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Duchenne Muscular Dystrophy (DMD) is an X-linked recessive disorder. Female carriers can manifest symptoms during pregnancy, complicating diagnosis and genetic counseling before conception. This is the first report of a DMD symptomatic carrier who was managed continuously from preconception through pregnancy for symptoms recognized before conception. A 31-year-old primipara woman was incidentally noted to have premature ventricular contractions, heart failure, and elevated creatine kinase levels 2 years before pregnancy. Genetic testing confirmed that the patient was a symptomatic carrier of DMD. She had no family history of muscular or cardiac disease, suggesting a de novo variant. She received genetic counseling and planned amniocentesis during pregnancy as prenatal diagnosis. After treatment with bisoprolol and flecainide, her cardiac function improved, and natural conception was achieved. Amniocentesis performed at 16 weeks of gestation indicated a 46, XX karyotype, leading to the decision to continue the pregnancy. From week 16 to 21, the fetus exhibited bradycardia due to blocked premature atrial contraction, which later improved, although the atrioventricular interval was prolonged. The mother delivered vaginally without any complications, and the infant's atrioventricular interval normalized. Preconceptional diagnosis and treatment for DMD carrier status are crucial for shared decision-making and to achieve favorable perinatal outcomes., (© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Pravastatin is a promising medication to treat preeclampsia. However, the appropriate dose of pravastatin for managing preeclampsia has not been established. In this in vitro study, we examined the effects of low concentrations of pravastatin (0.01 to 10 µM) under hypoxic conditions on two types of placental cells and found that pravastatin decreased sFlt-1 levels up to 34% in cytotrophoblast cells isolated from human term placentas. Furthermore, we showed that sFlt-1 levels in HTR-8/SVneo cells, a cell line derived from first trimester trophoblast cells, decreased after exposure to very low concentrations of pravastatin (0.01, 0.1 µM). We also examined the effects of pravastatin on uterine spiral artery remodeling-related events and showed in wound healing and tube formation assays that low concentrations of pravastatin upregulated cell migration and invasion in HTR-8/SVneo cells. These results demonstrated that a low dose of pravastatin has in vitro effects that suggest a potential for anti-preeclamptic effects in vivo., (© 2024. The Author(s).)

Objectives: To elucidate the outcomes of periviable infants receiving active care (AC) and explore perinatal factors associated with neurodevelopmental outcomes., Methods: This is a single-center retrospective study on infants born at 22-25 weeks of gestation, all of whom received AC. A developmental quotient (DQ) ≥ 85 at corrected 18 months was judged as normal., Results: Fifty-seven infants were included in the study. The survival rates at discharge were 83%, 86%, 93%, and 93% at 22, 23, 24, and 25 gestational weeks, respectively. The overall percentage of normal DQ was 26/47 (55%). Acidemia in the arterial blood gas measured within 6 h after birth was identified as a factor significantly associated with subnormal DQ., Conclusions: Not only high survival rates, but also favorable neurodevelopmental outcomes may be achieved by AC in periviable infants. Moreover, impaired neurodevelopmental outcomes may be associated with early postnatal acidemia following initial resuscitation., (© 2024. The Author(s).)

Background: It is clinically challenging to determine when to intervene in the prolonged second stage. Although individualized prediction of spontaneous vaginal delivery is crucial to avoid maternal and neonatal complications associated with operative deliveries, the approach has not been fully established., Objective: We aimed to evaluate the predictability of spontaneous vaginal delivery using the difference in angle of progression between pushing and rest, delta angle of progression, to establish a novel method to predict spontaneous vaginal delivery during the prolonged second stage in nulliparous women with epidural anesthesia., Study Design: We retrospectively analyzed deliveries of nulliparous women with epidural anesthesia between September 2018 and October 2023. Women were included if their delta angle of progression during the second stage was available. Operative deliveries were defined as the cases that required forceps, vacuum, and cesarean deliveries due to labor arrest. Women requiring operative deliveries due to fetal and maternal concerns, or women with fetal occiput posterior presentation were excluded. The second stage was stratified into the prolonged second stage, the period after 3 hours in the second stage, and the normal second stage, the period from the beginning until the third hour of the second stage. The association of the delta angle of the progression measured during each stage with spontaneous vaginal delivery and operative deliveries was investigated. Furthermore, the predictability of spontaneous vaginal delivery was evaluated by combining the delta and rest angle of progression., Results: A total of 129 women were eligible for analysis. The delta angle of progression measured during the prolonged second stage and normal second stage were significantly larger in women who achieved spontaneous vaginal delivery compared to operative deliveries (p<.001 and p<.05, respectively). During the prolonged second stage, a cutoff of 18.8 derived from the receiver operative characteristic curves in the context of the delta angle of progression predicted the possibility of spontaneous vaginal delivery (sensitivity, 81.8%; specificity, 60.0%; AUC, 0.76). Combining the rest angle of progression (>140) and delta angle of progression (>18.8) also provided quantitative prediction of spontaneous vaginal delivery (sensitivity, 86.7%; specificity, 70.0%; AUC, 0.80)., Conclusion: The delta angle of progression alone or in combination with the rest angle of progression can be used to predict spontaneous vaginal delivery in the second stage in nulliparous women with epidural anesthesia. Quantitative analysis of the effect of pushing using the delta angle of progression provides an objective guide to assist with an assessment of labor dystocia in the prolonged second stage on an individualized basis, which may optimize labor management in the prolonged second stage by reducing neonatal and maternal complications related to unnecessary operative deliveries and prolonged second stage of labor., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aim: We aimed to investigate the associations of endometriosis and adenomyosis with pregnancy complications by using a large-scale Japanese database., Methods: We retrospectively analyzed 145 590 singleton pregnancies from the Japan Perinatal Registry Network Database. Pregnant women registered as having endometriosis or adenomyosis were designated as the case group (EA), whereas the control group (non-EA) was selected using propensity-score matching adjusted for variables such as age, parity, BMI, smoking history, and the use of assisted reproductive technology. The main outcomes included placental malposition, preterm birth, and hypertensive disorders of pregnancy (HDP)., Results: In total, 1203 patients from both the EA and non-EA groups were matched and evaluated. The EA group showed significantly higher rates of placenta previa (odds ratio [OR], 3.01; 95% confidence interval [CI], 1.84-4.92), low-lying placenta (OR, 2.02; 95% CI, 1.06-3.86), and preterm birth (OR, 1.44; 95% CI, 1.13-1.84) than the non-EA group. However, no significant difference was observed in the incidence of HDP (OR, 1.22; 95% CI, 0.90-1.66)., Conclusion: The use of propensity-score matching to analyze a nationwide perinatal database in Japan clarified that EA was associated with increased pregnancy complications, specifically placental malposition, including placenta previa and low-lying placenta, and preterm birth, but not with HDP., (© 2023 The Authors. Journal of Obstetrics and Gynaecology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Obstetrics and Gynecology.)

Objectives: Adenomyosis is associated with unfavorable perinatal outcomes, and recent case reports show that some women with adenomyosis experience pain at the adenomyosis lesion during pregnancy and have detrimental perinatal outcomes. This study aimed to clarify the clinical characteristics of this pain and perinatal outcomes associated with this phenomenon., Methods: This was a single-center retrospective analysis of pregnant women with adenomyosis. The incidence of pain onset at adenomyosis lesions, defined as persistent pain at the adenomyosis site with administration of analgesics for pain relief, and its association with perinatal outcomes were analyzed., Results: Among 91 singleton pregnancies with adenomyosis, 12 pregnancies (13.2 %) presented with pain. One pregnancy resulted in second-trimester miscarriage, and 5 of the 11 pregnancies (45 %) developed preeclampsia, which resulted in preterm delivery, and 3 of the 12 pregnancies (25 %) achieved term delivery. The incidence of preeclampsia and preterm delivery was higher in those who experienced pain than in those without (45 % [5/11] vs. 15 % [11/74]; p<0.05, and 73 % [8/11] vs. 34 % [25/74]; p<0.05, respectively). Among women with pain, the maximum C-reactive protein level was significantly higher in women who developed preeclampsia than in those who did not (5.45 vs. 0.12 mg/dL, p<0.05)., Conclusions: Our study revealed that adenomyosis can cause pain in over one of eight pregnancies with adenomyosis, which may be associated with the increased incidence of preeclampsia resulting in preterm delivery. Women with pain, especially those with high C-reactive protein levels, may be at high risk for future development of preeclampsia and consequent preterm delivery., (© 2023 the author(s), published by De Gruyter, Berlin/Boston.)

Objectives: Although adenomyosis is reportedly associated with adverse pregnancy outcomes, clinical factors related to the high risk of obstetric complications are unclear. This study aimed to elucidate the characteristics of adenomyosis lesions associated with the increased incidence of obstetric complications based on imaging findings., Methods: This was a retrospective, observational cohort study conducted in a tertiary perinatal care center. Eighty-eight singleton pregnant women with adenomyosis were included in the study. Based on magnetic resonance imaging or ultrasonography before and/or during pregnancy, patients were classified according to three types of image characteristics: the extent of adenomyosis lesion (focal type or diffuse type), location of the lesion (extrinsic type, intrinsic type, or indeterminate type), the positional relationship between the lesion and the placenta (placenta distant from adenomyosis or placenta over adenomyosis), and the incidence of obstetric complications were examined., Results: Patients with diffuse type adenomyosis are significantly more likely to have spontaneous second-trimester miscarriage (diffuse type vs. focal type: 16.7 vs. 0%, p  < .01), preterm premature rupture of membranes (19.4 vs. 1.9%, p  < .01), and preeclampsia (25.0 vs. 7.7%, p  = .02), as compared to those with focal type adenomyosis. In a comparison of the three location types, the incidence of placental malposition was higher in patients with the extrinsic type adenomyosis (extrinsic type vs. intrinsic type vs. indeterminate type: 20.0 vs. 6.7 vs. 2.3%, p  = .03). Comparisons between the types of the placenta over or distant from adenomyosis lesion displayed no significant differences in the frequencies of obstetric complications., Conclusions: We demonstrated that the frequency of obstetric complications related to adenomyosis varies depending on the extent and location of the lesion; patients with diffuse type adenomyosis have an increased risk of spontaneous second-trimester miscarriage, preterm premature rupture of membranes, and preeclampsia, while patients with extrinsic type adenomyosis have an increased risk of placental malposition. Imaging evaluation of adenomyosis prior to conception or early in pregnancy may be useful for the obstetrical risk assessment among patients with adenomyosis.

The response of autotaxin (ATX)-lysophosphatidic acid (LPA) signaling system to placental oxidative stress (OS) and its significance to preeclampsia were investigated. For this purpose, oxidative stress index (OSI) and ATX levels were measured in the serum of pregnant women with preeclampsia. The expression levels of ATX and LPA receptors were assessed in trophoblast cells under high OS and glucose deprivation/re-oxygenation (OGD/R) conditions, with particular emphasis on the antioxidative nuclear factor erythroid 2-related factor 2 (NRF2) pathway. The influence of ATX-LPA signaling on cell migration was also evaluated using the wound healing assay. ATX concentrations and OSI in the serum were found to be elevated in preeclamptic women. The serum ATX levels were also positively correlated with OSI. Trophoblast cells responded to OS by increasing ATX mRNA expression concomitantly with intranuclear translocation of Nrf2, whereas inhibition of Nrf2 activation reverted this effect. The ATX-LPA signaling pathway facilitated trophoblast cell motility after Nrf2 activation. In conclusion, OS accumulation in preeclamptic placenta may activate the ATX-LPA system in trophoblasts via the Nrf2 pathway to sustain trophoblast functionality., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Objective: Since fetal presentation is an essential factor for planning mode of delivery, the estimation of fetal presentation at delivery is important in prenatal management. This study aimed to clarify the transition of fetal presentation during pregnancy and to propose practical strategy to predict final fetal presentation., Methods: During the period of 2 years, fetal presentations were analyzed using ultrasonography during the prenatal visits at and after 22 weeks of gestation in a single facility. The relationship between the transition of fetal presentation and final presentation at delivery was analyzed. Further, a prediction model was developed to predict the final fetal presentation at birth., Results: Among 1737 singleton pregnancies with full-term delivery, non-cephalic delivery occurred in 76 pregnancies (4.4%). Non-cephalic presentation in later half of the gestational period was associated with low incidence of spontaneous cephalic version. Furthermore, we found that in 46% of women with a final non-cephalic delivery, the non-cephalic presentation continued during whole of the observational period without spontaneous cephalic version. Based on the analyzed data of this cohort, we show that in a group of women with non-cephalic presentation at 35/36 weeks, the best predictability for spontaneous cephalic version depended on whether the cephalic presentation was observed at least once at and after 30 weeks of gestation., Conclusion: Our findings suggest that information on the changes in fetal presentation during gestation contributes to the prediction of the fetal presentation at delivery and planning mode of delivery.

Aim: Cryoprecipitate (CRYO) is a concentrated preparation of coagulation factors formulated from fresh frozen plasma (FFP), which can replenish coagulation factors rapidly. Preeclampsia (PE) is frequently associated with postpartum hemorrhage (PPH), and the rapid replenishment of coagulation factors is vital in the management. We conducted a retrospective cohort study to determine the efficacy of administering CRYO irrespective of fibrinogen levels in patients with PE who experienced severe PPH., Methods: Patients with PPH accompanied by PE and those who required red blood cell (RBC) transfusion were included. Cases were divided into two groups: those treated with CRYO (N = 16) and those not treated with CRYO (N = 10). The total transfusion volume, blood loss before and after transfusion initiation, duration of hospitalization, presence of pulmonary edema, and performance of either interventional radiology or hysterectomy were compared., Results: The median fibrinogen levels before transfusion were 2.24 and 2.34 g/L in the CRYO group and the not using group, respectively. Although blood loss before transfusion was comparable between the two groups, blood loss after transfusion was significantly less in the CRYO group (median: 520 vs. 2352 mL, p = 0.015), as well as the total blood loss (median: 2285 vs. 3825 mL, p = 0.005) and total transfusion volume (median: RBC 6 vs. 16 U, p = 0.01, FFP 10 vs. 20 U, p = 0.017)., Conclusion: Prompt replenishment of coagulation factors using CRYO to patients with PE who experience severe PPH could decrease further bleeding., (© 2023 Japan Society of Obstetrics and Gynecology.)

Objective: The characteristics of pregnancy and delivery in patients with moyamoya disease (MMD) remain unclear. We retrospectively investigated perinatal outcomes in patients with MMD to evaluate the risks associated to this condition., Materials and Methods: Clinical data of women with MMD who delivered at the University of Tokyo Hospital between 2000 and 2021 were collected. Maternal characteristics including genetic data, obstetric complications, method of delivery and anesthesia, neonatal outcomes, neurological events during pregnancy, delivery, and postpartum course, were reviewed., Results: Thirteen pregnancies with MMD were identified. The median maternal age was 30 years. The initial clinical symptoms were identified as transient ischemic attack, infarction, and headache. Eight patients had a history of bypass surgery. The median gestational age at delivery was 37 weeks. DNA samples were collected from five patients, responsible for six pregnancies. Of these six cases, five had the RNF213 c.14429G > A (p.Arg4810Lys) heterozygous variant. Of the 13 pregnancies, seven had hypertensive disorder of pregnancy (HDP). Additionally, three of five pregnancy cases with RNF213 p.Arg4810Lys heterozygous variant presented with HDP. Nine patients underwent cesarean section, and four delivered vaginally with epidural anesthesia. One case of ischemic stroke was confirmed during the postpartum period. Regarding newborns, neither Apgar scores lower than 7 nor neonatal intensive care unit admissions were reported., Conclusions: This study suggests that the frequency of HDP is higher in patients with MMD compared to those with normal pregnancies. Strict blood pressure control should be performed in patients with MMD during pregnancy and postpartum period., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Adenomyosis is associated with unfavorable perinatal outcomes; however, the effect of an adenomyomectomy on pregnancy outcomes remains unclear. Pregnancy following an adenomyomectomy has been reported to be associated with a high risk for uterine rupture; however, the actual incidence remains unknown., Objective: This study aimed to evaluate the effect of an adenomyomectomy on pregnancy outcomes by retrospectively comparing the pregnancy outcomes of women who underwent an adenomyomectomy with those of women with adenomyosis., Study Design: This was a single-center retrospective study in which the pregnancy outcomes of women who underwent an adenomyomectomy and for whom complete resection of the affected tissue under laparotomy was achieved were compared with those of women with adenomyosis. The following pregnancy outcomes were examined: second-trimester miscarriage, preterm prelabor rupture of membranes, preterm delivery, spontaneous preterm delivery, preeclampsia, rate of cesarean delivery, blood loss during cesarean delivery, incidence of placenta accreta spectrum, neonatal body weight, and small for gestational age infants., Results: A total of 18 pregnant women who underwent an adenomyomectomy and 105 pregnant women with adenomyosis were included in this study. All women who underwent an adenomyomectomy delivered via cesarean delivery, and among them, 1 had a uterine rupture at 30 weeks of gestation. Although there was no significant difference between pregnant women who underwent an adenomyomectomy and those with adenomyosis in the incidence of second-trimester miscarriage (0% [0/18] vs 7.6% [8/105], respectively; P =.22), preterm delivery (50% [9/18] vs 32% [34/105], respectively; P =.15), and spontaneous preterm delivery (6% [1/18] vs 15% [16/105], respectively; P =.26), a significant decrease in preterm prelabor rupture of membrane (0% [0/18] vs 12% [13/105], respectively; P <.05), preeclampsia (0% [0/18] vs 12% [13/105], respectively; P <.05), and small for gestational infants (0% [0/18] vs 15% [16/105], respectively; P <.05), as well as a significant increase in the incidence of placenta accreta spectrum (50% [9/18] vs 0% [0/105], respectively; P <.01) and blood loss during cesarean delivery (1748 mL vs 1330 mL, respectively; P <.05) were observed., Conclusion: Uterine rupture following an adenomyomectomy may occur because of the high incidence of placenta accreta spectrum. However, an adenomyomectomy may reduce adverse pregnancy outcomes associated with adenomyosis, such as preterm prelabor rupture of membranes, preeclampsia, and small for gestational age infants. An adenomyomectomy may be a viable option for women among whom the procedure is inevitable before conception., (© 2023 The Authors.)

Background: Management of a bladder tumor during pregnancy is an uncommon clinical situation. Leiomyosarcoma of the urinary bladder is a rare histological type of bladder tumor and a rare secondary cancer in survivors of retinoblastoma (RB). However, there has been no report of RB-associated bladder leiomyosarcoma during pregnancy., Case Presentation: A 37-year-old pregnant woman with a medical history of RB in infancy presented with gross hematuria at the 17 th week of gestation. Cystoscopy revealed a 40-mm papillary tumor on the left lateral wall of the urinary bladder. At the 25 th week of gestation, she underwent transurethral resection of the bladder tumor, and the pathological diagnosis was bladder leiomyosarcoma with loss of RB1 expression. At the 31 st week of gestation, she gave birth by caesarean section. One month after the delivery (to allow for involution of the uterus), she underwent partial cystectomy, and the specimen contained no residual leiomyosarcoma tissue., Conclusions: We have reported a case of RB-associated bladder leiomyosarcoma that was successfully treated during and after pregnancy., (© 2023. The Author(s).)

Background: No previous study has evaluated the transitions of intrapartum transperineal ultrasound parameters during labor progression in cephalic malposition., Objective: We aimed to quantitate the characteristic trends of fetal head position and descent in cephalic malposition by analyzing the transitions of intrapartum transperineal ultrasound parameters and explore an indicator associated with the degree of cephalic malposition., Study Design: We retrospectively analyzed pregnant women who delivered at term from January 2018 to December 2020 at the University of Tokyo Hospital. The fetal occipital position was classified as occiput anterior and nonocciput anterior according to the fetal occipital angle of 0° to 75° and 75° to 180°, respectively. Fetal occipital angle was defined by the midline angle and position of the ocular orbit. The differences in the trends of head direction, head-symphysis distance, and progression distance relative to the angle of progression between occiput anterior and nonocciput anterior cases were evaluated. In addition, the parameters that showed differences were analyzed to evaluate their relationship to the degree of cephalic malposition., Results: A total of 502 images (occiput anterior, 319; nonocciput anterior, 183) met the inclusion criteria. The distribution of head direction values relative to the angle of progression was smaller in the nonocciput anterior group than in the occiput anterior group, whereas the head-symphysis distance and progression distance values relative to the angle of progression showed no difference in their distribution between the occiput anterior and nonocciput anterior groups. The ratio of head direction to the angle of progression was significantly smaller in the nonocciput anterior group than in the occiput anterior group (median [interquartile range], 0.03 [-0.02 to 0.10] vs 0.21 [0.12-0.28]; P<.0001). Furthermore, this ratio was negatively correlated with fetal occipital angle (Spearman correlation coefficient, -0.66)., Conclusion: Our results indicated that the head direction to angle of progression ratio reflects the deviation in the fetal head direction toward the maternal dorsal side, and decreases in proportion to the degree of cephalic malposition. This concept of deviation in the head direction as an indicator for evaluating cephalic malposition with intrapartum transperineal ultrasound may contribute to improving labor management in the case of cephalic malposition., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Preeclampsia (PE) is a hypertensive obstetric disorder with poor prognosis for both the mother and offspring. Infants born to mothers with PE are known to be at increased risk of developing higher brain dysfunction, such as autism. However, how maternal PE can affect the environment in the fetal brain has not been fully elucidated. Here, we examined the impact of PE on the fetal brain in a mouse model of PE induced by angiotensin II (Ang II), focusing on changes in the inflammatory condition. We confirmed that pregnant mice which were continuously administered Ang II exhibited PE phenotypes, including high blood pressure, proteinuria, and fetal growth restriction. Quantitative RT-PCR analysis demonstrated that the brain of fetuses on embryonic day 17.5 (E17.5) in the Ang II-administered pregnant mice showed increased expression of cytokines, interleukin (IL)- 6, IL-17a, tumor necrosis factor-α, interferon-γ, IL-12, IL-4, and IL-10. Immunohistochemical analysis over a wide area, from the tip of the frontal lobe to the posterior cerebral end, on E17.5 revealed that the microglia in the fetal brain of the Ang II-administered group displayed higher solidity and circularity than those of the control group, indicating that the microglia had transformed to an amoeboid morphology and were activated. Our findings suggest that maternal PE may cause altered inflammatory conditions in the fetal brain, which might be associated with the pathological mechanism connecting maternal PE and brain dysfunction in the offspring., Competing Interests: Conflicts of Interest The authors declare no conflicts of interest associated with this manuscript., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: Intrapartum transperineal ultrasound is considered useful in judging fetal head descent; however, the inability to detect ischial spines on ultrasound images has been a drawback to its legitimacy. The current study aimed to determine the anatomical location of ischial spines, which can be directly applied to intrapartum transperineal ultrasound images., Method: Based on magnetic resonance imaging (MRI) of 67 pregnant women at 33 +2 [31 +6 -34 +0 ] weeks gestation (median [interquartile range: IQR]), we calculated the angle between the pubic symphysis and the midpoint of ischial spines (midline symphysis-ischial spine angle; mSIA), which is theoretically equivalent to the angle of progression at fetal head station 0 on ITU, by determining spatial coordinates of pelvic landmarks and utilizing spatial vector analysis. Furthermore, we measured symphysis-ischial spine distance (SID), defined as the distance between the vertical plane passing the lower edge of the pubic symphysis and the plane that passes the ischial spines., Results: As a result, mSIA was 109.6° [105.1-114.0] and SID 26.4 mm [19.8-30.7] (median, [IQR]). There was no correlation between mSIA or SID and maternal characteristics, including physique., Conclusions: We established a novel method to measure the components of the pelvic anatomy by analyzing the three-dimensional coordinates of MRI data and identified the anatomical location of ischial spines which can be applied to ultrasound images. Our results provide valuable evidence to enhance the reliability of intrapartum transperineal ultrasound in assessing fetal head descent by considering the location of ischial spines.

The purpose of this study was to establish a novel mouse model of adenomyosis suitable for longitudinal and quantitative analyses and perinatal outcome studies. Using a 30 G needle, the entire uterine wall of one horn was mechanically punctured at a frequency of 100 times/1 cm (adenomyosis horn). The other horn was left unpunctured (control horn). Balb/c mice were sacrificed on day 14 (D14) or day 65 (D65) (n = 3 each). The uterus was fixed, paraffin-embedded, sliced, and stained. Lesions were detected and counted, and their volumes were measured. Cell proliferation and fibrosis were assessed by Ki67 and Masson's Trichrome staining, respectively. Blood vessels were detected using CD31 immunostaining. Some of the mice (n = 4), were mated and the date of delivery, litter size, number of implantations, and number and volume of postpartum lesions were measured. The number of lesions per horn did not differ between D14 and D65. The volume of the entire lesion was significantly greater on D65 than on D14 (p < 0.0001). The volume of the epithelial part of the lesion was significantly greater in D65 (p < 0.0001). The volume of the stromal part of the lesion was also greater on D65 (p < 0.0001). The percentage of Ki67 positive cells in the epithelial part of the lesion was significantly higher on D14 (p < 0.05). In contrast, the percentage of Ki67-positive cells in the stromal part was significantly higher on D65 (p < 0.01). Vascular density in the lesions was higher in on D65 (p < 0.05). The percentage of fibrotic area was significantly higher on D65 (p < 0.01). The date of delivery was slightly earlier than that reported for healthy mice of the same strain. The litter size was smaller than that reported in previous research. The number of implantation sites did not differ between the control and the adenomyosis horn. The number and volume of lesions did not differ between the non-pregnant and postpartum groups. This model can be applied to evaluate the pathogenesis of adenomyosis, validate the efficacy of therapeutic agents, and evaluate the effect of adenomyosis on pregnancy and vice versa., (© 2022. The Author(s).)

The purpose of this study was to establish a new mouse model of endometriosis that mimics real-world women's health problems, in which women continue to be affected by endometriosis long before they wish to become pregnant, and to evaluate the impact of "chronic exposure to endometriosis" on perinatal outcome. Endometriosis was established by the intraperitoneal injection of homologous minced mouse uteri. Vehicle was injected for the control. Mating was initiated either 1 or 43 days after disease establishment (Young or Aged studies, respectively). Mice were sacrificed on 18 dpc. The number pups and resorptions were counted and pups' body weights (BW) were measured, and the endometriosis lesion was identified and weighted. In the Young study, the number of resorptions and BW were comparable between the groups. In the Aged study, the number of resorptions was significantly higher and BW was significantly lower in endometriosis than that in control. The total weight of endometriosis lesion per dam was significantly lower in the Aged compared to the Young endometriosis group; however, not a single mouse was found to have any lesions at all. These results suggest that in addition to the presence of endometriosis per se, "chronic exposure to endometriosis" prior to pregnancy affect perinatal outcomes.

Aim: We aimed to assess the impact of fetal growth restriction (FGR) as a diagnostic criterion for preeclampsia (PE) on the severity of maternal preeclamptic features by comparing it with other diagnostic criteria for PE, maternal organ dysfunction., Methods: We performed a retrospective cohort study of singleton pregnancies. Based on the status at diagnosis, PE cases preceded by FGR without maternal organ dysfunction (Group F; n = 28) and those preceded by maternal organ dysfunction without FGR (Group M; n = 87) were analyzed., Results: Group F had an earlier PE diagnosis (32.5 ± 4.9 vs. 36.7 ± 3.5 weeks, p < 0.01) and delivery (33.7 ± 4.5 vs. 37.5 ± 3.1 weeks, p < 0.01) than Group M. No significant differences in maternal morbidities were observed between the groups, including severe hypertension (75.0 vs. 60.0%), need for intravenous antihypertensives (42.9 vs. 48.3%) or magnesium sulfate (60.7 vs. 54.5%), or a composite of major maternal complications (17.9 vs. 21.8%). When limited to early-onset PE diagnosed before 34 weeks of gestation (17 and 17 cases in Group F and M, respectively), the frequencies of maternal morbidities (severe hypertension: 70.6 vs. 52.9%, intravenous antihypertensives: 35.3 vs. 35.3%, magnesium sulfate: 58.8 vs. 47.1%, major complications: 29.4 vs. 23.5%) and the duration from diagnosis until delivery (11.2 ± 14.7 vs. 16.5 ± 21.7 days) were comparable between two groups., Conclusions: Our results suggest that the presence of FGR on PE diagnosis is associated with the development of severe maternal symptoms as much as that of maternal organ dysfunction at diagnosis, and it may be reasonable to include FGR in PE diagnostic criteria., (© 2022 Japan Society of Obstetrics and Gynecology.)

Introduction: Placental dysfunction triggers fetal growth restriction in congenital human cytomegalovirus (HCMV) infection. Studies suggest that HCMV infection interferes with the differentiation of human trophoblasts. However, the underlying mechanisms have not been clarified. This study investigated the impact of HCMV infection on gene transcriptomes in cytotrophoblasts (CTBs) associated with placental dysfunction., Methods: CTBs were isolated from human term placentas, and spontaneous syncytialization was observed in vitro. The transcriptome profiles were compared between CTB groups with and without HCMV infection by cap analysis gene expression sequencing. The effect of HCMV infection on trophoblast differentiation was evaluated by examining cell fusion status using immunocytochemical staining for desmoplakin and assessing the production of cell differentiation markers, including hCG, PlGF, and soluble Flt-1, using ELISA., Results: The expression of the genes categorized in the signaling pathways related to the cell cycle was significantly enhanced in CTBs with HCMV infection compared with uninfected CTBs. HCMV infection hindered the alteration of the gene expression profile associated with syncytialization. This suppressive effect under HCMV infection was concurrent with the reduction in hCG and PlGF secretion. Immunostaining for desmoplakin revealed that HCMV infection reduced the cell fusion of cultured CTBs. These findings imply that HCMV infection has a negative impact on syncytialization, which is indispensable for the maintenance of villous function., Discussion: HCMV infection interferes with gene expression profiles and functional differentiation of trophoblasts. Suppression of syncytialization may be a survival strategy for HCMV to expand infection and could be associated with placental dysfunction., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Loeys-Dietz syndrome (LDS) is a connective tissue disorder with a high incidence of aortic dissection (AD). After treating two previously reported cases of postpartum AD in women with LDS following prophylactic aortic root replacement (ARR), we succeeded in managing a 30-year-old primigravida with no AD during her peripartum period. On the basis of the patient's stated desire to conceive during preconception counseling, a multidisciplinary team was assembled. She conceived naturally after receiving prophylactic ARR and beta-blocker treatment. Multidisciplinary patient care included precise blood pressure management, continuation of beta-blocker treatment, cardiovascular assessment with echocardiogram, regional anesthesia during labor, prevention of lactation, and resumption of angiotensin II receptor blocker therapy immediately after delivery. On the basis of our assessment of three cases, including this case, and a literature review, we propose a peripartum management strategy for patients with LDS following prophylactic ARR.

Introduction: Disturbance in placental epigenetic regulation contributes to the pathogenesis of preeclampsia (PE). Although aberrant placental DNA methylation status in PE has been thoroughly studied, the role of histone modifications, including histone methylation, in PE remains unclear. Moreover, no study has ever reported the association between PE and placental histone methylation status by focusing on histone methyltransferases. The present study aimed to investigate the possible involvement of placental epigenetic regulation by histone methylation via histone methyltransferases in the pathophysiology of PE., Methods: Placental mRNA expression of histone methyltransferases was examined using quantitative RT-PCR. Protein expression of histone methyltransferases and histone methylation status in placentas and trophoblast cell lines were assessed by immunoblotting and immunohistochemistry., Results: Expression profile of histone methyltransferases in the placentas using quantitative RT-PCR revealed that the mRNA expression levels of histone 3 lysine 4 (H3K4) methyltransferases, SETD1A and SMYD3, were significantly increased in placentas from PE patients. Immunoblotting and immunohistochemistry revealed that not only protein expression levels of SETD1A and SMYD3, but also H3K4 methylation status was increased in the trophoblasts from PE placentas. In vitro studies using HTR-8/SV-neo and BeWo cells showed that hypoxia induced the expression levels of SETD1A and SMYD3, and subsequently enhanced H3K4 methylation. Furthermore, the overexpression of SETD1A and SMYD3 in HTR-8/SV-neo cells enhanced H3K4 methylation in response to hypoxia., Discussion: Our study results suggest that placental epigenetic alteration by enhanced histone H3K4 methylation through upregulated SETD1A and SMYD3 might play a role in the pathophysiological process of PE associated with hypoxia., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Two prospective multicenter studies demonstrated that a soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio cutoff of ≤38 can rule out preeclampsia within 1 week with a negative predictive value (NPV) of 99.3% (PROGNOSIS) and 98.6% (PROGNOSIS Asia). We report a subanalysis of the Japanese cohort from the PROGNOSIS Asia study. Pregnant women with suspected preeclampsia between gestational weeks 18 + 0 days and 36 + 6 days were enrolled at eight Japanese sites. Primary objectives: Assess the performance of the Elecsys ® sFlt-1/PlGF ratio cutoff ≤38 to rule out preeclampsia within 1 week and of the cutoff >38 to rule in preeclampsia within 4 weeks. Key secondary objectives: Prediction of maternal and fetal adverse outcomes (MAOs/FAOs) and their relationship with duration of pregnancy. Of 192 women enrolled, 180 (93.8%)/175 (91.1%) were evaluable for primary/combined endpoint analyses. Overall preeclampsia prevalence was 13.3%. A sFlt-1/PlGF ratio of ≤38 provided an NPV of 100% (95% confidence interval [CI], 97.5-100) for ruling out preeclampsia within 1 week, and a ratio of >38 provided a positive predictive value of 32.4% (95% CI, 18.0-49.8) for ruling in preeclampsia within 4 weeks. The area under the curve for the prediction of preeclampsia/maternal/fetal adverse outcomes within 1 week was 94.2% (95% CI, 89.3-97.8). After adjusting for gestational age and final preeclampsia status, Cox regression indicated a 2.8-fold greater risk of imminent delivery for women with a sFlt-1/PlGF ratio >38 versus ≤38. This subanalysis of Japanese women with suspicion of preeclampsia showed high predictive value for a Elecsys sFlt-1/PlGF ratio cutoff of 38 for short-term prediction of preeclampsia.

Objectives: To investigate the spontaneous outcomes of vascularized retained products of conception (RPOC) detected by ultrasonography after second-trimester abortion, and to identify the predictive factors for the development of severe postpartum hemorrhage (SPPH). Study design: This is a retrospective cohort study on all cases after second-trimester abortion managed at our institute between January 2014 and December 2016. We assessed the associations between the occurrence of SPPH requiring invasive treatment and clinical factors including ultrasonographic findings (size and the vascularity status of RPOC classified as follows: type 1: vascularity confined to endometrium, type 2: vascularity reaching <1/2 myometrium, and type 3: vascularity reaching ≥1/2 myometrium) in vascularized RPOC cases. Results: Among 103 cases after second-trimester abortion, 19 patients (18.4%) were diagnosed as RPOC, and five patients eventually failed expectant management due to SPPH. Of them, 66.7% (4/6) of patients with type 3 developed SPPH as compared with 7.7% (1/13) of patients with type 1/type 2 ( p  < .05). The maximum vascularized mass diameter was significantly greater among the five patients who experienced SPPH than among the 14 patients who demonstrated spontaneous remission (43.0 ± 12.0 mm versus 20.7 ± 8.3 mm, p  < .01). Patients with type 3 RPOC and a maximum vascularized mass diameter ≥30 mm, compared with other patients, demonstrated sensitivity, specificity, and risk ratio related to SPPH of 80, 92.9%, and 11.2, respectively. Conclusions: Our findings suggest that the ultrasonographic assessment of RPOC focused on the depth of vascularity in combination with the measurement of its size appears to be essential in determining women with RPOC who are at high risk for SPPH.

Secretory leukocyte protease inhibitor (SLPI) and progranulin (PGRN) are secretory proteins with an anti-inflammatory property. Their involvement in cervical remodeling in pregnant uterus is not yet elucidated. Thus, this study aimed to explore the significance of SLPI and PGRN in the maintenance of pregnancy by investigating the factors associated with their expression levels at the cervix. Concentrations of SLPI and PGRN proteins were measured in cervical mucus samples collected from asymptomatic pregnant women at 24-26 weeks of gestation (n = 166). The concentrations of those molecules were analyzed with clinical parameters related to risk for preterm delivery (PD). In pregnant mice, we evaluated the effect of lipopolysaccharide-induced inflammation and progesterone effect modulation on cervical mRNA expression of SLPI and PGRN. The cervical PGRN level was significantly lower in women with short cervix (<35 mm) and with a history of threatened PD. In women with short cervix, cervical SLPI concentrations were positively correlated with inflammatory cytokines, interleukin-6 (R 2 = 0.75) and interleukin-8 (R 2 = 0.71). In pregnant mice, cervical mRNA expressions of PGRN and SLPI were increased in response to progesterone supplementation and were suppressed by a progesterone antagonist, mifepristone. Lipopolysaccharide-induced inflammation caused remarkable upregulation in cervical SLPI mRNA level but not in PGRN. Progesterone and local inflammation are the factors controlling expression levels of PGRN and SLPI at the cervix. The observed relationship of PGRN and SLPI levels in the cervical mucus with PD-related clinical parameters supports that those anti-inflammatory molecules possibly play a significant role in appropriate regulation of cervical remodeling., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Preeclampsia is characterized by the emergence of hypertension and proteinuria after 20 weeks of pregnancy, and it threatens both maternal and fetal lives if it proceeds unabated. Despite numerous studies, thus far the only fundamental therapy for preeclampsia is termination of pregnancy, leading to preterm birth. Furthermore, preeclamptic women are reported to be at risk for cardiovascular diseases for 10 years after delivery. Therefore, preventative and therapeutic strategies for preeclampsia are required. Recently, statins have been reported to improve the regeneration of vascular endothelium, and pravastatin has attracted attention as a potential preventative or therapeutic candidate for preeclampsia. Pravastatin has been demonstrated to have preventative effects in preeclampsia model mice, and a large volume of human data from pregnant women taking statins supports the safety of these drugs. Moreover, small clinical trials have reported that pravastatin has strong preventative or therapeutic effects on preeclampsia and it has the potential to improve the prognosis of pregnant women, fetuses and neonates affected by this condition., (© 2020 Japan Society of Obstetrics and Gynecology.)

Regulatory T (Treg) cells are a specialized subset of T cells possessing immunosuppressive functions indispensable for the maintenance of self-tolerance and pregnancy. However, how functional Treg cells dynamically change and are engaged in feto-maternal tolerance during human pregnancy is still unclear. Recent studies have shown that functionally distinct and immunosuppressive subsets of Treg cells, i.e., effector Treg (eTreg) and naïve Treg (nTreg) cells, can be delineated by combinations of molecular markers and that their proportions differ in normal and disease states. In this study, we examined how the proportion of eTreg and nTreg cells in peripheral blood changes in the 1 st , 2 nd , and 3 rd trimesters of pregnancy and the postpartum period. During the 2 nd trimester the proportion of eTreg cells was reduced while nTreg cells was increased. This pattern was maintained throughout the 3 rd trimester of pregnancy. The kinetics of eTreg reduction highly correlated with migration of eTreg cells into feto-maternal interface while stable nTreg proportion paralleled with their expression of the anti-apoptotic molecule Bcl-2 and production of thymic emigrant naïve Treg cells. These results suggest that further studies on divergence of functional Treg proportions will be helpful for predicting instability of pregnancy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aim: This study aimed at evaluating the additional anti-tumor effects of exogenous rVEGFR1 (sFlt1) on conventional chemotherapy in ovarian cancer cell lines., Methods: We utilized cells from two ovarian cancer cell lines, SKOV3 and HeyA8, and treated them with a combination of rVEGFR1 (sFlt1) and carboplatin as well as rVEGFR1 (sFlt1) alone. First, we evaluated cell survival after treatment by using cell counting and MTS assays. Next, we performed Ki67 staining for evaluating the inhibitory effects of the treatment on cell proliferation, and a lactate dehydrogenase (LDH) assay for evaluating cytotoxicity. Finally, to determine whether MAP kinase signaling is involved in this process, we performed western blot analysis of extracellular signal-regulated kinase (ERK), phospho-ERK, c-jun n-terminal kinase (JNK) and phospho-JNK., Results: The cytotoxic and growth-restriction effects were more pronounced in the group co-administered with rVEGFR1 (sFlt1) and carboplatin than in cells treated with either rVEGFR1 (sFlt1) or carboplatin alone. Quantitative analysis of Ki67-positive cells also showed a decreased proportion of Ki67-positive cells in SKOV3 cells treated with a combination of exogeneous rVEGFR1 (sFlt1) and carboplatin compared to that in cells treated with either rVEGFR1 (sFlt1) or carboplatin alone. In the LDH assay, we also found significantly enhanced cell toxicity from the combination therapy. Finally, western blotting analysis showed that the MAPK signaling pathway was not affected by sFlt1 treatment., Conclusion: This study confirmed the additive effects of rVEGFR1 (sFlt1) combined with conventional chemotherapy for ovarian cancer growth in in vitro assays, thus suggesting the combination of rVEGFR1 (sFlt1) and carboplatin as a potential novel therapeutic option for ovarian cancer., (© 2020 Japan Society of Obstetrics and Gynecology.)

Objective: Additional risk factors for preterm delivery in pregnant women with cervical shortening are not fully understood; however, mid-trimester cervical shortening is accepted as a risk factor for preterm delivery. This study aimed to identify risk factors associated with subsequent preterm delivery among patients with short cervix detected after late mid-trimester., Materials and Methods: This was a retrospective study of medical data from a single perinatal tertiary facility. We identified 134 asymptomatic women with singleton pregnancies where cervical shortening (≤25 mm) was detected during routine universal screening at 22-33 weeks. Statistical analyses were conducted to identify causal relationships between the incidence of preterm delivery and known risk factors for preterm delivery., Results: Incidence of preterm delivery was 27.6% (37/134) and preterm premature rupture of membrane was preceded in 46.0% (17/37) of the women with preterm delivery. Using logistic regression analysis, we identified uterine contractions [aOR 4.25, 95% confidence intervals (CI):1.68-12.1] and increased C-reactive protein (CRP) and increased white blood cell (WBC) in blood test (CRP: aOR 3.45, 95% CI:1.50-9.71; WBC: aOR 1.28, 95% CI: 1.08-1.55) as risk factors which significantly increased the risk of preterm delivery among women diagnosed with short cervix. Preterm delivery occurred in 91% of women positive for both uterine contractions and CRP >0.5 mg/dl., Conclusions: Uterine contraction and elevated CRP were additional risk factors for preterm delivery among women with short cervix. These results might be clinically useful to evaluate subsequent risk for preterm delivery in asymptomatic pregnant women presenting with short cervix in mid-pregnancy., (Copyright © 2020. Published by Elsevier B.V.)

Recent evidence indicates that elevated placental adenosine signaling contributes to preeclampsia (PE). However, the molecular basis for the chronically enhanced placental adenosine signaling in PE remains unclear. Here, we report that hypoxia-inducible factor-1α (HIF-1α) is crucial for the enhancement of placental adenosine signaling. Utilizing a pharmacologic approach to reduce placental adenosine levels, we found that enhanced adenosine underlies increased placental HIF-1α in an angiotensin receptor type 1 receptor agonistic autoantibody (AT 1 -AA)-induced mouse model of PE. Knockdown of placental HIF-1α in vivo suppressed the accumulation of adenosine and increased ecto-5'-nucleotidase (CD73) and adenosine A 2B receptor (ADORA2B) in the placentas of PE mouse models induced by AT 1 -AA or LIGHT, a TNF superfamily cytokine (TNFSF14). Human in vitro studies using placental villous explants demonstrated that increased HIF-1α resulting from ADORA2B activation facilitates the induction of CD73, ADORA2B, and FLT-1 expression. Overall, we demonstrated that (a) elevated placental HIF-1α by AT 1 -AA or LIGHT upregulates CD73 and ADORA2B expression and (b) enhanced adenosine signaling through upregulated ADORA2B induces placental HIF-1α expression, which creates a positive feedback loop that promotes FLT-1 expression leading to disease development. Our results suggest that adenosine-based therapy targeting the malicious cycle of placental adenosine signaling may elicit therapeutic effects on PE., (© 2020 Federation of American Societies for Experimental Biology.)

It is widely accepted that enhanced uterine inflammation associated with microbial infection is a main causative factor for preterm birth. However, little is known about the molecular basis by which inflammation is associated with preterm birth. Here, we demonstrate that apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein 3-kinase family, facilitates inflammation-induced preterm birth and that inhibition of ASK1 activity is sufficient to suppress preterm birth. ASK1-deficient pregnant mice exhibited reduced incidence of lipopolysaccharide (LPS)-induced preterm birth. ASK1 was required for the induction of LPS-induced inflammatory responses related to preterm birth, including pro-inflammatory cytokine production in the uterus and peritoneal cavities. In addition, selective suppression of uterine ASK1 activity through a chemical genetic approach reduced the incidence of LPS-induced preterm birth. Moreover, translational studies with human choriodecidua demonstrated that ASK1 was required for LPS-induced activation of JNK and p38 and pro-inflammatory cytokine production. Our findings suggest that ASK1 activation is responsible for the induction of inflammation that leads to preterm birth and that the blockade of ASK1 signaling might be a promising therapeutic target for preventing preterm birth.

Background: The uterus is an organ that is directly accessible via the transvaginal route, whereas the drug delivery system and the gene delivery system (GDS) for the uterus are very limited, even in animal models. In the present study, we optimized a bionanocapsule (BNC) comprising a hepatitis B virus envelope L-protein particle, for which a structurally similar particle has been used as an immunogen of a conventional HB vaccine worldwide for more than 30 years, as a local uterine GDS using a mouse model., Methods: To display various antibodies for re-targeting to different cells other than hepatic cells, the pre-S1 region of BNC was replaced with a tandem form of the protein A-derived immunoglobulin G Fc-interacting region (Z domain, ZZ-BNC). To induce strong cell adhesion after local administration into the uterine cavity, ZZ-BNC was modified with a transactivator of transcription (TAT) peptide., Results: Gene transfer using TAT-modified ZZ-BNC is approximately 5000- or 18-fold more efficient than the introduction of the same dose of naked DNAs or the use of the cationic liposomes, respectively. TAT-modified ZZ-BNC was rapidly eliminated from the uterus and had no effect on the pregnancy rate, litter size or fetal growth., Conclusions: TAT-modified ZZ-BNC could be a useful GDS for uterine endometrial therapy via local uterine injection., (© 2019 John Wiley & Sons, Ltd.)

Problem: Recent advances in lipid research have revealed that impairments in lipid mediator signaling can be involved in the pathoetiology of a variety of diseases. We previously reported aberrant expression of autotaxin, a key enzyme for lysophosphatidic acid (LPA) production, in placentas from women with preeclampsia. The present study aimed to further explore the involvement of LPA signaling in the pathoetiology of preeclampsia., Method of Study: Term placentas were obtained from deliveries after uncomplicated pregnancy (n = 18) and those complicated by preeclampsia (n = 24). First-trimester placental tissues were collected after elective terminations of pregnancy (n = 20). Placental expression of the six identified LPARs (LPAR1-6) was analyzed at protein and mRNA levels., Results: In normal pregnancy, the mRNA expression levels of all LPARs except LPAR4 were significantly higher in term. Levels of mRNA encoding LPAR2-5 were significantly increased in preeclampsia placentas compared with those in the normal term placentas. Using Western immunoblotting, only LPAR3 was noted to be increased at the protein level in placentas from preeclamptic pregnancies. This was validated by immunohistochemistry., Conclusion: In summary, the placental expression of LPARs, particularly LPAR3, is enhanced in preeclampsia, suggesting that disturbances in placental LPA signaling may be involved in the pathogenesis of preeclampsia., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Preeclampsia, a systemic vascular disorder characterized by new-onset hypertension and proteinuria after 20 weeks of gestation, is the leading cause of maternal and perinatal morbidity and mortality. Maternal endothelial dysfunction caused by placental factors has long been accepted with respect to the pathophysiology of preeclampsia. Over the past decade, increased production of placental antiangiogenic factors has been identified as a placental factor leading to maternal endothelial dysfunction and systemic vascular dysfunction. This review summarizes the recent advances in understanding the molecular mechanisms of endothelial dysfunction caused by placental antiangiogenic factors, and the novel clinical strategies based on these discoveries.

Recently, advanced maternal age (AMA) has been increasing due to late marriage and assisted reproductive technology. AMA is high-risk pregnancy associated with the life-threatening diseases such as hypertensive disorders of pregnancy (HDP). Recently we have reported novel AMA model mice using aged spontaneous pregnant mice, and found that the phenotypes of AMA model mice reflect the same characteristics as human AMA. We have also demonstrated that atypical angiogenic factors profiles including soluble VEGF-R1 (sFlt-1) and placental growth factor in both AMA pregnant women and AMA model mice. VEGF-endothelin-1 system have been also known as one of HDP-associated factors, however, there has been few reports on the relation between VEGF-endothelin-1 system and AMA. In this study, we investigated the profiles of VEGF-endothelin-1 system using our model mice's samples. As a result, VEGF and endothelin-1 levels were not significantly different between AMA and young individuals. Our results indicated that the mechanisms of hypertension in AMA may differ from those in young individuals from the point of VEGF-endothelin-1 system., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Hydatidiform moles are known to pose an extremely high risk of severe early-onset preeclampsia if left untreated. TNF superfamily cytokine, LIGHT has recently been reported to contribute to pathophysiology of preeclampsia. The present study aimed to investigate the involvement of LIGHT in hydatidiform moles. We measured the serum levels of LIGHT and sFlt-1 by ELISA in 17 women with complete hydatidiform mole (HM) and 20 gestational-age-matched normal pregnant women (control). As a result, the serum LIGHT levels were significantly higher in HM as compared with those in control (69.9 ± 9.6 pg/ml vs 25.4 ± 5.3 pg/ml, p = 0.0001) and the serum levels of LIGHT were significantly positively correlated with those of sFlt-1 in HM (r = 0.68, p = 0.0029). Immunohistochemical analysis revealed that the expression levels of LIGHT were increased in HM placentas as compared with controls, and LIGHT and sFlt-1 were co-localized in the trophoblast cells of HM. In vitro studies using primary syncytiotrophoblast cells demonstrated that LIGHT directly induced sFlt-1 expression in trophoblast cells. Our results indicated that elevated LIGHT in the trophoblast cells of hydatidiform mole induces sFlt-1, which might underlie the pathogenic mechanism of early-onset preeclampsia developing secondary to molar pregnancies.