高橋 宏典

OBJECTIVE: To clarify the natural history of retained products of conception (RPOC) following abortion at less than 22 weeks of gestation, and those who show major bleeding during course observation. STUDY DESIGN: We retrospectively reviewed 640 patients who had spontaneous or artificial abortion at less than 22 weeks of gestation between January 2011 and August 2019 in our institute. Of those, patients with RPOC were included. The maternal background, RPOC characteristics, and subsequent complications including additional interventions were reviewed. RESULTS: Fifty-four patients with RPOC were included. The incidence of RPOC was 6.7 %. The median (interquartile range: IQR) RPOC length was 29 (20-38) mm. RPOC hypervascularity was observed in 26 (48 %) patients. The median (IQR) periods of RPOC flow disappearance and RPOC disappearance on ultrasound from abortive treatment were 50 (28-76) and 84 (50-111) days, respectively. Of the 54, 44 patients were selected for expectant management. Of the 44, 34 (77 %) patients were observed without intervention (recovery group); the other 10 (23 %) patients required additional interventions associated with subsequent bleeding (intervention group). Compared with the recovery group, heavy bleeding (> 500 mL) at abortion (6/10: 60 %) and RPOC hypervascularity (8/10: 80 %) were more frequently observed in the intervention group. CONCLUSION: Expectant management was successful in almost 80 % of patients with RPOC following abortion. The additional interventions were required in patients with heavy bleeding at abortion and RPOC hypervascularity.

Subarachnoid hemorrhage is typically present in cerebral aneurysm rupture, whereas acute subdural hematoma without subarachnoid hemorrhage is rare. We herein report a case of cerebral aneurysm rupture during pregnancy resulting in acute subdural hematoma without subarachnoid hemorrhage. A 37-year-old gravida 4 para 3 pregnant woman was admitted for threatened preterm labor at 294/7 weeks of gestation. At 296/7 weeks of gestation (day -14), she developed mild left eye pain, which disappeared within one day. At 316/7 weeks of gestation (day 0), she developed the sudden onset of severe headache and nausea. A neurological examination revealed no abnormal findings, and analgesics ameliorated her headache. At 321/7 weeks of gestation (day 2), after consultations with neurosurgeons, magnetic resonance imaging showed acute subdural hematoma without subarachnoid hemorrhage. Further examinations revealed a cerebral aneurysm. Emergent clipping surgery was performed with the fetus in utero in consideration of the immaturity of the fetus and stable maternal/fetal general conditions. At 356/7 weeks of gestation (day 28), her headache of unknown cause recurred. Considering the maturity of the fetus, the patient underwent cesarean section with good maternal and neonatal outcomes. The absence of subarachnoid hemorrhage does not eliminate cerebral aneurysm rupture.

The invasion of extravillous trophoblast (EVT) cells into the maternal decidua, which plays a crucial role in the establishment of a successful pregnancy, is highly orchestrated by a complex array of regulatory mechanisms. Non-coding RNAs (ncRNAs) that fine-tune gene expression at epigenetic, transcriptional, and post-transcriptional levels are involved in the regulatory mechanisms of EVT cell invasion. However, little is known about the characteristic features of EVT-associated ncRNAs. To elucidate the gene expression profiles of both coding and non-coding transcripts (i.e., mRNAs, long non-coding RNAs (lncRNAs), and microRNAs (miRNAs)) expressed in EVT cells, we performed RNA sequencing analysis of EVT cells isolated from first-trimester placentae. RNA sequencing analysis demonstrated that the lncRNA H19 and its derived miRNA miR-675-5p were enriched in EVT cells. Although miR-675-5p acts as a placental/trophoblast growth suppressor, there is little information on the involvement of miR-675-5p in trophoblast cell invasion. Next, we evaluated a possible role of miR-675-5p in EVT cell invasion using the EVT cell lines HTR-8/SVneo and HChEpC1b; overexpression of miR-675-5p significantly promoted the invasion of both EVT cell lines. The transcription factor gene GATA2 was shown to be a target of miR-675-5p; moreover, small interfering RNA-mediated GATA2 knockdown significantly promoted cell invasion. Furthermore, we identified MMP13 and MMP14 as downstream effectors of miR-675-5p/GATA2-dependent EVT cell invasion. These findings suggest that miR-675-5p-mediated GATA2 inhibition accelerates EVT cell invasion by upregulating matrix metalloproteinases.

Objectives: The aims of this study were to clarify the following: (1) how often does prolonged pregnancy ≥34 weeks occur in patients with emergent cerclage without progesterone and (2) the risk factors preventing such pregnancy continuation. Materials and Methods: This retrospective observational study was performed using medical records of patients for whom emergent cerclage had been performed between April 2006 and December 2018 in our institute. Results: Emergent cerclage was performed in 123 patients (median age: 34, interquartile range: 31-36). Primiparous patients numbered 44 (36%). A history of spontaneous preterm birth (SPTB) was present in 30 (24%). The median presurgical cervical length (CL) was 16 (8-21) mm at surgery. Of the 123, 20 (16%) were delivered at 33 + 6 weeks or less (<34 weeks). We conducted logistic regression analysis of the risk factors of SPTBs <34 weeks after cerclage. Three risk factors were identified that increased the risk of SPTB <34 weeks: presurgical CL 0 mm (odds ratio (OR): 5.30; 95% confidence interval (CI): 1.58-17.7), a history of SPTB (OR: 4.65; 95% CI: 1.38-15.7), and the presence of sludge (OR: 4.14; 95% CI: 1.20-14.3). Conclusion: Three risk factors predicted SPTB <34 weeks after emergency cerclage without progesterone administration: unmeasurable CL (CL 0 mm), a history of SPTB, and the presence of sludge on ultrasound. SPTB <34 weeks occurred after emergency cerclage in 16% of patients, being comparable with the recent data with progesterone.

Uterine compression suture and intrauterine hemostatic balloon are important procedures to achieve hemostasis for obstetric hemorrhage. A combined use of these two, with B-Lynch suture + Bakri balloon being the most often employed ones, is referred to as a "uterine sandwich", which is an effective hemostatic procedure. Fundamentally, the former and latter stop bleeding from the uterine body and lower uterine segment, respectively. This represents the concept of "role sharing" for hemostasis. Recognizing this concept is of practical importance.

Maternal obesity is one of the major risk factors for pregnancy complications and is associated with low-grade chronic systemic inflammation due to higher levels of pro-inflammatory cytokines such as interleukin (IL)-1β. Pregnant women with obesity have abnormal lipid profiles, characterized by higher levels of free fatty acids, especially palmitic acid (PA). Previously, we reported that PA stimulated IL-1β secretion via activation of NLRP3 inflammasome in human placental cells. These observations led us to hypothesize that higher levels of PA induce NLRP3 inflammasome activation and placental inflammation, resulting in pregnancy complications. However, the effects of PA on NLRP3 inflammasome during pregnancy in vivo remain unclear. Therefore, PA solutions were administered intravenously into pregnant mice on day 12 of gestation. Maternal body weight was significantly decreased and absorption rates were significantly higher in PA-injected mice. The administration of PA significantly increased IL-1β protein and the mRNA expression of NLRP3 inflammasome components (NLRP3, ASC, and caspase-1) within the placenta. In murine placental cell culture, PA significantly stimulated IL-1β secretion, and this secretion was suppressed by a specific NLRP3 inhibitor (MCC950). Simultaneously, the number of macrophages/monocytes and neutrophils, together with the mRNA expression of these chemokines increased significantly in the placentas of PA-treated mice. Treatment with PA induced ASC assembling and IL-1β secretion in macrophages, and this PA-induced IL-1β secretion was significantly suppressed in NLRP3-knockdown macrophages. These results indicate that transient higher levels of PA exposure in pregnant mice activates NLRP3 inflammasome and induces placental inflammation, resulting in the incidence of absorption.

There are few case reports in which circulating levels of soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), and soluble endoglin (sEng) were measured before the onset of super-imposed preeclampsia in women with hemodialysis. A 40-year-old Japanese nulliparous women with hemodialysis due to diabetic nephropathy became pregnant by frozen embryo transfer. Intensive hemodialysis was started at 5 weeks of gestation. Her blood pressure (BP) in the first trimester was around 130/80 mmHg. At 20+3 weeks, she was admitted for close monitoring; her BP was 137/75 mmHg. Her BP increased to 157/88 mmHg at 31+2 weeks, and nifedipine at 20 mg/day was started at 31+6 weeks. However, the serial longitudinal measurements of sFlt-1, PlGF, and sEng did not predict the onset of super-imposed preeclampsia. Cesarean section was performed at 33+6 weeks due to uncontrollable hypertension. A healthy female infant weighing 2138 g was delivered. As for the changes of biomarkers between just before and just after hemodialysis, sFlt-1 was significantly higher just after compared with just before hemodialysis (5774 ± 1875 pg/mL vs. 2960 ± 905 pg/mL, respectively, p < 0.001). PlGF was also significantly higher just after compared with just before hemodialysis (2227 ± 1038 pg/mL vs. 1377 ± 614 pg/mL, respectively, p < 0.001). However, the sFlt-1/PlGF ratio and sEng levels were not significantly different between just before and just after hemodialysis (p = 0.115, p = 0.672, respectively). In conclusion, prediction of early-onset super-imposed preeclampsia using angiogenic and anti-angiogenic markers in pregnant women with hemodialysis might be difficult.

AIM: We examined whether critical conditions, which were defined as having hemoglobin (Hb) less than 7.0 g/dL, shock index ≥1.0, or need for transfusion, were associated with the presence of extravasation (EV) on dynamic computed tomography (CT) in women with late post-partum hemorrhage (PPH). METHODS: Forty post-partum women with late PPH without evident retained products of conception performed dynamic CT. Two radiologists retrospectively evaluated dynamic CT, and determined the presence or absence of EV and a sac-like structure within the uterine cavity with enhancement. RESULTS: Ultrasound images were available in 34/40 patients. Color Doppler flow in uterine cavity was evaluated in 33/34 (97%), and all women showed abnormal flow. Of 40 patients, dynamic CT revealed EV in 8 (20%), and a sac-like structure in 30 (75%). Thus, we diagnosed these 38 (95%) as having uterine artery pseudoaneurysm (UAP). Uterine artery embolization was performed in 36/38 diagnosed as having UAP, and in 2/2 patients with an unknown cause of hemorrhage. The incidence rates of critical conditions were significantly increased in PPH women with than without EV on dynamic CT: Hb <7.0 g/dL (62.5 vs 0%, [P < 0.001]), shock index ≥1.0 (50 vs 9.4% [P = 0.020]), and need for transfusion (37.5 vs 0% [P = 0.006]). Abnormal color Doppler flows were observed in all patients with either EV and sac on dynamic CT. CONCLUSION: Dynamic CT was useful for diagnosing UAP, and for evaluating critical conditions, in women with late PPH not complicated by retained products of conception.

An interstitial pregnancy that continues beyond the second trimester is a rare phenomenon. We report a patient with an interstitial pregnancy undiagnosed until the third trimester. A multiparous woman was referred to us because of preeclampsia at 26 weeks of gestation. The placental position was the right fundus, and color Doppler ultrasound revealed myometrial thinning and subplacental hypervascularity, leading to a suspicion of placenta accreta spectrum (PAS). Emergency cesarean section was performed at 281/7 weeks of gestation due to severe preeclampsia. The right tubal horn to the isthmus of the fallopian tube bulged with placental adhesion and a part of the tube had ruptured, with the omentum adhering to the ruptured part. Interstitial and tubal isthmic pregnancy with uterine rupture was diagnosed.

Introduction: Appropriate extravillous trophoblast (EVT) invasion is essential for successful pregnancy. Previously, we showed that EVTs express CD44, which accelerated EVT invasion. However, its regulation mechanism via CD44 remains unknown. Our hypothesis was that WNT signaling enhanced EVT invasion via CD44. To test this hypothesis, we investigated the effects of WNT ligands on CD44 expression and EVT invasion using EVT cell lines and isolated primary EVTs.Methods: We used EVT cell lines (HTR8/SVneo and HChEpC1b) and isolated primary EVTs, extracted from first-trimester trophoblasts. The cells were supplemented with WNT3A, 5A, and 10B. We examined cell invasion and the expressions of CD44 and matrix metalloproteinase (MMP) 9. Next, to clarify the pathway of WNT10B in EVTs, we knock-downed WNT10B using siRNA and activated or inhibited the WNT canonical pathway using an activator (lithium chloride) or inhibitor (FH535, XAV939) with WNT10B addition.Results: WNT3A, 5A, and 10B accelerated the invasion in the EVT lines and isolated primary EVTs. The expressions of CD44 and MMP9 were also upregulated by WNT ligands. WNT10B knockdown significantly inhibited EVT invasion concomitantly with CD44 expression. The WNT canonical pathway activator upregulated CD44 expression and its inhibitor downregulated it with WNT10B addition.Conclusions: The present study is the first to show the possibility that WNT3A, WNT5A, and WNT10B exist upstream of CD44 in EVTs. Among them, WNT10B may be a novel accelerator of EVT invasion. WNT signaling mediated by multiple WNT ligands may contribute to EVT invasion.

Objectives: To clarify the outcome of retained products of conception (RPOC) without placenta previa.Study design: This was a retrospective cohort study consisting of 59 patients who abdominally or vaginally gave birth to infants after 14 weeks without placenta previa and had RPOC between April 2006 and December 2018. Patients' background, characteristics, and outcomes were compared between those requiring and not-requiring intervention for RPOC.Results: Of the 59 patients, pregnancies after assisted reproductive technology accounted for 18 (31%). The ultrasound-measured RPOC length was 4 cm (median) and 39 (66%) showed hypervascularity within RPOC. Interventions were required in 36 patients (61%), with all due to bleeding-related events. Multivariate regression analyses revealed that the interventions were significantly more likely in the following situations: younger than 35 years (aOR: 4.2, 95%CI: 1.1-18.5), RPOC length >= 4 cm (aOR: 8.6, 95% CI: 2.4-39.2), and RPOC hypervascularity (aOR: 4.6, 95%CI: 1.3-18.8). Methotrexate was administered to 8 patients, of whom 4 (50%) required further hemostatic interventions.Conclusion: In patients with RPOC without previa, 61 and 39% did and did not require hemostatic interventions, respectively. In the latter, a wait-and-see strategy resulted in the resolution of RPOC. Patients with larger RPOC (>= 4-cm fragment length) and hypervascularity were significantly more likely to require hemostatic intervention. (C) 2019 Elsevier B.V. All rights reserved.

Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialized topics. At IFPA meeting 2018 there were nine themed workshops, four of which are summarized in this report. These workshops discussed new knowledge and technological innovations in the following areas of research: 1) viviparity in ocean-living species; 2) placental imaging; 3) epigenetics; and 4) extracellular vesicles in pregnancy.

Fetal seizure is rarely observed. Investigation of both video-recording of seizures and cardiotocography is crucial for a precise diagnosis. Here, we report a case of fetal seizure, and also show a video-ultrasound recording. A 40-year-old woman was admitted to us due to loss of variability in cardiotocography. Ultrasound repeatedly revealed opisthotonus-like and clonic-seizure-like movements. After the abnormal movement, tachycardia up to 210 bpm (postictal tachycardia) was noted. Ultrasound revealed a nuchal cord. A careful investigation of video-ultrasound recording by an epilepsy specialist led to the confirmation of epileptic seizures. At 36(4/7), she vaginally gave birth to an infant with an umbilical artery pH of 7.22. The infant died 30 min after birth. No clear video-recordings associated with fetal seizure were available for cases reported so far in the literature. The video provided in this case may be of use for further analyses.

常染色体優性多嚢胞性腎(Autosomal dominant polycystic kidney disease:ADPKD)の胎児診断例は非常に稀である。今回、胎児超音波検査において胎児超音波で腎臓の高輝度に加え、家族歴を聴取し、腎嚢胞の有病状況の家系図を作成したところ、ADPKDの可能性があることを胎児診断できた症例を報告した。(著者抄録)