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To clarify the relation between institutions capacity to manage venous thromboembolism (VTE) and its incidence in pregnant women throughout Japan.Among the 2299 institutions that received the surveillance questionnaire, 666 (29.0%) responded, after which data from 295 961 women who gave birth at those institutions in 2018 were analyzed. Incidences and characteristics of antepartum and postpartum VTE in perinatal medical centers (PMCs), general hospital with obstetric facilities (GHs), and maternal clinic with beds (MCs) were then determined.The frequencies at which routine antepartum and postpartum thromboprophylaxis for high-risk women and routine transport to the more advanced medical institutions upon antepartum and postpartum pulmonary thromboembolism (PE) onset were performed differed significantly according to types of institution (PMCs: 92.4%, 96.2%, 23.8%, and 21.2%; GHs: 76.5%, 80.6%, 58.8%, and 54.1%; MCs: 29.2%, 41.7%, 96.5%, and 96.2%, respectively). Among the 295 961 women analyzed, 243 (0.082%) developed VTE. Incidences of antepartum VTE differed significantly according to institution types (PMCs: 106.4, GHs: 51.6, and MCs: 11.6 per 100 000 women). PMCs and GHs had significantly higher incidences of postpartum VTE compared to MCs (43.3 and 26.6 vs. 10.7 per 100 000 women, respectively), although PMCs and GHs had similar incidences. Among the four women (1.4%) who died due to VTE, three and one developed a PE in a PMC and MC, respectively.PMCs had higher incidences of VTE despite their more frequent performance of thromboprophylaxis. Several pregnant women with higher risk of VTE transported to PMCs.

Aim To investigate the management of obstetrical disseminated intravascular coagulation (DIC) in Japan. Methods We sent a surveillance questionnaire to 2299 institutions to collect details about the deliveries they performed in 2018. We investigated differences in the management of obstetrical DIC among three types of institutions: perinatal medical centers (PMCs), general hospitals with obstetrical facilities (GHs), and maternal clinics with beds (MCs). Results We received responses from 703 institutions (30.6% of the total mailed) with results of 306 799 women who gave birth in 2018. In Japan, the potential to treat postpartum hemorrhage and obstetrical DIC was high in the PMC group, moderate in the GH group, and low in the MC group. The incidence of obstetrical DIC in the PMC group (0.44%) was significantly higher than that in the GH (0.21%) and MC (0.06%) groups. The mortality of women with obstetrical DIC in PMCs (1.3%) was similar to that in GHs (0.6%) and MCs (0.0%). The percentages of PMCs that always or sometimes transfused fresh frozen plasma or fibrinogen concentrates (100% and 42.2%, respectively) were significantly higher than those in the GH (88.2% and 29.5%, respectively) and MC groups (29.4% and 5.3%, respectively). Furthermore, institutions whose internal protocols mandated that replacement therapy be always administered in women with obstetrical DIC scores of ≥8 had similar protocols to those for women with fibrinogen levels of ≤1.5 g/L. Conclusions The capacity to provide therapy for postpartum hemorrhage and obstetrical DIC varied widely among the three groups of institutions.

Background: In Japan, deliveries by women of older maternal age and by women with overweight or obesity have recently increased. While, since 2008, the guidelines and practices to prevent the maternal VTE have been recommended. This study aims to clarify the incidence and characteristics of venous thromboembolism (VTE) in pregnant women in Japan to reduce the rate of mortality from VTE.Methods: Of 2299 institutions sent the surveillance questionnaire, 666 (29.0%) responded, and data from 295,961 women who gave birth in those institutions in 2018 were analyzed. We calculated the incidence and characteristics of VTE before and after the deliveries in the three types of institutions (perinatal medical centers, general hospital with obstetric facilities, and maternal clinic with beds). To clarify the incidence and characteristics of VTE, and to clarify the relationship between the incidence of the VTE and the types of institutions in 2018 in Japan.Results: At the responding institutions, 20 (0.0068%) died, and 243 women (0.082%) had VTE. Deep vein thrombosis was significantly more common (0.0053%) than pulmonary thromboembolism (0.0019%; p < 0.0001). The incidence of antepartum VTE (0.0055%) was significantly higher than that of postpartum VTE (0.0026%; p < 0.0001). Among the 165 women with antepartum VTE, perioperative pulmonary thromboembolism (30.0%) was more common than perioperative deep vein thrombosis (8.8%, p = 0.0150). The incidence of VTE after cesarean section (0.0074%) was significantly higher than that after vaginal delivery (0.0012%; p < 0.0001). After cesarean section, the incidence of pulmonary thromboembolism (46.4%) was significantly higher than that of deep vein thrombosis (10.8%; p < 0.0001). Of the women with VTE, four (1.6%) died.Conclusions: Obstetricians should be strongly encouraged to administer thromboprophylaxis to decrease the incidence of VTE because among women thought to have low risk of VTE, the incidence might have increased in Japan.

We previously reported that a low-protein diet caused animals to develop fatty liver containing a high level of triglycerides (TG), similar to the human nutritional disorder “kwashiorkor”. To investigate the underlying mechanisms, we cultured hepatocytes in amino acid-sufficient or deficient medium. Surprisingly, the intracellular TG level was increased by amino acid deficiency without addition of any lipids or hormones, accompanied by enhanced lipid synthesis, indicating that hepatocytes themselves monitored the extracellular amino acid concentrations to induce lipid accumulation in a cell-autonomous manner. We then confirmed that a low-amino acid diet also resulted in the development of fatty liver, and supplementation of the low-amino acid diet with glutamic acid to compensate the loss of nitrogen source did not completely suppress the hepatic TG accumulation. Only a dietary arginine or threonine deficiency was sufficient to induce hepatic TG accumulation. However, supplementation of a low-amino acid diet with arginine or threonine failed to reverse it. In silico analysis succeeded in predicting liver TG level from the serum amino acid profile. Based on these results, we conclude that dietary amino acid composition dynamically affects the serum amino acid profile, which is sensed by hepatocytes and lipid synthesis was activated cell-autonomously, leading to hepatic steatosis.

The fetus is a semi-allograft for the maternal host in natural pregnancy, but the fetus is a complete allograft after oocyte donation (OD), and there is greater antigenic dissimilarity with the mother. Thus, OD pregnancy is a good model for understanding how the fetus is protected by the maternal immune system. Recent clinical data have revealed a higher risk of miscarriage, gestational hypertension, preterm birth, and low birth weight with OD pregnancy. There is also a higher incidence of chorionic deciduitis, dense fibrinoid deposits in the chorionic basal plate, inflammatory lesions in the chorionic plate, and C4d deposition on syncytiotrophoblasts in OD pregnancy. Impaired accumulation of T cells, regulatory T (Treg) cells, natural killer (NK) cells, and monocytes in the decidua basalis and poor remodeling of spiral arteries are observed in OD pregnancy irrespective of whether preeclampsia occurs. These findings may partly explain why OD pregnancy is associated with a high risk of gestational hypertension and preeclampsia. We need to clarify the immunological and pathological differences between uncomplicated and complicated OD pregnancy. In uncomplicated OD pregnancy, the level of HLA match between mother and baby is significantly higher than would be expected by chance, suggesting that miscarriage may be frequent with marked HLA mismatch. This review discusses the relationship between various aspects of the immune system and complications of OD pregnancy.

In oocyte donation (OD) pregnancies, a fetus is a complete allograft to the maternal host and OD pregnancies are an independent risk factor for preeclampsia. Immunocompetent cells contribute to spiral artery remodeling and the failure of this process could contribute to the pathophysiology of preeclampsia. Recent data have shown that impaired autophagy of extravillous trophoblasts (EVT) may induce poor vascular remodeling in preeclampsia. We have studied the distribution of T cells, NK cells and macrophages in the decidua basalis of 14 normotensive OD pregnancies, 5 preeclamptic OD cases, 16 normotensive pregnancy cases, and 13 preeclamptic cases in natural pregnancy or autologous oocyte IVF-ET (NP/IVF). The populations of decidual CD3(+)T cells, CD8(+)T cells, CD4(+)T cells, Foxp3(+)Treg cells, CD56(+)NK cells, and CD68(+) macrophages in preeclampsia were significantly smaller than those in normal pregnancy in NP/IVF. Those frequencies in normotensive OD pregnancies or preeclamptic cases in OD pregnancies were similar to those in preeclamptic cases in NP/IVF. Impaired vascular remodeling was observed in OD pregnancies, regardless of the presence or absence of preeclampsia. The expression of p62, an impaired autophagy marker in EVT of normotensive or preeclamptic OD pregnancies, was significantly higher than that in normal pregnancies in NP/IVF. Immunological change in the decidua basalis and impairment of autophagy in EVT may induce impairment of spiral artery remodeling in OD pregnancies.

Oocyte donation (OD) is a high risk for preeclampsia because a fetus is a complete allograft to the maternal host. However the differences of immune status between preeclamptic OD cases and normotensive OD cases have not been clarified. Objective To clarify the immunological differences between preeclamptic OD cases and normotensive OD cases. Methods Deciduel CD3+Tcells, CD4+Tcells, CD8+Tcells, Foxp3+Treg cells CD56+NK cells and CD68+ macrophage were evaluated by immunohistochemistry. Peripheral blood effector Treg cells were evaluated by flow cytometry in 5 preeclamptic OD cases and 16 normotensive OD cases. Results The populations of CD3+ T cells, CD4+ T cells, CD8+ T cells, Foxp3+ Treg cells, CD56+ NK cells and CD68+ macrophage in placental bed biopsy samples of OD cases were significantly lower compare to those in normal pregnancy subjects. Those levels in preeclamptic OD cases were similar to those in normotensive OD cases. Same findings were observed in preeclamptic cases in natural conception. Vascular remodeling of spiral arteries was very poor in OD cases regardless of the presence of preeclampsia. These findings were quite similar to those in preeclampsia of natural conception. Peripheral blood-effector Treg cells was significantly decreased in preeclampsia, but these levels in OD pregnancies were not changed in preeclamptic OD cases and normotensive OD cases. Conclusion Poor vascular remodeling and some of the immunological changes were observed in uncomplicated OD pregnancy, but we have not yet identified the crucial factors that lead to preeclampsia in OD pregnancy.

Effects of blood amino acid and hormone level for triglyceride accumulation in the liver are revealed in some previous studies by experimental method. Since there are large individual differences in these effects, it needs a lot of rats for such experiments. Simulation can help, sometimes substitute experiment in various fields especially in engineering field. Recently, combining a supercomputer and Artificial Intelligence technique, simulation is expanding its scope. In this study, one of such a simulation technique, Self-Organizing Map (SOM), proposed by Kohonen and it is a kind of the Neural Networks and using for the competitive learning, is applied for classifying effects of blood amino acid and hormone level for controlling triglyceride accumulation in the liver of rats.

Introduction The pathogenesis of preeclampsia remains largely unknown. However, many researches support the immune maladaptation hypothesis. Epidemiological findings show that first pregnancy, the use of barrier contraceptive method or short cohabitation, oocyte donation cases and obesity are the risks for preeclampsia. These factors seem to be independent. Objective We tried to explain the relationship between the epidemiological risks for preeclampsia and immune maladaptation. Method We have studied the immune system in preeclamptic cases and oocyte donation cases using flow cytometry and immunohistochemical examination. Results Human pregnancy represents a semiallograft to the maternal host, therefore tolerance system is required. In oocyte donation cases, all the MHC of the fetus are allograft to maternal host, therefore more strict tolerance system is needed. Nevertheless, our study showed the number of regulatory T (Treg) cells which induce tolerance were scare at fetomaternal interface. Moreover, macrophage, T cell and NK cells that play important roles for vascular remodeling were also scarce in placental bed biopsy samples. Importantly, vascular remodeling was inadequate in oocyte donation cases regardless of the presence or absence of preeclampsia. These findings suggest that macrophage, T cell and NK cells play an important role for vascular remodeling of spiral artery and poor placentation is present in oocyte donation pregnancy. We also showed that effector Treg cells decreased and exhausted Treg cells increased in peripheral blood of preeclampsia. Expression of Bcl-2 in Treg cells was decreased and expression of Bax in Treg cells was increased suggesting that Treg cells in preeclampsia are more likely to die by apoptosis. In our mice model, seminal plasma plays an important role for induction of paternal antigen specific Treg in the uterus. This finding explains barrier contraceptive method or short cohabitation are the risk of preeclampsia. We also showed the positive relationship between BMI and the frequencies of cytotoxic T cells and cytotoxic NK cells. Conclusion These findings support that immune maladaptation is one of the mechanisms of preeclampsia.

Objectives Allograft pregnancy such as oocyte donation and embryo donation has higher risks of placental complications including preeclampsia. Altered spiral arterial remodeling and the regional T, NK cells and monocyte population characteristics were studied in oocyte donation. Methods Decidua basalis were collected during scheduled cesarean sections from 19 women who conceived by oocyte donation (OD) and 18 women with normal gestation (CTR). Spiral arterial remodeling was studied using extra-villous trophoblastic (EVT) marker CK7 and vascular endothelium marker CD31 by immunohistochemistry. The regional T cell population was studied using CD3, CD8, Foxp3, and CD56 for T cells, cytotoxic T cells, regulatory T cells and NK cells, respectively. Macrophages were stained with CD68. The staining of P62 immunohistochemistry was also included to detect impaired response to oxidative stress by autophagy. The helper T cell count was estimated by subtracting CD8+ cells counts from CD3+ cells counts. Quantitation was done by counting immunopositive cells in 4 high power fields (×100). This study was reviewed and approved by the institutional review boards of Aiiku hospital and University of Toyama. Results When OD is compared to CTR, the vascular endothelium was incompletely replaced by EVT, indicating attenuated remodeling. The regional T cell analysis showed decreased CD3+ (8.83 vs 25.5: median), CD8+ (4.17 vs 12.0), CD4+ (4.63 vs 13.5), Foxp3+ (0.63 vs 2.00) CD56+ (4.00 vs 15.3) and CD68+ (6.25 vs 16.5). P62/CK7 ratio was four times higher in OD than CTR. Conclusions OD pregnancies have inappropriate remodeling of the spiral arteries and decreased regulatory T cell expression, macrophage, NK cells accumulation in the region. The characteristic difference coincided with a decreased autophagy, thus impaired response to oxidative stress. Our novel findings may at least in part be the etiology of the clinically well-known higher incidence of preeclampsia in the oocyte donation gestation. Disclosures Y. Nakabayashi: None. A. Nakashima: None. T. Shima: None. H. Sakamoto: None. T. Adachi: None. T. Okai: None. M. Nakabayashi: None. S. Saito: None.