Evidence of Placental Villous Inflammation and Apoptosis in Third-Trimester Symptomatic SARS-CoV-2 Maternal Infection.

PURPOSE: In view of conflicting reports on the ability of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to infect placental tissue, this study aimed to further evaluate the impact of inflammation and placental damage from symptomatic third-trimester maternal COVID-19 infection. MATERIALS AND METHODS: This case-control study included 32 placenta samples each from symptomatic COVID-19 pregnancy and normal non-COVID-19 pregnancy. The villous placental area's inflammatory expression [angiotensin converting enzyme-2 (ACE-2), transmembrane protease serine-2 (TMPRSS2), interferon-γ (IFN-γ), interleukin-6 (IL-6), and SARS-CoV-2 spike protein] and apoptotic rate were examined using immunohistochemistry and Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL) assay. Comparison and correlation analysis were used based on COVID-19 infection, placental SARS-CoV-2 spike protein evidence, and maternal severity status. RESULTS: Higher expressions of TMPRSS2, IFN-γ, and trophoblast apoptotic rate were observed in the COVID-19 group (p<0.001), whereas ACE-2 and IL-6 expressions were not significantly different from the control group (p>0.05). Additionally, SARS-CoV-2 spike protein was detected in 8 (25%) placental samples of COVID-19 pregnancy. COVID-19 subgroup analysis revealed increased IFN-γ, trophoblast, and stromal apoptosis (p<0.01). Moreover, the results of the current study revealed no correlation between maternal COVID-19 severity and placental inflammation as well as the apoptotic process. CONCLUSION: The presence of SARS-CoV-2 spike protein as well as altered inflammatory and apoptotic processes may indicate the presence of placental disturbance in third-trimester maternal COVID-19 infection. The lack of correlation between placental disruption and maternal severity status suggests the need for more research to understand the infection process and any potential long-term impacts on all offsprings born to COVID-19-infected pregnant women.

Three-dimensional volume rendering ultrasound for assessing placenta accreta spectrum severity and discriminating it from simple scar dehiscence.

BACKGROUND: Prenatal ultrasound discrimination between placenta accreta spectrum and scar dehiscence with underlying nonadherent placenta is challenging both prenatally and intraoperatively, which often leads to overtreatment. In addition, accurate prenatal prediction of surgical difficulty and morbidity in placenta accreta spectrum is difficult, which precludes appropriate multidisciplinary planning. The advent of advanced 3-dimensional volume rendering and contrast enhancement techniques in modern ultrasound systems provides a comprehensive prenatal assessment, revealing details that are not discernible in traditional 2-dimensional imaging. OBJECTIVE: This study aimed to evaluate the use of 3-dimensional volume rendering ultrasound techniques in determining the severity of placenta accreta spectrum and distinguishing between placenta accreta spectrum and scar dehiscence with underlying nonadherent placenta. STUDY DESIGN: A prospective, cohort study was conducted between July 2022 and July 2023 in the fetal medicine unit of Dr Soetomo Academic General Hospital, Surabaya, Indonesia. All pregnant individuals with anterior low-lying placenta or placenta previa with a previous caesarean section who were referred with suspicion of placenta accreta spectrum were consented and screened using the standardised 2-dimensional and Doppler ultrasound imaging. Additional 3-dimensional volumes were obtained from the sagittal section of the uterus with a filled urinary bladder. These were analyzed by rotating the region of interest to be perpendicular to the uterovesical interface. The primary outcomes were the clinical and histologic severity in the cases of placenta accreta spectrum and correct diagnosis of dehiscence with nonadherent placenta underneath. The strength of association between ultrasound and clinical outcomes was determined. Multivariate logistic regression analyses and diagnostic testing of accuracy were used to analyze the data. RESULTS: A total of 70 patients (56 with placenta accreta spectrum and 14 with scar dehiscence) were included in the analysis. Multivariate logistic regression of all 2-dimensional and 3-dimensional signs revealed the 3-dimensional loss of clear zone (P<.001) and the presence of bridging vessels on 2-dimensional Doppler ultrasound (P=.027) as excellent predictors in differentiating scar dehiscence and placenta accreta spectrum. The 3-dimensional loss of clear zone demonstrated a high diagnostic accuracy with an area under the curve of 0.911 (95% confidence interval, 0.819-1.002), with a sensitivity of 89.3% (95% confidence interval, 78.1-95.97%) and specificity of 92.9% (95% confidence interval, 66.1-99.8%). The presence of bridging vessels on 2-dimensional Doppler demonstrated an area under the curve of 0.848 (95% confidence interval, 0.714-0.982) with a sensitivity of 91.1% (95% confidence interval, 80.4-97.0%) and specificity of 78.6% (95% confidence interval, 49.2-95.3%). A subgroup analysis among the placenta accreta spectrum group revealed that the presence of a 3-dimensional disrupted bladder serosa with obliteration of the vesicouterine space was associated with vesicouterine adherence (P<.001). CONCLUSION: Three-dimensional volume rendering ultrasound is a promising tool for effective discrimination between scar dehiscence with underlying nonadherent placenta and placenta accreta spectrum. It also shows potential in predicting the clinical severity with urinary bladder involvement in cases of placenta accreta spectrum.

Transabdominal and transvaginal ultrasound findings help to guide the clinical management of placenta accreta spectrum cases.

INTRODUCTION: The clinical management of placenta accreta spectrum (PAS) depends on placental topography and vascular involvement. Our aim was to determine whether transabdominal and transvaginal ultrasound signs can predict PAS management. MATERIAL AND METHODS: We conducted a retrospective cohort study of consecutive prenatally suspected PAS cases in a single tertiary-care PAS center between January 2021 and July 2022. When PAS was confirmed during surgery, abdominal and transvaginal ultrasound scans were analyzed in relation to PAS management. The preferred surgical approach of PAS was one-step conservative surgery (OSCS). Massive blood loss and PAS topography in the lower bladder trigone necessitated cesarean hysterectomy. Transvaginal ultrasound-diagnosed intracervical hypervascularity was split into three categories based on their quantity. Anatomically, the internal cervical os is located at the level of the bladder trigone and was used as landmark for upper and lower bladder trigone PAS. RESULTS: Ninety-one women underwent OSCS and 35 women underwent cesarean hysterectomy (total 126 women with PAS). Abdominal and transvaginal ultrasound features differed significantly between women that underwent OSCS and cesarean hysterectomy: decreased myometrial thickness (<1 mm), 82.4% vs. 100%, p = 0.006; placental bulge, 51.6% vs. 94.3%, p < 0.001; bladder wall interruption, 62.6% vs. 97.1%, p < 0.001; abnormal placental lacunae, 75.8% vs. 100%, p < 0.001; hypervascularity (large lacunae feeding vessels, 57.8% vs. 94.6%, p < 0.001; parametrial hypervascularity, 15.4% vs. 60%, p < 0.001; the rail sign, 6.6% vs. 28.6%, p = 0.003; three-dimensional Doppler intra-placental hypervascularity, 81.3% vs. 100%, p < 0.001; intracervical hypervascularity 60.4% vs. 94.3%, p < 0.001); and cervical length 2.5 ± 0.94 vs. 2.2 ± 0.73, p = 0.038. Other ultrasound signs were not significantly different. The results of multivariable logistic regression showed placental bulge (odds ratio [OR] 9.3; 95% CI 1.9-44.3; p = 0.005), parametrial hypervascularity (OR 4.1; 95% CI 1.541-11.085; p = 0.005), and intracervical hypervascularity (OR 9.2; 95% CI 1.905-44.056; p = 0.006) were weak predictors of OSCS. Intracervical hypervascularity Grade 1 (vascularity <50% of cervical tissue) was more present in OSCS than higher gradings two and three (91% vs. 27.6% vs. 14.3%; p < 0.001). CONCLUSIONS: Cesarean hysterectomy is associated with the PAS signs of placental bulge and Grade 2 and 3 intracervical hypervascularity. OSCS is associated with intracervical hypervascularity Grade 1 on transvaginal ultrasound. Prospective validation is required to formulate predictors for PAS management.

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

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.

The correlation between serum levels and placental tissue expression of PLGF and sFLT-1 and the FIGO grading of the placenta accreta spectrum disorders.

OBJECTIVE: This study aims to further explore the role of angiogenic vs anti-angiogenic factors in placenta accreta spectrum (PAS). METHODS: This cohort study included all patients with placenta previa and placenta accreta spectrum (PAS) disorders undergoing surgery at Dr. Soetomo Hospital (Academic Hospital of Universitas Airlangga, Surabaya, Indonesia) from May to September 2021. Venous blood samples for PLGF and sFlt-1 were drawn immediately prior to surgery. Placental tissue samples were taken during surgery. The FIGO grading was diagnosed intraoperatively by an experienced surgeon and confirmed by the pathologist and followed by immunohistochemistry (IHC) staining. The sFlt-1 and PLGF serum were performed by an independent laboratory technician. RESULTS: Sixty women were included in this study (20 women with placenta previa; 10 women with FIGO PAS grade 1; 8 women with FIGO PAS grade 2; 22 women with FIGO PAS grade 3). The median with 95% Confidence interval of PLGF serum values in placenta previa, FIGO grade I, grade II, and grade III were 233.68 (0.00-2434.00), 124.39 (10.42-663.68), 236.89 (18.83-418.99) and 237.31 (2.26-3101.00) (p = .736); the median values with 95% CI of serum sFlt-1 levels in placenta previa, FIGO grade I, grade II, and grade III were 2816.50 (418.00-12925.00), 2506.00 (227.50-16104.00), 2494.50 (888.52-20812.00), and 1601.00 (662.16-9574.00) (p = .037). Placental PLGF expression in placenta previa, FIGO grade 1, grade II, and grade III showed median values (with 95% CI) of 4.00 (1.00-9.00), 4.00 (2.00-9.00), 4.00 (4.00-9.00), and 6.00 (2.00-9.00) (p = .001); sFlt-1 expression median values (with 95% CI) were 6.00 (2.00-9.00), 6.00 (2.00-9.00), 4.00 (1.00-9.00), and 4.00 (1.00-9.00) (p = .004). Serum PLGF and sFlt-1 levels did not correlate with placental tissue expression (p = .228; p = .586). CONCLUSION: There are differences in PAS's angiogenic processes ​according to the severity of trophoblast cell invasion. But there is no overall correlation between serum levels and PLGF and sFlt-1 expression in the placenta, suggesting the imbalance between angiogenic and anti-angiogenic are local mechanisms in the placental and the uterine wall.

Correlation between interleukin-6 expression in post-mortem core liver biopsy and degree of liver injury in patients with fatal COVID-19.

Excessive release of interleukin-6 (IL-6) during the progression of coronavirus disease 2019 (COVID-19) induces cytokine storms, resulting in multi-organ damages including liver injury, similar in nature with mechanism of viral hepatitis. Systemic IL-6 has been associated with the incidence of liver injury among COVID-19 patients; however, studies on IL-6 expression in the liver tissue are completely lacking. The aim of this study was to measure the IL-6 expression in the liver tissues and to determine its correlation with the degree of liver injury in fatal COVID-19 patients. Through this first cross-sectional study, IL-6 expression was measured through immunohistochemical staining and the degree of liver injury was identified based on level of serum alanine aminotransferase (ALT). The Spearman correlation test was used to identify the correlation between IL-6 expression and the degree of liver injury. A total of 47 deceased COVID-19 patients were included and IL-6 expression was observed in all post-mortem liver specimens, ranging from mild to strong expression. Liver injury at various degrees (mild to severe) was found in more than half (59.5%) of the cases. The Spearman correlation analysis suggested a statistically insignificant correlation between liver IL-6 expression and the degree of liver injury (r=0.152; p=0.309). In conclusion, even IL-6 expression was observed in all post-mortem liver specimens, there was an insignificant correlation between IL-6 expression in the liver tissue with the degree of liver injury among fatal COVID-19 patients, suggesting that IL-6 was not the only main factor contributing to liver damage in COVID-19 patients.

Lifesaving diagnosis of placenta accreta spectrum using MRI: Report of five cases.

Placenta accreta spectrum (PAS) is defined as abnormal placental adherence or invasion of the myometrium or extrauterine organs. This case series will analyze MRI findings and PAS grading, in addition to emergency situations like massive hematuria and placental invasion with rupture. We report 5 cases of pregnant women with placenta previa with suspected PAS. MRI revealed 1 case of placenta accreta, one case of placenta increta, and 3 cases of placenta percreta. Two cases were emergency situations. All cases were managed with cesarean section. PAS is frequently related to severe obstetric hemorrhage associated with high maternal morbidity and mortality, making diagnosis and management challenging. Ultrasound is the initial diagnostic modality for PAS. Although ultrasound is preferred for PAS diagnosis, MRI provides an effective modality for the analysis of the depth of placental invasion and can be helpful in emergency situations.

Uterine conservative-resective surgery for selected placenta accreta spectrum cases: Surgical-vascular control methods.

INTRODUCTION: The incidence of placenta accreta spectrum (PAS) has increased, but the optimal management and the optimal way to achieve vascular control are still controversial. This study aims to compare maternal outcomes between different methods of vascular control in surgical PAS management. MATERIAL AND METHODS: A retrospective cohort study on consecutive cases diagnosed with PAS between 2013 and 2020 in single tertiary hospital. The final diagnosis of PAS was made following preoperative ultrasound and confirmation during surgery. Management of PAS using cesarean hysterectomy with internal iliac artery ligation (IIAL) was compared with two types of vascular control in uterine conservative-resective surgery (IIAL vs identification-ligation of the upper vesical, upper vaginal, and uterine arteries). RESULTS: Over an 8-year period, 234 pregnant women were diagnosed with PAS meeting the inclusion criteria. Uterine conservative-resective surgery (200 cases) was associated with lower mean blood loss compared with cesarean hysterectomy with IIAL (34 cases) in all PAS cases (1379 ± 769 mL vs 3168 ± 1916 mL; p < 0.001). In sub-analysis of the two uterine conservative-resective surgery subgroups, the group with identification-ligation of the upper vesical, upper vaginal, and uterine arteries had a significantly lower blood loss compared with uterine conservative-resective surgery with IIAL (1307 ± 743 mL vs 1701 ± 813 mL; p = 0.005). Women in the hysterectomy with IIAL group had more massive transfusion (35.3% vs 2.5%; p < 0.001; odds ratio [OR] 21.3, 95% confidence interval [CI] 6.9-66), major blood loss (>1500 mL) (70.6% vs 34%, p < 0.001; OR 4.7; 95% CI 2.1-10.3), catastrophic blood loss (>2500 mL) (64.7% vs 12.5%;p < 0.001; OR 12.8, 95% CI 5.7-29.1), other complications (32% vs 12.4%; p = 0.007; OR 3.4, 95% CI 1.5-7.7), and intensive care unit admission (32.4% vs 1.5%; p < 0.001; OR 31.4, 95% CI 8.2-120.7) compared with the uterine conservative-resective surgery groups. The identification-ligation of the upper vesical, upper vaginal and uterine arteries had a significant lower risk for major blood loss (30.5% vs 50%; p = 0.041; OR 0.44, 95% CI = 0.2-0.9) compared with IIAL for vascular control of uterine conservative-resective surgery. CONCLUSIONS: Cesarean hysterectomy is not the default treatment for PAS, PAS with invasion above the vesical trigone are suitable for uterine conservative-resective surgery with upper vesical, upper vaginal and uterine artery vascular control.