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PubMed This is a summary of 16 peer-reviewed journal articles Updated
Neonatology

The Biological Tug-of-War: Why ROP Happens

At a Glance

Retinopathy of Prematurity (ROP) happens in two phases when a premature baby's eye development is disrupted. First, high oxygen levels after birth stop normal blood vessel growth. Later, the oxygen-starved retina overproduces growth factors like VEGF, causing abnormal, fragile blood vessels to grow.

To understand Retinopathy of Prematurity (ROP), it helps to look at it as a story of two distinct biological phases. In the womb, a baby’s eyes develop in a low-oxygen environment, which is perfect for the slow, steady growth of healthy blood vessels [1][2]. When a baby is born very early, that development is interrupted by the higher oxygen levels of the outside world [2][3].

Phase 1: Vaso-obliteration (The “Stopping” Phase)

Phase 1 begins immediately after birth. Even the normal air we breathe has more oxygen than the womb, and many premature babies need extra supplemental oxygen to survive and protect their brain and organs [2][4].

When the developing retina is exposed to these higher oxygen levels (hyperoxia), it sends a signal that no more blood vessels are needed [2][5]. This causes:

  • Vaso-obliteration: Existing small blood vessels may actually shrivel up or disappear [2][6].
  • Halted Growth: The normal “map” of blood vessel growth toward the edges of the eye simply stops [1][2].

Phase 2: Neovascularization (The “Overgrowth” Phase)

As the baby grows, the parts of the retina that have no blood vessels begin to mature and require more energy. Because there are no vessels to deliver oxygen to these areas, the retina becomes “hungry” for oxygen—a state called hypoxia [2][7].

In a desperate attempt to get oxygen, the retina sends out an emergency signal to grow new vessels [2][8]. However, this signal is so strong that the new growth is disorganized:

  • Neovascularization: New, fragile, and leaky blood vessels grow in clumps rather than smooth lines [2][8].
  • Plus Disease: These abnormal vessels can become swollen and twisted, which doctors call plus disease—a sign that Phase 2 is very active [3][9].

The Role of Growth Factors

Two main “messengers” in the body control this process:

  1. VEGF (Vascular Endothelial Growth Factor): Think of this as the “Growth Signal.” In Phase 1, it is suppressed (low). In Phase 2, it is overproduced (high), leading to the chaotic growth of abnormal vessels [2][8][5].
  2. IGF-1 (Insulin-like Growth Factor-1): This is a “Permissive Signal” that babies usually get from the mother in the womb. Preterm babies often have low levels of IGF-1 [10][2]. Without enough IGF-1, vessels cannot grow normally in Phase 1. Later, as IGF-1 levels naturally rise, it “turns on” the VEGF signal, which can unfortunately trigger the overgrowth in Phase 2 [10][2][11].

The NICU Balance

Managing oxygen in the NICU is a delicate act of “fine-tuning” [12]. Your baby’s care team uses pulse oximeters to monitor oxygen saturation (SpO2) [13].

  • High Oxygen: Too much oxygen can worsen Phase 1 by telling vessels to stop growing [2][5].
  • Low Oxygen: Too little oxygen can be dangerous for the brain and may trigger the “emergency” signals of Phase 2 [2][7].
  • Fluctuations: Rapid swings between high and low oxygen can be particularly hard on the developing retina [12][14].

The goal of the NICU team is to keep oxygen levels in a “safe zone” that supports the baby’s overall life and growth while minimizing the triggers for ROP [15][16].

Common questions in this guide

Why does oxygen cause ROP in premature babies?
In the womb, a baby's eyes develop in a low-oxygen environment. After a premature birth, the higher oxygen levels in the air and from medical support can signal the eye to stop growing normal blood vessels, starting the first phase of ROP.
What are the two phases of ROP?
Phase 1 occurs shortly after birth when normal blood vessel growth stops due to higher oxygen levels. Phase 2 happens later when the developing eye lacks oxygen, triggering an emergency signal that causes abnormal, fragile blood vessels to grow rapidly.
What does plus disease mean for my baby's eyes?
Plus disease means the abnormal blood vessels in the retina have become swollen and twisted. Doctors use this term to indicate that the second phase of ROP is very active and requires careful monitoring or potential treatment.
How do NICU teams manage oxygen to prevent ROP?
The NICU team uses pulse oximeters to keep your baby's oxygen saturation in a careful safe zone. They balance providing enough oxygen to protect the brain and lungs while avoiding high levels or rapid swings that can trigger abnormal eye vessel growth.
What role do growth factors like VEGF and IGF-1 play in ROP?
VEGF and IGF-1 are natural growth factors that control blood vessel development. Premature babies often lack enough IGF-1 to grow normal vessels, while a later overproduction of VEGF acts as a strong emergency signal causing chaotic, abnormal vessel growth.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.At what stage or phase of ROP development is my baby currently?
  2. 2.How are we balancing my baby's oxygen needs for their lungs and brain with the need to protect their eyes?
  3. 3.How has my baby's weight gain and growth affected their IGF-1 levels and the progression of ROP?
  4. 4.What are the specific oxygen saturation (SpO2) targets you are using for my baby, and how do we handle fluctuations?
  5. 5.Are there other factors, like recent infections or transfusions, that might be influencing the growth factors in my baby's eyes?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (16)
  1. 1

    Advances in understanding and management of retinopathy of prematurity.

    Hartnett ME

    Survey of ophthalmology 2017; (62(3)):257-276 doi:10.1016/j.survophthal.2016.12.004.

    PMID: 28012875
  2. 2

    Retinopathy of Prematurity: Evolving Treatment With Anti-Vascular Endothelial Growth Factor.

    Hartnett ME

    American journal of ophthalmology 2020; (218()):208-213 doi:10.1016/j.ajo.2020.05.025.

    PMID: 32450064
  3. 3

    Commentary: Looking beyond anti-vascular endothelial growth factor - Novel therapeutic targets for retinopathy of prematurity.

    Dogra M, Singh SR

    Indian journal of ophthalmology 2021; (69(2)):374-375 doi:10.4103/ijo.IJO_3272_20.

    PMID: 33463596
  4. 4

    Retinopathy of Prematurity in the 21st Century and the Complex Impact of Supplemental Oxygen.

    Rodriguez SH, Ells AL, Blair MP, et al.

    Journal of clinical medicine 2023; (12(3)) doi:10.3390/jcm12031228.

    PMID: 36769876
  5. 5

    Intravitreal Delivery of VEGF-A165-loaded PLGA Microparticles Reduces Retinal Vaso-Obliteration in an In Vivo Mouse Model of Retinopathy of Prematurity.

    Mezu-Ndubuisi OJ, Wang Y, Schoephoerster J, et al.

    Current eye research 2019; (44(3)):275-286 doi:10.1080/02713683.2018.1542736.

    PMID: 30383455
  6. 6

    Protective effects of rapamycin on the retinal vascular bed during the vaso-obliteration phase in mouse oxygen-induced retinopathy model.

    Zhang J, Zhu M, Ruan L, et al.

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2020; (34(12)):15822-15836 doi:10.1096/fj.202001295R.

    PMID: 33103304
  7. 7

    Anti-VEGF therapy in the management of retinopathy of prematurity: what we learn from representative animal models of oxygen-induced retinopathy.

    Wang H

    Eye and brain 2016; (8()):81-90 doi:10.2147/EB.S94449.

    PMID: 28539803
  8. 8

    Vascular Endothelial Growth Factor Signaling in Models of Oxygen-Induced Retinopathy: Insights Into Mechanisms of Pathology in Retinopathy of Prematurity.

    Ramshekar A, Hartnett ME

    Frontiers in pediatrics 2021; (9()):796143 doi:10.3389/fped.2021.796143.

    PMID: 34956992
  9. 9

    Characteristics of Eyes Developing Retinal Detachment After Anti-vascular Endothelial Growth Factor Therapy for Retinopathy of Prematurity.

    Kondo C, Iwahashi C, Utamura S, et al.

    Frontiers in pediatrics 2022; (10()):785292 doi:10.3389/fped.2022.785292.

    PMID: 35463897
  10. 10

    The genetics of retinopathy of prematurity: a model for neovascular retinal disease.

    Swan R, Kim SJ, Campbell JP, et al.

    Ophthalmology. Retina 2018; (2(9)):949-962 doi:10.1016/j.oret.2018.01.016.

    PMID: 30250936
  11. 11

    Effect of Probenecid on Endothelial Cell Growth Rate and Retinal Angiogenesis in an Oxygen-Induced Retinopathy Model.

    Jiang J, Ou W, Luo X, et al.

    Frontiers in pharmacology 2021; (12()):717351 doi:10.3389/fphar.2021.717351.

    PMID: 34690760
  12. 12

    Epidemiological Profile of Retinopathy of Prematurity in Central India.

    Joshi RS, Singh H, Joshi R, et al.

    Cureus 2025; (17(7)):e87259 doi:10.7759/cureus.87259.

    PMID: 40761957
  13. 13

    Oxygen, weight gain, IGF-1 and ROP: not a straight-forward equation.

    Darlow BA, Binenbaum G

    Acta paediatrica (Oslo, Norway : 1992) 2018; (107(5)):732-733 doi:10.1111/apa.14114.

    PMID: 29083092
  14. 14

    Frequency of retinopathy of prematurity (ROP) in infants screened for ROP: two years follow-up results of a single center in Turkey.

    Ugurlu A

    BioMedicine 2021; (11(3)):38-42 doi:10.37796/2211-8039.1188.

    PMID: 35223409
  15. 15

    A Study of the Demographic Profile, Screening, and Management of Patients Visiting a Retinopathy of Prematurity Clinic.

    Mushtaq I, Agrawal T, Bhavsar D, et al.

    Cureus 2024; (16(4)):e58305 doi:10.7759/cureus.58305.

    PMID: 38752079
  16. 16

    Increased frequency of retinopathy of prematurity over the last decade and significant regional differences.

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    Acta ophthalmologica 2018; (96(2)):142-148 doi:10.1111/aos.13549.

    PMID: 29068172

This page explains the biological causes of Retinopathy of Prematurity (ROP) for educational purposes only. Always discuss your baby's specific oxygen targets, eye exams, and overall NICU care plan with their neonatologist and pediatric ophthalmologist.

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