Blood Transfusions for Very Premature Babies: Fewer, Better-Timed, and Perhaps One Day From Cord Blood

What two large US studies (Patel et al.; Hendrickson et al.) and a Dutch laboratory study (van Daelen et al., the All-Cord study) tell families about when babies get blood, what kind of blood they get, and what is coming next

Many very premature babies need a blood transfusion in their first weeks, and doctors now know it is safe to wait until a baby's blood count drops a little lower before giving one. New research shows that US hospitals have been following that advice more closely, hints that the way donated blood is stored may also matter, and describes a laboratory step toward transfusions made from umbilical cord blood.

Why premature babies so often need blood

Red blood cells carry oxygen around the body using a protein called hemoglobin. Babies born very early often become anemic, meaning they have too few red cells, and most of the tiniest babies receive at least one red blood cell transfusion, which means a small amount of blood from an adult donor given through a drip. For many years, the big question for doctors and families was simple: how low should a baby's hemoglobin be allowed to fall before a transfusion? Hospitals answered it very differently. In a study of 7 US hospitals between 2013 and 2016, 8 out of 10 babies born before 27 weeks of pregnancy received a transfusion, often at levels higher than the evidence supported [1].

Two large studies published in 2020 settled the question. The Transfusion of Prematures (TOP) trial, carried out in hospitals across the United States, included 1824 babies weighing 1000 g (about 2 pounds 3 ounces) or less at birth [2]. The Effects of Transfusion Thresholds on Neurocognitive Outcomes of Extremely Low-Birth-Weight Infants (ETTNO) trial included 1013 similar babies in 36 neonatal units in Europe [3]. In both, babies were randomly assigned to be transfused either earlier (at a higher blood count) or later (at a lower one). Survival and development in early childhood were about the same either way: in TOP, about half the babies in each group died or had developmental difficulties, a sign of how fragile these babies are rather than of harm from either approach. A 2025 review that combined six such studies, covering 3451 babies, reached the same conclusion, and found that waiting meant roughly one fewer transfusion per baby [4]. An international guideline published in 2024 now gives doctors week-by-week target levels that depend on how much breathing support a baby needs [5]. If you want to read more about those two trials, we covered them in an earlier article (A Two-Continent Verdict on Red-Cell Transfusion Thresholds).

Three new studies, three different questions

The first two studies come from the same large US research program, called the Recipient Epidemiology and Donor Evaluation Study-IV-Pediatric (REDS-IV-P). It is funded by the National Heart, Lung, and Blood Institute and links information about each blood donor, how each bag of blood was prepared, and the patient who received it [6]. Both studies looked at babies born between April 2019 and December 2023.

Patel and colleagues studied 981 babies born weighing less than 1000 g at 5 US hospitals with newborn intensive care units. They asked a practical question: did doctors actually start transfusing at lower blood counts after the 2020 trials [7]? Hendrickson and colleagues ran the Transfusion in Preterm Infants (TIPI) study, which followed 2605 babies born weighing less than 1500 g (about 3 pounds 5 ounces) at 8 US hospitals, 5 university hospitals and 3 community hospitals [8]. About half (1283 babies) received at least one transfusion. The team asked whether details of each transfusion, such as the baby's blood count beforehand, the amount given, the donor, and how the blood was stored, were linked to serious complications. Both are observational studies: they watched routine care rather than testing a treatment, so they can show links but not prove cause and effect.

The third study, called the All-Cord study, was a laboratory study in the Netherlands, led by researchers from Erasmus MC Sophia Children's Hospital in Rotterdam and the Dutch blood supply organization Sanquin [9]. No babies received any blood in this study. Instead, the researchers worked out how best to prepare and store red cells taken from umbilical cords donated after healthy full-term births.

Doctors are transfusing at lower blood counts

The Patel study found that practice did change. The average hemoglobin just before a transfusion fell from 10.2 to 9.5 g/dL (grams per deciliter, the usual unit for this measurement) between 2019 and the end of 2023 [7]. The biggest drop came from the third week of life onward, when the guideline allows the lowest levels. The same study found no change for platelet transfusions, which help blood clot, even though the Platelets for Neonatal Transfusion-2 (PlaNeT-2) trial, carried out in European hospitals and published in 2019, had found fewer deaths or serious bleeds when doctors waited for a lower platelet count [10]. Researchers often note that new evidence can take many years to change everyday care [11], and doctors in newborn medicine are often cautious about changing practice on the basis of a single study [12].

What TIPI found about the transfusions themselves

Babies in TIPI were very small and very premature, and 847 of the 1283 transfused babies (about 2 in 3) had at least one serious complication, such as a lung condition, a bowel or brain problem, a serious infection, a severe eye condition, or death [8]. Two transfusion features stood out. Babies who tended to be transfused at higher blood counts were somewhat more likely to have a complication. The authors stress that this may be because sicker babies are often transfused sooner, rather than because the transfusion itself caused harm, and the big trials did not find harm from transfusing earlier [4].

The second feature was how the blood had been stored. Donated blood is kept in a bag containing a liquid that keeps the cells alive. Babies who received more blood stored in newer "additive" solutions were less likely to have a complication than babies who received blood stored in older citrate-based solutions. Most transfusions in TIPI already used the newer solutions. This link weakened in one of the researchers' extra checks, so it needs confirming before it changes anything. Many other things, including the donor's sex and age, how long the blood had been stored, and whether it had been washed, showed no link with the main outcome. That last point matches an earlier review that found no proven benefit of washing [13]. Earlier hints that blood from female or older donors might be protective [14] were not clearly confirmed.

The researchers also looked at each complication separately. These extra analyses are best treated as ideas to test rather than firm answers. For example, babies who received larger or more frequent transfusions were more likely to die, although one possibility is that the sickest babies simply need the most blood. Almost all donated blood for babies is treated with radiation to prevent a rare but serious reaction in which donor white cells attack the baby's body, and babies who received blood within a day of that treatment had fewer serious bowel problems. This fits with a small New Zealand trial in which freshly treated blood seemed to deliver oxygen to the brain a little better than blood stored after treatment [15].

Could cord blood one day be a better match?

Before birth, babies make a special form of hemoglobin, called fetal hemoglobin, that is suited to life in the womb. Each adult transfusion replaces some of it with adult hemoglobin. Swedish researchers found that very premature babies with lower levels of fetal hemoglobin were more likely to develop a chronic lung condition and an eye condition called retinopathy of prematurity [16][17]. Baby red cells also differ from adult ones in size, shape and how they handle oxygen [18]. That raises the idea of transfusing red cells from umbilical cord blood, which is rich in fetal hemoglobin. An Italian trial in 8 hospitals, called the Umbilical or Adult Donor Red Blood Cells in Extremely Low Gestational Age Neonates and Retinopathy of Prematurity (BORN) trial, tested this. In its main analysis, severe eye disease was similar in both groups (16 of 56 babies assigned adult blood and 14 of 56 assigned cord blood). In a secondary analysis limited to babies who received only cord blood, severe eye disease was less common, a promising but not yet conclusive result [19]. We describe BORN in more detail in a separate article.

The All-Cord team tackled a practical hurdle: making cord-blood units that meet the same quality rules as ordinary donated blood [9]. They found that undiluted cord blood, stored for up to 21 days in a bag made without an older plastic softener called DEHP and in a solution called PAGGSM, kept red-cell breakdown at 0.30%, well below the 0.8% safety limit and similar to standard adult blood in the Netherlands.

What this means for your baby

If your baby needs a transfusion, it is reassuring that care teams now follow research-based blood-count targets, and that waiting a little longer has been shown to be safe. You can always ask your baby's team what level they use and why. The findings about storage solutions and cord blood are early, and they do not mean the blood your baby receives today is unsafe; blood banks follow strict quality rules.

What researchers are working on next

Researchers now want to test, in proper trials, whether the way blood is stored or the amount given makes a real difference. The Dutch team's next step is to show that cord blood can be collected and produced reliably, before clinical trials can find out whether it helps the smallest babies.

References

  1. Patel RM, Hendrickson JE, Nellis ME, et al. Variation in Neonatal Transfusion Practice. J Pediatr. 2021;235:92-99.e4. doi:10.1016/j.jpeds.2021.04.002 ↩
  2. 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 ↩
  3. Franz AR, Engel C, Bassler D, et al. Effects of Liberal vs Restrictive Transfusion Thresholds on Survival and Neurocognitive Outcomes in Extremely Low-Birth-Weight Infants: The ETTNO Randomized Clinical Trial. JAMA. 2020;324(6):560-570. doi:10.1001/jama.2020.10690 ↩
  4. Andersen C, Stark MJ, Crawford T, et al. Low versus high haemoglobin concentration threshold for blood transfusion for preventing morbidity and mortality in very low birthweight infants. Cochrane Database Syst Rev. 2025;12(12):CD000512. doi:10.1002/14651858.CD000512.pub3 ↩
  5. Deschmann E, Dame C, Sola-Visner MC, et al. Clinical Practice Guideline for Red Blood Cell Transfusion Thresholds in Very Preterm Neonates. JAMA Netw Open. 2024;7(6):e2417431. doi:10.1001/jamanetworkopen.2024.17431 ↩
  6. Josephson CD, Glynn S, Mathew S, et al. The Recipient Epidemiology and Donor Evaluation Study-IV-Pediatric (REDS-IV-P): A research program striving to improve blood donor safety and optimize transfusion outcomes across the lifespan. Transfusion. 2022;62(5):982-999. doi:10.1111/trf.16869 ↩
  7. Patel RM, Hendrickson JE, Birch R, et al. Temporal Trends in Red Blood Cell and Platelet Transfusion Thresholds for Extremely Low Birth Weight Infants. J Pediatr. 2026;288:114797. doi:10.1016/j.jpeds.2025.114797 ↩
  8. Hendrickson JE, Birch RJ, Rowley EAK, et al. Red Blood Cell Transfusion Characteristics and Morbidity or Mortality in Very-Low-Birth-Weight Infants. JAMA Netw Open. 2026;9(6):e2619301. doi:10.1001/jamanetworkopen.2026.19301 ↩
  9. van Daelen JH, Bestebroer J, Korsten H, et al. Development and production of allogeneic cord blood-derived red blood cell concentrates for transfusion to extremely preterm neonates, the All-Cord study. Transfusion. 2026;66(7):1336-1346. doi:10.1111/trf.70024 ↩
  10. Curley A, Stanworth SJ, Willoughby K, et al. Randomized Trial of Platelet-Transfusion Thresholds in Neonates. N Engl J Med. 2019;380(3):242-251. doi:10.1056/NEJMoa1807320 ↩
  11. Rubin R. It Takes an Average of 17 Years for Evidence to Change Practice-the Burgeoning Field of Implementation Science Seeks to Speed Things Up. JAMA. 2023;329(16):1333-1336. doi:10.1001/jama.2023.4387 ↩
  12. Foglia EE, DeMauro SB, Dysart K, Kirpalani H. When has enough evidence accumulated to change neonatal practice?. Semin Fetal Neonatal Med. 2015;20(6):424-430. doi:10.1016/j.siny.2015.09.003 ↩
  13. Keir AK, Wilkinson D, Andersen C, Stark MJ. Washed versus unwashed red blood cells for transfusion for the prevention of morbidity and mortality in preterm infants. Cochrane Database Syst Rev. 2016;2016(1):CD011484. doi:10.1002/14651858.CD011484.pub2 ↩
  14. Patel RM, Lukemire J, Shenvi N, et al. Association of Blood Donor Sex and Age With Outcomes in Very Low-Birth-Weight Infants Receiving Blood Transfusion. JAMA Netw Open. 2021;4(9):e2123942. doi:10.1001/jamanetworkopen.2021.23942 ↩
  15. Saito-Benz M, Bennington K, Gray CL, et al. Effects of Freshly Irradiated vs Irradiated and Stored Red Blood Cell Transfusion on Cerebral Oxygenation in Preterm Infants: A Randomized Clinical Trial. JAMA Pediatr. 2022;176(5):e220152. doi:10.1001/jamapediatrics.2022.0152 ↩
  16. Hellström W, Martinsson T, Hellstrom A, Morsing E, Ley D. Fetal haemoglobin and bronchopulmonary dysplasia in neonates: an observational study. Arch Dis Child Fetal Neonatal Ed. 2021;106(1):88-92. doi:10.1136/archdischild-2020-319181 ↩
  17. Hellström W, Martinsson T, Morsing E, Gränse L, Ley D, Hellström A. Low fraction of fetal haemoglobin is associated with retinopathy of prematurity in the very preterm infant. Br J Ophthalmol. 2022;106(7):970-974. doi:10.1136/bjophthalmol-2020-318293 ↩
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  19. Teofili L, Papacci P, Pellegrino C, et al. Cord red blood cell transfusions for severe retinopathy in preterm neonates in Italy: a multicenter randomized controlled trial. EClinicalMedicine. 2025;87:103426. doi:10.1016/j.eclinm.2025.103426 ↩