Ferric derisomaltose for the treatment of iron deficiency anemia with postpartum hemorrhage: Results of a single-arm, open-label, phase 3 study in Japan.

AIM: Single-arm, open-label, phase 3 study to evaluate the efficacy and safety of ferric derisomaltose (FDI) for iron deficiency anemia (IDA) in Japanese women with postpartum hemorrhage (PPH). METHODS: Postpartum women aged 20-39 years with serum ferritin <25.0 ng/ml, hemoglobin (Hb) <10.0 g/dl, and blood loss ≥500 ml within 24 h post-delivery were eligible to receive high-dose intravenous FDI. The primary endpoint was the maximum change in Hb concentration by Week 8. Key secondary endpoints included change in iron parameters and percentage of patients with a total Edinburgh Postnatal Depression Score (EPDS) ≥9. Safety assessments included treatment-emergent adverse events (TEAEs) and iron concentrations in maternal milk. RESULTS: All (n = 21 [100.0%]) patients received the predetermined total iron dose by Day 8. Hb concentrations increased rapidly and significantly (p < 0.001) following FDI. Serum ferritin levels also increased rapidly and were maintained near or above the upper limit of normal reference value (250 ng/ml). Following FDI, two (9.5%) patients had a total EPDS score of ≥9. TEAEs occurred in 23 of 42 (54.8%) patients and neonates overall, including 18 of 21 (85.7%) patients and 5 of 21 (23.8%) neonates. TEAEs were mild in all adult patients and four neonates, and moderate in one neonate. Iron concentrations in maternal milk remained within normal reference values. Appropriate patient selection and patient-adjusted dosage selection facilitated safe and effective administration of high-dose (≥1000 mg) FDI. CONCLUSIONS: Rapid and sustained improvements in Hb and iron stores occurred following FDI for IDA with PPH, with no new safety signals identified. CLINICAL TRIAL IDENTIFIER: JapicCTI-194888.

Investigating women's health issues and help-seeking intentions in primary care in Japan: a cross-sectional study.

BACKGROUND: Many women face a variety of barriers to seeing obstetricians and gynecologists (OB/GYNs). Primary care physicians (PCPs) in Japan are not well equipped to address and adequately handle women's health issues. Hence, opportunities for women to consult PCPs about women's health issues are often limited during busy outpatient encounters. It is essential to explore PCP's roles in women's health care by examining women's health needs in a primary care setting. The aim of the study is to describe the prevalence and distribution of women's health issues and help-seeking intentions among women visiting a primary care clinic. METHODS: This was a cross-sectional study using a questionnaire. We included women aged 20-60 years who visited a primary care clinic for any reason. The questionnaire comprised a list of women's health issues, the General Help Seeking Questionnaire to assess help-seeking intentions, and participants' demographics including their reasons for visiting and regularity of OB/GYN visits. RESULTS: We distributed the questionnaire to 294 women and analyzed 260 valid responses. The average age of the respondents was 40.5 years old, and they had an average of 5.2 clinic visits a year. Approximately half of them (50.4%) visited for their own care. One hundred thirty-nine (53.9%) reported at least one women's health issue, and 73.9% of them had no regular visit to an OB/GYN. The major concerns of women's health issues included gynecological cancer screenings and menstrual problems. The distribution of help-seeking intentions for each source of care appeared to be classified into three patterns. One fifth of the women indicated high help-seeking intentions for PCPs, and a greater number of women expressed higher help-seeking intentions for PCPs when they did not regularly see an OB/GYN. CONCLUSIONS: A significant number of women who visited a primary care clinic had a specific concern about women's health issues, and a majority of them had not regularly visited their OB/GYN. PCPs may have an important role in providing an opportunity for women to discuss their concerns about women's health issues as part of comprehensive care during a daily clinical encounter.

Intravenous ferric derisomaltose versus saccharated ferric oxide for iron deficiency anemia associated with menorrhagia: a randomized, open-label, active-controlled, noninferiority study.

A multicenter, randomized, open-label, phase III study was conducted to compare the efficacy and safety of intravenous ferric derisomaltose (FDI) versus saccharated ferric oxide (SFO) in Japanese patients with iron deficiency anemia associated with menorrhagia. FDI can be administered as a single dose up to 1000 mg, whereas SFO has a maximum single dose of 120 mg. The primary endpoint, which was the maximum change in hemoglobin concentration from baseline, was noninferior for the FDI group compared with the SFO group. The incidence of treatment-emergent adverse events was lower in the FDI group (66.2%) than in the SFO group (90.8%). Notably, the incidence of serum phosphorus level < 2.0 mg/dL was significantly lower in the FDI group (8.4%) than in the SFO group (83.2%), and severe hypophosphatemia (≤ 1.0 mg/dL) occurred in 6.7% of SFO­treated patients compared with none in the FDI group. The percentage of patients who achieved the cumulative total iron dose during the 8-week treatment period was higher in the FDI group (92.8%) than in the SFO group (43.2%). The study met its primary endpoint, and also demonstrated the tolerability of a high dose of FDI per infusion, with a lower incidence of hypophosphatemia.

Comparison of three classification systems of Prepregnancy Body Mass Index with Perinatal Outcomes in Japanese Obese Pregnant Women: A retrospective study at a single center.

In Japan, pregnant women are diagnosed as obese if the prepregnancy body mass index (BMI) is ≥25 kg/m2. However, this is different from other countries. The Institute of Medicine (IOM) classifies prepregnancy BMI as underweight (BMI <18.5 kg/m2), normal weight (BMI 18.5-24.9 kg/m2), overweight (BMI 25.0-29.9 kg/m2), and obese (BMI ≥30 kg/m2). In addition to these four categories, the American College of Obstetricians and Gynecologists (ACOG) classifies prepregnancy BMI as obesity class I (BMI 30.0-34.9 kg/m2), obesity class II (BMI 35.0-39.9 kg/m2), and obesity class III (BMI ≥40 kg/m2). We conducted a retrospective cohort study to compare obstetric outcomes by the three different categorizations in 6,066 pregnant women who gave birth between 2010 and 2019. According to Japanese classification, 668 (11%) pregnant women were classified as obese, and significant odds ratios (OR) were observed for hypertensive disorders of pregnancy (HDP; 3.32), gestational diabetes mellitus (GDM; 3.39), large for gestational age (LGA; 2.91), and macrosomia (4.01). According to the classification of IOM, 474 (7.8%) and 194 (3.1%) were classified as overweight and obese pregnant women, respectively. Specifically, a high OR was observed in obese pregnant women for HDP (5.85) and GDM (5.0). ACOG classification categorized 474 (7.8%) pregnant women as overweight, 141 (2.3%) as obesity class I, 41 (0.6%) as obesity class II, and 12 (0.2%) as obesity class III. In obesity class III, a significantly high OR was observed for HDP (12.89), GDM (8.37), and LGA (5.74). The Japanese classification may be useful for low-risk pregnancies, whereas IOM classification may be applicable to identify high-risk pregnancies. ACOG criteria may be useful for step-wise assessments of HDP and GDM risks in Japanese pregnant women; however, the number of class II and III obese pregnant women was small.

Chymotrypsin Enhances Soluble Fms-Like Tyrosine Kinase 1 Production Through Protease-Activated Receptor 2 in Placenta-Derived Immortalized Human Trophoblast Cells.

The production of soluble fms-like tyrosine kinase 1 (sFLT1) by exogenous chymotrypsin in trophoblast cells through protease-activated receptor (PAR) 2 was investigated to identify the role of a chymotrypsin-like serine protease in preeclampsia (PE) pathogenesis. We evaluated the expression of chymotrypsin, FLT1, and sFLT1 in monolayers of immortalized human trophoblast cells derived from placenta (TCL-1 cells). To investigate whether chymotrypsin enhances the production and release of sFLT1 through PAR-2, we examined changes in sFLT1 protein levels in conditioned medium by enzyme-linked immunosorbent assay and sFLT1 messenger RNA (mRNA) levels by real-time polymerase chain reaction in TCL-1 cells treated with exogenous chymotrypsin in the presence or absence of a PAR-2 antagonist or a chymotrypsin inhibitor (TPCK). We also examined changes in PAR-2 expression in TCL-1 cells treated with tumor necrosis factor (TNF) α in the presence or absence of a polyclonal anti-TNF-α antibody. Western blot analysis showed that TCL-1 trophoblast cells expressed chymotrypsin, FLT1, and sFLT1. Compared with the control cells, the sFLT1 level in the conditioned medium and sFLT1 mRNA level in cells were both significantly enhanced when treated with a PAR-2 agonist or chymotrypsin for 6 hours. In contrast, the sFLT1 level in the medium and sFLT1 mRNA level in cells treated with a PAR-2 agonist or chymotrypsin were suppressed in the presence of a PAR-2 antagonist or a chymotrypsin inhibitor. The PAR-2 expression was upregulated by TNF-α, which was suppressed in the presence of TNF-α antibodies. These results indicate that chymotrypsin-like serine protease enhances sFLT1 production through PAR-2 in trophoblast cells and thus plays an important additional role in PE pathogenesis.

Changes in pelvic shape among Japanese pregnant women over the last 5 decades.

AIM: Pelvic shape affects the progression of labor. The gynecoid-type pelvis has been the most common in women, but a previous study reported that the anthropoid type has increased in Japan. The purpose of this study was to examine: (i) the current prevalence of different pelvic shapes in Japanese pregnant women; and (ii) the changes in the prevalence of the pelvic shapes over the past 50 years. MATERIAL AND METHODS: We conducted a cross-sectional study using descriptive analysis for the prevalence of the pelvic shape and a historical comparison to assess the changes in the proportions of pelvic shapes with Japanese data from the 1960s to the 1980s. We reviewed a total of 517 delivery records from May 2010 to August 2012 at a rural Japanese hospital where prenatal X-ray pelvimetry had been routinely performed as local practice. We analyzed the readings of the digital imaging data in pregnant women who underwent X-ray pelvimetry. RESULTS: We identified the X-ray data in 326 Japanese pregnant women. The prevalence of the anthropoid, gynecoid and flat types was 151 (46.3%), 142 (43.6%), and 33 (10.1%), respectively. There were no differences in the maternal characteristics according to the pelvic shapes. The prevalence of the anthropoid-type pelvis has increased by approximately 40% and that of the gynecoid type has decreased by 20% since the 1960s. CONCLUSION: The prevalence of the anthropoid-type pelvis have significantly increased in Japan. Identifying a determinant of this phenomenon requires further research.

Multiple pregnancy, short cervix, part-time worker, steroid use, low educational level and male fetus are risk factors for preterm birth in Japan: a multicenter, prospective study.

AIM: To examine the relationship between preterm birth and socioeconomic factors, past history, cervical length, cervical interleukin-8, bacterial vaginosis, underlying diseases, use of medication, employment status, sex of the fetus and multiple pregnancy. METHODS: In a multicenter, prospective, observational study, 1810 Japanese women registering their future delivery were enrolled at 8⁺° to 12⁺6 weeks of gestation. Data on cervical length and delivery were obtained from 1365 pregnant women. Multivariate logistic regression analysis was performed. RESULTS: Short cervical length, steroid use, multiple pregnancy and male fetus were risk factors for preterm birth before 34 weeks of gestation. Multiple pregnancy, low educational level, short cervical length and part-timer were risk factors for preterm birth before 37 weeks of gestation. CONCLUSION: Multiple pregnancy and cervical shortening at 20-24 weeks of gestation was a stronger risk factor for preterm birth. Any pregnant woman being part-time employee or low educational level, having a male fetus and requiring steroid treatment should be watched for the development of preterm birth.

Time spatial labeling inversion pulse magnetic resonance angiography in pregnancy with adenomyosis.

Time spatial labeling inversion pulse (Time-SLIP) is a non-contrast magnetic resonance angiography (MRA) technique. No cases in which this technique was used during pregnancy have been reported. We report herein two cases with adenomyosis of the same size and location that underwent Time-SLIP MRA during pregnancy. In case 1, the blood flow within the adenomyosis was poor, and the uterine blood flow toward the placenta was normal, resulting in no fetal growth restriction (FGR). In case 2, the blood flow within the adenomyosis was quite rich, and placental blood flow seemed decreased, resulting in severe FGR. As well as the Doppler ultrasonography, Time-SLIP MRA was useful for evaluating uterine blood flow during pregnancy. This is the first report of the use of Time-SLIP MRA during pregnancy.

Effectiveness of Heparin during Long-Term Tocolysis.

Objective. Drip infusion during long-term tocolysis causes mechanical and infectious vasculitis and increases the frequency of peripheral venous catheter exchange (PVC), thereby placing a burden on patients. Our study aim is to confirm whether heparin ameliorates pain due to vasculitis during long-term tocolysis and reduces the frequency of peripheral venous catheter exchange. Design. Prospective study. Setting and Sample. All the patients requiring admission because of the presence of uterine contraction or progressive cervical dilatation from August 2009 to June 2011 at Juntendo University in Japan. Methods. Heparin was used for patients at the time the total number of peripheral venous catheter exchanges exceeded 5 in two weeks, and we evaluated whether heparin reduced the frequency of peripheral venous catheter exchange and improved the visual analog scale (VAS) for patients. The main outcome measures frequency of PVC exchange and VAS. Results. This study demonstrated that heparin reduced the frequency of peripheral venous catheter exchange (P = 0.0069) and VAS (P = 0.042). No side effects were noted. Conclusion. Heparin could satisfy patients during long-term tocolysis in terms of ameliorating pain due to vasculitis and reducing the PVC exchange frequency.

Double vertical compression sutures: A novel conservative approach to managing post-partum haemorrhage due to placenta praevia and atonic bleeding.

Compression has been regarded as the main haemostatic mechanism of compression sutures; however, we suggest that reduced uterine blood flow may be another important action. We suggest that our 'double vertical compression sutures' may have dual actions: haemostatic compression of the bleeding surface and reduced uterine blood flow.

Heparin/heparan sulfate/CD44-v3 enhances cell migration in term placenta-derived immortalized human trophoblast cells.

The function of CD44-v3 and heparin/heparan sulfate (HS) signaling was investigated during trophoblast cell migration to identify their role in the renewal of syncytial layer damage caused by increased hemodynamic turbulence in the intervillous space and maintenance of syncytial integrity in pre-eclampsia. We evaluated the effect of heparin/HS/CD44-v3-mediated processes during scratch wound closure in monolayer immortalized human trophoblast cells derived from term placenta (TCL-1 cells). Western blot analysis showed that these cultured human trophoblast cells express the epidermal growth factor receptor and CD44-v3 but do not express syndecan 4. An in vitro scratch wound healing assay showed enhanced migration of trophoblast cells in a dose-dependent manner in the presence of heparin compared with controls when cultured under serum-free conditions. Conversely, an anti-CD44 function-blocking antibody and CD44 siRNA suppressed the migration of trophoblast cells in the presence of heparin in a similar scratch assay. Furthermore, both heparin treatment and in vitro scratch wounding induced the phosphorylation of p21-activated kinase 1 (PAK1), whereas the anti-CD44-v3 antibody suppressed the heparin-induced phosphorylation of PAK1 in trophoblast cells. These results indicate that heparin/HS/CD44-v3-mediated signaling, in the absence of growth factor networks, enhances the direct repair of the damaged trophoblast layer through the migration of trophoblast cells. This renewed cell coverage may lead to the maintenance of syncytiotrophoblast cell function and an associated reduction in pathogenic soluble factors derived from the damaged trophoblast cells.

A rapid activated protein C sensitivity test as a diagnostic marker for a suspected venous thromboembolism in pregnancy and puerperium.

OBJECTIVE: The purpose of the study was to examine whether changes in response to activated protein C (APC) can be a diagnostic marker of venous thromboembolism (VTE) during pregnancy and puerperium. METHODS: The normalized APC sensitivity ratio (sr) was examined in arbitrarily selected healthy Japanese pregnant females and compared with those in non-pregnant females and patients with VTE at the onset before anticoagulation in pregnancy and puerperium using an endogenous thrombin potential-based assay with a computer-assisted calibrated automated thrombography. RESULTS: Sensitivity to APC in patients with VTE at onset was reduced in comparison to that in late pregnancy period and puerperium (p < 0.01, Student's t test). The odds ratio for VTE was 31.9 with statistical significance in pregnant females with suspected clinical symptoms and APC-sr (≥5), although the odds ratio for VTE was not significant with D-dimer (≥5). CONCLUSION: These data suggest that an APC sensitivity test can be a possible surrogate diagnostic marker of suspected VTE during pregnancy and puerperium.

Attempt to quantify uterine involution using acoustic radiation force impulse before and after placental delivery.

PURPOSE: The aim of the present study was to investigate whether baseline stiffness of the uterine corpus and cervix accurately estimated by acoustic radiation force impulse (AFRI) elastography changed after placental delivery. METHODS: Eleven patients with normal vaginal delivery underwent ARFI elastography before, immediately after, and 1 and 2 h after placental delivery, and the shear wave velocity was measured to determine the stiffness. Each measurement was performed in triplicate to obtain a mean ± SD. RESULTS: The shear wave velocity of the uterine corpus before, immediately after, and 1 and 2 h after placental delivery was 1.81 ± 0.60, 3.04 ± 0.76, 3.12 ± 0.95, and 2.72 ± 0.81 m/s, respectively, and the shear wave velocity of the uterine cervix was 1.35 ± 0.45, 1.87 ± 0.57, 1.68 ± 0.59, and 1.70 ± 0.5 m/s, respectively. The stiffness of the uterine corpus significantly changed over time, although that of the uterine cervix was not significantly altered. The stiffness of the uterine corpus was significantly higher immediately after and 1 and 2 h after placental delivery as compared with that before placental delivery. The uterine corpus had a significantly higher stiffness than the uterine cervix at each of the four time points examined. CONCLUSION: ARFI elastography may be useful to assess uterine involution using the shear wave velocity.

A case of a huge placental lake; prenatal differential diagnosis and clinical management.

Placental lakes are sonolucent or hypoechoic areas in images of the placenta, usually considered a physiological dilation of intervillous space with a rather good obstetrical outcome. However, diagnostic criteria for and the clinical significance of placental lakes are yet to be completely established, because of a wide variety of ultrasound findings, especially on color Doppler examination. We experienced a case of a huge placental lake, larger than the total placental area, located in an entire retroplacental space, concomitant with several penetrations of artery type blood flow. The antenatal differential diagnosis and course of clinical management are reported.

Chorangiosis and placental oxygenation.

Chorangiosis is a vascular hyperplasia in the terminal chorionic villi, usually diagnosed histologically using the criteria of Altshuler. Its true etiology has not been fully identified, but chorangiosis has been proposed to result from a longstanding, rather low-grade hypoxia in the placental tissue. To clarify a possible association of placental oxygenation status with the development of chorangiosis, we measured placental tissue oxygen index (TOI) values using near-infrared spectroscopy (NIRS) before delivery and retrospectively compared them to the detection of placental chorangiosis, in a total of 47 (46 singleton and one set of dichorionic diamniotic twins) pregnant women. Small for gestational age (SGA) and/or maternal complications were observed in all cases of placental chorangiosis. Placental TOI values were significantly elevated in cases of chorangiosis. This indicates high oxygen saturation in the intervillous spaces because placental TOI values are expected to represent the oxygenation of maternal blood in the placental tissue. A possible preceding low efficiency of oxygen transfer to the fetal circulation in the villi might not only augment the oxygen saturation of maternal blood in intervillous spaces, but also cause rather low oxygenation in the capillaries of the villi and result in chorangiosis.

Prostaglandin E2 receptor EP4-selective antagonist inhibits lipopolysaccharide-induced cervical ripening in rabbits.

BACKGROUND: The purpose of this study was to examine whether EP4 as prostaglandin (PG) E2 receptor is involved in lipopolysaccharide (LPS)-induced cervical ripening. METHODS: New Zealand White non-pregnant rabbits were randomly allocated to 4 equal groups and treated with vaginal suppositories containing LPS with various concentrations of EP4-selective antagonist once daily for 3 days, and then sacrificed for analysis. Analysis was performed in order to examine the inhibitory effect of EP4 antagonist on LPS-induced cervical ripening. The expression of EP4 in a cervix treated with LPS was examined immunohistochemically. The percent of cervical extensibility in the segment of cervix as the tensile strength was determined with 5.8 g of constant perpendicular stretching. The ripening area of the cervix with edematous changes in H&E sections was calculated by a microscopic system with a computer-assisted digital analyser. Type-1 collagenase activity was determined in cervical tissue using FITC-labelled type-1 collagen. RESULTS: Immunohistochemical study shows the positive staining of EP4 at the interstitial cells in the cervix treated with LPS. The extensibility, cervical edematous area and type-1 collagenase activity are significantly reduced in the cervix treated with LPS in the presence of EP4 antagonist compared with that treated with LPS alone. CONCLUSIONS: These data implicates the EP4 as the PGE2 receptor involved in LPS-induced cervical ripening.

Molecular basis of antithrombin deficiency in four Japanese patients with antithrombin gene abnormalities including two novel mutations.

We analyzed the antithrombin (AT) gene in four unrelated Japanese patients with an AT deficiency, and individually identified four distinct mutations in the heterozygous state. There were two novel mutations, 2417delT leading to a frameshift with a premature termination at amino acid -3 (FS-3Stop) and C2640T resulting in a missense mutation (Ala59Val). Previously reported mutations, T5342C (Ser116Pro) and T72C (Met-32Thr), were also found in the other two patients. To understand the molecular basis responsible for the AT deficiency in these patients, in vitro expression experiments were performed using HEK293 cells transfected with either wild type or respective mutant AT expression vector. We found that -3Stop-AT and -32Thr-AT were not secreted into the culture media, whereas 116Pro-AT and 59Val-AT were secreted normally. We further studied the heparin cofactor activity and the binding to heparin of each recombinant AT molecule. Ser116Pro mutation significantly impaired the binding affinity to heparin resulting in a reduced heparin cofactor activity. In contrast, we found that Ala59Val mutant AT unexpectedly showed a normal affinity to heparin, but severely impaired the heparin cofactor activity. Our findings suggested that FS-3Stop and Met-32Thr mutations are responsible for type I AT deficiency, whereas Ser116Pro and Ala59Val mutations contribute to type II AT deficiency, confirming that there were diverse molecular mechanisms of AT deficiency depend upon discrete AT gene abnormalities as reported previously.