How Supplied:

All Red Blood Cell (RBC) products supplied by Versiti undergo pre-storage leukocyte-reduction.

Empty, unlabeled pediatric aliquot bags (example 3 or 6 pedi-bags) may be attached to an adult RBC unit for filling and labeling at the hospital. Pediatric aliquots may also be supplied by Versiti as pre-filled aliquots (if 3 bags filled, each contain approximately 80-100 mL or if 6 bags filled, each contain 40-50 mL). Outdate for the filled aliquots is the original expiration date of the main donor unit. Check with your Hospital Relations Representative for availability and number of pediatric aliquot bags that may be supplied in your region.

General Comments:

• The neonatal period is defined as the first 4 weeks after birth (39 weeks of gestation) as well as premature infants (neonate born prior to 37 weeks of gestation).1 Very low birth weight (VLBW) is defined as <1500 mg and extremely low birth weight (ELBW) as <1000 mg.
• When evaluating neonates with anemia, thrombocytopenia, bleeding, or coagulopathy, the following should be taken into consideration¹:
  • Gestational and postnatal age,
  • Any congenital disorders,
  • Maternal factors,
  • Transplacental antibody transfer

Key Practice Points:

• For most neonates, a restrictive strategy or lower hemoglobin threshold for transfusion appears to be safe, and is recommended over a liberal transfusion strategy or higher hemoglobin threshold.^2,3
• Guidelines on the hemoglobin (Hgb) threshold for transfusion vary according to gestational age at birth, postnatal age, respiratory support, extracorporeal membrane oxygenation (ECMO) requirement, or the presence of congenital heart disease.4 Within professional guidelines in the literature there may be subtle differences for the published Hgb thresholds and criteria to guide transfusions in the neonate. Hgb thresholds cited in these guidelines are based on thoughtful review of the recent clinical trials and expert opinion of the Versiti Transfusion Medicine physicians.
• The decision to transfuse in the neonate should be based on clinical status, rather than solely on a hemoglobin (Hgb) or hematocrit (Hct) value. Several factors influence transfusion requirements in the premature neonate including postnatal age, severity of anemia, need for respiratory support or oxygen dependence, and tissue oxygen demand. Other clinical factors that may affect decision to transfuse include severity of illness, rate of fall of Hgb concentration, anticipated blood loss, and nutritional status. Accordingly, careful clinical assessment is paramount when deciding to transfuse the neonate.^3,4
• Important measures to limit the need for transfusion in the preterm neonate may include delayed cord clamping, minimizing phlebotomy losses, good nutritional and iron supplementation, and possible use of erythropoiesis-stimulating agents.^3,5
• Longer storage age of blood is not associated with increased morbidity in neonates.6 The potential risk of transfusion-associated hyperkalemia in neonates could be a concern when older blood is used in specific clinical situations (e.g. large-volume transfusion, exchange transfusion, cardiac surgery) and may warrant the use of RBCs with shorter storage times.^4,5
• Only one filtration step is necessary for infant transfusions. This can occur either in the hospital transfusion service between the blood component and syringe (if aliquots prepared on site) or at the bedside between the component/syringe and the infant.

Utilization Review Guidelines:

Red cell transfusions are primarily indicated to improve oxygen carrying capacity. Documentation of the indication(s) for transfusion and special circumstances for transfusion that take place outside these guidelines is recommended.

Transfusion May be Considered for:

1. Massive blood loss or acute blood loss due to trauma, surgery or other cause associated with hypovolemic shock.
2. Suggested Hgb thresholds based on infant’s postnatal age, severity of illness and supplemental respiratory needs include:^7-10

Note: Above recommendations are based on results of 2 large randomized controlled trials in VLBW infants, and should be applicable to older premature and term babies.

Note (*): Critically ill might include: hypotension or shock requiring vasopressor support; acute sepsis or necrotizing enterocolitis; significant apnea or bradycardia; significant tachycardia or tachypnea; deteriorating respiratory status; severe traumatic brain injury; or postoperative from major surgery.

Note (^): Significant respiratory support may include: mechanical ventilation, continuous airway support (CPAP) or other non-invasive positive pressure ventilation; O2 requirement >35%.

3. Hgb <7g/dL (Hct <24%) in stable neonates older than 21 days regardless of gestational age at birth who have clinical manefestations of anemia (tachycardia, tachypnea, poor feeding, poor weight gain, apnea).
4. Neonates with cyanotic congenital heart disease and Hgb <7 to 9 g/dL depending on the degree of cardiopulmonary reserve.¹¹
5. Neonates on ECMO. No prospective studies have been completed to evaluate optimal RBC transfusion threshold; recommendations are maintain Hgb between 10-12 g/dL.⁴

Dosing Recommendations:

• Volume of RBC is ordered per body weight, generally 10-15 mL/kg in a non-bleeding neonate. Small volume (SV) transfusion is considered
• Transfusion rate is dependent on the clinical condition and age of the infant; rate of transfusion should be prescribed by the ordering provider.

Outcome Indicators:

• 10-15 mL/kg of body weight should raise the Hgb by about 2-3 g/dL or Hct by 6%. Monitor for desired outcome
• Increase in Hgb may vary based on Hct of RBC unit which depends on preservative used (e.g. CPD vs. AS-1), whether a method to concentrate the red cells (i.e. washing, supernate removal) is performed, and clinical status of the neonate.
  • Typical Hct for the RBCs manufactured by Versiti are as follows: AS-1 RBC 55-60%; AS-3 RBC 55-60%; CPD RBC 70-75%.

Additional Information:

Transfusion Thresholds:

• Hemoglobin threshold in neonates with cyanotic congenital heart disease should be based on the degree of cardiopulmonary reserve of the neonate. Recommendations are to maintain Hgb between 7-9 g/dL since there is no evidence that transfusing to Hgb over 9 g/dL is beneficial.¹¹
• Two recent independent large trials [ETTNO (Effects of Transfusion Thresholds on Neurocognitive Outcomes of Extremely Low-Birth-Weight Infants)7 and TOP (Transfusion of Prematures)8] randomized over 2800 ELBW infants to compare the long term outcome of RBC transfusions based on either a liberal (higher Hgb) or restrictive (lower Hgb) transfusion threshold strategy. The transfusion threshold (Hct or Hgb depending on trial) for both cohorts was determined according to postnatal age and whether or not the infant was critically-ill and required respiratory support (higher threshold when critically ill or respiratory support was warranted). While there was differences in the number of infants receiving transfusion in the two trials, the primary outcome in both trials – death or neurodevelopmental impairment (cognitive delay, cerebral palsy, or hearing or vision loss) at 24 months of corrected age – were similar between restrictive and liberal transfusion groups. Coupled with prior studies which demonstrated no significant differences in short-term outcomes for restrictive versus liberal transfusion thresholds in neonates, the current evidence supports the use of a restrictive transfusion threshold.^1,4,13-15

Potential Risks of RBC Transfusion:

• The pathophysiology of necrotizing enterocolitis (NEC) is not clearly understood. Past data differed on the effect of enteral feeding during RBC transfusion and development of NEC. However, recent studies have shown that the degree of anemia at the time of the transfusion appears to play a more critical role than the transfusion itself.^3,16,17
• All neonates are at risk for transfusion-transmitted CMV infection, regardless of their serostatus since any antibodies will be passive maternal antibodies. Leukocyte-reduced RBCs are now the standard of care and reduce the risk for transfusion-transmitted CMV to a level similar to that of CMV-seronegative RBCs.1,4 See Versiti Blood Utilization Guidelines - Modifications of Blood Components and TxMDÔ News – In the Era of Leukoreduction, are CMV-Seronegative Tested Blood Products Beneficial?
• Neonates, especially those who are extremely preterm, are believed to be at risk for transfusion-associated graft-versus-host disease (TA-GVHD). However, the extent of risk and whether to mandate transfusion of irradiated blood components for all infants is controversial. To avoid overlooking a neonate who may be truly at risk for TA-GVHD (i.e. infant with immunodeficiency disorder) and the high mortality rate of TA-GVHD, many centers have implemented blanket protocols for infants admitted to a particular patient care unit (i.e. neonatal intensive care unit) or up to a specified age (i.e. at least until 4-6 months or even up to 1 year of age) to receive irradiated blood components. RBC units or prefilled pediatric aliquots supplied by Versiti designated for neonate transfusion may be irradiated prior to distribution.⁵ See Versiti Blood Utilization Guidelines - Modifications of Blood Components.
• Hypocalcemia is common in critically ill, premature neonates and is often asymptomatic. With multiple or large volume RBC transfusions, neonates could be at risk of citrate toxicity and resultant worsening hypocalcemia. Ionized calcium levels should be closely monitored when large volume transfusions are given.^1,18

RBC Product Selection:

• Transfusion of RBC units containing additive solution (e.g. AS-1, AS-3, AS-5 RBCs) in neonates is an acceptable practice for SV transfusion (up to 20 mL/kg), and commonly used at pediatric academic centers. While RBCs with additive solution could be considered for LV RBC transfusions (e.g. >20mL/kg per transfusion event), their use is an institutional choice and likely depends on several factors including indication and urgency for the transfusion, ability to remove the additive solution by washing or centrifugation, and availability to obtain RBCs without additive solution. See TxMD™ News – RBC Transfusions for Neonates: Are RBCs Stored in Additive Solutions Safe?
• While trials in LVBW infants have reported no difference on mortality or morbidity with transfusion of fresh (£7 days) versus standard-issue RBCs6, specific clinical conditions may warrant the use of “fresher” RBCs. Use of older RBC units with high extracellular potassium (K+) concentrations may be a concern for neonates with preexisting hyperkalemia or renal failure, need for rapid infusion of blood through a central line, or for LV transfusions as with exchange transfusion, ECMO or during cardiac surgery. Washing of the RBC units, removal of the supernatant, or use of fresh blood (i.e. less than 7 to 10 days old) are options to decrease the risk of transfusion-associated hyperkalemia in these clinical situations.^4,5,19,20
• Although the risk of transfusion-transmitted infectious disease is low today, some centers utilize a dedicated RBC unit protocol (e.g. one adult RBC unit reserved for 1 or 2 neonates receiving frequent transfusions). This approach can minimize donor exposures as well as be cost-effective. The use of empty pedi-packs connected to a fresh adult unit by the blood supplier and later filled when needed or on-demand preparation of aliquots (or syringes) at the hospital are options for providing multiple transfusions from a dedicated adult unit.⁵
• For hospitals that order pre-filled, irradiated aliquot units for neonates from the blood supplier, K+ will accumulate in these aliquots over time. For routine SV transfusions given slowly, this is generally not of clinical concern. However, as the unit ages, the increasing K+ load may place the neonate at risk for hypekalemia if an older unit is used for multiple transfusions over a short duration or for large volume transfusion (more than 25 mL/kg) given rapidly.
• Neonatal blood contains maternal ABO antibodies, thus any RBC units selected for transfusion must be compatible with the infant’s blood group as well as the maternal antibodies present in the neonatal circulation. For simplicity, many transfusion services provide group O, Rh compatible RBCs to all neonates. To conserve group O RBCs, especially O Negative RBCs, some transfusion services have policies for release of ABO-group-specific RBCs if the neonate’s serum lacks maternal anti-A and/or Anti-B which may be directed against the neonatal ABO antigens and the ABO group of the unit selected for transfusion. Because the antibodies in the neonate’s plasma are of maternal origin, maternal blood may be used as the source for antibody detection/identification testing. In addition, since the neonate’s immune system rarely produces antibodies in response to RBC transfusions, if the antibody screen is negative, it does not need to be repeated during the patient’s hospitalization until the infant is 4 months old.

Intrauterine and Exchange Transfusion

While less common today than in prior years, selection and preparation of blood for intrauterine or exchange transfusions may be requested at the hospital transfusion service. Intrauterine transfusion is often a scheduled procedure which allows time for coordination with the blood supplier and/or immunohematology reference lab to obtain a fresh, antigen-negative (if applicable) RBC unit that is collected in the preferred anticoagulant (CPD). On the other hand, an exchange transfusion for a newborn shortly after birth is typically a STAT request and availability of certain RBCs may be limited.

Exchange transfusion is an effective and immediate method for rapidly removing bilirubin in newborns who are at risk for developing bilirubin-induced neurologic disorders, and when present removal of antibody-coated neonatal RBCs and unbound maternal antibody.

Typical indications may include:

• Intrauterine transfusions:²¹
  • Fetal anemia due to Hemolytic Disease of the Fetus and Newborn (HDFN)
  • Severe fetal anemia due to other causes, e.g. hemoglobinopathy, infection (e.g. parvovirus B19), or maternal injury
• Exchange transfusions in the newborn:²²
  • Signs of acute bilirubin encephalopathy (ABE)
  • Severe hyperbilirubinaemia secondary to HDFN (see Note)
  • Severe hyperbilirubinaemia or rapidly rising total bilirubin despite intense phototherapy due to any cause and infant at risk of ABE (see Note)
  • Severe anemia (where there is normal or increased circulating blood volume)
  • Severe metabolic disturbances and/or circulating toxic substances

Note: The total bilirubin threshold for exchange transfusion is based on gestational age as well as other risks factors for neurotoxicity, including hemolytic conditions, clinical instability in the previous 24 hours, sepsis, and hypoalbuminemia^22,23

For exchange transfusion, the volume typically needed is based on 160 mL/kg (double exchange transfusion). This replaces approximately 85 percent of the infant's circulating red blood cells.

Infants may require more than 1 exchange transfusion to achieve an acceptable bilirubin level.

Attributes for the selection of blood for intrauterine and exchange transfusions are described in the Table.⁵

References

1. Zerra PE, Josephson C. Transfusion in the neonatal patient: review of evidence based guidelines. Clin Lab Med 2021 March;41(1):15-34.
2. Bell EF. Red cell transfusion thresholds for preterm infants: finally some answers. Arch Dis Child Fetal Neonatal Ed 2022 Mar;107(2):126–130.
3. Meyer MP, O’Connor KL, Meyer JH. Thresholds for blood transfusion in extremely preterm infants: A review of the latest evidence from two large clinical trials. Front Pediatr 2022. 10:957585.doi: 10.3389/fped.2022.957585
4. Villeneuve A, Arsenault V, Lacroix J. Tucci M. Neonatal red blood cell transfusion. Vox Sang 2021;116: 366-378. https://doi.org/10.1111/vox.13036.
5. Wong ECC and Roseff SD ed. Pediatric Transfusion: A Handbook. AABB Press 5th edition 2020.
6. Fergusson DA, Herbert P, Hogan DL, 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):1443-1451.
7. 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 Aug 11;324(6):560- 570.
8. Kirpalani, H, Bell EF, Hintz SR,et al for the Eunice Kennedy Shriver NICHD Neonatal Research Network*A randomized trial of higher versus lower hemoglobin thresholds for extremely low birth weight (ELBW) infants: The Transfusion of Prematures (TOP) Trial. N Engl J Med 2020;383:2639-2651.
9. New HV, Standworth SJ, Gottstein R, et al. British Society for Haematology Guidelines on transfusion for fetuses, neonates and older children. Br J Haematol. 2016;175:784-828.
10. Ohls R. Red blood cell (RBC) transfusions in the neonates. UpToDate.Last updated Apr 30, 2023.
11. Cholette JM, Willems A, Valentine SL, et al.: Recommendations on RBC transfusion in infants and children with acquired and congenital heart disease from the pediatric critical care transfusion and anemia expertise initiative. Pediatr Crit Care Med 2018;19(9S Suppl 1):S137–S148.
12. 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 Databse of Systematic Reviews 2011, Issue 11. Art. No.: CD000512. DOI: 10.1002/14651858.CD000512.pub2.
13. 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 Sep;149(3):301-307.
14. 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.
15. 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(9):889–97.
16. Le VT, Klebanoff MA, Talavera MM, et al. Transient effects of transfusion and feeding advances (volumetric and caloric) on necrotizing enterocolitis development: a case-crossover study. PLoS One 2017;12(6):e0179724.
17. Stark CM, Juul SE. New frontiers in neonatal red blood cell transfusion research. J Perinatol. 2023 Nov;43(11):1349-1356.
18. Burke M, Sinha P, Luban NLC, Posnack NG. Transfusion-associated hyperkalemic cardiac arrest in neonatal, infant, and pediatric patients. Front Pediatr. 2021 Oct 29;9:765306. doi: 10.3389/fped.2021.765306. PMID: 34778153; PMCID: PMC8586075.
19. Yamada C, Edelson M, Lee A, et al. Transfusion-associated hyperkalemia in pediatric population: Prevalence, risk factors, survival, infusion rate, and RBC unit features. Transfusion. 2021 Apr;61(4):1093-1101. doi: 10.1111/trf.16300. Epub 2021 Feb 10. PMID: 33565635.
20. Mo YD, Bahar B, Jacquot C. Intrauterine, neonatal and pediatric transfusion therapy. Ann Blood 2022;7:13
21. Wong, RJ, Bhutani VK. Unconjugated hyperbilirubinemia in term and late preterm newborns: Escalation of care. UpToDate. Last updated April 17, 2023.
22. Kemper AR, Newman TB, Slaughter JL, et al. Clinical Practice Guideline Revision: Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2022;150(3):e2022058859.

Additional Resources:

23. Joseph Chiofolo (ed). New York State Council On Human Blood And Transfusion Services Guidelines For Transfusion Of Pediatric Patients 2016.
24. Society for Maternal-Fetal Medicine (SMFM) Clinical Guideline #8: The fetus at risk for anemia-diagnosis and management. Society for Maternal-Fetal Medicine (SMFM); Giancarlo Mari, MD; Mary E. Norton, MD; Joanne Stone, MD; Vincenzo Berghella, MD; Anthony C. Sciscione, DO; Danielle Tate, MD; Mauro H. Schenone, MD AJOG 2008.
25. Luban NLC, Strauss RG, Hume HA. Commentary on the safety of red cells preserved in extended‐storage media for neonatal transfusions. Transfusion 1991;31:229–35.
26. Strauss RG. Data‐driven blood banking practices for neonatal RBC transfusions. Transfusion, 2000;40:1528-1540.