Blood Transfusion in

Neonates - Recent
Guidelines
Dr. Anand Bhattar
 Learning Outcomes
• Specific pre-transfusion processing done
before transfusing blood products to
neonates ?

• Recent guidelines for using various blood

products ?
 Introduction
• Sick neonates frequently receive transfusion of blood products

• Preterm neonates comprise the most heavily transfused group of patients

• About 85% of ELBW newborns receive a transfusion by the end of their

hospital stay*

• It is essential that one considers the risk- benefit ratio and strive to develop
treatment strategies that will result in the best patient outcomes

• Relatively immature immune status of the neonate predisposes them to

Graft versus Host Disease (GVHD), in addition to other complications
including transmission of infections, oxidant damage, allo-immunization
and so on…
*Ohls R J. Transfusions in the Preterm Neonates. NeoReviews 2007;8 :377-386.
 PRE-TRANSFUSION ISSUES
 Donor selection
a) Avoid blood donation from first and second degree relatives
b) In addition to routine screening tests, the donor should be
seronegative for Cytomegalovirus (CMV)

 Pre-transfusion testing (Donor Blood)

o Blood typing error can result from -
a) Weak expression of red blood cell(RBC) antigens in neonates
b) Presence of maternal antibodies that can mask the corresponding
antigens
c) Umbilical cord samples gets contaminated by maternal blood/
Wharton’s jelly
 Leucodepletion:
• Removal of white cells from blood product

• Done for Whole Blood, Packed RBC & Platelet concentrates

• Done in Blood bank (Pre-issue) or Bedside leukofilters (Post-issue)

 Gamma irrardiation:
• It renders donor T lymphocytes ineffetive which is unable to mount a graft
versus host reaction in the immunologically incompetent neonate

• Irradiation of packed RBC should be done within 14 days of collection of

the cells

• Once irradiated packed RBC should be transfused within 48 hours

• Irradiation does not change the shelf-life of platelet concentrates

 Indications for Irradiation –
• Intrauterine transfusion of packed RBC and platelets

• Transfusion of RBC and platelets in neonates with birth weight <1500grams

and/or < 30weeks gestation

• Donations from first or second degree relatives

• Neonates with congenital or acquired immunodeficiency

Hematocrit:
• Should be 0.5 +/- 0.05

 Use of satellite (piggyback) bags:

• This reduces wastage and exposure to multiple donors
Single vs multiple donors:
• As Preterm infants frequently require multiple blood transfusions

• A unit of blood with additional satellite packs should be ordered for each
infant & must be used up to its expiry date. This allows up to 8 transfusions
from a single donation

• This reduces the number of donor exposures

 Recommendations on use of
blood products in neonates
Blood for transfusion should be - < 5 days old, irradiated, CMV
negative, warmed & have a hematocrit of 0.5 to 0.6

Reconstituted whole blood - obtained by combining PRBC

with fresh-frozen plasma (FFP)
• Ideally FFP should be from the same donor bag from which the PRBC was
produced

• The final product should be used within 24h of reconstitution & it has the same
characteristics as whole blood except for reduced platelets
 Indications of whole blood:
o Exchange transfusion

o Replacement of blood loss in massive hemorrhage

o Cardiac surgery

 Exchange transfusion: The choice of donor blood group is dependent on

the mother and infant’s blood group

◦ a. Rh incompatibility:
• If Blood arranged prior to birth: O negative cross matched against mother

• If Blood arranged after birth: Rh negative of baby’s ABO group is cross matched
against infant & mother

◦ b. ABO incompatibility: Rh matched O group cross matched with mother

◦ c. Other indications (non-hemolytic): Blood group of infant cross matched

against infant and mother
 Packed red blood cell (PRBC)
transfusions
Various markers for tissue oxygenation (fractional extraction of
oxygen, serum lactate levels, echocardiographic parameters), other
than hemoglobin (or Hematocrit-PCV) which have been studied to
guide transfusion thresholds, but none are as easily/quickly
evaluated in clinical practice

The current recommendations on RBC transfusions in neonates

have therefore remained related to values of Hb (or PCV)

However, overall clinical picture rather than a particular figure

should be considered in the decision to transfuse a neonate
1) Severe anemia of antenatal onset:
• Anemia occurring before birth

• Characterised by Hb < 8/dL at birth

• This requires prompt transfusion, as specified below

a) Associated with congestive heart failure (due to immunohemolysis,

chronic feto-maternal or feto-fetal hemorrhage)

• Most appropriate treatment – “partial exchange transfusion” with

packed RBC with the aim of correcting the anemia while avoiding
volume overload

b) Associated with hypovolaemic shock (placenta previa, abruption

placentae, rupture of the cord), the intravascular volume must be
restored and the anemia is corrected
2) Early neonatal anemia:
• Anemia developing after birth or in the first week of life

• Values of Hb are moderately decreased

• Transfusion treatment is necessary in order to maintain the PCV

greater than 0.35 to 0.40

3) Late neonatal anemia:

◦ Acute blood loss
• > 10% of blood volume with features of decreased oxygen
delivery or > 20% of blood volume
The Premature Infants in Need of Transfusion (PINT) study* showed that a restrictive
transfusion policy in infants weighing less < 1 kg did not have any adverse effect on
short term or follow up mortality or morbidity. The effect on neurodevelopment and
cognitive delay is not yet clear. It is recommended that the following transfusion
thresholds be maintained until further evidence is available

* Kirpalani H, Whyte RK, Andersen C, Asztalos EV, Heddle N, Blajchman MA, Peliowski A, Rios A, LaCorte M, Connelly R, Barrington K, Roberts RS. 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):301-7
Refer tables for selection of blood in new-born baby
up to the age of 4 months

Reason -
• <4 month rarely produce antibodies
(anti-A, anti-B) against blood group
antigen

• ABO antibodies in baby’s blood at

birth are likely to be maternal origin
(placental transfer)
 Transfusion-associated Necrotizing Enterocolitis (TANEC)
• Transfusion-associated Necrotizing Enterocolitis (TANEC) has been described as
necrotizing enterocolitis (NEC) that arises within 48 hours of a blood transfusion
• TANEC is concerning to clinicians & has been shown to be associated with 25 to
35% of NEC in recent studies*
• Evidence related to TANEC is limited to observational, retrospective studies
• Infants who develop TANEC tend to be smaller, born at earlier gestation, more
severely ill and develop NEC after 30 days of age
• Evidence in two studies (Perciaccante et al, 2008** & El-Dib et al, 2011***)
support holding feedings before and during transfusion to protect the preterm gut
from the cascade of events that lead to NEC but higher quality research, including
prospective randomized controlled trials, is needed to evaluate the effect of
feeding on TANEC
* Mohamed A, Shah PS. Transfusion associated necrotizing enterocolitis: a meta-analysis of observational data. Pediatrics. 2012; 129(3):529–540.
** Perciaccante JV, Young TE. Necrotizing en-terocolitis associated with packed red blood cell transfusions in premature neonates. E-PAS. 2008;5839.8
*** El-Dib M, Narang S, Lee E, Massaro AN, Aly H. Red blood cell transfusion, feeding and necrotizing enterocolitis in preterm infants. J Perinatol. 2011;31(3):183–187
 Fresh frozen plasma (FFP)
Transfusion
• Current guidelines for FFP administration in neonates are mainly
based on poor-quality evidence and this contributes to the high level
of inappropriate FFP use

• The use of FFP in neonatology should primarily be done in neonates

with active bleeding and associated coagulopathy

• Interpretation of coagulation tests in the neonate is a crucial step in

the decision-making process for FFP administration
 Recommendation for FFP Transfusion
Clinical studies in which the intervention was transfusion of FFP in
neonates were identified by consulting the National Library of
Medicine’s MEDLINE, EMBASE, and the Cochrane Library

The methodology used to score the literature and transform it into

level of evidence and strength of recommendation was proposed by
the Grading of recommendation, assessment, development, and
evaluation (GRADE) Working Group
Atkins D, Best D, Briss PA, et al. Grading quality of evidence and strength of rec-ommendations. BMJ 2004;328:1490–4
 a Coagulopathy is defined as
coagulation tests outside the 95%
confidence limits of the
agerelated hemostatic
parameters.

b Currently, this applies only to

Factor V. However, FFP may be
also given if treatment is urgently
required before the diagnosis of
inherited clotting factor deficiency
(ie, hemophilia) has been
confirmed.

c The administration of FFP

should be combined with
intravenous infusion of vitamin K.

Recommendations for plasma administration to neonates, based on scientific evidence and according to
the GRADE system
 Recommended dose of FFP

• Assuming that FFP has an average clotting factor and inhibitor potency
of 1 IU/mL, dose of 10 mL/kg should increase clotting factors and
inhibitor levels by approximately 10 IU/dL (10%)

• Hence, the infusion of 10 mL/kg of FFP should increase the plasma

coagulations levels significantly

• Taking into account available clinical and pharmacokinetic data, an

effective dose of FFP should be 10 to 15 mL/kg

• Intravascular volume overload should also be considered when

deciding on the proper dose of FFP

Hellstern P, Muntean W, Schramm W, et al. Practical guidelines for the clinical use of plasma. Thromb Res 2002;107(Suppl 1):S53–7
*Andrew M, Paes B, Milner R, et al. Development of the human coagulation system in the full-term infant. Blood 1987;70:165–72.
*Andrew M, Paes B, Milner R, et al. Development of the human coagulation system in the healthy premature infant. Blood 1988;72:1651–7.
*Christensen RD, Baer VL, Lambert DK, et al. Reference intervals for common coagulation tests of preterm infants (CME). Transfusion
2014;54:627–32.
• Most appropriate use of FFP should be the treatment of active bleeding in
neonates with laboratory confirmed coagulopathy

• Prophylactic use of FFP in nonbleeding neonates, on the basis that their

coagulation test is abnormal, cannot be considered an evidence-based
practice

• Catford and colleagues* reported that the practice of drawing routine

clotting tests on admission to the NICU increases the prophylactic use of
FFP to correct isolated abnormal coagulation values without associated
bleeding

• So, routine coagulation testing on NICU admission is not indicated

* Catford K, Muthukumar P, Reddy C, et al. Routine neonatal coagulation testing increases use of fresh-frozen plasma. Transfusion
2014;54:1444–5.
• Although there are no officially accepted guidelines, current evidence does
not support FFP administration to asphyxiated cooled neonates with
isolated abnormal clotting tests in the absence of bleeding

• The assessment of bleeding is a critical point in the decision-making process

for use of FFP in a neonate with hemorrhage and coagulopathy

• A neonatal bleeding assessment tool (NeoBAT) has been developed, with

the aim of standardizing the clinical recording of bleeding in high risk
neonates

* Venkatesh V, Curley A, Khan R, et al. A novel approach to standardised recording of bleeding in a high risk neonatal population. Arch Dis Child Fetal
Neonatal Ed 2013;98:F260–3.
 Platelet Transfusion
• Asymptomatic thrombocytopenia occurs in about 1% of term and
25% of preterm neonates

• Platelet transfusions are common in the NICU, being administered to

2% - 9.4% of neonates admitted to NICUs

• Majority of platelet transfusions were used prophylactically in non-

bleeding neonates with platelet counts in the range of 30 to 50 x
109/L

Garcia MG, Duenas E, Sola MC, et al. Epidemiologic and outcome studies of patients who received platelet transfusions in the neonatal intensive care unit. J
Perinatol 2001;21:415–20.
Del Vecchio A, Sola MC, Theriaque DW, et al. Platelet transfusions in the neonatal intensive care unit: factors predicting which patients will require multiple
transfusions. Transfusion 2001;41:803–8
 • Repeated platelet transfusions were common with more than 50%
infants receiving more than one platelet transfusion during their
NICU stay

• Andrew et al* found no benefit in terms of hemorrhage when

maintaining a normal platelet count by platelet transfusion in a
study of preterm neonates compared with controls with moderate
thrombocytopenia (platelets 50 to 150 x 109/L)

*Andrew M, Vegh P, Caco C, et al. Randomized controlled trial of platelet transfusions in thrombocytopenic premature infants. J Pediatr 1993; 123; 285-91
• The incidence of thrombocytopenia is inversely proportional to
the gestational age, and it represents a risk factor for poor
neonatal outcomes

• Etiology of Thrombocytopenia
• Early onset (<3 days of life) - Intrauterine growth restriction, pregnancy-
induced hypertension or diabetes, perinatal infection, and transplacental
passage of maternal allo- or autoantibodies

• Late-onset (>3 days of life) - Bacterial infection or necrotizing

enterocolitis
 • Wiedmeier and colleagues* published the largest study on neonatal
platelet counts conducted till date (included approximately 47,000 infants
delivered between 22 and 42 weeks gestation)

• This study showed that platelet counts at birth increased with advancing
gestational age

*Wiedmeier SE, Henry E, Sola-Visner MC, et al. Platelet reference ranges for neonates, defined using data from over 47,000 patients in a
multihospital health-care system. J Perinatol 2009;29:130–6.
Joint United Kingdom (UK) Blood Transfusion and Tissue Transplantation Services Professional Advisory Committee
 • Evidence indicates that, there is a poor correlation between
severity of thrombocytopenia and clinically significant bleeding

• This suggests that thrombocytopenia might be a marker of severity

of illness & factors other than the platelet count determine the
bleeding risk

• This is supported by the finding that gestational age less than 28

weeks, postnatal age less than 10 days, and diagnosis of NEC are far
stronger predictive factors of bleeding among thrombocytopenic
neonates than the platelet count itself

*Baer VL, Lambert DK, Henry E, et al. Severe thrombocytopenia in the NICU. Pediatrics 2009;124:e1095–100.
*Von Lindern JS, van den Bruele T, Lopriore E, et al. Thrombocytopenia in neonates and the risk of intraventricular hemorrhage: a retrospective cohort
study. BMC Pediatr 2011;11:16.
 • Additional well designed randomized controlled trials are needed to
help identify safe and effective platelet transfusion thresholds for
neonates

• The Platelets for Neonatal Transfusion - study 2 (PlaNeT-2 study) is

a large multicenteric study conducted in several European countries
that is comparing liberal versus restrictive prophylactic platelet
transfusion strategies in thrombocytopenic preterm infants (50 vs
25 109/L, respectively)

• Approximately 350 infants have been enrolled to date, of a planned

total of 600 infants

• While awaiting for results from PlaNet-2 several guidelines have

been published, which in general adhere to restrictive practices
Curley A, Venkatesh V, Stanworth S, Clarke P, Watts T, New H, Willoughby K, Khan R, Muthukumar P, Deary A, Platelets for Neonatal Transfusion - Study 2: A Randomised Controlled
Trial to Compare Two Different Platelet Count Thresholds for Prophylactic Platelet Transfusion to Preterm Neonates. Neonatology 2014;106:102-106
 Factor VIII/ Cryoprecipitate
• Congenital factor deficiencies are rare in the neonatal period

• While treating bleeding neonates, cryoprecipitate is often

considered an alternative to FFP because of its small volume

• However, cryoprecipitate contains only factors VIII, XIII and

fibrinogen and is not effective in treating the more extensive
clotting factor deficiencies
 Take home message
• Use components wherever feasible/ available rather
than whole blood transfusion

• Follow transfusion guidelines :

• Transfusing according to agreed criteria limits both the number of
neonates undergoing transfusion and the number of donors to which each
neonate is exposed

• The use of "local" transfusion protocols in the various Neonatal Intensive

Care Units is therefore recommended
• Treat patient, not lab values :
• Because fallacies arise in the collection and processing of blood
samples

• Awareness of complications of blood transfusions :

• HIV, hepatitis B and C, cytomegalovirus, syphilis, and malaria

• The rates of transfusion associated infection increase when

multiple transfusions from multiple donors are given

• Other transfusion related complications of a non-infectious

nature may also occur (Fluid overload, graft-versus-host disease,
electrolyte and acid base disturbances, iron overload, increased
susceptibility to oxidant damage and allo-immunisation)
 Requirement of ABO & Rh compatibility
for transfusing blood components

ABO Compatibility Rh Compatibility

Red Cells Must Must

Platelets Preferred Preferred

FFP Must
Not required
Cryoprecipitate Preferred
Thank you…