大口 昭英

卵巣静脈血栓症は非常に稀で無症状に経過しその発症に気づかれないことも多い。今回、無症状であったが帝王切開術後に酸素飽和度の低下で判明した卵巣静脈血栓症、肺塞栓症を併発した双胎妊娠例を報告する。妊娠中に無症候性の卵巣静脈血栓症から、肺塞栓症を併発する場合があり、血栓リスクを考慮し、症状がなくともSpO2低下や血栓マーカー異常が認められた場合は、これらの疾患発症を念頭においた検査が必要と考える。(著者抄録)

嵌頓子宮とは、妊娠子宮が骨盤腔で高度に屈曲した状態を指す。今回、子宮頸管の強い伸展を伴う嵌頓子宮を呈し、かつ前置胎盤が疑われた妊婦の帝王切開を経験した。術前に画像検査で骨盤内臓器の位置関係を評価し、術中に超音波で胎盤位置を確認しながら切開創を決定したことで、臓器損傷なく安全に児を娩出することができた。(著者抄録)

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.

BACKGROUND: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk is needed to plan management. OBJECTIVES: To assess the performance of existing pre-eclampsia prediction models and to develop and validate models for pre-eclampsia using individual participant data meta-analysis. We also estimated the prognostic value of individual markers. DESIGN: This was an individual participant data meta-analysis of cohort studies. SETTING: Source data from secondary and tertiary care. PREDICTORS: We identified predictors from systematic reviews, and prioritised for importance in an international survey. PRIMARY OUTCOMES: Early-onset (delivery at < 34 weeks' gestation), late-onset (delivery at ≥ 34 weeks' gestation) and any-onset pre-eclampsia. ANALYSIS: We externally validated existing prediction models in UK cohorts and reported their performance in terms of discrimination and calibration. We developed and validated 12 new models based on clinical characteristics, clinical characteristics and biochemical markers, and clinical characteristics and ultrasound markers in the first and second trimesters. We summarised the data set-specific performance of each model using a random-effects meta-analysis. Discrimination was considered promising for C-statistics of ≥ 0.7, and calibration was considered good if the slope was near 1 and calibration-in-the-large was near 0. Heterogeneity was quantified using I 2 and τ2. A decision curve analysis was undertaken to determine the clinical utility (net benefit) of the models. We reported the unadjusted prognostic value of individual predictors for pre-eclampsia as odds ratios with 95% confidence and prediction intervals. RESULTS: The International Prediction of Pregnancy Complications network comprised 78 studies (3,570,993 singleton pregnancies) identified from systematic reviews of tests to predict pre-eclampsia. Twenty-four of the 131 published prediction models could be validated in 11 UK cohorts. Summary C-statistics were between 0.6 and 0.7 for most models, and calibration was generally poor owing to large between-study heterogeneity, suggesting model overfitting. The clinical utility of the models varied between showing net harm to showing minimal or no net benefit. The average discrimination for IPPIC models ranged between 0.68 and 0.83. This was highest for the second-trimester clinical characteristics and biochemical markers model to predict early-onset pre-eclampsia, and lowest for the first-trimester clinical characteristics models to predict any pre-eclampsia. Calibration performance was heterogeneous across studies. Net benefit was observed for International Prediction of Pregnancy Complications first and second-trimester clinical characteristics and clinical characteristics and biochemical markers models predicting any pre-eclampsia, when validated in singleton nulliparous women managed in the UK NHS. History of hypertension, parity, smoking, mode of conception, placental growth factor and uterine artery pulsatility index had the strongest unadjusted associations with pre-eclampsia. LIMITATIONS: Variations in study population characteristics, type of predictors reported, too few events in some validation cohorts and the type of measurements contributed to heterogeneity in performance of the International Prediction of Pregnancy Complications models. Some published models were not validated because model predictors were unavailable in the individual participant data. CONCLUSION: For models that could be validated, predictive performance was generally poor across data sets. Although the International Prediction of Pregnancy Complications models show good predictive performance on average, and in the singleton nulliparous population, heterogeneity in calibration performance is likely across settings. FUTURE WORK: Recalibration of model parameters within populations may improve calibration performance. Additional strong predictors need to be identified to improve model performance and consistency. Validation, including examination of calibration heterogeneity, is required for the models we could not validate. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015029349. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 72. See the NIHR Journals Library website for further project information.

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.

The role of plasmacytoid dendritic cells (pDCs), and myeloid dendritic cells (mDCs) in women with preeclampsia has not been elucidated. We compared the frequency of peripheral pDCs, mDCs, NK cells, and T helper 17 (Th17) cells among non-pregnant/pregnant women, and women with early-/late-onset preeclampsia. We examined pDCs and mDCs using Anti-Human Lineage Cocktail 3 (CD3, CD14, CD19, and CD20), HLA-DR, CD11c, and CD123. We detected NK cells using Lineage cocktail, CD8, CD16, and CD56. We determined Th17 cells using CD3, CD4, CD8, CXCR3, and CCR6. We recruited 13 non-pregnant women, 50 normal pregnant women, 13 women with early-onset preeclampsia (onset at &lt 34 gestational weeks), and 10 women with late-onset preeclampsia. The fraction of pDCs in women with early-onset preeclampsia was significantly lower than in non-pregnant women and normal pregnant women at 19−29 gestational weeks (4.1 % vs. 41.2 % and 19.0 %, respectively [p = 0.0005, and p = 0.025]), however, the fraction of pDCs in late-onset preeclampsia was not significantly different from normal pregnant women at 37 gestational weeks (11.1 % vs. 29.1 %, respectively [p = 0.149]), although it was significantly lower than in non-pregnant women (11.1 % vs. 41.2 %, respectively [p = 0.044]). The fraction of Th17 cells in women with early-onset preeclampsia was significantly higher than in normal pregnant women at 19−29 gestational weeks (p = 0.022). In conclusion, the level of circulating pDCs was lower in early-onset preeclampsia than in non-pregnant and pregnant women, suggesting the role of pDCs in the pathogenesis of early-onset preeclampsia.

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.

Our aim was to evaluate the association between ritodrine and magnesium sulfate (MgSO4) and the occurrence of neonatal hyperkalemia or hypoglycemia among late preterm infants in a retrospective cohort study. We used a nationwide obstetrical database from 2014. A total of 4,622 live preterm infants born at 32-36 gestational weeks participated. Fourteen risk factors based on both clinical relevance and univariate analysis were adjusted in multivariable logistic regression analyses. Neonatal hyperkalemia and hypoglycemia occurred in 7.6% (284/3,732) and 32.4% (1,458/4,501), respectively. Occurrence of hyperkalemia was associated with concomitant usage of ritodrine and MgSO4 compared with no usage (adjusted odds ratio [aOR] 1.53, 95% confidence interval [CI] 1.09-2.15). Occurrence of hypoglycemia was associated with ritodrine alone (aOR 2.58 [CI 2.21-3.01]) and with concomitant usage of ritodrine and MgSO4 (aOR 2.59 [CI 2.13-3.15]), compared with no usage, and was associated with long-term usage (≥ 48 hours) of ritodrine and cessation directly before delivery. In conclusion, in late preterm infants, usage of ritodrine together with MgSO4 was associated with occurrence of critical neonatal hyperkalemia, and long-term usage of ritodrine and cessation directly before delivery were associated with neonatal hypoglycemia.

妊娠合併子宮頸癌では、妊娠中の治療方針決定に苦慮することが多い。症例は、31歳、2妊1産、妊娠初期の細胞診異常を契機として、妊娠19週で子宮頸部腺癌IB1期と診断した。強い妊娠継続希望があり、妊娠21週から術前化学療法としてカルボプラチン・パクリタキセル療法を行い、妊娠32週で帝王切開と広汎子宮全摘出を行った。妊娠中の化学療法による母児への大きな影響は認めなかった。妊娠合併子宮頸癌では、妊娠中の化学療法も選択肢のひとつである。(著者抄録)

羊水を用いた染色体分析には、G分染法(G-banding)とFISH(fluorescent in situ hybridization)法がある。G分染法は確定診断であり広く採用されているが、検体細胞の培養が必要で結果判定までに数週間を要する。一方、FISH(fluorescent in situ hybridization)法は確定診断ではないが、診断率は高く培養が不要なため、結果判定まで数日しかかからず染色体異常の可能性を迅速に評価できる。FISHでは、このため、患者の意思決定までの時間的余裕が増加し、小児科医によるプレネイタルビジットの機会も増す可能性が高い。FISH導入前・後の診療上の変化を論じる。(著者抄録)

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.

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.

次世代を残すための妊娠機構は厳密に管理され、その制御に免疫機構が関与している。NLRP3インフラマソームは感染の関与しない『無菌性炎症』を制御する免疫機構であるが、このNLRP3インフラマソームが妊娠高血圧腎症(PE)を含む多くの異常妊娠に関与することが分かってきた。実際に、PE患者の体内では、NLRP3インフラマソーム活性化を誘導する様々な内因性物質(尿酸結晶やコレステロール結晶等)が増加し、胎盤を中心として過度の炎症応答が誘導される。一方、NLRP3インフラマソームを抑制制御することによってPE病態が軽減できる可能性も分かってきている。妊娠機構におけるNLRP3インフラマソームを理解することで、新たな治療法等への応用に繋がることが期待される。(著者抄録)

Current diagnostic criteria have limited clinical value for prediction of preeclampsia and fetal adverse outcomes. The prediction of short-term outcome in pregnant women with suspected preeclampsia study in Asia (PROGNOSIS Asia) was a prospective, multicenter study designed to investigate the value of the sFlt-1 (soluble fms-like tyrosine kinase 1)/PlGF (placental growth factor) ratio for predicting adverse outcomes in pregnant Asian women with suspected preeclampsia. Seven hundred sixty-four pregnant women at gestational week 20+ 0 days (18+ 0 days in Japan) to 36+ 6 days were enrolled at 25 sites in Asia. The primary objectives were to demonstrate the value of the sFlt-1/PlGF ratio for ruling out preeclampsia within 1 week and ruling in preeclampsia within 4 weeks. The value of the ratio for predicting fetal adverse outcomes was also assessed. Seven hundred patients were evaluable for primary end point analysis. The prevalence of preeclampsia was 14.4%. An sFlt-1/PlGF ratio of = 38 had a negative predictive value of 98.6% (95% CI, 97.2%-99.4%) for ruling out preeclampsia within 1 week, with 76.5% sensitivity and 82.1% specificity. The positive predictive value of a ratio of > 38 for ruling in preeclampsia within 4 weeks was 30.3% (95% CI, 23.0%-38.5%), with 62.0% sensitivity and 83.9% specificity. An sFlt-1/PlGF ratio of = 38 had a negative predictive value of 98.9% (95% CI, 97.6%-99.6%) for ruling out fetal adverse outcomes within 1 week and a ratio of > 38 had a positive predictive value of 53.5% (95% CI, 45.0%-61.8%) for ruling in fetal adverse outcomes within 4 weeks. The sFlt-1/PlGF ratio cutoff of 38 demonstrated clinical value for the short-term prediction of preeclampsia in Asian women with suspected preeclampsia, potentially helping to prevent unnecessary hospitalization and intervention.

The authors regret that an error occurred in Fig. 3 of the published article indicated above. The correct Fig. 3 is shown below. (Figure presented.) The authors would like to apologise for any inconvenience caused.