Vertical transmission of methicillin-resistant Staphylococcus aureus at delivery and its clinical impact: An observational, prospective cohort study.

INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) infection has a significant clinical impact on both pregnant women and neonates. The aim of this study was to assess accurately the vertical transmission rate of MRSA and its clinical impacts on both pregnant mothers and neonates. MATERIAL AND METHODS: We conducted a prospective observational cohort study of 898 pregnant women who were admitted to our department and 905 neonates from August 2016 to December 2017. MRSA was cultured from nasal and vaginal samples taken from the mothers at enrollment and from nasal and umbilical surface swabs taken from neonates at the time of delivery. We examined the vertical transmission rate of MRSA in mother-neonate pairs. We used multivariable logistic regression to identify risk factors for maternal MRSA colonization and maternal/neonatal adverse outcomes associated with maternal MRSA colonization. RESULTS: The prevalence of maternal MRSA colonization was 6.1% (55 of 898) at enrollment. The independent risk factors were multiparity and occupation (healthcare provider) (odds ratio [OR] 2.35, 95% confidence interval [CI] 1.25-4.42 and OR 2.58, 95% CI 1.39-4.79, respectively). The prevalence of neonatal MRSA colonization at birth was 12.7% (7 of 55 mother-neonate pairs) in the maternal MRSA-positive group, whereas it was only 0.12% (one of 843 pairs) in the maternal MRSA-negative group (OR 121, 95% CI 14.6-1000). When maternal vaginal samples were MRSA-positive, vertical transmission was observed in four of nine cases (44.4%) in this study. Skin and soft tissue infections developed more frequently in neonates in the maternal MRSA-positive group than in the MRSA-negative group (OR 7.47, 95% CI 2.50-22.3). CONCLUSIONS: The prevalence of MRSA in pregnant women was approximately 6%. Vertical transmission caused by maternal vaginal MRSA colonization was observed in four of nine cases (44.4%). Although our study includes a limited number of maternal MRSA positive cases, the vertical transmission of MRSA may occur in up to 44% of neonates of mothers with vaginal MRSA colonization. Maternal MRSA colonization may be associated with increased development of skin and soft tissue infections in neonates via vertical transmission.

A novel classification of glucose profile in pregnancy based on continuous glucose monitoring data.

AIM: To investigate the glucose profile of women with and without gestational diabetes mellitus (GDM) by simultaneously analyzing several factors of continuous glucose monitoring (CGM) data. METHODS: CGM was conducted for 2 weeks in the second trimester of pregnant women whose random blood glucose level was ≥100 mg/dl. A 75-g oral glucose tolerance test was performed around day 7, and the index of hyperglycemia, relative hypoglycemia, and indices of glucose variability were extracted from CGM data. Unsupervised hierarchical clustering was performed to categorize glucose profiles of the participants. RESULTS: CGM data were obtained from 29 women. Glucose profiles were categorized into three clusters: low glucose levels with less glucose variability group (L group, n = 7); moderate glucose levels with moderate-to-high glucose variability group (M group, n = 18); and high glucose levels with high glucose variability group (H group, n = 4). The waveforms of the glucose profiles were very different among the three groups. Women with GDM tended to be more frequent in the H group than in the M and L groups (75.0%, 16.7%, and 14.3%, respectively; p = 0.053). Maternal age was significantly higher and the proportion of multiparous women was significantly larger in the H group compared to L group (p = 0.002 and 0.015, respectively). CONCLUSIONS: A comprehensive analysis of CGM data could help us extract a subgroup of women with characteristics of GDM.

Versican V1 in human endometrial epithelial cells promotes BeWo spheroid adhesion in vitro.

The endometrium extracellular matrix (ECM) is essential for embryo implantation. Versican, a large chondroitin sulfate proteoglycan that binds hyaluronan and forms large ECM aggregates, can influence fundamental physiological phenomena, such as cell proliferation, adhesion and migration. The present study investigated the possible role of versican in human embryo implantation. Versican V1 expression and secretion in human endometrial epithelial cells (EECs) was most prominent in the mid-secretory phase. Versican expression in EECs significantly increased after treatment with estrogen and progesterone, but not by estrogen alone. We also established versican V1-overexpressing Ishikawa (endometrial cancer cell line) cells (ISKW-V1), versican V3-overexpressing (ISKW-V3) and control GFP-overexpressing (ISKW-GFP) Ishikawa cells. By the in vitro implantation model, the attachment ratio of BeWo (choriocarcinoma cell line) spheroids to the monolayer of ISKW-V1, but not of ISKW-V3, was found significantly enhanced compared with attachment to the ISKW-GFP monolayer. The conditioned medium derived from ISKW-V1 (V1-CM) also promoted the attachment of BeWo spheroids to the ISKW monolayer. However, this attachment-promoting effect was abolished when V1-CM was pretreated with chondroitinase ABC, which degrades chondroitin sulfate. Therefore, out of the ECM components, versican V1 may facilitate human embryo implantation.

Vaginal delivery after placental abruption with intrauterine fetal death: A 20-year single-center experience.

AIM: The aim of this study was to elucidate the feasibility and safety of vaginal delivery (VD) when placental abruption causes fetal demise. METHODS: We conducted a retrospective study of women who were managed for placental abruption with intrauterine fetal death at Kyoto University Hospital during the period from 1995 to 2015. RESULTS: Sixteen cases were identified during the study period. VD was attempted in 15 cases and was accomplished in 14 (93.3%) cases. The median gestational age was 36 (24-39) weeks, and there were eight primiparas. The median Bishop score on admission was 2.5 (1-9). Eight pregnancies were complicated with pregnancy-induced hypertension. The median duration of labor was 5 h and 18 min (30 min-12 h 43 min), and the median amount of hemorrhage was 2503 (445-6808) mL. Fresh frozen plasma (≥ 20 U) and red cell concentrate (≥ 10 U) were administered in 10 (71%) and 9 (64%) cases, respectively. Two cases required uterine artery embolization for post-partum hemorrhage, while there was no case of maternal death or hysterectomy. Patients with Bishop score > 3 (n = 6) experienced shorter-duration deliveries (P = 0.020) and had significantly larger blood loss volume (P = 0.020) compared to patients with Bishop score ≤ 3. The duration of labor was negatively correlated with the amount of blood loss (R2 = -0.56, P = 0.039). CONCLUSION: After placental abruption with intrauterine fetal death, VD is feasible and safe regardless of gestational age, parity, cervical maturity, and duration of labor when intensive medical resources are available.

Eph-ephrin A system regulates human choriocarcinoma-derived JEG-3 cell invasion.

OBJECTIVES: The Eph-ephrin system is a unique system that can induce multiple cellular responses such as cell migration, regulation of angiogenesis, and axonal guidance. Previously, the Eph-ephrin system was reported to regulate human extravillous trophoblast invasion. In this study, we examined the possible involvement of the Eph-ephrin system in the invasion of malignant gestational trophoblastic diseases using a human choriocarcinoma-derived cell line, JEG-3. METHODS: The mRNA expression of class A Ephs and ephrins on JEG-3 cells was examined by reverse transcription-polymerase chain reaction. The effects of recombinant human Eph A1 (r-Eph A1) and r-ephrin A4 on the proliferation and invasion of JEG-3 cells were investigated by cell proliferation and Matrigel invasion assays. The alterations of integrin expression on JEG-3 cells in the presence of r-Eph A1 and r-ephrin A4 were investigated by flow cytometry. The induction of phosphorylation of focal adhesion kinase in JEG-3 cells by r-ephrin A4 was examined by Western blot analysis. RESULTS: By reverse transcription-polymerase chain reaction, mRNAs of Eph A1, A2, and A4 and ephrin A1, A4, and A5 were detected on JEG-3 cells. In Matrigel invasion assay, both r-Eph A1 and r-ephrin A4 promoted the invasion of JEG-3 cells without affecting cell proliferation. During 24-hour culture with r-Eph A1 and r-ephrin A4, the increase in integrin α 5 expression on JEG-3 cells was observed by flow cytometry. Western blotting analysis showed that r-ephrin A4 induced dephosphorylation of focal adhesion kinase in JEG-3 cells. CONCLUSIONS: These findings suggest that Eph-ephrin interaction plays some role in the regulation of choriocarcinoma invasion in cooperation with integrins.

Laeverin/aminopeptidase Q induces trophoblast invasion during human early placentation.

BACKGROUND: In primate placenta, extravillous trophoblast (EVT) invades maternal tissue in temporally- and spatially-regulated fashions. We previously identified a novel placenta-specific cell-surface aminopeptidase, laeverin/aminopeptidase Q, which is expressed on EVT-lineage cells in the fetal membrane. Laeverin possesses a peptide-binding site that is evolutionally unique to primates, suggesting possible involvement of laeverin in a primate-specific phenomenon during placentation. Thus, this study was designed to elucidate the molecular characteristics and physiological roles of laeverin in human EVT. METHODS: Placental tissues of various developmental stages were subjected to immunostaining and western blotting. Effects of siRNA and a soluble form of recombinant laeverin on EVT cells isolated from primary villous explant cultures were examined using Matrigel invasion assays and cell proliferation assays. RESULTS: Laeverin was specifically immunolocalized to HLA-G-positive EVT in placentas from early and term pregnancy. In primary villous explant cultures, laeverin expression was induced on the cell surface of the outgrowing EVT. In western blotting, laeverin protein was detected as two distinct bands at 130 and 160 kDa along with a broad band ranging from 200 to 270 kDa. De-glycosylation treatment showed that these native laeverin isotypes are N-linked glycoproteins sharing a common 115-kDa core protein. In invasion assays, the reduction of laeverin expression by siRNA suppressed migration of the isolated EVT, while the soluble form of recombinant laeverin enhanced its migration. CONCLUSIONS: Laeverin is a specific cell-surface marker for human EVT and plays a regulatory role in EVT migration.

A Case of Recurrent Hemorrhagic Corpus Luteum with Elevated Follicle-Stimulating Hormone, Controlled by Estrogen/Gestagen Therapy.

A high secretion of follicle-stimulating hormone (FSH) in reproductive-aged women is unusual. We report a case of recurrent corpus luteum hemorrhage and subsequent ovarian torsion with markedly elevated FSH levels in a reproductive-aged woman in the absence of functional gonadotroph adenoma (FGA) or premature ovarian failure (POF). A 22-year-old nulligravid woman with a history of bilateral hemorrhagic corpus luteum and subsequent ovarian torsion presented with acute abdominal pain. An emergency salpingo-oophorectomy of the right side was performed, and the right ovarian torsion due to hemorrhagic corpus luteum was diagnosed. Laboratory tests revealed markedly elevated FSH levels (77.6 mIU/mL). FGA was suspected, but no evidence of tumor was identified. The left ovary enlarged again at one-month follow-up. Estrogen/gestagen therapy (EGT) was started, which reduced the enlarged ovary to normal size. Two years later, her pituitary hormonal status was evaluated in detail. Besides markedly elevated FSH level, slightly elevated LH (31.2 mIU/mL), normal total inhibin B (35.3 pg/ml), abnormally low anti-Müllerian hormone (AMH) (<0.03 ng/mL), and poor FSH response to gonadotropin-releasing hormone stimulation test were found. In the absence of FGA, we conclude that certain disorders of inhibitory factors for FSH function, including inhibin and AMH may exist, which could attribute to the patient's symptoms. EGT was very effective in suppressing the ovarian hyperactivity.

A Case of Synchronous Primary Corpus and Ovarian Cancer with Pseudo-Meigs Syndrome: Utilization of a Diagnostic Laparoscopy for the Accurate Diagnosis.

We report a case of synchronous primary corpus and ovarian cancer (SPC) with massive ascites due to Pseudo-Meigs syndrome (PMS). A 48-year-old woman presented with complaints of abnormal genital bleeding and abdominal discomfort. Massive ascites and tumors in the endometrium and right ovary were detected. Although imaging tests showed no evidence of dissemination, and ascites cytology was negative, we performed a diagnostic laparoscopy to exclude the possibility of microdissemination because pathological findings of the corpus tumor were suggested to be so-called Type-2 endometrial cancer. Laparoscopy clearly confirmed no dissemination in the peritoneum. We ultimately diagnosed this patient with SPC with massive nonmalignant ascites due to PMS and performed an appropriate treatment. This report is the first case of SPC that developed PMS.

A Case of Pregnancy Complicated with ATIII Deficiency in a Patient Who Developed Severe Venous Thromboembolism in Her Fourth Pregnancy and Had a Favourable Outcome in Her Subsequent Pregnancy with Careful Management of Anticoagulation Therapy including Edoxaban.

Congenital ATIII deficiency is one of the congenital thrombophilia diseases that can cause severe venous thromboembolism (VTE) in pregnant patients. A 30-year-old female, 4 gravida and 2 para, came to the emergency department with a complaint of oedema and pain in the left lower leg at 11 weeks of gestation. An inferior vena cava thrombus and pulmonary embolism were found. Because VTE was very severe, artificial abortion was performed, and VTE disappeared rapidly. She maintained oral administration of edoxaban (NOAC) and got pregnant naturally fifty-five weeks later after the abortion. Anticoagulation therapy was changed from NOAC to ATIII formulation and unfractionated heparin at 5 weeks of gestation. The course of pregnancy was good, and a healthy female newborn of 2310 g was delivered vaginally at 37 weeks 6 days of gestation. In puerperium, anticoagulation therapy was changed to warfarin. Currently one and one-half years had passed after delivery and no major adverse events or thrombosis has occurred. This case indicates that severe VTE can develop even in multipara pregnancy and that those who take NOAC may be able to continue pregnancy when they get pregnant.

A Case of Pregnancy Complicated with Evans Syndrome with Sequential Development of Autoimmune Warm Antibody Hemolytic Anemia and Idiopathic Thrombocytopenic Purpura.

The simultaneous or sequential development of autoimmune hemolytic anemia (AIHA) and idiopathic thrombocytopenic purpura (ITP) is known as Evans syndrome. We experienced a case of Evans syndrome that developed AIHA during pregnancy and ITP long after delivery. The patient was a 35-year-old pregnant woman (gravida 2, para 1). A routine blood test at 28 weeks of gestation revealed moderate macrocytic anemia. Her haptoglobin level was markedly low, and a direct antiglobulin test (DAT) was positive. Based on these results, AIHA was considered. A healthy female newborn with bodyweight 3575 g was vaginally delivered uneventfully. After delivery, the DAT remained positive, but anemia did not develop. At 203 days after delivery, ITP was detected. Because AIHA and ITP developed sequentially, she was diagnosed with Evans syndrome. When AIHA occurs during pregnancy, long-term follow-up is needed because ITP can develop sequentially.

A Case of Pelvic Abscess Caused by Edwardsiella tarda followed by Laparoscopic Resection of a Hematoma Derived from Caesarean Section.

Edwardsiella tarda (E. tarda) infections are rare and can be fatal. We report a case of an E. tarda abscess which developed in the hematoma originally derived from a caesarean section. A 24-year-old gravida 1 woman was admitted to our hospital with a complaint of abdominal pain. Approximately one month before her admission, pelvic hematoma had developed derived from caesarean section. Followed by the failure of conservative management, she underwent laparoscopic surgery to remove the hematoma 6 days before her admission. On computed tomography examination, we found that the abscess with a diameter of 9 cm was located in the right pelvic space. We punctured the abscess and identified E. tarda in the abscess. We continued administering antibiotics, but her symptoms, including fever and abdominal pain, became worse, and the abscess enlarged. We performed laparotomy drainage and ileocecal resection on the 10th posthospitalization day. After drainage surgery, the patient's condition improved gradually, and the patient was discharged uneventfully. There are no reports in patients of E. tarda infection during the perinatal period. E. tarda infection can be a life-threatening illness even in immunocompetent patients. In the case of E. tarda infection, intensive care and surgical procedures should be considered.

Large-cell neuroendocrine carcinoma arising in the endometrium: A case report.

Large-cell neuroendocrine carcinoma (LCNEC) of the endometrium is an extremely rare, high-grade malignant tumor. We herein report a case of a rapidly growing LCNEC arising in the endometrium. A 52-year-old woman was referred to Toyooka Hospital (Tooyoka, Japan) due to genital bleeding in February 2016. There had been no abnormalities on a regular gynecological and physical examination 3 months prior to the consultation. Imaging (computed tomography and magnetic resonance imaging) and a pelvic examination revealed a tumor sized 16.9×8.4×7.8 mm occupying the intrauterine cavity and extending into the vaginal cavity. Multiple metastatic pelvic and paraaortic lymph nodes were also identified. Continuous bleeding from the tumor was observed, and a blood examination revealed anemia, which was likely due to that bleeding. Biopsy of the tumor was performed, and large atypical cells were identified. The tumor cells were negative for cytokeratin AE1/AE3 and chromogranin A, but positive for CD56 and synaptophysin. There was also an abundance of Ki-67-positive cells in the tumor, altogether suggesting that the tumor was an LCNEC. The patient succumbed to the disease 36 days after the first consultation. Based on the findings of the present case and previously published cases, LCNECs arising in the endometrium may progress rapidly and are associated with an unfavourable outcome. LCNEC should be included in the differential diagnosis in cases of rapidly growing tumors of the uterine corpus.

Platelets are a possible regulator of human endometrial re-epithelialization during menstruation.

PROBLEM: The human endometrium periodically breaks down and regenerates. As platelets have been reported to contribute to the tissue remodeling process, we examined the possible involvement of platelets in endometrial regeneration. METHOD OF STUDY: The distribution of extravasating platelets throughout the menstrual cycle was immunohistochemically examined using human endometrial tissues. EM-E6/E7/hTERT cells, a human endometrial epithelial cell-derived immortalized cell line, were co-cultured with platelets, and the effects of platelets on the epithelialization response of EM-E6/E7/hTERT cells were investigated by attachment and permeability assays, immunohistochemical staining, and Western blot analysis. RESULTS: Immunohistochemical study showed numerous extravasated platelets in the subluminar stroma during the menstrual phase. The platelets promoted the cell-to-matrigel attachment of EM-E6/E7/hTERT cells concomitantly with the phosphorylation of focal adhesion kinase. They also promoted cell-to-cell contact among EM-E6/E7/hTERT cells in parallel with E-cadherin expression. CONCLUSION: These results indicate the possible involvement of platelets in the endometrial epithelial re-epithelialization process.

Platelet-derived microparticles and soluble factors differentially regulate human endometrial epithelial cell movement.

PROBLEM: We previously proposed that platelets promote re-epithelialization during menstruation. As cell movement is one of the important cell behaviors in the process of tissue remodeling, we examined the effects of platelets on endometrial epithelial cell invasion. METHOD OF STUDY: The platelets were isolated from healthy women. Using a human endometrial epithelial cell-derived immortalized cell line, EM-E6/E7/hTERT cells, we examined the effects of platelets and platelet-derived condition media with or without microparticles on the morphological and invasive properties of EM-E6/E7/hTERT cells. RESULTS: Platelets and microparticle-containing conditioned media inhibited Matrigel invasion by EM-E6/E7/hTERT cells along with an increase in cortical ring formation, whereas microparticle-depleted conditioned media promoted their invasion without any significant changes of cortical ring formation. CONCLUSION: These results support our previous proposal and newly suggest the dual roles of platelets: platelet-derived soluble factors that promote cell movement in the distant area, and microparticles that induce re-epithelialization by endometrial epithelial cells in the proximal area.

Role of Versican in the Pathogenesis of Peritoneal Endometriosis.

CONTEXT: Sampson's theory cannot explain why only some cycling women develop peritoneal endometriosis. Few studies have focused on the pelvic peritoneum, which receives regurgitated endometrial tissues. We hypothesized that molecular alterations in the peritoneum are involved in the development of peritoneal endometriosis and conducted a microarray analysis to compare macroscopically normal peritoneum sampled from women with peritoneal endometriosis (endometriotic peritoneum) and those without (non-endometriotic peritoneum). Versican, a major proteoglycan component of the extracellular matrix, is one of the molecules up-regulated in endometriotic peritoneum. OBJECTIVE: To investigate the role of versican in peritoneal endometriosis. Design, Patients, and Main Outcome Measure: Endometriotic peritoneum and non-endometriotic peritoneum were subjected to RT-PCR, immunostaining, and Western blotting. The versican V1 isoform was stably transfected into Chinese hamster ovary cells (CHO-V1), and the effects of CHO-V1-derived conditioned medium (V1-CM) on primary human endometrial stromal cells were investigated with attachment, invasion, and proliferation assays. The effects of peritoneal fluid collected from endometriotic women (endometriotic PF) or cytokines/growth factors, which were shown to be elevated in endometriotic PF, on versican expression in a human peritoneal cell line (HMrSV5) were also examined. RESULTS: Versican V1 expression levels were significantly higher in endometriotic peritoneum. In vitro, V1-CM promoted attachment to the HMrSV5 cell monolayer as well as the Matrigel invasion of endometrial stromal cells. Although versican V1 expression was up-regulated by TGF-ß1 in HMrSV5 cells, it remained unchanged in endometriotic PF. CONCLUSIONS: Our results suggest the involvement of peritoneal versican in the development of peritoneal endometriosis.

CD9 suppresses human extravillous trophoblast invasion.

During human placentation, the extravillous trophoblast (EVT) invades the maternal decidua and reconstructs maternal spiral arteries. However, the precise mechanisms that control EVT behavior have not yet been elucidated in detail. CD9 has been reported to be a cell-motility-related molecule. Since we previously observed that CD9 was expressed on human EVT, we examined the possible involvement of CD9 in the invasion process of EVT. Placental and umbilical samples were obtained from patients who underwent legal abortions, normal delivery, or hysterectomy. The expression of CD9 at the implantation site and on isolated EVT from a villous explant culture, an EVT-derived immortalized cell line, Swan71, and HUVEC was examined by immunocytochemical staining, flow cytometry, and RT-PCR. The effects of anti-CD9 functional antibody (ALB6) on EVT and Swan71 cell invasion were further examined by matrigel invasion assay along with shRNAmir gene knockdown treatment. CD9 was highly expressed on EVT at the boundary region of EVT invasion and intravascular EVT. EVT and Swan71 cell invasions were promoted by ALB6 or shRNAmir treatment. CD9 expression on Swan71 cells was reduced under hypo-oxygenic conditions, while its expression was increased by the co-culture with HUVEC. These findings suggest that CD9 could attenuate EVT invasion under the influence of an oxygen environment and maternal endothelial cells, proposing that CD9 is a potential regulator of human placental formation.