大口 昭英

AimOur aim was to investigate the effects of angiogenesis-related factor levels at 19-25 and 26-31weeks of gestation (WG) on the later occurrence of a small-for-gestational-age (SGA) placenta (small placenta) or an SGA infant delivered at 35-41WG. MethodsWe measured plasma levels of soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF), and the serum level of soluble endoglin (sEng) in 679 pregnant women with blood sampling at both 19-25 and 26-31WG in a prospective study. A small placenta and an SGA infant were defined as <10th percentile, respectively. Multivariate logistic regression analyses were performed using maternal factors, a high mean pulsatility index (high mPI) of the uterine artery in the second trimester, and angiogenesis-related factor levels. ResultsRegarding the occurrence of a small placenta, low PlGF at 19-25WG (adjusted odds ratio [95% confidence interval]: 2.4 [1.01-5.7]) and a high mPI (2.5 [1.4-4.3]) were independent risk factors. Moreover, low PlGF at 26-31WG (3.3 [1.5-7.0]) was also an independent risk factor after adjusting for the effect of mPI. Concerning the occurrence of an SGA infant, a high mPI (2.8 [1.6-5.2]) and high sEng at 26-31WG (2.3 [1.2-4.5]) were independent risk factors. ConclusionLow levels of PlGF at 19-25 and 26-31WG were independent risk factors for a small placenta at 35WG; and a high sEng at 26-31WG was an independent risk factor for an SGA infant at 35WG.

Maternal obesity is a major risk factor for pregnancy complications, causing inflammatory cytokine release in the placenta, including interleukin-1 beta (IL-1 beta), IL-6, and IL-8. Pregnant women with obesity develop accelerated systemic and placental inflammation with elevated circulating advanced glycation end products (AGEs). IL-1 beta is a pivotal inflammatory cytokine associated with obesity and pregnancy complications, and its production is regulated by NLR family pyrin domain containing 3 (NLRP3) inflammasomes. Here, we investigated whether AGEs are involved in the activation of NLRP3 inflammasomes using human placental tissues and placental cell line. In human placental tissue cultures, AGEs significantly increased IL-1 beta secretion, as well as IL-1 beta and NLRP3 mRNA expression. In human placental cell culture, although AGE treatment did not stimulate IL-1 beta secretion, AGEs significantly increased IL-1 beta mRNA expression and intracellular IL-1 beta production. After pre-incubation with AGEs, nano-silica treatment (well known as an inflammasome activator) increased IL-1 beta secretion in placental cells. However, after pre-incubation with lipopolysaccharide to produce pro-IL-1 beta, AGE treatment did not affect IL-1 beta secretion in placental cells. These findings suggest that AGEs stimulate pro-IL-1 beta production within placental cells, but do not activate inflammasomes to stimulate IL-1 beta secretion. Furthermore, using pharmacological inhibitors, we demonstrated that AGE-induced inflammatory cytokines are dependent on MAPKJNF-kappa B/AP-1 signaling and reactive oxygen species production in placental cells. In conclusion, AGEs regulate pro-IL-1 beta production and inflammatory responses, resulting in the activation of NLRP3 inflammasomes in human placenta. These results suggest that AGEs, as an endogenous and sterile danger signal, may contribute to chronic placental cytokine production. Key words: Advanced glycation end products, Inflammation, NLRP3 inflammasome, Placenta

Background and AimLiver dysfunction with decreased antithrombin (AT) activity and/or thrombocytopenia is life threatening in pregnant women. Whether AT is clinically useful for prediction of liver dysfunction remains unclear. MethodsA total of 541 women were registered prospectively at gestational week 34.7 (20.0-41.4) with available data on antenatal AT and platelet count (PLC). ResultsLiver dysfunction defined as serum aspartate aminotransferase>45IU/L concomitant with lactate dehydrogenase>400IU/L occurred in five women antenatally (2weeks before delivery) and in 17 women post-partum (within 1week post-partum). Median (5th-95th) antenatal value was 85 (62-110)% for AT and 202 (118-315)x10(9)/L for PLC in the 541 women and was significantly lower in women with than without perinatal liver dysfunction; 75 (51-108) versus 86 (62-110)% and 179 (56-244) versus 203 (121-316)x10(9)/L, respectively. Nineteen (86%) women with liver dysfunction showed AT62% or thrombocytopenia (PLC118x10(9)/L) perinatally, but five lacked thrombocytopenia throughout the perinatal period. The best cut-off (AT, 77%; PLC, 139x10(9)/L) suggested by receiver operating characteristic curve gave antenatal AT and PLC sensitivity of 59% and 41% with positive predictive value of 8.6% and 14%, respectively, and combined use of AT and PLC improved sensitivity to 73% (16/22) with positive predictive value of 9.2% for prediction of perinatal liver dysfunction. ConclusionsReduced AT not accompanied by thrombocytopenia can precede liver dysfunction. Clinical introduction of AT may enhance the safety of pregnant women.

Aim: Dipstick results for proteinuria are affected by urine concentration, and thus urine creatinine concentration ([Cr]). This study was performed to determine whether spot urine [Cr] changes significantly during pregnancy, leading to a significantly different false-negative rate (FNR) on dipstick test between trimester. Methods: The [Cr] and protein concentrations ([P]) were analyzed in 631 spot urine samples with negative/equivocal dipstick from 425 pregnant women. False-negative dipstick was defined as [P] : [Cr] ratio (P/Cr) > 0.27 mg/mg. Results: Median [Cr] was 117 mg/dL (range, 6.5-326 mg/dL), 72 mg/dL (range, 4.3-477 mg/dL), and 73 mg/dL (range, 8.4-396 mg/dL) in the first (n = 96), second (n = 344), and third (n = 191) trimester urine samples, respectively (P = 0.000, Kruskal-Wallis). Both [P] and P/Cr increased significantly with advancing gestation. FNR 9.4% (18/191) in the third trimester was significantly higher than that of 0.0% (0/96) in the second trimester and that of 0.5% (2/344) in the third trimester. In the 20 urine samples with false-negative dipstick, median [Cr] was 47.0 mg/dL (range, 11.0-358 mg/dL) and the proportion of samples with dilute urine, that is, [Cr] <47 mg/dL, was significantly higher than in the remaining 611 urine samples (50%, 10/20 vs 28%, 174/611, respectively, P = 0.046). Conclusions: Urine samples in the second and third trimesters were more likely to be diluted compared with the first trimester. This was associated with high FNR in third trimester urine samples.

Objective: The intrauterine balloon (Balloon) has recently been widely used to achieve hemostasis for postpartum hemorrhage (PPH). We concomitantly used a novel method, "holding the cervix", with the Balloon to prevent Balloon prolapse and achieve hemostasis. We aimed to clarify the following three factors: 1) hemostatic success rate of Balloon use for PPH, 2) effect of holding the cervix on Balloon prolapse, and, 3) the rate of bleeding after Balloon insertion, possibly predictive of Balloon failure. Study design: We retrospectively examined 80 patients undergoing Balloon application for PPH in our institution. We defined "success" as achieving hemostasis with no requirement of additional invasive procedures, and "failure" as their requirement. Between success vs. failure, several parameters were compared. For statistical analyses, Fisher's exact test and Wilcoxon rank sum test were applied. Results: Excluding "unable to insert" patients, "holding the cervix" was performed in 56 (75%). Prolapse was less likely to occur in patients with than in those without "holding the cervix" (4 vs. 11%, respectively). The success rate in patients with "Balloon + holding the cervix" was 94%. Treatment for atonic bleeding and placenta previa (PP) showed similarly high success rates (97 and 94%, respectively). The rate of bleeding following Balloon insertion was significantly higher in failure than success cases (P =0.03) and all failure cases showed bleeding >250 mL/h. Conclusions: The "Balloon + holding the cervix" strategy achieved hemostasis in over 90% of primary PPH. Treatment: for not only atonic bleeding but also PP showed a high success rate. Bleeding >250 mL/h after Balloon insertion may indicate the requirement of additional invasive procedures. (C) 2017 Elsevier B.V. All rights reserved.

Introduction: Adequate extravillous trophoblast (EVT) invasion is essential for successful placentation. Although miR-520c-3p plays an important role in CD44-mediated invasion in cancer cells, there is little information on whether miR-520c-3p is involved in the regulatory mechanisms of CD44-mediated EVT invasion. Methods: We screened first trimester trophoblast cells and trophoblast cell lines for expression of miR-520c-3p using real-time polymerase chain reaction. The cell invasion assay was performed using EVT cell lines, HTR8/SVneo and HChEpC1b, to investigate the capability of suppressing EVT invasion by miR-520c-3p. Laser microdissection analysis was then used to determine whether miR-520c-3p was present in the first trimester decidua. Finally, the possibility of chorionic villous trophoblast (CVT)-EVT communication via exosomal miR-520c-3p was determined using an in vitro model based on BeWo exosomes and the EVT cell lines as recipient cells. Results: The miR-520c-3p level was significantly downregulated in EVT cell lines and EVTs. Cell invasion was significantly inhibited in miR-520c-3p-overexpressing cell lines, involving a significant reduction of CD44. Laser microdissection analysis showed that miR-520c-3p in the periarterial area of the decidua was significantly higher than that in the non-periarterial area. Using an in vitro model system, BeWo exosomal miR-520c-3p was internalized into the EVT cells with subsequently reduced cell invasion via CD44 repression. Conclusions: EVT invasion is synergistically enhanced by the reciprocal expression of endogenous miR-520c-3p and CD44. The present study supports a novel model involving a placenta-associated miRNA function in cell-cell communication in which CVT exosomal miR-520c-3p regulates cell invasion by targeting CD44 in EVTs. (C) 2016 Elsevier Ltd. All rights reserved.

Purpose of investigation: Cesarean scar pregnancy (CSP) is a life-threatening condition that requires early pregnancy termination. Its early ultrasound diagnosis is clinically important; however, previous studies focused on the CSP site itself. The present study was conducted to investigate the authors' clinical impression that a uterine-fundal hypoechoic mass is more frequently observed in CSP. Such a finding, if confirmed, may contribute to ultrasound diagnosis of CSP. The authors also determined the relationship between the treatment strategy and outcome, with special emphasis on conditions eventually requiring uterine artery embolization (UAE). Materials and Methods: This was a case-control study of CSP, and the authors analyzed all 14 women that were treated in this single tertiary institute over a period of ten years. Control subjects consisted of all pregnant women with prior cesarean section (CS) but no CSP. Results: Patients with CSP were significantly more likely to have a hypoechoic mass than controls (42.9 vs. 15.4%, respectively; p = 0.028). On confining results to a "fundal" hypoechoic mass, only CSP(+) patients showed it (CSP vs. control: 28.6 vs. 0%, respectively; p < 0.001). Six (43%: 6/14) received UAE: four following vaginal evacuation (artificial or spontaneous), and two for bleeding after methotrexate (MTX) treatment. Conclusion: Patients with CSP more frequently had a uterine-fundal hypoechoic mass, whose detection may trigger a detailed observation of the CSP site, possibly leading to CSP diagnosis.

The most common classifications of hypertensive disorders of pregnancy consist of chronic hypertension, gestational hypertension, preeclampsia (PE) and superimposed PE. A common final pathophysiology of PE is endothelial dysfunction. The most successful translational research model for explaining the cause-effect relationship in the genesis of PE is the angiogenic/angiostatic balance theory, involving soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF) and soluble endoglin (sEng). In a systematic review of articles on the prediction of early-onset PE using angiogenesis-related factors, we revealed that the prediction of early-onset PE in the first trimester is clinically possible, but the prediction of early-onset PE in the early third trimester might be ideal. In addition, an onset threshold or a serial approach appeared to be clinically useful for predicting the imminent onset of PE, with onset at <4 weeks after blood sampling in the second and early third trimesters, because the positive likelihood ratio was >10 and the positive predictive value was >20%. The National Institute for Health and Care Excellence guidelines state that the Triage PlGF testing and Elecsys immunoassay for the sFlt-1/ PlGF ratio could help to exclude PE in women with suspected PE at 20-34 weeks of gestation. Until now, we have not found any effective therapies to prevent PE. However, low-dose aspirin treatment starting at. 16 weeks of gestation might be associated with a marked reduction in PE. In addition, early statin treatment might prevent the occurrence of PE. Currently, a clinical trial using pravastatin for the prevention of PE is ongoing.

AimDuring cesarean section (CS) for placenta previa (PP), the size/area/portion of the lower uterine segment occupied by the placenta may affect the bleeding amount and the subsequent need for a blood transfusion (BT). We propose a new concept, indiscernible edge total PP (IEPP), when vaginal ultrasound does not discern the lower placental edge because the placenta covers the visible lower segment. We characterized IEPP, focusing on its allogeneic BT requirement. MethodsWe classified PP (n = 307) into four types: marginal, partial, discernible edge total PP (DEPP) and IEPP: internal ostium (os)-placental edge distance measurable or unmeasurable on vaginal ultrasound in DEPP or IEPP, respectively. We determined the clinical characteristics according to the four types; the relationship between the intraoperative blood loss and os-edge distance in DEPP; and risk factors for allogeneic BT. ResultsThe following were significantly higher/larger in cases of IEPP: previous CS; anterior placentation; lacunae; elective cesarean hysterectomy; intraoperative blood loss; autologous BT; allogeneic BT; intensive care unit admission; and an abnormally invasive placenta (AIP). In DEPP, the os-edge distance was weakly correlated with the bleeding amount (r = 0.214). Multivariate logistic regression analysis showed that previous CS, lacunae, AIP and IEPP were independent risk factors for allogeneic BT (odds ratios 3.8, 3.1, 13.8 and 4.6, respectively). After excluding patients undergoing hemostatic procedures during CS, IEPP remained the only independent risk factor for allogeneic BT (odds ratio 5.2). ConclusionsThe new concept of IEPP may be useful for predicting BT in CS for patients with PP.

Objectives: Uterine artery pseudoaneurysm (UAP) has been considered to occur very rarely after traumatic delivery/abortion, and is usually detected after its rupture, yielding massive bleeding. Our hypothesis is: some UAP may be undetected without massive bleeding and may spontaneously resolve, and, thus, may not require transarterial embolization (TAE). We attempted: (1) to detect both ruptured and non-ruptured UAP, thereby characterizing candidates of spontaneously resolving UAP, and (2) to confirm that UAP is not rare and not always associated with traumatic events. Study design: This was a retrospective observational study of 50 women with angiographically confirmed UAP and treated by TAE. Angiograms and medical charts were retrieved to examine the associations among symptoms, ultrasound findings, and extravasation. Gray-scale ultrasound was performed for all women after delivery or abortion as our routine practice. Results: UAP occurred in 3-6/1000 deliveries and 40% occurred after non-traumatic deliveries/abortion. While 36% had active vaginal bleeding at admission, 64% did not. While 100% of patients with current active bleeding showed extravasation from the pseudoaneurysmal sac, patients without it showed a varied incidence of extravasation depending on the bleeding pattern/history and ultrasound findings. Interestingly, all patients with current bleeding (-), bleeding history (+), and ultrasound-discernable intrauterine low echoic mass (-) were devoid of extravasation, suggesting that UAP may show progression to thrombosis and, thus, resolve spontaneously. Conclusions: UAP may not be so rare and not associated with traumatic delivery/abortion. Some UAP may resolve, and, thus, may not require TAE, at least immediately. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

Introduction. Some pregnant women develop significant proteinuria in the absence of hypertension. However, clinical significance of isolated gestational proteinuria (IGP) is not well understood. This study aimed to determine the prevalence of IGP in singleton pregnancies and the proportion of women with IGP who subsequently developed preeclampsia (IGP-PE) among all PE cases. Material and methods. This was an observational study of 6819 women with singleton pregnancies at 12 centers, including 938 women with at least once determination of protein-to-creatinine ratio (P/Cr). Significant proteinuria in pregnancy (SPIP) was defined as P/Cr (mg/mg) level >0.27. IGP was defined as SPIP in the absence of hypertension. Gestational hypertension (GH) preceding preeclampsia (GH-PE) was defined as preeclampsia (PE) in which GH preceded SPIP. Simultaneous PE (S-PE) was defined as PE in which both SPIP and hypertension occurred simultaneously. Results. IGP and PE were diagnosed in 130 (1.9%) and 158 (2.3%) of 6819 women, respectively. Of 130 women with IGP, 32 (25%) progressed to PE and accounted for 20% of all women with PE. Hence, women with IGP had a relative risk of 13.1 (95% CI; 9.2-18.5) for developing PE compared with those without IGP [25% (32/130) vs. 1.9% (126/6689)]. At diagnosis of SPIP, P/Cr levels already exceeded 1.0 more often in women with S-PE than in those with IGP-PE [67% (33/49) vs. 44% (14/32), respectively, p = 0.031]. Conclusions. IGP is a risk factor for PE, and IGP-PE accounts for a considerable proportion (20%) of all PE.

Maternal obesity, a major risk factor for adverse pregnancy complications, results in inflammatory cytokine release in the placenta. Levels of free fatty acids are elevated in the plasma of obese human. These fatty acids include obesity-related palmitic acids, which is a major saturated fatty acid, that promotes inflammatory responses. Increasing evidence indicates that nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasomes mediate inflammatory responses induced by endogenous danger signals. We hypothesized that inflammatory responses associated with gestational obesity cause inflammation. To test this hypothesis, we investigated the effect of palmitic acid on the activation of NLRP3 inflammasomes and inflammatory responses in a human Sw.71 trophoblast cell line. Palmitic acid stimulated caspase-1 activation and markedly increased interleukin (IL)-1 beta secretion in Sw.71 cells. Treatment with a caspase-1 inhibitor diminished palmitic acid-induced IL-1 beta release. In addition, NLRP3 and caspase-1 genome editing using a CRISPR/Cas9 system in Sw.71 cells suppressed IL-1 beta secretion, which was stimulated by palmitic acid. Moreover, palmitic acid stimulated caspase-3 activation and inflammatory cytokine secretion (e.g., IL-6 and IL-8). Palmitic acid-induced cytokine secretion were dependent on caspase-3 activation. In addition, palmitic acid-induced IL-1 beta, IL-6, and IL-8 secretion was depended on reactive oxygen species (ROS) generation. In conclusion, palmitic acid caused activation of NLRP3 inflammasomes and inflammatory responses, inducing IL-1 beta, IL-6, and IL-8 secretion, which is associated with ROS generation, in human Sw.71 placental cells. We suggest that obesity-related palmitic acid induces placental inflammation, resulting in association with pregnancy complications. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

AimIn hypertensive pregnant women, the protein-to-creatinine (P/C) ratio is well correlated with 24-h proteinuria and a P/C ratio of 0.27 (g/gCr) is used to reflect significant proteinuria (>0.3 g/day). The aim of this study was to obtain data on normotensive pregnant women, which have so far been lacking. MethodsThe study population consisted of 74 pregnant women who met the following criteria: (i) 22 gestational weeks; (ii) a positive result (1+) on dipstick test; (iii) a positive result (>0.27) for P/C ratio; and (iv) 24-h urine test performed within 2 days of the P/C ratio. The correlation between the P/C ratio and 24-h proteinuria, the incidence rates of significant proteinuria according to P/C ratios, and appropriate threshold of the P/C ratio to rule in significant proteinuria were determined using the appropriate statistical methods. ResultsThe P/C ratio was moderately correlated with the 24-h proteinuria, with a correlation coefficient of 0.64 (95% confidence interval, 0.487-0.76). The area under the receiver-operator curve was 0.76 (95% confidence interval, 0.66-0.87); however, no clear shoulder was identifiable. The incidence rates of significant proteinuria according to P/C ratios of 0.27-0.49, 0.50-0.74, 0.75-0.99, and >1 were 41, 66, 100, and 100%, respectively, indicating that all normotensive pregnant women with a P/C ratio > 0.75 had significant proteinuria. ConclusionNormotensive pregnant women showed a significant correlation between the P/C ratio and 24-h urine protein level. All normotensive pregnant women with a P/C ratio > 0.75 had significant proteinuria, suggesting that a P/C ratio > 0.75 may be the rule-in' threshold of significant proteinuria in this population.

Post-delivery/-abortion uterine artery pseudoaneurysm (UAP) sometimes causes life-threatening bleeding, requiring transarterial embolization (TAE). It is unclear whether some UAP resolve spontaneously. In three patients, UAP resolved spontaneously without TAE. Case 1 was after vacuum delivery with slight bleeding: at day 5 post-partum, a yin-yang sign on Color Doppler and an enhanced intrauterine sac-like structure were observed, leading to the diagnosis of UAP, which disappeared at 4 weeks post-partum. Case 2 was after vacuum delivery with manual placental removal and was asymptomatic: a hypoechoic intrauterine mass with a yin-yang sign were observed during a post-partum routine check-up and the intrauterine flow disappeared at 4 weeks post-partum. Case 3 was after dilatation and curettage in the first trimester with slight bleeding: UAP was detected at 4 weeks post-abortion, which disappeared at 6 weeks post-abortion. All three cases had a small UAP (diameter: 10-15 mm) and low-level or no symptoms. Some UAP may resolve spontaneously and, thus, may not require TAE.

ProblemAdvanced glycation end products (AGEs) and high-mobility group box-1 (HMGB1) are considered contributing to placental inflammation. We examined the effect of AGEs and HMGB1 on cytokines from Sw.71 human trophoblast cell lines and the interactions between Sw.71 cells and THP-1-monocytes. Methods of studySw.71 cells were cultured with/without AGEs or HMGB1. We examined the role of AGEs or HMGB1 on THP1 migration and effect of AGEs on IL-6 from Sw.71 cells using co-cultures or conditioned medium from THP-1 cells. ResultsAGEs and HMGB1 increased interleukin (IL)-6, IL-8, and chemokine C-C motif ligand 2 (CCL2) secretion from Sw.71 cells. The secretion of IL-6 was dependent on reactive oxygen species (ROS) and NF-B. AGEs stimulated IL-6 secretion through receptor RAGE and TLR4, whereas HMGB1 stimulated it through TLR4. AGEs, but not HMGB1, increased monocyte migration via IL-8 and CCL2 from Sw.71 cells. THP-1 monocytes induced IL-6 secretion from Sw.71 cells, and AGEs further stimulated it. ConclusionsAGEs and HMGB1 may promote sterile placental inflammation cooperating with monocytes/macrophages.

The authors tested the hypothesis that central hemodynamic parameters in women with hypertensive disorders of pregnancy (HDP) change between before and after delivery. A total of 137 pregnant women were studied: 72 with HDP, 42 with chronic hypertension (CH), and 23 with white-coat hypertension (WCH; control group). Aortic augmentation index adjusted by heart rate 75 beats per minute (AIx@75), central pulse pressure (PP), total peripheral resistance (TPR), and cardiac output (CO) before and after delivery were recorded. AIx@75 and central PP were higher in the HDP group than in the control group, but both parameters declined after delivery until they were similar to the controls. AIx@75 and central PP, but not TPR or CO, were significantly decreased after delivery in the HDP group, but no such effects were seen in the other groups. These findings suggest that increased wave reflection caused by the stiffened aorta could be a key factor in the pathophysiology of HDP.

There have been few reports regarding the improvement of hyperammonemic hepatic encephalopathy after the extirpation of a large uterine leiomyoma. We present a case of a 53-year-old postmenopausal woman who experienced a clouding of consciousness. She had been suffering from mild hepatitis and a large uterine leiomyoma. On admission, she had experienced constipation for seven days and exhibited a high serum ammonia level (251 g/dL). She was diagnosed with liver cirrhosis as a result of autoimmune hepatitis, combined with Sjogren's syndrome. A total hysterectomy was performed 29 days after admission. Severe diarrhea lasted for three days after surgery. By the sixth postoperative day, the patient's consciousness level had normalized and her serum ammonia level had fallen to 47 g/dL. Although the true mechanism of hyperammonemia in this case is unclear, we speculate that organic constipation following chronic obstruction of the colon might have played a role in the development of the condition.

The significance of ambulatory blood pressure (ABP) monitoring during pregnancy has not been established. We performed a prospective study to elucidate whether ABP measures are associated with small-for-gestational-age birth weight (SGA). We studied 146 pregnant women who were seen for maternal medical checkups or suspected hypertension. ABP monitoring was performed for further assessment of hypertension. The outcome measure was SGA. The subjects were classified by their medical history and ABP as having preeclampsia or gestational hypertension (n = 68 cases), chronic hypertension (n = 48) or white-coat hypertension (n = 30). There were 50 (34.2%) cases of SGA by the fetal growth reference standard. In multivariable logistic regression analyses adjusting for age, body mass index, the presence of prior pregnancy, current smoking habit and the use of antihypertensive medications, 24-h SBP (per 10 mm Hg (odds ratio (OR): 1.74; 95% confidence interval (CI): 1.28-2.38; P < 0.001)) was more closely associated with SGA than clinic BP (OR: 1.40; 95% CI: 0.92-2.13; P = 0.11). The results were essentially the same if 24-h BP was replaced by awake or sleep SBP. Ambulatory diastolic BP showed the same tendency. However, abnormal circadian rhythm was not associated with the outcome. In conclusion, ambulatory BP monitoring measures performed during pregnancy were more closely associated with SGA than clinic BP.

Introduction. To identify factors that determine blood loss during peripartum hysterectomy for abnormally invasive placenta (AIP-hysterectomy). Methods. We reviewed all of the medical charts of 11,919 deliveries in a single tertiary perinatal center. We examined characteristics of AIP-hysterectomy patients, with a single experienced obstetrician attending all AIP-hysterectomies and using the same technique. Results. AIP-hysterectomy was performed in 18 patients (0.15%: 18/11,919). Of the 18, 14 (78%) had a prior cesarean section (CS) history and the other 4 (22%) were primiparous women. Planned AIP-hysterectomy was performed in 12/18 (67%), with the remaining 6 (33%) undergoing emergent AIP-hysterectomy. Of the 6, 4 (4/6: 67%) patients were primiparous women. An intra-arterial balloon was inserted in 9/18 (50%). Women with the following three factors significantly bled less in AIP-hysterectomy than its counterpart: the employment of an intra-arterial balloon (4, 448 ± 1, 948 versus 8, 861 ± 3, 988 mL), planned hysterectomy (5, 003 ± 2, 057 versus 9, 957 ± 4, 485 mL), and prior CS (5, 706 ± 2, 727 versus 9, 975 ± 5, 532 mL). Patients with prior CS (-) bled more: this may be because these patients tended to undergo emergent surgery or attempted placental separation. Conclusion. Patients with intra-arterial balloon catheter insertion bled less on AIP-hysterectomy. Massive bleeding occurred in emergent AIP-hysterectomy without prior CS.

<p>Aim: To evaluate whether there are any women with postpartum hemorrhage (PPH) showing a hemoglobin (Hb) concentration of <7.0 g/dl in cases with estimated blood loss of <1,500 ml or a shock index (SI) of >1.5 in cases with estimated blood loss of <2,500 ml.</p><p>Methods: We reviewed the records of 36 women transferred due to PPH in our tertiary center in 2002-2005. We collected the patients' information including the estimated blood loss, Hb concentration, and SI on arrival.</p><p>Results: In the group of 500–1,499 ml, 13% (2/16) showed Hb concentrations of <7.0 g/dl. In the group of 1,500–2,499 ml, one woman with uterine inversion whose estimated blood loss was 1,600 ml showed SI of 1.9 with a Hb concentration of 6.3 g/dl. SI in women with uterine inversion was significantly higher than in those with atonic bleeding, retention of placenta/accreta, and vaginal/cervical lacerations, respectively. SI in all women with uterine inversion was >1.0, although in three quarters of the cases, the blood loss was reported as <2,500 ml.</p><p>Conclusions: Our chart review clearly demonstrates that there are some PPH cases showing mismatch between the reported estimated blood loss and the Hb concentration and/or SI. Especially, SI may be clinically useful for judging transfusion in women with uterine inversion. We should identify the factors in such mismatching cases, and reveal the pitfalls of the current guideline for obstetrical critical hemorrhage mainly based on SI.</p>

Background: The dipstick test is widely used as a primary screening test for detection of significant proteinuria in pregnancy (SPIP). However, it often shows a false positive test result. This study was performed to determine which pregnant women should be recommended to undergo determination of urinary protein-to-creatinine ratio (mg/mg, P/Cr test) after dipstick test for confirmation of SPIP. Methods: This was a multicenter, prospective, and observational study of 2212 urine specimens from 1033 pregnant women who underwent simultaneous dipstick and P/Cr tests in the same spot urine samples at least once. SPIP was defined as P/Cr &gt; 0.27. Preeclampsia was diagnosed in women with both hypertension and SPIP. Results: Preeclampsia, hypertension alone, and SPIP alone developed in 202 (20 %), 73 (7.1 %), and 120 (12 %) women, respectively. Creatinine concentration [Cr] varied greatly, ranging from 8.1 to 831 mg/dL in the 2212 urine samples. Rate of positive dipstick test results increased with increasing [Cr], while SPIP prevalence rate was lower in urine samples with higher [Cr], yielding higher false positive rates in samples with higher [Cr]. Postpartum urine samples had significantly lower [Cr] compared to those obtained antepartum (60 [8.7-297] vs. 100 [10-401] mg/dL, respectively). At the first P/Cr test among women with similar dipstick test results, the risk of having SPIP was consistently and significantly higher for hypertensive women than for normotensive women at any dipstick test result: 18 % (14/77) vs. 3.2 % (8/251), 47 % (26/55) vs. 8.7 % (37/425), 91 % (82/90) vs. 59 % (44/75) for negative/equivocal, 1+, and &gt;= 2+ test results, respectively. The risk of SPIP was 16 % (9/55) for normotensive women when two successive antenatal urine samples showed a dipstick test result of 1 +. Conclusions: For prediction of SPIP, the dipstick test was more likely to show a false positive result in concentrated urine samples with higher [Cr]. Hypertensive women with &gt;= 1+ as well as normotensive women with &gt;= 2+ on dipstick test should be advised to undergo the P/Cr test.

Pancytopenia in the first trimester is very rare. A 33-year-old multiparous woman presented with nausea, loss of appetite, and bodyweight loss of 7.4 kg at 9(1/7) weeks of gestation due to hyperemesis gravidarum. Her laboratory data demonstrated pancytopenia involving white blood cell count of 3500/mu L, a hemoglobin level of 9.8 g/dL, and a platelet count of 10.5 x 10(4)/mu L. An extensive investigation into the causes of the pancytopenia detected true hyperthyroidism: thyroid-stimulating hormone, &lt;0.02 mu U/mL; free triiodothyronine, 11.25 pg/mL; free thyroxine, 4.74 ng/dL; and anti-thyroid-stimulating hormone receptor antibodies, 12.2 IU/L. Propylthiouracil was started at a dose of 300 mg/day at 10(5/7) weeks of gestation, which resulted in the normalization of her blood parameters and concomitant improvements in her free triiodothyronine and free thyroxine levels at 12(0/7) weeks of gestation. Pancytopenia in the first trimester might be indicative of hidden hyperthyroidism.

Preeclampsia is a pregnancy-specific syndrome characterized by elevated blood pressure, proteinuria, and intrauterine growth restriction (IUGR). Although sterile inflammation appears to be involved, its pathogenesis remains unclear. Recent evidence indicates that sterile inflammation is mediated through the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes, composed of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and caspase-1. Here we investigated the role of the NLRP3 inflammasomes in the pathogenesis of preeclampsia using Nlrp3(-/-) and Asc(-/-) (Nlrp3 and Asc deficient) pregnant mice. During pregnancy in mice, continuous infusion of high-dose angiotensin II (AngII) induced hypertension, proteinuria, and IUGR, whereas infusion of low-dose AngII caused hypertension alone. AngII-induced hypertension was prevented in Nlrp3(-/-) mice but not in Asc(-/-), indicating that NLRP3 contributes to gestational hypertension independently of ASC-mediated inflammasomes. Although NLRP3 deficiency had no effect on IUGR, it restored the IL-6 up-regulation in the placenta and kidney of AngII-infused mice. Furthermore, treatment with hydralazine prevented the development of gestational hypertension but not IUGR or IL-6 expression in the placenta and kidney. These findings demonstrate that NLRP3 contributes to the development of gestational hypertension independently of the inflammasomes and that IUGR and kidney injury can occur independent of blood pressure elevation during pregnancy.

Objective: We compared the frequency of peripheral blood Treg cells in women with pre-eclampsia (PE) and in those without, and investigated whether the frequency of Treg cells in women with high-risk factor for PE changed during pregnancy. Methods: We examined the frequency of CD4(+)FoxP3(+) Treg cells in the peripheral blood using flow cytometry. Eleven women with PE and 10 women without PE (controls) were included. Every control had any risk factors for PE, such as high blood pressure, bilateral notching or a past history of PE or gestational hypertension. Blood sampling was conducted 1-3 times in the controls. Results: No significant differences were observed in the frequency of Treg cells between women with PE and the controls [mean +/- SE (%): 5.74 +/- 0.91 versus 5.48 +/- 0.94, p=0.843]. In five controls with serial sampling, the frequency of Treg cells significantly decreased from 5.83 +/- 1.20 to 2.99 +/- 0.54 (p=0.046) (week of the first sampling to that of the last sampling [mean +/- SD]: 21.5 +/- 1.6 weeks to 31.2 +/- 2.5 weeks). Conclusion: The frequency of Treg cells in women with PE was almost identical to that in the controls. The frequency of Treg cells in the controls was reduced by half from the second trimester to the third trimester. These results suggested that the levels of Treg cells in a high-risk pregnant cohort were decreased to those in women with PE in the third trimester irrespective of the occurrence of PE.

Background/Aims: The placenta is a vital organ for pregnancy. Many in vitro placental experiments are conducted under 21% O-2; however, O-2 tension could influence cellular functions, including cytokine secretion. We investigated the effects of oxygen tension between moderate hypoxia (5% O-2) and normoxia (21% O-2) by testing the hypothesis that moderate hypoxia regulates cellular phenotypes differently from normoxia in human trophoblast cells. Methods and Results: Sw.71 trophoblast cells were incubated under normoxic or moderately hypoxic conditions. Cells were also treated with lipopolysaccharide (LPS) as a Toll-like receptor 4 (TLR4) ligand inducing inflammation. Interleukin-6 (IL-6) as an inflammatory cytokine was determined, and TLR4, hypoxia-induced factor-1 alpha (HIF1 alpha), and reactive oxygen species (ROS) production were detected. Moderate hypoxia increased HIF1 alpha expression and cell proliferation and acted by two different mechanisms to decrease IL-6 secretion compared with normoxia: it limits the TLR4 expression and ROS production. Treatment with cobalt chloride as an HIF1 activator inhibited IL-6 secretion and TLR4 expression; this effect was reversed on treatment with PX-12 as an HIF1 suppressor. Conclusion: IL-6 secretion, TLR4 expression, and ROS production, classical markers of inflammation, are down-regulated by moderate hypoxia, and HIF1 alpha and ROS have a potential to regulate these responses in human trophoblast cells. Copyright (C) 2015 S. Karger AG, Basel

Although recent studies have demonstrated that microRNAs (miRNAs or miRs) regulate fundamental natural killer (NK) cellular processes, including cytotoxicity and cytokine production, little is known about the miRNA-gene regulatory relationships in maternal peripheral blood NK (pNK) cells during pregnancy. In the present study, to determine the roles of miRNAs within gene regulatory networks of maternal pNK cells, we performed comprehensive miRNA and gene expression profiling of maternal pNK cells using a combination of reverse transcription quantitative PCR (RT-qPCR)-based miRNA array and DNA microarray analyses and analyzed the differential expression levels between first-and third-trimester pNK cells. Furthermore, we constructed regulatory networks for miRNA-mediated gene expression in pNK cells during pregnancy by Ingenuity Pathway Analysis (IPA). PCR-based array analysis revealed that the placenta-derived miRNAs [chromosome 19 miRNA cluster (C19MC) miRNAs] were detected in pNK cells during pregnancy. Twenty-five miRNAs, including six C19MC miRNAs, were significantly upregulated in the third-compared to first-trimester pNK cells. The rapid clearance of C19MC miRNAs also occurred in the pNK cells following delivery. Nine miRNAs, including eight C19MC miRNAs, were significantly downregulated in the post-delivery pNK cells compared to those of the third-trimester. DNA microarray analysis identified 69 NK cell function-related genes that were differentially expressed between the first-and third-trimester pNK cells. On pathway and network analysis, the observed gene expression changes of pNK cells likely contribute to the increase in the cytotoxicity, as well as the cell cycle progression of third-compared to first-trimester pNK cells. Thirteen of the 69 NK cell function-related genes were significantly downregulated between the first-and third-trimester pNK cells. Nine of the 13 downregulated NK-function-associated genes were in silico target candidates of 12 upregulated miRNAs, including C19MC miRNA miR-512-3p. The results of this study suggest that the transfer of placental C19MC miRNAs into maternal pNK cells occurs during pregnancy. The present study provides new insight into maternal NK cell functions.

To construct a model to calculating probability of requiring allogeneic blood transfusion on cesarean section (CS) for placenta previa (PP). A retrospective cohort study involving all 205 patients with PP who underwent CS in our institute. We determined the relationship between allogeneic blood transfusion and nine preoperative factors: (1) maternal age, (2) parity, (3) uterine myoma, (4) previous CS, (5) the placenta covering the previous CS scar (referred to as "scar covering"), (6) degree of previa, (7) ultrasound finding of lacunae, (8) preoperative anemia, and (9) preparation of autologous blood. Independent risk factors of allogeneic blood transfusion were identified by multivariate logistic regression analysis. These significant factors were included in the final model, and, the probability of allogeneic blood transfusion was calculated. Independent risk factors of allogeneic blood transfusion were scar covering, previous CS without scar covering, and lacunae. These three factors were used to create a predictive model. The model revealed that patients with scar covering and lacunae had the highest probability (0.73), while those with no risk factors had the lowest probability (0.02). This simple model may be useful to calculate probability of requiring allogeneic blood transfusion on CS for placenta previa.