CESAREAN

SECTION LEADS TO
ABNORMAL PLACENTAL IMPLANTATION
•  Because the early embryo requires a hypoxic environment,
it may preferentially implant into a cesarean section scar,
which tends to be acellular and avascular. This tendency
may explain the increased risk for placenta previa and
accreta in individuals with an increasing number of
cesarean sections. Alternatively, the placenta may
preferentially develop in a hypoxic scar, not involuting over
this area, as it would in an unscarred uterus.
•  Trophoblast implanting over an avascular scar may invade
more deeply into the uterine wall because of the prolonged
maintenance of an invasive phenotype. This delay in arrest
of mitosis with subsequent initiation of differentiation is
likely secondary to the absence of underlying tissue with
normal vasculature and high oxygen tension. (4)
 VASCULOENDOTTHELIAL GROWTH FACTOR,
PLACENTAL GROWTH FACTOR, AND THEIR
RECEPTORS
•  Vasculoendothelial growth factor (VEGF), placenta
growth factor (PlGF), and their receptors (VEGFR-1, -2
and -3) are well-known angiogenic factors of VEGF,
VEGF-B and PlGF bind to VEGFR-1/Flt-1; VEGF and
VEGF-C bind to VEGFR-2/KDR, and VEGF-C binds to
VEGFR-3/Flt-4.
•  During normal pregnancy, the expression of VEGF and
its receptors in the trophoblasts regulates the
secretion of a wide range of proteins and hormones.
•  Soluble isoforms of VEGFR, sVEGFR-1 and sVEGFR-2
regulate the biological activities of PlGF and VEGF.
•  Accumulating evidence indicates that these proteins
are involved in the pathogenesis of placental disorders.
In hypoxic/ ischemic regions of pathologic placentas,
expression of PlGF and VEGFR-1 is enhanced in villous
trophoblasts via autocrine regulation, whereas
expression of VEGF and VEGFR-2 is increased within
the villous vessels through paracrine regulation. Villi
from missed abortion and blighted ovum show
diminished immunoreactivity of VEGF in the
trophoblasts, VEGFR-1 in the syncytium, and VEGFR-2
in the trophoblasts. Furthermore, increased VEGFR-1
expression in the trophoblasts from pregnancies
complicated by preeclampsia and IUGR indicates
abnormal placental function and hypoxia. Increased
sVEGFR-1 might explain the low PlGF concentrations
found in preeclamptic subjects.
•  The study of Shainker et al worked with formalin-fixed tissue
section from 11 peripartum hysterectomies with invasive
placentation and 5 controls were stained for sFlt-1. (7) The
morphology of the cases was typical of invasive placentation. In
areas of invasion, histologic sections showed lack of decidua,
increased myometrial trophoblasts, and trophoblast infiltration
(i.e., conversion) of arteries in the outer myometrial wall. Oedema
and chronic inflammation in the myometrium adjacent to the
placenta were seen in most cases. It appeared (from Fig2) that
median sFlt-1 expression was significantly less in invasive areas of
cases [5.0 (2.0–6.0)] compared to control placentas [12.0 (9.0–
15.0), p = 0.003, Fig. 2]. Median sFlt-1 expression also was
significantly less in non-invasive areas of cases [5.5 (5.0–7.0)]
compared to control placentas (p = 0.01). There was no significant
difference between the invasive and non-invasive areas of cases (p
= 0.23). Cases showed a gradient of sFlt-1 expression from fetal to
maternal (high to low).
Fig 2. Box-plot of sFlt-1 expression in
groups 1, 2, and 3

Fig 3. Scoring scale for immunohistochemical

staining of sFlt-1 in villous trophoblasts, with 0
correspondings to no staining (a) and 3 being
the most intense staining (c). Moderate
staining is illustrated in panel b. Expression of
sFlt-1 in villous trophoblast (asterisk) as
evaluated relative to intermediate trophoblast
in at the maternal
surface (arrow)
Fig 3. Scoring scale for immunohistochemical
staining of sFlt-1 in villous trophoblasts, with 0
correspondings to no staining (a) and 3 being the
most intense staining (c). Moderate staining is
illustrated in panel b. Expression of sFlt-1 in villous
trophoblast (asterisk) as evaluated relative to
intermediate trophoblast in at the maternal
surface (arrow)
Fig 4. Areas of variable sFlt-1
expression in selected cases. a Low
power image of sFlt-1 gradient from
fetal (high, asterisk) to maternal (low,
arrow) side. b sFlt-1 hot spot. Villi with
high sFlt-1 expression (asterisk)
entrapped in fibrin (arrow). c sFLT-1
hot spot. Villi with high sFlt-1
expression (asterisk) within a vein
(arrows). d Corresponding Masson
trichrome stain for panel c highlighting
a vein (arrows).
•  In this study, Shainker et al demonstrated decreased
expression of sFlt-1 in villous trophoblasts in patients
with invasive placentation, specifically placenta increta
and percreta.When compared to controls, both
invasive and non-invasive areas from cases show lower
sFlt-1 expression, although the findings for non-
invasive areas are less dramatic than for invasive areas.
No statistically significant difference in expression,
however, was observed between invasive and non-
invasive areas among cases. Their findings are
consistent with the data published by another study
(McMahon et al.) who also reported that expression of
sFlt-1 was lower in areas of invasive placentation,
suggesting a functional role for sFlt-1 in invasive
placental implantation.
•  Trophoblast expression of sFlt-1 near the
implantation site is normally moderated by VEGF
expression in the decidua. They hypothesize that
low expression in our cases may be due to the
lack of decidua at the implantation site, which is
the defining feature of invasive implantation. The
diminished sFlt-1 expression also might be an
adaptation to increased blood flow. sFlt-1
expression is sensitive to perfusion, showing
higher expression with increasing hypoxia. In the
setting of invasive implantation, trophoblasts
infiltrate into deep myometrial vessels leading to
increased blood flow into the intervillous space.
A low sFlt-1 expression may indicate high levels
of local perfusion within the intervillous space.
•  This model also is compatible with data in that
the sFlt-1 expression profile in all cases
demonstrates a gradient from lowest at the
myometrial interface to highest toward the
fetal surface. Sections also show frequent
sFlt-1 ‘‘hot spots’’ in areas with increased
perivillous fibrin, areas of erratic maternal
blood flow, and areas where villi are
entrapped within uterine veins along with the
myometrial interface (Fig. 4)
 Surgical Activities
•  1. Niche
•  2. Adhesion
•  3. Related Factors : Infection,Nutrition &
Medical Disorder

Impaired Wound Healing

ANGIOGENIC & ANTIANGIOGENIC
FACTOR IN IAP
Erry Gumilar
What they are doing now the Obstetrician (the new generation?)
are often doing large episiotomy on the belly
than very vew on the vagina
•  Todd Rosen ,2008 clinical perinatol, div. MFM
columbia univ.
•  The term ‘niche’ describes the presence of a hypoechoic area within the
myometrium of the lower uterine segment, reflecting a discontinuation of
the myometrium at the site of a previous CS
•  Niches were defined as indentations of the myometrium of at least 2 mm
 (Niche – pre pregnancy)
Hypothesis of
Niche
Hypothesis : Surgical activities that may induce adhesion formation
and as a consequence induce impaired wound healing due to
counteracting forces on the uterine scar

In theory, several factors that influence adhesion formation after CS

can be postulated. In general it is known that factors such as
inadequate haemostasis, inflammation due to infection, tissue
ischaemia, tissue devascularisation and tissue manipulation can cause
formation of adhesions
Hypothesis : Patient or disease related factors that impair wound
healing.

•  Nutrition
•  infection
•  Medical disorder condition
Vervoort A.J.M.W. Human Reproduction, Vol.30, No.12 pp. 2695–2702, 2015
 The early embryo requires a hypoxic environment
Implant into a cesarean section scar, which is acellular and avascular

The placenta develop in a hypoxic scar, not involuting (curled or
curved inward) over this area

Trophoblast implanting over an avascular scar may invade more
deeply into the uterine wall

This delay in arrest of mitosis
(the absence of underlying tissue with normal vasculature and high
oxygen tension)

 VASCULOENDOTHELIAL GROWTH FACTOR,
PLACENTAL GROWTH FACTOR, AND THEIR
RECEPTORS
•  Vasculoendothelial growth factor (VEGF), placenta
growth factor (PlGF), and their receptors (VEGFR-1, -2
and -3) are well-known angiogenic factors of VEGF,
VEGF-B and PlGF bind to VEGFR-1/Flt-1; VEGF and
VEGF-C bind to VEGFR-2/KDR, and VEGF-C binds to
VEGFR-3/Flt-4.
•  During normal pregnancy, the expression of VEGF and
its receptors in the trophoblasts regulates the
secretion of a wide range of proteins and hormones.
•  Soluble isoforms of VEGFR, sVEGFR-1 and sVEGFR-2
regulate the biological activities of PlGF and VEGF.
•  Soluble fms-like tyrosine
kinase-1 (sFlt-1 or
sVEGFR-1) is a tyrosine
kinase protein with
antiangiogenic properties.
•  sFlt-1 is important in the
regulation of blood vessel
formation in diverse
tissues, including the
kidneys, cornea, and
uterus.
 These proteins are involved in the
pathogenesis of placental disorders
•  In hypoxic/ ischemic regions of pathologic
placentas, expression of PlGF and VEGFR-1 is
enhanced in villous trophoblasts via autocrine
regulation
•  Expression of VEGF and VEGFR-2 is increased
within the villous vessels through paracrine
regulation
•  Villi from missed abortion and blighted ovum
show diminished immunoreactivity of VEGF in
the trophoblasts, VEGFR-1 in the syncytium, and
VEGFR-2 in the trophoblasts.
•  . It appeared that median sFlt-1
expression was significantly less
in invasive areas of cases [5.0
(2.0–6.0)] compared to control
placentas [12.0 (9.0–15.0), p =
0.003, Fig. 2]. Median sFlt-1
expression also was significantly
less in non-invasive areas of
cases [5.5 (5.0–7.0)] compared to
control placentas (p = 0.01).
There was no significant
difference between the invasive
and non-invasive areas of cases (p
= 0.23). Cases showed a gradient
of sFlt-1 expression from fetal to
maternal (high to low).
•  In this study, Shainker et al demonstrated decreased
expression of sFlt-1 in villous trophoblasts in patients
with invasive placentation, specifically placenta increta
and percreta.
•  When compared to controls, both invasive and non-
invasive areas from cases show lower sFlt-1
expression, although the findings for non-invasive
areas are less dramatic than for invasive areas. No
statistically significant difference in expression,
however, was observed between invasive and non-
invasive areas among cases.
•  Their findings are consistent with the data published
by another study (McMahon et al.) who also reported
that expression of sFlt-1 was lower in areas of invasive
placentation, suggesting a functional role for sFlt-1 in
invasive placental implantation.
Stage 2 (Conception and implantation)
Placenta Accreta Spectrum Disorder Implantation

Low
O2
Uterine HIF-1
(Hypoxia inducible factor-1)
Defect

Huppertz, B; Gauster, M; Orendi, K; König, J; Moser, G. Oxygen as modulator of trophoblast invasion. J Anat. 2009; 215(1):
14-20
Cha J, Sun X, Dey SK. Mechanisms of implantation: strategies for successful pregnancy. Endocr Rev 2004;25(3):341–73. 3
Rosario GX, Konno T, and Soares MJ. Maternal hypoxia activates endovascular trophoblast cell invasion. Dev Biol. 2008
February 15; 314(2): 362–375 28
Stage 3 (Increase of angiogenic factor)
Placenta Accreta Spectrum Disorder
Implantation

HIF-1

Induce
angiogenic
growth factor

Angiogenic factors that have increased have occurred

in early pregnancy in Cesarean Scar Pregnancy
29
Stage 2 (Conception and implantation)
Placenta Accreta Spectrum Disorder Implantation

Langhans Fibroid
Layer

Rohr’s Fibroid
Layer
Poor quality of previous CS Desidual Nitabuch’s Fibroid
scar Defect Layer
Increase the
collagen
 SUMMARIES
1.  Pre-conceptional care, ANC & Family
Planning
2.  Quality of surgical activities toward good
wound healing
3.  Avoiding disease related factors
(infection,nutrition & medical disorder)
4.  ANGIOGENIC & ANTIANGIOGENIC are
involved in the pathogenesis of placental
disorders
•  Trophoblast expression of sFlt-1 near the implantation
site is normally moderated by VEGF expression in the
decidua. They hypothesize that low expression in our
cases may be due to the lack of decidua at the
implantation site, which is the defining feature of
invasive implantation. The diminished sFlt-1 expression
also might be an adaptation to increased blood flow.
sFlt-1 expression is sensitive to perfusion, showing
higher expression with increasing hypoxia.
•  In the setting of invasive implantation, trophoblasts
infiltrate into deep myometrial vessels leading to
increased blood flow into the intervillous space. A low
sFlt-1 expression may indicate high levels of local
perfusion within the intervillous space.
•  This model also is compatible with data in that
the sFlt-1 expression profile in all cases
demonstrates a gradient from lowest at the
myometrial interface to highest toward the
fetal surface. Sections also show frequent
sFlt-1 ‘‘hot spots’’ in areas with increased
perivillous fibrin, areas of erratic maternal
blood flow, and areas where villi are
entrapped within uterine veins along with the
myometrial interface (Fig. 4)
•  From their study, Jenn-Jhy Tseng and Min-Min Chou showed that VEGFR-2
expression in syncytiotrophoblast, rather than villous and extravillous
cytotrophoblasts, is significantly lower in cases than controls in both the
second and third trimesters (p_0.005 and 0.002, respectively).
•  However, the expression of VEGFR-1 and VEGFR-3 in trophoblast
populations was not significantly different in controls and cases (p>0.05).
•  Endothelial cells of the larger vessels in specimens from placenta accreta
stained stronger for Ki-67 (a proliferating cell nuclear antigen marker) than
those from the normal placenta. Western blot analyses and reverse
transcription-polymerase chain reaction (RT-PCR) showed that VEGFR-2
expression correlated with the trend in immunohistochemical data
(p<0.05).
•  Furthermore, enzyme-linked immunosorbent assay (ELISA) on the
placental lysates showed that women with placenta accreta had
significantly higher VEGF (p_0.001) and lower sVEGFR-2 concentrations
(p_0.015) than those with normal pregnancy. However, PlGF and
sVEGFR-1 concentrations did not show a dramatic difference between
cases and controls (p_0.149 and 0.354, respectively).
Scoring scale for immunohistochemical staining of
sFlt-1 in villous trophoblasts, with 0 correspondings
to no staining (a) and 3 being the most intense
staining (c). Moderate staining is illustrated in panel
b. Expression of sFlt-1 in villous trophoblast (asterisk)
as evaluated relative to intermediate trophoblast in
at the maternal
surface (arrow)
Fig 4. Areas of variable sFlt-1
expression in selected cases. a Low
power image of sFlt-1 gradient from
fetal (high, asterisk) to maternal (low,
arrow) side. b sFlt-1 hot spot. Villi with
high sFlt-1 expression (asterisk)
entrapped in fibrin (arrow). c sFLT-1
hot spot. Villi with high sFlt-1
expression (asterisk) within a vein
(arrows). d Corresponding Masson
trichrome stain for panel c highlighting
a vein (arrows).
Stage 1 (Niche – pre pregnancy)

•  In the last decades we became aware of gynaecological

symptoms after a CS, such as postmenstrual spotting,
dysmenorrhoea, chronic pelvic pain and dyspareunia that could
be related to an incompletely healed uterine scar, also called a
niche.
•  The presence of a niche may be associated with obstetric
complications in future pregnancies.
•  Morphological ‘abnormalities’ in the Caesarean scar can be
visualized using transvaginal sonography (TVS), gel or saline
instillation sonohysterography (SIS) or hysteroscopy.
•  The term ‘niche’ describes the presence of a hypoechoic area
within the myometrium of the lower uterine segment, reflecting
a discontinuation of the myometrium at the site of a previous
CS
•  Niches were defined as indentations of the myometrium of at least 2
mm Vervoort AJMW. Human Reproduction, Vol.30, No.12 pp. 2695–2702, 2015
Jordans, IPM. Ultrasound Obstet Gynecol 2019; 53: 107–115
Stage 1 (Niche – pre pregnancy)
Surgery – related
factors
1.  Low (cervical) location of the uterine incision during a CS
2.  Incomplete closure of the uterine wall, due to single - layer,
endometrial saving closure technique or use of locking
sutures.
3.  Surgical activities that may induce adhesion formation (i.e. non
– closure of peritoneum, inadequate haemostasis, applied
Patient – related
sutures, use of adhesion barriers).
factors
Factors that possibly hamper normal wound healing and related
angiogenesis.
•  history of gestational diabetes
•  advanced maternal body mass index
•  longer duration of active labor
•  Nutrition
•  etc Vervoort A.J.M.W. Human Reproduction, Vol.30, No.12 pp. 2695–2702, 2015
Stage 1 (Niche – pre pregnancy)
Hypothesis of
Niche
Hypothesis 1 : Cervical location of the uterine incision induces
impaired wound healing
•  One study reported very low uterine incisions to be an independent
risk factor for the development of large niches
•  CS performed in active labour, after the cervix has effaced and has
become part of the uterine wall, to be associated with a higher
prevalence of niches
•  The routine creation of a bladder flap by opening the utero-vesical
fold of the peritoneum. Dissection of the bladder is commonly
performed to keep the bladder dome out of the surgical field, but
might also influence the location of the uterine incision during CS.
The necessity of this step has only recently begun to be examined,
and there is some evidence that in routine cases the creation of a
bladder flap can be omitted safely
Vervoort A.J.M.W. Human Reproduction, Vol.30, No.12 pp. 2695–2702, 2015
Stage 1 (Niche – pre pregnancy)
Hypothesis of
Niche
Hypothesis 2 : Incomplete closure of the uterine wall

Schematic diagram of incomplete closure of the myometrium and counteracting forces

on the uterine scar due to the retraction of adhesions between the scar and the
abdominal wall in a retroflected uterus. (a) Single-layer closure of the uterus or locking
suture may increase niche formation due to greater risk of incomplete closure. (b)
Counteracting forces on the Caesarean section uterine scar, due to retraction of
adhesions between the uterine scar and the abdominal wall in a retroflected uterus,
may impair wound healing and increase the formation of niches.

Vervoort A.J.M.W. Human Reproduction, Vol.30, No.12 pp. 2695–2702, 2015

Stage 1 (Niche – pre pregnancy)
Hypothesis of
Niche
Hypothesis 3 : Surgical activities that may induce adhesion formation
and as a consequence induce impaired wound healing due to
counteracting forces on the uterine scar

In theory, several factors that influence adhesion formation after CS

can be postulated. In general it is known that factors such as
inadequate haemostasis, inflammation due to infection, tissue
ischaemia, tissue devascularisation and tissue manipulation can cause
formation of adhesions
Hypothesis 4 : Patient or disease related factors that impair wound
healing.

•  Nutrition
•  infection
•  Medical disorder condition
Vervoort A.J.M.W. Human Reproduction, Vol.30, No.12 pp. 2695–2702, 2015
Pendahuluan

•  Kelainan Spektrum Plasenta Akreta meningkat akhir

– akhir ini di Indonesia
•  Mortalitas dan morbiditas sangat tinggi
•  Faktor risiko utama adalah bekas seksio sesarea
•  Angka seksio sesarea di Indonesia berdasarkan data
BPJS setinggi 58%

Mengapa bisa
terjadi ?
Stage 4 (increase of growth factors and decrease
of inhibin factors)
Menginduksi Angiogenesis:
1.  Peningkatan regulasi faktor pertumbuhan
angiogenik: VEGF, Ang-2, RLN, RXFPI
2.  Faktor antiangiogenik yang ditekan: ekspresi sFlt-1

Mengaktifkan replikasi terus Sinyal proliferative yang

menerus: berkelanjutan
(1) Telomer yang dipersingkat (1) EGFR
(2) Perubahan penuaan seluler
Kelainan (2) c-erB-2 onkogen

Menekan destruksi imun : Spektrum Mengaktifkan Invasi:

(1) Meningkat: - FoxP3 +
Tregs, CD25 + T-sel
Plasenta (1) EMT persisten
sepanjang kehamilan
(2) Menurun: - Sel T CD4 +, Akreta (2) Peningkatan MMP-2,
CD209 + DC, dNK, CD56 + MMP-9

Menekan kematian sel

Menekan growth supressor: (1) INSL4
Pemrograman ulang
(1) ekspresi p53 berkurang (2) microRNA-29a/b/c
metabolisme energi:
Kadar PAPP-A rendah à upregulated MCL1
insulin like growth factor

Bartels HC, Postle JD, Downey P, Brennan DJ. Placenta Accreta Spectrum: A Review of Pathology, Molecular Biology, and Biomarkers %J Disease
Markers. 2018;2018:11.
Stage 4 (increase of growth factors and decrease
of inhibin factors)

•  Saffer C, Olson G, Boggess KA, Beyerlein R, Eubank C, Sibai BM. Determination of placental growth factor (PlGF) levels in healthy pregnant
women without signs or symptoms of preeclampsia. Pregnancy hypertension. 2013;3(2):124-132.
•  Benton SJ, McCowan LM, Heazell AEP, et al. Placental growth factor as a marker of fetal growth restriction caused by placental dysfunction.
Placenta. 2016;42:1-8.
•  De Falco S. The discovery of placenta growth factor and its biological activity. Experimental & molecular medicine. 2012;44(1):1-9.
Stage 5 (Massive Vascular system)
Diagram showing a normal and an
accreta placental cotyledon. Note
the accreta villi reaching the
arcuate artery through the
junctional zone (JZ) of the inner
third of the myometrium, the
dilatation of the arcuate
circulation, and the absence of a
cleavage zone.

It may be that in the absence of a decidua, the normal release of proteases

and cytokines from activated maternal immune cells is missing, impairing
arterial remodelling. Invasion of larger vessels in the outer myometrium and
near the serosa in Placenta Accreta Spectrum Disorder (PASD) is probably
determined by access rather than a pre-existing defect in trophoblastic growth
that would produce uncontrolled invasion of Extra Villous Trophoblast (EVT)
through the entire depth of the myometrium, transforming the arterial
vasculature beyond the level of the Junctional Zone (JZ). Excessive dilatation of
the arcuate arteries is the most prominent feature of PA prenatally on
ultrasound and macroscopically on the uterine surface at delivery.