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Background: The prevalence of cesarean section procedures is on the rise worldwide, necessitating a deeper understanding of the factors driving this trend to mitigate potential adverse consequences associated with unnecessary cesarean section deliveries., Objectives: This study aims to investigate the rate of primary cesarean deliveries (PCD), a potential key indicator of obstetric care quality., Study Design: A national retrospective cohort study was conducted utilizing extensive data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan spanning the years 2012 to 2018. The study examined the temporal trends in PCD rates and the indications for these procedures across different prefectures. Additionally, the study employed the obstetrician disproportionality index, as published by the Ministry of Health, Labour, and Welfare, to assess the influence of obstetrician availability on PCD rates., Results: Throughout the study period from 2012 to 2018, the rate of PCD in Japan remained relatively stable at approximately 14%. The primary indications for PCD in 2018 included labor arrest (18.3%), malpresentation (16.5%), nonreassuring fetal status (6.5%), and macrosomia (6.0%). Substantial regional disparities in PCD rates were observed, ranging from 8.9% to 20.4% among prefectures in 2018. Notably, prefectures categorized in the bottom 10 of the obstetrician disproportionality index exhibited significantly higher PCD rates compared to the top 10 prefectures ( P =.0232), with a similar trend noted for PCD due to labor arrest ( P =.0288). Furthermore, a negative correlation was identified between the obstetrician disproportionality index and PCD rates at the prefectural level ( r =-0.3119, P =.0328)., Conclusions: Our study presents a comprehensive analysis of PCD rates in Japan, shedding light on regional disparities and highlighting the notable influence of obstetrician availability on clinical decision-making. This study contributes to the ongoing discourse on the escalating global trend in cesarean sections and the importance of healthcare resource allocation in maternal care., (© 2024 The Authors.)

Meiotic prophase progression is differently regulated in males and females. In males, pachytene transition during meiotic prophase is accompanied by robust alteration in gene expression. However, how gene expression is regulated differently to ensure meiotic prophase completion in males remains elusive. Herein, we identify HSF5 as a male germ cell-specific heat shock transcription factor (HSF) for meiotic prophase progression. Genetic analyzes and single-cell RNA-sequencing demonstrate that HSF5 is essential for progression beyond the pachytene stage under non-stress conditions rather than heat stress. Chromatin binding analysis in vivo and DNA-binding assays in vitro suggest that HSF5 binds to promoters in a subset of genes associated with chromatin organization. HSF5 recognizes a DNA motif different from typical heat shock elements recognized by other canonical HSFs. This study suggests that HSF5 is an atypical HSF that is required for the gene expression program for pachytene transition during meiotic prophase in males., (© 2024. The Author(s).)

Problem: Excisional surgery for cervical intraepithelial neoplasia is a risk factor for preterm birth in subsequent pregnancies. However, the underlying mechanisms of this association remain unclear. We previously showed that cervical MUC5B, a mucin protein, may be a barrier to ascending pathogens during pregnancy. We thus hypothesized that hyposecretion of cervical MUC5B is associated with preterm birth after cervical excisional surgery., Method of Study: This prospective nested case-control study (Study 1) included pregnant women who had previously undergone cervical excisional surgery across 11 hospitals. We used proteomics to compare cervicovaginal fluid at 18-22 weeks of gestation between the preterm and term birth groups. In another case-control analysis (Study 2), we compared MUC5B expression in nonpregnant uterine tissues between 15 women with a history of cervical excisional surgery and 26 women without a history of cervical surgery., Results: The abundance of MUC5B in cervicovaginal fluid was significantly decreased in the preterm birth group (fold change = 0.41, p = .035). Among the 480 quantified proteins, MUC5B had the second highest positive correlation with gestational age at delivery in the combined preterm and term groups. The cervicovaginal microbiome composition was not significantly different between the two groups. Cervical length was not correlated with gestational age at delivery (r = 0.18, p = .079). Histologically, the MUC5B-positive area in the nonpregnant cervix was significantly decreased in women with a history of cervical excisional surgery (0.85-fold, p = .048). The distribution of MUC5B-positive areas in the cervical tissues of 26 women without a history of cervical excisional surgery differed across individuals., Conclusions: This study suggests that the primary mechanism by which cervical excisional surgery causes preterm birth is the hyposecretion of MUC5B due to loss of the cervical glands., (© 2024 The Authors. American Journal of Reproductive Immunology published by John Wiley & Sons Ltd.)

The intervillous space of human placenta is filled with maternal blood, and villous trophoblasts are constantly exposed to the shear stress generated by maternal blood pressure and flow throughout the entire gestation period. However, the effects of shear stress on villous trophoblasts and their biological significance remain unknown. Here, using our recently established naïve human pluripotent stem cells-derived cytotrophoblast stem cells (nCTs) and a device that can apply arbitrary shear stress to cells, we investigated the impact of shear stress on early-stage trophoblasts. After 72 h of exposure to 10 dyn/cm2 shear stress, nCTs became fused and multinuclear, and mRNA expression of the syncytiotrophoblast (ST) markers, such as glial cell missing 1, endogenous retrovirus group W member 1 envelope, chorionic gonadotropin subunit beta 3, syndecan 1, pregnancy specific beta-1-glycoprotein 3, placental growth factor, and solute carrier family 2 member 1 were significantly upregulated compared to static conditions. Immunohistochemistry showed that shear stress increased fusion index, human chorionic gonadotropin secretion, and human placental lactogen secretion. Increased microvilli formation on the surface of nCTs under flow conditions was detected using scanning electron microscopy. Intracellular cyclic adenosine monophosphate significantly increased under flow conditions. Moreover, transcriptome analysis of nCTs subjected to shear stress revealed that shear stress upregulated ST-specific genes and downregulated CT-specific genes. Collectively, these findings indicate that shear stress promotes the differentiation of nCTs into ST., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Hypogonadism is a significant late complication in childhood cancer survivors (CCS). The aim of this study was to elucidate the advantages and limitations of estrogen replacement therapy (ERT) for CCS with hypogonadism., Methods: Seventeen CCS were divided into two groups: gonadal hypogonadism (GH) group (n = 8) and central hypogonadism (CH) group (n = 9). Pearson correlation coefficients were used to investigate the impact of cancer management on final height, bone density, and uterine development., Results: Seven of GH group had hematologic malignancies, and all of them underwent total body irradiation before bone marrow transplantation. The GH group showed significant positive correlations between the onset age of disease treatment and final height (p < 0.05, R = 0.712) and uterine size following ERT (p < 0.05, R = 0.775). All CCS in the CH group had brain tumors, and seven of them received chemotherapy. There were trends towards positive and negative correlations between the onset age of disease treatment and final height (p = 0.09, R = 0.598) or uterine size (p = 0.07, R = - 0.669), respectively. A negative correlation trend was observed between the age at ERT initiation and final height (p = 0.07, R = - 0.769) or bone density (p = 0.18, R = - 0.626) in six CH patients who received growth hormone therapy. Five CCS in both groups experienced osteoporosis, despite receiving ERT., Conclusion: Individualized management strategies beyond ERT are essential to reduce long-term complications in CCS with hypogonadism, considering the type and timing of cancer treatment., (© 2023. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Objective: To assess the clinical characteristics and endocrinological background of women with vascular retained products of conception (RPOC) after miscarriage or abortion and evaluate the effect of estrogen-progestogen therapy (EPT) as an initial treatment on this population based on their endocrinological background., Materials and Methods: Women with vascular RPOC after miscarriage or abortion at less than 20 weeks of pregnancy who were given EPT (conjugated estrogen and norethisterone) were retrospectively reviewed. Their clinical characteristics, hormonal parameters, ultrasonographic findings, and outcomes were evaluated., Results: Of 35 women with vascular RPOC, 30 (86%) presented with vaginal bleeding at a visit, and 6 (17%) required inpatient management due to heavy bleeding. Among women who presented with vaginal bleeding, serum progesterone levels were significantly lower (0.25 vs. 6.5 ng/mL, p = 0.004) than those in women who did not present with vaginal bleeding. There were no differences in serum hCG levels (10.5 vs. 3.1 mIU/mL) or serum estradiol levels (65.4 vs. 162.3 pg/mL). After withdrawal bleeding following the first course of EPT, vaginal bleeding was stopped in 27 of the 30 women (90%), and 23 (66%) of all women had a thin and linear endometrium. All women could be treated by up to two courses of EPT and did not require additional interventions. The median duration to hCG normalization after the initial EPT was 24.5 (9-88) days., Conclusion: Women with vascular RPOC who have no bleeding had significantly higher levels of serum progesterone, indicating that administration of progestogen may have an effect on hemostasis. Endometrial bleeding can be prevented or stopped, and retained tissues can be conservatively expelled by oral administration of EPT, including norethisterone, in women with vascular RPOC., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated in cancer development 1-3 . However, our knowledge is still missing with regard to what additional driver events take place in what order, before one or more of these clones in normal tissues ultimately evolve to cancer. Here, using phylogenetic analyses of multiple microdissected samples from both cancer and non-cancer lesions, we show unique evolutionary histories of breast cancers harbouring der(1;16), a common driver alteration found in roughly 20% of breast cancers. The approximate timing of early evolutionary events was estimated from the mutation rate measured in normal epithelial cells. In der(1;16)(+) cancers, the derivative chromosome was acquired from early puberty to late adolescence, followed by the emergence of a common ancestor by the patient's early 30s, from which both cancer and non-cancer clones evolved. Replacing the pre-existing mammary epithelium in the following years, these clones occupied a large area within the premenopausal breast tissues by the time of cancer diagnosis. Evolution of multiple independent cancer founders from the non-cancer ancestors was common, contributing to intratumour heterogeneity. The number of driver events did not correlate with histology, suggesting the role of local microenvironments and/or epigenetic driver events. A similar evolutionary pattern was also observed in another case evolving from an AKT1-mutated founder. Taken together, our findings provide new insight into how breast cancer evolves., (© 2023. The Author(s).)

Objective: Preterm prelabor rupture of fetal membranes (pPROM) is a leading cause of preterm birth. When pPROM occurs around the pre- and periviable period, the perinatal outcome is unfavorable. However, there have been a few cases in which the leakage of amniotic fluid ceases and the ruptured fetal membranes are spontaneously sealed., Materials and Methods: The prognosis of 38 cases of pPROM at less than 27 weeks of gestation in Kyoto University Hospital were studied. The clinical factors related to the sealing of fetal membranes were investigated., Results: Spontaneous sealing was confirmed in five patients (13%), and sealing occurred within 14 days of pPROM. Women in the no sealing group delivered at 26.3 ± 0.5 weeks of gestation, whereas women in the sealing group delivered at term at 38.8 ± 0.4 weeks (p < 0.0001). The maximum vertical pocket (MVP) of amniotic fluid at the time of pPROM diagnosis was 2.2 ± 0.3 cm in the no sealing group and 3.8 ± 0.5 cm in the sealing group (p = 0.043). All cases of sealing occurred when the MVP at diagnosis was more than 2 cm, and there were no cases of sealing if the MVP at diagnosis was less than 2 cm. In addition, the value of C-reactive protein at ROM was less than 0.4 mg/dL in all cases in the sealing group., Conclusion: The residual volume of sterile amniotic fluid at the onset of pPROM may predict the possibility of fetal membrane sealing., Competing Interests: Declaration of competing interest There are no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Aim: The pathogenic mechanism of chronic abruption-oligohydramnios sequence (CAOS) remains unknown, and there are no objective standards for diagnosis on imaging or using pathological evidence. We aimed to reconsider and clarify the true pathology of CAOS by integrating clinical, magnetic resonance imaging (MRI) and histopathological findings of the placenta., Material and Methods: This is a case series of patients with CAOS managed at our hospital between 2010 and 2020. The clinical data of the patients, including MRI findings and placental pathology, were reviewed retrospectively., Results: A total of 18 patients were eligible. Preterm birth occurred in 17 (94%) cases; the median gestational age at delivery was 25. Three neonates (17%) died within two years, and 10 neonates (56%) developed chronic lung disease. MRI was performed in 13 cases and clearly showed intrauterine hematoma and hemorrhagic amniotic fluid. Pathologically, in all cases, retroplacental hematoma was not detected, and fetal membranes were extremely fragile and ragged. Shedding and necrosis of the amniotic epithelium was a characteristic finding, which was confirmed in 17 cases (94%). Diffuse chorionic hemosiderosis (DCH) was detected in all cases., Conclusions: The fundamental cause of CAOS is repeated intrauterine hemorrhage and subsequent subchorionic hematoma, which induces hemorrhagic amniotic fluid and DCH. Consequently, these factors result in the necrosis and weakening of the amnion. Therefore, the true pathology of CAOS is believed to be premature rupture of membranes rather than chronic abruption.

Context: Cervical excision is a risk factor for preterm birth. This suggests that the cervix plays an essential role in the maintenance of pregnancy., Objective: We investigated the role of the cervix through proteomic analysis of cervicovaginal fluid (CVF) from pregnant women after trachelectomy surgery, the natural model of a lack of cervix., Methods: The proteome compositions of CVF in pregnant women after trachelectomy were compared with those in control pregnant women by liquid chromatography-tandem mass spectrometry and label-free relative quantification. MUC5B/AC expression in the human and murine cervices was analyzed by immunohistochemistry. Regulation of MUC5B/AC expression by sex steroids was assessed in primary human cervical epithelial cells. In a pregnant mouse model of ascending infection, Escherichia coli or phosphate-buffered saline was inoculated into the vagina at 16.5 dpc, and the cervices were collected at 17.5 dpc., Results: The expression of MUC5B/5AC in cervicovaginal fluid was decreased in pregnant women after trachelectomy concomitant with the anatomical loss of cervical glands. Post-trachelectomy women delivered at term when MUC5B/AC abundance was greater than the mean normalized abundance of the control. MUC5B levels in the cervix were increased during pregnancy in both humans and mice. MUC5B mRNA was increased by addition of estradiol in human cervical epithelial cells, whereas MUC5AC was not. In a pregnant mouse model of ascending infection, E. coli was trapped in the MUC5B/AC-expressing mucin of the cervix, and neutrophils were colocalized there., Conclusion: Endocervical MUC5B and MUC5AC may be barriers to ascending pathogens during pregnancy., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: To identify predictors of systemic lupus erythematosus (SLE) flares during pregnancy in patients previously considered to be at low risk., Materials and Methods: The retrospective cohort study included 54 singleton pregnancies, managed between 2005 and 2019, involving maternal diagnosed SLE at a low disease activity (SLE Disease Activity Index ≤4) for ≥12 months before conception and without anti-phospholipid antibodies. Pregnancy outcomes were compared between patients who had SLE exacerbations during pregnancy (flare group, n  = 21) and patients that did not have a flare (non-flare group, n  = 33)., Results: The flare group had shorter gestational durations ( p  = .01), lower birth weights ( p  = .02), and a higher risk of emergent cesarean section ( p  = .002) compared with the non-flare group. The flare group demonstrated higher doses of prednisone ( p  = .04) at the time of conception as well as an increased rate of low 50% hemolytic complement (CH50) activity ( p  = .03) in the first trimester compared to the non-flare group. A decision tree drawn using a prednisone dose ≥10.5 mg/day and a low CH50 predicted SLE flares with a net accuracy of 78%., Conclusions: A prednisone dose ≥10.5 mg daily and CH50 hypocomplementemia in early pregnancy are useful in the early detection of patients at a high risk of SLE exacerbation.

The premature rupture of the amniotic sac, a condition referred to as a preterm prelabor rupture of membranes (pPROM), is a leading cause of preterm birth. In some cases, these ruptured membranes heal spontaneously. Here, we investigated repair mechanisms of the amnion, a layer of epithelial cells in the amniotic sac closest to the embryo. Macrophages migrated to and resided at rupture sites in both human and mouse amnion. A process called epithelial-mesenchymal transition (EMT), in which epithelial cells acquire a mesenchymal phenotype and which is implicated in tissue repair, was observed at rupture sites. In dams bearing macrophage-depleted fetuses, the repair of amnion ruptures was compromised, and EMT was rarely detected at rupture sites. The migration of cultured amnion epithelial cells in wound healing assays was mediated by EMT through transforming growth factor-β (TGF-β)-Smad signaling. These findings suggest that fetal macrophages are crucial in amnion repair because of their ability to induce EMT in amnion epithelial cells.

Large-scale data on maternal and neonatal outcomes of pregnancy-associated cervical cancer in Japan are scarce, and treatment strategies have not been established. This multicenter retrospective observational study investigated clinical features and trends in pregnancy-associated cervical cancer treatments at 523 hospitals in Japan. We included cervical cancer cases that were histologically diagnosed (between 1 January 2012, and 31 December 2017), and their clinical information was retrospectively collected. Of 40 patients diagnosed with pregnancy-associated cervical cancer at ≥22 gestational weeks, 34 (85.0%) were carefully followed until delivery without intervention. Of 163 diagnosed at <22 gestational weeks, 111 continued and 52 terminated their pregnancy. Ninety patients with stage IB1 disease had various treatment options, including termination of pregnancy. The 59 stage IB1 patients who continued their pregnancy were categorized by the primary treatment into strict follow-up, conization, trachelectomy, and neoadjuvant chemotherapy groups, with no significant differences in progression-free or overall survival. The birth weight percentile at delivery was smaller in the neoadjuvant chemotherapy group than in the strict follow-up group (p = 0.029). Full-term delivery rate was relatively higher in the trachelectomy group (35%) than in the other groups. Treatment decisions for pregnancy-associated cervical cancer are needed after estimating the stage, considering both maternal and fetal benefits.

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., (© 2022. The Author(s).)

Objectives: To evaluate the oncologic and obstetric outcomes of cervical conization followed by pelvic lymphadenectomy, which is used as a fertility-sparing procedure, in reproductive-aged patients with early-stage cervical cancer., Methods: We performed a retrospective study of patients with stage IA1-IB1 cervical cancer who underwent cervical conization followed by pelvic lymphadenectomy from 2011 to 2020 at Kumamoto University Hospital., Results: In total, eight patients underwent conization followed by pelvic lymphadenectomy. The median age of the patients was 33 (range: 28-36) years. Four (50.0%) patients were nulliparous. Seven (87.5%) patients were diagnosed with squamous cell carcinoma (87.5%) and one (12.5%) with adenocarcinoma. Five (62.5%), two (25.0%), and one (12.5%) presented with stage IA1, IA2, and IB1 disease, respectively. Five (62.5%) patients had lymphovascular space invasion (LVSI) based on the assessment of specimens obtained via conization. However, none had lymph node metastasis based on pelvic lymphadenectomy. Regarding long-term oncologic outcomes, recurrence was not observed at a median follow-up of 60 (range: 8-107) months. In addition, obstetric outcomes were consistently favorable in terms of achieving pregnancy, preterm delivery, and live birth. During the study period, two patients who actively attempted to conceive had four pregnancies, resulting in full-term deliveries, and one was on her first trimester of pregnancy., Conclusion: Cervical conization combined with pelvic lymphadenectomy represents a feasible conservative management for histologically well-selected patients with early-stage cervical cancer. Furthermore, an optimal histopathological evaluation of conization specimens will contribute to decision-making regarding the use of this fertility-sparing procedure., (© 2022 Japan Society of Obstetrics and Gynecology.)

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., Competing Interests: Declaration of competing interest The authors report no conflict of interest., (Copyright © 2022. Published by Elsevier B.V.)

Objective: Although cyclooxygenase inhibitors effectively suppress uterine contraction, constriction of the fetal ductus arteriosus (DA) and oligohydramnios are major concerns. Celecoxib, a selective cyclooxygenase 2 inhibitor, is a potential potent tocolytic agent, but there are no studies that have evaluated the beneficial or adverse effects of celecoxib use on fetuses for more than 48 hours in pregnant women. We therefore aimed to evaluate the effect of middle-long-term celecoxib administration on the fetus during the second trimester of pregnancy, particularly in terms of fetal DA and amniotic fluid volume., Materials and Methods: We retrospectively extracted and reviewed data from patients with preterm labor who received celecoxib for tocolysis for more than 48 hours between 2016 and 2020. Celecoxib was used for tocolysis only when treatment of patients with conventional tocolytic agents was ineffective. Data on the peak systolic velocity in ductus arteriosus (PSV-DA) and the maximum vertical pocket (MVP) were collected., Results: A total of 15 patients were eligible. The median gestational age at celecoxib introduction was 22.6 weeks, and the median period of administration was 9 days (range 3-40 days). The median gestational age at delivery was 27.1 weeks, and the median duration from initial celecoxib administration to delivery was 40 days. The Z scores of PSV-DA and MVP did not change significantly after celecoxib administration. During administration, PSV-DA exceeded the 95th percentile of the corresponding normal reference range in three cases, but the levels returned to normal after reduction or discontinuation of treatment. There was no oligohydramnios during the treatment., Conclusion: Celecoxib administration for more than 48 hours in the second trimester of pregnancy might be safe and tolerable in terms of fetal PSV-DA and amniotic fluid volume as long as careful ultrasound monitoring is performed. Celecoxib could be an alternative for preterm labor when conventional tocolysis is not effective., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2022. Published by Elsevier B.V.)

To clarify the impact of blood pressure (BP) management ranges on pregnancy outcomes, we conducted a multicenter retrospective analysis of 215 women with singleton pregnancies diagnosed with essential hypertension either before or within 14 weeks of gestation. Patients were classified according to systolic BP (sBP; <130, 130-139, 140-159, and ≥160 mmHg) or diastolic BP (dBP; <80, 80-89, 90-109, and ≥110 mmHg) at 8-11, 12-15, and 16-19 weeks of gestation. The risk of early-onset superimposed preeclampsia and small-for-gestational-age neonates was assessed in each BP group. Moreover, a subgroup analysis was performed in 144 eligible patients whose BP was measured at both 12-13 and 14-15 weeks of gestation. At 16-19 weeks of gestation, higher sBP significantly increased the incidence of early-onset superimposed preeclampsia (13.3%, 24.6%, 32.2% and 75.0%, respectively) and small-for-gestational-age neonates (6.0%, 13.1%, 16.9% and 50.0%, respectively). Multivariate logistic regression analyses showed that women with sBP < 130 mmHg at 16-19 weeks of gestation had a significantly lower risk of early-onset superimposed preeclampsia than women with sBP of 140-159 mmHg. Subgroup analyses also showed that even at 14-15 weeks of gestation, sBP < 130 mmHg was associated with a significantly lower risk of early-onset superimposed preeclampsia than an sBP of 140-159 mmHg. In conclusion, sBP < 130 mmHg within 14 weeks of gestation reduced the risk of developing early-onset superimposed preeclampsia in women with chronic hypertension., (© 2021. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Radical hysterectomy is a standard operation for invasive cervical cancers. However, if the invasion to the parametrium is more advanced than estimation in the operation, it is difficult to perform usual radical hysterectomy. Superradical hysterectomy was developed by Prof. Ryukichi Mibayashi of Kyoto University and was published in 1941, and has been performed for the limited cases by a part of Japanese gynecologic surgeons. Superradical hysterectomy is a procedure in which the soft tissues in the pelvis are removed en bloc by sequential processing of the internal iliac vessels, which leads to a complete dissection of the lymphatic tissue in the pelvis to the pelvic wall., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Objectives: To investigate the epidemiologic and clinical characteristics of maternal near-misses attributable to haemorrhagic stroke (HS) occurring in patients with hypertensive disorders of pregnancy (HDP), with a focus on severe neurological morbidity., Methods: A national retrospective cohort study was conducted using the national database of health insurance claims for the period 2010 to 2017. The subjects were all insured women with a diagnosis of both HDP and HS. Severe neurological morbidity requiring rehabilitation, types of HDP, types of HS, and magnesium sulphate use were tabulated., Results: The number of women with HDP who were diagnosed with HS was 3.4 per 100,000 deliveries between 2010 and 2017. Forty percent of HDP-related HS cases had neurological morbidities requiring rehabilitation (1.4 per 100,000 deliveries), and 4.4% were in a persistent vegetative state after HS. Of the HDP cases who developed HS, 69.2% were severe HDP, of which 55.6% were without eclampsia. The most common type of HS was intracerebral haemorrhage (2.5 per 100,000 deliveries), followed by subarachnoid haemorrhage due to cerebral aneurysm (1.2 per 100,000 deliveries). The frequency of magnesium sulphate use increased in all patients with HDP-related HS in the second half of the study period (2014-2017) compared with the first half (2010-2013) (p < 0.0001). This was more evident in cases of HDP-related HS with eclampsia (31.9% to 83.8%) compared to those without eclampsia (25.0% to 42.9%)., Conclusion: Of the maternal near-miss cases due to HDP-related HS, 40.0% were rehabilitated and 69.2% were HDP without either eclampsia or severe hypertension., (Copyright © 2021 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Study Objective: To describe a direct approach to the deep uterine vein in laparoscopic radical hysterectomy., Design: Demonstration of the laparoscopic technique with narrated video footage., Setting: Securing sufficient radicality is extremely important when performing a radical hysterectomy for cervical cancer, either by laparotomy or by minimally invasive surgery. The nerve-sparing Okabayashi radical hysterectomy (NS-RH) was originally aimed at achieving both radical resection and function preservation [1-3]. A key procedure when performing NS-RH is intraoperative identification of the relationship between the deep uterine vein and pelvic splanchnic nerve fibers [4]. With this in mind, a safe and easy method for identifying the crossing point of the deep uterine vein and pelvic splanchnic nerve in the initial phase of the surgery may greatly improve the safety and efficacy of functional preservation in NS-RH. Herein, we describe a minimally invasive "direct approach" to the deep uterine vein., Interventions: Before undergoing the pelvic lymphadenectomy, all steps of laparoscopic radical hysterectomy were performed. First, we identified the ureter on the posterior peritoneum, and the peritoneum was dissected just above the ureter. By continuously exploring the pelvic cavity along the ureter, especially through the opening of the space below the ureter in a cranial to caudal direction, we could easily identify the deep uterine vein. This procedure also exposed the fibers of the hypogastric nerve, clarifying the relationship of these structures., Conclusion: Because the relationship between the deep uterine vein and nerve fibers is the most important guidepost of this surgery, their identification in the early phase of the surgery enables us to perform the subsequent procedure precisely and securely. This direct approach to the deep uterine vein can be easily and safely performed., (Copyright © 2020 AAGL. Published by Elsevier Inc. All rights reserved.)

Placental dysfunction is related to the pathogenesis of preeclampsia and fetal growth restriction, but there is no effective treatment for it. Recently, various functional three-dimensional organs have been generated from human induced-pluripotent cells (iPSCs), and the transplantation of these iPSCs-derived organs has alleviated liver failure or diabetes mellitus in mouse models. Here we successfully generated a three-dimensional placental organ bud from human iPSCs. The iPSCs differentiated into various lineages of trophoblasts such as cytotrophoblast-like, syncytiotrophoblast-like, and extravillous trophoblast-like cells, forming organized layers in the bud. Placental buds were transplanted to the murine uterus, where 22% of the buds were successfully engrafted. These iPSC-derived placental organ buds could serve as a new model for the study of placental function and pathology.

Trophoblasts are extraembryonic cells that are essential for maintaining pregnancy. Human trophoblasts arise from the morula as trophectoderm (TE), which, after implantation, differentiates into cytotrophoblasts (CTs), syncytiotrophoblasts (STs), and extravillous trophoblasts (EVTs), composing the placenta. Here we show that naïve, but not primed, human pluripotent stem cells (PSCs) recapitulate trophoblast development. Naive PSC-derived TE and CTs (nCTs) recreated human and monkey TE-to-CT transition. nCTs self-renewed as CT stem cells and had the characteristics of proliferating villous CTs and CTs in the cell column of the first trimester. Notably, although primed PSCs differentiated into trophoblast-like cells (BMP4, A83-01, and PD173074 [BAP]-treated primed PSCs [pBAPs]), pBAPs were distinct from nCTs and human placenta-derived CT stem cells, exhibiting properties consistent with the amnion. Our findings establish an authentic paradigm for human trophoblast development, demonstrating the invaluable properties of naive human PSCs. Our system provides a platform to study the molecular mechanisms underlying trophoblast development and related diseases., Competing Interests: Declaration of interests S.I. and Y.T. are co-inventors on a patent describing the generation of trophectoderm-like cells from naïve human pluripotent stem cells., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Placenta accreta spectrum (PAS) disorder is a potentially life-threatening complication. The incidence of PAS has increased over the past few decades, mainly due to the increased cesarean section rate. While cesarean hysterectomy remains the most standard treatment for the management of PAS, expectant management is becoming increasingly prevalent to avoid serious maternal morbidity and maintain future fertility. Expectant management is defined as leaving the placenta either partially or fully in situ, and waiting for its spontaneous resorption or expulsion. The success rate of expectant management is high, but intraoperative uncontrolled hemorrhage results in hysterectomy. Moreover, some individuals fail expectant management and require delayed hysterectomy due to complications such as secondary postpartum hemorrhage, sepsis, uterine necrosis, and vesicouterine fistula. As a result of the very limited data currently available, there is no consensus on the optimal strategy for the expectant management of PAS. However, it is clear that a multidisciplinary team approach in tertiary centers is essential for women with PAS. In addition, meticulous preparation is the key to successful expectant management. Here, we describe a surgical strategy designed to reduce perioperative blood loss, which is a minimum requirement to ensure maternal safety. This article also addresses practical issues in expectant management of PAS, based on the published literature and our own experience., Competing Interests: Conflict of Interest None., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

The in vitro growth (IVG) of human follicles is a potential fertility option for women for whom cryopreserved ovarian tissues cannot be transplanted due to the risk of cancer cell reintroduction; however, there is currently no established method. Furthermore, optimal IVG conditions may differ between the follicles of adult and pre-pubertal females due to molecular differences suggested by basic research. To systematically identify differences between the secondary follicles of adult and pre-pubertal females, a comparative transcriptomic study using mice was conducted herein. Among differentially expressed genes (DEGs), Figla was up-regulated in mature mice. We successfully down-regulated Figla expression in secondary follicle oocytes by a Figla siRNA microinjection, and the subsequent IVG of follicles showed that the diameter of these follicles was smaller than those of controls in mature mice, whereas no significant difference was observed in premature mice. The canonical pathways of DEGs between control and Figla-reduced secondary follicles suggest that Figla up-regulates VDR/RXR activation and down-regulates stem cell pluripotency as well as estrogen signaling. We demonstrated for the first time that folliculogenesis of the secondary follicles of premature and mature mice may be regulated by different factors, such as Figla with its possible target genes, providing insights into optimal IVG conditions for adult and pre-pubertal females, respectively.

Background: Premature rupture of membranes occurring in previable midtrimester patients is associated with perinatal mortality, and optimal therapeutic methods are yet to be established., Objective: This study's objective was to investigate whether an elastomeric sealant, which has been used as a hemostatic agent for arterial anastomosis, could plug the uterine endocervical canal to prevent leakage of intrauterine fluid in an ex vivo model., Methods: The elastomeric sealant or fibrin glue was applied to the cervix of uteri removed for benign gynecological disease ( n  = 4). Normal saline was administered into the ex vivo uterine cavity through a catheter using a pressure infusion bag. Intrauterine pressure was measured using a digital pressure gauge, and the pressure at which normal saline started leaking out of the uterine cervix was compared between both the sealants., Results: No fluid leakage was observed with the elastomeric sealant until the pressure exceeded 20 kPa (150 mmHg), while the leakage onset pressure with fibrin sealant was 6.6 ± 1.8 kPa (50 ± 14 mmHg). The threshold leak pressure where the onset of liquid flow was initiated was significantly different between both the sealants ( p  < .0001)., Conclusions: Intracervical elastomeric sealant exhibited powerful fluid leakage prevention in an ex vivo model. The sealant would have potential to prevent the leakage of amniotic fluid in pregnancies with previable premature rupture of membranes.

Introduction: There is a paucity of data on the risk of preterm birth subcategorized by gestational age in pregnancies after the pre-pregnancy excisional treatment for cervical lesions. In addition, little is known about the effect of prophylactic cerclage on the risk of preterm birth. The aim of this study was to investigate the risk of preterm birth stratified by gestational period and its reduction by the prophylactic cerclage in women with prior excisional surgery., Materials and Methods: We retrospectively analyzed a cohort of singleton pregnancies in the Japan Perinatal Registry Network Database (2013-2014, n  = 307,001). Cases included pregnancies after the surgery (i.e. conization and loop electrosurgical excision procedure). Controls comprised the propensity-score matched pregnancies without pre-pregnancy surgery. The main outcome was the occurrence of preterm birth. The effect of prophylactic cervical cerclage on the risk of preterm birth after the excisional surgery was also examined using cases., Results: In the propensity-score matched population (cases, n  = 1389; controls, n  = 1389), cases exhibited a higher risk of preterm birth and preterm prelabor rupture of membranes (PROM), compared with controls (preterm birth: 25.3 versus 10.6%; preterm PROM: 14.0 versus 3.5%: both p  < .0001). Odds ratios (OR; 95% confidence interval [CI]) for preterm birth at 22-27 weeks, 28-31 weeks, 32-33 weeks, and 34-36 weeks were 3.4 [1.8-6.5], 4.6 [2.7-7.7], 2.2 [1.4-3.5], and 2.1 [1.6-2.7], respectively. The association was stronger for preterm PROM at earlier gestational age (22-27 weeks, 28-31 weeks, 32-33 weeks, and 34-36 weeks: 5.2 [2.3-11.8], 7.1 [3.4-15.0], 3.8 [1.7-8.3], and 3.9 [1.8-4.6], respectively). In cases, 171 underwent the prophylactic cervical cerclage. The occurrence of preterm birth and preterm PROM was comparable between those with and without the cerclage (28.7 versus 24.2, and 12.9 versus 13.3%, respectively)., Conclusions: Pre-pregnancy excisional cervical surgery was associated with the increased risk of preterm birth, especially before 32 weeks of gestation. The prophylactic cerclage did not reduce the risk of preterm birth.

Aim: To ascertain the actual outcomes of oncofertility care in young women to provide more appropriate care., Materials & Methods: We analyzed the data of 67 female patients under 43 years of age who underwent oncofertility care between January 2015 and September 2019., Results: There were 28 patients with breast cancer, 19 patients with hematologic cancer and 20 patients with other cancer diagnoses. Breast cancer patients tended to take longer than hematologic cancer patients to initiate oncofertility treatment. Despite undergoing oncofertility care, seven of nine pregnant patients did not choose assisted reproductive technology (ART)., Conclusion: As spontaneous pregnancies were more common than ART pregnancies in our study, pregnancy by not only ART but also non-ART method is a viable option for young cancer survivors., Competing Interests: Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript., (© 2021 Sayuri Takahashi.)

Introduction: Chronic abruption oligohydramnios sequence (CAOS) is histologically characterized by diffuse chorioamniotic hemosiderosis (DCH). However, the criteria for the histological evaluation of the extent of CAOS-related hemosiderin deposition (HD) of the membranes and the difference in HD between the chorionic plate (CP) and fetal membrane (FM) are not well studied. This case control study compared the degree and distribution pattern of HD on CP and FM to present the histological features of DCH and the criteria for histological evaluation., Methods: From the medical records of Kyoto University Hospital (2010-2019), we selected 20 CAOS cases that were clinically diagnosed by Elliot's criteria. Twenty non-CAOS cases matched to the CAOS group by gestational age were selected as controls. We compared the clinical data and pathological features in the two groups. We performed iron staining in all the cases and analyzed HD in CP and FM according to the histological score (H-Score: 0-12), which was determined as the density (0-3) multiplied by the extent of staining (0-4)., Results: HD was found in 100% (20/20) of CAOS and 15% (3/20) of control cases. In both the FM and CP, CAOS cases showed a significantly higher HS than control cases (CAOS, HS = 4-12; Control, HS = 0-1, p < 0.0001). Three CAOS patients presented HD alone in the CP. The HS of the CP was significantly higher than that of the FM (p = 0.0003)., Discussion: CAOS presented DCH with HS ≥ 4. This study showed that the CP might be more suitable for evaluating DCH than the FM., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Umbilical vein varix is associated with a high incidence of fetal anomalies and perinatal complications. There are two types of umbilical vein varix: fetal intra-abdominal and extra-abdominal. Herein, a case is reported of severe fetal anemia with extra-abdominal umbilical vein varix. A 33-year-old primigravida was referred to our hospital for fetal growth restriction, fetal cardiomegaly, and decreased fetal movements at 26 weeks' gestation. A Doppler assessment showed an elevated middle cerebral artery peak systolic velocity at 2.2 MoM, suggesting fetal anemia. Umbilical vein varix had caused intermittent turbulent flow, provoking hemolytic anemia. Intrauterine transfusion improved fetal circulatory failure and anemia and prolonged gestational period. At 33 weeks' gestation, the patient underwent cesarean delivery due to nonreassuring fetal status. Pathological analysis revealed focal loss of vascular smooth muscle of the umbilical vein. Extra-abdominal umbilical vein varix has been reported in 14 cases including this case. The antenatal diagnosis rate is reported to be 79%; fetal heartbeat abnormalities and fetal deaths were reported as 50% and 14%, respectively. Eighty-six percent of patients had intra-umbilical cord thrombosis, but currently this is the only case of hemolytic anemia. Furthermore, extra-abdominal umbilical vein varix may present as fetal hydrops with anemia. During ultrasound examination of fetal anemia, umbilical cord screening should be performed with caution., (© 2020 Japanese Teratology Society.)

Spheroids exhibit drug resistance and slow proliferation, suggesting involvement in cancer recurrence. The protein kinase C inhibitor UCN-01 (7-hydroxystaurosporine) has shown higher efficacy against slow proliferating and/or quiescent ovarian cancer cells. In this study, tumorigenic potential was assessed using anchorage-independent growth assays and spheroid-forming capacity, which was determined with ovarian cancer cell lines as well as primary ovarian cancers. Of 12 cell lines with increased anchorage-independent growth, 8 formed spheroids under serum-free culture conditions. Spheroids showed reduced proliferation ( P < 0.0001) and Ki-67 immunostaining (8% vs. 87%) relative to monolayer cells. Spheroid formation was associated with increased expression of mitochondrial pathway genes ( P ≤ 0.001) from Affymetrix HT U133A gene expression data. UCN-01, a kinase inhibitor/mitochondrial uncoupler that has been shown to lead to Puma-induced mitochondrial apoptosis as well as ATP synthase inhibitor oligomycin, demonstrated effectiveness against spheroids, whereas spheroids were refractory to cisplatin and paclitaxel. By live in vivo imaging, ovarian cancer xenograft tumors were reduced after primary treatment with carboplatin. Continued treatment with carboplatin was accompanied by an increase in tumor signal, whereas there was little or no increase in tumor signal observed with subsequent treatment with UCN-01 or oltipraz. Taken together, our findings suggest that genes involved in mitochondrial function in spheroids may be an important therapeutic target in preventing disease recurrence., (©2020 American Association for Cancer Research.)

Aim: The aim of the study was to investigate the efficacy of conservative treatment in cases of retained products of conception (RPOC) with a preceding pregnancy of less than 22 weeks and to assess whether serum beta-human chorionic gonadotropin (hCG) levels could be a useful index to monitor the progress of treatment., Methods: This is a case series of patients with RPOC developed after less than 22 weeks of gestation and managed expectantly with serial serum hCG measurement between 2011 and 2017. The clinical data of subjects were reviewed retrospectively. Cases that did not require invasive treatment such as surgery were designated as conservative management success., Results: A total of 19 cases were eligible: 14 miscarriages and 5 induced abortions. Eleven patients underwent dilatation and curettage. The diagnosis of RPOC was made 35 (8-80) days after abortion. All patients were successfully treated with conservative management. Serum hCG levels at diagnosis were 29.6 (3.2-1585) mIU/mL. Serial measurement of serum hCG was continued until the levels became lower than the cutoff value, and the mean duration to hCG disappearance was 67.5 (6-183) days. In all cases, RPOC vanished spontaneously 77 (27-184) days after diagnosis. The disappearance of RPOC in the uterine cavity was subsequent to a significant decrease in serum hCG. Once serum hCG levels reached the cutoff value, no bleeding episodes were observed., Conclusion: Conservative management for RPOC might be acceptable and effective. Furthermore, serial serum hCG levels reflect the activity of RPOC, and hCG may be a reliable index to monitor the progress of treatment., (© 2020 Japan Society of Obstetrics and Gynecology.)

Background: Uterine atony is the leading cause of severe postpartum hemorrhage (PPH); however, the underlying cause of intractable atonic PPH unresponsive to conventional treatments (such as uterotonics and intrauterine balloon tamponade) remains unclear. Objectives: The aim of this study was to investigate whether intractable atonic PPH is associated with the type of bleeding (arterial or nonarterial) and its location, along with variations in the size and shape of the uterine cavity after delivery. Study design: This retrospective study included women who had undergone a dynamic computed tomography (CT) scan for the management of severe PPH at Kyoto University Hospital between April 2011 and March 2017. Patients' electronic medical records were reviewed, and relevant clinical information was collected. The presence of contrast extravasation (CE) on CT images in the early phase (40 s) was regarded as active arterial bleeding. Bleeding sites and size of the uterine cavity were evaluated using an xyz coordinate system. The size of the uterine cavity was compared between groups with CE into the upper and lower parts of the uterine body. Results: Of the 60 women assessed for eligibility, 30 were included in the current analysis. Contrast extravasation was detected in 19 women, with 14 showing CE in the early phase. The presence of CE in the early phase was significantly associated with the need for transarterial embolization (Fisher's exact test, p  = .0017). The upper and lower parts of the uterine cavity were 97.4 ± 2.7 mm (mean ± standard error of the mean) and 87.2 ± 3.5 mm in length, respectively. The maximum anteroposterior diameters of the upper and lower parts of the uterine cavity were 23.1 ± 2.6 and 76.0 ± 3.0 mm, respectively, and the largest transverse diameters were 67.3 ± 1.9 and 81.1 ± 2.3 mm, respectively. The group that showed CE into the upper uterine cavity had significantly larger qualitative parameters of the upper uterine cavity compared to the group with CE into the lower uterine cavity. The gate from the lower uterine cavity toward the upper uterine cavity was narrow (anteroposterior diameter of 22.6 ± 2.0 mm, transverse diameter of 40.7 ± 3.3 mm), and the intrauterine balloon was always found in the lower uterine cavity on the CT scan. The upper uterine body was characterized by a flat oval-shaped cavity ( xy plane), thick uterine wall, and lack of uniformity among bleeding sites ( z   =  62.4 ± 14.8 mm). In contrast, the lower uterine cavity was a circular shape ( xy plane) with thin walls, and bleeding sites were located at lateral sides around the level of the internal os ( z  =  -18.8 ± 4.9 mm). Conclusions: Atonic PPH has a significant subtype, named "PRACE," which is characterized by PPH, resistance to treatment, and arterial CE. The need for embolization can be predicted by the presence of arterial bleeding and its location, along with the shape of the uterine cavity.

Many pregnancy complications are the result of dysfunction in the placenta. The pathogenic mechanisms of placenta-mediated pregnancy complications, however, are unclear. Abnormal placental development in these conditions begins in the first trimester, but no symptoms are observed during this period. To elucidate effective preventative treatments, understanding the differentiation and development of human placenta is crucial. This review elucidates the uniqueness of the human placenta in early development from the aspect of structural characteristics and molecular markers. We summarise the morphogenesis of human placenta based on human specimens and then compile molecular markers that have been clarified by immunostaining and RNA-sequencing data across species. Relevant studies were identified using the PubMed database and Google Scholar search engines up to March 2020. All articles were independently screened for eligibility by the authors based on titles and abstracts. In particular, the authors carefully examined literature on human placentation. This review integrates the development of human placentation from morphological approaches in comparison with other species and provides new insights into trophoblast molecular markers. The morphological features of human early placentation are described in Carnegie stages (CS), from CS3 (floating blastocyst) to CS9 (emerging point of tertiary villi). Molecular markers are described for each type of trophoblast involved in human placental development. We summarise the character of human trophoblast cell lines and explain how long-term culture system of human cytotrophoblast, both monolayer and spheroid, established in recent studies allows for the generation of human trophoblast cell lines. Due to differences in developmental features among species, it is desirable to understand early placentation in humans. In addition, reliable molecular markers that reflect normal human trophoblast are needed to advance trophoblast research. In the clinical setting, these markers can be valuable means for morphologically and functionally assessing placenta-mediated pregnancy complications and provide early prediction and management of these diseases., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Intrauterine bleeding during pregnancy is a major risk factor for preterm birth. Thrombin, the most abundant coagulation factor in blood, is associated with uterine myometrial contraction. Here, we investigated the molecular mechanism and signaling of thrombin-induced myometrial contraction. First, histologic studies of placental abruption, as a representative intrauterine bleeding, revealed that thrombin was expressed within the infiltrating hemorrhage and that thrombin receptor (protease-activated receptor 1, PAR1) was highly expressed in myometrial cells surrounding the hemorrhage. Treatment of human myometrial cells with thrombin resulted in augmented contraction via PAR1. Thrombin-induced signaling to myosin was then mediated by activation of myosin light chain kinase- and Rho-induced phosphorylation of myosin light chain-2. In addition, thrombin increased prostaglandin-endoperoxidase synthase-2 (PTGS2 or COX2) mRNA and prostaglandin E2 and F2α synthesis in human myometrial cells. Thrombin significantly increased the mRNA level of interleukine-1β, whereas it decreased the expressions of prostaglandin EP3 and F2α receptors. Progesterone partially blocked thrombin-induced myometrial contractions, which was accompanied by suppression of the thrombin-induced increase of PTGS2 and IL1B mRNA expressions as well as suppression of PAR1 expression. Collectively, thrombin induces myometrial contractions by two mechanisms, including direct activation of myosin and indirect increases in prostaglandin synthesis. The results suggest a therapeutic potential of progesterone for preterm labor complicated by intrauterine bleeding., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To determine the rates of trial of labor after cesarean delivery (TOLAC) and complications in Japan., Methods: We conducted a descriptive study of pregnant women with one prior cesarean section registered between January 2013 and December 2015 in the perinatal database of the Japan Society of Obstetrics and Gynecology. This database is a nationwide institution-based registry in Japan. This study included women who had undergone one prior cesarean delivery and who delivered a singleton by cephalic presentation between 37 and 41 weeks of gestation. We collected data on delivery method, particularly with regard to the involvement of TOLAC or elective repeated cesarean deliveries (ERCD). Rates of TOLAC were investigated by facility type, and we calculated the rates of maternal and perinatal complications including uterine rupture in TOLAC., Results: During the study period, 647,098 births were registered. Among the 34,460 women who met the inclusion criteria, 1730 (5.0%) and 32,730 (95.0%) underwent TOLAC and ERCD, respectively. In total, 76.4% of hospitals did not perform TOLAC at all. Generally in perinatal medical centers, which are better equipped with facilities, 58.7% women did not perform TOLAC. With regard to complications, we identified eight cases (0.46%) of uterine rupture with TOLAC. TOLAC births did not include maternal death and perinatal death. Among women attempting TOLAC, 1532 (88.6%) had successful vaginal births., Conclusion: The TOLAC rate in Japan was considerably lower than that reported in other countries, despite comparable complication rates.

Introduction: Postpartum hemorrhage is the most common cause of maternal death worldwide. Although intrauterine balloon tamponade has been widely used as an effective procedure to control atonic postpartum hemorrhage, intrauterine balloon tamponade fails to control postpartum hemorrhage in approximately one-fifth of cases. The aim of this study was to evaluate the efficacy of novel intrauterine balloon tamponade systems for postpartum hemorrhage., Material and Methods: We have developed two novel intrauterine balloon tamponade systems to maintain proper balloon placement. One was a shaft cover with its fixture system and the other was "the Kyoto balloon system" designed to provide direct pressure onto the upper uterine cavity. The efficacy of the intrauterine balloon tamponade systems was evaluated using a silicone three-dimensionally printed postpartum uterine cavity model., Results: Measurements of balloon displacement during inflation showed that the shaft cover significantly prevented the Bakri balloon from being displaced. The residual fluid volume in the upper uterine cavity was significantly less with the Kyoto balloon system than with the Bakri balloon system, indicating the effectiveness of the Kyoto balloon for upper uterine cavity tamponade., Conclusions: These innovative intrauterine balloon tamponade systems were effective for prevention of balloon displacement and for balloon tamponade of the upper uterine cavity in a 3D-printed postpartum-specific uterine cavity model., (© 2019 Nordic Federation of Societies of Obstetrics and Gynecology.)

Aim: The aim of this study was to investigate epidemiological and clinical aspects of severe postpartum hemorrhage (PPH) in Japan. Methods: We used national health insurance claims from 2011 to 2014 provided by the Ministry of Health, Labour and Welfare. The data included randomly selected claims that covered 10% of all inpatients in October, a so-called sampling dataset (covering 1/120 inpatients per year). We extracted claims for transfused blood, and further narrowed down the claims by names of diseases linked to PPH. As most referral obstetric facilities have adopted the diagnosis procedure combination (DPC)-based payment system while small-scale obstetric facilities have not (non-DPC facilities), the claims were also analyzed separately for DPC and non-DPC facilities. We assessed the incidence and causes of PPH, transfusion volume of red blood cells (RBC) and fresh frozen plasma (FFP), and surgical hemostatic management. Results: The number of PPH cases that required blood transfusion in the sampling dataset was 29, 29, 32, and 36 in 2011, 2012, 2013, and 2014, respectively. The leading cause of PPH was uterine atony followed by placental abruption. Although no specific trends were observed for the volume of transfused RBC (1467 ± 234 ml in 2014), there was a steady increase in the rate of FFP utilization in non-DPC facilities from 37% to 79% over the 4-year sampling period. Intrauterine balloon tamponade emerged in 2014. Conclusion: This nationwide survey indicates that the annual incidence of severe PPH is increasing. Furthermore, FFP has become more prevalent in small-scale obstetric facilities.