Pediatrics and Neonatology (2017) 58, 216e222

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ORIGINAL ARTICLE

Red Blood Cell Transfusion and Clinical

Outcomes in Extremely Low Birth Weight
Preterm Infants
Yu-Cheng Wang a, Oi-Wa Chan b, Ming-Chou Chiang b,
Peng-Hong Yang b, Shih-Ming Chu b, Jen-Fu Hsu b,
Ren-Huei Fu b, Reyin Lien b,*

a
Department of Pediatrics, Ton-Yen General Hospital, Hsinchu, Taiwan
b
Division of Neonatology, Department of Pediatrics, Chang-Gung Memorial Hospital, School of
Medicine, Chang Gung University, Taoyuan, Taiwan

Received Jan 25, 2016; received in revised form Mar 11, 2016; accepted Mar 25, 2016
Available online 5 July 2016

Key Words Background: Red blood cell (RBC) transfusion is often considered a life-saving measure in crit-
extremely low birth ically ill neonates. The smallest and least mature infants tend to receive the largest amount of
weight; transfusions. RBC transfusion itself has also been suggested as an independent risk factor of
mortality; poor clinical outcome in critical patients. Our aim is to study if there are associations between
neurodevelopmental RBC transfusion and in-hospital mortality, short-term morbidities, and late neurodevelopmen-
outcome; tal outcome in extremely low birth weight (ELBW) preterm infants.
preterm infants; Methods: A cohort of ELBW preterm infants admitted to our neonatal intensive care unit from
RBC transfusion January 2009 to December 2010 were recruited. The number of RBC transfusions within 7 days,
30 days, and 60 days of life were recorded. Clinical outcomes including in-hospital mortality,
development of retinopathy of prematurity (ROP), necrotizing enterocolitis, chronic lung dis-
ease, and later neurodevelopmental outcome were assessed with follow-up of up to 2 years of
age. Multivariable logistic regression was used to estimate the associations between RBC trans-
fusion and clinical outcomes.
Results: A total of 98 ELBW preterm infants survived at the time of discharge. Of these survi-
vors, the mean numbers of RBC transfusions were 2.5  1.7, 7.4  3.1, and 11.3  4.5 times
within 7 days, 30 days, and 60 days after birth, respectively. The number of transfusions within
7 days of life was correlated with risk of death before 1 month of age (odds ratio: 1.54, 95%
confidence interval: 1.04e2.27, p Z 0.03) and the number of transfusions within 30 days
was correlated with risk of developing threshold ROP (odds ratio: 1.27, 95% confidence

* Corresponding author. Division of Neonatology, Department of Pediatrics, Chang Gung Memorial Hospital, 5, Fu-Shing Street, Kwei-Shan,
Taoyuan 333, Taiwan.
E-mail address: reyinl@cgmh.org.tw (R. Lien).

http://dx.doi.org/10.1016/j.pedneo.2016.03.009
1875-9572/Copyright ª 2016, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-
NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
RBC transfusion in ELBW infants 217

interval: 1.04e1.55, p Z 0.02). The number of transfusions within 7 days of life was positively
correlated with cognitive performance (Mental Developmental Index score) at 18e24 months
of corrected age.
Conclusion: RBC transfusion has a negative impact on survival in ELBW infants. It increases the
risk of developing ROP and affects late neurodevelopment. Decisions of blood transfusion in
these very immature infants should be made cautiously taking these deleterious results into
consideration.
Copyright ª 2016, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/).

1. Introduction 2. Methods

Red blood cell (RBC) transfusion in anemic patients pro-
vides an immediate increase in tissue oxygenation. It is
common practice in critically ill patients with cardiopul-
monary compromise. Neonatal patients, with their rela-
tively small blood volume and immature hematopoietic
system, are among the most heavily transfused pop-
ulations.1 The smaller the infants are, the more likely they
are to receive frequent transfusions. It has been reported
that between 50% and 94% of the very low birth weight
(VLBW) infants (birth weight < 1500 g) and as high as 95% of
extremely low birth weight (ELBW) infants (birth weight <
1000 g) receive at least one transfusion during their hospital
stay.2
However, in the past 2 decades, there have been
increasing concerns of possible deleterious effects from RBC
transfusion in patients under critical care. The association of
transfusion and poor outcome, including risk of death, car-
diopulmonary failure, multiorgan dysfunction, and pro-
longed length of hospital stay, has been reported in patients
across all age groups.3e6 Preterm infants are particularly
vulnerable to tissue injuries related to a disturbed oxygen
delivery. Unique and serious complications of premature
birth are often attributed to such unbalanced tissue
oxygenation. Studies on neonatal populations have sug-
gested associations between RBC transfusion and increased
risk of specific complications such as chronic lung disease
(CLD), necrotizing enterocolitis (NEC), retinopathy of pre-
maturity (ROP), and extension of intraventricular hemor-
rhage (IVH).7e15 Nonetheless, there were contradictory
reports from the literature. Association between RBC
transfusion and NEC, ROP, or CLD has been refuted individ-
ually.16e18 One study even showed benefits on preventing
the development of severe IVH in anemic preterm infants.19
One report discussed the advantageous effect of RBC
transfusion on long-term outcome in premature infants.2
The publication subsequently provoked profound contro-
versy because it is one of the few studies to find beneficial
effects of RBC transfusion in preterm infants.
The aim of this study is to examine if there are associ-
ations between RBC transfusion and in-hospital mortality,
short-term morbidities, and, specifically, late neuro-
developmental outcome in ELBW preterm infants. This
study was carried out in a single neonatal intensive care
unit (NICU) with a standard blood transfusion protocol.
Follow up was extended up to 2 years of age.
This is a retrospective cohort study by medical record re-
view of patients in the NICU of Chang Gung Memorial Hos-
pital in Lin Kou, Taiwan. The study was approved by the
Institutional Review Board of Chang Gung University. Our
NICU is a 30-bed Level III nursery in northern Taiwan, with
an average admission of 1300 infants per year, both in-born
and out-born. The study period was from January 2009 to
December 2010. All infants with a birth weight < 1000 g
(ELBW) and admission within 24 hours after birth were
included. Exclusion criteria were infants with chromosomal
anomalies or major congenital structural abnormalities that
would compromise normal physiological function, and in-
fants who died within 7 days of life.
In our NICU, we adopt a widely accepted transfusion
guideline for premature infants.20,21 For ELBW infants, RBC
transfusion is performed under the following conditions: (1)
patient is asymptomatic with a hematocrit of < 21% and no
compensatory reticulocytosis; (2) patient is symptomatic
with oxygen dependency, ventilator dependency, poor
weight gain despite adequate nutritional provision, and a
hematocrit of < 31%; (3) patient has a hematocrit of < 36%
but oxygen requirement is > 35% or needs ventilator-
assisted breathing; and (4) phlebotomy blood loss reaches
15% of patient’s total blood volume in the 1st week of life.
All transfusions were provided with type-specific, Rh
compatible, leukocyte-poor RBCs to reduce risk of cyto-
megalovirus infection. Packed RBCs were transfused in a
volume of 10e15 mL/kg of body weight over 2e3 hours.
Numbers of PRBC transfusions within 7 days, 30 days,
and 60 days of life were recorded for each patient. The
following perinatal-neonatal variables were collected:
gender, gestational age (GA) at birth, birth body weight
(BBW), 1 minute and 5 minute Apgar scores, and initial
hemoglobin level. The primary outcomes were in-hospital
mortality and short term morbidities of NEC, ROP, bron-
chopulmonary dysplasia (BPD), and late-onset sepsis. The
secondary outcome was severe neurodevelopmental
impairment at 24 months of corrected age assessed by
Bayley Scales of Infant Development, 2nd edition.22
Diagnosis of NEC was based on systemic and radiographic
signs (pneumatosis intestinalis, portal venous air, or pneu-
moperitoneum). Its severity was assessed by Bell’s staging.
Diagnosis of IVH was made by ultrasound and graded ac-
cording to Papile’s system. ROP screening was performed
by ophthalmologists on all infants, and ROP was classified
218 Y.-C. Wang et al

according to the International Classification of Retinopathy hemoglobin level was 14.8  2.7 g/dL. In-hospital mortality
of Prematurity. Diagnostic criteria of BPD were based on rate was 18%. Of the 98 survivors, mean initial hemoglobin
those described in NICHD/NHLBI/ORD BPD Workshop Sum- level was 15.0  2.4 g/dL. The number of RBC transfusions
mary by need for oxygen and positive pressure ventilation ranged from 0e7, 1e18, and 2e29 times, with an average
at 36 weeks’ postmenstrual age.23 Late-onset sepsis was of 2.5  1.7, 7.4  3.1, and 11.3  4.5 times within 7 days,
defined as culture-proven sepsis occurring 7 days after 30 days, and 60 days after birth, respectively (Table 1). NEC
birth.
Statistical analysis was performed using SPSS program
(SPSS Inc., Chicago, IL, USA). Correlation between trans-
fusion and mortality and risks of morbidities were evalu- Table 1 Demographic data and red blood cell transfusion
ated using a logistic regression model adjusted for GA, of survivor infants (n Z 98).
BBW, Apgar scores, and initial hemoglobin levels. A p value Mean Standard Minimum Maximum
< 0.05 was defined as statistically significant. The odds deviation
ratio (OR) and its 95% confidence interval (CI) for each risk
Gestational age (wk) 26.6 2.3 23 33
factor were calculated.
Birth body weight (g) 808 122 472 1000
Initial hemoglobin 15.0 2.4 9.7 21.2
(mg/dL)
3. Results Apgar score
1 min 5 2 1 8
During the 2-year study period, 1249 premature infants (< 5 min 7 2 1 9
37 weeks) were admitted to our NICU, 365 of VLBW, and 145 Hospital days 115 37 46 323
of ELBW. Among the 145 ELBW infants, 120 were enrolled in Transfusion in 2.5 1.7 0 7
our study. Twenty-five infants were excluded due to death 7 d (times)
within 3 days of life (n Z 24) or presence of major Transfusion in 7.4 3.1 1 18
congenital anomalies (n Z 1). There were 61 male infants 30 d (times)
and 59 female infants in our cohort (Figure 1). The average Transfusion in 11.3 4.5 2 29
GA at birth was 26.3  2.3 (mean  standard deviation) 60 d (times)
weeks and BBW was 785  140 g. The average initial

Figure 1 Flow chart of study patients. ELBW Z extremely low birth weight; IVH Z intraventricular hemorrhage;
NEC Z necrotizing enterocolitis.
RBC transfusion in ELBW infants 219

(Stage IIb and above) occurred in six patients (6/120, 5%)

Table 2 Association of red blood cell (RBC) transfusion
and three of the surviving infants (3/98, 3%). Three infants
(times) during specific period and neonatal death/relevant
died from NEC. The incidences of moderate-to-severe BPD,
morbidities.
threshold ROP, and late-onset sepsis in the surviving infants
were 71% (70/98), 34% (33/98), and 45% (44/98), Transfusion RBC Transfusion OR (95% CI)
respectively. period (times)
Twelve infants died within 30 days of age due to various (postnatal days)
causes (respiratory failure 4; NEC 2; sepsis 3, 2 bacterial Neonatal Survival
and 1 fungal; IVH 2; and renal failure 1). The numbers of death ‡ 30 d
RBC transfusions within 7 days of life were 4.7  2.6 times <7d 4.7  2.6 2.7  1.8 1.54 (1.04e2.27)*
in infants who died between 7 days to 30 days after birth, Severe IVH No IVH
compared to 2.7  1.8 times in patients who survived for 4.3  2.6 2.6  1.8 1.53 (1.09e2.16)*
more than 30 days. The number of RBC transfusions within 7 NEC No NEC
days of life was associated with mortality within 1 month of 3.0  2.6 2.8  1.7 0.92 (0.70e1.20)
age (neonatal death). The OR was 1.55, with a 95% CI of Late-onset No sepsis
1.16e2.05 (p Z 0.003). After adjusting for GA, BBW, 1 sepsis
minute and 5 minute Apgar scores, and initial hemoglobin 2.4  1.6 2.5  1.8 0.87 (0.65e1.17)
level, risk of death within 1 month of age was still increased
with increased number of RBC transfusions, (OR: 1.54, 95% Threshold No ROP
CI: 1.04e2.27, p Z 0.03). ROP
The number of RBC transfusions within 7 days of life was <7d 3.2  1.7 2.1  1.6 1.21 (0.87e1.70)
slightly higher in patients with NEC (3.0  2.6 times) than < 30 d 9.2  3.5 6.5  2.4 1.27 (1.04e1.55)*
patients without NEC (2.8  1.7 times), but this was not < 60 d 13.7  5.2 10.2  3.6 1.11 (0.98e1.28)
statistically significant (p Z 0.521). The number of RBC Moderatee No BPD
transfusions within 7 days of life was associated with severe severe BPD
IVH ( Grade III) (OR: 1.53, 95% CI: 1.09e2.16, p Z 0.014). <7d 2.8  1.6 1.7  1.6 1.15 (0.80e1.66)
The number of RBC transfusions within 7 days, 30 days, and < 30 d 7.9  3.1 6.1  2.7 1.03 (0.83e1.28)
60 days in patients with and without threshold ROP was 3.2 < 60 d 12.2  4.5 9.1  3.8 1.07 (0.92e1.25)
 1.7, 9.2  3.5, and 13.7  5.2 times and 2.1  1.6, 6.5 
* p < 0.05 indicates statistical significance.
2.4, and 10.2  3.6 times, respectively. There was an as-
BPD Z bronchopulmonary dysplasia; CI Z confidence interval;
sociation between the number of RBC transfusions within 30 IVH Z intraventricular hemorrhage  Grade III; NEC Z necro-
days of life and late development of threshold ROP tizing enterocolitis  Stage IIb; OR Z adjusted odds ratio; ROP
(adjusted OR: 1.27, 95% CI: 1.04e1.55, p Z 0.02). In pa- Z retinopathy of prematurity.
tients with moderate-to-severe BPD, the number of RBC
transfusions was 2.8  1.6, 7.9  3.1 and 12.2  4.5 times
within 7 days, 30 days, and 60 days of life, respectively, number of RBC transfusions within 7 days of life. There was
compared to 1.7  1.6, 6.1  2.7, and 9.1  3.8 times in no significant correlation between psychomotor develop-
patients with no or mild BPD. The association between RBC mental indexes and RBC transfusion (Table 3).
transfusion and development of BPD did not reach statis-
tical significance (Table 2). The number of RBC transfusions
within 7 days of life was similar: 2.4  1.6 vs. 2.5  1.8 4. Discussion
times in patients with and without late-onset sepsis.
Since severe IVH (Grade III and above) and surgical NEC In this study, RBC transfusion in the ELBW infants was
have both been identified as risk factors for late neuro- associated with increased risk of neonatal death. RBC
developmental impairment, in this study, 12 of such pa- transfusion was also correlated with an increased risk of
tients were excluded for the assessment to determine threshold ROP. However, our study revealed a favorable
association of RBC transfusion and late neuro- effect of RBC transfusion on the late cognitive develop-
developmental outcome (at 18 to 24 months of age). ment, as assessed by MDI score assessed at 18e24 months of
Another infant was excluded due to death after discharge corrected age.
but before 2 years of age (Figure 1). Eighty-two infants Although detrimental effects of RBC transfusion have
were eligible for neurodevelopmental assessment. Howev- been reported in critically ill patients of various age groups,
er, only 62 of the infants completed assessment at 18 most of these studies were based on observational cohort
months and 24 months of corrected age. The reasons for studies and failed to provide any cellular or molecular ev-
loss to follow up included transferring care to other hos- idence of causality. Histological studies have suggested
pitals, parents’ refusal, and relocation. The mean mental perturbation of microcirculatory regulation by RBC trans-
developmental indexes (MDI) at corrected age of 18 months fusion is involved, hence compromising tissue oxygena-
and 24 months were 86  15, and 88  17; and psychomotor tion.24 In preterm infants, evidence accumulated on the
developmental indexes were 87  17, and 90  18, association between RBC transfusion and adverse outcomes
respectively. Using adjusted linear regression analysis, MDI in this population. The most serious outcomes are death
scores at both 18 months (ß: 3.989, 95% CI: 1.375e6.602, p and the development of BPD, NEC, IVH, and ROP. Most
Z 0.003) and 24 months (ß: 3.767, 95% CI: 0.565e6.968, p previous prospective studies compared outcomes in mostly
Z 0.022) corrected age showed a positive correlation with VLBW infants receiving care under a liberal (keeping a
220 Y.-C. Wang et al

Table 3 Adjusted linear regression coefficients for frequency of red blood cell (RBC) transfusion and Bayley scores at 18e24
months of corrected age.
MDI PDI
b 95% CI p b 95% CI p
Lower Upper Lower Upper
18 mo
Transfusion <7d 3.989 1.375 6.602 0.003* 2.281 1.07 5.632 0.178
Transfusion < 30 d 1.137 0.347 2.62 0.13 0.84 0.975 2.654 0.358
Transfusion < 60 d 0.789 0.202 1.78 0.117 0.587 0.627 1.801 0.337
24 mo
Transfusion <7d 3.767 0.565 6.968 0.022* 1.664 2.033 5.361 0.371
Transfusion < 30 d 1.2 0.586 2.985 0.184 0.511 1.496 2.518 0.612
Transfusion < 60 d 0.611 0.527 1.749 0.287 0.222 1.052 1.496 0.728
* p < 0.05 indicates statistical significance.
CI Z confidence interval; MDI Z mental developmental index; PDI Z psychomotor developmental index.

higher hematocrit level) versus a restrictive (keeping a
lower hematocrit level) rule of transfusion. Our study,
based on a retrospective chart review of a cohort of ELBW
infants, followed a relatively liberal rule of transfusion.
Because factors associated with the need of RBC trans-
fusion could overlap with those contributing to neonatal
mortality and morbidities, we used logistic regression an-
alyses to delineate the influence of confounding factors
such as GA, birth weight, Apgar scores, and initial hemo-
globin level.
The association between RBC transfusion and mortality
has been shown in critically ill patients across all age
groups.3,6 Our study demonstrated that frequency of RBC
transfusion within the 1st week of life was an independent
risk factor of mortality within 1 month of age in ELBW in-
fants. This was in agreement with the study by dos Santos
et al,7 showing that VLBW infants who received any number
of RBC transfusions in the first 28 days of life had a 50%
increased risk of in-hospital mortality compared to those
who did not. This association is considered one of the
manifestations of transfusion-related immunomodulation
which involves serious effects attributable to blood trans-
fusion by proinflammatory mechanisms.25
Previous studies have also reported an association of RBC
transfusion and development of ROP.11,12 Our study
demonstrated a correlation between frequency of RBC
transfusion within 30 days of life and later development of
threshold ROP (OR: 1.27, 95% CI: 1.04e1.55). Our obser-
vation is in agreement with the report by Dani et al,13 who
showed that RBC transfusion volume during the 1st week
and the first 60 days of life was associated with develop-
ment of ROP, with OR of 1.16 and 2.93, respectively. The
possible mechanism of RBC transfusion causing complica-
tions in the preterm infants includes increased oxidative
injury (caused by an increase in non-transferrin bound iron)
or inflammatory mediators present in stored blood prod-
ucts.26 Dani et al13 also demonstrated that iron from RBC
transfusions independently contributed to the development
of ROP, providing evidence of iron overload and free
radical-induced injury being a key role in its pathogenesis.
Controversy also exists in this seemingly agreed upon cor-
relation; however, a study by Brooks et al27 examining a
more restrictive transfusion policy failed to find a decrease
in incidence of ROP.
RBC transfusion in preterm infants has been associated
with an increased risk of NEC.8,9 Mally et al8 described a
subset of premature infants who developed NEC within 48
hours following RBC transfusion. Altered oxygenation or a
perturbed mesenteric perfusion during transfusion was
implicated. It was given the term of transfusion-related
(acute) gut injury, or TRAG.9 However, Wallenstein et al16
recently reviewed 2889 consecutive RBC transfusions in
414 VLBW infants and refuted the correlation. In our study,
the number of RBC transfusions within 7 days of life was
slightly higher in patients who developed NEC than patients
who did not. However, this correlation did not reach sta-
tistical significance.
Although our analyses showed an association of RBC
transfusion within the 1st week of life and severe IVH, by
the design of this study we could not delineate whether
transfusion was the result or the cause of severe IVH,
because the majority of IVH also occurred during the first 7
days of life.
Pulmonary consequences of RBC transfusion have been
clearly described in adult patients. Acute lung injury
resulted from increased pulmonary microvascular perme-
ability, with pulmonary edema being the most serious.5 In
neonatal patients, studies have revealed an association
between BPD and RBC transfusion.17,28,29 Its mechanism is
thought to involve iron and free radical injury. Chen et al29
reported a 29 times higher risk of developing CLD in VLBW
infants who received RBC transfusion of more than 30 mL
over the 1st month of life than those who did not, with an
adjusted OR of 29.13. In this study, infants who developed
moderate to severe BPD received more frequent RBC
transfusions within 7 days, 30 days, and 60 days of life than
those with no or mild BPD. However, the correlation did not
reach statistical significance.
In our study, there is an association of RBC transfusion
within 7 postnatal days with higher MDI scores, indicating
favorable cognitive outcome at 18 months and 24 months of
corrected age. A randomized study involving 100 ELBW
preterm infants showed infants treated with a restrictive
rule of transfusion had a higher incidence of
RBC transfusion in ELBW infants
intraparenchymal brain hemorrhage or periventricular
leukomalacia.19 In the PINT (Preterm Infant in Need of
Transfusion) study of 451 ELBW infants, there was no dif-
ference in incidence of brain injury defined by ultrasonog-
raphy between infants keeping low versus high
hematocrit.18 Nopoulos et al30 reported that premature
infants exposed to liberal transfusion threshold had a sub-
stantially smaller intracranial volume at 12 years of age,
whereas Chen et al29 revealed no differences in intracranial
pathology in the VLBW infants. The report by Whyte et al2
on the follow-up assessment of infants previously enrolled
in the PINT study (the PINTOS study) provoked further
argument on this issue. In 430 of the 451 infants in the PINT
study who also completed neurodevelopmental assessment
at 18 months of corrected age, the difference in cognitive
delay (BSID II, MDI  70) favoring high hemoglobin threshold
approached statistical significance (OR 1.74, 95% CI
0.98e3.11, p Z 0.06.) A post hoc analysis with cognitive
delay redefined (MDI  85) showed a significant lower risk in
the group receiving liberal RBC transfusion.2 The authors
addressed and excluded other possible confounding effects
for neurodevelopment such as hemoglobin level on growth,
or abnormal iron status from different transfusion practice.
They thought there was weak evidence of benefit from
higher hemoglobin threshold for blood transfusion (to keep
a higher hemoglobin level) with clinical and statistical sig-
nificance, which could not be dismissed as accidental.
However, they advocated caution in interpretation of these
results and called for additional investigation of the effects
of transfusion in ELBW infants. Our results of beneficial
effect from early RBC transfusion on late cognitive per-
formance were similar to those from the PINTOS study. We
postulate that this could be the result of neuronal salvage
through avoidance of central nervous system hypoxia. We
further speculate that in the very immature individuals like
ELBW preterm infants, the appraisal of benefits and risks of
RBC transfusion should be different than for patients of
other age populations. However, immediate remedy for
anemia of prematurity should be prevention by imple-
menting strategies like delayed cord clamping, reducing
phlebotomy blood loss, and improving erythropoiesis by
exogenous erythropoietin and early aggressive nutritional
support. As for impacts of RBC transfusion on the ELBW
infants, further study is warranted.
4.1. Limitations
The main limitation is that this is a retrospective observa-
tional study and impacts of various confounding factors for
the same outcome could only be assessed by statistical
methods. Also, in this study we only adjusted for severity of
patient illness by GA, birth weight, Apgar scores, and initial
hemoglobin levels. While sicker patients may require more
transfusions to compensate for their pulmonary or circula-
tory compromise, they are also at higher risk to sustain
neurological disabilities. Our study revealed the effect of
RBC transfusion on mortality and part of the morbidities.
Such association might not be of causal relevance. Instead,
transfusion could be taken as a proxy for unmeasured fac-
tors such as disease severity. It would be prudent to
delineate confounding factors attributable to different
221
degrees of disease severity while analyzing effects of RBC
transfusion. To date, there is a lack of a well validated
scoring system for disease severity to be applied to ELBW
infants.
We conclude that anemia still holds a significant threat
to the health of ELBW infants. Detrimental impacts could
originate from RBC transfusion in these most immature in-
fants. Decisions on transfusion should be made with
tremendous caution, and taking patients’ developmental
pathophysiology into account.
Conflicts of interest
The authors have no conflicts of interest relevant to this
article.
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