Status Active PolicyStat ID 14200566

Effective 8/21/2023 Owner Michelle

Labrecque
Next Review 8/15/2026
Department Neonatal
Intensive Care
Unit (NICU)

Applicability Boston Children's

Hospital-
Guidelines

Red Blood Cell Transfusion in Neonates [NICU] - Guideline

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Internal Approval
• Policy Steering Committee
• Executive Vice President Patient Care Operations & System CNO
• Patient Care Operations Policy and Procedure Committee
• NICU Steering Committee;
• CVCC P&P

Background
Neonatal anemia is common, and all neonates (both term and preterm) experience a decrease in hemoglobin
(Hb) during their physiological adaptation to the relative oxygen-rich extrauterine environment. The Hb
usually drops from 14-22 to 10-12 g/dl by 2-3 months of age in term infants (termed physiological anemia of
infancy). However, in preterm neonates, the Hb drops more rapidly and steeply (termed anemia of
prematurity) due to additional physiological (i.e. lower levels of and decreased responsiveness to
erythropoietin, shorter RBC life, higher growth rate), pathophysiological (i.e. infection, hemolysis, impaired red
cell production) and iatrogenic factors (phlebotomy losses).1,2 Due to these factors, red blood cell (RBC)
transfusion is one of the most common therapies administered in the Neonatal Intensive Care Unit (NICU). A
recent large retrospective cohort study of neonatal transfusion practices in the U.S. found that approximately
70% of all neonates with a gestational age <27 weeks will receive at least one RBC transfusion during their
NICU stay, with an average number of transfusions per patient of 4.7.3

Several studies have shown that RBC transfusion in neonatal anemia improves cardiac output and tissue
oxygenation,4-7 decreases the number of apneic episodes,8-11 and improves blood pressure in mechanically
ventilated preterm infants.12 Currently, the hemoglobin (Hb) and hematocrit (Hct) remain the most commonly

Red Blood Cell Transfusion in Neonates [NICU] - Guideline. Retrieved 06/2024. Official copy at http://childrenshospital- Page 1 of 7
allpolicies.policystat.com/policy/14200566/. Copyright © 2024 Boston Children's Hospital- All Documents
 used laboratory values to determine which neonates would benefit from transfusion, with low values
interpreted as markers of diminished oxygen carrying capacity and impaired tissue oxygenation that could be
improved with transfusion. Optimal tissue oxygenation is particularly important in neonates because of the
rapidly developing and growing body, especially the brain, but whether or not the Hct and Hb are the best
metrics to evaluate tissue oxygenation (and guide transfusion practices) remains unclear and is an area of
ongoing research.13-17

Despite reports of benefit in the neonatal population, RBC transfusions are not risk-free. In addition to the
known general risks of RBC transfusions (i.e. transfusion-related acute lung injury, transfusion-associated
circulatory overload, excessive iron load, hemolytic transfusion reactions, and infections), transfusions given
to preterm infants have been associated with increases in systemic pro-inflammatory cytokines,18-20
bronchopulmonary dysplasia, and necrotizing enterocolitis (NEC).21,22 Multiple observational studies
investigating the association between transfusion and NEC have implicated severe anemia, RBC transfusion,
or both in its pathogenesis, but meta-analyses of the data are conflicting in their findings.23-26 Investigating
the association between anemia and development of NEC, a recent prospective study of 598 very low birth
weight infants found that infants with severe anemia (Hb≤8 g/dL) had significantly increased rates of NEC
compared to those without severe anemia.27 Similarly, a case-control study of 333 premature infants with

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NEC found a 10% increase risk of NEC for every 1 g/dL decrease in hemoglobin nadir in multivariate
modeling.28 Preclinical models suggest that both the degree of anemia and the RBC transfusion together
contribute to transfusion-associated necrotizing enterocolitis, but this remains an area of active clinical and
preclinical research.29,30

The Hb level at which the benefits of a RBC transfusion outweigh the risks in a preterm infant is unknown.
This issue is further complicated by the fact that oxygen consumption may be higher in critically ill compared
to stable neonates, and that the level of fetal hemoglobin decreases with advancing postnatal age, which
affects the oxygen delivery at the tissue level.31 These factors strongly suggest that different transfusion
thresholds should be used at different times after birth, and for different levels of respiratory support.

In total, four randomized controlled trials have been published comparing different hemoglobin (or
hematocrit) levels as triggers for transfusion (restrictive vs. liberal strategies) in neonates born < 32 weeks,
taking into account postnatal age and level of respiratory support. The first two of these trials (the Iowa trial
and the PINT study) reported short-term outcomes,32,33 with follow-up studies looking at long-term
outcomes, such as brain volume, cerebral palsy and cognitive function.34-36 Both studies reported fewer
transfusions in the low-threshold groups, but none of the pre-defined short-term outcomes were different
between the two treatment groups. The long term follow up outcomes were strikingly different in the two
studies, however: the Iowa study (which had a significant drop-out rate, 44%) favored the restrictive
transfusion practices according to the 12 year neurocognitive and neuroradiological follow-up, while the PINT
trial (93% follow-up rate) found improved cognitive function in the liberal transfusion group at 18-21 months
of age.

As a consequence of these discrepant findings and in the absence of local guidelines, RBC transfusions were
administered to neonates mostly based on physicians’ preferences, leading to large variations in treatment
practices until the recent publication of the TOP and ETTNO trials in 2020. These larger trials compared
restrictive and liberal transfusion thresholds in premature infants and found no differences between the

Red Blood Cell Transfusion in Neonates [NICU] - Guideline. Retrieved 06/2024. Official copy at http://childrenshospital- Page 2 of 7
allpolicies.policystat.com/policy/14200566/. Copyright © 2024 Boston Children's Hospital- All Documents
 groups in the primary outcome of death or neurodevelopmental impairment at 24 months of age.37,38 In
contrast to prior observational studies, these trials found no increase in complications of prematurity
(including bronchopulmonary dysplasia and necrotizing enterocolitis) in infants transfused more liberally.
However, the neurodevelopmental outcomes evaluated in both RCTs measured severe deficits and so it
remains unclear whether RBC transfusions (or anemia) are associated with more subtle neurodevelopmental
problems (i.e. attention deficits) that manifest later in life. A school-age follow up study of infants in the TOP
trial is in progress, and will answer this question.

Regarding transfusion volume, studies suggest that larger transfusion volumes (15-30 ml/kg) may be
beneficial and reduce the number of transfusions and donor exposures.39-41 The biggest cohort study
comparing 15 vs. 20 ml/kg RBC transfusion volumes in neonates <32 weeks gestation favored 15 ml/kg in
infants <28 weeks gestation, and 20 ml/kg in neonates ≥28 weeks gestation, resulting in reduced donor
exposure.41

Scope
This policy covers all members of the Boston Children’s Hospital Medical Staff irrespective of their

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appointment category or employer, and includes Associate Clinical Staff and House Staff caring for neonatal
patients. The policy also covers all Boston Children’s Hospital W-2 Employees and Associated Personnel who
provide patient care or who do not provide patient care to neonatal patients but whose duties and
responsibilities may involve contact with Boston Children’s patients and families (“Covered Personnel”).
Covered Personnel includes, but is not limited to, Scientific Staff, research staff, nurses, advanced practice
clinicians, interpreters, administrative personnel assigned to patient care settings, students, interns,
volunteers, travelers and other contracted professional staff, and security personnel.

Guideline Statements
• Currently available data from randomized controlled trials of red cell transfusion thresholds only
includes infants < 32 weeks (or with a birth weight <1500g) until PMA of 36 weeks and little to no
data is available to guide transfusion decisions in infants born outside of these parameters.
• Low hemoglobin is commonly interpreted as a marker of diminished O2 carrying capacity and
impaired tissue oxygenation
◦ Particularly important in neonates with developing and growing body

• Besides the general risks (transfusion associated lung injury, transfusion associated circulatory
overload, excessive iron load, infection, hemolytic reactions), transfusions may carry further risks in
preterms.
• O2 consumption may be higher in critically ill compared with stable neonates.
• Thresholds for RBC transfusion used in local guidelines should be within the thresholds used
across clinical trials - the safety of these thresholds is established.
• The best available evidence to date, from the TOP and ETTNO trials, suggest there to be no
difference in survival without neurodevelopmental impairment at 22 to 26 months of age between
infants transfused at higher hemoglobin transfusion thresholds compared to lower. The proposed
guidelines are within the ranges used in the TOP and ETTNO studies for those specific populations
studied in the trials.

Red Blood Cell Transfusion in Neonates [NICU] - Guideline. Retrieved 06/2024. Official copy at http://childrenshospital- Page 3 of 7
allpolicies.policystat.com/policy/14200566/. Copyright © 2024 Boston Children's Hospital- All Documents
 • These guidelines DO NOT apply to cases of acute bleeding or anticipated bleeding (perioperative).

Purpose
• The purpose of this guideline is to standardize hematocrit/hemoglobin thresholds for transfusion
based on the best available evidence and to provide guidelines for general clinical management
during transfusion.

Process Steps
Assessment
Patient population:

• All neonates admitted to the neonatal intensive care unit

Transfusion thresholds:

• Different transfusion thresholds should be used based on gestational age, postmenstrual age, and
key clinical parameters at the time of assessment.

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◦ Respiratory support is defined as requiring mechanical ventilation, non-invasive positive
pressure ventilation (NIPPV), continuous positive airway pressure (CPAP) or high flow
nasal cannula (HFNC) or low flow nasal cannula (LFNC) at a flow > 1 L/min.

• We recommend transfusing at the following hematocrit/hemoglobin levels:

Implementation
• Volumes of transfusion: The recommended standard transfusion volume is 15 ml/kg, which is

Red Blood Cell Transfusion in Neonates [NICU] - Guideline. Retrieved 06/2024. Official copy at http://childrenshospital- Page 4 of 7
allpolicies.policystat.com/policy/14200566/. Copyright © 2024 Boston Children's Hospital- All Documents
 expected to raise the hemoglobin level by approximately 4 g/dL (hematocrit increase of
approximately 12%). Consider 20 ml/kg for infants 28 – 32 weeks of gestation (in two 10ml/kg
aliquots).
• Transfusion time: The recommended transfusion time is 3-4 hours to minimize the circulatory
effects (fluid overload), but no longer than 4 hours or the expiration time on the product.
• Transfusion and enteral nutrition: Please refer to the Enteral Feeding During Red Blood Cell
Transfusion in Neonates guideline.

Documentation
Complete patient care documentation as described in the Standards and Guidelines.

References/Citations
1. Strauss RG. Anaemia of prematurity: pathophysiology and treatment. Blood Rev 2010;24:221-5.
2. Venkatesh V, Khan R, Curley A, New H, Stanworth S. How we decide when a neonate needs a
transfusion. Br J Haematol 2013;160:421-33.
3. Patel RM, Hendrickson JE, Nellis ME, et al. Variation in Neonatal Transfusion Practice. J Pediatr

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2021;235:92-9 e4.
4. Alverson DC, Isken VH, Cohen RS. Effect of booster blood transfusions on oxygen utilization in
infants with bronchopulmonary dysplasia. J Pediatr 1988;113:722-6.
5. Hudson I, Cooke A, Holland B, et al. Red cell volume and cardiac output in anaemic preterm infants.
Arch Dis Child 1990;65:672-5.
6. Lachance C, Chessex P, Fouron JC, Widness JA, Bard H. Myocardial, erythropoietic, and metabolic
adaptations to anemia of prematurity. J Pediatr 1994;125:278-82.
7. Bard H, Fouron JC, Chessex P, Widness JA. Myocardial, erythropoietic, and metabolic adaptations
to anemia of prematurity in infants with bronchopulmonary dysplasia. J Pediatr 1998;132:630-4.
8. Joshi A, Gerhardt T, Shandloff P, Bancalari E. Blood transfusion effect on the respiratory pattern of
preterm infants. Pediatrics 1987;80:79-84.
9. DeMaio JG, Harris MC, Deuber C, Spitzer AR. Effect of blood transfusion on apnea frequency in
growing premature infants. J Pediatr 1989;114:1039-41.
10. Sasidharan P, Heimler R. Transfusion-induced changes in the breathing pattern of healthy preterm
anemic infants. Pediatr Pulmonol 1992;12:170-3.
11. Stute H, Greiner B, Linderkamp O. Effect of blood transfusion on cardiorespiratory abnormalities in
preterm infants. Arch Dis Child Fetal Neonatal Ed 1995;72:F194-6.
12. Cooke RW, Drury JA, Yoxall CW, James C. Blood transfusion and chronic lung disease in preterm
infants. Eur J Pediatr 1997;156:47-50.
13. Banerjee J, Aladangady N. Biomarkers to decide red blood cell transfusion in newborn infants.
Transfusion 2014;54:2574-82.
14. Seidel D, Blaser A, Gebauer C, Pulzer F, Thome U, Knupfer M. Changes in regional tissue
oxygenation saturation and desaturations after red blood cell transfusion in preterm infants. J
Perinatol 2013;33:282-7.
15. Bailey SM, Hendricks-Munoz KD, Wells JT, Mally P. Packed red blood cell transfusion increases

Red Blood Cell Transfusion in Neonates [NICU] - Guideline. Retrieved 06/2024. Official copy at http://childrenshospital- Page 5 of 7
allpolicies.policystat.com/policy/14200566/. Copyright © 2024 Boston Children's Hospital- All Documents
 regional cerebral and splanchnic tissue oxygen saturation in anemic symptomatic preterm infants.
Am J Perinatol 2010;27:445-53.
16. Wardle SP, Yoxall CW, Crawley E, Weindling AM. Peripheral oxygenation and anemia in preterm
babies. Pediatr Res 1998;44:125-31.
17. Alkalay AL, Galvis S, Ferry DA, Simmons CF, Krueger RC, Jr. Hemodynamic changes in anemic
premature infants: are we allowing the hematocrits to fall too low? Pediatrics 2003;112:838-45.
18. Crawford TM, Andersen CC, Hodyl NA, Robertson SA, Stark MJ. The contribution of red blood cell
transfusion to neonatal morbidity and mortality. J Paediatr Child Health 2019;55:387-92.
19. Crawford TM, Andersen CC, Stark MJ. Effect of repeat transfusion exposure on plasma cytokine
and markers of endothelial activation in the extremely preterm neonate. Transfusion
2020;60:2217-24.
20. Dani C, Poggi C, Gozzini E, et al. Red blood cell transfusions can induce proinflammatory cytokines
in preterm infants. Transfusion 2017;57:1304-10.
21. Josephson CD, Wesolowski A, Bao G, et al. Do red cell transfusions increase the risk of necrotizing
enterocolitis in premature infants? J Pediatr 2010;157:972-8 e1-3.
22. Christensen RD. Association between red blood cell transfusions and necrotizing enterocolitis. J
Pediatr 2011;158:349-50.

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23. Hay S, Zupancic JA, Flannery DD, Kirpalani H, Dukhovny D. Should we believe in transfusion-
associated enterocolitis? Applying a GRADE to the literature. Semin Perinatol 2017;41:80-91.
24. Kirpalani H, Zupancic JA. Do transfusions cause necrotizing enterocolitis? The complementary role
of randomized trials and observational studies. Semin Perinatol 2012;36:269-76.
25. Garg P, Pinotti R, Lal CV, Salas AA. Transfusion-associated necrotizing enterocolitis in preterm
infants: an updated meta-analysis of observational data. J Perinat Med 2018;46:677-85.
26. Mohamed A, Shah PS. Transfusion associated necrotizing enterocolitis: a meta-analysis of
observational data. Pediatrics 2012;129:529-40.
27. Patel RM, Knezevic A, Shenvi N, et al. Association of Red Blood Cell Transfusion, Anemia, and
Necrotizing Enterocolitis in Very Low-Birth-Weight Infants. JAMA 2016;315:889-97.
28. Singh R, Visintainer PF, Frantz ID, 3rd, et al. Association of necrotizing enterocolitis with anemia and
packed red blood cell transfusions in preterm infants. J Perinatol 2011;31:176-82.
29. Arthur CM, Nalbant D, Feldman HA, et al. Anemia induces gut inflammation and injury in an animal
model of preterm infants. Transfusion 2019;59:1233-45.
30. MohanKumar K, Namachivayam K, Song T, et al. A murine neonatal model of necrotizing
enterocolitis caused by anemia and red blood cell transfusions. Nat Commun 2019;10:3494.
31. Sacks LM, Delivoria-Papadopoulos M. Hemoglobin-oxygen interactions. Semin Perinatol
1984;8:168-83.

Approval Signatures

Step Description Approver Date

Red Blood Cell Transfusion in Neonates [NICU] - Guideline. Retrieved 06/2024. Official copy at http://childrenshospital- Page 6 of 7
allpolicies.policystat.com/policy/14200566/. Copyright © 2024 Boston Children's Hospital- All Documents
Co-chair Approval David Davis 08/2023
Site Administrator: Education/ Ian Weijer: Site Admin 08/2023
Training Requirement
Steering Committee Ian Weijer: Site Admin 08/2023
NPCO Signatory 2 Laura Wood: EVP Patient Care 08/2023
Operations & System CNO
NPCO Signatory 1 Patricia Hickey 08/2023
NPCO Quality Team Julie Murphy: Sr. Clinical Quality 08/2023
Improvement Specialist [AR]
NPCO Policy and Procedure Ashley Renaud 08/2023
Committee
NICU Steering Committee Anne Hansen 08/2023
NICU Steering Committee Cheryl Toole: Director Patient 08/2023
Care Operations
NICU Steering Committee Michelle Labrecque 08/2023

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Contributor(s) Michelle Labrecque 08/2023
Document Owner Michelle Labrecque 08/2023

Applicability

Boston Children's Hospital- Guidelines

Red Blood Cell Transfusion in Neonates [NICU] - Guideline. Retrieved 06/2024. Official copy at http://childrenshospital- Page 7 of 7
allpolicies.policystat.com/policy/14200566/. Copyright © 2024 Boston Children's Hospital- All Documents