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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PEDIATRICS Volume 137 , number 3 , March 2016

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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