularization of the retina and characterizes ROP by its position (zone), severity (stage), and extent (clock hours):

1. Location (Figure 1)

    Zone I : Circle with optic nerve at centre and a radius of twice the distance from optic nerve to macula.
    Zone II: From edge of Zone I to the nasal ora serrata nasally and equator temporally.
    Zone III: Lateral most crescent shaped area from Zone II to ora-serrata temporally.

2. Severity

    Stage 1:    Presence of thin white demarcation line separating the vascular from avascular retina.
    Stage 2:    The line becomes prominent because of lifting    of retina to form a ridge having height and width.
    Stage 3:     Presence of extra retinal fibro-vascular proliferation with abnormal vessels and fibrous tissue arising from the ridge and extending into vitreous.
    Stage 4:    Partial retinal detachment; not involving macula (4A) or involving macula (4B).
    Stage 5:    Complete retinal detachment.

3. Plus disease: Presence of dilatation and tortuosity of posterior retinal vessels. Associated with vitreous haze, pupillary rigidity

4. Pre-plus disease: Vascular abnormalities of the posterior pole that are insufficient for the diagnosis of plus disease but that demonstrate more arterial tortuosity and more venous dilatation than normal.

5. Aggressive posterior ROP (AP-ROP): A rapidly progressing, severe form of ROP. If untreated, it usually progresses to stage 5 ROP. The characteristic features of this type of ROP are its posterior location, prominence of plus disease, and the ill-defined nature of the retinopathy. Previously referred to as “type II ROP” and “Rush disease”. Observed most commonly in Zone I, but may also occur in posterior Zone II.

6. Extent: Extent of involvement of the retina as expressed as clock hours (30 degree sectors)


Screening Criteria (Table 1)

• All babies less than 32 weeks gestational age (up to 31 weeks and 6 days) or less than 1501g birth weight must be screened for ROP.

Screening Protocol

• Minimum frequencies of screening

Weekly when:

    I. the vessels end in zone I or posterior zone II; or
    II. there is any plus or pre-plus disease or
    III. there is any stage 3 disease in any zone.

Every 2 weeks:

• In all other circumstances until the criteria for termination have been reached.

• All babies <32 weeks gestational age or birth weight <1501g should have their first ROP screening examination prior to discharge.

Screening method

Screening can be carried out using the following instruments:
    •    Indirect ophthalmoscope with a 20, 28 or 30 D lens (28D or 30D lens are usually preferred as they allow easier viewing of the peripheral retina).
    •    Eye speculum
    •    Scleral indentor

Indications of treatment\

• According to the CRYO ROP study ablative treatment of avascular retina should be considered in patients with the following features8-10:

Threshold disease of ROP

Defined as having all the following features
  • Stage 3 ROP in zone 1, or zone 2
  • Involving 5 or more contiguous clock hours; or 8 or more cumulative clock hours
  • the presence of plus disease.
High risk pre-threshold disease of ROP

    Defined as any of the following
  • Zone 1, any stage ROP with plus diseas
  • Zone 1, stage 3 ROP without plus disease or
  • Zone 2, stage 2 or 3 ROP with plus disease
The early treatment of high-risk pre-threshold ROP significantly reduces unfavorable outcome.

• Based on results of the Early Treatment for Retinopathy of Prematurity study (ETROP)4 two new terminologies have been suggested:

    Type 1 ROP:
  • Zone I, any stage ROP with plus disease
  • Zone I, stage 3 ROP with or without plus disease
  • Zone II, stage 2 or 3 ROP with plus disease
    Type 2 ROP:
  • Zone I, stage 1 or 2 ROP without plus disease
  • Zone II, stage 3 ROP without plus disease
Peripheral retinal ablation should be carried out for all cases with type 1 ROP and continued serial examinations are advised for type 2 ROP

This study suggested that treatment should be carried out as soon as possible, ideally within 2-3 days of the diagnosis. Laser treatment earlier than threshold ROP has shown better results and outcome after the ETROP guidelines. The rational is that the disease can advance rapidly and any delay in treatment will reduce the chances of success.

• Types of treatment

The principle of treatment is to remove the stimulus for growth of new blood vessels by ablating the peripheral avascular retina. This will in turn reduce the incidence of retinal detachment and consequent blindness. The various modalities available are:


Cryotherapy significantly improves the outcome of severe ROP. This has been largely superceded by laser photocoagulation due to its higher incidence of treatment related complications.

Cryotherapy can result in ocular complications like eyelid edema, laceration of the conjunctiva, and pre-retinal and vitreous haemorrhage as well as systemic complications like bradycardia, cyanosis and respiratory depression.

Although cryotherapy was the standard method of treating ROP in the CRYO-ROP study, 810nm diode laser therapy is now the technique of choice.

Laser Therapy

It is the procedure of choice, being less invasive, less traumatic to the eye and minimal discomfort to the infant. Both argon and diode laser can be delivered through an indirect ophthalmoscope .Laser burns should be applied to peripheral avascular retina and placed one half width apart. Complications include burns in cornea and iris , cataract, vitreous haemorrhage, retinal breaks and detatchment.

Laser therapy has been cited as causing lower rates of postoperative ocular and systemic complications and less damage to the adjacent tissues compared with cryotherapy[11] (Table 2)


The BEAT-ROP[12] trial was underpowered to evaluate the safety of intravitreal bevacizumab in premature infants. Despite the assertion by Mintz-Hittner et al that bevacizumab does not penetrate the retina and enter the systemic circulation, bevacizumab has been measured in both the contralateral eyes and serum in animal models. Concerns that systemic vascular endothelial growth factor (VEGF) suppression following intravitreal injections may lead to adverse events such as strokes, myocardial infarctions, hypertension and proteinuria have been evaluated in numerous trials and meta-analyses, but firm conclusions have still not been reached.[4]

The BEAT-ROP study points out the need for careful follow-up of treated infants until a definable endpoint is reached: full vascularization of the retina or treatment failure. Recurrent retinopathy was discovered at an average of 6.6 weeks in the eyes treated with laser photoablation. Whereas previous reports have hinted that recurrences following intravitreal bevacizumab could be seen up to 2 months later, the BEAT-ROP study found that ROP recurrence in eyes treated with bevacizumab was seen an average of 16.0 weeks after injection.

Treatment of advanced disease

Neither cryotherapy nor laser photocoagulation is successful in all cases of advanced disease. Despite meticulous management there may be serious sequelae.

Scleral buckling/ Vitreoretinal surgery

Scleral buckling is advocated for stage 4B and stage 5 ROP.[14] Lens sparing vitreous surgery can also be carried out, preferably at 38 to 42 weeks of postmenstrual age.[15]

Lens sparing vitrectomy is the most promising recent innovation for stage 4A and 4B ROP retinal detachment. Lens sparing vitrectomy has shown reattachment in 60% to 85% of such cases with good visual outcomes in various reported series.[4] A lensectomy- vitrectomy is performed in stage 5 ROP. The reattachment of retina is possible in less than one third of such cases and visual results are usually very poor. Most babies with stage 5 ROP result in bilateral irreversible blindness and require visual rehabilitation.

Disorganised anterior segment

Lens aspiration should be considered in children with advanced cicatricial ROP with shallow or flat anterior chamber. It is done to prevent secondary glaucoma which may develop due to anterior pulling of lens iris diaphragm.

Complications of ROP
  • Myopia occurs in about 80% of infants with ROP.[16]
  • Strabismus and amblyopia are also common residual findings.[17] The prevalence of strabismus ranges from 23% to 47% in infants with ROP and found to be 20% in a regional study.
  • Retinal detachment has been seen in 22% patients.[18]
  • Retinal detachment may even occur in sub-threshold ROP.[19]
  • Acute angle closure glaucoma can be seen in cicatricial ROP.[20]

Judicious oxygen therapy[21]

Oxygen is a drug and it should be administered in a quantity that is absolutely necessary. If a preterm neonate born at < 32 weeks gestation needs resuscitation at birth, inhaled oxygen concentration (FiO2) should be titrated to prevent hyperoxia and achieve gradual increase in oxygen saturation (70% at 3 minute and 80% at 5 minute after birth).

Judicious use of blood transfusions

Transfusion of packed RBCs is another risk factor of ROP. Adult RBCs are rich in [2,3] DPG and adult Hb binds less firmly to oxygen, thus releasing excess oxygen to the retinal tissue.

Vitamin E Supplementation[22]

Very low birth weight neonates should receive 15-25 IU of vitamin E daily as supplement. However, higher doses given by intravenous route have been associated with increased risk of neonatal sepsis.

Follow up

Post screening

•    Assessment of vision should be carried out in all pre-term infants throughout the first year of life to detect associated disorders like neurological abnormalities and amblyopia.
•    Periodic monitoring of visual acuity is also carried out since severe ROP may be associated with impaired visual development.

Children treated for ROP

Post treatment follow- up should be carried out for all infants till they reach pre-school years, to monitor the development of vision, refractive status and strabismus.

Children with threshold ROP
  • Follow - up examinations should be tailored individually.
  • If adequate laser/cryotherapy treatment has been given, and the disease has fully regressed, a follow-up examination should be carried out at 3 months.
  • Cycloplegic refraction should be performed at 6 months.
Children with complications of ROP

Ophthalmologist must ensure that the child gains early access to the services for the visually impaired. The social and educational services provide much needed support to these children.


To summarise ROP is potentially blinding disease of premature infants. An effective screening protocol can detect all the babies who require treatment. Laser therapy and cryotherapy have been the accepted modalities of treatment for uncomplicatede disease, Laser being the current standard of treatment. Till adequate safety data is available, use of intravitreal anti-VEGF therapy should be restricted to the cases not showing adequate response to standard laser therapy. Stage 4  ROP treated with lens sparing vitrectmyusuallyshows fairly good results.

  1. Flynn JT. The premature retina: a model for the in vivo study of molecular genetics? Eye 1992; 6 ( Pt 2):161-5.
  2. Terry TL: Extreme prematurity and Fibroplastic overgrowth of persistent vascular sheath behind each crystalline lens. Am J Ophthalmol 1942; 25:203-4.
  3. Zacharias L: Retrolental fibroplasia survey. Am J Ophthalmol 1952; 35:1427-54.
  4. Early Treatment for Retinopathy of Prematurity Cooperative Group. Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial. Arch Ophthalmol 2003; 121:1684-94.
  5. Chow LC, Wright KW, Sola A; CSMC Oxygen Administration Study Group. Can changes in clinical practice decrease the incidence of severe retinopathy of prematurity in very low birth weight infants? Pediatrics 2003; 111:339-45.
  6. An international classification of retinopathy of prematurity. The Committee for the Classification of Retinopathy of Prematurity Arch Ophthalmol 1984; 102:1130-4.
  7. The report of a Joint Working Party of The Royal College of Ophthalmologists and the British Association of Perinatal Medicine. Retinopathy of prematurity: guidelines for screening and treatment. Early Hum Dev 1996; 46:239-58.
  8. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity. Preliminary results. Arch Ophthalmol 1988; 106:471–9.
  9. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity. One-year outcome—structure and function. Arch Ophthalmol 1990; 108:1408 –16.
  10. Cryotherapy for Retinopathy of Prematurity Cooperative Group. 15-year outcomes following threshold retinopathy of prematurity: final results from the multicenter trial of cryotherapy for retinopathy of prematurity. Arch Ophthalmol 2005; 123:311– 8.
  11. Paysse EA, Lindsey JL, Coats DK, Contant CF Jr, Steinkuller PG. Therapeutic outcomes of cryotherapy versus transpupillary diode laser photocoagulation for threshold retinopathy of prematurity. J AAPOS 1999; 3:234-40.
  12. Mintz-Hittner HA1, Kennedy KA, Chuang AZ; BEAT-ROP Cooperative Group. Efficacy of intravitreal bevacizumab for stage 3_ retinopathy of prematurity. N Engl J Med 2011; 364:603–15.
  13. Tolentino M. Systemic and ocular safety of intravitreal anti- VEGF therapies for ocular neovascular disease. Surv Ophthalmol 2011; 56:95–113.
  14. Trese MT. Scleral buckling for retinopathy of prematurity. Ophthalmology 1994; 101:23-6.
  15. Capone A, Trese MT. Lens sparing vitreous surgery for Tractional 4A ROP retinal detachments, Opthalmology 2001; 108:2068–70.
  16. O’Connor AR, Stephenson T, Johnson A, Tobin MJ, Moseley MJ, Ratib S, et al. Long-term ophthalmic outcome of low birth weight children with and without retinopathy of prematurity. Paediatrics 2002; 109:12-8.
  17. Theng JT, Wong TY, Ling Y. Refractive errors and strabismus in premature Asian infants with and without ROP. Sing Med J 2000; 41:393-7.
  18. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity: ophthalmological outcome at 10 years. Arch Ophthalmol 2001; 119:1110 - 8.
  19. Gurdian SJ, Gehlbach PL, Hunyor AP, Robertson JE. Retinal detachment associated with subthreshold ROP. J Pediatr Ophthalmol Strabismus 2001; 38:279-83.
  20. Ritch R, Chang BM & Liebmann JM. Angle closure in younger patients. Ophthalmology 2003; 110:1880-9.
  21. Supplemental Therapeutic Oxygen for Prethreshold Retinopathy Of Prematurity (STOPROP), a randomized, controlled trial. I: primary outcomes. Pediatrics 2000; 105:295-310.
  22. Brion LP, Bell EF, Raghuveer TS. Vitamin E supplementation for prevention of morbidity and mortality in preterm infants. Cochrane Database Syst Rev 2003:CD003665.
  23. Prenner JL, Capone A Jr, Trese MT. Visual outcomes after lens-sparing vitrectomy for stage 4A retinopathy of prematurity. Ophthalmology 2004; 111:2271-3.


Neha Rathie, Birbala Okram, Lavi Mangla, Pragya SainiRetinopathy of Prematurity.DJO 2016;27:92-96


Neha Rathie, Birbala Okram, Lavi Mangla, Pragya SainiRetinopathy of Prematurity.DJO [serial online] 2016[cited 2021 Mar 2];27:92-96. Available from: