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This study was conducted to examine whether babies born small develop cardiovascular problems in later life.Data were examined retrospectively for 1241 city dwellers (men 521, women 720) aged 40-69 years who received a medical examination at a single institution. Blood tests, physical measurements, and a questionnaire survey regarding birth weight (small, medium, large), medication history and lifestyle (alcohol consumption, smoking, exercise) was administered. We selected 28 persons (12 men and 16 women) from and studied the rate of conformity between the participants' memory (small, medium, large) and the actual birth weight recorded in their maternal and child health handbook (2500, 2500-3500,3500 g).Participants' recall of their birth weight correlated well with the weight recorded in the maternal notebook (r = 0.73; P0.025). Low-density lipoprotein (P0.05), and total cholesterol (P0.01) levels in men, and systolic (P0.05) and diastolic (P0.05) blood pressure in women were significantly inversely related to birth weight when controlling for age, body mass index, medication, and lifestyle. The percentage of women born small, medium, and large taking antidiabetic agents was 17.8%, 2.9% and 0% (P0.05), respectively.A low birth weight was associated with high low-density lipoprotein and total cholesterol levels in men, and hypertension and diabetes mellitus in women aged 40-69.

We designed a safety and dose-finding trial of tadalafil administered for fetal growth restriction (FGR).Three cases were initially commenced on 10 mg/day and monitored for major adverse events. Should a major adverse event be observed in one or more of the three cases, an examination into its relation with tadalafil would be conducted by a safety evaluation committee. If one or more of these new cases exhibited the same adverse event, the trial would be stopped completely. If there were no harmful side-effects, the trial would be extended to three cases at 20 mg/day, and the protocol would continue as in the 10-mg/day dose. The 40-mg/day dosage was tried in six cases as the dosage was considered to be high.The study population consisted of pregnant women with FGR. Maternal adverse events in all doses were recorded as least one grade 1 adverse events, as tadalafil was considered acceptable from the viewpoint of the mothers. However, a dose of 40 mg/day increased the number of grade 1 adverse events. The only fetal adverse event was a case of intrauterine fetal death related to the velamentous insertion of the umbilical cord. Neonatal adverse events showed no correlation to tadalafil dose, but were found more frequently in preterm births and, therefore, were correlated to infant prematurity.This safety and dose-finding trial showed that tadalafil had a favorable safety profile for pregnant women and fetuses with FGR.

Congenital thrombophilia which is characterized by deficiencies in proteins such as antithrombin (AT), protein C (PC) and protein S (PS), is a major cause of venous thromboembolism (VTE). A total of 130 patients with VTE were evaluated for congenital thrombophilia based on the activity of AT, PC, or PS. Fifteen VTE patients with congenital AT deficiency (11.5 %), 16 with congenital PC deficiency (12.3 %) and eight with congenital PS deficiency (6.2 %) were diagnosed using DNA analysis. The frequency of congenital AT deficiency was significantly higher in subjects with pregnancy-related and idiopathic VTE than in those with VTE due to other causes, and congenital PC and PS deficiency were frequently associated with idiopathic VTE. Among the groups examined, the plasma levels of AT were the lowest in subjects with pregnancy-related VTE. Although our findings may have been influenced by some unintentional bias, congenital thrombophilia is nevertheless a major cause of VTE in pregnant patients as well as in young or middle-aged patients without any underlying diseases.

Peripartum cardiomyopathy (PPCM) is a rare, but life-threatening condition that occurs during the peripartum period in previously healthy women. Although its etiology remains unknown, potential risk factors include hypertensive disorders during pregnancy, such as preeclampsia, advanced maternal age, multiparity, multiple gestation, and African descent. Several cohort studies of PPCM revealed that the prevalence of these risk factors was quite similar. Clinically, approximately 40% of PPCM patients are complicated with hypertensive disorders during pregnancy. Because PPCM is a diagnosis of exclusion, heterogeneity is a common element in its pathogenesis. Recent genetic research has given us new aspects of the disease. PPCM and dilated cardiomyopathy (DCM) share genetic predisposition: 15% of PPCM patients were found to have genetic mutations that have been associated with DCM, and they showed a lower recovery rate. Other basic research using PPCM model mice suggests that predisposition genes related to both hypertensive and cardiac disorders via angiogenic imbalance may explain common elements of hypertensive disorders and PPCM. Furthermore, hypertensive disorders during pregnancy are now found to be a risk factor of not only PPCM, but also cardiomyopathy in the future. Understanding genetic variations allows us to stratify PPCM patients and to guide therapy. (Circ J 2016; 80: 1684-1688).

To make recommendations for saving mothers' lives, issues related to maternal deaths including diseases, causes, treatments, and hospital and regional systems are analyzed by the Maternal Death Exploratory Committee in Japan. In this report, we present ten clinical important recommendations based on the analysis of maternal deaths between 2010 and 2014 in Japan.

The aim of this retrospective study was to assess tadalafil treatment in pregnant women with fetal growth restriction (FGR) in terms of maternal and perinatal outcomes.We retrospectively analyzed 11 Japanese singleton pregnant women with FGR who received tadalafil along with conventional management for FGR at Mie University Hospital from July 2015 to February 2016 (tadalafil group). These women were matched for maternal age, parity, gestational age, and estimated fetal weight at enrollment with 14 singleton pregnant women who received only the conventional management for FGR in 2014 (conventional management group). The conventional management for FGR was performed according to guidelines for obstetric practice in Japan.Both birthweight and fetal growth velocity from enrollment to birth were significantly higher in the tadalafil group than in the conventional management group. The cesarean delivery rate was approximately twofold higher in the conventional management group than in the tadalafil group. Importantly, cesarean section due to non-reassuring fetal status was performed in seven pregnant women in the conventional management group (58.3%) but in none in the tadalafil group (P0.05, chi-squared test).Tadalafil may improve perinatal outcome in FGR by modulating fetal growth through maintenance or improvement of fetal well-being.

Thrombophilia such as protein C (PC), antithrombin (AT), or protein S (PS) deficiency can cause either fatal or frequent venous thromboembolism (VTE); however, Japanese individuals have few factor V Leiden or prothrombin mutations. The a-fibrinogen (FGA): p.Thr331Ala polymorphism occurs in a region that is important for FXIII-dependent cross-linking, and it may therefore affect the clot structure or degree of rigidity. A significant association has been observed between FGA: p.Thr331Ala and poststroke mortality in participants with atrial fibrillation, and this fibrinogen polymorphism has also been reported to be associated with VTE; the genotype distribution of patients with pulmonary embolism (TT 1⁄4 49%, TA 1⁄4 36%, AA 1⁄4 15%) differed significantly from healthy control participants (TT, wild type 1⁄4 60%, TA, heterozygous 1⁄4 34%, AA, homozygous 1⁄4 6%). The frequency of the FGAThr312Ala polymorphism was reported to be 46.5% in Japanese individuals and 29.9% in Europeans. A previous report suggested that FGA: p.Thr331Ala may cause early pregnancy loss. Therefore, FGA: p.Thr331Ala polymorphism was examined in 27 pregnant women without early pregnancy loss and 26 those with more than 1 experience of suffering early pregnancy loss, including 14 patients with thrombophilia according to a genetic analysis (4 with hereditary AT deficiency, 9 with hereditary PC deficiency, and 1 with hereditary PS deficiency) and 8 patients with hypofibrinogenemia (less than 1.5 g/L vs normal range 1.8-2.8 g/L). Of 14 patients with hereditary thrombophilia, 12 patients experienced VTE and 5 patients experienced pregnancy loss. All patients with AT deficiency were diagnosed during pregnancy, but 9 patients with PC deficiency and 1 with PS deficiency were diagnosed after delivery. The diagnosis of AT, PC, or PS deficiency was reported previously. Thirtyseven cases of thrombophilia (14 with AT deficiency, 16 with PC deficiency, and 7 with PS deficiency) with VTE were diagnosed at Mie University Hospital. The Japanese birth rate was 8.0 per 1000 in 2015, and the pregnancy loss rate varied with age. Early pregnancy loss was defined as an unknown cause, and more than 1 abortion before 10 weeks of pregnancy occurred. Early pregnancy loss was found to be associated with 8 (57.1%) of 14 women demonstrating homozygous FGA: p.Thr331Ala polymorphism, in 17 (54.8%) of 31 women with heterozygous FGA: p.Thr331Ala polymorphism and in 1 (12.5%) of 8 women with FGA: p.Thr331. The rate of pregnancy loss was 1 in 10 cases, 2 in 9 cases, 3 in 6 cases, and 8 in 1 case, respectively. Although FGA: p.Thr331Ala polymorphism was found to increase the risk of early pregnant loss, thrombophilia reduced the risk of early pregnant loss (Table 1). The risk of early pregnancy loss was significantly higher in women with homozygous or heterozygous FGA: p.Thr331Ala polymorphism than in women with FGA: p.Thr331 (Odds ratio: 8.84, P < .05). Although the risk of early pregnancy loss tended to be low in the thrombophilic women with either homozygous or heterozygous FGA: p.Thr331Ala polymorphism than in the other women, it was significantly higher in the nonthrombophilic women with homozygous or heterozygous FGA: p.Thr331Ala polymorphism than in the other women (odds ratio: 4.85, P < .01). These findings suggest that thrombophilia might provide some advantage for preserving pregnancy in women with an abnormal fibrinogen function, but thrombophilia causes thrombosis in pregnant women. As our analysis was small and there may have been some bias in the selection of samples, further investigation is therefore required. In conclusion, although FGA: p.Thr331Ala polymorphism increased the risk of early pregnant loss, thrombophilia reduced the incidence of early pregnant loss in women with FGA

The Japan Association of Obstetricians and Gynecologists (JAOG) recommends transfusion with a fresh-frozen plasma (FFP):red blood cell (RBC) ratio of 1 or more in postpartum hemorrhage. However, no global consensus exists concerning this, and little is known regarding the impact of FFP:RBC ratio on maternal mortality. This study evaluates the efficacy of transfusion with FFP:RBC ratio of 1 or more for amniotic fluid embolism (AFE) with coagulopathy.The Maternal Death Exploratory Committee, established by the JAOG, conducted this retrospective nationwide case-control study in Japan. Women with AFE and coagulopathy were included in the study and were stratified into survival and death groups. Obstetric variables and therapy methods (hysterectomy, uterine artery embolism, and transfusion with FFP:RBC ratio ≥ 1) were compared between the survival and death groups.A total of 54 women had AFE and coagulopathy (death group, n = 22; survival group, n = 32). Only nine (40.9%) women in the death group were transfused with FFP:RBC ratio of 1 or more, whereas 29 (90.6%) women in the survival group were transfused with FFP:RBC ratio of 1 or more. FFP:RBC ratio of 1 or more was found to be associated with better survival rate (adjusted odds ratio, 28.32; 95% confidence interval, 4.26-188.37). No difference was found in obstetric variables, hysterectomy, and uterine artery embolism between survival and death groups.Transfusion with FFP:RBC ratio of 1 or more is associated with higher survival rate in women with AFE with coagulopathy.

Objective To describe the safety and efficacy of thoracoamniotic shunting for fetal pleural effusion using a doublebasket catheter with a very small diameter (1.47mm). Method In this 2-year multicenter, prospective single-arm clinical studyregistered with the University hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN00001095); shunting was performed between 18w0d and 33w6d of gestation with this catheter in cases of fetal pleural effusions reaccumulating after thoracocentesis. The primary endpoint measures were maternal and fetal adverse effects and survival in the neonatal period. Results A total of 24 cases were included, of which 17 had hydrops (71%). The median gestational ages at shunting and delivery were 27.4 and 34.8weeks, respectively. There were no fetal deaths, lung injuries, or severe maternal complications. Preterm rupture of the membranes occurred in 7/24 (29%) cases at a median of 62days after the shunting. Preterm rupture of the membranes within 28days of the procedure occurred in 1/24 (4%) cases. Catheter displacement towards the fetal thoracic cavity occurred in 4/42 (10%) cases. The overall survival rate was 79% (19/24), whereas it was 71% (12/17) in the cases with hydrops. Conclusion Drainage of fetal pleural effusions with a double-basket shunt is safe and effective, and the shunt could be an alternative device. © 2012 John Wiley & Sons, Ltd.

The aeroacoustic sound generated from the flow around two NACA four-digit airfoils is investigated numerically, at relatively low Reynolds numbers that do not prompt boundary-layer transition. By using high-order finite-difference schemes to discretize compressible Navier–Stokes equations, the sound scattered on airfoil surface is directly resolved as an unsteady pressure fluctuation. As the wavelength of an emitted noise is shortened compared to the airfoil chord, the diffraction effect on non-compact chord length appears more noticeable, developing multiple lobes in directivity. The instability mechanism that produces sound sources, or unsteady vortical motions, is quantitatively examined, also by using a linear stability theory. While the evidence of boundary-layer instability waves is captured in the present result, the most amplified frequency in the boundary shear layer does not necessarily agree with the primary frequency of a trailing-edge noise, when wake instability is dominant in laminar flow. This contradicts the observation of other trailing-edge noise studies at higher Reynolds numbers. However, via acoustic disturbances, the boundary-layer instability may become more significant, through the resonance with the wake instability, excited by increasing a base-flow Mach number. Evidence suggests that this would correspond to the onset of an acoustic feedback loop. The wake-flow frequencies derived by an absolute-instability analysis are compared with the frequencies realized in flow simulations, to clarify the effect of an acoustic feedback mechanism, at a low Reynolds number.

Progesterone and its metabolite, allopregnanolone, are neurosteroids that are present at high concentrations in fetal brains that decrease right after birth. Allopregnanolone is a potent positive modulator of γ-aminobutyric acid A (GABA(A)) receptor function. We examined the effect of exogenous administration of these steroids on hypoxic-ischemic encephalopathy in immature rats. Progesterone (10mg/kg), allopregnanolone (10mg/kg), or vehicle alone was intraperitoneally administered immediately before and then subcutaneously 6h and 24h after hypoxia-ischemia to postnatal day 7 (P7), day 14 (P14), and day 21 (P21) rats. The effects of the treatments were evaluated using histological analyses (hemispheric volumes and semi-quantitative scoring for neuropathologic injury). Both progesterone and allopregnanolone significantly exacerbated brain injury in P7 and P14 rats, but not in P21 rats. This detrimental effect was similar across the examined brain regions (the cortex, striatum, hippocampus, and thalamus) and showed no sex differences. Co-administration of the GABA(A) receptor antagonist, bicuculline, partially mitigated the exacerbating effect of allopregnanolone. Based on the similarity of the effects of these neurosteroids, we speculate that progesterone accentuates neuronal injury mainly via the activity of allopregnanolone. The present study indicates that the detrimental effects of allopregnanolone were, at least in part, mediated via GABAergic neuroexcitability. This is in line with the notion that GABA is excitatory for immature neurons, while it is inhibitory for mature neurons.

Stroke during pregnancy associated with moyamoya disease (MMD) has been reported sporadically, but no systematic surveys have been undertaken. To reveal the current clinical situation, the authors conducted Japan's first nationwide survey of pregnancy and delivery associated with MMD. A questionnaire was sent to all 270 perinatal medical centers across Japan to survey their experiences with delivery associated with MMD within the preceding 5 years (Survey I); another questionnaire was sent to 554 adult female patients with MMD regarding their experience with childbirth (Survey II). Survey I included 59 deliveries among patients with previously diagnosed MMD. The incidence of perinatal neurological events and morbidity was 5.1% and 1.7%, respectively. In another five cases, newly diagnosed after perinatal attacks, disability was noted in three cases, including one death from intracranial hemorrhage. Survey II included 278 deliveries. The perinatal attack rate was 6.6% in 76 previously diagnosed cases and 2.0% in 202 cases undiagnosed at pregnancy, but neither group reported permanent morbidity. Caesarean section in previously diagnosed cases accounted for 76.3% of deliveries in Survey I and 69.7% in Survey II, but no significant difference in event rate was found between caesarean section and vaginal delivery in either survey. Although the incidence of perinatal neurological events is low when MMD has been diagnosed, careful monitoring is required in light of the potential for stroke. Serious events, especially intracranial hemorrhage, can occur if MMD has not been diagnosed at pregnancy. Further efforts to establish management guidelines are required to ensure safer childbirth in patients with MMD.

Background: Improved medical techniques have allowed most women with repaired tetralogy of Fallot (TOF) to reach childbearing age. The predictors of adverse events and the effects of pregnancy on cardiac function have not been clearly described in these patients. Methods and Results: In the present study we retrospectively reviewed 40 deliveries in 25 patients with repaired TOF. There were 23 patients in New York Heart Association (NYHA) class I, and 2 in classes II-III before pregnancy. The mean age at delivery was 29.1 years and the mean gestational period was 37.8 weeks. Seven pregnancies (17.5%) in 7 patients were complicated with cardiac events such as a decline in NYHA class and arrhythmia. History of ablation and the baseline cardiothoracic ratio on chest radiography were predictors of adverse events. Peak plasma brain natriuretic peptide (BNP) level after the second trimester was higher in patients with cardiac events. Left ventricular size and contraction did not change from before to after pregnancy, but the right ventricle was enlarged at 6 months after delivery. Conclusions: Many of the pregnancies in women with repaired TOF were successful. However, careful management is required for some patients and the BNP level may be a useful marker to identify these patients. Because the right heart tended to be enlarged in the late postpartum period, pregnancy may also affect the long-term prognosis of patients with repaired TOF. (Circ J 2012; 76: 957-963)

Background: There are few large studies of fetal congenital bradyarrhythmia. The aim of the present study was to investigate the effects and risks of transplacental treatment for this condition. Methods and Results: Using questionnaires, 128 cases of fetal bradyarrhythmia were identified at 52 Japanese institutions from 2002 to 2008. Of the 128 fetuses, 90 had structurally normal hearts. Among these 90 fetuses, 61 had complete atrioventricular block (CAVB), 16 had second-degree AVB, 8 had sinus bradycardia, and 5 had other conditions. The 61 CAVB fetuses were divided into those who did (n=38) and those who did not (n=23) receive transplacental medication. Monotherapy with β-sympathomimetics, steroid monotherapy, and combination therapy with these agents was given in 11, 5 and 22 cases, respectively. Beta-sympathomimetics improved bradycardia (P 10 weeks on steroids (P=0.043). Conclusions: Treatment with β-sympathomimetics improved bradycardia, but survival rate did not differ significantly in fetuses with and without transplacental medication. It is recommended that steroid use should be limited to

The Maternal Death Exploratory Committee in Japan analyzed 313 maternal deaths that occurred in the country between January 1, 2010 and March 31, 2017. The details of the Committee have been described previously.1 The study was approved by the ethics board of the National Cerebral and Cardiovascular Center (Osaka, Japan) and the Japan Association of Obstetricians and Gynecologists. This investigation was conducted according to the principles expressed in the Declaration of Helsinki. Informed consent was not obtained from patients or their families, because the study was based on the analysis of institutional forms, and the patient records/information was anonymized. This article is protected by copyright. All rights reserved.

Clinical guidelines for obstetrical practice were first published by the Japan Society of Obstetrics and Gynecology (JSOG) and the Japan Association of Obstetricians and Gynecologists (JAOG) in 2008, and a revised version was published in 2011. The aims of this publication include the determination of current standard care practices for pregnant women in Japan, the widespread use of standard care practices, the enhancement of safety in obstetrical practice, the reduction in burdens associated with medico-legal and medico-economical problems, and a better understanding between pregnant women and maternity-service providers. These guidelines include a total of 87 Clinical Questions followed by several Answers (CQ&A), a Discussion, a List of References, and some Tables and Figures covering common problems and questions encountered in obstetrical practice. Each answer with a recommendation level of A, B or C has been prepared based principally on 'evidence' or a consensus among Japanese obstetricians in situations where 'evidence' is weak or lacking. Answers with a recommendation level of A or B represent current standard care practices in Japan. All 87 CQ&A are presented herein to promote a better understanding of the current standard care practices for pregnant women in Japan.

Clinical guidelines for obstetrical practice were first published by the Japan Society of Obstetrics and Gynecology (JSOG) and the Japan Association of Obstetricians and Gynecologists (JAOG) in 2008, and a revised version was published in 2011. The aims of this publication include the determination of current standard care practices for pregnant women in Japan, the widespread use of standard care practices, the enhancement of safety in obstetrical practice, the reduction in burdens associated with medico-legal and medico-economical problems, and a better understanding between pregnant women and maternity-service providers. These guidelines include a total of 87 Clinical Questions followed by several Answers (CQ&A), a Discussion, a List of References, and some Tables and Figures covering common problems and questions encountered in obstetrical practice. Each answer with a recommendation level of A, B or C has been prepared based principally on "evidence" or a consensus among Japanese obstetricians in situations where "evidence" is weak or lacking. Answers with a recommendation level of A or B represent current standard care practices in Japan. All 87 CQ&As are presented herein to promote a better understanding of the current standard care practices for pregnant women in Japan.

The goal of the study was to determine risk factors for maternal cardiac failure in pregnancy complicated with dilated cardiomyopathy (DCM). The subjects were 29 patients diagnosed with DCM before conception or during the first 7 months of pregnancy. DCM was defined as left ventricle end-diastolic dimension (LVDd)⩾48 mm and/or fractional shortening (%FS)⩽30% on echocardiography. Patients were followed until at least 1 year after delivery and were categorized into a poor prognosis group (n=6; death or end stage heart failure of New York Heart Association (NYHA) class III and IV) and a good prognosis group (n=23; all other cases). DCM was initially diagnosed during pregnancy in 6/6 and 8/23 patients in the poor and good prognosis groups, respectively (P

Deep vein thrombosis (DVT) is a serious pregnancy-related complication. Recent studies indicate that the genetic background for DVT differs with ethnicity. In our study, we enrolled 18 consecutive Japanese patients who had developed DVT during pregnancy and postpartum. We performed a genetic analysis of three candidate genes for DVT, protein S, protein C and antithrombin, in these patients. We found that four patients had missense mutations in the protein S gene, including the K196E mutation in two patients, the L446P mutation in one patient, and the D79Y and T630I mutations in one patient, as well as one patient with the C147Y mutation in the protein C gene. All five patients with genetic mutations had DVT in their first two trimesters. Nine of the patients without genetic mutations developed DVT in the first two trimesters, and four in the postpartum period. Thus, genetic mutations in the protein S gene were predominant in pregnant Japanese DVT women, and DVT in pregnant women with genetic mutations occurred more frequently at the early stage of pregnancy than postpartum. Considering the rapid decrease in protein S activity during pregnancy, we may need to assess thrombophilia in women before pregnancy.

Background: Aortic dilatation and dissection are severe complications of pregnancy that may cause maternal death. The purpose of the present study was to investigate risk factors for aortic dilatation or dissection in pregnant Japanese women with Marfan syndrome. Methods and Results: A total of 28 patients with Marfan syndrome were investigated retrospectively during pregnancy and after delivery at 1 institution. These patients were divided into 2 groups: those who experienced aortic dilatation or dissection (group D, n=11) and those who did not (group ND, n=17). In group D, aortic dilatation or dissection occurred in 7 cases during pregnancy (2 in the 2nd trimester, 5 in the 3rd trimester) and 4 cases after birth. The 2 cases in the 2nd trimester involved aortic dilatation >60mm and those patients underwent hemiarch replacement and a David operation, respectively. Delivery by cesarean section (64% vs. 18%, P

Adrenomedullin (AM) is a novel vasoactive peptide which regulates vascular tone and vascular endothelial cell growth. We recently reported that lymphatic endothelial cells (LECs) are also an attractive target of AM and concluded that AM is a potent mediator of lympangiogenesis. In the present study, we conducted a genome-wide analysis of genes that are regulated by AM in LECs. AM profoundly suppressed gene expression of cell adhesion receptors and inflammatory factors in LECs, such as intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), endothelial adhesion molecule-1 (E-selectin), interleukin-8, and chemokines, QRT-PCR and flow cytometry analysis showed that AM dose-dependently suppressed the TNF-a-induced mRNA and protein expression of ICAM-1 and VCAM-l. Treatment of LECs with a cell permeable cyclic adenosine monophosphate (cAMP) analog, 8-Br-cAMP, mimicked the suppressive effect of AM on the expression of adhesion molecules. Moreover, both AM and 8-Br-cAMP suppressed TNF-α-induced NF-κB activation in LECs, indicating that AM reduces expression of adhesion molecules in LECs via a cAMP/NF-kB dependent pathway. These results suggest that AM may have an important role in the regulation of the expression of adhesion molecules in lymphatic endothelium, which is critical in the control of immune and inflammatory responses.

Background: There has been no nationwide survey concerning peripartum cardiomyopathy (PPCM) among the Asian population, and clinical profiles of PPCM complicated with hypertensive disorders complicating pregnancy (HD) as the major risk factor of PPCM have not been characterized. Methods and Results: A retrospective, nationwide survey of PPCM in 2007 and 2008 all over Japan was performed and the clinical characteristics were compared between patients with and without HD. We obtained data for 102 patients. HD during pregnancy occurred in 42 patients (41%). Patients with HD were older than those without HD (33.8 vs. 31.9 years old, P

Serious group A streptococcal (GAS) infections and its toxic shock syndrome (TSS) are associated with early onset and rapid progression, often resulting in death [1, 2]. The initial symptoms of a high fever and abdominal or chest pain are characteristics and are attributable to a common cold syndrome or viral infection [1]. The incidence rate is extremely low, with rates largely between 2 and 4 per 1,00,000 [3]. However, GAS-TSS is still one of the causes of maternal death. The perinatal and infant mortality rates in Japan are lowest worldwide (3:1,000). On the other hand, the maternal mortality rate is relatively high (4:1,00,000) [4]. Therefore, the Japan Association of Obstetricians and Gynecologists (JAOG) established a registration system for maternal death in 2010. If maternal death occurs, detailed reports are to be submitted to the JAOG. The individual data are analyzed by the Maternal Death Exploratory Committee (Chairman: Ikeda, T.). This committee consists of 15 obstetricians, four anesthesiologists, two pathologists, an emergency physician and some specialists who attend review sessions every month, in order to make recommendations for reducing the maternal mortality every year. The present study was performed as part of a series which analyzed maternal deaths in Japan by this committee. Report forms regarding the maternal death cases where a female patient died during pregnancy or within a year after delivery are submitted to this registration system. The 12 pages of the report form contain approximately 100 questions, and elicit detailed information about the clinical history of each death, the facility characteristics and which personnel participated in the patient’s care. All of the anonymized reports were analyzed for factors associated with the maternal mortality and the circumstances of death. A total of 155 reports of maternal death were completely analyzed by the Maternal Death Exploratory Committee between 2010 and 2012, while 128 cases of maternal death that occurred during pregnancy or within 42 days after delivery were reported by the Ministry of Health, Labour and Welfare, Japan [4]. Because GAS-TSS is still one of the causes of maternal death, though number of maternal death is decreasing in Japan, we thought it was necessary to clarify the clinical course and features of maternal death due to serious GAS infection in order to reduce the maternal mortality rate. In the analyzed reports of maternal deaths between 2010 and 2013, the clinical features in the pregnant patients who died due to serious GAS-TSS were reviewed in the present study. Cases were enrolled when the diagnosis of GASTSS based upon the previously published criteria [5] was made, and when culture findings were positive or the GAS toxin was detected. J. Hasegawa (&) A. Sekizawa Department of Obstetrics and Gynecology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo 142-8666, Japan e-mail: hasejun@oak.dti.ne.jp

Aim: To clarify the cause of maternal deaths, an autopsy is essential. However, there has been no systemic analysis of maternal death in Japan based on autopsy cases. Material & Methods: Maternal death reports were retrieved from a large amount of registered autopsy data on maternal death in the series of ‘Annual of pathological autopsy cases in Japan’. These files contain 468 015 autopsy records from 1989 to 2004. We collected 193 cases of maternal death due to direct obstetric causes. We recorded all the data into Excel files. Then we analyzed the causes of death and classified them into 11 categories. Results: The causes of maternal death were as follows: amniotic fluid embolism (AFE), 24.3%; disseminated intravascular coagulation (DIC) related to pregnancy-induced hypertension, 21.2%; pulmonary thromboembolism, 13.0%; injury to the birth canal, 11.4%; medical and surgical complications, 9.8%; and atonic bleeding or DIC of unknown cause, 8.3%. A discrepancy between the clinical diagnosis and pathological diagnosis was frequently observed in cases of AFE, septic DIC and injury to the birth canal. AFE diagnosed by autopsy was often clinically diagnosed as atonic bleeding or DIC of unknown cause before death. Half of the cases of AFE diagnosed by autopsy were associated with DIC. Conclusion: We found that AFE, DIC related to pregnancy-induced hypertension, pulmonary thromboembolism and injury to the birth canal were the major causes of maternal death in Japan. AFE had various clinical features such as uterine atony and DIC in addition to pulmonary cardiac collapse.

We reported previously that the autologous administration of bone marrow-derived mesenchymal stem cells (BM-MSC) significantly attenuated myocardial dysfunction and injury in a rat model of acute myocarditis by stimulating angiogenesis and reducing inflammation. Because BM aspiration procedures are invasive and can yield low numbers of MSC after processing, we focused on fetal membranes (FMs) as an alternative source of MSC to provide a large number of cells. We investigated whether the allogeneic administration of FM-derived MSC (FM-MSC) attenuates myocardial injury and dysfunction in a rat myocarditis model. Experimental autoimmune myocarditis (EAM) was induced in male Lewis rats by injecting porcine cardiac myosin. Allogeneic FM-MSC obtained from major histocompatibility complex-mismatched ACI rats (5 × 10(5) cells/animal) were injected intravenously into Lewis rats one week after myosin administration. At day 21, severe cardiac inflammation and deterioration of cardiac function were observed. The allogeneic administration of FM-MSC significantly attenuated inflammatory cell infiltration and monocyte chemoattractant protein 1 expression in the myocardium and improved cardiac function. In a T-lymphocyte proliferation assay, the proliferative response of splenic T lymphocytes was significantly lower in cells obtained from FM-MSC-treated EAM rats that reacted to myosin than in cells obtained from vehicle-treated rats with EAM. T-lymphocyte activation was significantly reduced by coculture with FM-MSC. The allogeneic administration of FM-MSC attenuated myocardial dysfunction and inflammation, and the host cell-mediated immune response was attenuated in a rat model of acute myocarditis. These results suggest that allogeneic administration of FM-MSC might provide a new therapeutic strategy for the treatment of acute myocarditis.

The interface condition provides flexibility to handle complex geometries on a set of structured grids. However, when used with a compact scheme to apply in computational aeroacoustics, its accuracy and stability may be degraded seriously by the boundary treatment that arises at a grid interface. To minimize this effect, a modified characteristic condition is incorporated in the finite difference compact scheme by using an explicit difference form at the boundary. The extension of this approach is naturally attained through the coordinate transformation of convective terms across an interface in multidimensions. The validity of current development is demonstrated through a simulation of trailing-edge noise generation from an airfoil at a low Mach number.

Objective: We assessed the utility of the pulse oximeter perfusion index (PI) in maternal monitoring immediately after delivery.Methods: We examined 30 pregnant women without any complications using the Rad7 device at delivery. The correlations between heart rate (HR), systolic blood pressure (BP), oxygen saturation SpO2, PI, Pleth variability index (PVI), shock index and blood loss were assessed.Results: Blood loss at 20-min postpartum was not correlated with the difference in heart rate, systolic BP, SpO2, shock index or PVI taken immediately after delivery and at 20-min postpartum, but showed a strong negative correlation with the difference in the PI taken immediately after delivery and at 20-min postpartum (r = −0.70).Conclusion: PI changes were correlated with post-delivery blood loss and can be used for maternal monitoring at delivery.

Thrombotic thrombocytopenic purpura (TTP) frequently develops in patients with connective tissue diseases (CTDs). ADAMTS13 and von Willebrand factor (VWF) are closely related to the onset of TTP. We investigated the roles of ADAMTS13 and VWF in thrombotic events of patients with CTD. ADAMTS13 activity and VWF and VWF propeptide (VWFpp) levels in CTD, primary antiphospholipid antibody syndrome (pAPS), and controls were measured to examine their relationship with thrombosis. ADAMTS13 activity levels were significantly low in the patients with CTD but not in the patients with pAPS. No significant difference in the ADAMTS13 activity levels among the various CTD subgroups was found. The levels of VWF and VWFpp were significantly elevated in the patients with pAPS and CTD compared with that of control groups. Eleven patients with CTD developed TTP, and their ADAMTS13 activity levels were significantly lower than patients having CTD without TTP. However, the ADAMTS13 activity levels showed no difference between the patients having CTD with and without thrombotic events. The VWF antigen levels were significantly high in the patients having CTD with TTP. There were no significant differences in the VWF levels of the patients having CTD with TTP and thrombosis. The VWFpp levels were significantly high in the patients having CTD with TTP and thrombosis. The VWF and VWFpp levels were significantly high in the patients with pAPS. Decreased ADAMTS13 activity and elevated VWF and VWFpp levels were observed in patients with CTD. These abnormalities in patients with CTD may represent the increased risk of thrombosis in CTD.

Fetal magnetocardiography (FMCG) was recorded for 20 min to investigate its clinical efficacy. The multichannel SQUID system (MC-6400, Hitachi-Hightechnologies, Japan), which covers a wide area of the torso of pregnant women was used for recording FMCG. We also used simple methods to relieve adverse problems in long-duration measurement for pregnant women in the supine position: (1) light 10-min walking before FMCG measurement to reduce fetal movement, (2) placing a soft cushion under the patient's back to relieve back pains and (3) bending the knees to avoid supine hypotensive syndrome. All these methods were useful in relieving adverse problems.

The occurrence of hypoxia-ischemia (HI) during early fetal or neonatal stages of an individual leads to the damaging of immature neurons resulting in behavioral and psychological dysfunctions. Free radical-mediated lipid peroxidation is the main cause of neurotoxicity including neonatal brain damage. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a novel anti-oxidant agent and the drug of choice in the treatment of acute ischemic brain disorders in adult patient. The purpose of this study is to determine the direct effects of edaravone in inhibiting the lipid peroxidation production in the neonatal rat brains during hypoxic-ischemic insult by electron paramagnetic resonance (EPR) spectoroscopy and in vivo brain microdialysis. Seven-day-old Wistar rats were subjected to left common carotid artery ligation and a probe was inserted in the rat hippocampus. Edaravone (5, 50, or 100 microM) or saline was perfused with a spin trap agent (alpha-(4-pyridyl-N-oxide)-N-tert-butylnitrone; POBN) before, during and after hypoxia (1h of 8% O2 exposure) and then analyzed by EPR. Edaravone (100 microM) did not show any EPR evidence of POBN adduct formation during and after hypoxic-ischemic insult. However, the EPR signal increased, but not significantly during the hypoxic period in the hypoxic and edaravone 50 microM-treated groups compared to control. Edaravone at 5 microM significantly increased the EPR signals compared to control. This study shows that edaravone directly and dose-dependently inhibited the formation of lipid free radicals produced during hypoxic-ischemic insult in the neonatal rat brain. These results suggest that edaravone is able to attenuate neuronal damage in the rat neonatal brain by inhibiting the formation of lipid radicals.

Background: The dipstick test is widely used as a primary screening test for detection of significant proteinuria in pregnancy (SPIP). However, it often shows a false positive test result. This study was performed to determine which pregnant women should be recommended to undergo determination of urinary protein-to-creatinine ratio (mg/mg, P/Cr test) after dipstick test for confirmation of SPIP. Methods: This was a multicenter, prospective, and observational study of 2212 urine specimens from 1033 pregnant women who underwent simultaneous dipstick and P/Cr tests in the same spot urine samples at least once. SPIP was defined as P/Cr > 0.27. Preeclampsia was diagnosed in women with both hypertension and SPIP. Results: Preeclampsia, hypertension alone, and SPIP alone developed in 202 (20 %), 73 (7.1 %), and 120 (12 %) women, respectively. Creatinine concentration [Cr] varied greatly, ranging from 8.1 to 831 mg/dL in the 2212 urine samples. Rate of positive dipstick test results increased with increasing [Cr], while SPIP prevalence rate was lower in urine samples with higher [Cr], yielding higher false positive rates in samples with higher [Cr]. Postpartum urine samples had significantly lower [Cr] compared to those obtained antepartum (60 [8.7-297] vs. 100 [10-401] mg/dL, respectively). At the first P/Cr test among women with similar dipstick test results, the risk of having SPIP was consistently and significantly higher for hypertensive women than for normotensive women at any dipstick test result: 18 % (14/77) vs. 3.2 % (8/251), 47 % (26/55) vs. 8.7 % (37/425), 91 % (82/90) vs. 59 % (44/75) for negative/equivocal, 1+, and >= 2+ test results, respectively. The risk of SPIP was 16 % (9/55) for normotensive women when two successive antenatal urine samples showed a dipstick test result of 1 +. Conclusions: For prediction of SPIP, the dipstick test was more likely to show a false positive result in concentrated urine samples with higher [Cr]. Hypertensive women with >= 1+ as well as normotensive women with >= 2+ on dipstick test should be advised to undergo the P/Cr test.

Elevated vasoinhibin derived from prolactin and cathepsin D activities in sera of patients with preeclampsia

The usage of Computational Fluid Dynamics (CFD) in noise prediction typically has been a two part process: accurately predicting the flow conditions in the near-field and then propagating the noise from the near-field to the observer. Due to the increase in computing power and the cost benefit when weighed against wind tunnel testing, the usage of CFD to estimate the local flow field of complex geometrical structures has become more routine. Recently, the Benchmark problems in Airframe Noise Computation (BANC) workshops have provided a community focus on accurately simulating the local flow field near the body with various CFD approaches. However, to date, little effort has been given into assessing the impact of the propagation phase of noise prediction. This paper includes results from the BANC-III workshop which explores variability in the propagation phase of CFD-based noise prediction. This includes two test cases: an analytical solution of a quadrupole source near a sphere and a computational solution around a nose landing gear. Agreement between three codes was very good for the analytic test case, but CFD-based noise predictions indicate that the propagation phase can introduce 3dB or more of variability in noise predictions.

Previous studies suggest that the endotoxin lipopolysaccharide (LPS) may have dual effects on brain damage induced by hypoxia-ischemia (HI) in 7-d-old rats, depending on the exposure paradigm. Although a 4-h interval between LPS administration and HI results in sensitization to HI brain injury, tolerance is observed when LPS is administered 24 h before HI. Our hypothesis is that endogenous corticosteroids are important in acquiring tolerance to HI. Neonatal rats received a single injection of LPS (1.0 mg/kg) either 4 h or 24 h before HI, or two LPS injections (4 h and 24 h) before HI. Increased brain injury was seen in animals subjected to a single LPS injection made 4 h before HI. In contrast, both the single 24-h exposure and the double injections of LPS resulted in tolerance to HI brain damage. To study the effects of corticosteroids on HI tolerance, RU486, a glucocorticoid receptor blocker, was subcutaneously injected at the same time as LPS (1.0 mg/kg), 24 h before HI stress. RU486-LPS treatment counteracted the LPS-induced tolerance effect, and aggravated the HI-induced brain injury compared with the vehicle-LPS-treated group. RU486 did not aggravate the HI-induced brain injury produced 24 h later in saline-injected animals. LPS (1.0 mg/kg) injected into 6-d-old rats transiently up-regulated serum corticosterone levels (119.6, 57.9, 56.8, and 28.3 ng/mL at 6, 12, 24, and 48 h after the LPS injection, respectively). We conclude that endotoxin-induced up-regulation of endogenous corticosterone appears to be critical for acquiring endotoxin-induced HI tolerance.

The purpose of this study was to elucidate a role for edaravone, a free radical scavenger 3-methyl-1-phenyl-2-pyrazolin-5-one, in neonatal hypoxic-ischemic brain damage. We determined the level of thiobarbituric acid reactive substances as an index of lipid peroxidation and nitric oxide metabolites as nitric oxide production.Seven-day-old Wistar rats were subjected to left common carotid artery ligation followed by 2 hours of 8% oxygen exposure. Then, the rats were administered edaravone (9 mg/kg) or saline solution intraperitoneally. Cerebrospinal fluid was withdrawn just before the rats were killed at 2, 5, 24, and 48 hours after hypoxia, and brains were removed. The thiobarbituric acid reactive substances and nitric oxide metabolites levels were measured in the brain tissue and cerebrospinal fluid, respectively.On the ligated side, edaravone significantly decreased thiobarbituric acid reactive substances levels at 5 and 24 hours after hypoxia, compared with saline group (P.01). Edaravone significantly decreased the nitric oxide metabolites level in the cerebrospinal fluid only at 5 hours, compared with saline group (P.01).Edaravone potently and transiently inhibited lipid peroxidation and the production of nitric oxide in the neonatal rat brain after hypoxic-ischemic insult.