The relation between maternal obesity and placenta accreta spectrum: A multinational database study.

INTRODUCTION: It has been suggested that women with obesity have increased risk of developing placenta accreta spectrum (PAS). It is unclear if this is independent of the increased risk of cesarean delivery seen with obesity itself. The aim of this study was to explore the association between maternal obesity and PAS, particularly severe PAS (percreta). MATERIAL AND METHODS: This is a cohort study based on cases recorded in the International Society for Placenta Accreta Spectrum (IS-PAS) database between April 2008 and May 2019. Multivariable logistic regression was used to explore the effect of maternal obesity on severity of PAS; this model was adjusted for other known risk factors including previous cesarean deliveries, maternal age, and placenta previa. The estimated rate of obesity in a hypothetical cohort with similar characteristics (previous cesarean delivery and same parity) was calculated and compared with the observed rate of obesity in the women of the PAS cohort (one sample test of proportions). RESULTS: Of the 386 included women with PAS, 227 (58.8%) had severe disease (percreta). In univariable analysis, maternal obesity initially appeared to be associated with increased odds of developing the most severe type of PAS, percreta (odds ratio [OR] 1.87; 95% CI 1.14-3.09); however, this association was lost after adjustment for other risk factors including previous cesarean delivery (OR 1.44; 95% CI 0.85-2.44). There was no difference in the observed rate of obesity and the rate estimated based on the risk of cesarean delivery from obesity alone (31.3% vs 36.8%, respectively; P = .07). CONCLUSIONS: Obesity does not seem to be an independent risk factor for PAS or severity for PAS. These findings are relevant for clinicians to provide accurate counseling to women with obesity regarding increased risks related to pregnancy.

Maternal and neonatal outcomes in planned versus emergency cesarean delivery for placenta accreta spectrum: A multinational database study.

INTRODUCTION: Placenta accreta spectrum (PAS) is a condition often resulting in severe maternal morbidity. Scheduled delivery by an experienced team has been shown to improve maternal outcomes; however, the benefits must be weighed against the risk of iatrogenic prematurity. The aim of this study is to investigate the rates of emergency delivery seen for antenatally suspected PAS and compare the resulting outcomes in the 15 referral centers of the International Society for PAS (IS-PAS). MATERIAL AND METHODS: Fifteen centers provided cases between 2008 and 2019. The women included were divided into two groups according to whether they had a planned or an emergency cesarean delivery. Delivery was defined as "planned" when performed at a time and date to suit the team. All the remaining cases were classified as "emergency". Maternal characteristics and neonatal outcomes were compared between the two groups according to gestation at delivery. RESULTS: In all, 356 women were included. Of these, 239 (67%) underwent a planned delivery and 117 (33%) an emergency delivery. Vaginal bleeding was the indication for emergency delivery in 41 of the 117 women (41%). There were no significant differences in terms of blood loss, transfusion rates or major maternal morbidity between planned and emergency deliveries. However, the rate of maternal intensive therapy unit admission was increased with emergency delivery (45% vs 33%, P = .02). Antepartum hemorrhage was the only independent predictor of emergency delivery (aOR: 4.3, 95% confidence interval 2.4-7.7). Emergency delivery due to vaginal bleeding was more frequent with false-positive cases (antenatally suspected but not confirmed as PAS at delivery) and the milder grades of PAS (accreta/increta). The rate of infants experiencing any major neonatal morbidity was 25% at 34+1 to 36+0  weeks and 19% at >36+0  weeks. CONCLUSIONS: Emergency delivery in centers of excellence did not increase blood loss, transfusion rates or maternal morbidity. The single greatest risk factor for emergency delivery was antenatal hemorrhage. When adequate expertise and resources are available, to defer delivery in women with no significant antenatal bleeding and no risk factors for pre-term birth until >36+0  weeks can be considered to improve fetal outcomes. Further studies are needed to investigate this fully.

Association of peripartum management and high maternal blood loss at cesarean delivery for placenta accreta spectrum (PAS): A multinational database study.

INTRODUCTION: Placenta accreta spectrum (PAS) carries a high burden of adverse maternal outcomes, especially significant blood loss, which can be life-threatening. Different management strategies have been proposed but the association of clinical risk factors and surgical management options during cesarean delivery with high blood loss is not clear. MATERIAL AND METHODS: In this international multicenter study, 338 women with PAS undergoing cesarean delivery were included. Fourteen European and one non-European center (USA) provided cases treated retrospectively between 2008 and 2014 and prospectively from 2014 to 2019. Peripartum blood loss was estimated visually and/or by weighing and measuring of volume. Participants were grouped based on blood loss above or below the 75th percentile (>3500 ml) and the 90th percentile (>5500 ml). RESULTS: Placenta percreta was found in 58% of cases. Median blood loss was 2000 ml (range: 150-20 000 ml). Unplanned hysterectomy was associated with an increased risk of blood loss >3500 ml when compared with planned hysterectomy (adjusted OR [aOR] 3.7 [1.5-9.4], p = 0.01). Focal resection was associated with blood loss comparable to that of planned hysterectomy (crude OR 0.7 [0.2-2.1], p = 0.49). Blood loss >3500 ml was less common in patients undergoing successful conservative management (placenta left in situ, aOR 0.1 [0.0-0.6], p = 0.02) but was more common in patients who required delayed hysterectomy (aOR 6.5 [1.7-24.4], p = 0.001). Arterial occlusion methods (uterine or iliac artery ligation, embolization or intravascular balloons), application of uterotonic medication or tranexamic acid showed no significant effect on blood loss >3500 ml. Patients delivered by surgeons without experience in PAS were more likely to experience blood loss >3500 ml (aOR 3.0 [1.4-6.4], p = 0.01). CONCLUSIONS: In pregnant women with PAS, the likelihood of blood loss >3500 ml was reduced in planned vs unplanned cesarean delivery, and when the surgery was performed by a specialist experienced in the management of PAS. This reinforces the necessity of delivery by an expert team. Conservative management was also associated with less blood loss, but only if successful. Therefore, careful patient selection is of great importance. Our study showed no consistent benefit of other adjunct measures such as arterial occlusion techniques, uterotonics or tranexamic acid.

Performance of antenatal imaging to predict placenta accreta spectrum degree of severity.

INTRODUCTION: In cases of placenta accreta spectrum, a precise antenatal diagnosis of the suspected degree of invasion is essential for the planning of individual management strategies at delivery. The aim of this work was to evaluate the respective performances of ultrasonography and magnetic resonance imaging for the antenatal assessment of the severity of placenta accreta spectrum disorders included in the database. The secondary objective was to identify descriptors related to the severity of placenta accreta spectrum disorders. MATERIAL AND METHODS: All the cases included in the database for which antenatal imaging data were available were analyzed. The rates of occurrence of each ultrasound and magnetic resonance imaging descriptor were reported and compared between the Group "Accreta-Increta" (FIGO grades 1 & 2) and the Group "Percreta" (FIGO grade 3). RESULTS: Antenatal imaging data were available for 347 women (347/442, 78.5%), of which 105 were included in the Group "Accreta - Increta" (105/347, 30.2%) and 213 (213/347, 61.4%) in the Group "Percreta". Magnetic resonance imaging was performed in addition to ultrasound in 135 women (135/347, 38.9%). After adjustment for all ultrasound descriptors in multivariate analysis, only the presence of a bladder wall interruption was associated with a significant higher risk of percreta (Odds ratio 3.23, Confidence interval 1.33-7.79). No magnetic resonance imaging sign was significantly correlated with the degree of severity. CONCLUSIONS: The performance of ultrasound and magnetic resonance imaging to discriminate mild from severe placenta accreta spectrum disorders is very poor. To date, the benefit of additional magnetic resonance imaging has not been demonstrated.

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.

Online survey on uterotomy closure techniques in caesarean section.

OBJECTIVES: Uterine closure technique in caesarean section (CS) influences the rate of late complications in subsequent pregnancies. As no common recommendation on suture techniques exists, we developed a questionnaire to determine the techniques currently used and the frequencies of late complications. METHODS: The online questionnaire consisted of 13 questions and was sent to 648 obstetric hospitals (level I-IV) in Germany. Number of CS, rate of vaginal birth after caesarean section (VBAC), the type of uterus suturing technique and the frequency of uterine dehiscences, ruptures and placenta accreta spectrum (PAS) were queried. The answers were anonymous, and results were evaluated descriptively. RESULTS: The response rate was 24.7%. The mean CS rate was 27.3% (±6.2), the repeat CS rate 33.2% (±18.1). After CS, 46.2% (±20.2) women delivered vaginally. To close the uterotomy, 74.4% of hospitals used single layer continuous sutures, 16.3% single layer locked sutures, 3.8% interrupted sutures, 3.1% double layer continuous sutures and 2.5% used other suture techniques. The percentages of observed uterine dehiscences did not differ significantly between the different levels of care nor did the uterotomy suture techniques. CONCLUSIONS: There is no uniform suturing technique in Germany. A detailed description of suture technique in surgery reports is required to evaluate complications in subsequent pregnancies. National online surveys on obstetric topics are feasible and facilitate the discussion on the need to define a standardized uterine closure technique for CS.

[Prenatal Diagnostics and Postnatal Complications in a Case of Extremely Rare Tetra-Amelia]. / Pränatale Diagnostik und postnatale Komplikationen im Fall einer extrem seltenen Tetraamelie.

Tetra-amelia is extremely rare with an incidence of 2.4 per 10,000,000 births. It describes the absence of all 4 outer extremities and can be associated with other malformations. The boy presented here was diagnosed at 22 1/7 weeks of gestation by sonography in 2D and 3D mode. The parents decided to continue the pregnancy; vaginal birth occurred after external rotation at 38 1/7 weeks of pregnancy. Postnatally, surgical closure of a cleft of the soft palate was performed. External abnormalities manifested themselves increasingly in the area of the spine and the face. The anatomically limited psychomotor development of the child is supported by physiotherapy, occupational therapy, and speech therapy. Various aids enable the child to participate in activities appropriate to his age.

Prenatally detected umbilical cord tumor as a sign of diffuse neonatal hemangiomatosis.

We report a case of a prenatally detected hemangioma of the umbilical cord as an early sign of diffuse neonatal hemangiomatosis (DNH). The newborn was diagnosed with multiple hemangiomas in the liver, intestines, skin, and brain. Prenatal ultrasound findings, neonatal appearance of the hemangiomas, and the associated complications are illustrated. Interdisciplinary investigations as well as operative and systemic treatment approaches proved to be challenging. This case illustrates how prenatal ultrasound with color Doppler facilitates the early diagnosis of DNH and can help through the early referral to specialized centers for appropriate treatment.

miR-142-3p attenuates breast cancer stem cell characteristics and decreases radioresistance in vitro.

Effectively targeting cancer stem cells, a subpopulation of tumorigenic, aggressive, and radioresistant cells, holds therapeutic promise. However, the effects of the microRNA miR-142-3p, a small endogenous regulator of gene expression on breast cancer stem cells, have not been investigated. This study identifies the influence of miR-142-3p on mammary stemness properties and breast cancer radioresistance to establish its role in this setting. miR-142-3p precursor transfection was performed in MDA-MB-468, HCC1806, and MCF-7 cells, and stem cell markers CD44, CD133, ALDH1 activity and mammosphere formation were measured. ß-catenin, the canonical wnt signaling effector protein, was quantified by Western blots and cell fluorescence assays both in miR-142-3p-overexpressing and anti-miR-142-3p-treated cells. Radiation response was investigated by colony formation assays. Levels of BRCA1, BRCA2, and Bod1 in miR-142-3p-overexpressing cells as well as expression of miR-142-3p, Bod1, KLF4, and Oct4 in sorted CD44+/CD24-/low cells were determined by quantitative polymerase chain reaction. miR-142-3p overexpression resulted in a strong decline in breast cancer stem cell characteristics with a decrease in CD44, CD133, ALDH1, Bod1, BRCA2, and mammosphere formation as well as reduced survival after irradiation. miR-142-3p expression was strongly reduced in sorted CD44+/CD24-/low stem cells, while Bod1, Oct4, and KLF4 were overexpressed. ß-catenin levels strongly decreased after miR-142-3p overexpression, but not after anti-miR-142-3p treatment. We conclude that miR-142-3p downregulates cancer stem cell characteristics and radioresistance in breast cancer, mediated by a reduced role of ß-catenin in miR-142-3p-overexpressing cells. miR-142-3p might therefore help to target cancer stem cells.

Placenta Percreta Presents with Neoangiogenesis of Arteries with Von Willebrand Factor-Negative Endothelium.

In placenta percreta cases, large vessels are present on the precrete surface area. As these vessels are not found in normal placentation, we examined their histological structure for features that might explain the pathogenesis of neoangiogenesis induced by placenta accreta spectrum disorders (PAS). In two patients with placenta percreta (FIGO grade 3a) of the anterior uterine wall, one strikingly large vessel of 2 cm length was excised. The samples were formalin fixed and paraffin-embedded. Gomori trichrome staining was used to evaluate the muscular layers and Weigert-Van Gieson staining for elastic fibers. Immunohistochemical staining of the vessel endothelium was performed for Von Willebrand factor (VWF), platelet endothelial cell adhesion molecule (CD31), Ephrin B2, and EPH receptor B4. The structure of the vessel walls appeared artery-like. The vessel of patient one further exhibited an unorderly muscular layer and a lack of elastic laminae, whereas these features appeared normal in the vessel of the other patient. The endothelium of both vessels stained VWF-negative and CD31-positive. In conclusion, this study showed VWF-negative vessel endothelia of epiplacental arteries in placenta accreta spectrum. VWF is known to regulate artery formation, as the absence of VWF has been shown to cause enhanced vascularization. Therefore, we suppose that PAS provokes increased vascularization through suppression of VWF. This process might be associated with the immature vessel architecture as found in one of the vessels and Ephrin B2 and EPH receptor B4 negativity of both artery-like vessels. The underlying pathomechanism needs to be evaluated in a greater set of patients.

Feasibility of Umbilical Cord Blood Collection in Neonates at Risk of Brain Damage-A Step Toward Autologous Cell Therapy for a High-risk Population.

Evidence for umbilical cord blood (UCB) cell therapies as a potential intervention for neurological diseases is emerging. To date, most existing trials worked with allogenic cells, as the collection of autologous UCB from high-risk patients is challenging. In obstetric emergencies the collection cannot be planned. In preterm infants, late cord clamping and anatomic conditions may reduce the availability. The aim of the present study was to assess the feasibility of UCB collection in neonates at increased risk of brain damage. Infants from four high-risk groups were included: newborns with perinatal hypoxemia, gestational age (GA) ≤30 + 0 weeks and/or birthweight <1,500 g, intrauterine growth restriction (IUGR), or monochorionic twins with twin-to-twin transfusion syndrome (TTTS). Feasibility of collection, quantity and quality of obtained UCB [total nucleated cell count (TNC), volume, sterility, and cell viability], and neonatal outcome were assessed. UCB collection was successful in 141 of 177 enrolled patients (hypoxemia n = 10; GA ≤30 + 0 weeks n = 54; IUGR n = 71; TTTS n = 6). Twenty-six cases were missed. The amount of missed cases per month declined over the time. Volume of collected UCB ranged widely (median: 24.5 ml, range: 5.0-102 ml) and contained a median of 0.77 × 108 TNC (range: 0.01-13.0 × 108). TNC and UCB volume correlated significantly with GA. A total of 10.7% (19/177) of included neonates developed brain lesions. To conclude, collection of UCB in neonates at high risk of brain damage is feasible with a multidisciplinary approach and intensive training. High prevalence of brain damage makes UCB collection worthwhile. Collected autologous UCB from mature neonates harbors a sufficient cell count for potential therapy. However, quality and quantity of obtained UCB are critical for potential therapy in preterm infants. Therefore, for extremely preterm infants alternative cell sources such as UCB tissue should be investigated for autologous treatment options because of the low yield of UCB.

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.

microRNA miR-142-3p Inhibits Breast Cancer Cell Invasiveness by Synchronous Targeting of WASL, Integrin Alpha V, and Additional Cytoskeletal Elements.

MicroRNAs (miRNAs, micro ribonucleic acids) are pivotal post-transcriptional regulators of gene expression. These endogenous small non-coding RNAs play significant roles in tumorigenesis and tumor progression. miR-142-3p expression is dysregulated in several breast cancer subtypes. We aimed at investigating the role of miR-142-3p in breast cancer cell invasiveness. Supported by transcriptomic Affymetrix array analysis and confirmatory investigations at the mRNA and protein level, we demonstrate that overexpression of miR-142-3p in MDA-MB-231, MDA-MB-468 and MCF-7 breast cancer cells leads to downregulation of WASL (Wiskott-Aldrich syndrome-like, protein: N-WASP), Integrin-αV, RAC1, and CFL2, molecules implicated in cytoskeletal regulation and cell motility. ROCK2, IL6ST, KLF4, PGRMC2 and ADCY9 were identified as additional targets in a subset of cell lines. Decreased Matrigel invasiveness was associated with the miR-142-3p-induced expression changes. Confocal immunofluorescence microscopy, nanoscale atomic force microscopy and digital holographic microscopy revealed a change in cell morphology as well as a reduced cell volume and size. A more cortical actin distribution and a loss of membrane protrusions were observed in cells overexpressing miR-142-3p. Luciferase activation assays confirmed direct miR-142-3p-dependent regulation of the 3'-untranslated region of ITGAV and WASL. siRNA-mediated depletion of ITGAV and WASL resulted in a significant reduction of cellular invasiveness, highlighting the contribution of these factors to the miRNA-dependent invasion phenotype. While knockdown of WASL significantly reduced the number of membrane protrusions compared to controls, knockdown of ITGAV resulted in a decreased cell volume, indicating differential contributions of these factors to the miR-142-3p-induced phenotype. Our data identify WASL, ITGAV and several additional cytoskeleton-associated molecules as novel invasion-promoting targets of miR-142-3p in breast cancer.