1

Pints for Half-Pints: Neonatal Transfusion Therapy

Susan D. Roseff, M.D.Department of PathologyVirginia Commonwealth University

Neonatal Transfusion Medicine

Describe the differences in neonatal immunity and physiology• How this impacts transfusion decisions for

neonates• Why AABB Standards are different for

neonatesUnique indications for RBC transfusion• Controversy around storage solutionsUnique indications for platelet transfusion

Neonatal transfusion medicine

Challenges for evidence-based studies:• Fragile patient population/co-morbidities• Parental consent• EthicsPediatric Transfusion Medicine Academic Awardees (2008) - NHLBI• “One size will never fit all: the future of

pediatric transfusion medicine.”• Josephson, et al 2014 Pediatric Research

A unique patient population

In tertiary care medical centers, low birth weight neonatal patients were traditionally among the most likely to be transfused More than 80% VLBW infants transfused(Bednarek, et al. 1998)Data from 2000 US Statistics of Live Births 41,699 of 56,350 VLBW infants transfused

RBCs Average 3 transfusions per infant > 250,000 transfusions(Josephson, et al. 2014)

A unique patient population

Blood volume: Full term neonates - 85 mL/kg Premature/low birth weight - 100 mL/kgAdults and older children will compensate for hypovolemia by heart rate Shut down peripheral vasculature tissue perfusionIatrogenic loss through excessive sampling oxygen consumption for rapid growth

2

A unique patient population

Hematologic considerations:Hemoglobin F: At birth ~ 60 – 80 % High affinity for O2 from maternal

circulation Switch from F to A occurs ~ 32 weeksHealthy newborn Hgb is 16.9±1.6 g/dL, preemie 1 g/dL lower

A unique patient-populationHematologic considerations:

Erythropoeitin (EPO) made in fetal liver, less responsive to hypoxia/anemia Complete switch to kidneys occurs after

birth (prevent hyperviscosity in utero?)With O2 at birth, turn off EPO, anemia Physiologic - Hgb A releases O2 to tissue -

Hgb drops but well oxygenatedPreemie has lower EPO levels, lower Hgb

EPO suppressed by transfusion

A unique patient population

Other physiologic considerations:Renal function is immature – K+ loadImmature hepatic function - citrateResponse to hypothermia Blood brain barrier’s permeability

A unique patient population

Immunologic considerations:Passive immunity (IgG) from mother In-utero infection (IgM)White cell function and risk of infectionTolerant/naïve Risk of not seeing foreign as foreign Less likely to form certain responses

to foreign antigens: RBC, HLA Back type not yet developed

The AABB Standards: Infants less than 4 months oldRed cell transfusions in infants 29th Edition of Standards: 5.17 (p 39)*ABO Grouping:

Pre-transfusion sample for ABO group and Rh type – reverse type not necessary (5.17.1.1) No further ABO testing necessary for

rest of hospitalization ( sampling) or until 4 months old

* AABB Standards, 2014

The AABB Standards:

Immunologic differencesExtremely rare formation of alloantibodiesIgG from mom No need for antibody screens Mom’s plasma for antibody screens No crossmatches

3

The AABB Standards:

29th Edition of Standards: 5.17.1.2 (p 39)Unexpected antibodies:

Screen for unexpected antibodies using serum/plasma either from baby or mother; if negative: Crossmatches not necessary No further testing for alloantibodies

required for rest of hospitalization or 4 months old

Applying the AABB Standards27th Edition of Standards: 5.17.2 (p 39)

Mom and baby of different ABO types:Use group O RBCsTo use non-group O RBCs, must check baby’s serum/plasma for anti-A or anti-B, and must test at AHG phaseIf anti-A or anti-B detected, select RBCs lacking the corresponding ABO antigen

The AABB Standards:

Reduce the risk of iatrogenic blood loss through decreased testing and knowledge of the extremely low risk of alloantibody formation:

1) ABO and antibody screen once in 4 months2) No need for crossmatch if antibody screen

negative3) If use O RBCs, no need for crossmatch, if

mom and baby have different ABO-types

Unique RBC transfusion indications

Indications:Increase oxygenation and improve signs and symptoms of anemia Severe if Hgb < 13 g/dL in first 24 hours

Congenital cardiac anomalies Different parameters based on physiologyIatrogenic sampling loss - studies showing RBC transfusion with less phlebotomy

15±5 ml/kg Hgb about 1-2 g/dL

Unique RBC transfusion indications

Conflicting data on the role of exogenous erythropoietin /darbepoietinSome showing reduced transfusion requirements with one study showing better cognitive outcomesNeed for additional iron/higher costUse of strict transfusion criteria and reduction of phlebotomy loss as effective Shannon KM, et al. 1995; Becquet O, et al. 2013Suppression of endogenous EPO

Pediatric Transfusion: A Physician’s Handbook. 4th ed. 2015.

4

Unique RBC transfusion indications

“Age of Red Blood Cells in Premature Infants (ARIPI)” Fergusson, et al. 2012 Compared 7 day RBCs vs other (mean 14.6)

for infants less than 1250 gms No difference in outcomes Study design?

Unique RBC transfusion indications

Restrictive transfusion“Randomized trial of liberal versus restrictive guidelines for red blood cell transfusion in preterm infants.” Bell, Strauss, Widness, et al. 2005 Restrictive arm had less transfusion, but no

statistical significance in donor exposures Adverse neurologic outcomes

Unique RBC transfusion indicationsRestrictive transfusion

“The Premature Infants in need of Transfusion Study (PINT)” Kirpalani, et al. 2006 – restrictive vs liberal transfusion ELBW (<1000 gm)/ algorithms for hemogloin No change in measured outcomes 2009 follow-up at 18-21 month, additional

analysis may favor liberal arm

Transfusion of Premature (TOP)

Unique RBC transfusion indications

Hemolytic disease of the fetus and newborn- HDFNExchange transfusion in-utero

Hemolytic disease of the newborn- HDNExchange transfusion after birthFollow titers of maternal serumNon – invasive Doppler studies Percutaneous umbilical blood samplingTransfuse in utero

Liley Curve

Goodbye to amniocentesis! Courtesy of K. Moise

5

Courtesy of K. Moise

Unique RBC transfusion indicationsManagement in-utero:

Peritoneal or intra-vascular (or both) O-, antigen -, CMV-, irradiated, Hgb

S-, < 7 days oldManagement after birth

Exchange transfusion Remove antibody, hemolyzed RBCs &

bili (kernicterus); give new, antigen negative RBCs

Special requirements as above

Unique delivery of RBCs

Neonatal transfusion characteristics:Receive multiple small aliquots over period of days/weeksProblem of exposure to multiple donors, increases risk of pathogen transmission

Unique delivery of RBCs

Small volume transfusionsTake out small volume from a unit; unit outdates in 24 hoursBag configurations at collection centerSterile connecting device to preserve original outdate Decrease exposure Decrease waste

The sterile connecting device Use of syringe sets

1. Place on syringe pump

2. Easy to measure

3. Labeling in compliance with FDA

6

RBC storage-solutions

Extending the outdate of blood will reduce donor exposureCPDA-1 35 day outdateAdditive solutions 42 day outdate ? Safety profile for neonates?

Pediatric Transfusion: A Physician’s Handbook. 4th ed. 2015.

RBC storage-solutionsConcerns about anticoagulant/preservative

Adenine nephrotoxic in high concentrationMannitol nephrotoxic and diuretic: Effects on cerebral blood flowBenefits of extra sugar in AS-1 Goodstein, et al. 1993

Small volume transfusions, AS-1 and 3 safe, no data on AS-5 and 7No studies in large volume transfusion

RBC storage-solutions

Concerns about K+ as blood agesK+ leaches out of cells as blood agesIrradiation accelerates this processIn neonates with heart problems?In neonates with immature kidneys?Giving 15 mL/kg of 42 day RBCs would deliver .3 mEq K+ (2-3 mEq) to a 1 kg infant (Strauss RG, 2000) Olson, et al. 2013 using AS-5 at outdate,

mean K+ in patient 0.08 mmol/L through central line (1 – 14 years old).

Caveat: large volume, push, central line

Focus on RBC Transfusions

Concerns about K+ as blood ages – Is it necessary to wash blood?Usually unnecessaryMay be necessary with blood > 7 – 14 days, rapidly infused into central lineChanges outdate to 24 hours Lose RBCs risk of introducing bacteria

Focus on RBC Transfusions

Fresh blood and 2,3-DPG2,3-diphosphoglycerate necessary for RBC metabolismLevels fall as blood agesIn adults, 2,3-DPG will regenerate in 3 – 8 hours after transfusionUse fresher blood: exchange transfusion, IUTWeigh fresher blood versus donor exposureNo clinical consequence

7

NHLBI State of the Science Symposium on Transfusion Medicine, March 25, 2015

Focus on Platelet Transfusions

Thrombocytopenia, like adult levels, occurs at < 150,000Premature neonates more likely to bleed at higher counts due to coagulation factors, platelet dysfunction, vascular fragilityRisk of intraventricular hemorrhage multifactoral Controversial use of ≥ 100,000/uL 50K unstable; 20-30K stable

ECMO (extracorporeal membrane oxygenation)

Focus on Platelet Transfusions

One study, ~ 70% of ELBW infants transfused, but not all infants with platelets bleed:Use platelet mass = size of platelet (MPV) x #Platelet function tests for need for transfusion “Neonatal hemorrhagic risk assessment in

thrombocytopenia study” Neo-Hat

< 34 week infants higher (50K) versus lower (25K) threshold “Platelets for neonatal transfusion – study 2: a

randomized controlled trial to compare two different platelet count thresholds for prophylactic platelet transfusion to preterm neonates” PlaNet-2

Pediatric Transfusion: A Physician’s Handbook. 4th ed. 2015.

Focus on Platelet Transfusions

Causes:SepsisViral diseaseCongenitalMaternalNeonatal AlloimmuneThrombocytopenia (NAIT) (Severe, < 50,000/uL)

Goal: raise platelet count for hemostasis

Focus on Platelet Transfusions

NAITBaby inherits platelet antigen that mother lacksMother forms antibody that crosses the placenta - occurs during 1st pregnancyBaby becomes thrombocytopenicRisk of head bleed during pregnancy and the trauma of labor and delivery

8

Focus on Platelet Transfusions

NAIT- managementIntrauterine platelet counts and transfusionUse IVIG (intravenous immune globulin)Transfuse antigen negative platelets Mom best source, but wash plasma Most are PLA-1a (HPA1) antibodiesImportant role of random donor platelets

Focus on Platelet Transfusions

AdministrationDose ~ 10 ml/kg 50,000 – 100,000/uLAliquots - large volume apheresis unitUsually unnecessary to volume reduce or wash unless: Volume constraints (IUT) To remove antibody in plasma ABO incompatible (not recommended)

Pediatric Transfusion: A Physician’s Handbook. 4th ed.