Placenta accreta spectrum with severe morbidity: fibrosis associated with cervical-trigonal invasion

Abstract Objective Describe the clinical-surgical results of patients with PAS in the low-posterior cervical-trigonal space associated with fibrosis (PAS type 4) compared with PAS types in other locations (Types 1, upper bladder, 2 in upper parametrium) and in particular with PAS type 3, corresponding to dissectible cervical-trigonal invasion. The clinical-surgical results of using a standard hysterectomy were analyzed with a modified subtotal hysterectomy (MSTH) in patients with PAS type 4. Material and methods A descriptive, retrospective, multicenter study included 337 patients of PAS; thirty-two corresponding to PAS type 4, from three PAS reference hospitals, CEMIC, Buenos Aires, Argentina, Fundación Valle de Lili, Cali, Colombia, and Dr. Soetomo General Hospital, Surabaya, Indonesia, between January 2015 and December 2020. PAS was diagnosed by abdominal and transvaginal ultrasound and topographically characterized by ultrafast T2 weighted MRI. In persistent macroscopic hematuria after MSTH, the surgeon performs an intentional cystotomy and uses a square compression suture to achieve the hemostasis inside the bladder wall. According to a PAS topographical classification, the patients with low-vesical cervical involvement compared with PAS located in relation with the upper blader (type1), upper parametrium (type 2 upper), and also with PAS situated in the lower vesical-trigon space (type 3). PAS 3 and 4 are located in identical area, but in type 3, group A, the vesicouterine space was dissectible, and in type 4, group B, significant fibrosis made surgical dissection extremely challenging. Furthermore, group B was divided into patients treated with total hysterectomy (HT) and those treated with a modified subtotal hysterectomy (MSTH). The surgical requirements to perform an MSHT included the availability of proximal vascular control at the aortic level (internal manual aortic compression, aortic endovascular balloon, aortic loop, or aortic cross-clamping). Then surgeon performed an upper segmental hysterotomy, avoiding the abnormal placenta invasion area; after that, the fetus was delivered, and the umbilical cord was ligated. After uterine exteriorization, the surgeon applies a continuous circular suture with number 2 polyglactin 910, taking some portions of the myometrium -to avoid unintentional slipping- around the lower uterine segment and a 3–4 cm proximal to the abnormal adhesion of the placenta. After tightening hard the circular suture, the uterine segment was circumferentially cut, three centimeters proximal to the circular hemostatic sutures. Next, the surgery follows the upper steps of conventional hysterectomy without changes. Additionally, the histological presence of fibrosis was examined in all samples. Results Modified subtotal hysterectomy in patients with PAS type 4 (cervical-trigonal fibrosis) resulted in a significant clínico-surgical improvement over total hysterectomy. The median operative time and intraoperative bleeding were 140 min (IQR 90–-240) and 1895 mL (IQR 1300–2500) in patients undergoing modified subtotal hysterectomy, and 260 min (IQR 210–287) and 2900 mL (IQR 2150–5500) in patients treated with total hysterectomy, respectively. The complication rate was 20% for MSHT and 82.3% for patients with a total hysterectomy. Conclusions PAS in the cervical trigonal area associated with fibrosis implies a greater risk of complications due to uncontrollable bleeding and organ damage. MSTH is associated with lower morbidity and difficulties in PAS type 4. Prenatal or intrasurgical diagnosis is essential to plan surgical alternatives to improve the results.


Introduction
The placenta accreta spectrum (PAS) describes a wide range of lesions characterized by abnormal placenta attachment to the uterine wall [1]. Patients affected by PAS have a high risk of massive bleeding and visceral injuries. Still, most women with this condition present partial-thickness invasions mainly located in the upper part of the uterine segment [2] (Supplemental material, image 1). In a minority of PAS cases, patients have uterine full-thickness involvement (placenta percreta), and their surgical characteristics are associated with extreme technical complexity and an elevated risk of maternal morbidity [3].
Experienced surgical groups in the management of PAS habitually perform most surgeries without requiring vascular procedures [2][3][4] since they may be able to perform an accurate pelvic fascia dissection and manage different uterine hemostasis techniques. The low-posterior bladder involvement is topographically known as PAS type 3. Although it could have many vessels, there is a dissectible plane between the lower uterus, cervix, and the trigon (Supplemental material, image 2) that allows the separation between two organs. However, in some cases (PAS type 4), intense fibrosis in the posterior cervical-trigon area is so severe that it is almost impossible to safely separate the bladder from the uterus (Supplemental material, image 3).
In cases of massive low vesicouterine involvement, surgical options include the use of expectant management (leaving the placenta in situ) [5], intentional cystotomy with resection of a part of the bladder [6], retrograde hysterectomy [7] or compressive sutures placed in the posterior bladder and position of the uterine wall is left adhered [8].
However, these interventions could be ineffective or dangerous, especially when dissection is hard or impossible, mainly because reiterated separation attempts increase the possibility of further damage between involved organs. Additionally, a particular structure named a lower anastomotic circle [9] connects the blood supply of the bladder, the cervix, and the vagina [10], the attempt to separate both organs from the fibrous tissue can trigger uncontrollable massive bleeding or produce a severe urinary tract injury.
A manuscript describes the clinical-surgical results of patients with PAS located in the low-posterior vesicouterine space associated with dense fibrosis (PAS type 4) compared to PAS types in other locations (types 1, upper type 2, and 3). In addition, both types were matched to PAS types 3 and 4, also located in the same space (low posterior cervical-trigonal area). Finally, to establish a tactical advantage in cases of PAS type 4, the use of a standard hysterectomy compared to a modified subtotal hysterectomy (MSTH).

Materials and methods
A descriptive, retrospective, multicenter study included 337 patients with a confirmed diagnosis of PAS between January 2015 and December 2020 and collected from three reference hospitals for PAS (CEMIC, Buenos Aires, Argentina, Fundaci on Valle del Lili, Cali, Colombia, and Dr. Soetomo General Hospital, Indonesia). PAS was diagnosed by abdominal and transvaginal ultrasound and topographically characterized by ultrafast T2-weighted MRI (sagittal, coronal, and axial slices). The final surgical procedure was defined after intraoperative staging [11]. In the case of evident and dense lower vesicouterine fibrosis, PAS type 4 was surgically identified.
According to a topographical classification of PAS [2] , the patients with low-vesical cervical involvement and fibrosis (type 4) were compared with PAS located about the upper blader (type1), with the upper parametrium (type 2 high), and also with PAS situated in the lower vesical-trigon space (type 3). PAS type 3 (group A) was compared with PAS type 4 (group B). PAS in the lower parametrium (type 2 lower) was excluded from being considered a group with distinctive morbidity. PAS types 3 and 4 are located in the same area; however, the vesicouterine space was dissectible in type 3 (A). In type 4 (B), significant fibrosis involves the placenta invasion space. Furthermore, group B was divided into patients treated with total hysterectomy (HT) and those treated with a modified subtotal hysterectomy (MSTH). The surgical requirements to perform a modified subtotal hysterectomy included the availability of proximal vascular control at the aortic level (internal manual aortic compression, aortic endovascular balloon, aortic loop, or aortic cross-clamping).
Then surgeon performed an upper segmental hysterotomy, avoiding the abnormal placenta invasion area; next, the fetus was delivered, and the umbilical cord was ligated.
After uterine exteriorization, the surgeon inserted a continuous circular suture using a 7 cm half-circle needle with # 2 polyglactin 910 or any absorbable ones, taking some portions of the myometrium to avoid unintentional slipping around the lower uterine segment and approximately 3-4 cm proximal to the abnormal adhesion of the placenta (Supplemental material, image 4). After tightening hard the circular suture, the uterine segment was circumferentially cut, proximal to the circular hemostatic sutures (Supplemental material, image 5). Next, the surgery follows the upper steps of conventional hysterectomy. As a result, the cervix and the lower uterine segment (caudal to the level where vesicouterine fibrosis begins) remain stuck to the posterior lower bladder (Supplemental material, image 6), avoiding the injuries of the lower anastomotic circle (Supplemental material, image 7). When the surgeon removes the remaining placenta from the attached lower uterine segment, persist a possibility of some bleeding, and for this reason, some proximal aortic vascular control should be available. Finally, the surgeon suture of lower uterine segment edges to ensure any additional bleeding.
Moreover, the surgeon obliterates the colpouterine pedicles that arise from vaginal arteries in the posterior low segment area. Finally, compression sutures in the uterine segment and cervix compress the anterior and posterior uterine segment walls. As a result, the placental bed is compressed (Supplemental material, image 8) with the posterior wall and the residual uterus. These sutures are applied in an axial plane to obliterate the primary collateral anastomotic network of vesical, vaginal, and cervical branches. In persistent cases of gross hematuria after MSTH, the surgeon performs an intentional cystotomy and uses a square compression suture to achieve the hemostasis inside the bladder wall. (Supplemental material, image 9). A newly formed bleeding inside the bladder has an underdeveloped muscular tunica; consequently, it is not suggested to use electrocautery to control them because it could produce more damage and increase blood loss. In addition, a comparison between lower cervical-trigonal invasion without fibrosis (Group A, PAS type 3. N ¼ 90) and others with the presence of fibrous adherent tissue (Group B, PAS type 4) was performed to analyze fibrosis as an individual morbidity factor.
Besides, a low-cost training model was created with inexpensive materials to simulate and improve the expertise technique acquisition (Video F). According to the specialist recommendation, three samples of PAS specimens, including placenta and myometrium, were sent for pathology analysis with the hematoxylin-eosin technique. The pathologist confirmed PAS under histological criteria and analyzed the presence of fibrosis in the vesical-uterine interphase in a case of in-block resection (Supplemental material, image 10).
Continuous variables were expressed as medians and interquartile ranges and analyzed with the Mann-Whitney U test. Categorical variables are presented as proportions, and comparisons were made with the chi-square or Fisher exact test, depending on the case. Statistical significance was defined as p < .05. All data were analyzed using the statistical package Stata, version 14.0 (StataCorp, Texas, USA). Approval was obtained from the ethics committee under protocol number 550 À 2015.

Main findings
The placenta accreta spectrum associated with fibrosis and located between the lower uterine segment, the anterior cervix, and the vesical trigon (PAS type 4) implies a longer operative time, requirement of aortic vascular control, an extra intraoperative bleeding [12], a high risk of urinary lesions [6], the requirement of relaparotomy, number of transfusions, and higher morbidity [13] than PAS in other locations (Table 1). Comparison between PAS 3 and 4, both located in the same place and only differentiated by fibrosis (type 4), demonstrated that fibrous tissue is a specific factor that increases the operative time, the possibility of bleeding, organ damage, and maternal morbidity [2] ( Table 2). To perform a subtotal modified hysterectomy (MSTH) in PAS type 4, avoid damaging arterial anastomotic components arising from the bladder, the cervix, and the vagina. The surgical procedure removes all the placenta tissue, keeping the attached organ and the fibrotic adhesion process untouched because these tissues are naturally fragile and prone to massive bleeding [14]. The application of simple compression sutures in the remaining tissues or into the bladder (gross hematuria) allows for straightforwardly controlling any additional bleeding during MSTH. The use of aortic vascular control [11] (ballooning, manual compression, or aortic cross-clamping) was efficient to manage blood loss by internal iliac, external iliac, or aortic anastomotic components during a definitive surgery. Using a modified subtotal hysterectomy in PAS type 4 cases were associated with less operative time, reduced bleeding [14], need for transfusions, reoperations rate, and the possibility of organ damage concerning total hysterectomy (Table 3).

Clinical implications
Although it is not a usual presentation form, prenatal or surgical identification of PAS type 4 is essential to avoid severe complications and reduce maternal morbidity. An active source of bleeding into dense fibrosis is demanding and challenging to be controlled [14]. Furthermore, vascular connections among arteries of  PAS: placenta accreta spectrum. RBC: red blood cells unit. Ã Median (IQR). a PAS type 3: Placenta accreta spectrum affecting the lower part of the uterine segment and cervix, with a dissectible plane to separate both organs. b PAS type 4: Placenta accreta spectrum affecting the lower part of the uterine segment and cervix, with fibrosis between the uterus and the bladder and the impossibility of separating both organs. c Invaded uterine segment and placenta "in block" resection þ uterine repair. d Aortic or common iliac artery occlusion. e Urinary tract injuries, the requirement of relaparotomy, more than 4 RBCU transfused.
the lower uterine segment, the cervix, and the bladder trigone [9], also known as a lower anastomotic circle (LAC), could cause severe hemostasis trouble because flow occlusion from the blood loss branch is replaced immediately by other vessels that arise from multiple sources (Supplemental material, image 11). LAC is located at the intersection of the cervix, upper vagina, and low bladder. In addition, when a surgeon performs a total hysterectomy in PAS type 4, dissection of the lower tissues implies a high risk of tissue rupture [14] (Supplemental material, image 12) and LAC damage (Supplemental material, image 13). For this reason, the presence of dense fibrosis in type 4 suggested an immediate surgical technique modification.
The vast arterial anastomotic network between these organs is also a cause of embolization failure [15] or unwanted ischemic complications [16].
Subtotal hysterectomy (STH) has previously been used to manage severe cases of PAS [14,17,18]; however, there are a few references to specific procedures to prevent bleeding after placental detachment cases [6,19]. In another way, some authors describe using this procedure for all patients with PAS (without discriminating its degree of severity) [20] or all patients with suspected severe cases [14].
Life-threatening hematuria manifests in 25% of the cases of placenta percreta [21]. Maternal and fetal mortality in percreta with hematuria is high, mainly because of operative difficulties in managing blood loss (up to 5% of maternal deaths) [6]. Type 4 is a PAS location randomly associated with macroscopic hematuria; however, it is common to see that vascular pressure over the trigonal area is released after delivery, and bleeding stops spontaneously in most patients (Palacios-Jaraquemada JM unpublished data). When bleeding continues, internal aortic compression stops bleeding immediately [11]; on the contrary, an internal iliac ligature is associated with the need for massive transfusions [22]. In similar cases, some urologists decided to perform the hemostasis using an "in-block technique resection," which includes a partial bladder excision with an invaded myometrium [23,24].
Nevertheless, this procedure causes severe morbidity by reducing bladder capacity that habitually needs organ augmentation [25]. Therefore, to reduce maternal morbidity, in case of persistent macroscopic hematuria, it is recommended to open the bladder [26], identify the bleeding site, and perform a compression suture around the bleeding area. Compression suture applied on the bleeding site is an effortless technique with excellent results (Palacios-Jaraquemada JM, unpublished data) and avoids vesical resection and consequent maternal morbidity.
Although PAS type 4 is not habitual, it is strongly recommended that all PAS teams discuss and plan this situation to apply specific and distinctive surgical strategies to reduce the risk of massive bleeding, visceral injuries, and morbidity.

Research implications
The prenatal and surgical identification of severe PAS forms reduces maternal morbidity and determines the use of alternative tactics or techniques [2]. Although some opinions consider that, PAS is not primarily an invasive disorder of placentation [27], the consequence of previous myometrial damage. Specialists need to be cautious because semantic difference does not imply less risk of blood loss or organ damage. PAS type 4 cases leaving attached tissues intact imply a  (20) .045 PAS: placenta accreta spectrum; RBC: red blood cells unit. Ã Median (IQR). a PAS type 4: Placenta accreta spectrum affecting the lower part of the uterine segment and cervix, with firm adhesion between the uterus and the bladder (Fibrosis). b Urinary tract injuries, the requirement of relaparotomy, more than 4 RBCU transfused.
significant reduction in maternal morbidity compared with a classical hysterectomy. A low uterine cervical-trigonal placenta involvement produces notable vascular hyperplasia (Supplemental material, image 14) that could confuse the remained placenta tissue, even for experienced PAS specialists. However, due to the low frequency of these cases, it is not always easy to know what to do or what not to do, especially when the controlled procedure turns into unmanageable blood loss in a few seconds.
Experts need to open their minds to modify procedures according to surgical findings. MSTH is an election technique for patients with PAS that compromise the lower part of the uterine segment and cervix, in whom a tenacious attempt to perform of total hysterectomy may produce catastrophic effects [28].
There are few histological descriptions of PAS with vesicouterine fibrosis [7] (Supplementary material, image 14); however, some PAS skilled surgeons find their solutions after operating on these singular cases. Although under research, fibrosis predisposition is associated with an individual genetic polimorformist [29] and related to estrogen exposure and endometriosis [30]. A high percentage of collagen tissue in the uterine segment near the cervix could play a role during hysterotomy healing, but this process is not fully demonstrated. But due to, a low rate of PAS type 4 suggested an unusual coincidence of two or more etiologic factors.
A low anastomotic uterine blood supply was rediscovered some years ago [31], but its importance acquired more relevance after special procedures (uterine transplantation, trachelectomy, and others). Probably, there is no unique optimal technique for all PAS types [32], and some techniques could be helpful or not, depending on particular situations or where they are applied [5].

Strengths and limitations
The study has design biases, mainly due to the small number of cases of PAS type 4. Therefore, although the differences between MSTH and TH appear to be significant, the relative values for PAS complications are not enough to estimate a real statistical significance [33].
But considering that most publications included small series or case reports, the sample probably represents a large series worldwide. Although all patients were operated on in reference centers for PAS, some specific problems need to be tailored [34] or solved by expert instinct experience rather than the scientific guide. The main manuscript strengths are why STHT is recommended and the importance of getting the final invasion picture after deciding. In addition, another study's strong point is to explain why placenta invasion topography has a better correlation with maternal morbidity [2] than invasion degree [35], the basis of FIGO PAS classification. The placenta invasion topography is closely related to the specific vessels, their connections, and arising site, while the invasion degree could vary among PAS areas in the same patient [35]. To leave the placenta in situ is a probability, but conservative management in severe forms may result in deleterious effects, such as hemorrhage, sepsis, and coagulopathy, with unpredictable risks [36].
Furthermore, a video with a low-cost surgical training model allows expert groups and others to see and practice all the surgical steps.

Conclusions
PAS in the cervical-trigonal area associated with fibrosis implies a greater risk of complications due to uncontrollable bleeding and organ damage. MSTH is associated with lower morbidity and difficulties than a total hysterectomy in this specific type of PAS. Prenatal or intrasurgical diagnosis in this location is essential to plan surgical alternatives to improve the results.