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Aim To assess whether FOXL2 p. C134W mutation may play a role in the development of human ovarian tumors in the Japanese, we investigated the FOXL2 codon 134 mutation and protein expression of inhibin-α, bone morphogenetic protein 2 ( BMP2) and follistatin ( FST) in Japanese patients with granulosa cell tumor ( GCT) of the ovary and other ovarian tumors. Methods We analyzed 114 tumor tissues from ovarian tumors, including 44 adult-type and two juvenile-type GCT of the ovary and 68 ovarian tumors by DNA sequencing. Immunohistochemistry was also performed in the adult and juvenile GCT tissues by immunostaining inhibin-α, BMP2 and FST. Results We found the FOXL2 p. C134W mutation in 27 out of 44 (61.4%) adult-type GCT of the ovary, but none in other ovarian tumors. Histologically, all of the adult-type GCT sections were positive for inhibin-α, and the expression of BMP2 and FST was detected in 14 of 44 (31.8%) and zero of 47 (0%), respectively. No significant differences regarding the diagnosed age, preoperative serum carbohydrate antigen 125 levels, or BMP2 immunopositivity between the FOXL2 p. C134W mutation-positive and mutation-negative were found in the adult-type GCT patients. Conclusion Our findings suggest that FOXL2 p. C134W mutation-positive adult-type GCT of the ovary may not be common in the Japanese as compared to the previous data. [ABSTRACT FROM AUTHOR]

Background: To assess applicability of noninvasive methods for prenatal sex determination, both intact fetal cells and cell-free DNA from maternal blood were studied. Methods: Maternal peripheral blood samples were obtained from 41 women carrying chromosomally normal fetuses and from 3 women with aneuploid fetuses (47,XX,+18; 47,XY,+18 and 47,XY,+21) at 9-22 weeks of gestation. DNA was extracted from the plasma fraction and analyzed by the nested polymerase chain reaction (PCR) using Y chromosome specific primers. After fetal cells were enriched by MACS, fluorescence in situ hybridization (FISH) with chromosome X and Y specific probes was performed to detect XY cells. Results: Although Y-chromosome-specific DNA was detected by PCR analysis in all maternal plasma samples with male fetuses, 26% women bearing female fetuses also gave positive results. By FISH analysis, XY cells were detected in not only 58% of women bearing male fetuses, but also 13% of their counterpoints with female fetuses. Conclusions: Our findings suggested that consistent results for fetal gender using PCR or FISH cannot be obtained with intact fetal cells and cell-free DNA present in maternal blood and plasma at 9-22 weeks of gestation, despite their apparent abundant presence. [ABSTRACT FROM AUTHOR]

Assesses variations in proteolytic enzyme cathepsin D levels in peritoneal fluid and serum from women with endometriosis by enzyme-linked immunosorbent assay. Implications for the therapeutic efficacy of gonadotrophin-releasing hormone agonists; Stage distribution of endometriosis patients during surgery; Correlation of cathepsin D levels with tumor invasiveness.

We examined the influence of confined placental mosaicism (CPM) as a cause of fetal growth restriction (FGR), and whether CPM can be screened using cell-free DNA (cfDNA) analysis of the maternal plasma. We analyzed cfDNA in the maternal plasma of 40 FGR cases with an estimated fetal weight of less than − 2.0 SD using massively parallel sequencing to detect chromosomal aberrations. Fetal and placental genotyping was performed to confirm CPM cases. cfDNA analyses of maternal plasma detected suspected CPM cases with chromosomal aneuploidy or copy number variations in 5 of 40 cases (12.5%). For 4 cases in which the entire placenta consisted of cells with chromosomal abnormalities, fetal growth was severely restricted. CPM can be screened by cfDNA analysis in maternal plasma, accounting for approximately 10% of the causes of moderate or severe FGR, and the higher the proportion of abnormal karyotype cells in the placenta, the more severe the placental dysfunction and FGR. [ABSTRACT FROM AUTHOR]

Objective: To determine the predictive value of preconceptional peripheral blood natural killer (pNK) cell activity in patients with recurrent pregnancy loss (RPL). Design: Cohort study. Setting: University department. Patient(s): A total of 552 patients with a history of two to six consecutive miscarriages. Intervention(s): None. Main Outcome Measure(s): The predictive value of preconceptional pNK cell activity for subsequent miscarriage was analyzed using multivariable logistic regression analysis, with age, number of previous miscarriages, and presence/absence of previous live births and bed rest as covariates. Result(s): Age and number of previous miscarriages, but not high pNK cell activity, were found to be independent risk factors for a subsequent miscarriage. No effect of bed rest and previous live birth on the likelihood of live birth was observed (odds ratios 1.28 [95% confidence interval 0.81–2.02] and 0.91 [0.52–1.59], respectively). Conclusion(s): Elevated pNK cell activity was found to not be an independent risk factor for subsequent miscarriage. Clinicians should not measure the plasma NK activity as a systematic recurrent pregnancy loss examination, because its clinical significance is yet to be established. [Copyright &y& Elsevier]

Objective: To investigate whether polymorphisms at the promoter or 5′-untranslated region of annexin A5 gene (ANXA5) influence miscarriage. Design: Case-control study and nested case-control study. Setting: Hospitals. Patient(s): A total of 264 patients with two to nine recurrent pregnancy losses (RPLs) and 195 fertile control subjects. Intervention(s): None. Main Outcome Measure(s): The frequency of six single-nucleotide polymorphisms (SNPs) of the ANXA5 gene in RPL patients versus control subjects, and subsequent live birth rate with and without risk alleles in RPL patients. Result(s): The minor allele was significantly more frequent in RPL patients than in control subjects for SNP5 (rs1050606). The live birth rates of patients with and without risk alleles of SNP5 were 84.0% and 84.3%, respectively, after excluding cases with abnormal embryonic karyotype, with no significant difference. Conclusion(s): The variations with the ANXA5 gene upstream region, especially SNP5, were confirmed to be risk factors of RPL. However, presence/absence of the ANXA5 risk allele did not have any predictive effect for subsequent pregnancy outcome. This was the first study indicating the influence of ANXA5 SNP5 for pregnancy outcome. [ABSTRACT FROM AUTHOR]

Primordial ovarian follicles in mice form when somatic cells surround individual oocytes. We show that lack of Nobox, an oocyte-specific homeobox gene, accelerates postnatal oocyte loss and abolishes the transition from primordial to growing follicles in mice. Follicles are replaced by fibrous tissue in female mice lacking Nobox in a manner similar to nonsyndromic ovarian failure in women. Genes preferentially expressed in oocytes, including Oct4 and Gdf9, are down-regulated in Nobox[sup -/-] mice, whereas ubiquitous genes such as Bmp4, Kit, and Bax remain unaffected. Therefore, Nobox is critical for specifying an oocyte-restricted gene expression pattern essential for postnatal follicle development. [ABSTRACT FROM AUTHOR]

Aim: In Japan, noninvasive prenatal testing (NIPT) has been performed by facilities accredited by the Japanese Society of Obstetrics and Gynecology since 2013. However, since 2016, with the implementation of NIPT, which can only be performed by blood sampling, non-obstetricians have been involved in prenatal testing. Therefore, in July 2022, a new government-involved NIPT certification system based on Health Sciences Council guidelines was introduced to ensure access to prenatal testing information for pregnant women., Methods: This survey was conducted in February 2023 and was the first survey after the certification system implementation. We conducted a web-based survey of 1227 pregnant women and nursing mothers who underwent NIPT after July 2022 to evaluate their experiences., Results: Respondents were categorized by certification status as certified (C: 56%), non-certified (non-C: 23%), or uncertain (Q: 20%). The C group with a higher mean age at examination (35.0 ± 4.5 years) paid lower examination fees, received longer pre- and post-examination explanations, and underwent more weekday examinations (80%) than the other groups. Most respondents, 67%, 48%, and 53% in the C, non-C, and Q groups, respectively (p < 0.0001), stated that "NIPT needs to be regulated by the government or academic societies." The non-C group was more likely to say, "Insufficient post-test explanations at the laboratory made me more anxious," than the other groups when the testing results were non-negative (p = 0.015)., Conclusions: Despite government regulation, some pregnant women choose convenience over certified facilities, risking inadequate care. The government should ensure that NIPT is a safe option for all pregnant women., (© 2024 Japan Society of Obstetrics and Gynecology.)

The incidence of chromosomal abnormalities in twin pregnancies is not well-studied. In this retrospective study, we investigated the frequency of chromosomal abnormalities in twin pregnancies and compared the incidence of chromosomal abnormalities in dichorionic diamniotic (DD) and monochorionic diamniotic (MD) twins. We used data from 57 clinical facilities across Japan. Twin pregnancies of more than 12 weeks of gestation managed between January 2016 and December 2018 were included in the study. A total of 2899 and 1908 cases of DD and MD twins, respectively, were reported, and the incidence of chromosomal abnormalities in one or both fetuses was 0.9% (25/2899) and 0.2% (4/1908) in each group (p = 0.004). In this study, the most common chromosomal abnormality was trisomy 21 (51.7% [15/29]), followed by trisomy 18 (13.8% [4/29]) and trisomy 13 (6.9% [2/29]). The incidence of trisomy 21 in MD twins was lower than that in DD twins (0.05% vs. 0.5%, p = 0.007). Trisomy 21 was less common in MD twins, even when compared with the expected incidence in singletons (0.05% vs. 0.3%, RR 0.15 [95% CI 0.04-0.68]). The risk of chromosomal abnormality decreases in twin pregnancies, especially in MD twins., (© 2021. The Author(s).)

Aims: Noninvasive prenatal testing (NIPT) of pregnant women has been performed worldwide since 2011, and it is currently performed in more than 90 countries. However, the rate of adoption in Japan remains at less than 2%. This review seeks to identify the ethical and practical issues surrounding noninvasive prenatal screening-including the purpose of the test, its pros and cons, issues surrounding fair treatment, and social factors-to better understand why the adoption rate remains low., Methods: This study examines the complex ethical issues surrounding noninvasive prenatal testing, including the purpose of the test, its pros and cons, issues related to fair treatment, and social factors., Results: Although cell-free DNA analysis for common fetal trisomies using maternal blood is highly accurate, lack of access to such testing and discriminatory attitudes in society remain important barriers. Personal choices such as whether to undergo noninvasive prenatal screening and whether to continue a pregnancy are sometimes criticized by those who believe that it leads to the "selection of life" or discrimination against people with disabilities., Conclusions: Obstetrics has changed dramatically in recent years, and prenatal diagnosis technology has also advanced. To keep up with these advances, better information should be provided to ensure the public has a more nuanced understanding of the screening beyond the overused argument that it leads to "selection of life.", (© 2021 Japan Society of Obstetrics and Gynecology.)

Objective: Maternal characteristics and neonatal outcomes associated with cell-free DNA (cfDNA) results were analysed retrospectively to assess the details of false-positive and false-negative results after initial blood sampling in non-invasive prenatal testing (NIPT)., Study Design: A multicentre retrospective study was performed for women undergoing NIPT who received discordant cfDNA results between April 2013 and March 2018. The NIPT data obtained using massive parallel sequencing were studied in terms of maternal background, fetal fraction, z-scores, invasive procedure results and neonatal outcomes after birth., Results: Of the 56,545 women who participated in this study, 54 false-positive (0.095 %) and three false-negative (0.006 %) cases were found. Seven of the 54 false-positive cases (13.0 %) had vanishing twin on ultrasonography. Among the 18 false-positive cases of trisomy 18, confined placental mosaicism (CPM) was confirmed in three cases (16.7 %), while CPM was present in one of the three false-negative cases of trisomy 21., Conclusion: These data suggest that the incidence of women with false-positive or false-negative results is relatively low, that such false results can often be explained, and that vanishing twin and CPM are potential causes of NIPT failure. Genetic counselling with regard to false results is important for clients prior to undergoing NIPT., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Noninvasive prenatal testing (NIPT) has been performed worldwide to detect common fetal chromosomal aneuploidies., Methods: Pregnant women (n=3743) with advanced maternal age who visited Nagoya University for NIPT were enrolled in this study. The K6 mental stress scores, that is non-specific psychological distress scores were obtained by questionnaires which were administered pre-NIPT and postpartum. High K6 scores (≥10) indicate anxiety or depression. The K6 stress scores at pre-NIPT and postpartum were evaluated about the relationship between mode of conception and non-specific psychological distress using binomial logistic regression., Results: In general, 7.5% of pre-NIPT women (179/2393) and 5.1% of postpartum women (121/n) were found with high K6 scores. They also did not differ significantly based on maternal age, previous live birth, previous miscarriage, and mode of conception, i.e. , natural conception, artificial insemination with husband (AIH), or assisted reproductive technology (ART). Moreover, the prenatal K6 scores were not significantly higher than those at postpartum., Conclusion: Our present data suggest that mental distress in women undergoing NIPT during pregnancy and after birth has no statistical relationship with maternal age, previous live birth, previous miscarriage, or infertility treatment, and continuous mental care may help reduce mental distress in the postpartum period., Competing Interests: Conflict of Interest None of the authors had any personal or financial conflicts of interest., (Copyright© 2020, Avicenna Research Institute.)

The data collected by nation-wide study of noninvasive prenatal genetic testing (NIPT) for trisomy 21 from 21,610 pregnant women with advanced maternal age in Japan were reported. Among 188 NIPT-positive cases, 180 cases were true positive. The incidence of aneuploidy according to maternal age was estimated using a state-space model. Although, the frequency of trisomy increased exponentially with maternal age as previously reported, the maternal age-specific risk for trisomy 21 that was based on the clinical performance of NIPT was lower than the predicted risk in previous Western cohorts based on the data from invasive prenatal testing (Bayesian two-sided tail-area probability P = 0.0156). The empirical positive predictive value (PPV) of NIPT is likely to turn out higher than that of the theoretical PPV calculated from the sensitivity/specificity of the test and the incidence of trisomy 21 from this study.

Objective: The purpose of this study is to compare the fetal fractions during non-invasive prenatal testing (NIPT) in singleton pregnancies according to gestational age and maternal characteristics to evaluate the utility of this parameter for the prediction of pregnancy complications including gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy (HDP)., Study Design: This study was a multicenter prospective cohort study. The present data were collected from women whose NIPT results were negative. The relationships between the fetal fractions and the gestational age, maternal weight and height, and incidences of miscarriage, preterm delivery, and pregnancy complications including GDM, HDP and placental abruption were assessed., Results: A total of 5582 pregnant women with verified NIPT negative results were registered in the study. The demographic characteristics of the study populations were statistically analyzed, and the women with HDP tended to have a low fetal fraction in samples taken during early gestation. The area under the curve (AUC) in a receiver operating characteristic curve (ROC) analysis was 0.608 for women with HDP., Conclusion: A low fetal fraction on NIPT might be correlated with future HDP. However, predicting HDP during early pregnancy in women with a low fetal fraction might be difficult., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aim: The purpose of this study was to clarify the characteristics of psychological mental distress in post-partum women after non-invasive prenatal testing (NIPT) in Japan., Methods: Psychological mental distress was assessed using the Kessler Psychological Distress Scale (K6). We compared patients with (i) low pre-NIPT K6 and low post-partum K6 scores (control group), and (ii) low pre-NIPT K6 and a high post-partum K6 scores (case group)., Results: Among the 697 women who underwent NIPT, 29 (4.2%) had low pre-NIPT K6 and high post-partum K6 scores (case group) and 668 (95.8%) had low pre-NIPT K6 and low post-partum K6 scores (control). Among women with negative NIPT findings, post-partum women with a high K6 score were compared to a control group of women with a low K6 score. Logistic regression analysis showed that primiparity (P = 0.007), low birthweight (P = 0.005) and use of intracytoplasmic sperm injection (P = 0.02) and assisted reproductive technology (P = 0.05) were significantly different between the groups., Conclusion: Even if women do not feel mental distress before NIPT, they may develop mental stress post-partum. In particular, primipara women who conceived through assisted reproductive technology (especially intracytoplasmic sperm injection) and gave birth to a low birthweight baby were more susceptible to developing post-partum distress. Thus, it is important to educate women that support is available, with consultation with other healthcare professionals during genetic counseling if necessary. Further studies are needed in order to determine the factors associated with post-partum mental distress., (© 2017 Japan Society of Obstetrics and Gynecology.)

Parental decision-making to terminate or continue a pregnancy was studied after prenatal diagnosis of a chromosome aneuploidy among a sample of patients around the city of Nagoya, Japan. A total of 1,051 amniocentesis cases at 15-18 weeks of gestation were analyzed. Of these, 60 cases of chromosomal anomalies with aneuploidies were diagnosed by conventional cytogenetic analysis. Of the 45 diagnoses of autosomal chromosome aneuploidies, pregnancy was terminated in 93.3 % of the cases. Of the 15 cases diagnosed with sex chromosome aneuploidy, pregnancy was terminated in 46.7 %. Differences in parental decisions with respect to maternal age, gestational week at diagnosis, number of pregnancies per individual and existing number of children were not significant in patients diagnosed either with autosomal or sex chromosome aneuploidy. The findings indicate that when diagnosed with a chromosome aneuploidy in which a severe prognosis was expected, most couples decided to terminate the pregnancy in Japan. Implications of these findings for expanding the profession of genetic counseling are discussed and research recommendations are provided.

Oocyte meiosis and early mitotic divisions in developing embryos rely on the timely production of cell cycle regulators and their clearance via proteasomal degradation. Ret Finger Protein-Like 4 (Rfpl4), encoding a RING finger-like protein with a B30.2 domain, was discovered during an in silico search for germ cell-specific genes. To study the expression and functions of RFPL4 protein, we performed immunolocalizations and used yeast two-hybrid and other protein-protein interaction assays. Immunohistochemistry and immunofluorescence showed that RFPL4 accumulates in all growing oocytes and quickly disappears during early embryonic cleavage. We used a yeast two-hybrid model to demonstrate that RFPL4 interacts with the E2 ubiquitin-conjugating enzyme HR6A, proteasome subunit beta type 1, ubiquitin B, as well as a degradation target protein, cyclin B1. Coimmunoprecipitation analyses of in vitro translated proteins and extracts of transiently cotransfected Chinese hamster ovary (CHO)-K1 cells confirmed these findings. We conclude that, like many RING-finger containing proteins, RFPL4 is an E3 ubiquitin ligase. The specificity of its expression and these interactions suggest that RFPL4 targets cyclin B1 for proteasomal degradation, a key aspect of oocyte cell cycle control during meiosis and the crucial oocyte-to-embryo transition to mitosis.