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Aims Information on breastfeeding and the safety of biologics in infants is lacking due to difficulties in case collection. We evaluated a method for determining the concentration of biologics in breast milk using a dry filter method that can simplify the collection, storage, and transport of breast milk. Methods To generate dried filter paper (DFP) samples, approximately 30 L of breast milk was placed onto a Whatman 903 card and punched out. After extraction, the supernatant was measured using an enzyme-linked immunosorbent assay. Three concentrations of each drug were prepared in liquid breast milk (LBM) and DFP samples for stability testing, which confirmed that samples were stable up to 28 days after storage at 2–8 ºC or -20 ºC for LBM and at 25±5 ºC for DFP. LBM and DFP samples were provided by lactating mothers using biologics during lactation. Drug concentrations were compared. Results Breast milk was provided by 12 lactating mothers (tocilizumab, n=4; abatacept, n=2; etanercept, n=1; golimumab, n=1; sarilumab, n=1; and belimumab, n=3). The accuracy and precision of measurements for the six drugs were within acceptable limits. After 28 days, concentrations remained at more than 90% under all storage conditions. The quantitative values of the provided LBM and DFP samples were similar. The maximum relative infant dose ranged from 0.09% to 1.12%, which was an acceptable range. Conclusion A method for determining the concentration of biologics using DFP is expected to help improve pharmacotherapy for lactating women.

This study aimed to evaluate the perioperative outcomes of laparoscopic fundoplication (LF) for gastroesophageal reflux disease (GERD) in children with scoliosis. Data of consecutive patients with GERD who underwent LF from January 2015 to December 2020 at a single pediatric institution were retrospectively analyzed. Eighty-two patients underwent laparoscopic Nissen fundoplication. The median [interquartile range (IQR)] body weight was 9.3 [7; 14] kg. Seventy-five patients were neurologically impaired (91%), and other comorbidities included scoliosis (n = 33), lung disease (n = 39), and cardiac disease (n = 14). The median (IQR) operative time including the creation of the gastrostomy and volume of bleeding were 160 [143; 190] min and 2 [1; 5] mL, respectively. There were no significant differences between patients with and those without scoliosis (p = 0.17 and p = 0.90, respectively). Patients with cardiac disease had a longer operative time (167 [161; 193] vs. 157 [141; 190] min, p = 0.01). There were three post-operative complications in children with neurological impairment; however, there was no clear relationship between the severity of scoliosis and complications. Severity of scoliosis did not correlate with perioperative results and post-operative complications. This suggests that the same LF technique can be used regardless of the presence or absence of scoliosis in children.

Cytokine storm is recognized as one of the factors contributing to organ failures and mortality in patients with COVID-19. Due to chronic inflammation, COVID-19 patients with diabetes mellitus (DM) or renal disease (RD) have more severe symptoms and higher mortality. However, the factors that contribute to severe outcomes of COVID-19 patients with DM and RD have received little attention. In an effort to investigate potential treatments for COVID-19, recent research has focused on the immunomodulation functions of mesenchymal stem cells (MSCs). In this study, the correlation between DM and RD and the severity of COVID-19 was examined by a combined approach with a meta-analysis and experimental research. The results of a systematic review and meta-analysis suggested that the odd of mortality in patients with both DM and RD was increased in comparison to those with a single comorbidity. In addition, in the experimental research, the data showed that high glucose and uremic toxins contributed to the induction of cytokine storm in human lung adenocarcinoma epithelial cells (Calu-3 cells) in response to SARS-CoV Peptide Pools. Of note, the incorporation of Wharton's jelly MSC-derived extracellular vesicles (WJ-EVs) into SARS-CoV peptide-induced Calu-3 resulted in a significant decrease in nuclear NF-κB p65 and the downregulation of the cytokine storm under high concentrations of glucose and uremic toxins. This clearly suggests the potential for WJ-EVs to reduce cytokine storm reactions in patients with both chronic inflammation diseases and viral infection.

Combustible cigarette smoking impacts fetal growth during pregnancy. However, the risk associated with heated tobacco products (HTPs) remains unclear. This nationwide cross-sectional study investigated whether HTP use during pregnancy is associated with small for gestational age (SGA) outcomes among 5647 post-delivery women with singleton pregnancies, which were divided into four groups: lifetime never-smokers, former smokers before pregnancy, and current smokers for each of the tobacco products during pregnancy (sole HTP and sole combustion smokers). Information on the prevalence of SGA, defined as birth weight and height below the 10th percentile, was retrieved from the Maternal and Child Health Handbooks of post-delivery women. Using logistic regression, the association between sole HTP smokers during pregnancy and SGA, adjusted for covariates, with lifetime never-smokers as reference, was investigated. The prevalence was: current sole HTP smokers during pregnancy, 1.8% (102/5647); and SGA, 2.9% (164/5647). Sole HTP smokers during pregnancy had a higher prevalence of SGA (5.9% [6/102] vs. 2.7% [111/4144]) with an adjusted odds ratio (OR) of 2.50 (95% confidence interval [CI], 1.03–6.05) than lifetime never-smokers. Among sole combustion smokers, the adjusted OR for SGA was 1.95 (95% CI, 0.81–4.67). In Japan, HTP smoking during pregnancy may be associated with an increased risk for SGA.

ImportanceThe risk of premature infants in neonatal incubators exposed to evaporated alcohol from alcohol-based disinfectants (ABDs) is unknown.ObjectiveTo assess alcohol concentrations in the peripheral blood of premature infants and neonatal incubators.Design, Setting, and ParticipantsA quality improvement study comparing 2 different populations before and after introduction of ABD practice (ABD-PRAC) was conducted in a neonatal intensive care unit of a single tertiary hospital in Japan. Participants included premature infants who were born before 34 weeks of gestational age and received medical care in neonatal incubators. The study consisted of 3 periods: (1) September 1, 2020, to August 1, 2021 (prospective observation of pre–ABD-PRAC, (2) August 2 to August 22, 2021 (introduction of ABD-PRAC to medical staff and parents in the neonatal intensive care unit), and (3) August 23, 2021, to March 31, 2022 (prospective observation of post–ABD-PRAC). No follow-up studies were initiated.InterventionsAn ABD-PRAC that aimed to reduce alcohol evaporation from ABDs inside neonatal incubators was instituted: (1) place alcohol preps in the incubator just before use and remove them from the incubator as soon as possible and (2) withhold placing hands into the incubators until 60 seconds after using ABDs for disinfection (applied only to family members).Main Outcomes and MeasuresBlood alcohol concentration and evaporated alcohol concentrations in neonatal incubators.ResultsDisinfectant practice was assessed among 28 infants during the pre–ABD-PRAC (17 infants [10 girls]; median gestational age at birth, 29.4 [IQR, 26.3-30.3] weeks) and post–ABD-PRAC (11 infants [3 girls]; median gestational age at birth, 30.0 [IQR, 25.3-32.2] weeks) study periods. The median blood alcohol concentration was 7.0 (IQR, 5.4-9.3) mg/dL pre–ABD-PRAC and 4.2 (IQR, 2.5-7.2) mg/dL post–ABD-PRAC. The median evaporated alcohol concentration inside neonatal incubators during pre–ABD-PRAC during the day was 23.6 (IQR, 15.9-36.5) ppm and, at night, was 13.2 (IQR, 8.9-19.4) ppm; during post–ABD-PRAC, the concentration was 9.4 (IQR, 6.0-16.0) ppm during the day and 5.7 (IQR, 3.6-9.7) ppm at night. The introduction of ABD-PRAC at 22 weeks’ corrected gestational age was associated with a lower blood alcohol concentration in premature infants: regression coefficient value, −8.3 (95% CI, −12.0 to −4.7).Conclusions and RelevanceIn this study, alcohol evaporated from ABDs was absorbed by premature infants in neonatal incubators. The findings suggest that introduction of ABD-PRAC was associated with lower alcohol concentrations in neonatal incubators and in the blood of premature infants.

Pulmonary embolism remains a leading cause of maternal mortality in developed countries despite developments in venous thromboembolism prophylaxis strategies. This study aimed to evaluate the effectiveness of our approach involving risk-scoring, D-dimer level assessment, and ultrasonography for obstetric venous thromboembolism.This retrospective cohort study included women who delivered at 22-41 weeks of gestation in The University of Tsukuba Hospital, Japan between January and December 2020. Venous thromboembolism risk (determined according to Japanese guidelines) and D-dimer levels were evaluated within 20 weeks of gestation, 30-34 weeks of gestation, and during the pre-delivery period (36 weeks of gestation or any time before preterm delivery). Compression and color Doppler ultrasonography for lower extremity deep vein thrombosis were performed if D-dimer levels were ≥3.2 μg/mL (for those undergoing cesarean delivery, 1.0 μg/mL).Of 1026 women, 6 women had deep vein thrombosis during pregnancy and 1 during the puerperium period. Pulmonary embolism was not observed. The D-dimer screening result was positive for 8 women (2%) within 20 weeks of gestation (deep vein thrombosis was confirmed in 3 of them), 87 women (10%) (no deep vein thrombosis) at 30-34 weeks of gestation, and 367 women (36%) during the pre-delivery period (asymptomatic deep vein thrombosis in one). Based on the Japanese guidelines, 1%, 11%, 33%, and 55% of women had high, intermediate, low, and no postpartum risk factors, respectively.Our approach appears useful for antenatal venous thromboembolism screening in the first trimester. For postpartum prophylaxis, more cost-effective strategies are needed.

AIM To evaluate the efficacy and safety of dinoprostone vaginal insert (PROPESS) in pregnant post-term Japanese women requiring cervical ripening. METHODS This randomized, double-blind, placebo-controlled study included 114 pregnant Japanese women at term (41 weeks of gestation) requiring cervical ripening (baseline Bishop score (BS) ≤ 4). The primary end-point was the proportion of subjects with successful cervical ripening defined as BS ≥ 7 or vaginal delivery in 12 h. The secondary end-points were changes in BS, proportion of women with vaginal delivery, proportion of women receiving mechanical cervical ripening procedure and use of oxytocic drugs. RESULTS PROPESS administration for a maximum of 12 h showed significantly higher successful cervical ripening rate (47.4% vs 14.3%, respectively; treatment contrast [TC]: 33.1%; P = 0.0002). The median time from administration to vaginal delivery was significantly shorter in the PROPESS group than in the placebo group (26.18 h vs 33.02 h; OR 2.51; 95% CI [1.60-3.92]; P

A 28-year-old woman was admitted during the eighth week of her pregnancy because her clinical course was consistent with rapid progressive glomerulonephritis (RPGN). Anti-glomerular basement membrane antibody (anti-GBM Ab) and myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) were positive, and the anti-GBM Ab titer being extremely high. She was treated with hemodialysis, plasma exchange and prednisolone. She survived the illness; however, neither the fetus nor her kidney function could be rescued. She had human leukocyte antigen (HLA)-DRB1*1502:01, which differs from the DRB1*1501 associated with anti-GBM GN. When patients have particular symptoms, we should check the urine and serum creatinine to exclude RPGN, even in cases of pregnancy.

The incidence of chromosomal abnormalities in twin pregnancies is not well-studied. In this retrospective study, we investigated the frequency of chromosomal abnormalities in twin pregnancies and compared the incidence of chromosomal abnormalities in dichorionic diamniotic (DD) and monochorionic diamniotic (MD) twins. We used data from 57 clinical facilities across Japan. Twin pregnancies of more than 12 weeks of gestation managed between January 2016 and December 2018 were included in the study. A total of 2899 and 1908 cases of DD and MD twins, respectively, were reported, and the incidence of chromosomal abnormalities in one or both fetuses was 0.9% (25/2899) and 0.2% (4/1908) in each group (p = 0.004). In this study, the most common chromosomal abnormality was trisomy 21 (51.7% [15/29]), followed by trisomy 18 (13.8% [4/29]) and trisomy 13 (6.9% [2/29]). The incidence of trisomy 21 in MD twins was lower than that in DD twins (0.05% vs. 0.5%, p = 0.007). Trisomy 21 was less common in MD twins, even when compared with the expected incidence in singletons (0.05% vs. 0.3%, RR 0.15 [95% CI 0.04–0.68]). The risk of chromosomal abnormality decreases in twin pregnancies, especially in MD twins.

Maternal glucocorticoid exposure increases the risk of preterm delivery; however, the association between glucocorticoids and preterm premature rupture of membranes (pPROM)-a direct cause of preterm delivery-has rarely been investigated.To examine this association, we evaluated the clinical data of patients with systemic lupus erythematosus (SLE). Mechanism analysis was performed in both human amnion-derived mesenchymal cells (as a model for fetal membranes) and the amnion from SLE patients. We characterized the effects of glucocorticoids on the amnion in both models through comprehensive gene expression profiling and by electric cell-substrate impedance sensing in the mesenchymal cells.The average glucocorticoid dose in cases with pPROM (13.3 mg/day, n = 10) was significantly higher than in those without pPROM (8.5 mg/day, n = 65; P 0.01) among pregnant patients with well-controlled SLE (SLEDAI4, n = 75); however, we did not observe a statistically significant difference in it between cases with or without chorioamnionitis. Glucocorticoid-treated human amnion mesenchymal cells showed decreased electric resistance between cells, indicating increased permeability. Differentially expressed genes upon glucocorticoid treatment were significantly enriched with cell adhesion-related genes. Among them, ITGA8 was strikingly induced in both the amnion mesenchymal cells and in amnion derived from patients with SLE.We observed an association between glucocorticoids and pPROM with non-infectious etiology. Our findings indicate that glucocorticoids increase amnion permeability and modulate cell-adhesion related genes. ITGA8 represents a primary molecule that triggers pPROM through fibrotic remodeling and preventing resealing of the rupture site in fetal amnion.

Aim We aimed to evaluate the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of noninvasive prenatal testing (NIPT) in high-risk pregnant women. Methods Pregnant women who underwent GeneTech NIPT, the most commonly used NIPT in Japan, between January 2015 and March 2019, at Japan NIPT Consortium medical sites were recruited for this study. The exclusion criteria were as follows: pregnant women with missing survey items, multiple pregnancy/vanishing twins, chromosomal abnormalities in the fetus other than the NIPT target disease, and nonreportable NIPT results. Sensitivity and specificity were calculated from the obtained data, and maternal age-specific PPV and NPV were estimated. Results Of the 45 504 cases, 44 263 cases fulfilling the study criteria were included. The mean maternal age and gestational weeks at the time of procedure were 38.5 years and 13.1 weeks, respectively. Sensitivities were 99.78% (95% confidence interval [95% CI]: 98.78-99.96), 99.12% (95% CI: 96.83-99.76), and 100% (95% CI: 88.30-100) for trisomies 21, 18, and 13, respectively. Specificities were more than 99.9% for trisomies 21, 18, and 13, respectively. Maternal age-specific PPVs were more than 93%, 77%, and 43% at the age of 35 years for trisomies 21, 18, and 13, respectively. Conclusion The GeneTech NIPT data showed high sensitivity and specificity in the detection of fetal trisomies 21, 18, and 13 in high-risk pregnant women, and maternal age-specific PPVs were obtained. These results could provide more accurate and improved information regarding NIPT for genetic counseling in Japan.

Background The human-to-rat hematopoietic stem cell transplantation (HSCT) model is rare, unlike its human-to-mouse counterpart. The rat models are desired, especially in areas of physiology, toxicology, and pharmacology. In addition to lymphocytes, macrophages are also considered to be important for xenotransplantation. We generated a rat xenotransplantation model to prove the role of macrophages as a xenotransplantation barrier. Methods Immunodeficiency in SRG rats, which are Sprague-Dawley (SD) rats lacking Rag2 and Il2rg, was confirmed by flow cytometry and spleen immunostaining. Human umbilical cord blood was collected after scheduled cesarean section at the University of Tsukuba Hospital. Cord blood mononuclear cells (CB-MNCs) were transplanted into the SRG rats administered several injections of clodronate liposome (CL), which cause macrophage depletion. Survival of human cells was observed by flow cytometry. Rat macrophage phagocytosis assay was performed to check the species-specific effects of rat macrophages on injected human/rat blood cells. Results SRG rats were deficient in T/B/NK cells. Without CL pretreatment, human CB-MNCs were removed from SRG rats within 7 hours after transplantation. The rats pretreated with CL could survive after transplantation. Prolonged survival for more than 4 weeks was observed only following a one-time CL injection. Rat macrophages had a species-specific potential for the phagocytosis of human blood cells in vivo. Conclusion In human-to-rat HSCT, the short period of early macrophage control, leading to macrophage immunotolerance, is important for engraftment. The generated model can be useful for the creation of future xenotransplantation models or other clinical research.

Introduction: Obstetric severe perineal laceration can frequently occur as a surgical site infection (SSI), which sometimes leads to rectovaginal fistula after repair. We encountered a rare case of a rectoperineal fistula 5 months after repair of a severe perineal laceration.Case presentation: The patient was a 39-year-old woman who underwent repair of a fourth-degree perineal laceration after vaginal delivery. Five months after primary repair, she presented with perineal swelling and pain followed by uncontrollable flatulence or passage of feces at the perineum, which was finally diagnosed as a rectoperineal fistula. Transperineal repair with fistulous tract excision was performed for the rectoperineal fistula. Closure of the rectum, perineal body, and vagina was performed layer-by-layer constructing a thick perineum to prevent anal dysfunction. The fistula was successfully closed, and the patient did not show any symptoms of fecal incontinence 6 months after surgery.Discussion: As the rectoperineal fistula might have resulted in SSI at the primary repair of the obstetric injury, the delayed occurrence of the rectoperineal fistula was unusual. A perineal approach should be performed for complete fistulous tract excision, reconstruction of a robust perineal structure, and preservation of anal sphincter function.

BACKGROUND To solve the problem of liver transplantation donor insufficiency, an alternative cell transplantation therapy was investigated. We focused on amniotic epithelial cells (AECs) as a cell source because, unlike induced pluripotent stem cells, they are cost-effective and non-tumorigenic. The utilization of AECs in regenerative medicine, however, is in its infancy. A general profile for AECs has not been comprehensively analyzed. Moreover, no hepatic differentiation protocol for AECs has yet been established. To this end, we independently compiled human AEC libraries, purified amniotic stem cells (ASCs), and co-cultured them with mesenchymal stem cells (MSCs) and human umbilical vein endothelial cell (HUVECs) in a 3D system which induces functional hepatic organoids. AIM To characterize AECs and generate functional hepatic organoids from ASCs and other somatic stem cells METHODS AECs, MSCs, and HUVECs were isolated from the placentae and umbilical cords of cesarean section patients. Amnion and primary AEC stemness characteristics and heterogeneity were analyzed by immunocytochemistry, Alkaline phosphatase (AP) staining, and flow cytometry. An adherent AEC subpopulation was selected and evaluated for ASC purification quality by a colony formation assay. AEC transcriptomes were compared with those for other hepatocytes cell sources by bioinformatics. The 2D and 3D culture were compared by relative gene expression using several differentiation protocols. ASCs, MSCs, and HUVECs were combined in a 3D co-culture system to generate hepatic organoids whose structure was compared with a 3D AEC sphere and whose function was elucidated by immunofluorescence imaging, periodic acid Schiff, and an indocyanine green (ICG) test. RESULTS AECs have certain stemness markers such as EPCAM, SSEA4, and E-cadherin. One AEC subpopulation was also either positive for AP staining or expressed the TRA-1-60 and TRA-1-81 stemness markers. Moreover, it could form colonies and its frequency was enhanced ten-fold in the adherent subpopulation after selective primary passage. Bioinformatics analysis of ribose nucleic acid sequencing revealed that the total AEC gene expression was distant from those of pluripotent stem cells and hepatocytes but some gene expression overlapped among these cells. TJP1, associated with epidermal growth factor receptor, and MET, associated with hepatocyte growth factor receptor, were upregulated and may be important for hepatic differentiation. In conventional flat culture, the cells turned unviable and did not readily differentiate into hepatocytes. In 3D culture, however, hepatic gene expression of the AEC sphere was elevated even under a two-step differentiation protocol. Furthermore, the organoids derived from the MSC and HUVEC co-culture showed 3D structure with polarity, hepatic-like glycogen storage, and ICG absorption/elimination. CONCLUSION Human amniotic epithelial cells are heterogeneous and certain subpopulations have high stemness. Under a 3D co-culture system, functional hepatic organoids were generated in a multicellular microenvironment.

There is a paucity of data on the risk of preterm birth subcategorized by gestational age in pregnancies after the pre-pregnancy excisional treatment for cervical lesions. In addition, little is known about the effect of prophylactic cerclage on the risk of preterm birth. The aim of this study was to investigate the risk of preterm birth stratified by gestational period and its reduction by the prophylactic cerclage in women with prior excisional surgery.We retrospectively analyzed a cohort of singleton pregnancies in the Japan Perinatal Registry Network Database (2013-2014,In the propensity-score matched population (cases,Pre-pregnancy excisional cervical surgery was associated with the increased risk of preterm birth, especially before 32 weeks of gestation. The prophylactic cerclage did not reduce the risk of preterm birth.

Objective To examine the association between the risk of postpartum hemorrhage (PPH) and poor uterine contractility, which is suggested by the characteristics of labor. Methods This case-control study used cases recorded in the Japan Perinatal Registry database during the period 2013-2016. After exclusion of women with specified known risk factors for PPH, we enrolled 174 082 primiparas who had a full-term live singleton vaginal birth. Participants were classified into four classes according to the diagnosis of abnormal labor patterns and use of uterotonics. χ2 tests were used to compare PPH cases with controls, and odds ratios (OR) were calculated by univariate and multivariate analyses. Results Among the enrolled women, 10 508 (6.0%) had PPH. Abnormal labor patterns were significantly associated with an increased risk of PPH. Compared with women without any abnormal labor patterns who had not used uterotonics, women with abnormal labor patterns were at a significantly increased risk for PPH regardless of whether they had used uterotonics (adjusted OR 1.23, 95% confidence interval [CI] 1.10-1.37) or not (adjusted OR 1.30, 95% CI 1.23-1.37). Conclusion Our study suggests that among low-risk women with PPH, poor uterine contractility in labor could be a significant predisposing risk factor for PPH.

Aim To evaluate the efficacy and safety of dinoprostone vaginal insert (PROPESS) in pregnant post‐term Japanese women requiring cervical ripening. Methods This randomized, double‐blind, placebo‐controlled study included 114 pregnant Japanese women at term (41 weeks of gestation) requiring cervical ripening (baseline Bishop score (BS) ≤ 4). The primary end‐point was the proportion of subjects with successful cervical ripening defined as BS ≥ 7 or vaginal delivery in 12 h. The secondary end‐points were changes in BS, proportion of women with vaginal delivery, proportion of women receiving mechanical cervical ripening procedure and use of oxytocic drugs. Results PROPESS administration for a maximum of 12 h showed significantly higher successful cervical ripening rate (47.4% vs 14.3%, respectively; treatment contrast [TC]: 33.1%; P = 0.0002). The median time from administration to vaginal delivery was significantly shorter in the PROPESS group than in the placebo group (26.18 h vs 33.02 h; OR 2.51; 95% CI [1.60–3.92]; P

Background Postpartum hemorrhage (PPH) is a major cause of maternal mortality. Even seemingly low-risk women may suddenly develop postpartum hemorrhage, and these cases are often unpredictable and threatens maternal life. We hypothesized that innate poor uterine contractility may be a risk factor of PPH. In this study, we examined the association between the innate poor uterine contractility, suggested by the characteristics of labor and PPH in obstetrically low-risk women.Methods We used the Japan Perinatal Registry database of the Japan Society of Obstetrics and Gynecology registered in 2013–2016. With exclusion of women with well-known risk factors for PPH (maternal basal disease of hematologic disease, uterine leiomyoma, pregnancy by assisted reproductive technology, placenta abruption, placenta accrete, low-lying placenta, hypertensive disorders of pregnancy, macrosomia, polyhydramnios, or epidural analgesia), we analyzed 174,082 primiparous women who had one live singleton birth via vaginal delivery in cephalic presentation at 37 weeks’ gestation. Information about abnormal labor patterns (hypotonic uterine dysfunction, prolonged labor, and arrest of labor) diagnosed by obstetricians were also used in this study. In order to focus on innate maternal poor uterine contractility, we classified subjects into four classes according to whether they were diagnosed with abnormal labor patterns and whether they had used uterotonics, and Odds ratios and their 95% CI were calculated as well.Results Among the enrolled women, 10,508 (6.0%) had PPH. Abnormal labor patterns, including hypotonic uterine dysfunction (adjusted OR 1.28, 95% CI 1.22 to 1.34), prolonged labor (adjusted OR 1.41, 95% CI 1.30 to 1.52) and arrest of labor (adjusted OR 2.02, 95% CI 1.78 to 2.29) were significantly associated with an increased risk of PPH. Compared to women who were not diagnosed any abnormal labor patterns and did not use any uterotonics, women who were diagnosed with abnormal labor patterns were at a significantly increased risk for PPH regardless of whether they had used uterotonics(adjusted OR 1.23, 95% CI 1.10 to 1.37) or not (adjusted OR 1.30, 95% CI 1.23 to 1.37).Conclusion Our study suggests that innate poor uterine contractility is a significant predisposing risk factor in otherwise low-risk women.Trial Registration: This study is retrospectively registered.

This study aimed to assess characteristics of pregnant women taking antiepileptic drugs with inadequate folic acid intake. This cross-sectional study examined pregnant women taking antiepileptic drugs who were registered in the Japanese Drug Information Institute in Pregnancy (JDIIP) database between October 2005 and December 2016. Participants were classified into two groups according to when they started folic acid supplementation (before pregnancy: 'adequate', after pregnancy or never: 'inadequate'). Logistic regression analysis was performed to investigate factors associated with inadequate folic acid intake. Of 12,794 registrants, 468 pregnant women were taking antiepileptics during the first trimester. Of these, we analysed data from 456 women who had no missing data. As a result, inadequate folic acid intake was noted among 83.3% of them, suggesting that the current level of folic acid intake is insufficient overall. Younger age, smoking, alcohol drinking, multiparity, unplanned pregnancy, and being prescribed AEDs by paediatric or psychiatric departments were independent factors associated with inadequate folic acid intake. As planned pregnancy was the strongest factor, healthcare professionals should ensure that childbearing women taking antiepileptics are informed of the importance of planned pregnancy. In addition, healthcare professionals must gain a better understanding of folic acid intake, as the prevalence of adequate intake differed according to which departments prescribed antiepileptic drugs.

To compare the prevalence of enlarged ovarian and intrapelvic parasitic arteries to the gravid uterus between cases of placenta accreta spectrum (PAS) and those with normal placentation using unenhanced magnetic resonance (MR) angiography.Unenhanced time-of-flight MR angiography was performed in 12 consecutive women with PAS (mean age, 34 years; range, 23-42 years) and 24 women with normal placentation (mean age, 31 years; range, 24-42 years) in their third trimester and reviewed by two independent observers. The consensus reading served as the reference standard. Findings of pelvic arteriography performed at cesarean hysterectomy were reviewed in all cases of PAS. The prevalence of enlarged ovarian and intrapelvic parasitic arteries was compared using Fisher's exact test. The interobserver agreement was assessed with Kappa statistics.The prevalence of enlarged ovarian arteries was not significantly different between cases of PAS and normal placentation (17% [4/24 pelvic sides] vs. 4% [2/48 pelvic sides], P = .091). The prevalence of intrapelvic parasitic arteries was significantly higher in cases of PAS than in those with normal placentation (67% [16/24 pelvic sides] vs. 0% [0/48 pelvic sides], P .0001). On a patient-by-patient basis, the intrapelvic parasitic artery was frequently present in women with PAS (92% [11/12 patients]). The Kappa values were 0.915 and 0.852 for detecting enlarged ovarian and intrapelvic parasitic arteries, respectively, indicating excellent interobserver agreement.The development of intrapelvic parasitic arteries was an anomalous phenomenon observed on unenhanced MR angiography in the majority of women with PAS but was not observed in those with normal placentation.

Aims The objective of this study was to determine how many pregnant Japanese women with diabetes mellitus (DM)/gestational diabetes mellitus (GDM) experience perinatal mortality in the presence of fetal anomalies. Methods Our investigation included data from 205 secondary/tertiary obstetric facilities located widely in Japan. The Japan Ministry of Health, Labour and Welfare Vital Statistics of Japan was used for comparison. Results Of 237 941 women giving birth at 205 hospitals, 1796 (0.8%) and 13 037 (5.5%) had DM and GDM, respectively. The perinatal mortality rates (per 1000 births) were 10.6 (19/1796) for women with DM, 5.2 (68/13037) for women with GDM, and 3.7 (7612/2039504) for the general Japanese population. Detailed information was available for 63 (72%) of the 87 perinatal deaths occurring in women with diabetes including DM and GDM; fetal anomalies were associated with 40% (25/63) of perinatal deaths, exceeding 16% (1211/7612) in the general Japanese population (P

Background and Aim Liver dysfunction with decreased antithrombin activity (AT) and/or thrombocytopenia is life-threatening in pregnant women. Whether AT is clinically useful for prediction of liver dysfunction remains unclear. Methods A total of 541 women were registered prospectively at gestational week 34.7 (20.0 – 41.4) with available data on antenatal AT and platelet count (PLC). Results Liver dysfunction defined as serum AST > 45 IU/L concomitant with lactate dehydrogenase (LDH) > 400 IU/L occurred in five women antenatally (≤ 2 weeks before delivery) and in 17 women postpartum (within 1 week postpartum). Median (5th – 95th) antenatal value was 85 (62 – 110)% for AT and 202 (118 – 315) × 109/L for PLC in the 541 women, and was significantly lower in women with than without perinatal liver dysfunction; 75 (51 – 108) vs. 86 (62 – 110)% and 179 (56 – 244) vs. 203 (121 – 316) × 109/L, respectively. Nineteen (86%) women with liver dysfunction showed AT ≤ 62% or thrombocytopenia (PLC ≤ 118 × 109/L) perinatally, but five lacked thrombocytopenia throughout the perinatal period. The best cut-off (AT, 77%; PLC, 139 × 109/L) suggested by receiver operating characteristic curve gave antenatal AT and PLC sensitivity of 59% and 41% with positive predictive value (PPV) of 8.6% and 14%, respectively, and combined use of AT and PLC improved sensitivity to 73% (16/22) with PPV of 9.2% for prediction of perinatal liver dysfunction. Conclusions Reduced AT not accompanied by thrombocytopenia can precede liver dysfunction. Clinical introduction of AT may enhance safety of pregnant women. This article is protected by copyright. All rights reserved.

This study aimed to assess characteristics of pregnant women taking antiepileptic drugs with inadequate folic acid intake. This cross-sectional study examined pregnant women taking antiepileptic drugs who were registered in the Japanese Drug Information Institute in Pregnancy (JDIIP) database between October 2005 and December 2016. Participants were classified into two groups according to when they started folic acid supplementation (before pregnancy: ‘adequate’, after pregnancy or never: ‘inadequate’). Logistic regression analysis was performed to investigate factors associated with inadequate folic acid intake. Of 12,794 registrants, 468 pregnant women were taking antiepileptics during the first trimester. Of these, we analysed data from 456 women who had no missing data. As a result, inadequate folic acid intake was noted among 83.3% of them, suggesting that the current level of folic acid intake is insufficient overall. Younger age, smoking, alcohol drinking, multiparity, unplanned pregnancy, and being prescribed AEDs by paediatric or psychiatric departments were independent factors associated with inadequate folic acid intake. As unplanned pregnancy was the strongest factor, healthcare professionals should ensure that childbearing women taking antiepileptics are informed of the importance of planned pregnancy. In addition, healthcare professionals must gain a better understanding of folic acid intake, as the prevalence of adequate intake differed according to which departments prescribed antiepileptic drugs.

Mesenchymal stem cells (MSCs) are defined as multipotent cells that can give rise to various kinds of differentiated mesenchymal cells, and are thus considered to be useful for clinical therapy. However, the big hurdles of MSC therapy are the inability of MSCs to reach the appropriate tissues or sites with high efficiency and engraftment after transplantation. In this study, we investigated how adipose tissue-derived MSCs (AT-MSCs) improve their homing ability after intravenous injection. We previously found that human endothelial progenitor cells with low aldehyde dehydrogenase activity (Alde-Low EPCs) are suitable for the treatment of ischemic tissues. In addition, we demonstrated that microvesicles (MVs) derived from Alde-Low EPCs possessed the ability to improve the homing ability of non-functional Alde-High EPCs, resulting in wound healing. We initially transfected MVs derived from Alde-Low EPCs (EMVs) to human AT-MSCs, which were originally unable to cure ischemic tissues by intravenous transplantation. Remarkably, AT-MSC transfected EMVs dramatically repaired the ischemic skin flap compared with AT-MSC derived-MV (MMVs) transfected AT-MSCs or control AT-MSCs. We then found that the expression of CXCR4, an important chemokine receptor for cell migration, was highly elevated in EMV-transfected AT-MSCs. Moreover, AT-MSCs transfected with EMVs, but not control AT-MSCs, migrated to wound sites after intravenous injection. Consequently, CD45(+) inflammatory cells were successfully recruited at the wound sites after the injection of EMV-transfected AT-MSCs. These results demonstrate that EMVs are a useful source to improve the homing ability and wound healing ability of MSCs at the wound sites.

Introduction Some pregnant women develop significant proteinuria in the absence of hypertension. However, clinical significance of isolated gestational proteinuria (IGP) is not well understood. This study aimed to determine the prevalence of IGP in singleton pregnancies and the proportion of women with IGP who subsequently developed preeclampsia (IGP-PE) among all PE cases. Material and methods This was an observational study of 6819 women with singleton pregnancies at 12 centers, including 938 women with at least once determination of protein-to-creatinine ratio (P/Cr). Significant proteinuria in pregnancy (SPIP) was defined as P/Cr (mg/mg) level >0.27. IGP was defined as SPIP in the absence of hypertension. Gestational hypertension (GH) preceding preeclampsia (GH-PE) was defined as preeclampsia (PE) in which GH preceded SPIP. Simultaneous PE (S-PE) was defined as PE in which both SPIP and hypertension occurred simultaneously. Results IGP and PE were diagnosed in 130 (1.9%) and 158 (2.3%) of 6819 women, respectively. Of 130 women with IGP, 32 (25%) progressed to PE and accounted for 20% of all women with PE. Hence, women with IGP had a relative risk of 13.1 (95% CI; 9.2–18.5) for developing PE compared with those without IGP [25% (32/130) vs. 1.9% (126/6689)]. At diagnosis of SPIP, P/Cr levels already exceeded 1.0 more often in women with S-PE than in those with IGP-PE [67% (33/49) vs. 44% (14/32), respectively, p = 0.031]. Conclusions IGP is a risk factor for PE, and IGP-PE accounts for a considerable proportion (20%) of all PE.

Endothelial progenitor cells (EPCs) have the ability to form new blood vessels and protect ischemic tissues from damage. We previously reported that EPCs with low activity of aldehyde dehydrogenase (Alde-Low EPCs) possess the greater ability to treat ischemic tissues compared with Alde-High EPCs. The expression level of the hypoxia-inducible factors (HIFs), HIF-1α and HIF-2α, was found to be greater in Alde-Low EPCs than in Alde-High EPCs. However, the precise role of the HIF factors in the regulation of EPC activity remains obscure. In this study, we demonstrate a critical role of HIF-2α and its target gene CXCR4 for controlling the migratory activity of EPC to ischemic tissue. We found that coculture of Alde-High EPCs with microvesicles derived from Alde-Low EPCs improved their ability to repair an ischemic skin flap, and the expression of CXCR4 and its ligand SDF1 was significantly increased following the coculture. In Alde-Low EPCs, the expression of CXCR4 was suppressed by short hairpin RNA (shRNA)-mediated HIF-2α, but not HIF-1α downregulation. Chromatin immunoprecipitation assays showed that HIF-2α, but not HIF-1α, binds to the promoter region of CXCR4 gene. The CXCR4 shRNA treatment in Alde-Low EPCs almost completely abrogated their migratory activity to ischemic tissues, whereas the reduction of vascular endothelial growth factor (VEGF) showed much less effect. The CXCR4 overexpression in Alde-High EPCs resulted in a partial, but significant improvement in their repairing ability in an ischemic skin flap. Collectively, these findings indicate that the CXCR4/SDF-1 axis, which is specifically regulated by HIF-2α, plays a crucial role in the regulation of EPC migration to ischemic tissues.

Perinatal care in Japan has progressed rapidly in recent decades, remarkably reducing maternal, perinatal and neonatal mortality rates. This is attributable not only to the sustained efforts and dedication of past obstetricians and midwives, but also to the collective results achieved by the Japan Society of Obstetrics and Gynecology and healthcare administration, including research on advanced medical care, education, medical care improvements and establishing perinatal care centers. Although the maternal mortality rate was in steady decline until 2007 (3.1/100 000 births), it repeatedly fluctuated thereafter, plateauing at 3.4 per 100 000 births in 2013 and 2.7 per 100 000 births in 2014. Thus, the Perinatology Committee has analyzed the current situation of maternal deaths and has proposed countermeasures to reduce such death. The items deliberated upon by related subcommittees in 2015 are presented herein. The addition of indications for ‘fibrinogen concentrate’, ‘eptacog alfa’ and approval of the PGE2 vaginal tablet for cervical ripening were discussed in the subcommittee for unapproved drug review. Thus, a request for approval for health insurance coverage was submitted to the ‘Evaluation committee on unapproved or off-label drugs with high medical needs’ of the Ministry of Health, Labour and Welfare. Maternal and late-maternal deaths from suicide during the 10 years from 2005 to 2014 in Tokyo's 23 wards were jointly examined with the Tokyo Medical Examiner's Office. The suicide rate in the 23 wards is very high, at 8.7 per 100 000 births. Thus, the subcommittee for the reduction of maternal death discussed countermeasures for the eradication of maternal death and maternal suicide and the revision of death certificates.

Aim Post-partum hematomas are a serious obstetrical complication. Choosing treatments for post-partum hematomas is difficult, and the application of transcatheter arterial embolization remains unclear. We aimed to clarify the clinical characteristics, identify the treatment indications and create a treatment algorithm for post-partum hematomas. Methods Fifty-four patients with post-partum hematomas were enrolled. Hematomas were categorized according to location: upper vaginal, lower vaginal and vulvar. Blood loss, treatment methods and other clinical data were collected from the patients' medical records and analyzed retrospectively. Results Five, 19 and 30 patients had upper vaginal wall, lower vaginal wall and vulvar hematomas, respectively. All upper vaginal wall hematomas required transcatheter arterial embolization to control bleeding, and the average blood loss was 2473 ± 1689 mL. Most lower vaginal wall hematomas were treated surgically; however, two patients required transcatheter arterial embolization, and the average blood loss in these patients was much higher (2010 ± 1145 mL) than that in patients with lower vaginal wall hematomas (395 ± 316 mL). No patient with vulvar hematomas was treated with transcatheter arterial embolization. Two and four patients with vulvar and lower vaginal wall hematomas, respectively, were managed with observation. Conclusion We created an algorithm for post-partum hematoma management. Post-partum hematoma location should guide treatment selection. Transcatheter arterial embolization should be selected for upper vaginal wall hematomas. Most lower vaginal wall hematomas are treatable with surgery, but transcatheter arterial embolization should be considered for hemostasis in difficult cases. Management with observation may also be possible for lower vaginal wall and vulvar hematomas.

Recent studies have revealed unique biological characteristics of molecular hydrogen (H2) as an anti-inflammatory agent. We developed a novel haemodialysis (E-HD) system delivering an H2 (30–80 ppb)-enriched dialysis solution by water electrolysis, and conducted a non-randomized, non-blinded, prospective observational study exploring its clinical impact. Prevalent chronic HD patients were allocated to either the E-HD (n = 161) group or the conventional HD (C-HD: n = 148) group, and received the respective HD treatments during the study. The primary endpoint was a composite of all-cause mortality and development of non-lethal cardio-cerebrovascular events (cardiac disease, apoplexy, and leg amputation due to peripheral artery disease). During the 3.28-year mean observation period, there were no differences in dialysis parameters between the two groups; however, post-dialysis hypertension was ameliorated with significant reductions in antihypertensive agents in the E-HD patients. There were 91 events (50 in the C-HD group and 41 in the E-HD group). Multivariate analysis of the Cox proportional hazards model revealed E-HD as an independent significant factor for the primary endpoint (hazard ratio 0.59; [95% confidence interval: 0.38–0.92]) after adjusting for confounding factors (age, cardiovascular disease history, serum albumin, and C-reactive protein). HD applying an H2-dissolved HD solution could improve the prognosis of chronic HD patients.

Aim Monoacyglycerol acyltransferases (MGATs) are known to play important roles in intestinal TG absorption. In contrast, the role of MGATs in the liver is still unclear. We investigated the effects of JTP-103237, a novel MGAT inhibitor, on hepatic MGAT activity and hepatic lipid metabolism. Results JTP-103237 reduced hepatic triglyceride content and hepatic MGAT activity in a high sucrose very low fat (HSVLF) diet induced fatty liver model. Interestingly, JTP-103237 suppressed not only triglyceride (TG) and diacylglycerol (DG) synthesis, but also fatty acid (FA) synthesis (de novo lipogenesis) in this model. JTP-103237 also suppressed lipogenesis-related gene expression, such as sterol regulatory element-binding protein 1-c. Moreover, JTP-103237 decreased plasma glucose levels and total cholesterol and reduced the accumulation of epididymal fats in HSVLF diet fed mice. Conclusion In the present study, JTP-103237 prevented carbohydrate-induced fatty liver and suppressed both TG synthesis and de novo lipogenesis, suggesting MGAT inhibitor may prevent carbohydrate-induced metabolic disorders, including NAFLD, obesity and diabetes.

Toxoplasma gondii is an obligate intracellular protozoan pathogen that can cross the placenta, resulting in congenital toxoplasmosis with severe fetal brain abnormalities. The molecular mechanisms of immune responses against T. gondii infection in the placenta have largely remained unclear. An analytical method for characterizing phenotypes of immune cells in the placenta by flow cytometry was established and it was found that numbers of CD11b(+) Gr-1(+) cells in the placenta increased significantly after T. gondii infection. These results suggest that innate immune responses play an important role in immunity against T. gondii infection via the feto-maternal interface.

Objective To report a case of gas gangrene in a fetus at term, which was diagnosed by antenatal computed tomography (CT) imaging. Case Report A 23-year-old primiparous woman, who did not undergo any prenatal health checks until term, developed hypertension, proteinuria, and clouding of consciousness, and experienced intrauterine fetal death. A single, mature fetus with voluminous gas bubbles was observed on CT, which was consistent with a diagnosis of fetal gas gangrene. Following the induction of labor, a dead, malodorous infant was delivered, along with foul-smelling and frothy amniotic fluid. The patient's condition deteriorated, and intensive care support was required to treat the patient for septic shock and disseminated intravascular coagulation during the postpartum period. She died on the 2 nd postpartum day. Conclusion Fetal gas gangrene is a very rare and potentially lethal event in pregnant women. To our knowledge, this is the first report on the antenatal diagnosis of fetal gas gangrene in a term pregnancy through CT. CT was useful for evaluating the extent of emphysematous change in the fetal and maternal organs.