高橋 宏典

Small extracellular vesicles (small EVs) play pivotal roles in intercellular communication and pregnancy maintenance, but their clinical significance in preeclampsia (PE) remains unclear. We obtained plasma samples from non-pregnant women, healthy pregnant women, and patients with early-onset (EoPE) and late-onset PE (LoPE). Small EVs were isolated using ultracentrifugation and validated using transmission electron microscopy and nanoparticle tracking analysis; in addition, Western blotting was performed to identify suitable surface markers for plasma-derived small EVs. In our analysis, we consistently detected cluster of differentiation 9 (CD9), whereas classical markers such as cluster of differentiation 63 (CD63) and tumor susceptibility gene 101 (TSG101) were absent. In a prospective, nested case-control study, we analyzed first-trimester samples by using a CD9-based ELISA for small-EV quantification. The number of small EVs did not significantly differ between non-pregnant and healthy pregnant women regardless of the gestational age. However, EVs were significantly elevated in both EoPE (3.5-fold) and LoPE (1.5-fold) compared with matched controls. First-trimester EV levels did not show differences between women who later developed PE and normal controls. These findings indicate that CD9 is a promising marker for plasma-derived small EVs and that an elevated number of small EVs is associated with established PE but has limited predictive value in early pregnancy. Further studies are required to elucidate the cellular origin and clinical implications of small EVs in PE.

We aimed to investigate the effects of serum sFlt-1/PlGF ratio levels in women with suspected or confirmed early-onset preeclampsia and super-imposed preeclampsia (PE/SPE) on composite and individual adverse maternal and fetal outcomes, stratified by gestational age at blood sampling (<34, 34-36, and ≥37 weeks). We also evaluated whether serum sFlt-1/PlGF ratio levels influenced the time interval from blood sampling to delivery. This prospective cohort study assessed serum levels of sFlt-1, PlGF, and the sFlt-1/PlGF ratio in women with suspected or confirmed PE/SPE admitted to a tertiary maternal-fetal-neonatal center between 2012 and 2023. Finally, 241 women were analyzed. An elevated sFlt-1/PlGF ratio at <34 weeks of gestation, but not at 34-36 or ≥37 weeks, was significantly associated with composite adverse maternal and fetal outcomes in women with suspected or confirmed PE/SPE. An sFlt-1/PlGF ratio of 400 was identified as the optimal cut-off level for predicting composite adverse maternal and fetal outcomes at <34 weeks. Among women with suspected or confirmed early-onset PE/SPE, HELLP syndrome alone was significantly associated with an sFlt-1/PlGF ratio ≥400. Additionally, the sFlt-1/PlGF ratio was significantly higher in women with HELLP syndrome, abnormal umbilical artery Doppler findings, or non-reassuring fetal status (NRFS) requiring immediate delivery, compared with those without these conditions. Furthermore, the interval from blood sampling to delivery significantly shortened with increasing sFlt-1/PlGF ratio. In conclusion, elevated sFlt-1/PlGF ratios were significantly associated with HELLP syndrome, abnormal umbilical artery Doppler findings, and NRFS requiring immediate delivery in women with suspected or confirmed early-onset PE/SPE. The sFlt-1/PlGF ratio at <34 weeks of gestation, but not at 34-36 or ≥37 weeks, was associated with composite adverse maternal and fetal outcomes in women with suspected or confirmed preeclampsia and super-imposed preeclampsia (PE/SPE). In women with suspected or confirmed early-onset PE/SPE, the sFlt-1/PlGF ratio was significantly higher not only in those with HELLP syndrome, but also in those with abnormal umbilical artery Doppler findings and non-reassuring fetal status (NRFS) requiring immediate delivery. Among women with suspected or confirmed early-onset PE/SPE, time to delivery from blood sampling decreased with increasing sFlt-1/PlGF ratio.

AIM: To describe how decreased fetal movement (DFM) was managed in patients with fetomaternal hemorrhage (FMH) and to evaluate the diagnostic limitations of this condition in real-world settings. METHODS: This retrospective cohort study included individuals who developed FMH with cerebral palsy from the Japanese nationwide cerebral palsy registry between 2009 and 2022. We investigated whether patients experienced DFM or were prenatally diagnosed with FMH. Furthermore, we assessed how DFM was managed. RESULTS: This study included 57 patients who developed FMH with cerebral palsy, and none were prenatally diagnosed with FMH. DFM was present in 43/57 (75.4%) patients. A sinusoidal pattern was observed in 29/57 (50.9%) patients, and elevated middle cerebral artery peak systolic velocity (MCA-PSV) was detected in 6/10 (60.0%) patients who underwent this test. Of the 43 patients with DFM, 42 (97.7%) sought medical care for this symptom; however, only 12 (27.9%) underwent examinations on the same day as the onset of DFM, and 9 (20.9%) were admitted on that same day. Furthermore, 6/43 (14.0%) were instructed to stay home after telephone consultation or medical examination for this symptom. In five of the 43 patients (11.6%) who experienced DFM, the initial non-stress test was reactive. However, all these patients eventually developed either a non-reactive or non-reassuring fetal status. CONCLUSIONS: DFM was prevalent among pregnancies complicated by FMH; however, it was often inadequately managed, resulting in diagnostic delays. Furthermore, fetal heart rate monitoring and MCA-PSV evaluations had diagnostic limitations. To facilitate early treatment, clinicians need to promptly assess preceding DFM while recognizing the limitations of existing tests.

OBJECTIVE: To clarify whether the maternal backgrounds and perinatal outcomes of the three types of vasa previa (VP) differ based on placental location and cord insertion. METHODS: A retrospective questionnaire survey of VP cases in all 408 perinatal centers in Japan was conducted. The survey covered the clinical information of VP cases, including maternal characteristics, prenatal management, and perinatal outcomes, between January 2020 and December 2022. These backgrounds and events were compared among the three types of VP. RESULTS: Two-hundred and seventy-nine cases of VP were analyzed. The type of VP was confirmed postnatally in 254 cases. The rates of confirmed type diagnoses were 67.7 % of Type 1, 17.7 % of Type 2, and 14.6 % of Type 3. Pre- and postnatal VP type diagnoses matched in 97.6, 92.6, and 76.5 % of cases of Types 1, 2, and 3, respectively. A low-lying placenta was less common in Type 1 (29.1 %) than in Type 2 (51.1 %) and Type 3 (45.9 %), while no significant differences were observed in other maternal characteristics. In all cases, VP was diagnosed prenatally with a high probability (Type 1: 98.8 %, Type 2: 95.6 %, Type 3: 100 %). There were no cases of fetal or neonatal death. Furthermore, no significant differences were noted in pre- or perinatal management or in the frequency of poor short-term perinatal outcomes (e.g., the rate of umbilical artery pH < 7.2 and Apgar score 5 mins < 7). CONCLUSION: In all VP types, VP was diagnosed prenatally in > 95 % of cases. A low-lying placenta was less common in Type 1 VP, while no significant differences were observed in maternal backgrounds or short-term perinatal outcomes among the three types of VP.

INTRODUCTION: Neonatal haemochromatosis, considered to be a gestational alloimmune liver disease (NH-GALD), is a rare but serious disease that results in fulminant hepatic failure. The recurrence rate of NH-GALD in a subsequent infant of a mother with an affected infant is 70%-90%. Recently, antenatal maternal high-dose intravenous immunoglobulin (IVIG) therapy has been reported as being effective for preventing recurrence of NH-GALD in a subsequent infant. However, no clinical trial has been conducted to date. METHODS AND ANALYSIS: This is a multicentre open-label, single-arm study of antenatal maternal high-dose IVIG therapy in pregnant women with a history of documented NH in a previous offspring. The objective of this study is to evaluate the efficacy and safety of antenatal maternal high-dose IVIG therapy in preventing or reducing the severity of alloimmune injury to the fetal liver. ETHICS AND DISSEMINATION: The clinical trial is being performed in accordance with the Declaration of Helsinki. The trial protocol was approved by the Clinical Research Review Board at four hospitals. Before enrolment, written informed consent would be obtained from eligible pregnant women. The results are expected to be published in a scientific journal. PROTOCOL VERSION: 28 October 2024, V.8.0. TRIAL REGISTRATION NUMBER: jRCT1091220353.

Given the decline in birthweights over the past 30 years in Japan and advancements in ultrasound technology, this study aimed to establish new reference values for ultrasound fetal biometry in Japan and to compare them with international and Asian studies. We conducted a cross-sectional prospective study involving singleton pregnancies who received prenatal checkups at obstetric facilities across Japan. During routine prenatal care, ultrasound measurements-biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), and femur length (FL)-were recorded. Estimated fetal weight (EFW) was calculated using both the Shinozuka formula, commonly used in Japan, and the Hadlock-3 formula, widely used internationally. Using the collected data, we developed gestational-age-specific reference values for BPD, HC, AC, FL, and EFW by applying best-fitted fractional polynomial regression, and compared them with existing international standards and reference values from other Asian countries. The mean EFW calculated by the Hadlock formula in this study tended to be smaller than that reported in other international studies, and BPD, HC, AC, and FL were also generally smaller than those observed in other Asian references. These findings indicate that fetal biometry values in the Japanese population are smaller not only than international standards but also compared with those from other Asian countries, and suggest that these population-specific data may contribute to improving the accuracy of fetal growth assessment in Japan and other parts of Asia.

Systemic lupus erythematosus (SLE) may be exacerbated at any stage of pregnancy, complicating maternal and fetal outcomes. Additionally, pregnancies with SLE have a higher risk of preeclampsia (PE), requiring careful differentiation between SLE flare and PE when symptoms such as proteinuria emerge. We herein describe a 36-year-old pregnant woman with SLE who developed severe proteinuria (13 g/day) at 30 weeks of gestation without hypertension or thrombocytopenia. No abnormal urinary segments were observed. The differential diagnosis between SLE flare and the preliminary sign of PE was challenging. The soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio was utilized for diagnostic clarification. A normal sFlt-1/PlGF ratio at 29+4 weeks of gestation suggested SLE flare rather than the preliminary sign of PE. Intensified immunosuppressive therapy with increased prednisolone (30 mg/day) attenuated proteinuria, allowing for late-term pregnancy. At 37+4 weeks of gestation, the patient developed late-onset PE with a hypertensive crisis, necessitating emergency cesarean delivery. The infant was delivered safely without complications. Postpartum recovery was uneventful, with stable maternal renal function. This case underscores the importance of angiogenic markers in distinguishing SLE flare from PE. An elevated sFlt-1/PlGF ratio is typically associated with PE, but not SLE flare, aiding in a differential diagnosis and guiding treatment strategies.

OBJECTIVE: Fetomaternal hemorrhage (FMH) causes severe neonatal outcomes; however, due to its rarity, risk factors for FMH occurrence and prognostic factors for its outcomes remain unclear. Thus, we aimed to investigate factors for FMH occurrence and related outcomes. MATERIALS AND METHODS: We included singleton pregnant women from the Japanese nationwide perinatal registry database between 2013 and 2019. To investigate the association between characteristics and FMH occurrence, we conducted multivariable logistic regression model analyses. In addition, we employed multivariable logistic regression models to evaluate prognostic factors of stillbirth or neonatal death among FMH. We used multiple imputation to handle missing data in all analyses. RESULTS: Of 1,500,309 women, FMH occurred in 141 (1/10,640). A sinusoidal pattern was detected in only 20.6 % of women with FMH. The proportion of women who had fetal growth restriction (FGR) was 10/141 (7.1 %) in those with FMH and 54,989/1,500,168 (3.7 %) in those without FMH. A single umbilical artery was found in 2/141 (1.4 %) and 3845/1,500,168 (0.3 %) women with and without FMH, respectively. FGR and a single umbilical artery were significantly associated with FMH occurrence (adjusted odds ratio [OR], 2.01; 95 % confidence interval [CI], 1.06-3.83; p = 0.033) (adjusted OR, 5.51; 95 % CI, 1.36-22.27; p = 0.017), respectively. In addition, abnormal umbilical cord insertion was significantly associated with stillbirth or neonatal death among FMH (adjusted OR, 19.95; 95 % CI, 2.33-170.63; p = 0.006). CONCLUSION: The occurrence of FMH was significantly associated with FGR and a single umbilical artery. In addition, abnormal umbilical cord insertion was significantly associated with stillbirth or neonatal death among those with FMH. We need to be cautious regarding FMH occurrence in women with FGR or a single umbilical artery. In addition, perinatal outcomes in women with FMH, especially those with abnormal umbilical cord insertion, would be adverse.

A new natural course of spontaneous twin anemia polycythemia sequence (TAPS) was clarified. A 29-year-old woman, who conceived monochorionic diamniotic twins, showed elevation of the peak systolic velocity of the middle cerebral artery (MCA-PSV) in one twin at 24+2 weeks. The other twin showed a decrease in MCA-PSV. The amniotic volume did not differ between the twins. We diagnosed them with TAPS. Four days later, maximum vertical pockets were 19 and 97 mm in the donor and recipient, respectively. We diagnosed them with twin-twin transfusion syndrome, Quintero stage 1. Fetoscopic laser photocoagulation was employed, and the post-operative course was uneventful. Emergent cesarean section was conducted at 33+0 weeks because of premature rupture of the membranes. Neither twin showed anemia nor polycythemia. Only one patient with spontaneous TAPS followed by twin-to-twin transfusion syndrome (TTTS) has been reported so far. To our knowledge, this is the first report of a pregnant woman with TAPS developing TTTS within a few days.

The villous trophoblast cells are of fundamental importance because they fulfill a variety of functions that are vital for the growth of the fetus and the maintenance of pregnancy. A simple in vitro villous trophoblast cell model that grows on standard tissue culture plates has been utilized for various functional studies on villous trophoblast cells. Despite the potential value of incorporating electron microscopy analysis in reports on functional analysis of primary human trophoblast cells, electron microscopy analysis is exclusively ancillary to functional analysis in previous publications. In the context of autophagy research of villous trophoblast cells using primary trophoblast cells, a detailed ultrastructural analysis of autophagy flux using electron microscopy is imperative; however, it has not been conducted to date. In this study, we isolated term villous trophoblast cells (i.e., cytotrophoblast cells, CTB cells) using the most up-to-date isolation method for isolating pure CTB cells from human term placenta and investigated the ultrastructural dynamic process of autophagy of cultured CTB cells by means of transmission electron microscopy. The initial 6 h culture resulted in CTB cell aggregation; however, the majority of CTB cells did not differentiate into syncytial cells. In contrast, after 72 h, CTB cells exhibited a promotion of differentiation into syncytial cells. The electron microscopy analysis revealed the upregulation of autophagy and visualized unique autophagic profiles during differentiation into syncytial cells, which exhibited perinuclear accumulation of extremely large autophagosomes/autolysosomes. This study provides novel insights into the reproductive biology of primary trophoblast cells, thereby demonstrating the substantial value of primary trophoblast cells as research resources.

AIM: We reviewed case reports of acute fatty liver of pregnancy (AFLP) in Japan and summarized its characteristics, including coagulation factors, fibrinolytic factors, and platelet counts. METHODS: PubMed/Medline and Ichushi databases from 2000 to 2022 were used to survey articles related to AFLP, and 93 articles (102 patients) were ultimately identified. RESULTS: The characteristics of the coagulation and fibrinolysis systems in AFLP were as follows: the prothrombin time-international normalized ratio and activated partial prothrombin time were prolonged (median value [quartiles]: 1.59 [1.31, 2.02] and 47.5 s [28.2, 97.5], respectively), and antithrombin and alpha 2-antiplasmin levels were low (23.0% [17.0, 33.0] and 44.6%, respectively), indicating non-productive coagulopathy due to severe liver damage. The concentrations of the thrombin-antithrombin complex and fibrinogen/fibrin degradation products were high (60.0 ng/mL [49.1, 82.8] and 49.2 μg/mL [20.8, 143.7], respectively), while the level of fibrinogen was low (82.0 mg/dL [52.5, 153.5]), suggesting disseminated intravascular coagulation with increased coagulation activity. A platelet count ≥12 × 104/μL was detected in approximately 70% of AFLP cases, and the median was within the normal range (16.1 × 104/μL [11.1, 19.2]). CONCLUSIONS: Coagulopathy changes in AFLP may be based on non-productive coagulopathy of coagulation and fibrinolytic factors as well as disseminated intravascular coagulation with mild or no thrombocytopenia.

AIM: To clarify the current situation and outcomes of vasa previa (VP) in Japan. METHODS: A questionnaire survey on VP was conducted at all 408 perinatal centers in Japan. The content of the survey included (1) the management strategy for pregnant women who were diagnosed with VP and (2) the number and outcomes of VP cases managed between January 2020 and December 2022. RESULTS: Questionnaires were collected from 220 (53.9%: 220/408) perinatal centers. (1) A total of 78.8% (164/208) of facilities implemented routine hospitalization. Routine hospitalization was initiated at 32 (22-36) [median (range)] weeks of gestation. The timing of planned cesarean section (CS) was at 36 (33.5-39) weeks of gestation in 198 facilities. (2) Of the 220 facilities that responded, 109 (49.5%: 109/220) accommodated patients with VP during the observation period. The total number of VP cases was 351, with a frequency of one case (0-33) per single perinatal center for 3 years. Emergency CS was required in 89 cases (25.4%: 89/351). There were no fetal or neonatal deaths in this study. The number of undiagnosed patients with VP prenatally was seven (2.0%: 7/351). Umbilical vessel rupture occurred in two cases (0.6%: 2/351). CONCLUSIONS: Current management strategies in Japanese perinatal centers that responded to this survey appear to yield good perinatal outcomes in VP. Additional studies and comparisons are needed to elucidate the necessity of routine hospitalization, the optimal duration of hospitalization, and the timing of planned CS.

Baller-Gerold syndrome (BGS, OMIM: 218600), RAPADILINO syndrome (OMIM 266280), and Rothmund-Thomson syndrome (RTS, OMIM 266280), which are caused in some cases by RECQL4 pathogenic variants, show autosomal recessive inheritance. Some refer to them collectively as RECQL4 syndromes. Most cases have been reported during infancy and childhood periods. However, there have been no reports of phenotypes resulting in a lethal course in the perinatal period. We identified two fetuses with biallelic RECQL4 pathogenic variants during the perinatal period. The two fetuses with RECQL4 syndrome showed structural abnormalities, including severely hypoplastic forearms and lower legs. One fetus also had severe pulmonary hypoplasia. One case resulted in neonatal death because of respiratory failure, and the other was artificially terminated during pregnancy. The RECQL4 pathogenic variants were identified by exome sequencing followed by Sanger sequencing. The biallelic RECQL4 pathogenic variants can induce a lethal skeletal disorder.

A 31-year-old primiparous woman underwent non-invasive prenatal testing. The result was trisomy 13 (T13) positive. The chromosome 13 t-statistics (Z-score) was significantly high. The result of amniocentesis was normal karyotype (46,XX). Detailed ultrasound showed no fetal structural abnormalities. We suspected T13 confined placental mosaicism (CPM) and observed the course naturally. From the late second trimester, severe fetal growth restriction manifested followed by proteinuria and hypertension, diagnosing her with preeclampsia (PE). At 35 + 5 weeks, emergent cesarean section was required, yielding a 1480 g female infant. We sampled five locations of chorionic villi in the placenta. T13 cells dominated cells with normal karyotypes in all parts and the rate of trisomic cells ranged from 57% to 96%, which were generally high rate. None developed PE in reported T13 CPM cases and this is the first case of PE. The dominancy of T13 cells can be associated with PE development.

The placenta plays a fundamental role in fetal growth and maintenance of pregnancy. Its cellular components include a large multinucleated syncytiotrophoblast (STB) and its progenitor, cytotrophoblasts (CTBs), both of which perform vital functions in the human placenta. Primary cytotrophoblasts isolated from term human placentas that spontaneously fuse and differentiate into syncytiotrophoblast-like cells in vitro have been utilized to investigate the functions of the syncytiotrophoblast and placenta with multiple modifications. Although recent advances have enabled the use of trophoblast stem cell-derived organoids as a model for villous trophoblasts, primary CTBs offer several advantages, including spontaneous differentiation, easy access to materials (from term-delivered human placentas), and simple methodology. Here, we present a precise step-by-step process for isolating pure CTBs from term human placenta based on previously reported placenta digestion, density centrifugation, and CTB purification using anti-HLA-A, B, C antibody. Subsequently, we provide a method to improve CTB viability and differentiation into STB-like cells using epidermal growth factor (EGF) and a ROCK inhibitor (Y-27632) that ensures long-term and stable cultures without altering their proliferation. Because these cells can grow on standard tissue culture plates, this model can be easily utilized for various placental investigations, including innate immune responses, drug resistance, and STB metabolism. Employing this approach considerably enhances our understanding of placental functions, which are key to maternal and offspring health.

PURPOSE: This study aimed to clarify associations between subacute hematoma on placental magnetic resonance imaging (MRI), antenatal bleeding, and preterm deliveries in patients with placenta previa (PP) without placenta accreta spectrum (PAS). MATERIALS AND METHODS: This retrospective study investigated 78 consecutive patients with PP (median age, 34.5 years; interquartile range [IQR], 31-37 years) who underwent placental MRI in the third trimester. Patients with PAS detected intraoperatively or pathologically were excluded. Two radiologists evaluated the presence of subacute hematomas and their locations on placental MRI. We examined associations between presence of subacute hematoma and antenatal bleeding, emergency cesarean section (CS), hysterectomy, gestational age (GA) at delivery, birth weight, and amount of blood loss at CS. We also examined the association between perinatal outcome and subacute hematoma location: marginal, retro-placental, or intra-placental. Inter-observer agreement for the detection of subacute hematoma was calculated using kappa analysis. RESULTS: Subacute hematomas were identified on MRI in 39 of the 78 patients (50.0%). Antenatal bleeding and emergency CS were more prevalent in patients with subacute hematoma on MRI (20 patients [51.3%] and 18 patients [46.2%], respectively) than in patients without (7 patients [17.9%], Fisher's exact test, p = 0.004 and 7 patients [17.9%], p = 0.014, respectively). GA at delivery was significantly lower in patients with subacute hematoma (median 36w3d, IQR 35w4d-37w1d) than in patients without (median 37w1d, IQR 36w4d-37w2d; Mann-Whitney test: p = 0.048). Marginal hematoma was significantly associated with antenatal bleeding and emergency CS. Inter-observer agreement for the presence of subacute hematoma was moderate (κ = 0.573). CONCLUSION: Subacute hematoma on placental MRI was associated with antenatal bleeding, emergency CS and shorter GA at delivery in patients with PP. Marginal hematoma was also associated with antenatal bleeding and emergency CS. Placental MRI appears useful for predicting antenatal bleeding and preterm delivery in patients with PP.

Our aims were to obtain the gestational-age-specific median of common logarithmic placental growth factor (PlGF) values in the first trimester in women with a singleton pregnancy in order to generate the gestational-age-specific multiple of the median (MoM) of log10PlGF at 9-13 weeks of gestation, to evaluate screening parameters of MoM of log10PlGF at 9-13 weeks of gestation to predict preterm preeclampsia (PE), and to construct an appropriate prediction model for preterm PE using minimum risk factors in multivariable logistic regression analyses in a retrospective sub-cohort study. Preterm PE occurred in 2.9% (20/700), and PE in 5.1% (36/700). Serum PlGF levels were measured using Elecsys PlGF®. MoMs of log10PlGF at 9-13 weeks of gestation in Japanese women with a singleton pregnancy followed a normal distribution. We determined the appropriate cut-off value of MoM of log10PlGF to predict preterm PE at around a10% false-positive rate (0.854). The MoM of log10PlGF < 0.854 yielded sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio (95% confidence interval [CI]), and negative likelihood ratio (95% CI) of 55.0%, 91.9%, 17.5%, 98.5%, 6.79 (4.22-10.91), and 0.49 (0.30-0.80), respectively. The combination of MoM of log10PlGF and presence of either chronic hypertension or history of PE/gestational hypertension (GH) yielded sensitivity and specificity of 80.0 and 85.7%, respectively, to predict preterm PE. In conclusion, the automated electrochemiluminescence immunoassay for serum PlGF levels in women with singleton pregnancy at 9-13 weeks of gestation may be useful to predict preterm PE.

We systematically reviewed case reports of posterior reversible encephalopathy syndrome (PRES), and investigated the characteristics of PRES in pregnant Japanese women and the clinical relevance of reversible cerebral vasoconstriction syndrome (RCVS) in pregnant women with PRES. Articles were collected using the PubMed/Medline and Ichushi-Web databases. This review was ultimately conducted on 121 articles (162 patients). The clinical characteristics of PRES, individual sites of PRES lesions, edema types, and clinical characteristics of RCVS in PRES cases were examined. The most common individual site of PRES lesion was the occipital lobe (83.3%), followed by the basal ganglia, parietal lobe, frontal lobe, brain stem, cerebellum, temporal lobe, thalamus, and splenium corpus callosum (47.5, 42.6, 24.7, 16.1, 9.3, 5.6, 4.3, and 0.0%, respectively). Edema types in 79 cases with PRES were mainly the vasogenic edema type (91.1%), with very few cases of the cytotoxic edema type (3.8%) and mixed type (5.1%). Among 25 PRES cases with RCVS, RCVS was not strongly suspected in 17 (68.0%) before magnetic resonance angiography. RCVS was observed at the same time as PRES in 13 cases (approximately 50%), and between days 1 and 14 after the onset of PRES in the other 12. These results suggest that the basal ganglia is a frequent site of PRES lesions in pregnant women. RCVS may occur at or after the onset of PRES, even if there are no symptoms to suggest RCVS.

OBJECTIVES: To investigate the association between adenomyosis and placenta accreta spectrum (PAS) and to evaluate the effect of assisted reproductive technology (ART) in mediating this association. METHODS: We retrieved data for singleton women from the Japanese nationwide perinatal registry between 2013 and 2019, excluding women with a history of adenomyomectomy. To investigate the association between adenomyosis and PAS among women, we used a multivariable logistic regression model with multiple imputation for missing data. We evaluated mediation effect of ART including in vitro fertilization and intracytoplasmic sperm injection on the association between adenomyosis and PAS using causal mediation analysis based on the counterfactual approach. RESULTS: Of 1 500 173 pregnant women, 1539 (0.10%) had adenomyosis. The number receiving ART was 489/1539 (31.8%) and 117 482/1 498 634 (7.8%) in women with and without adenomyosis, respectively. The proportion of women who developed PAS was 21/1539 (1.4%) in women with adenomyosis and 7530/1 498 634 (0.5%) in women without adenomyosis. Adenomyosis was significantly associated with PAS (odds ratio [OR] 1.95; 95% confidence interval [CI] 1.26-3.00; P = 0.002). Mediation analysis showed that OR of the total effect of adenomyosis on PAS was 1.98 (95% CI 1.13-3.04), OR of natural indirect effect (effect explained by ART) was 1.15 (95% CI 1.01-1.41), and OR of natural direct effect (effect unexplained by ART) was 1.72 (95% CI 0.86-2.82). The proportion mediated (natural indirect effect/total effect) was 26.5%. Adenomyosis was also significantly associated with PAS without previa (OR 1.96; 95% CI 1.23-3.13, P = 0.005). CONCLUSION: Adenomyosis was significantly associated with PAS. ART mediated 26.5% of the association between adenomyosis and PAS.

A 27-year-old multiparous woman conceived her fetus naturally. Early second-trimester ultrasound showed short extremities with systemic subcutaneous edema. The pregnancy was artificially terminated at 19 weeks of gestation because of the abnormalities based on the parents' wishes. The parents desired whole-exome sequencing to detect a causative gene using the umbilical cord and the parents' saliva. Compound heterozygous variants (NC_000003.11(NM_052989.3):c.230 T > G/NC_000003.11(NM_052985.4):c.1178A > T) were identified. We described a fetus with a novel compound heterozygous variant in IFT122. The phenotype of this case was severer than of other types of cranioectodermal dysplasia.

OBJECTIVE: To evaluate assisted reproductive technology-associated risk factors for retained products of conception among live births. DESIGN: Registry-based retrospective cohort study. SETTING: Not applicable. PATIENT(S): Cycle-specific data for a total of 369,608 singleton live births after fresh and frozen-thawed embryo transfers (FETs) between 2007 and 2017 were obtained from the Japanese assisted reproductive technology registry. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Retained products of conception after delivery. Odds ratios and 95% confidence intervals for risk factors associated with retained products of conception during fresh and frozen cycles. RESULT(S): In total, 132 deliveries (0.04% of eligible assisted reproductive technology registry deliveries) had retained products of conception; 122 (92.4%) of these deliveries occurred after FET transfer cycles. Cases with retained products of conception were significantly more likely to have undergone vaginal delivery than cases without retained products of conception (78.0% vs. 61.1%); they were also more likely to have been complicated with the placenta accreta spectrum (24.2% vs. 0.45%). Among patients undergoing FETs, factors associated with a significantly increased risk of retained products of conception were embryo stage at transfer, use of hormone replacement cycles, and assisted hatching. Use of hormone replacement cycles represented the largest risk factor (adjusted odds ratio, 4.9; 95% confidence interval, 2.0-12.4), such that retained products of conception occurred in 0.05% (51 of 97,958) of deliveries after hormone replacement cycles but only 0.01% (5 of 47,079) of deliveries after natural cycles. Subgroup analysis showed that hormone replacement cycles and assisted hatching remained significant risk factors for retained products of conception in cases without polycystic ovary syndrome and anovulation and cases with vaginal delivery, but not cases with cesarean section. Among fresh embryo transfers, an increased number of retrieved oocytes was the only significant risk factor for retained products of conception. CONCLUSION(S): Our analyses demonstrated that most of the cases involving retained products of conception were derived from FETs, and we identified the use of hormone replacement cycles as the largest risk factor for retained products of conception within this group.

Preeclampsia (PE) is a serious complication, and soluble fms-like tyrosine kinase (sFLT1) released from the placenta is one of the causes of PE pathology. Trophoblasts are the primary source of sFLT1; however, monocytes/macrophages exist enough in the placenta can also secrete sFLT1. Sterile inflammatory responses, especially NLRP3 inflammasome and its downstream gasdermin D (GSDMD)-regulated pyroptosis, may be involved in the development of PE pathology. In this study, we investigated whether human monocyte/macrophage cell line THP-1 cells secrete sFLT1 depending on the NLRP3 inflammasome and GSDMD. To differentiate THP-1 monocytes into macrophages, treatment with phorbol 12-myristate 13-acetate (PMA) induced sFLT1 with interleukin (IL)- 1β, but did not induce cell lytic death. IL-1β secretion induced by PMA inhibited by deletion of NLRP3 and inhibitors of NLRP3 and caspase-1, but deletion of NLRP3 and these inhibitors did not affect sFLT1 secretion in THP-1 cells. Both gene deletion and inhibition of GSDMD dramatically decreased IL-1β and sFLT1 secretion from THP-1 cells. Treatment with CA074-ME (a cathepsin B inhibitor) also reduced the secretion of both sFLT1 and IL-1β in THP-1 cells. In conclusion, THP-1 macrophages release sFLT1 in a GSDMD-dependent manner, but not in the NLRP3 inflammasome-dependent manner, and this sFLT1 release may be associated with the non-lytic role of GSDMD. In addition, sFLT1 levels induced by PMA are associated with lysosomal cathepsin B in THP-1 macrophages. We suggest that sFLT1 synthesis regulated by GSDMD are involved in the pathology of PE.

In villous trophoblasts, DROSHA is a key ribonuclease III enzyme that processes pri-microRNAs (pri-miRNAs) into pre-miRNAs at the placenta-specific, chromosome 19 miRNA cluster (C19MC) locus. However, little is known of its other functions. We performed formaldehyde crosslinking, immunoprecipitation, and sequencing (fCLIP-seq) analysis of terminal chorionic villi to identify DROSHA-binding RNAs in villous trophoblasts. In villous trophoblasts, DROSHA predominantly generated placenta-specific C19MC pre-miRNAs, including antiviral C19MC pre-miRNAs. The fCLIP-seq analysis also identified non-miRNA transcripts with hairpin structures potentially capable of binding to DROSHA (e.g., SNORD100 and VTRNA1-1). Moreover, in vivo immunohistochemical analysis revealed DROSHA in the cytoplasm of villous trophoblasts. DROSHA was abundant in the cytoplasm of villous trophoblasts, particularly in the apical region of syncytiotrophoblast, in the full-term placenta. Furthermore, in BeWo trophoblasts infected with Sindbis virus (SINV), DROSHA translocated to the cytoplasm and recognized the genomic RNA of SINV. Therefore, in trophoblasts, DROSHA not only regulates RNA metabolism, including the biogenesis of placenta-specific miRNAs, but also recognizes viral RNAs. After SINV infection, BeWo DROSHA-binding VTRNA1-1 was significantly upregulated, and cellular VTRNA1-1 was significantly downregulated, suggesting that DROSHA soaks up VTRNA1-1 in response to viral infection. These results suggest that the DROSHA-mediated recognition of RNAs defends against viral infection in villous trophoblasts. Our data provide insight into the antiviral functions of DROSHA in villous trophoblasts of the human placenta.

Extracellular vesicles (EVs), including exosomes, are carriers of extracellular microRNAs (miRNAs). Exomeres, non-vesicular extracellular nanoparticles (NVEPs), are novel extracellular cargo carriers. However, little is known of the characteristics of placental trophoblast-derived exomeres. In this study, we characterized trophoblast-derived exomeres and investigated the cell-cell communication of placenta-specific miRNAs carried by those exomeres using an in vitro model system (BeWo trophoblasts and Jurkat T cells). BeWo exomeres (∼ 40 nm diameter) had pilling-like nanoparticle structures, which were distinct from cup-shaped exosomes (∼ 90-110 nm diameter). BeWo cells secreted more exomeres than exosomes. Exomeres were positive for AGO2 but negative for exosome markers (CD63, CD9, CD81, FLOT1, and TSG101). The levels of placenta-specific miRNAs in exomeres were significantly higher than in exosomes. In a cell-cell communication analysis using a placenta-specific miRNA, BeWo exomeres delivered significantly more miR-517a-3p to recipient Jurkat cells compared with exosomes. Moreover, exomere-miR-517a-3p significantly reduced the expression of PRKG1 in miR-517a-3p-inhibitor (-) Jurkat cells compared with miR-517a-3p-inhibitor (+) cells, suggesting that miR-517a-3p inhibition reversed the exomere-miR-517a-3p-mediated repression of PRKG1 expression in recipient cells. Therefore, BeWo trophoblast exomeres are enriched with bioactive extracellular placenta-specific miRNAs, which were formerly considered to be carried by exosomes. Our findings provide insight into trophoblast-derived NVEPs.

A new anti-vascular endothelial growth factor agent, brolucizumab, was approved by the United States Food and Drug Administration in 2019. We evaluated whether brolucizumab reduces the treatment burden of neovascular age-related macular degeneration (nAMD) after switching by examining 1-year treatment outcomes in a real-world setting. This retrospective single-institution study included 107 consecutive eyes with nAMD treated with brolucizumab. Among these eyes, 30 with treatment-naïve nAMD and 77 treated with other anti-VEGF agents for more than a year were included. All eyes were managed using a treat and extend (TAE) or modified TAE regimen. The last injection intervals at 52 weeks were 12.9 and 12.1 weeks in the treatment-naïve and switch therapy groups, respectively. Among switch therapy group patients whose pre-switch injection intervals were shorter than 120 days (n = 62 eyes), the injection interval was significantly longer after the switch than before, with a mean difference of 2.7 weeks (P < 0.0001). Intraocular inflammation events occurred in 2 and 7 treatment-naïve and switch therapy patients, respectively. In conclusion, brolucizumab might reduce the treatment burden in patients who required the injection of other anti-VEGF agents with a 120-day interval or shorter, despite a relatively high discontinuation rate due to intraocular inflammation.

BACKGROUND: Evidence for the association between earthquakes and adverse perinatal outcomes is limited. OBJECTIVES: To evaluate the association between earthquakes and perinatal outcomes including preterm birth and low birth weight. SEARCH STRATEGY: We searched studies using MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, World Health Organization International Clinical Trials Platform Search Portal, and ClinicalTrials.gov on February 9, 2023. SELECTION CRITERIA: We included before-and-after studies that evaluated the associations between earthquakes and perinatal outcomes in women living in affected areas. DATA COLLECTION AND ANALYSIS: Two independent reviewers extracted data. We calculated the pooled odds ratio (OR) with the random-effects model. We analyzed outcomes in subgroups of Asians and others. We evaluated the certainty of evidence with the Grading of Recommendations Assessment, Development and Evaluation system. MAIN RESULTS: We included 2 607 405 women in 13 studies. Earthquakes may not increase preterm birth (nine studies, 1 761 760 participants: OR 1.10, 95% confidence interval [CI] 0.98-1.24, low certainty of evidence) or low birth weight (seven studies, 1 753 891 participants: OR 1.10, 95% CI 0.94-1.28, low certainty of evidence). Subgroup analyses showed that earthquakes may be associated with an increase of preterm birth among populations in Asia (OR 1.44, 95% CI 1.07-1.95), but this was not evident in others (OR 0.93, 95% CI 0.83-1.05). CONCLUSIONS: Perinatal outcomes might not change after earthquakes. Further research on the association between earthquakes and perinatal outcomes, combined with an assessment of the characteristics of the region, is needed.

Menkes disease is an X-linked disorder of copper metabolism caused by mutations in the ATP7A gene, and female carriers are usually asymptomatic. We describe a 7-month-old female patient with severe intellectual disability, epilepsy, and low levels of serum copper and ceruloplasmin. While heterozygous deletion of exons 16 and 17 of the ATP7A gene was detected in the proband, her mother, and her grandmother, only the proband suffered from Menkes disease clinically. Intriguingly, X chromosome inactivation (XCI) analysis demonstrated that the grandmother and the mother showed skewing of XCI toward the allele with the ATP7A deletion and that the proband had extremely skewed XCI toward the normal allele, resulting in exclusive expression of the pathogenic ATP7A mRNA transcripts. Expression bias analysis and recombination mapping of the X chromosome by the combination of whole genome and RNA sequencing demonstrated that meiotic recombination occurred at Xp21-p22 and Xq26-q28. Assuming that a genetic factor on the X chromosome enhanced or suppressed XCI of its allele, the factor must be on either of the two distal regions derived from her grandfather. Although we were unable to fully uncover the molecular mechanism, we concluded that unfavorable switching of skewed XCI caused Menkes disease in the proband.

OBJECTIVE: To investigate whether conisation increases chorioamnionitis (CAM) and assess whether this risk differs between preterm and term periods. Furthermore, we estimated mediation effects of CAM between conisation and preterm birth (PTB). DESIGN: A nationwide observational study. SETTING: Japan. POPULATION: Singleton pregnant women derived from the perinatal registry database of the Japan Society of Obstetrics and Gynaecology between 2013 and 2019. METHODS: The association between a history of conisation and clinical CAM was examined using a multivariable logistic regression model with multiple imputation. We conducted mediation analysis to estimate effects of CAM on PTB following conisation. MAIN OUTCOME MEASURES: Clinical CAM. RESULTS: Of 1 500 206 singleton pregnant women, 6961 (0.46%) underwent conisation and 1 493 245 (99.5%) did not. Clinical CAM occurred in 150 (2.2%) and 11 484 (0.8%) women with and without conisation, respectively. Conisation was associated with clinical CAM (odds ratio [OR] 3.09; 95% confidence interval (CI) 2.63-3.64; p < 0.001) (risk difference 1.57%; 95% CI 1.20-1.94). The association was detected among 171 440 women with PTB (OR 3.09; 95% CI 2.57-3.71), whereas it was not significant among 1 328 284 with term birth (OR 0.88; 95% CI 0.58-1.34). OR of total effect of conisation on PTB was 2.71, OR of natural indirect effect (effect explained by clinical CAM) was 1.04, and OR of natural direct effect (effect unexplained by clinical CAM) was 2.61. The proportion mediated was 5.9%. CONCLUSIONS: Conisation increased CAM occurrence. Obstetricians should be careful regarding CAM in women with conisation, especially in preterm period. Bacterial infections may be an important cause of PTB after conisation.

Assisted reproductive technology (ART) requires transvaginal oocyte retrieval (TVOR), and ovarian bleeding after TVOR rarely occurs. We present a case of a 37-year-old woman (0-gravida) who was diagnosed with possible hemorrhagic telangiectasia (HHT) and had a history of three laparotomies for ovarian bleeding and an inclusion cyst adjacent to the right ovary after the third operation. HHT is a hereditary disease characterized by spontaneous hemorrhage of some organs, such as the nose, brain, lungs, gastrointestinal tract, and liver. She desired ART after fertility treatment and then had abdominal pain with ovarian swelling five days after TVOR. Moreover, both the right ovary and inclusion cyst were gradually swollen with hematoma. Finally, abdominal pain and the hemoglobin level deteriorated, necessitating an emergency surgery on the eighth day. We notify reproductive physicians that patients with HHT may readily develop ovarian bleeding with or without inclusion cysts after TVOR, although inclusion cysts may also be associated with late-onset bleeding.

Some specialties require publishing a paper as a prerequisite for becoming a Japanese Medical Specialty Board Specialist. Taking obstetrics and gynecology as an example, we wish to describe some concerns about this. Time limitations oblige residents to publish papers in non-PubMed journals with smaller circulations. Once data have been published, later attempts at secondary publication are difficult. This may bury some important data. Requiring an English presentation and writing an English abstract as a prerequisite for a board specialty may be an option to avoid this. Although we believe that the experience of publishing a paper during residency is important, how to deal with this issue needs further consideration.

INTRODUCTION: Placental abruption is a serious complication, especially when accompanied by intrauterine fetal death. The optimal delivery route for placental abruption with intrauterine fetal death for reducing maternal complications is still unclear. In this study we aimed to compare the maternal outcomes between cesarean delivery and vaginal delivery in women with placental abruption with intrauterine fetal death. MATERIAL AND METHODS: Using the Japan Society of Obstetrics and Gynecology nationwide perinatal registry database, we identified pregnant women with placental abruption with intrauterine fetal death between 2013 and 2019. The following women were excluded: those with multiple pregnancies, placenta previa, placenta accreta spectrum, amniotic fluid embolism, or whose delivery route was missing data. The association between delivery routes (cesarean delivery and vaginal delivery) and the maternal outcome was examined using a linear regression model with inverse probability weighting. The primary outcome was the amount of bleeding during delivery. Missing data were imputed using multiple imputation. RESULTS: The number of women with placental abruption with intrauterine fetal death was 1218/1601932 (0.076%). Of 1134 women analyzed, 608 (53.6%) underwent cesarean delivery. Bleeding during delivery (median [interquartile range]) was 1650.00 (950.00-2450.00) (mL) and 1171.00 (500.00-2196.50) (mL) in cesarean and vaginal delivery, respectively. Bleeding during delivery (mL) was significantly greater in cesarean delivery than in vaginal delivery (regression coefficient, 1086.39; 95% confidence interval, 130.96-2041.81; p = 0.026). Maternal death and uterine rupture occurred in four (0.4%) and five (0.4%) women, respectively. The four maternal deaths were noted in the vaginal delivery group. CONCLUSIONS: Bleeding during delivery was significantly greater in cesarean delivery than that in vaginal delivery in women with placental abruption with intrauterine fetal death. However, severe complications, including maternal death and uterine rupture, occurred in vaginal delivery-related cases. The management of women with placental abruption with intrauterine fetal death should be cautious regardless of the delivery route.