Blood, a Natural Hormone, and Protecting a Tiny Baby's Eyes and Brain

What a large re-analysis of the PENUT study tells families about erythropoietin, transfusions, and the risks premature babies face

A large new analysis of nearly a thousand extremely premature babies found that the blood transfusions these infants often need were linked to a higher chance of serious eye disease and brain injury, while the babies' own natural levels of a hormone called erythropoietin mostly reflected how much stress they had been through rather than causing those problems. The findings do not mean transfusions are usually avoidable or that any baby who received one will be harmed; they add weight to the careful, ongoing effort in newborn intensive care units to give as little donor blood as safely possible, especially in the first week of life.

Why This Research Matters

Babies born extremely early — around 24 to 27 weeks of pregnancy, when a full-term birth is 40 weeks — face a long list of challenges as organs that expected many more weeks in the womb are asked to work too soon. Two of the most feared complications involve the eyes and the brain. Retinopathy of prematurity, or ROP, is a disease in which the blood vessels of the developing retina grow abnormally; in its severe forms it can threaten vision and sometimes requires laser treatment or an eye injection. Brain injury in premature babies, often affecting the "white matter" that connects different regions, can contribute to later difficulties with movement and thinking. Families naturally want to know what raises these risks and what the medical team can do about them. The study discussed here set out to untangle two things that often travel together in a sick premature baby: a natural hormone and the blood transfusions used to treat anemia [1].

The Problem Families Used to Face

For a long time, giving premature babies blood transfusions was simply routine. Tiny infants become anemic quickly — partly because their bodies cannot yet make red blood cells efficiently, and partly because the frequent, necessary blood tests in intensive care draw out small amounts that add up. Transfusions corrected the anemia, and the question of whether they carried hidden costs went largely unasked. Meanwhile, doctors grew interested in erythropoietin, a hormone the body makes to stimulate red blood cell production. Researchers wondered whether giving a manufactured version of it could both reduce the need for transfusions and, because the hormone also appears in the developing brain, perhaps protect that brain from injury. This hope led to a major study called the Preterm Erythropoietin Neuroprotection Trial, or PENUT, which gave high-dose erythropoietin or an inactive placebo to 941 extremely premature babies. The disappointing headline result, reported in 2020, was that the hormone did not protect the brain overall — though it did reduce how many transfusions babies needed [2], [3]. Later work from the same study raised a sobering point in the other direction: babies who received more transfusions tended to have lower developmental scores at age two [4]. That is the puzzle this new analysis stepped into.

What the Researchers Did

The team, led by Dr. Nancy Fahim and Dr. Ellen Ingolfsland, went back to the detailed records of the PENUT babies [1]. They looked at each baby's own natural erythropoietin level in a blood sample taken in the first day of life, before any study medicine was given, and again over the first two weeks. A baby's own erythropoietin rises when the body senses a shortage of oxygen, so the researchers treated it as a kind of gauge of how much oxygen stress the baby had experienced around the time of birth [5]. They then compared these hormone levels — and, separately, how many blood transfusions each baby received — against two outcomes: whether the baby developed ROP, and what a brain MRI scan showed around the time the baby would otherwise have been due. MRI scans were available for 220 of the babies, read by two specialists who did not know which treatment each baby had received.

What They Found

The clearest and most important finding was about blood, not the hormone. Babies who received any transfusion were more than three times as likely to have any ROP, and about twelve times as likely to have severe ROP — the kind needing treatment. The more blood a baby received, and the more of it given in just the first week of life, the stronger this link became. There was also a surprising difference between the sexes: the amount of blood given in the first week was tied to severe ROP in boys but not in girls, a finding the researchers flag as new and in need of confirmation. The same pattern appeared in the brain scans. Babies who received more transfusions, and more blood volume, tended to have higher brain injury scores, especially in the vulnerable white matter. These associations echo what smaller studies had hinted at before [6] and what older trials comparing generous versus sparing transfusion practices had suggested [7].

The story of the baby's own erythropoietin turned out to be more about explanation than action. Higher natural hormone levels at birth went along with being smaller and less mature, having lower Apgar scores, having more bleeding in the brain, and, modestly, a higher risk of not surviving. In other words, a high level marked a baby who had already been through more — it was a messenger, not the cause. One gentle and encouraging detail stood out: babies whose umbilical cords were clamped a little later, allowing more blood to flow from the placenta, had lower natural erythropoietin, which the researchers read as a sign of better oxygen delivery. Importantly, a baby's own erythropoietin did not predict ROP once prematurity and anemia were taken into account, correcting an earlier impression from a much smaller study [6]. On the brain scans, the hormone's relationship to injury pointed in opposite directions depending on whether it was the baby's own hormone or the manufactured drug — a complex, still-unexplained pattern that the researchers were careful to call preliminary. The brain scans were scored with a well-established method [8], and such scans are known to give useful, though not perfect, information about how children tend to do later [9].

What This Means for Your Baby

If your baby is in intensive care and has needed a transfusion, it is important to hear this clearly: transfusions are often necessary and can be life-saving, and this study cannot say that any individual baby was harmed by receiving one. What the study adds is a good reason for the care team to keep working, as many units already do, to give blood thoughtfully and sparingly — using the smallest safe amounts, limiting the blood drawn for tests, and favoring practices like delayed cord clamping. Much of the leverage seems to be in the very first week, when tiny blood draws, rather than the hormone, drive most of the losses [3]. You may hear the team talk about "restrictive" transfusion thresholds; this simply means waiting until a transfusion is truly needed rather than giving one automatically. It is reasonable to ask your baby's doctors how they approach transfusions and blood conservation. As for the manufactured hormone, it is not currently recommended to protect the brain outside of research studies, because larger reviews have not found a clear benefit [10], even though some brain-scan studies have been encouraging [11].

It also helps to keep the numbers in perspective. The strong-sounding figures — such as roughly twelve times higher odds of severe eye disease among transfused babies — describe a comparison across a whole group, not the fate of one child, and they largely reflect that the smallest, sickest babies are both the ones most likely to need blood and the ones most prone to complications of extreme prematurity. That is exactly why researchers are cautious about saying transfusions cause these problems. For a parent, the useful message is not fear of a necessary treatment but confidence that the team is weighing every transfusion carefully and looking for ways to need fewer of them. If it would help, you can ask whether your baby's unit uses a written transfusion guideline, how they limit the blood drawn for laboratory tests, and whether delayed cord clamping was possible at your baby's birth — all reasonable questions that show you are engaged in your child's care.

What Researchers Are Working On Next

The honest limitation of this study is that it looked back at information gathered for a different purpose, so it can reveal links but cannot prove that transfusions directly cause eye or brain injury; the sickest, most fragile babies both need the most blood and are most prone to these complications, which can blur the picture. The most valuable next step will be studies designed from the start to test whether deliberately limiting blood in the first week reduces severe ROP and brain injury, and whether the male-female difference is real. Researchers also continue to study how anemia itself — how long and how severe — affects the developing eye [12], and how a baby's early hormone levels reflect the stresses of a very early birth [13]. For families, the reassuring bottom line is that this work reflects a field paying ever closer attention to the small, everyday decisions — how much blood, how many blood draws, when to clamp a cord — that add up to protecting a premature baby's eyes and brain.

References

  1. Fahim NM, Lunos S, Rao RB, Georgieff MK, Juul S, Ingolfsland EC. Erythropoietin, transfusions, and outcomes of retinopathy of prematurity and brain injury in extremely preterm infants: A post hoc analysis of the PENUT Trial. PLoS One. 2026;21(6):e0348061. doi:10.1371/journal.pone.0348061 ↩
  2. Juul SE, Comstock BA, Wadhawan R, et al. A Randomized Trial of Erythropoietin for Neuroprotection in Preterm Infants. N Engl J Med. 2020;382(3):233–43. doi:10.1056/NEJMoa1907423 ↩
  3. Juul SE, Vu PT, Comstock BA, et al. Effect of High-Dose Erythropoietin on Blood Transfusions in Extremely Low Gestational Age Neonates. JAMA Pediatr. 2020;174(10):933–43. doi:10.1001/jamapediatrics.2020.2271 ↩
  4. Vu PT, Ohls RK, Mayock DE, et al. Transfusions and neurodevelopmental outcomes in extremely low gestation neonates enrolled in the PENUT Trial. Pediatr Res. 2021;90(1):109–16. doi:10.1038/s41390-020-01273-w ↩
  5. Teramo KA, Klemetti MM, Widness JA. Robust increases in erythropoietin production by the hypoxic fetus is a response to protect the brain and other vital organs. Pediatr Res. 2018;84(6):807–12. doi:10.1038/s41390-018-0054-4 ↩
  6. Fahim NM, Georgieff MK, Zhang L, Naisbitt S, Rao RB, Inder TE. Endogenous erythropoietin concentrations and association with retinopathy of prematurity and brain injury in preterm infants. PLoS One. 2021;16(6):e0252655. doi:10.1371/journal.pone.0252655 ↩
  7. Kirpalani H, Whyte RK, Andersen C, et al. The Premature Infants in Need of Transfusion (PINT) study. J Pediatr. 2006;149(3):301–7. doi:10.1016/j.jpeds.2006.05.011 ↩
  8. Kidokoro H, Neil JJ, Inder TE. New MR imaging assessment tool to define brain abnormalities in very preterm infants at term. AJNR Am J Neuroradiol. 2013;34(11):2208–14. doi:10.3174/ajnr.A3521 ↩
  9. Mayock DE, Gogcu S, Puia-Dumitrescu M, et al. Association between Term Equivalent Brain MRI and 2-Year Outcomes in Extremely Preterm Infants: A Report from the PENUT Cohort. J Pediatr. 2021;239:117–125.e6. doi:10.1016/j.jpeds.2021.08.040 ↩
  10. Ohlsson A, Aher SM. Early erythropoiesis-stimulating agents in preterm or low birth weight infants. Cochrane Database Syst Rev. 2020;2(2):CD004863. doi:10.1002/14651858.CD004863.pub6 ↩
  11. Leuchter RH-V, Gui L, Poncet A, et al. Association between early administration of high-dose erythropoietin in preterm infants and brain MRI abnormality at term-equivalent age. JAMA. 2014;312(8):817–24. doi:10.1001/jama.2014.9645 ↩
  12. Lundgren P, Athikarisamy SE, Patole S, et al. Duration of anaemia during the first week of life is an independent risk factor for retinopathy of prematurity. Acta Paediatr. 2018;107(5):759–66. doi:10.1111/apa.14187 ↩
  13. Holm M, Skranes J, Dammann O, Fichorova RN, Allred EN, Leviton A. Systemic endogenous erythropoietin and associated disorders in extremely preterm newborns. Arch Dis Child Fetal Neonatal Ed. 2016;101(5):F458–63. doi:10.1136/archdischild-2015-309127 ↩