A Weekly Injection That Reduced Blood Transfusions for Premature Babies — but Did Not Boost Brain Development

What a large U.S. study of darbepoetin (Ohls et al., JAMA Pediatrics 2025) found, and what it means for families of very premature newborns

When a baby is born many weeks early, their tiny body cannot make enough red blood cells, and most premature babies end up needing blood transfusions. A large United States study tested whether a weekly injection of darbepoetin — a long-lasting version of a natural hormone that tells the body to make red blood cells — could both reduce the need for transfusions and help protect these babies' developing brains. The injection did reduce transfusions, but it did not improve thinking and learning skills measured at about age two.

Why This Question Matters

Babies born extremely early — in this study, between 23 and 29 weeks of pregnancy, compared with a full 40 weeks — face a long list of challenges in the neonatal intensive care unit (NICU). One of the most common is anemia, meaning too few red blood cells. Red blood cells carry oxygen around the body, so having too few is a real problem [1]. Premature babies become anemic for several reasons at once: their bodies are not yet good at making red blood cells, they are growing very fast, and — perhaps surprisingly — the small, frequent blood samples doctors must draw for testing add up to a meaningful loss for someone who weighs less than a kilogram [2].

For a long time, the only way to treat this anemia was to give blood transfusions. Transfusions can be lifesaving, but doctors prefer to give as few as possible, because each one exposes a fragile baby to blood from another person. Over the years, researchers ran careful studies to find out how low a baby's blood count should be allowed to fall before a transfusion is truly needed [3],[4]. The largest of these studies found that giving transfusions earlier and more often did not help babies' brains develop any better — which told doctors that avoiding unnecessary transfusions is a sensible goal [5].

How Families and Doctors Faced This Before

This is where darbepoetin enters the story. The body naturally makes a hormone called erythropoietin, which signals the bone marrow to produce red blood cells. Scientists learned long ago that giving extra erythropoietin, or a longer-lasting version called darbepoetin, could help premature babies make more of their own red cells and therefore need fewer transfusions [6],[7]. Darbepoetin had a practical advantage: because it lasts longer in the body, it only needs to be given once a week instead of several times.

But there was a second, more exciting hope. Laboratory research suggested that these hormones might do more than build blood — they might also protect the delicate, still-forming brain by reducing inflammation and helping brain cells grow and survive [8]. Some earlier, smaller studies hinted that babies who received these medicines scored a little better on tests of thinking and learning as they grew [9]. That possibility was tantalizing, because brain-development difficulties are one of the hardest long-term consequences of being born extremely early. However, two large, carefully run studies that used very high doses of erythropoietin found no improvement in brain development [10],[11]. That left an important open question: would a more standard dose of darbepoetin — the kind already used to reduce transfusions — protect the brain where high-dose erythropoietin had not? This new study was designed to find out.

What the Researchers Did

The study was run by the Neonatal Research Network, a group of expert NICUs across the United States funded by the National Institutes of Health, in 33 hospitals' intensive care units [1]. It was what scientists call a randomized, double-masked, placebo-controlled trial — the most reliable kind of medical study. "Randomized" means each baby was assigned by chance to one of two groups. "Placebo-controlled" means one group received the real medicine and the other received a harmless dummy treatment (salt water). "Double-masked" means neither the families nor the bedside doctors and nurses knew which baby was getting which, so that hopes or expectations could not color the results [1].

Altogether, 650 babies took part — 322 received darbepoetin and 328 received the placebo [1]. Treatment began within a day and a half of birth and continued, as a once-weekly injection, until the baby reached about 35 weeks of corrected age [1]. Both groups also received iron, which the body needs as a building block to make red blood cells [1]. The main thing the researchers wanted to measure was each child's score on a standard test of thinking and learning skills, called the Bayley test, given at about two years of age [1].

A study like this is convincing for a few reasons that are worth understanding. It was large, which means the result is unlikely to be a fluke. The families and bedside staff were "blinded," so no one could unconsciously treat the two groups differently. And the researchers managed to follow up and test 9 out of every 10 babies enrolled — a high rate for a study that has to track families for two years, and one that gives confidence the answer reflects what really happened [1]. When a careful study of this size and quality finds no difference, doctors can trust that finding.

What They Found

On the central question — does darbepoetin help brain development? — the answer was clear: it did not. The average thinking-and-learning scores were almost identical, 80.7 in the darbepoetin group and 80.1 in the placebo group, a difference small enough to be considered no real difference at all [1]. This was true for the most premature babies and the slightly more mature ones alike [1]. In plain terms, the medicine did not make children's developmental outcomes any better at age two.

On the blood, though, darbepoetin worked just as hoped. Forty percent of babies given darbepoetin never needed a single blood transfusion, compared with only 21 percent of babies given the placebo [1]. The treated babies who did need transfusions needed fewer of them, were exposed to fewer different blood donors, and received smaller amounts of donated blood overall [1]. Their own red-blood-cell counts were higher within the first two weeks of life [1]. So the injection succeeded at its blood-building job; it simply did not deliver the hoped-for brain benefit.

There were two other encouraging signals. Babies who received darbepoetin had a lower rate of a serious chronic lung condition of prematurity called bronchopulmonary dysplasia (about 35 percent versus 46 percent) [12]. And importantly, the medicine appeared safe: there was no increase in blood clots, high blood pressure, or seizures, and the number of babies who survived was the same in both groups [1]. The lung finding is promising but needs to be confirmed by future studies before doctors can rely on it [1].

What This Means for Families

If your baby is in the NICU, the practical takeaway is this. Darbepoetin is a safe and effective way to reduce how many blood transfusions a premature baby needs and how many blood donors they are exposed to — and for many families, that is a genuinely worthwhile benefit [1],[5]. What it cannot be expected to do, based on this strong evidence, is improve a child's thinking and learning later on [1]. If a care team discusses darbepoetin, the honest reason to use it is transfusion reduction, not brain protection.

A few practical questions often come up for parents. Is the injection safe? In this study it was: there was no increase in blood clots, high blood pressure, or seizures, and just as many babies survived in both groups [1]. Does it hurt the baby's development to receive it? No — the children who received darbepoetin scored the same as those who did not, so there is no developmental downside to weigh against the blood benefit [1]. And does every baby need it? Not at all. Many NICUs already keep transfusions low simply by being careful about when they give them, and that approach remains perfectly reasonable on its own [5]. Darbepoetin is best thought of as an optional extra tool for reducing transfusions further, not as something every premature baby must receive.

It is also worth knowing that this kind of clear "no" is exactly how good science is supposed to work. A promising idea was tested as rigorously as possible, in a large group of babies, and the result was honest even though it was not the hoped-for one [1]. That protects future families from being offered a treatment for a benefit it does not provide, and it lets doctors concentrate their energy and research dollars on the approaches most likely to truly help.

What Researchers Are Working On Next

The neuroprotection question for these medicines now appears largely settled at the doses tested, which frees researchers to focus on more productive directions [10],[11]. Future work is likely to look at how to use darbepoetin most cost-effectively as a transfusion-reducing tool, how to fine-tune the iron supplements babies need alongside it (the study found treated babies could run low on iron despite extra supplementation), and whether the encouraging signal about reduced lung disease holds up in studies designed specifically to test it [1]. For families, the lasting message is reassuring in its clarity: a safe medicine can spare your baby some transfusions, and scientists will keep searching, carefully and honestly, for the treatments that truly protect these smallest patients' futures.

References

  1. Ohls RK, Das A, Tan S, et al. Darbepoetin, Red Cell Mass, and Neuroprotection in Preterm Infants: A Randomized Clinical Trial. JAMA Pediatrics. 2025;179(8):836–845. doi:10.1001/jamapediatrics.2025.0807 ↩
  2. Strauss RG. Anaemia of prematurity: pathophysiology and treatment. Blood Rev. 2010;24(6):221–225. doi:10.1016/j.blre.2010.08.001 ↩
  3. Bell EF, Strauss RG, Widness JA, et al. Randomized Trial of Liberal Versus Restrictive Guidelines for Red Blood Cell Transfusion in Preterm Infants. Pediatrics. 2005;115(6):1685–1691. doi:10.1542/peds.2004-1884 ↩
  4. Kirpalani H, Whyte RK, Andersen C, et al. The Premature Infants in Need of Transfusion (PINT) Study: A Randomized, Controlled Trial of a Restrictive (Low) Versus Liberal (High) Transfusion Threshold for Extremely Low Birth Weight Infants. J Pediatr. 2006;149(3):301–307. doi:10.1016/j.jpeds.2006.05.011 ↩
  5. Kirpalani H, Bell EF, Hintz SR, et al. Higher or Lower Hemoglobin Transfusion Thresholds for Preterm Infants. N Engl J Med. 2020;383(27):2639–2651. doi:10.1056/NEJMoa2020248 ↩
  6. 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 ↩
  7. Ohls RK, Christensen RD, Kamath-Rayne BD, et al. A Randomized, Masked, Placebo-Controlled Study of Darbepoetin Alfa in Preterm Infants. Pediatrics. 2013;132(1):e119–e127. doi:10.1542/peds.2013-0143 ↩
  8. Juul SE, Pet GC. Erythropoietin and Neonatal Neuroprotection. Clin Perinatol. 2015;42(3):469–481. doi:10.1016/j.clp.2015.04.004 ↩
  9. Ohls RK, Kamath-Rayne BD, Christensen RD, et al. Cognitive Outcomes of Preterm Infants Randomized to Darbepoetin, Erythropoietin, or Placebo. Pediatrics. 2014;133(6):1023–1030. doi:10.1542/peds.2013-4307 ↩
  10. 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):233–243. doi:10.1056/NEJMoa1907423 ↩
  11. Natalucci G, Latal B, Koller B, et al. Effect of Early Prophylactic High-Dose Recombinant Human Erythropoietin in Very Preterm Infants on Neurodevelopmental Outcome at 2 Years: A Randomized Clinical Trial. JAMA. 2016;315(19):2079–2085. doi:10.1001/jama.2016.5504 ↩
  12. Jensen EA, Dysart K, Gantz MG, et al. The Diagnosis of Bronchopulmonary Dysplasia in Very Preterm Infants. An Evidence-Based Approach. Am J Respir Crit Care Med. 2019;200(6):751–759. doi:10.1164/rccm.201812-2348OC ↩