Safety and dose-finding trial of tadalafil administered for fetus in labor: A phase I clinical study.

AIM: This study aimed to investigate the safety and efficacy of tadalafil in protecting the fetus from hypoxic stress caused by repeated labor pains during delivery and preventing fetal hypoxic-ischemic encephalopathy. METHODS: The study used a three-case cohort approach. Three patients were administered 10 mg tadalafil and monitored for serious adverse events. In the absence of serious tadalafil-associated adverse events as assessed by the Safety Evaluation Committee, three new patients were added to the study and treated with 20 mg/dose. The blood levels of tadalafil were recorded before and after 2, 4, 8, and 12 h of administration and 2 h after delivery. RESULTS: A total of seven patients were enrolled, and after excluding one patient who delivered before 37 weeks, tadalafil was administered to six patients. Maternal adverse events were considered acceptable from the maternal perspective, with grade 1 headache, anorexia, and myalgia and no obstetrical complications after delivery at both doses. No serious neonatal adverse events were associated with tadalafil. Tadalafil blood levels remained stable at both doses. In addition, the level of soluble fms-like tyrosine kinase-1 did not alter, while that of the placental growth factor differed significantly before and after tadalafil administration. CONCLUSIONS: The study confirmed the safety of tadalafil administration during delivery for both mothers and newborns. The stable tadalafil blood levels confirmed the efficacy of the tested administration regime at 12 h interval. These findings would assist in conducting phase II trials to further verify the optimal dose and safety of tadalafil.

The efficacy of vaginal treatment for non-Lactobacillus dominant endometrial microbiota-A case-control study.

AIM: Reduced Lactobacillus occupancy in the uterine microflora has been associated with implantation failure. This study aimed to evaluate a treatment for improving the uterine microflora. METHODS: This study included patients diagnosed with repeated implantation failure-defined as failure to achieve pregnancy after two or more transfers of viable embryos-who were classified as non-Lactobacillus dominant. Treatment A comprised oral administration of antibiotics for 1 week, followed by oral probiotic butyrate tablets (3 g/day) for approximately 30 days. Treatment B comprised a 1-week course of oral (750 mg/day) and vaginal (250 mg/day) metronidazole, followed by a 1-week intravaginal administration of probiotic capsules (1 capsule/day) and continued oral administration of probiotics (1 capsule/day). Both treatments were compared in terms of efficacy in improving vaginal flora. Improvement was defined as Lactobacillus occupancy >90% or an increase in Lactobacillus occupancy >20%. RESULTS: Seven (41.2%) of 17 patients in the Treatment A group improved in response to the treatment. Contrastingly, 9 (90.0%) of 10 patients improved in the Treatment B group (p = 0.0127). Following treatment, Lactobacillus occupancy in the Treatment B group (62.9% ± 12.7%) was significantly higher than that in the Treatment A group (5.7% ± 9.8%) (p = 0.0242). CONCLUSIONS: This study demonstrates the effectiveness of combining antibiotics and probiotics in vaginal formulations for treating abnormal uterine microflora. However, its potential impact on in vitro fertilization outcomes remains unclear and warrants further investigation through larger, more comprehensive studies.

Cadmium body burden and health effects after restoration of cadmium-polluted soils in cadmium-polluted areas in the Jinzu River basin.

BACKGROUND: Itai-itai disease is caused by environmental cadmium (Cd) pollution in the Jinzu River basin in Japan. To reduce the Cd contamination of rice, soil restoration of paddy fields was carried out. We evaluated the effect of soil restoration on the health status of residents of the former Cd-polluted area. METHODS: Participants were 1,030 men and 944 women who lived in the area of restoration of Cd-polluted rice paddies. First morning urine was collected and urinary Cd, ß2-microglobulin (ß2MG), and N-acetyl-ß-D-glucosaminidase (NAG) levels were measured. Associations among age, years of residence before and after soil restoration, and urinary Cd, ß2MG, and NAG levels were evaluated by multiple regression analysis. RESULTS: The geometric mean (interquartile range) of urinary Cd (µg/g Cr) was 1.00 (0.58-1.68) in men and 1.67 (1.02-2.91) in women. The geometric means of urinary ß2MG (µg/g Cr) and NAG (U/g Cr) were 174.6 (92.6-234.2) and 1.47 (0.72-3.14) in men, and 217.6 (115.3-28.7) and 1.48 (0.73-2.96) in women, respectively. Urinary Cd, ß2MG, and NAG were significantly positively correlated (p < 0.01 all). Age and duration of residence in the Cd-polluted area before soil restoration were independently associated with urinary Cd, ß2MG, and NAG. Among the 916 participants who had resided in the area before the soil restoration, urinary Cd concentrations were significantly higher, thus by 1.03-fold (95% CI, 1.01-1.04) in men and 1.03-fold (95% CI, 1.01-1.05) in women, when the years of residence before soil restoration by each 5-years increment. By contrast, urinary Cd concentrations were significantly lower, thus 0.97-fold (95% CI, 0.96-0.99) lower in men and 0.97-fold (95% CI, 0.95-0.99) lower in women, by each 5-year increment of residence after soil restoration. A similar association was observed for urinary ß2MG concentration, and no significant association was observed for urinary NAG levels in men or women. CONCLUSIONS: Cd exposure and associated renal tubular dysfunction in residents of a former Cd-polluted area were influenced by Cd exposure from the environment prior to soil restoration. Soil restoration in Cd-polluted areas reduced the Cd exposure of local residents.

Fetal Biometric Assessment and Infant Developmental Prognosis of the Tadalafil Treatment for Fetal Growth Restriction.

Background and Objectives: Tadalafil is expected to treat fetal growth restriction (FGR), a risk factor for stillbirth and neonatal morbidity. This study aimed to evaluate the fetal biometric growth pattern of fetuses with FGR treated with tadalafil by ultrasonographic assessment. Materials and Methods: This was a retrospective study. Fifty fetuses diagnosed with FGR and treated by maternal administration of tadalafil and ten controls who received conventional treatment at Mie University Hospital from 2015 to 2019 were assessed. Fetal biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), femur length (FL), and estimated fetal weight (EFW) at the start of treatment and at two weeks and four weeks of treatment were mainly assessed by ultrasound examination. The Wilcoxon signed-rank test was used to assess the measures. The Kyoto Scale of Psychological Development (KSPD) was used to assess the developmental prognosis on tadalafil-treated children at 1.5 years of corrected age (CA) and 3 years old. Results: The median gestational age at the start of treatment was 30 and 31 weeks in the tadalafil and control groups, respectively, and the median gestational age at delivery was 37 weeks in both groups. The Z-score of HC was significantly increased at 4 weeks of treatment (p = 0.005), and the umbilical artery resistance index was significantly decreased (p = 0.049), while no significant difference was observed in the control group. The number of cases with an abnormal score of less than 70 on the KSPD test was 19% for P-M, 8% for C-A, 19% for L-S, and 11% for total area at 1.5 years CA. At 3 years old, the respective scores were 16%, 21%, 16%, and 16%. Conclusions: Tadalafil treatment for FGR may maintain fetal HC growth and infants' neuro-developmental prognosis.

Placental growth factor level is correlated with intrapartum fetal heart rate findings.

OBJECTIVE: Here, we tested the correlation between maternal placental growth factor (PlGF) and fetal heart rate (FHR) monitoring findings. METHODS: We included 35 women with single pregnancies from 35 to 42 weeks of gestation who were hospitalized owing to onset of labor. Blood samples were collected at the start of labor. Intrapartum FHR monitoring parameters included total deceleration area, average deceleration area (mean deceleration area per 10 min), and five-tier classification level. RESULTS: Of the 35 women, 26 (74%) had vaginal delivery and 9 (26%) had cesarean section. After excluding 2 women who had cesarean section for arrest of labor, we analyzed 26 women who had vaginal delivery (VD group) and 7 who had cesarean section for fetal indications (CSF group). PlGF level was significantly higher in the VD group (157 ± 106 pg/ml) than in the CSF group (74 ± 62 pg/ml) (P = 0.03). There were no significant correlations between PlGF and total (r = -0.07) or average (r = -0.08) deceleration area.　There was a significant negative correlation (r = -0.42, P = 0.01) between PlGF and the percentage of level 3 or higher in the five-level classification. CONCLUSION: PlGF was correlated with FHR monitoring findings and might be a promising biomarker of intrapartum fetal function.

Tadalafil Treatment of Mice with Fetal Growth Restriction and Preeclampsia Improves Placental mTOR Signaling.

Fetal growth restriction (FGR) is a major cause of poor perinatal outcomes. Although several studies have been conducted to improve the prognosis of FGR in infants, no effective intrauterine treatment method has been established. This study aimed to use tadalafil, a phosphodiesterase 5 inhibitor (PDE5) inhibitor, as a novel intrauterine treatment and conducted several basic and clinical studies. The study investigated the effects of tadalafil on placental mTOR signaling. Tadalafil was administered to mice with L-NG-nitroarginine methyl ester (L-NAME)-induced FGR and associated preeclampsia (PE). Placental phosphorylated mTOR (p-mTOR) signaling was assessed by fluorescent immunohistochemical staining and Western blotting. The expression of p-mTOR was significantly decreased in mice with FGR on 13 days post coitum (d.p.c.) but recovered to the same level as that of the control on 17 d.p.c. following tadalafil treatment. The results were similar for 4E-binding protein 1 (4E-BP1) and S6 ribosomal (S6R) protein, which act downstream in the mTOR signaling pathway. We demonstrate that the tadalafil treatment of FGR in mice improved placental mTOR signaling to facilitate fetal growth. Our study provides the key mechanistic detail about the mode of action of tadalafil and thus would be helpful for future clinical studies on FGR.

Reference range for C1-esterase inhibitor (C1 INH) in the third trimester of 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.

Pulmonary thromboembolism during pregnancy and puerperium: Comparison of survival and death cases.

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.

Comparison of perinatal outcomes between controlled-release dinoprostone vaginal delivery system (PROPESS) and metreurynter for cervical ripening in labor induction: A retrospective single-center study in Japan.

AIM: This study aimed to compare the efficacy and safety of a controlled-release dinoprostone vaginal delivery system (PROPESS) and a metreurynter for labor induction. METHODS: This retrospective case-controlled study included 117 pregnant women (51 and 66 in the PROPESS and metreurynter groups, respectively) who required labor induction after >37 weeks' gestation at Mie University Hospital between January 2018 and September 2020. The primary outcome was the success rate of vaginal delivery. The secondary outcomes were changes in the Bishop score from the first insertion of PROPESS or the metreurynter to removal, uterine hyperstimulation and non-reassuring fetal status during the first insertion, proportion of pregnant women who needed pre-delivery oxytocin after removal, time to vaginal delivery after the first insertion, proportion of pregnant women who delivered vaginally within 12 or 24 h after the first insertion, and neonatal outcomes. RESULTS: The proportion of pregnant women, especially primiparas, who delivered vaginally was significantly higher in the PROPESS group (26/34 [76.5%]) than in the metreurynter group (25/52 [48.1%]; p = 0.01). Moreover, among multiparas in the PROPESS group who delivered vaginally, nine (56.3%) out of 16 women delivered vaginally within 3 h of labor onset. CONCLUSIONS: PROPESS for cervical ripening may reduce the risk of undergoing cesarean section in pregnant women requiring labor induction, especially primiparas. It is important to consider the possibility of precipitate labor when using the PROPESS in multiparas.

Aortic dissection during pregnancy and puerperium: A Japanese nationwide survey.

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.

Tadalafil alleviates preeclampsia and fetal growth restriction in RUPP model of preeclampsia in mice.

BACKGROUND: - Tadalafil, a long-acting phosphodiesterase 5 (PDE5) inhibitor, alleviates preeclampsia (PE), and decreases the fetal and infant deaths associated with fetal growth restriction (FGR) in phase II clinical trial. Recently, we demonstrated that tadalafil alleviates FGR and hypertension in the dams with PE induced by l-NAME. OBJECTIVE: -The aim of present study was to clarify the effect of tadalafil in another mouse model of PE, murine reduced uterine perfusion pressure (RUPP) model we have recently developed. METHODS: -At 14.5 dpc we performed RUPP operation in mice to induce PE, administered the animals with tadalafil or vehicle in the drinking water daily from 15.5 dpc, and sacrificed them at 18.5 dpc for analyses. RESULTS: -Tadalafil improved maternal hypertension and glomerular endotheliosis in RUPP mice. Moreover, tadalafil prolonged pregnancy period, and improved survival and growth of the embryos. RUPP increased content of sFlt-1 protein in the placenta, and tadalafil corrected it back to control levels. CONCLUSION: - Tadalafil alleviates PE-like phenotype and FGR in RUPP murine model. RUPP model could help understand the mechanism of how tadalafil works on PE and FGR.

Evaluation of Maternal and Neonatal Outcomes of Assisted Reproduction Technology: A Retrospective Cohort Study.

BACKGROUND: To evaluate maternal and neonatal outcomes of assisted reproductive technology (ART). MATERIALS AND METHODS: Pregnant women registered from 2015 through 2017 (n = 6994) at five perinatal centers that managed high-risk pregnancies in Mie, Japan, retrospectively. Rates of preterm birth (<37 gestational weeks), early onset preeclampsia (<34 gestational weeks), late onset preeclampsia (≥34 gestational weeks), low-lying placenta, placenta previa, placenta accreta, placental abruption, atonic bleeding, uterine rupture, and amniotic fluid embolism after ART were evaluated. ART was defined as in vitro fertilization and micro-fertilization. Fisher's exact test, Mann-Whitney's U test, and logistic regression analysis were used to analyze the data. RESULTS: Rates of obstetrical complications including low-lying placenta, placenta previa, placenta accreta, and atonic bleeding were increased with ART compared to those with the control. Particularly, ART was associated with a significantly increased rate of placenta accreta (adjusted odds ratio: 7.35, 95% confidence interval (CI): 3.20-16.6) and significantly decreased rate of placental abruption (adjusted odds ratio: 0.24, 95% CI: 0.07-0.61). CONCLUSIONS: This study showed that ART may reduce placental abruption and increase placenta previa. There is a possibility that the placenta attaches deeper in the myometrium because of ART.

Tadalafil Treatment Ameliorates Hypoxia and Alters Placental Expression of Proteins Downstream of mTOR Signaling in Fetal Growth Restriction.

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.

The most common causative bacteria in maternal sepsis-related deaths in Japan were group A Streptococcus: A nationwide survey.

The present retrospective study provides an in-depth analysis of the maternal sepsis-related deaths reported in Japan, and aims to guide future care regarding maternal sepsis. This is a nationwide, retrospective, descriptive cohort study. Data were retrospectively analyzed on all maternal death cases related to sepsis reported in Japan from 2010 through 2016. A total of 7,347,727 births and 317 maternal deaths were reported during the study period. The cause of maternal death was sepsis in 24 women (7.5%). Causative bacteria were Streptococcus pyogenes (54.2%), Chlamydia psittaci (8.3%), Mycobacterium tuberculosis (8.3%), Escherichia coli (4.2%), Neisseria meningitidis (4.2%), Epstein-Barr virus (4.2%), and unknown (16.6%). In maternal death due to S. pyogenes (13 women), onset periods ware antepartum in 10 women (76.9%) and postpartum in 3 (23.1%); death within 24 h after hospital admission occurred in 7 women (53.8%); and the median time from hospital admission to death was 12 h (6-744 h). The most common causative bacteria in to maternal sepsis-related death were GAS. When encountering severe sepsis during the peripartum period, we recommend considering severe GAS infection and early intervention.

Maternal Blood Concentration of Tadalafil and Uterine Blood Flow in Pregnancy.

: Background and Objectives: Tadalafil for treatment of fetal growth restriction (FGR) or preeclampsia is given once a day orally. The drug kinetics of tadalafil were investigated to determine the ideal dosage to promote uterine blood flow. Materials and Methods: We recruited five pregnant women with FGR or preeclampsia before administration of tadalafil, all of which were administered tadalafil (20 mg/day, once-daily dosing). The blood concentration of tadalafil was measured 1, 2, 4, 6, 8, and 24 h after administration, and uterine blood flow was measured before tadalafil administration and 2-4 and 20-24 h after. We then analyzed the correlation between tadalafil blood concentration and uterine artery blood flow. Results: The blood concentration of tadalafil correlated with uterine artery blood flow in pregnant women. The blood concentration of tadalafil and uterine artery blood flow decreased 5 h after administration of tadalafil. Conclusions: The blood concentration of tadalafil and uterine artery blood flow fluctuate in parallel, the latter was decreased by reduced blood concentration. Thus, a study of tadalafil administered twice a day in pregnant women will be needed to stabilize uterine artery blood flow.

Pivotal Role of TNF-α in the Development and Progression of Nonalcoholic Fatty Liver Disease in a Murine Model.

Previously, we have shown that the adipocyte-specific nuclear form of sterol regulatory element-binding protein-1c (nSREBP-1c) transgenic mice spontaneously developed hepatic lesions that are similar to those of human nonalcoholic steatohepatitis (NASH) with a concomitant elevation of plasma TNF-α. In this study, we analyzed the role of TNF-α in the progression of nonalcoholic fatty liver disease (NAFLD). We established a Tnf knockout nSREBP-1c transgenic mouse line. Glucose tolerance and liver histology were examined at the age of 20 weeks. The gene expression and protein levels were assessed by quantitative RT-PCR and Western blot, respectively. The Tnf knockout improved glucose tolerance and significantly reduced the prevalence of hepatic steatosis (20% vs. 100%, p<0.0001) and fibrosis (15% vs. 65%, p=0.0057). The expressions of Acaca, Scd1, Mcp1, Tgfb1, Col1a1, and Timp1 were increased in the liver from the original nSREBP-1c transgenic mice. However, gene upregulation was reduced in the livers from the Tnf(-/-) nSREBP-1c transgenic mice. Furthermore, the hepatic levels of TIMP1 protein were increased in the original nSREBP-1c transgenic mice but not in Tnf(-/-) nSREBP-1c transgenic mice. To assess the direct effect of TNF-α on the expression of the genes, we cultured primary hepatocytes in the presence of TNF-α and found that TNF-α increased the expression of Mcp1, Tgfb1, and Timp1 in hepatocytes. These observations indicate that TNF-α plays a pivotal role in the development of NAFLD and progression to NASH through upregulating key molecules associated with lipid metabolism, inflammatory cytokines, and fibrosis in the liver.

Management of pregnancy complicated with intracranial arteriovenous malformation.

AIM: To clarify the perinatal outcomes in pregnancy complicated with intracranial arteriovenous malformation (i-AVM). METHODS: A retrospective study was performed in 36 pregnancies complicated by i-AVM from 1981 to 2013 at one institution. RESULTS: In total, 6 women miscarried, and 30 had live births. The median (range) gestational age at delivery was 38 (24-40) weeks; 11 cases experienced initial i-AVM rupture during pregnancy (first, second and third trimester: 18%, 64% and 18%, respectively). At onset, 4 cases had a Glasgow Coma Scale ≤10, 10 cases needed emergency maternal transport, 4 underwent neurosurgery with the fetus in utero and 4 had termination of pregnancy in the second trimester for emergent treatment for i-AVM. Two cases delivered vaginally. Another 25 cases had already been diagnosed as i-AVM at conception. Of these, as an indication for epidural birth, 18 cases had either residual lesion of i-AVM or neurological symptoms, although 18 cases had received treatments of i-AVM before conception. Without rupture of i-AVM and worsening of symptoms, 15 cases succeeded in epidural birth. One case was delivered by cesarean section for residual i-AVM with indication of treatment. Another case who had refused treatment of i-AVM experienced rupture of i-AVM 1 year after delivery. CONCLUSION: Most of the cases with residual i-AVM lesion and neurological symptoms could deliver vaginally without worsening of symptoms. However, pregnancy with i-AVM can be complicated by rupture of i-AVM. In cases with a residual lesion with indication of treatment and rupture of i-AVM during pregnancy, meticulous care is required during pregnancy and after delivery.

Beta-Blockers and Fetal Growth Restriction in Pregnant Women With Cardiovascular Disease.

BACKGROUND: The effects of ß-adrenergic blockers on the fetus are not well understood. We analyzed the maternal and neonatal outcomes of ß-adrenergic blocker treatment during pregnancy to identify the risk of fetal growth restriction (FGR). METHODS AND RESULTS: We retrospectively reviewed 158 pregnancies in women with cardiovascular disease at a single center. Maternal and neonatal outcomes were analyzed in 3 categories: the carvedilol (α/ß-adrenergic blocker; α/ß group, n=13); ß-adrenergic blocker (ß group, n=45), and control groups (n=100). Maternal outcome was not significantly different between the groups. FGR occurred in 1 patient (7%) in the α/ß group, in 12 (26%) in the ß group, and in 3 (3%) in the control group; there was a significant difference between the incidence of FGR between the ß group and control group (P<0.05). The ß group included propranolol (n=22), metoprolol (n=12), atenolol (n=6), and bisoprolol (n=5), and the individual incidence of FGR with these medications was 36%, 17%, 33%, and 0%, respectively. CONCLUSIONS: As a group, ß-adrenergic blockers were significantly associated with FGR, although the incidence of FGR varied with individual ß-blocker. Carvedilol, an α/ß-adrenergic blocker, had no association with FGR. More controlled studies are needed to fully establish such associations. (Circ J 2016; 80: 2221-2226).

Recommendations for saving mothers' lives in Japan: Report from the Maternal Death Exploratory Committee (2010-2014).

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.