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Year : 2017  |  Volume : 9  |  Issue : 1  |  Page : 1-4

Advances in clinical concept of retinopathy of prematurity treatment

1 Department of Eye, Student Research Committee, Tehran University of Medical Sciences, Tehran, Iran
2 Department of Eye, Bu Ali-Sina Hospital, Medical Faculty of Medicine, Mazandaran University of Medical Sciences, Mazandaran, Iran

Date of Web Publication19-Sep-2017

Correspondence Address:
Ahmad Ahmadzadeh-Amiri
Department of Eye, Bu Ali-Sina Hospital, Medical Faculty of Medicine, Mazandaran University of Medical Sciences, Mazandaran
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/sjopthal.sjopthal_8_17

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Retinopathy of prematurity (ROP) continues a major cause of premature infants' blindness and rises the incidence with improved survival of very premature infants. Timely screening for ROP risk and treatment is important to retain visual rehabilitation. Recent advance in genetic studies shows a Wnt pathway ROP linking genes predispose to the evolution of severe ROP. A newly screening method is recommended based on weight gain postnatally in combination with insulin-like growth factor levels for prediction of ROP risk. Anti-vascular endothelial growth factor treatment options for severe cases of ROP have been showed safe in preterm infants. However, several studies suggest that early laser therapy for Type 1 but not Type 2 high-risk ROP makes better visual results. This review gives an outline of the recent advances on ROP with treatment options and screening methods.

Keywords: Insulin-like growth factor, laser photocoagulation, postnatal weight gain, retinopathy of prematurity, vascular endothelial growth factor

How to cite this article:
Ahmadzadeh-Amiri A, Ahmadzadeh-Amiri A. Advances in clinical concept of retinopathy of prematurity treatment. Sudanese J Ophthalmol 2017;9:1-4

How to cite this URL:
Ahmadzadeh-Amiri A, Ahmadzadeh-Amiri A. Advances in clinical concept of retinopathy of prematurity treatment. Sudanese J Ophthalmol [serial online] 2017 [cited 2023 Jan 31];9:1-4. Available from: https://www.sjopthal.net/text.asp?2017/9/1/1/215110

  Introduction Top

Retinopathy of prematurity (ROP) is an important leading cause of blindness in infant.[1] ROP was initially reported premature infant in the 1940s and later connected to highly oxygen supplementation in these infants.[2] ROP incidence rises inversely with weight and gestation at birth. Several studies reported that more than 80% of infants weighing 1000 g and less had ROP while <40% of those weighing more than 1000 g developed ROP.[3],[4],[5] ROP evolve in two phases of disease processes consisting of an initially incomplete retinal vascularization, followed by a second phase of new vascularization.[6] The first phase of ROP occurs from birth to gestational age of 30–32 weeks because of the difference in levels of partial pressure of arterial oxygen 30–35 mm Hg and 55–80 mm Hg, in utero and extrauterine, respectively. Suppression of angiogenic factors from hypoxic retina, leads to decreasing level of vascular endothelial growth factor (VEGF), and the attenuation of already vascularized retina. Anti-VEGF drugs should be withheld in this vaso-obliterative phase. As the retinal maturation progress, its metabolic activity increase and tissue hypoxia may aggravate. This neovascular phase of ROP occurs approximately in 32–42 weeks of gestational age. In this phase, proangiogenic growth factors such as VEGF and erythropoietin (Epo) upregulated, leading to retinal vasoproliferation. As the infant gestational age increases to 43 to at least 54 weeks, there is either a ROP regression with clearance of fibrovascular tissues or a progression of ROP with fibrotic membrane formation. At this cicatrization stage, VEGF downregulated while transforming growth factor beta 1 rises. Although ROP treatments can reduce the chance of blindness, the infants with late-stage diseases often still have poor visual development. This review focuses on the current perspectives in new screening tools to predict methods and newly treatment options of ROP.

  Retinopathy of Prematurity Classification Top

The most popular guideline for the diagnosis of retinopathy of ROP was developed by the International Classification of ROP in 1984.[7] The most important finding in revised classification now put plus disease as a significant sign. Although many computer-assisted systems of plus disease are being evolved, none of these analytic systems has been lie as an accepted care in ROP. Spectral domain optical coherence tomography can be used as a mobile instrument (iVue) for ROP following in infants.[8] Fluorescein angiography also can use in vascular diseases of infant to make a more accurate diagnosis.[9]

The extension of retinal lesion reported by clock hours, area involvement, stage of disease, and plus disease existence are the basic aspects of classification. The retina has three distinct zones. Zone I remarks a circle with a radius from the optic disk to twice the distance from the optic disk and the macula center. Zone II extends from Zone I to the nasal ora serrata. Zone III is the remaining temporal retina forward to Zone II. ROP is categorized in five stages according to vascularity of the retina. The observer rates the disease according to the most severe manifestation observed. The Multicenter Trial of Cryotherapy for ROP appointed the description of threshold disease as at least five contiguous or eight cumulative parts in clock hours of Stage 3 ROP in Zone I or II in the presence of plus disease.[10],[11] The early treatment for ROP was defined the term prethreshold ROP as any ROP in Zone I, or plus disease in Zone I with Stage 2, or Stage 3 disease in Zone II without plus disease, or incomplete Stage 3 with plus disease in Zone II.[12]

  Retinopathy of Prematurity Risk Factors Top

The excessive oxygen intake was recognized as an associated risk of ROP disease.[13],[14] This propels to modify supplemental oxygen protocols to eliminate hyperoxia to the premature retina.[15] However, surprisingly, with controlled oxygen, the ROP incidence has more raised, may be due to the increased survival of premature infants.[16] Oxygen use and prematurity are known risk factors for ROP. Other factors that indicated the overall health of the newborn, such as anemia, hyperglycemia, sepsis, and lung disease may also be associated with ROP evolution.[17],[18] In addition to birth weight and gestational age, early postnatal weight gain and insulin-like growth factor 1 (IGF-1) levels were important for ROP prediction.[19],[20]

In addition, a recent study identified maternal risk factors associated with ROP development. Maternal age also is a risk factor and may suggest population-different maternal risk factor for ROP.[21],[22] Furthermore, recent studies show that three genes (Norrin, Frizzled 4, and Lrp5) in Wnt signaling pathways were found mutated in association with advanced forms of ROP.[23],[24],[25],[26] These finding might explain why ROP in some patients despite timely intervention progresses to severe stage of retinal complication.

  Retinopathy of Prematurity Screening Top

The screening guideline of ROP in developed nations is dilated fundus examination by indirect ophthalmoscopy for all infants below 30 weeks of gestational age or whose birth weight was <1500 g, with the first examination performed by 31 weeks postmenstrual age or by 4 weeks postnatal age whichever comes earlier. Additional follow-up examinations performed repeatedly thereafter according to the presence and severity of the ROP to detect late stage that required treatment.[27],[28] In developing nations, screening should begin at 34 weeks gestational age or weight was <2400 g. Finally, treatment required only in about 10% of those screened for ROP. A major clinical problem occurred in poor early weight gain, as well as low serum levels of IGF-1 after birth that correlated with the progression of severe ROP.[29],[30] Based on these findings, weight, IGF-1, neonatal, ROP is recommend weekly measurements of body weight and serum IGF-1 levels from birth until gestational age 36 weeks.[31] The usefulness of this algorithm in ROP prediction independent of gestational age was confirmed in another study.[32] Recent study showed that plasma sE-selectin rising, an adhesion molecule, can be used as an additional new marker for ROP prediction.[33]

  Retinopathy of Prematurity Treatment Modalities Top

Laser photocoagulation is the current gold standard treatment for Phase II (Type 1 ROP).[34] (defined as Zone I any stage with plus disease, Zone I Stage 3 with or without plus disease, or Zone II Stage 2 or 3 with plus disease). Unfortunately, peripheral retinal ablation is destructive and the retinal vessels never advance beyond the ablated areas. Laser therapy should be considered for eye with threshold or Type 1 ROP. Continued examination before laser therapy should be considered for prethreshold Type 2 ROP (defined as Zone I Stage 1–2 without plus, Zone II Stage 3 without plus). Type 2 ROP progresses to Type 1 or an established threshold ROP are indication for treatment.[35] As in Christiansen et al.'s study finding, approximately 22% of Type 2 ROP eye developed Type 1 ROP with greatest risk of progression between 33 and 36 weeks gestational age.[36] Laser therapy becomes the treatment of choice for ROP soon after clinical studies showed that it is superior to cryotherapy.[37],[38] Recently, Parvaresh et al. found that transscleral diode laser instead of transpupillary laser treatment for threshold ROP also had effective outcomes.[39]

Anti-VEGF therapy is nondestructive which can be used in Phase II-ROP.[40],[41] There are lesser risks of corneal edema, cataract formation, and intraocular hemorrhage in compared with laser photocoagulation. Recent study on premature Korean infants showed that intravitreal bevacizumab injection combined with laser photocoagulation can lead to more rapid ROP regression of plus disease and development of the peripheral retinal vascular bed.[42] The authors reported no significant systemic or ocular complications. Systemic analysis of off-label use of bevacizumab in ROP, alone or in conjunction with other treatments, reported considerable variability in dosing, timing, and treatment frequency.[43] Recent studies suggest that intravitreal bevacizumab in severe ROP reduces the risk of high myopic refractive errors during childhood while complementary intravitreal pegaptanib with laser therapy reduces the risk of retinal detachment.[44] The inadequate documentation precludes strong deductions to advocate common use of intravitreal anti-VEGF agents in Type 1 ROP.

Several studies showed Epo is another growth factor that promotes retinal new vessel formation similarly to VEGF.[45] Recombinant Epo is a known promoter of red blood cell formation, used to treat anemia in some premature infants. Although some studies revealed that Epo levels were significantly elevated in the vitreous from infants with active ROP and as a significant risk factor for ROP,[46],[47] however, in another study of preterm infants, there was no significant correlation between Epo treatment and ROP incidence and severity.[48]

Recently, numerous breakthroughs in angiogenesis research also suggest a number of new ways to potentially intervene in ROP progression such as targeting the IGF-1 pathway and dietary supplementation with omega-3 polyunsaturated fatty acids (PUFAs).[47] Serum IGF-1 is an essential for vascular growth through regulation of VEGF signaling, and maternal/fetal circulation interruption can substantially reduced it after preterm birth.[48] Therefore, supplemental IGF-1 in ROP would hypothetically prevent retinal neovascularization.[49],[50]

Recently studies showed that dietary omega-3 PUFAs defend retina against vasoproliferation in ROP. Transfer of omega-3 PUFAs from mother to her infant in the third trimester may insufficient due to food diets. Adding omega-3 PUFAs intake to premature infants may be logical to hinder retinopathy.[35],[49],[50] According to pediatric research study, prophylactic Vitamin A in premature infants could not reduce the incidence and severity of ROP.[51] At this time, only laser therapy stay as the main therapeutic option for severe cases of ROP. Whether medical methods will go with surgical design remains a topic to perceive over the times.

  Conclusion Top

Improvement survival of premature infants required close observation and proper treatment with ROP. The present screening and treatment of laser ablation therapy allow early identification of high-risk patients with fewer complications. However, novel treatment approaches, such as anti-VEGF therapies, have not yet been adequately assessed to be concluded for clinical use in Phase II ROP. Emerging new medical treatments ongoing adding omega-3 PUFAs intake, as well as the IGF-1, may prevent the vessel loss of phase I ROP to promote the normal vascular growth. Although severe ROP required emergent treatment, regular follow-ups should also be taken for children with low-stage ROP that regresses spontaneously. Myopia and strabismus are significantly more prevalent in ROP infants requiring lifelong follow-up of affected patients.

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Conflicts of interest

There are no conflicts of interest.

  References Top

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