Retinopathy of prematurity (ROP) is among the most common causes of childhood blindness. Three phases of ROP epidemics have been observed worldwide since ROP was first described in the 1940s. Despite advances in neonatal care, the occurrence of ROP and associated visual impairment has been increasing somewhere on Earth and remains difficult to control. Conventional treatment options for preventing ROP progression include retinal ablation using cryotherapy or laser therapy. With the emergence of anti-vascular endothelial growth factor (anti-VEGF) treatment for ocular diseases, the efficacy and safety of anti-VEGF therapy for ROP have recently been actively discussed. In the advanced stage of ROP with retinal detachment, surgical treatment including scleral buckling or vitrectomy is needed to maintain or induce retinal attachment. At this stage, the visual outcome is usually poor despite successful anatomical retinal attachment. Therefore, preventing ROP progression by timely screening examinations and treatment remains the most important part of ROP management.
There have been global tri-phasic epidemic periods of retinopathy of prematurity (ROP). In recent years, its incidence has reportedly been 10%–40% depending on country and study population. Current treatment strategies for ROP include laser photocoagulation, surgical treatment, and anti-vascular endothelial growth factor treatment, the role of which has drawn attention in recent years.
Retinopathy of prematurity (ROP) is a leading cause of childhood vision loss worldwide [
To prevent the acquired childhood blindness caused by ROP, it is important to understand its epidemiology and develop appropriate treatment plans. This review addresses recent epidemiology and treatment strategies for ROP.
Since it was first described in 1942 [
The first epidemic was observed in the late 1940s and early 1950s, when ROP occurred due to unrestricted oxygen use without adequate monitoring [
There have been several explanations for this third epidemic. In middle-income countries, even if there are sufficient resources to save premature infants, either neonatal care levels are inadequate to prevent ROP or there are insufficient resources to examine and treat at-risk babies [
Several nationwide or population-based studies have used various definitions of population.
In several countries, there have been population-based studies using national registry database of national neonatology societies or national ROP consortia [
A detailed incidence according to ROP stage or need for treatment was also provided in these population-based studies. The incidence of premature infants requiring treatment was 0.2% in 1990 and 1.5% in 2011 in infants with a GA<32 weeks and/or BW<1,501 g in the UK (cryotherapy or laser coagulation) [
In a Swedish study, the incidence of ROP was 9.5% (544 of 5,734) for stage 1, 11.6% (666 of 5,734) for stage 2, 10.4% (597 of 5,734) for stage 3, 0.2% (11 of 5,734) for stage 4, and 0.2% (11 of 5,734) for stage 5 among infants with a GA<31 weeks between 2007 and 2015 [
In addition to these population-based studies, many multitertiary center-based studies have been published. In 2 NICUs in Hong Kong, among neonates with a BW≤1,500 g and/or GA≤32 weeks who were screened for ROP between January 2007 and December 2012, 18.5% (95 of 513) tested positive [
The development and progression of ROP are characterized by abnormal neovascularization, which typically occurs in 2 postnatal phases [
ROP is categorized according to the International Classification of Retinopathy of Prematurity (ICROP), which was first published in 1984 [
In addition to this staged ROP, aggressive posterior ROP (AP-ROP) indicates a more virulent form of ROP in extremely low BW babies and involves very central neovascularization with plus disease. AP-ROP is limited to the posterior pole of zone 1 or 2 and does not classically progress through stages 1–3 of ROP, and it can progress very quickly to retinal detachment [
The zone and stage of ROP can be combined and reclassified into 2 types according to the study of the Early Treatment for Retinopathy of Prematurity (ETROP) [
The terms threshold and prethreshold were originally introduced in the Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) study in the late 1980s to determine when to begin treatment [
A more recent classification was suggested by the Telemedicine Approaches for the Evaluation of Acute-Phase Retinopathy of Prematurity (e-ROP) study in 2014 [
Current indications for treatment are based on the ETROP study of type 1 ROP, which is characterized as zone 1, any stage ROP with plus disease; zone 1, stage 3 ROP without plus disease; zone 2, stage 2 or 3 ROP with plus disease [
Conventional treatment focused on inhibiting aberrant intravitreal angiogenesis to prevent fibrovascular retinal detachment. Ablation of the peripheral avascular retina is believed to reduce the hypoxic retina that expresses angiogenic factors or treat cells expressing angiogenic factors. Cryotherapy was established in the late 1980s as a conventional treatment for ROP to ablate the avascular retina according to the CRYO-ROP study [
However, cryotherapy reportedly causes more inflammation, which is involved in the pathogenesis of ROP [
As a result, cryotherapy has been used less commonly for severe ROP since the advent of indirect laser delivery systems in the late 1980s, and the American Academy of Ophthalmology recommends that laser photocoagulation be performed whenever possible for infants with ROP who meet the treatment criteria [
The current standard treatment option for severe ROP is laser ablation of the peripheral avascular retina. Since the ETROP trial study showed a reduction in unfavorable structural outcomes after earlier treatment for high-risk prethreshold ROP [
The procedure can be performed in the operating room or in the neonatal care unit under general anesthesia or sedation [
Nevertheless, the limitations or side effects of ablation of the avascular retina remain. While evidence of retinal vessels growing between treated areas toward the ora serrata is lacking, there is strong evidence that eyes underwent spontaneous regression of preretinal neovascularization and vascularization of the previously peripheral avascular retina [
The introduction of intravitreal anti-VEGF therapy is a recent development in the treatment of ROP [
There have been a few multicenter trials of anti-VEGF therapy for ROP. The first clinical trial, Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEAT-ROP) in 2011, reported significant treatment effects of bevacizumab over laser therapy for zone 1 (but not zone 2) disease in infants with stage 3+ ROP [
In 2018, a Cochrane review of intravitreal anti-VEGF treatment for ROP reported that intravitreal bevacizumab or ranibizumab as a monotherapy reduced the risk of refractive errors but did not reduce the risk of retinal detachment or ROP recurrence in type 1 ROP [
The Pediatric Eye Disease Investigator Group (PEDIG) ROP phase 1 study investigated the efficacy of lower-dose bevacizumab and found that, even at a dose of 0.031 mg, it was effective in a small sample of infants with type 1 ROP through 6 months [
The Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity (CARE-ROP) study, an interventional investigator-initiated study, was performed in Germany and investigated the use of ranibizumab 0.12 mg and 0.20 mg in infants with ROP, corresponding to 24% and 40% of the adult dose, respectively [
The RAnibizumab compared with laser therapy for the treatment of INfants BOrn prematurely With retinopathy of prematurity (RAINBOW) study used ranibizumab (0.2 mg, 0.1 mg), which is cleared more rapidly from the blood and eyes compared to laser treatment [
Regarding long-term ophthalmic outcomes, intravitreal bevacizumab injection reportedly induces less myopia than laser treatment [
Despite the promising outcomes of anti-VEGF treatment in ROP, there are concerns about anti-VEGF therapy, including reports that the effect may be transient with later ROP recurrence [
For these reasons, the American Academy of Pediatrics suggests that detailed informed consent should be obtained if anti-VEGF therapy is contemplated [
Once retinal detachment occurs, surgical treatment is needed; regardless, the visual outcomes are generally poor [
Scleral buckling has been proposed for stage 4 ROP to reduce traction and stabilize vascular activity [
Lens-sparing vitrectomy has been ideally performed for stage 4 ROP in posterior zone 2 or zone 1, or stage 5 ROP [
Previous treatments have focused on retinal reattachment in stage 5 ROP, and while successful anatomical reattachment was technically possible, visual outcomes were often limited [
In stage 5 ROP, retinal reattachment is performed in infants through 2 years of age. Even after successful reattachment, complications related to earlier ROP, including rhegmatogenous retinal detachment and cataracts requiring surgery to restore or preserve vision, can occur throughout life [
Most cases with mild ROP including stage 1 and 2 ROP and all ROP cases not meeting type 1 criteria usually resolve spontaneously after some time, and the visual prognosis is known to be associated with ROP severity in the acute phase [
Among eyes with severe ROP requiring treatment, a high proportion of those untreated and a proportion of those treated develop structural changes including retinal scarring, distortion, or detachment with irreversible vision loss [
ROP can lead to various short- and long-term ophthalmic complications, even after spontaneous regression or treatment. Such complications include early or late retinal detachment, cataracts, glaucoma, strabismus, refractive problems, amblyopia, and nystagmus [
In the past few decades, neonatal care has developed significantly. Nevertheless, ROP is still the leading cause of childhood visual impairment worldwide. Understanding the heterogeneity of ROP epidemics worldwide is essential to reduce this considerable global burden. The most important aspect in ROP prognosis is preventing it before it progresses to an advanced stage, and in an effort to make it efficient, the classification system of ROP has been created and revised. Established or developing treatment options to date include cryotherapy, laser ablation, surgical treatment, and anti-VEGF therapy. Anti-VEGF agents, with the exception of one (ranibizumab) approved in Europe, are still used as off-label, which requires the establishment of its safety and effectiveness and will require long-term research results like other treatments.
Supplementary Table 1 can be found via
No potential conflict of interest relevant to this article was reported.
We are thankful to Dr. Sang Jin Kim (Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea) for allowing us to use the fundus photographs.
Classification of retinopathy of prematurity (ROP) according to zone and stage. (A) Scheme of retina of the right eye representing 3 distinct zones. (B) ROP severity is classified as stages. In stage 1, a demarcation line is observed; in stage 2, an elevated ridge is observed; in stage 3, an extraretinal fibrovascular proliferation with neovascularization is observed, which can lead to partial (stage 4) or total retinal detachment (stage 5).
Fundus photos of stages 1–4 retinopathy of prematurity (ROP). (A) In stage 1, a demarcation line (arrow) between a normally vascularized retina and the peripheral avascular retina is shown. (B) In stage 2, the demarcation line becomes an elevated ridge (arrow). (C) In stage 3, extraretinal fibrovascular proliferation appears (arrow). (D) Partial retinal detachment (arrow) in the nasal side of the fundus and preretinal hemorrhage (dashed arrow) are shown. (Fundus photos courtesy of Dr. Sang Jin Kim).
Population-based epidemiological studies of ROP published in the last 10 years
Study | Country | Study period | Database | Population | Incidence of ROP | Trend during the study period |
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Painter et al. [ |
UK | 1990–2011 | Nationwide (Hospital Episode Statistics, representing all National Health Service inpa tient events) | GA<32 weeks and/or BW <1,501 g | 1.28% in 1990; 12.6% in 2011 | Increased: 1.28% in 1990; 12.6% in 2011 |
Ludwig et al. [ |
US | 2000–2012 (2000, 2003, 2006, 2009, 2012) | Nationwide (National Healthcare Cost and Utilization Project Kids’ Inpatient Database) | Premature infants with LOS | 16.4% (39,191/238,813) | Increased: 14.7% (6,201/42,178) in 2000; 19.9% (10,483/52,720)in2012 |
Kang et al. [ |
Taiwan | 2002–2011 | Nationwide (National Health Insurance Research Database) | Premature infants with LOS >28 days | 36.6% (4,096/11,180) | Fluctuated between 31% and 41% |
Hong et al. [ |
South Korea | 2007–2018 | Nationwide (National Health Insurance Service database) | GA<37 weeks | 29.8% (42,300/141,964) | Decreased: 39.5% (3,308/8,366) in 2007; 23.5% (2,943/12,539) in 2018 |
Na et al. [ |
South Korea | 2006–2014 | Nationwide (National Health Insurance Service database) | Newborn with BW< 1,500 g; BW 1,500 g– 2,499 g; BW≥2,500 g | (BW<1,500 g) 31.7%; (BW 1,500–2,499 g) 2.54%; (BW≥2,500 g) 0.03% | (BW<1,500 g) fluctuated; (1,500–2,499 g, ≥2,500 g) decreased |
Hwang et al. [ |
South Korea | Jan 2013–July 2014 | Populationbased (Korean Neo natal Network database) | GA≤30 weeks or BW <1,500 g | 34.1% (686/2,009) | N/A |
Gerull et al. [ |
Switzerland | 2006–2015 | Populationbased (Swiss Society of Neonatology registry) | GA<32 weeks and/or BW <1,500 g | 9.3% (557/5,973) | N/A |
Holmström et al. [ |
Sweden | 2008–2015 | Populationbased (Swedish re gister for ROP “SWEDROP”) | GA<31 weeks | 31.9% (1,829/5,734) | Increased from 2008 to 2015 |
van Sorge et al. [ |
Netherlands | 2009 | Populationbased (prospective data collection from all hospitals, “Netherlands ROP (NEDROP)” database) | GA<32 weeks and/or BW <1,500 g | 21.9% (302/1,380) | N/A |
Bas et al. [ |
Turkey | 2011–2013 | Populationbased (Turkish Neonatology Society) | BW≤1,500 g or GA≤32 weeks and infants with a BW >1,500 g or GA>32 weeks with an unstable clinical course | 30.0% (4,729/15,745) | N/A |
Bas et al. [ |
Turkey | Apr 2016–Apr 2017 | Populationbased (Turkish Neonatology Society) | BW≤1,500 g or GA≤32 weeks and infants with a BW >1,500 g or GA >32 weeks with an unstable clinical course | 27.7% (1,695/6,115) | N/A |
ROP, retinopathy of prematurity; UK, United Kingdom; US, United States; GA, gestational age; BW, body weight; LOS, length of hospital stay; N/A, not available.
Classification of retinopathy of prematurity [
Stage 1 | Demarcation line separating avascular from vascularized retina |
Stage 2 | Ridge arising in region of demarcation line which may have small isolated tufts of neovascular tissue on its surface known as “popcorn” |
Stage 3 | Ridge with extraretinal fibrovascular proliferation/neovascularization extending into the vitreous |
Stage 4 | Partial retinal detachment |
Stage 5 | Total retinal detachment |
Plus disease | Increased venous dilatation and arteriolar tortuisity of the posterior retinal vessels in at least 2 quadrants of the retina |
Preplus disease | More vascular dilatation and tortuisity than normal but insufficient to make the diagnosis of plus disease |
Type 1 ROP | Zone 1 – any stage plus ROP as well as stage 3 ROP without plus disease |
Zone 2 – stage 2 or 3 plus ROP | |
Type 2 ROP | Zone 1 – stage 1 or 2 ROP without plus disease |
Zone 2 – stage 3 ROP without plus disease |
ROP, retinopathy of prematurity.
Prognosis of retinopathy of prematurity after ETROP study and in the anti-VEGF era
Recommendation | Severity of ROP | Management | Prognosis |
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Wait and see | Mild ROP (type 2 ROP) | No treatment | Spontaneous regression |
Retinal abnormalities, even at old age [ |
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Requiring treatment | Severe ROP (type 1 ROP) | Laser photocoagulation | 34.6%, 14.3% 26.4%, and 15.7% achieved VA of 20/40 or better, worse than 20/40 and better than or equal to 20/60, worse than 20/60 and better than 20/200, and worse or equal to 20/200 at 6 years of age [ |
59.2%, 31.7%, and 9.1% achieved normal, below normal, and unfavorable VA at 3 years of age [ |
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Visual impairment (VA of 20/60 or worse, or below the fifth percentile for age) was present in 9.6% at 4–6 years of age [ |
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Need for repeated laser more than one session [ |
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AP-ROP | Laser photocoagulation | Long-term visual outcomes are generally poor even after good anatomical success [ |
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Progress rapidly to intractable retinal detachment [ |
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Stage 4–5 ROP | Vitrectomy | Long-term visual outcomes are generally poor even after good anatomical success [ |
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(Not established) | Anti-VEGF | Late recurrences occurred between postmenstrual age 45–55 weeks, up to 64.9 weeks (→longer follow-up until 65 weeks is recommended) [ |
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Retinal fibrosis and need for vitrectomy [ |
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Much less induced myopia and astigmatism than laser [ |
ETROP, Early Treatment for Retinopathy of Prematurity; VEGF, vascular endothelial growth factor; ROP, retinopathy of prematurity; VA, visual acuity; AP-ROP, aggressive posterior ROP.