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Background: The expenses related to fertility preservation or subsequent assisted reproductive treatments are significant for adolescents and young adult patients in Japan's current healthcare system. With fertility preservation becoming more widespread in developed countries, it is expected that these costs will be covered by insurance or subsidies. It is critical for patients, healthcare providers, and the government to know the costs that patients will be responsible for. In Japan, the costs of fertility preservation and subsequent assisted reproductive technology are not covered by insurance, but patients can apply for subsidies from the local and central governments if certain conditions are met. Presently, the above-mentioned costs, as well as the amount paid by the patient, vary by facility. Therefore, it is essential to ensure patients' continued access to necessary medical care despite the associated costs., Methods: In this study, questionnaires were mailed to 186 certified fertility preservation facilities in Japan to assess patients who had undergone fertility preservation or assisted reproduction. The questionnaires were sent between October 27, 2023 and March 31, 2024, with 140 of the 186 facilities responding (response rate: 75.3%)., Results: Our findings show that approximately one-third of the costs was borne by the patients., Conclusion: Given these circumstances, sustainable pricing and insurance coverage are necessary for both patients and facilities., (© 2024. The Author(s).)

Aim: In Japan, unlike Western countries, tocolytic agents are administered in long-term protocols to treat threatened preterm labor. Evaluating the side effects of this practice is crucial. We examined whether ritodrine hydrochloride had been administered in cases of maternal death, aiming to investigate any relationship between ritodrine administration and maternal death., Methods: This retrospective cohort study used reports of maternal deaths from multiple institutions in Japan between 2010 and 2020. Data on the reported cases were retrospectively analyzed, and data on the route of administration, administered dose, and clinical findings, including causes of maternal death, were extracted. The amount of tocolytic agents was compared between maternal deaths with ritodrine administration and those without., Results: A total of 390 maternal deaths were reported to the Maternal Death Exploratory Committee in Japan during the study period. Ritodrine hydrochloride was administered in 32 of these cases. The frequencies (n) and median doses (range) of oral or intravenous ritodrine hydrochloride were 34.4% (11) and 945 (5-2100) mg and 84.4% (27) and 4032 (50-18 680) mg, respectively. Frequencies of perinatal cardiomyopathy, cerebral hemorrhage, diabetic ketoacidosis, and pulmonary edema as causes of maternal death were significantly higher with ritodrine administration than without it., Conclusions: Our results suggest a relationship between long-term administration of ritodrine hydrochloride and an increased risk of maternal death due to perinatal cardiomyopathy, cerebral hemorrhage, diabetic ketoacidosis, and pulmonary edema. In cases where ritodrine should be administered to prevent preterm labor, careful management and monitoring of maternal symptoms are required., (© 2024 Japan Society of Obstetrics and Gynecology.)

Objective: Cardiovascular disease (CVD) is the leading cause of maternal deaths in high-income countries. This study aimed to assess the characteristics of maternal deaths due to CVDs and the quality of care provided to patients, and to identify elements to improve maternal care in Japan., Methods: This descriptive study used the maternal death registration data of the Maternal Deaths Exploratory Committee of Japan between 2010 and 2019., Results: Of 445 eligible pregnancy-related maternal deaths, 44 (9.9%) were attributed to CVD. The most frequent cause was aortic dissection (18 patients, 40.9%), followed by peripartum cardiomyopathy (8 patients, 18.2%), and pulmonary hypertension (5 patients, 11.4%). In 31.8% of cases, cardiopulmonary arrest occurred within 30 min after initial symptoms. Frequent symptoms included pain (27.3%) and respiratory symptoms (27.3%), with 61.4% having initial symptoms during the prenatal period. 63.6% of the patients had known risk factors, with age ≥35 years (38.6％), hypertensive disorder (15.9%), and obesity (15.9%) being the most common. Quality of care was assessed as suboptimal in 16 (36.4%) patients. Cardiac risk assessment was insufficient in three patients with preexisting cardiac disease, while 13 patients had symptoms and risk factors warranting intensive monitoring and evaluation., Conclusion: Aortic dissection was the leading cause of maternal death due to CVDs. Obstetrics care providers need to be familiar with cardiac risk factors and clinical warning signs that may lead to impending fatal cardiac events. Timely risk assessment, patient awareness, and a multidisciplinary team approach are key to improving maternal care in Japan.

Although digital examination of the cervix is the standard method used worldwide for evaluating the progress of delivery, it is subjective. Transperineal ultrasound (TPU) is combined with digital evaluation for accurate assessment of fetal descent and rotation of the advanced part of the fetus. This retrospective study aimed to clarify the impact of introducing TPU on perinatal outcomes at Mie University Hospital. We analyzed singleton pregnant women who underwent delivery management at our hospital between April 2020 and March 2021. Perinatal outcomes were compared between patients who used TPU (TPU+ group) and those who did not (TPU- group). The angle of progression and head direction were measured. The rate of vaginal delivery was significantly increased (90.9% vs. 71.6%; P = 0.0017), and the second stage of labor was significantly prolonged in the TPU+ group (148.1 vs. 75.8 min; P < 0.0001). A significant difference was observed in termination in the latent phase between the TPU+ group [3/8 (37.5%) cases] and TPU- group [20/25 (80.0%) cases] (P = 0.036). The rate of vaginal delivery can be increased through accurate evaluation of the progress of delivery with TPU., (© 2023. The Author(s).)

This study aimed to clarify the relationship between maternal mortality and advanced maternal age in Japan and to provide useful information for future perinatal management. Maternal death rates by age group were investigated for all maternal deaths in Japan for an 11-year period, from 2010 to 2021. Maternal deaths among those aged ≥ 40 years were examined in detail to determine the cause, and the number of deaths by cause was calculated. The causes of onset of the most common causes of death were also investigated. The maternal mortality rates were 0.8 (95% confidence interval [CI] 0.3-4.7) for < 20 years, 2.6 (95% CI 1.7-3.8) for 20-24 years, 2.9 (95% CI 2.3-3.6) for 25-29 years, 3.9 (95% CI 3.3-4.5) for 30-34 years, 6.8 (95% CI 5.9-7.9) for 35-39 years, and 11.2 (95% CI 8.8-14.3) for ≥ 40 years of age. Patients who were ≥ 40 years of age had a significantly higher mortality rate compared to that in other age groups. Hemorrhagic stroke was the most common cause of death in patients aged ≥ 40 years (15/65 [23%]), and preeclampsia (8/15 [54%]) was the most common cause of hemorrhagic stroke. Maternal mortality is significantly higher in older than in younger pregnant women in Japan, with hemorrhagic stroke being the most common cause of maternal death among women > 40 years of age. More than half of hemorrhagic strokes are associated with hypertension disorder of pregnancy. These facts should be considered by women who become pregnant at an advanced age and by healthcare providers involved in their perinatal care., (© 2023. Springer Nature Limited.)

Aims: The aim of this study is to investigate whether consumption of sturgeon fillets reduces the oxidative stress marker urinary 8-hydroxy-2'-deoxyguanosine (8OHdG) in top-ranked Japanese female long-distance runners., Methods: In a before-and-after study, nine professional long-distance female athletes ate 100 g/day of sturgeon fillets for 2 weeks. Urinalysis (8OHdG, an oxidative stress marker, and creatinine), blood tests (fatty acids and 25-hydroxyvitamin D [25OHD]), exercise intensity, subjective fatigue, muscle elasticity, muscle mass, body fat mass, and nutritional intake using image-based dietary assessment (IBDA) were compared before, immediately after, and 1 month after the intervention., Results: Consumption of sturgeon fillets suppressed 8OHdG (p < 0.05) in the increased exercise intensity female athletes. Eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and 25OHD levels in blood increased from before to immediately after and 1 month after the intervention (p < 0.05). IBDA showed that intake of n-3 fatty acid increased after and one month after the intervention, whereas DHA, imidazole dipeptide and vitamin D intake increased after the intervention (p < 0.05) and then decreased after 1 month (p < 0.05). There were no significant changes in subjective fatigue, muscle elasticity, muscle mass, and body fat., Conclusions: The results suggest that eating sturgeon fillets during intense training may increase blood levels of EPA, DHA, and 25OHD, which may suppress urinary oxidative stress (8OHdG) in top-ranked Japanese long-distance runners., (© 2023 Japan Society of Obstetrics and Gynecology.)

Background: High mobility group box 1 (HMGB-1) has been extensively studied in adults and to a certain extent in neonates as well. Clinical examination of neonates, especially unwell neonates soon after birth, should be minimally invasive., Objective: This study aimed to investigate whether the urinary HMGB-1 level is comparable to the serum HMGB-1 level in neonates., Methods: In all, 87 neonates (37.5 ± 2.9 weeks of gestation and a mean birth weight of 2588 ± 649 g) were enrolled. Of these, 53 were males and 34 were females. The umbilical cord blood and the first or second spontaneous voiding urine samples were stored, and the HMGB-1 level in the samples was measured., Results: HMGB-1 was detected in all urinary samples. In these samples, we found acetylated HMGB-1 and may be devoid of nine residues at the N-terminal amino acid sequence. There was a significant correlation between the serum HMGB-1 level and urinary HMGB-1 level (r = 0.73, p < 0.001). Urinary HMGB1 levels in fetal neonatal asphyxia were significantly higher than those in healthy controls (p = 0.09)., Conclusion: Urinary excretion may be one of the metabolic pathways of HMGB-1. The urinary HMGB-1 level may be comparable to the serum HMGB-1 level in the early neonatal period., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. There is no other., (© 2023 The Authors.)

Background: Unlike Europe and the United States, Japan has seen numerous maternal deaths from hemorrhagic strokes related to hypertensive disorders of pregnancy (HDP). This study retrospectively analyzed deaths associated with HDP-related hemorrhagic stroke in Japan to determine the number of deaths that may have been prevented with blood pressure control during pregnancy., Methods: This study included maternal deaths related to hemorrhagic stroke cases. The proportion of patients without proteinuria whose blood pressure exceeded 140/90 mmHg between 14+0 and 33+6 weeks of gestation were determined. Lastly, the application of tight antihypertensive management was evaluated., Results: Among 34 HDP-related maternal deaths, 4 cases involved patients without proteinuria whose blood pressures exceeded 140/90 mmHg between 14+0 and 33+6 weeks of gestation. These included two chronic hypertension and two gestational hypertension cases. None of the patients received antihypertensive agents, and their blood pressures were managed leniently., Conclusion: Among HDP-related hemorrhagic stroke deaths in Japan, only a few cases of maternal death could have been prevented with tight blood pressure management, as described in the CHIPS randomized controlled trial. Therefore, to prevent HDP-related hemorrhagic stroke in Japan, new preventive strategies during pregnancy should be established.

We herein report a case of ovarian cancer recurrence detected every time with symptoms of remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome. A 46-year-old woman who had a history of ovarian cancer 9 months earlier developed joint pain along with pitting edema in both hands and was diagnosed with RS3PE syndrome. Two and four years after initial surgery for ovarian cancer, symptoms of RS3PE syndrome appeared, and a recurrent site was detected. With resection of the relapsed sites and increased maintenance dose of methylprednisolone, these symptoms improved within a month.

Purpose: Serious group A streptococcal (GAS) infections and toxic shock syndrome (TSS) are rare conditions, but their rapid progression often results in death. The purpose of the present study was to clarify recent trend after the coronavirus disease (COVID-19) pandemic of GAS infection in Japan. Materials and Methods: Maternal death statistics were analyzed by the Japan Maternal Death Exploratory Committee. Results: Maternal deaths due to GAS-TSS accounted for 4.2% ( n  = 22) of all maternal deaths in Japan ( n  = 525) in the last 12 years. GAS-TSS remains one of the leading causes of maternal death after obstetric hemorrhage and hypertensive disorder. However, no maternal deaths due to GAS-TSS have been reported since the COVID-19 pandemic in Japan after the last death occurred in February 2020. Conclusions: The major change during this period was that most Japanese people wore facemasks at all times and did frequent disinfection. It is considered that the reduction in the incidence of GAS infections itself reduced the number of serious GAS-related maternal deaths. Wearing facemasks and frequent disinfection during pregnancy might to be recommended to prevent various infectious diseases including serious GAS infection, even after the COVID-19 pandemic era.

Purpose: The aim of this study was to measure the blood levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) before and after tadalafil treatment in patients with fetal growth restriction., Materials and Methods: Maternal blood was collected from 13 women before and 2 weeks after tadalafil administration in the TADAFER II trial. The tadalafil treatment was conducted in addition to the conventional FGR treatment. As a control, maternal blood was also collected from 11 women before and 2 weeks after conventional treatment for fetal growth restriction. Blood sFlt-1 and PlGF were measured and the sFlt-1/PlGF ratio was calculated. Student's t -test was used to statistically analyze differences in the sFlt-1 and PlGF levels, and in the sFlt-1/PlGF ratios., Results: In both treatment groups, the levels of sFlt-1 and PlGF before and after treatment were not significantly different from each other. The sFlt-1/PlGF ratio was 2.0 ± 1.0 before and 17.6 ± 11.3 after treatment in the control group ( p =.04). The sFlt-1/PlGF ratio was 2.2 ± 1.1 before and 22.2 ± 10.6 after tadalafil treatment in the tadalafil group ( p =.06). The sFlt-1/PlGF ratios before and after tadalafil treatment were significantly increased in the control group. In both treatment groups, the sFlt-1/PlGF ratios before and after treatment were less than 38., Conclusions: We conclude that the levels of sFlt-1 and PlGF were not significantly different as a result of tadalafil treatment. Further studies are needed to understand the mechanism of action of tadalafil in the treatment of fetal growth restriction.

Preeclampsia, a multisystem pregnancy-specific hypertensive disorder, results in significant maternal and perinatal morbidity and mortality. This condition is associated with placental histopathological abnormalities and particularly affects the decidual spiral arteries. Reportedly, aspirin prevents preeclampsia, specifically early-onset preeclampsia, although findings in decidual arteries in women treated with aspirin therapy remain unclear. We compared the clinical and histopathological placental findings between women with a history of preeclampsia, who did and did not receive low-dose aspirin therapy (LDA and non-LDA groups, respectively). We identified 26 women with a history of preeclampsia; 9 women received LDA (aspirin ≤ 100 mg/day, initiated at < 16 weeks, LDA group), and 17 women did not receive LDA (non-LDA group). The mean gestational age was higher (36.7 weeks vs. 32.3 weeks, P = 0.0221) and the incidence of preeclampsia was lower (11% vs. 59%, P = 0.0362) in the LDA than in the non-LDA group. Histopathologically, the incidence of decidual arteriopathy, particularly that of fibrinoid necrosis and thrombosis, was lower in the LDA than in the non-LDA group (44% vs. 88%, P = 0.0283). Immunohistologically, endothelial marker (CD31 and CD39) expression was stronger in the LDA than in the non-LDA group. Notably, we observed no significant intergroup differences in inflammatory changes (chronic perivasculitis, protease-activated receptor 1 expression, and CD3-positive cells). This study highlights that LDA inhibits hypertension-induced endothelial injury and thrombosis, and thereby protects maternal placental perfusion and prevents preeclampsia., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: The goal of this study is to find clues to improve perinatal outcomes in the case of cerebrovascular acute disorders during pregnancy., Study Design: We analyzed 35 cases of cerebrovascular diseases related to maternal deaths in Japan those that occurred during pregnancy and reported to the Committee of the Ministry of Health, Labor, and Welfare from 2010 to 2018., Results: Cerebrovascular acute disorders occurred at 34.6 ± 6.6 gestational weeks. There were seven intrauterine fetal deaths (IUFD), and eight cases showed neonatal asphyxia with umbilical arterial pH between 6.7 and 7.0 (asphyxia cases, n  = 15). In two of eight newborns, brain hypothermia therapy was given, and all survived without neurological sequelae. Maternal dyspnea was significantly related to severe prolonged decelerations of the fetus ( p  < .05), and asphyxia cases ( p  < .005). Median time from maternal onset to delivery (OD time) was significantly longer in asphyxia cases than in the non-asphyxia cases (84 vs 29 min, p  < .05). OD time over 30 min was significantly related to the antepartum occurrence, cervical dilatation <5 cm ( p  < .05), onset outside of the hospital ( p  < .001), and maternal transfer before delivery ( p  < .001)., Conclusion: More than 40% of cases experienced fetal asphyxia, and 20% ended in IUFD in maternal deaths related to cerebrovascular acute disorders. Maternal respiratory support and rapid delivery would be the keys to improve perinatal outcomes in case of cerebrovascular acute disorders during pregnancy.

Transient abnormal myelopoiesis (TAM), also known as transient myeloproliferative disorder or transient leukemia, is a self-regressing neoplasia that afflicts infants with trisomy 21. A recent review article documented "myeloid cell thrombus (MCT)" and "fetal vascular malperfusion (FVM)" in placentas with TAM, although the characteristic TAM placental findings have not been clarified. Here, we compared the clinical and pathological placental findings between trisomy 21 patients with or without TAM. In 13 cases of trisomy 21, we identified six placentas with TAM and seven placentas without TAM. The six placentas with TAM included two stillborn cases. Microscopically, MCT was noted in all the cases, and a high incidence of FVM (50%) was observed in TAM cases. Immunohistochemically, MCT was found to be a platelet-rich thrombus. The placentas were grouped according to the presence or absence of TAM and subsequently compared. Clinically, the incidences of abnormal fetal heart rate pattern and fetal or neonatal death were significantly higher in TAM cases. Pathologically, placenta in TAM cases weighted more than those in cases without TAM, and the incidence of MCT was significantly higher in placentas with TAM. Moreover, the incidence of FVM was higher in placentas with TAM, but this difference was not statistically significant. We propose that MCT is a diagnostic feature of placentas with TAM and may be associated with poor fetal outcomes., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: In this study, the drug kinetics of tadalafil were compared between pregnant and non-pregnant women to determine the ideal dosage to promote uterine blood flow., Materials and Methods: We recruited five pregnant and five non-pregnant women, all of which were administered tadalafil (20 mg/day). The blood concentration of tadalafil was measured 1, 2, 4, 6, 8, and 24 h after administration. We investigated the side effects within 4 days of tadalafil administration and compared the cumulative frequency between the two groups., Results: The mean area under the concentration-time curve and maximum blood concentration of tadalafil were not different between the pregnant and non-pregnant groups. Time to maximum blood concentration was delayed by 1 min on average in the pregnant group compared with the non-pregnant group. The cumulative frequency of side effects was significantly lower in the pregnant group than in the non-pregnant group (P = 0.026). No side effects were observed in either group after the fifth day of the tadalafil administration., Conclusion: Although there was no difference in maximum blood concentration between non-pregnant and pregnant women, the rate of side effects was lower in pregnant women than in non-pregnant women. Therefore, pregnant women may tolerate tadalafil better., Competing Interests: Declaration of competing interest None of the authors have any conflicts of interest to declare., (Copyright © 2022. Published by Elsevier B.V.)

Syphilis is an infectious disease caused by Treponema pallidum (T. pallidum). A cervical smear is useful when screening for sexually transmitted diseases; however, T. pallidum is not detected in the usual Papanicolaou smear. We report the detection of T. pallidum by immunocytological examination of a cervical smear. A 22-year-old woman presented with nephrotic syndrome. On admission, we performed screening tests for infections, and her serology was positive for syphilis. A Papanicolaou cervical smear (Thin-Prep) showed slight nuclear enlargement, nuclear irregularity, and mild hyperchromasia in the superficial cells, but no organism was detected. T. pallidum was detected in the remaining specimen using immunocytochemistry. We also detected the T. pallidum DNA in a cervical biopsy specimen by polymerase chain reaction (PCR). Our findings suggest that immunocytological examination and PCR assay examination are useful tests for syphilis diagnosis., (© 2021 Wiley Periodicals LLC.)

There are many reports that pharmacotherapy has been optimized to ensure collaboration between physicians and pharmacists. Various scales assess the relationship between physicians and pharmacists as well as medical students and pharmacy students. The Scale of Attitudes Toward Physician-Pharmacist Collaboration (SATP 2 C) can be applied not only to the physician-pharmacist relationship but also to the medical-pharmacy student relationship. As there is no Japanese version of the SATP 2 C, we developed one and examined its psychometric properties. SATP 2 C scores were measured before and after interprofessional education (IPE) to verify responsiveness. The scale showed confirmed reliability: Cronbach's alphas were 0.79 for Responsibility and Accountability, 0.68 for Shared Authority, and 0.67 for Interdisciplinary Education. Pre and post-IPE, each mean subscale score increased: Responsibility and Accountability, 0.7 ± 0.4; Shared Authority, 0.2 ± 0.3; and Interdisciplinary Education, 0.3 ± 0.2. Although the total score increased (1.2 ± 0.7), this was non-significant. The Japanese version of the SATP 2 C can be considered, at least initially, to have reached an acceptable level of reliability and validity. The new measure is currently the only scale in Japan that can evaluate attitudes toward physician-pharmacist collaboration regarding IPE. Further studies are needed to confirm responsiveness pre- and post-IPE.

Background: Bronchopulmonary dysplasia (BPD) is a chronic lung disease in premature neonates. Classical BPD is caused by hyperoxia and high-pressure mechanical ventilation, whereas BPD in recent era is caused by impaired pulmonary angiogenesis and alveolarization in extreme prematurity. Although sildenafil was reported to be effective in a hyperoxia-induced rat BPD model, several clinical trials could not demonstrate any significant improvement in the respiratory statuses of BPD infants. Riociguat is a soluble guanylate cyclase stimulator that increases cyclic guanosine monophosphate activity in a nitric oxide independent manner. However, a beneficial effect in BPD has not been established yet., Methods and Results: We established BPD model in rats by injection of SU5416 on day 1 followed by maintenance under normoxia, which resulted in oversimplified alveoli, sparse pulmonary capillary vessels, severe pulmonary hypertension, and growth retardation, which mimicked the features observed in recent clinical management of BPD. We administered riociguat from day 10, when BPD rats exhibited growth retardation. Histological analyses demonstrated that riociguat treatment significantly but partially ameliorated lung alveolarization, vascularization, and pulmonary hypertension. However, the survival rate was not significantly improved by riociguat treatment., Conclusions: Riociguat could ameliorate pulmonary alveolarization, vascularization, and hypertension in the SU5416 induced BPD rat model, but could not improve the overall survival.

Background: Stroke is one of the major causes of maternal death. This study aimed to analyze the maternal and fetal outcomes of stroke occurred during pregnancy and puerperium., Methods: We conducted a retrospective analysis of patients admitted to our perinatology center between 1982 and 2012 with a diagnosis of acute cerebral stroke during pregnancy or within 6 weeks postpartum., Results: Thirty-four patients were registered and all the patients had never been diagnosed as stroke nor detected cerebrovascular abnormalities before the current pregnancies. They were divided into 8 ischemic strokes (ISs) and 26 intracranial hemorrhage group. In the hemorrhage group, there was a spontaneous abortion and two patients chose artificial abortions to avoid rehemorrhage, and there were another three intrauterine fetal deaths (IUFDs) in the acute stage of maternal stroke. More patients in hemorrhage group delivered in preterm than in IS group for the treatment of stroke, 10/23 (43%) versus 0/8 (0%), p  < .05. More patients in hemorrhage group had low Glasgow Coma Scale (GCS) (3-8) than in IS group at the onset of the stroke, 12/26 (46%) versus 0/8 (0%), p  < .05. There were three maternal deaths and 6/23 (26%) were neurologically dependent in hemorrhage group in the chronic stage, whereas 87% were independent in IS group, p  < .05., Conclusions: Hemorrhagic stroke was more common etiology of stroke related to pregnancy than IS in this study. Intensive and multidisciplinary care was needed especially in hemorrhagic stroke related to pregnancy as in the hemorrhagic stroke the fetal survival rate was lower, and maternal conscious levels at the onset of the stroke and neurological outcomes in the chronic stage were worse than IS.

Background: Idiopathic pulmonary arterial hypertension (IPAH) is a progressive disease caused by vascular remodeling of the pulmonary arteries with elevated pulmonary vascular resistance. Recently, various pulmonary vasodilator drugs have become available in the clinical field, and have dramatically ameliorated the prognosis of IPAH. However, little is known about how the mechanical properties of pulmonary arterial smooth muscle cells (PASMCs) are altered under drug supplementation., Methods: Atomic force microscopy (AFM) was used to investigate the mechanical properties of PASMCs derived from a patient with IPAH (PAH-PASMCs) and a healthy control (N-PASMCs) which received the supplementation of clinically used drugs for IPAH: sildenafil, macitentan, and riociguat., Results: PASMCs derived from PAH-PASMCs were stiffer than those derived from N-PASMCs. With sildenafil treatment, the apparent Young's modulus ( E 0 ) of cells significantly decreased in PAH-PASMCs but remained unchanged in N-PASMCs. The decrease in E 0 of PAH-PASMCs was also observed in macitentan and riociguat treatment. The stress relaxation AFM revealed that the decrease in E 0 of PAH-PASMCs resulted from a decrease in the cell elastic modulus and/or increase in cell fluidity. The combination treatment of macitentan and riociguat showed an additive effect on cell mechanical properties, implying that this clinically accepted combination therapy for IPAH influences the intracellular mechanical components., Conclusions: Pulmonary vasodilator drugs affect the mechanical properties of PAH-PASMCs, and there exists a mechanical effect of combination treatment on PAH-PASMCs., Competing Interests: None to declare., (Copyright 2021, Katsuragi et al.)

Sudden unexpected death in epilepsy (SUDEP) is defined as the sudden death of a patient with epilepsy in the absence of an anatomic or toxicologic cause. Whether pregnancy is a risk factor for SUDEP is unclear. Using data submitted to the Japan Association of Obstetricians and Gynecologists (JAOG), which has been collating information regarding all maternal deaths in Japan since 2000, this study evaluated maternal mortality data from 2010 to 2019 to evaluate the current circumstances of maternal death related to SUDEP in Japan. Six women died due to SUDEP during this period; the maternal mortality rate related to SUDEP was 0.066/100,000 individuals. Two women each died during the second trimester, third trimester, and postpartum period. Four and two women were receiving monotherapy and no therapy with anti-epileptic drugs, respectively. The duration of epilepsy was ≤15 years in three women, >15 years in one woman, and unknown in two women. This study furthers our understanding of the prevalence of maternal deaths due to SUDEP in Japan. Further studies are needed to confirm whether pregnancy is a risk factor for SUDEP.

Aim: The number of maternal deaths due to pregnancy-associated hemorrhagic stroke has not decreased despite a gradual decrease of maternal death in Japan. This study aimed to clarify the risk factors of hypertensive disorders of pregnancy-associated hemorrhagic stroke., Methods: This retrospective study analyzed pregnancy-associated hemorrhagic stroke patients with hypertensive disorders of pregnancy between 2013 and 2017 among 407 Japanese maternal and perinatal centers. Patients were divided into good or poor outcome groups and their maternal backgrounds and neonatal prognoses were compared., Results: We analyzed 61 cases, including 41 survival and 20 death cases, obtained from a secondary survey. Among the 61 hemorrhagic stroke cases, 62% were related to hypertensive disorders. Hypertensive disorders of pregnancy were observed in 75% of death cases. Use of MgSO 4 or antihypertensive medication did not differ between the poor and good outcomes groups. In cases with antepartum onset of hypertensive disorders of pregnancy, outcomes were poor in 12 and good in 6 cases. Nine patients with poor outcomes and one with a good outcome had hypertension at the outpatient department without systemic evaluation (p = 0.043). Six poor outcomes patients and one good outcome spent more than 1 day from diagnosis at an outpatient clinic. Neurosurgery was performed in 11 poor outcome patients., Conclusion: Pregnant women who present with a hypertensive disorder at an outpatient clinic probably need to undergo blood tests and careful observation. Delayed systemic evaluation and intensive care for only a few days may result in the development of hemorrhage., (© 2021 Japan Society of Obstetrics and Gynecology.)

Aim: In Japan, the frequency of maternal deaths due to obstetric hemorrhage has been decreasing in the last decade, while that resulting from other causes such as pulmonary thromboembolism (PTE) was consistent. To help reduce maternal deaths due to PTE, we investigated PTE during pregnancy and puerperium and compared the survival and death cases, and aimed to find out life and death factors., Methods: This study was a retrospective analysis based on a clinical chart review in 407 maternal and perinatal centers. We compared the survival and death cases of PTE during pregnancy and puerperium from 2013 to 2017., Results: In PTE during pregnancy, the survival cases underwent significantly earlier diagnoses than the death cases, and thromboprophylaxis was performed in most of both the survival and death cases of PTE during puerperium according to the existing Japanese guidelines; however, only one fourth of the total cases underwent anticoagulation to prevent venous thromboembolism (VTE)., Conclusions: Early diagnosis of PTE in suspected cases was associated with better survival during pregnancy., (© 2021 Japan Society of Obstetrics and Gynecology.)

Aim: This study aimed to characterize the incidence and clinical significance of pregnancy-related aortic dissection using a large-scale survey in Japan., Methods: A questionnaire requesting the detailed information included in the clinical charts of pregnancy-related aortic dissection cases (without any personally identifying information) was designed between 2013 and 2017 and administered to 407 perinatal centers in Japan. The response rate was 70.5%. Seventeen cases of pregnancy-related aortic dissection were identified., Results: Maternal death due to aortic dissection was observed in nine patients (56.2%) while seven survived (43.8%). Dissection occurred during the postpartum period in 10 cases (62.5%), the third trimester in 4 (25.0%), labor in 1 (6.2%), and the second trimester in 1 (6.2%). The most common underlying diseases were: Marfan syndrome (25.0%), Loeys-Dietz syndrome (6.2%), hypertension (6.2%), and Takayasu aortitis (6.2%). Stanford type A aortic dissection was associated with maternal death during both pregnancy and the postpartum period. However, deceased patients showed lower rates of pre-diagnosed connective tissue disease than did survivors., Conclusions: The mortality rate of aortic dissection that occurred during pregnancy or postnatal periods was more than 50%. Aortic dissection occurred more frequently in the postnatal period than during pregnancy, and less frequently in women previously diagnosed with connective tissue disease than in women without any medical history of aortic disorders. If symptoms suggestive of aortic dissection, such as severe back pain, are observed, even after the end of pregnancy, exhaustive diagnostic examinations should be carried out., (© 2021 Japan Society of Obstetrics and Gynecology.)

Objective: We reviewed malignancy related maternal deaths in Japan to ascertain if there were avoidable factors. Methods: Malignancy-related maternal death in Japan reported to the Maternal Death Exploratory Committee, from 2010 to 2016 inclusive. Results: There were 12 cases of maternal death caused by malignancy. There were four gastric cancers (two poorly differentiated adenocarcinoma, one signet ring cell carcinoma with adenocarcinoma, one histology not available), 3 leukemia (two acute myeloid leukemia, one aggressive NK cell leukemia), two ureteral cancers (histology not available), one malignant lymphoma (diffuse large B-cell lymphoma with translocation), one brain tumor (gliomatosis cerebri), and one cervical cancer (glassy cell carcinoma). Two gastric cancer patients had chronic gastric pain before conception. In two cases the physicians commented that they had avoided computed tomography and the brain biopsy needed for diagnosis because the patient was pregnant. At diagnosis, the clinical stages were II-IV in 9, and the performance status was 3-5 in 8. Indication for delivery was exacerbated maternal condition in 5, for treatment in 3, spontaneous labor in 3, and one patient declined elective delivery. Median [interquartile rage] (range) gestational weeks of delivery was 29 [24-30] (19-40). One cervical cancer patient had a radical hysterectomy and chemotherapy for 10 months. However, three leukemia and one gastric cancer patients had chemotherapy within 10 d because they deteriorated rapidly. Another seven cases did not have any treatment because of poor general condition or because they remained undiagnosed. In all cases, the Committee considered that there was no evidence of substandard care. Conclusion: In these cases, both the clinical stages and biological degree of malignancy were high. In two-thirds of cases, early termination of the pregnancy was indicated because of deteriorating maternal condition. Chemotherapy was not effective because of short available time for therapy and the advanced stage of the cancers when diagnosed. Encouraging women to have a thorough medical assessment before conception, and early diagnosis and treatment before pregnancy, appears to be the only practical way to reduce deaths from malignancy while a woman is pregnant.

We aimed to investigate the effects of maternal tadalafil therapy on fetal programming of metabolic function in a mouse model of fetal growth restriction (FGR). Pregnant C57BL6 mice were divided into the control, L-NG-nitroarginine methyl ester (L-NAME), and tadalafil + L-NAME groups. Six weeks after birth, the male pups in each group were given a high-fat diet. A glucose tolerance test (GTT) was performed at 15 weeks and the pups were euthanized at 20 weeks. We then assessed the histological changes in the liver and adipose tissue, and the adipocytokine production. We found that the non-alcoholic fatty liver disease activity score was higher in the L-NAME group than in the control group (p < 0.05). Although the M1 macrophage numbers were significantly higher in the L-NAME/high-fat diet group (p < 0.001), maternal tadalafil administration prevented this change. Moreover, the epididymal adipocyte size was significantly larger in the L-NAME group than in the control group. This was also improved by maternal tadalafil administration (p < 0.05). Further, we found that resistin levels were significantly lower in the L-NAME group compared to the control group (p < 0.05). The combination of exposure to maternal L-NAME and a high-fat diet induced glucose impairment and non-alcoholic fatty liver disease. However, maternal tadalafil administration prevented these complications. Thus, deleterious fetal programming caused by FGR might be modified by in utero intervention with tadalafil.

Background and Objectives: Fetal growth restriction (FGR) is associated with fetal mortality and is a risk factor for cerebral palsy and future lifestyle-related diseases. Despite extensive research, no effective treatment strategy is available for FGR. Mammalian target of rapamycin (mTOR) signaling is important for the growth of fetal organs and its dysregulation is associated with miscarriage. Here, we focused on mTOR signaling and investigated how the activities of phospho-ribosomal protein S6 (rps6) and phospho-eukaryotic translation initiation factor 4E (eIF-4E), which act downstream of mTOR signaling in the human placenta, change following treatment of FGR with tadalafil and aimed to elucidate the underlying mechanism of action. Placental hypoxia was investigated by immunostaining for hypoxia-inducible factor (HIF)-2α. Materials and Methods: Phosphor-rps6 and phosphor-eIF4E expression were examined by Western blotting and enzyme-linked immunosorbent assay, respectively. Results: HIF-2α expression significantly increased in FGR placenta compared with that in the control placenta but decreased to control levels after tadalafil treatment. Levels of phospho-rps6 and phospho-eIF-4E were significantly higher in FGR placenta than in control placenta but decreased to control levels after tadalafil treatment. Conclusions: Tadalafil restored the levels of HIF-2α, phospho-rps6, and eIF-4E in FGR placenta to those observed in control placenta, suggesting that it could be a promising treatment strategy for FGR.

Background: We aimed to retrospectively review data of pregnant women with the α-fibrinogen Thr331Ala polymorphism; evaluate the relationship between this polymorphism and spontaneous abortion (SA), fetal growth restriction (FGR), and intrauterine fetal death (IUFD); and assess the effects of aspirin and/or heparin. Materials and methods: We examined the outcomes of 29 pregnancies (nine women) in women with the α-fibrinogen Thr331Ala polymorphism. Of these, 16 were untreated, whereas 13 were treated with heparin and/or aspirin. Results: The live birth rate was significantly higher in the treated group than in the nontreated group (69.2 versus 6.2%; p = .0004). In addition, the prophylactic use of a low dose of aspirin and/or heparin during early pregnancy in women with Thr331Ala may be an effective method for reducing fetal loss in these patients. Conclusions: This polymorphism interacts with pregnancy to result in poor obstetrical outcomes, but these effects can be mitigated with medical intervention. This study is the first to report outcomes of pregnancies complicated by the Thr331Ala polymorphism, which we believe may cause thrombophilia, SA, and IUFD. This study highlights the need for further research on this polymorphism in pregnancy.

Objectives: The objectives of this study were to (i) establish the reference range and mean value for normal levels of C1-esterase inhibitor (C1 INH) during pregnancy, and (ii) investigate the association between C1 INH and uterine atony, as measured by blood loss at delivery., Methods: We prospectively studied 200 healthy pregnant women who were registered. We studied C1 INH levels in 188 women at 34 and 35 gestational weeks of pregnancy. The reference range for C1 INH during the third trimester of pregnancy was calculated using the value of C1 INH that was determined at registration., Results: The mean value of C1 INH was determined to be 70.3% (95% confidence interval, 68.7-71.9). While the C1 INH levels in four women were determined to be 40% lower than the calculated mean value, amniotic fluid embolism (AFE) did not occur in any of the women studied., Conclusions: This study successfully demonstrated that a reference value for C1 INH activity can be established using the methods described herein. Further research is needed to determine whether C1 INH is involved in obstetric coagulopathy syndrome such as amniotic fluid embolism., (© 2020 Walter de Gruyter GmbH, Berlin/Boston.)