Objective: To investigate the immunohistochemical staining of hypoxia-inducible factor 1-alpha (HIF-1α) and Ki-67 expression in the placenta of pregnant women with placenta previa and placenta accreta. Study Design: Thirty placentas (10 normotensive, 10 placenta previa, and 10 placenta accreta) were processed for routine histological tissue processing. The biochemical parameters of patients were recorded. Placentas were stained with hematoxylin-eosin and HIF-1α and Ki-67 immunostaining. Results: Normal histology was observed in placentas of normotensive pregnant women. Placenta previa sections showed increased syncytial knots, intervillous hemorrhage, fibrin accumulation, and hyalinization. In placenta accreta sections, increased syncytial nodes, vascular dilation/congestion, fibrin accumulation, and hyalinization were observed. Normotensive placentas showed no HIF-1α expression. In placenta previa tissues, high HIF-1α expression was observed in vascular endothelial cells, villous stromal cells, and syncytial knots. High HIF-1α expression was recorded in villous stromal cells and cytotrophoblast cells in placenta accreta. In normotensive placental tissues, no Ki-67 expression was observed. In placenta previa sections, high Ki-67 expression was observed mostly in root villi stromal cells and some endothelial cells. High Ki-67 expression was observed mostly in villi stromal cells of placenta accreta. Conclusion: It is thought that HIF-1α is an important regulatory gene in the development of villus in trophoblast invasion such as placenta accreta and previa, while Ki-67 will play a key role in the development of abnormal placenta with its stimulating effect on inflammatory cell development and angiogenesis in accreta and preeclampsia.

1. 143
OBJECTIVE: To investigate the immunohistochemical
staining of hypoxia-inducible factor 1-alpha (HIF-1α)
and Ki-67 expression in the placenta of pregnant women
with placenta previa and placenta accreta.
STUDY DESIGN: Thirty placentas (10 normotensive,
10 placenta previa, and 10 placenta accreta) were
processed for routine histological tissue processing.
The biochemical parameters of patients were recorded.
Placentas were stained with hematoxylin-eosin and HIF-
1α and Ki-67 immunostaining.
RESULTS: Normal histology was observed in placentas
of normotensive pregnant women. Placenta previa
sections showed increased syncytial knots, intervillous
hemorrhage, fibrin accumulation, and hyalinization.
In placenta accreta sections, increased syncytial nodes,
vascular dilation/congestion, fibrin accumulation, and
hyalinization were observed. Normotensive placentas
showed no HIF-1α expression. In placenta previa tis­
sues, high HIF-1α expression was observed in vascular
endothelial cells, villous stromal cells, and syncytial
knots. High HIF-1α expression was recorded in villous
stromal cells and cytotrophoblast cells in placenta ac-
creta. In normotensive placental tissues, no Ki-67 ex-
pression was observed. In placenta previa sections,
high Ki-67 expression was observed mostly in root villi
stromal cells and some endothelial cells. High Ki-67
expression was observed mostly in villi stromal cells of
placenta accreta.
CONCLUSION: It is thought that HIF-1α is an im-
portant regulatory gene in the development of villus
in trophoblast invasion such as placenta accreta and
previa, while Ki-67 will play a key role in the develop­
ment of abnormal placenta with its stimulating effect
on inflammatory cell development and angiogenesis in
accreta and preeclampsia. (Anal Quant Cytopathol
Histpathol 2021;43:143–149)
Keywords: female; hypoxia; hypoxia-inducible
factor 1, alpha subunit; placenta; placenta accreta;
placenta previa; placental lactogen; pregnancy,
physiology; preeclampsia.
The placenta is a temporary organ that nourishes
the fetus, regulates many metabolic activities, and
produces hormones necessary for the continuation
of pregnancy; its function ends at the end of
pregnancy.1 The placenta is implanted in any area
of the uterine wall; however, in some clinical
complications, it can prevent the fetal head from
descending during delivery if it is too low in the
uterus. Low-lying placentas can also cause unusual
bleeding during pregnancy or delivery.2
Analytical and Quantitative Cytopathology and Histopathology®
0884-6812/21/4303-0143/$18.00/0 © Science Printers and Publishers, Inc.
Analytical and Quantitative Cytopathology and Histopathology®
Immunohistochemical Analysis of Hypoxia-
Inducible Factor 1-Alpha and Ki-67 Expression
in Placenta Previa and Accreta
Serap Otçu, M.D., and Engin Deveci, Ph.D.
From the Department of Obstetrics and Gynecology, Health Sciences University, Diyarbakır Gazi Yaşargil Training and Research Hospi-
tal, Diyarbakır; and the Department of Histology and Embryology, Faculty of Medicine, Dicle University, Diyarbakır, Turkey.
Serap Otçu is Physician, Department of Obstetrics and Gynecology, Health Sciences University, Diyarbakır Gazi Yaşargil Training and
Research Hospital.
Engin Deveci is Professor and Head, Department of Histology and Embryology, Faculty of Medicine, Dicle University.
Address correspondence to: Engin Deveci, Ph.D., Department of Histology and Embryology, Faculty of Medicine, Dicle University,
21280 Diyarbakır, Turkey (engindeveci64@gmail.com)
Financial Disclosure: The authors have no connection to any companies or products mentioned in this article.

2. As the embryo develops, substance exchange
between fetal and maternal blood circulation to-
wards the end of pregnancy can decrease due to
some abnormal structural changes such as thick­
ening of the basement membrane of fetal capil-
laries, increased fibrous tissue in the villous stro-
ma, and fibrinoid accumulation in the chorionic
plate and on root villi in the junction.3,4
Placenta previa occurs when the placenta at-
taches to the inside of the uterus, near or above the
cervical opening. It affects about 0.5% of pregnan­
cies. Risk factors include pregnancy in advanced
age, smoking, pre-aspiration and curettage, mul­
tiparity, previous cesarean surgery, labor induc-
tion, or termination of pregnancy. Incidence of
placenta previa is 1 in 300 deliveries.5,6 Placenta
previa can cause severe complications, such as
maternal placenta accreta, low blood pressure
or postpartum hemorrhage, and fetal growth re-
striction. The etiology of placenta previa is not
fully known, but there is a relationship between
abnormal endometrial vascularization due to scar­
ring or atrophy from previous trauma, surgery,
infection, and uterine scarring.7,8
Placenta accreta is the abnormal adhesion of the
placenta to the uterine cavity. It is characterized
by the absence of decidua basalis and by the
incomplete development of the fibrinoid layer.
Placenta accreta occurs in 5–10% of pregnancies
complicated with placenta previa. Its incidence
ranges from about 533 to 70,000 births.9 The best-
defined risk factors are previous uterine surgery
and placenta previa. Although risk factors for
placental attachment anomaly are well defined,
the correct etiology is largely unknown. Abnormal
or increased trophoblast invasion is seen. The
etiology of the placenta accreta is that the oxygen
imbalance in the uterine scar area causes this
con­
dition. The development of the embryo in a
relatively hypoxic environment causes prolifera-
tion or increased invasion of cytotrophoblasts.10,11
The aim of this study is to investigate HIF-1α
and Ki-67 expression in placenta previa and accreta
and to compare the expression differences.
Materials and Methods
Ethical approval was obtained from Dicle Univer­
sity Faculty of Medicine Non-Interventional Clin-
ical Research Ethics Committee (record no. 2020/
68). In our study, 10 normotensive, 10 placenta
previa, and 10 placenta accreta tissue samples
from pregnant women (regardless of age) were
obtained from Gynecology and Obstetrics Clinics,
Gazi Yasargil Training and Research Hospital.
All patients signed the informed patient consent
form. Biochemical parameters for each patient
were recorded. Placental tissues were processed
for routine paraffin wax embedding protocol.
Histological Tissue Processing
Placental tissues were fixed with zinc-formalin so-
lution (catalog no. Z2902, Sigma-Aldrich, St. Louis,
Missouri, USA) and washed under tap water for
5 minutes. Tissues were passed through ascend­
ing alcohol series for about 24 hours. Tissues were
washed with xylene 2×30 minutes and incubated
within paraffin wax. Sections of 5 µm were cut
with a microtome (catalog no. RM2265, Leica,
Wetzlar, Germany). Deparaffinized within xylene
for 2×30 minutes, sections were brought to dis­
tilled water. Some of the sections were stained with
routine hematoxylin and eosin, and the rest were
kept for immunohistochemical staining.
HIF-1α and Ki-67 Immunostaining
All placental tissues were brought to distilled
water. Hydrogen peroxide solution (catalog no.
TA-015-HP, Thermo Fisher, Fremont, California,
USA) was dropped on sections for 20 minutes.
After washing in PBS for 3×5 minutes, Ultra V
Block (catalog no. TA-015-UB, Thermo Fisher) was
applied to sections for 8 minutes. Sections were
incubated with primary antibodies anti-HIF-1α
(catalog no. ab216842, Abcam, Cambridge, Massa­
chusetts, USA) and anti-Ki-67 (catalog no. ab16667,
Abcam) at +4°C overnight. Sections were allowed
to warm at room temperature for 30–60 minutes.
Sections were washed with biotinylated secondary
antibody (catalog no. TP-015-BN, Thermo Fisher)
for 14 minutes. Streptavidin-peroxidase (catalog
no. TS-015-HR, Thermo Fisher) was dropped onto
sections for 15 minutes. Clearing with PBS, DAB
(catalog no. TA-001-HCX, Thermo Fisher) was
used as chromogen. Sections were counterstained
with Gill hematoxylin (catalog no. 105174, Sigma-
Aldrich) and mounted with Entellan (catalog no.
107961, Sigma-Aldrich). Slides were analyzed with
Zeiss Imager A2 Zen 3.0 software (Carl Zeiss,
Oberkochen, Germany) and photomicrographed.
Statistical Analysis
The data were recorded as arithmetic mean±
standard deviation with mean rank value. Statis­
tical analysis was done using the IBM SPSS 25.0
144 Analytical and Quantitative Cytopathology and Histopathology®
Otçu and Deveci

3. software (IBM SPSS Statistics for Windows, Version
25.0, released 2017. IBM Corp., Armonk, New York,
USA). One-way ANOVA with Tukey’s test was
used for multiple comparisons. P<0.05 was used as
the significance level.
Results
Statistical analysis of multiple comparisons be-
tween normotensive, placenta previa, and placen­
ta accreta is shown in Table I. No statistical dif-
ferences were recorded within group comparisons
for any parameters (ALT, AST, glucose, albumin,
total protein, urea, creatinine). Graphical illustra-
tions of all parameters are shown in Figures 1–2.
Placenta previa and accreta were stained with
hematoxylin-eosin and HIF-1α and Ki-67 immu­
nohistochemical staining. The staining is present­
ed in Figure 2. Normotensive placentas showed
normal placental histology (Figure 2A). In sections
of placenta previa, increased syncytial knots, in-
tervillous hemorrhage, fibrin accumulation, and
hyalinized regions were observed (Figure 2B).
Similar to placenta previa, placenta accreta show­
ed similar histopathology with increased syncytial
nodes, vascular dilation/congestion, fibrin accu­
mulation, and hyalinization (Figure 2C). In HIF-
1α immunohistochemical staining, no expression
was recorded in normotensive placental tissues.
In placenta previa tissues, high HIF-1α expres-
sion was observed in vascular endothelial cells,
villous stromal cells, and syncytial knots (Figure
2E). High HIF-1α expression was recorded in
villous stromal cells and cytotrophoblast cells in
placenta accreta (Figure 2F). No Ki-67 expression
was recorded in normotensive placental tissues
(Figure 2G). Placenta previa showed high Ki-67
expression mostly in root villi stromal cells and
some endothelial cells (Figure 2H). High Ki-67
expression was observed mostly in villi stromal
cells of placenta accreta (Figure 2I).
Discussion
In this study we investigated the tissues of placen­
ta previa and placenta accreta by biochemical and
immunohistochemical methods. Placenta previa is
a pregnancy complication in which placentation
is abnormally localized in the lower segment of
the uterus.12 It is one of the important causes of
maternal, fetal, and neonatal morbidity and mor­
tality characterized by third trimester bleeding. Al-
though its etiology is unknown, advanced mater­
nal age, multiparity, multiple pregnancy, previous
cesarean delivery, and smoking are risk factors,
causing placenta previa.6 Studies on histopathol­
ogy of placenta previa revealed fibrinoid necrosis,
polymorphonuclear cell infiltration, abnormal vas­
culatures, and dilated vessels. Biswas et al recorded
increased trophoblastic giant cells, hemorrhage,
absence of chorionic villi in the myometrium, and
inflammation in placenta previa tissues.13 Silver et
al also reported increased villous infarction with
fibrinoid and congested vessels in pathological
examination of placenta previa.14 In our study, we
observed increased syncytial knots, intervillous
hemorrhage, fibrin accumulation, and hyalinized
regions in placenta previa sections (Figure 1B).
Placenta accreta is defined as abnormally deep
adhesion of the placenta to the uterine muscles.
Its etiology is not fully known, but placenta previa
and previous cesarean deliveries are risk factors.
Complications include premature birth, maternal
bleeding, and morbidity.15 Histopathological anal­
ysis of placenta accreta showed chorionic villi
adjacent to myometrial fibers, fibrinoid formation,
intravascular chorionic villi, hemorrhage, and vas­
cular changes.14 In our study we observed in-
creased syncytial nodes, vascular dilation/conges­
tion, fibrin accumulation, and hyalinization in
placenta accreta tissues.
Perinatal studies have focused on the role of
oxygen and hypoxia during placentation and
pregnancy. Researchers have shown that oxygen
has vital functions to regulate trophoblast differ­
entiation.14 Hypoxia-inducible factor-1α (HIF-1α)
is a transcription regulator of genes in adaptive re-
sponse to hypoxic conditions. HIF-1α is involved
in activation of transcription of over 40 genes
such as erythropoietin, glucose transporters, gly-
colytic enzymes, and vascular endothelial growth
factor during hypoxia. HIF-1α regulates vessel
formation in the embryonic stage, tumor angio­
genesis, and ischemia.16 During placental forma­
tion, cellular hypoxia develops, and thus HIF-1α
is activated to induce trophoblast proliferation and
the formation of specific cell subtypes.17,18 Zamudio
et al investigated HIF-1α expression and its regu­
latory mechanisms in placentas from pregnancies
of women living at different altitudes. HIF-1α
were overexpressed in placentas of women living
at high altitudes.19 Ietta et al investigated the
role of HIF-1α expression during human placen­
tal development. Expression of HIF-1α was high
when oxygen tension was low but decreased when
placental oxygen tension increased. They also
Volume 43, Number 3/June 2021 145
HIF-1-α and Ki-67 in Placenta Previa and Accreta

4. showed that during early placentation, HIF-1α
localized in cytotrophoblasts.20 In our study we
found that placenta previa tissues showed high
HIF-1α expression in vascular endothelial cells,
146 Analytical and Quantitative Cytopathology and Histopathology®
Otçu and Deveci
Table I Means and Standard Deviations of Age, ALT, AST, Glucose, Albumin, Total Protein, Urea, and Creatinine with Group Comparisons
One-way ANOVA
Parameter Group N Mean+SD (p value)
Age, years (1) Normotensive 20 33.35±4.72 (2): 0.868
(3): 0.082
(2) Placenta previa 20 32.55±5.04 (1): 0.868
(3): 0.221
(3) Placenta accreta 20 29.90±5.18 (1): 0.082
(2): 0.221
ALT, U/L (1) Normotensive 20 29.90±5.18 (2): 0.241
(3): 1.00
(2) Placenta previa 20 32.55±5.04 (1): 0.241
(3): 0.241
(3) Placenta accreta 20 29.90±5.18 (1): 1.00
(2): 0.241
AST, U/L (1) Normotensive 20 13.14±8.60 (2): 1.00
(3): 1.00
(2) Placenta previa 20 13.11±6.34 (1): 1.00
(3): 1.00
(3) Placenta accreta 20 13.14±8.60 (1): 1.00
(2): 1.00
Glucose, mg/dL (1) Normotensive 20 18.67±7.41 (2): 0.886
(3): 1.00
(2) Placenta previa 20 20.13±13.43 (1): 0.886
(3): 0.886
(3) Placenta accreta 20 18.67±7.41 (1): 1.00
(2): 0.886
Albumin, g/L (1) Normotensive 20 86.80±25.99 (2): 0.425
(3): 1.00
(2) Placenta previa 20 97.06±25.39 (1): 0.425
(3): 0.425
(3) Placenta accreta 20 86.80±25.99 (1): 1.00
(2): 0.425
Total protein, g/dL (1) Normotensive 20 21.84±16.42 (2): 0.479
(3): 1.00
(2) Placenta previa 20 27.72±14.97 (1): 0.479
(3): 0.479
(3) Placenta accreta 20 21.84±16.42 (1): 1.00
(2): 0.479
Urea, mg/dL (1) Normotensive 20 38.38±27.08 (2): 0.736
(3): 1.00
(2) Placenta previa 20 31.59±31.53 (1): 0.736
(3): 0.479
(3) Placenta accreta 20 38.38±27.08 (1): 1.00
(2): 0.736
Creatinine, mg/dL (1) Normotensive 20 16.43±4.91 (2): 0.337
(3): 1.00
(2) Placenta previa 20 19.19±8.03 (1): 0.337
(3): 0.337
(3) Placenta accreta 20 16.43±4.91 (1): 1.00
(2): 0.337
SD = standard deviation.

5. Volume 43, Number 3/June 2021 147
HIF-1-α and Ki-67 in Placenta Previa and Accreta
Figure 1
Graphical illustration of
patient parameters regarding
placenta complication.
Figure 2
Normotensive, placenta
previa, and placenta accreta
tissues with H-E staining (A–C)
and HIF-1α (D–F) and Ki-67
(G–I) immunostainings. (A)
Normal placental histology.
(B) Increased syncytial nodes
(black arrow), intervillous
hemorrhage (red star),
fibrinoid (black star), and
hyalinization (arrowhead). (C) Increased syncytial nodes (black arrow), vascular dilation/congestion (red star), villous fibrinoid (black
star), and hyalinization (arrowhead). (D) No HIF-1α in normotensive placental tissues. (E) High HIF-1α expression in vascular
endothelial cells (red arrow), villous stromal cells (arrowhead), and syncytial nodes (black arrow). (F) High HIF-1α expression in villous
stromal cells (arrowhead) and cytotrophoblast cells (black arrow). (G) No Ki-67 expression in normotensive placental tissues. (H) High
Ki-67 expression mostly in root villi stromal cells (arrow) and some endothelial cells (red arrow). (I) High Ki-67 expression in mostly villi
stromal cells (arrows).

6. villous stromal cells, and syncytial knots (Figure
1E). Placenta accreta tissues showed high HIF-1α
expression in villous stromal cells and cytotro­
phoblast cells in placenta accreta (Figure 1F).
Ki-67 is a cellular marker for proliferation which
functions in interphase and mitotic cells. Mea-
surement of Ki-67 expression level can be used for
the prognosis of many tumors.21 Ki-67 expression
index has been used in the normal placenta, hy-
datidiform moles, and choriocarcinoma. Aberrant
placenta formation may be related with abnor-
mal regulation of molecular changes and the
proliferation of trophoblast cells so that tropho­
blasts are able to migrate and invade the uterine
wall.21,22 Kaya et al recorded that Ki-67 expression
was increased in villous cytotrophoblasts of pre-
eclamptic placentas relative to controls. They
showed an increased number of villous cytotro­
phoblasts in preeclampsia as compared to in nor-
mal pregnancy by analyzing with Ki-67 immuno­
histochemical staining.23 Unek et al showed that
Ki-67 expression was increased in placental villi
of preeclampsia.24 Another preeclampsia study
recorded that the Ki-67 index was high in villous
trophoblasts of preeclamptic patients.25 A study
demonstrated that Ki-67 expression was high in
trophoblast columns of accreta subtypes.26 In our
study we found that placenta previa showed high
Ki-67 expression mostly in root villi stromal cells
and some endothelial cells (Figure 1H). We re-
corded high Ki-67 expression mostly in villi stro-
mal cells (Figure 1I).
In conclusion, it is thought that HIF-1α is an
important regulatory gene in the development
of villus in trophoblast invasion such as placenta
accreta and placenta previa, while Ki-67 will play
a key role in the development of abnormal placen­
ta with its stimulating effect on inflammatory cell
development and angiogenesis in accreta and pre­
eclampsia
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