Customizing EV-CATCHER to Purify Placental Extracellular Vesicles from Maternal Plasma to Detect Placental Pathologies.

Placenta Accreta Spectrum (PAS) is a life-threatening condition in which placental trophoblastic cells abnormally invade the uterus, often up to the uterine serosa and, in extreme cases, tissues beyond the uterine wall. Currently, there is no clinical assay for the non-invasive detection of PAS, and only ultrasound and MRI can be used for its diagnosis. Considering the subjectivity of visual assessment, the detection of PAS necessitates a high degree of expertise and, in some instances, can lead to its misdiagnosis. In clinical practice, up to 50% of pregnancies with PAS remain undiagnosed until delivery, and it is associated with increased risk of morbidity/mortality. Although many studies have evaluated the potential of fetal biomarkers circulating in maternal blood, very few studies have evaluated the potential of circulating placental extracellular vesicles (EVs) and their miRNA contents for molecular detection of PAS. Thus, to purify placental EVs from maternal blood, we customized our robust ultra-sensitive immuno-purification assay, termed EV-CATCHER, with a monoclonal antibody targeting the membrane Placental Alkaline Phosphatase (PLAP) protein, which is unique to the placenta and present on the surface of placental EVs. Then, as a pilot evaluation, we compared the miRNA expression profiles of placental EVs purified from the maternal plasma of women diagnosed with placenta previa (controls, n = 16); placenta lying low in uterus but not invasive) to those of placental EVs purified from the plasma of women with placenta percreta (cases, n = 16), PAS with the highest level of invasiveness. Our analyses reveal that miRNA profiling of PLAP+ EVs purified from maternal plasma identified 40 differentially expressed miRNAs when comparing these two placental pathologies. Preliminary miRNA pathway enrichment and gene ontology analysis of the top 14 upregulated and top nine downregulated miRNAs in PLAP+ EVs, purified from the plasma of women diagnosed with placenta percreta versus those diagnosed with placenta previa, suggests a potential role in control of cellular invasion and motility that will require further investigation.

Analysis of risk factors for massive intraoperative bleeding in patients with placenta accreta spectrum.

BACKGROUND: To analyze relevant factors for massive postpartum hemorrhage in women with placenta accreta spectrum in order to improve the ability to identify those at risk for intraoperative bleeding and improve outcome. METHODS: This study is a retrospective study and based on data from Hospital electronic medical record. Placenta accreta patients who delivered by cesarean section at Peking University Third Hospital from September 2017 to December 2019 were selected and included. According to the amount of intraoperative bleeding, they were categoried into the massive bleeding group (bleeding volume ≥ 2000 mL, 68 cases) and non-massive bleeding group (bleeding volume < 2000 mL, 99 cases). Univariate analysis and multivariate logistic regression were used to analyze the correlations between related risk factors or ultrasound imaging characteristics and the severity of bleeding during operation. RESULTS: (1) There were statistically significant differences in gravidity, parity, number of prior cesarean deliveries and placenta accreta ultrasound scores (P < 0.05) between the two groups of patients. (2) Among the ultrasonographic indicators, the disappearance of the post-placental clear space, the emergence of cross-border blood vessels in the region of subplacental vascularity, interruption or disappearance of the bladder line, and the presence of the cervical blood sinus had the most significant correlation with hemorrhage during PAS (P < 0.05). CONCLUSION: The presence of cervical blood sinus, interruption or disappearance of bladder line, the disappearance of the post-placental clear space and abnormal subplacental vascularity are independent risk factors for massive hemorrhage during PAS. We should pay more attention to these indicators in prenatal ultrasound examination in order to reduce the intraoperative bleeding and improve maternal outcomes.

A multicenter observational survey of management strategies in 442 pregnancies with suspected placenta accreta spectrum.

INTRODUCTION: Management options for women with placenta accreta spectrum (PAS) comprise termination of pregnancy before the viable gestational age, leaving the placenta in situ for subsequent reabsorption of the placenta or delayed hysterectomy, manual removal of placenta after vaginal delivery or during cesarean section, focal resection of the affected uterine wall, and peripartum hysterectomy. The aim of this observational study was to describe actual clinical management and outcomes in PAS in a large international cohort. MATERIAL AND METHODS: Data from women in 15 referral centers of the International Society of PAS (IS-PAS) were analyzed and correlated with the clinical classification of the IS-PAS: From Grade 1 (no PAS) to Grade 6 (invasion into pelvic organs other than the bladder). PAS was usually diagnosed antenatally and the operators performing ultrasound rated the likelihood of PAS on a Likert scale of 1 to 10. RESULTS: In total, 442 women were registered in the database. No maternal deaths occurred. Mean blood loss was 2600 mL (range 150-20 000 mL). Placenta previa was present in 375 (84.8%) women and there was a history of a previous cesarean in 329 (74.4%) women. The PAS likelihood score was strongly correlated with the PAS grade (P < .001). The mode of delivery in the majority of women (n = 252, 57.0%) was cesarean hysterectomy, with a repeat laparotomy in 20 (7.9%) due to complications. In 48 women (10.8%), the placenta was intentionally left in situ, of those, 20 (41.7%) had a delayed hysterectomy. In 26 women (5.9%), focal resection was performed. Termination of pregnancy was performed in 9 (2.0%), of whom 5 had fetal abnormalities. The placenta could be removed in 90 women (20.4%) at cesarean, and in 17 (3.9%) after vaginal delivery indicating mild or no PAS. In 34 women (7.7%) with an antenatal diagnosis of PAS, the placenta spontaneously separated (false positives). We found lower blood loss (P < .002) in 2018-2019 compared with 2009-2017, suggesting a positive learning curve. CONCLUSIONS: In referral centers, the most common management for severe PAS was cesarean hysterectomy, followed by leaving the placenta in situ and focal resection. Prenatal diagnosis correlated with clinical PAS grade. No maternal deaths occurred.

Enhanced expression of αVß3 integrin in villus and extravillous trophoblasts of placenta accreta.

BACKGROUND: Placenta accreta is one of the most serious complications in obstetrics and gynecology. Villous trophoblasts (VT) and extravillous trophoblasts (EVT) play a central role in normal placentation. Placenta accreta is characterized by abnormal invasion of EVT cells through the uterine layers, due to changes in several parameters, including adhesion proteins. Although αvß3 integrin is a central adhesion molecule, participating in multiple invasive pathological conditions including cancer, data on placenta accreta are lacking. OBJECTIVE: To study the expression pattern of αvß3 integrin in placenta accreta in comparison with normal placentas. STUDY DESIGN: We collected tissue samples from placentas defined as percreta, the most severe presentation of placenta accreta and from normal control placentas (n = 10 each). The samples underwent protein extractions for analyses of αvß3 expression by Western blots (WB) and a parallel tissue assessment by immunohistochemistry (IHC). RESULTS: WB results indicated significantly elevated αvß3 integrin expression in the percreta samples compared to normal placentas. These elevated levels were mainly contributed by EVT cells, as demonstrated by IHC. αvß3 integrin demonstrated a classical membranal expression in the VT cells, whereas a uniformly distributed expression was documented in the EVT cells. These patterns of the αvß3 integrin localization were similar in both accreta and normal placental samples. CONCLUSIONS: Enhanced αvß3 integrin expression, mainly in extra villous trophoblasts of placenta percreta, implies for a role of this adhesion molecule in pathological placentation.

First trimester serum PAPP-A is associated with placenta accreta: a retrospective study.

PURPOSE: Our objective of this study was to investigate whether first trimester serum pregnancy-associated plasma protein-A (PAPP-A) differed amongst pregnancies with placenta previa-accreta and non-adherent placenta previa and healthy pregnancies by a retrospective cohort analysis. METHODS: A total of 177 pregnant females were included in the study, as follows: 35 cases of placenta previa-accreta, 30 cases of non-adherent placenta previa, and 112 cases of BMI and age matched, healthy pregnant controls. PAPP-A multiples of the median (MoM) were acquired from laboratory data files in 1 January 2017-30 September 2019. The probable maternal serum biochemical predictor of placenta accreta was analyzed by using multiple logistic regression analysis. RESULTS: PAPP-A MoM of placenta previa-accreta group was significantly higher than those of the non-adherent placenta previa group and control group (p = 0.009 < 0.05, p < 0.001). Serum PAPP-A was found to be significantly positively associated with placenta accreta after adjusted gestational week at time of blood sampling, BMI, age, smoking, and previous cesarean section history (OR: 3.51; 95% CI: 1.77-6.94; p = 0.0003 < 0.05). In addition, smoking (OR: 9.17; 95% CI: 1.69-49.62; p = 0.010 < 0.05) and previous cesarean section history (OR: 2.75; 95% CI: 1.23-6.17; p = 0.014 < 0.05) were also significantly associated with placenta accreta. CONCLUSION: Increased first trimester serum PAPP-A was significantly positively associated with placenta accreta, suggesting that the potential role of PAPP-A in identifying pregnancies at high risk for placenta accreta. Smoking and previous cesarean section history may be the risk factors for accreta in placenta previa patients.

Placenta accreta spectrum: biomarker discovery using plasma proteomics.

BACKGROUND: Many cases of placenta accreta spectrum are not diagnosed antenatally, despite identified risk factors and improved imaging methods. Identification of plasma protein biomarkers could further improve the antenatal diagnosis of placenta accreta spectrum . OBJECTIVE: The purpose of this study was to determine if women with placenta accreta spectrum have a distinct plasma protein profile compared with control subjects. STUDY DESIGN: We obtained plasma samples before delivery from 16 participants with placenta accreta spectrum and 10 control subjects with similar gestational ages (35.1 vs 35.5 weeks gestation, respectively). We analyzed plasma samples with an aptamer-based proteomics platform for alterations in 1305 unique proteins. Heat maps of the most differentially expressed proteins (T test, P<.01) were generated with matrix visualization and analysis software. Principal component analysis was performed with the use of all 1305 proteins and the top 21 dysregulated proteins. We then confirmed dysregulated proteins using enzyme-linked immunosorbent assay and report significant differences between placenta accreta spectrum and control cases (Wilcoxon-rank sum test, P<.05). RESULTS: Many of the top 50 proteins that significantly dysregulated in participants with placenta accreta spectrum were inflammatory cytokines, factors that regulate vascular remodeling, and extracellular matrix proteins that regulate invasion. Placenta accreta spectrum, with the use of the top 21 proteins, distinctly separated the placenta accreta spectrum cases from control cases (P<.01). Using enzyme-linked immunosorbent assay, we confirmed 4 proteins that were dysregulated in placenta accreta spectrum compared with control cases: median antithrombin III concentrations (240.4 vs 150.3 mg/mL; P=.002), median plasminogen activator inhibitor 1 concentrations (4.1 vs 7.1 ng/mL; P<.001), soluble Tie2 (13.5 vs 10.4 ng/mL; P=.02), soluble vascular endothelial growth factor receptor 2 (9.0 vs 5.9 ng/mL; P=.003). CONCLUSION: Participants with placenta accreta spectrum had a unique and distinct plasma protein signature.

Human placental lactogen mRNA in maternal plasma play a role in prenatal diagnosis of abnormally invasive placenta: yes or no?

Objective: To determine whether maternal plasma human placental lactogen (hPL) mRNA levels can predict abnormally invasive placenta. Study design: Sixty-eight singleton pregnant women with prior Cesarean deliveries were classified into three groups: 35 with normal placentation (control group); 21 with placenta previa alone (placenta previa group); 12 with placenta previa and placenta accreta (placenta accreta group). Maternal plasma hPL mRNA concentrations were measured by real-time reverse-transcription polymerase chain reaction Result: The multiple of the median (median, range) for hPL mRNA was significantly higher for the placenta accreta group (2.78, 1.09-4.56) than the control (1.00, 0.29-2.98) or placenta previa (1.12, 0.33-3.25) groups (Steel-Dwass test, p < .001 and p = .005, respectively), was not significantly different between the women with placenta accreta who underwent hysterectomies (2.96, 1.38-4.56) and the women whose deliveries did not result in hysterectomy (2.36, 1.09-3.25) in the placenta accreta group (Mann-Whitney U test, p = .372). Conclusion: hPL mRNA in maternal plasma may indicate abnormally invasive placenta but cannot predict whether abnormally invasive placenta will result in hysterectomy.

Significance of the routine first-trimester antenatal screening program for aneuploidy in the assessment of the risk of placenta accreta spectrum disorders.

Objective To select a group at high risk of placenta accreta spectrum disorders (PAS) based on the data of serum screening in the first trimester. Methods A retrospective analysis of 48 patients with abnormal placental location (AP), including placenta previa (PP) only (n = 23) and PP and PAS (n = 25), was performed. Additionally, the AP group was divided depending on the blood loss volume: not higher than 1000 mL (LBL) (n = 29) and higher than 1000 mL (HBL) (n = 19); diagnostic term of PAS by ultrasound, data pregnancy-associated plasma protein-A (РAРР-A) and free ß subunit of human chorionic gonadotropin (free ß-hCG) multiple of median (MоM) at 11+0-13+6 weeks of gestation were evaluated. Serological markers were compared with the data of 39 healthy pregnant women with scar after previous cesarean section and normal placental location (control). Results The mean gestation at diagnostic term of PAS was 29 weeks. PAPP-Р MоM [mean (M) ± standard deviation (SD)] was: in controls, 1.07 ± 0.47; in the AP group, 1.59 ± 0.24; in PP, 1.91 ± 1.52; in PAS, 1.30 ± 0.85; in LBL, 1.37 ± 1.20; in HBL, 1.91 ± 1.24. The difference between control/AP, control/PP, control/PAS, PP/PAS, control/LBL, control/HBL and LBL/HBL was Р = 0.256, 0.145, 0.640, 0.311, 0.954, 0.025 and 0.09, respectively. Free ß-hCG MoM (M ± SD) was: in controls, 1.08 ± 0.69, in AP, 1.31 ± 0.96; in PP, 1.46 ± 0.19; in PAS, 1.16 ± 0.65; in LBL, 1.30 ± 0.06; in HBL, 1.32 ± 0.78. Comparison of free ß-hCG AP with controls and between subgroups did not reveal a significant difference. Conclusion Underestimation of PAS risk factors in pregnant women with AP leads to late diagnostics of pathology only in the third trimester. The assessment of the РAРР-A level in the first trimester may be helpful for the early prognosis of pathological blood loss at delivery for pregnant women with AP and for forming the high-risk group for PAS.

Hyperglycosylated hCG and Placenta Accreta Spectrum.

OBJECTIVE: We aimed to evaluate the relationship between hyperglycosylated human chorionic gonadotropin (hCG-H) and placenta accreta spectrum (PAS) in the second and third trimesters of pregnancy. STUDY DESIGN: This was a case-control study of PAS and controls. hCG-H was measured in the second and third trimesters of pregnancy in women with pathologically confirmed cases of PAS and in gestational age-matched controls without PAS. We compared serum hCG-H levels in cases and controls, calculated summary statistics for diagnostic accuracy, and used receiver operating characteristic (ROC) curves to define an optimal cut-point for diagnosis of PAS using hCG-H. RESULTS: Thirty case samples and 30 control samples were evaluated for hCG-H. Mean hCG-H was lower in the case compared with control group (7.8 ± 5.9 µg/L vs. 11.8 ± 8.8 µg/L, p = 0.03). At an optimal cut-point for hCG-H of ≤7.6 µg/L, the sensitivity, specificity, positive likelihood ratios, negative likelihood ratios, and area under the ROC curve were 66.7%, 69.7%, 2.20%, 0.48%, and 0.68%, respectively. CONCLUSION: Hyperglycosylated hCG levels in the second and third trimesters of pregnancy were lower in patients with PAS than in controls, but hCG-H showed only modest capability as a diagnostic test for PAS.

Second Trimester Biochemical Markers as Possible Predictors of Pathological Placentation: A Retrospective Case-Control Study.

OBJECTIVE: We aimed to evaluate the association between second trimester biochemical markers and pathological placentation. METHODS: This was a retrospective case-control study (2007-2014) of singleton gestations at a university-affiliated tertiary center. Women with pathologic placentation were subdivided into three groups: placenta accreta (group A), placenta previa (group B), or both (group C). We compared second trimester biochemical screening markers taken between 16 + 0 and 19 + 6 weeks of gestation between groups A, B, and C, and women with normal placentation (group D). Obstetrical and neonatal outcomes, risk factors for pathologic placentation, and second trimester biochemical marker values were compared between groups. RESULTS: Overall, 301 deliveries were evaluated: 64 (21%) in group A, 66 (22%) in group B, 17 (6%) in group C, and 153 (51%) in group D. Each of the pathological placentation groups individually had a higher median alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG) multiples of median (MoM) than the controls, with the highest values of AFP and hCG observed among women with placenta accreta and the lowest values among the controls. When a multivariant analysis was applied, the hCG levels remained significantly correlated with pathological placentation. Receiver operation characteristic curves for AFP, hCG, or both were computed. For AFP the area under the ROC curve (AUC) was 0.573 (95% CI 0.515-0.630, p < 0.0274) and a cut-off value above 0.99 MoM demonstrated a sensitivity and specificity of 71 and 46%, respectively, for the prediction of pathological placentation. For hCG, the AUC was 0.662 (95% CI 0.605-0.715, p < 0.0001) and a cut-off value of 1.25 MoM demonstrated a sensitivity and specificity of 53 and 68%. When both markers were plotted, the AUC was 0.668 (95% CI 0.611-0.721, p < 0.0001) and sensitivity and specificity were 63 and 64%, respectively. A percentile MoM cut-off approach distinguished between two groups: a high-risk group (patients with AFP or hCG or both above the 75th percentile, odds ratio (OR) for pathological placentation 2.27, 95% CI 1.42-3.63), and a low-risk group (patients with AFP or hCG or both below the 25th percentile, OR for pathological placentation 0.38, 95% CI 0.24-0.60). CONCLUSION: Second trimester biomarkers such as hCG and AFP can be used to raise a suspicion towards characterizing women into high-risk and low-risk groups for pathological placentation.

Serum ischemia modified albumin level and its relationship with the thiol/disulfide balance in placenta percreta patients.

The pathogenesis of placenta percreta (PP) is not very well known. This study was designed to analyse the oxidative stress (OS), the thiol/disulphide balance, and ischaemia-modified albumin (IMA) the women with PP. The study included 38 pregnant women with PP and 40 similarly aged healthy pregnant women in their third trimester of gestation. We measured the IMA, native and total thiols, and disulphide concentrations in the maternal sera of all of the participating women. The IMA levels were higher and the native and total thiols were lower in the PP group than in the control group. However, there was no statistical significance with respect to the thiol/disulphide balance between the two groups. The results of this study suggest that an increase in the ischaemia and OS and a decrease in the antioxidant status may contribute to the pathogenesis of PP. Impact statement What is already known on this subject? Placenta percreta (PP) is a serious complication of pregnancy. Although there are several studies investigating the pathophysiological mechanism of PP, whether the pathology results from a lack of decidua or from the over-invasiveness of trophoblasts remains controversial. The pathology of PP is poorly understood. What do the results of this study add? This prospective study has shown an increased ischaemia modified albumin (IMA) and a decreased antioxidant capacity in the patients with placenta percreta. The results from 38 women with PP suggest that the serum concentrations of IMA and the oxidative stress parameters may be able to predict PP in cases of uncertainty. What are the implications of these findings for clinical practice and/or further research? The implication of these findings shed light on understanding the pathogenesis of PP for further research.

The association between placenta previa and leukocyte and platelet indices - a case control study.

OBJECTIVES: Despite medical advances, rising awareness, and satisfactory care facilities, placenta previa (PP) remains a challenging clinical entity due to the risk of excessive obstetric hemorrhage. Etiological concerns gave way to life-saving concerns about the prediction of maternal outcomes due to hemorrhage. Our study aimed to detect an early predictive marker of placenta previa. MATERIAL AND METHODS: Ninety-three pregnant patients diagnosed with PP and 247 controls were recruited for this retro-spective study. Platelet and leukocyte indices were compared between the two groups. RESULTS: The groups were similar with regard to age distribution (31.2 ± 5.1 years [mean ± SD] in the PP group and 31.7 ± 4.2 years in controls), body mass index (BMI) (27.7 ± 3.6 kg/m2 in the PP group and 27.4 ± 4.6 kg/m2 in controls), and most characteristics of the obstetric history. Total leukocyte count, neutrophil count, and neutrophil-to-lymphocyte ratio were significantly higher in the PP group. Mean platelet volume (MPV) and large platelet cell ratio (P-LCR) values were significantly lower in the PP group as compared to controls, with regard to third trimester values. However, patients who were diagnosed postnatally with placenta percreta had lower MPV and P-LCR values than other patients with PP. There were no statistically significant differences between the two groups as far as first trimester values were concerned. CONCLUSIONS: Platelet and leukocyte indices in the third trimester of pregnancy may be valuable predictors of placenta previa and placenta percreta. More comprehensive studies are needed to address this issue.

First trimester maternal serum biochemical markers of aneuploidy in pregnancies with abnormally invasive placentation.

OBJECTIVE: To examine whether differences exist in routine first trimester maternal serum screening analyte measurements between normal pregnancies, placenta praevia and abnormally invasive placentation (AIP). DESIGN: Multidisciplinary audit. SETTING: Associated university teaching hospital with 9000 annual deliveries. POPULATION: Five hundred and sixteen pregnancies in total, including 344 normal controls, 17 with AIP and 155 placenta praevia cases. METHODS: Comparison of maternal serum free ßhCG and PAPP-A MoMs distribution in pregnancies with abnormally invasive placentation, placenta praevia and normal controls, after correcting for known confounding factors between October 2005 and September 2013. Data from a previously published first trimester AIP and biochemistry study were combined with our study data and compared in the above way to complete the analysis. MAIN OUTCOME MEASURES: Differences in first trimester maternal serum PAPP-A and free ßhCG in AIP, placenta praevia, and normal pregnancies. RESULTS: Median free ßhCG MoM in the control group was 1.04, and 1.08 (P = 0.859) in the placenta praevia group compared with 0.81 in the AIP group (P = 0.06). Median PAPP-A MoM was 1.01 in the control group and 1.05 (P = 0.83) in praevia, compared with 1.22 in AIP cases (0.16). The combined AIP dataset gave an overall PAPP-A median MoM of 1.40, and free ßhCG of 0.85. Both markers showed a significantly different distribution from controls (PAPP-A P = 0.002 and free ßhCG P = 0.031). CONCLUSIONS: There may be differences between first trimester maternal serum biochemical markers between normal pregnancies and those complicated by abnormally invasive placentation. If upheld, this may provide useful information for the early identification of abnormally invasive placentation. More studies are required.

Expression of sirtuins 1 in placenta, umbilical cord, and maternal serum of patients diagnosed with placenta accreta spectrum.

OBJECTIVE: Placenta accreta spectrum (PAS) is defined as the attachment of the placenta to the uterine wall in varying degrees. However, the studies have explored that the underlying molecular mechanisms of the PAS are very limited. Sirtuins 1 (SIRT1) is associated with placental development by controlling trophoblast cell invasion and remodeling of spiral arteries. We aimed to determine the expression level of SIRT1 in placentas, and maternal and umbilical cord serum of patients with PAS. METHODS: In total, 30 individuals in control, 20 patients in the placenta previa group, and 30 patients in the PAS group were included in this study. The expression levels of SIRT1 in the placentas were determined by Western blot and immunohistochemistry. Serum levels of SIRT1 in maternal and umbilical cord blood were determined by ELISA. RESULTS: SIRT1 was significantly lower in placentas of the PAS. However, maternal and umbilical cord serum samples were not significantly different between groups. CONCLUSION: SIRT1 may play an important role in the pathogenesis of the PAS.

Shedding of Syncytiotrophoblast-Derived Extracellular Vesicles Is Increased in Placenta Previa and Accreta Spectrum.

Placenta accreta spectrum (PAS) refers to excessive placental invasion into the maternal uterus and it is associated with high risk of obstetric haemorrhage and adverse maternal-neonatal outcomes. Currently, no specific circulating biomarkers of PAS have been identified. Given that in PAS disorders, the depth and the extension of placental invasion into the uterus are expected to be increased, in this study, we analysed plasma levels of syncytiotrophoblast-derived extracellular vesicles (STBEVs) in women with placenta previa (PP), at a high risk of PAS disorders, and pregnant women with normal placentation. Venous blood samples were collected from 35 women with ultrasonographic diagnosis of PP and 35 women with normal placentation, matched for gestational age. Plasma samples were ultracentrifuged at 120.000 g to collect extracellular vesicles (EVs). To identify and quantify plasma placenta-derived EVs (or STBEVs), EVs were analysed by flow cytometry using a monoclonal antibody against placental alkaline phosphatase (PLAP). Plasma levels of STBEVs were significantly higher in PP patients compared to controls. Plasma levels of STBEVs in women with PP and PAS showed a trend to a higher concentration compared to women with PP without PAS, although not reaching a statistical significance. Circulating STBEVs are potential candidates as biological markers to be integrated to ultrasonography in the antenatal screening programme for PAS. More studies are needed to confirm our observation in a larger cohort of patients and to analyse a possible association between high circulating levels of STBEVs and PAS.

Fraction of cell-free fetal DNA in the maternal serum as a predictor of abnormal placental invasion-a pilot study.

OBJECTIVE: Pilot studies have suggested the amount of cell-free fetal DNA (cffDNA) in the maternal serum is increased in pregnancies complicated by placenta accreta. Our objective was to determine if levels of cffDNA can predict invasive placentation. METHODS: We enrolled women with antenatally suspected placenta accreta compared with gestational age-matched cases of placenta previa and women with prior cesarean deliveries (CDs) and normal placentation. The fetal fraction of cffDNA was quantified using DANSR™ as compared with total DNA. Patient characteristics were compared between the three groups using ANOVA, and linear regression was used to compare the fraction of cffDNA between pathologically confirmed cases of placenta accreta, placenta previa and normal placentation. RESULTS: Twenty women were enrolled, (seven cases of placenta accreta, six cases of placenta previa and seven cases of normal placentation with prior CD). The groups did not differ by maternal weight, placental weight, number of prior CD or years from prior CD. The mean fraction of cffDNA did not differ significantly by group when controlling for the aforementioned factors (accreta = 19.1%, previa = 27.2%, prior CD = 28.9%, p = 0.26), nor did the median (accreta = 17.0%, previa = 30.1%, prior CD = 22.7%). CONCLUSIONS: We could not confirm diagnostic benefit. Further investigation of other biomarkers including placental mRNA is warranted.

Postpartum monitoring of retained placenta.Two cases of abnormally adherent placenta.

To save fertility, hysterectomy may be avoided with abnormal placental adherence by leaving the placenta in situ. Several reports support this strategy, but no reports are available on optimal follow-up strategies. We present two women with conservative treatment of placenta accreta and describe the prospective monitoring of the clinical course, placental regression, and recovery of the uterine anatomy using serial sonography, hysteroscopy and magnetic resonance imaging. There was no postpartum hemorrhage. Menstrual cyclicity resumed within 18 weeks. The human chorionic gonadotropin serum levels normalized within 10 weeks, whereas regression of placenta tissue was slow and continued up to nine months after delivery. In both cases placental remnants persisted; in one woman they were removed and uterine anatomy restored. She had a subsequent uneventful pregnancy afterwards. The presented systematic follow-up provides tools to monitor and treat other women in similar ways.

Spontaneous rupture of unscarred uterus in the early second trimester: a case report of placenta percreta.

BACKGROUND: Prevalence of uterine rupture at delivery has been recently estimated at less than 1 in 2500 deliveries. Spontaneous uterine rupture in the early mid-trimester (16 weeks gestation or less), is far less frequent. We report a case of uterine rupture due to placenta percreta in otherwise uncomplicated pregnancy CASE: A 35-year-old, gravida 5, para 5, at 15wk 2d gestation (menstrual age) with negative history of uterine scarring suddenly developed symptoms of incipient hypovolemic shock while being hospitalized for imminent miscarriage. On exploratory laparotomy we found a midline uterine rupture infiltrated by the placenta. Supracervical hysterectomy was performed. Postoperative lab analysis confirmed the elevated serum AFP levels. CONCLUSION: Abnormal placentation and subsequent uterine rupture should be taken into consideration also in women in the second trimester who have no history of uterine instrumentation.

Association Between Pre-delivery Coagulation Indicators and Invasive Placenta Accreta Spectrum.

OBJECTIVES: To analyze the association between pre-operational coagulation indicators and the severity of placenta accreta spectrum (PAS), as well as blood loss volume during operation. METHODS: Hospitalized patients of the obstetric department in a major hospital from 2018 to 2020 who were clinically and/or pathologically diagnosed with invasive PAS were included. Univariate and multivariate logistic regression and Poisson regression models were used to quantify the association between each of the 6 coagulation indicators and PAS severity (measured by FIGO grade) as well as maternal outcomes. RESULTS: Ninety-five patients (46 FIGO grade 2 and 49 FIGO grade 3) were included. Higher PT [adjusted OR (aOR): 5.54; 95% CI, 1.80 to 17.07] and FDP (aOR: 1.19; 95% CI, 1.01-1.42) levels were associated with an increased risk of FIGO grade 3 after adjusting for covariates. D-dimer [incidence rate ratio (IRR): 1.19; 95% CI, 1.05 to 1.35)] and FDP (IRR: 1.03; 95% CI, 1.01-1.04) levels were significantly associated with higher blood loss volume after adjusting for covariates. CONCLUSION: Preoperative coagulation indicators, especially PT, D-dimer and FDP, are associated with disease severity and blood loss volume during operation of invasive PAS. The underlying mechanism for the coagulation profile of PAS patients warrants further analysis. SYNOPSIS: Preoperative coagulation indicators, especially PT, D-dimer and FDP, are associated with disease severity and blood loss volume during operation among invasive placenta accreta spectrum patients.

Distinguishing placenta accreta from placenta previa via maternal plasma levels of sFlt-1 and PLGF and the sFlt-1/PLGF ratio.

INTRODUCTION: Our study aimed to distinguish patients with placenta accreta (crete, increta, and percreta) from those with placenta previa using maternal plasma levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PLGF) and the sFlt-1/PLGF ratio. METHODS: We obtained maternal plasma from 185 women in late pregnancy and sorted them into three groups: 72 women with normal placental imaging results (control group), 50 women with placenta previa alone (PP group), and 63 women with placenta previa and placenta accreta (PAS group). The concentrations of sFlt-1 and PLGF in the maternal plasma were measured using ELISA kits and the sFlt-1/PLGF ratio was calculated. RESULT: The median (min-max) sFlt-1 levels and the sFlt-1/PLGF ratio in the PAS group (12.8 ng/ml, 3.8-34.2 ng/ml) (133, 14-361) were lower than in the PP group (28.7 ng/ml, 13.1-60.3 ng/ml) (621, 156-2013) (p < 0.0001 and P < 0.0001, respectively). The median (min-max) PLGF levels in the PAS group (108 pg/ml, 38-679 pg/ml) was higher than that in the PP group (43 pg/ml, 12-111 pg/ml) (p < 0.0001 and p < 0.0001, respectively). The area under the ROC of the sFlt-1 levels, PLGF levels, and sFlt-1/PLGF ratio were 0.91, 0.90, and 0.99, respectively; the cut-off values were 18.9 ng/ml, 75.9 pg/ml, and 229.5, respectively. The concentration of sFlt-1 and sFlt-1/PLGF ratio were associated with the volume of blood loss (-.288*, -.301*). DISCUSSION: The concentrations of sFlt-1 and PLGF and ratio of plasma sFlt-1/PLGF may distinguish patients with placenta accreta from those with placenta previa.