大口 昭英

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.

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.

Our aim was to evaluate whether the serum level of galectin-1 (Gal-1) at 18-24 and 27-31 weeks of gestation is a risk factor for predicting the later occurrence of not only preeclampsia (PE) but also gestational hypertension (GH). We measured serum levels of soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), and Gal-1 using an enzyme-linked immunosorbent assay in 81 and 73 normal pregnant women, 22 and 16 women with a later onset of GH, and 37 and 29 women with a later onset of PE at 18-24 and 27-31 weeks, respectively. We also measured Gal-1 in 33 women with GH and 78 women with PE after the onset. The levels of Gal-1 after the onset of GH, late-onset PE (onset at ≫34 weeks), and earlyonset PE (onset at o34 weeks) were significantly higher than those in normal pregnant women at 27-31 weeks. However, the low levels of Gal-1 (o8.1 ng ml-1) at 18-24 weeks, but not at 27-31 weeks, predicted the later occurrence of not only earlyonset PE and late-onset PE but also GH. The low level of Gal-1 at 18-24 weeks was an independent risk factor for the later occurrence of GH and PE, after adjusting for the effects of a high BP and increased sFlt-1/PlGF ratio at 18-24 weeks. In conclusion, the serum level of Gal-1 is a novel risk factor for both GH and PE, specifically its expression at a low level in the second trimester and a high level after onset.