A Single Eye Injection for Premature Babies: How Are These Children Doing Two Years Later?

A plain-language look at the FIREFLEYE next study, which followed babies treated with aflibercept or laser for a serious eye condition of prematurity

Why This Research Matters

Premature babies can develop a serious eye condition called retinopathy of prematurity, or ROP, in which blood vessels in the back of the eye grow abnormally and, in severe cases, can pull the retina loose and cause blindness. A recent study called FIREFLEYE next followed 100 very premature children who had been treated for severe ROP — half with a single injection of a medicine called aflibercept and half with traditional laser treatment — to see how their eyes, growth, and development were doing at 2 years of age. The encouraging headline: nearly all the children's eyes were healthy and stable, no child developed a new detached retina, those who received the injection tended to be less nearsighted, and there was no sign that the injection harmed the children's growth or development [1].

ROP matters because it is one of the most common serious complications of being born very early, and it is a leading cause of childhood blindness that can be prevented with timely treatment. Worldwide, tens of thousands of premature babies lose vision to ROP each year, and as more tiny babies survive, that number has grown — especially in middle-income countries [2]. For a family, the stakes are deeply personal: the right treatment at the right moment can be the difference between a child who sees normally and one who does not.

How Families and Doctors Used to Face This Problem

For decades, the only way to stop severe ROP was to destroy the underdeveloped edge of the retina so the dangerous blood vessels would stop growing. The first proven version of this was freezing treatment, tested in a large study in the 1980s, which showed that treating the eye roughly halved the chance of a blinding outcome [3]. Freezing was later replaced by laser treatment, which was more precise, and a major trial in 2003 showed it was best to treat earlier, as soon as the disease became high-risk [4]. Laser became the standard of care and saved the sight of countless children.

But laser has real downsides. It permanently destroys part of the retina, which can shrink the edges of a child's vision and very often leaves the child quite nearsighted. The treatment is also hard on a fragile baby: it usually requires anesthesia, often a breathing tube, and can take a long time. Doctors and families wanted a gentler option. The breakthrough came from understanding what drives ROP — a natural growth signal in the body called VEGF, which tells blood vessels to grow. In ROP, too much of this signal makes vessels grow the wrong way [5]. Researchers reasoned that a medicine blocking this signal might calm the disease without destroying the retina. Early studies of such injection medicines were promising [6], but they raised an important worry. VEGF is not only in the eye — it helps the brain, lungs, and other organs develop. Could blocking it, even briefly, affect a baby's overall development? Earlier reviews said the long-term safety simply was not yet known, and called for careful, long-term follow-up of treated children [7].

What the Study Did and Found

FIREFLEYE next was designed to answer that exact question. It followed children who had taken part in an earlier trial, called FIREFLEYE, that compared a single aflibercept injection with laser treatment in premature babies with severe ROP across many countries. In that first trial, the injection worked at least as well as laser in the short term [8]. The follow-up study then watched these children grow, checking their eyes, their height and weight, and their development at ages 1 and 2 — with plans to continue to age 5 [1].

The children were among the most premature: most were born around 26 weeks (a full-term pregnancy is about 40 weeks) and weighed less than a kilogram — under about two pounds — at birth. By age 2, the results were reassuring across the board. Almost every child's ROP was gone: about 97 out of 100 in the injection group and 94 out of 100 in the laser group had no active disease. Crucially, no child in either group developed a new retinal detachment, the most feared outcome [1]. A few children in the injection group (about 6 in 100) needed extra eye treatment, but these were all handled before the first birthday, and most were children whose eyes were already severely affected from the start.

Two differences stood out in the children's favor. First, the injection let the retina's own blood vessels keep growing toward the edges — something laser cannot allow, because it destroys that area; by age 2, most injection-treated eyes had grown vessels almost completely [1]. Second, children who got the injection were much less likely to be severely nearsighted: very high nearsightedness was found in about 1 in 100 injection-treated eyes compared with about 13 in 100 laser-treated eyes [1]. In everyday terms, that can mean the difference between needing very strong glasses and needing little or none. Most importantly, the children's overall vision was similar in both groups, and standard development tests of thinking, language, and movement at age 2 showed no meaningful difference between the two treatments — and no evidence that the injection had harmed the children's growth or development [1].

What This Means for Families

If your baby is facing treatment for severe ROP, this study offers genuine reassurance about the injection option. Two years on, children treated with a single aflibercept injection had stable, healthy eyes, no new retinal detachments, generally better nearsightedness outcomes than laser, and were growing and developing just like the children who received laser [1]. The injection is also gentler to give — quick, and usually without the need for the more involved anesthesia that laser often requires.

There is one practical point every family should hear clearly: choosing the injection is a commitment to careful, ongoing eye checks. Because the eye keeps developing for months afterward and the disease can sometimes flare back up, children treated this way need to keep all their follow-up eye appointments well after leaving the hospital. The good news in this study is partly that the families and teams stuck with it — most children were successfully followed all the way to age 2 [1]. It is also worth knowing that some children in the study did have other health challenges, such as cerebral palsy; these come from being born extremely early, not from the eye treatment itself.

It also helps to understand what the study could and could not promise. A few children — about 6 in 100 in the injection group — did need extra eye treatment, and a small number had serious eye problems such as a detached retina. When the researchers looked closely, almost all of these were in eyes that had been very severely affected from the very beginning, before any follow-up started. In other words, the injection did not create new problems out of nowhere; rather, the eyes that were already in the most trouble stayed the hardest to treat. That is an important reason why doctors do not consider any single treatment a guaranteed cure, and why they watch the most fragile eyes especially closely. On the other side of the ledger, the children who received the injection actually had slightly fewer serious health problems of the body overall, and the everyday illnesses they did get — fevers, coughs, and colds — were the ordinary ones any toddler born very early tends to face, not signs that the medicine had caused harm [1].

Another piece of context families sometimes ask about is why this matters so much around the world. ROP is one of the biggest causes of childhood blindness that can actually be prevented, and the number of affected babies has been rising as more very premature infants survive — especially in countries with growing newborn-care programs [2]. An injection that is quick to give and does not require a laser machine or heavy anesthesia could be especially valuable in places where those resources are scarce — as long as the careful follow-up that the treatment depends on can also be provided.

What Researchers Are Working On Next

This report is an early look, not the final word. It was not a head-to-head lottery-style comparison at this stage, the number of children was modest, and the study's main goal — measuring how well the children actually see at age 5 — is still ahead [1]. The same research team and others are continuing to follow these children to age 5, watching both their vision and their development. Encouragingly, a separate research program using a different injection medicine (ranibizumab) has followed its children to 2 and even 5 years and reached similar conclusions: stable eyes, less severe nearsightedness, and no sign of developmental harm [9],[10]. Researchers are also working out the best dose to use the smallest effective amount of medicine, and comparing the different injection medicines directly so that families and doctors can make the most informed choice possible — all while doctors continue to use a shared, careful system for classifying and tracking the disease [11].

References

  1. Stahl A, Nakanishi H, Lepore D, et al. Intravitreal aflibercept vs laser therapy for retinopathy of prematurity: two-year efficacy and safety outcomes in the nonrandomized controlled trial FIREFLEYE next. JAMA Netw Open. 2024;7(5):e248383. doi:10.1001/jamanetworkopen.2024.8383 ↩
  2. Blencowe H, Lawn JE, Vazquez T, Fielder A, Gilbert C. Preterm-associated visual impairment and estimates of retinopathy of prematurity at regional and global levels for 2010. Pediatr Res. 2013;74(Suppl 1):35-49. doi:10.1038/pr.2013.205 ↩
  3. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity: preliminary results. Arch Ophthalmol. 1988;106(4):471-479. doi:10.1001/archopht.1988.01060130517027 ↩
  4. Early Treatment for Retinopathy of Prematurity Cooperative Group. Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial. Arch Ophthalmol. 2003;121(12):1684-1694. doi:10.1001/archopht.121.12.1684 ↩
  5. Hartnett ME, Penn JS. Mechanisms and management of retinopathy of prematurity. N Engl J Med. 2012;367(26):2515-2526. doi:10.1056/NEJMra1208129 ↩
  6. Mintz-Hittner HA, Kennedy KA, Chuang AZ; BEAT-ROP Cooperative Group. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med. 2011;364(7):603-615. doi:10.1056/NEJMoa1007374 ↩
  7. Sankar MJ, Sankar J, Chandra P. Anti-vascular endothelial growth factor (VEGF) drugs for treatment of retinopathy of prematurity. Cochrane Database Syst Rev. 2018;1(1):CD009734. doi:10.1002/14651858.CD009734.pub3 ↩
  8. Stahl A, Sukgen EA, Wu WC, et al. Effect of intravitreal aflibercept vs laser photocoagulation on treatment success of retinopathy of prematurity: the FIREFLEYE randomized clinical trial. JAMA. 2022;328(4):348-359. doi:10.1001/jama.2022.10564 ↩
  9. Marlow N, Stahl A, Lepore D, et al. 2-year outcomes of ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW extension study). Lancet Child Adolesc Health. 2021;5(10):698-707. doi:10.1016/S2352-4642(21)00195-400195-4) ↩
  10. Marlow N, Reynolds JD, Lepore D, et al. Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): five-year outcomes of a randomised trial. EClinicalMedicine. 2024;71:102567. doi:10.1016/j.eclinm.2024.102567 ↩
  11. Chiang MF, Quinn GE, Fielder AR, et al. International classification of retinopathy of prematurity, third edition. Ophthalmology. 2021;128(10):e51-e68. doi:10.1016/j.ophtha.2021.05.031 ↩