高橋 宏典

OBJECTIVE: X-linked hydrocephalus (XLH), the most common genetic hydrocephalus, is caused by mutation of the L1 cell adhesion molecule (L1CAM). A fetus/neonate with this disorder frequently shows an adducted thumb, which has been employed as a helpful finding in the prenatal diagnosis of XLH. MATERIALS AND METHODS: We describe a male fetus with hydrocephalus without an adducted thumb: the pregnancy was terminated at 21 weeks' gestation on the parents' request. Direct sequencing of the umbilical cord revealed L1CAM mutation, which confirmed the diagnosis of XLH. RESULTS: Our literature review demonstrated that while an adducted thumb was observed in almost all fetuses with this disorder after 24 weeks' gestation, it was noted in only 57% (8/14) of fetuses/neonates at less than 24 weeks: it was absent in 43%. CONCLUSION: Even if an adducted thumb is not observed, XLH should not be ruled out, especially in early gestation.

AIM: The study aimed to examine the usefulness of modified transabdominal cervicoisthmic cerclage (TAC) using monofilament thread for the prevention of preterm delivery in women with an extremely short cervix after deep conization. METHODS: We devised a monofilament thread for picking up the seromuscular layer of the site that is slightly cephalad to the internal ostium to prevent injury of the vessels around the uterine cervix. From 2017 to 2020, we performed this modified operation in eight women (nine pregnancies) at 12-16 weeks of gestation with a history of deep cervical conization. RESULTS: A modified TAC was successfully performed in all patients. There was no measurable bleeding, and all patients were discharged without postoperative complications. Their pregnancy courses after the operation were uneventful. Of nine, one patient had premature uterine contractions and underwent cesarean section at 36 weeks (preterm delivery). In the other eight pregnancies, planned cesarean section was performed after 37 weeks of gestation. The median birth weight of the babies was 2996 g (range 2604-3374 g). All patients were discharged on the sixth postoperative day without complications. CONCLUSION: A modified TAC can be safely performed and may prolong pregnancy without adverse events in patients with an extremely short cervix.

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

Disruption of well-controlled reproductive functions leads to pregnancy complications such as hypertensive disorders of pregnancy (HDP). Uncaria tomentosa (Wild), known as cat's claw, is widely used for the treatment of a various types of health problems; AC-11 (AC-11®, hot-water extract of U. tomentosa) is unique phytochemical compound and has potential roles as anti-inflammatory or anti-oxidant processes. We investigated whether AC-11 has a protective effect on pathogenesis of HDP in vivo and production of anti-angiogenic factors (sFlt-1 and sEng, major factors for the onset of HDP) in in vitro. Non-pregnant or pregnant mice were administered AC-11 (4 mg/mL), then, angiotensin II (Ang II) was subcutaneously infused to increase blood pressure. Human placental tissues or human umbilical vein endothelial cells (HUVECs) were incubated with or without AC-11. Treatment with AC-11 significantly reduced blood pressure induced by Ang II infusion. The population of CD8+T cells, the ratio of CD8/CD4, and plasma interleukin-6 levels were increased by Ang II infusion, and were decreased by AC-11 both in pregnant and non-pregnant mice. In pregnant mice, plasma levels of sFlt-1 and sEng were decreased by AC-11. In in vitro cell culture of HUVECs or placental tissue culture, treatment with AC-11 significantly inhibited secretion of sFlt-1 and sEng. We suggest a novel role of AC-11 in regulating blood pressure by controlling the balance of T cell population and inflammatory cytokine production both in non-pregnant and pregnant conditions. In addition, AC-11 inhibits HDP-related factors, including sFlt-1 and sEng, suggesting that AC-11 may useful for relieving HDP.

OBJECTIVES: Various procedures have been introduced to achieve hemostasis for postpartum hemorrhage (PPH) in placenta previa (PP). This study attempted to clarify the effectiveness of the combined use of three hemostatic procedures: Matsubara-Takahashi cervix-holding (MT-holding), intrauterine balloon (IUB), and uterine compression suture (UCS). STUDY DESIGN: This was a historical cohort study on the hemostatic effect of combined procedures for patients with placenta previa (PP) undergoing cesarean section between April 2006 and December 2018. Until 2011 (2006-2011), we used MT-holding alone, whereas since 2012 we have also been using IUB and UCS: MT-holding alone was used in the former period whereas three procedures (MT-holding, IUB, UCS, and their combinations) have been used in the latter period. Perinatal outcomes were compared between 2006-2011 (before group) and 2012-2018 (after group). RESULTS: Of 416 patients with PP, excluding 273 patients with cesarean hysterectomy or no hemostatic procedure, the remaining 143 patients were analyzed. In the after group, intraoperative blood loss, the percentage of patients with postoperative blood loss ≥ 500 ml, and incidence of autologous blood transfusion were significantly lower than in the before group. Multivariate analysis showed that postoperative blood loss ≥ 500 ml decreased in the after group (adjusted OR: 0.3, 95%CI: 0.1-0.8, compared with the before group). CONCLUSION: PPH decreased after introducing the combination of hemostatic procedures in patients with PP. Further studies are needed to determine the best combination and optimal indication for combining hemostatic procedures for PP.

The immune system contributes to the regulation of pregnancy, and the disruption of well-controlled immune functions leads to pregnancy complications. Recently, the nucleotide-binding oligomerization domain, leucine-rich repeat-, and pyrin domain-containing 3 (NLRP3) inflammasome mechanisms [(a protein complex of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and caspase-1)] have been reported to play roles in controlling placental inflammation involved in pregnancy pathologies. The ketone body β-hydroxybutyrate (BHB) can suppress NLRP3 inflammasome activation and improve various inflammatory diseases. Therefore, we hypothesized that BHB could suppress activation of the NLRP3 inflammasome in the placenta, resulting in the improvement of pregnancy complications. In human placental tissue culture, treatment with BHB suppressed the secretion levels of inflammatory cytokines, such as interleukin (IL)-1β, IL-6, and IL-8, but did not affect the mRNA expression levels of NLRP3 inflammasome-associated factors. Treatment with BHB reduced IL-1β secretion and the amount of mature IL-1β protein induced by lipopolysaccharide (LPS) stimulation in the placenta. In human trophoblast cells, BHB reduced ASC and activated-caspase-1 expression, resulting in the inhibition of IL-1β secretion. To investigate the effect of BHB during pregnancy, we used an animal model of LPS (100 μg/kg intraperitoneally [i.p.] on gestational day 14)-induced pregnancy complications. Administration of BHB (100 mg/kg i.p.) clearly suppressed the absorption rate and IL-1β production in the placenta induced by LPS in pregnant mice. Moreover, LPS-induced pregnancy abnormalities were improved in NLRP3-deficient mice. These findings suggest that BHB play a role in reducing placental inflammation and pregnancy complications via inhibition of NLRP3 inflammasome activation.

OBJECTIVE: To validate the use of placenta accreta risk-antepartum (PAR-A) score as a predictive tool of clinical outcomes of placenta accreta spectrum (PAS). METHODS: This is a prospective study, conducted in six PAS specialized centers in six different countries. The study was conducted between October 1, 2020 and March 31, 2021. Women who were provisionally diagnosed with PAS during pregnancy were considered eligible. A machine-learning-based PAR-A score was calculated. Diagnostic performance of the PAR-A score was evaluated using a receiver operating characteristic curve, for perioperative massive blood loss and admission to intensive care unit (ClinicalTrials.gov identifier NCT04525001). RESULTS: Of 97 eligible women, 86 were included. PAS-associated massive blood loss occurred in 10 patients (11.63%). Median PAR-A scores of massive blood loss in the current cohort were 8.9 (interquartile range 6.9-14.1). In predicting massive blood loss, the area under the curve of PAR-A scores was 0.85 (95% confidence interval [CI] 0.74-0.95), which was not significantly different from the original cohort (P = 0.2). PAR-A score prediction of intensive care unit admission was slightly higher compared with the original cohort (0.88, 95% CI 0.81-0.95; P = 0.06). CONCLUSION: PAR-A score is a novel scoring system of PAS outcomes, which showed external validity based on current data.

OBJECTIVE: Cystic hygroma often ameliorates or disappears with pregnancy progression. Fetuses/neonates with amelioration, when without chromosomal or major structural abnormality, generally show a favorable outcome at birth. The present study was aimed to clarify the short/long-term outcomes of fetuses/neonates with the amelioration of cystic hygroma during pregnancy. MATERIAL AND METHODS: This was a retrospective observational study. We focused on fetuses with cystic hygroma managed in our institute between January 2006 and June 2019. The infants were followed by pediatricians (neonatologist, pediatric cardiologist, and pediatric neurologist) and pediatric outcomes were retrieved from the medical records up to 3 years old. RESULTS: One hundred and seven fetuses with cystic hygroma were included. Of the 107, cystic hygromas ameliorated in 31 fetuses (31/107: 29%). Of the 31, there were 26 livebirths. Half (n = 13) of the 26 fetuses had a good outcome, whereas the remaining half (n = 13) had abnormalities. Various abnormalities were detected in their infancies. A nuchal thickness (diameter of hygroma) of ≥5 mm was significantly correlated with abnormalities (P = 0.047). CONCLUSION: Physicians should pay attention to fetuses/neonates with ameliorated cystic hygroma. Of those, special attention should be paid to fetuses/neonates with a nuchal thickness at diagnosis ≥5 mm.

Advanced maternal age is a risk factor for female infertility, and placental dysfunction is considered one of the causes of pregnancy complications. We investigated the effects of advanced maternal aging on pregnancy outcomes and placental senescence. Female pregnant mice were separated into three groups: young (3 months old), middle (8-9 months old), and aged (11-13 months old). Although the body weights of young and middle dams gradually increased during pregnancy, the body weight of aged dams only increased slightly. The placental weight and resorption rate were significantly higher, and live fetal weights were reduced in a maternal age-dependent manner. Although mRNA expression of senescence regulatory factors (p16 and p21) increased in the spleen of aged dams, mRNA expression of p16 did not change and that of p21 was reduced in the placenta of aged dams. Using a cytokine array of proteins extracted from placental tissues, the expression of various types of senescence-associated secretory phenotype (SASP) factors was decreased in aged dams compared with young and middle dams. The aged maternal placenta showed reduced immune cell accumulation compared with the young placenta. Our present results suggest that models using pregnant mice older than 8 months are more suitable for verifying older human pregnancies. These findings suggest that general cellular senescence programs may not be included in the placenta and that placental functions, including SASP production and immune cell accumulation, gradually decrease in a maternal age-dependent manner, resulting in a higher rate of pregnancy complications.

OBJECTIVES: Maternal systemic and placental inflammatory responses participate in the pathogenesis of hypertensive disorders of pregnancy including preeclampsia, a pregnancy-specific syndrome, although the role of inflammation remains unclear. The NLRP3 inflammasome has been implicated in the control of sterile inflammation involved in preeclampsia. In the present study, we hypothesized that S100A9, as major alarmin, are associated with the pathogenesis of preeclampsia and induction of a preeclampsia-like phenotype in pregnant mice. METHODS: Plasma were taken from normal pregnant women and preeclampsia patients. Human placental tissues, trophoblast cell line Sw.71 cells, and human umbilical vein endothelial cells (HUVEC) were treated with S100A9 with or without inhibitors associated with NLRP3 inflammasome. Pregnant mice were administered S100A9. RESULTS: S100A9 was elevated in plasma and released from placentas of preeclampsia patients. S100A9 activated the NLRP3 inflammasome, resulting in IL-1β secretion, by human placental tissues and trophoblasts. In addition, secretion of soluble endoglin, a main contributor to the pathogenesis of preeclampsia, is regulated via S100A9-stimulated NLRP3 inflammasome activation in the human placenta and HUVECs. S100A9 administration significantly elevated maternal blood pressure and neutrophil accumulation within the placentas of pregnant mice, and both were significantly decreased in Nlrp3-knock out pregnant mice. CONCLUSION: The results of this study demonstrated that S100A9 acts as a danger signal to activate the NLRP3 inflammasome in the placenta, associating with hypertension during pregnancy.

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.

Objective: To clarify whether isolated proteinuria (IP) is an independent risk factor for blood transfusion (BT) for postpartum hemorrhage (PPH), and whether risk factors for BT identified in single pregnancy also apply to twin pregnancy. Materials and Methods: A retrospective cohort study of consecutive women who gave birth at Jichi Medical University Hospital, Japan, between 1 April 2006 and 31 December 2016 was performed. Single or diamniotic twin deliveries producing healthy infants of ≥ 22 weeks were included. We analyzed the correlations between BT and 13 candidate risk factors that may be potentially associated with PPH in single and twin pregnancies. Results: We included 11,423 pregnancies: 10,523 (92.2%) single and 900 (7.8%) twin pregnancies. In single pregnancies, multivariate analysis indicated that placenta previa (PP), abruptio placentae, IP, chronic or gestational hypertension, preeclampsia (PE), HELLP syndrome, and tocolytic treatment (OR: 10.4, 19.1, 3.7, 3.6, 4.0, 18.9, and 2.0, respectively) were independent factors for the increased risk of allogenic BT. In twin pregnancies, multivariate analysis revealed that PP, abruptio placentae, IP, PE, and HELLP syndrome were independent factors for the increased risk of allogeneic BT (OR: 8.3, 103, 3.9, 4.3, and 39.6, respectively). Conclusion: IP was a novel risk factor for BT in both single and twin pregnancies. Although risk factors for BT were very similar between single and twin pregnancies, intravenous tocolysis was and was not a risk factor in single and twin pregnancies, respectively.

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.

Objective: At cesarean section (CS) for placenta previa (PP), previous CS, especially multiple CS, is reported to be associated with massive bleeding. The authors attempted to determine which causes massive bleeding, previous CS per se or previous-CS-associated factors. The need for allogeneic blood transfusion (BT) at CS was set as a marker representing massive bleeding. Materials and Meth- ods: This retrospective cohort study involved all 326 patients with PP who delivered in one institute using the same management pro- tocol. The authors evaluated the associations between the number of previous CS, maternal characteristics, and perinatal outcomes, and calculated the odds ratio (OR) for allogeneic BT according to the number of previous CS. Results: With an increasing number of pre- vious CS, the following significantly increased: Abnormally invasive placenta, anterior placentation, total previa, and ultrasound-de- tectable lacunae. The rates of allogeneic BT for patients with previous CS of 0×, 1×, and &gt 2× were 6% (16/273), 37% (14/38), and 60% (9/15), respectively (p &lt 0.001). On adjustment for anterior placentation, total previa, and lacunae, ORs (95% confidence interval) of allogeneic BT for previous CS 1× and &gt 2× were 6.3 (2.5-16.4) and 11.4 (3.0-42.2), respectively, with CS 0× being referent. On analy- sis of 308 (326-18) patients excluding 18 with an abnormally invasive placenta, the adjusted ORs of allogeneic BT for CS 1× and &gt 2× were 3.5 (1.1-10.8) and 6.2 (1.1-37.3), respectively, remaining high. Conclusion: The number of prior CS, and, thus the previous CS per se, increases the requirement for allogeneic BT, irrespective of the presence/absence of an AIP, anterior placentation, total previa, or lacunae. Management protocol of PP women with multiple CS should be adapted accordingly.

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.