Retinopathy of prematurity - ROP

 

INTRODUCTION: 

Retinopathy of prematurity (ROP) stands as a formidable challenge in the realm of neonatal care, posing a significant threat to the delicate ocular health of premature infants. As these tiny newborns undergo life-saving oxygen therapy, an unintended consequence unfolds within their developing retinas – a cascade of vascular and capillary proliferation that marks the onset of ROP. This disease, characterized by aberrant vessel growth, holds the potential to inflict irreversible damage upon the retina, including daunting complications such as retinal detachment and macular folds.

Guidelines for screening, the cornerstone of combating this leading cause of childhood blindness, hinge upon a nuanced interplay of factors, notably gestational age and birth weight. Yet, the complexity of ROP extends beyond these metrics, with numerous contributors augmenting both the incidence and severity of its progression. In the face of this multifaceted challenge, early intervention emerges as a beacon of hope, offering improved visual outcomes through treatment modalities such as cryotherapy, laser photocoagulation, and anti-vascular endothelial growth factor (VEGF) therapy.

However, the crux of addressing ROP lies not only in treatment but in proactive prevention – a journey that demands a comprehensive, multidisciplinary approach spanning from prenatal care to the formative years of childhood. In this blog, we embark on a journey to unravel the intricacies of ROP, delving into its etiology, screening protocols, treatment options, and the imperative quest for prevention. Join us as we navigate through the labyrinth of ROP, seeking to shed light on this critical aspect of neonatal healthcare.

ROP: 

Retinopathy of prematurity (ROP) is a disease of retinal vascular and capillary proliferation affecting premature infants undergoing oxygen therapy. Oxygen treatment results in pathologic growth of vessels in the developing retina that may lead to permanent damage to the retina as well as retinal detachment and macular folds.

ETIOLOGY: 

  • In Utero Development:

  • The retina develops in a state of physiological hypoxia during pregnancy.
  • Vascular endothelial growth factor (VEGF) plays a crucial role in promoting retinal blood vessel growth during this time.


  • Normal Vascular Development:

  • There are two phases of normal vascular development: vasculogenesis and angiogenesis.
  • Vasculogenesis occurs from the 14th week to the 21st week of pregnancy.
  • Angiogenesis begins at the 22nd week and continues until the retina is fully vascularized after birth.


  • Incomplete Vascularization in Preterm Infants:

  • The nasal and temporal portions of the retina develop late in pregnancy, around 32 and 40 weeks respectively.
  • Preterm infants are born before these portions of the retina are fully vascularized.
  • Physiological hypoxia, which drives vessel development, is replaced by hyperoxia in preterm infants due to exposure to supplemental oxygen in addition to atmospheric oxygen.

EPIDEOMIOLOGY:

Incidence of ROP:

  1. In infants weighing less than 1251g, the incidence of any stage of ROP was 68%.
  2. Globally in 2010, approximately 184,700 infants and 14.9 million preterm infants developed any stage of ROP.
  3. Out of these, 20,000 infants suffered blindness or severe visual impairment, while 12,300 developed mild to moderate visual impairment.

Key Risk Factors:

  1. Gestational age (GA) and birth weight (BW) are the strongest known risk factors for ROP.
  2. For each 100g increase in BW, the odds of developing threshold ROP decreased by 27%, and for each additional week in GA, the odds decreased by 19%.

  • Role of Oxygen:

    Oxygen therapy, particularly when combined with atmospheric oxygen, reverses physiological hypoxia, leading to retinal ischemia and subsequent overgrowth of retinal vessels in ROP.
    Higher concentrations of oxygen delivered independently increase the risk of ROP.
    For every 12-hour period with transcutaneous PO2≥80mmHg, the risk of ROP doubles.
    Duration of oxygen therapy is also a significant risk factor for severe ROP.


  • Other Risk Factors:

    • Hypertensive disorders of pregnancy, maternal diabetes, medication use, maternal age, smoking, assisted conception, birth outside of a study center hospital, and multiple gestations are possible risk factors for ROP.


    PATHOPHYSIOLOGY:

    Vasculogenesis and Angiogenesis:
      1. Vascular precursor cells (VPCs) exit from the optic nerve during vasculogenesis to form the four major arcades of the posterior retina.
      2. Angiogenesis involves the proliferation of endothelial cells from the existing vasculature formed during vasculogenesis.


    3. Incomplete Retinal Development:

      1. Certain portions of the retina, specifically the nasal and temporal portions, do not complete development until 32 and 40 weeks respectively.
      2. After birth, exposure to atmospheric and supplemental oxygen leads to a rapid shift from relative hypoxia in utero to hyperoxia.


    5. Role of IGF1:

      1. Insulin-like growth factor 1 (IGF1), which regulates vascular endothelial growth factor (VEGF)-mediated vascular growth, is synthesized dependent upon adequate amino acid and energy supplies.
      2. Preterm infants may experience relative nutritional deficiency after birth, leading to depressed serum IGF1 levels.


    7. Phase 1 of ROP:

      1. Hyperoxia and low IGF1 result in delayed retinal vascularization.
      2. Developing capillaries undergo vasoconstriction and eventual obliteration, constituting phase 1 of ROP.


    9. Phase 2 of ROP:

      1. Normal angiogenesis declines, and pathologic angiogenesis becomes predominant.
      2. There is an increase in VEGF release into the vitreous, a drop in IGF1 levels, and hypoxic injury damages peripheral avascular retinal neurons.
      3. High levels of VEGF in the vitreous lead to the growth of pathologic vessels out of the retina.

    1. EVALUATION:

    2. Indications for Screening:

      1. Perform a dilated fundus exam on infants born at ≤30 weeks gestational age (GA) and infants with birth weight (BW) ≤1500g.
      2. Screening should start at 4 weeks postnatal age or corrected GA of 30 to 31 weeks in the neonatal intensive care unit (NICU) or special newborn care unit, but can also be done outpatient.


    4. Preparation for Examination:

      1. Dilate pupils with 2.5% phenylephrine hypochloride and 1% cyclopentolate or tropicamide.
      2. Administer two instillations in a 15-minute period to achieve dilation, with care taken to prevent systemic absorption.
      3. Note that pupils may fail to dilate in advanced ROP, and a nurse should be present during the examination due to potential apnea and bradycardia in infants


    6. Use of Screening Criteria (G-ROP):

      1. Utilize the Postnatal Growth and Retinopathy of Prematurity Screening Criteria (G-ROP) to limit unnecessary screenings while capturing every case of ROP.
      2. These guidelines include weight gain as a variable in deciding whether or not to screen, reducing screened infants by 30%.


    8. Classification of ROP:

      1. Classify ROP in terms of zone and stage of the disease using the International Classification of Retinopathy of Prematurity.
      2. Zone I, II, and III refer to specific locations of the retina.

    1. - The three zones of ROP are centered on the optic disc. - Zone I is a small circle around the optic disc, with a radius twice the distance from the macula to the center of the optic disc. - Zone II is a ring-shaped section surrounding Zone I, extending to the ora serrata on the nasal side. - Zone III is a crescent-shaped area in the temporal retina. - ROP in Zone I is more likely to progress and become severe compared to ROP in Zones II or III.

    3. 3. There are 5 stages to describe the severity of ROP, with each stage indicating specific retinal and vascular patterns at the border of the vascular and avascular retina.

    Stage 1 ROP: The demarcation line. a whitish line is visible between the normally vascularised retina and the peripheral retina in which there are no blood vessels. 

    Stage 2 ROP: The demarcation line develops into a ridge, with height and width, between the vascular retina and peripheral retina

    Stage 3 ROP: Ridge with extra retinal fiber vascular proliferation into the vitreous. This stage is further divided into my moderate and severe, depending on the amount of fiber vascular proliferation.

    Stage 4a ROP: Subtotal retinal detachment not involving the macular is a feature of this stage. occurs as a result of exudation from incompetent blood vessels or traction from the fibrous tissue.

    Stage 4b ROP: Subtotal retinal detachment involving the macula occurs in this stage. Vitreoretinal surgery may be indicated.

    Stage 5 ROP: This is the most severe stage where a complete detachment of the retina happens, often rendering treatment ineffective.

    2. Plus Disease:
    • Presence of engorged veins and tortuous arteries in at least two quadrants at the posterior pole with any stage of ROP.
    • Associated with engorgement and dilation of iris vessels, leading to poor pharmacological dilation of pupils.
    • Indicates a tendency to progression, noted by adding "plus" sign after the stage of ROP.

    1. Preplus Disease:

    • Venous dilation and arterial tortuosity are more than normal but not sufficient to be defined as plus disease.

    1. Aggressive Posterior ROP (APROP):

    • Also known as "rush disease."
    • ROP located in zone one with disease out of proportion to peripheral retinopathy or in posterior zone 2 with severe disease.
    • Requires immediate treatment as it may progress rapidly to stage five ROP without passing through other stages.

    Threshold Disease:

    • Refers to stage 3 + ROP.
    • Located in zone one or two, involving five continuous or eight discontinuous clock hours.
    • Requires therapy within 72 hours to prevent progression

    1. TREATMENT/MANAGEMENT:

    3. Early Detection and Classification:

    • Not all cases of retinopathy of prematurity (ROP) require treatment.
    • Treatment decisions depend on the type of ROP classified as Type I or Type II.

      1. Type I ROP Treatment:


        • Type I ROP includes any stage zone I ROP with plus disease, zone I, stage 3 with or without plus disease, or zone II, stage 2 or 3 with plus disease.
        • Observation is recommended for Type II ROP.

      1. Surgical Treatment Options:

        1. Cryotherapy was the first surgical treatment for ROP but has been largely replaced by laser photocoagulation.
        2. Laser photocoagulation is the standard treatment for ROP, offering improved outcomes compared to cryotherapy.
        3. Surgical interventions are indicated in advanced stages of ROP (Stage 4A, 4B, and 5) to prevent retinal detachment and improve visual outcomes.


      3. Anti-VEGF Therapy:

        1. Anti-VEGF agents, such as intravitreal bevacizumab, are being explored as treatment options for ROP.
        2. Studies have shown promising results in reducing the recurrence of ROP, particularly in zone I disease.
        • However, concerns regarding late reactivation of ROP and potential systemic effects of anti-VEGF therapy persist.

      4. Considerations for Surgical Outcomes:

        1. Surgical interventions aim for both anatomical success (retinal attachment) and functional success (visual acuity).
        2. Modalities for surgical intervention include scleral buckling, vitrectomy, and lensectomy, depending on the stage of ROP.
        3. Anatomical success rates vary but may range between 13% and 45.5%.

      1. Surgical Intervention for Advanced ROP:

      • Retinal detachment poses a higher risk of poor visual outcome in advanced ROP.
      • Stage 4A, 4B, and 5 ROP require surgical intervention.
      • Surgical approaches include scleral buckling, lens sparing vitrectomy, lensectomy with vitrectomy, or open sky vitrectomy.
        • DIFFERENTIAL DIAGNOSIS:
        1. Familial exudative vitreoretinopathy
        2. Persistent fetal vasculature
        3. Incontinetia pigmenti

        • PROGNOSIS

          • Improved Treatment Outcomes:


          • Advances in treatment have improved outcomes for retinopathy of prematurity (ROP) patients.
          • Despite improvements, many treated patients still experience adverse visual acuity outcomes.

          • Avoidance of Unfavorable Structural Outcomes:

          • One treatment goal is to avoid unfavorable retinal structural outcomes defined by the ETROP study.
          • These outcomes include posterior retinal fold involving the macula, macular-involved retinal detachment, retrolental tissue obscuring the posterior pole, or need for vitrectomy/scleral buckling.


          • Reduction in Unfavorable Structural Outcomes:

          • Follow-up to the ETROP study revealed a reduction in unfavorable structural outcomes to 9.1% in high-risk pre-threshold eyes treated early at 2 years.


          • Visual Acuity Outcomes:

          • Six-year follow-up of the same sample showed varying visual acuity outcomes:
            • 34.6% had a visual acuity (VA) of 20/40 or better.
            • 40.3% had an acuity greater than 20/40 and less than 20/200.
            • 23.7% had an acuity worse than 20/200, including light perception and blindness.
          COMPLICATION:

          • Retinal Detachment:

            • Most frequent complication of retinopathy of prematurity (ROP).
            • Strongly associated with poor visual outcome.

          • Macular Folds:

            • Another common complication of ROP.

          • Threats to Visual Acuity:

            • Persist through childhood.
            • Most common sequelae is myopia.

          • Late Complications:

            • Glaucoma, amblyopia, cataract, and strabismus are other late complications associated with ROP.

          • Low Vision Impact:

            • Low vision secondary to ROP leads to higher rates of developmental, educational, and social challenges.
            • Unfavorable visual status (limited to light perception or no light perception) associated with:
              • Higher rates of developmental disability.
              • Epilepsy.
              • Need for special education.
              • Below-grade-level academic performance.
        • Reference: 
        1. Tomita Y, Usui-Ouchi A, Nilsson AK, Yang J, Ko M, Hellström A, Fu Z. Metabolism in Retinopathy of Prematurity. Life. 2021; 11(11):1119. https://doi.org/10.3390/life11111119
        2. Molinari A, Weaver D, Jalali S. Classifying retinopathy of prematurity. Community Eye Health. 2017;30(99):55-56. PMID: 29434438; PMCID: PMC5806220.
        3. Khurana, A. K. (2019). Comprehensive ophthalmology. Jaypee brothers medical publishers.

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