#156: A Blink Too Soon: Retinopathy of Prematurity

October 22, 2025 | By Sam Masur

Audio

This week we take a closer look at Retinopathy of Prematurity (ROP) –  from screening and staging to treatment and long-term outcomes. Join us as we shine some light on this sight-saving topic with insights from Dr. Nimesh Patel – Assistant Professor of Ophthalmology at Harvard Medical School and the director of Pediatric Vitreoretinal Surgery at Boston Children’s Hospital. You won’t believe your eyes at how much there is to see in the world of ROP care!

Retinopathy of Prematurity Pearls

1. ROP develops from a two-step process requiring both prematurity and oxygen exposure. 
2. All infants with a birth weight < 1500 g or a gestational age <30 weeks should receive a screening exam for ROP.
3. The first ROP screening exam should occur at 31 weeks postmenstrual age or 4 weeks chronological age – whichever is later. 
4. Not every baby with ROP will require treatment! However, the most common treatment modalities are laser photocoagulation and intravitreal injection of anti-VEGF medications directly into the eye.
5. Most children with mild/non-severe ROP often go on to achieve normal (or near normal) visual acuity long term!

Retinopathy of Prematurity Show Notes 

Pathophysiology of ROP

To fully understand retinopathy of prematurity, it’s first important to understand in-utero developmental milestones.

The blood vessels in the retina first appear between 15-18 weeks of gestation. They are first seen around the optic nerve (the central part of the retina) and then extend outwards towards the  peripheral retina.  The nasal portion of the retina is fully vascularized by 36 weeks of gestation. The temporal retina is fully vascularized between 36-40 weeks of gestation. Thus, being born premature means that the growth of the retinal blood vessels is stalled and does not fully extend/reach the periphery of the retina. 

It is also important to remember that pulmonary surfactant production begins around 24 weeks, increases significantly from 34-35 weeks, and then our alveoli continue to form and mature as we age (even after birth!). Thus, infants born before this 34 week mark are at high risk for respiratory distress syndrome because they have inadequate surfactant and under-developed alveoli.  Because of this, when they are admitted to the nicu, they often require supplemental oxygen. 

The development of blood vessels in the retina is driven by many factors, but primarily the signaling molecule VEGF ( vascular endothelial growth factor). 

• Hypoxia (low O2) stimulates VEGF to increase angiogenesis, creating new blood vessels. 
• Hyperoxia (high O2) stops VEGF, inhibiting angiogenesis, halting the creation of new blood vessels.

For ROP to occur, it requires both prematurity and oxygen exposure. It typically develops via a 2-phase process.

Phase 1 (immediately after birth) = Vaso-obliterative phase

• Baby is born premature → retina is not fully vascularized → the baby requires supplemental oxygen, with this excess oxygen causing retinal hyperoxia → high O2 inhibits the production of VEGF → inhibition of angiogenesis/retinal blood vessel development. 

Phase 2 (approximately 4-8 weeks after birth) = Vaso-proliferative phase

• As the baby matures, the metabolic demand of the retina increases but the avascular areas remain hypoxic → low O2 environment stimulates VEGF → stimulates angiogenesis of abnormal blood vessels that are fragile and leaky to form at the junction of the central vascularized and peripheral avascular retina (creating a “demarcation ridge” that is visible on dilated eye exam) → pathologic neovascularization can cause hemorrhages, retinal detachments, vision loss, etc. 

Epidemiology

According to a recent study published in Pediatrics titled ‘Retinopathy of Prematurity: A Global Perspective and Recent Developments’, it was estimated that 184,700 premature infants developed any stage of ROP worldwide in 2010. Of those cases, 10.7% developed severe visual impairment and two-thirds of those cases belonged to middle income countries.  This same article went on to say that “ROP-related blindness may be associated with the infant mortality rate (IMR)  of a country. Countries with intermediate levels of IMR reported the highest incidence of ROP.” Additionally, middle- or lower-income countries may lack an ROP screening program. 

In the United States, the rate of premature infants diagnosed with ROP has increased from 4.4% in 2003 to 8.1% in 2019. While the rate of ROP incidence during this time increased across all races and ethnicities, the incidence of ROP was persistently highest among African Americans relative to other races in ethnicities, doubling from 5.8% in 2003 to 11.6% in 2019. 

In the US (and other higher-income countries), there are typically oxygen protocols in place that are able to limit the amount of oxygen or titrate it within specific windows  to optimize oxygen exposure to our premature infants.

• See this table comparing the demographics of infants with ROP.

In lower/middle income countries, they may not necessarily have an ROP screening program altogether, let alone the same resources at their disposal while caring for premature infants. The above study mentioned a recent survey of sub-Saharan African ophthalmologists and neonatologists which found that “the median number of oxygen blenders per unit was 0. Most of their units lacked the in-wall oxygen and air lines required for oxygen blenders, resulting in most neonates receiving unregulated oxygenation that in turn can explain the increasing incidence of severe ROP.” It went on to clarify that The most important intervention to decrease the incidence of ROP  in these countries is to look at regulating oxygen administration.

• See this table comparing the reported incidence of ROP across the world.

Expert opinion: Dr. Patel is performing research on ROP and while evaluating injections for treatment of ROP and its outcomes, found that >60% of those receiving injections were male and it was a significant data point. Thus, there is some evidence to suggest that males may be affected by ROP more than females (but more research to come!). 

Risk Factors

There are a few clinical risk factors for developing ROP.  The strongest predictors being lower gestational age and lower birth weight. 

• Prematurity (specifically, <30 weeks)
• Low birth weight (<1500 g)
• High and fluctuating oxygen levels at birth and during the neonatal period

There are other social determinants of health that should be taken into account. For example, a retrospective cohort study published in JAMA Ophthalmology evaluating 125,212 cases of ROP found that the incidence of ROP was highest amongst African American and Hispanic infants. It also found that infants from low income areas and those born in the South or Midwest had higher rates of ROP. 

Addressing other causes for prematurity (such as illicit substance use, younger age pregnancy, decreased health literacy) will also help to address development of ROP.

Screening Guidelines

The American Academy of Pediatrics has ROP screening guidelines!

Before we talk about when these babies should be screened, let’s clarify some terms. 

• Gestational Age (GA) = the age of the fetus or newborn in weeks measured from the first day of the mother’s last menstrual period to the time of birth. For example, a baby born at 30 weeks has a GA of 30. Remember: the GA always stays the same, it does not keep increasing after delivery! 

• Postmenstrual Age (PMA) = the gestational age at birth + the time elapsed since birth. For example: a baby was born at 32 weeks GA and it has now been 4 weeks since their birth, their PMA = 36 weeks.
• Chronologic Age (CA) = the time elapsed since birth regardless of gestational age (AKA, the baby’s real-world age). For example: a baby was born at 32 weeks GA and is now 4 weeks old, their CA = 4 weeks. 
• Corrected (Adjusted) Age = represents how old the baby would be if they had been born at term; it is calculated with the formula: (Chronologic Age) – (Weeks preterm). For example, if a baby was born at 32 weeks GA (AKA, 8 weeks early) and today they are 12 weeks old (AKA, chronologic age = 12 weeks), their corrected age is (12 – 8) or 4 weeks. Therefore, although the baby has been alive for 12 weeks, developmentally they should be compared to a 4-week old infant since they had 8 fewer weeks in utero.

The above terms are important because the American Academy of Pediatrics recommends initiation of ROP screening exams based on an infant’s postmenstrual age (gestational age + chronologic age)! That is, the more preterm an infant is at birth, the longer the time to develop serious ROP. 

The AAP screening recommendations (see below) are that all infants with a birth weight < 1500 g or a gestational age 30 weeks or less be screened for ROP. The first ROP screening exam should occur at 31 weeks postmenstrual age or 4 weeks chronological age – whichever is later.

Expert opinion: Dr. Patel is currently working on research that attempts to risk-stratify and tailor the guidelines to maximize screening effectiveness and efficacy. They are evaluating whether some very low-risk patients could be screened later (such as once right before discharge or even as an outpatient) to reduce the ROP screening burden without compromising safety. See his recent study published in the American Academy of Ophthalmology sponsored journal, Ophthalmology Retina.  More information to come! 

In summary: 

• The first screening ROP exam is usually done at 31 weeks postmenstrual age or 4 weeks after birth – whichever is later.
  • EX: If you are born at 27 weeks, we screen at 31 weeks. 
  • EX: If you are born at 26 weeks, we screen at 31 weeks.
  • EX: If you are born at 25 weeks, we screen at 31 weeks.
  • EX: If you are born at 28 weeks, we screen at 32 weeks. 
• All infants with a birth weight of < 1500 g or a gestational age of 30 weeks or less should be screened for ROP.
• Other select infants with a birth weight between 1500-2000 g or a gestational age >30 weeks that are otherwise at risk from other comorbidities (ie, hypotension requiring inotropic support, infants who received oxygen supplementation for more than a few days or those who received oxygen without saturation monitoring, sepsis, etc) should also be screened for ROP.

See a list of ROP screening guidelines across the world: https://publications.aap.org/view-large/13015297 

Diagnosis

Examination

The screening examination should be done by an ophthalmologist with experience in managing and treating ROP. It is generally rather quick (1-2 minutes per eye) and consists of application of dilating eye drops, the use of lid speculums (to hold the eyes open), scleral depressors (to gently press on the eye) and the indirect ophthalmoscope (headset instrument used to visualize the posterior portion of the eye). 

Expert opinion: Dr. Patel mentions how there has been a recent uptick in the use of telemedicine screening exams for ROP while patients are in the NICU! It typically occurs with the help of nursing staff who are obtaining the photos and then submitting them to an ROP specialist to interpret. Of course, this has the potential for significant limitations and does not replace the sensitivity of an in-person exam, but it can be helpful for resource-poor regions (ie, those without access to an Ophthalmologist) or otherwise under-resourced areas to perform screening exams. Expect to see some coupled AI-Telemedicine ROP detection on the horizon!

Management

We’ve made it to the point where all applicable infants have received their first ROP screening examination. Next step: the follow-up. 

The follow-up exams are based on the initial exam’s retinal findings and disease severity and are recommended by the Ophthalmologist. In short, when they are evaluating the retina during their exam, they split the retina into three distinct, anatomic zones (Zones 1-3) to evaluate where ROP has affected the eye (ie, is only the peripheral retina affected? Is the central retina affected?). Zone 1 is the highest risk and zone 3 is the lowest risk.

Then, the exam is further categorized based on Stages, which indicate the severity of disease. The stages describe the morphologic appearance at the junction between the vascularized and avascular retina. 

5 stages of severity (with stage 5 being the most severe form):

• Stage 1: Demarcation Line (mildly abnormal blood vessel growth in a demarcated line).
• Stage 2: Ridge (moderately abnormal blood vessel growth in a ridge with width/height).
• Stage 3: Extraretinal Neovascular Proliferation (severely abnormal blood vessel growth that extends into the vitreous jelly).
• Stage 4: Partial Retinal Detachment.
• Stage 5: Total Retinal Detachment. 

ROP specialists also use the term “Plus Disease” which is an independent modifier of severity. It is used when the Ophthalmologist identifies venous dilation and arteriolar tortuosity in the posterior pole (AKA the central most part of the retina, where the macula and fovea are located). The presence of Plus Disease indicates more active, severe disease and often requires treatment. 

You can read more about the anatomic zones and extent of disease according to the Internal Classification of Retinopathy of Prematurity here!

For follow-up, in general, they usually see high-risk patients every week and low-risk patients every other week. This screening continues usually until ~40 weeks when the retina vessels are fully vascularized (or later if concerns arise).

Treatment

There are three mainstays of treatment for ROP: 

1. Laser Photocoagulation
2. Intravitreal injection of anti-VEGF therapy
3. Surgical intervention (only reserved for advanced stages of disease)

Lifelong ophthalmologic follow-up is recommended for treated infants, especially in the first 5 years of life due to the risk of reactivation and long-term visual impairment. This is important to remember for our adolescents making the transition to an adult primary care provider!

Laser photocoagulation is the historical gold standard (and still a popular mainstay of treatment) that uses a laser to ablate (burn) the avascular peripheral retina. The laser reduces the stimulus for VEGF  production which decreases abnormal blood vessel development. It’s important to note that the peripheral retina has lower resolution and is not as good at seeing fine details or colors. Thus, laser to the peripheral retina does not impact central vision! However, since the peripheral retina is responsible for our peripheral vision and night vision, the risks of using laser  therapy include some peripheral visual field loss, high myopia, cataracts and other procedural challenges (difficult in small infants). It is usually performed under sedation or anesthesia. It has excellent long-term outcomes and a low recurrence rate.

Intravitreal injections of anti-VEGF medications is another option in the treatment of ROP. It consists of a medication injection directly into the vitreous humor (the clear jelly that fills the inside of the eye). The medications work to directly inhibit VEGF, which decreases abnormal blood vessel development. It is used for ROP that is located in regions of the eye that are inaccessible by (or unsafe to use) laser. It is performed at the bedside with a numbing medication applied to the eye where the injection will follow under sterile conditions. It is easier and faster to perform than a laser. It also preserves the peripheral retina because it does not cause any tissue destruction. However, there is a (very small) risk of infection (called Endopthalmitis) and a higher recurrence risk when using anti-VEGF therapy (thus, it requires long-term follow-up). Infants treated with anti-VEGF medications need particularly close follow-up during the time of highest risk for disease reactivation (between postmenstrual age 45-55 weeks).

Expert opinion: Dr. Patel says the common practice pattern now is that a lot of patients are being injected first and then laser later.  The initial injection is used as a temporizing measure in an attempt to minimize the surface area that has to be lasered. The laser is usually initiated around age 55-60 weeks of age where the infant is (1) more stable from a cardiorespiratory standpoint and may not require general anesthesia, (2) treatment with anti-VEGF typically starts around 36 weeks and then wears off around 55 weeks, and (3) the age of 55-60 weeks may alleviate a patient/family from having to stay overnight in the hospital (based on that organization’s protocols).

Expert opinion: Typically, most patients who receive a single anti-VEGF injection do very well without laser treatments in the long run!

Surgical intervention is only indicated for advanced stages of ROP,  specifically when a partial or total retinal detachment is present. The surgery includes removal of the vitreous jelly that fills the center of the eye (‘Pars Plana Vitrectomy’)  followed by the placement of a silicone band around the eyeball itself (‘Scleral Buckle’) that functions to indent the wall of the eye making a retinal detachment less likely to reoccur. This is a technically challenging operation to perform, especially in very small eyes. Additionally, the presence of a retinal detachment indicates likely some underlying vision loss and the prognosis is often poor (especially in Stage 5).  

In general, however, treatment with one of the above modalities should be initiated within at least 72 hours of determination of the presence disease for the following retinal findings: 

• Zone 1 ROP: any stage with plus disease
• Zone 1 ROP: stage 3, no plus disease; and 
• Zone II: stage 2 or 3 with plus disease

Given that ROP is one of the leading causes of childhood blindness, it is important to recognize the long-term visual potential in children with ROP. It varies based on disease severity, treatment modality and gestational age (amongst other factors). In general, children with mild ROP often achieve normal (or near normal) visual acuity. Children with severe ROP will have some form of underlying visual impairment that varies in severity.  Extremely premature infants (<24 weeks GA or <600 g BW)  have the poorest visual potential with higher rates of severe ROP, amblyopia and other developmental delays. At the end of the day,  the key to preventing long-term visual impairment is early screening and treatment! 

Future Innovations

As mentioned briefly,  artificial intelligence (AI) systems and other telemedicine/smartphone-based imaging are being used to detect ROP! While these do not have the same sensitivity of an in-person examination, they are potentially promising in resource deprived areas where an infant otherwise would not be appropriately screened for ROP  which could be devastating to their long-term visual potential. 

Read more about AI Screening for ROP and the use of smartphone-based fundus imaging that are on the horizon in the world of ROP! 

Citation

1. Qayyum S. Development of retinopathy of prematurity. Community Eye Health. 2018;31(101):S3.
2. Hartnett ME, Penn JS. Mechanisms and management of retinopathy of prematurity. N Engl J Med. 2012;367(26):2515-2526. doi:10.1056/NEJMra1208129.
3. Kourosh Sabri, Anna L Ells, Elizabeth Y. Lee, Sourabh Dutta, Anand Vinekar; Retinopathy of Prematurity: A Global Perspective and Recent Developments. Pediatrics August 2022; 150 (3): e2021053924. 10.1542/peds.2021-053924.
4. Bhatnagar A, Skrehot HC, Bhatt A, Herce H, Weng CY. Epidemiology of Retinopathy of Prematurity in the US From 2003 to 2019. JAMA Ophthalmol. 2023;141(5):479–485. doi:10.1001/jamaophthalmol.2023.0809.
5. Walter M. Fierson, American Academy of Pediatrics Section on Ophthalmology, American Academy of Ophthalmology, American Association for Pediatric Ophthalmology and Strabismus, American Association of Certified Orthoptists,, Michael F. Chiang, William Good, Dale Phelps, James Reynolds, Shira L. Robbins, Daniel J. Karr, Geoffrey E. Bradford, Kanwal Nischal, John Roarty, Steven E. Rubin, Donny Won Suh, Sharon S. Lehman, George S. Ellis; Screening Examination of Premature Infants for Retinopathy of Prematurity. Pediatrics December 2018; 142 (6): e20183061. 10.1542/peds.2018-3061.
6. Validation of the “TWO-ROP” Algorithm at a Multi-Neonatal Intensive Care Unit Tertiary Referral Center. Patel, Nimesh A. et al. Ophthalmology Retina, Volume 9, Issue 1, 63 – 68.
7. International Classification of Retinopathy of Prematurity, Third Edition. Chiang, Michael F. et al. Ophthalmology, Volume 128, Issue 10, e51 – e68.
8. Ortiz A, Patiño S, Torres J, et al. AI-Enabled Screening for Retinopathy of Prematurity in Low-Resource Settings. JAMA Netw Open. 2025;8(4):e257831. doi:10.1001/jamanetworkopen.2025.7831.
9. Young BK, Cole ED, Shah PK, et al. Efficacy of Smartphone-Based Telescreening for Retinopathy of Prematurity With and Without Artificial Intelligence in India. JAMA Ophthalmol. 2023;141(6):582–588. doi:10.1001/jamaophthalmol.2023.1466.

Goal

Listeners will be able to explain the basic pathophysiology, screening guidelines and common treatment and management of retinopathy of prematurity (ROP) to improve patient care and counseling on long-term vision potential. 

Learning Objectives

After listening to this episode listeners will…  

1. Recall the two-step pathophysiologic process in the development of ROP. 
2. Be familiar with the screening guidelines of ROP and when to enact them.
3. Recognize the influence of social determinants of health and inequalities in ROP.  
4. Describe the most common treatments for ROP.
5. Feel comfortable counseling patients about long-term complications.

Disclosures

Dr. Patel reports consulting fees from Regeneron, Adverum, Amneal, Apellis, Allergan, Biogen, Dorc, Alimera, Eyepoint, Genentech, Guidepoint, GLG, Maple Sciences, Kyoto, Life Science Oyster Point, Regenx, Young MD Connect, and Olyver Wynman. The Cribsiders report no relevant financial disclosures. 

Citation

Hogue T, Patel N, Berk J, Chiu C, Masur S. “#156: A Blink Too Soon: Retinopathy of Prematurity”. The Cribsiders Pediatric Podcast. https:/www.thecribsiders.com/ October 22, 2025.