Retinopathy of prematurity: a review of pathogenesis, risk factors,

diagnostics, classification, and management

Kristupas Bartuška

1

, Greta Miškinaitė

1

, Dalia Jarušaitienė

2

1

Lithuanian University of Health Sciences, Faculty of Medicine, Kaunas, Lithuania

2

factors, classification and management.

Material and Methods. A comprehensive literature review was conducted using the PubMed database, focusing

on English-language studies. Articles published in English were included in the analysis. Studies were selected

based on relevance to pathogenesis, diagnostics, risk factors, classification and treatment.

Results. ROP remains a significant complication of prematurity: interrupted VEGF-driven vascularization causes

early vessel loss followed by hypoxia-driven neovascularization. Major risk factors - low gestational age and birth

weight, unstable oxygenation, infection, blood transfusions, and inadequate nutrition - help determine which

infants need treatment. Laser, intravitreal anti-VEGF, and vitreoretinal surgery can improve structural outcomes

but carry risks of late recurrence and long-term visual impairment.

Conclusion. Primary prevention (careful oxygen management, antenatal steroids, optimized nutrition and

neovascularization, risk factors, screening, laser photocoagulation, anti-VEGF therapy, vitreoretinal surgery.

Neišnešiotų naujagimių retinopatija: patogenezės, diagnostikos,

rizikos veiksnių, klasifikacijos ir gydymo apžvalga

Kristupas Bartuška

1

, Greta Miškinaitė

1

, Dalia Jarušaitienė

2

1

Lietuvos sveikatos mokslų universitetas, Medicinos fakultetas, Kaunas, Lietuva

praradimo.

Tyrimo tikslas. Atlikti išsamią apžvalgą vertinant esamas žinias apie neišnešiotų naujagimių retinopatija,

įskaitant patogenezę, diagnostiką, rizikos veiksnius, klasifikaciją ir gydymą.

Medžiaga ir metodai. Išsamiai išanalizuota mokslinė literatūra, pasitelkus PubMed duomenų bazę. Buvo

analizuoti anglų kalba publikuoti straipsniai. Atrinkti straipsniai buvo vertinami pagal jų svarbą patofiziologijos,

diagnostikos, rizikos veiksnių, klasifikacijos ir gydymo sričiai.

Rezultatai. NNR išlieka viena iš svarbiausių neišnešiotų naujagimių komplikacijų: sutrikusi VEGF reguliuojamas

kraujagyslių formavimosi procesas sukelia ankstyvą kraujagyslių nykimą, po kurio pasireiškia hipoksijos sukelta

patologinė neovaskuliarizacija. Pagrindiniai rizikos veiksniai - mažas gestacinis amžius ir gimimo svoris,

nestabilus įsotinimas deguonimi, infekcijos, kraujo perpylimai ir nepakankama mityba - padeda nustatyti, kuriems

metodai gerina anatominius rezultatus, būtinas ilgesnis stebėjimas (ypatingai po anti-VEGF gydymo) ir papildomi

tyrimai, dėl fazėms pritaikytų biologinių terapijų bei saugesnių sisteminių strategijų, kad būtų pagerinti ilgalaikiai

regėjimo ir raidos rezultatai.

Raktažodžiai: NNR, neišnešiotų naujagimių retinopatija, kraujagyslių endotelio augimo faktorius (VEGF),

neovaskuliarizacija, rizikos veiksniai, lazerinė fotokoaguliacija, anti-VEGF terapija, vitreoretinalinė chirurgija

1. Introduction

Approximately one in ten infants in United States is

born prematurely, that is, before 37 weeks of

gestation, whereas rates are lower in Europe, raging

from 5 % to 8 %. In the United States, prematurity

the retina and its vasculature are usually fully

developed, development of ROP highly unlikely. In

contrast, preterm birth interrupts normal retinal

maturation, and the earlier the infant is born, the

more underdeveloped the retina is at birth [4].

The condition was first recognized over 80 years ago

under the name retrolental fibroplasia. In the

following decade, it became a major cause of

childhood blindness in the United States,

particularly among infants with very low birth

[6].

ROP is categorized based on the location of retinal

involvement (zones I–III) and the extent of disease

severity (stages 1–5). More advanced or high-risk

forms (type 1 ROP) require prompt treatment,

typically with laser photocoagulation or intravitreal

anti-VEGF injections, while less severe cases (type

2 ROP) are carefully observed for possible

spontaneous regression [1]. The primary aim of

screening programs is to detect disease early and

published within the last 10 years, whereas the

remaining sources were older articles included for

contextual relevance.

3. Results

by 40 - 44 weeks of postmenstrual age (PMA),

therefore prematurity interrupts retinal vascular

development during this critical process [3,9].

The two-phase hypothesis of retinopathy of

prematurity (ROP) pathogenesis is essential in

screening and neonatal intensive care unit (NICU)

management by pediatricians, as well as staging and

treatment decisions made by ophthalmologists

(Figure 1). Phase I, immediately after birth, is

erythropoietin.

Oxidative and nitrosative stress contribute to the

early obliterative phase of ROP by stabilizing HIF-

1α and activating pro-angiogenic and inflammatory

pathways, including VEGF and JAK/STAT

signaling. In this context, oxidative stress also

whereas arginase 1, expressed by anti-inflammatory

M2 macrophages, helps reduce oxidative stress and

inflammation. Although targeting ROS/NO

signaling and arginase pathways represents a

promising therapeutic approach, current evidence

EPO - erythropoietin; IGF-1 - insulin-like growth factor 1; RPE - retinal pigment epithelium; PEDF - pigment

epithelium-derived factor; PLGF - placental growth factor; VEGF - vascular endothelial growth factor; Ang-2 -

angiopoietin-2; ROP - retinopathy of prematurity.

3.2. Risk factors

Several maternal, prenatal, and perinatal factors

contribute to the development of retinopathy of

(SpO₂ <80 % for at least 1 minute) and large oxygen

fluctuations have also been associated with an

increased risk of ROP [3,15,16].

Maintaining appropriate oxygen saturation is central

to ROP prevention in the NICU, as early hyperoxia

these steroids [19]. Optimizing parenteral nutrition

lowers the risk of ROP at any stage, and

observational studies suggest that vitamin E or

inositol supplementation and breastfeeding may

further reduce the risk of severe disease [20].

infants shared similar risk factors with extremely

preterm neonates, while bronchopulmonary

dysplasia appeared to play a more prominent role

[21].

Antenatal inflammation is considered an important

contributor to the development of severe retinopathy

of prematurity. Preterm infants exposed to

chorioamnionitis have a higher likelihood of

developing aggressive posterior ROP and zone I

disease, and severe ROP has been associated with all

remains inconsistent. Some studies report no

significant association while others suggest that the

combination of placental infection and inflammation

increases the risk of zone I ROP. In contrast one

study found that progression of acute histologic

chorioamnionitis in infants without fetal growth

restriction may have a protective effect [22–25].

Postnatal infection is a major risk factor for

retinopathy of prematurity. Sepsis reduces retinal

perfusion and causes ischemia. It also promotes

Erythropoietin is given to reduce transfusion needs

in preterm and low–birth-weight infants, but

because it is a hypoxia-sensitive pro-angiogenic

factor it may contribute to retinopathy of

prematurity [31]. Elevated endogenous EPO in the

Additionally, infants weighing 1500–2000 g or born

after 30 weeks of gestation should also undergo

examination if the clinical team considers them at

increased risk. This applies particularly to infants

with marked clinical instability, including those who

settings, apply broader criteria and screen infants

born at <32 weeks of gestation [3].

In addition to standard screening criteria, several

risk-based algorithms have been developed to

improve risk stratification and reduce the number of

unnecessary examinations. One such tool is the

weight, Insulin-like growth factor 1, Neonatal

Retinopathy Of Prematurity (WINROP) algorithm,

which uses postnatal weight gain to identify infants

at risk for severe ROP. Rather than replacing the

After determining which infants qualify for

screening, the next critical consideration is the

timing of the initial examination. The timing of the

first ROP examination is determined by

postmenstrual age, and clinicians should consider

beginning screening before 31 weeks’ postmenstrual

age in infants born before 24 weeks’ gestation or

with very low birth weight, as these infants may

develop pre-plus or plus disease earlier than older

preterm infants [35]. Conversely, in infants born at

solutions, nonnutritive sucking, swaddling, or gentle

physical containment [40,41]. In modern neonatal

intensive care settings, however, only a minority of

screened infants approximately 5–10 % ultimately

require treatment [42].

attention. In this approach, wide-angle retinal

images are captured in the neonatal intensive care

unit and transmitted electronically for remote

interpretation by trained specialists. Studies have

demonstrated high sensitivity and specificity for

detecting treatment-requiring ROP, making

telemedicine a valuable alternative in regions with

limited access to pediatric ophthalmologists. This

model also facilitates documentation, quality

assurance, and standardized grading [43]. Artificial

supporting its role as a triage adjunct in settings with

limited specialist availability, although clinical

follow-up remains essential [44].

During ROP screening, diagnosis is established

through detailed examination of the dilated retina.

The ophthalmologist evaluates the extent of retinal

vascular development and identifies the boundary

between vascularized and avascular retina.

Abnormal findings may include a demarcation line,

ridge formation, extraretinal fibrovascular

weight, unstable oxygenation, infection, blood

transfusions and inadequate nutrition. These factors

determine which infants require screening and closer

monitoring. Diagnosis and classification rely on

timely, risk-based ophthalmoscopic screening

necessitates prolonged follow-up, and further

research into phase-specific biologic therapies and

safer systemic strategies is needed to optimize long-

term visual and neurological development.

References

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Disabilities, et al. Primary Care Framework to

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American Association Of Certified Orthoptists,

Chiang MF, et al. Screening Examination of

Premature Infants for Retinopathy of Prematurity.

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doi:10.1542/peds.2018-3061.

3. Sabri K, Ells AL, Lee EY, Dutta S, Vinekar A.

Retinopathy of Prematurity: A Global Perspective

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