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
1. Moser RW. Plazentaforschung an der Universität Bern. Bulletin des médecins suisses| Schweizerische Ärztezeitung| Bollettino dei medici svizzeri. 2011;92(51/52):2023.
2. Irving F. A study of placenta accreta. Surg Gynecol Obstet. 1937;64:178-200.
3. Luke RK, Sharpe JW, Greene R. Placenta accreta: the adherent or invasive placenta. American journal of obstetrics and gynecology. 1966;95(5):660-8.
4. Diag FPA, Jauniaux E, Ayres-de-Campos D, Tikkanen M. FIGO consensus guidelines on placenta accreta spectrum disorders: introduction. 2018.
5. Jauniaux E, Burton GJ. Pathophysiology of placenta accreta spectrum disorders: a review of current findings. Clinical obstetrics and gynecology. 2018;61(4):743-54.
6. Jauniaux E, Collins SL, Jurkovic D, Burton GJ. Accreta placentation: a systematic review of prenatal ultrasound imaging and grading of villous invasiveness. American journal of obstetrics and gynecology. 2016;215(6):712-21.
7. Jauniaux E, Alfirevic Z, Bhide A, Belfort M, Burton G, Collins S, et al. Placenta Praevia and Placenta Accreta: Diagnosis and Management: Green-top Guideline No. 27a. BJOG. 2018;126(1):e1-e48.
8. Obstetricians ACo, Gynecologists, Medicine SfM-F. Obstetric care consensus no. 7: placenta accreta spectrum. Obstetrics and gynecology. 2018;132(6):e259-e75.
9. Carusi DA, Fox KA, Lyell DJ, Perlman NC, Aalipour S, Einerson BD, et al. Placenta accreta spectrum without placenta previa. Obstetrics & Gynecology. 2020;136(3):458-65.
10. Einerson BD, Comstock J, Silver RM, Branch DW, Woodward PJ, Kennedy A. Placenta accreta spectrum disorder: uterine dehiscence, not placental invasion. Obstetrics & Gynecology. 2020;135(5):1104-11.
11. Jauniaux E, Bhide A. Prenatal ultrasound diagnosis and outcome of placenta previa accreta after cesarean delivery: a systematic review and meta-analysis. American journal of obstetrics and gynecology. 2017;217(1):27-36.
12. Kaufmann P, Burton G. Anatomy and genesis of the placenta. The physiology of reproduction. 1994;1:441-84.
13. Fox H, Sebire N. Pathology of the Placenta: Elsevier Health Sciences; 2007.
14. Millar WG. A clinical and pathological study of placenta accreta. BJOG: An International Journal of Obstetrics & Gynaecology. 1959;66(3):353-64.
15. Khong T, Robertson W. Placenta creta and placenta praevia creta. Placenta. 1987;8(4):399-409.
16. Tantbirojn P, Crum C, Parast M. Pathophysiology of placenta creta: the role of decidua and extravillous trophoblast. Placenta. 2008;29(7):639-45.
17. Strickland S, Richards WG. Invasion of the trophoblasts. Cell. 1992;71(3):355-7.
18. Wehrum MJ, Buhimschi IA, Salafia C, Thung S, Bahtiyar MO, Werner EF, et al. Accreta complicating complete placenta previa is characterized by reduced systemic levels of vascular endothelial growth factor and by epithelial-to-mesenchymal transition of the invasive trophoblast. American journal of obstetrics and gynecology. 2011;204(5):411. e1-. e11.
19. Tseng J-J, Chou M-M. Differential expression of growth-, angiogenesis-and invasion-related factors in the development of placenta accreta. Taiwanese Journal of Obstetrics and Gynecology. 2006;45(2):100-6.
20. Earl U, Bulmer J, Briones A. Placenta Accreta: An Immunohistological Study of Trophoblast Populations. Obstetrical & Gynecological Survey. 1988;43(4):210-4.
21. Lunghi L, Ferretti ME, Medici S, Biondi C, Vesce F. Control of human trophoblast function. Reproductive Biology and Endocrinology. 2007;5(1):1-14.
22. Timor‐Tritsch I, Monteagudo A, Cali G, Vintzileos A, Viscarello R, Al‐Khan A, et al. Cesarean scar pregnancy is a precursor of morbidly adherent placenta. Ultrasound in Obstetrics & Gynecology. 2014;44(3):346-53.