Placenta Accreta Spectrum
Disorder; is the main pathology placental invasion?Research articlePlacenta Accreta Spectrum Disorder (running title)Alev Esercan¹, Emre Ekmekci², Ferhat Coskun³¹Department of Obstetrics and Gynecology, Sanliurfa Education
and Research Hospital, Sanliurfa, Turkey² Department of Perinatology, Sanliurfa Education and Research
Hospital, Sanliurfa, Turkey
³ Department of Pathology, Sanliurfa Education and Research Hospital,
Sanliurfa, TurkeyCorresponding author: Alev Esercan,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 wordsAbstract
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,IntroductionThe 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.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 35th 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 <0.05.ResultsA 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
35-37th gestational weeks. The median gestational age
at operation time is 35 weeks (21-37 weeks). 11 cases have undergone
surgery before the 34th 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).Discussion, and (in light of other evidence)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).Strengths and LimitationsThe 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.Interpretation and ConclusionPlacenta 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).References
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