Hypertension in Pregnancy

ISSN: 1064-1955 (Print) 1525-6065 (Online) Journal homepage: http://www.tandfonline.com/loi/ihip20

Preeclampsia with and without intrauterine

growth restriction–Two pathogenetically different
entities?

Jelena Milosevic-Stevanovic, Miljan Krstic, Dragana Radovic-Janosevic, Milan

Stefanovic, Vladimir Antic & Ivana Djordjevic

To cite this article: Jelena Milosevic-Stevanovic, Miljan Krstic, Dragana Radovic-Janosevic,

Milan Stefanovic, Vladimir Antic & Ivana Djordjevic (2016): Preeclampsia with and without
intrauterine growth restriction–Two pathogenetically different entities?, Hypertension in
Pregnancy, DOI: 10.1080/10641955.2016.1212872

To link to this article: http://dx.doi.org/10.1080/10641955.2016.1212872

Published online: 13 Sep 2016.

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HYPERTENSION IN PREGNANCY
http://dx.doi.org/10.1080/10641955.2016.1212872

Preeclampsia with and without intrauterine growth

restriction–Two pathogenetically different entities?
Jelena Milosevic-Stevanovica,c, Miljan Krsticb,d, Dragana Radovic-Janosevica,c,
Milan Stefanovica,c, Vladimir Anticc, and Ivana Djordjevicb
a
Department of Gynecology and Obstetrics, Faculty of Medicine, University of Nis, Nis, Serbia; bDepartment of
Pathology, Faculty of Medicine, University of Nis, Nis, Serbia; cClinic of Gynecology and Obstetrics, Clinical
Center Nis, Nis, Serbia; dCenter for Pathology, Clinical Center Nis, Nis, Serbia

ABSTRACT ARTICLE HISTORY

Objective: The objective of this study is to determine the differences in Received 12 November 2015
histopathological features of basal decidua and placenta in cases of Revised 13 April 2016
preeclampsia with or without fetal intrauterine growth restriction Accepted 9 July 2016
(IUGR). Methods: A prospective case–control study included a study KEYWORDS
group consisting of 30 pregnant women with preeclampsia completed Decidua; intrauterine growth
by cesarean section (CS), in 19 of whom preeclampsia was associated restriction; placenta;
with IUGR, and in 11 it was not. The control group consisted of 20 preeclampsia; throphoblast
healthy pregnant women delivered by elective CS. Placentas and sam-
ples of placental bed obtained during CS were histopathologically (HP)
analyzed after hematoxylin–eosin staining and immunohistochemical
labeling of Cytokeratin 7 (CK7) trophoblastic cells in decidua. Results:
Regarding the HP changes in the spiral arteries in preeclampsia, the
most frequent features were inadequate transformation of spiral arteries
with poor trophoblastic invasion (70.0%) and fibrinoid necrosis of the
media (66.7%), and rarely acute atherosis (33.3%) and thrombosis
(30.0%). Villous hypermaturity was more frequently found in placentas
of patients with preeclampsia with IUGR (p < 0.05), while there were no
differences between subgroups of preeclampsia with and without IUGR
regarding some of HP alterations of placental bed. Conclusion:
Alterations of the placental bed in terms of decidual vasculopathy are
more the characteristics of the preeclampsia itself than IUGR, while
changes in placental villi primarily follow the presence of IUGR, which
could indicate that preeclampsia with and without IUGR are two patho-
genetically different entities.

Introduction
Preeclampsia is a serious condition, unique for human pregnancies, characterized by general-
ized maternal systemic inflammatory response associated with generalized dysfunction of
endothelial cells. It is a pregnancy-specific, complex disease in which numbers of genetic,
immunological, and environmental factors interact. The dominant scientific state today is that
the preeclampsia has its cause in abnormal vascular development of the placenta, which then
leads to systemic maternal endothelial effects and clinical manifestations of the disease (1,2).

CONTACT Jelena Milosevic-Stevanovic, MD, PhD jelamilostev@gmail.com Department of Gynecology and

Obstetrics, Faculty of Medicine, University of Nis, Blvd. Dr Zorana Djindjica 81, 18000 Nis, Serbia; Clinic of Gynecology and
Obstetrics, Clinical Center Nis, Blvd. Dr Zorana Djindjica 48, 18000 Nis, Serbia.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/ihip
© 2016 Taylor & Francis
2 J. MILOSEVIC-STEVANOVIC ET AL.

The absence of spiral artery remodeling leads to pathological changes in the placenta
during the process that is yet not fully understood (1). Preeclampsia is characterized by the
abnormally shallow extravillous trophoblastic (EVT) invasion and spiral artery remodeling
that is therefore restrictive in their proximal part. After the incomplete modification of the
spiral arteries by EVT they keep the ability to contract in their myometrial part. Phases of
contraction followed by relaxation lead to cycles of hypoxia–reoxygenation within pla-
centa (3,4). Burton and colleagues underline that the quality of placental perfusion could
be more important factor in the pathogenesis of preeclampsia, than the absolute blood
flow quantity (5,6). It is aberrant intervillous hemodynamics, not oxygenation per se,
initiates excessive syncytiotrophoblastic decline.
Preeclampsia is a heterogeneous disorder that occurs in at least two subsets, one with
normal placental function and another involving placental dysfunction and intrauterine
growth restriction (IUGR) (7). In the majority of late-onset preeclampsia (>34 weeks), the
newborn has a normal birth weight (8). The objective of our study is to determine the
differences in pathohistological features of basal decidua and placenta in cases of pre-
eclampsia with or without IUGR.

Methods
A prospective case–control study was conducted at the Clinic of Gynecology and
Obstetrics and at the Center for Pathology of Clinical Center in Nis. The study group
consisted of 30 pregnant women whose pregnancies were complicated by preeclampsia,
terminated by cesarean section, singletons, with no fetal anomalies and preexisting clinical
disorders, as well as without complicating actual pregnancy by chorioamnionitis. Cesarean
section was performed due to fetal distress or was planned due to other obstetric indica-
tions. The criteria for diagnosis of preeclampsia were new-onset arterial hypertension, or
diastolic pressures of ≥90 mmHg and systolic pressures of ≥140 mmHg, measured on two
separate occasions within 24 h, more than 6 h apart and proteinuria of ≥300 mg of protein
in 24 h urine samples which were developed after the 20th week of pregnancy in
previously normotensive women (9). In the analysis of clinical parameters, the highest
recorded values of arterial blood pressure were used. The criterion for the diagnosis of
severe preeclampsia was the presence of one of the following criteria: systolic blood
pressure ≥160 mmHg or diastolic ≥110 mmHg, proteinuria ≥2 g/24 h, increased serum
creatinine, persistent headache or cerebro-visual disorders, persistent epigastric pain,
platelet count <100,000/mm3, and/or findings of microangiopathic hemolytic anemia
(with increased lactate dehydrogenase) (10). The study group was divided into two
subgroups based on the presence or absence of IUGR of the fetus (19 cases of preeclamp-
sia associated with IUGR and 11 without) and the neonatal birth weight that was below
the tenth percentile for a given gestational age was taken as a criterion for setting the
diagnosis of IUGR. The control group consisted of 20 healthy pregnant women with
singleton pregnancies, with no fetal anomalies, delivered by elective cesarean section due
to obstetric indications that cannot be linked to the etiology of tested disorders (previous
cesarean section, breech presentation, and ophthalmological indication). The research has
been approved by Ethical Committee of Medical Faculty University of Nis and with the
informed consent of involved participants.
 HYPERTENSION IN PREGNANCY 3

Immediately after birth placentas were transported to the center for pathology, and then
the macroscopic examination was conducted followed by sampling of standard samples for
making paraffin specimens after routine fixation. The slides were stained by standard
hematoxylin–eosin (HE) staining followed by the analysis of histopathological (HP) char-
acteristics of the placental villi of the study and control group. Villous hypermaturity is
presented by the modification of terminal villi in the sense that they are elongated, with
smaller diameter, they are less vascularized to avascular, with enlarged nuclei in syncytio-
trophoblast, with increased stromal deposits of collagen and with increased number of
syncitial nodules as well. We used visually descriptive method to estimate predominant
finding as a basis for qualification of findings: present or absent villous hypermaturity.
Decidual tissue was obtained during cesarean section from the placental bed of uterus
by using large curette after the placenta was born. Placental bed is located below the
placenta and includes basal decidua and myometrial layer underneath which contains
uterine spiral arteries. After a routine fixation, processing, and molding, 4 μm thick
sections of decidua tissue were stained with HE method and quality control of the sampled
tissues was performed first, and only the samples containing EVT were selected and
included in further analysis. We analyzed the HP characteristics of decidua in the study
and in the control group as well, which was used as a basis for qualification of HE stained
samples:

– Physiological HP findings (when there were recorded normal, pregnancy-related,

morphological changes – transformation of spiral arteries (the vessel wall lacks leio-
muscular cells, and there is fibrinoid deposition));
– Pathological HP findings (when there were at least two of the following HP criteria:
inadequate transformation of spiral arteries with poor trophoblastic invasion; acute
atherosis, thrombosis, or obliteration of the lumen of spiral arteries; and fibrinoid
necrosis of the media of spiral arteries) (11).

Following the selection of appropriate sections, immunohistochemical analysis was

conducted using EnVision + System – HRP method. We used a monoclonal antibody
manufactured by Dako – Agilent Technologies (Glostrup, Denmark) – Monoclonal Mouse
Anti-Human Cytokeratin 7 (CK7) Clone OV-TL 12/30 antibody, a trophoblastic cell
marker. The trophoblastic cells labeled by anti-CK7 antibody were determined by their
presence within the decidual arteries as a visually estimated predominant finding:

– The trophoblastic cells are present in less than a half of the circumference of the
vessel or absent;
– The trophoblastic cells are present in more than a half of the circumference of the
decidual arteries.

The investigators that performed the pathohistologic analysis were not aware of the
specimens’ group (study/control).
The results are systematized and grouped in the database. Statistical analysis was
performed by SPSS 15.0 program. Continuous variables are presented as mean values,
standard deviations, and median, while the qualitative variables are presented by their
frequency and percentage. Determination of the normality of distribution of continuous
4 J. MILOSEVIC-STEVANOVIC ET AL.

variables was performed by Shapiro–Wilk test. If the distribution of continuous data was
normal, comparison of arithmetical mean values of two independent samples was per-
formed by Student’s t-test for independent samples, and if not Mann–Whitney U-test was
used. Comparison of absolute frequencies of categorical variables was performed by χ2 test
and its variants according to the size of the samples.

Results
Table 1 shows the clinical characteristics of pregnancies complicated by preeclampsia
compared with those associated with IUGR. The values of systolic and diastolic blood
pressure were higher in the group of preeclampsia with IUGR, and the number of patients
with values of blood pressure which categorize them in the severe preeclampsia is also
higher. However, there is no statistically significant difference. In this group, there was a
significantly lower gestational age at the time of delivery, higher proteinuria, lower birth
weight of neonates, and lower Apgar score.
Preeclampsia was associated with statistically significant lower weight of the placenta (p
< 0.001) compared with the control group (Table 2). The marginal and velamentous
insertions were present only in the group with preeclampsia. Villous hypermaturity
(Figure 1) and pathological HP findings of placental bed are statistically far more common
in patients with preeclampsia than in the control group (p < 0.001).

Table 1. The clinical characteristics of pregnancies complicated by preeclampsia with and without
intrauterine growth restriction (IUGR).
Clinical parameters Preeclampsia with IUGRa (n = 19) Preeclampsia without IUGRa (n = 11)
Age (years) 30.26 ± 6.14 30.00 33.09 ± 5.34 34.00
Parity 1.42 ± 0.61 1.00 1.36 ± 0.67 1.00
Gestational age (weeks) 35.47 ± 2.41 36.00 38.64 ± 1.50** 39.00
Systolic blood pressure 169.47 ± 19.21 160.00 160.00 ± 14.14 160.00
Diastolic blood pressure 108.53 ± 10.50 110.00 104.55 ± 9.86 105.00
Incidence of severe preeclampsia 15 (78.95%) 7 (63.64%)
Proteinuria (g/24 h) 3.16 ± 4.22* 0.50 0.45 ± 0.19 0.36
Birth weight (g) 1848.95 ± 447.80 1800.00 3281.82 ± 546.93** 3400.00
APGAR score 1 min 7.16 ± 1.64 8.00 8.18 ± 1.25* 9.00
APGAR score 5 min 7.89 ± 0.99 8.00 8.45 ± 0.93 9.00
a
Data are presented as mean values ± standard deviation, median, or as incidences and percentages.
*p < 0.05; **p < 0.001.

Table 2. The characteristics of placenta, umbilical cord, and histopathological (HP) findings in the group
with preeclampsia and control group.
Placental and umbilical parameters Preeclampsiaa (n = 30) Control groupa (n = 20)
Placental weight (g) 437.67 ± 118.34 405.00 585.50 ± 82.11* 580.00
Placental thickness (cm) 3.03 ± 0.83 3.00 3.44 ± 0.78 3.50
Insertion site of the umbilical cord
Central 13 (43.33%) 14 (70.00%)
Paracentral 12 (40.00%) 6 (30.00%)
Marginal 4 (13.33%) 0 (0.00%)
Velamentous 1 (3.33%) 0 (0.00%)
Villous hypermaturity 19 (63.33%)* 1 (5.00%)
Pathological HP findings of placental bed 19 (63.33%)* 1 (5.00%)
a
Data are presented as mean values ± standard deviation, median, or as incidences and percentages.
*p < 0.001.
 HYPERTENSION IN PREGNANCY 5

Figure 1. (A, B) Villous hypermaturity – villi are less vascularized to avascular with increased number of
syncitial nodules and with intervillous fibrin deposition – preeclampsia with intrauterine growth
restriction, 36 gestational weeks placenta (hematoxylin–eosin; A: 100×; B: 200×); (C, D) Normal
placental villi, physiological pregnancy (control group), 37 gestational weeks placenta (hematoxylin–
eosin; C: 100×; D: 200×).

There was a significantly lower placental weight (p < 0.001) and the thickness of
the placenta (p < 0.01) in pregnancies with preeclampsia associated with IUGR
compared with preeclampsia without IUGR. Villous hypermaturity is statistically
far more common in the study subgroup with IUGR in relation to preeclampsia
without IUGR (p < 0.05), while there was no difference in the presence of placental
bed HP features (Table 3).
After immunohistochemical visualization, it was found that the trophoblastic cells’
presence within the decidual blood vessels was significantly different between the
control group and the group with preeclampsia (p < 0.001) (Table 4). Throphoblastic
cells were present in less than a half of the circumference of the vessel (poor
trophoblastic invasion) in 76.7% of cases of the study group (Figure 2). According
to HE analysis, following features were significantly different in the study group
compared with the control: inadequate transformation of spiral arteries (p < 0.001),
acute atherosis of spiral arteries (Figure 3) and their thrombosis (p < 0.01), and
fibrinoid necrosis of the media of the spiral arteries (p < 0.05). There was no
significant difference in HP characteristics of decidual arterial vessels in preeclampsia
regarding the presence of IUGR.
6 J. MILOSEVIC-STEVANOVIC ET AL.

Table 3. The characteristics of placenta, umbilical cord, and histopathological (HP) findings in the group
with preeclampsia regarding the presence of intrauterine growth restriction (IUGR).
Placental and umbilical parameters Preeclampsia with IUGRa (n = 19) Preeclampsia without IUGRa (n = 11)
Placental weight (g) 370.53 ± 69.80 370.00 553.64 ± 92.12** 540.00
Placental thickness (cm) 2.70 ± 0.77 2.50 3.61 ± 0.61* 3.50
Insertion site of the umbilical cord
Central 8 (42.11%) 5 (45.45%)
Paracentral 7 (36.84%) 5 (45.45%)
Marginal 3 (15.79%) 1 (9.09%)
Velamentous 1 (5.26%) 0 (0.00%)
Villous hypermaturity 17 (89.47%)** 2 (18.18%)
Pathological HP findings of placental bed 12 (63.16%) 7 (63.64%)
a
Data are presented as mean values ± standard deviation, median, or as incidences and percentages.
*p < 0.01; **p < 0.001.

Table 4. The characteristics of decidual spiral arteries in the group with preeclampsia, control group,
and within the subgroups of preeclampsia with or without intrauterine growth restriction (IUGR).
Characteristics of decidual spiral Preeclampsiaa Control groupa Preeclampsia with Preeclampsia without
arteries (n = 30) (n = 20) IUGRa (n = 19) IUGRa (n = 11)
Presence of trophoblastic cells (CK7)
More than a half of the 7 (23.33%) 17 (85.00%)*** 5 (26.32%) 2 (18.18%)
circumference of the arteries
Less than a half of the 23 (76.67%)*** 3 (15.00%) 14 (73.68%) 9 (81.82%)
circumference of the arteries
Inadequate transformation of 21 (70.00%)*** 1 (5.00%) 14 (73.68%) 7 (63.64%)
spiral arteries (HE)
Acute atherosis 10 (33.33%)** 0 (0.00%) 7 (36.84%) 3 (27.27%)
Thrombosis 9 (30.00%)** 0 (0.00%) 5 (26.32%) 4 (36.36%)
Fibrinoid necrosis 20 (66.67%)* 7 (35.00%) 13 (68.42%) 7 (63.64%)
a
Data are presented as incidences and percentages.
CK7, Cytokeratin 7. HE, hematoxylin–eosin.
*p < 0.05; **p < 0.01; ***p < 0.001.

Figure 2. Transformation of spiral arteries and degree of trophoblastic invasion. (A) Transformed spiral
artery with trophoblastic cells in the wall of the artery (CK7, 400×). (B) Inadequate transformed spiral
artery with poor trophoblastic invasion – trophoblastic cells are present only in the decidual stroma
(CK7, 400×).
 HYPERTENSION IN PREGNANCY 7

Figure 3. Decidual vasculopathy: (A) acute atherosis – a great number of foam cells (arrow) (hematox-
ylin–eosin; 200×); (B) acute atherosis (hematoxylin–eosin; 400×).

Discussion
In our study, the incidence of IUGR in preeclampsia was 63.3%, which is much higher
than the incidence of that reported in the literature and is about 1/4–1/3 of cases of
preeclampsia (12,13) which may be due to the composition of our study group in which
73% patients dominated with severe preeclampsia, which is often associated with fetal
growth restriction, as well as presence of slighter criteria for the diagnosis of IUGR. The
association of IUGR and preeclampsia is well known (14,15). As there are cases in
preeclampsia which are associated with IUGR and cases with eutrophic fetal growth,
this suggests existence of at least two pathogenetical modalities concerning the presence
of placental dysfunction (7,16–18).
We are aware of the existing difference in gestational age between the examined groups, but
since the control group consisted of healthy women with uncomplicated pregnancies, without
premature rupture of membranes and chorioamnionitis, delivered by caesarean section which
was mostly indicated by previous cesarean section, hence the term delivery. Also, preeclampsia
without IUGR is mainly a late-onset preeclampsia with mild clinical manifestations resulting
in delivery at term and often a vaginal delivery because the fetoplacental and fetal circulations
are normal and fetal growth is eutrophic. Decidual tissue samples were obtained exclusively
during the cesarean section. Therefore, for ethical reasons, we could not make a control group
of preterm delivery. We see the difference in the gestational age between the examined groups
as the main limiting factor of the study, but we were unable to avoid it.
The preeclampsia was associated with lower weight of the placenta compared with the
control group. Placenta in preeclampsia is characterized by smaller size, lower weight and
thickness compared with uncomplicated pregnancy (19–21). In our study, in preeclampsia
with IUGR there are significantly lower weight and thickness of placenta compared with
the group without IUGR. The average weight of the placenta in preeclampsia without
IUGR subgroup was close to that in the control group without preeclampsia. It indicates
that placentas from pregnancies complicated with preeclampsia associated with IUGR
demonstrate significantly lower size, but not those from alone preeclampsia, what is
consistent with the findings of other studies (20,22). In the literature, it is also supported
that the abnormal insertion of the umbilical cord is associated with impaired placental
development and function, and thus affects fetal growth (23–25).
8 J. MILOSEVIC-STEVANOVIC ET AL.

Regarding the HP characteristics of the placenta and placental bed, villous hyperma-
turity as well as pathological HP findings of placental bed are statistically far more
common in patients with preeclampsia than in the control group. Villous hypermaturity
is present in 63.3% cases of the study group, which is consistent with the findings of other
authors who state that with 1/3–1/2 of the placenta in preeclampsia these changes are not
present (26,27). Analyzing the characteristics of the arterial blood vessels of decidua in
preeclampsia and control group after immunohistochemical visualization of trophoblast, it
was found that the distribution of trophoblastic cells within the blood vessel of decidua is
significantly different between these groups. We are aware of the fact that EVT never
covers the entire decidual artery endothelium without accumulating into groups, and its
invasion is never uniform in all blood vessels of a decidua. However, we would like to
quantify the visual descriptive impression in some way. After visual analysis of all sections
in a decidua and all blood vessels on them, we decided upon a predominant finding in that
decidua. In group with preeclampsia, trophoblastic cells were present in less than half of
the circumference of the vessel (poor trophoblastic invasion) in 76.7% of cases. However,
there were no significant differences in these characteristics of the arterial blood vessels of
decidua in preeclampsia regarding the presence of IUGR of the fetus.
In the group with preeclampsia compared with the control group, there were signifi-
cantly more findings of each and every HP element that represents the pathological
modality of decidual vessels transformation: inadequate transformation of spiral arteries,
thrombosis, acute atherosis, and fibrinoid necrosis of the media of spiral arteries. If we
analyze the separate appearance of each HP entity in preeclampsia, we can detect that the
most common findings were inadequate trophoblastic invasion of spiral arteries and
fibrinoid necrosis of the media that have appeared in about 2/3 of cases each, and not
frequent as the last was the acute atherosis and spiral artery thrombosis that were found in
about 1/3 of cases each. These histopathological changes in the spiral arteries are collec-
tively called decidual vasculopathy (28). In the study of Stevens et al., it is stated that the
infiltration of foamy cells that is characteristic of acute atherosis and spiral artery throm-
bosis is characteristic of a later stage in the process of decidual vasculopathy development
(28), which may explain the lower prevalence of these two histopathological phenomena
in our study. In fact, more frequent finding of inadequate trophoblastic invasion of spiral
arteries and fibrinoid necrosis of the media are typical for the early stages of decidual
vasculopathy.
In our study, villous hypermaturity was statistically far more common in the subgroup
of preeclampsia associated with IUGR compared with the subgroup of preeclampsia
without delay in growth, while pathology of the placental bed showed no significant
difference between the two subgroups of preeclampsia. This can be explained by the fact
that changes in terms decidual vasculopathy are rather the characteristics of the pree-
clampsia than the growth restriction of the fetus (16). An alone, early-onset preeclampsia
is associated with abnormal placental morphology, but the placentas in the late onset of
preeclampsia are similar to the placentas of the same gestation with normal pregnancy and
with newborns who are of the normal birth weight (20). In our study villous hyperma-
turity was present in 89.5% of cases of preeclampsia associated with IUGR, compared with
only 18.2% of cases of preeclampsia without IUGR. Many researches have confirmed that
it is primarily IUGR, but not alone preeclampsia, that is associated with changes in
placental morphology (17,18,29,30). So the placentas from the late onset of preeclampsia
 HYPERTENSION IN PREGNANCY 9

which is not associated with IUGR are similar to placentas from normal pregnancies,
confirming the hypothesis that emerged late preeclampsia is maternal, but not placental
disorder, that confirms the existence of at least two subgroups of entities (17).
These differences in HP findings in preeclampsia associated with IUGR in relation to
alone preeclampsia, which means that the changes in placental bed are rather the char-
acteristics of the preeclampsia itself than the growth restriction of the fetus, but the
changes in placental villi are primarily related to presence of growth retardation of the
fetus, suggest that probably two different pathogenetical entities are present.

Declaration of interest
The authors report no conflicts of interest. The authors alone are responsible for the content and
writing of the paper.

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