Retinopathy of prematurity (ROP) is caused by abnormal blood vessel growth in the retina of premature infants, triggered primarily by the disruption of normal vascular development that occurs when a baby is born too early. About 32% of premature infants develop some degree of ROP, with roughly 7.5% developing a severe form. The condition is most common in babies born before 31 weeks of gestation or weighing less than 3.3 pounds (1,500 grams) at birth.
The root issue is timing. A baby’s retinal blood vessels don’t finish growing until close to full term, around 40 weeks. When a baby arrives weeks or months early, those vessels are only partially formed, and the outside world creates conditions that derail their normal development.
How the Retina Develops Before Birth
Inside the womb, retinal blood vessels begin growing from the optic nerve at the back of the eye around 16 weeks of gestation and slowly extend outward toward the edges of the retina. This growth is driven by signaling molecules that respond to the relatively low-oxygen environment of the uterus. The process is gradual and orderly, with vessels spreading in a flat, organized network across the retinal surface.
When a baby is born prematurely, this process is far from complete. The more premature the birth, the larger the area of retina that has no blood supply at all. That unfinished vascular landscape is where ROP begins.
Phase 1: Vessel Growth Stalls
The first phase of ROP happens in the days and weeks after premature birth. The baby’s retina, accustomed to the low-oxygen womb, is suddenly exposed to much higher oxygen levels, both from room air and from supplemental oxygen often needed to keep the baby alive. This relative flood of oxygen suppresses the signaling molecules that were guiding normal vessel growth, essentially telling the retina it has enough blood supply when it doesn’t.
A key growth factor involved in building blood vessels gets dialed down in response to the higher oxygen. At the same time, premature infants have very low levels of a hormone called insulin-like growth factor 1 (IGF-1), which is normally supplied by the placenta and the mother’s body during the third trimester. Without adequate IGF-1, retinal vessels can’t grow properly even when signaling molecules try to restart the process. The result is that vessel growth stalls, leaving large portions of the retina without a blood supply.
Phase 2: Abnormal Vessels Overgrow
As the infant matures over the following weeks, the retina’s metabolic demands increase. The areas without blood vessels become increasingly oxygen-starved, and the retina responds by flooding the area with vessel-growth signals. But instead of the orderly, flat growth that happens in the womb, these signals are now wildly overactive. The vessels that form grow in the wrong direction, pushing up off the retinal surface and into the gel-like interior of the eye (the vitreous) rather than spreading across the retina where they’re needed.
This abnormal overgrowth can create scar tissue. In severe cases, that scar tissue contracts and pulls the retina away from the back of the eye, causing partial or complete retinal detachment and potentially permanent vision loss.
The Role of Supplemental Oxygen
Oxygen management in the NICU is one of the most carefully balanced decisions in neonatal care because it directly affects ROP risk. Premature infants often need supplemental oxygen to survive, but too much accelerates the vessel-suppression process in Phase 1.
Large clinical trials have compared lower oxygen saturation targets (85-89%) against higher targets (91-95%) in infants born before 28 weeks. The lower target group needed ROP treatment at about half the rate: 10.9% versus 14.9%. However, the higher target group had lower mortality rates and fewer cases of severe intestinal complications. This tradeoff means clinicians can’t simply reduce oxygen to prevent ROP without risking other serious consequences. Modern NICUs carefully monitor oxygen levels and aim to avoid both prolonged high-oxygen exposure and dangerously low levels.
Other Risk Factors
While prematurity and oxygen exposure are the primary drivers, several other factors increase the likelihood and severity of ROP.
- Low birth weight: Babies under 3.3 pounds (1,500 grams) are at highest risk. Lower weight generally reflects greater prematurity and less developed retinal vasculature.
- Neonatal sepsis: Bloodstream infections, particularly late-onset sepsis, are now considered a direct cause of ROP rather than just an associated risk factor. Sepsis triggers systemic inflammation throughout the body, which disrupts the same growth-factor signaling pathways responsible for normal vessel development. Research published in a 2023 review argued that sepsis meets all criteria for being classified as an oxygen-independent cause of ROP.
- Inflammation: Even without full-blown infection, inflammatory processes from other sources (prenatal infections, lung disease, or surgical complications) can contribute to abnormal vessel growth.
- Poor postnatal growth: Infants who grow slowly after birth tend to have persistently low IGF-1 levels, which compounds the vessel-growth problems already caused by prematurity.
Genetics Play a Larger Role Than Expected
One of the most striking findings in ROP research is how much genetics matter. A study published in Pediatrics that controlled for known environmental factors found that genetic factors accounted for 70.1% of the variance in ROP susceptibility. That means two premature infants with similar birth weights, gestational ages, and oxygen exposures can have very different outcomes based on their genetic makeup. The specific genes involved are still being studied, but this finding helps explain why some extremely premature babies never develop ROP while others with seemingly lower risk do.
How ROP Is Classified
Doctors classify ROP by both location and severity, which determines whether treatment is needed.
Location is described in three zones radiating outward from the optic nerve at the back of the eye. Zone 1 is the innermost circle, closest to the nerve, and ROP here is the most concerning because it affects the central vision area. Zone 2 extends further out, and Zone 3 covers the outermost edges. ROP closer to the center of the retina tends to be more aggressive.
Severity is graded in five stages:
- Stage 1: A thin line marks the boundary between the area with blood vessels and the area without. This is the mildest form.
- Stage 2: That line thickens into a raised ridge of tissue.
- Stage 3: New, abnormal blood vessels begin growing from the ridge up into the interior of the eye. This is where the disease becomes sight-threatening.
- Stage 4: Scar tissue from those abnormal vessels begins pulling the retina partially away from the eye wall.
- Stage 5: The retina detaches completely, which can cause blindness if untreated.
Doctors also watch for “plus disease,” a sign of severity marked by twisted, dilated blood vessels near the optic nerve. Plus disease at any stage signals that ROP is progressing aggressively and typically triggers treatment.
Why Most Cases Resolve on Their Own
The majority of ROP cases are mild (stages 1 or 2) and resolve without any intervention as the infant matures and retinal vessels eventually complete their growth. Screening exams, which begin a few weeks after birth for at-risk infants, track whether the disease is progressing or stabilizing. Treatment is reserved for cases reaching stage 3 with plus disease or worse, where the risk of retinal detachment becomes significant. The goal of treatment, whether laser therapy or injections that block the overactive growth signals, is to stop abnormal vessel proliferation before it causes permanent structural damage.