Randomized trial of the efficacy of intravaginal ulinastatin administration for the prevention of preterm birth in women with a singleton pregnancy and both cervical shortening and inflammation of lower genital tract.

AIM: To assess the preventive effect on preterm birth of intravaginal ulinastatin (urinary trypsin inhibitor; UTI) administration during the mid-trimester in women with singleton pregnancy and both cervical shortening and lower genital infections. METHODS: Pregnant women with a short cervical length < 25 mm between 16 and 26 weeks of gestation and who had been diagnosed with a lower genital infection were randomly assigned for intravaginal UTI administration or placebo. All of the women were screened for infection or inflammation of the lower genital tract, and women with negative results were excluded. RESULTS: Of the 92 patients with a short cervical length who were assessed for eligibility for this study, 86 singleton patients were enrolled. All patients were randomized to one of two treatment groups: patients administered UTI (n = 35) and placebo (n = 35). There were no differences between the two groups in the incidence of preterm delivery before 28, 30, 32, 34 and 37 weeks of gestation and in perinatal outcomes. CONCLUSION: For women diagnosed with a short cervical length < 25 mm) between 16 and 26 weeks of gestation and lower genital infection, who were at risk of preterm birth, administration of transvaginal UTI with vaginal irrigation showed no apparent benefit. Future research on the efficacy of UTI should evaluate modified modes of UTI application.

Current status of non-invasive prenatal testing in Japan.

AIM: The purpose of this study was to report the 3-year experience of a nationwide demonstration project to introduce non-invasive prenatal testing (NIPT) of maternal plasma for aneuploidy, and review the current status of NIPT in Japan. METHODS: Tests were conducted to detect aneuploidy in high-risk pregnant women, and adequate genetic counseling was provided. The clinical data, test results, and pregnancy outcomes were recorded. We discuss the problems of NIPT on the basis of published reports and meta-analyses. RESULTS: From April 2013 to March 2016, 30 613 tests were conducted at 55 medical sites participating in a multicenter clinical study. Among the 30 613 women tested, 554 were positive (1.81%) and 30 021 were negative (98.1%) for aneuploidy. Of the 289, 128, and 44 women who tested positive for trisomies 21, 18, and 13, respectively, and underwent definitive testing, 279 (96.5%), 106 (82.8%), and 28 (63.6%) were determined to have a true-positive result. For the 13 481 women with negative result and whose progress could be traced, two had a false-negative result (0.02%). The tests were performed on the condition that a standard level of genetic counseling be provided at hospitals. CONCLUSION: Here, we report on the 3-year nationwide experience with NIPT in Japan. It is important to establish a genetic counseling system to enable women to make informed decisions regarding prenatal testing. Moreover, a welfare system is warranted to support women who decide to give birth to and raise children with chromosomal diseases.

Improving the Accuracy of Diagnosing Placenta Previa on Transvaginal Ultrasound by Distinguishing between the Uterine Isthmus and Cervix: A Prospective Multicenter Observational Study.

OBJECTIVE: To clarify whether distinguishing between the uterine isthmus and cervix can improve the accuracy of diagnosing placenta previa at term. METHODS: A multicenter prospective observational study was conducted among pregnant women with suspected placenta previa at 20-24 weeks' gestation. Subjects were divided into the open isthmus group and closed isthmus group. The accuracy of diagnosing placenta previa at term was compared between the 2 groups. RESULTS: We screened 9,341 patients, and 53 (0.6%) met the inclusion criteria. Nineteen cases with an open isthmus and 34 with a closed isthmus were followed. The accuracy for diagnosing placenta previa or a low-lying placenta at term was 94.7% in the open isthmus group and 26.5% in the closed isthmus group (p < 0.001). Elective or emergency Cesarean section was required in 100% of cases in the open isthmus group and 20.6% in the closed isthmus group (p < 0.001). CONCLUSION: A high prediction rate of placenta previa was obtained by using transvaginal ultrasound at 20-24 weeks' gestation after the isthmus opened by carefully distinguishing between the cervix and isthmus.

A survey on awareness of genetic counseling for non-invasive prenatal testing: the first year experience in Japan.

The purpose of this study is to summarize the results from a survey on awareness of genetic counseling for pregnant women who wish to receive non-invasive prenatal testing (NIPT) in Japan. As a component of a clinical study by the Japan NIPT Consortium, genetic counseling was conducted for women who wished to receive NIPT, and a questionnaire concerning both NIPT and genetic counseling was given twice: once after pre-test counseling and again when test results were reported. The responses of 7292 women were analyzed. They expressed high satisfaction with the genetic counseling system of the NIPT Consortium (94%). The number of respondents who indicated that genetic counseling is necessary for NIPT increased over time. Furthermore, they highly valued genetic counseling provided by skilled clinicians, such as clinical geneticists or genetic counselors. The vast majority (90%) responded that there was sufficient opportunity to consider the test ahead of time. Meanwhile, women who received positive test results had a poor opinion and expressed a low-degree satisfaction. We confirmed that the pre-test genetic counseling that we conducted creates an opportunity for pregnant women to sufficiently consider prenatal testing, promotes its understanding and has possibilities to effectively facilitate informed decision making after adequate consideration. A more careful and thorough approach is considered to be necessary for women who received positive test results.

Randomized trial of ultrasound-indicated cerclage in singleton women without lower genital tract inflammation.

AIM: This is the first report of a randomized trial of cerclage on pure cervical shortening without vaginosis or cervicitis. The objective of our multicenter randomized controlled trial was to assess the benefits of ultrasound-indicated cervical cerclage in the mid-trimester to prevent preterm birth in women who have no signs of infection or inflammation of the lower genital tract. MATERIAL AND METHODS: Women with a short cervical length < 25 mm between 16 and 26 weeks of gestation were randomly assigned to receive a Shirodkar cerclage, McDonald cerclage, or bedrest (no cerclage). Before being randomly assigned to one of the three groups, all women were screened for infection/inflammation of the lower genital tract; those with positive results were excluded from the study. The ratio of preterm delivery as a primary end-point was evaluated in the groups. RESULTS: A total of 106 singleton patients with a short cervical length were assessed for study eligibility; 106 patients were randomized to the three treatment options. Ultimately, 98 patients (in the Shirodkar [n = 34], McDonald [n = 34] and bedrest [n = 30] groups) were analyzed. No differences in preterm delivery or perinatal outcomes were found between the three groups. Significantly fewer patients in the Shirodkar group required hospitalization for treatment of threatened preterm labor when compared to patients in the bedrest group. CONCLUSION: For women with a short cervical length < 25 mm between 16 and 26 weeks of gestation, Shirodkar cerclage might be considered to reduce the occurrence of threatened preterm labor.

Administration of oral and vaginal prebiotic lactoferrin for a woman with a refractory vaginitis recurring preterm delivery: appearance of lactobacillus in vaginal flora followed by term delivery.

Lactoferrin (LF) is one of the prebiotics present in the human body. A 38-year-old multiparous woman with poor obstetrical histories, three consecutive preterm premature rupture of membrane at the 19th, 23rd and 25th week of pregnancy, was referred to our hospital. She was diagnosed as having refractory vaginitis. Although estriol vaginal tablets were used for 4 months, the vaginitis was not cured. We administrated vaginal tablets and oral agents of prebiotic LF, resulting in a Lactobacillus predominant vaginal flora. When she was pregnant, she continued to use the LF, and the Lactobacillus in the vaginal flora was continuously observed during pregnancy. An elective cesarean section was performed at the 38th week of pregnancy. When the administration of LF was discontinued after the delivery, Lactobacillus in the vaginal flora was disappeared.

Defect in the uterine wall with prolapse of amniotic sac into it at 32 weeks' gestation in a primigravida woman without any previous uterine surgery.

We experienced a case of uterine wall defect with amniocele in a primigravida woman without any history of uterine surgery. On admission due to acute abdominal pain at 32 weeks' gestation, an ultrasound examination showed a 9 × 7-cm sized echogenic cystic area in the Morrison pouch. Color Doppler revealed a flow from the uterus into the cystic area through a myometrial defect. During the operation, a 1-cm defect in the uterine myometrium was found on the right fundus. An intact amniotic sac was prolapsed into the abdominal cavity through the myometrial defect. This was an extremely rare case of unexplained uterine wall defect.

Sonohysterography is a useful diagnostic approach for uterine arteriovenous malformation.

Uterine arteriovenous malformation (AVM) is a rare cause of abnormal uterine bleeding; nevertheless, it is a potentially life-threatening condition when the diagnosis is not made. We report a case of uterine AVM with a secondary uterine hematoma diagnosed 2 weeks after curettage due to spontaneous abortion. Ultrasound examination revealed a mixed echogenic mass of approximately 4 cm × 1.5 cm with no blood flow and an additional contiguous heterogeneous mass with turbulent blood flow depicted by color Doppler. Transvaginal sonohysterography enabled us to exclude residual chorionic tissues and to make precise diagnosis of uterine AVM with a secondary hematoma.

Is maternal anemia associated with small placental volume in the first trimester?

AIM: To clarify whether maternal anemia could reduce placental volume in the early gestation. METHODS: A prospective cross-sectional study was conducted. Consecutive women who visited at 11-13 + 6 weeks' gestation were enrolled. Subjects were divided into two groups by maternal hemoglobin concentration. Cases with maternal anemia were defined as a hemoglobin level less than 11 g/dl on a blood test (cases), and the others were defined as controls. An ultrasound examination was performed to measure the placental volume and the uterine arterial blood flow. The three-dimensional volume of the placenta using virtual organ computer-aided analysis (VOCAL) technique was acquired by transabdominal ultrasonography. Placental volumes were compared in women with and without anemia. RESULTS: 31 cases and 486 controls were analyzed. Maternal characteristics were not different between two groups except anemia. Placental volumes were 63.6 ± 22.2 and 60.9 ± 22.8 cm(3) (ns), uterine arterial RIs were 0.7 ± 0.1 and 0.8 ± 0.1 (ns), and PIs were 1.7 ± 0.5 and 1.8 ± 0.6 (ns) in cases and controls, respectively. CONCLUSIONS: Maternal anemia was not associated with reduced placental volume and uterine arterial Doppler wave form at 11-13 weeks' gestation.

Exposure to pyrethroids insecticides and serum levels of thyroid-related measures in pregnant women.

Possible association between environmental exposure to pyrethroid insecticides and serum thyroid-related measures was explored in 231 pregnant women of 10-12 gestational weeks recruited at a university hospital in Tokyo during 2009-2011. Serum levels of free thyroxine (fT4), thyroid stimulating hormone (TSH) and thyroid biding globulin (TBG) and urinary pyrethroid insecticide metabolite (3-phenoxybenzoic acid, 3-PBA) were measured. Obstetrical information was obtained from medical records and dietary and lifestyle information was collected by self-administered questionnaire. Geometric mean concentration of creatinine-adjusted urinary 3-PBA was 0.363 (geometric standard deviation: 3.06) µg/g cre, which was consistent with the previously reported levels for non-exposed Japanese adult females. The range of serum fT4, TSH and TBG level was 0.83-3.41 ng/dL, 0.01-27.4 µIU/mL and 16.4-54.4 µg/mL, respectively. Multiple regression analysis was carried out by using either one of serum levels of thyroid-related measures as a dependent variable and urinary 3-PBA as well as other potential covariates (age, pre-pregnancy BMI, parity, urinary iodine, smoking and drinking status) as independent variables: 3-PBA was not found as a significant predictor of serum level of thyroid-related measures. Lack of association may be due to lower pyrethroid insecticide exposure level of the present subjects. Taking the ability of pyrethroid insecticides and their metabolite to bind to nuclear thyroid hormone (TH) receptor, as well as their ability of placental transfer, into consideration, it is warranted to investigate if pyrethroid pesticides do not have any effect on TH actions in fetus brain even though maternal circulating TH level is not affected.

The volume of the chorion villosum is associated with the location of the umbilical cord in the first trimester.

AIMS: To clarify whether villous placental volumes in cases with low cord insertion (CI) are smaller than those with normal cord insertion. METHODS: A prospective cohort study was conducted to evaluate the association between location of umbilical CI and placental volume at 11 to 13 weeks' gestation. An ultrasound examination was performed to measure the crown-rump length, the distance between the histological internal cervical os and the CI site, the placental volume, and the uterine arterial blood flow. To standardize the distribution of the ultrasonographic measurements, we transformed data by crown-rump length-weighted linear regression. RESULTS: Six hundred fifty-nine subjects were analyzed. Scatter plots showed a slightly positive correlation between the z-scores of the distance from the CI site to the internal cervical os and villous placental volume (r = 0.102, p = 0.009) and a negative correlation between the z-scores of the villous placental volume and the uterine arterial pulsatility index (r = -0.165, p < 0.001) as well as the uterine arterial resistance index (r = -0.187, p < 0.001). CONCLUSION: The placental volume was likely to be smaller in cases with CI located in the lower uterine segment.

Relationship between the umbilical cord coiling index and the umbilical blood flow at 11-13 weeks of gestation.

OBJECTIVES: The aim of this study was to clarify the effects of umbilical cord coiling on the umbilical blood flow at 11-13 weeks of gestation. METHODS: A cross-sectional study was conducted among consecutive pregnant females at 11-13 weeks of gestation. Transabdominal ultrasound examinations were performed to obtain the umbilical coiling index (CI), the maximum umbilical arterial peak velocity at the free loop, the venous velocities at the free loop and the umbilical ring, and the umbilical arterial and venous flow volumes. After every measurement was standardized according to the crown-rump length (CRL), correlations between the CI and these measurements were analyzed. RESULTS: A total of 364 subjects were enrolled. The CI significantly decreased in association with advancing gestation. There were significant correlations between the CRLs and the umbilical arterial peak velocities, the venous velocities at the free loop and the umbilical ring, and the umbilical arterial and venous flow volumes. The z-scores of the umbilical arterial and venous velocimetries exhibited no significant correlations with the CI. The umbilical arterial and venous flow volumes were also not found to correlate with the CI. CONCLUSIONS: The CI does not affect either the umbilical arterial or venous blood flow at 11-13 weeks of gestation.

Distribution of nuchal translucency thickness in Japanese fetuses.

AIM: To establish reference values for the nuchal translucency (NT) thickness in Japanese fetuses. MATERIAL AND METHODS: Ultrasonographic measurements of the crown-rump length (CRL) and NT were performed from 11 to 13 + 6 weeks of gestation in consecutive Japanese fetuses examined during prenatal visits between February 2011 and January 2012. The median, 5th and 95th percentiles of the NT thickness with 5 mm intervals of the CRL were confirmed. RESULTS: A total of 970 cases were enrolled in the study. The median NT thickness for a CRL between 45 and 80 mm ranged from 1.2 mm to 1.9 mm, and the 95th percentile of these values ranged from 2.1 mm to 3.2 mm, respectively. CONCLUSION: The reference values for the NT thickness in Japanese fetuses were determined. These values should be useful for fetal biometry, morphological assessment and first trimester screening for chromosomal abnormalities in Japan.

Serum levels of hydroxylated PCBs, PCBs and thyroid hormone measures of Japanese pregnant women.

OBJECTIVES: The purpose of this study was to investigate the associations between serum concentrations of hydroxylated PCBs (OH-PCBs) and PCBs and measures of thyroid hormone status of Japanese pregnant women. METHODS: The concentrations of free thyroxine (fT4), thyroid stimulating hormone (TSH), and thyroxine binding globulin (TBG) as well as 16 OH-PCB isomers and 29 PCB isomers were analyzed in the serum of 129 women sampled in the first trimester of gestation. Dietary and lifestyle information of the subjects was obtained by self-administered questionnaire. Multiple regression analysis was performed using measures of thyroid hormones as the dependent variable and serum levels of OH-PCBs/PCBs, urinary iodine concentration, and other potential covariates (age, BMI, smoking, etc.) as independent variables. RESULTS: Geometric mean (GM) concentration of the sum of 16 isomers of OH-PCBs was 120 pg/g wet wt. and that of 29 isomers of PCBs was 68 ng/g lipid wt., respectively, in the serum of the subjects. Iodine nutrition was considered adequate to high from urinary iodine level (GM, 370 µg/g creatinine). The mean concentration of TSH, fT4 and TBG was 1.34 ± 1.37 µIU/mL, 1.22 ± 0.16 ng/dL and 33.0 ± 6.4 µg/mL, respectively, with a small number of subjects who were outside the reference range. Multiple regression analysis revealed that serum concentrations of OH-PCBs/PCBs were not significantly associated with any of the measures of thyroid hormone status. CONCLUSIONS: Exposure/body burden of OH-PCBs and PCBs at environmental levels does not have a measurable effect on thyroid hormones.

A case of aggressive angiomyxoma of the vulva.

Aggressive angiomyxoma (AA) is a rare mesenchymal neoplasm of the female pelvis and vulva, which has a tendency for local recurrence. AA is occasionally misdiagnosed as Bartholin's gland cyst or abscess, lipoma, simple labial cyst, or soft tissue tumors. We describe a case of AA on the outside of the left labium majus pudendi in a 28-year-old female. We were able to make the preoperative diagnosis of AA by magnetic resonance imaging (MRI) and ultrasound (US), and to perform complete surgical excision with a transperineal minimally invasive approach. The novelty of this case is the use of ultrasound for the diagnostic workup of the perineal tumor and determination of the incision line.

Application of high-intensity focused ultrasound for fetal therapy: experimental study using an animal model of lower urinary tract obstruction.

OBJECTIVE: The purpose of this study is to investigate whether high-intensity focused ultrasound (HIFU) exposure is able to produce a fistula between the bladder and abdominal wall of a fetus with lower urinary tract obstruction (LUTO). MATERIALS AND METHODS: We constructed a prototype HIFU transducer in combination with an imaging probe. HIFU was applied to the lower abdomen of a rabbit neonate that was complicated by LUTO as an experimental model to produce a fistula; HIFU was applied in a tank filled with degassed water. Exposed lesions were assessed by histological analysis at necropsy. RESULTS: When HIFU was applied at 5.5 kW/cm(2) of spatial-peak temporal average intensity (SPTA), a fistula was created between the lower abdominal wall and the urinary bladder; urine gushed out from the bladder through the fistula within 60 s after HIFU exposure. CONCLUSION: The findings suggest that fetal diseases such as LUTO can be non-invasively treated using HIFU exposure from even outside the maternal body, though this study was performed in a water tank.

A case report of umbilical ring constriction with application of amnioinfusion.

This is a case report of a pregnant 38-year-old primigravida woman. Due to severe fetal growth restriction and oligohydramnios, she was referred to our tertiary perinatal center at 24 weeks' gestation. To rule out chromosomal abnormalities and facilitate ultrasound evaluation of fetal morphology, we performed amniocentesis and subsequent amnioinfusion. Thereafter, a precise ultrasound examination revealed no obvious fetal morphological abnormalities except for a hyper-coiled cord and marginal placenta previa. During expectant management, the amount of amniotic fluid was maintained at 20-26 mm for a few days; however, the pregnancy resulted in intrauterine fetal death after 26 weeks + 5 days of gestation. The stillborn infant weighed 530 g (-3.3 SD) and had no obvious external abnormalities apart from umbilical ring constriction. Although a postmortem autopsy was not performed, it is suspected that the fetal growth restriction and the intrauterine fetal death were associated with the hyper-coiled cord and the umbilical ring constriction. It is thought that umbilical ring constriction might therefore be an irreversible fatal condition in cases with a hyper-coiled cord.

Attitudes toward non-invasive prenatal diagnosis among pregnant women and health professionals in Japan.

OBJECTIVE: This study aims to assess the attitudes toward non-invasive prenatal diagnosis (NIPD) and NIPD problems in clinical practice in Japan. METHODS: A mail-in survey using a self-reported questionnaire was conducted among pregnant women and health professionals. The questionnaire enquired about attitudes, concerns, and expectations regarding NIPD. RESULTS: The responses from 252 respondents revealed that pregnant women have more positive attitudes toward NIPD than health professionals. In addition, there were wide discrepancies in concerns and expectations about NIPD, between medical professionals and pregnant women. The respondents with less NIPD knowledge had a more positive attitude toward the clinical application of NIPD. There was concern expressed by clinical geneticists whether an NIPD test should be performed or not when there is a lack of knowledge about the NIPD. All of the health professionals emphasized the importance of providing genetic counseling prior to and after the testing. CONCLUSION: Pregnant women place importance on the safety and non-invasiveness of the NIPD tests, whereas medical professionals consider the diagnostic accuracy and reliability of the test to be the most important. Health professionals pointed out that the tests might be frequently performed without the pregnant women having adequate knowledge or counseling.

Maternal cell-free messenger RNA in twin pregnancies: the effects of chorionicity and severe twin to twin transfusion syndrome (TTTS).

OBJECTIVE: To investigate the effects of chorionicity and severe twin to twin transfusion (TTTS) on maternal circulating cell-free messenger RNA (cf-mRNA). DESIGN: Prospective cohort study. SETTING: A UK tertiary referral Fetal Medicine Center. POPULATION: All monochorionic (MC) twins complicated by severe TTTS (n= 23) and a cohort of uncomplicated dichorionic (DC) (n= 10) and MC (n= 7) pregnancies, between October 2006 and December 2007. METHODS: Maternal cf-mRNA encoding glyceraldehyde 3-phosphate dehydrogenase (GAPDH), vascular endothelial growth factor receptor 1(VEGFR-1(Flt-1)), vascular endothelial growth factor A (VEGF-A), Endoglin, placental growth factor (PlGF), tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (Tie-1), angiopoietin 1 (Ang-1) and angiopoietin 2 (Ang-2) were measured by a quantitative two-step real-time PCR assay after extraction from maternal plasma. RESULTS: The amounts of cf-mRNA detectable are reported for uncomplicated DC, MC and TTTS pregnancies, respectively: GAPDH - 80, 100 and 96%; VEGFR-1 - 10, 0 and 26%; VEGF-A- 80, 71 and 96%; Endoglin-70, 71 and 91%; PlGF-70, 57, 26%; Tie-1 0, 43, 0%; Ang-1 71, 50 and 60% and Ang-2 83, 50 and 89%. There was a significant difference in VEGF-A (medians DC -337.3, MC - 390.8, TTTS - 618.6 copies/mL plasma p= 0.024), Endoglin (medians DC-14.49, MC-1171, TTTS - 2896 copies/mL plasma p= 0.027) and Ang-2 (medians DC-13.66, MC-8.49, TTTS 44.80 copies/mL plasma p= 0.007). CONCLUSION: Maternal cf-mRNA could be reliably detected for GAPDH, PlGF, VEGF-A, Endoglin, Ang-1 and Ang-2 in twin pregnancies and a significant difference was demonstrated in VEGF-A, Endoglin and Ang-2 between uncomplicated twins and MC twin pregnancies complicated by TTTS. If such alterations in maternal cf-mRNA precede the onset of clinically apparent disease, this may be used as an adjuvant blood test to complement ultrasound screening.

Amount of hemorrhage during vaginal delivery correlates with length from placental edge to external os in cases with low-lying placenta whose length between placental edge and internal os was 1-2 cm.

AIM: The aim of the present study was to investigate whether amount of hemorrhage during a vaginal delivery associates with the cervical length, length from the placental edge to the os and the sum of the two in cases with a low-lying placenta. MATERIAL AND METHODS: A retrospective study was performed on cases with low-lying placenta diagnosed at 35-36 weeks of gestation based on a distance of 1-2 cm from the lower placental edge to the internal os, and subject to the trial of labor. The total amount of intrapartum hemorrhage in association with the distance from the placental lowest edge to the internal os (placenta-internal os distance, A); cervical length, B; and sum of the two (placenta-external os distance; A + B) were reviewed from our medical records. RESULTS: Twenty-three cases of low-lying placenta that underwent trial of labor were analyzed. Twenty (87%) of 23 patients with low-lying placenta delivered transvaginally and patients underwent emergency cesarean section due to intrapartum bleeding. The length from the placental edge to the external os (length from placental edge to internal os + cervical length) was correlated significantly with the total amount of hemorrhage during delivery (r = -0.598, P = 0.004), though neither the length from the placental edge to the internal os nor the cervical lengths correlated with it. CONCLUSION: Our results suggest that the length from the placental lowest edge to the external os negatively correlated with the amount of hemorrhage during vaginal delivery, but did not correlate with cervical length and distance from the placental edge to the internal os.