Retinopathy of prematurity: clinical guidelines

List of Abbreviations

anti-VEGF therapy/anti-VEGF drugs – drugs from the ATC group: S01LA Antineovascularization agents

g – gram

GA – gestational age

BW – body weight

ONH – optic nerve head

D – diopters

APROP – aggressive posterior retinopathy of prematurity

ICD-10 – International Classification of Diseases, 10th Revision

IBO – indirect binocular ophthalmoscope

PMA – postmenstrual age

ROP – retinopathy of prematurity

SLPC – sector laser photocoagulation of the retina

et al. – and others

CNS – central nervous system

ELBW – extremely low birth weight

VEGF – vascular endothelial growth factor

OCT – optical coherence tomography

US – ultrasound examination

FA – fluorescein angiography

EP – electrophysiological studies

ERG – electroretinogram

VEP – visual evoked potentials

Terms and Definitions

At-risk group – a conditional group of premature infants with a high probability of developing retinopathy of prematurity, and therefore subject to mandatory ophthalmological screening.

Gestational age (GA) – the age of the child in weeks from conception to birth.

Postmenstrual age of the child (PMA) – the complete age of the child in weeks from the start of the mother's last menstrual period, determining the degree of maturity. PMA = gestational age at birth in weeks + chronological age in weeks.

Aggressive posterior retinopathy of prematurity (APROP) – a rapidly progressive form of the disease localized in the posterior pole of the eye, accompanied by pronounced vascular activity and characterized by the absence of distinct stages.

"Plus disease" – an indicator of pronounced vascular activity of the process, which is characterized by dilation and tortuosity of the central (zone I) and terminal retinal vessels.

Threshold stage – stage 3, "plus disease" with an extent of extraretinal proliferation equal to 5 continuous (adjacent along the circumference) or 8 in total (with gaps) clock hours on the fundus.

Spontaneous regression – cessation of ROP progression in the active phase without treatment, with/without residual changes in the fundus.

Induced regression – cessation of ROP progression after treatment in the active phase with the formation of residual changes in the fundus.

Reactivation – the appearance of new signs of ROP (from a demarcation line to reactivation of stage 3 with plus disease) and vascular changes.

Favorable outcome of ROP – minimal residual changes in the fundus after ROP (ROP stage 0-III ), determining a favorable visual prognosis.

Unfavorable outcome of ROP – pronounced cicatricial changes in the anatomical structures of the eye (ROP stage IV-V), determining an unfavorable visual prognosis.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Retinopathy of prematurity (ROP) is a vasoproliferative vitreoretinal eye disease of extremely premature infants, based on the immaturity of the structures of the eyeball, particularly the retina, by the time of premature birth [1].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The clinical manifestations of ROP are based on a disruption of normal retinal angiogenesis, which is completed only by the time of the scheduled birth of the child (38–40 weeks of GA) [1]. Almost all children born prematurely have ophthalmoscopic differences from full-term infants. Avascular zones are normally detected on the periphery of the retina in the fundus of premature infants, and their extent is greater the smaller the gestational age (GA) of the child at the time of examination. The presence of avascular zones on the periphery of the fundus is not a disease or a manifestation of ROP; it is merely evidence of retinal underdevelopment, incomplete vascularization, and, accordingly, the possibility of developing ROP in the future.

According to modern concepts, a key role in the development of ROP is played by an imbalance of factors regulating retinal angiogenesis. These include various growth factors, components of the extracellular matrix and neuroendocrine system, and a number of cytokines interacting in a complex system. The developing imbalance is a consequence of the fact that the process of retinal vascularization in a premature birth is "forced" to occur against the background of biochemical and immunological disorders of the child's homeostasis due to general somatic pathology, as well as the impact of "external" environmental factors [2].

1.3 Epidemiology of the Disease or Condition

Blindness and low vision due to ROP dominate the structure of childhood visual impairment in both developed and developing countries, despite all advances in science and practical medicine [3,4]. The introduction of modern evidence-based protocols for nursing premature newborns minimizes the risk of ROP in children with a birth weight (BW) of more than 1500 g and GA of more than 32 weeks. With relatively stable rates of premature birth per year (from 5 to 12%), the survival rate of newborns with extremely low birth weight (ELBW) is increasing, but it is precisely in this cohort of infants that ROP occurs not only more frequently but also more severely, leading to unfavorable outcomes and irreversible vision loss despite adequate management [4-7].

The frequency and severity of ROP in individual countries, regions, and cities depend not only on the number of surviving extremely premature children, but also on the nursing conditions and somatic burden of the infants [4-6]. With an average ROP incidence in the "at-risk group" of 27–37%, its specific weight in children with a birth weight of less than 1500 g reaches 40–50%, in those under 1000 g – 52–73%, and in children under 750 g it rises to 81–95%. At the same time, severe forms of the disease with significant visual impairment do not occur in all patients, but only in 10–40% of children. According to WHO data, blindness due to ROP is 60 people per 10 million children in developed countries, 450 per 10 million in developing countries, and is practically non-existent in low-income countries because premature infants do not survive there. It should be emphasized that over the past decade, due to the active introduction of monitoring and treatment systems for active ROP, the situation in the Russian Federation has changed radically. Today, severe, disabling forms of ROP develop in 9.1–20.5% according to various regions, which is comparable to the figures of other developed countries [4, 7-9, 53].

1.4 Features of Coding the Disease or Condition

H35.1 – Retinopathy of prematurity (incomplete retinal vascularization)

H35.2 – Other proliferative retinopathy (Retinopathy of prematurity)

1.5 Classification of the disease or condition

The clinical course of ROP has two phases: 1) active and 2) regressive or cicatricial. International Classification (IC) of active ROP (adopted in 1984, expanded in 1987, supplemented in 2005, and revised in 2021). The IC of active ROP takes into account not only the stage of the pathological process, but also its localization (zone) on the retina, extent, and the presence or absence of signs of "plus disease," which makes it possible to predict the course of the disease [10]. In 1987, the ICROP was expanded by including retinal detachment [11]. In 2005, the ICROP was supplemented with two concepts: "pre-plus disease" and "aggressive posterior ROP" [12]. In 2021, the revised ICROP3 was published [13]. The new edition retains current definitions (zone, stage, and extent of the disease). Key updates in ICROP3 include refined classification indicators (e.g., posterior zone II region, notch, plus disease, aggressive ROP, stage 5 subcategories). Regression and reactivation of ROP are characterized in detail with an additional description of long-term consequences [13].

Localization of retinal vascularization or ROP: fundus zone.

The state of retinal vascularization or signs of ROP are recorded in the form of circles centered on the optic disc (zones).

There are three zones located concentrically around the optic disc and extending to the ora serrata:

Zone I (posterior) – a conditional circle whose radius is equal to twice the distance from the center of the optic disc to the fovea.

Zone II – a annular region extending nasally from the outer boundary of zone I to the nasal ora serrata and extending the same distance temporally, superiorly, and inferiorly.

Zone III – the remaining area of the peripheral retina in the shape of a crescent, extending anteriorly beyond zone II.

The posterior zone II region is separately identified and defined, beginning at the border between zone I and zone II and extending into zone II for 2 optic disc diameters, to indicate a potentially more dangerous disease than ROP in more peripheral zone II [13].

The term "notch" has been proposed to describe the extension of an ROP lesion in a 1-to-2-clock-hour segment along the horizontal meridian into a more posterior zone. If a notch is present, ROP should be recorded by the most posterior zone of retinal vascularization with the qualifier "secondary, due to notch." For example, ROP primarily concentrated in zone II, but with a temporal notch extending into zone I, should be noted as "zone I, secondary, due to notch" to distinguish such an eye from one in which most of the disease is in zone I [13].

Stages of active ROP

In a premature infant, the retina is not fully vascularized, and ophthalmoscopy may reveal avascular zones of various locations and areas. These clinical features are not a disease. In these cases, in the absence of signs of ROP, it is suggested to use the term "incomplete retinal vascularization" indicating the localization of the avascular zone (e.g., "incomplete vascularization in zone II" or "avascular zone II") rather than terms such as "absence of ROP" or "immature retina" [13].

There are 5 stages of active ROP, based on the severity of vascular abnormalities (if more than one stage of ROP is present in a single eye, the eye is classified by the most severe stage):

Stage 1 – appearance of a demarcation line (flat, white) at the junction of the vascularized and avascular retina. The posterior pole of the eye may remain virtually unchanged, with occasional tortuosity and dilation of vessels in the peripheral retina anterior to the line.

Stage 2 – formation of a ridge at the site of the demarcation line, which increases in volume and rises above the retina. The retina in this zone thickens and protrudes into the vitreous body. The color of the ridge can vary from white to pink (hyperemic) due to ingrowth of vessels. Retinal vessels anterior to the ridge are typically dilated, tortuous, branching irregularly, and forming arteriovenous shunts – the "brush" sign at the ends of the vessels.

Stage 3 – characterized by the appearance of extrarinal fibrovascular proliferation at the ridge. Vascular activity in the posterior pole often increases, arteriovenous shunts in the periphery become more robust, forming extensive arcades and plexuses. Extraretinal proliferation may appear as delicate strands with vessels or dense tissue located outside the retina above the ridge.

Stage 4 – partial retinal detachment – subdivided into 4A (without macular involvement) and 4B (with macular retinal detachment). The developing retinal detachment is exudative-tractional in nature. It occurs due to both a serous-hemorrhagic component and the developing traction from the newly formed fibrovascular tissue.

Stage 5 – complete or total retinal detachment. Definition of stage subcategories: stage 5A, in which the optic disc is visible on ophthalmoscopy (indicating an open-funnel detachment); stage 5B, in which the optic disc is not visible due to retrolental fibrovascular tissue, or a closed-funnel detachment; and stage 5C, in which stage 5B is accompanied by anterior segment anomalies (e.g., anterior displacement of the lens, marked reduction in anterior chamber depth, iridocorneolenticular adhesions, corneal opacity, or a combination thereof) resembling a closed-funnel configuration. Additional funnel configuration descriptors (e.g., open-closed) may be used if clinically helpful [13].

The term "plus disease" indicates marked vascular activity of the process, characterized by dilation and tortuosity of the central (Zone I) and terminal retinal vessels.

The term "pre-plus disease" is characterized by dilation and tortuosity of retinal vessels, but less pronounced than in plus disease [13].

A particularly prognostically unfavorable form of active ROP is singled out, designated as "Aggressive Posterior Retinopathy of Prematurity" (AP-ROP) [12]. The characteristic features of AP-ROP are: early onset, rapid disease progression without distinct stages (bypassing stages 1 and 2), and localization of vascular anomalies (vessels acquiring a closed circular appearance) in the posterior pole of the eye (Zone I or posterior Zone II).

AP-ROP presents with pronounced vascular activity, marked dilation and tortuosity of central retinal vessels, formation of robust vascular arcades, arteriovenous shunts, extraretinal growth of fibrovascular proliferative tissue circumferentially (1 to 12 clock hours), flat neovascularization, retinal and vitreous hemorrhages, media opacification, rubeosis iridis, and frequently, a rigid pupil [12, 13].

The extent (spread) of the pathological process across the fundus is evaluated by clock hours (from 1 to 12 meridians).

It is also customary to distinguish two types of ROP that differ in clinical course and prognosis [14].

Type 1 ROP – Zone I: any stage of ROP with plus disease, or Stage 3 without plus disease; Zone II, Stages 2–3 with plus disease. Follow-up once in 3 days.

Type 2 ROP – Zone I: Stages 1–2 without plus disease; Zone II: Stage 3 without plus disease. Follow-up every 7 days.

The active phase of ROP in a classic course lasts on average 3–6 months and transitions into a regressive or cicatricial phase with varying degrees of residual fundus changes.

ROP regression or the regressive phase of ROP occurs as a result of spontaneous arrest of the disease and regression of clinical signs of active ROP (spontaneous regression) or after laser treatment and/or anti-VEGF therapy (induced regression). Residual clinical changes may persist in the fundus following regression. Vascularization of the peripheral avascular retina may be complete or incomplete, referred to as "persistent avascular retina" (PAR). The location (e.g., posterior Zone II) and extent of PAR must be documented [13].

Reactivation of ROP may occur following anti-VEGF therapy, characterized by the emergence of new signs of ROP and vascular alterations. Signs of reactivation range from the development of a new self-limiting demarcation line to the reactivation of Stage 3 with plus disease. The presence and localization of new ROP signs (stage and zone) must be specified using the modifier "reactivated" (e.g., reactivated Stage 2) [13].

There is currently no unified clinical and functional classification of cicatricial ROP. It is advisable to use the working classification of cicatricial ROP developed in 2009 by researchers at the Helmholtz Moscow Research Institute of Eye Diseases, which evaluates the degree of residual fundus changes following active ROP [15].

Grade I – minimal vascular and intraretinal changes in the retinal periphery that virtually do not affect visual function. Specific changes are absent in the central retina.

Grade II – absence of macular deformation and cicatricial changes, residual avascular zones in the retinal periphery, coarser pigment deposits, zones of intra- and preretinal fibrosis extending no more than 5–6 clock hours, dystrophic changes, and laser scars from active-phase treatment. Visual function also remains at a fairly high level.

Grade III – deformation of the optic disc and vascular bundle with marked macular ectopia due to residual fibrovascular tissue outside the retina. Visual function may be significantly reduced.

Grade IV – retinal folds (duplications) of varying extent, protruding into the vitreous body without macular involvement (4a) or with macular involvement (4b) and anterior fixation relative to the equator, combined with limited retinal detachment. Visual function is significantly impaired, especially when the macula is involved in the fold.

Grade V – total retinal detachment: open, closed, or semi-closed funnel type. Only residual light perception or, rarely, light projection is detected.

It is practical to designate Grade 0 ROP – absence of residual fundus changes following ROP as a result of spontaneous regression [15].

1.6 Clinical presentation of the disease or condition

Parents report no symptoms during the active phase of ROP. Physical examination does not reveal symptoms of early-stage ROP. The disease is diagnosed via screening of premature infants at risk for ROP using indirect binocular ophthalmoscopy of the fundus or examination with a wide-field pediatric retinal camera and a portable digital ophthalmic camera under medical mydriasis [16, 17].

Evaluation of clinical fundus changes is performed in accordance with the International Classification of Active ROP (see Section 1.5).

Active ROP progresses to a regressed or cicatricial phase with varying severity of residual fundus changes. The cicatricial phase reveals vascular, retinal, and vitreal changes, including incomplete peripheral retinal vascularization, abnormal vessel branching, arcades, arteriovenous shunts, telangiectasia, etc. In the posterior pole, retinal changes may include pigment redistribution, areas of retinal atrophy, formation of pre-, sub-, and intraretinal membranes, tractional displacement, and atrophy of neuroepithelial layers. In severe cases, macular ectopia, retinal folds and detachment, as well as vitreoretinal cords, bands, and membranes develop. The severity of fundus changes determines the grade of cicatricial (regressed) ROP (see section 1.5).

The factors contributing to visual impairment in ROP are complex and combined. First of all, visual functions are determined by the severity of clinical fundus changes. Clinical outcomes of ROP with grade 0–III residual changes indicate a favorable functional prognosis, whereas grade IV–V cicatricial ROP results in significantly reduced vision, down to light perception and blindness, which is an unfavorable disease outcome. However, the formation and development of visual functions are significantly influenced by the state of the central nervous system and visual pathway tracts, refractive errors, oculomotor disorders (various types of strabismus, nystagmus), concomitant eye pathologies (congenital cataracts, glaucoma, anomalies, and developmental malformations), as well as retinal functional insufficiency and impaired normal physiological development of the visual system as a whole due to premature birth. All the above necessitates a comprehensive ophthalmological examination using modern diagnostic and imaging methods, as well as an interdisciplinary approach to patient management in ROP to identify the causes, level, and extent of visual system damage, determine the functional prognosis, and establish follow-up observation tactics [18].

Although the regressed/cicatricial phase of the disease is considered a relatively stable condition, late complications may develop in both favorable and unfavorable ROP outcomes (Table 1). The development of late complications leads not only to decreased vision, but also to cosmetic defects and a worsened quality of life, causing difficulties in social adaptation [18-20].

Table 1.

Late complications of cicatricial ROP

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the disease or condition: The diagnosis of ROP is established based on the presence of risk factors, complaints, anamnestic data, and the results of a clinical ophthalmological examination, which includes a set of standard and highly informative additional diagnostic methods.

2.1 Complaints and Anamnesis

Comments: risk factors for ROP development (at-risk group) include gestational age of less than 35 weeks and birth weight of less than 2000 g [18, 20, 21].

2.2 Physical Examination

Physical examination is not performed.

2.3 Laboratory Diagnostics

Laboratory examination is not used for the diagnosis of ROP.

2.4 Instrumental Diagnostics

Comments: the examination of a premature infant should be performed in the neonatal unit, avoiding transportation to other facilities, in a specially equipped, darkened or low-light ophthalmological room (on a changing table) or directly in the neonatal intensive care unit inside the incubator.

A prerequisite for high-quality fundus ophthalmoscopy is maximal mydriasis. For better visualization of the peripheral retina, it is advisable to use sterile instruments—an eyelid speculum and a scleral depressor (with caution)—intended for use in neonatal practice. For short-term topical anesthesia of the cornea and conjunctiva, instillations of a local anesthetic (0.4% oxybuprocaine**) can be used.

For ROP screening and monitoring, neonatal units must be equipped in accordance with Order of the Russian Ministry of Health No. 614n dated October 9, 2025, "On Approval of the Procedure for Providing Medical Care to Children in the Profile 'Ophthalmology'" [23].

Recording of ophthalmological examination results

Comments:

"Pre-plus disease" and "plus disease" are diagnosed based on the assessment of vessel status in Zone I, rather than by individual fundus sectors or the number of quadrants with pathological changes. If a "notch" is present, it is indicated in the diagnosis, and the ROP zone is specified according to the localization of the "notch". When active ROP regresses, it is necessary to indicate whether the regression is complete or incomplete, as well as the localization and width of the residual avascular zone, if present. Identified ROP reactivation must be noted in the diagnosis with indication of the stage and localization zone [13].

Examples of diagnosis formulation:

1. OU – Retinopathy of prematurity, active phase, stage 2 with plus disease, zone II, type 1

2. OU – Retinopathy of prematurity, active phase, stage 2, zone II, type 2

3. OU – Aggressive posterior retinopathy of prematurity, type 1

4. Retinopathy of prematurity, active phase, OD – stage 1, zone III, OS – stage 2, zone II, type 2

If multiple stages of active ROP are present in one eye, the diagnosis is established based on the more severe stage.

The results of the ophthalmological examination and the ophthalmologist's recommendations for follow-up observation, indicating the timeframe and location (medical institution) of the next examination, should be entered into the patient's medical record. Information regarding detected ROP or the risk of ROP development, as well as the necessity of adhering to follow-up timelines, must be communicated by the attending physician to the parents (legal representatives) in accordance with Order of the Russian Ministry of Health No. 614n dated October 9, 2025, "On Approval of the Procedure for Providing Medical Care to Children in the Profile 'Ophthalmology'" [23].

Timeframe for primary neonatal screening of at-risk children and monitoring of active ROP

Comments:

• Identification of newborn premature infants at risk for ROP based on the above criteria is carried out by anesthesiologist-resuscitators in neonatal intensive care units and neonatologists in departments of pathology of newborns and premature infants of medical organizations;

• Anesthesiologist-resuscitators and neonatologists arrange for examination and follow-up monitoring of at-risk premature infants by an ophthalmologist prior to discharge from the medical facility;

• Anesthesiologist-resuscitators and neonatologists inform parents about the risk of developing ROP in accordance with Order of the Russian Ministry of Health No. 614n dated October 9, 2025, "On Approval of the Procedure for Providing Medical Care to Children Profiled in 'Ophthalmology'" [23].

Table 2.

Timeframes for the initial ophthalmological examination (start of screening) of at-risk premature infants

Comments: the initiation of neonatal screening for active ROP should be based on PMA, which is the full gestational age of the infant in weeks from the mother's last menstrual period, determining the degree of maturity. PMA = gestational age at birth + chronological age (weeks).

In premature infants with severe comorbid pathology of the neonatal period, an initial ophthalmological examination (inspection, consultation) may be performed one week earlier than the specified timeframes (Table 2) to rule out rare cases of early-onset retinopathy of prematurity [22].

Subsequent examination tactics depend on the results of the initial screening.

Comments: monitoring of at-risk premature infants and children with active ROP is carried out until discharge from the medical organization, followed by follow-up until 1 year of age in the consultative and diagnostic room for the identification and monitoring of children with ROP in accordance with Order of the Russian Ministry of Health No. 614n dated October 9, 2025, "On Approval of the Procedure for Providing Medical Care to Children Profiled in 'Ophthalmology'" [22, 23].

Comments: the duration and frequency of monitoring for active ROP after treatment depend on the type of treatment (sectoral laser photocoagulation of the retina and/or anti-VEGF therapy) and its efficacy (see the "Treatment" section). This information is communicated by the physician to the parents (legal representatives).

2.5 Other Procedures

Comments: approximate visual acuity testing using the preferential looking method is performed in young (preverbal) children [25].

Comments: to measure intraocular pressure in children, the following are performed: Maklakov tonometry (under local anesthesia); pneumotonometry (used for screening); Goldmann tonometry (under local anesthesia); approximate palpation measurement.

Comments: biomicroscopy of the eye (anterior segment and vitreous body) may not be performed in children with active ROP, as the assessment of the anterior segment is carried out during ophthalmoscopy and/or examination using a wide-field pediatric digital retinal camera.

Comments: the minimum age of children at which objective computer perimetry is possible without prior training is approximately 8 years. For children aged 6–8 years, a shortened training examination is performed beforehand [56]. The minimum visual acuity sufficient for computer perimetry is 0.2 [29].

Comments: the necessity and frequency of OCT are determined by the ophthalmologist depending on the clinical course of the disease.

Comments: the necessity and frequency of FA are determined by the ophthalmologist depending on the clinical course of the disease.

It is advisable to perform FA in patients with residual avascular zones both after spontaneous regression and after anti-VEGF therapy and sectoral laser photocoagulation of the retina. Residual avascular zones increase the risk of ROP reactivation, as well as the development of peripheral vitreochorioretinal dystrophy (PVCRD) and retinal detachment at a later age [32, 35].

Comments: the necessity and frequency of OCT-A are determined by the ophthalmologist depending on the specific course of the disease.

Comments: performing EPS is advisable in cases of decreased, uncorrectable visual acuity to determine the degree and level of visual system impairment, which is important for predicting visual functions and planning rehabilitation tactics for patients with ROP. In infants, ERG examinations are performed under sedation/medication-induced sleep [18, 38-42].

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Indications for treatment in active ROP

There is no conservative therapy with proven efficacy for active ROP. Medical care for children with active progressive ROP includes 2 treatment methods: sectoral laser retinal photocoagulation (LPC), which is currently the universally recognized standard of treatment for the disease, and/or intravitreal administration of anti-angiogenic medicinal products [3, 43]. The mechanism of action of photocoagulation is explained by the destruction of ischemic areas of avascular retina—the source of ischemic stimuli, the most significant and studied of which is vascular endothelial growth factor (VEGF). The administration of anti-angiogenic medicinal products also helps reduce VEGF levels in the second proliferative phase of the disease and, consequently, reduce intravitreal vasoproliferation, restore physiological homeostasis and retinal angiogenesis [43].

Comments: also indications for the preferential choice of intravitreal administration of anti-angiogenic drugs include: ROP localization in Zone I, technical difficulties in performing laser photocoagulation (incomplete transparency of optical media, pupillary rigidity), and the inability to provide prolonged anesthesia for laser photocoagulation [44,57,59].

The administration of anti-angiogenic medicinal products is not indicated for peripheral localization of ROP due to the high efficacy of LPC in these cases, as well as the likelihood of persistent peripheral avascular areas and vascular malformations that subsequently contribute to the development of lattice vitreoretinal degeneration, and the need for prolonged regular follow-up of children after anti-VEGF therapy [57].

Comments: "Insufficient" or inadequate sectoral retinal laser photocoagulation may be the cause of further ROP progression and a higher rate of abandoning LPC in favor of anti-VEGF therapy [3, 43, 44]

3.2 Sectoral retinal laser photocoagulation in active ROP

Depending on the localization zone of active ROP and the equipment of the medical facility, LPC can be performed via transpupillary or transscleral access. For transpupillary access, ophthalmic laser systems with a laser indirect binocular ophthalmoscope (LIO) and ophthalmic laser systems with a slit lamp adapter are used. Currently, ophthalmologists have access to ophthalmic laser systems with various wavelengths (from 532 nm to 659 nm; 810 nm diode laser system), with the capability of delivering both single pulses and performing retinal photocoagulation in continuous automatic mode and matrix pattern mode (depending on the area of avascular retinal zones).

Comments: great attention should be paid to the correct dosage of the procedure. Overdosage (especially with transscleral retinal photocoagulation methods) leads to marked exudation, hemorrhages, excessive proliferation, retinal traction, and late retinal detachments. Hypocoagulation does not allow for complete coagulation of the avascular retina and does not lead to ROP stabilization. In cases of extensive avascular zones, panretinal photocoagulation is advisable. In APROP, additional coagulation of vascular arcade zones anterior to the border with the avascular retina should be performed. It should be noted that burns (coagulates) subsequently increase in size and may coalesce. The parameters (power, exposure time) of LPC depend on the laser type, retinal state (edema, exudative manifestations, etc.) and are selected individually. The number of coagulates depends on the area of avascular zones and the coagulation technique.

Comments: Sectoral retinal laser photocoagulation via LIO (transpupillary) is performed using the following instruments: lid speculum, scleral depressor, non-contact diagnostic ophthalmic lenses (20 D or 28 D). Coagulates are applied from the ridge to the retinal periphery; the distance between coagulates should be 0.5-1.0 of the coagulate size, covering at least 75% of the avascular retina; they should be round in shape and pale (not white) in color. Optimal conditions for the infant include a physiological supine position, ensuring better monitoring of the child's condition by the anesthesiologist-resuscitator, and a non-contact technique for sectoral retinal laser photocoagulation. If conditions for performing LPC via LIO are lacking, treatment of ROP should not be delayed. In this situation, other available techniques (retinal photocoagulation using laser systems with a slit lamp adapter or the transscleral technique) may be used [18, 47].

Comments: laser treatment for active ROP is performed:

1. In a medical facility with a neonatal pathology department, by a specially trained ophthalmologist;

2. Upon the child's discharge from the neonatal pathology department—in a specialized ophthalmological center or multidisciplinary children's hospital licensed to provide medical care to children, equipped with the necessary devices and a specially trained ophthalmologist.

Parents (legal representatives) of the child must be informed about the upcoming treatment, the goals of the intervention, potential treatment stages, and complications.

Comments: postoperative follow-up is important for monitoring the disease course and determining indications for re-treatment. Treatment is considered effective when the pathological process stabilizes and signs of induced regression appear.

Comments: if properly performed laser photocoagulation is ineffective or insufficiently effective, the possibility and expediency of intravitreal administration of an anti-angiogenic drug or microsurgical intervention are evaluated, as determined by the specific clinical manifestations of retinopathy of prematurity [43].

3.3 Intravitreal anti-VEGF injection

Despite numerous publications on the successful use of anti-VEGF therapy for the treatment of active retinopathy of prematurity, to date only isolated studies on the safety of these drugs and their impact on long-term structural and functional outcomes, not only of the organ of vision but of the entire body as a whole, have been conducted.

Comments: currently, for the treatment of active ROP an intravitreal solution is approved for use as an anti-angiogenic medicinal product – ranibizumab**. Intravitreal administration of ranibizumab** is performed taking into account the anatomical features of the eyeball in a premature infant compared to adult patients, at a dose corresponding to the instructions for use of the medicinal product for ROP.

Immediately after the intravitreal injection, patient monitoring is required for increased intraocular pressure (approximate palpation measurement of intraocular pressure).

Comments: injections, if necessary, can be performed in both eyes on the same day.

Advantages of anti-VEGF therapy:

1. Relative rapidity of the procedure, possibility of treating patients with difficulty in visualizing the fundus (rigid pupil, impaired transparency of the optic media)

2. Higher treatment efficacy for type 1 retinopathy of prematurity localized in the posterior pole of the eye (zone I and posterior zone II)

3. More rapid development of the primary effect (within 1–3 days, often with a decrease in vascular activity already after 24 hours)

4. Absence of peripheral retinal "blockade" with the possibility of continued vessel growth and retinal maturation (no chorioretinal atrophy)

5. Lower frequency and severity of refractive errors [43].

Disadvantages of anti-VEGF therapy:

1. Risk of local side effects (intraocular hemorrhage, traumatic cataract, inflammatory and infectious processes, increased vitreoretinal traction and development of retinal detachment, etc.)

2. Potential for disease reactivation in the long-term period (up to 70 weeks of postmenstrual age), which requires prolonged subsequent regular monitoring of patients

3. Persistent risk of systemic side effects [43,44,57]

Comments: options for re-treatment in the presence of signs of disease activity include anti-VEGF therapy or sectoral laser photocoagulation of the retina; if necessary, a combination of these methods is possible [59].

Comments: a clinical precursor of ROP reactivation after intravitreal administration of an anti-angiogenic medicinal product may be very slow fundus vascularization or cessation of vessel growth toward the retinal periphery. Signs of reactivation range from the development of a new self-limiting demarcation line to stage 3 reactivation with plus disease, accompanied by vessel tortuosity and dilation, and hemorrhages. Neovascularization can develop both in the zone of the initial localization of extraretinal proliferation and at the border of the vascularized retina that has advanced to the periphery. ROP reactivation requiring additional treatment is most frequently observed in aggressive posterior retinopathy of prematurity (AP-ROP) developing in the central zones of the fundus (zone I and the posterior region of zone II) – in 75% of cases [49,50]. Reactivation after intravitreal ranibizumab** administration develops at various time points ranging from 2 to 29 weeks, most commonly 8 weeks after the injection [49,50]. Due to the possibility of late-onset ROP reactivation, long-term regular follow-up of patients after anti-VEGF therapy is necessary until complete retinal vascularization or up to 70 weeks of PMA [43,49,50] according to the following schedule: with ongoing retinal vascularization, weekly up to 50 weeks of PMA; every two weeks from 50 to 60 weeks of PMA; every three weeks after 60 weeks of PMA. When vessel growth arrests and/or vascular activity appears, weekly (or more frequent) examinations by an ophthalmologist are required. [57]

3.4 Microsurgical treatment of ROP

Comments: vitrectomy is the most effective treatment method for stage 4a ROP and for preventing the development of total retinal detachment with loss of visual functions. The mechanism of action of vitrectomy on the pathological process is explained by the alleviation of the tractional component in the development of retinal detachment and the reduction of the concentration of vascular endothelial growth factor contained in the vitreous body. In stages 4b and 5 of active ROP, the timing of the intervention and the feasibility of preserving the crystalline lens during surgery are determined by the ophthalmologist of the eye microsurgery department.

3.5 Other treatments

Comments: upon the development of peripheral vitreoretinal chorioretinal degeneration (PVRCD) or local retinal detachment, barrier laser photocoagulation and/or local scleral buckling is indicated.

When rhegmatogenous or traction-rhegmatogenous retinal detachment develops, local scleral buckling, circumferential scleral buckling, and/or vitrectomy are performed.

When retinal detachment with a predominant tractional component develops, vitrectomy is performed.

When shallow anterior chamber syndrome develops, reconstruction of the anterior chamber angle of the eye is performed, and if necessary, lensectomy and lensvitrectomy.

When dry eye syndrome and corneal opacities develop, keratoprotective therapy and tear substitute therapy are prescribed.

When complicated cataract develops, lensectomy is performed. The issue of intraocular lens (IOL) implantation is decided on an individual basis depending on the clinical and functional state of the eye.

When secondary glaucoma develops as a result of pronounced scar changes in the vitreous body and anterior segments of the eye, reconstruction of the anterior chamber angle of the eye with lensectomy and/or vitrectomy is performed.

When "congenital"-type glaucoma develops with favorable outcomes of ROP, fistulizing surgical interventions (trabeculectomy) should be performed [3,52].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Rehabilitation is not performed in children with the active phase of ROP. Ophthalmological care consists of screening, monitoring, and treatment of active ROP.

5. Prevention and Dispensary Observation

To prevent the development of active ROP and its severe forms, it is necessary to prevent premature birth and improve neonatal care protocols for premature infants, especially those with extremely low birth weight (ELBW), strictly adhere to the schedule for initiating ROP screening, and conduct regular ophthalmological monitoring of premature infants for the timely identification of medical indications for ROP treatment.

6. Organization of Medical Care

Primary specialized medical care for children with active ROP is provided by an ophthalmologist in medical organizations (a perinatal center or children's inpatient hospital) that include departments for the treatment and care of premature infants, specifically in the neonatal intensive care unit, neonatal pathology department, and the consultation and diagnostic room for the detection and monitoring of at-risk premature infants and children with ROP. Primary specialized medical care for patients with scarred ROP is provided by an ophthalmologist in the children's outpatient polyclinic department of a medical organization.

Treatment (laser and surgical interventions, intravitreal administration of an anti-angiogenic drug) is performed by an ophthalmologist in a perinatal center or a children's 24-hour inpatient hospital.

Intravitreal administration of anti-angiogenic drugs for active ROP is performed:

1. In a medical institution that includes a neonatal intensive care unit and a neonatal pathology department, under sterile operating room conditions.

2. Upon discharge of the child from the neonatal pathology department – in a specialized ophthalmological center or a multidisciplinary children's inpatient hospital licensed to provide medical care to children, under sterile operating room conditions.

The parents (legal representatives) of the child must be informed about the upcoming treatment.

Physiotherapy or conservative medical treatment is performed by an ophthalmologist on an outpatient basis or in an inpatient setting (day or 24-hour inpatient facility).

Indications for emergency hospitalization in a medical organization: active, progressive ROP (type I), threshold stage of the disease. Treatment is carried out no later than 72 hours after the identification of medical indications.

Indications for planned hospitalization in a medical organization: the need for surgical interventions for late complications of ROP and/or a comprehensive, in-depth examination under medicinal sleep or general anesthesia in young children or children with behavioral characteristics, and/or medical and/or physiotherapeutic treatment when outpatient therapy is not feasible.

Indications for patient discharge from a medical organization:

1. Completion of treatment or one of the stages of specialized, including high-tech, medical care in a 24-hour or day hospital setting, provided there are no treatment complications requiring medical correction and/or inpatient medical interventions.

2. Refusal of the patient or their legal representative from specialized, including high-tech, medical care in a 24-hour or day hospital setting.

3. Need to transfer the patient to another medical organization.

7. Additional Information

Despite the fact that screening and monitoring of children at risk for ROP must be carried out in accordance with the Order of the Russian Ministry of Health No. 614n dated October 9, 2025, "On Approval of the Procedure for Providing Medical Care to Children in the Profile of 'Ophthalmology'," clinical circumstances (severity of the child's condition) or organizational circumstances may arise that prevent its implementation. The reason for non-compliance must be justified by a medical commission (attending physician, ophthalmologist, head of department, or deputy chief physician for medical work) in the patient's medical record, and the examination may be postponed for a period of no more than 1 week from the expected date.

Physicians in neonatal intensive care units and neonatal and premature infant pathology departments must have written protocols for ROP screening, monitoring, and treatment, as well as parental information leaflets on ROP. Heads of the aforementioned departments should monitor compliance with the Protocol.

When transferring an at-risk premature infant or an infant with signs of ROP to another inpatient department, another medical institution, or upon discharge to their place of residence, the attending physician must indicate the results of the ophthalmological examination, the diagnosis, and the ophthalmologist's recommendations regarding the timing of further follow-up of the child, as well as the medical institution where it should be carried out.

Information on the need for further follow-up by an ophthalmologist of an at-risk premature infant or an infant with signs of ROP must be communicated to the parents (legal representatives).

Visual impairment in patients with ROP depends not only on the degree of residual fundus changes (degree of scarred ROP), but also on the state of the central nervous system, visual pathway conduction, oculomotor disorders (strabismus, nystagmus), refractive errors, concomitant pathology of the eyes and other organs and body systems, and late complications.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Lyudmila A. Katargina – Head of the Research Group, Chief Freelance Pediatric Ophthalmologist of the Russian Ministry of Health, Deputy Director for Research at the National Medical Research Center for Eye Diseases named after Helmholtz of the Russian Ministry of Health, D.Sc. (Medicine), Professor, Chairperson of the Specialized Commission on Pediatric Ophthalmology of the Russian Ministry of Health, Deputy Chairperson of the Specialized Commission on Ophthalmology of the Russian Ministry of Health, Honored Doctor of the Russian Federation, Honored Scientist of the Russian Federation, Presidium Member of the All-Russian Public Organization "Association of Ophthalmologists", Presidium Member of the Ophthalmological Society of Russia

2. Lyudmila V. Kogoleva – Chief Freelance Pediatric Ophthalmologist of the Russian Ministry of Health in the Central Federal District, Head of the Pediatric Outpatient Department at the National Medical Research Center for Eye Diseases named after Helmholtz of the Russian Ministry of Health, D.Sc. (Medicine), Member of the All-Russian Public Organization "Association of Ophthalmologists"

3. Elvira I. Saidasheva – Chief Freelance Pediatric Ophthalmologist of the Russian Ministry of Health in the North-Western Federal District, D.Sc. (Medicine), Professor at the Department of Ophthalmology, North-Western State Medical University named after I.I. Mechnikov of the Russian Ministry of Health, Presidium Member of the All-Russian Public Organization "Association of Ophthalmologists", Presidium Member of the Ophthalmological Society of Russia, Honored Doctor of the Russian Federation.

4. Elena A. Stepanova – Chief freelance pediatric ophthalmologist of the Russian Ministry of Health in the Ural Federal District, Cand. Sc. (Med.), Associate Professor at the Department of Eye Diseases, Ural State Medical University of the Russian Ministry of Health, member of the All-Russian Public Organization "Association of Ophthalmologists"

5. Elena Yu. Markova – Head of the Pediatric Department at the S.N. Fyodorov Eye Microsurgery Federal State Institution of the Russian Ministry of Health, D.Sc. (Medicine), Member of the Ophthalmological Society of Russia

6. Irina G. Trifanenkova – Deputy Director for Research at the Kaluga Branch of the S.N. Fyodorov Eye Microsurgery Federal State Institution of the Russian Ministry of Health, D.Sc. (Medicine), Professor at the Department of Surgery, K.E. Tsiolkovsky Kaluga State University, Presidium Member of the Ophthalmological Society of Russia

7. Irina B. Astasheva – Ph.D. (Medicine), Associate Professor at the Department of Ophthalmology, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Member of the Ophthalmological Society of Russia

8. Elena N. Demchenko – Ph.D. (Medicine), Researcher at the Department of Pediatric Eye Pathology, National Medical Research Center for Eye Diseases named after Helmholtz of the Russian Ministry of Health, Member of the All-Russian Public Organization "Association of Ophthalmologists"

The working group members had no conflicts of interest in the preparation of these clinical guidelines.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. ophthalmologists

2. neonatologists

3. pediatricians

Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2.Level of Evidence (LoE) rating scale for preventive, therapeutic, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitation interventions)

Table 3. Scale for assessing the grades of recommendation (GR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. Current instructions for the medicinal products mentioned in these clinical guidelines can be found at http://grls.rosminzdrav.ru

Table 1. Dose, route of administration, and regimens of medicinal products

2. International Statistical Classification of Diseases and Related Health Problems (10th revision) (ICD-10),

1. Order of the Ministry of Health of the Russian Federation No. 804n dated October 13, 2017, "On Approval of the Nomenclature of Medical Services."

2. Order of the Russian Ministry of Health No. 205n of May 2, 2023, "On Approval of the Nomenclature of Positions of Medical Workers and Pharmaceutical Workers".

3. Federal Law No. 323-FZ of November 21, 2011, "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation".

4. Order of the Russian Ministry of Health No. 614n dated October 9, 2025, "On Approval of the Procedure for Providing Medical Care to Children in the Field of Ophthalmology"

5. Decree of the Government of the Russian Federation No. 2406-r dated October 12, 2019, "On Approval of the List of Vital and Essential Drugs, as well as Lists of Drugs for Medical Use and the Minimum Assortment of Drugs Required for the Provision of Medical Care"

6. Order of the Russian Ministry of Health No. 203n dated April 14, 2025, "On Approval of Criteria for Assessing the Quality of Medical Care"

7. Decree of the Government of the Russian Federation No. 1940 dated December 27, 2024, "On the Program of State Guarantees of Free Medical Care to Citizens for 2025 and for the Planning Period of 2026 and 2027".

8. Resolution of the Chief State Sanitary Doctor of the Russian Federation No. 44 dated December 24, 2020, "On Approval of Sanitary Rules SP 2.1.3678-20 'Sanitary and epidemiological requirements for the operation of premises, buildings, structures, equipment and vehicles, as well as the conditions of activities of business entities engaged in the sale of goods, performance of work or provision of services'."

Timeframes for the initial ophthalmological examination (start of screening) of at-risk premature infants

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

From the first minutes of a premature infant's life, experienced specialists—neonatal intensive care physicians and neonatologists—monitor and provide necessary care. Their main objective is to save the child's life and prevent potential severe diseases arising from the organism's immaturity at the time of premature birth. One such condition is retinopathy of prematurity, a retinal disorder affecting premature infants.

Retinopathy of prematurity is one of the leading causes of blindness, low vision, and visual impairments in early childhood. The earlier the gestational age and the lower the birth weight, the higher the risk of developing severe forms of retinopathy.

To detect the early signs of retinopathy of prematurity, an ophthalmological examination is required 3–4 weeks after birth. The timing of the examination is determined and overseen by the attending neonatologist. Based on the results of the initial examination, follow-up intervals are scheduled and must be strictly observed. Retinopathy of prematurity does not develop in all premature infants, and when it does, spontaneous regression occurs in 70% of cases, requiring no treatment—only dispensary observation.

In the progressive course of ROP, the only way to preserve vision is timely and adequate treatment: sectoral laser photocoagulation of the retina and/or intravitreal anti-VEGF injection. Treatment is performed strictly according to indications under sedation or general anesthesia, which also carries certain health and life risks for the premature infant. Due to severe somatic pathology, extreme prematurity, or the severity of ROP, vision cannot always be preserved even after treatment. Treatment and rehabilitation of a patient with ROP involve multiple stages and necessitate lifelong dispensary follow-up.

When prescribing sectoral retinal laser photocoagulation in the active phase of ROP, the parents (legal representatives) of the child must be informed about the possibility of peripheral vision impairment, night vision loss, development of myopia, as well as potential complications: anterior segment ischemia, cataract, angle-closure, vitreous and retinal hemorrhage, and the risks of general anesthesia.

With anti-VEGF therapy, drug penetration into systemic circulation is possible, carrying a risk of adverse effects on the cardiovascular system, gastrointestinal problems, and death. There are data regarding the risk of neurodevelopmental delay in infants who received anti-VEGF therapy. Furthermore, children require longer monitoring following intravitreal injection due to the possibility of disease reactivation and recurrence. Potential complications include retinal tear, retinal detachment, eye perforation, cataract, and endophthalmitis. In addition, peripheral retinal changes and a high risk of retinal detachment may persist, necessitating lifelong follow-up.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

No.