15. RBC Transfusion in Neonates

At least half of infants born preterm (<30 weeks gestation) and more than 80% of infants with a birthweight of less than 1000 grams will receive at least one RBC transfusion during their initial hospital stay.(1).

Despite data from recent trials supporting more restrictive RBC thresholds in preterm infants, a more liberal approach persists, as a recent survey of European neonatal units found.(2)

Anaemia of prematurity (AOP)

Anaemia of prematurity is a multifactorial condition defined by early (after birth) and significant anaemia associated with phlebotomy blood losses, lower erythropoietin (EPO) production, and a limited bone marrow response. (3)

Diagnosis of AOP relies upon a combination of parameters, such as non-specific clinical symptoms of anaemia coupled with haemoglobin and haematocrit levels. However, the exact threshold for haemoglobin or haematocrit levels where inadequate tissue oxygenation (critical anaemia hypoxaemia) occurs in either term or preterm infants is unknown. Overall, this makes the timing of transfusion in a neonate challenging.

Systematic reviews comparing liberal versus restrictive RBC transfusion thresholds in preterm infants

Several systematic reviews comparing liberal and restrictive RBC transfusion triggers in preterm infants were published from 2008 to 2021 (4-7). With the publication of the ETTNO (8) and Transfusion of Prematures (TOP) trial (9) in 2020, it seems prudent to include a summary of these two trials (Table 1).

Table 1: Summary of ETTNO (8) and TOP (9) trials

When to transfuse?

A recently published high-quality consensus statement considering the trials mentioned above (8,9) recommends a restrictive RBC transfusion strategy, with moderate certainty of evidence, for preterm neonates with less than 30 weeks’ gestation(10).  Another international guideline for RBC transfusion in adults and children was recently published, providing guidance for RBC transfusion thresholds for term infants and younger infants.(11) Both these guidelines were developed using best-practice methodology for guideline development, including the input of consumers and families.

Haemoglobin thresholds for transfusion in preterm and term neonates

For preterm infants

Table 2 shows the transfusion threshold considering the postnatal week based on previously mentioned consensus work by an international steering committee that reviewed evidence from a systematic review of six RCTs comparing high versus low haemoglobin-based or haematocrit-based transfusion thresholds (10). The review included RCTs encompassing 3483 participants (mean [SD] age range, 25.9-29.8 [1.5-3.0] weeks) and was used as the basis of the recommendations.

Table 2: Transfusion threshold recommendations considering postnatal week (10). 

*Defined as invasive mechanical ventilation, continuous positive airway pressure or non-invasive intermittent positive pressure ventilation or nasal flow cannula flow rate ≥ 1L/minute

The recommendations above are for infants born at <30 weeks gestation. The evidence to guide practice for infants born at a later gestation is lacking, and many neonatal units will use the same thresholds for all preterm infants.

For term infants

Only a few studies examine RBC thresholds for term infants; most are part of larger trials involving older infants and children. The most well-known is the TRIPICU study (12), which showed no difference in oxygenation markers, duration of ventilation, cardiac dysfunction, and length of hospital stay between critically ill infants and children transfused with a threshold of 70 g/L compared with 95 g/L.

The previously mentioned international guideline for RBC transfusion in adults and children provides further guidance in this area.(11) It included RCTs were critically ill infants and children (n = 2) (12, 13) , those with haematologic conditions (n = 1) (14), those with acquired and congenital heart disease (n = 3),(15-17) and those with severe (malarial) anaemia (n = 1) (18) with the direct evidence dominated by a single trial.(12)

Recommendation (strong recommendation, moderate certainty evidence):

For critically ill children and hospitalised children at risk of critical illness who are hemodynamically stable and without a transfusion-dependent hemoglobinopathy, cyanotic cardiac condition, or severe hypoxaemia, consider transfusing when the haemoglobin level is <70g/L compared with one <95 g/L (restrictive threshold).

Recommendation (conditional recommendation, low certainty evidence):

Consider a transfusion threshold for haemodynamically stable children with congenital heart disease based on the cardiac abnormality and stage of surgical repair:

• 70 g/L (biventricular repair)
• 90 g/L (single-ventricle palliation), or
• 70-90 g/L (uncorrected congenital heart disease)

Safety considerations in neonatal and paediatric transfusion practice

The Serious Hazards of Transfusion (SHOT) reporting scheme has shown disproportionate transfusion errors in the paediatric age group.(19) Furthermore, there is often confusion about maternal and baby samples, multiple births (especially using consecutive identification numbers), babies without first names, failure to apply wristbands, removal of wristbands by children and/or parents or during procedures and failure to make wristbands accessible during surgery (note alternatives may be used). For these reasons, collection of a second sample for confirmation of the ABO group before cross-matching is recommended unless reliable electronic patient identification systems are available. To reduce neonatal blood testing, it may be acceptable to use a cord sample. All prescriptions should be ordered and expressed in millilitres (mL) rather than units to prevent over-transfusion of blood components. Paedipacks are aliquots made from one batch of adult blood donation. By using paedipacks, the exposure of infant recipients to multiple donors can be avoided. Hospital transfusion laboratories should liaise with neonatal units to develop policies and procedures for using paedipacks.

Foetal and neonatal ABO grouping and antibody screening differ from adult grouping. Antibody screening of a foetus/neonate represents the maternal antibody status rather than the foetal/neonatal antibody status. Therefore, within the first four months after birth, samples from both mother and infant should be obtained for initial ABO and RhD group determination. Besides, antibody screening should also be initiated on the maternal sample when available. Since sample collection from the infant exacerbates the AOP and it is more convenient to collect sufficient volumes from the mother, a maternal sample is preferred for antibody testing.

Maintaining the neonatal and maternal transfusion history (including foetal transfusions) is essential for all new neonatal admissions. Also, obtaining a maternal sample for initial testing and cross-matching is recommended when necessary. Laboratory control measures are required to ensure that donor blood units are ABO and RhD compatible with both mother and baby and to determine that it is antigen-negative for clinically significant maternal antibodies.

Other considerations

Age of blood used in neonatal RBC transfusions

The ARIPI trial (20) found that using fresh (5.1±2.0 days) RBCs compared with standard (14.6±8.3 days) RBCs did not improve outcomes in very low birth weight infants receiving RBC transfusions.

Routine use of furosemide in neonatal RBC transfusions

To prevent fluid overload, loop diuretic agent furosemide (0.5-2 mg/kg) is sometimes used during transfusions in preterm infants. One RCT (21) demonstrated minimal clinical benefit of co-administered furosemide on cardiorespiratory parameters in preterm infants beyond the first week of life. Therefore, while furosemide can be beneficial for cardiorespiratory parameters, in the short term, its established potential adverse effects should be considered (electrolytes imbalances and prolonged and higher doses associated with ototoxicity and nephrocalcinosis) and is not routinely recommended.

Use of erythropoietin (EPO) in RBC transfusions

Low levels of EPO are frequently used to stimulate RBC production, avoid haemoglobin decreases, and attempt to reduce RBC transfusions after birth. However, recent studies demonstrate that the use of EPO, either early or late in the neonatal course, has not been associated with reduced rates of mortality or significant morbidities.(22) Moreover, there is an increased risk for retinopathy of prematurity (ROP) with EPO treatment, which remains a major concern.(22) The use of EPO to attempt to reduce the use of RBC transfusion in neonates is not routinely recommended. Darbepoetin is a synthetic form of EPO that may have neuroprotective effects and might be a valuable alternative to EPO in some neonatal clinical scenarios.(23)

The importance of clinical guidelines and the need for their implementation

Clinical guidelines alone are not usually enough to change practice.(24) A systematic review of transfusion guidelines for RBCs (25) found that the most common limitation to implementation was the lack of implementation tools. Coordinated international efforts for guideline development, focusing on implementation tools, which may be one way of addressing this.(25) The presence of two internationally developed guidelines for RBC transfusion is exciting (10, 11) and an essential first step; however, neither guides implementation.

Relevant guidelines

Both these guidelines are recommended based on their best-practice methodology and recency in publication.

For preterm infants:

Clinical Practice Guideline for Red Blood Cell Transfusion Thresholds in Very Preterm Neonates (10)

For term and older infants:

Red Blood Cell Transfusion: 2023 AABB International Guidelines (11)

References

1. Keir AK, Yang J, Harrison A, Pelausa E, Shah PS, Network oBotCN. Temporal changes in blood product usage in preterm neonates born at less than 30 weeks' gestation in Canada. Transfusion. 2015;55(6):1340-6.
2. Scrivens A, Reibel NJ, Heeger L, Stanworth S, Lopriore E, New HV, et al. Survey of transfusion practices in preterm infants in Europe. Archives of Disease in Childhood - Fetal and Neonatal Edition. 2023;108(4):360-6.
3. Strauss RG. Anaemia of prematurity: pathophysiology and treatment. Blood Rev. 2010;24(6):221-5.
4. Whyte R, Kirpalani H. Low versus high haemoglobin concentration threshold for blood transfusion for preventing morbidity and mortality in very low birth weight infants. Cochrane Database Syst Rev. 2011(11):Cd000512.
5. Wang P, Wang X, Deng H, Li L, Chong W, Hai Y, et al. Restrictive versus liberal transfusion thresholds in very low birth weight infants: A systematic review with meta-analysis. PLoS One. 2021;16(8):e0256810.
6. Bassler D, Weitz M, Bialkowski A, Poets C. Restrictive Versus Liberal Red Blood Cell Transfusion Strategies for Preterm Infants: A Systematic Review of Randomized Controlled Trials. Current Pediatric Reviews. 2008;4:143-50.
7. Ibrahim M, Ho SK, Yeo CL. Restrictive versus liberal red blood cell transfusion thresholds in very low birth weight infants: a systematic review and meta-analysis. J Paediatr Child Health. 2014;50(2):122-30.
8. Franz AR, Engel C, Bassler D, Rüdiger M, Thome UH, Maier RF, 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):560-70.
9. Kirpalani H, Bell EF, Hintz SR, Tan S, Schmidt B, Chaudhary AS, et al. Higher or Lower Hemoglobin Transfusion Thresholds for Preterm Infants. New England Journal of Medicine. 2020;383(27):2639-51.
10. Deschmann E, Dame C, Sola-Visner MC, Fustolo-Gunnink SF, Guyatt GH, Patel RM, et al. Clinical Practice Guideline for Red Blood Cell Transfusion Thresholds in Very Preterm Neonates. JAMA Network Open. 2024;7(6):e2417431-e.
11. Carson JL, Stanworth SJ, Guyatt G, Valentine S, Dennis J, Bakhtary S, et al. Red Blood Cell Transfusion: 2023 AABB International Guidelines. JAMA. 2023;330(19):1892-902.
12. Lacroix J, Hébert PC, Hutchison JS, Hume HA, Tucci M, Ducruet T, et al. Transfusion strategies for patients in pediatric intensive care units. N Engl J Med. 2007;356(16):1609-19.
13. Akyildiz B, Ulgen Tekerek N, Pamukcu O, Dursun A, Karakukcu M, Narin N, et al. Comprehensive Analysis of Liberal and Restrictive Transfusion Strategies in Pediatric Intensive Care Unit. J Trop Pediatr. 2018;64(2):118-25.
14. Robitaille N, Lacroix J, Alexandrov L, Clayton L, Cortier M, Schultz KR, et al. Excess of veno-occlusive disease in a randomized clinical trial on a higher trigger for red blood cell transfusion after bone marrow transplantation: a canadian blood and marrow transplant group trial. Biol Blood Marrow Transplant. 2013;19(3):468-73.
15. Cholette JM, Powers KS, Alfieris GM, Angona R, Henrichs KF, Masel D, et al. Transfusion of cell saver salvaged blood in neonates and infants undergoing open heart surgery significantly reduces RBC and coagulant product transfusions and donor exposures: results of a prospective, randomized, clinical trial. Pediatr Crit Care Med. 2013;14(2):137-47.
16. Cholette JM, Swartz MF, Rubenstein J, Henrichs KF, Wang H, Powers KS, et al. Outcomes Using a Conservative Versus Liberal Red Blood Cell Transfusion Strategy in Infants Requiring Cardiac Operation. Ann Thorac Surg. 2017;103(1):206-14.
17. de Gast-Bakker DH, de Wilde RB, Hazekamp MG, Sojak V, Zwaginga JJ, Wolterbeek R, et al. Safety and effects of two red blood cell transfusion strategies in pediatric cardiac surgery patients: a randomized controlled trial. Intensive Care Med. 2013;39(11):2011-9.
18. Maitland K, Kiguli S, Olupot-Olupot P, Engoru C, Mallewa M, Saramago Goncalves P, et al. Immediate Transfusion in African Children with Uncomplicated Severe Anemia. N Engl J Med. 2019;381(5):407-19.
19. Stainsby D, Jones H, Wells AW, Gibson B, Cohen H. Adverse outcomes of blood transfusion in children: analysis of UK reports to the serious hazards of transfusion scheme 1996-2005. Br J Haematol. 2008;141(1):73-9.
20. Fergusson DA, Hebert P, Hogan DL, LeBel L, Rouvinez-Bouali N, Smyth JA, et al. Effect of fresh red blood cell transfusions on clinical outcomes in premature, very low-birth-weight infants: the ARIPI randomized trial. JAMA. 2012;308(14):1443-51.
21. Balegar VK, Kluckow M. Furosemide for packed red cell transfusion in preterm infants: a randomized controlled trial. J Pediatr. 2011;159(6):913-8.e1.
22. Aher SM, Ohlsson A. Early versus late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database of Systematic Reviews. 2020(2).
23. Ree IMC, de Haas M, van Geloven N, Juul SE, de Winter D, Verweij EJT, et al. Darbepoetin alfa to reduce transfusion episodes in infants with haemolytic disease of the fetus and newborn who are treated with intrauterine transfusions in the Netherlands: an open-label, single-centre, phase 2, randomised, controlled trial. The Lancet Haematology. 2023;10(12):e976-e84.
24. Baer VL, Lambert DK, Schmutz N, Henry E, Stoddard RA, Miner C, et al. Adherence to NICU transfusion guidelines: data from a multihospital healthcare system. J Perinatol. 2008;28(7):492-7.
25. Pavenski K, Stanworth S, Fung M, Wood EM, Pink J, Murphy MF, et al. Quality of Evidence-Based Guidelines for Transfusion of Red Blood Cells and Plasma: A Systematic Review. Transfus Med Rev. 2018;32(3):135-43.

 The authors

Amy Keir

Consultant Neonatologist, University of Adelaide and the South Australian Institute of Health and Medical Research (SAHMRI), Australia

Flavia Miranda Bandeira

Associate Professor, State University of Rio de Janeiro, Faculty of Medical Sciences, Department of Hematology and Hemotherapy, Brazil.

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Flavia Miranda Bandeira

Associate Professor, State University of Rio de Janeiro, Faculty of Medical Sciences, Department of Hematology and Hemotherapy, Brazil.

Flavia is Deputy Technical Director of the Blood Bank at Pedro Ernesto University Hospital, State University of Rio de Janeiro, Brazil.
Member of the Technical Board of Hematology and Hemotherapy of the State Health Department of Rio de Janeiro, Brazil. 

Email:

academy@isbtweb.org

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