AMJ Vol 10 No 2 June 2023(1).indd


Althea Medical Journal. 2023;10(2)

115

Profile of Apoptotic Marker Genes and Histopathology of the Placenta 
in Pregnancies with Pre-Eclampsia  

Herlambang Herlambang,1 Rina Nofri Enis,2 Susan Tarawifa,2 Huntari Harahap,3 
Anggelia Puspasari,4 Citra Maharani,4 Erny Kusdiyah5

1Department of Obstetrics and Gynecology, Faculty of Medicine and Health Sciences Universitas 
Jambi/Raden Mattaher Hospital Jambi, 2Department of Anatomy, Faculty of Medicine and 

Health Sciences, Universitas Jambi, 3Department of Physiology, Faculty of Medicine and Health 
Sciences, Universitas Jambi, 4Department of Biochemistry, Faculty of Medicine and Health 
Sciences,Universitas Jambi, 5Department of Public Health, Faculty of Medicine and Health 

Sciences,Universitas Jambi

Correspondence: Dr. dr. Herlambang, Sp. OG.KFM, Department of Obstetrics and Gynecology, Faculty of Medicine and Health Sciences 
Universitas Jambi/Raden Mattaher Hospital, Jl. Letjen Suprapto No.33, Telanaipura, Jambi, Indonesia,  Email: herlambang_fkik@unja.ac.id

Introduction

Maternal mortality rate (MMR) in developing 
countries is still a problem. The MMR ratio 
for the Southeast Asian region in 2015 was 
164 deaths for every 100,000 live births. 
In Indonesia, the MMR in 2017 was 177 
for every 100,000 live births;1 whereas in 
Jambi Province in 2020 was 94 per 100,000 
live births.2 The causes of maternal death in 

Indonesia are bleeding (30%), pre-eclampsia 
(27.1%), infection (7.3%), and other causes 
(40.8%). It is obvious that pre-eclampsia is the 
second leading cause of maternal death after 
bleeding.3

Pre-eclampsia is a hypertension and a renal 
organ dysfunction that causes proteinuria after 
20 weeks of gestation, and usually appears 
during the gestational period. Hypertension 
during pregnancy is characterized by systolic 

Althea Medical Journal. 2023;10(2):115–122

Abstract

Background: Pre-eclampsia (PE) is a hypertensive disorder in pregnancy and a significant cause of 
maternal and perinatal mortality and morbidity. Failure of spiral artery remodeling due to abnormal 
apoptosis, triggers disturbances in the mother and the baby’s growth. This study aimed to identify the 
profile of apoptotic marker genes and histopathological features of the placenta in pregnancies with 
pre-eclampsia.
Methods: This study had used case-control method. Samples were taken from normal pregnancies 
(n=25) and pregnant women with pre-eclampsia (n=25) using a purposive sampling method from 
several hospitals in Jambi. qRT-PCR was used to examine apoptotic gene expression from placental 
tissue and hematoxyline eosin staining to view the placenta’s microscopic appearance. The targeted 
genes were BCL2-associated X (BAX) and B-cell lymphoma 2 (BCL-2). Histopathological changes of the 
placenta observed were syncytial node, cytotrophoblast, villous edema, hypervascularization, fibrosis 
stroma, atherosis, infarction, and thrombosis. 
Results: Relative BAX genes expression were increased once in placenta pre-eclampsia compared 
to controls, but not statistically significant (p-value>0.05). There was no difference between the 
decline of BCL-2 gene expression in pre-eclampsia placenta compared to the control (p-value >0.05). 
Histopathological changes in the placenta were syncytial node and cytotrophoblast (25 of 25), villous 
edema (19 of 25), hypervascularization (24 of 25), fibrosis stroma (22 of 25), atherosis (12 of 25), 
infarction (17 of 25), and thrombosis (24 of 25). 
Conclusion: The expression of BAX genes in pre-eclampsia tends to increase compared to normal 
pregnancy, and the expression of BCL-2 decreases. The histopathological features of pre-eclampsia 
pregnancy placenta are mostly syncytial nodes, cytotrophoblasts, stromal fibrosis, and thrombosis.

Keywords: BAX, BCL-2, histopathology placenta, pre-eclampsia  

https://doi.org/10.15850/amj.v10n2.3088



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blood pressure in excess of 140 mmHg and 
diastolic blood pressure in excess of 90 
mmHg or both.4 Among all pregnant women 
worldwide, 5–8% suffer from Pre-eclampsia, 
which is associated with an increased risk of 
maternal and infant morbidity and mortality.5,6 

The exact pathogenesis of pre-eclampsia is 
still unknown. In a normal pregnancy, apoptosis 
plays an essential role in regulating placental 
development. Trophoblast apoptosis increases 
with placental growth and advancing gestation. 
Pre-eclampsia is commonly associated with 
multiple theories, such as vascular disease 
and placental endothelial dysfunction.7 
Epidemiological studies in previously 
different populations has shown that placental 
apoptosis is primarily associated with pre-
eclampsia related pregnancy complications of 
various etiologies, including oxidative stress 
and hypoxia.8 Damage to the structure and 
reduced number of endothelial cells of the 
trophoblast will result in hypoperfusion of 
blood to the placenta. This process inhibits the 
implantation, regulation and proliferation of 
trophoblast development.9,10 

Placental hypoxia induces apoptosis 
through two mechanisms; the initiation phase 
(activation of caspase) and the execution 
phase. The initiation phase occurs through 
the intrinsic pathway (mitochondria pathway) 
and the extrinsic pathway (death receptor 
pathway). Placental hypoxia mainly leads to 
apoptosis through the intrinsic pathway. In 
the intrinsic pathway, the apoptosis signal is 
mediated directly from the mitochondria in 
response to cellular stress, such as DNA damage 
that will initiate the activation of the apoptosis 
signal. There is thus an imbalance between 
the pro-apoptotic protein (BAX) and the 
antiapoptosis (Bcl-2). Trophoblasts exposed to 
hypoxia causes an increase in Bax expression 
and a decrease in Bcl-2 expressions.8,9 This 
apoptotic expression might serve as a marker 
for pre-eclampsia.  

Histopathological examination of the 
placenta with pre-eclampsia has shown 
infarcts, and sclerotic lesions, also narrowed 
arteries and arterioles.11 The lesions are 
characterized by atherosis, infarction, and 
thrombosis of the placenta. Therefore, this 
study aimed to identify apoptotic marker gene 
profiles and histopathological features of the 
placenta in pregnancies with pre-eclampsia.  

 
Methods

The research was a descriptive-analytic 
study with a case-control approach, 

including pregnant women diagnosed with 
pre-eclampsia according to the American 
College of Obstetricians and Gynecologists 
2013, such as hypertension (systolic blood 
pressure ≥ 140 mmHg and or diastolic blood 
pressure ≥ 100 mmHg) after 20 weeks of 
pregnancy. The respondents were recruited 
by purposive sampling method at Raden 
Mattaher Hospital Jambi and Mitra Hospital 
Jambi City. As for control group, normotensive 
healthy women with gestational age matched 
with the preeclamptic group were recruited. 
The exclusion criteria were twin pregnancy, 
the mother with signs of active clinical 
infection, pregnancy with assisted technology 
for fertilization, and kidney as well as hepatic 
failure history. All respondents were followed 
until childbirth.

Placental specimens were taken after birth, 
from the full thickness section from maternal 
and fetal side, in 2 cm x 2 cm size, then put 
into a pot containing 10% buffer formalin. 
The placental tissues were then made into a 
paraffin block to proceed to the microscopic 
examination stage. The hematoxyline-eosin 
staining was performed to view the placenta’s 
macroscopic appearances. After staining, the 
image J application was used for counting 
cells and another microscopic finding in 
magnification 40 times. The histopathological 
variables evaluated in the placenta were 
syncytial node, cytotrophoblast, villous 
edema, hypervascularization, fibrosis stroma, 
atherosis, infarction, and thrombosis. 

All examinations were carried out in 
The Biomolecular Laboratorium Faculty of 
Medicine and Health Sciences. This research 
had received ethical approval from the Medical 
and Health Research Ethics Committee from 
the Faculty of Medicine, Public Health and 
Nursing Universitas Gadjah Mada with Ref. No. 
KE/FK/1189/EC/2020.

The identification of apoptotic gene 
profiles was examined using qRT-PCR. RNA 
isolation from placenta samples was carried 
out according to the manufacturer’s protocol 
using an RNA extraction kit (Promega, USA). 
Before RNA isolation, the placental tissue 
was put into RNA lysis buffer, and then the 
tissue was homogenized using a sterile 
pestle, followed by centrifugation at 14,000 
rpm for 10 minutes at 40 to separate the 
insoluble material. Reverse transcription was 
performed on approximately 7 µg of each RNA 
sample to synthesize complementary DNA 
(cDNA). The cDNA was prepared using Arctic 
Thermal Cycler PCR (Thermo Fisher, USA) 
and a cDNA synthesis kit (Promega, USA). The 

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Table 1 Primers and Sequences in Realtime PCR Studies   
Genes Name Forward Primer Reverse Primer

BAX 5ʹ-CCTTTTCTACTTTGCCAGCAAAC-3ʹ 5ʹ-GAGGCCGTCCCAACCAC-3ʹ
BCL-2 5ʹ-ATG TGT GTG GAG AGC GTC AAC 

C-3ʹ
5ʹ-TGA GCA GAG TCT TCA GAG ACA 
GCC-3ʹ

GAPDH 5’-AGC CAC ATC GCT CAG ACA C-3’ 5’-GCC CAA TAC GAC CAA ATC C-3’

Herlambang Herlambang et al.: Profile of Apoptotic Marker Genes and Histopathology of the Placenta in 
Pregnancies with Pre-Eclampsia

thermal cycle used for cDNA synthesis was 
performed at 25°C for 5 minutes, 42°C for 60 
minutes, and 70°C for 15 minutes. Synthesized 
cDNA was stored at -20 °C until later use. Gene 
expression was then analyzed using the cDNA 
template for qRT-PCR reactions

The human glyceraldehyde-3-phosphate 
dehydrogenase (GAPDH) gene was used as a 
standard to normalize the relative expression 
of the BAX and BCL-2 genes. Amplification of 
the BAX and BCL-2 genes was performed in 
a 20 µl reaction mix containing the following 
reagents: 2 µl of BAX and BCL-2 forward 
primer, 2 µl of BAX and BCL-2 reverse primer, 
10.0 µl of sybr green master mix (Promega, 
USA), 2.8 µl of nuclease-free water, 0.2 µl of 
DNA dye, and 3 µl of cDNA. All the qRT-PCR was 
performed according to the manufacturer’s 
instructions using the PicoReal96 real-time 
PCR system (Thermo Fisher, USA). Thermal 
cycling conditions for the BAX and BCL-2 genes 
were 1 cycle for 2 min at 95oC, followed by 40 
cycles for the denaturation process at 95oC for 
15 sec and 1 min for annealing at 60oC, and for 
dissociation at 60oC for 2 min. Thermal cycling 

conditions for GAPDH were 1 cycle at 95oC for 
5 min, followed by 55 cycles of denaturation 
process at 95oC for 10 sec, annealing at 60oC 
for 20 sec, and elongation at 72°C for 10 
seconds. Fold changes in relative expression 
levels of BAX and BCL-2 were quantified using 
the 2-ΔΔCq method (Livak), using an average 
of a housekeeping gene as a reference.

Statistical analysis used was independent 
student T-test for parametric data and a 
Mann-Whitney test for non-parametric to find 
the differences between the PE and normal 
pregnancy groups. The data were considered 
statistically significant if p<0.05. 

Results 

In total, pre-eclampsia (PE) pregnant women 
(n=25) and the normal (normotension) 
pregnant women (n=25) were included. 
Maternal characteristics showed that the age 
of pregnant women in the PE group was higher 
than the control, however, the difference was 
not significant (Table 2). The proportion of 
PE was higher in women with primigravida 

Table 2 Characteristic Research Subject
Characteristic Control (n=25) PE (n=25) p-value

Maternal ages (year) Mean
High risk, n
Low risk, n

29 ± 6.16
8

17

29.28 ± 6.65
10
15

0.924*
0.556***

Blood Pressure (BP) SBP (mmHg)
DBP (mmHg)

110 (100–130)
70 (60–80)

170 (150–210)
100.00 (80–150)

< 0.001**
<0.001**

Gravidity, n Primigravida
Multigravida

10
20

13
17

0.426***

Parity, n Nulliparous
Multiparous

11
19

14
16

0.432***

Gestasional age, n Pre term
A term

5
25

14
16

0.012***

Birth weight IUGR
Normal

1
 24

 12
 13

0.000***

Note: PE=Pre-eclampsia, SBP=Systolic blood pressure, DBP= Diastolic blood pressure, IUGR=Intrauterine growth 
retardation, * Independent t-test, ** non-parametric test-MannWhitney Test, ***chi-square test



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or nulliparous, but again was not significantly 
different. Gestational characteristics such 
as gestational age at birth was a term, and 
low birth weight or known as intra uterine 
growth retardation (IUGR) showed a higher 
percentage in infants born to pregnant 
women with PE compared to infants born to 
normotensive pregnant women.

The mean value of BAX gene expression was 
higher in the case group; whereas the mean 
value of BCL-2 gene expression was lower in 
the case group, however, the statistical test 
(independent t-test) showed no significant 
difference (p-value >0.005). Furthermore, the 
Cq value from running qPCR was lower in pre-
eclamptic pregnancies than in normotensive 
pregnancies, with fold changes indicating 

the Bax gene increased one time in the pre-
eclamptic pregnancy group compared to the 
normotensive pregnancy group. Cq values of 
BCL-2 were lower in pre-eclamptic pregnancies 
than in normotensive pregnancies, with fold 
changes indicating the BCL-2 gene increased 
one time in the normal pregnancy group 
compared to the pre-eclamptic pregnancy 
group. The expression of the BCL-2 gene in 
pregnancies with PE was even lower than in 
normal pregnancies (Figure 1).

The histopathology of the placenta of PE 
patients after staining with hematoxylin-eosin 
showed syncytial nodes, cytotrophoblast 
cells, villous edema, hypervascularization, 
stromal fibrosis, atherosis, infarction, and 
thrombosis. Most PE subjects in the pregnancy 

Althea Medical Journal June 2023

Figure 1 Relative Expression of BAX and BCL-2 Genes between Pregnancies with Pre-  
    eclampsia and Normal Pregnancies. P-value BAX and BCL-2 Genes >0.005

Pre-eclampsiaControl Pre-eclampsiaControl

Table 3 Overview of Pre-eclampsia Placental Histopathological Changes

Characteristics
Pre-eclampsia Normal pregnancy

n n
Syncytial knot 25 25
Cytotrophoblast cells 25 25
Villous edema 19 9
Hypervascularization 24 12
Stromal Fibrosis 22 8
Atherosis 12 5
Infarction 17 2
Thrombosis 24 12



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group had syncytial nodes, cytotrophoblast 
cells, hypervascularization, stromal fibrosis, 
infarction, and thrombosis. Some subjects also 
showed atherosis and villous edema in their 
histopathological placental samples.

Discussion

Data from maternal characteristics in this 
study showed that 10/25 of pregnancies with 
PE were in the high-risk age range, conform a 
high risk of pregnant women suffering from 
PE at the age of <20 years or >35 years.12 
The reproductive organs in women aged 
<20 years are still immature, and not ready 
for a pregnancy process, that is at risk for 
an abnormal placenta. In the other side, the 
female reproductive organs older age at 
>35 years begin to develop a degenerative 
process that interferes the implantation 
process and the development of trophoblasts 
in the placenta. Poor trophoblast invasion will 
further interfere with the remodeling of spiral 
arteries, followed by ischemic placenta and 
inflammation, which is one of the pathogenesis 
of PE. Moreover, a woman at this age has a 
5% chance of giving birth to a baby with a 
chromosomal abnormality.13

Our results has shown that PE pregnant 
women are mostly nulliparas, conforms to 
another study that also found a relationship 
between nullipara and PE.14 Pre-eclampsia 
is at risk for nulliparas or primigravidas, as 
endothelial dysfunction in the placenta causes 
vasoconstriction, resulting in increased of 
blood pressure and PE.15

In addition, the increased of blood pressure 
associated with PE occurs during pregnancy 
and resolves after birth. In pregnancy, 

apoptosis plays a role in placental growth. 
Apoptosis is a cell regulation in maintaining 
homeostatic conditions of tissue remodeling. 
Apoptosis plays a role during the attachment 
process, followed by trophoblast invasion, 
spiral artery transformation, trophoblast 
differentiation, and the process of immune 
tolerance to paternal antigens expressed by 
trophoblast cells. Apoptotic trophoblast cells 
are also found in normal pregnancy placentas 
on both the maternal and perinatal sides.11,16 

In response to genotoxic or cellular 
stress, abnormal placental apoptosis affects 
the placenta’s endothelial cells and induces 
extensive placental apoptosis.17 Hypoxia-
induced cellular stress is the most frequent 
factor triggering increased p53 gene 
expression in PE.18 Increased expression of 
the pro-apoptotic gene p53 leads to excess 
apoptosis leading to trophoblast damage. 
Another study found a change in the 
expression of the p53 gene from the placenta 
of pregnant women with PE compared to 
the normotensive pregnancy group.19 In pre-
eclampsia, increased p53 expression occurs 
in the trophoblast layer due to the previous 
transcription of other pro-apoptotic proteins, 
including p21 and BAX. 19,20,21

The expression imbalance between 
pro-apoptotic and anti-apoptotic genes is 
associated with excessive apoptosis and 
syncytial degeneration. The expression of 
Bcl-2, an anti-apoptotic gene, is higher than 
the expression of the BAX gene, which is 
an essential pro-apoptotic gene for normal 
placental development and pregnancy 
continuity. On the other hand, overexpression 
of BAX in placental tissue may lead to failure 
of placental development through excessive 

Pre-eclampsia PlacentaNormal Placenta

Figure 2. Histopatological of Placenta. (A) Placental Vascular in Normal Pregnancy. (B) 
      Cytotrophoblast Cells. (C) Syncytial Knot in Normal Pregnacy. (D) Placental Villous. 
     (E) Infarction in PE Placenta (F) Hypervascularisation in PE. (G) Syncytial Knot in  
     PE. Original magnification x40

Herlambang Herlambang et al.: Profile of Apoptotic Marker Genes and Histopathology of the Placenta in 
Pregnancies with Pre-Eclampsia

A B

C D

E

G

F

H



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apoptotic mechanisms.22,23 The results 
obtained in this study showed an increase in 
BAX gene expression levels one time higher 
in pregnancies with PE compared to normal 
pregnancies. The increased apoptosis in PE 
occurs via an intrinsic pathway in response 
to cellular stress. This condition initiates the 
pro-apoptotic BAX protein, which is produced 
further to suppress the regulation of the anti-
apoptotic gene BCL-2, so that the expression of 
the BCL-2 gene is lower than the pro-apoptotic 
gene expression. This study found that the level 
of BCL-2 gene expression was one time lower 
in pregnancies with PE compared to normal 
pregnancies. So that in pregnancies with PE, 
the ratio of BAX gene expression compared 
to BCL-2 is 1:1, even though not statistically 
significant. In previous studies, the intrinsic 
and extrinsic pathways are related because 
p53 can also increase the expression of 
several death receptors through the extrinsic 
pathway.24,25

Histopathological examination of PE 
placenta showed placental infarction and 
sclerosis, causing narrowing of the arteries 
and arterioles. Another factor that triggers 
PE is apoptosis, which results from placental 
hypoxia leading to placental ischemia. 
Furthermore, there are changes in syncytial 
nodes, cytotrophoblasts, villous edema, 
hypervascularization, atherosis, stromal 
fibrosis, infarction, and thrombosis, similar 
to other study.26 The PE may thus harm 
placental morphology and consequently 
affects the fetus.26 Several other studies have 
proofed the significance relationship between 
the microscopic changes of the placenta 
with the incidence of PE.27,28,29 The changes 
are due to a lack of oxygen perfusion in the 
preeclamptic placenta. In the mature placenta, 
cytotrophoblast cells will be reduced, but in PE, 
many new villi are formed to support the lack 
of placental perfusion. The more trophoblast 
cells and new villi are formed. Inflation of 
trophoblasts that will become cytotrophoblasts 
occurs due to inadequate oxygen perfusion. 
The function of the cytotrophoblast itself is 
for gas exchange, where the cytotrophoblast 
will replace the endothelial function of the 
arterioles. The typical mature placenta in 
each villus only has 20% of cytotrophoblasts; 
while in PE cytotrophoblasts that functions as 
gas exchange is increased to compensate the 
hypoxic state.29

The ischemic process in pregnant women 
with PE triggers the inflammatory process 
in the endothelial wall. This proliferation is 
characterized by the thickening of the tunica 

intima, resulting in constriction of blood 
vessels. Stromal fibrosis is also found in 
the placentas due to the presence of tissues 
that have not experienced a lack of oxygen 
perfusion. The formation of stromal fibrosis 
is associated with impaired vascularization. 
However, fibrosis can be referred as a repair 
process in damaged tissue with fibroblastic 
proliferation due to chronic inflammation due 
to hypoxia and a lot of tissue necrosis in blood 
vessels in the long term.28

In pre-eclampsia placenta, there is 
a change in vascularization in the form 
of hypervascularization, which is due to 
angiogenesis or the formation of new vessels. 
Angiogenesis occurs due to reduced oxygen 
perfusion and is a normal response of oxygen-
deprived tissues. Vascular endothelial growth 
factor (VEGF) is essential in forming new 
blood vessels. The placenta is in inadequate 
perfusion in PE until the spiral arteries 
change. The placenta in this state undergoes 
hypoxia and ischemia resulting in necrosis and 
infarction.25

Atherosis is also found in preeclamptic 
placentas caused by abnormalities of blood 
vessels, blood flow, and blood composition. 
Vascular abnormalities in the PE placenta 
are caused by the absence or only part of the 
spiral arteries being invaded by trophoblast 
cells. Abnormal blood flow in PE affects the 
spiral arteries, where the spiral arteries are 
arteries that supply the villi. The reduced 
oxygen supply of the villi causes smooth 
muscle cells to move toward the tunica 
intima. The proliferation of smooth muscle 
cells and deposition of extracellular matrix 
by smooth muscle in the intima transforms 
fatty patches into mature fibrofatty atheroma 
and plays a role in the progressive growth of 
atherosclerotic lesions. Oxygen deprivation 
due to damage to spiral arteries causes 
necrosis, and hypoxic trophoblasts secrete 
thromboxane as a vasoactive factor, leading 
to thrombosis. Thromboxane is produced 
as a vasoactive agent that compensates for 
endothelial damage.27

The limitation of the study is that the 
pregnancy is a late pregnancy. Ideally, the 
respondents are from several trimesters, to 
determine the histopathological results and 
apoptosis pattern at each pregnancy stage.  

In conclusion, pre-eclampsia pregnant 
women are mostly delivered a term with 
intra uterine growth. Expression of BAX 
gene in PE is higher and of the BCL-
2 gene is lower than in normotensive 
pregnancies. The histopathological findings 

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of most PE pregnancies have syncytial nodes, 
cytotrophoblasts, stromal fibrosis, and 
thrombosis. 

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Althea Medical Journal June 2023