Infection route associated with invasive group A streptococcal toxic shock syndrome in maternal deaths: Nationwide analysis of maternal mortalities in Japan.

OBJECTIVE: To clarify the infection route in maternal death due to invasive group A streptococcal (GAS) infection and toxic shock syndrome (TSS). METHODS: A retrospective study was conducted on maternal deaths due to GAS-TSS in Japan between January 2010 and March 2024. The final causal diagnosis of maternal death and the infection routes of GAS were analysed using medical records, laboratory data, and autopsy findings. RESULTS: Among the 616 maternal deaths during the study period, 48 (8%) involved infectious diseases. The most common infection was invasive GAS (56%, n=27), 21 (78%) and six cases occurred during the antepartum and puerperium periods, respectively. In the GAS-TSS group, 71% (15/21) infections were originated the upper respiratory tract. However, in the puerperium cases, 67% (4/6) were infected from the genital tract. In addition, no maternal deaths due to GAS-TSS were reported during the COVID-19 pandemic period in Japan from 2020-2023. CONCLUSION: Most antepartum GAS infections were from the upper respiratory tract. They may be reduced by preventive measures, including frequent disinfection, wearing masks, and isolation from persons at high risk of carrying GAS, such as symptomatic children. On the other hand, GAS-TSS during puerperium infection via the genital tract.

Relationship between maternal mortality and ritodrine hydrochloride as a tocolytic agent in Japan.

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.

Accurate evaluation of the progress of delivery with transperineal ultrasound may improve vaginal delivery: a single-center retrospective study.

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.

Urinary and serum levels of high mobility group box 1.

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.

High maternal mortality rate associated with advanced maternal age in Japan.

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.

Effects of sturgeon fillet intake on top-ranked Japanese female long-distance runners.

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.

Are There Maternal Deaths Related to Hemorrhagic Stroke Due to Hypertensive Disorder of Pregnancy That Could Be Potentially Preventable by Tight Hypertension Management in Antepartum? A Retrospective Study from the Maternal Death Exploratory Committee in Japan.

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.

Pregnancy-related maternal deaths due to cardiovascular diseases in Japan from 2010 to 2019: an analysis of maternal death exploratory committee data.

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.

Remitting Seronegative Symmetrical Synovitis with Pitting Edema Syndrome as a Manifestation of Recurrent Ovarian Cancer.

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.

Fetal Distress and Neonatal Death After Thoracoamniotic Shunting Therapy Due to Hydrops Associated With Transient Abnormal Myelopoiesis.

We present the case of a pregnant woman who developed fetal bradycardia, which required an emergency cesarean delivery immediately after thoracoamniotic shunting (TAS), resulting in neonatal death four hours after birth due to hemodynamic deterioration. A 35-year-old Japanese female was referred to our hospital at 30+0 weeks of gestation due to fetal hydrops. Blood and ultrasonography examinations suggested that transient abnormal myelopoiesis (TAM) due to trisomy 21 could contribute to the development of hydrops fetalis. We performed thoracocentesis and TAS replacement as well as chromosomal testing of the amniotic fluid. However, the fetus developed persistent bradycardia soon after the treatment, and a sonographic examination revealed a recurrence of fluid retention in the thoracic cavity. A 1,558-g male neonate received life-saving resuscitation after being born via emergency surgery. Blood analysis revealed the occurrence of TAM in utero. At autopsy, there were no injuries to the intrathoracic organs. The G-banded karyotype revealed trisomy 21 (47, XY, +21). Our case offers new perspectives on providing prenatal information about potential complications to family members and selecting fetuses for TAS in the case of trisomy 21 complicated with TAM.

Maternal death due to serious group A streptococcal toxic shock syndrome reduced after the coronavirus disease pandemic in Japan.

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.

Low-dose aspirin therapy improves decidual arteriopathy in pregnant women with a history of preeclampsia.

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.

Maternal blood concentration of tadalafil in pregnancy: Comparison of pregnant and non-pregnant women.

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.

Myeloid cell thrombus and fetal vascular malperfusion in placentas with transient abnormal myelopoiesis.

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.

Perinatal outcome in case of maternal death for cerebrovascular acute disorders: a nationwide study in Japan.

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.

Assessment of the value of measuring soluble fms-like tyrosine kinase-1 and placental growth factor levels following administration of tadalafil to treat fetal growth restriction.

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.

Maternal Death Related to Sudden Unexpected Death in Epilepsy: A Nationwide Survey in Japan.

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.

Detection of Treponema pallidum by immunocytochemistry of cervical smear: A case report.

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.