吉澤 ひかり

BACKGROUND: When using assisted reproductive technology, there are cases where, despite the transfer of a good embryo, sometimes pregnancy may not be the case. Thus, during hormone replacement cycle implantation, it is important to synchronize the number of days of progesterone administration with the degree of embryo maturity. This study aimed to compare the outcomes of the administration of oral dydrogesterone for the duration of progestin use during the hormone replacement cycle for frozen-thawed blastocyst transfer. MATERIAL AND METHODS: The primary outcome of this study was the clinical pregnancy rate. We performed a retrospective cohort study of patients who underwent frozen-thawed blastocyst transfers between January 2017 and December 2024. According to our standard protocol, a vitrified-warmed blastocyst transfer was performed using dydrogesterone, which was administered orally at our center. A total of 554 cases were included in the study. Using the Gardner classification to evaluate the quality of blastocysts, grade AA was classified as the best quality, the AB/BA group as good quality, and the BB group as fair quality. We classified the 554 cases into 317 AA, 163 AB/BA, and 74 BB cases using the Gardner classification. Based on the duration of progestin administration, patients were divided into four groups: 120 hours (120 h), 132 hours (132 h), 144 hours (144 h), and 156 hours (156 h). We used the Shapiro-Wilk method and the Steel-Dwass test to determine whether there were differences in patients' background age and BMI among the four groups (120 h, 132 h, 144 h, and 156 h). We used Fisher's exact test and the Bonferroni method to determine whether there were differences in the final outcome of pregnancy rate between the four groups of 120 h, 132 h, 144 h, and 156 h. RESULTS: In the analysis of all embryos, the pregnancy rate at each timepoint of the primary evaluation was significantly higher in the 144-h group than in the 132-h group. Next, on analyzing the results by embryo grade, there was no difference in the pregnancy rate at each timepoint in the AA group. In the AB/BA group, the pregnancy rate was higher in the 144-h group than in the 132-h group. In the BB group, the pregnancy rate was higher in the 144-h group than in the 132-h group. CONCLUSION: This study clarified two aspects. First, the pregnancy rate in the 144-h group was significantly higher than that in the 132-h group in the analysis of all embryos. Second, the window of implantation may be more important for poor-quality embryos. This study showed that the oral administration of dydrogesterone requires a window of implantation of at least 144 hours.

OBJECTIVES: Nectin-4 is a cell adhesion molecule with vital functions at adherens and tight junctions. Cumulative evidence now indicates that the NECTIN4 gene is overexpressed in a variety of cancers, and that the nectin-4 protein is both a disease marker and therapeutic target in a subset of these cancers. We previously demonstrated that NECTIN4 is overexpressed in placenta during pre-eclamptic pregnancy, which is one of the most serious obstetric disorders. METHODS: Nectin-4 protein levels were measured in maternal sera from pregnant women with pre-eclampsia and its related disorder, unexplained fetal growth retardation. RESULTS: Maternal serum concentrations of nectin-4 were significantly elevated in pre-eclamptic women compared with those with an uncomplicated normotensive pregnancy. However, no increase was observed in pregnancies with unexplained fetal growth retardation. Serum nectin-4 levels were higher in cases with early-onset pre-eclampsia that generally showed more severe clinical symptoms, but levels were not correlated to other clinical indicators of disease severity. CONCLUSIONS: Nectin-4 is a potential new diagnostic and predictive biomarker for severe pre-eclampsia.

BACKGROUND: FLT1 is one of the significantly overexpressed genes found in a pre-eclamptic placenta and is involved with the etiology of this disease. METHODS: We conducted genome-wide expression profiling by RNA-seq of placentas from women with pre-eclampsia and those with normotensive pregnancy. RESULTS: We identified a lncRNA gene, MG828507, located ~80 kb upstream of the FLT1 gene in a head-to-head orientation, which was overexpressed in the pre-eclamptic placenta. MG828507 and FLT1 are located within the same topologically associated domain in the genome. The MG828507 mRNA level correlated with that of the FLT1 in placentas from pre-eclamptic women as well as in samples from uncomplicated pregnancies. However, neither the overexpression nor knockdown of MG828507 affected the expression of FLT1. Analysis of pre-eclampsia-linking genetic variants at this locus suggested that the placental genotype of one variant was associated with the expression of MG828507. The MG828507 transcript level was not found to be associated with maternal blood pressure, but showed a relationship with birth and placental weights, suggesting that this lncRNA might be one of the pivotal placental factors in pre-eclampsia. CONCLUSION: Further characterization of the MG828507 gene may elucidate the etiological roles of the MG828507 and FLT1 genes in pre-eclampsia in a genomic context.

Objectives: Alterations in the vaginal bacterial flora reflect the status of various obstetric conditions and are associated with mechanisms that underlie certain pregnancy-associated complications. These changes are also a predictive biomarker for clinical outcomes of these adverse events. Methods: We examined the vaginal microbiome in samples from pregnant Japanese women with preterm labor. Results: The microbiota composition in preterm delivery (PD) samples differed from those of control or threatened preterm delivery (TPD) samples in principal component analysis. An increase in Firmicutes and a decrease in Actinobacteria were significantly associated with PD only (both P<0.01). In the Firmicutes phylum, Lactobacillus tended to be abundant, and the abundance of L. iners and L. crispatus was especially high, whereas the L. gasseri population was low in PD samples. Longitudinal analysis showed that the abundance of L. iners decreased after commencing tocolytic treatment in TPD samples compared with before treatment, but it remained high in PD samples. Conclusions: The vaginal microbiome may be a useful prognostic indicator of preterm labor and a monitoring tool for tocolytic treatment to prevent preterm birth.

OBJECTIVE: The proprotein convertase furin is known to be involved in the processing of pro-B-type natriuretic peptide (proBNP) and prorenin receptor (PRR), suggesting that it has a potential function in blood pressure regulation. We investigated the role of furin in the etiology of pre-eclampsia and its related disorder, unexplained fetal growth restriction (FGR) without hypertension. METHODS: We evaluated serum and placental furin levels in pre-eclampsia, FGR and uncomplicated pregnancy. Additionally, we investigated the correlation between the serum furin levels and products of furin enzymatic activity or clinical parameters. RESULTS: We demonstrated that the maternal circulation in cases of pre-eclampsia and FGR had lower levels of soluble furin than uncomplicated pregnancies. Both NT-proBNP and soluble PRR were elevated in pre-eclampsia, whereas only soluble PRR was at higher levels in unexplained FGR. Linear regression analysis revealed a negative correlation between the serum furin level and that of NT-proBNP or soluble PRR. While we observed that the serum furin or soluble PRR level correlated with blood pressure, a stronger correlation was observed with birth and placental weights. Further to this, the FURIN mRNA levels were significantly reduced in placental pre-eclamptic placentas as well as in FGR cases. CONCLUSION: These data suggest the possibility that reduced levels of furin may be the result of a negative feedback from the activation of the renin-angiotensin pathway that leads to feto-placental dysfunction with or without maternal hypertension. This may represent an etiologic pathway of pre-eclampsia and unexplained FGR.

単一遺伝子疾患に対する着床前診断(PGT-M)は、胚を生検して得られた細胞に対し遺伝学的解析を行うことで、その遺伝情報を着床前に明らかにする技術である。その適応は、重篤な遺伝性疾患児を出産する可能性のある遺伝子変異を保因する場合とされているが、現在までに解析技術の進歩や新たな治療法の確立、また希少疾患診断数の増加など、その適応疾患を取り巻く環境は大きく変化している。したがって、PGT-Mの実施にあたっては、遺伝学的な診断・解析方法とともに倫理的な観点についても、十分に検討することが重要である。(著者抄録)

BACKGROUND: Soluble fms-like tyrosine kinase 1 (sFlt-1) is believed to be a prominent component in the pathogenesis of pre-eclampsia, although the precise etiology has remained elusive. In this study, the etiological role of FLT1 variant was further validated in pre-eclampsia by examining this association in a Japanese sample population. METHODS: The genotypes of three variants (rs4769613, rs12050029 and rs149427560) were examined in the upstream region of the FLT1 gene in placentas from pre-eclamptic (n=47) or normotensive control (n=49) pregnancy samples. Additionally, FLT1 mRNA levels in placenta were determined by qRT-PCR. ELISA was further used to detect circulating sFlt-1 levels in maternal sera. The intergroup comparisons were made using the Mann-Whitney U test or one way analysis of variance and P values of less than 0.05 were considered statistically significant. RESULTS: First, the rs4769613 (C>T) and rs12050029 (G>A) genotypes were examined in placentas but no significant differences were found in the genotype or allele-type frequencies. Next, nearby short tandem repeat, rs149427560, was examined which manifested four size variants. In the genotypewise analysis, the frequency of the 474/476 heterozygote was significantly lower in pre-eclampsia (p<0.05). As expected, the FLT1 mRNA levels were significantly elevated in the pre-eclamptic placentas and sFlt-1 was higher in pre-eclamptic maternal sera. However, the genotype of these variants did not affect the FLT1 mRNA or serum sFlt-1 levels. CONCLUSION: Our findings did not support the hypothesis that genetic variations around the FLT1 gene affect the subtle expression changes underlying the etiologic pathway of pre-eclampsia. The hypothesis deserves further investigation through a larger sample size.

第一分割異常胚の違いがその後の胚発生に影響を及ぼすかについて比較検討した。採卵し胚盤胞培養を行った胚のうち、タイムラプスモニタリングシステムでの観察により、第一分割で3割球以上となり、第一分割終了時のフラグメントが10%以下であった1135個の胚を対象とした。また、第一分割において正常分割が確認された9428個の胚を対照群とした。3核群は524個(46.2%)、2核群は611個(53.8%)であった。3核群、2核群の良好胚盤胞発生率はそれぞれ5.2%、26.0%となり、2核群が有意に高率であった。対照群の良好胚盤胞発生率は44.7%となり、3核群、2核群はともに対照群と比較すると有意に低率であった。凍結融解単一胚盤胞移植妊娠率はそれぞれ40.0%、46.9%であり、有意差を認めなかった。また、生産率はそれぞれ65.8%、83.3%であり、両群間で有意差を認めなかった。対照群の凍結融解単一胚盤胞移植妊娠率は47.2%、生産率は68.3%であり、いずれも有意差を認めなかった。

遺伝性乳癌卵巣癌症候群(以下HBOC:hereditary breast and ovarian cancer syndrome)はBRCA遺伝子の変異があり、乳癌や卵巣癌などに罹患するリスクが高い遺伝性腫瘍症候群の一つである。当施設では、HBOC関連癌のうち卵巣癌、卵管癌および腹膜癌の診療にあたり、卵巣癌未発症のBRCA変異保持者に対してサーベイランスおよびリスク低減卵管卵巣摘出術(以下RRSO:risk-reducing salpingo-oophorectomy)を提供している。今回は、HBOCに対してRRSOを施行した一例について考察を加えて報告する。【症例】47歳。2妊2産。子宮筋腫の既往あり。乳癌に罹患した姉にBRCA2遺伝子に変異を認めたことから、BRCA遺伝学的検査目的にカウンセリング室を来談し、検査の結果HBOCと診断され、RRSO施行の是非について相談のため産婦人科に紹介受診となった。患者はRRSO施行推奨年齢に達していたため、RRSOのメリットとデメリットを説明し、RRSOを行う方針となった。手術は腹腔鏡下で両側付属器切除を行い、切除検体については詳細な病理学的検討を行って、STIC(Serous tubal intraepithelial carcinoma)や浸潤癌がないことを確認した。術後は腹膜癌発症の有無を経過観察中である。HBOCは通常の産婦人科患者のうち一定の割合を占める比較的頻度の高い遺伝性腫瘍である。産婦人科医師はBRCA1/2変異保持者に対しては卵巣癌サーベイランスの限界、リスク低減手術の予想される効果と副作用を説明できる知識をもち、RRSOを行うにあたっては、卵巣癌の易罹患者であることを念頭においた手術操作、術後管理が必要である。(著者抄録)

Thanatophoric dysplasia and achondroplasia are allelic disorders caused by a constitutively active mutation in the FGFR3 gene. Because thanatophoric dysplasia is a lethal disorder and achondroplasia is non-lethal, they need to be distinguished after ultrasound identification of fetal growth retardation with short limbs. Accordingly, we have developed a noninvasive prenatal test using cell-free fetal DNA in the maternal circulation to distinguish thanatophoric dysplasia and achondroplasia. A multiplex PCR system encompassing five mutation hotspots in the FGFR3 gene allowed us to efficiently identify the responsible mutation in cell-free DNA in all examined pregnancies with a suspected thanatophoric dysplasia or achondroplasia fetus. This system will be helpful in the differential diagnosis of thanatophoric dysplasia and achondroplasia in early gestation and in couples concerned about the recurrence of thanatophoric dysplasia due to germinal mosaicism.