Published papers

近年,遺伝子解析の進歩に伴い,さまざまな疾患原因検索のためにエピゲノム解析が行われるようになった.妊娠糖尿病母体(GDM)から出生した児は将来の生活習慣病や肥満の発症リスクが高く,これらの原因として糖代謝に関連する遺伝子にエピゲノム変化が起こっていることが報告されている.本稿ではGDM母体から出生した児におけるエピゲノム変化について概説する.当院のデータではGDM母体から出生した児には明らかなエピゲノム変化は認めなかった.一方で,新生児低血糖例では新生児非低血糖例と比較して,GDM発症との関連が示唆されているZNF696のプロモーター領域が高メチル化状態となっていた.GDMにおけるエピジェネティクスを意識した管理とは,まさに次世代の健康を意識した管理であるといえる.いまだ課題はあるものの,新たな技術の開発により周産期医療は次世代の長期的な健康も担っていると認識すべき時代が到来したと考えられる.(著者抄録)

子宮頸がんに対する妊孕性温存術式としては子宮頸部円錐切除術および広汎子宮頸部摘出術があるが、術後妊娠例は早産ハイリスクである。また、子宮体がんに対する高用量黄体ホルモン療法は頻回な子宮内膜全面爬術の影響による癒着胎盤のリスクおよび肥満に伴う周産期合併症のリスクを伴う。各々の治療法は悪性腫瘍に対する治療というのみならず、妊孕性温存手術であるため、周産期リスクまでを念頭に置いたインフォームド・コンセントが重要である。(著者抄録)

血流評価にあたっては常に最適なドプラ波形を描出するよう心がける.臍帯動脈拡張末期途絶疑い例ではwall motion filterの設定に注意し,途絶の有無を慎重に判断する.中大脳動脈血流評価ではドプラウインドウ幅およびドプラ入射角に注意する.胎児発育不全例において子宮動脈血流異常を認める場合には,妊娠高血圧症候群の発症に留意する.(著者抄録)

広汎性子宮頸部摘出術後妊娠では早産期前期破水や子宮頸部静脈叢からの出血に留意する。また、残存子宮頸管長測定は早産発症リスクの評価に有用であると考えられるため、特に妊娠中期(妊娠21～23週時)の残存子宮頸管長短縮例では注意して管理を行う。(著者抄録)

腹式広汎性子宮頸部摘出術後妊娠は早産のハイリスクである.preterm PROMと絨毛膜羊膜炎は腹式広汎性子宮頸部摘出術後妊娠における妊娠34週未満の早産リスク因子である.腹式広汎性子宮頸部摘出術後妊娠では,残存頸部静脈叢からの異常出血に注意する必要がある.(著者抄録)

広汎性子宮頸部摘出術後妊娠は早産のハイリスクである.広汎性子宮頸部摘出術後妊娠では,頸管拡張術などの頸管縫縮糸が断裂する可能性のある処置を極力回避する.広汎性子宮頸部摘出術後妊娠では,妊娠中期以降に子宮頸部静脈叢からの大量出血を生じることがある.(著者抄録)

＜文献概要＞はじめに　子宮筋腫,子宮腺筋症,子宮内膜症は生殖年齢女性で合併する代表的な婦人科良性疾患である。晩婚化および出産年齢の高齢化に伴い,これら疾患罹病女性の妊娠成立例も多い。また,若年女性における子宮頸部上皮内腫瘍(cervical intraepithelial neoplasia:CIN)および子宮頸がん患者も増加傾向にあり,今後,CINおよび頸がん治療後妊娠例の増加も予想される。本稿では,子宮筋腫,子宮腺筋症,子宮内膜症合併,およびCIN3(高度異形成,上皮内がん)に対する治療後妊娠の留意点について概説する。

Germline variants in ARID1A have been associated with the so-called BAFopathies, including Coffin-Siris syndrome, which is characterized by hypertrichosis, short fifth finger, thin upper lip, and thick lower lip, is associated with a unique episignature. Hydrocephalus has not been considered part of BAFopathy until recently, when ARID1A variants were implicated in prenatal-onset hydrocephalus. It remains unknown whether ARID1A-associated hydrocephalus is linked to a specific class of variants and whether it exhibits an episignature comparable to that of BAFopathies. We conducted genomic and epigenomic analyses on a fetus diagnosed with severe hydrocephalus on prenatal ultrasound at 19 weeks. After detailed genetic counseling, the pregnancy was terminated at 21 weeks. The delivered fetus exhibited short fifth fingers, thin upper lip, and thick lower lip. Postmortem exome sequencing using umbilical cord blood identified a de novo heterozygous frameshift variant in the last exon of ARID1A (NM_006015.6:c.5259_5262dupGTCT, p.(Ser1755Valfs∗2)). The frameshift variant in the last exon was expected to escape nonsense-mediated mRNA decay (NMD), and we did confirm this through RNA-seq. Concurrent episignature analysis by nanopore sequencing and a support vector machine-based classifier showed that the fetus maps to the BAFopathy group rather than a separate position on the UMAP. Genotype-phenotype correlation analysis of unpublished data from previous reports regarding hydrocephalus and potential NMD escape, with input from the original authors, indicated that the association remains ambiguous. Hence, ARID1A-associated hydrocephalus occurs within the broader clinical and epigenomic spectrum of BAFopathies, but a distinct genetic mechanism caused by NMD escape is unlikely to play a role.

既報の新基準妊娠糖尿病(GDM)の臨床像は、旧基準でのデータベース解析をもとに推測されたものが多く、基準改定後の実際の臨床像に関して十分な知見は得られていない。そこでわれわれは、基準改定後に当院にて妊娠初期から周産期管理を行った単胎妊婦853例を対象に、GDMの臨床像について後方視的検討を行った。853例中GDM例は101例(11.8%)、overt diabetesは3例(0.3%)であった。さらに経口糖負荷試験(OGTT)陽性ポイント数に関して、OGTT 1点陽性例は69例(68%)、2点/3点陽性例は32例(2点陽性例:24例、3点陽性例:8例)であった。また101例中55例は妊娠初期スクリーニングにて検出された。分娩までの血糖コントロールに関して、OGTT 1点陽性例に比べてOGTT 2点/3点陽性例のインスリン導入率は有意に高値であった(20%vs.84%、p<0.05)。なお、OGTT 1点陽性例のなかでは、糖尿病家族歴を有する場合にインスリン療法を要する頻度が高率であった。本検討により、OGTT 1点陽性例はGDMの過半数を占めることが示され、糖尿病家族歴を有するOGTT 1点陽性例では、インスリン療法を要する可能性を念頭においた周産期管理が必要と考えられた。(著者抄録)

Objective: This study aimed to describe the perinatal and neonatal outcomes of chronic abruption oligohydramnios sequence in the Kanto region of Japan. Methods: This survey was conducted at 123 perinatal centers affiliated to this area. Data on the experience of managing chronic abruption oligohydramnios sequence between 1 January 2017, and 31 December 2022, were collected and analyzed. Results: Among the 82 cases of chronic abruption oligohydramnios sequence that were included in this study, there were seven miscarriages, five artificial abortions, and 70 deliveries beyond 22 gestational weeks (singleton: 68; twin: 2). In 82 patients, vaginal bleeding was the initial symptom of chronic abruption oligohydramnios sequence (88%). The mean gestational duration at the initial symptom onset was 17.3 ± 5.0 weeks. Of the 68 singleton pregnancies delivered after 22 gestational weeks, the mean gestational duration at delivery was 25.2 ± 2.8 weeks. In patients with chronic abruption oligohydramnios sequence, the mean white blood cell count at diagnosis and mean of the maximum white blood cell count during pregnancy were 11,589 ± 2885 and 15,357 ± 4745/μL, respectively; and the mean C-reactive protein at diagnosis and mean of the maximum C-reactive protein during pregnancy were 1.0 ± 1.2 and 2.0 ± 2.1 mg/L, respectively. Chorioamnionitis was identified in 43 patients (63%). All neonates were admitted to the neonatal intensive care unit. Of the 68 singleton neonates, 5 died immediately after birth. Conclusions: Chronic abruption oligohydramnios sequence is a rare perinatal complication that is possibly associated with infections, such as chorioamnionitis, and linked to adverse perinatal and neonatal outcomes.

Aims/Introduction: We evaluated a simple diagnostic gestational diabetes mellitus (GDM) strategy (Japanese COVID-19 GDM strategy) published by the Japanese Society of Diabetes and Pregnancy using GDM group data from the Diabetes and Pregnancy Outcomes for Mother and Baby (DREAMBee) study. Materials and Methods: The study included 803 mothers with GDM diagnosed after 24 gestational weeks using an oral glucose tolerance test and 1,356 with normal glucose tolerance (NGT) from the DREMBee study. They were reclassified by the Japanese COVID-19 GDM strategies (COVID-19 GDM and COVID-19 NGT) using glycated hemoglobin (HbA1c) and random plasma glucose or fasting plasma glucose (FPG) levels. We evaluated the usefulness of the Japanese COVID-19 GDM strategy and investigated the parameters for diagnosing GDM managed with insulin therapy. Results: Participants (n = 2,159) were assigned to COVID-19 GDM (n = 413) and COVID-19 NGT (n = 1,746) groups. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the Japanese COVID-19 GDM strategy were 35.4, 90.5, 68.9, and 70.3%, respectively. When the risk factors for insulin therapy were analyzed using a regression model, HbA1c and FPG levels were risk factors for GDM with insulin therapy (P < 0.0001). The cut-off value of HbA1c was 5.4% (sensitivity, 0.69; specificity, 0.66; PPV, 0.11; NPV, 0.97), and that of FPG was 86 mg/dL (sensitivity, 0.60; specificity, 0.77; PPV, 0.16; NPV, 0.96). Conclusions: The Japanese COVID-19 GDM strategy for GDM diagnosis after 24 weeks of gestation might be useful in emergency situations. However, further analysis of GDM outcomes diagnosed using this approach is necessary.

Childhood obesity is a substantial health problem worldwide. The origin of obesity (increased adiposity) can be partly traced back to intrauterine life. However, the determinants of fetal fat deposition remain unclear. This study investigated the association between cord blood adipocytokines related to lipid metabolism (leptin, adiponectin, and insulin-like growth factor-1 [IGF-1]) and fetal adiposity during gestation. A prospective study was conducted in a cohort of 94 singleton pregnancies. Fetal ultrasonography was performed at 24, 30, and 36 weeks of gestation. Estimated fetal adiposity (EFA) was calculated by integrating measurements of cross-sectional arm and thigh fat area percentages and anterior abdominal wall thickness. Plasma cytokine levels and C-peptide immunoreactivity (as a proxy for fetal insulin resistance) were evaluated in cord blood samples obtained at delivery. The associations of cord blood leptin, adiponectin and IGF-1 levels with EFA at 24, 30, and 36 weeks were determined by multiple linear regression, adjusted for potential covariates. The multivariate analyses indicated that leptin was significantly correlated with EFA at 30 and 36 weeks. Leptin was also positively correlated with C-peptide immunoreactivity in the umbilical cord. Cord adiponectin levels were not associated with EFA across gestation. Cord IGF-1 levels were significantly correlated with EFA and estimated fetal body weight (EFW) at 36 weeks. In conclusion, cord leptin was associated with EFA at 30 and 36 weeks, and IGF-1 was associated with EFA at 36 and EFW at 36 weeks. In Conclusion, cord leptin was associated with EFA at 30 and 36 weeks, and IGF-1 was associated with EFA and EFW at 36 weeks. Considering the effects of leptin and IGF-1 on fetal insulin resistance and lipid metabolism, increased levels of leptin and IGF-1 are potential plasma biomarkers of increased fetal adiposity, which may predispose to infant obesity and metabolic dysfunction in later life.

Mirror syndrome is a rare obstetric condition characterized by maternal fluid retention mirroring fetal hydrops. Placental ectopic liver tissue is an extremely rare non-trophoblastic placental tumor, potentially arising from aberrant hepatoblast migration. While its association with fetal hydrops has been reported, the clinical significance remains uncertain. We present a patient of maternal mirror syndrome linked to fetal hydrops due to a de novo SOS1 variant, with histopathological identification of placental ectopic liver tissue. A 32-year-old woman was admitted at 31 weeks’ gestation with fetal hydrops, presenting with bilateral pleural effusions, ascites, and subcutaneous edema. Due to worsening maternal pleural effusion, she was transferred to our hospital at 31 weeks and 6 days. Given progressive maternal and fetal deterioration, an emergency cesarean section was performed at 32 weeks due to concerns regarding maternal mirror syndrome. The female infant was delivered with severe respiratory distress and succumbed at 9 days of age. Trio-based exome sequencing identified a de novo heterozygous SOS1 variant (NM_005633.4:c.512T > A [p.V171G]), confirming a postmortem diagnosis of Noonan syndrome. Histopathological analysis of the placenta revealed ectopic liver tissue within the villi, confirmed by positive immunostaining for hepatocyte markers. A recent report of RIT1-associated mirror syndrome and non-immune hydrops fetalis (NIHF) further supports the role of Rasopathies in the pathogenesis of mirror syndrome. Our findings confirm that mirror syndrome is a potential manifestation of Rasopathies, while the role of ectopic liver tissue in the placenta remains uncertain. Future research should focus on genetic factors underlying mirror syndrome rather than incidental placental anomalies.