Active Retinopathy of Prematurity

Definition [1]: Retinopathy of prematurity is a severe vitreoretinal pathology of the eye that develops only in premature infants, under the influence of a number of factors that disrupt the normal maturation of retinal vessels and remains one of the main potentially preventable causes of childhood blindness [1]. Aberrant angiogenesis and the development of severe proliferative vitreoretinopathy in ROP are due to the characteristics of the developing vascular system of the retina in premature infants.

CLINICAL PROTOCOL FOR DIAGNOSIS AND TREATMENT

Further management: • postoperative observation has two goals: determining the need for repeat intervention and monitoring disease regression; • the first examination after laser coagulation of the retina for ROP is performed within the first 24 hours after surgery. Weekly examinations continue at least until signs of decreased disease activity or its regression are identified; • repeat intervention after intravitreal administration of angiogenesis inhibitors is required if there are no signs of regression of active ROP (the choice of treatment method has a differentiated approach and depends on the presence and extent of extraretinal proliferation and vascular activity of the disease; the general condition of the child and the possibility of providing anesthetic support); • repeat intervention after transpupillary laser coagulation of the retina is usually performed 7-14 days after treatment, in the absence of ROP regression;

Approved by the Joint Commission on Quality of Medical Services of the Ministry of Health

of the Republic of Kazakhstan dated August 05, 2022

Protocol No. 166

ACTIVE RETINOPATHY OF PREMATURITY

INTRODUCTORY PART 1.1 ICD-10 Code(s):

ICD-10 H 35.0 Background retinopathy and retinal vascular changes H 35.2 Other proliferative retinopathy

Date of protocol development/revision: 2017 (revised 2019).

Abbreviations used in the protocol:

ROP

• retinopathy of prematurity

PCA – postconceptual age A-ROP – aggressive retinopathy of prematurity LCS – laser coagulation of the retina

IA

• angiogenesis inhibitors

IVAI - intravitreal administration of angiogenesis inhibitors

HBO – headband binocular ophthalmoscope CNS – central nervous system PHPV – primary persistent hyperplastic vitreous ONH – optic nerve head US – ultrasound examination USDG – ultrasound Doppler examination of the eye

CT

• computed tomography

EBM - expressed breast milk OCT - optical coherence tomography PAS - persistent avascular retina

DD

• disc diameter

Protocol users: ophthalmologists, neonatologists, pediatricians.

Patient category: children.

Evidence level scale:

Level of Evidence I

II

III

IV V

Type of evidence

Evidence obtained from meta-analysis of a large number of well-designed randomized studies. Randomized studies with low levels of false-positive and false-negative errors. Evidence based on results of at least one well-designed randomized study. Randomized studies with high levels of false-positive and false-negative errors Evidence based on results of well-designed non-randomized studies. Controlled studies with one patient group, studies with historical control group, etc. Evidence obtained from non-randomized studies. Indirect comparative, descriptive correlational studies and clinical case studies Evidence based on clinical cases and examples

Grade A

B

C D

Gradation

Level I evidence or consistent multiple data of level II, III or IV evidence Level II, III or IV evidence, considered generally consistent data Level II, III, IV evidence, but data generally inconsistent Weak or unsystematic empirical evidence.

Classification [7]: According to the third revision of the International Classification of ROP (ICROP-3,

), active ROP is characterized by location and extent of the pathological process, stage of disease, presence of "plus" or "pre-plus" disease. Also separately identified are A-ROP, ROP regression, ROP reactivation and long-term complications of ROP [7].

Location of the pathological process in active ROP is characterized in 3 zones arranged concentrically around the ONH. The boundaries of each zone are determined in relation to the optic nerve disc (Figure 1).

Zone I – represents a circle whose radius equals twice the distance from the center of the ONH to the center of the macula.

Zone II – an annular area from the edge of the first zone with width equal to the distance to the ora serrata on the nasal side. The International Expert Committee on ROP (hereinafter-Committee) recommends identifying an annular area 2 DD wide, located peripherally from the Zone I boundary, as posterior Zone II, to emphasize potentially more severe disease than ROP localized more peripherally.

Zone III - the remaining crescent-shaped area of retina located on the temporal side peripherally from Zone II.

Conventionally, Zones II and III are considered mutually exclusive, as anatomical landmarks in some cases are difficult to recognize. If retinal vascularization reaches the ora serrata on the nasal side, existing changes on the temporal side are defined as in Zone III. If one cannot be completely certain of this, it is assumed to be Zone II.

Figure 1 – Image of ROP location and extent.

Stages of active ROP Stages 1-3 of active ROP are determined by the presence of pathological process at the border of vascularized and avascular retina and are characterized as stage 1 (demarcation line), stage 2 (ridge), stage 3 (extraretinal neovascular proliferation or flat neovascularization). In the absence of ROP signs, the Committee recommends using the term "incomplete vascularization," specifying the zone (e.g., "incomplete vascularization in Zone II"). Stage 1: demarcation line – a thin whitish demarcation line that separates the avascular zone of the retina from the vascular zone. The line characterizes

are accumulations of spindle-shaped cells. Vessels in the area of the demarcation line are dilated and tortuous.

Stage 2: ridge (crest) – voluminous and prominent above the plane of the retina, changing color from whitish to bright pink. Vessels behind the ridge are sharply dilated and tortuous, with an increase noted. Small isolated tufts of neovascular tissue on the retinal surface, called "popcorn," may be located more centrally than the ridge. Tufts of neovascular tissue may merge with each other and form a bifurcation of the ridge.

Stage 3: extraretinal neovascular proliferation from the ridge into the vitreous body. Flat extraretinal neovascular proliferation may be observed when the disease is localized in zone I or posterior zone II without development of an obvious ridge or demarcation line. In this case, vascular activity in the posterior pole of the eye significantly increases, arteriovenous shunts at the periphery become more powerful, forming extended arcades and plexuses. Extraretinal proliferation may appear as delicate fibers with vessels or dense tissue located beyond the retina above the ridge, with increased exudation into the vitreous body.

By severity, stage 3 is subdivided into mild (3a), moderate (3b), and severe (3c), depending on the extent of extraretinal fibrovascular tissue infiltrating the vitreous body.

"Plus" disease – a sign indicating severe course of active ROP. Characterized by sharp dilation of veins and tortuosity of arteries of the posterior pole of the retina, which may increase in severity, accompanied by dilation of iris vessels, iris neovascularization, pupil rigidity, and vitreous exudation, making examination of the fundus difficult.

Pre-plus disease (hereinafter "pre+" disease) – an intermediate stage that precedes the development of "plus" disease and is characterized by vascular activity of the disease. Characterized by dilation and tortuosity of retinal vessels, insufficiently pronounced for a diagnosis of "plus" disease, but which are not considered normal.

The presence of "plus" or "pre-plus" disease is noted alongside the stage (active ROP zone II stage 2 "+" or "pre+"). These changes are assessed by the condition of vessels within zone I.

Aggressive retinopathy of prematurity (A-ROP) – a rapidly progressive, malignant form of the disease characterized by fulminant course and rapid development of volcano-like retinal detachment.

The term posterior aggressive ROP (AP-ROP) was previously used to characterize severe, rapidly progressive ROP localized in the posterior zones I and II. Understanding that a similar process may be localized beyond the posterior zones of the retina and in more mature premature newborns,

especially in regions of the world with limited resources, the Committee recommends using the term A-ROP instead of AP-ROP.

A distinctive feature of A-ROP is rapid progression of pathological neovascularization and development of severe plus-disease without the presence of characteristic signs of classical staged course of ROP. An early manifestation of A-ROP may be the presence of capillary abnormalities more central than the border of the vascular retina – arteriovenous shunts resembling dilated vascular loops framing the zone of vascular damage and almost always having a return of vascular loops to the optic disc. Characteristic sharp dilation and tortuosity of vessels is noted in all 4 quadrants, presence of multiple arteriovenous shunts throughout the retinal area, and rapid development of extraretinal proliferation, bypassing the classical transition from stage I to stage III. A-ROP typically spreads circumferentially and is often accompanied by a circumferential vessel. Without treatment, it rapidly progresses to stage V ROP.

A-ROP often manifests with the presence of a deceptively inconspicuous network of flat neovascularization characteristic of stage III, which cannot always be discerned using a 28D lens; ophthalmoscopy with an aspheric lens with greater magnification (20D) or fluorescent angiography may be more informative. Retinal detachment in ROP (stages 4 and 5) Retinal detachment develops at stages: • 4 (partial): 4a without involvement of the macular zone; • 4b with involvement of the macular area; • 5 (total) Signs indicating the presence of retinal detachment are loss of visualization of choroidal details, granularity of the pigment epithelium and/or a ground-glass appearance corresponding to the area of detached retina. Macular ectopia and straightening of vessels are characteristic signs of peripheral traction.

Retinal detachment at stage 4 is exudative or tractional in nature, and may develop both in the absence of timely treatment and after treatment.

In the early postoperative period after laser retinal coagulation, partial exudative retinal detachment (stage 4) may be observed.

Tractional retinal detachment is associated with progressive fibrovascular proliferation, vitreous opacification, and may be accompanied by the presence of lipid exudate and/or hemorrhage under the retina.

In A-ROP, severe posterior volcano-like tractional retinal detachment may develop, usually involving the macula with areas of adjacent

of the retinal periphery. Although clinically the retinal detachment resembles the funnel-shaped detachment of stage 5, it is correct to classify this condition as stage 4b, since the laser-treated peripheral areas of the retina remain attached, and the retinal detachment is partial in nature.

Total retinal detachment characterizes stage 5 ROP and can be classified by funnel configuration: open-open (open anteriorly and posteriorly), open-closed (open anteriorly and closed posteriorly), closed-open (closed anteriorly and open posteriorly), closed-closed (closed anteriorly and posteriorly). When visualization of the posterior segment is not possible, the nature of retinal detachment can be assumed based on ultrasound scanning results.

The Committee recommends distinguishing the following subcategories of stage 5 ROP: 5a – optic disc is visible on ophthalmoscopy (open funnel); 5b – optic disc is not visible on ophthalmoscopy due to retrolental fibroplasia or retinal detachment of the closed funnel type; 5c – characteristic changes of stage 5b are accompanied by anterior segment changes (shallow anterior chamber, iridocorneolenticular adhesions, corneal opacity).

Extent of ROP - the extent of ROP is assessed by clock-hour meridians from 1 to 12, with the 12th clock-hour meridian extending from 12 to 1 o'clock.

Regression of ROP. The pattern of regression of active ROP with spontaneous regression differs from regression after treatment. The Committee identified features of regression related to vascularization and peripheral manifestations of ROP. The first signs of regression are typically vascular and appear more rapidly (within 1-3 days) after anti-VEGF therapy than after laser coagulation (approximately 7-14 days) or with spontaneous regression. Signs indicating regression of ROP include: • reduction in the severity of "plus" disease, with dilation and tortuosity of vessels potentially regressing non-simultaneously (after anti-VEGF therapy, vessel dilation normalizes earlier, whereas vessel tortuosity may regress much later or not occur at all); • vascularization of the peripheral retina (with spontaneous regression or after anti-VEGF therapy); • vessels crossing the demarcation line and ridge with subsequent penetration of avascular retina, growth of retinal vessels into the coagulation zone; • involution of the anterior vascular membrane of the lens (tunica vasculosa lentis); • restoration of optical media transparency; • resolution of intraretinal hemorrhages; • flattening and blanching of neovascular tissue;

• complete resolution or replacement of active manifestations of ROP with scar tissue. The listed signs must be noted in at least two consecutive examinations.

Regression of ROP may be complete or incomplete with persistence of pathological retinal changes. Areas of persistent PAS may remain in the periphery. PAS after anti-VEGF therapy occurs more frequently and extends over a larger area of the retina. It is essential to specify the location (for example, posterior zone II) and extent (for example, nasal) of PAS.

The introduction of anti-VEGF therapy into practice creates new challenges. The clinical features and time frames characteristic of ROP regression after anti-VEGF therapy differ from those after laser treatment. To characterize the late phases of ROP, it is recommended to use 2 definitions: (1) regression – means involution and resolution; and (2) reactivation – return of signs of active ROP.

Reactivation of ROP. Reactivation of ROP after treatment is characterized by the development of new foci of ROP and vascular changes. When determining the stage of the pathological process during reactivation of ROP, it is recommended to use the notation reactivated (for example, ROP reactivated stage 2). Reactivation is more commonly observed after anti-VEGF therapy than with spontaneous regression, and does not occur after complete laser photocoagulation. Reactivation may be observed against the background of complete or incomplete regression of ROP. The maximum time interval to reactivation after anti-VEGF therapy remains unknown, but according to available data, reactivation most often occurs between 37 and 60 weeks PMA. This may depend on the type and dose of the drug used. If multiple injections of anti-VEGF drug were administered, there is a risk of ROP reactivation at significantly later times. Signs of reactivation can vary from development of a demarcation line to signs characteristic of stage 3 disease with "plus" disease. During reactivation, the staged course characteristic of active ROP may be disrupted. Vascular changes during ROP reactivation include recurrent dilation and/or tortuosity of vessels characteristic of "pre-plus" and "plus" disease. Areas of extraretinal vascularization may appear as a fibrovascular ridge, may progress, become fibrotic, contract, and be accompanied by the development of tractional retinal detachment. When documenting ROP reactivation, it is necessary to indicate the presence and location of the new area of ROP, detailing the stage, zone, and extent with the notation reactivated. For example, the presence of a demarcation line with

reactivation of ROP will be noted as "ROP reactivated stage 1". Upon reactivation, the pathological process is typically localized at the site of the original ridge and/or at the ends of retinal vessels or in any other zone of vascularized retina. If there are multiple sites of ROP reactivation, the notation "reactivated" applies to the site with more anterior localization, typically more active. Progression of reactivated ROP to stages 4 and 5 is associated with vitreous exudation, development of vitreous opacities and their fibrous shortening, and formation of retinal breaks.

Late complications of ROP In premature patients, even if there is no history of ROP, a number of abnormalities may lead to complications: • late tractional, rhegmatogenous and, rarely, exudative retinal detachment. Retinal detachment without signs of ROP activity should be regarded not as reactivation but as a complication; • retinoschisis: from an area of chronic traction resulting from regression of stage 3 ROP, it may extend without retinal detachment to the macula and cause decreased visual function and visual field impairment; • persistent avascular retina: high risk of developing areas of thinning, breaks, lattice degeneration, associated with development of retinal detachment in the late period; • macular zone abnormalities include narrowing of the foveal avascular zone, flattening or complete absence of the foveal pit, possibly related to the severity of active ROP and better visualized on fluorescein angiography or OCT; • retinal vascular changes, including persistent tortuosity, straightening of vascular arcades with formation of macular ectopia, sickle-shaped retinal fold, abnormal non-dichotomous branching of retinal vessels, annular vascular arcade connections and telangiectasias are often observed, may cause recurrent vitreous hemorrhage; • glaucoma may develop in patients with a history of ROP during long-term follow-up.

METHODS, APPROACHES AND DIAGNOSTIC PROCEDURES: (principles of organization of neonatal screening, monitoring and diagnosis of ROP): 2.1 Diagnostic criteria for ROP screening:

Mandatory ophthalmological ROP screening is required for premature newborns born with:

• body weight up to 2000 grams - gestational age up to 34 weeks, - body weight ≥2000 grams, with complicated peri- and neonatal history, severe somatic condition and having signs of high risk of ROP development The presence of one of the above criteria is sufficient to select a child for the ROP risk group.

The first screening examination of the fundus is performed: - at 30-31 weeks PMA in premature newborns with gestational age less than 27 weeks; - at 4 weeks of postnatal age in premature newborns with gestational age ≥ 27 weeks.

Repeat screening examinations of the fundus are performed with the following frequency:

• at least once every 3 days: when AP-ROP is suspected; - at least once every 7 days:

incomplete vascularization in zone I or in posterior zone II, signs of "plus" or "pre-plus" disease are present regardless of stage and localization, stage 3 ROP, regardless of localization; - once every 2 weeks: in all other circumstances, until criteria for discontinuation of screening are met. ROP screening (fundus examinations) can be completed in the absence of risk of developing severe forms of sight-threatening ROP: The decision to complete ophthalmological ROP screening is made in the presence of one of the following criteria (absence of risk of developing severe forms of sight-threatening ROP): 1) complete retinal vascularization; 2) retinal vascularization to zone III without preceding signs of ROP in zones I or II; 3) complete regression of ROP. Complaints and history: prematurity.

Laboratory tests: necessary mandatory minimum for anesthesia support when there are indications for treatment

Instrumental studies: Ophthalmological ROP screening is performed by fundus examination with medically dilated pupils (using mydriatic drugs). For medical pupil dilation, a combination of drugs in the form of eye drops 2.5% phenylephrine and 0.5% tropicamide (2 or 3 instillations at 15-minute intervals) or combined drugs (fixed combinations) is used. Fundus examination during ROP screening is performed using: • indirect binocular headband ophthalmoscope and non-contact aspheric lenses with optical power of 20-28 diopters; for complete visualization of the retinal periphery, a lid speculum and scleral depressor suitable for use in neonatal practice are used; • digital fundus photography with a wide-field retinal pediatric camera.

Indications for specialist consultations: • consultations with cardiologist, pediatrician, neurologist – for planning laser surgical treatment.

Diagnostic algorithm: (Appendix 1).

Differential diagnosis and justification for additional studies:

Diagnosis Justification for differential diagnosis Examinations Exclusion criteria Retinoblastoma (exophytic growth)

Leukocoria, exophthalmos, eversion of pigment border, tumor nodules in the iris, pupil dilation, pseudohypopyon with tumor decay. Hereditary predisposition, bilateral involvement is characteristic only in 19.2% of cases, and there is usually an interval between eye involvement, which can reach several years.

Biomicroscopy, ophthalmoscopy, ultrasound of the visual organ; Doppler ultrasound of the visual organ; Computed tomography

History indicates prematurity; Always bilateral involvement. Absence of hereditary predisposition. In ROP, computed tomography does not yield results. Signs on computed tomography of retinoblastoma include the presence of calcification foci in the tumor, enlargement and darkening of the orbit, as well as enlargement

Coats' retinitis

Retinal dysplasia, Norrie disease, Wagner syndrome of the optic foramen when the tumor invades the cranial cavity.

Predominantly affects boys (3:1); in 98% of cases, one eye is affected.

The dominant symptom of Coats' disease, besides characteristic vascular manifestations (telangiectasias, dilated arterioles, capillaries and venules, micro- and macroaneurysms), is prominent deposits of bright yellow hard exudate in the retinal layers and subretinal space, localized predominantly in the posterior pole.

hereditary predisposition (recessive type), male gender involvement, Biomicroscopy, ophthalmoscopy,

Ultrasound of the visual organ

Optic disc

Chorioretinal focus in the posterior segment, with clear borders; in inflammation, borders may be blurred, with perifocal inflammation and exudation in the vitreous body.

Microphthalmia, shallow anterior chamber, elongated ciliary specific mutations in the NDP gene).

Ophthalmoscopy, ophthalmoscopy

Biomicroscopy, Ophthalmoscopy, genetic predisposition.

vitreous body (PHPV) processes, cataract.

The most reliable differential features are considered to be full-term birth and unilateral involvement.

Pathological manifestations in PHPV appear as a dense, tubular mass extending from the lens to the retina along the hyaloid canal.

Hemorrhages in PHPV are preretinal or subretinal, often with a characteristic blood level.

Ultrasound of the visual organ Always bilateral involvement.

MANAGEMENT TACTICS AT THE OUTPATIENT LEVEL: none.

MANAGEMENT TACTICS AT THE INPATIENT LEVEL [8-11, 14,16]: 5.1 patient observation chart, patient routing (schemes, algorithms): none. 5.2 non-drug treatment: • regimen – mother and child; • diet – infant formula or breastfeeding;

drug treatment is carried out:

• during surgical intervention of transpupillary laser coagulation of avascular retina – mydriatic drugs, moisturizing drops.

• in the postoperative period to prevent secondary infection – topical antibiotics; for anti-inflammatory purposes – glucocorticosteroids;

• List of essential medicines (with 100% probability of use) [22-26]

Pharmacotherapeutic group International nonproprietary name of drug Route of administration and frequency of use Single dose Level of evidence

M-anticholinergics, prolonged-action mydriatics Fixed combination of phenylephrine hydrochloride/tropicamide - eye drops Instillations into the conjunctival cavity 1 drop in each eye, three times with an interval of 10 minutes, 30 minutes before examination B

Angiogenesis inhibitors Ranibizumab solution for injection Intravitreal injection (0.2 mg) – 0.02 ml from one to three intravitreal injections B

Glucocorticosteroids Dexamethasone 0.1% eye drops Instillations into the conjunctival cavity 2 drops 6 times daily after surgery, then according to a tapering schedule 2 times B

Antimicrobial agents Levofloxacin eye drops/ Ofloxacin eye drops Instillations into the conjunctival cavity 2 drops 4 times daily after surgery – for five days C

Surgical intervention [17-20]: is the main universally recognized method of treating active ROP and preventing the development of severe forms of the disease. The mechanism of coagulation action is explained by the destruction of ischemic zones of avascular retina – the source of ischemic stimuli. As a result of coagulation, the retina transforms into thin glial tissue with atrophy of the pigment epithelium, exposure of Bruch's membrane, and atrophy of underlying choroidal vessels and capillaries (formation of chorioretinal scar). For effective action, it is necessary to block at least 75% of avascular zones.

• Transpupillary laser coagulation. During transpupillary laser coagulation with fixation on indirect ophthalmoscope, special eyelid retractors for newborns are used for eyelid immobilization. Depending on the diopter power of the aspheric lens (20 or 28 diopters), the focal distance from the surgeon's eye to the patient's retina is selected and a fixation laser mark is set. Clear visualization of the aiming mark on the retina must be achieved (adjusted by changing the surgeon's head position). A correctly focused mark on the retina has clear borders, and when the focal distance changes, it "blurs." The laser beam should be directed perpendicular to the plane of the retina being coagulated. Coagulation spots are placed from the ridge to the periphery; the distance between coagulation spots should be 0.5-1 spot size and cover the entire avascular retina (at least 75%). Laser coagulation spots should have a rounded shape and pale (not white) color. In extensive avascular zones, confluent coagulation is advisable. In aggressive ROP, additional coagulation of vascular arcade zones anterior to the border with avascular retina should be performed. It should be noted that coagulation spots subsequently increase in size and may merge. Coagulation parameters are selected individually in each case and depend on the severity of ROP and the wavelength of laser radiation (532 nm and/or 810 nm): power varies and averages from 150 to 300 (400) mW, exposure time – 0.2-0.3 sec. The number of coagulation spots depends on the area of avascular zones and the coagulation technique.

NB! Coagulation parameters in each case depend on the type of laser and equipment used. Transpupillary laser coagulation is performed under anesthesia support.

• Transpupillary laser coagulation of avascular retina

Treatment Efficacy Indicators:

• reduction of vascular activity in the posterior pole of the eye; • disappearance of tortuosity, normalization of retinal vessel caliber, and initial regression of arteriovenous shunts; • continued growth of retinal vessels after intravitreal anti-VEGF injection into the previously avascular zone or after laser coagulation surgery into the laser coagulation zone (previously avascular zone); • on day 14, resorption and disappearance of retinal hemorrhages, initial flattening of the demarcation ridge "ridge," change in its color to pale gray; • on day 30, disappearance of the "ridge," complete regression of extraretinal vasoproliferation (after transpupillary laser coagulation).

ORGANIZATIONAL ASPECTS OF THE PROTOCOL:

6.1 List of protocol developers with qualification data: 1) Sharipova Asel Usenbayevna – Candidate of Medical Sciences, LLP "Kazakh Research Institute of Eye Diseases," Head of the ROP Center Department; leading instructor of postgraduate education, Almaty.

2) Tuletova Aigerim Serikbayevna - Candidate of Medical Sciences, Director of the branch of LLP "Kazakh Research Institute of Eye Diseases," Nur-Sultan.

3) Zhetimkarinova Gaukhar Erlanovna – clinical pharmacologist (physician), Department of Medical and Regulatory Affairs, CF "University Medical Centre."

4) Saukenova Dinara Maulyutovna – ophthalmologist, Department of Surgery, CF "University Medical Centre."

5) Smagulova Sabina Asylbekovna - LLP "Kazakh Research Institute of Eye Diseases," instructor of the postgraduate education department.

Declaration of absence of conflict of interest: none.

Reviewers:

1) Utelbayeva Zauresh Tursynovna – Doctor of Medical Sciences, JSC "National Medical University," Department of Ophthalmology.

Indication of conditions for protocol revision: revision of the protocol 5 years after its publication and from the date of its entry into force or in the presence of new methods with level of evidence.

List of references:

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Summarized Version, 2017

APPENDIX 1

DIAGNOSTIC ALGORITHM FOR ACTIVE RETINOPATHY OF PREMATURITY

Indirect binocular ophthalmoscopy of premature newborns in the target risk group (birth weight up to 2000 grams; gestational age less than 34 weeks) First screening examination:

at 30-31 weeks PMA in premature newborns with gestational age less than 27 weeks 2. at 4 weeks of postnatal age in premature newborns with gestational age ≥ 27 weeks.

Incomplete vascularization

of the retina:

• in zone I or in posterior zone II (at least once every 7 days)
• in anterior zone II (at least once every 14 days)

Complete vascularization

of the retina

(completion of ophthalmological

screening) If A-ROP is

suspected

monitoring frequency once every 3 days

RETINOPATHY OF PREMATURITY

RETINOPATHY OF PREMATURITY TYPE

1

• Zone I, any stage of ROP with plus disease; - Zone I, stage 3 with/without plus disease; - Zone II, stage 2 or 3 ROP with plus disease; - A-ROP – any manifestation of the disease

Transpupillary laser coagulation of the retina and/or intravitreal

administration of angiogenesis inhibitors

OF PREMATURITY TYPE 2:

• Zone I, stage 1 or 2 ROP without plus disease; - Zone II, stage 3 ROP without plus disease

Monitoring should be continued at least once every 7 days

INDICATIONS FOR HOSPITALIZATION WITH INDICATION OF TYPE OF HOSPITALIZATION: 4.1 Indications for planned hospitalization for active ROP are:

• any ROP in zone I with plus disease; - ROP stage 3 in zone I with or without plus disease; - ROP stage 2 or 3 in zone II with plus disease

NB! Although there is no specific evidence to recommend a definite time interval between identification of indications for treatment and actual treatment administration, treatment within 48-72 hours, this time interval should be the standard to strive for. 4.2 Indications for emergency hospitalization (within 24 hours) are:

• aggressive ROP (any manifestation of the disease).

Indications:

Absolute indications for laser coagulation of the retina are: Type 1 ROP (high risk of developing severe forms):

• aggressive ROP (any manifestation of the disease);

Relative indications for laser coagulation of the retina are:

• ROP stage 3 in zone II without plus disease;

• ROP stages 1 and 2 in zone I without plus disease.

Contraindications: Retinal detachment – stages 4a-b and 5 [9]

• Intravitreal administration of angiogenesis inhibitors (IVAI) Intravitreal administration of AI is a surgical manipulation of scleral perforation in the area of the pars plana of the ciliary body with an injection needle followed by introduction of a therapeutic substance into the vitreous body. As a result, the highest concentration is created in the eye tissues (up to 51.4% of the drug substance remains in the vitreous body, 13.2% of the administered dose penetrates into the retina and choroid). Intravitreal administration of AI is performed by an ophthalmologist with experience in performing intravitreal injections. IVAI for active ROP is performed in operating room conditions with observance of aseptic and antiseptic principles required for performing surgical interventions in ophthalmology. The recommended dose of angiogenesis inhibitor (Ranibizumab) for premature newborns is 0.2 mg and is administered as an injection into the vitreous body. This volume corresponds to an injection volume of 0.02 ml. Treatment of active ROP in premature newborns begins with a single injection into the vitreous body of the eye and may be administered to both eyes on the same day. In this case, IVAI to the fellow eye is performed as an independent intervention. Within six months after the start of treatment, up to three IVAIs may be performed in one eye if there are signs of disease activity. Administration of more than three IVAIs in one eye for active ROP has not been studied [27]. Method and route of administration of IVAI Intravitreal administration. Ranibizumab should be administered only by an ophthalmologist with experience in performing intravitreal injections. Technique - direct intravitreal injection.

This technique is applied separately for each eye with observance of aseptic and antiseptic principles required for performing surgical interventions in ophthalmology.

During this procedure the following occurs: opening of arteriovenous shunts throughout the retina, reduction of vascular activity of the disease. According to digital morphometry data, the caliber of retinal vessels improves, tortuosity decreases and multiple hemorrhages resolve, which ultimately leads to regression of the disease. Intravitreal administration of angiogenesis inhibitors (IVAI)

Indications for IVAI are ROP: - zone I any stage with plus disease - zone II - stage 3 with plus disease - zone 1-2: A-ROP (any manifestation of the disease) Contraindications:

• hypersensitivity to the active substance or to any excipient of the drug;
• confirmed or suspected ocular infections or infectious processes of periocular localization;
• active severe intraocular inflammation [27].