大口 昭英

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.

Degeneration of adenomyosis during pregnancy and the post-partum period is very rare. A 42-year-old Japanese parous woman with four normal-term deliveries, who presented with abdominal pain and fever at 22 weeks of gestation with transient increases of the white blood cell count and C-reactive protein, demonstrated sustained inflammation after cesarean section at 29 weeks of gestation due to the occurrence of gestational hypertension with late deceleration. The noncontrast-enhanced magnetic resonance imaging (MRI) at 22 weeks demonstrated a poorly demarcated hypointense area at the posterior uterine wall on T1- and T2-weighted imaging. The 2nd MRI 2 weeks after the cesarean section showed hypointensity on a T1-weighted image and hyperintensity on a T2-weighted image, allowing confirmation of the diagnosis of degeneration of adenomyosis. Repeated MRIs were clinically useful to diagnose the degeneration of adenomyosis.

Problem: We investigated the effect of oxygen concentrations on cellular senescence and autophagy and examined the role of autophagy in human trophoblast cells. Method of study: Human first-trimester trophoblast cells (Sw.71) were incubated under 21%, 5%, or 1% O2 concentrations for 24 hours. We examined the extent of senescence caused using senescence-associated β-galactosidase (SA-β-Gal) and senescence-associated secretory phenotype (SASP) as markers. Moreover, we examined the role of autophagy in causing cellular senescence using an autophagy inhibitor (3-methyladenine, 3MA). Results: Physiological normoxia (5% O2) decreased SA-β-Gal-positive cells and SASP including interleukin-6 (IL-6) and IL-8 compared with cultured cells in 21% O2. Pathophysiological hypoxia (1% O2) caused cytotoxicity, including extracellular release of ATP and lactate dehydrogenase, and decreased senescence phenotypes. 3MA-treated trophoblast cells significantly suppressed senescence markers (SA-β-Gal-positive cells and SASP secretion) in O2-independent manner. Conclusion: We conclude that O2 concentration modulates cellular senescence phenotypes regulating autophagy in the human trophoblast cells. Moreover, inhibiting autophagy suppresses cellular senescence, suggesting that autophagy contributes to oxygen stress-induced cellular senescence.

Objective: Our first aim was to construct gestational-age-specific reference ranges of serum levels of soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), and the sFlt-1/PlGF ratio at 19–38 weeks of gestation. Our second aim was to compare the serum levels of sFlt-1, PlGF, and the sFlt-1/PlGF ratio in 81 women with PE which occurred at &lt 32, 32–33, 34–35, and ≥36 weeks. Method: Serum levels of sFlt-1 and PlGF were measured by automated immunoassays (Elecsys sFlt-1 and Elecsys PlGF). We constructed the normal reference ranges of log10sFlt-1, log10PlGF, and the log10(sFlt-1/PlGF) between 19 and 38 weeks using 309 samples, which could be represented by a quadratic curve. The cut-off levels were defined as the 5th and 95th percentiles of their gestational-age-specific reference ranges. Results: The frequencies of high sFlt-1, low PlGF, and a high sFlt-1/PlGF ratio in women with an onset at &lt 32 weeks were all 100%, whereas there were no groups showing 100% abnormalities of sFlt-1, PlGF or the sFlt-1/PlGF ratio in women with an onset at 32–33, 34–35, and ≥36 weeks. The levels of sFlt-1, PlGF, and the sFlt-1/PlGF ratio in women with an onset at &lt 32 weeks were significantly different from those in women with an onset at ≥32–33 weeks, although the levels of sFlt-1, PlGF, and the sFlt-1/PlGF ratio in women with an onset at 32–33, 34–35, and ≥36 weeks were almost the same. Conclusion: The appropriate threshold weeks for defining early-onset PE might be 32+0 weeks rather than 34+0 or 36+0 weeks.

Objective: To determine the efficacy and safety of the Matsubara–Takahashi cervix-holding technique (MT-holding) for achieving hemostasis for postpartum hemorrhage (PPH). Methods: The present retrospective observational study included data from deliveries that occurred between January 1, 2004, and December 31, 2014, at the Department of Obstetrics and Gynecology, Jichi Medical University, Shimotsuke, Japan. Deliveries were included where patients experienced blood loss greater than 2500 mL and MT-holding was used. The success rates of the technique in patients with placenta accreta spectrum (PAS) disorders and PPH were determined subsequent pregnancy outcomes were also examined. Results: There were 53 deliveries included in the study 29 patients had placenta previa and 8 of these patients also had PAS disorders. MT-holding achieved hemostasis in 15 (71%) and 4 (50%) patients with placenta previa without and with PAS disorders, respectively the placenta was removed in the latter. Overall, MT-holding achieved hemostasis in 40 (75%) deliveries. Of nine patients who became pregnant after this procedure, six went on to have full-term deliveries. Conclusion: MT-holding achieved hemostasis in 50% of patients with PAS disorders and had an overall success rate of 75% for PPH, comparable to other uterus-sparing procedures. MT-holding is suggested as a simple, effective, safe technique available to less-experienced obstetrician these findings require confirmation in larger studies.