Early Human Development (2008) 84, 493498

a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m

w w w. e l s e v i e r. c o m / l o c a t e / e a r l h u m d e v

BEST PRACTICE GUIDELINE ARTICLE

Management of anemia in the newborn

Naomi L.C. Luban

Departments of Pediatrics and Pathology, The George Washington University School of Medicine, United States
Laboratory Medicine and Pathology, Transfusion Medicine/The Edward J. Miller Blood Donor Center,
Children's National Medical Center, Washington, DC, United States

KEYWORDS Abstract
Neonate;
Premature; Red blood cell (RBC) transfusions are administered to neonates and premature infants using
Blood transfusion poorly defined indications that may result in unintentional adverse consequences. Blood
products are often manipulated to limit potential adverse events, and meet the unique needs of
neonates with specific diagnoses. Selection of RBCs for small volume (520 mL/kg) transfusions
and for massive transfusion, defined as extracorporeal bypass and exchange transfusions, are of
particular concern to neonatologists. Mechanisms and therapeutic treatments to avoid
transfusion are another area of significant investigation. RBCs collected in anticoagulant-
additive solutions and administered in small aliquots to neonates over the shelf life of the
product can decrease donor exposure and has supplanted the use of fresh RBCs where each
transfusion resulted in a donor exposure. The safety of this practice has been documented and
procedures established to aid transfusion services in ensuring that these products are available.
Less well established are the indications for transfusion in this population; hemoglobin or
hematocrit alone are insufficient indications unless clinical criteria (e.g. oxygen desaturation,
apnea and bradycardia, poor weight gain) also augment the justification to transfuse.
Comorbidities increase oxygen consumption demands in these infants and include bronchopul-
monary dysplasia, rapid growth and cardiac dysfunction. Noninvasive methods or assays have
been developed to measure tissue oxygenation; however, a true measure of peripheral oxygen
offloading is needed to improve transfusion practice and determine the value of recombinant
products that stimulate erythropoiesis. The development of such noninvasive methods is
especially important since randomized, controlled clinical trials to support specific practices are
often lacking, due at least in part, to the difficulty of performing such studies in tiny infants.
2008 Elsevier Ireland Ltd. All rights reserved.

Contents

1. Red blood cells for small volume transfusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494

2. Iatrogenic anemia of infancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495
3. Criteria and guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495

Department of Laboratory Medicine, Children's National Medical Center, 111 Michigan Avenue, N.W., Washington, DC 20010, United States.
Tel.: +1 202 884 5292; fax: +1 202 884 2007.
E-mail address: nluban@cnmc.org.

0378-3782/$ - see front matter 2008 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.earlhumdev.2008.06.007
494 N.L.C. Luban

4. Measurements to define the need to transfuse. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495

5. In-line devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496
6. Autologous transfusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496
6.1. Cord clamping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496
7. Cord blood collection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
Key guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
Research directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497

1. Red blood cells for small volume transfusion gravity sedimentation [14]. We evaluated the potential
toxicities arising from the use of three then common
Most premature infants of 2427 weeks gestation require anticoagulant solutions in the settings of massive or large
transfusions of red blood cells (RBCs) during their neonatal volume transfusion (i.e., exchange transfusion, cardiopul-
course [1]. Most of these transfusions will be administered monary bypass pump prime, extracorporeal membrane
in the first postnatal month [2]. Restrictive guidelines have oxygenation) and small volume transfusions [15]. We
been developed which have decreased donor exposure and estimated that concentrations of the solutes might reach
transfusion number, but several factors continue to con- dangerous or toxic levels in the setting of massive transfu-
tribute to the need to transfuse. These include iatrogenic sion while the quantity of additives in small volume
anemia, oxidative hemolysis secondary to sepsis, and rapid transfusions are unlikely to result in either acute or
growth with concomitant protein and iron deficiency. The cumulative toxicity over time; solutes could be further
selection of the transfusion product continues to be reduced by hard packing a-RBCs to a hematocrit of 80%. Our
controversial. Issues include 1) intraerythrocyte, 2,3DPG theoretical calculations have been supported by more than
and subsequent oxygen offloading capacity which decrease nine infant studies (Table 2). While each study differs in
during storage; 2) potassium content which increases during the age of the product used, volume per kilogram (kg)
storage; 3) solute load from the anticoagulant solutions transfused, type of anti-coagulant-additive solution, clinical
which might result in osmotic diuresis with subsequent and laboratory parameters measured, none demonstrated
alteration of cerebral microcirculation and result in adverse metabolic consequences that might be expected
intracranial (periventricular) hemorrhage; 4) transfusion- from the solute loads.
associated viral diseases and graft-versus-host-disease In a two arm randomized study of infants weighing 0.6 to
resulting from passive transfer of viral-infected white 1.3 kg, 31 infants received CPDA-1 RBCs stored up to 7 days,
blood cells (monocytes) and engraftable lymphocytes, while 30 received either AS-1 (19) or AS-3 RBCs (11) stored up
respectively. to 42 days. Approximately half of the AS-1 and AS-3 units
Several clinical articles and reviews have addressed the were greater than 15 days of age at transfusion. Changes in
transfusion of RBCs packaged in small volumes in different pH, glucose, lactate, calcium, sodium and potassium were
anticoagulant-additive solutions (herein called a-RBCs) to minimal. In an expanded open safety study, 33 infants
reduce donor exposure [312]. The solutions have in common weighing 0.6 to 1.25 kg received 120 transfusions of AS-3
the use of mannitol, glucose, sodium chloride, phosphate RBCs, of which 42 were older than 21 days at time of
and other additives (Table 1). To ensure that the hematocrit transfusion [4]. No clinical adverse consequences or sig-
is more comparable to a standard packed RBCs, and to nificant differences in chemical analyses were observed.
increase the red cell mass of the product, a-RBCs can be Mangel et al. [10] reported on their experiences with AS-3
concentrated by either centrifugation [13] or inverted units stored for up to 35 days in 56 infants who received 263
transfusions. Donor exposures were minimal (mean of 1.7)
despite 4.7 transfusion episodes per infant. This study did not
evaluate pre- and post-blood chemistries (other than
Table 1 Formulation of anticoagulant-additive solutions in hematocrit) and the indications for transfusion were not
blood collection sets detailed. Of note are the volume of RBCs in mL/kg transfused
Constituent CPDA-1 AS-1 AS-3 AS-5 (7 mL/kg), which is much lower than U.S. and UK practice
and the lower hematocrit (5560%), which likely increased
Volume (mL) 63 100 100 100 the donor exposure number when compared to U.S. and UK
Hematocrit (%) 7080 5560 5560 5560 practice. Van Stratten et al. [16] performed a study of
Sodium chloride (mg) None 900 410 877 different design utilizing a bag system with SAG-M. Blood
Dextrose (mg) 2000 2200 1100 900 units were split using a sterile docking device into 4 equal
Adenine (mg) 17.3 27 30 30 volumes in small bags integrally attached to the main bag.
Mannitol (mg) None 750 None 525 These units were arbitrarily held for 21 days. Ninety-six
Trisodium citrate (mg) 1660 None 588 None preterm infants were classified as high or low risk based on
Citric acid (mg) 206 None 42 None the expected need for transfusion. Mean donor exposure
Sodium phosphate 140 None 276 None was 1.1 with 3.2 2.1 transfusion/infant in the high and 1.1
(monobasic) (mg) with 0.4 transfusions/infant in the low risk groups, with
limited wastage. This study was not designed to evaluate
Management of anemia in the newborn 495

Table 2 Quantity (total mg/kg) of additives infused during a 3. Criteria and guidelines
transfusion of 15 mL per kg of AS-1 or AS-3 RBCs at Hct of 60%
Additive AS-1 AS-3 Toxic dose Transfusion practices can be guided by the use of guidelines
which should be evidence-based, weigh benefits and risks and
Sodium chloride 42 7.5 137 mg/kg/day ensure that improved patient outcome is the primary end
Dextrose 129 23 240 mg/kg/hr point. Optimally, well powered, randomized clinical trials,
Adenine 0.6 0.6 15 mg/kg/dose blinded and/or placebo controlled, would inform practice. In
Citrate 9.8 12.6 180 mg/kg/hr fact, such rigor is rare outside of large network trials. There
Phosphate 2.0 5.6 N 60 mg/kg/day are, however, at least two sets of transfusion guidelines that
Mannitol 33 0 360 mg/kg/day have been established based on consensus. These include
From Luban et al. [15], 11 those prepared by members of the Pediatric Hemotherapy
Committee of the American Association of Blood Banks [22]
and by the UK's National Blood Service [23]. These guidelines
are often abstracted from clinical trials whose focus were
safety or efficacy. In all published studies to date (Table 3),
neither reduction in transfusion nor morbidity and mortality
exposure of one to two donors is common with variable
(and so may not accurately reflect clinical practice in a
transfusion number and volume, despite the use of single
rapidly changing area of neonatal medicine). Liberal versus
unit assignment.
restrictive transfusion strategies have been tested in several
adult studies, in a few pediatric ICU and two recent NICU
2. Iatrogenic anemia of infancy studies. In an effort to guide transfusion practices, Bell et al.
[24] conducted a randomized single institution study compar-
Despite limiting donor exposures and transfusion episodes,
ing two sets of guidelines utilizing a threshold hematocrit
premature infants still require transfusions of RBCs for
below which a RBC transfusion was administered. Their
iatrogenic loss [17] and for cardiorespiratory instability. A
hypothesis was that infants on the restrictive arm would
few studies [1720] have addressed blood sampling as a
require fewer transfusions with no more adverse outcomes
cause of iatrogenic anemia. Iatrogenic blood loss in 99
than the liberally transfused infants. Among the 100 infants
extremely premature infants was studied in relationship to
with birth weights of 500 to 1300 g in the study, the liberal
severity of disease and gestational age. Sampling in mL/kg
group received more RBC transfusions (5.2 + 4.5) than the
body weight exhibited a wide range (0.9 to 39 mL in the first
restrictive (3.3 + 2.9) with no difference in donor exposure
week of life) and was correlated directly with volume
(2.8 + 2.5 versus 2.2 + 2.0). The restrictive group had more
transfused (mean 33.3 mL/kg) over a 4 week period [20].
brain hemorrhage, periventricular leukomalacia and apnea,
Since some NICUs now use indwelling catheters more often
ascribed to lower arterial oxygen and compensatory increase
than heel picks to obtain blood for testing and point of care
in cerebral blood flow. However, these findings were not
testing (POCT) has dramatically decreased iatrogenic blood
repeated in the PINT study [25], a randomized trial of similar
loss, the relevance of this study should be questioned. In a
design of over 200 infants highlighting the need for further
retrospective chart review, the effect of introduction of
large, multi-institution randomized clinical trials in this area.
POCT on RBC transfusion frequency in the first 2 weeks of life
was reviewed. There were 46 infants less than 1000 g pre
POCT who received 5.7 + 3.7 transfusions and 78.4 + 51.6 mL/ 4. Measurements to define the need to transfuse
kg transfusion volume versus 3.1 + 2.07 and 44.4 + 32.9 mL/kg
in 34 infants in post POCT period [21]. These studies highlight The observation that infants may be asymptomatic with low
the need to analyze the necessity of every blood draw, hemoglobin concentrations while others are symptomatic
support the use of noninvasive monitoring methods and with similar or higher hemoglobin concentrations supports
develop measures of true tissue oxygenation as a guide to the the concept that hemoglobin alone is an inadequate measure
need for transfusion. of the need to transfuse. The ability to reliably and non-

Table 3 Small-volume RBC transfusions given as stored RBCs to limit donor exposure without causing apparent adverse effects
Reference Solution Storage Dose Hct (%) Transfusions Donors
Liu CPDA-1 35 days 15 mL/kg 75 5.6 2.1
Lee CPDA-1 35 days 13 mL/kg 6875 6.0 2.0
Wood NR 35 days 15 mL/kg NR 5.6 4.9
Strauss AS-1 42 days 15 mL/kg 85 3.5 1.2
Strauss AS-3 42 days 15 mL/kg 85 3.6 1.3
van Straaten SAG-M 35 days 15 mL/kg NR 3.2 1.1 high risk
SAG-M 35 days 15 mL/kg NR 0.4 1.1 low risk
Mangel AS-3 21 days 7 mL/kg 5560 4.7 1.7
da Cunha CPDA-1 28 days 15 mL/kg NR 4.4 1.6
Jain AS-1 42 days 15 mL/kg 60 6.7 1.8
NR = not recorded.
496
invasively measure tissue hypoxia could provide improved
methods to evaluate different interventions and confirm the
clinical significance of measured hemoglobin. Compensatory
responses to decreased tissue oxygen concentration include
increases in heart rate, cardiac output and cerebral blood
flow. Fractional oxygen extraction (FOE) increases to
maintain oxygen consumption. There is a progressive shift
to anaerobic respiration which results in an increase in lactic
acid. Several authors [26,27] have shown post-transfusion
decrease in lactic acid and hypothesize that this reflects
improved oxygen delivery. However, there are the technical
and biological variables that affect the FOE measurement,
which include fasting, cold, increased activity, hemolysis and
venous occlusion, especially when the specimen is obtained
from a peripheral vein. In a study by Fey and Losa [28] that
attempted to control these variables, capillary whole blood
lactic acid was analyzed pre- and 48 h post-transfusion in 18
premature infants. Lactic acid measurements did not
correlate with either respiratory rate or bradycardiac
episodes when regression analysis was performed [28]. The
high coefficient of variation of 19.8% of repeated measures
of lactic acid likely contributed to the poor correlation. Some
have suggested that elevated lactic acid results from the
catecholamine surge associated with sepsis or injury. In this
circumstance, post-transfusion lactate might fall as a result
of decrease in catecholamine response rather than from
improvement in anaerobic metabolism.
Utilizing a different approach, Wardle et al. present
support for the use of near infrared spectroscopy (NIRS)
measurement of FOE [29,30]. In a pilot study, 37 infants were
randomized to one of two groups: the decision to transfuse
was based on peripheral FOE or based on the hemoglobin
concentration. The NIRS group was determined by an FOE of
greater than 0.47 while the conventional group was
transfused based on clinical need. Of the 56 transfusions
given to the NIRS group, 33 (59%) were given because of
clinical concerns. The investigators concluded that either
their FOE criteria were insensitive or clinical indications
complicated the study design. In another pilot study using a
technique similar to NIRS, absolute concentrations of tissue
hemoglobin, including oxygen bound and oxygen free
hemoglobin was measured in 10 very low birth weight infants
using diffuse optical spectroscopy (DOS) [31]. This metho-
dology measured tissue oxygen concentrations non-inva-
sively in muscle pre- and post-transfusion. Increases in tissue
oxygenation were noted post-transfusion and correlated
with mean hemoglobin increases for all 10 infants.
Mock et al. [32] correlated hematocrit to RBC volume in
26 premature infants of birth weight less than 1300 g, studied
on 43 occasions using a non-radioactive biotinylated RBC
labeling flow cytometric method. Their goal was to develop
an accurate RBC volume measurement and establish the
relationship between circulating red cell volume and
hematocrit to assess whether previously reported poor
correlations between hematocrit and RBC volume was due
to artifact or unique preterm physiology. They hypothesized
that if RBC volume and hematocrit correlated, then
hematocrit could be used as a definitive test for transfusion
need. Despite good correlation between the two assays
(r = 0.907), 95% confidence limits for predicting the circula-
tory RBC volume ranges were so broad as to make the RBC
volume measurement of questionable clinical significance
N.L.C. Luban
and usefulness. Other measurements like paired pre- and
post-transfusion measurements of oxygen consumption
(VO2 ), mixed venous oxygen saturation (M VO 2 ) and
hemoglobin-oxygen dissociation curve alone or in combina-
tion would theoretically demonstrate post-transfusion
improvement in oxygen delivery. Any method must be
available real time or its usefulness will be limited.
5. In-line devices
If methods are insufficient to guide transfusions, combining
methods to decrease iatrogenic loss and improve erythropoi-
esis might prove to be advantageous to the infant. Since blood
gas analyses are a primary source of iatrogenic loss, in-line
devices that permit continuous pH, pO2, and pCO2 measure-
ments should theoretically decrease venous blood loss. Using
229 paired samples, an in-line intra-umbilical artery device
versus specimens collected by phlebotomy were compared in
16 neonates monitored over 37 days. Blood volume loss and
hemolysis were assessed as well as bias, precision and
correlation of the in-line devices readout compared to
reference methods. A dramatic difference in blood volume
loss was observed: 24 7 L in those infants with in-line
monitors versus 250 L for reference methods of commonly
performed laboratory tests. The devices were not without
problems which included large flush volumes, software
issues, cost and practicality [33]. Using an in-line, ex vivo
bedside monitor that withdraws blood through an umbilical
artery catheter and returns it to the patient, Madan et al. [21]
noted 25% less cumulative phlebotomy loss in the first two
weeks of life in the monitored (n = 46) versus control group
(n = 47). Based on previous studies, there was an anticipated
35% decrease in phlebotomy losses, which was only achieved
in week one of the two-week analysis [21]. Because the
analyte panel was limited, additional phlebotomy was still
required. In future studies, technical issues and cost will need
to be addressed as well as impact on mortality and morbidity,
for which this study was underpowered. Time and technology
will ultimately yield improvements with such devices.
6. Autologous transfusion
6.1. Cord clamping
True autologous transfusion in an infant can occur by delaying
cord clamping or by collecting, storing, and re-infusing cord
blood as a blood product. In a randomized study, 39 infants of
b 33 weeks gestation were randomized to a 20 s (n = 20) or 45 s
(n = 19) delay in cord clamping with oxytoxin administration
after delivery of the first shoulder in mothers delivering by
Caesarian section. By day 42 of life, 16 of 20 infants in the
immediate and 9 of 19 in the delayed clamp group had
been transfused. This resulted in 2.4 transfusions in the
immediate versus 1.2 transfusions in the delayed group
(p b 0.05) despite equivalent iatrogenic blood loss [34]. This
supports the early work of Kinmond who demonstrated less
hypovolemia and fewer days of both oxygen dependency and
transfusion need in premature infants delivered vaginally [35],
but refutes the work of others who showed no advantage of late
clamping to the infant. McDonnell and Henderson-Smart [36]
measuring circulating red cell volume using biotinylated RBCs
Management of anemia in the newborn
could provide the physiological basis of delay of cord clamping.
In another study, infants born following delayed clamp had
greater circulatory red cell volumes (42.1 mL/kg) as compared
to immediate (36.8 mL/kg). Clinical benefit was not measured
in this study [37]. Most recently, blood volume measurements
using either a dilution of fetal hemoglobin or biotin-labeled
autologous red blood cell method were performed in 46
preterm infants, 24 to 32 weeks gestation, randomized to
either an early or delayed clamping. This study confirmed that
infants born with delayed clamp time had a greater blood
volume (74.4 mL/kg) than early clamp group (62.7 mL/kg) for
both vaginal and cesarean deliveries. Of interest no differences
were noted for hematocrit measured at 4 h [38].
The potential advantages and disadvantages of clamping
have been debated and are different for term versus preterm
infants. In countries with limited access to safe blood for
transfusion, the value of late cord clamping might be of
significant value. A meta-analysis of early versus late cord
clamping including 7 studies of 297 preterm infants, defined as
less than 37 weeks gestation has been published recently. In this
analysis, Rabe demonstrated that delayed cord clamping (30 to
120 s) was associated with fewer transfusions for anemia (RR
2.01) or lower blood pressure (RR 2.58) and less intraventricular
hemorrhage (RR 1.74) [39]. This meta-analysis supports the
need to implement changes in clinical obstetrical practice.
7. Cord blood collection
Collection of autologous cord blood for storage and re-
infusion has been studied infrequently. In one study, there
were 44 collections into a closed blood collection system
with CPD from infants with a mean gestational age of 32
4 weeks while the placenta was still in utero. A mean of
forty-four 3.4 mL of cord blood was collected which, at a
transfusion volume of 1015 mL/kg, could provide one or 2
transfusions. Bacterial contamination rate was high (15.8%)
[40]. While autologous collections can be transfused without
adverse consequences [41], smaller collection volumes with
poor product quality in infants weighing less than 1000 g raise
issues as to whether this process, while feasible, is
worthwhile. In another study of infants with congenital
anomalies diagnosed prenatally, 26 infants had blood
collected and transfused during the first 3 days post delivery.
No bacterial contamination was noted. The unusual success
in collection and transfusion was ascribed to patient
selection, meticulous preparation, and the short storage
time [42]. This level of success has been repeated in a recent
study of 52 newborns where autologous blood was held for up
to 23 days; 40% of infants between 1000 and 2500 g were
supported using only autologous blood in this study [43].
Key guidelines
Utilize transfusion guidelines based on published recom-
mendations, updated regularly based on randomized
clinical trials.
Assign one or two infants to a single RBC unit for small
volume transfusions to limit donor exposure without
concern for age/anticoagulant.
r-EPO should be limited to selected premature infants
until studies better inform its use [4452].
497
Encourage delayed cord clamping to increase newborn
red cell mass/volume.
Research directions
Perform well powered studies of restrictive vs. liberal
transfusion criteria.
Develop real time noninvasive measures of tissue oxygen
delivery.
Develop in-line and reflectometric devices to diminish
iatrogenic blood loss.
Establish systems to select, screen and collect blood from
a single donor that can be processed and packaged to
further limit donor exposure.
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