Uterine-fundal hypoechoic mass: a possible ultrasound sign for cesarean scar pregnancy.

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.

Congenital mesoblastic nephroma: Its diverse clinical features - A literature review with a case report.

To characterise congenital mesoblastic nephroma (CMN), with special emphasis on polyhydramnios and the neonatal prognosis, we summarise 31 CMN patients (30 reported patients and the present patient). CMN was detected at a median of 30 weeks' gestation, and infants were delivered at a median of 34 weeks' gestation. Of 27 patients with available data, 19 (70%) had polyhydramnios, of which 8 required amnio- drainage. Women with amnio-drainage gave birth significantly earlier (30.4 weeks' gestation) than those without polyhydramnios (36.7 weeks' gestation). Thus, CMN was frequently associated with polyhydramnios and this polyhydramnios was associated with a significant increase in the risk of preterm birth. Of 20 patients with available data, the affected-side kidney was 'compressed' in 16 and 'replaced' in 4: polyhydramnios was present in a half vs 100%, respectively, suggesting that a 'replaced' kidney may suggest a more aggressive tumour and may be associated with a poorer prognosis. Univariate analysis showed that early gestational week at diagnosis was the only feature significantly associated with poor prognosis. Thus, polyhydramnios, 'replaced' kidney and early gestational week at diagnosis, may indicate poor prognosis, to which obstetricians should pay attention.

Changes in standing body sway of pregnant women after long-term bed rest.

Pregnant women tend to fall and increased body postural instability, namely body sway, may be one of the causative factors. We had a clinical impression that pregnant women after long-term bed rest tend to fall. We hypothesised that such women may show increased body sway, which we attempted to determine. Pregnant women (n = 161) were divided into three groups: (i) women with preterm labour after 2-week bed rest, (ii) those after 4-week bed rest, and (iii) those without bed rest or preterm labour. Body sway was analysed using stabilometry, that is, computed analysis of movement of the centre of gravity. The 3 groups fundamentally showed the same stabilometric measurements. Women with oedema showed greater medial-lateral sway than those without it. Factors other than oedema yielded no differences in stabilometric parameters. Long-term bed rest fundamentally did not increase body sway to the extent that stabilometry could reveal it. It may be prudent to consider that pregnant women with oedema tend to fall.

Supporting rural remote physicians to conduct a study and write a paper: experience of Clinical Research Support Team (CRST)-Jichi.

CONTEXT: Jichi Medical University (JMU) is the only medical school in Japan that is devoted solely to producing rural and remote doctors. To support research activities of its graduates, mainly young graduates under obligatory rural service, JMU established a voluntary team, Clinical Research Support Team (CRST)-Jichi. ISSUES: CRST-Jichi consists of current and past JMU faculty members; all of them are specialists of certain medical fields and many are also graduates of JMU who have completed rural service. A client who asks the CRST for advice on study design or editing a paper emails the CRST to ask for support in conducting a study. Then, core members of the CRST assign the job to a registered specialist of the corresponding topic, who becomes a 'responsible supporter' and continues to support the client until a paper has been published. During the 3 years from July 2010, 12 English papers have been published in international peer-review journals, two Japanese papers in domestic journals, and 13 studies are in progress. Ninety-one percent of clients were satisfied with the service, and eighty-two percent considered their papers would not have been published if they had not used the service. Sense of commitment, existence of JMU-graduated specialists, and quick response were reported by clients as major strengths of CRST-Jichi. LESSONS LEARNED: The experience of CRST-Jichi can potentially be transferred to not only other Japanese medical schools with rural doctor production programs, which are now rapidly increasing as part of a national policy, but also rural medical education systems in other countries.

Value of adding second-trimester uterine artery Doppler to patient characteristics in identification of nulliparous women at increased risk for pre-eclampsia: an individual patient data meta-analysis.

OBJECTIVE: To investigate the value of adding second-trimester uterine artery Doppler ultrasound to patient characteristics in the identification of nulliparous women at risk for pre-eclampsia. METHODS: For this individual patient data meta-analysis, studies published between January 1995 and December 2009 were identified in MEDLINE and EMBASE. Studies were eligible in which Doppler assessment of the uterine arteries had been performed among pregnant women and in which gestational age at ultrasound, Doppler ultrasound findings and data on the occurrence of pre-eclampsia were available. We invited corresponding authors to share their original datasets. Data were included of nulliparous women who had had a second-trimester uterine artery Doppler ultrasound examination. Shared data were checked for consistency, recoded to acquire uniformity and merged into a single dataset. We constructed random intercept logistic regression models for each of the patient and Doppler characteristics in isolation and for combinations. We compared goodness of fit, discrimination and calibration. RESULTS: We analyzed eight datasets, reporting on 6708 nulliparous women, of whom 302 (4.5%) developed pre-eclampsia. Doppler findings included higher, lower and mean pulsatility index (PI) and resistance index (RI) and any or bilateral notching. Of these, the best predictors were combinations of mean PI or RI and bilateral notching, with areas under the receiver-operating characteristics curve (AUC) of 0.75 (95% confidence interval (CI), 0.56-0.95) and 0.70 (95% CI, 0.66-0.74), respectively. Addition of Doppler findings to the patient characteristics blood pressure or body mass index (BMI) significantly improved discrimination. A model with blood pressure, PI and bilateral notching had an AUC of 0.85 (95% CI, 0.67-1.00). CONCLUSIONS: The addition of Doppler characteristics of mean PI or RI and bilateral notching to patient characteristics of blood pressure or BMI improves the identification of nulliparous women at risk for pre-eclampsia.

Initial dose of vancomycin based on body weight and creatinine clearance to minimize inadequate trough levels in Japanese adults.

Our aims were to elucidate the factors that affected vancomycin (VCM) serum trough levels and to find the optimal initial dose based on creatinine clearance (CrCl) and body weight (BW) to minimize inadequate trough levels in a retrospective observational study among Japanese adults. One hundred and six inpatients, in whom VCM trough levels were measured after completing the third dosing, were consecutively recruited into our study in a tertiary hospital. We considered the frequency of <30% as low. In the generalized linear model, initial VCM total daily dose, CrCl, and BW were independent risk factors of VCM trough levels. In patients with CrCl ≥30 and <50 mL/min, 1 g/day yielded low frequencies of a trough level of ≥20 mcg/mL, regardless of BW. In patients with CrCl ≥50 mL/min, 2 g/day yielded low frequencies of a trough level of <10 mcg/mL in patients weighing <55 kg, but not in patients weighing ≥55 kg. Optimal VCM initial total daily dose may be 1 g/day in patients with CrCl ≥30 and <50 mL/min regardless of BW and 2 g/day in patients weighing <55 kg with CrCl ≥50 mL/min among Japanese adults.

Ambulatory BP monitoring and clinic BP in predicting small-for-gestational-age infants during pregnancy.

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.

[Survival in patients with clear cell carcinoma of the ovary].

Thirty-one patients with clear cell ovarian carcinoma who underwent primary surgery and postoperative therapy were retrospectively evaluated. Eighteen patients (58%) had International Federation of Gynecology and Obstetrics (FIGO) stage I disease, 3 patients (9.7%) stage II disease, and 10 patients (32.3%) stage III and IV disease. Patients with stage III and IV disease demonstrated a significantly poor prognosis compared with patients who had stage I or II disease (p < 0.01). No patients with stage III and IV disease survived 5 years. p53 protein expression and proliferative activity (PA) were studied by immunohistochemical methods using p53 molecule and antibodies to PCNA (proliferative cell nuclear antigen). Intranuclear accumulations of p53 product were observed in 15 of 31 (48.4%). On the other hand, 15 of 31 (48.4%) patients stained positively for PCNA (> or = 60% of cancer cells stained positively). Positive p53 staining and highly PA were associated with poor survival. Two patients with stage I a relapsed were positive p53 and highly PA. Accordingly, consolidation chemotherapy is necessary for patients with stage I a who are positive p53 and highly PA. Platinum-based chemotherapy for patients who had minimal residual tumor was effective, but 5 patients who had > or = 2 cm tumor burden were not effective at all. The response rate for platinum-based chemotherapy was 20% (1/5) among p53 positive, in contrast to 66.7% (4/6) among p53 negative patients. So it seems that p53 positive patients are chemoresistant.

Extravillous trophoblast cell invasion is promoted by the CD44-hyaluronic acid interaction.

INTRODUCTION: Extravillous trophoblast (EVT) cell invasion plays a crucial role in establishment of successful pregnancy. CD44, a cell-surface receptor for hyaluronic acid (HA), plays a key role in HA-mediated remodeling and degradation that triggers cancer cell invasion. However, few studies have reported on the expression or functions of CD44 in human EVT cells. We hypothesized that CD44-HA interaction was involved in invasion by EVT cells. METHODS: To test our hypothesis, we conducted in situ examinations of CD44 and HA expression in the human first-trimester placenta. We also assessed the methylation status of CD44 promoter and exon 1 regions in EVT cells. Finally, we conducted transwell cell invasion assays using EVT cell lines and EVT cells isolated from first-trimester human villous explant cultures. RESULTS AND DISCUSSION: EVT cells, but not villous trophoblast cells, in the first-trimester placenta expressed CD44. HA was strongly expressed in adventitia surrounding the spiral uterine arterial walls of the decidua. The extent of demethylation of CD44 promoter and exon 1 CpG islands was increased in EVT cells compared to those of first-trimester chorionic villi (including villous trophoblast cells), suggesting that CD44 expression was, at least in part, associated with methylation status. Data from transwell cell invasion assay with siRNA knockdown of CD44 revealed that CD44 expression significantly promoted invasion by EVT cells in an HA-dependent manner. CONCLUSIONS: The discovery of a CD44-HA interaction between EVT cells and the extracellular matrix contributes to our understanding of the mechanism underlying invasion by EVT cells.

PP058. The additive effect of plasma levels of sFlt-1/PLGF ratio following the risk classification using both blood pressure levels and uterine artery blood flow impedance in the second trimester on the later occurrence of preeclampsia.

INTRODUCTION: The multivariate model including circulating levels of soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratios, maternal factors, blood pressure (BP) levels and uterine artery (UtA) doppler in the first to second trimester has been reported to be clinically useful to predict PE more accurately. However, the effects of levels of sFlt-1/PlGF ratio after the stratification of women using two major risk factors for PE, BP levels and UtA blood flow imdedance (BFI) have not been evaluated. OBJECTIVES: Our aim was to evaluate the additive effect of plasma levels of sFlt-1/PlGF ratio following the risk classification using both mean blood pressure (MBP) levels and the combination of two UtABFI, mean pulsatility index (mPI) and mean notch depth index (mNDI), on the later occurrence of PE. METHODS: 1161 women were recruited into a prospective cohort study during 2004 and 2008. Clinical BPs were measured twice during 16 and 23 weeks, UtA doppler was performed twice during 16 and 23 weeks, and the mPI and mNDI was measured. Plasma samples were drawn once at 20-23weeks, and were stored at -20°C until use. The levels of sFlt-1/PlGF ratio were measured by automated electrochemiluminescent immunoassay (Roche Diagnostics K.K.). The cutoff value of mean BP (MBP) was determined as 91.3mmHg using ROC curve, and that of sFlt-1/PlGF ratio was 13.0, the 97.5th percentile of log10(sFlt-1/PlGF) at 20-23 weeks in normal pregnant women. If the mPI was <90th percentile of the gestational-age specific reference range of mPI, or the mNDI was <90th percentile of the gestational-age specific reference range of mNDI, we defined that the UtABFI was low; if the mPI was ⩾90th percentile and the mNDI was ⩾90th percentile, we defined that the UtABFI was high. RESULTS: When women were stratified to 4 groups: low BP and low UtABFI, high BP but low UtABFI, high UtABFI but low BP, high BP and high UtABFI, the PPVs were 0.7%, 6.9%, 6.2% and 39.1%, respectively. In women with low BP and low UtABFI, the high sFlt-1/PlGF changed the PPV to 11.1%; the interval from the sampling to the onset of PE in women with high sFlt-1/PlGF ratio was significantly shorter than in those with low sFlt-1/PlGF ratio (mean±SD [weeks]: 5.9±1.5 vs. 16.5±2.1, p<0.01). In women with high BP but low UtABFI, the high sFlt-1/PlGF changed the PPV to 18.2%; the interval from the sampling to the onset of PE in women with high sFlt-1/PlGF ratio was significantly shorter than in those with low sFlt-1/PlGF ratio (8.0±5.7 vs. 12.6±3.7, p<0.05). Although these effects of sFlt-1/PlGF ratio on the occurrence of PE were not confirmed in women with high BP and high UtABFI, PE occurred in all women with three risk factors (5/5), and the interval from the sampling to the onset of PE was6.8±4.1 weeks. CONCLUSION: Women with both high BP and high UtABFI, especially those with additional risk of high sFlt-1/PlGF ratio, were the highest risk of PE. In the lowest risk group of low BP and low UtABFI, the addition of sFlt-1/PlGF ratio improved the PPV and the interval from the sampling to the onset of PE. These results clearly indicated the clinical importance of measuring sFlt-1/PlGF ratio in addition to BP levels and UtABFI in all pregnant women in the second trimester.

PP111. The preceding features before onset of gestational hypertension and preeclampsia in home blood pressure monitoring: The existence of the inflection point and the rapid increased speed of blood pressure.

INTRODUCTION: It has not been clarified whether home blood pressure monitoring (HBPM) during pregnancy is useful to detect high risk pregnant women with later onset of gestational hypertension (GH) and preeclampsia (PE). OBJECTIVES: We thought to determine the preceding features of blood pressure (BP) in HBPM before the onset of GH and PE. We especially focused on the existence of the inflection point, its level, when it occurs, and the increased speed of BP after the inflection point. We compared these features in normal pregnant women (NP), women with GH, and women with PE. METHODS: In this prospective cohort study, 361 singleton pregnant women, among them 100 women recruited due to high risk for GH/PH in the second trimester, participated in a couple of tertiary perinatal centers between 2008 and 2010. HBPM were measured with the validated OMRON HEM-5001(R) automated digital oscillometric sphygmomanometer (OMRON Healthcare Japan). The device was programmed to take three consecutive readings at 15-second interval. HBPM was measured twice a day, at the time of awakening and sleep, through the first to third trimester, and the average systolic blood pressure (SBP) and diastolic blood pressure (DBP) of each gestational week (almost 42 times a week) were calculated. We defined the data of HBPM which started before 28 gestational weeks and continued until 2 weeks before the onset of GH/PE or delivery are eligible. The increased speed of systolic or diastolic BP after the inflection point was defined as ("BP at the onset in GH/PE or at delivery in NP" - "BP at the inflection point") / ("Gestational weeks at the onset in GH/PE or at delivery in NP" - "Gestational weeks at the inflection point"). If there was no inflection point in HBPM, the increased speed of BP was defined as zero. The comparisons were performed using one-way analysis of variance (ANOVA) followed by multiple comparison. Data were shown as mean±SE. RESULTS: A total of 17 (4.7%) women developed PE, and 12 (3.3%) GH.The systolic blood pressure (SBP) levels at the inflection point in NP, GH and PE was 102.4±1.3, 118.7±2.9 and 117.4±2.2mmHg, respectively (Significant pairs: NP < GH, PE); the diastolic blood pressure (DBP) levels at the inflection point was 59.2±1.0, 74.5±2.0 and 73.1±2.0mmHg, respectively (NP < GH, PE). The inflection point in NP, GH and PE occurred at 31.3±0.9, 28.4±1.5 and 22.3±1.4weeks, respectively (PE < GH, NP). The increased speed of SBP in NP, GH and PE was 1.2±0.1, 3.0±0.4 and 4.7±0.7mmHg/wk, respectively (NP < GH, PE); the increased speed of DBP was1.1±0.1, 2.1±0.3 and 2.8±0.4mmHg/wk, respectively (NP < GH, PE). CONCLUSION: In women with later onset of GH/PE, the BP level at the inflection points was higher than in NP. The average inflection point in PE was earlier gestational weeks than in GH and NP. The average increased speed of blood pressure after the inflection point in GH/PE was faster than in NP. The preceding features of BP in HBPM may be clinically useful to detect high risk women with later onset of GH/PE.

Liver dysfunction in late pregnancy: cytomegalovirus-induced hepatitis or the HELLP syndrome?

A 27-year-old primiparous preeclamptic woman developed a skin rash in late pregnancy and was persistently febrile for 10 days after giving birth. Blood tests suggested that she developed the HELLP syndrome and had concomitant cytomegalovirus (CMV) infection. Hemolysis, slightly impaired liver function, and thrombocytopenia were explainable by either only the CMV infection or only the HELLP syndrome. A literature review of a limited number of such cases and our case suggests that laboratory data in patients with CMV infection can mimic those of the HELLP syndrome. Thus, it may be important to consider CMV infection as a possible cause of abnormal laboratory data similar to the HELLP syndrome.

Expansion of the fraction of Th1 cells in women with preeclampsia: inverse correlation between the percentage of Th1 cells and the plasma level of PAI-2.

PROBLEM: The fractions of Th1 cells and Tcl cells may be increased in preeclamptic women compared with healthy pregnant women. METHOD OF STUDY: Eleven healthy non-pregnant women, nine healthy pregnant women (34.1+/-3.1 weeks of gestation), and 10 women with preeclampsia (32.0+/-5.4 weeks) were studied. The fractions of Th1 cells, Th2 cells, Tc1 cells, and Tc2 cells in the peripheral blood mononuclear cells were determined using a three-color flow cytometric technique. The concentrations of plasma plasminogen activator inhibitor-2 (PAI-2) were simultaneously determined. RESULTS: The fraction of Thl cells was significantly larger in women with preeclampsia (18.7+/-5.2%) than in normal pregnant women (11.0+/-5.7%), and it increased with a decrease in the PAI-2 level (r = -0.706, P = 0.002), which was significantly lower in preeclamptic women (83.4+/-46.8 ng/mL) than in normal pregnant women (225.3+/-82.0 ng/mL). The fraction of Tc1 cells increased with increases in the fraction of Th1 cells (r=0.657. P<0.001) and the ratio of Th1-to-Th2 cells (r=0.535, P=0.002). The ratio of Tc1-to-Tc2 cells also increased with an increase in the ratio of Th1-to-Th2 cells (r = 0.394, P = 0.031). CONCLUSIONS: The fraction of Th1 cells appears to be expanded in women with preeclampsia compared with healthy pregnant women.

Intrauterine death of one twin, with rescue of the other, in twin-twin transfusion syndrome.

Single intrauterine death may occur in twin-twin transfusion syndrome. We investigated why the outcome of the surviving twin is fairly good when the donor twin dies first compared with when the recipient twin dies first. A detailed hemodynamic study was performed using Doppler ultrasound in a twin pregnancy affected by twin-twin transfusion syndrome before and after a single intrauterine death that occurred in the donor twin at 26 weeks' gestation. The recipient twin was expected to die due to severe right cardiac failure with functional stenosis of the pulmonary artery 2 days before the cotwin's death. The donor twin's death caused a prompt resolution of cardiac failure and improvement in other indices, including flow velocity waveform patterns of the umbilical vein, the middle cerebral artery and the ductus venosus. A healthy, premature female neonate weighing 1630 g with a hemoglobin concentration of 17.8 g/dL was delivered by Cesarean section following rupture of the fetal membranes 28 days after the episode. Hemorrhaging from the surviving twin to the dead twin that occurred just before or after the cotwin's death may have contributed to the decrease in volume overload in the recipient twin, leading to a prompt amelioration of the critical hemodynamic indices. The early death of the donor twin may thus have played a significant role in improving the status of the recipient twin in this case of twin-twin transfusion syndrome.

First-trimester ultrasonographic investigation of cardiovascular anatomy in thoracoabdominally conjoined twins.

Options for the treatment of thoracoabdominally conjoined twins are dependent on the anatomy of the cardiovascular system. It is important to increase the accuracy of diagnosis of conjoined twins with a fused heart. Color Doppler imaging performed in a 23-year-old nulliparous Japanese woman at 12 weeks of gestation revealed synchronized blood flow in 2 aortic arches arising from a single heart. The patient underwent a therapeutic abortion, and the diagnosis of conjoined twins with a fused heart was confirmed. Thus, color Doppler imaging is useful for investigating the cardiovascular anatomy in conjoined twins suspected of having a fused heart, even in an early gestational age.

Predicting the risk of pre-eclampsia and a small-for-gestational-age infant by quantitative assessment of the diastolic notch in uterine artery flow velocity waveforms in unselected women.

OBJECTIVES: To develop a new quantitative index, the notch depth index (NDI), to evaluate its association with the risk of pre-eclampsia and a small-for-gestational-age (SGA) infant and to compare its clinical usefulness with that of the uterine artery resistance index (RI) and the peak systolic to early diastolic velocity (A/C) ratio. METHODS: Uterine artery color Doppler ultrasound was performed in 288 consecutive healthy pregnant women at 20.2 +/- 2.0 (range 16.0-23.9) weeks of gestation. The NDI represents the depth of the early diastolic notch divided by the maximal diastolic velocity. RESULTS: Nine (3.1%) of the 288 women developed pre-eclampsia and 18 women (6.3%) delivered an SGA infant. The NDI was associated with subsequent onset of pre-eclampsia. The optimal cutoff value for the NDI in predicting pre-eclampsia was 0.14, giving a sensitivity, specificity and a positive predictive value (PPV) of 67, 92, and 22%, respectively. The PPV of the NDI was the largest of the three indices evaluated (12% for the RI and 16% for the A/C ratio). The relative risk for pre-eclampsia in women with values equal to or greater than the optimal cutoff values of the RI, A/C ratio and the NDI was 9.7 (95% confidence interval, 2.5-3.7), 19.2 (4.2-91), and 19.2 (5.1-71), respectively. The NDI of 0.14 improved the PPV of 18% determined by the presence of notches in bilateral uterine arteries. The optimal cutoff value of 0.14 for the NDI in predicting an SGA infant yielded a higher PPV (22%) than those for the RI (9%) and A/C ratio (12%). CONCLUSIONS: The NDI value in the second trimester is associated with the later onset of pre-eclampsia, and is clinically more useful in predicting pre-eclampsia than the two conventional indices.