Effect of preeclampsia on umbilical cord blood hematopoietic

progenitor-stem cells
Daniel V. Surbek, MD,a Enrico Danzer,a Christian Steinmann, MD,a André Tichelli, MD,b
Aleksandra Wodnar-Filipowicz, PhD,c Sinuhe Hahn, PhD,a and Wolfgang Holzgreve, MS, MDa
Basel, Switzerland

OBJECTIVE: The aim of the present study was to determine the influence of preeclampsia on cord blood
hematopoietic progenitor-stem cells obtained at delivery because cord blood is increasingly used clinically
for stem cell retrieval as an alternative to bone marrow.
STUDY DESIGN: Umbilical cord blood was collected from patients fulfilling the criteria for preeclampsia and
from gestational age– and birth weight–matched control subjects at delivery (patient/control subjects ratio,
1:2). Cord blood volume and nucleated cell content were measured, and the number of hematopoietic pro-
genitor-stem cells was determined by means of fluorescence-activated cell sorting with the CD34+ epitope
and by means of colony assays with different hematopoietic growth factors. In addition, the expression of ad-
hesion molecules by CD34+ progenitor-stem cells was examined.
RESULTS: In pregnancies affected by preeclampsia, volume and nucleated cell and total CD34+ cell con-
tents in the collected cord blood were significantly smaller compared with those of control subjects. Further-
more, there was a trend toward a smaller relative number of CD34+ cells and colony-forming units per nucle-
ated cell in cord blood samples from preeclamptic patients. No difference in the expression of the
cell-adhesion molecules leukocyte function–associated antigen 1, very late activation antigen 4, and L-
selectin by CD34+ cells could be found.
CONCLUSION: This study shows that preeclampsia affects umbilical cord blood volume and nucleated cell
and progenitor-stem cell numbers obtained at birth. (Am J Obstet Gynecol 2001;185:725-9.)

Key words: Umbilical cord blood, hematopoietic stem cells, preeclampsia

Umbilical cord blood (also referred to as residual pla-
cental blood) is increasingly used as a source of
hematopoietic stem cells for related1 and unrelated2
transplantation. Cord blood stem-progenitor cells have
been shown to have increased proliferative capacity com-
pared with that of adult bone marrow.3 Furthermore, re-
cipients of stem cell transplants from cord blood are less
likely to have severe graft-versus-host disease.4 One major
disadvantage, however, is the limited amount of cells ob-
tainable after a full-term delivery, and many samples do
not contain enough cells for successful marrow reconsti-
tution in adults.5 This is of particular importance because
the outcome of hematopoietic stem cell transplantation
From the Department of Obstetrics and Gynecology,a and the Laboratory
of Hematologyb and the Department of Research,c Division of Experi-
mental Hematology, University of Basel.
Supported by a research grant from the Basel Cord Blood Project Foun-
dation.
Received for publication January 3, 2001; revised April 27, 2001; ac-
cepted May 18, 2001.
Reprint requests: Daniel V. Surbek, MD, Department of Obstetrics and
Gynecology, University Hospital, Schanzenstrasse 46, 4031 Basel,
Switzerland.
Copyright © 2001 by Mosby, Inc.
0002-9378/2001 $35.00 + 0 6/1/117343
doi:10.1067/mob.2001.117343
with cord blood has been shown to correlate with the
number of nucleated and hematopoietic progenitor-stem
cells transplanted in relation to the recipient’s weight.2
The yield of nucleated cells and hematopoietic progen-
itor-stem cells collected from cord blood is therefore im-
portant, especially if the cells are collected for transplan-
tation in a sibling affected by a genetic or malignant
disorder.
We and others have previously shown that gestational
and obstetric factors, including gestational age,6 length of
labor,7 stress during labor,8 mode of delivery,9 cord blood
collection technique,10, 11 and positioning of the newborn
after delivery,12 can have an influence on the amount of
cord blood cells obtained after delivery. However, little in-
formation about the effect of common disorders compli-
cating pregnancy is available. In particular, it is not known
whether preeclampsia affects cord blood hematopoietic
cells. Because previous studies have suggested that fetuses
from preeclamptic mothers show reduced hepatic
hematopoiesis,13 the amount of circulating progenitor-
stem cells in cord blood might be altered. The aim of our
study was therefore to determine whether there is a differ-
ence between number of cord blood hematopoietic cells
obtained from preeclamptic versus nonpreeclamptic pa-
tients. In addition to obtaining new knowledge about the

725
726 Surbek et al
pathophysiology of preeclampsia, we wanted to find out
for practical reasons whether cord blood from preeclamp-
tic women is suitable for stem cell retrieval.
Patients and methods
This prospective case-control study was approved by
the institutional review board of the University Hospital
of Basel. We consecutively included patients with pre-
eclampsia fulfilling the following criteria: (1) minimum
gestational age of 24 weeks, as confirmed by first-
trimester ultrasonography; (2) blood pressure above
140/90 mm Hg on 2 or more occasions and proteinuria
of at least 0.3 g/L; and (3) willingness to participate in
the study with written informed consent. The control
group consisted of gestational age– and estimated fetal
weight–matched pregnant women delivered of their in-
fants preterm or at term without signs of preeclampsia.
Matching for gestational age and birth weight was per-
formed to exclude bias from these factors, which have
been shown to affect cord blood hematopoietic cells.6, 14
For every preeclamptic patient, control subjects were
matched according to gestational age and birth weight at
a patient/control subject ratio of 1:2.
Cord blood collection. At delivery, cord blood was col-
lected from the umbilical vein with the placenta in situ
by using a closed collection system containing citrate-
phosphate-dextrose. Briefly, the cord was clamped and
dissected within 30 seconds after delivery of the newborn,
according to the routine management protocol of our ob-
stetric service. Modification of cord clamping during the
study was not allowed. Initially, an umbilical cord frag-
ment of 3 to 5 cm in length was obtained to assess arterial
and venous cord blood acid-base status. Thereafter, the
umbilical vein was punctured, and cord blood was col-
lected by means of passive drainage into a sterile, closed
blood-collection system containing citrate-phosphate-
dextrose. If collection of cord blood could not be per-
formed before placenta expulsion for any reason, it was
done after expulsion in the same fashion. In case of ce-
sarean section, the same procedure was performed, as de-
scribed elsewhere.11 The identical collection technique
was used for both the preeclamptic and control groups.
Cord blood analysis. The volume of collected cord
blood was determined by subtracting the volume of
citrate-phosphate-dextrose in the bag before collection
from the total measured volume in the bag. Nucleated
cell content per milliliter of cord blood was assessed with
a Technicon H*3 RTC (Bayer Technicon), and the total
amount of nucleated cells per cord blood sample was cal-
culated by multiplication with the volume contained in
the bag.
The fraction of CD34+ cells within the leukocyte popu-
lation was determined by means of dual-color flow cytom-
etry (fluorescence-activated cell sorting) with FACScan
(Becton-Dickinson). Briefly, red blood cell lysis was per-
September 2001
Am J Obstet Gynecol
formed with Ortho-mune lysing reagent (Ortho Pharma-
ceuticals). For staining of progenitor-stem cells, phyco-
erythrin cyanid–labeled anti-CD45 (Immunotech) and
phycoerythrin-labeled anti-CD34 (Becton-Dickinson)
were used, with CD34 being a surrogate marker for
hematopoietic stem cells.15 The gating strategy consisted
of a first gate (G1) of CD45+ intermediate-to-high for-
ward-scatter events (leukocyte gate) and a second gate
(G2) of CD34+ high-low side-scatter events (CD34+ gate).
The proportion of CD34+ cells among the leukocytes (nu-
cleated cells) was calculated as the proportion of G1
within G2; a minimum of 75,000 events were acquired
and analyzed with Cellquest 3.1f software (Becton-Dick-
inson). The total amount of CD34+ cells per cord blood
sample was calculated by multiplication of the relative
CD34+ cell count (percentage) with the total amount of
nucleated cells.
We also compared the profile of β2-integrin leukocyte
function–associated antigen (LFA-1; CD11a/CD18), the
β1-integrin very late activation antigen 4 (VLA-4;
CD49d/CD29), and L-selectin (CD62L) expression on
CD34+ cells. These adhesion molecules were chosen be-
cause of previous reports about their role in the migration
(mobilization and homing) of hematopoietic stem cells.16
Fluorescein isothiocyanate–labeled CD11a, CD49d, and
CD62L antibodies (all from Immunotech) were applied
for cell adhesion molecule staining. Three-color flow cy-
tometry (FACScan, Becton-Dickinson) was used for cell
analysis. The CD34hi population was gated versus low side
scatter. At least 1000 events were obtained within the
CD34 gate. The proportion of CD34+ cells coexpressing
the respective adhesion molecule was calculated.
A 2-week assay of colony-forming units (CFUs) was
used to assess the proliferative capacity of hematopoietic
progenitors in vitro. Mononuclear cells were isolated by
means of Ficoll density centrifugation, resuspended in Is-
cove’s modified Dulbecco’s medium, and allowed to ad-
here overnight. Nonadherent mononuclear cells were
plated into 1% methylcellulose culture medium contain-
ing fetal calf serum, bovine serum albumin, and transfer-
rin supplemented with either erythropoietin alone or in
combination with granulocyte colony-stimulating factor,
granulocyte monocyte colony-stimulating factor, inter-
leukin 3, and stem cell factor. After 14 days, the number
of CFUs per 105 plated mononuclear cells was counted.
Statistical analysis. The number of nucleated cells per
cord blood sample was chosen as the primary outcome
parameter because of the known relation to outcome
after transplantation.2 The sample size had a power of
80% to detect a clinically significant difference of 40% in
the cord blood nucleated cell number at a significance
level of .05, assuming a standard deviation of ± 4.5 × 108
nucleated cells, as observed in previous studies.11 Contin-
uous nonparametric data of preeclamptic and control
pregnancies were compared with the Mann-Whitney U
Volume 185, Number 3 Surbek et al 727
Am J Obstet Gynecol

Table I. Maternal characteristics and perinatal data

Preeclamptic group (n = 11) Control group (n = 22) P value*

Maternal age (y) 29.4 ± 1.8 31.7 ± 1.2 .358

Gestational age (wk) 37.3 ± 1.0 37.2 ± 0.7 .985
BP (systolic; mm Hg) 174 ± 5 120 ± 2 .001
BP (diastolic; mm Hg) 100 ± 3 73 ± 2 .001
Proteinuria (>0.3 g/L) 11 (100%) 3 (14%) .001
Vaginal delivery 7 (64%) 10 (46%) .465
Birth weight (g) 2910 ± 236 2939 ± 172 .864
Placental weight (g) 496 ± 32 507 ± 39 .571
Fetal sex male 7 (64%) 11 (50%) .712
Apgar score <8 at 5 min 0 0
Umbilical artery pH 7.25 ± 0.02 7.27 ± 0.01 .446
Umbilical vein pH 7.32 ± 0.02 7.35 ± 0.01 .116

Values are means ± SEM where indicated. BP, Maximum blood pressure.
*Mann-Whitney U test (continuous data) or Fisher exact test (categoric data) comparing preeclamptic group versus control group.

Table II. Cord blood data

Preeclamptic group (n = 11) Control group (n = 22) P value*

Volume (mL) 37 ± 6 67 ± 7 .018

Nucleated cells (×108) 4.6 ± 0.8 8.3 ± 1.0 .031
CD34+ cells (×105) 11.3 ± 2.8 25.0 ± 3.9 .023
CD34+ cells (%) 0.22 ± 0.02 0.35 ± 0.04 .229
CFUs (EPO)† 56 ± 9 64 ± 10 .834
CFUs (EPO/G-CSF/GM-CSF/IL-3/SCF)† 135 ± 15 148 ± 17 .849
CD11a+ cells (%)‡ 49.7 ± 4.7 52.8 ± 3.1 .564
CD49d+ cells (%)‡ 92.1 ± 2 92.8 ± 1.1 .741
CD62L+ cells (%)‡ 76.4 ± 5 77.5 ± 2.2 .869

Values are means ± SEM where indicated.

EPO, Erythropoietin; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte monocyte colony-stimulating factor; IL-3, in-
terleukin 3; SCF, stem cell factor.
*Mann-Whitney U test comparing preeclamptic versus control group.
†Numbers of CFUs in methylcellulose cultures with erythropoietin alone or in combination with granulocyte colony-stimulating factor,
granulocyte monocyte colony-stimulating factor, interleukin 3, and stem cell factor are given per 1 × 105 nonadherent mononuclear
cells.
‡Proportion of CD34+ cells coexpressing the adhesion molecules CD11a, CD49d or CD62L, respectively.

test, and the Fisher exact test was used for categoric vari-
ables. A 2-tailed P value of less than .05 was considered
significant. The SPSS for Windows software package was
used for calculations.
Results
The results of the comparison of maternal characteris-
tics and perinatal data between the preeclamptic and
control groups are summarized in Table I. Although the
difference in maximum systolic and diastolic blood pres-
sure and presence of proteinuria was pronounced (as ex-
pected), there was no difference regarding perinatal pa-
rameters, including gestational age, neonatal and
placental weight, and short-term neonatal outcome. No
statistically significant difference between the groups
could be found regarding intrapartum fetal distress (as
defined by nonreassuring fetal heart rate tracings) or ob-
structed labor as an indication for cesarean section. Intra-
venous β-mimetics were administered to 18% and 23% in
the preeclampsia and control groups, respectively (P =
not significant), and 27% and 23%, respectively, received
1 or 2 courses of betamethasone for induction of lung
maturation (P = not significant). In the preeclamptic
group 73% were given intravenous magnesium sulfate for
prevention of eclamptic seizures.
We found, however, a statistically significant and large
difference in cord blood volume and total nucleated cell
number, being almost twice as low in the preeclamptic
group compared with the control group (Table II).
There was also a lower relative number of CD34 + cells in
cord blood from preeclamptic patients (0.22% vs
0.35%), although this difference did not reach statistical
significance. Functional progenitor cell assessment
showed only a very limited and nonsignificant difference
in the number of CFUs among nucleated cells; samples
from preeclamptic patients produced less CFUs in
erythropoietin- and mixed growth factor–supplemented
cultures. Nevertheless, in conjunction with the smaller
number of nucleated cells, a significantly lower absolute
CD34+ cell count per cord blood sample was seen in the
728 Surbek et al
preeclamptic group. In contrast, no clear difference in
expression of the adhesion molecules LFA-1, VLA-4, and
L-selectin could be identified between the cord blood
from preeclamptic patients and that from control sub-
jects. The comparison between patients with mild-to-
moderate preeclampsia (n = 6) and those with severe pre-
eclampsia (n = 5) did not show any difference in cord
blood values.
Comment
In this study we found that cord blood volume and
nucleated cell and CD34+ cell counts were smaller in
pregnant patients affected by preeclampsia compared
with gestational age– and birth weight–matched con-
trol subjects. These differences are not due to lower
placental weight or intrapartum factors (eg, fetal dis-
tress or prolonged labor) because there was no signifi-
cant variation between the groups regarding these fac-
tors. Accordingly, the numbers of patients receiving
β-mimetics and betamethasone were similar, and mag-
nesium sulfate (which was used in most patients with
preeclampsia) is not known to have a significant influ-
ence on hematopoietic cells or fetoplacental blood vol-
ume.
Although other studies have examined the influence
of gestational and perinatal factors on umbilical cord
blood hematopoietic cells,7-9, 14 this is the first pub-
lished study addressing the question of effects of pre-
eclampsia on cord blood hematopoietic cells. Hiett et
al14 have previously studied cord blood obtained from
small-for-gestational-age neonates. They found a signif-
icantly smaller number of progenitors compared with
numbers found in gestational age–matched neonates
of appropriate weight. Although some fetuses from
mothers affected by pregnancy-induced hypertension
or preeclampsia were included in this series, this sub-
group was not identified separately from other growth-
restricted fetuses.
Recently, a histomorphometric study found a de-
creased number of erythroid precursors and early gran-
ulopoietic cells in the liver of fetuses affected by pre-
eclampsia.13 The authors of this report suggested that
these alterations in fetal hematopoiesis are a conse-
quence of preeclampsia itself rather than growth restric-
tion alone. Our data support these findings. The smaller
amount of hematopoietic cells in the fetal liver and in
fetal blood might be the result of an unspecific suppres-
sion of hematopoietic activity in the fetus. The exact
pathophysiologic mechanism leading to the reduced
number of hematopoietic progenitors in cord blood
from fetuses affected by preeclampsia, however, is un-
known. One possible explanation might be the influence
of cytokine and growth factor patterns in fetuses affected
by preeclampsia. The regulation of hematopoiesis in the
fetus, including the physiologic change of the predomi-
September 2001
Am J Obstet Gynecol
nant site of hematopoiesis from the fetal liver to the fetal
bone marrow toward the end of gestation, depends on
complex interactions between hematopoietic cells,
hematopoietic stroma (microenvironment), and circu-
lating cytokine-growth factors, leading to ontogenetically
predetermined patterns of self-renewal, proliferation,
apoptosis, lineage-specific differentiation, and migration
of hematopoietic progenitor cells and stem cells. 17, 18
Several studies have shown that the level of cytokines and
growth factors in fetal blood are altered in preeclamp-
sia.13, 19 Although the addition of granulocyte colony-
stimulating factor in escalating doses in vitro apparently
does not affect the short-term proliferative capacity of
progenitors,20 a long-term alteration of the pattern of
hematopoietic growth factors and cytokines in the fetus
induced by preeclampsia might have an influence on
hematopoietic activity in the progenitor cell population.
In this study we further determined whether the ex-
pression of LFA-1, VLA-4, and L-selectin on hematopoi-
etic progenitors differs in preeclampsia. These cell-adhe-
sion molecules are involved in molecular interactions
between hematopoietic and stromal cells, which are im-
portant determinants of the process of migration, mobi-
lization, and homing of hematopoietic progenitor-stem
cells.21 We and others22, 23 have described development
stage-specific differences of expression patterns in fetal
hematopoietic cells, suggesting that these patterns are
likely to be involved in the ontogenesis of the predomi-
nant site of hematopoiesis. In the present study we did
not find a difference in the expression of LFA-1, VLA-4,
and L-selectin in preeclampsia. From this finding, we
conclude that it does not seem likely that the lower num-
ber of hematopoietic cells in the fetal peripheral blood is
due to increased homing in the bone marrow niches me-
diated by increased adhesion molecule expression.
Regarding the question of whether cord blood from
preeclamptic patients can be used for stem cell re-
trieval, it must be realized that the difference in the
relative progenitor-stem cell content among nucleated
cells was rather limited and statistically nonsignificant
in our study. However, the difference in absolute num-
bers of CD34+ cells is clinically significant in conjunc-
tion with the decreased cord blood volume, leading to
a clearly lower yield of hematopoietic cells per cord
blood sample. Accordingly, the content of CFUs per
cord blood sample is also lower (data not shown). The
large SD of the relative content of these cells might be
the cause for the lack of statistical significance in our
limited sample size. This large variation in relative
hematopoietic cell content has to be taken into ac-
count if only the nucleated cell number is used to de-
termine whether a cord blood sample is appropriate
for transplantation.
From our findings, we conclude that patients with
preeclampsia should be excluded a priori from unre-
Volume 185, Number 3
Am J Obstet Gynecol
lated cord blood banking. In contrast, if targeted cord
blood collection and banking for stem cell transplanta-
tion in a family member is planned and preeclampsia
occurs, the collection of cord blood is still justified. This
is because despite the lower cord blood progenitor-stem
cell yield in preeclampsia, many patients might still be
adequate donors of cord blood for transplantation, es-
pecially if the recipient is small. However, on the basis of
our results, the use of cord blood from preeclamptic pa-
tients should be considered on a case-by-case basis. Most
importantly, modified cord blood collection techniques
aiming to increase cord blood yield, such as very early
cord clamping, should not be applied in preterm infants
born to mothers with preeclampsia because of the in-
creased risk for severe anemia of prematurity necessitat-
ing blood transfusion.24 Furthermore, because transpla-
cental cell traffic has been shown to be increased in
preeclampsia,25 a potentially increased contamination
of maternal cells in the cord blood graft is of some con-
cern and has to be taken into account.
In summary, we have shown that umbilical cord blood
collected after delivery contains fewer nucleated cells and
hematopoietic progenitor-stem cells if the pregnancy is
affected by preeclampsia.
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