大口 昭英

In this study, to search for novel preeclampsia (PE) biomarkers, we focused on microRNA expression and function in the human placenta complicated with PE. By comprehensive analyses of microRNA expression, we identified 22 microRNAs significantly upregulated in preeclamptic placentas, 5 of which were predicted in silico to commonly target the mRNA encoding hydroxysteroid (17-beta) dehydrogenase 1 (HSD17B1), a steroidogenetic enzyme expressed predominantly in the placenta. In vivo HSD17B1 expression, at both the mRNA and protein levels, was significantly decreased in preeclamptic placentas. Of these microRNAs, miR-210 and miR-518c were experimentally validated to target HSD17B1 by luciferase assay, real-time PCR, and ELISA. Furthermore, we found that plasma HSD17B1 protein levels in preeclamptic pregnant women reflected the decrease of its placental expression. Moreover, a prospective cohort study of plasma HSD17B1 revealed a significant reduction of plasma HSD17B1 levels in pregnant women at 20 to 23 and 27 to 30 weeks of gestation before PE onset compared with those with normal pregnancies. The sensitivities/specificities for predicting PE at 20 to 23 and 27 to 30 weeks of gestation were 0.75/0.67 (cutoff value = 21.9 ng/mL) and 0.88/0.51 (cutoff value = 30.5 ng/mL), and the odds ratios were 6.09 (95% CI: 2.35-15.77) and 7.83 (95% CI: 1.70-36.14), respectively. We conclude that HSD17B1 is dysregulated by miR-210 and miR-518c that are aberrantly expressed in preeclamptic placenta and that reducing plasma level of HSD17B1 precedes the onset of PE and is a potential prognostic factor for PE. (Hypertension. 2012; 59: 265-273.). Online Data Supplement

It has not been clarified whether thresholds of soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), soluble endoglin, and the sFlt-1/PlGF ratio for the imminent onset of preeclampsia (PE) exist. We hypothesized that onset thresholds for the imminent onset of PE could be determined by the distributions of these 4 markers just after the onset of PE. Study subjects were 51 PE after the onset of PE; 36 of PE, 20 of gestational hypertension, 142 of a small-for-gestational-age infant, and 400 of normal pregnant controls at 19 to 25 and 27 to 31 weeks of gestation in a prospective cohort study. The current data supported our hypothesis that onset thresholds of sFlt-1 and the sFlt-1/PlGF ratio exist. The onset thresholds of the sFlt-1/PlGF at 26 to 31 weeks of gestation were useful for detecting imminent PE with the onset at <36 weeks of gestation, showing sensitivity of 0.36 and a positive likelihood ratio and 95th percent CIs of 38 (11-132); when positive, PE occurred at 2.2 +/- 0.6 weeks (range: 1.4-3.0 weeks) after the measurement of the sFlt-1/PlGF ratio. The combination of sFlt-1 at 26 to 31 weeks of gestation, past history of gestational hypertension or PE, prepregnancy body mass index, and mean blood pressure at 16 to 23 weeks of gestation was useful for detecting PE with onset of <36 weeks of gestation, showing sensitivity of 0.82, and a positive likelihood ratio (95% CI) of 42 (20-88). In conclusion, the onset threshold of sFlt-1/PlGF existed and might be useful for detecting the imminent onset of PE. (Hypertension. 2011; 58: 859-866.). Online Data Supplement

Clinical guidelines for obstetrical practice were first published by the Japan Society of Obstetrics and Gynecology (JSOG) and the Japan Association of Obstetricians and Gynecologists (JAOG) in 2008, and a revised version was published in 2011. The aims of this publication include the determination of current standard care practices for pregnant women in Japan, the widespread use of standard care practices, the enhancement of safety in obstetrical practice, the reduction in burdens associated with medico-legal and medico-economical problems, and a better understanding between pregnant women and maternity-service providers. These guidelines include a total of 87 Clinical Questions followed by several Answers (CQ&A), a Discussion, a List of References, and some Tables and Figures covering common problems and questions encountered in obstetrical practice. Each answer with a recommendation level of A, B or C has been prepared based principally on 'evidence' or a consensus among Japanese obstetricians in situations where 'evidence' is weak or lacking. Answers with a recommendation level of A or B represent current standard care practices in Japan. All 87 CQ&A are presented herein to promote a better understanding of the current standard care practices for pregnant women in Japan.

Aims: To investigate the relation between serum levels of C-reactive protein (CRP) at pre-/post-cerclage points and preterm birth at < 33 weeks of gestation in women with indicated cervical cerclage (CC). Methods: Fifty-eight women with CC indicated for a short or soft cervix, but no visible or protruding fetal membranes into the vagina, between 17 and 26 weeks of gestation, were reviewed. Serum CRP levels were examined three times: just before cerclage, and on day 1 and day 2 post-cerclage. Results: Serum CRP levels on day 1 and day 2, but not just before cerclage, predicted the occurrence of very preterm birth. In women with cervical dilatation of < 3.0 cm, serum CRP levels on post-cerclage day 1 were associated with the increase of very preterm birth [CRP >= 1.5 mg/dL vs. < 1.5 mg/dL: 4/5 (80%) vs. 8/31 (26%), P=0.033]. In women with cervical dilatation of < 3.0 cm, serum CRP >= 3.0 mg/dL on post-cerclage day 2 was also associated with the increase of very preterm birth. Conclusion: In women with indicated CC between 17 and 26 weeks of gestation, increased levels of serum CRP on post-cerclage day 1 or 2 might be ominous signs for very preterm birth.

It is controversial whether gestational hypertension (GH) and preeclampsia (PE) have the same pathophysiology. Our aim was to clarify whether the serum soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio and levels of soluble endoglin (sEng) are different in women with GH and with PE. In women with GH (15 cases), hypertension preceding PE (h-PE, 10 cases) and PE in which hypertension and proteinuria occurred simultaneously (si-PE, 36 cases), blood samples were collected after disease onset. The levels of log(10)(sFlt-1/PlGF) in women with GH were significantly lower than in women with h-PE and si-PE (1.65 +/- 0.39 vs. 2.22 +/- 0.35 and 2.15 +/- 0.46). The levels of log(10)sEng in women with GH were also significantly lower than in women with h-PE and si-PE (1.51 +/- 0.43 vs. 1.87 +/- 0.21 and 1.85 +/- 0.32). The incidence rates of the sFlt-1/PlGF ratio >= 95th percentile of the reference value were 73, 100 and 92%, respectively, (P=0.080), and those of sEng >= 95th percentile were 67, 100 and 89%, respectively, (P=0.053). In conclusion, the levels of sFlt-1/PlGF ratio and sEng in women with GH were lower than in those with h-PE and with si-PE; however, the majority of women with GH showed abnormal increases of both sFlt-1/PlGF ratio and sEng, suggesting that GH may be a subclinical PE in view of serum levels of angiogenesis-related factors. Hypertension Research (2011) 34, 212-217; doi: 10.1038/hr.2010.212; published online 4 November 2010

Vasohibin-1 (VASH1) is a VEGF-inducible gene of endothelial cells (ECs) that acts as a negative feedback regulator of angiogenesis. To further characterize the function of VASH1, we transfected human VASH1 gene into the mouse EC line MS1, established stable VASH1 expressing clones, and determined gene alteration by cDNA microarray analysis. Among the various angiogenesis-related genes, vascular endothelial growth factor type 1 receptor (VEGFR-1) and its alternative spliced form, soluble VEGFR1 (sVEGFR-1), were found to be the most significantly down-regulated genes. Transient overexpression of VASH1 in human umbilical vein endothelial cells confirmed the down-regulation of VEGFR-1 and sVEGFR-1. sVEGFR-1 is a decoy receptor for VEGF and inhibits angiogenesis. Interestingly, when sVEGFR-1 was overexpressed in ECs, it inhibited the expression of VASH1 in turn. These results suggest that VASH1 and sVEGFR-1, two angiogenesis inhibitors, mutually balance their expressions in ECs. © 2011 by the authors licensee MDPI, Basel, Switzerland.

Aims: To evaluate uterine cervical consistency using a vaginal ultrasound gray-level histogram. Methods: Vaginal ultrasound and digital examination were performed for 214 women with low-risk singleton pregnancy during 27-30(th) pregnancy week. The mean gray-level (MGL) of an ultrasound gray-level histogram, representing the echogenicity of a region of interest, was measured in the midsection of anterior and posterior cervical walls. The difference in MGL between anterior and posterior (AP difference) was related to the Bishop sub-score for cervical consistency (0, 1, or 2), determined before ultrasound. Results: A larger positive AP difference indicated significantly lower Bishop sub-score. After analyzing the receiver operator characteristic curves for the AP difference, a value of 1.42 and -1.98 was the best cut-off value to determine a hard cervix (score 0) and a soft cervix (score 2), respectively. To identify a hard cervix, this test had 71% sensitivity and 82% specificity. For a soft cervix, it was 66% and 87%, respectively. Conclusions: A more echogenic anterior than posterior cervix indicates a hard cervix; the greater the difference in echogenicity between anterior and posterior walls the harder the cervix. The difference in MGL of the ultrasound gray-level histogram may enable objective evaluation of cervical consistency.

Peripartum cardiomyopathy (PPCM) is a rare but potentially life-threatening disorder that occurs in late pregnancy or the early puerperium despite optimal medical therapy. Recently, oxidative stress-mediated generation of antiangiogenic and proapoptotic 16-kDa prolactin, and subsequent impaired cardiac microvascularization have been related to PPCM. In turn, prolactin blockade with bromocriptine has been proven successful in preventing the onset of PPCM in mice and in patients at high risk for the disease. Here, we report the efficacy of bromocriptine for treatment of a patient with PPCM. © 2010 Japanese College of Cardiology.

The first commercial automated immunoassays specific for soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) (Elecsys sFlt-1 and Elecsys PlGF, respectively) have recently been introduced. We constructed reference range values of plasma levels of sFlt-1 and PlGF, and the sFlt-1/PlGF ratio using Elecsys sFlt-1 and Elecsys PlGF during the second half of pregnancy and evaluated their sensitivity and specificity for the diagnosis of preeclampsia. Plasma samples were collected from 144 normal pregnant women at 19-25, 27-31 and 34-38 weeks of gestation and from 34 women with preeclampsia. The most appropriate reference range curves for plasma levels of sFlt-1 and PlGF, and the sFlt-1/PlGF ratio are presented as quadratic curves after logarithmic transformation. The sFlt-1/PlGF ratio showed the best diagnostic power for both early-onset and late-onset preeclampsia. In addition, a cutoff value of 45 for the sFlt-1/PlGF ratio resulted in the best sensitivity and specificity for the diagnosis of all preeclampsia (97 and 95%, respectively), and for the diagnosis of early-onset preeclampsia (100 and 95%, respectively). Using another 50 pairs of serum and plasma samples, including those from normal pregnant women and preeclamptic women, the plasma recovery rates of sFlt-1 and PlGF were 0.89 and 0.85, respectively; the correlation determinations between serum and plasma samples were 0.999 for sFlt-1, 0.990 for PlGF and 0.987 for sFlt-1/PlGF ratio. In conclusion, measurement of the plasma sFlt-1/PlGF ratio determined by Elecsys sFlt-1 and Elecsys PlGF and using a cutoff value of 45 might assist in the diagnosis of preeclampsia, especially for early-onset preeclampsia. Hypertension Research (2010) 33, 422-427; doi: 10.1038/hr.2010.15; published online 12 February 2010

Aim: Hemorrhage is an important complication of heparin-thromboprophylaxis after surgery. We attempted to clarify the incidence rate of prolonged activated partial thromboplastin time (APTT), representative of hemorrhagic tendency, in Japanese women who received thromboprophylaxis with unfractionated subcutaneous heparin administration after cesarean section (CS). We also determined factors which affected postoperative APTT. Methods: We studied 280 women who were administered thromboprophylaxis with unfractionated subcutaneous heparin 5000 IU two times per day after CS. Postoperative APTT under heparin was measured and the incidence of its prolongation was determined. Preoperative APTT, blood loss during surgery, postoperative hematocrit, postoperative serum total protein level, and postpartum body weight were measured, and their correlation with postoperative APTT was determined. Results: Preoperative and postoperative APTT values were 28.3 (26.7-30.3) and 33.8 (31.0-37.5) seconds for median (interquartile range), respectively. Overall, 7.1% of patients showed >= 45 s postoperative APTT. Two patients (0.7%) showed >= 60 s APTT, one of whom suffered subcutaneous hemorrhage around the abdominal incision with complete healing. There were no other hemorrhagic complications. Preoperative APTT positively, and postpartum body weight inversely, correlated with postoperative APTT. The amount of blood loss, postoperative hematocrit, and postoperative serum total protein level did not correlate with postoperative APTT. No discernible deep vein thrombosis or pulmonary embolism occurred. Conclusion: Although 7.1% of women under heparin-thromboprophylaxis showed a prolonged APTT that was 150% of the preoperative APTT, serious side effects were not observed. Subcutaneous administration of unfractionated heparin, if checking APTT prolongation 1 day after surgery, may be safe method of thromboprophylaxis after CS.

Premenstrual dysphoric disorder (PMDD), a severe type of premenstrual syndrome (PMS), is characterized mainly by psychological symptoms confined to the premenstrual period, which reduce not only patients' quality of life, but also their working activities. Although various therapies have been employed for PMDD, some patients do not respond to them. We recently employed acupuncture treatment for a patient in PMDD. Symptoms ameliorated during the acupuncture (+) period, but deteriorated during the acupuncture (-) period. This review describes the clinical course of this case. The diagnosis and treatment of PMDD are briefly summarized and previous acupuncture treatment for PMS are reviewed. The difficulties in evaluating the effectiveness of acupuncture for PMS/PMDD are addressed. It is suggested that acupuncture may be a treatment option for PMDD.

The first aim of our study was to develop a pregnant mouse model for preeclampsia using adenoviral vector containing mouse full-length soluble fms-like tyrosine kinase 1 (sFlt-1) but not truncated sFlt-1. The second aim was to evaluate effects of recombinant mouse (rm) vascular endothelial growth factor (VEGF) and rm placental growth factor (PlGF) on a preeclampsia model induced by adenoviral vector containing mouse full-length sFlt-1. We injected adenoviral vector containing mouse full-length sFlt-1 on day 8.5 or 9.5 of gestation into pregnant Institute of Cancer Research mice, resulting in hypertension, proteinuria, and similar glomerular histological changes as those seen in human preeclamptic women with glomerular endotheliosis on day 16.5 or 17.5 of gestation. The preeclampsia models were treated with 100 mu g/kg of rmVEGF164 (n=5), 100 mu g/kg of rmPlGF-2 (n=5), or vehicle (n=7) twice a day for 2 days IP. The rmVEGF164 treatment significantly decreased the mean blood pressure on day 16.5 or 17.5 of gestation compared with the vehicle treatment (85 +/- 4 versus 97 +/- 2 mm Hg; P=0.018). The rmPlGF-2 treatment also significantly decreased the mean blood pressure on day 16.5 or 17.5 of gestation compared with the vehicle treatment (86 +/- 3 versus 97 +/- 2 mm Hg; P=0.018). However, proteinuria was not affected by either rmVEGF164 or rmPlGF-2. In conclusion, we, for the first time, created a mouse preeclampsia model using mouse full-length sFlt-1. VEGF and PlGF may be promising for ameliorating hypertension in women with preeclampsia. Additional study of PlGF as a potential drug for preeclampsia is warranted. (Hypertension. 2009;54:1129-1135.)

In this study, we performed small RNA library sequencing using human placental tissues to identify placenta-specific miRNAs. We also tested the hypothesis that human chorionic villi could secrete miRNAs extracellularly via exosomes, which in turn enter into maternal circulation. By small RNA library sequencing, most placenta-specific miRNAs (e. g., MIR517A) were linked to a miRNA cluster on chromosome 19. The miRNA cluster genes were differentially expressed in placental development. Subsequent validation by real-time PCR and in situ hybridization revealed that villous trophoblasts express placenta-specific miRNAs. The analysis of small RNA libraries from the blood plasma showed that the placenta-specific miRNAs are abundant in the plasma of pregnant women. By real-time PCR, we confirmed the rapid clearance of the placenta-specific miRNAs from the plasma after delivery, indicating that such miRNAs enter into maternal circulation. By using the trophoblast cell line BeWo in culture, we demonstrated that miRNAs are indeed extracellularly released via exosomes. Taken together, our findings suggest that miRNAs are exported from the human placental syncytiotrophoblast into maternal circulation, where they could target maternal tissues. Finally, to address the biological functions of placenta-specific miRNAs, we performed a proteome analysis of BeWo cells transfected with MIR517A. Bioinformatic analysis suggests that this miRNA is possibly involved in tumor necrosis factor-mediated signaling. Our data provide important insights into miRNA biology of the human placenta.

We report the case of a pregnant woman who suffered from hypotension after first exposure to intravenous administration of a combination drug containing vitamins B1, B6 and B12 (Vitamedin; Daiichi-Sankyo, Tokyo, Japan). A 27-year-old Japanese woman received an intravenous infusion of fluid containing a vitamin B complex due to hyperemesis gravidarum. Thirty minutes after the start of infusion she was found to be in hypotension. The patient had stupor, general sweating, blood pressure of 82/50 mmHg, and low percutaneous oxygen saturation (SpO(2)) of 88%. We immediately stopped the infusion, lifted her legs and administered oxygen. Three minutes after these treatments, she quickly recovered to a good general condition. A skin prick test for vitamin B12 was positive, but tests for B1, B6, mannitol and saline were negative, indicating this adverse reaction was one of drug hypersensitivity due to the vitamin B12 in Vitamedin. Patients should be observed carefully immediately after the administration of Vitamedin.

Ehlers-Danlos syndrome (EDS) type IV is an autosomal dominantly inherited connective tissue disorder caused by abnormal type III collagen resulting from heterogenous mutations of the type III procollagen gene (COL3A1). The maternal mortality rate per pregnancy in EDS type IV has been reported as 11.5%, to 25%. A 30-year-old Japanese primiparous woman, with a brother who had suffered a bowel rupture due to EDS type IV, became pregnant. She also suffered from myocardial infarction due to coronary artery dissections at 24 years old, and underwent coronary artery bypass grafting. Due to uncontrollable uterine contractions, beta 2-stimulants were administered during 18 to 29 weeks of gestation. Therefore, we performed a cesarean section at 29 weeks of gestation to prevent uterine rupture. She and her baby were discharged without any complications. It was revealed that she had the same mutation as her brother, Gly220Trp, in the (Gly-X-Y)n repeat of the triple-helical domain of COL3A1.

Aims: To identify risk factors for a short interval to birth in women with preterm labor, and to construct a statistical model to predict birth within seven days from the diagnosis of preterm labor at 22-35 weeks of gestation. Methods: Vaginal flora was obtained from 126 singleton pregnant women hospitalized for preterm labor at 22-35 weeks' gestation. The amount of vaginal large Gram-positive rods (GPR) was counted in a bright field under X400 magnification and classified semiquantitively as loss of GPRs, decreased GPRs (<10), and normal flora (10 or more). The effects of vaginal GPRs, cervical dilatation, and previous history of preterm birth on the subsequent occurrence of birth were analyzed using proportional hazards model, and the effects on birth within seven days from the diagnosis of preterm labor were analyzed using multivariate logistic regression. Results: Fifty-four women (42.9%) delivered preterm. Both loss of GPRs and decreased GPRs were independent risk factors for a short interval from threatened preterm labor to birth, after adjusting the effect of cervical dilatation and past history of preterm birth (hazard ratio 3.4 [95% CI 2.0-5.5] and 2.0 [95% CI 1.1-3.6], respectively). Cervical dilatation of <4.0 cm and 2.0-3.9 cm, and past history of preterm birth were also independent risk factors for a short interval to birth. Loss of GPRs and decreased GPRs, and cervical dilatation of <4.0 cm and 2.0-3.9 cm were independently associated with birth within seven days from the diagnosis of preterm labor (OR 26 [95% CI 5.3-130], 11 [1.9-69], 76 [8.0-720], and 6.4 [1.5-27], respectively). Conclusions: Loss of GPRs and decreased GPRs may be independently important for developing birth in women with preterm labor.

Cesarean hysterectomy for placenta previa percreta with bladder invasion often induces not only massive hemorrhage but also severe bladder/ureter injuries. A 37-year-old woman with previous cesarean delivery suffered placenta previa percreta with bladder invasion. At the 34th week, we performed cesarean hysterectomy. Without separating the bladder from the uterus/cervix, we incised the bladder lateral wall using an automatic stapling/cutting device, leaving the bladder posterior wall adhering to the uterus and resecting it with the uterus. The bladder was easily repaired without urological sequelae. We suggest a new, simple and safe technique for cesarean hysterectomy for this disease.

Objective: It was recently reported that both a high soluble fms-like tyrosine kinase 1 (sFlt1): placental growth factor (PlGF) ratio (sFlt1:PlGF ratio) and high soluble endoglin (sEng) levels are related to the later occurrence of preeclampsia. We compared the serum sFlt1:PlGF ratio, PlGF and sEng levels in women with gestational proteinuria (GP) to those in women with preeclampsia. Methods: Seven women with GP and 34 women with preeclampsia were recruited in this study. The 95th percentile values in the reference curves of sFlt1, sFlt1:PlGF ratio and sEng, and the 5th percentile values in the reference curve of PlGF were respectively set as the cutoff values. Results: The incidence rates of a high sFlt1:PlGF ratio, low PlGF and high sEng in women with GP were 57%, 29% and 86%, respectively, whereas those in women with preeclampsia were 94%, 77%, and 88%, respectively (p = 0.028, p = 0.024, and p = 1.000, respectively). The incidence rates of a both high sFlt1:PlGF ratio and high sEng in women with GP and preeclampsia were 57% and 88%, respectively (p = 0.082). Conclusion: The majority of women with GP showed both increases of the sFlt1:PlGF ratio and sEng, thus suggesting some women with GP may represent subclinical preeclampsia. In addition, women with GP showed a significantly lower sFlt1:PlGF ratio and higher PlGF level than those with preeclampsia, suggesting that the PlGF level is a key regulator for developing hypertension in some pregnant women, even with increases of both sFlt1:PlGF ratio and sEng levels.

Objective: To reconfirm that a low-lying placenta, with placental edge-internal os distance of 0-4 cm, is a risk factor for blood loss during delivery, and to determine whether blood loss differs between edge-os distance of <= 2 cm vs. >2 cm. Methods: We compared total blood loss between 73 singleton pregnant women with edge-os distance of 0-4.0 cm vs. controls. We also compared total blood loss between pregnant women with distance of 0-2.0 cm (lower) vs. 2.1-4.0 cm (higher). Results: Total blood loss was significantly greater in women with placental edge-os distance of <= 4 cm than controls in both delivery modes. The lower group showed a significantly higher incidence of excessive hemorrhage during vaginal delivery (60 vs. 19%, P=0.046) and bled more (median 1240 vs. 860 mL, P=0.059) than the higher group. Although this did not reach statistical significance, the lower group more frequently bled antepartum, required emergent cesarean section, and delivered abdominally. Regression analysis showed no association between the amount of blood loss and the edge-os distance in both delivery modes. Conclusion: Pregnant women with edge-os distance of 2.1-4.0 cm are of highest level of concern as are women with 0-2.0 cm distance.

It has been established that serum soluble endoglin (sEng) increases in women with preeclampsia. However, sEng levels have not been evaluated using a normal reference value specific to each gestational age. First, we established the normal reference value for sEng using 85 pregnant controls without preeclampsia, from whom serum samples were collected three times at 20-23, 27-30, and 36-38 weeks of gestation. Second, we evaluated the serum sEng levels after the onset of preeclampsia in 56 preeclamptic patients. In three women (3.5%) with normal pregnancies, sustained high sEng levels (>15 ng/mL) were observed. We calculated the reference value for sEng using the remaining 82 normal controls. The log(10)sEng was almost normally distributed at each gestational week during 20-38 weeks, and the mean log(10)sEng was represented as a quadratic curve of gestational week. The SD of log(10)sEng was represented as a linear equation of gestational week. The mean log(10)sEng significantly and gradually increased from 20-23 weeks to 27-30 weeks of gestation and then rapidly increased at 36-38 weeks of gestation. Ninety-three percent of preeclamptic women showed sEng >= 95th percentile of the reference value. The log(10)sEng levels and the SD score (SDS) of log(10)sEng in women with early-onset preeclampsia (onset<32 weeks of gestation) were significantly higher than those in women with late-onset preeclampsia (onset >= 32 weeks of gestation) (1.97 +/- 0.23 vs. 1.78 +/- 0.28, 9.94 +/- 2.61 vs. 4.47 +/- 2.06, respectively). In conclusion, alteration of serum sEng levels after the onset of preeclampsia was more pronounced in women with early-onset preeclampsia compared to those with late onset. (Hypertens Res 2008; 31: 1541-1548)

Background The efficacy of maternal administration of ritodrine in cases of congenital atrioventricular block (CAVB), especially with fetal heart failure, is not yet determined. Case At 21 2/7 weeks of gestation, isolated CAVB with a ventricular/atrial rate of 55-70/130-140 bpm was found in a fetus from a 30-year-old Japanese nulliparous woman with anti-SSA antibody. Cardiothoracic area ratio (CTAR) was 40% and no fetal hydrops was observed. At 30 2/7 weeks, the ventricular rate decreased to 49 bpm with an atrial rate of 125 bpm. CTAR increased to 53.8% and ascites appeared. Maternal continuous ritodrine infusion was started with rapid improvement of fetal cardiac function; increment in the ventricular rate to 57 bpm and atrial rate to 137 bpm, with a decrement in CTAR to 44.6%. Ascites also gradually decreased and by the fourth day, it had completely disappeared with CTAR of 40.2%. On the 12th day after ritodrine treatment (32 1/7), amniotic fluid volume decreased and fetal weight gain stopped, which led us to assume a worsening intrauterine environment, and cesarean section was performed. A 1,178 g male infant was born with a 5-min Apgar score of 8. Continuous isoproterenol infusion was started, increasing the ventricular rate from 71 to 80 bpm. Pacemaker implantation is under consideration to treat this infant. Conclusion Maternal administration of ritodrine not only increased the fetal heart rate but also ameliorated the signs of fetal heart failure, and thus is considered one treatment of choice in CAVB.

Aims: To establish a reference value for the frequency of fetal movements perceived by the mother during the second half of pregnancy. Methods: The study subjects consisted of 705 low risk Japanese pregnant women who continuously received antenatal care. We asked women to record the time required to perceive 10 fetal movements ('count to 10' time) everyday. We asked women to record it, not at a fixed time (i.e. evening time), but whenever they felt the fetus move the most actively. The position during counting (i.e. sitting position) was also not specified, and thus we named this method as modified 'count to 10' method. Satisfactory recordings were obtained from 690 women, which we used for analysis. Results: The 'count to 10' time was almost the same from 22 weeks (10.9; 7.3-18.0 (median; interquartile range)) until 32 weeks (10.0; 6.2-15.6), and it Thirty-two weeks showed the shortest time, which gradually increased toward 40 weeks (14.8; 9.5-24.0). Its 90th percentile was approximately 25 and 35 min at 22-36 weeks and at 37-40 weeks, respectively. Conclusions: For the first time we established a reference value for perceived fetal movements throughout the second half of pregnancy. The present modified 'count to 10' method requires less time than the previous method. Approximately 98% (690/705) of women gave us satisfactory recordings. This reference value may be of use in identifying mothers with decreased fetal movements.

We report on three pregnant women with ritodrine-induced neutropenia who were successfully treated with granulocyte-colony stimulating factor (G-CSF). The neutropenia occurred after continuous intravenous infusion of ritodrine for preterm labor. Ritodrine was discontinued and G-CSF was administered. Neutrophil counts returned to normal an average of 4.3 days after the administration. No infectious morbidity or adverse side-effects occurred in the mothers or infants. G-CSF is one possible treatment in women with ritodrine-induced neutropenia.

Objective To identify fetal heart rate (FHR) patterns reflecting the severity of placental abruption, and to determine the incidence of normal FHR pattern in cases of placental abruption. Materials and methods We analyzed FHR tracings from 40 pregnant Japanese women with placental abruption. We analyzed which FHR patterns appeared more frequently in cases of low 5-min Apgar score, low cord arterial pH, and large separation. Results Eight out of 40 cases showed a normal FHR pattern, while 32 cases did not show a normal FHR pattern. Undetectable variability and bradycardia appeared more frequently in cases with 5-min Apgar < 7, with cord blood pH < 7.1, and with larger placental separation than in cases without these features. The normal FHR pattern was associated with 5-min Apgar >= 7, cord blood pH >= 7.1, and separation of < 25%. Conclusion Fetal heart rate pattern reflected the severity of placental abruption. Undetectable variability and bradycardia occurred significantly more frequently in cases of severe placental abruption, and thus may reflect the severity of placental abruption.

Background Disseminated intravascular coagulation (DIC) caused by placental abruption usually improves rapidly after prompt delivery and adequate anti-DIC treatment. Case A 30-year-old nulliparous woman suffered from placental abruption at the 25th week of pregnancy, and emergent cesarean section was done immediately. She exhibited DIC, which continued even after termination of the pregnancy and anti-DIC treatment. She also showed neutropenia. We closely observed her, and at the 58th day postpartum, blast cells appeared in the peripheral blood and she was diagnosed with acute promyelocytic leukemia (APL). Induction chemotherapy was done successfully. The close observation after delivery enabled us to make the prompt diagnosis/treatment, leading to the complete remission. Conclusion APL should be added to the list of differential diagnosis when DIC persists even after prompt delivery and appropriate anti-DIC treatment after placental abruption.

Objectives: Mirror syndrome is the association of triple edema, i.e. fetal, placental and maternal edema, with maternal preeclampsia. We here report the first case of mirror syndrome resulting from hydropic acardius in triplet pregnancy. Methods/Results: A 26-year-old nulliparous woman spontaneously conceived two living fetuses and one acardius, and suffered preterm rupture of the membranes at 23 2/7 weeks of gestation. We observed triple edema, hydropic acardius, placental edema, and maternal edema, together with maternal high blood pressure, proteinuria and low hematocrit, and therefore suspected the presence of mirror syndrome. Due to the prematurity of the fetuses, we closely observed her, awaiting fetal maturity. Three days later (23 5/7 weeks), cord prolapse occurred, leading to emergent cesarean section. Female infants, weighing 492 and 554 g, respectively, were born alive; the former died on the 13th postnatal day and the latter was healthy with no sequelae. An acardius weighing 860 g had vascular communication with the 492-gram fetus. Histological examination confirmed a monochorionic, triamniotic single placenta. The mother suffered from pulmonary edema and was treated in the intensive care unit under respiratory support, but soon improved. Conclusions: When dealing with multifetal pregnancy, especially when complicated by an acardius, obstetricians must have the highest level of concern for the occurrence of mirror syndrome, a life-threatening condition both to the mother and the fetus. Copyright (C) 2008 S. Karger AG, Basel

It has been established that the serum placental growth factor (PIGF) decreases and the soluble fms-like tyrosine kinase-1 (sFit-1) increases in women with preeclampsia. However, there have been no studies on the relation between preeclampsia onset time and the changes in PIGF and sFit-1. Furthermore, the PIGF and sFlt-1 levels have not been evaluated using their reference values specific to each gestational age. In this study we reevaluated the serum PIGF and sFit-1 levels before and after the clinical manifestation of early and late onset severe preeclampsia using the new reference values developed in our recent longitudinal study. Blood specimens were obtained immediately after the clinical manifestation of severe preeclampsia in 34 referred women, and both before and after the clinical manifestation in 8 women receiving a routine checkup at our institute. Both women with early and those with late preeclampsia showed decreased PIGF and increased sFit-1 levels compared to normotensive controls at 28 and 37 weeks (n=68). However, those with early onset preeclampsia had a higher incidence of low PIGF (< 5th percentile on the reference values) and high sFlt-1 (>= 95th percentile) than those with late onset (low PIGF: 93% vs. 55%; high sFit-1: 100% vs. 60%). log(10)PIGF (r=0.574, p < 0.001) and log(10)(sFlt-1/PIGF) (r=-0.556, p < 0.001) were correlated with the week of onset of preeclampsia. Before the onset of preeclampsia, the incidence rate of low PIGF in the women with early onset preeclampsia was 100% (5/5), whereas that in the women with late onset preeclampsia was 0% (0/2) (p=0.048). Therefore, alterations in the PIGF levels both before and after the onset of preeclampsia may be more pronounced in women with early onset than those with late onset severe preeclampsia.

Although laparoscopic adenomyomectomy may be a possible risk factor for uterine rupture in subsequent pregnancy, few reports have described it. A 35-year-old woman became pregnant 1 month after laparoscopic adenomyomectomy. At the 28th week, uterine contraction occurred, leading to intravenous ritodrine infusion. Severe abdominal pain and a non-reassuring fetal heart rate occurred abruptly and an emergency cesarean section was carried out. The uterus ruptured at the site of previous surgery of the uterine body, which was reconstructed. The mother and the infant did well postoperatively. We report the second case of uterine rupture during pregnancy subsequent to laparoscopic adenomyomectomy. A history of adenomyomectomy and a short interval to subsequent pregnancy may be risk factors for uterine rupture. © 2007 The Authors Journal compilation © 2007 Japan Society for Reproductive Medicine.

We report the first case of an obstructive hydrocephalus after intraventricular hemorrhage in a woman with HELLP syndrome and eclampsia. A 25-year-old primiparaous woman had severe preeclampsia at 36 weeks of gestation. She complained of epigastric pain and nausea. The levels of AST, ALT, and LDH were 539, 560, and 1051 IU/L, respectively; the platelet count was 101 x 10(9)/L. Cesarean section was promptly performed. Intraoperatively, she had a first convulsion. The CT scan revealed only mild brain edema. The platelet count deteriorated to 30 x 10(9)/L at 5 hour after the operation, and she had a second convulsion with an intraventricular hemorrhage. On the 6 < sup > th </sup > post-cesarean day, she complained severe headache followed by coma. The CT scan revealed the enlargement of both lateral ventricles, indicating the occurrence of obstructive hydrocephalus. Drainage into cerebral ventricle was performed, resulting in the recovery of consciousness to a normal level.

Blood pressure (BP) levels and body mass index (BMI) are known as risk factors for preeclampsia and gestational hypertension. However, there have been few investigations regarding the effects of BID and BMI levels on preeclampsia and gestational hypertension in the same cohort. In the present study, we conducted a retrospective cohort study using multiple logistic regression analysis. The cohort included 1,518 patients without nephritis. The unadjusted odds ratios (ORs) of preeclampsia and gestational hypertension were increased in pregnant women with normal BP (120-129 mmHg systolic or 80-84 mmHg diastolic), high-normal BID and hypertension in the second trimester compared to those with optimal BP. The unadjusted ORs of preeclampsia and gestational hypertension were also increased in obese women in the pre-pregnancy period compared to women with normal range BML When adjustment was made for both the BP levels and pre-pregnancy BMI levels, the ORs (95% confidence intervals) of normal BID, high-normal BID, hypertension and obesity for the subsequent occurrence of preeclampsia were 5.1 (2.2-12), 8.3 (3.1-22), 16 (5.0-50) and 2.0 (0.67-5.9), and those for the subsequent occurrence of gestational hypertension were 7.0 (2.6-19), 7.4 (2.1-25), 22 (6.1-83) and 1.3 (0.33-4.8), respectively. For the subsequent occurrence of preeclampsia or gestational hypertension, normal BID, high-normal BP and hypertension in the second trimester may be independent risk factors. Obesity in the pre-pregnancy period, however, may not be an independent risk factor.

The purpose of this study was to examine whether dichorionic twins conceived by assisted reproductive technology (ART; intracytoplasmic sperm injection [ICSI], in vitro fertilization [IVF], gamete-intrafallopian tube transfer [GIFT]) have a higher risk of birth defects compared to dichorionic twins conceived naturally. We reviewed the medical records of 406 mothers with dichorionic twin pregnancies, who received continuous antenatal care from ! 20 weeks of gestation and gave birth to infants after ! 24 weeks of gestation in our institute. Birth defects were diagnosed at the time of hospital discharge according to the International Classification of Diseases, 10th Revision. Occurrence of birth defects was compared between twins conceived by ART and those conceived naturally using logistic regression analysis. Overall, 51 of 812 infants (51/812 = 6.2%) had birth defects. The incidence of birth defects in ART-conceived twins was significantly higher than that of naturally conceived twins with an odds ratio of 6.9 (95% confidence interval [CI] 2.1, 22.5), 3.7 (95% CI 1.2, 12.0), and 4.3 (95% CI 1.4, 14.3) for ICSI, IVF, and GIFT, respectively. The higher frequency of birth defects in ART-conceived twins was still significant after adjusting for higher maternal age in the ART group, with an adjusted odds ratio of 6.7 (95% CI 2.1, 21.9), 3.6 (95% CI 1.1, 11.5), and 3.7 (95% CI 1.2-11.8) for ICSI, IVF, and GIFT, respectively. Dichorionic twins conceived by ART, compared to dichorionic twins conceived naturally, had a much higher risk for birth defects diagnosed at hospital discharge.

PROBLEM: While activated/phagocytosing phagocytes infiltrating to the chorioamnion are considered to be one of the causal agents of preterm labor onset, whether placental villous macrophages (Hofbauer cells) are activated/phagocytosing in this condition is not known. METHOD OF STUDY: We concomitantly localized two important phagocytosis-related enzymes, acid phosphatase (ACP) and glucose-6-phosphate dehydrogenase (G6PD), in Hofbauer cells in second trimester placental villi, and compared them with those from infection-related second trimester-spontaneous abortion (miscarriage) placentas. RESULTS: There were two types of Hofbauer cells. The first cells exhibited ACP stainings confined to the lysosomes, suggesting that they are dormant/non-activated cells. Approximately two-thirds of these cells showed weak G6PD labeling on the cytosolic side of endoplasmic reticula, and G6PD labeling was hardly recognizable in the remaining one-third. The second cells, possessing large phagosomes, showed marked ACP labeling in the phagosomes, suggesting that they are activated/phagocytosing cells. All these cells exhibited G6PD labeling, and in 'bursting cells' (possibly hyperactivated cells) G6PD deposits were marked. The percentage of activated cells in miscarriage placentas was significantly higher (44.8 +/- 6.0%) than that in gestational age-matched controls (17.4 +/- 5.3%). CONCLUSIONS: These observations indicated that (1) G6PD activity increased in activated/phagocytosing Hofbauer cells, and (2) the percentage of phagocytosing cells increased in infection-related miscarriage placentas. Hofbauer activation and G6PD may play an role in the pathogenesis/pathophysiology of preterm labor onset.

We counted nucleated red blood cells (NRBC) per 100 white blood cells (WBC) in the umbilical cord blood from 98 twins born to 49 women with uncomplicated twin pregnancies at greater than or equal to 34 weeks of gestation to better characterize NRBC in twins. Twelve women with monochorionic (MC) placentas and 37 with dichorionic (DC) placentas gave birth at 36.7 +/- 1.9 and 36.5 +/- 2 weeks of gestation, respectively. All twins were born with an Apgar score of greater than or equal to7 at 1 min. Log(10) (NRBC/100 BC) in 98 twins exhibited a nearly normal distribution, and was significantly associated with gestational age for both MC (r = -0.457, p = 0.025) and DC twins (r = -0.275, p = 0.018), and with birth weight for both MC (r = -0.682, p < 0.001) and DC twins (r = -0.336, p = 0.003). Log(10) (NRBC/100 WBC) tended to be larger in smaller twins than in larger twins in the MC group, and significantly larger in smaller twins than in larger twins in the DC group (p < 0.05). Intertwin difference in Log(10) (NRBC/100 WBC) was defined as the value of Log(10) (NRBC/100 WBC) of the smaller twin minus Log(10) (NRBC/100 WBC) of the larger twin, and became greater with increasing intertwin difference in birth weight (r = 0.411, p = 0.003). These findings suggest that neonatal NRBC reflected gestational age and birth weight in twins. This preliminary observation using a small number of twins suggests that the smaller twin may have experienced a relative lack of oxygen compared with the larger twin in utero.

Background. Chorioamnionitis (CAM) may accelerate lung maturation in fetuses. It is possible that CAM prevents infant death after live birth., Methods. A retrospective study of live-born singletons at <32 weeks of gestation between 1993 and 1997, Perinatal risk factors for adverse outcomes were analyzed using a logistic regression model, with special reference to the presence of histologically confirmed CAM. Adverse outcomes included infant death before 1 year of age, and survival with cerebral palsy and/or mental retardation. Results. A total of 81 infants, weighing 1181+/-426 g, were born at 28.1+/-2.3 weeks of gestation. Of those, 15 (19%) died before 1 year of age, while 16 (20%) infants developed major handicaps by 1.5 years of age (six with cerebral palsy, eight with mental retardation, and two with both cerebral palsy and mental retardation). CAM, present in 44 women, was significantly associated with a reduced risk of death after live birth, with an odds ratio of 0.11 (p=0.01). Only the presence of such intracranial lesions as periventricular leukomalacia and intraventricular hemorrhage were significantly associated with an increased risk of major handicaps (odds ratio of 11.0, p=0.04). Adverse outcomes occurred in a similar proportion of infants in groups without CAM (14/37) and with CAM (17/44). However, among infants with adverse outcomes, the number of deaths was significantly higher in the group without CAM (10/14),a. with CAM (5/12) (p<0.05). Conclusions. The presence of CAM may somehow prevent infant death after live birth. Larger studies are required to confirm this phenomenon.

Background. The number and percentage of viable vaginal polymorphonuclear leukocytes (vPMNs) are known to be increased in women who experience preterm labor. Whether those parameters may be associated with the presence of histologic chorioamnionitis (CAM) is not known. Methods. We investigated prospectively 39 women at 26.3 +/- 6.2 weeks of gestation. The following were determined in vaginal washings. total number of vPMNs and the percent that were viable, the pH, and the concentrations of granulocyte elastase and interleukin-8 (IL-8). In addition, the while blood cell count and the serum level of C-reactive protein were determined in peripheral blood. The placenta and the umbilical cord were examined histologically with special reference to the presence of CAM. The optimal cutoff value for prediction of histologic CAM was obtained for each variable using receiver operating characteristic curves. A multivariate logistic-regression model was used to determine the independent risk factors for this disorder. Results. Histologic CAM was present in ten women (37.1+/-3.8 weeks) and absent in 29 women (38.2+/-1.5 weeks). The total number of vPMNs, the percent of viable vPMNs, and the IL-8 level were all significantly increased in the women with CAM, in contrast to those without CAM. When the optimal cutoff value for each of seven covariates was entered into the model, only the percent of viable vPMNs, greater than or equal to 11%, demonstrated a significant relationship with histologic CAM (odds ratio 26.9; 95% confidence interval 1.3 to 545; p<0.05). Conclusions. Women with a % viability of vPMNs of greater than or equal to 11% were at a significantly higher risk for histologic CAM. Data suggest that an influx of PMNs into the vagina occurs continuously in patients with histologic CAM.

Objective: To devise preventive measures for stillbirths, which account for more than 70% of perinatal deaths in Japan. Methods: We retrospectively reviewed the medical records of 77 women with singleton pregnancies who gave birth to stillborn infants at ≥ 30 weeks between 1979 and 1996 at our hospital. Results: Major malformations were present in 21 (27%) of 77 infants, including 11 infants with anencephaly. Two infants (2.6%) were severely hydropic. Preeclampsia preceded the stillbirth and might have been an indirect cause of stillbirth in 21 (39%) of 54 women whose infants had normal formations. The cause of stillbirth in 33 non-preeelamptic women was unclear in 15 (28%), abruptio placentae in 9, fetal growth retardation in 3, the HELLP syndrome in 3, chorioamnionitis in 2, and cord accident in 1. Abruptio placentae also occurred in 9 of 21 preeclamptic patients. Thus, abruptio placentae was responsible for 18 (33%) of 54 stillborn infants with a grossly normal appearance. An autopsy was performed on only 13 (24%) of 54 infants with grossly normal appearance and did not provide new information relating to deaths. Conclusions: The causes of stillbirth were many and varied, with a large proportion having no obvious cause, although autopsies were underused. Increased monitoring for women with preeclampsia and early diagnosis and prompt delivery for women with abruptio placentae might be helpful in reducing the number of stillbirths.

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 HI and IV disease. Patients with stage ffi and IV disease demonstrated a significantly poor prognosis compared with patients who had stage I or II disease (p&lt 0.01). No patients with stage HI 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 (≥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 Ia who are positive p53 and highly PA. Platinum-based chemotherapy for patients who had minimal residual tumor was effective, but 5 patients who had ≥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.