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\begin{document}

\title{Placenta Accreta Spectrum Disorder; is the main pathology placental
invasion?}



\author[1]{alev esercan}%
\author[1]{emre ekmekci}%
\author[1]{ferhat coskun}%
\affil[1]{Sanliurfa Egitim ve Arastirma Hastanesi}%


\vspace{-1em}



  
  \date{May 16, 2024}


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\selectlanguage{english}
\begin{abstract}
Objective: Placenta accreta spectrum disorder(PAS) is a wide spectrum of
disease defining adherence of placenta. In the literature, the
definition of PAS it s still changing after new studies. Design: Despite
the definition is still changing, the exact pathophysiology is not
clear. Setting and population: Pathology reports of all patients who had
undergone peripartum hysterectomy in Sanliurfa Training and Research
Hospital with the diagnosis of PAS, were evaluated retrospectively.
Methods: Diagnosis of PAS was made preoperatively according to the
findings with sonography or MRI from May 2017 to September 2021. Main
outcome measures: Pathology reports of hysterectomy specimens and
comparison of pre and postoperative diagnosis of PAS were the main
outcome measures. Results: A total of 45 cases of peripartum
hysterectomy due to PAS were identified retrospectively during these
four years from the hospital's medical records. Only 17 of 45 patients
who underwent hysterectomy with the diagnosis of placenta accreta
spectrum were found to have a histopathological diagnosis that supported
placental invasion. In 20 patients, the histopathological diagnosis was
consistent with a normal placenta protruding from a uterine wall defect
independent of placental invasion. Histopathological diagnosis was
compatible with the normal placenta in 8 patients. Conclusion: Although
PAS is defined as `anormal placentation'; in new studies myometrial
defect and placental protrusion may be the main cause of PAS. Funding:
None.%
\end{abstract}%



\sloppy


\textbf{Placenta Accreta Spectrum Disorder; is the main pathology
placental invasion?Research articlePlacenta Accreta Spectrum Disorder
(running title)}Alev Esercan\selectlanguage{ngerman}¹, Emre Ekmekci², Ferhat
Coskun³\textbf{¹}Department of Obstetrics and Gynecology, Sanliurfa
Education and Research Hospital, Sanliurfa, Turkey\textbf{²} Department
of Perinatology, Sanliurfa Education and Research Hospital, Sanliurfa,
Turkey ³ Department of Pathology, Sanliurfa Education and Research
Hospital, Sanliurfa, Turkey\textbf{Corresponding author:} Alev
Esercan,\emph{alevesercan@gmail.com}, Sanliurfa Education and Research
Hospital, Yenice Mah. Yeni Cad.63200 Sanliurfa/Turkey, +(90) 5052634609.
ORCID ID: 0000-0002-6215-6532 Word Count: 2812 words\textbf{Abstract} ~
Objective: Placenta accreta spectrum disorder(PAS) is a wide spectrum of
disease defining adherence of placenta. In the literature, the
definition of PAS it s still changing after new studies. Design: Despite
the definition is still changing, the exact pathophysiology is not
clear. Setting and population: Pathology reports of all patients who had
undergone peripartum hysterectomy in Sanliurfa Training and Research
Hospital with the diagnosis of PAS, were evaluated retrospectively.
Methods: Diagnosis of PAS was made preoperatively according to the
findings with sonography or MRI from May 2017 to September 2021. Main
outcome measures: Pathology reports of hysterectomy specimens and
comparison of pre and postoperative diagnosis of PAS were the main
outcome measures. Results: A total of 45 cases of peripartum
hysterectomy due to PAS were identified retrospectively during these
four years from the hospital's medical records. Only 17 of 45 patients
who underwent hysterectomy with the diagnosis of placenta accreta
spectrum were found to have a histopathological diagnosis that supported
placental invasion. In 20 patients, the histopathological diagnosis was
consistent with a normal placenta protruding from a uterine wall defect
independent of placental invasion. Histopathological diagnosis was
compatible with the normal placenta in 8 patients. Conclusion: Although
PAS is defined as `anormal placentation'; in new studies myometrial
defect and placental protrusion may be the main cause of PAS. Funding:
None. Keywords: adherent placenta, cesarean hysterectomy, placenta
percreata,\textbf{Introduction}The placenta accreta term was first used
by Baisch in 1907, and the first case series of placenta accreta was
published by Irving and Hertig in 1937. The earlier previous reports
have been used the term `adherent placenta' to describe the main
pathology(1, 2). Lukes et al. classified the pathology in three
histopathological categories according to the depth of villous invasion
of the placenta in 1966. If the placenta adheres to myometrium without
the decidual interface, described the pathology as accreta. If the
placenta invades the myometrium, called increta and placenta, invades
all uterine walls, they are described as percrata(3). The term placenta
accreta spectrum (PAS) is now the preferred and recommended description
of pathology by FIGO, ACOG, RCOG, and SMFM, including all subtypes of
this heterogeneous condition(4). Before the widespread use of
ultrasonography and magnetic resonance imaging (MRI), placenta accreta
cases could only be diagnosed clinically and during delivery. Irving and
Hertig defined cases in which the placenta did not separate entirely or
partially after delivery as placenta accreta, and this definition became
clinically standard for years(2). However, this definition has included
the `stick placenta' cases that cannot be described as PAS. The
confusion in the definition is still not resolved. Some prefer to use
the term morbidly adherent placenta and argue that this definition
should be used in cases where the placenta does not separate within 30
minutes despite all medical interventions and active management(5). If
we look at the historical process in defining these phenomena, the
confusion continues. For example, morbidly adherent placenta, pernicious
placenta, abnormally invasive placenta, and today's placenta accreta
spectrum; all these descriptions are being used in literature. In
addition, even the patient group mentioned by the authors using the
exact definition does not address cases of similar severity. This lack
of precise diagnosis can explain the wide variation in incidence and
prevalence of PAS in literature in the last two decades(4, 6). In the
last ten years, there has been a dramatic increase in the diagnosis of
PAS, and there has been a tremendous increase in the publications
published in this field(7). Although it is shown as the increase in
cesarean rates is the main reason for this, how much accurate is it to
put this as the only factor? Although the worldwide increase in cesarean
delivery rates is an obvious fact, can other factors be associated with
this increase in the diagnosis of PAS cases? More than 90\% of PAS cases
are encountered in association with placenta previa(8). The combination
placenta previa on a previous cesarean section scar and PAS is the
leading factor of maternal morbidity and mortality due to massive
peripartum hemorrhage. Carusi et al. reported their experience on PAS
cases that were not associated with placenta previa in 2020. They
reported less severity at PAS cases when not associated with Previa(9).
This relationship may show that the presence of scar tissue and the
location of the placenta in an area with less myometrial tissue are
associated with morbidity. Today, we primarily use ultrasonography and,
in some cases, MRI in the prenatal diagnosis of PAS. However, especially
in cases with risk factors, the patients are being managed more
carefully if imaging methods detect findings compatible with PAS. The
findings of PAS described on both ultrasonography and MRI include
placental ``bulge,'' loss of the retroplacental clear or hypoechoic
zone, imperceptible myometrium, and bladder wall interruption or
irregularity. Vascular findings include subplacental or ureterovesical
hypervascularity and intraplacental abnormal vascularity or lacunae(10).
Although PAS cases that have been diagnosed prenatally or intrapartum
are substantially managed by hysterectomy, more than half of the authors
do not provide detailed data on the macroscopic clinical description at
birth and histopathologic confirmation of the diagnosis of placenta
accreta(11). In addition, there are very few studies histopathologically
distinguishing these cases from other adherent placentas. This study
evaluated cases diagnosed as PAS prenatally and who have undergone
hysterectomy. Also, we evaluated the histopathological results and the
presence of placental invasion in the hysterectomy specimens. Finally,
we aimed to evaluate whether the primary pathology in PAS cases is a
placental invasion or other factors.\textbf{Methods} Study design and
patient selection We conducted a retrospective cohort study using
Sanliurfa Training and Research Hospital (Sanliurfa, Turkey).
Institutional Review Board approval was obtained from Harran University,
School of Medicine (HRU/21.18.24). We included all patients who had
undergone a peripartum hysterectomy with the diagnosis of PAS, and the
diagnosis of all was made preoperatively according to the findings with
sonography or MRI from May 2017 to September 2021. The cases that were
managed with uterine sparing approaches and have not undergone
hysterectomy were not included in the study. Cases with a history of
cesarean section were only included. Patients without any prior cesarean
section were not included in patient selection. Verbal and written
informed consent were taken from the patients for the study. The
antepartum diagnosis of PAS was made according to the sonographic
findings and, when necessary, along with MRI. Ultrasound examinations
were performed at the same center prenatally, and all were confirmed by
the same maternal-fetal medicine physician (Ekmekci E.) about the
findings of PAS. All patients were followed, and the deliveries were
planned electively at 35\textsuperscript{th} gestational week if there
was no need for emergency delivery beforehand. All elective deliveries
have been performed by the same surgical team. However, different
physicians have performed emergent operations at the same hospital.
Decisions for conservative management or hysterectomy were made
according to multiple factors, patients' desire, disease severity,
intraoperative surgical conditions, etc. However, these results would
not affect our results, as only subjects who had a hysterectomy were
included in the study. Collected outcome data included maternal age,
gravidity, number of cesarean deliveries, gestational age at delivery,
red blood cell unit transfusion, the occurrence of planned or unplanned
cystotomy, operation time, and the need for hospital readmission. In
addition, the presence of placenta previa in cases was recorded. The
final pathologic diagnosis was determined from pathology reports. The
histopathologic diagnosis of all cases was reevaluated microscopically
by a pathologist (Coskun F.). In addition, the invasion of placental
tissue and the condition of myometrial tissue on the scar line was
reevaluated. Statistical analyses were performed using the Statistical
Package for the Social Sciences (SPSS.22, IBM SPSS Statistics for
Windows, Version 22.0, IBM Corp., Armonk, NY, USA). The
Kolmogorov--Smirnov test was used to verify the normality of
distribution. Mean or median values were used for descriptive analysis
of the characteristics of the data for normal distribution. Categorical
data were given as percentages. Chi-square and Fisher Exact tests were
used for categorical data. T-test was used for calculating two
independent means; for all tests, the significance level was defined as
p \textless{}0.05.\textbf{Results}A total of 45 cases of peripartum
hysterectomy due to PAS were identified retrospectively during these
four years from the hospital's medical records. The median maternal age
was 35(24-42). All patients had a history of previous cesarean sections.
No hysterectomy case due to PAS was detected without a history of
cesarean section. The median number of previous cesarean sections was
4(3-7). One pregnancy was a twin pregnancy, and the other 44 were
singleton pregnancies. While placenta previa was not present in only 3
cases, total placenta previa was present in 42 cases. Placenta was
located at the posterior in only 2 cases; however, it was located on the
anterior uterine wall in 43 cases. Patient and pregnancy characteristics
are reported in Table 1. Thirty-four cases have undergone surgery
electively at 35-37\textsuperscript{th} gestational weeks. The median
gestational age at operation time is 35 weeks (21-37 weeks). 11 cases
have undergone surgery before the 34\textsuperscript{th} gestational
week due to emergencies like obstetrical hemorrhage or uterine rupture.
Three cases have undergone an emergency hysterectomy due to uterine
rupture from a previous uterine scar, and eight have undergone surgery
for obstetrical hemorrhage. The mean operation time was 137±22 minutes
(70-180). The median red blood cell transfusion was four units (2-10).
Transfusion of 5 units or more red blood cells was required in seven
cases. Intraoperative cystotomy and bladder wall repair are required for
seven cases. One maternal death occurred at postoperative 36. hours due
to disseminated intravascular coagulation induced by massive
transfusion. All patients were followed up in the hospital for 3-7 days
after the operation and were discharged. No patient required hospital
readmission after discharge. All the histopathology results of the
hysterectomy materials were reached. Histopathology results are listed
in Figure 3. In addition, materials with pathological diagnosis of
placenta accreta, increta, and percrata were reevaluated in terms of
invasion. Figures of histopathological some selected specimens are
presented (Figure1-2). Only 17 of 45 patients who underwent hysterectomy
with the diagnosis of placenta accreta spectrum were found to have a
histopathological diagnosis that supported placental invasion (placenta
accreta, increta, and percrata). In 20 patients, the histopathological
diagnosis was consistent with a normal placenta protruding from a
uterine wall defect independent of placental invasion. Histopathological
diagnosis was compatible with the normal placenta in 8 patients (Figure
3). In the re-examination of the histopathology preparations of the
specimens, some specimens that were previously interpreted as placental
invasion were evaluated as placental dehiscence or as usual rather than
invasion. In the re-evaluation of the pathological specimens of 17 cases
with a previous histopathological diagnosis compatible with placental
invasion, the histopathological diagnosis of 12 patients was interpreted
as an abnormal appearance consisting of a thinned or absent myometrium
and placenta located on an abnormal decidua rather than a placental
invasion. In these cases, it was observed that the previously considered
placental invasion areas were evaluated as the process resulting from
abnormal choriodecidual relations formed by the placement of placenta on
a damaged, insufficiently healed myometrium and decidua. In the
remaining five patients, although the diagnosis was not sufficient to
say placental invasion, a clear interpretation was not made for the
histopathological diagnosis since the presence of chorionic villi
extending between myometrial fibers could not be differentiated from the
presence of invasion or dehiscence of chorionic villi located on the
myometrial defect that had not healed adequately (Figure
4-5).\textbf{Discussion}, and (in light of other evidence)\textbf{Main
Findings} Although risk factors for PAS are well defined, the underlying
mechanisms leading to abnormal placentation are not yet clearly
understood. Human placentation is a unique developmental process, which
is a highly invasive process that confines itself entirely to the
decidua and superficial myometrium in the uterus(12). Various hypotheses
have been proposed to explain this abnormal placentation in PA. First,
the abnormal trophoblast function leading to excessive invasion of the
uterine myometrium was emphasized(13-15). Then, the other prevailing
hypothesis has been postulated that abnormally deep trophoblastic
infiltration is secondary to failure of decidua basalis formation in the
uterine scar area (13, 16, 17). Recently, decidualization disorder and
the appearance of increased trophoblastic invasion have been proposed
due to localized hypoxia and abnormally vascularized scar tissue(18).
Tseng et al. blamed excessive angiogenesis due to increased VEGF and
EGFR expression from trophoblasts based on PAS(19). Contrary to studies
defending the differentiation of trophoblastic cells, Earl et al. stated
that extravillous trophoblasts of PAS have the same immunophenotype as
those of normal placenta and emphasized that overactive trophoblastic
invasion is not likely in the pathogenesis of PAS, and the absence of
decidua is of greater importance in the pathogenesis(20). Tantbirojn et
al. explained that trophoblastic invasion of the great vessels of the
myometrial outer layer and serosa is more likely due to cracking and
separation in the existing myometrial scar area in PAS, rather than
trophoblastic growth defects or other immunologic factors. They
presented the first opinion in 2008 that the main factor in the
pathophysiology of the PAS is anatomical factors rather than
immunohistochemical factors(16). As seen in our results, in the
histopathological evaluation of the specimens of 45 patients who
underwent hysterectomy with PAS diagnosis, the placental invasion was
not detected in 40 patients. However, the primary pathology was the
anatomical defects at the myometrium. Although the placental invasion
was not defined in the remaining 5 cases, it was not interpreted as
non-invasion due to the microscopic appearance of chorionic villi
located between myometrial fibers. Although this is a retrospective
study, the diagnosis of the placenta accreta spectrum was confirmed
ultrasonographically at the antepartum period of all the cases included
in the study. All included cases were severe cases requiring
hysterectomy, which eliminates the subjective variations in the
diagnosis of PAS. In all cases, the need for hysterectomy is clear proof
that all were cases of severe and challenging nature. However, when the
pathological diagnoses were examined, the placental invasion was not
excluded in only 5 cases, but histopathology compatible with placental
invasion was not observed in 40 cases. Pathological diagnosis was
compatible with a normal placenta protruding from a uterine wall defect
independent of placental invasion in 20 cases, and placental pathology
was utterly normal in 8 cases. Maternal morbidity (massive transfusion,
urinary tract injury, intensive care unit admission, hysterectomy, and
maternal death) in PAS is associated with different factors. When we
look at the results in our case series, it does not seem compatible with
the accepted entity that placental invasion severity is the main factor
associated with morbidity. The coexistence at 43 of 45 cases with total
placenta previa suggests the presence of placenta previa as an essential
factor in morbidity. In addition, the size of the myometrial defect and
the severity of the anatomical defect is also seen as important factors
related to morbidity. In our case series, the median history of previous
cesarean section is 4. The presence of increased previous cesarean
section and associated more severe adhesions seems essential in
morbidity. Einerson et al. reported the most important factors
associated with morbidity in PAS cases: the degree of uterine scar
dehiscence, the degree and location of pelvic adhesions, and the extent
of abnormal vasculature in and around hysterectomy planes(10). Abnormal
vasculature in and around the previous uterine scar area, especially the
parametrial area, is a poor prognostic factor at PAS surgery. During the
antepartum period, this abnormal vascularization appears as `lacunae'
with irregular borders and low resistance flow in sonography. More
lacunas are a poor prognostic factor in terms of the difficulty of the
operation before surgery. These lacunae have always been interpreted as
evidence of invasion. Normal placentation involves the invasion of
extravillous trophoblasts into uterine spiral arteries(21). When the
decidua is harmed or abnormal, the extravillous trophoblasts behave the
same way but do not stop and are not confined to decidua. They do so in
the myometrium and access deep myometrial vessels, adhesions, and deeper
pelvic vessels. This should not be interpreted as an invasion of the
placenta like choriocarcinoma. Access to deeper myometrial structures of
extravillous trophoblasts induces more extensive vascular signaling and
more dramatic uterine scar dehiscence(10). As it can be understood from
here, although lacunae are related to the severity of the cases, they
should not be interpreted as an indicator of placental invasion. The
fact that placental lacunae are more common in placenta previa cases
without a myometrial scar and are associated with postpartum bleeding
may be related to insufficient decidual development in the lower uterine
segment and invasion of extravillous trophoblasts into deep myometrial
arteries. Defective decidual layer and pelvic hypervascularity resulting
from the extension of extravillous trophoblasts into deep myometrial
arteries is the first important factor related to the severity of the
surgery. The second factor is the progressive scar dehiscence causing
the placental extension into the niche of the uterine scar in the first
trimester and extending to the serosa as it progresses in later
pregnancy. Timor-Tritsch et al. defined cesarean scar pregnancy as a
precursor of the placenta accreta spectrum, and both are
histopathologically indistinguishable. And they described that the
leading pathology and process of PAS are abnormal attachment, abnormal
recruitment of uterine vasculature, and slow progressive uterine scar
dehiscence(22).\textbf{Strengths and Limitations}The retrospective
design of our study is a significant limitation. In addition, including
only hysterectomy cases in the study is a limitation for comparison for
all PAS cases. Still, on the other hand, it is an advantage in
preventing variations in the diagnosis of PAS. In addition, the fact
that all cases required hysterectomy is an indication that cases with
severe features were included. Finally, it is an advantage in terms of
diagnostic variation that the same physician-diagnosed all cases during
the antenatal period, and the same pathologist evaluated all pathology
materials.\textbf{Interpretation and Conclusion}Placenta accreta is
associated with severe morbidity, especially in cases with a history of
cesarean section and where the placenta is located on the uterine scar.
However, contrary to classical belief, the main factor associated with
morbidity in these cases is placental dehiscence, which occurs due to
the abnormal placement of the placenta on the decidua rather than
placental invasion associated with the placenta previa. Disclosure of
interest: None. Acknowledgments: None. Conflicts of interest: The
authors declare that there is no conflict of interest regarding the
publication of this article. Funding: None Contribution of authorship:
Esercan A: Conception and design, acqusition of data, analysis and
interpretation of data, drafting of the manuscript Ekmekci E: Drafting
of the manuscript, Critical revision of the manuscript for important
intellectual content, statistical analysis, supervision Coskun F:
Administrative technical or material support, drafting of the manuscript
Details of ethics approval: Institutional Review Board approval was
obtained from Harran University, School of Medicine, Turkey
(HRU/21.18.24).\textbf{References}

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