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BASIC SCIENCE: OBSTETRICS

Vascularization in first-trimester chorionic villi

in complicated and uncomplicated pregnancies
Monique A. Huisman, MD; Bert Timmer, PhD; Janet Stegehuis, MD;
Bert Swart, MD; Jan G. Aarnoudse, PhD; JanJaap H. M. Erwich, PhD
OBJECTIVE: The purpose of this study was to investigate possible al-

tered chorionic vascularization patterns that are seen already in the first
trimester of pregnancies that are complicated by hypertensive disorders
or intrauterine growth restriction (IUGR) in the third trimester of
pregnancy.
STUDY DESIGN: After chorionic villous sampling, surplus of villi were

stored, and a selection was made of pregnancies that were complicated

further by hypertensive disorders (n 26), normotensive IUGR (n
13), and matched control subjects (n 60). Vascular parameters of
these villi were analyzed with a video-image-analysis system.
RESULTS: In pregnancies that are complicated by early-onset hyper-

tensive disorders and IUGR, the mean distance of the peripheral vessels

to the intervillous space and the total of the distances (central and peripheral) are significantly smaller, compared with control subjects
(9.3% and 13.8% for hypertensive disorders and 12.2% and 16.1% for
IUGR, respectively).
CONCLUSION: Differences in vascularization patterns in the placenta

already in the first trimester of pregnancies that are complicated later by

hypertensive disorders or IUGR confirm the hypothesis of early changes
by means of more vessels and more peripheral vessels that are located
in chorionic villi.
Key words: chorionic villi, intrauterine growth restriction,
preeclampsia, vascularization

Cite this article as: Huisman MA, Timmer B, Stegehuis J, et al. Vascularization in first-trimester chorionic villi in complicated and uncomplicated pregnancies.
Am J Obstet Gynecol 2010;202:88.e1-7.

fter delivery, placentas of pregnancies that were complicated by preeclampsia or intrauterine growth restriction (IUGR) show morphologically
different vascularization patterns in the
chorionic villi, compared with those pla-

From the Departments of Obstetrics and

Gynecology (Drs Huisman, Stegehuis, Swart,
Aarnoudse, and Erwich) and Pathology and
Laboratory Medicine (Dr Timmer),
University Medical Center Groningen, The
Netherlands.
Presented at the 52nd Annual Meeting of the
Society for Gynecologic Investigation, Los
Angeles, CA, March 23-26, 2005.
Received March 19, 2009; revised June 14,
2009; accepted Aug. 20, 3009.
Reprints: M.A. Huisman, MD, Department of
Obstetrics and Gynaecology, Deventer
Hospital, Nico Bolkesteinlaan 75,7416 SE
Deventer, The Netherlands.
M.A.Huisman@dz.nl.
Authorship and contribution to the article is
limited to the 6 authors indicated. There was
no outside funding or technical assistance with
the production of this article.
0002-9378/$36.00
2010 Mosby, Inc. All rights reserved.
doi: 10.1016/j.ajog.2009.08.036

88.e1

centas of uncomplicated pregnancies.1,2

The cause of the described differences is
not completely known, and differences
in early vascularization patterns between
early and late onset preeclampsia are not
well described. Kingdom and Kaufmann3 proposed a common model to
explore the origins of fetal hypoxia with
different vascularization patterns. In
their model, they distinguish preplacental, uteroplacental, and postplacental
(fetal) hypoxia, with each specific morphologic or physiologic antecedents. In
the case of uteroplacental hypoxia that is
associated with hypertension, failed extravillous cytotrophoblast invasion of
the maternal spiral arteries causes a restriction for the normally oxygenated
maternal blood to enter the intervillous
space. Branching angiogenesis increases,
which results in a greater amount of
highly vascularized villi and a dilation of
the villous capillaries, and causes an increased capillary volume fraction and an
increased fetal syncytial surface area for
diffusional exchange. In postplacental
hypoxia that is associated with IUGR,
angiogenesis is nonbranching, and few
slender and fibrotic chorionic villi are

American Journal of Obstetrics & Gynecology JANUARY 2010

found with reduced numbers of

capillaries.
In the current study, we investigated
whether the morphologically altered
vascularization patterns can be found already in first-trimester chorionic villi of
ongoing pregnancies that were complicated with early- or late-onset hypertensive disorders such as preeclampsia
and/or IUGR in the third trimester of
pregnancy, compared with the vascularization patterns of further uncomplicated pregnancies. In accordance to the
model of Kingdom and Kaufman,3 we
hypothesized to find more and larger
and perhaps more peripherally situated
vessels in pregnancies that were complicated by hypertensive disorders to allow
optimal maternal-fetal exchange of oxygen and nutrition between the intervillous maternal blood and the villi. Subsequently, concerning IUGR, fewer and
smaller vessels were expected to be found
in pregnancies that were complicated
with IUGR, because at term, these pregnancies seemed to lack the adaptive response that was seen in pregnancies that
were complicated with preeclampsia.
Villi were stained with a monoclonal an-

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FIGURE

Analysis of CD34-stained human chorionic villi

A, Random selection of structurally intact parts of villi; B, contours of immature intermediate villi were traced and drawn on screen (green); C centrally
located vascular elements (green) drawn on screen, followed by D, the peripherally located vessels; E, measurement of the distance from the luminal
borders of a vascular element to the intervillous space (arrow).
Huisman. Vascularization in first-trimester chorionic villi. Am J Obstet Gynecol 2010.

tibody against the CD34 antigen to visualize vascular elements and subsequently
were analyzed with a video-image analysis system.

P ATIENTS AND M ETHODS

Patients
Over the years, 2000 woman have undergone vaginal chorionic villous sampling between 10 and 12 weeks of gestation, mainly for maternal age or serum
screening that was related risk of aneuploidy. Gestational age was calculated
according to the last menstrual period
and subsequently confirmed by ultrasound evaluation (crown-rump length).
Tissue was obtained with a biopsy catheter (K-CMA-5000; Cook Medical Inc,
Bloomington, IN). Surplus material,
which was not needed for karyotyping,

was obtained, and decidua was mechanically separated from the villi. The villi
were placed in formaldehyde immediately and stored until further processing.
Villi were embedded in paraffin, subsequently cut into 4-m sections and
fixed on 3-aminopropyl-triethoxy-silane coated (A3648; Sigma Chemical
Company, St. Louis, MO) slides.
Follow-up evaluation of the pregnancies was available in 85% of cases and
consisted of a questionnaire that was returned by the patient after delivery; additional data were extracted from the
clinical notes. A selection was made of
pregnancies that were complicated by
hypertensive disorders (n 26), such as
preeclampsia and pregnancy-induced
hypertension, and pregnancies that were
complicated by normotensive IUGR

(n 13). Pregnancy-induced hypertension, preeclampsia, and HELLP (hemolysis, elevated liver enzymes, and low
platelet count) syndrome were defined
according to the International Society
for the Study of Hypertension in Pregnancy criteria4: pregnancy-induced hypertension was defined as blood pressure
140/90 mm Hg after 20 weeks of gestation on 2 occasions at least 6 hours apart;
preeclampsia was defined as an increase
in blood pressure to at least 140/90 mm
Hg after week 20 of gestation in a previously normotensive woman, combined
with proteinuria (protein excretion at
least 0.3 g per 24 hours, spot urine protein/creatinine ratio of 530 mg/mmol or
at least 2 protein by dipstick); HELLP
(hemolysis, elevated liver enzymes, and
low platelet count) syndrome was defined

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TABLE 1

Clinical data of study population

Hypertensive disorderb

Intrauterine growth restriction

Cases (n 26)

Control subjects
(n 37)

Cases (n 10)c

Control subjects
(n 18)

38 (3642)

39 (3543)

38 (3643)

37 (3640)

Chorionic villous sampling, d

76 (7183)

77 (7185)

76 (7280)

75 (6981)

Delivery, wk

39 (3242)

39 (3543)

38 (3643)

38 (3640)

Variablea
Maternal age, y

................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................

Birthweight, g

3090 (14004325)

3586 (25254620)

2555 (21102840)

3840 (32804590)

................................................................................................................................................................................................................................................................................................................................................................................
a

Data are given as mean (range); Consisted of 13 cases of pregnancy-induced hypertension, 10 cases of preeclampsia, and 3 cases of HELLP (hemolysis, elevated liver enzymes, and low platelet
count) syndrome, according to the criteria of the International Society for the Study of Hypertension in Pregnancy; c All intrauterine growth restriction cases were normotensive.

Huisman. Vascularization in first-trimester chorionic villi. Am J Obstet Gynecol 2010.

as hemolysis, lactic dehydrogenase 600

U/L, aspartate aminotransferase 70
U/L, alanine aminotransferase 90 U/L,
and platelet-count 100 g/L. For IUGR,
birthweight was corrected for gestational
age, and percentiles were computed.
IUGR was defined as a corrected birthweight below the 5th percentile, according to Kloosterman.5 All the included
cases in the IUGR group concerned normotensive pregnancies. For each case,
control subjects were selected and
matched for maternal age, parity, and
gestational age at time of sampling (n
60). Patients with concurrent morbidity
(eg, preexisting hypertension or diabetes
mellitus) who were smoking or receiving
medication were excluded. Fetal karyotyping showed no chromosomal abnormalities. Patients were informed that
surplus material could be used for research, according to the Code for
proper use of human tissue, version
2002, of the Federation of Dutch Medical
Scientific Societies and the Local Ethics
Committee of the University Medical

Center Groningen. Patients who were

included gave informed consent; after
the outcome of the pregnancy was
known, data were made anonymous.

Immunohistochemistry
After the slides were deparaffinized with
a series of xylene and alcohol and washed
in phosphate-buffered saline solution
(PBS; pH 7.4) 3 times for 5 minutes, the
nonspecific peroxidase activity was
blocked with 1% H2O2 (Merck, Darmstadt, Germany) in PBS for 30 minutes.
Antigen retrieval was performed by incubation in Tris-HCL (buffer) for 30
minutes by 94C in a microwave. Subsequently the slides were incubated with
the mouse monoclonal primary antibody against the CD34 antigen (Clone
QBEND10; Immunotech, Marseille,
France) for 1 hour.3 The CD34 antibody
was used at 1:100 dilution in PBS, in
which 1% bovine serum albumin and
1% normal human AB serum were included, both to minimize nonspecific reactivity. The second and third step of an-

tibody labeling was carried out with

peroxidase-conjugated rabbit anti-mouse
immunoglobulin (RAMpo; DAKO A/S,
Glostrup, Denmark) and peroxidase conjugated goat anti-rabbit immunoglobulin
(GARpo; DAKO), respectively, both 1:50 in
PBS/1% bovine serum albumin/1% AB serum for 30 minutes. All incubation steps
were followed by 3 washes in PBS for 5
minutes. Finally, the peroxidase reaction
was visualized with diaminobenzidine
(Sigma Chemical Company). Subsequently the slides were counterstained
with hematoxylin, dehydrated, and
mounted with mounting medium (International Medical Products, Zutphen, The
Netherlands).

Video Image Analysis

To quantify vascular development in the
chorionic villi, a video-image analysis system was used (Qwin 2.4; Leica, Cambridge, England). Microscope images were
recorded with a color video camera (DC
300 V2.0; Leica) that was mounted on a
light microscope (Axioskop 130 VA Type

TABLE 2

Data of pregnancies with early-onset hypertensive disorders

Case

Disorder

Neonatal weight, ga

Week of delivery

Pregnancy-induced hypertension

1940 (25-50)

34

HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome

1610 (5)

36

HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome

1400 (25)

32

Preeclampsia

1885 (10)

36

Preeclampsia

2110 (25)

35

................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................

HELLP, hemolysis, elevated liver enzymes, and low platelet count.

a

Percentile given in parentheses.

Huisman. Vascularization in first-trimester chorionic villi. Am J Obstet Gynecol 2010.

88.e3

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TABLE 3

Vascular parameters of the pregnancies complicated with intrauterine

growth restriction, compared with control subjects

Parameter

Intrauterine growth restriction

(n 10)

Control subjects (n 18)

Mean

Mean

SD

SD

P value

Vascular surface, %

.......................................................................................................................................................................................................................................................................................................................................................................

Central

1.77

0.86

1.94

1.13

NS

Peripheral

1.61

0.49

1.60

0.64

NS

Total

3.38

1.11

3.53

1.38

NS

.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
2

Vessel no., mm

.......................................................................................................................................................................................................................................................................................................................................................................

Central

40.28

17.64

47.21

17.15

NS

Peripheral

137.87

37.78

124.03

28.81

NS

Total

178.15

42.16

171.24

39.23

NS

.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
2

Perimeter, mm

.......................................................................................................................................................................................................................................................................................................................................................................

Central

3697

1152

4200

1365

NS

Peripheral

6863

1587

6776

1931

NS

10831

2328

10,976

2749

NS

.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................

Total

................................................................................................................................................................................................................................................................................................................................................................................

Distance luminal border

to intervillous space, m

.......................................................................................................................................................................................................................................................................................................................................................................

Central

58.09

11.53

60.49

10.35

NS

Peripheral

24.91

3.22

28.38

3.04

.012

Total

37.27

9.11

44.43

6.33

.045

.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................

NS, not significant.

Huisman. Vascularization in first-trimester chorionic villi. Am J Obstet Gynecol 2010.

B; Carl Zeiss, Goettingen, Germany) with a

20 objective. For each case, 5-15 images
with (parts of) structurally intact immature intermediate villi were recorded randomly and evaluated. Random fields were
chosen by means of knights move selection. Once recorded, no adjustments were
done to provide structurally intact villi to
prevent selection bias.
First, from the recorded chorionic villi
(Figure, A), the contours were traced
manually on the computer monitor and
drawn on screen with a mouse-controlled cursor, after which the villous
area could be measured by the analysis
system (Figure, B). Subsequently, every
single central vascular element, which
was made visible by the CD34-stained
endothelial cells, was traced manually
and drawn on screen, and the vascular
area was measured (Figure, C). Any
brown-stained endothelial cell or endothelial cell cluster (hemangioblastic
cord), with or without a vessel lumen,
that was clearly separate from adjacent

vessels was considered to be a single

countable vessel. The same was done for
every single peripheral vascular element
(Figure, D). Division of the vascular elements into central or peripheral was
done by the judgment of the investigator
regarding the position of the vascular element to the syncytio-/cytotrophoblast.
The total vascular area, the total vascular
perimeter, and the number of vascular
elements per square millimeter were
measured for both central and peripheral vascular elements. Furthermore, the
total villous area and perimeter per vascular element were measured. Finally,
the shortest distance from the luminal
border of each central and peripheral
vascular element to the intervillous space
was drawn on screen and subsequently
measured (Figure, E). The investigator
was blinded for pregnancy outcome.

Statistics
Statistical comparisons were performed
with the Student t test for independent

samples to compare groups with their

matched control subjects. Kruskal-Wallis test was used where appropriate. A
2-sided probability value of .05 was
considered to be statistically significant.
Statistical analysis was performed with
SPSS software (version 11.0 for Windows; Microsoft Corporation, Redmond, WA). Data are presented as mean
SD, unless otherwise stated.

R ESULTS
Clinical data
From the selected 99 samples, 26 cases of
pregnancies that had been complicated
by hypertensive disorders and 37 control
subjects could be included. In the IUGR
group, 10 cases with 18 control subjects
were included. Nine samples were not
representative because of very small
amounts or damaged tissue. The clinical
data from the cases and control subjects
are listed in Table 1. There were no significant differences between the cases

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TABLE 4

Mean vascular parameters of the 5 pregnancies that were complicated with early-onset
hypertensive disorders (n 5), compared with the control subjects (n 37)
Hypertensive disorder
Parameter

Mean

Control subjects
SD

Mean

SD

P value

Vascular surface, %

.......................................................................................................................................................................................................................................................................................................................................................................

Central

2.01

0.85

1.99

1.02

NS

Peripheral

1.52

0.36

1.38

0.55

NS

Total

3.54

0.87

3.38

1.31

NS

.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
2

Vessel no., mm

.......................................................................................................................................................................................................................................................................................................................................................................

Central

51.26

11.49

50.08

17.81

NS

Peripheral

134.70

45.73

112.88

27.67

NS

Total

185.96

50.13

162.96

36.27

NS

.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
2

Perimeter, mm

.......................................................................................................................................................................................................................................................................................................................................................................

Central

5061.09

1388.45

4248.25

1548.20

NS

Peripheral

6715.56

1973.22

5891.04

1836.81

NS

11776.65

1659.54

10,139.30

2901.54

NS

.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................

Total

................................................................................................................................................................................................................................................................................................................................................................................

Distance luminal border

to intervillous space, m

.......................................................................................................................................................................................................................................................................................................................................................................

Central

57.38

11.08

60.41

11.95

Peripheral

24.91

1.52

27.46

3.17

.014

NS

Total

37.89

4.04

43.93

6.81

.023

.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................

NS, not significant.

Huisman. Vascularization in first-trimester chorionic villi. Am J Obstet Gynecol 2010.

and control subjects regarding maternal

age, gestational age at chorion villous
sampling, or week of delivery, except for
birthweight (P .005 for both hypertensive and IUGR cases compared with their
control subjects). In the hypertensive
group, there were 5 cases with early onset
of complications at 36 weeks of gestation. Specifications of these pregnancies
are listed in Table 2.

Villous vascular measurements.

In the IUGR group, the distance of the
peripheral vessels to the intervillous
space was significantly smaller, compared with the control subjects (24.91 vs
28.38 m; P .02). The same was found
for the sum of the distances of the central and peripheral vessels to the intervillous space (37.27 vs 44.43 m; P .05;
Table 3).
In the early hypertensive group, we
also observed a significantly smaller distance of the peripheral vessels to the intervillous space (24.91 vs 27.46 m; P
.02) and that the sum of the distances
88.e5

(central and peripheral) was also

smaller, compared with the control subjects (37.89 vs 43.93 m; P .03). Details of these measurements are listed in
Table 4.
Regarding the late-onset hypertensive
group, no significant differences were
found for any of the vascular variables
that were measured, compared with the
control group (Table 5).

C OMMENT
The results of our study show that the
altered vascularization patterns, which
were seen in chorionic villi at term from
pregnancies that were complicated with
either hypertensive disorders or IUGR of
the fetus, can be seen already in the first
trimester of pregnancy. Almost all studies on human chorionic villous vasculature of complicated pregnancies are performed on third-trimester placental
tissue. A study from Roberts et al6 that
compared trisomic and chromosomally
normal pregnancies demonstrated that

American Journal of Obstetrics & Gynecology JANUARY 2010

detailed histomorphologic analysis is

possible with the use of chorionic villi
from ongoing pregnancies and has allowed normal values for some morphometric parameters. These 2-dimensional
parameters may not give the more extensive morphometric data that stereologic
(3-dimensional) parameters would, as
described by Mayhew et al1 in the third
trimester, but they do provide the possibility to compare data from first-trimester villi from normal and later complicated pregnancies.
Exploring the results of our study, we
found significantly more peripherally located vessels in the pregnancies with
early-onset hypertensive disorders and a
trend for an increase in the number of
vascular elements per square millimeter,
especially peripheral vessels. This is in
accordance with our hypothesis and the
uteroplacental hypoxia model of
Kingdom and Kaufmann.3 In this
model, the maternal blood is normally
oxygenated but is partly restricted to en-

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TABLE 5

Vascular parameters of pregnancies complicated with hypertensive

disorders (n 21) compared with controls (n 37)
Hypertensive disorders
Parameter

Mean

Control subjects
SD

Mean

SD

P value

Vascular surface, %

.......................................................................................................................................................................................................................................................................................................................................................................

Central

2.11

1.48

1.99

1.03

NS

Peripheral

1.46

0.76

1.38

0.56

NS

Total

3.21

0.90

3.38

1.32

NS

.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
2

Vessel no., mm

.......................................................................................................................................................................................................................................................................................................................................................................

Central

45.22

12.84

50.08

17.82

NS

Peripheral

131.63

67.31

112.88

27.67

NS

Total

176.85

66.34

162.96

36.27

NS

.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
2

Perimeter, mm

.......................................................................................................................................................................................................................................................................................................................................................................

Central

4031

Peripheral

6547

10,579

723.81

4248

1548

NS

3242

5891

1837

NS

3367

10,139

2902

NS

.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................

Total

................................................................................................................................................................................................................................................................................................................................................................................

Distance luminal border

to intervillous space, m

.......................................................................................................................................................................................................................................................................................................................................................................

Central

58.25

11.42

60.41

11.96

NS

Peripheral

25.75

3.17

27.46

3.18

NS

Total

39.99

9.69

43.93

6.82

NS

.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................

NS, not significant.

Hypertensive disorders: pregnancy-induced hypertension (n 12), preeclampsia (n 8) and hemolysis, elevated liver enzymes, and low platelet count.
Huisman. Vascularization in first-trimester chorionic villi. Am J Obstet Gynecol 2010.

ter the intervillous space because of

failed remodeling of spiral arteries by extravillous cytotrophoblast. As a result,
the milieu in the placental parenchyma is
hypoxic, and villous branching angiogenesis is increased.3,7 Vis et al8 observed
a tendency for larger birthweights in relation to larger and more vascularized
villi of first-trimester chorionic villous
samples; Kadyrov et al9 found altered
vascularization patterns in the first trimester of pregnancy of anemic women.
In the 5 cases of early hypertensive disorders, there was a tendency toward
lower birthweights for gestational age,
with 2 of 5 pregnancies resulting in
birthweights at 10th percentile. The
pregnancies with late-onset hypertensive
disorders showed a normal (p10 to p90)
birthweight in all but 1 case. In 1 case, the
birthweight percentile was below p5
(percentiles according to Kloosterman5). Egbor et al10,11 showed that
isolated early-onset preeclampsia was
associated with abnormal placental mor-

phologic condition, but placentas from

late-onset preeclampsia were morphologically similar to placentas from gestational-agematched control subjects.
This is in accordance with our results, in
which we also found a significant difference in vascularization patterns in the
early-onset group, but not in the late-onset group.
Concerning vascularization, on the
contrary, fewer and smaller vessels are
expected to be found in pregnancies that
are complicated with IUGR. These pregnancies seem to lack the adaptive response that is seen in pregnancies that
are complicated with preeclampsia.
Third-trimester studies revealed chorionic villi with impaired vascularization
patterns in pregnancies that were complicated with IUGR.12,13
In the cases of IUGR and the models
of postplacental hypoxia of Kingdom
and Kaufmann,3,7 our results not only
show some kind of adaptive response
but also seem to show a decrease in

centrally located vessels. In the model

of Kingdom and Kaufmann, postplacental hypoxia seems to be associated
with early onset IUGR with absent end
diastolic flow velocity in the umbilical
arteries. Normally, oxygenated blood
enters the intervillous space, but a failure of the fetoplacental circulation to
extract oxygen from the intervillous
space places the fetus at risk for hypoxia, and the relatively high oxygen
levels in the intervillous space will now
stimulate nonbranching angiogenesis,
with a reduced number of elongated
villi with few unbranched and uncoiled
capillaries.3,8,12,14 We found more and
more peripherally situated vessels not
only in IUGR but also in hypertensive
disorders. In the IUGR group, however, the adaptive response seems to be
ineffective, considering the lower
birthweight, which is contrary to the
cases with hypertensive disorders in
which the neonatal birthweight is less
compromised.

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Subsequently, Mayhew et al1,13,15

found no morphologic differences between preeclampsia and control cases
but do describe an impoverished villous
development in the IUGR group. In an
earlier study, they concluded that it was
possible that branching angiogenesis occurred, although overall growth of capillaries and villi was impaired. Ness and
Sibai16 and Sibai et al17 stated that IUGR
and preeclampsia are pregnancy-specific
disorders that have in common abnormal placental implantation. They propose a shared complex placental pathophysiologic condition, but different
interaction with the metabolic syndrome. However, both IUGR and preeclampsia seem to arise from a maternal
predisposition to endothelial dysfunction. Shibata et al18 describe a placental
system of amino acid transport, which is
reduced in pregnancies with small-forgestational-age infants but not in preeclampsia with small-for-gestationalage infants. They suggest that growth
reduction in the 2 settings may be substantially different and that several of the
metabolic changes of preeclampsia (like
insulin resistance19,20) are consistent
with an adaptive change in preeclampsia
to increase nutrient availability that is
not present in IUGR. Our findings are in
line with the early onset of complications
in human pregnancy and may widen the
window for therapeutic interventions
that are already in early pregnancy,
thereby reducing maternal and fetal
morbidity.
f

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