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ARTICLEPEDIATRICS Volume 137 , number 3 , March 2016 :e 20153236
Benefits of Delayed Cord Clamping in Red Blood Cell AlloimmunizationCharles Garabedian, MD,a Thameur Rakza, MD,b Elodie Drumez, MS,c Marion Poleszczuk, MD,a Louise Ghesquiere, MD,a Bénédicte Wibaut, MD,d Marie-Hélène Depoortere, MD,a Pascal Vaast, MD,a Laurent Storme, MD, PhD,b,e Véronique Houffl in-Debarge, MD, PhDa,e
abstractBACKGROUND AND OBJECTIVE: Several studies have shown the benefits of delayed cord clamping
(DCC) in preterm and in healthy newborns at short and long term. Our objective was to
evaluate the potentials benefits and risks of DCC in red cell alloimmunization.
METHODS: This was a comparative before/after study of all living born neonates followed after
fetal anemia requiring in utero transfusion. DCC was defined as cord clamping 30 seconds
after birth.
RESULTS: We included a continuous series of 72 neonates: 36 without DDC (group 1) and
36 with DDC (group 2). Hemoglobin at birth was lower in group 1 (10.2 vs 13.4 g/dL, P =
.0003); 7 (25%) neonates in group 1 vs 24 (70.6%) in group 2 had no anemia at birth (P
= .004). The rate of transfusion was similar between the 2 groups. Postnatal exchange
transfusions were more likely performed in the group without DCC than in the group with
DCC (47.2% vs 19.4%, P = .0124). Delay between birth and first transfusion was higher
in group 2 (0 [0–13] vs 1 [0–21], P = .0274). The maximum level of bilirubin, the rate of
intensive phototherapy, and the total duration of phototherapy were similar in the 2 groups.
CONCLUSIONS: This study highlights a significant benefit of DCC in anemia secondary to red
blood cell alloimmunization with a resulting decreased postnatal exchange transfusion
needs, an improvement in the hemoglobin level at birth and longer delay between birth and
first transfusion with no severe hyperbilirubinemia.
aDepartment of Obstetrics, bNeonatology Unit, and dInstitute of Hematology and Transfusion, Jeanne de Flandre
Hospital, CHRU of Lille, France; cDepartment of Biostatistics, University of Lille North of France, CHRU Lille,
France; and eFaculty of Medicine, University of Lille North of France, CHRU Lille, France
Drs Garabedian, Poleczuck, Wibaut, and Ghesquiere conceptualized and designed the study,
and drafted the initial manuscript; Drs Rakza, Vaast, Depoortere, Storme, and Houffl in-Debarge
carried out the initial analyses, and reviewed and revised the manuscript; Ms Elodie Drumez did
the biostatistical analysis; and all authors approved the fi nal manuscript as submitted.
DOI: 10.1542/peds.2015-3236
Accepted for publication Nov 24, 2015
Address correspondence to Charles Garabedian, MD, Pôle d’Obstétrique, Hôpital Jeanne de
Flandre, CHRU Lille, Avenue Eugène Avinée, 59037 Lille Cedex, France. E-mail: charles.garabedian@
chru-lille.fr
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2016 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have no fi nancial relationships relevant
to this article to disclose.
FUNDING SOURCE: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential confl icts of
interest to disclose.
To cite: Garabedian C, Rakza T, Drumez E, et al. Benefi ts of
Delayed Cord Clamping in Red Blood Cell Alloimmunization.
Pediatrics. 2016;137(3):e20153236
WHAT’S KNOWN ON THIS SUBJECT: Delayed cord
clamping in preterm birth and in healthy newborns
allows a signifi cant increase in hematocrit and
hemoglobin at birth, and in ferritin level leading to a
signifi cant decrease in the risk of anemia in the fi rst
months of life.
WHAT THIS STUDY ADDS: This is the fi rst study
evaluating delayed cord clamping in red cell
alloimmunization. It allows an increase of
hemoglobin at birth, longer delay before fi rst
neonatal transfusion and a diminution of exchange
transfusion without more neonatal complication due
to hyperbilirubinemia.
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GARABEDIAN et al
Immune hemolytic disease of the
newborn is responsible for neonatal
anemia and jaundice. Therapeutic
support of this pathology requires,
according to the degree of severity,
phototherapy (PT), and/or exchange
transfusion (ET), and/or blood
transfusions, and/or immunoglobulin
infusion.1–3
Approximately 25% to 60% of the
total blood volume of fetal placental
circulation (54–160 mL) and 60% of
fetal red blood cells is found in the
placental circulation.4,5 This blood
is rich in hematopoietic stem cells.6
At birth, delayed cord clamping
(DCC) allows placental blood
transfusion, which can represent up
to one-quarter to one-third of the
total blood volume of the newborn
at term.5 Several trials and meta-
analyses have studied the benefits of
DCC versus early cord clamping.7–17
In preterm infants, Rabe et al16
showed, in a meta-analysis of
10 studies describing a total of
454 preterm infants, that major
benefits of the DCC were higher
circulating blood volume during the
first 24 hours of life, less need for
blood transfusions (P = .004), and
less incidence of intraventricular
hemorrhage (P = .002). Recently,
Chiruvolu et al18 confirmed those
results with a reduction of early
red blood cell transfusion in the
DCC group compared with an
historical cohort (13.3% vs 33%)
(odds ratio 0.11, 0.03–0.41). In
healthy newborns, after delayed
clamping, it was observed at birth a
significant increase in hematocrit and
hemoglobin (Hb) in the physiologic
range, and an increase in ferritin level
leading to a significant decrease in
the risk of anemia in the first months
of life.9,12 At 4 years of age, DCC
compared with early cord clamping
improved scores in the fine-motor
and social domains, especially in
boys.19 However, DCC has never been
studied in case of alloimmunization.
Our hypothesis is that DCC allows a
higher rate of Hb at birth allowing
less need for transfusions (blood
transfusions or ET), which can
decrease neonatal morbidity linked
to those procedures. However,
reserves concerning DCC in red blood
cell alloimmunization are the risks
of overloading the newborn with
additional incompatible red blood
cells, leading to increased levels of
bilirubin.
In 2009, we began DCC in cases of red
cell alloimmunization with a history
of utero transfusions. Our objective
was to evaluate the potentials
benefits and risks of DCC in a
comparative before/after study.
METHODS
This is a comparative before/
after study, from January 2001
to December 2014, of all living
neonates followed after fetal anemia
requiring in utero transfusion (IUT).
We included a continuous series of
neonates with DCC and compared it
with a similar continuous series of
historic cohort with immediate cord
clamping (ICC). Ethical approval
was granted by the French Ethics
Committee of research in Obstetrics
and Gynecology (CEROG OBS
2012-02-04).
In the first few years of the study, IUT
was indicated whenever the optical
index at 450 nm (DOD450) fell in
zone III of the Liley diagram.20 This
technique was progressively replaced
by the middle cerebral artery peak
systolic velocity (MCA PSV). Fetal
anemia was defined as MCA PSV
greater than 1.5 to 1.55 MoM.21
Technical realization of IUT was the
same as previously described.22 IUT
was performed until the 34th week
of gestation. Beyond this age, fetal
extraction was discussed with the
perinatal specialists.
In our center, we have a systematic
policy of DCC in premature
infants born before 34 weeks of
gestation, in agreement with the
recommendations of the European
Resuscitation Council.23 Since
2009, we have extended our DCC
protocol to include cases of red cell
alloimmunization with a history of
utero transfusions. We have defined
DCC as cord clamping 30 seconds
after birth.
Hb level was evaluated during
the first hour of life. Our neonatal
management was similar as
previously described.24 Phototherapy
(PT) was administered with 2 devices
(Tunnel MIDEPREMA, Tours, France,
and NATUS NeoBlue, Natus Medical
Inc, San Carlos, CA). During the
study period, the neonatal protocol
changed and PT was systematically
done in case of alloimmunization
since. ET was performed with
double-volume transfusion (160 mL/
kg) using irradiated and leukocyte-
depleted erythrocytes and our
criteria for ET were bilirubin level at
birth >3.5 mg/dL or bilirubin levels
above threshold in combination with
failure of PT. Indication for red blood
cell transfusion was Hb level at birth
<10 g/dL or if clinical symptoms of
anemia were present.
Data concerning obstetric history,
antenatal management, and neonatal
outcome until the discharge from the
NICU were collected.
Statistics
We compared 2 groups: 1 without
DCC (ICC group) during the first
period of the study (January
2001–June 2009) and 1 with DCC
(June 2009–December 2014). The
primary outcome was the need of
blood transfusion or ET after birth.
Secondary outcomes were Hb level at
birth, free serum bilirubin postnatal
maximum levels, duration of PT,
transfer rate to the neonatal unit, and
duration of initial hospitalization.
Qualitative variables are expressed
as frequency (percentage) and
quantitative variables as mean ± SD
or median (range) in case of non-
Gaussian distribution (normality of
distribution was checked graphically
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and by using the Shapiro–Wilk
test). Comparisons between the
2 groups were made using the χ2
test (or Fisher exact test when
expected cell frequency was <5) for
qualitative variables and the Student
t test (or Mann-Whitney U test for
non-Gaussian distribution) for
quantitative variables.
Statistical testing was done at the
2-tailed α level of 0.05. Data were
analyzed by using the SAS software
package, release 9.4 (SAS Institute,
Inc, Cary, NC).
RESULTS
We included a continuous series
of 72 neonates: 36 with ICC and
36 with DCC. Cord clamping was
done in all neonates of group DCC.
Characteristics of the population
are summarized in Table 1. The
main antibody was Rhesus D (80.6%
in group 1 and 72.2% in group 2).
There were no differences between
the 2 groups regarding the age, the
gestity, and the rate of hydrops
fetalis.
Gestational age and Hb at first
IUT were comparable (Table 2).
Antenatal management was similar
during the periods with comparable
delay between last IUT and birth,
and same rate of MCA PSV ≥1.5 MoM
before delivery. We observed
5 emergency cesarean deliveries
(4 in ICC group and 1 in DCC group)
secondary to bradychardia during
the IUT. Cord clamping was
done before resuscitation by the
pediatrician.
Gestational age at birth and birth
weight were lower in the ICC group
(Table 3). Hemoglobin at birth was
higher in the DCC group (5.6 ± 2.4 vs
6.7 ± 2.5 g/dL, P = .0003); 7 (25%)
neonates in the ICC group versus 24
(70.6%) in the DCC group had no
anemia at birth (Hb >12 g/dL)
(P = .004).
The rate of neonatal transfusion
was similar between the 2 groups.
Postnatal ETs were more likely
performed in the ICC group than in
the DCC group (47.2% vs 19.4%, P
= .0124). The delay between birth
and first transfusion was higher in
DCC group (0 [0–13] vs 1 [0–21] day,
P = .0274). The maximum level of
bilirubin was comparable between
the 2 groups; 83.3% of neonates
required PT (intensive or not)
in ICC group versus 97.1% in
DCC group. The rate of intensive
PT and the total duration of PT
were similar in the 2 groups (P = .49
and P = .66).
No neonatal death was observed
during the study period.
DISCUSSION
To our knowledge, this is the first
description of DCC in moderate or
severe immune anemia since red
blood cell alloimmunization was
excluded from all previous studies.
Our study demonstrated a significant
benefit of DCC in immune anemia
managed by IUT. We observed a
significant increase in Hb levels at
birth, a longer delay between birth
3
TABLE 1 Population
ICC, n = 36 DCC, n = 36
Age, y 30 (22–40) 35 (20–41)
Gestity 3 (1–6) 3 (1–8)
Maternel Ab
RH1 (RhD) 29 (80.6) 26 (72.2)
RH 3 (Anti-E) 2 (5.6) 1 (2.8)
RH 4 (Anti-c) 1 (2.8) 3 (8.3)
Kell 4 (11.1) 6 (16.7)
Presence of 2 Ab 22 (61.1) 17 (47.2)
Presence of 3 Ab 5 (13.9) 6 (16.7)
Hydrops fetalis 6 (16.7) 4 (11.1)
TABLE 2 Ante Natal Management
Group 1, n = 36 Group 2, n = 36 P
Number IUT /pregnancy 2.5 (1.0–5.0) 2.0 (1.0–6.0) .10
Gestational age at fi rst IUT, wk 26.4 ± 3.5 27.6 ± 4.1 .19
Hb at fi rst IUT, g/dL 5.6 ± 2.4 6.7 ± 2.5 .06
Complications
Emergency cesarean delivery 4 (11.1) 1 (2.8) —
Premature rupture of membranes 0 (0.0) 0 (0.0) —
Chorioamnionitis 0 (0.0) 0 (0.0) —
Delay between last IUT and delivery, d 20.5 ± 11.8 22.9 ± 9.9 .34
MCA PSV ≥1.5 MoM before delivery 5/10 (50.0) 25 (69.4) .30
—, not applicable.
TABLE 3 Neonatal Data
Group 1, n = 36 Group 2, n = 36 P
Gestational age at birth, wk 34.1 (27.6–37.0) 34.9 (28.6–37.9) .0350
Vaginal birth 6 (17.7) 16 (44.4) .0158
Birth weight, g 2107.6 ± 437.0 2455.0 ± 507.0 .0029
Apgar <7 at 5 min 1 (3.1) 2 (5.6) —
Hemoglobin at birth, g/dL 10.2 (6.0–16.8) 13.4 (7.7–22.5) .0003
Transfer to ICU 33 (91.7) 22 (61.1) .0023
Top-up transfusion 22 (61.1) 18 (50.0) .34
No. of top-up transfusion 1 (1–6) 1 (1–10) .80
Postnatal ET 17 (47.2) 7 (19.4) .0124
Bilirubin maximal, units 111 (28–259) 126 (58–353) .19
Intensive PT 28 (77.8) 24 (70.6) .49
Total duration of PT (intensive or not), d 4.5 (1.0–7.0) 5.0 (2.0–9.0) .66
Neonatal death 0 (0.0) 0 (0.0) —
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GARABEDIAN et al
and first transfusion, and a decrease
in the postnatal ET with no maternal
or neonatal adverse impact of DCC.
The rationale for the benefits of
DCC in infants with red blood cell
alloimmunization is to allow a higher
rate of Hb at birth, decreasing the
numbers of postnatal exchange
and top-up transfusions. Previous
studies in preterm and term neonates
shown an increase of Hb and of
hematocrit in case of DCC.7,9,13,14,25
In our population, we observed an
increase of Hb at birth in the DDC
group. We can relate this higher Hb
rate to the implementation of DDC
and not to a change in our practice:
delay between last IUT and birth was
similar between the groups and we
showed in a previous study that the
use of PSV MCA did not modify our
antenatal management.20
Our series found a significant
decrease of ET in children with
immune hemolytic disease after
DCC. This procedure is attempted
in severe anemia and/or severe
hyperbilirubinemia, particularly if
the PT fails. Postnatal ET rate usually
varies from 16% to 71% in case of
alloimmunization.1–3 This result is
particularly interesting because of
neonatal morbidity linked to this
procedure. The mortality rate is
estimated to be between 0.5% and
2.0% and the morbidity rate varies
from 5.0% to 74.0%.26,27 The main
complications are mostly linked to
the umbilical vein catheterization
and to the transfusion risks.28 On the
contrary, the rate of transfusions and
the median number of transfusions
were similar between the 2 groups.
One major benefit of DCC is the delay
between birth and first transfusion.
We observed in our population a
gain of 4 days of life before first
transfusion in the DCC group. This
avoids transfusion in emergencies
and allows a better organization of
neonatal care.
Reserves concerning DCC in red
blood cell alloimmunization were
the risks of overloading the newborn
with additional incompatible red
blood cells, leading to increased
levels of bilirubin and, in very
severe cases, severe jaundice and
kernicterus.29 In our study we did
not find a difference in maximal
bilirubin levels in the 2 groups. In
red blood cell alloimmunization,
all newborns are subjected to PT
in the first hours of life as well as
enhanced surveillance to prevent the
progression into a severe jaundice.28
We observed a high rate and of PT
in the DCC group but a lower rate of
intensive PT. There was no severe
complication, such as kernicterus.
This high rate of PT can be also
explained by a change in our
neonatal practice with systematic
PT during the first hours of
life in case of red blood cell
alloimmunization. Data on late-
onset jaundice and DCC are variable
in the literature. Van Rheenen et
al17 found an increased risk of
hyperbilirubinemia of 12%, with
no increase in the PT or ET needs.
On the contrary, Arca et al30 and
McDonald et al12 found a significant
increase in neonates requiring PT
after delayed clamping.
Although many randomized
controlled trials have evaluated
the benefits of DCC versus ICC in
term and preterm infants, the ideal
timing for cord clamping has yet to
be established.31 The definition of
delayed umbilical cord clamping
varied between studies from 30
and 180 seconds. McDonnel et al32
had a mean DCC of 31 seconds.
Kugelman et al33 and Mercer et al13
proposed a DCC of 30 to 45 seconds,
whereas Aladangady et al34 had
60 to 90 seconds. The longest was
180 seconds.35 Our protocol was a
preliminary study and we chose the
minimal duration recommended (30
seconds).
This study is the first to
evaluate the impact of DCC in
neonatal management in red cell
alloimmunization. Due to the
study design (before/after study),
potentially covariates may be
unevenly distributed between
groups. One potential bias is the
change in neonatal practices for PT
during the study period. In the ICC
group, neonates were smaller, born
earlier, and more likely by cesarean.
These factors may influence the
study findings. However, it seems
difficult to conduce a randomized
trial due to the low prevalence of
alloimmunization and to the known
benefits of DCC.
CONCLUSIONS
DCC has already demonstrated its
benefits in preterm birth, with a
decrease in the transfusion needs.
This study highlights a significant
benefit of DCC in moderate to severe
anemia secondary to red blood cell
alloimmunization with resulting
decreased postnatal ET needs, and an
improvement in the Hb level at birth,
with no severe hyperbilirubinemia.
We recommend DCC with duration of
30 seconds in infants at risk for red
blood cell alloimmunization neonatal
anemia only if the monitoring and
management of jaundice can be
optimal. It will be interesting to
evaluate the long-term effects of DCC
in this population.
ABBREVIATIONS
DCC: delayed cord clamping
ET: postnatal exchange
transfusion
Hb: hemoglobin
ICC: immediate cord clamping
IUT: in utero transfusion
MCA PSV: middle cerebral artery
peak systolic velocity
PT: phototherapy
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DOI: 10.1542/peds.2015-3236 originally published online February 18, 2016; 2016;137;Pediatrics
Storme and Véronique Houfflin-DebargeGhesquiere, Bénédicte Wibaut, Marie-Hélène Depoortere, Pascal Vaast, Laurent
Charles Garabedian, Thameur Rakza, Elodie Drumez, Marion Poleszczuk, LouiseBenefits of Delayed Cord Clamping in Red Blood Cell Alloimmunization
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DOI: 10.1542/peds.2015-3236 originally published online February 18, 2016; 2016;137;Pediatrics
Storme and Véronique Houfflin-DebargeGhesquiere, Bénédicte Wibaut, Marie-Hélène Depoortere, Pascal Vaast, Laurent
Charles Garabedian, Thameur Rakza, Elodie Drumez, Marion Poleszczuk, LouiseBenefits of Delayed Cord Clamping in Red Blood Cell Alloimmunization
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