Versican provides the provisional matrix for uterine spiral artery dilation and fetal growth.

The extracellular matrix (ECM) in the endometrium plays a crucial role in mammalian pregnancy. We have shown that versican secreted from the endometrial epithelium promotes embryo implantation. Versican is a proteoglycan, a major player in the provisional matrix, and versikine, its N-terminal fragment cleaved by ADAMTS proteinases, serves as a bioactive molecule. Here, since versican expression in the placenta was dynamically altered in humans and mice, we investigated the role of versican in pregnancy using uterine-specific Vcan deletion mice (uKO mice) and ADAMTS-resistant versican expressing mice (V1R mice). uKO mice exhibited insufficient spiral artery dilation, followed by fetal growth restriction and maternal hypertension. Further analysis revealed impaired proliferation of tissue-resident natural killer cells required for spiral artery dilation. V1R mice showed the same results as the control, eliminating the involvement of versikine. Our results provide a new concept that versican, one factor of ECM, contributes to placentation and following fetal growth.

Ex vivo reconstitution of fetal oocyte development in humans and cynomolgus monkeys.

In vitro oogenesis is key to elucidating the mechanism of human female germ-cell development and its anomalies. Accordingly, pluripotent stem cells have been induced into primordial germ cell-like cells and into oogonia with epigenetic reprogramming, yet further reconstitutions remain a challenge. Here, we demonstrate ex vivo reconstitution of fetal oocyte development in both humans and cynomolgus monkeys (Macaca fascicularis). With an optimized culture of fetal ovary reaggregates over three months, human and monkey oogonia enter and complete the first meiotic prophase to differentiate into diplotene oocytes that form primordial follicles, the source for oogenesis in adults. The cytological and transcriptomic progressions of fetal oocyte development in vitro closely recapitulate those in vivo. A comparison of single-cell transcriptomes among humans, monkeys, and mice unravels primate-specific and conserved programs driving fetal oocyte development, the former including a distinct transcriptomic transformation upon oogonia-to-oocyte transition and the latter including two active X chromosomes with little X-chromosome upregulation. Our study provides a critical step forward for realizing human in vitro oogenesis and uncovers salient characteristics of fetal oocyte development in primates.

Impact of efforts to prevent maternal deaths due to obstetric hemorrhage on trends in epidemiology and management of severe postpartum hemorrhage in Japan: a nationwide retrospective study.

BACKGROUND: The Japan Society of Obstetrics and Gynecology and the Japan Association of Obstetricians and Gynecologists have issued the guidelines and recommendations on postpartum hemorrhage since 2010 and have been conducted widespread educational activities from 2012. The aim of this study was to investigate the impact of these efforts by the Societies to prevent maternal deaths due to obstetric hemorrhage on trends in epidemiology and management of severe postpartum hemorrhage in Japan. METHODS: A national retrospective cohort study was conducted using the national database of health insurance claims for the period 2012 and 2018. The subjects were all insured women who received a blood transfusion for postpartum hemorrhage. The primary endpoints of this study were hysterectomy and maternal mortality. The etiology of hemorrhage, treatment facility, type of procedure, and blood transfusion volume were tabulated. RESULTS: Women with postpartum hemorrhage that underwent transfusion increased from 3.5 to 5.5 per 1000 deliveries between 2012 and 2018. The most common cause of postpartum hemorrhage was atonic hemorrhage. After insurance coverage in 2013, the intrauterine balloon tamponade use increased to 20.3% of postpartum hemorrhages treated with transfusion in 2018, while the proportion of hysterectomy was decreased from 7.6% (2013-2015) to 6.4% (2016-2018) (p < 0.0001). The proportion of postpartum hemorrhage in maternal deaths decreased from 21.1% (2013-2015) to 14.1% (2016-2018) per all maternal deaths cases (p = 0.14). Cases with postpartum hemorrhage managed in large referral hospitals was increased (65.9% in 2012 to 70.4% in 2018) during the study period (p < 0.0001). CONCLUSIONS: The efforts by the Societies to prevent maternal mortality due to obstetric hemorrhage resulted in a significant decrease in the frequency of hysterectomies and a downward trend in maternal mortality due to obstetric hemorrhage.

The significance of clinical symptoms of subchorionic hematomas, "bleeding first", to stratify the high-risk subgroup of very early preterm delivery.

OBJECTIVE: To investigate the factors that stratify high-risk cases among subchorionic hematomas (SCHs) patients with persistent vaginal bleeding in early pregnancy. MATERIALS AND METHODS: A total of 56 patients who required hospitalization for SCH with vaginal bleeding in early pregnancy were classified into two groups: 1) no hematoma by ultrasonography when vaginal bleeding occurred, and then hematoma was observed by ultrasonography "bleeding to hematoma (BH group, n = 15)" and 2) no vaginal bleeding when hematoma was observed by routine ultrasonography, and then vaginal bleeding occurred later "hematoma to bleeding (HB group, n = 41)". Retrospective cohort study was performed and maternal and neonatal outcomes were evaluated. RESULTS: The duration of SCHs and/or vaginal bleeding was significantly longer in the BH group than in the HB group (mean: 60.8 days [BH group] vs. 33.3 days [HB group], p = 0.015). BH group patients delivered earlier than HB group patients significantly (mean: 27.3 weeks [BH group] vs. 35.6 weeks [HB group], p = 0.0028). The frequency of chronic abruption and oligohydramnios sequence (CAOS) was significantly higher in the BH group than in the HB group (3/15; 20.0% [BH group] vs. 0/41; 0.0% [HB group], p = 0.016). The frequency of sever fetal distress (Apgar score <4 points) was significantly higher in the BH group than in the HB group (4/15; 26.7% [BH group] vs. 0/41; 0.0% [HB group], p = 0.0037). The levels of factor XIII were relatively lower in the BH group than in the HB group (mean: 54.8% (n = 4) [BH group] vs. 76.1% (n = 7) [HB group], p = 0.077). CONCLUSION: The order of the symptoms, bleeding first, is an important feature that reflects the subsequent prolonged duration of SCHs/vaginal bleeding, resulting in very early preterm delivery. Continuous hemorrhage consumes coagulation factor XIII, which further worsen the hemostasis.

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.

Case of soluble fms-like tyrosine kinase 1 apheresis in severe pre-eclampsia developed at 15 weeks' gestation.

Soluble fms-like tyrosine kinase-1 (sFlt1), a circulating vascular endothelial growth factor receptor 1 antagonist, is associated with the pathogenesis of pre-eclampsia. Extracorporeal removal of sFlt1 (sFlt1 apheresis) is emerging as a treatment for pre-eclampsia. We performed sFlt1 apheresis for a patient with very early onset pre-eclampsia, beginning at 15 weeks' gestation. She underwent sFlt1 apheresis 13 times from 19 to 23 weeks' gestation. The series of treatments lowered circulating sFlt1, stabilized blood pressure, reduced urinary protein, and preserved renal function, which contributed to a successful prolongation of pregnancy for 4 weeks and a live birth at 23(+3) weeks' gestation. Further studies are necessary for clinical application of sFlt1 apheresis as sFlt1 might have a protective function for the placenta and fetus in pre-eclampsia.

Clear cell carcinoma arising from a uterus-like mass.

A uterus-like mass is an extrauterine mass with a cavity lined by endometrial tissue and a smooth muscle layer resembling the uterine corpus. It is a rare condition of unknown histogenesis. Herein, we describe a case of clear cell carcinoma arising from a uterus-like mass located in the retroperitoneal space. The patient, a 67-year old nulliparous woman, had been followed with the diagnosis of an ovarian endometriotic cyst for 14 years until ultrasonography and magnetic resonance imaging (MRI) demonstrated an enlargement of the cystic mass with a thickened irregular wall. Suspicion of malignant transformation prompted us to excise the lesion. At laparotomy, the uterus and right ovary appeared normal, and a mass measuring 8 cm was identified in the retroperitoneal space without any connection to the uterus. Grossly, the removed mass was composed of a cyst filled with blackish-brownish fluid and a thick wall resembling uterine myometrium. Microscopically, endometrial tissue inside the cyst, which was diffusely lined by clear cell carcinoma, was identified. Although the histogenesis of a uterus-like mass remains unclear, this case indicates that malignant tumors may occur from a uterus-like mass through the pathway similar to the carcinogenesis of endometriosis-related ovarian neoplasms.