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REVIEW ARTICLE
Year : 2018  |  Volume : 4  |  Issue : 3  |  Page : 116-120

Retinopathy of Prematurity


Department of Ophthalmology, DDU ZH, Shimla, Himachal Pradesh, India

Date of Web Publication31-Dec-2018

Correspondence Address:
Dr. Mukta Sharma
DDU ZH, Shimla, Himachal Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mamcjms.mamcjms_66_17

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  Abstract 


Retinopathy of Prematurity (ROP) is a bilateral proliferative retinopathy affecting premature infants with low birth weight,who have been exposed to excessive oxygenation, resulting in dysregulated vascular endothelial growth factor expression and thus untimely vasoobliteration or exaggerated vasoproliferation.Screening for ROP is mandatory in such infants so as to prevent this blinding disorder.

Keywords: Prematurity, retinopathy, retrolental fibroplasias


How to cite this article:
Sharma M, Sareen A, Negi SS. Retinopathy of Prematurity. MAMC J Med Sci 2018;4:116-20

How to cite this URL:
Sharma M, Sareen A, Negi SS. Retinopathy of Prematurity. MAMC J Med Sci [serial online] 2018 [cited 2019 Oct 18];4:116-20. Available from: http://www.mamcjms.in/text.asp?2018/4/3/116/249034




  Introduction Top


Retinopathy of prematurity (ROP), previously known as retrolental fibroplasia, is a bilateral proliferative retinopathy affecting premature infants with low birth weight who have been exposed to high concentration of oxygen. The retinopathy was first reported by Terry[1] in 1942. ROP can be seen in 85% to 90% of children with low birth weight when exposed to high concentration of oxygen.[2] The incidence of ROP in India varies between 24% and 48% in low birth weight infants.[3]


  Pathogenesis Top


A vanguard of mesenchymal cells initially grows outwards in the nerve fibre layer (NFL) from the region of the optic disc beginning at around 16 weeks of gestation. These mesenchymal cells give rise to retinal capillary endothelial cells, which then form the capillary system. When excessive oxygenation is used in the nursing of premature infants, ex utero changes in oxygen tension cause abnormal up or downregulation of vascular endothelial growth factor (VEGF) expression. Dysregulated VEGF expression leads to untimely vaso-obliteration or exaggerated vasoproliferation. Retinal arteries and eventually the veins are obliterated, inciting a phase of neovascularization and fibrous proliferation, resulting in different stages of ROP.[4] In rare cases, ROP has been found in some patients with a mutation in norrie disease protein (NDP) gene, which is normally associated with Norrie disease.[5],[6]

Various risk factors which contribute to the development of ROP are prematurity, high exposure to oxygen, low birth weight, cardiac defects, and infections.[7],[8]

Epidemiology

ROP prevalence varies from 5% to 8% in developed countries to up to 30% in developing countries. ROP is now a public health problem in middle-income countries.[9],[10]

Incidence of ROP is increasing in developing countries including India, because of improved neonatal survival rate. This is referred to as the third epidemic of ROP. Out of 26 million annual live births, approximately 2 million are less than 2000 g in weight and are at risk of developing ROP. In India, approximately one in 1000 children is blind. The incidence of ROP in India varies between 39% and 51.9% in low birth weight infants.

In 2012, WHO published data on rates of preterm birth and the number of premature babies born in different regions of the world. According to this report, premature birth has many different causes, and the prevention is challenging. Prematurity is the most common cause of neonatal death.[11] The first case of the epidemic was seen on St. Valentine’s Day in 1941, when the premature baby in Boston was diagnosed.[12]


  Classification Top


International Classification of ROP was developed in 1984, modified in 1987, and revisited in 2005.[13],[14] It takes into account the following:
  1. Location of ROP by zone
    • Zone I: Optic disc (OP) at the center and twice the distance between optic disc and the fovea as its radius
    • Zone II: Extends from the zone 1 to the nasal ora serrata anteriorly
    • Zone III: Remaining temporal peripheral retina
  2. Extent of ROP by the number of clock-hours involved
  3. Severity of ROP by the stage
    • Stage 1: The presence of a demarcation line between vascularized and avascularized retina
    • Stage 2: The presence of demarcation ridge that has height, width, and volume
    • Stage 3: A ridge with extraretinal fibrovascular proliferation [[Figure 1]]
      Figure 1 Fundus photograph showing extraretinal fibrovascular proliferation, stage 3 retinopathy of prematurity (ROP)

      Click here to view
    • Stage 4: Subtotal retinal detachment
      1. Extrafoveal
      2. Retinal detachment including fovea [[Figure 2]]
        Figure 2 Fundus photograph showing partial retinal detachment involving macula, stage 4B retinopathy of prematurity (ROP)

        Click here to view
    • Stage 5: Total retinal detachment


Plus disease: It is not a disease different from ROP but is a descriptive term for vascularly active eye with the potential to progress rapidly. It is characterized by the presence of engorged and tortuous vessels in at least two quadrants at the posterior pole with any stage of ROP, along with the vitreous haze [[Figure 3]]. In addition, the anterior segment in plus disease often shows dilated iris vessels [[Figure 4]]. A “+” or “plus” is added following the ROP stage number to designate the presence of plus disease. Stage 3 ROP with plus disease would be written as 3+ ROP.[14]
Figure 3 Fundus photograph of venous dilation and arteriolar tortuosity characteristic of plus disease

Click here to view
Figure 4 Anterior segment photograph of an eye with iris vessel engorgement

Click here to view


Prethreshold disease: Defined as ROP in
  • Zone 1: any stage
  • Zone 2: Stage 2 with plus component
  • Zone 2 or 3: Stage 3 with plus component but not reaching threshold clock-hours


It needs very close observation, as it can rapidly progress to threshold disease which needs prompt treatment.

Threshold disease: It is characterized by more than 5 contiguous clock-hours or 8 cumulative clock-hours of extraretinal neovascularization in association with plus disease and location of the retinal vessels within zone 1 or 2 [[Figure 5]]. It is an indication for treatment. It needs laser or cryotherapy in less than 72 h.[15],[16]
Figure 5 Zones of the retina with the threshold criteria for retinopathy

Click here to view



  Screening in India Top


National Neonatology Forum guidelines for screening are followed in India.[17] According to these guidelines, screening for ROP should be performed in all preterm neonates who are born at
  • Gestational age: 34 weeks or less and/or
  • Birth weight: 1750 g or less
  • As well as in babies 34 to 36 weeks gestation or 1750 to 2000 g birth weight, if they have risk factors for ROP



  Timing of Screening Examinations Top


  • The first retinal examination should be performed not later than 4 weeks of age or 30 days of life in infants born ≥28 weeks of gestational age (30 days rule).
  • Infants born <28 weeks or <1200 g birth weight should be screened early, by 2 to 3 weeks of age, to enable early identification of aggressive posterior (AP)-ROP


Indirect ophthalmoscope with a 28-D condensing lens is used to examine the fundus. Scleral depression is then used to examine the nasal retina, followed by the temporal retina to establish the proximity of retinal vessels to the ora serrata [[Figure 5]].

The standard approach is to assess
  • The peripapillary vessels to determine whether plus disease is present or not
  • The status of retinal vascularization by examining the nasal retina to determine if the vessels have reached the nasal ora serrata
  • The presence and severity of retinopathy
  • The extent of the retinopathy


Careful determination of these four parameters allows the clinician to assess most accurately the severity of the retinopathy and to develop an appropriate plan for follow-up. It is advisable to screen the baby every 1 week at least until the infant is 38 to 40 weeks of postmenstrual age. Conclusion of the retinal screening examinations should be based on whether full retinal vascularization has occurred or not. This usually occurs at about the 40th week of postmenstrual age and mostly completes by the 45th week.[17],[18],[19]


  Treatment Top


The ultimate goals of treatment of threshold ROP are
  • Prevention of any retinal detachment or scarring
  • Optimization of visual outcome



  Laser Photocoagulation Top


Laser has become the instrument of choice. The aim of the treatment is to ablate the entire peripheral avascular retina up to the ora serrata in a near-confluent burn pattern getting as close to the edge of the ridge as possible. Photocoagulation is delivered through a dilated pupil with a 20 or 28-D condensing lens using a portable diode or argon laser with an indirect ophthalmoscope. The endpoint is near-confluent ablation, with burns spaced one-half burn width apart, from the ora serrata up to, but not including the ridge for 360°. The retina should be inspected for skip areas. Treated eyes are evaluated in about a week to consider retreatment. Persistent plus disease or fibrovascular proliferation is an indication for additional treatment.[20],[21],[22]

Indications for utilizing cryotherapy over laser in the management of ROP include poor fundus visibility, lack of availability of laser, or treating physician’s unfamiliarity with indirect laser retinopexy techniques.[23]

Intravitreal injection of injection bevacizumab has been reported as a supportive measure in aggressive progressive ROP.[24],[25],[26],[27]

Oral propanolol is being evaluated for countracting the progression of ROP, but safety is a concern. A study in a mouse model of human ROP has shown that the beta blocker is protective against retinal angiogenesis and ameliorates blood retinal barrier dysfunction.[28],[29]


  Surgical Treatment Top


Goal of surgical intervention varies with the severity of the detachment for extramacular retinal detachment (stage 4A ROP):
  • Undistorted or posterior pole
  • Total retinal reattachment
  • Preservation of the lens


Surgery for stage 4B ROP is performed:
  • To minimize retinal distortion and prevent total detachment (stage 5)
  • The functional goal is ambulatory vision


The surgical techniques for stage 4 include scleral buckling and vitrectomy. The surgical techniques used in stage 5 are confined to:
  • Closed lensectomy and pars plicata vitrectomy with membrane peeling accompanied occasionally by drainage of subretinal fluid
  • Open-sky vitrectomy with intracapsular lensectomy and membrane peeling has also been used for those eyes in which the anterior segment is clouded and will not allow closed vitrectomy.[30]


The Early Treatment for Retinopathy of Prematurity Cooperative Group sought to reevaluate the timing of intervention in eyes with ROP.[31],[32]

As infants afflicted with ROP have matured, the ophthalmic community has gained experience with “Adult ROP” with early nuclear sclerotic cataract, glaucoma, exudative retinopathy, and rhegmatogenous retinal detachment.


  Future Therapeutic Targets Top


The discovery of the importance of VEGF and immunoglobulin (Ig1) in the development of ROP is a step forward in our understanding of the pathogenesis of the disease.[33] Investigation of other conditions with incomplete retinal vascularization such as Norrie’s disease, familial exudative vitreoretinopathy, and incontinentia pigmenti might provide insight into the treatment of ROP. One form of VEFR is caused by Frizzled 4 gene defect. Both Norrin (protein product of Norrie disease gene) and Frizzled 4 gene causes similar defects in human and mice with incomplete retinal vascularization and lack of deep retinal vessels.[34],[35],[36] It has been shown that Norrin ligand binds to Frizzled 4, a Wnt receptor, and ectopic Norrin restores retinal vascularization in Norrie’s disease mice. These findings give us a possibility of new pharmacological therapy for eye diseases with incomplete vascularization of peripheral retina.[37] Supplementation with vitamin A, omega-3 fatty acids, and inositol are all exciting arenas for further trials as preliminary data show promising results in ROP prevention.[38]

Strategies for control of ROP: According to guidelines issued by American Academy of Pediatrics[39],[40],[41]:
  • Prevention of premature births
  • Improved neonatal care
    • Reduce sepsis
    • Better oxygen monitoring
  • [Arterial oxygen tension at 45 to 80 mmHg with oxygen saturation limits of 85% and 93% for preterm infants with gestational age (GA) <32 weeks]*
  • Regular screening


Thus, collaborative efforts involving the pediatrician, neonatologist, and the ophthalmologist are required to prevent this preventable cause of blindness in children. Failure to diagnose and treat ROP and its complications in a timely fashion increases the legal exposure of physicians caring for children with ROP.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Dickinson JL, Sale MM, Passmore A, Fitzgerald LM, Wheatley CM, Burdon KP et al. Mutations in the NDP gene: Contribution to Norrie disease, familial exudative vitreoretinopathy and retinopathy of prematurity. Clin Exp Ophthalmol 2006;34:682-8.  Back to cited text no. 5
    
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Repka MX, Palmer EA, Tung B. Involution of retinopathy of prematurity (ROP). Arch Ophthalmol 2000;118:645-9.  Back to cited text no. 16
    
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Jalali S, Hussain A, Matalia J, Anand R. Modification of screening criteria for retinopathy of prematurity in India and other middle-income group countries. Am J Ophthalmol 2006;141:966-8.  Back to cited text no. 17
    
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Ells A, Holmes JM, Astle WF, Williams G, Leske DA, Fielden M et al. Telemedicine approach to screening for severe retinopathy of prematurity: A pilot study. Ophthalmology 2003;110:2113-7.  Back to cited text no. 18
    
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[PUBMED]  [Full text]  
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Dobson V, Quinn GE, Summers CG, Hardy RJ, Tung B, Good WV. Grating visual acuity results in the early treatment for retinopathy of prematurity study. Arch Ophthalmol 2011;129:840-6.  Back to cited text no. 39
    
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Shah PK, Prabhu V, Karandikar SS, Ranjan R, Narendran V, Kalpana N. Retinopathy of prematurity: Past, present and future. World J Clin Pediatr 2016;5:35-46.  Back to cited text no. 40
    
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Filippi L, Cavallaro G, Bagnoli P, Dal Monte M, Fiorini P, Donzelli G et al. Oral propranolol for ROP.Risks, safety concerns and perspective. J Pediatr 2013 163:1570-7.  Back to cited text no. 41
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]



 

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  In this article
Abstract
Introduction
Pathogenesis
Classification
Screening in India
Timing of Screen...
Treatment
Laser Photocoagu...
Surgical Treatment
Future Therapeut...
References
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