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.

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.

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.

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.

Clinical value of serum VEGF and sFlt-1 in pernicious placenta previa.

This study was designed to explore the expression and the diagnostic value of vascular endothelial growth factor (VEGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) in pernicious placenta previa (PPP) combined placental accreta/increta. A total of 140 PPP patients were enrolled and divided into two groups: 56 patients with placenta accreta/increta (PA group), and 84 patients without placenta accreta/increta (non-PA group). In the same period, 46 pregnant women without PPP who had undergone caesarean section were selected as controls. The levels of VEGF and sFlt-1 in serum were detected by enzyme-linked immunosorbent assay. Diagnostic efficiency of VEGF and sFlt-1 in serum were evaluated by receiver operating characteristics curve. It was found that both VEGF and sFlt-1 had diagnostic value for PPP and placenta accreta/increta combined PPP. In addition, the levels of VEGF and sFlt-1 could be used to distinguish placenta accreta from placenta increta. VEGF was negatively correlated with sFlt-1 in PPP patients. In summary, the levels of VEGF and sFlt-1 could be used as auxiliary indicators to diagnose PPP and distinguish between placenta accreta and increta.KEY POINTSThe levels of VEGF and sFlt-1 could be used to distinguish placenta accreta from placenta increta.VEGF is negatively correlated with sFlt-1 in PPP patients.The levels of VEGF and sFlt-1 could be used as auxiliary indicators to diagnose PPP and distinguish between placenta accreta and increta.

Circulating trophoblast cell clusters for early detection of placenta accreta spectrum disorders.

Placenta accreta spectrum (PAS) is a high-risk obstetrical condition associated with significant morbidity and mortality. Current clinical screening modalities for PAS are not always conclusive. Here, we report a nanostructure-embedded microchip that efficiently enriches both single and clustered circulating trophoblasts (cTBs) from maternal blood for detecting PAS. We discover a uniquely high prevalence of cTB-clusters in PAS and subsequently optimize the device to preserve the intactness of these clusters. Our feasibility study on the enumeration of cTBs and cTB-clusters from 168 pregnant women demonstrates excellent diagnostic performance for distinguishing PAS from non-PAS. A logistic regression model is constructed using a training cohort and then cross-validated and tested using an independent cohort. The combined cTB assay achieves an Area Under ROC Curve of 0.942 (throughout gestation) and 0.924 (early gestation) for distinguishing PAS from non-PAS. Our assay holds the potential to improve current diagnostic modalities for the early detection of PAS.

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.

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.

Maternal Serum VEGF Predicts Abnormally Invasive Placenta Better than NT-proBNP: a Multicenter Case-Control Study.

The aim of this study was to test if maternal serum vascular endothelial growth factor (VEGF) or N-terminal pro B-type natriuretic peptide (NT-proBNP) predicts abnormally invasive placenta (AIP) better. Secondary objective was to test whether the serum levels of VEGF and NT-proBNP can predict the degree of invasion. In a multicenter case-control study design, gestational age-matched serum samples from pregnant women with AIP (n = 44) and uncomplicated pregnancies (n = 55) who had been enrolled at Charité - Universitätsmedizin Berlin, Germany and Centre Hospitalier Régional de la Citadelle in Liège, Belgium were analyzed. Maternal blood serum VEGF and NT-proBNP levels were immunoassayed from samples taken immediately before delivery (GA median: 35 weeks). Biomarker levels were compared between AIP and control group. The correlation of biomarker levels with the clinical AIP degree was assessed. The predictive biomarker ability was characterized through a multivariate regression model and receiver operating characteristic curves. Women with AIP had significantly lower maternal serum VEGF levels (AIP mean 285 pg/ml, 95% CI 248-322, vs. control: 391 pg/ml, 95% CI 356-426, p < 0.01) and higher NT-proBNP levels (AIP median 329 pg/ml, IQR 287-385, vs. control 295 pg/ml, IQR 273-356, p = 0.03). Maternal serum VEGF levels were able to predict AIP better (AUC = 0.729, 0.622-0.836, p < 0.001; VEGF + number of previous cesarean deliveries: AUC = 0.915, 0.853-0.977, p < 0.001). Maternal serum VEGF levels correlated inversely with the clinical AIP degree (r = - 0.32, p < 0.01). In short, maternal serum VEGF, more than NT-proBNP, can help in predicting AIP and hints at the degree of invasion.

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.

Serum miRNA biomarker discovery for placenta accreta spectrum.

Placenta accreta spectrum (PAS) disorder is a major cause of maternal and fetal morbidity, and in vitro biomarkers are highly desired in clinic. This study enrolled three phases of 186 pregnant women, including controls, PAS patients, placenta previa (PP) patients, and pre-eclamptic (PE) patients. Initial miRNA array screened 42 out of 768 serum miRNAs in the screening phase, and then validated four miRNAs by quantitative RT-PCR in the training phase and validation phase. Their performance for PAS prenatal screening was analyzed by the receiver operating characteristic (ROC) curve, sensitivity, and specificity. Data validated that four miRNAs (miR-139-3p, miR-196a-5p, miR-518a-3p, and miR-671-3p) were down-regulated in PAS group comparing with controls in three phases of subjects. Except for miR-518a-3p, the expression levels of these miRNAs also were significantly different between the PAS and the group including PP and PE. In addition, these biomarkers demonstrated modest screening efficiency, as the AUC ranged from 0.59 to 0.74, sensitivity 0.54 to 0.80, and specificity 0.62 to 0.76. However, the AUC and specificity can improve greatly (AUC 0.91, specificity 0.92) using a 'diagnostic signature' that combined the four miRNAs and four clinical parameters into one panel. GO and KEGG signaling pathway analysis indicated their target genes were involved in angiogenesis, embryonic development, cell migration and adhesion, and tumor-related pathways. In conclusion, the four miRNAs discovered in this study not only can be used for future non-invasive prenatal PAS screening, but also provide a new experimental basis for future research on PAS etiology.

First trimester serum PIGF is associated with placenta accreta.

OBJECTIVES: In this retrospective study, we investigated whether first trimester serum placental growth factor (PIGF) differed amongst pregnancies with placenta previa-accreta and non-adherent placenta previa and healthy pregnancies. METHODS: In 1 January 2017-30 September 2019, 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 age and BMI-matched, healthy pregnant controls. PIGF multiples of the median (MoM) were acquired from laboratory data files. The predictor of placenta accreta was analyzed by using multiple logistic regression analysis. RESULTS: PIGF MoM of placenta previa-accreta group was significantly higher than those of the non-adherent placenta previa group and control group (p = 0.0098 < 0.01, p = 0.0002 < 0.01). Serum PIGF was found to be significantly positively associated with placenta accreta after adjusted gestational week at time of blood sampling, BMI, and age (OR: 4.83; 95% CI: 1.91-12.24；p = 0.0009 < 0.01). In addition, previous cesarean section history (OR: 2.75; 95% CI: 1.23-6.17; p = 0.014 < 0.05) and smoking (OR: 9.17; 95% CI: 1.69-49.62; p = 0.010 < 0.05) were also significantly associated with placenta accreta. CONCLUSION: Increased first trimester serum PIGF was significantly positively associated with placenta accreta, suggesting that the potential role of PIGF in identifying pregnancies at high risk for placenta accreta. Previous cesarean section history and smoking 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.

Biomarkers of abnormally invasive placenta.

INTRODUCTION: Abnormally invasive placenta (AIP, aka placenta accreta spectrum; PAS) is an increasingly common pregnancy pathology, which, despite significant morbidity risk to the mother, is often undiagnosed prior to delivery. We tested several potential biomarkers in plasma from PAS mothers to determine whether any were sufficiently robust for a formal, diagnostic accuracy study. METHODS: We examined hyperglycosylated hCG (h-hCG), decorin and IL-8, based on biological plausibility and literature indications that they might be altered in PAS. These analytes were assayed by ELISA in maternal plasma from five groups, comprising (1) normal term controls, (2) placenta previa controls, and cases of (3) placenta increta/percreta without placenta previa, (4) placenta previa increta/percreta and (5) placenta previa accreta. RESULTS: There were no differences in h-hCG, ß-hCG or the h-hCG/ß-hCG ratio between the groups. Mean decorin levels were increased in previa controls (Group 2) compared to the other groups, but there was substantial overlap between the individual values. While an initial multiplex assay showed a greater value for IL-8 in the placenta previa increta/percreta group (Group 4) compared to placenta previa controls (Group 2), the subsequent validation ELISA for IL-8 showed no differences between the groups. DISCUSSION: We conclude that the absence of differences and the extent of overlap between cases and controls does not justify further assessment of these biomarkers.

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.

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.

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.

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.

Ovarian reserve after uterine artery embolization in women with morbidly adherent placenta: A cohort study.

OBJECTIVE: To evaluate ovarian reserve in women after preservative cesarean delivery using uterine artery embolization due to morbidly adherent placenta. STUDY DESIGN: A historical cohort study including all women admitted to a single tertiary care center, with morbidly adherent placenta that had preservative cesarean delivery with bilateral uterine artery embolization. Inclusion criteria included gestational age >24 weeks, singleton pregnancy and placenta increta / percreta. Exclusion criteria included maternal age > 43 years old and cesarean hysterectomy. Control group included women attending the infertility clinic due to male factor or single women conceiving via sperm donation, matched by age. Blood samples were collected on day 2-5 of menstruations for hormonal profile and Anti Mullarian Hormone (AMH) levels. Primary outcome was ovarian reserve evaluated by the levels of AMH. RESULTS: 59 women underwent preservative cesarean delivery using uterine artery embolization during the study period. 21 women met inclusion criteria (33.9%) and were matched controls (n = 40). Circulating levels of E2 and FSH did not differ significantly between the two groups (p = 0.665, p = 0.396, respectively). AMH was lower in the study group (median 0.8 IQR 0.44-1.80) compared to the controls (median 2.08 IQR 1.68-3.71) (p = 0.001). This finding was consistent in linear multivariate regression analysis where the group of cesarean delivery using bilateral artery embolization due to placenta accrete was significantly predictive for the levels of AMH (B = -1.308, p = 0.012). CONCLUSION: Women post preservative cesarean delivery using uterine artery embolization due to placenta accrete have lower ovarian reserve compare to controls matched by age.

Placenta Accreta Spectrum: A Review of Pathology, Molecular Biology, and Biomarkers.

Background. Placenta accreta spectrum (PAS) is a condition of abnormal placental invasion encompassing placenta accreta, increta, and percreta and is a major cause of severe maternal morbidity and mortality. The diagnosis of a PAS is made on the basis of histopathologic examination and characterised by an absence of decidua and chorionic villi are seen to directly adjacent to myometrial fibres. The underlying molecular biology of PAS is a complex process that requires further research; for ease, we have divided these processes into angiogenesis, proliferation, and inflammation/invasion. A number of diagnostic serum biomarkers have been investigated in PAS, including human chorionic gonadotropin (HCG), pregnancy-associated plasma protein-A (PAPP-A), and alpha-fetoprotein (AFP). They have shown variable reliability and variability of measurement depending on gestational age at sampling. At present, a sensitive serum biomarker for invasive placentation remains elusive. In summary, there are a limited number of studies that have contributed to our understanding of the molecular biology of PAS, and additional biomarkers are needed to aid diagnosis and disease stratification.