Retinopathy of Prematurity

Retinopathy of prematurity (ROP) is a condition seen in premature infants of low birth weight that is characterized by progressive and excessive neovascularization. In this condition, the inappropriate proliferation of blood vessels and fibrovascular tissue behind the lens prevents retinal development. The end result is severe visual deficits or even blindness of the infant afflicted. Treatment with laser photocoagulation prevents vision loss in 95% of cases.

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Overview

Epidemiology

  • Retinopathy of prematurity is the leading cause of blindness in infants.
  • The incidence of the disease is:
    • Directly proportional to the gestational age of the patient
    • Inversely proportional to their birth weight

Risk factors

  • Low birth weight
  • Low gestational age
  • Supplemental oxygen therapy
  • Genetic predisposition
  • Infections
  • Congenital cardiac defects

Pathophysiology

Premature infants of low birth weight are at risk of developing hyperoxia during their care; this can lead to:

  • Reactive oxygen species production → causing damage to the retina
  • Abnormal vascular endothelial growth factor (VEGF) production → causing abnormal neovascularization
  • Newly formed vessels are different than normal ones:
    • Abnormally permeable
    • Grow outside retina
  • Development of abnormal fibrovascular tissue occurs and pulls the retina, causing retinal detachment.

Progression of retinopathy of prematurity

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Classification

International classification of retinopathy uses a number of parameters to describe the disease:

  • Defining which “zone” is involved
  • Defining the “extent” of retinal involvement (expressed as segments on a clock)
  • Defining the severity of disease, or “stage” (see table below)
  • The presence or absence of  “plus disease” (e.g., venous dilation and arterial tortuosity of the posterior retinal vessels)

Representation of the classification of retinopathy of prematurity

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Table: Stages of retinopathy of prematurity
StagesCharacteristics
1A demarcation line between the vascular and avascular retina
2A demarcation line grows to occupy a volume and a ridge is formed above the plane of the retina, protruding into the vitreous.
3
  • Retinal fibrovascular proliferation
  • Fibrovascular tissue formation; may extend from the abnormal retinal ridge into the vitreous
4Retinal detachment (partial or subtotal)
  • Stage 4A: without macular involvement
  • Stage 4B: with macular involvement
5
  • There is total retinal detachment.
  • The patient presents with leukocoria (white pupillary reflex).

Retinopathy of prematurity: stages

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Screening

Indication to screen

  • All infants of low birth weight (< 1,500 g)
  • All infants born before 30 weeks‘ gestational age
  • Infants between 1,500 g and 2,000 g birth weight and born after 30 weeks’ gestation who are exposed to potential risk factors (see above)

Screening methods

  • When to screen:
    • For infants born between 22 and 26 weeks, when they reach 30 weeks’ corrected gestational age
    • For infants ≥ 27 weeks’ gestational age, starting at 4 weeks after birth
    • Follow-up exams weekly
  • How to screen:
    •  Use indirect ophthalmoscopy or a RetCam digital camera
    • The aim is to look for the features that stage retinopathy.
    • Patients are classified into 2 categories:
      1. Infants with low risk 
      2. Infants with proliferative retinopathy who require laser treatment
    • Risk of progression is determined by:
      • Weight gain 
      • Serum levels of insulin-like growth factor 1 (IGF-1) 
      • Degree of aggressiveness of the retinopathy

Management

  • Early stages (stage 1 or 2 in zone I without plus disease OR stage 3 in zone II without plus disease) require close follow-up without intervention.
  • Indications for treatment:
    • Any stage of retinopathy in zone I with plus disease
    • Stage 3 in zone I without plus disease
    • Stage 2 or 3 in zone II with plus disease
  • Treatment options:
    • Cryotherapy: done under general anesthesia
    • Indirect laser photocoagulation
    • Anti-vascular endothelial growth factor drugs, such as intravitreal bevacizumab
    • Vitrectomy for retinal detachment

Differential Diagnosis

The following conditions are differential diagnoses for blindness in infancy:

  • Cataracts: a condition defined as painless clouding or opacity of the lens that leads to a decrease in vision. Cataracts often develop slowly in one or both eyes. Symptoms may include blurry or double vision, trouble with bright lights, halos around light, faded colors, and trouble seeing at night. Ophthalmologic inspection often shows darkening of or opacities in the red reflex. Slit-lamp examination will show the extent and location of the cataract. Cataracts have a diverse etiology including TORCH infections, trauma, side effects of glucocorticoids, and radiation.
  • Retinal detachment: the separation of the neurosensory retina from the retinal pigmented epithelium. The retina is the innermost layer of the eye, containing cones and rods that are specialized sensory organs used to detect light. Anything affecting the connection between the retina and the choroid can lead to photoreceptor ischemia and painless vision loss as a consequence.
  • Retinoblastoma: the most common primary intraocular malignancy of childhood, accounting for 2% of malignant tumors in children. The condition typically presents as leukocoria (abnormal white reflection in the eye) in children under the age of 2 years. The disease may affect one or both eyes and can appear sporadically or cumulatively in families. Untreated, the condition is fatal, but with age-appropriate treatment there is a > 95% survival rate.

References

  1. International Committee for the Classification of Retinopathy of Prematurity. (2005). The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol. https://pubmed.ncbi.nlm.nih.gov/16009843/ 
  2. Smith LE. (2005). IGF-1 and retinopathy of prematurity in the preterm infant. Biol Neonate. https://pubmed.ncbi.nlm.nih.gov/16210846/
  3. Walter M. Fierson (2018). AMERICAN ACADEMY OF PEDIATRICS Section on Ophthalmology, AMERICAN ACADEMY OF OPHTHALMOLOGY, AMERICAN ASSOCIATION FOR PEDIATRIC OPHTHALMOLOGY AND STRABISMUS, AMERICAN ASSOCIATION OF CERTIFIED ORTHOPTISTS Pediatrics. https://pediatrics.aappublications.org/content/142/6/e20183061

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