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染色体異常を伴わない胎児臍帯ヘルニアの2例

木村由実子, 玉井順子, 春日義史, 秋田啓介, 田中邦生, 葉室明香, 福間優花, 長谷川慶太, 大谷利光, 池ノ上学, 青木大輔, 田中守

東京産科婦人科学会会誌（(一社)東京産科婦人科学会） 72 （ 2 ） 327 - 331 2023年04月

ISSN 2186-0599

緒言:今回我々は染色体異常を伴わない胎児臍帯ヘルニアの2例の周産期管理を行ったので報告する.症例1は41歳,1妊0産.体外受精-胚移植により妊娠成立し,妊娠13週に臍帯ヘルニアを指摘された.症例2は40歳,1妊0産.自然妊娠にて妊娠成立し,妊娠12週に胎児腹部腫瘤を指摘された.いずれも妊娠16週の羊水検査で正常核型であり,超音波断層法では肝脱出型臍帯ヘルニアと単一臍帯動脈以外の形態異常は指摘されなかった.出生後の精査にて症例1は食道閉鎖,鎖肛,軟口蓋裂,左多合指症等を認めたためVATER連合,症例2は耳介の形態や高インスリン血症からBeckwith-Wiedemann症候群が疑われた.結論:染色体異常を伴っていない臍帯ヘルニアでは,他の症候群の1症候であり出生後に判明する場合があることを念頭に胎児の慎重な観察と家族への十分な説明を行うことが望ましいと考えられた.(著者抄録)

Ultrasonographic Prediction of Placental Invasion in Placenta Previa by Placenta Accreta Index

Hasegawa K., Ikenoue S., Tanaka Y., Oishi M., Endo T., Sato Y., Ishii R., Kasuga Y., Ochiai D., Tanaka M.

Journal of Clinical Medicine （Journal of Clinical Medicine） 12 （ 3 ） 2023年02月

ISSN 2077-0383

This study aimed to investigate the diagnostic accuracy of the placenta accreta index (PAI) for predicting placenta accreta spectrum (PAS) in women with placenta previa. We analyzed 33 pregnancies with placenta previa at Keio University Hospital. The PAI was assessed in the early third trimester, and PAS was diagnosed histologically or clinically defined as retained placenta after manual removal attempts. The PAI and incidence of PAS were analyzed. Ten women (30%) were diagnosed with PAS and had higher volumes of perioperative bleeding (p = 0.016), higher rate of requiring uterine artery embolization (p = 0.005), and peripartum hysterectomy (p = 0.0002) than women without PAS. A PAI > 2 was the most useful cut-off point for predicting PAS and was more sensitive than prediction values using traditional evaluation (history of cesarean section and placental location). Post-hoc analysis revealed a higher rate of previous history of cesarean delivery (30% vs. 4.4%, p = 0.038), severe placental lacunae (≥grade2) (70% vs. 8.7%, p = 0.0003), thin myometrial thickness (90% vs. 22%, p = 0.0003), anterior placenta (100% vs. 30%, p = 0.0002), and presence of bridging vessels (30% vs. 0%, p = 0.0059) in PAS women. PAI could help predict the outcomes of women with placenta previa with and without a history of cesarean delivery to reduce PAS-induced perinatal complications.

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Obstetric outcomes after medroxyprogesterone acetate treatment for early stage endometrial cancer or atypical endometrial hyperplasia: a single hospital-based study.

Oishi M, Kasuga Y, Fukuma Y, Hamuro A, Tamai J, Tanaka Y, Hasegawa K, Yoshimura T, Ikenoue S, Ochiai D, Yamagami W, Tanaka M

International journal of clinical oncology （International Journal of Clinical Oncology） 28 （ 4 ） 587 - 591 2023年01月

ISSN 1341-9625

Background: To investigate perinatal outcomes in pregnancy after high-dose medroxyprogesterone acetate (MPA) therapy for early stage endometrial cancer (EC) and atypical endometrial hyperplasia (AEH) and to determine whether pregnancy after MPA therapy is at a higher risk of placenta accreta. Methods: Data of 51 pregnancies in 46 women who received MPA therapy for EC or AEH and delivered after 22 weeks of gestation at Keio University Hospital were reviewed. A retrospective matched case–control study was performed to determine the risk of placenta accreta in pregnancy after MPA therapy compared with singleton pregnancies without any history of maternal malignancy treatments. Results: The incidence of placenta accreta was higher in the MPA group than in the control group (15.7 vs. 0%, p = 0.0058). However, no differences in other perinatal outcomes were observed between groups. While gestational weeks at delivery in the MPA group were later than those in the control group (p = 0.0058), no difference in the incidence of preterm delivery was recorded between groups. In the MPA therapy group, the number of patients who underwent ≥ 6 dilation and curettage (D&C) was higher in the placenta accreta group than in the non-placenta accreta group (50.0 vs. 14.0%, p = 0.018). Patients with ≥ 6 D&Cs demonstrated a 6.0-fold increased risk of placenta accreta (p = 0.043, 95% CI 1.05–34.1) than those receiving ≤ 3 D&Cs. Conclusion: Pregnancy after MPA therapy is associated with a high risk of placenta accreta. In cases in which the frequency of D&C is high, placenta accreta should be considered.

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Pregnancy outcomes and vaccine effectiveness during the period of omicron as the variant of concern, INTERCOVID-2022: a multinational, observational study.

Villar J, Soto Conti CP, Gunier RB, Ariff S, Craik R, Cavoretto PI, Rauch S, Gandino S, Nieto R, Winsey A, Menis C, Rodriguez GB, Savasi V, Tug N, Deantoni S, Fabre M, Martinez de Tejada B, Rodriguez-Sibaja MJ, Livio S, Napolitano R, Maiz N, Sobrero H, Peterson A, Deruelle P, Giudice C, Teji JS, Casale RA, Salomon LJ, Prefumo F, Cheikh Ismail L, Gravett MG, Vale M, Hernández V, Sentilhes L, Easter SR, Capelli C, Marler E, Cáceres DM, Albornoz Crespo G, Ernawati E, Lipschuetz M, Takahashi K, Vecchiarelli C, Hubka T, Ikenoue S, Tavchioska G, Bako B, Ayede AI, Eskenazi B, Thornton JG, Bhutta ZA, Kennedy SH, Papageorghiou AT, INTERCOVID-2022 International Consortium

Lancet (London, England) （The Lancet） 401 （ 10375 ） 447 - 457 2023年01月

ISSN 0140-6736

Background: In 2021, we showed an increased risk associated with COVID-19 in pregnancy. Since then, the SARS-CoV-2 virus has undergone genetic mutations. We aimed to examine the effects on maternal and perinatal outcomes of COVID-19 during pregnancy, and evaluate vaccine effectiveness, when omicron (B.1.1.529) was the variant of concern. Methods: INTERCOVID-2022 is a large, prospective, observational study, involving 41 hospitals across 18 countries. Each woman with real-time PCR or rapid test, laboratory-confirmed COVID-19 in pregnancy was compared with two unmatched women without a COVID-19 diagnosis who were recruited concomitantly and consecutively in pregnancy or at delivery. Mother and neonate dyads were followed until hospital discharge. Primary outcomes were maternal morbidity and mortality index (MMMI), severe neonatal morbidity index (SNMI), and severe perinatal morbidity and mortality index (SPMMI). Vaccine effectiveness was estimated, adjusted by maternal risk profile. Findings: We enrolled 4618 pregnant women from Nov 27, 2021 (the day after WHO declared omicron a variant of concern), to June 30, 2022: 1545 (33%) women had a COVID-19 diagnosis (median gestation 36·7 weeks [IQR 29·0–38·9]) and 3073 (67%) women, with similar demographic characteristics, did not have a COVID-19 diagnosis. Overall, women with a diagnosis had an increased risk for MMMI (relative risk [RR] 1·16 [95% CI 1·03–1·31]) and SPMMI (RR 1·21 [95% CI 1·00–1·46]). Women with a diagnosis, compared with those without a diagnosis, also had increased risks of SNMI (RR 1·23 [95% CI 0·88–1·71]), although the lower bounds of the 95% CI crossed unity. Unvaccinated women with a COVID-19 diagnosis had a greater risk of MMMI (RR 1·36 [95% CI 1·12–1·65]). Severe COVID-19 symptoms in the total sample increased the risk of severe maternal complications (RR 2·51 [95% CI 1·84–3·43]), perinatal complications (RR 1·84 [95% CI 1·02–3·34]), and referral, intensive care unit (ICU) admission, or death (RR 11·83 [95% CI 6·67–20·97]). Severe COVID-19 symptoms in unvaccinated women increased the risk of MMMI (RR 2·88 [95% CI 2·02–4·12]) and referral, ICU admission, or death (RR 20·82 [95% CI 10·44–41·54]). 2886 (63%) of 4618 total participants had at least a single dose of any vaccine, and 2476 (54%) of 4618 had either complete or booster doses. Vaccine effectiveness (all vaccines combined) for severe complications of COVID-19 for all women with a complete regimen was 48% (95% CI 22–65) and 76% (47–89) after a booster dose. For women with a COVID-19 diagnosis, vaccine effectiveness of all vaccines combined for women with a complete regimen was 74% (95% CI 48–87) and 91% (65–98) after a booster dose. Interpretation: COVID-19 in pregnancy, during the first 6 months of omicron as the variant of concern, was associated with increased risk of severe maternal morbidity and mortality, especially among symptomatic and unvaccinated women. Women with complete or boosted vaccine doses had reduced risk for severe symptoms, complications, and death. Vaccination coverage among pregnant women remains a priority. Funding: None.

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Pregnancy outcomes following radical trachelectomy for early-stage cervical cancer: A retrospective observational study in the Kanto area, Japan

Kasuga Y., Hasegawa K., Hamuro A., Fukuma Y., Tamai J., Tanaka Y., Ikenoue S., Tanaka M.

International Journal of Gynecology and Obstetrics （International Journal of Gynecology and Obstetrics） 2023年

ISSN 00207292

Objective: The authors aimed to investigate the prevalence of pregnancy and obstetric outcomes in patients who underwent radical trachelectomy (RT) for early-stage cervical cancer in the Kanto area, Japan. Method: A survey among 113 perinatal centers affiliated with the Kanto Society of Obstetrics and Gynecology was conducted to investigate their experience in managing pregnancies following RT, between 2010 and 2020. The association between preterm delivery (before 34 gestational weeks) and a midtrimester short cervix (<13 mm) was evaluated. Results: The authors retrospectively collected maternal and perinatal data from 13 hospitals. There were 135 pregnancies among 115 women following RT. Of the 135 pregnancies, 32 were miscarriages (<12 gestational weeks: n = 22; >12 gestational weeks: n = 10), and 103 were delivered after 22 gestational weeks. The incidences of preterm delivery before 28 and 34 gestational weeks were 8.7% and 30.1%, respectively. A midtrimester short residual cervix was associated with preterm delivery (P = 0.046). Conclusion: Since more than 100 pregnancies were recorded after RT in the Kanto area, many physicians had more opportunities to manage pregnancy after RT. Pregnancy following RT is associated with increased risk of preterm delivery, and midtrimester short residual cervix is a good predictor of preterm delivery.

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Risk factors of neonatal hypoglycemia in neonates born to mothers with gestational diabetes

Arimitsu T., Kasuga Y., Ikenoue S., Saisho Y., Hida M., Yoshino J., Itoh H., Tanaka M., Ochiai D.

Endocrine Journal （Endocrine Journal） 70 （ 5 ） 511 - 517 2023年

ISSN 09188959

Hypoglycemia is one of the most significant problems in neonates born to mothers with gestational diabetes (GDM). This study aimed to identify novel predictors of hypoglycemia in neonates born to mothers with GDM. A total of 443 term singleton infants from mothers diagnosed with GDM and cared for at Keio University Hospital between January 2013 and December 2019 were included in this study. Neonatal hypoglycemia was defined as hypoglycemia of less than 47 mg/dL at 1 or 2 or 4 h after birth, according to previous studies. Among 443 full-term singleton neonates born to mothers with GDM, 200 developed hypoglycemia (45%). Gestational weight gain (GWG), HbA1c at 1st trimester, HbA1c at GDM diagnosis, and the incidence of insulin therapy in the neonatal hypoglycemia group were significantly higher than those in the non-neonatal hypoglycemia group (p = 0.016, p = 0.032, p = 0.011, and p = 0.017, respectively). Regarding the multiple regression analysis adjusted for nulliparity, GWG, and gestational weeks at delivery, the odds ratio for maternal HbA1c ≥5.2% at 1st trimester was 1.63 (p = 0.034), and maternal insulin therapy during pregnancy was 1.72 (p = 0.015). In conclusion, HbA1c in the 1st trimester and insulin therapy during pregnancy were good predictors of hypoglycemia in neonates born to GDM mothers, especially when their HbA1c was 5.2% or more. Further research will be necessary to improve the perinatal management of hypoglycemia.

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Factors associated with low birthweight among late preterm singletons in Japan using pregnancy birth registry data

Kasuga Y., Tanaka K., Akita K., Tamai J., Hamuro A., Fukuma Y., Hasegawa K., Ikenoue S., Tanaka M.

Journal of Developmental Origins of Health and Disease （Journal of Developmental Origins of Health and Disease） 1 - 7 2023年

ISSN 20401744

Late preterm (LP, born between 34 0/7 and 36 6/7 weeks of gestation) infants may experience several adverse outcomes, similar to those experienced by low birthweight (LBW, birthweight <2500 g) infants. However, while LP infants are often born with LBW, the association between LP and LBW remains unknown. This study aimed to investigate LBW rate and independent risk factors for LBW in LP singleton neonates. We retrospectively analyzed data of LP singleton neonates, born between 2013 and 2017, from the Japan Society of Obstetrics and Gynecology Successive Pregnancy Birth Registry System. The exclusion criteria included stillbirths and infants with missing data. Logistic regression analyses were performed to investigate maternal and perinatal factors associated with LBW in LP singletons. LBW was observed in 62.5% (n = 35,113) of 56,160 LP singleton births. In the multiple logistic regression analysis, LBW in LP neonates was independently associated with modifiable maternal factors, including pre-pregnancy underweight, inadequate gestational weight gain, and smoking during pregnancy, as well as non-modifiable factors, including younger maternal age, nulliparity, hypertensive disorder of pregnancy, preeclampsia, cesarean section delivery, and female offspring. According to the Japanese pregnancy birth registry data, more than half of LP neonates were LBW. We previously discussed the issue of LBW regarding infants with different backgrounds, as there are many different causes of LBW. Several risk factors should be subdivided and considered for the risk of LP and LBW.

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Fetal growth restriction and a single umbilical artery are independent predictors of hypospadias during pregnancy

Endo T., Iida M., Ichihashi Y., Oishi M., Ikenoue S., Kasuga Y., Sato T., Hida M., Ishii T., Asanuma H., Hasegawa T., Tanaka M., Ochiai D.

Placenta （Placenta） 130 53 - 59 2022年12月

ISSN 01434004

Introduction: Little is known about the association between hypospadias and small fetuses, as well as the pathological implications of fetal growth restriction (FGR). Thus, we aimed to investigate the association between hypospadias and small fetuses using a database of fetal ultrasound and obstetric events. Methods: A cohort of male singleton infants delivered after 22 weeks of gestation at Keio University Hospital between 2013 and 2019 was retrospectively reviewed. FGR was defined according to the Delphi criteria. Logistic regression analysis was performed to identify the significant predictors of hypospadias. Placental pathology was reviewed in cases with hypospadias. Results: Of the 2,040 male infants included in the present study, 23 had hypospadias. The prevalences of a single umbilical artery (SUA), small for gestational age, maternal hypertensive disorders of pregnancy, and a small placenta, were significantly higher in infants with hypospadias. Multiple logistic regression analysis revealed that FGR (odds ratio [OR] = 9.39; 95% confidence interval [CI], 2.50–35.3) and the presence of a SUA (OR = 33.4; 95% CI, 8.00–139.5) were independently and significantly associated with hypospadias. When FGR was stratified by the time of onset, its association with hypospadias was significant regardless of the time of onset. Moreover, placental histological findings suggested that fetal vascular malperfusion might play a role in hypospadias. Discussion: FGR and SUAs are independent prenatal predictors of the development of hypospadias, and fetal vascular malperfusion of the placenta may be involved in the etiology of hypospadias.

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Exponential increase of the gestational-age-specific incidence of preeclampsia onset (COPE study): a multicenter retrospective cohort study in women with maternal check-ups at <20 weeks of gestation in Japan

Ohkuchi A., Suzuki H., Matsubara K., Watanabe K., Saitou T., Oda H., Obata S., Kondo S., Noda K., Miyoshi J., Ikenoue S., Nomiyama M., Seki H., Sukegawa S., Ichigo S., Ando H., Fuseya C., Shimomura T., Suzuki R., Mimura K., Yasuhi I., Fukuda M., Hara S., Kurashina R., Shiozaki A., Matsubara S., Saito S.

Hypertension Research （Hypertension Research） 45 （ 11 ） 1679 - 1689 2022年11月

ISSN 09169636

According to the 2004 Japanese definition, early-onset (EO) preeclampsia (PE) is defined as PE occurring at <32 weeks of gestation. This was based on the presence of “dual peaks” (30–31 and 34–35 weeks) in the prevalence of severe forms of hypertension. In contrast, the international definition adopted a cutoff of 34 weeks based on the consensus. Our aim was to investigate whether there were “dual peaks” in the gestational-age-specific incidence or prevalence of PE onset in pregnant women who underwent maternal check-ups at <20 weeks of gestation in a multicenter retrospective cohort study. Diagnoses of PE and superimposed preeclampsia (SPE) were based on the new Japanese definition. A total of 26,567 pregnant women with singleton pregnancy were investigated. The best fitting equations for the distribution of the onset of gestational-age-specific incidence (hazard) rates of PE/SPE, PE, and PE with severe hypertension (a systolic blood pressure ≥160 and/or a diastolic blood pressure ≥110 mmHg) were investigated using the curve estimation function in SPSS. PE/SPE occurred in 1.83% of the patients. EO-PE/SPE with onset at <32 and <34 weeks of gestation and preterm PE/SPE occurred in 0.38, 0.56, and 1.07% of the patients, respectively. Gestational-age-specific incidence rates of PE/SPE, PE, and PE with severe hypertension showed exponential increases, with very high R2 values (0.975, 0.976, and 0.964, respectively). There were no “dual peaks” in the prevalence rates of women with SPE/PE, PE, and PE with severe hypertension. In conclusion, the absence of “dual peaks” refutes the previous rationale of EO-PE being defined as PE at <32 weeks of gestation. Further studies to determine an appropriate definition of EO-PE/SPE are needed.

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Effects of prenatal exposure to maternal COVID-19 and perinatal care on neonatal outcome: results from the INTERCOVID Multinational Cohort Study

Giuliani F., Oros D., Gunier R.B., Deantoni S., Rauch S., Casale R., Nieto R., Bertino E., Rego A., Menis C., Gravett M.G., Candiani M., Deruelle P., García-May P.K., Mhatre M., Usman M.A., Abd-Elsalam S., Etuk S., Napolitano R., Liu B., Prefumo F., Savasi V., Do Vale M.S., Baafi E., Ariff S., Maiz N., Aminu M.B., Cardona-Perez J.A., Craik R., Tavchioska G., Bako B., Benski C., Hassan-Hanga F., Savorani M., Sentilhes L., Carola Capelli M., Takahashi K., Vecchiarelli C., Ikenoue S., Thiruvengadam R., Soto Conti C.P., Cetin I., Nachinab V.B., Ernawati E., Duro E.A., Kholin A., Teji J.S., Easter S.R., Salomon L.J., Ayede A.I., Cerbo R.M., Agyeman-Duah J., Roggero P., Eskenazi B., Langer A., Bhutta Z.A., Kennedy S.H., Papageorghiou A.T., Villar J.

American Journal of Obstetrics and Gynecology （American Journal of Obstetrics and Gynecology） 227 （ 3 ） 488.e1 - 488.e17 2022年09月

ISSN 00029378

Background: The effect of COVID-19 in pregnancy on maternal outcomes and its association with preeclampsia and gestational diabetes mellitus have been reported; however, a detailed understanding of the effects of maternal positivity, delivery mode, and perinatal practices on fetal and neonatal outcomes is urgently needed. Objective: To evaluate the impact of COVID-19 on fetal and neonatal outcomes and the role of mode of delivery, breastfeeding, and early neonatal care practices on the risk of mother-to-child transmission. Study Design: In this cohort study that took place from March 2020 to March 2021, involving 43 institutions in 18 countries, 2 unmatched, consecutive, unexposed women were concomitantly enrolled immediately after each infected woman was identified, at any stage of pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed up until hospital discharge. COVID-19 in pregnancy was determined by laboratory confirmation and/or radiological pulmonary findings or ≥2 predefined COVID-19 symptoms. The outcome measures were indices of neonatal and perinatal morbidity and mortality, neonatal positivity and its correlation with mode of delivery, breastfeeding, and hospital neonatal care practices. Results: A total of 586 neonates born to women with COVID-19 diagnosis and 1535 neonates born to women without COVID-19 diagnosis were enrolled. Women with COVID-19 diagnosis had a higher rate of cesarean delivery (52.8% vs 38.5% for those without COVID-19 diagnosis, P<.01) and pregnancy-related complications, such as hypertensive disorders of pregnancy and fetal distress (all with P<.001), than women without COVID-19 diagnosis. Maternal diagnosis of COVID-19 carried an increased rate of preterm birth (P≤.001) and lower neonatal weight (P≤.001), length, and head circumference at birth. In mothers with COVID-19 diagnosis, the length of in utero exposure was significantly correlated to the risk of the neonate testing positive (odds ratio, 4.5; 95% confidence interval, 2.2–9.4 for length of in utero exposure >14 days). Among neonates born to mothers with COVID-19 diagnosis, birth via cesarean delivery was a risk factor for testing positive for COVID-19 (odds ratio, 2.4; 95% confidence interval, 1.2–4.7), even when severity of maternal conditions was considered and after multivariable logistic analysis. In the subgroup of neonates born to women with COVID-19 diagnosis, the outcomes worsened when the neonate also tested positive, with higher rates of neonatal intensive care unit admission, fever, gastrointestinal and respiratory symptoms, and death, even after adjusting for prematurity. Breastfeeding by mothers with COVID-19 diagnosis and hospital neonatal care practices, including immediate skin-to-skin contact and rooming-in, were not associated with an increased risk of newborn positivity. Conclusion: In this multinational cohort study, COVID-19 in pregnancy was associated with increased maternal and neonatal complications. Cesarean delivery was significantly associated with newborn COVID-19 diagnosis. Vaginal delivery should be considered the safest mode of delivery if obstetrical and health conditions allow it. Mother-to-child skin-to-skin contact, rooming-in, and direct breastfeeding were not risk factors for newborn COVID-19 diagnosis, thus well-established best practices can be continued among women with COVID-19 diagnosis.

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Diabetes mellitus, maternal adiposity, and insulin-dependent gestational diabetes are associated with COVID-19 in pregnancy: the INTERCOVID study

Eskenazi B., Rauch S., Iurlaro E., Gunier R.B., Rego A., Gravett M.G., Cavoretto P.I., Deruelle P., García-May P.K., Mhatre M., Usman M.A., Elbahnasawy M., Etuk S., Napolitano R., Deantoni S., Liu B., Prefumo F., Savasi V., Marques P.F., Baafi E., Zainab G., Nieto R., Serrano B., Aminu M.B., Cardona-Perez J.A., Craik R., Winsey A., Tavchioska G., Bako B., Oros D., Benski C., Galadanci H., Savorani M., Oberto M., Sentilhes L., Risso M., Takahashi K., Vecciarelli C., Ikenoue S., Pandey A.K., Soto Conti C.P., Cetin I., Nachinab V.B., Ernawati E., Duro E.A., Kholin A., Firlit M.L., Easter S.R., Sichitiu J., John-Akinola Y., Casale R., Cena H., Agyeman-Duah J., Roggero P., Langer A., Bhutta Z.A., Kennedy S.H., Villar J., Papageorghiou A.T.

American Journal of Obstetrics and Gynecology （American Journal of Obstetrics and Gynecology） 227 （ 1 ） 74.e1 - 74.e16 2022年07月

ISSN 00029378

Background: Among nonpregnant individuals, diabetes mellitus and high body mass index increase the risk of COVID-19 and its severity. Objective: This study aimed to determine whether diabetes mellitus and high body mass index are risk factors for COVID-19 in pregnancy and whether gestational diabetes mellitus is associated with COVID-19 diagnosis. Study Design: INTERCOVID was a multinational study conducted between March 2020 and February 2021 in 43 institutions from 18 countries, enrolling 2184 pregnant women aged ≥18 years; a total of 2071 women were included in the analyses. For each woman diagnosed with COVID-19, 2 nondiagnosed women delivering or initiating antenatal care at the same institution were also enrolled. The main exposures were preexisting diabetes mellitus, high body mass index (overweight or obesity was defined as a body mass index ≥25 kg/m2), and gestational diabetes mellitus in pregnancy. The main outcome was a confirmed diagnosis of COVID-19 based on a real-time polymerase chain reaction test, antigen test, antibody test, radiological pulmonary findings, or ≥2 predefined COVID-19 symptoms at any time during pregnancy or delivery. Relationships of exposures and COVID-19 diagnosis were assessed using generalized linear models with a Poisson distribution and log link function, with robust standard errors to account for model misspecification. Furthermore, we conducted sensitivity analyses: (1) restricted to those with a real-time polymerase chain reaction test or an antigen test in the last week of pregnancy, (2) restricted to those with a real-time polymerase chain reaction test or an antigen test during the entire pregnancy, (3) generating values for missing data using multiple imputation, and (4) analyses controlling for month of enrollment. In addition, among women who were diagnosed with COVID-19, we examined whether having gestational diabetes mellitus, diabetes mellitus, or high body mass index increased the risk of having symptomatic vs asymptomatic COVID-19. Results: COVID-19 was associated with preexisting diabetes mellitus (risk ratio, 1.94; 95% confidence interval, 1.55–2.42), overweight or obesity (risk ratio, 1.20; 95% confidence interval, 1.06–1.37), and gestational diabetes mellitus (risk ratio, 1.21; 95% confidence interval, 0.99–1.46). The gestational diabetes mellitus association was specifically among women requiring insulin, whether they were of normal weight (risk ratio, 1.79; 95% confidence interval, 1.06–3.01) or overweight or obese (risk ratio, 1.77; 95% confidence interval, 1.28–2.45). A somewhat stronger association with COVID-19 diagnosis was observed among women with preexisting diabetes mellitus, whether they were of normal weight (risk ratio, 1.93; 95% confidence interval, 1.18–3.17) or overweight or obese (risk ratio, 2.32; 95% confidence interval, 1.82–2.97). When the sample was restricted to those with a real-time polymerase chain reaction test or an antigen test in the week before delivery or during the entire pregnancy, including missing variables using imputation or controlling for month of enrollment, the observed associations were comparable. Conclusion: Diabetes mellitus and overweight or obesity were risk factors for COVID-19 diagnosis in pregnancy, and insulin-dependent gestational diabetes mellitus was associated with the disease. Therefore, it is essential that women with these comorbidities are vaccinated.

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Human Amniotic Fluid Stem Cells Ameliorate Thioglycollate-Induced Peritonitis by Increasing Tregs in Mice

Abe Y., Ochiai D., Taguchi M., Kanzaki S., Ikenoue S., Kasuga Y., Tanaka M.

International Journal of Molecular Sciences （International Journal of Molecular Sciences） 23 （ 12 ） 2022年06月

ISSN 16616596

Mesenchymal stem cells (MSCs) affect immune cells and exert anti-inflammatory effects. Human amniotic fluid stem cells (hAFSCs), a type of MSCs, have a high therapeutic effect in animal models of inflammation-related diseases. hAFSCs can be easily isolated and cultured from amniotic fluid, which is considered a medical waste. Hence, amniotic fluid can be a source of cells for MSC therapy of inflammatory diseases. However, the effect of hAFSCs on acquired immunity in vivo, especially on regulatory T cells, has not yet been fully elucidated. Therefore, in this study, we aimed to understand the effects of hAFSCs on acquired immunity, particularly on regulatory T cells. We showed that hAFSCs ameliorated the thioglycollate-induced inflammation by forming aggregates with host immune cells, such as macrophages, T cells, and B cells in the peritoneal cavity. Further, the regulatory T cells increased in the peritoneal cavity. These results indicated that, in addition to helping the innate immunity, hAFSCs could also aid the acquired immune system in vivo against inflammation-related diseases by increasing regulatory T cells.

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The associated factors of low birthweight among term singletons in Japan: a pregnancy birth registry analysis.

Kasuga Y, Iida M, Tanaka Y, Tamagawa M, Hasegawa K, Ikenoue S, Sato Y, Tanaka M, Ochiai D

Journal of epidemiology 2022年04月

ISSN 0917-5040

BackgroundProgress in reducing the global low birthweight (LBW) has been insufficient. Although the focus has been on preventing preterm birth, evidence regarding LBW in term births is limited. Despite its low preterm birth prevalence, Japan has a higher LBW proportion than other developed countries. This study aimed to examine the prevalence of LBW in term singleton births and its associated factors using a national database.MethodsWe retrospectively analyzed the data of neonates registered in the Japan Society of Obstetrics and Gynecology Successive Pregnancy Birth Registry System who were born 2013-2017. Exclusion criteria included stillbirths, delivery after 42 gestational weeks, and missing data. Logistic regression analyses were performed to investigate the maternal and perinatal factors associated with LBW in term singletons using the data of 715 414 singleton neonates.ResultsThe overall prevalence of LBW was 18.3%, and 35.7% of LBWs originated from singleton term pregnancies. Multiple logistic regression analyses indicated that both modifiable and non-modifiable factors were independently associated with LBW in term neonates. The modifiable maternal factors included pre-pregnancy underweight, inadequate gestational weight gain, and smoking during pregnancy, while the non-modifiable factors included younger maternal age, nulliparity, hypertensive disorders of pregnancy, cesarean section delivery, female offspring, and congenital anomalies.ConclusionsUsing the Japanese pregnancy birth registry data, more than one-third of LBWs were found to originate from singleton term pregnancies. Both modifiable and non-modifiable factors were independently associated with LBW in term neonates. Prevention strategies on modifiable risk factor control will be effective in reducing LBW worldwide.

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切迫早産管理中に肺血栓塞栓症を発症した1例

緒形恵, 田中雄也, 春日義史, 内田志穂, 明石一浩, 池ノ上学, 西尾浩, 落合大吾, 青木大輔, 田中守

東京産科婦人科学会会誌（(一社)東京産科婦人科学会） 71 （ 2 ） 349 - 354 2022年04月

ISSN 2186-0599

緒言:肺血栓塞栓症(Pulmonary Thromboembolism:PTE)は母体死亡の7%に認める予後不良な疾患である。今回我々は切迫早産管理中にPTEを発症した1例を経験したので報告する。症例:42歳、2妊0産、妊娠29週4日に切迫早産の診断で入院した。安静度は病棟内フリーとした。妊娠33週3日、ベッドより離床した際に呼吸苦、動悸、脱力感を自覚し、胸部造影CTで両側肺動脈本幹および末梢に多数の造影欠損を認めたことから急性PTEと診断した。発症当日に緊急帝王切開術を施行し、児は2010gの女児、Apgar scoreは9/10点(1/5分値)であった。術後1日目より抗凝固療法を開始し、経過良好にて術後23日目に退院した。結論:安静臥床としていない切迫早産でもPTEを発症する可能性が示唆され、入院期間が長期になる場合はPTE発症に留意する必要があると考えられた。(著者抄録)

DNA methylation analysis of cord blood samples in neonates born to gestational diabetes mothers diagnosed before 24 gestational weeks

Kasuga Y., Kawai T., Miyakoshi K., Hori A., Tamagawa M., Hasegawa K., Ikenoue S., Ochiai D., Saisho Y., Hida M., Tanaka M., Hata K.

BMJ Open Diabetes Research and Care （BMJ Open Diabetes Research and Care） 10 （ 1 ） 2022年01月

Introduction Genome-wide methylation analyses of gestational diabetes mellitus (GDM) diagnosed after 24 gestational weeks (late GDM (L-GDM)) using cord blood have been reported. However, epigenetic changes in neonates born to mothers with GDM diagnosed before 24 gestational weeks (early GDM (E-GDM)) have not been reported. We investigated DNA methylation in neonates born to mothers with E-GDM using cord blood samples. Research design and methods Genome-wide DNA methylation analysis was performed using an Illumina EPIC array to compare methylation rates of 754 255 autosomal sites in cord blood samples from term neonates born to 162 mothers with GDM (E-GDM: n=84, L-GDM: n=78) and 60 normal glucose tolerance (normal OGTT) pregnancies. GDM was diagnosed based on Japan Society of Obstetrics and Gynecology criteria modified with International Association of Diabetes in Pregnancy Study Group criteria. In this study, all GDM mothers underwent dietary management, while self-monitoring of blood glucose and insulin administration was initiated when dietary modification did not achieve glycemic control. Results There were no significant differences in genome-wide DNA methylation of cord blood samples between the GDM (E-GDM and L-GDM) groups and normal OGTT group or between the E-GDM and normal OGTT groups, L-GDM and normal OGTT groups, and E-GDM and L-GDM groups. Conclusions This is the first report to determine the DNA methylation patterns in neonates born to mothers with E-GDM. Neonates born to mothers with GDM, who were diagnosed based on Japan Society of Obstetrics and Gynecology criteria, may not differ in DNA methylation compared with those born to normal OGTT mothers.

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Prophylactic administration of human amniotic fluid stem cells suppresses inflammation-induced preterm birth via macrophage polarization

Abe Y., Ochiai D., Kanzaki S., Sato Y., Otani T., Ikenoue S., Kasuga Y., Tanaka M.

Molecular and Cellular Biochemistry （Molecular and Cellular Biochemistry） 478 （ 2 ） 363 - 374 2022年

ISSN 03008177

Ascending inflammation from the vagina is a major cause of preterm birth. Currently, this condition—especially when uncontrolled—has no effective treatment. Human amniotic fluid stem cells (hAFSCs) are mesenchymal stem cells known to exert potent anti-inflammatory effects in animal models of perinatal diseases, such as periventricular leukomalacia, myelomeningocele, and neonatal sepsis. However, hAFSC therapy for inflammation-induced preterm birth has not been tested. In order to determine the therapeutic effect of hAFSC transplantation, we employed a preterm mouse model of ascending infection; this model was constructed by administering lipopolysaccharide to pregnant mice. We investigated the preterm birth rate and evaluated the inflammation of tissues, which is related to progressive infections, such as those involving the cervix, placenta, and lavage cells, using real-time qPCR. Further, we tracked the fluorescence of fluorescently labeled hAFSCs using an in vivo imaging system, and hAFSC aggregation was evaluated using immunohistochemistry analysis. We also investigated the presence of multiple types of peritoneal macrophages via flow cytometry analysis. Finally, we performed sphere culturing and co-culturing to determine the therapeutic effects of hAFSCs, such as their anti-inflammatory effects and their potential to alter macrophage polarization. We found that hAFSC administration to the peritoneal cavity significantly reduced inflammation-induced preterm birth in the mouse model. The treatment also significantly suppressed inflammation of the placenta and cervix. Transplanted hAFSCs may have aggregated with peritoneal macrophages, switching them from an inflammatory to an anti-inflammatory type. This property has been reported in vivo previously, but here, we examined the effect in vitro. Our findings support the hypothesis that hAFSCs suppress inflammation and reduce preterm birth by switching macrophage polarity. This study is the first to demonstrate that hAFSCs are effective in the treatment and prevention of inflammation-induced preterm birth.

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Maternal insulin resistance in pregnancy is associated with fetal fat deposition: findings from a longitudinal study

Ikenoue S., Waffarn F., Sumiyoshi K., Ohashi M., Ikenoue C., Tanaka M., Gillen D.L., Buss C., Entringer S., Wadhwa P.D.

American Journal of Obstetrics and Gynecology （American Journal of Obstetrics and Gynecology） 228 （ 4 ） 455.e1 - 455.e8 2022年

ISSN 00029378

Background: Newborns exhibit substantial variation in fat mass accretion over gestation. These individual differences in newborn adiposity extend into infancy and childhood and relate to subsequent risk of obesity and metabolic dysregulation. Maternal glucose homeostasis in pregnancy has been proposed as an underlying mechanism; however, the timing in gestation when maternal glucose regulation influences the progression of fetal fat deposition remain unclear. Objective: This study aimed to investigate the cross-sectional and longitudinal association of maternal insulin resistance in early, mid, and late pregnancy with fetal fat deposition in uncomplicated pregnancies. We hypothesized that maternal insulin resistance at early, mid, and late gestation is positively associated with fetal fat deposition, and that the magnitude of the association is greater for the mid and late gestation measures than for the early gestation measure. Study Design: In a longitudinal study of 137 low-risk pregnancies, a fasting maternal blood sample was obtained and fetal ultrasonography was performed at ≈ 12, 20, and 30 weeks’ gestation. Maternal insulin resistance was quantified using the homeostasis model assessment of insulin resistance (fasting insulin×fasting glucose/405). Estimated fetal adiposity was calculated by integrating measurements of cross-sectional arm and thigh percentage fat area and anterior abdominal wall thickness. The associations between maternal homeostasis model assessment of insulin resistance and estimated fetal adiposity and estimated fetal weight were determined by multiple linear regression adjusted for potential confounding factors including maternal age, parity, race and ethnicity, prepregnancy body mass index, gestational weight gain per week, fetal sex, and gestational age at assessments. Results: Maternal homeostasis model assessment of insulin resistance at ≈ 12, 20, and 30 weeks was 2.79±1.79 (±standard deviation), 2.78±1.54, and 3.76±2.30, respectively. Homeostasis model assessment of insulin resistance at 20 weeks was positively associated with estimated fetal adiposity at 20 weeks (r=0.261; P=.005). Homeostasis model assessment of insulin resistance at 20 weeks (r=0.215; P=.011) and 30 weeks (r=0.285; P=.001) were also positively associated with estimated fetal adiposity at 30 weeks. These relationships remained significant after adjustment for confounding factors. There was no significant correlation between homeostasis model assessment of insulin resistance and estimated fetal weight at 20 and 30 weeks’ gestation. Conclusion: In low-risk pregnancies, maternal insulin resistance at mid and late but not early pregnancy is significantly associated with fetal adiposity but not with fetal weight. Maternal insulin resistance in mid-gestation could provide a basis for risk identification and interventions that target child adiposity.

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Impaired early phase insulin secretion associated with gestational diabetes mellitus in underweight women

Kasuga Y., Miyakoshi K., Saisho Y., Ikenoue S., Ochiai D., Tanaka M.

Journal of Maternal-Fetal and Neonatal Medicine （Journal of Maternal-Fetal and Neonatal Medicine） 35 （ 12 ） 2411 - 2413 2022年

査読有り, ISSN 14767058

Background: No reports have focused on the clinical and metabolic characteristics of gestational diabetes (GDM) in underweight women. The aim of this study is to investigate the clinical and metabolic features of underweight GDM (pregravid BMI, <18.5 kg/m2: U-GDM). Materials and methods: Women diagnosed with GDM were categorized based on their pre-pregnancy BMI as either underweight (n = 49) or normal weight (pregravid BMI, 18.5–25.0 kg/m2: n = 271: N-GDM). During the study period, GDM was diagnosed using the International Association of Diabetes in Pregnancy Study Group criteria. Women with multi-fetal pregnancies, fetal congenital anomalies, overt diabetes in pregnancy, and pre-gestational diabetes mellitus were excluded. Results: There were no notable differences in maternal age at delivery and the rate of nulliparous between the U-GDM and N-GDM groups. Regarding antepartum oral glucose tolerance test profiles, women with U-GDM exhibited significantly lower fasting plasma glucose (FPG) levels than those with N-GDM (p <.01). The Insulinogenic Index of women with U-GDM was significantly lower than that of women with N-GDM (p <.05). Conclusion: Impaired early phase insulin secretion was associated with GDM onset in underweight women.

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Adenocarcinoma in situ or early-stage cervical cancer is a risk factor for preterm delivery after cervical conization: a multicenter observational study

Kasuga Y., Ikenoue S., Nishio H., Yamagami W., Ochiai D., Tanabe K., Tashima Y., Hirao N., Miyakoshi K., Kasai K., Suda Y., Nemoto T., Shiraishi S., Yoshida H., Kurahashi T., Takamatsu K., Iwasaki S., Yamashita H., Akiba Y., Arase T., Hara S., Nakada S., Tanaka M., Aoki D.

Journal of Maternal-Fetal and Neonatal Medicine （Journal of Maternal-Fetal and Neonatal Medicine） 35 （ 25 ） 9837 - 9842 2022年

ISSN 14767058

Objective: Pregnancy after conization is associated with a high risk of preterm delivery. However, because risk factors for preterm delivery after conization remain unknown, we conducted a multicenter observational study to investigate risk factors associated with preterm delivery. Methods: We selected patients who had previously undergone conization and reviewed medical records from 18 hospitals in cooperation with Keio University School of Medicine between January 2013 and December 2019. Women were classified as nulliparous and primiparous, and a multiple logistic regression analysis was performed to evaluate the relative contributions of the various maternal risk factors for preterm delivery (i.e. delivery before 37 gestational weeks). Results: Among 409 pregnant women after conization, 68 women delivered preterm (17%). The incidence of nulliparity (p =.014) was higher and a history of preterm delivery (p =.0010) was more common in the preterm delivery group than in the term delivery group. Furthermore, the proportion of women diagnosed with adenocarcinoma in situ (AIS) and cervical cancer in the preterm delivery group was higher than that in the term delivery group (p =.0099 and.0004, respectively). In multiple regression models in nulliparous women, cervical cancer or AIS (Odds ratio [OR]: 4.16, 95% CI: 1.26–13.68, p =.019) and a short cervix in the second trimester (OR: 13.41, 95% CI: 3.88–46.42, p <.0001) increased the risk of preterm delivery. Furthermore, a history of preterm delivery (OR: 7.35, 95% CI: 1.55–34.86, p =.012), cervical cancer or AIS (OR: 5.07, 95% CI: 1.24–20.73, p =.024), and a short cervix in the second trimester (OR: 4.29, 95% CI: 1.11–16.62, p =.035) increased the risk of preterm delivery in the multiple regression models in primiparous women. Conclusion: Pregnant women who previously underwent conization are at risk for preterm delivery. The histological type of AIS and cervical cancer was evaluated as a risk factor for preterm delivery. KEY MESSAGES Prior preterm delivery, presence of a short cervix, and cervical cancer or AIS were predictors of preterm delivery after conization. The depth of conization in cervical cancer or AIS group was significantly larger than that in the CIN group.

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Deep neural network-based classification of cardiotocograms outperformed conventional algorithms

Ogasawara J., Ikenoue S., Yamamoto H., Sato M., Kasuga Y., Mitsukura Y., Ikegaya Y., Yasui M., Tanaka M., Ochiai D.

Scientific Reports （Scientific Reports） 11 （ 1 ） 13367 - 13367 2021年12月

Cardiotocography records fetal heart rates and their temporal relationship to uterine contractions. To identify high risk fetuses, obstetricians inspect cardiotocograms (CTGs) by eye. Therefore, CTG traces are often interpreted differently among obstetricians, resulting in inappropriate interventions. However, few studies have focused on quantitative and nonbiased algorithms for CTG evaluation. In this study, we propose a newly constructed deep neural network model (CTG-net) to detect compromised fetal status. CTG-net consists of three convolutional layers that extract temporal patterns and interrelationships between fetal heart rate and uterine contraction signals. We aimed to classify the abnormal group (umbilical artery pH < 7.20 or Apgar score at 1 min < 7) and the normal group from CTG data. We evaluated the performance of the CTG-net with the F1 score and compared it with conventional algorithms, namely, support vector machine and k-means clustering, and another deep neural network model, long short-term memory. CTG-net showed the area under the receiver operating characteristic curve of 0.73 ± 0.04, which was significantly higher than that of long short-term memory. CTG-net, a quantitative and automated diagnostic aid system, enables early intervention for putatively abnormal fetuses, resulting in a reduction in the number of cases of hypoxic injury.

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Prepregnancy assessment of liver function to predict perinatal and postpregnancy outcomes in biliary atresia patients with native liver

Takahashi N., Ochiai D., Yamada Y., Tamagawa M., Kanamori H., Kato M., Ikenoue S., Kasuga Y., Kuroda T., Tanaka M.

Journal of Clinical Medicine （Journal of Clinical Medicine） 10 （ 17 ） 2021年09月

ISSN 2077-0383

Considering that some biliary atresia (BA) survivors with native liver have reached reproductive age and face long‐lasting complications, specific attention needs to be paid to pregnant cases. This study aimed to investigate the relationship between liver function, perinatal outcomes, and prognosis. A database review was conducted to identify pregnant BA cases with native liver and perinatal data, and clinical information on BA‐related complications was analyzed. Perinatal serum cholinesterase (ChE) levels, model for end‐stage liver‐disease (MELD) score, and platelet trends were analyzed, and the association between these indicators and perinatal outcomes was investigated. Patients were categorized into three groups according to the perinatal clinical outcomes: favorable (term babies with or without several episodes of cholangitis; n = 3), borderline (term baby and following liver dysfunction; n = 1), and unfavorable (premature delivery with subsequent liver failure; n = 1). Lower serum ChE levels, lower platelet counts, and higher MELD scores were observed in the unfavorable category. Borderline and unfavorable patients displayed a continuous increase in MELD score, with one eventually needing a liver transplantation. Pregnancy in patients with BA requires special attention. Serum ChE levels, platelet counts, and MELD scores are all important markers for predicting perinatal prognosis.

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Clinical results of a massive blood transfusion protocol for postpartum hemorrhage in a university hospital in japan: A retrospective study

Ochiai D., Abe Y., Yamazaki R., Uemura T., Toriumi A., Matsuhashi H., Tanaka Y., Ikenoue S., Kasuga Y., Tanosaki R., Tanaka M.

Medicina (Lithuania) （Medicina (Lithuania)） 57 （ 9 ） 2021年09月

ISSN 1010660X

Background and objectives: Massive postpartum hemorrhage (PPH) is the most common cause of maternal death worldwide. A massive transfusion protocol (MTP) may be used to provide significant benefits in the management of PPH; however, only a limited number of hospitals use MTP protocol to manage massive obstetric hemorrhages, especially in Japan. This study aimed to assess the clinical outcomes in patients in whom MTP was activated in our hospital. Materials and Methods: We retrospectively reviewed the etiology of PPH, transfusion outcomes, and laboratory findings among the patients treated with MTP after delivery in our hospital. Results: MTP was applied in 24 cases (0.7% of deliveries). Among them, MTP was activated within 2 h of delivery in 15 patients (62.5%). The median estimated blood loss was 5017 mL. Additional procedures to control bleeding were performed in 19 cases, including transarterial embolization (18 cases, 75%) and hysterectomy (1 case, 4.2%). The mean number of units of red blood cells, fresh frozen plasma, and platelets were 17.9, 20.2, and 20.4 units, respectively. The correlation coefficients of any two items among red blood cells, fresh frozen plasma, platelets, blood loss, and obstetrical disseminated intravascular coagulation score ranged from 0.757 to 0.892, indicating high levels of correlation coefficients. Although prothrombin time and activated partial thromboplastin time levels were significantly higher in the <150 mg/dL fibrinogen group than in the ≥150 mg/dL fibrinogen group at the onset of PPH, the amount of blood loss and blood transfusion were comparable between the two groups. Conclusions: Our MTP provides early access to blood products for patients experiencing severe PPH and could contribute to improving maternal outcomes after resuscitation in our hospital. Our study suggests the implementation of a hospital-specific MTP protocol to improve the supply and utilization of blood products to physicians managing major obstetric hemorrhage.

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The efficacy of transarterial embolization for postpartum hemorrhage complicated with disseminated intravascular coagulation: A single‐center experience

Ochiai D., Nakatsuka S., Abe Y., Ikenoue S., Kasuga Y., Inoue M., Jinzaki M., Tanaka M.

Journal of Clinical Medicine （Journal of Clinical Medicine） 10 （ 18 ） 2021年09月

ISSN 2077-0383

Indications for the use of transarterial embolization (TAE) for postpartum hemorrhage (PPH) have been established. However, the efficacy of TAE for PPH complicated by disseminated intravascular coagulation (DIC) remains controversial. In this study, we investigated the efficacy of TAE for PPH complicated by DIC. A database review was conducted to identify patients who were treated with TAE for PPH at our hospital. TAE was performed in 41 patients during the study period. Effective hemostasis was achieved in all cases, but additional procedures, such as reembolization or hysterectomy, were required in five patients (12.2%). The typical causes of PPH included uterine atony (18 cases), placenta previa (15 cases), amniotic fluid embolism (DIC‐type) (11 cases), and placenta accreta spectrum (10 cases). The mean blood loss was 3836 mL. The mean obstetrical DIC and the International Society on Thrombosis and Hemostasis DIC scores were 7.9 and 2.6, respectively. The efficacy of hemostasis was comparable between patients with and without DIC. However, the complete success rate of TAE was lower in patients with DIC as the condition worsened than that in non‐DIC patients. Overall, TAE is effective as a minimally invasive treatment for PPH complicated by DIC.

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Preeclampsia and COVID-19: results from the INTERCOVID prospective longitudinal study

Papageorghiou A.T., Deruelle P., Gunier R.B., Rauch S., García-May P.K., Mhatre M., Usman M.A., Abd-Elsalam S., Etuk S., Simmons L.E., Napolitano R., Deantoni S., Liu B., Prefumo F., Savasi V., do Vale M.S., Baafi E., Zainab G., Nieto R., Maiz N., Aminu M.B., Cardona-Perez J.A., Craik R., Winsey A., Tavchioska G., Bako B., Oros D., Rego A., Benski A.C., Hassan-Hanga F., Savorani M., Giuliani F., Sentilhes L., Risso M., Takahashi K., Vecchiarelli C., Ikenoue S., Thiruvengadam R., Soto Conti C.P., Ferrazzi E., Cetin I., Nachinab V.B., Ernawati E., Duro E.A., Kholin A., Firlit M.L., Easter S.R., Sichitiu J., Bowale A., Casale R., Cerbo R.M., Cavoretto P.I., Eskenazi B., Thornton J.G., Bhutta Z.A., Kennedy S.H., Villar J.

American Journal of Obstetrics and Gynecology （American Journal of Obstetrics and Gynecology） 225 （ 3 ） 289.e1 - 289.e17 2021年09月

ISSN 00029378

Background: It is unclear whether the suggested link between COVID-19 during pregnancy and preeclampsia is an independent association or if these are caused by common risk factors. Objective: This study aimed to quantify any independent association between COVID-19 during pregnancy and preeclampsia and to determine the effect of these variables on maternal and neonatal morbidity and mortality. Study Design: This was a large, longitudinal, prospective, unmatched diagnosed and not-diagnosed observational study assessing the effect of COVID-19 during pregnancy on mothers and neonates. Two consecutive not-diagnosed women were concomitantly enrolled immediately after each diagnosed woman was identified, at any stage during pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed until hospital discharge using the standardized INTERGROWTH-21st protocols and electronic data management system. A total of 43 institutions in 18 countries contributed to the study sample. The independent association between the 2 entities was quantified with the risk factors known to be associated with preeclampsia analyzed in each group. The outcomes were compared among women with COVID-19 alone, preeclampsia alone, both conditions, and those without either of the 2 conditions. Results: We enrolled 2184 pregnant women; of these, 725 (33.2%) were enrolled in the COVID-19 diagnosed and 1459 (66.8%) in the COVID-19 not-diagnosed groups. Of these women, 123 had preeclampsia of which 59 of 725 (8.1%) were in the COVID-19 diagnosed group and 64 of 1459 (4.4%) were in the not-diagnosed group (risk ratio, 1.86; 95% confidence interval, 1.32–2.61). After adjustment for sociodemographic factors and conditions associated with both COVID-19 and preeclampsia, the risk ratio for preeclampsia remained significant among all women (risk ratio, 1.77; 95% confidence interval, 1.25–2.52) and nulliparous women specifically (risk ratio, 1.89; 95% confidence interval, 1.17–3.05). There was a trend but no statistical significance among parous women (risk ratio, 1.64; 95% confidence interval, 0.99–2.73). The risk ratio for preterm birth for all women diagnosed with COVID-19 and preeclampsia was 4.05 (95% confidence interval, 2.99–5.49) and 6.26 (95% confidence interval, 4.35–9.00) for nulliparous women. Compared with women with neither condition diagnosed, the composite adverse perinatal outcome showed a stepwise increase in the risk ratio for COVID-19 without preeclampsia, preeclampsia without COVID-19, and COVID-19 with preeclampsia (risk ratio, 2.16; 95% confidence interval, 1.63–2.86; risk ratio, 2.53; 95% confidence interval, 1.44–4.45; and risk ratio, 2.84; 95% confidence interval, 1.67–4.82, respectively). Similar findings were found for the composite adverse maternal outcome with risk ratios of 1.76 (95% confidence interval, 1.32–2.35), 2.07 (95% confidence interval, 1.20–3.57), and 2.77 (95% confidence interval, 1.66–4.63). The association between COVID-19 and gestational hypertension and the direction of the effects on preterm birth and adverse perinatal and maternal outcomes, were similar to preeclampsia, but confined to nulliparous women with lower risk ratios. Conclusion: COVID-19 during pregnancy is strongly associated with preeclampsia, especially among nulliparous women. This association is independent of any risk factors and preexisting conditions. COVID-19 severity does not seem to be a factor in this association. Both conditions are associated independently of and in an additive fashion with preterm birth, severe perinatal morbidity and mortality, and adverse maternal outcomes. Women with preeclampsia should be considered a particularly vulnerable group with regard to the risks posed by COVID-19.

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Maternal and Neonatal Morbidity and Mortality Among Pregnant Women With and Without COVID-19 Infection: The INTERCOVID Multinational Cohort Study.

Villar J, Ariff S, Gunier RB, Thiruvengadam R, Rauch S, Kholin A, Roggero P, Prefumo F, do Vale MS, Cardona-Perez JA, Maiz N, Cetin I, Savasi V, Deruelle P, Easter SR, Sichitiu J, Soto Conti CP, Ernawati E, Mhatre M, Teji JS, Liu B, Capelli C, Oberto M, Salazar L, Gravett MG, Cavoretto PI, Nachinab VB, Galadanci H, Oros D, Ayede AI, Sentilhes L, Bako B, Savorani M, Cena H, García-May PK, Etuk S, Casale R, Abd-Elsalam S, Ikenoue S, Aminu MB, Vecciarelli C, Duro EA, Usman MA, John-Akinola Y, Nieto R, Ferrazi E, Bhutta ZA, Langer A, Kennedy SH, Papageorghiou AT

JAMA pediatrics 175 （ 8 ） 817 - 826 2021年08月

ISSN 2168-6203

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Maternal and Neonatal Morbidity and Mortality among Pregnant Women with and without COVID-19 Infection: The INTERCOVID Multinational Cohort Study

Villar J., Ariff S., Gunier R.B., Thiruvengadam R., Rauch S., Kholin A., Roggero P., Prefumo F., Do Vale M.S., Cardona-Perez J.A., Maiz N., Cetin I., Savasi V., Deruelle P., Easter S.R., Sichitiu J., Soto Conti C.P., Ernawati E., Mhatre M., Teji J.S., Liu B., Capelli C., Oberto M., Salazar L., Gravett M.G., Cavoretto P.I., Nachinab V.B., Galadanci H., Oros D., Ayede A.I., Sentilhes L., Bako B., Savorani M., Cena H., García-May P.K., Etuk S., Casale R., Abd-Elsalam S., Ikenoue S., Aminu M.B., Vecciarelli C., Duro E.A., Usman M.A., John-Akinola Y., Nieto R., Ferrazi E., Bhutta Z.A., Langer A., Kennedy S.H., Papageorghiou A.T.

JAMA Pediatrics （JAMA Pediatrics） 175 （ 8 ） 817 - 826 2021年08月

ISSN 21686203

Importance: Detailed information about the association of COVID-19 with outcomes in pregnant individuals compared with not-infected pregnant individuals is much needed. Objective: To evaluate the risks associated with COVID-19 in pregnancy on maternal and neonatal outcomes compared with not-infected, concomitant pregnant individuals. Design, Setting, and Participants: In this cohort study that took place from March to October 2020, involving 43 institutions in 18 countries, 2 unmatched, consecutive, not-infected women were concomitantly enrolled immediately after each infected woman was identified, at any stage of pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed up until hospital discharge. Exposures: COVID-19 in pregnancy determined by laboratory confirmation of COVID-19 and/or radiological pulmonary findings or 2 or more predefined COVID-19 symptoms. Main Outcomes and Measures: The primary outcome measures were indices of (maternal and severe neonatal/perinatal) morbidity and mortality; the individual components of these indices were secondary outcomes. Models for these outcomes were adjusted for country, month entering study, maternal age, and history of morbidity. Results: A total of 706 pregnant women with COVID-19 diagnosis and 1424 pregnant women without COVID-19 diagnosis were enrolled, all with broadly similar demographic characteristics (mean [SD] age, 30.2 [6.1] years). Overweight early in pregnancy occurred in 323 women (48.6%) with COVID-19 diagnosis and 554 women (40.2%) without. Women with COVID-19 diagnosis were at higher risk for preeclampsia/eclampsia (relative risk [RR], 1.76; 95% CI, 1.27-2.43), severe infections (RR, 3.38; 95% CI, 1.63-7.01), intensive care unit admission (RR, 5.04; 95% CI, 3.13-8.10), maternal mortality (RR, 22.3; 95% CI, 2.88-172), preterm birth (RR, 1.59; 95% CI, 1.30-1.94), medically indicated preterm birth (RR, 1.97; 95% CI, 1.56-2.51), severe neonatal morbidity index (RR, 2.66; 95% CI, 1.69-4.18), and severe perinatal morbidity and mortality index (RR, 2.14; 95% CI, 1.66-2.75). Fever and shortness of breath for any duration was associated with increased risk of severe maternal complications (RR, 2.56; 95% CI, 1.92-3.40) and neonatal complications (RR, 4.97; 95% CI, 2.11-11.69). Asymptomatic women with COVID-19 diagnosis remained at higher risk only for maternal morbidity (RR, 1.24; 95% CI, 1.00-1.54) and preeclampsia (RR, 1.63; 95% CI, 1.01-2.63). Among women who tested positive (98.1% by real-time polymerase chain reaction), 54 (13%) of their neonates tested positive. Cesarean delivery (RR, 2.15; 95% CI, 1.18-3.91) but not breastfeeding (RR, 1.10; 95% CI, 0.66-1.85) was associated with increased risk for neonatal test positivity. Conclusions and Relevance: In this multinational cohort study, COVID-19 in pregnancy was associated with consistent and substantial increases in severe maternal morbidity and mortality and neonatal complications when pregnant women with and without COVID-19 diagnosis were compared. The findings should alert pregnant individuals and clinicians to implement strictly all the recommended COVID-19 preventive measures.

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Newer Insights Into Fetal Growth and Body Composition

Ikenoue S., Kasuga Y., Endo T., Tanaka M., Ochiai D.

Frontiers in Endocrinology （Frontiers in Endocrinology） 12 708767 - 708767 2021年07月

ISSN 1664-2392

Based on epidemiological and experimental evidence, the origins of childhood obesity and early onset metabolic syndrome can be extended back to developmental processes during intrauterine life. It is necessary to actively investigate antecedent conditions that affect fetal growth by developing reliable measures to identify variations in fetal fat deposition and body composition. Recently, the resolution of ultrasonography has remarkably improved, which enables better tissue characterization and quantification of fetal fat accumulation. In addition, fetal fractional limb volume has been introduced as a novel measure to quantify fetal soft tissue volume, including fat mass and lean mass. Detecting extreme variations in fetal fat deposition may provide further insights into the origins of altered fetal body composition in pathophysiological conditions (i.e., fetal growth restriction or fetal macrosomia), which are predisposed to the metabolic syndrome in later life. Further studies are warranted to determine the maternal or placental factors that affect fetal fat deposition and body composition. Elucidating these factors may help develop clinical interventions for altered fetal growth and body composition, which could potentially lead to primary prevention of the future risk of metabolic dysfunction.

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Expectant management for early pregnancy miscarriage after radical trachelectomy: A single hospital-based study

Kasuga Y., Ikenoue S., Tanaka Y., Tamagawa M., Hasegawa K., Oishi M., Endo T., Sato Y., Tanaka M., Ochiai D.

Acta Obstetricia et Gynecologica Scandinavica （Acta Obstetricia et Gynecologica Scandinavica） 100 （ 7 ） 1322 - 1325 2021年07月

ISSN 00016349

Introduction: Women who have undergone radical trachelectomy as a fertility-sparing treatment for early-stage cervical cancer may be at higher risk for retained tissues after early-term miscarriage due to cervical cerclage or cervical necrosis. Dilatation and curettage or aspiration may present additional risks in these women. The aim of this study was to assess the efficacy of expectant management for early pregnancy miscarriage after radical trachelectomy. Material and methods: Keio University Hospital records were reviewed for women who conceived after abdominal radical trachelectomy and received perinatal care between 1 April 2012 and 31 March 2020. A total of 62 women (76 pregnancies) were identified, and 13 of these women experienced miscarriage before 12 gestational weeks. The management and outcome of these cases were reviewed in detail. Results: The median maternal age at miscarriage was 39 years (range 31–42 years) and the median duration from abdominal radical trachelectomy to conception was 2.60 years (range 0.49–7.30 years). Cervical necrosis before conception occurred in one case (8%). One patient requested treatment with aspiration and the remaining 12 cases were managed with observation for a median of 23 days (range 7–50 days). There were no cases of endometritis or cases requiring dilatation and curettage for residue tissue. Further, no cases developed laceration of the residual cervix and no loss of cerclage sutures after discharge was noted. Conclusions: Expectant management seems to be safe and appropriate for first trimester miscarriage after abdominal radical trachelectomy.

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Management of pregnancy after radical trachelectomy

Kasuga Y., Ikenoue S., Tanaka M., Ochiai D.

Gynecologic Oncology （Gynecologic Oncology） 162 （ 1 ） 220 - 225 2021年07月

ISSN 00908258

Radical trachelectomy (RT) is a surgery for early-stage cervical cancer treatment that preserves the childbearing ability, and its use has become increasingly common worldwide. Thus, the rate of conception in women who have undergone RT is increasing. However, pregnancy after RT is associated with a higher risk of several obstetric complications such as preterm delivery, preterm premature membrane rupture, and abnormal bleeding from varices at the site of uterovaginal anastomosis. Furthermore, since RT have a residual prophylactic cerclage, it is difficult to manage first- and second-trimester miscarriages. There is little previous data on the management of pregnancy after RT. In this review article, we summarize various management methods and experiences to provide a guide to clinicians for perinatal management after RT.

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Epigenetic Changes in Neonates Born to Mothers With Gestational Diabetes Mellitus May Be Associated With Neonatal Hypoglycaemia

Kasuga Y., Kawai T., Miyakoshi K., Saisho Y., Tamagawa M., Hasegawa K., Ikenoue S., Ochiai D., Hida M., Tanaka M., Hata K.

Frontiers in Endocrinology （Frontiers in Endocrinology） 12 690648 - 690648 2021年06月

ISSN 1664-2392

The detection of epigenetic changes associated with neonatal hypoglycaemia may reveal the pathophysiology and predict the onset of future diseases in offspring. We hypothesized that neonatal hypoglycaemia reflects the in utero environment associated with maternal gestational diabetes mellitus. The aim of this study was to identify epigenetic changes associated with neonatal hypoglycaemia. The association between DNA methylation using Infinium HumanMethylation EPIC BeadChip and neonatal plasma glucose (PG) level at 1 h after birth in 128 offspring born at term to mothers with well-controlled gestational diabetes mellitus was investigated by robust linear regression analysis. Cord blood DNA methylation at 12 CpG sites was significantly associated with PG at 1 h after birth after adding infant sex, delivery method, gestational day, and blood cell compositions as covariates to the regression model. DNA methylation at two CpG sites near an alternative transcription start site of ZNF696 was significantly associated with the PG level at 1 h following birth (false discovery rate-adjusted P < 0.05). Methylation levels at these sites increased as neonatal PG levels at 1 h after birth decreased. In conclusion, gestational diabetes mellitus is associated with DNA methylation changes at the alternative transcription start site of ZNF696 in cord blood cells. This is the first report of DNA methylation changes associated with neonatal PG at 1 h after birth.

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What are the causes for low birthweight in Japan? A single hospital-based study

Kasuga Y., Ikenoue S., Tamagawa M., Oishi M., Endo T., Sato Y., Iida M., Sato Y., Tanaka M., Ochiai D.

PLoS ONE （PLoS ONE） 16 （ 6 June ） e0253719 2021年06月

Low-birthweight (LBW; <2,500 g) babies are at a higher risk of poor educational achievement, disability, and metabolic diseases than normal-birthweight babies in the future. However, reliable data on factors that contribute to LBW have not been considered previously. Therefore, we aimed to examine the distribution of the causes for LBW. A retrospective review of cases involving 4,224 babies whose mothers underwent perinatal care at Keio University Hospital between 2013 and 2019 was conducted. The LBW incidence was 24% (1,028 babies). Of the 1,028 LBW babies, 231 babies were from multiple pregnancies. Of the 797 singleton LBW babies, 518 (65%) were born preterm. Obstetric complications in women with preterm LBW babies included premature rupture of membrane or labor onset (31%), hypertensive disorders of pregnancy (HDP, 64%), fetal growth restriction (24%), non-reassuring fetal status (14%), and placental previa/vasa previa (8%). Of the 279 term LBW babies, 109 (39%) were small for gestational age. Multiple logistic regression analyses revealed the following factors as LBW risk factors in term neonates: low pre-pregnancy maternal weight, inadequate gestational weight gain, birth at 37 gestational weeks, HDP, anemia during pregnancy, female sex, and neonatal congenital anomalies. HDP was an LBW risk factor not only in preterm births but also in term births. Our results suggest that both modifiable and non-modifiable factors are causes for LBW. It may be appropriate to consider a heterogeneous rather than a simple classification of LBW and to evaluate future health risks based on contributing factors.

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A case of abdominal compartment syndrome caused by amniotic fluid embolism treated with ABTHERA™ therapy: World's first report in the obstetric field

Hirata M., Hasegawa K., Kasuga Y., Haiden A., Ikenoue S., Yamamoto R., Tanaka M., Sasaki J., Ochiai D.

Taiwanese Journal of Obstetrics and Gynecology （Taiwanese Journal of Obstetrics and Gynecology） 60 （ 3 ） 579 - 580 2021年05月

ISSN 10284559

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胎児心循環機能のモニタリングによる周産期管理を実施した高拍出性心不全を呈した胎児巨大肝血管腫の1例

林彩世, 小澤克典, 室本仁, 杉林里佳, 小杉洋平, 柴田優花, 池ノ上学, 和田誠司, 伊藤裕司, 左合治彦

超音波医学（(公社)日本超音波医学会） 48 （ 3 ） 133 - 137 2021年05月

ISSN 1346-1176

胎児巨大肝血管腫は動静脈シャントによって高拍出性心不全を呈し,胎盤循環も悪化する.そのため胎盤循環を含めた胎児循環の評価を行い適切な娩出時期を決定する必要があるが,いまだ確立した評価方法がない.臍静脈血流量(UVFV)の総心拍出量(CCO)における割合(UVFV/CCO)は胎盤循環の指標となることが報告されており,この指標を含めた心循環機能評価を行うことで早期に病状の変化をとらえた胎児巨大肝血管腫の症例を報告する.妊娠27週に心胸郭断面積比(CTAR)48.5%の心拡大と軽度の僧帽弁・三尖弁逆流を認めた.CCO 1,214ml/min,UVFV 350ml/minと増加を認めたが,UVFV/CCOは28.9%と保たれ,羊水量は正常で胎児水腫を認めなかった.しかし,妊娠30週1日にCTAR 62.9%と増悪,CCO 1,620ml/min,UVFV 236ml/minとなり,UVFV/CCOは14.6%に低下した.胎児水腫は認めなかったが羊水過少となり,Biophysical profiling score 2/10点と低値であった.妊娠30週4日に胎児心拍数陣痛図において基線細変動の減少が出現し,胎児機能不全と診断,緊急帝王切開術を施行した.児は2,340g,Apgar score 1点(1分値),5点(5分値),臍帯動脈血pH 7.254で出生した.日齢1.5に肝血管腫に対してコイル塞栓術を行ったが原病のコントロールがつかず,グラム陽性球菌による敗血症で日齢70に永眠した.UVFV/CCOの減少が巨大肝血管腫による胎児胎盤循環の悪化を反映すると思われた.(著者抄録)

帝王切開術後の腹腔内出血に対し、腹部コンパートメント症候群に準じて治療介入した1例

大石真希, 落合大吾, 春日義史, 田中雄也, 玉川真澄, 遠藤豊英, 佐藤佑, 池ノ上学, 田中守, 青木大輔

東京産科婦人科学会会誌（(一社)東京産科婦人科学会） 70 （ 2 ） 231 - 236 2021年04月

ISSN 2186-0599

産科領域における腹部コンパートメント症候群(abdominal compartment syndrome:ACS)の報告は稀である。今回我々は、帝王切開術後に腹腔内出血を認め、ACSに準じて加療した症例を経験した。症例は43歳、妊娠39週0日に分娩中に児の持続徐脈を認め、超緊急帝王切開術を施行し常位胎盤早期剥離と診断した。帰室1時間後、出血性ショック状態のため産科危機的出血を宣言し子宮動脈塞栓術を施行した。術後1日目、著明な腹部膨隆を認め、ACSを疑い腹部造影CT検査を行ったが臓器血流障害は認めなかった。また、膀胱内圧は14mmHgと上昇しており、約4Lの血性腹水を経腹的にドレナージしたところ呼吸状態が劇的に改善した。そして、その後の経過は順調で術後7日目に退院した。ACS疑いの症例では、腹腔内圧の推定には膀胱内圧が有用であり、早期の治療介入が病態改善に寄与する可能性が示唆された。(著者抄録)

Placental Corticotrophin-Releasing Hormone is a Modulator of Fetal Liver Blood Perfusion

Ikenoue S., Waffarn F., Ohashi M., Tanaka M., Gillen D.L., Buss C., Entringer S., Wadhwa P.D.

Journal of Clinical Endocrinology and Metabolism （Journal of Clinical Endocrinology and Metabolism） 106 （ 3 ） 646 - 653 2021年03月

ISSN 0021972X

Context: Variation in fetal liver blood flow influences fetal growth and postnatal body composition. Placental corticotrophin-releasing hormone has been implicated as a key mediator of placental-fetal perfusion. Objective: To determine whether circulating levels of placental corticotrophin-releasing hormone across gestation are associated with variations in fetal liver blood flow. Design: Prospective cohort study. Methods: Fetal ultrasonography was performed at 30 weeks' gestation to characterize fetal liver blood flow (quantified by subtracting ductus venosus flow from umbilical vein flow). Placental corticotrophin-releasing hormone was measured in maternal circulation at approximately 12, 20, and 30 weeks' gestation. Multiple regression analysis was used to determine the proportion of variation in fetal liver blood flow explained by placental corticotrophin-releasing hormone. Covariates included maternal age, parity, pre-pregnancy body mass index, gestational weight gain, and fetal sex. Results: A total of 79 uncomplicated singleton pregnancies were analyzed. Fetal liver blood flow was 68.4 ± 36.0 mL/min (mean ± SD). Placental corticotrophin-releasing hormone concentrations at 12, 20, and 30 weeks were 12.5 ± 8.1, 35.7 ± 24.5, and 247.9 ± 167.8 pg/mL, respectively. Placental corticotrophin-releasing hormone at 30 weeks, but not at 12 and 20 weeks, was significantly and positively associated with fetal liver blood flow at 30 weeks (r = 0.319; P = 0.004) and explained 10.4% of the variance in fetal liver blood flow. Conclusions: Placental corticotrophin-releasing hormone in late gestation is a possible modulator of fetal liver blood flow and may constitute a biochemical marker in clinical investigations of fetal growth and body composition.

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Defining the normal growth curve of fetal fractional limb volume in a japanese population

Ikenoue S., Akiba Y., Endo T., Kasuga Y., Yakubo K., Ishii R., Tanaka M., Ochiai D.

Journal of Clinical Medicine （Journal of Clinical Medicine） 10 （ 3 ） 1 - 9 2021年02月

ISSN 2077-0383

Fetal fractional limb volume is a useful measure for predicting birth weight and newborn adiposity; however, a normal growth curve has been reported solely in the United States. As the birth weight of neonates in Japan is significantly lower than that in the US, fetal fractional limb volume is likely to be smaller in the Japanese population. This study aimed to define the normal growth curve of fractional arm volume (AVol) and thigh volume (TVol) in the Japanese population. Ultrasound scans of 453 AVol and TVol pairs were obtained; each AVol and TVol percentile at each gestational age was calculated. The measured AVol and TVol at each gestational week were also converted to z-scores based on a previous report. The growth curves increased linearly until the second trimester and exponentially in the third trimester. Linear regression showed a significant negative correlation between gestational age and AVol and TVol z-scores. The growth pattern of fetal fractional limb volume in the Japanese population is consistent with, but smaller than, that reported in the US; this difference becomes greater as the gestational age progresses.

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Cell sheets using human amniotic fluid stem cells reduce tissue fibrosis in murine full-thickness skin wounds

Ochiai D., Abe Y., Fukutake M., Sato Y., Ikenoue S., Kasuga Y., Masuda H., Tanaka M.

Tissue and Cell （Tissue and Cell） 68 101472 - 101472 2021年02月

ISSN 00408166

The use of mesenchymal stem cell sheets is a promising strategy for skin regeneration. The injection of dissociated human amniotic fluid stem cells (hAFSCs) was recently found to accelerate cutaneous wound healing with reduced fibrotic scarring, similar to fetal wound healing. However, the use of hAFSCs in applications of cell sheet technology remains limited. The aim of this study was to determine the in vivo efficacy of in vitro-cultured hAFSC sheets in wound healing. The cell sheets were characterized by immunohistochemistry and RT-qPCR and grafted onto full-thickness wounds in BALB/c mice. The wound size was measured, and re-epithelialization, granulation tissue area, and collagen content of the regenerated wound were analyzed histologically. Although the hAFSC sheet contained abundant extracellular matrix molecules and expressed high levels of anti-fibrotic mediators, its grafting did not affect wound closure or the size of the granulation tissue area. In contrast, the organization of type I collagen bundles in the regenerated wound was markedly reduced, while the levels of type III collagen were increased after implantation of the hAFSC sheet. These results suggest that hAFSC sheets can exert anti-fibrotic properties without delaying wound closure.

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Amniotic fluid stem cells as a novel strategy for the treatment of fetal and neonatal neurological diseases

Abe Y., Ochiai D., Sato Y., Otani T., Fukutake M., Ikenoue S., Kasuga Y., Tanaka M.

Placenta （Placenta） 104 247 - 252 2021年01月

ISSN 01434004

Even in the context of modern medicine, infants with fetal and neonatal neurological diseases such as cerebral palsy and myelomeningocele suffer serious long-lasting impairment due to the irreversible neuronal damage. The promotion of neurologically intact survival in patients with perinatal intractable neurological diseases requires the development of novel strategies. One promising strategy involves the use of human amniotic fluid stem cells (hAFSCs), which have attracted much attention in recent years and are known to exert anti-inflammatory and neuroprotective effects. In recent years, the therapeutic effects of hAFSCs on fetal-neonatal neurological diseases have become evident as per intense research efforts by our group and others. Specifically, hAFSCs administered into the nasal cavity migrated to the brain and controlled local inflammation in a rodent model of neonatal hypoxic-ischemic encephalopathy. In contrast, hAFSCs administered intraperitoneally did not migrate to the brain; they rather formed spheroids in the abdominal cavity, resulting in the suppression of systemic inflammation (including in the brain) via the secretion of anti-inflammatory cytokines in concert with peritoneal macrophages in a rodent model of periventricular leukomalacia. Moreover, studies in a rat model of myelomeningocele suggested that hAFSCs administered in utero secreted hepatocyte growth factor and protected the exposed spinal cord during pregnancy. Importantly, autologous hAFSCs, whose use for fetal-neonatal treatment does not raise ethical issues, can be collected during pregnancy and prepared in sufficient numbers for therapeutic use. This article outlines the results of preclinical research on fetal stem cell therapy, mainly involving hAFSCs, in the context of perinatal neurological diseases.

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A safe delivery system to prevent COVID-19 transmission without negative-pressure isolation delivery rooms: Experience from a hospital with nosocomial outbreak

Kasuga Y., Ochiai D., Tamagawa M., Oishi M., Endo T., Sato Y., Iida M., Ikenoue S., Tanaka M.

Taiwanese Journal of Obstetrics and Gynecology （Taiwanese Journal of Obstetrics and Gynecology） 60 （ 1 ） 183 - 184 2021年01月

ISSN 10284559

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Differences in fetal fractional limb volume changes in normal and gestational diabetic pregnancies: an exploratory observational study

Akiba Y., Ikenoue S., Endo T., Kasuga Y., Ochiai D., Miyakoshi K., Ishii R., Yakubo K., Tanaka M.

BJOG: An International Journal of Obstetrics and Gynaecology （BJOG: An International Journal of Obstetrics and Gynaecology） 128 （ 2 ） 329 - 335 2021年01月

査読有り, ISSN 14700328

Objective: Fetal fractional limb volume has been proposed as a useful measure for quantifying fetal soft tissue development. The aim of this study was to investigate the growth of fractional arm volume (AVol) and fractional thigh volume (TVol) of fetuses with maternal gestational diabetes (GDM) compared with those of fetuses with normal glucose tolerance (NGT). We hypothesised fetal fractional limb volume would be larger in the GDM group than in the NGT group in late gestation. Design: Exploratory observational study. Setting: Saitama Municipal Hospital. Sample: A total of 165 (125 NGT and 40 GDM) singleton Japanese pregnant women. Methods: AVol and TVol were assessed between 20 and 37 weeks’ gestation as cylindrical limb volumes based on 50% of the fetal humeral or femoral diaphysis length. Women were diagnosed as GDM based on the criteria of the Japan Society of Obstetrics and Gynecology. Main outcome measures: AVol and TVol were compared between women with NGT and those with GDM at each gestational age period (2-week intervals from 20 to 37 weeks’ gestation). Results: Overall, 287 ultrasound scans were performed (NGT group, 205 scans; GDM group, 82 scans). There was no significant difference of AVol between the groups before 32 weeks’ gestation. AVol was significantly larger in the GDM group than in the NGT group after 32 weeks’ gestation (P < 0.05). TVol was not statistically different between the groups across gestation. Conclusions: Detection of variations in fetal AVol may provide greater insight into understanding the origins of altered fetal body proportion in GDM. Tweetable abstract: AVol, but not TVol, is significantly larger in fetuses with GDM than in those with NGT after 32 weeks’ gestation.

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Predictors of later insulin therapy for gestational diabetes diagnosed in early pregnancy

Tamagawa M., Kasuga Y., Saisho Y., Tanaka Y., Hasegawa K., Oishi M., Endo T., Sato Y., Ikenoue S., Tanaka M., Ochiai D.

Endocrine Journal （Endocrine Journal） 68 （ 11 ） 1321 - 1328 2021年

ISSN 09188959

Interventions for gestational diabetes mellitus (GDM), diagnosed in early pregnancy, have been a topic of controversy. This study aimed to elucidate factors that predict patients with GDM diagnosed before 24 gestational weeks (early GDM: E-GDM) who require insulin therapy later during pregnancy. Furthermore, we identified patients whose impaired glucose tolerance should be strictly controlled from early gestation onward. Women diagnosed with GDM were categorized based on the gestational age at diagnosis into E-GDM (n = 388) or late GDM (L-GDM, diagnosed after 24 weeks, n = 340) groups. Clinical features were compared between the groups, and the predictors for insulin therapy was evaluated in the E-GDM group. There were no significant between-group differences in terms of perinatal outcomes (e.g., gestational weeks at delivery, fetal growth, hypertensive disorder of pregnancy), with the exception of the Apgar score at 5 min. Moreover, there was no significant difference in the frequency of insulin therapy during pregnancy between the two groups. Using multiple logistic regression analysis, pre-pregnancy body mass index (BMI) ≥25 kg/m2, a family history of diabetes, and higher fasting plasma glucose (FPG), 1 h-plasma glucose (PG), and 2 h-PG values increased insulin therapy risk during pregnancy in the E-GDM group. Furthermore, since E-GDM patients with abnormal levels of FPG, as well as 1 h-PG or 2 h-PG, and those with pre-pregnancy BMI ≥25 kg/m2 and a family history of diabetes had a higher risk of later insulin therapy during pregnancy, they may require more careful follow-up in the perinatal period.

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Prophylactic therapy with human amniotic fluid stem cells improves long-term cognitive impairment in rat neonatal sepsis survivors

Abe Y., Ochiai D., Sato Y., Kanzaki S., Ikenoue S., Kasuga Y., Tanaka M.

International Journal of Molecular Sciences （International Journal of Molecular Sciences） 21 （ 24 ） 1 - 12 2020年12月

ISSN 16616596

A systemic inflammatory response induces multiple organ dysfunction and results in poor long-term neurological outcomes in neonatal sepsis. However, there is no effective therapy for treating or preventing neonatal sepsis besides antibiotics and supportive care. Therefore, a novel strategy to improve neonatal sepsis-related morbidity and mortality is desirable. Recently, we reported that prophylactic therapy with human amniotic stem cells (hAFSCs) improved survival in a rat model of lipopolysaccharide (LPS)-induced neonatal sepsis through immunomodulation. Besides improving the mortality, increasing survival without major morbidities is an important goal of neonatal intensive care for neonatal sepsis. This study investigated long-term neurological outcomes in neonatal sepsis survivors treated with hAFSCs using the LPS-induced neonatal sepsis model in rats. We found that prophylactic therapy with hAFSCs improved spatial awareness and memory-based behavior in neonatal sepsis survivors at adolescence in rats. The treatment suppressed acute reactive gliosis and subsequently reduced astrogliosis in the hippocampal region over a long period of assessment. To the best of our knowledge, this is the first report that proves the concept that hAFSC treatment improves cognitive impairment in neonatal sepsis survivors. We demonstrate the efficacy of hAFSC therapy in improving the mortality and morbidity associated with neonatal sepsis.

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腹腔鏡下術後、生児を得た正所異所同時妊娠の2例

片倉慧美, 山田満稔, 池ノ上学, 田中守

日本産科婦人科内視鏡学会雑誌（(一社)日本産科婦人科内視鏡学会） 36 （ Suppl.I ） [O - 383] 2020年11月

ISSN 1884-9938

妊娠糖尿病と正常耐糖能例における胎児Fractional limb volumeの発育の比較

池ノ上学, 秋葉洋平, 遠藤豊英, 春日義史, 落合大吾, 宮越敬, 矢久保和美, 田中守

超音波医学（(公社)日本超音波医学会） 47 （ Suppl. ） S170 - S170 2020年11月

ISSN 1346-1176

前置血管との鑑別を要した子宮頸管内静脈瘤合併妊娠の1例

遠藤豊英, 宮越敬, 玉川真澄, 長谷川慶太, 大石真希, 大谷利光, 池ノ上学, 春日義史, 落合大吾, 田中守

超音波医学（(公社)日本超音波医学会） 47 （ Suppl. ） S406 - S406 2020年11月

ISSN 1346-1176

Placenta accreta indexによる前置癒着胎盤発症予測に関する検討

長谷川慶太, 池ノ上学, 玉川真澄, 大石真希, 遠藤豊英, 大谷利光, 春日義史, 落合大吾, 宮越敬, 田中守

超音波医学（(公社)日本超音波医学会） 47 （ Suppl. ） S374 - S374 2020年11月

ISSN 1346-1176

Survey on the use of personal protective equipment and COVID-19 testing of pregnant women in Japan

Umazume T., Miyagi E., Haruyama Y., Kobashi G., Saito S., Hayakawa S., Kawana K., Ikenoue S., Morioka I., Yamada H.

Journal of Obstetrics and Gynaecology Research （Journal of Obstetrics and Gynaecology Research） 46 （ 10 ） 1933 - 1939 2020年10月

査読有り, ISSN 13418076

Aim: To clarify the status of personal protective equipment (PPE) and coronavirus disease 2019 (COVID-19) tests for pregnant women, we conducted an urgent survey. Methods: The survey was conducted online from April 27 to May 1, 2020. Questionnaires were sent to core facilities and affiliated hospitals of the obstetrics and gynecology training program and to hospitals of the national perinatal medical liaison council. Results: A total of 296 institutions participated in our survey; however, 2 institutions were excluded. Full PPE was used by doctors in 7.1% of facilities and by midwives in 6.8%. Our study also determined that around 65.0% of facilities for doctors and 73.5% of facilities for midwives used PPE beyond the “standard gown or apron, surgical mask, goggles or face shield” during labor of asymptomatic women. N95 masks were running out of stock at 6.5% of the facilities and goggles and face shields at 2.7%. Disposable N95 masks and goggles or face shields were re-used after re-sterilization in 12% and 14% of facilities, respectively. Polymerase chain reaction (PCR) testing of asymptomatic patients was performed for 9% of vaginal deliveries, 14% of planned cesarean sections and 17% of emergency cesarean sections. The number of PCR tests for obstetrics and gynecology per a week ranged from zero to five in 92% of facilities. Conclusion: The shortage of PPE in Japan is alarming. Sufficient stockpiling of PPE is necessary to prevent unnecessary disruptions in medical care. Appropriate guidelines for PPE usage and COVID-19 testing of pregnant women at delivery are needed in Japan.

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Universal screening for SARS-CoV-2 in asymptomatic obstetric patients in Tokyo, Japan

Ochiai D., Kasuga Y., Iida M., Ikenoue S., Tanaka M.

International Journal of Gynecology and Obstetrics （International Journal of Gynecology and Obstetrics） 150 （ 2 ） 268 - 269 2020年08月

査読有り, ISSN 00207292

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Prophylactic therapy with human amniotic fluid stem cells improved survival in a rat model of lipopolysaccharide-induced neonatal sepsis through immunomodulation via aggregates with peritoneal macrophages

Sato Y., Ochiai D., Abe Y., Masuda H., Fukutake M., Ikenoue S., Kasuga Y., Shimoda M., Kanai Y., Tanaka M.

Stem Cell Research and Therapy （Stem Cell Research and Therapy） 11 （ 1 ） 300 - 300 2020年07月

査読有り

Background: Despite recent advances in neonatal care, sepsis remains a leading cause of mortality in neonates. Mesenchymal stem cells derived from various tissues, such as bone marrow, umbilical cord, and adipose tissue, have beneficial effects on adult sepsis. Although human amniotic fluid stem cells (hAFSCs) have mesenchymal stem cell properties, the efficacy of hAFSCs on neonatal sepsis is yet to be elucidated. This study aimed to investigate the therapeutic potential of hAFSCs on neonatal sepsis using a rat model of lipopolysaccharide (LPS)-induced sepsis. Methods: hAFSCs were isolated as CD117-positive cells from human amniotic fluid. Three-day-old rat pups were intraperitoneally treated with LPS to mimic neonatal sepsis. hAFSCs were administered either 3 h before or at 0, 3, or 24 h after LPS exposure. Serum inflammatory cytokine levels, gene expression profiles from spleens, and multiple organ damage were analyzed. hAFSC localization was determined in vivo. In vitro LPS stimulation tests were performed using neonatal rat peritoneal macrophages co-cultured with hAFSCs in a cell-cell contact-dependent/independent manner. Immunoregulation in the spleen was determined using a DNA microarray analysis. Results: Prophylactic therapy with hAFSCs improved survival in the LPS-treated rats while the hAFSCs transplantation after LPS exposure did not elicit a therapeutic response. Therefore, hAFSC pretreatment was used for all subsequent studies. Inflammatory cytokine levels were elevated after LPS injection, which was attenuated by hAFSC pretreatment. Subsequently, inflammation-induced damages in the brain, lungs, and liver were ameliorated. hAFSCs aggregated with peritoneal macrophages and/or transiently accumulated in the liver, mesentery, and peritoneum. Paracrine factors released by hAFSCs induced M1-M2 macrophage polarization in a cell-cell contact-independent manner. Direct contact between hAFSCs and peritoneal macrophages further enhanced the polarization. Microarray analysis of the spleen showed that hAFSC pretreatment reduced the expression of genes involved in apoptosis and inflammation and subsequently suppressed toll-like receptor 4 signaling pathways. Conclusions: Prophylactic therapy with hAFSCs improved survival in a rat model of LPS-induced neonatal sepsis. These effects might be mediated by a phenotypic switch from M1 to M2 in peritoneal macrophages, triggered by hAFSCs in a cell-cell contact-dependent/independent manner and the subsequent immunomodulation of the spleen.

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臨床的羊水塞栓症を契機に発症した腹部コンパートメント症候群の1例

平田桃, 長谷川慶太, 春日義史, 秋田啓介, 大石真希, 遠藤豊英, 大谷利光, 池ノ上学, 落合大吾, 宮越敬, 田中守, 青木大輔

関東連合産科婦人科学会誌（(一社)関東連合産科婦人科学会） 57 （ 2 ） 233 - 233 2020年06月

ISSN 2186-0610

妊娠中に発症した特発性中枢性尿崩症の1例

島田紗也葵, 春日義史, 吉村拓馬, 山下博, 長谷川慶太, 大石真希, 遠藤豊英, 池ノ上学, 落合大吾, 宮越敬, 田中守, 青木大輔

関東連合産科婦人科学会誌（(一社)関東連合産科婦人科学会） 57 （ 2 ） 226 - 226 2020年06月

ISSN 2186-0610

頭痛および視野欠損を契機に診断に至った脳動脈解離による脳梗塞合併妊娠の1例

秋田啓介, 春日義史, 玉川真澄, 上條慎太郎, 大石真希, 遠藤豊英, 大谷利光, 池ノ上学, 落合大吾, 宮越敬, 田中守, 青木大輔

東京産科婦人科学会会誌（(一社)東京産科婦人科学会） 69 （ 2 ） 212 - 217 2020年04月

ISSN 2186-0599

緒言:脳動脈解離は若年発症脳梗塞の原因となり、リスク因子としては片頭痛や高血圧が挙げられるが、妊婦における初発例は稀である。今回我々は妊娠中に発症した脳動脈解離による脳梗塞の1例を経験したので報告する。症例:31歳、3妊1産。既往歴として片頭痛を認めた。妊娠26週0日に激しい頭痛が出現し、その1週間後に右側半盲を認めた。頭部MRI/MRA検査で左後大脳動脈の狭小化と左後頭葉の虚血性変化が認められ、脳動脈解離による脳梗塞の診断となった。神経学的症状の増悪や血圧の変動なく経過し、妊娠37週5日に経腟分娩に至った。児は2926gの女児でApgar score 8/10点(1/5分値)であった。分娩中や分娩後に血圧の変動や新規の神経学的異常所見の出現は認めなかった。結論:神経学的異常所見を伴う頭痛を認める際には脳動脈解離を含めた脳血管障害を念頭に頭蓋内病変精査を行う必要があると考えられた。(著者抄録)

妊娠中期に卵巣癌と診断し、手術療法と化学療法治療後に生児を得られた1例

田中邦生, 長谷川慶太, 吉村拓馬, 大石真希, 大谷利光, 池ノ上学, 春日義史, 落合大吾, 岩田卓, 宮越敬, 田中守, 青木大輔

東京産科婦人科学会会誌（(一社)東京産科婦人科学会） 69 （ 2 ） 387 - 391 2020年04月

ISSN 2186-0599

緒言:卵巣癌合併妊娠は1万から5万例に1例と頻度が低く、対応に一定の見解はない。今回我々は妊娠中期に卵巣癌を診断され、手術療法と化学療法を行い生児を得られた症例を経験した。症例:44歳、1妊0産。妊娠16週時に卵巣癌を疑われ、妊娠18週時に右付属器摘出術、左卵巣腫瘍摘出術、大網生検を施行した。右卵巣原発の高異型度漿液性癌IIIC期の診断にて術後パクリタキセルとカルボプラチン(TC)併用療法を4サイクル施行し、妊娠35週5日時に選択的帝王切開術とinterval debulking surgeryを同時に施行した。2118gの女児を娩出し、術後TC療法を2サイクル施行した。術後母体は再発を認めず、児の発育も良好である。結論:卵巣癌合併妊娠に対して、予め分娩時期を想定した管理・治療を行ったことで母児ともに合併症なく手術療法と化学療法を行うことができた。(著者抄録)

自然陣痛発来群におけるivPCAを用いた和痛分娩の有用性に関する後方視的検討

長谷川慶太, 春日義史, 玉川真澄, 大石真希, 遠藤豊英, 佐藤佑, 大谷利光, 池ノ上学, 落合大吾, 宮越敬, 田中守, 青木大輔

日本産科婦人科学会雑誌（(公社)日本産科婦人科学会） 72 （臨増） S - 369 2020年03月

ISSN 0300-9165

自然陣痛発来群におけるivPCAを用いた和痛分娩の有用性に関する後方視的検討

長谷川慶太, 春日義史, 玉川真澄, 大石真希, 遠藤豊英, 佐藤佑, 大谷利光, 池ノ上学, 落合大吾, 宮越敬, 田中守, 青木大輔

日本産科婦人科学会雑誌（(公社)日本産科婦人科学会） 72 （臨増） S - 369 2020年03月

ISSN 0300-9165

当院における高用量黄体ホルモン療法後妊娠の周産期臨床像

大石真希, 春日義史, 山上亘, 長谷川慶太, 遠藤豊英, 佐藤佑, 大谷利光, 池ノ上学, 落合大吾, 宮越敬, 田中守, 青木大輔

日本産科婦人科学会雑誌（(公社)日本産科婦人科学会） 72 （臨増） S - 547 2020年03月

ISSN 0300-9165

妊娠初期に診断された妊娠糖尿病の臨床像に関する検討

玉川真澄, 春日義史, 長谷川慶太, 遠藤豊英, 大石真希, 佐藤佑, 大谷利光, 池ノ上学, 落合大吾, 宮越敬, 田中守, 青木大輔

日本産科婦人科学会雑誌（(公社)日本産科婦人科学会） 72 （臨増） S - 458 2020年03月

ISSN 0300-9165

妊娠初期に診断された妊娠糖尿病の臨床像に関する検討

玉川真澄, 春日義史, 長谷川慶太, 遠藤豊英, 大石真希, 佐藤佑, 大谷利光, 池ノ上学, 落合大吾, 宮越敬, 田中守, 青木大輔

日本産科婦人科学会雑誌（(公社)日本産科婦人科学会） 72 （臨増） S - 458 2020年03月

ISSN 0300-9165

当院における高用量黄体ホルモン療法後妊娠の周産期臨床像

大石真希, 春日義史, 山上亘, 長谷川慶太, 遠藤豊英, 佐藤佑, 大谷利光, 池ノ上学, 落合大吾, 宮越敬, 田中守, 青木大輔

日本産科婦人科学会雑誌（(公社)日本産科婦人科学会） 72 （臨増） S - 547 2020年03月

ISSN 0300-9165

In Utero Amniotic Fluid Stem Cell Therapy Protects Against Myelomeningocele via Spinal Cord Coverage and Hepatocyte Growth Factor Secretion

Abe Y., Ochiai D., Masuda H., Sato Y., Otani T., Fukutake M., Ikenoue S., Miyakoshi K., Okano H., Tanaka M.

Stem Cells Translational Medicine （Stem Cells Translational Medicine） 8 （ 11 ） 1170 - 1179 2019年08月

ISSN 2157-6564

© 2019 The Authors. Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press Despite the poor prognosis associated with myelomeningocele (MMC), the options for prenatal treatments are still limited. Recently, fetal cellular therapy has become a new option for treating birth defects, although the therapeutic effects and mechanisms associated with such treatments remain unclear. The use of human amniotic fluid stem cells (hAFSCs) is ideal with respect to immunoreactivity and cell propagation. The prenatal diagnosis of MMC during early stages of pregnancy could allow for the ex vivo proliferation and modulation of autologous hAFSCs for use in utero stem cell therapy. Therefore, we investigated the therapeutic effects and mechanisms of hAFSCs-based treatment for fetal MMC. hAFSCs were isolated as CD117-positive cells from the amniotic fluid of 15- to 17-week pregnant women who underwent amniocentesis for prenatal diagnosis and consented to this study. Rat dams were exposed to retinoic acid to induce fetal MMC and were subsequently injected with hAFSCs in each amniotic cavity. We measured the exposed area of the spinal cord and hepatocyte growth factor (HGF) levels at the lesion. The exposed spinal area of the hAFSC-treated group was significantly smaller than that of the control group. Immunohistochemical analysis demonstrated a reduction in neuronal damage such as neurodegeneration and astrogliosis in the hAFSC-treated group. Additionally, in lesions of the hAFSC-treated group, HGF expression was upregulated and HGF-positive hAFSCs were identified, suggesting that these cells migrated to the lesion and secreted HGF to suppress neuronal damage and induce neurogenesis. Therefore, in utero hAFSC therapy could become a novel strategy for fetal MMC. Stem Cells Translational Medicine 2019;8:1170–1179.

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日本人妊娠糖尿病既往女性における産後糖代謝異常発症予測因子に関する後方視的検討

春日義史, 宮越敬, 税所芳史, 池ノ上学, 荒田尚子, 田中守

糖尿病と妊娠（(一社)日本糖尿病・妊娠学会） 19 （ 2 ） S - 67 2019年08月

ISSN 1347-9172

日本人妊娠糖尿病(Gestational Diabetes Mellitus:GDM)既往女性における産後糖代謝異常(Postpartum Abnormal Glucose Tolerance:pAGT)発症予測因子を検討した。対象は日本人GDM合併単胎妊婦のうち、分娩後1年以内に75gOGTTを受けた女性である(pAGT[n=59]、正常耐糖能型[n=154])。GDM診断時OGTT血糖値ならびに遺伝因子とpAGTとの関連解析を行ったところ、OGTT2時間値のpAGT発症予測能が高かった(AUC=0.72)。遺伝因子では4遺伝子がpAGT群においてリスクアレルを多く持つ傾向にあり、検出された4遺伝子中、3遺伝子はインスリン分泌関連遺伝子であった。日本人GDM既往女性において、GDM診断時OGTT 2時間値がpAGT発症予測に有用であり、遺伝学的にインスリン分泌不全の関与が示唆された。(著者抄録)

妊娠糖尿病における抗Glutamic Acid Decarboxylase抗体と周産期事象との関連

池ノ上学, 宮越敬, 遠藤豊英, 大石真希, 税所芳史, 田中守

糖尿病と妊娠（(一社)日本糖尿病・妊娠学会） 19 （ 2 ） S - 84 2019年08月

ISSN 1347-9172

抗Glutamic Acid Decarboxylase(GAD)抗体は、自己免疫性1型糖尿病の診断や発症予知に用いられる膵島関連自己抗体であるが、妊娠糖尿病(Gestational diabetes mellitus:GDM)との関連に関する知見は乏しい。今回、抗GAD抗体の測定を行ったGDM妊婦172例を対象とし、GDM妊婦におけるGAD抗体の陽性率と、その母体背景および周産期予後との関連について検討した。GDMにおけるGAD抗体陽性率は3.5%であり、抗GAD抗体陽性例では妊娠高血圧腎症が有意に高率であった。その他の周産期事象や母体背景には有意差を認めなかった。GDM妊婦において、抗GAD抗体は妊娠高血圧腎症のリスク因子となる可能性が示唆された。(著者抄録)

性分化疾患を含む多発先天異常を胎内診断し周産期管理を行った1例

明石一浩, 池ノ上学, 遠藤豊英, 大石真希, 落合大吾, 宮越敬, 田中守, 長谷川奉延, 飛彈麻里子, 有光威志, 高橋萌, 若林大樹, 玉岡哲, 黒田達夫

日本周産期・新生児医学会雑誌（(一社)日本周産期・新生児医学会） 55 （ 2 ） 591 - 591 2019年06月

ISSN 1348-964X

子宮内膜異型増殖症および早期子宮体癌に対する高用量黄体ホルモン療法後妊娠の産科的予後に関する検討

大石真希, 宮越敬, 遠藤豊英, 池ノ上学, 落合大吾, 田中守

日本周産期・新生児医学会雑誌（(一社)日本周産期・新生児医学会） 55 （ 2 ） 485 - 485 2019年06月

ISSN 1348-964X

ヒト羊水幹細胞投与はLPS誘発性新生仔炎症モデルラットの予後を改善する

佐藤佑, 落合大吾, 大谷利光, 福武麻里絵, 池ノ上学, 宮越敬, 田中守

日本周産期・新生児医学会雑誌（(一社)日本周産期・新生児医学会） 55 （ 2 ） 551 - 551 2019年06月

ISSN 1348-964X

Changes in bone metabolic profile associated with pregnancy or lactation

Miyamoto T., Miyakoshi K., Sato Y., Kasuga Y., Ikenoue S., Miyamoto K., Nishiwaki Y., Tanaka M., Nakamura M., Matsumoto M.

Scientific Reports （Scientific Reports） 9 （ 1 ） 6787 - 6787 2019年05月

ISSN 2045-2322

© 2019, The Author(s). Calcium and nutrients are transferred from mothers to fetuses or infants during pregnancy or lactation, respectively, promoting metabolic changes in the mother, many uncharacterized. To evaluate these changes, we undertook two parallel studies. In one we analyzed fourteen clinical cases of vertebral fragility fractures, at or before three months after partum, in mothers who breastfed their infants. In the other, we enrolled 79 additional pregnant subjects, some who chose to breastfeed and others who did not, and analyzed changes in bone metabolic status starting between 34 and 36 weeks of gestation and ending one month after partum. In the larger group, bone-resorbing and bone-forming parameters such as serum TRACP5b and osteocalcin, respectively, significantly increased after partum. Among parameters that changed after partum, serum PTH and the bone-resorbing markers serum TRACP5b and urine NTX were significantly higher in mothers who only breastfed infants compared to mothers who fed infants formula or a mix of both. However, bone-forming parameters were comparable between breastfeeding and non-breast-feeding groups after partum, suggesting that elevated bone-resorption occurs only in the breastfeeding group. Radiographic analysis after partum demonstrated that no subject among the 79 analyzed showed vertebral fractures, even those who breastfed exclusively. Among fracture cases analyzed, subjects exhibited significantly lower bone mineral density than did non-fracture cases in breastfeeding-only subjects. We conclude that bone metabolic status significantly changes over the period between pregnancy and post-partum lactation, and that low bone mineral density seen in a small subset of breastfeeding-only cases likely causes post-partum vertebral fragility fractures.

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Glycemic and metabolic features in gestational diabetes: singleton versus twin pregnancies

Akiba, Y., Miyakoshi, K., Ikenoue, S., Saisho, Y., Kasuga, Y., Ochiai, D., Matsumoto, T. and Tanaka, M.

Endocr J 66 （ 7 ） 647 - 651 2019年04月

ISSN 1348-4540

A number of data on gestational diabetes mellitus (GDM) in singleton pregnancy is available, however, little is known about the glycemic characteristics of twin pregnancy with GDM. The aim of this study was to compare the severity of dysglycemia between twin and singleton pregnancies with GDM (T-GDM and S-GDM). We retrospectively analyzed pregnancies with GDM defined by the Japan Diabetes Society criteria (T-GDM, n = 20; S-GDM, n = 451) in our hospital. During the study period, women with GDM underwent self-monitoring of blood glucose measurements as well as dietary management. Insulin treatment was initiated when dietary treatment did not achieve the glycemic goal. The glycemic and metabolic characteristics were compared between T-GDM and S-GDM, as follows: gestational week at the diagnosis of GDM, 75 g oral glucose tolerance test (OGTT) results, HbA1c, insulin secretion (i.e. insulinogenic index [IGI] and Insulin Secretion-Sensitivity Index-2 [ISSI-2]), and insulin requirement before delivery. The rate of one abnormal OGTT value in T-GDM was similar to that in S-GDM (60% vs. 71%). There were no significant differences in gestational week and levels of HbA1c at diagnosis, levels of IGI and ISSI-2 between T-GDM and S-GDM (median, 20 weeks vs. 17 weeks, 5.0% vs. 5.2%, 0.58 vs. 0.71, 1.7 vs. 1.8, respectively). The rate of insulin treatment and a median dosage of insulin needed before delivery was comparable between the two groups (T-GDM vs. S-GDM: 45% vs. 32% and 14 vs. 13 unit/day). Our data suggested that the severity of dysglycemia in T-GDM was similar to that in S-GDM during pregnancy.

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分娩後に急性腎不全を発症し非典型溶血性尿毒症症候群(aHUS)と診断した1例

竹田将人, 池ノ上学, 坂井健良, 遠藤豊英, 大石真希, 落合大吾, 宮越敬, 田中守, 青木大輔

東京産科婦人科学会会誌（(一社)東京産科婦人科学会） 68 （ 2 ） 339 - 343 2019年04月

ISSN 2186-0599

血栓性微小血管症(TMA)は溶血性貧血、血小板減少、臓器機能障害を三徴とする病態であり、非典型溶血性尿毒症症候群(atypical hemolytic uremic syndrome:aHUS)はその一つである。今回、分娩後経過から早期にaHUSを診断し、良好な予後を得た症例を経験したため報告する。症例は33歳、1妊1産。妊娠経過は良好で、妊娠38週に自然経腟分娩となった。分娩後、弛緩出血に対して輸血および子宮内バルーンタンポナーデを行い止血を得たが、産後2日目より腎機能障害、肝機能障害を認め当院へ搬送となった。TMAの三徴を認め、ADAMTS-13活性は正常値でありaHUSと診断した。血液透析と血漿補充により腎機能は改善し、産後22日目に退院となった。溶血性貧血と血小板減少を伴う急激な腎機能障害を認めた場合、早期からaHUSを鑑別疾患に挙げることが肝要である。(著者抄録)

三次元スフェア培養はヒト羊水幹細胞の抗炎症性サイトカイン分泌と未分化マーカー発現を増強する

佐藤佑, 落合大吾, 阿部雄志, 遠藤豊英, 大石真希, 大谷利光, 福武麻里絵, 池ノ上学, 升田博隆, 宮越敬, 田中守, 青木大輔

日本産科婦人科学会雑誌（(公社)日本産科婦人科学会） 71 （臨増） S - 382 2019年02月

ISSN 0300-9165

Maternal Daily Intake of Polyphenol-Rich Dark Chocolate and Premature Closure of Ductus Arteriosus

Anko, Mayuka, Ikenoue, Satoru, Kawamura, Makoto, Yakubo, Kazumi

Biomed J Sci & Tech Res 21 （ 2 ） 2019年

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Impaired fetal growth in mothers with inadequate gestational weight gain: a retrospective study in Japanese uncomplicated pregnancy.

Ikenoue S, Miyakoshi K, Kasuga Y, Ochiai D, Matsumoto T, Tanaka M

The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians （Journal of Maternal-Fetal and Neonatal Medicine） 33 （ 13 ） 1 - 5 2018年12月

ISSN 1476-4954

Introduction: The average birth weight in Japan has gradually decreased and the number of low birth weight infant has increased over the last 30 years. Japanese pregnant women are characterized with lower prevalence of obesity than those in other developed countries, and maternal underweight before pregnancy is independently associated with low birth weight. However, the association between maternal inadequate gestational weight gain (GWG) and the risk of small for gestational age (SGA) in Japanese uncomplicated pregnant women has not been fully understood. This study aimed to examine the effect of maternal inadequate GWG on the risk of SGA in Japanese uncomplicated pregnancies. Methods: We retrospectively analyzed uncomplicated Japanese singleton pregnancies that delivered at term gestation in our institution from 2006 to 2016. The association between GWG and birth weight was analyzed by multiple linear regression. Potential confounding factors included maternal age, parity, prepregnancy BMI, and neonatal sex. The association between inadequate GWG and SGA was also examined by logistic regression. Results: A total of 3837 mother–neonate dyads were analyzed. Maternal GWG was 10.1 ± 3.7 kg (mean ± SD), and 2529 (66%) had inadequate GWG. After adjusting for confounding factors, GWG significantly correlated with birth weight (standardized β = 0.199, p <.001). Inadequate GWG increased the risk of delivering SGA neonate (adjusted odds ratio (aOR) = 1.97 [1.45–2.68], p <.001). This association was particularly pronounced in underweight (aOR = 2.95 [1.38–6.29], p =.005) and normal weight mothers (aOR = 1.79 [1.27–2.52], p =.001), and not in overweight/obese mothers (p =.115). Conclusion: Maternal GWG is associated with birth weight in Japanese women with uncomplicated singleton pregnancies. Inadequate GWG is an important risk factor of SGA, particularly in non-obese women. The present finding would potentially provide further evidence that promoting adequate gestational weight gain in Japanese underweight and normal weight mothers would reduce SGA, as well as metabolic dysfunction in later life.

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多胎妊娠と糖代謝異常　より良い管理を目指して　双胎妊娠における妊娠糖尿病の糖代謝異常重症度に関する検討

秋葉洋平, 宮越敬, 税所芳史, 佐藤佑, 池ノ上学, 落合大吾, 松本直, 田中守

糖尿病と妊娠（(一社)日本糖尿病・妊娠学会） 18 （ 2 ） S - 46 2018年08月

ISSN 1347-9172

双胎妊娠における妊娠糖尿病(GDM)の糖代謝異常重症度に関する知見は少ない。本研究の目的は双胎GDMにおける糖代謝異常重症度の解析である。自施設で周産期管理を行ったGDM例を双胎(n=20)と単胎(n=451)に分類し、両群の糖代謝異常重症度を比較検討した(リトドリン使用例は除外)。まず、両群の母体背景(年齢、非妊時BMI、GDM既往、糖尿病家族歴、初期随時血糖)は同等であった。また、インスリン療法導入率および導入週数、投与量について両群間に有意差を認めなかった。したがって、双胎GDMの糖代謝異常重症度は単胎と同等であることが示唆された。(著者抄録)

妊娠中の母体体重増加不良と出生体重に関する後方視的検討

池ノ上学, 宮越敬, 佐藤佑, 秋葉洋平, 大谷利光, 福武麻里絵, 春日義史, 落合大吾, 松本直, 田中守

糖尿病と妊娠（(一社)日本糖尿病・妊娠学会） 18 （ 2 ） S - 86 2018年08月

ISSN 1347-9172

本邦では近年、やせ妊婦の増加と妊娠中の体重増加不良が指摘されている。今回、当院で単胎正期産分娩に至った3837例について、米国Institute of Medicine基準による母体体重増加不良と、在胎期間別出生時体格標準値(日本小児科学会)によるlight-for-date(LFD:出生体重<10パーセンタイル)との関連を年齢、経産数、非妊時BMI、児の性別を交絡因子として解析した。体重増加不良群では、LFDが有意に高率であり(adjusted odds ratio:1.94)、とくにやせ群(BMI < 18.5)と標準群(18.5 ≦ BMI< 25)でのみ有意差を認めた。やせ群と標準群では母体体重増加不良がLFDのリスク因子であることが示された。(著者抄録)

妊娠関連乳癌の骨転移による脊髄圧迫のため緊急帝王切開術を施行した1例

遠藤豊英, 村上功, 小泉和恵, 白橋真由, 池ノ上学, 横田めぐみ, 天方朋子, 池田俊之, 矢久保和美

埼玉産科婦人科学会雑誌（埼玉産科婦人科学会） 48 （ 1 ） 11 - 14 2018年03月

ISSN 2186-4349

近年、妊娠関連乳癌(Pregnancy Associated Breast Cancer:PABC)は、出産年齢の高齢化に伴い増加傾向である。今回我々は、PABCの骨転移による脊髄圧迫のため緊急帝王切開術を施行した症例を経験した。症例は36歳0経妊0経産の生来健康な女性である。妊娠30週より腰痛及び下肢の痺れを自覚し、妊娠32週1日、歩行困難のため当院へ搬送となった。MRIで多発骨転移による腰椎圧迫骨折および脊髄圧迫を疑う所見を認め、単純CTにて右乳腺腫瘍、右腋窩リンパ節腫大を認めた。PABCの骨転移による脊髄圧迫に対し、緊急放射線照射が必要なOncologic Emergencyであった。妊娠週数を考慮し、ベタメタゾン投与を施行し、妊娠32週4日、緊急帝王切開術及び右乳腺腫瘍針生検を施行した。術後緊急放射線照射を施行したが、下肢麻痺及び膀胱直腸障害は残存した。一方、児は経過良好であった。本症例は転移性脊髄圧迫のため妊娠中にも関わらず緊急放射線照射を要するOncologic Emergencyであった。今後増加が予想されるPABCに対して妊娠前後の乳癌検診の啓蒙が望まれる。(著者抄録)

Discordant fetal phenotype of hypophosphatasia in two siblings

Ikenoue S., Miyakoshi K., Ishii T., Sato Y., Otani T., Akiba Y., Kasuga Y., Ochiai D., Matsumoto T., Ichihashi Y., Matsuzaki Y., Tachikawa K., Michigami T., Nishimura G., Ikeda K., Hasegawa T., Tanaka M.

American Journal of Medical Genetics, Part A （American Journal of Medical Genetics, Part A） 176 （ 1 ） 171 - 174 2018年01月

ISSN 1552-4825

© 2017 Wiley Periodicals, Inc. Hypophosphatasia (HPP) is an autosomal recessive metabolic disorder with impaired bone mineralization due to mutations in the ALPL gene. The genotype-phenotype correlation of this disorder has been widely described. Here, we present two affected siblings, whose fetal phenotypes were discordant. A 31-year-old Japanese woman, G0P0, was referred to our institution because of fetal micromelia. After obstetric counseling, the pregnancy was terminated at 21 weeks’ gestation. Post-mortem radiographs demonstrated severely defective mineralization of the skeleton. The calvarial, spinal, and tubular bones were mostly missing. Only the occipital bones, mandible, clavicles, ribs, one thoracic vertebra, ilia, and tibia were relatively well ossified. The radiological findings suggested lethal HPP. Genetic testing for genomic DNA extracted from the umbilical cord identified compound heterozygous mutations in the ALPL gene (c.532T>C, p.Y178H; c.1559delT, p.Leu520Argfs*86). c.532T>C was a novel variant showing no residual activity of the protein by the functional analysis. The parents were heterozygous carriers. In the next pregnancy, biometric values on fetal ultrasonography at 20 and 26 weeks’ gestation were normal. At 34 weeks, however, a small chest and shortening of distal long bones came to attention. The neonate delivered at 41 weeks showed serum ALP of <5U/L. Radiological examination showed only mild thoracic hypoplasia and metaphyseal mineralization defects of the long bones. ALP replacement therapy was introduced shortly after birth, and the neonate was discharged at day 22 without respiratory distress. Awareness of discordant fetal phenotypes in siblings with HPP precludes a diagnostic error, and enables early medical intervention to mildly affected neonates.

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Clinical and genetic characteristics of abnormal glucose tolerance in Japanese women in the first year after gestational diabetes mellitus

Kasuga Y., Miyakoshi K., Tajima A., Saisho Y., Ikenoue S., Ochiai D., Matsumoto T., Arata N., Hata K., Tanaka M.

Journal of Diabetes Investigation （Journal of Diabetes Investigation） 10 （ 3 ） 817 - 826 2018年01月

ISSN 2040-1116

© 2018 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd Aims/Introduction: Risk factors of type 2 diabetes mellitus in Japanese women with recent gestational diabetes mellitus are unknown. The objective of the present study was to investigate the clinical and genetic characteristics associated with postpartum abnormal glucose tolerance in Japanese women with gestational diabetes mellitus. Materials and Methods: A total of 213 Japanese women with recent gestational diabetes mellitus who underwent a postpartum 2-h oral glucose tolerance test were investigated. The association between antepartum clinical characteristics and postpartum abnormal glucose tolerance (diabetes or prediabetes based on the Japan Diabetes Society criteria) was examined. Frequencies of 45 known type 2 diabetes mellitus-associated genetic variants were also compared between women with and without postpartum abnormal glucose tolerance. Results: A total of 59 women showed postpartum abnormal glucose tolerance (prediabetes, n = 51; diabetes, n = 8). Plasma glucose levels at 1 or 2 h, the insulinogenic index and the insulin secretion-sensitivity index-2 of the antepartum oral glucose tolerance test were independent of postpartum abnormal glucose tolerance risk factors (P = 0.006, P = 0.00002, P = 0.01 and P = 0.006, respectively). Four genetic variants (rs266729 [ADIPOQ], rs6017317 [HNF4A], rs5215 [KCNJ11] and rs7177055 [HMG20A]) showed a nominally significant association with postpartum abnormal glucose tolerance (P < 0.05, respectively). Among these, three were related to insulin secretion. Postpartum abnormal glucose tolerance risk significantly increased with increasing risk-allele number (P = 0.0005; odds ratio 1.91). Conclusions: Clinical features and genetic variants related to impaired insulin secretion are risk factors of postpartum abnormal glucose tolerance in Japanese women with recent gestational diabetes mellitus.

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Cover Image, Volume 176A, Number 1, January 2018

American journal of medical genetics. Part A （American journal of medical genetics. Part A） 176 （ 1 ） i 2018年01月

ISSN 1552-4825

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Association between supraclavicular brown adipose tissue composition at birth and adiposity gain from birth to 6 months of age

Entringer Sonja, Rasmussen Jerod, Cooper Dan M., Ikenoue Satoru, Waffarn Feizal, Wadhwa Pathik D., Buss Claudia

Pediatric Research 82 （ 6 ） 1017 - 1021 2017年12月

ISSN 0031-3998

BackgroundBrown adipose tissue (BAT) is associated with higher energy expenditure and lower adiposity in adults. However, the relationship between BAT composition and adiposity in early life is unknown. The objective of this study was to test the hypothesis that brown fat composition at birth is prospectively associated with adiposity gain during the first 6 months of postnatal life.MethodsN=35 healthy infants were followed up prospectively from intrauterine life and birth through 6 months of age. Dixon magnetic resonance imaging (MRI) scans were conducted during the neonatal period to characterize supraclavicular BAT composition. Dual-energy X-ray absorptiometry to assess total body composition was performed within the first and sixth months of life.ResultsAfter adjusting for potential confounding factors, a more brown-like composition (smaller fat fraction) of the supraclavicular BAT depot was associated with a smaller increase in percent body fat over the first 6 months of postnatal life.ConclusionsA more brown-like BAT composition at birth appears to be protective against excess adiposity gain in early life. Newborn BAT tissue may constitute a target for prevention strategies against the subsequent development of obesity.

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Prospective association of fetal liver blood flow at 30 weeks gestation with newborn adiposity

Ikenoue S., Waffarn F., Ohashi M., Sumiyoshi K., Ikenoue C., Buss C., Gillen D., Simhan H., Entringer S., Wadhwa P.

American Journal of Obstetrics and Gynecology （American Journal of Obstetrics and Gynecology） 217 （ 2 ） 204.e1 - 204.e8 2017年08月

ISSN 0002-9378

© 2017 Elsevier Inc. Background The production of variation in adipose tissue accretion represents a key fetal adaptation to energy substrate availability during gestation. Because umbilical venous blood transports nutrient substrate from the maternal to the fetal compartment and because the fetal liver is the primary organ in which nutrient interconversion occurs, it has been proposed that variations in the relative distribution of umbilical venous blood flow shunting either through ductus venosus or perfusing the fetal liver represents a mechanism underlying this adaptation. Objective The objective of the present study was to determine whether fetal liver blood flow assessed before the period of maximal fetal fat deposition (ie, the third trimester of gestation) is prospectively associated with newborn adiposity. Study Design A prospective study was conducted in a cohort of 62 uncomplicated singleton pregnancies. Fetal ultrasonography was performed at 30 weeks gestation for conventional fetal biometry and characterization of fetal liver blood flow (quantified by subtracting ductus venosus flow from umbilical vein flow). Newborn body fat percentage was quantified by dual energy X-ray absorptiometry imaging at 25.8 ± 3.3 (mean ± standard error of the mean) postnatal days. Multiple regression analysis was used to determine the proportion of variation in newborn body fat percentage explained by fetal liver blood flow. Potential confounding factors included maternal age, parity, prepregnancy body mass index, gestational weight gain, gestational age at birth, infant sex, postnatal age at dual energy X-ray absorptiometry scan, and mode of infant feeding. Results Newborn body fat percentage was 13.5% ± 2.4% (mean ± standard error of the mean). Fetal liver blood flow at 30 weeks gestation was significantly and positively associated with newborn total fat mass (r=0.397; P<.001) and body fat percentage (r=0.369; P=.004), but not with lean mass (r=0.100; P=.441). After accounting for the effects of covariates, fetal liver blood flow explained 13.5% of the variance in newborn fat mass. The magnitude of this association was pronounced particularly in nonoverweight/nonobese mothers (prepregnancy body mass index, <25 kg/m2; n=36) in whom fetal liver blood flow explained 24.4% of the variation in newborn body fat percentage. Conclusion Fetal liver blood flow at the beginning of the third trimester of gestation is associated positively with newborn adiposity, particularly among nonoverweight/nonobese mothers. This finding supports the role of fetal liver blood flow as a putative fetal adaptation underlying variation in adipose tissue accretion.

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Association of ultrasound-based measures of fetal body composition with newborn adiposity

Ikenoue S., Waffarn F., Sumiyoshi K., Ohashi M., Ikenoue C., Buss C., Gillen D., Simhan H., Entringer S., Wadhwa P.

Pediatric Obesity （Pediatric Obesity） 12 86 - 93 2017年08月

ISSN 2047-6302

© 2016 World Obesity Federation Background: Newborns exhibit substantial variation in gestational age-adjusted and sex-adjusted fat mass proportion. The antecedent characteristics of fetal body composition that are associated with newborn fat mass proportion are poorly understood. Objective: The aim of this study was to determine whether a composite measure of fetal fat mass is prospectively associated with newborn adiposity. Methods: In a longitudinal study of 109 low-risk pregnancies, fetal ultrasonography was performed at approximately 12, 20 and 30 weeks gestation. Estimated fetal adiposity (EFA) was derived by integrating cross-sectional arm and thigh per cent fat area and anterior abdominal wall thickness. Newborn per cent body fat was quantified by Dual Energy X-Ray Absorptiometry. The association between EFA and newborn per cent body fat was determined by multiple linear regression. Results: After controlling for confounding factors, EFA at 30 weeks was significantly associated with newborn per cent body fat (standardized β = 0.41, p < 0.001) and explained 24.0% of its variance, which was substantially higher than that explained by estimated fetal weight (8.1%). The observed effect was driven primarily by arm per cent fat area. Conclusions: A composite measure of fetal adiposity at 30 weeks gestation may constitute a better predictor of newborn per cent body fat than estimated fetal weight by conventional fetal biometry. Fetal arm fat deposition may represent an early indicator of newborn adiposity. After replication, these findings may provide a basis for an improved understanding of the ontogeny of fetal fat deposition, thereby contributing to a better understanding of its intrauterine determinants and the development of potential interventions.

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Association between supraclavicular brown adipose tissue composition at birth and adiposity gain from birth to 6 months age

Entringer, S., Rasmussen, J., Cooper, D. M., Ikenoue, S., Waffarn, F., Potkin, S. G., Wadhwa, P. D. and Buss, C.

Pediatr Res 2017年07月

ISSN 0031-3998

BACKGROUND: Brown Adipose Tissue (BAT) is associated with higher energy expenditure and lower adiposity in adults. However, the relationship between BAT composition and adiposity in early life is unknown. The objective of this study was to test the hypothesis that brown fat composition at birth is prospectively associated with adiposity gain during the first six months of postnatal life. METHODS: N=35 healthy infants were followed prospectively from intrauterine life and birth through 6 months age. Dixon MRI scans were conducted during the neonatal period to characterize supraclavicular BAT composition. Dual-energy X-ray absorptiometry to assess total body composition was performed within the first month of life and at 6 months age. RESULTS: After adjusting for potential confounding factors, a more brown-like composition (smaller fat fraction) of the supraclavicular BAT depot was associated with a smaller increase in percent body fat over the first six months of postnatal life. CONCLUSIONS: A more brown-like BAT composition at birth appears to be protective against excess adiposity gain in early life. Newborn BAT tissue may constitute a target for prevention strategies against the subsequent development of obesity.Pediatric Research accepted article preview online, 19 July 2017. doi:10.1038/pr.2017.159.

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Mid-trimester residual cervical length and the risk of preterm birth in pregnancies after abdominal radical trachelectomy: a retrospective analysis

Kasuga Y., Miyakoshi K., Nishio H., Akiba Y., Otani T., Fukutake M., Ikenoue S., Ochiai D., Matsumoto T., Tanaka K., Minegishi K., Kuji N., Roberts R., Aoki D., Tanaka M.

BJOG: An International Journal of Obstetrics and Gynaecology （BJOG: An International Journal of Obstetrics and Gynaecology） 124 （ 11 ） 1729 - 1735 2017年04月

ISSN 1471-0528

© 2017 Royal College of Obstetricians and Gynaecologists Objective: To investigate the association between mid-trimester residual cervical length (CL) and the risk of preterm birth in pregnancies after abdominal radical trachelectomy (RT). Design: Retrospective cohort study. Setting: University hospital. Population: A total of 33 deliveries after 22 weeks’ gestation in 30 women who underwent abdominal RT including prophylactic cervical cerclage and perinatal care between January 2002 and May 2016. Methods: The association between mid-trimester residual CL (the distance between the cerclage and the external cervical os) and gestational age at delivery was investigated. Receiver–operating characteristics (ROC) curve analysis was performed to estimate the optimal cut-off values of the mid-trimester residual CL for the prediction of preterm birth. Main outcome measures: Preterm birth before 34 weeks’ gestation. Results: Mid-trimester residual CL showed a significant correlation with gestational age at delivery (r = 0.36, P < 0.05). There was a significant difference in residual CL between women who did and those who did not give birth before 34 weeks (P < 0.05). Mid-trimester residual CL < 13 mm was a good predictor of birth before 34 weeks, with a sensitivity of 67%, specificity of 75%, positive predictive value of 55% and negative predictive value of 86% (area under ROC curve, 0.75). Conclusions: Mid-trimester residual CL is significantly correlated with gestational age at delivery. Residual CL assessment could be used to reassure physicians and women that there is only a small chance of preterm birth in pregnancies after abdominal RT. Tweetable abstract: Mid-trimester residual cervical length is a good predictor of preterm birth after radical trachelectomy.

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Mid-trimester residual cervical length and the risk of preterm birth in pregnancies after abdominal radical trachelectomy

Kasuga Y., Miyakoshi K., Nishio H., Akiba Y., Otani T., Fukutake M., Ikenoue S., Ochiai D., Matsumoto T., Tanaka K., Minegishi K., Kuji N., Roberts R., Aoki D., Tanaka M.

BJOG: An International Journal of Obstetrics and Gynaecology 2017年

ISSN 1470-0328

Objective: To investigate the association between mid-trimester residual cervical length (CL) and the risk of preterm birth in pregnancies after abdominal radical trachelectomy (RT). Design: Retrospective cohort study. Setting: University hospital. Population: A total of 33 deliveries after 22 weeks' gestation in 30 women who underwent abdominal RT including prophylactic cervical cerclage and perinatal care between January 2002 and May 2016. Methods: The association between mid-trimester residual CL (the distance between the cerclage and the external cervical os) and gestational age at delivery was investigated. Receiver-operating characteristics (ROC) curve analysis was performed to estimate the optimal cut-off values of the mid-trimester residual CL for the prediction of preterm birth. Main outcome measures: Preterm birth before 34 weeks' gestation. Results: Mid-trimester residual CL showed a significant correlation with gestational age at delivery (r = 0.36, P < 0.05). There was a significant difference in residual CL between women who did and those who did not give birth before 34 weeks (P < 0.05). Mid-trimester residual CL < 13 mm was a good predictor of birth before 34 weeks, with a sensitivity of 67%, specificity of 75%, positive predictive value of 55% and negative predictive value of 86% (area under ROC curve, 0.75). Conclusions: Mid-trimester residual CL is significantly correlated with gestational age at delivery. Residual CL assessment could be used to reassure physicians and women that there is only a small chance of preterm birth in pregnancies after abdominal RT. Tweetable abstract: Mid-trimester residual cervical length is a good predictor of preterm birth after radical trachelectomy.

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Clinical impact of women with gestational diabetes mellitus by the new consensus criteria

Ikenoue Satoru, Miyakoshi Kei, Saisho Yoshifumi, Sakai Kensuke, Kasuga Yoshifumi, Fukutake Marie, Izumi Yoko, Matsumoto Tadashi, Minegishi Kazuhiro, Yoshimura Yasunori

Endocrine Journal 61 （ 4 ） 353 - 358 2014年

ISSN 0918-8959

There is a paucity of information on perinatal data regarding gestational diabetes mellitus (GDM) by the new criteria from a real experience because the number of health care associations implementing the new criteria is still limited. The aim of this study is to investigate perinatal features of the new criteria-defined GDM. We reviewed a total of 995 women with singleton pregnancy that underwent GDM screening followed by a diagnostic oral glucose tolerance test (OGTT). All women found to have GDM underwent self-monitoring of blood glucose measurements as well as dietary management. Insulin treatment was initiated when dietary treatment did not achieve the glycemic goal. Of the 995 women, 141 had GDM (14.2%): 104 with one, 27 with two, and 10 with three abnormal OGTT values. Women with two or three abnormal OGTT values (2/3-AV) needed insulin treatment more frequently than those with one abnormal OGTT value (1-AV) (70.3% vs 23.1%, P<0.0001). After adjustment for age, pregravid overweight, gestational weeks at diagnosis, a first-degree family history of diabetes was correlated with the implementation of insulin treatment in women with 1-AV (adjusted odds ratio 3.9; 95% Confidence Interval 1.7-9.2; P = 0.001). When compared perinatal outcomes between women with normal glucose tolerance and GDM, fetal growth and the occurrence of pregnancy-induced hypertension were comparable between the two groups. Our data suggest that the IADPSG-defined GDM with 1-AV show less severe glucose intolerance, but might be at risk of insulin requirement when a first-degree family history of diabetes exists.

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Clinical impact of women with gestational diabetes mellitus by the new consensus criteria: Two year experience in a single institution in Japan

Ikenoue S., Miyakoshi K., Saisho Y., Sakai K., Kasuga Y., Fukutake M., Izumi Y., Matsumoto T., Minegishi K., Yoshimura Y.

Endocrine Journal （Endocrine Journal） 61 （ 4 ） 353 - 8 2014年

ISSN 0918-8959

There is a paucity of information on perinatal data regarding gestational diabetes mellitus (GDM) by the new criteria from a real experience because the number of health care associations implementing the new criteria is still limited. The aim of this study is to investigate perinatal features of the new criteria-defined GDM. We reviewed a total of 995 women with singleton pregnancy that underwent GDM screening followed by a diagnostic oral glucose tolerance test (OGTT). All women found to have GDM underwent self-monitoring of blood glucose measurements as well as dietary management. Insulin treatment was initiated when dietary treatment did not achieve the glycemic goal. Of the 995 women, 141 had GDM (14.2%): 104 with one, 27 with two, and 10 with three abnormal OGTT values. Women with two or three abnormal OGTT values (2/3-AV) needed insulin treatment more frequently than those with one abnormal OGTT value (1-AV) (70.3% vs 23.1%, P<0.0001). After adjustment for age, pregravid overweight, gestational weeks at diagnosis, a first-degree family history of diabetes was correlated with the implementation of insulin treatment in women with 1-AV (adjusted odds ratio 3.9; 95% Confidence Interval 1.7-9.2; P = 0.001). When compared perinatal outcomes between women with normal glucose tolerance and GDM, fetal growth and the occurrence of pregnancy-induced hypertension were comparable between the two groups. Our data suggest that the IADPSG-defined GDM with 1-AV show less severe glucose intolerance, but might be at risk of insulin requirement when a first-degree family history of diabetes exists. © The Japan Endocrine Society.

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Complete chorion-amnion separation presenting as a stuck fetus

Kasuga Yoshifumi, Miyakoshi Kei, Ikenoue Satoru, Kadohira Ikuko, Matsumoto Tadashi, Minegishi Kazuhiro, Yoshimura Yasunori

Acta Obstetricia et Gynecologica Scandinavica 92 （ 8 ） 990 - 991 2013年08月

ISSN 0001-6349

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Marked decline in beta cell function during pregnancy leads to the development of glucose intolerance in Japanese women

Saisho Y., Miyakoshi K., Ikenoue S., Kasuga Y., Matsumoto T., Minegishi K., Yoshimura Y., Itoh H.

Endocrine Journal （Endocrine Journal） 60 （ 4 ） 533 - 539 2013年

ISSN 0918-8959

The aim of this study is to investigate glucose metabolism longitudinally during pregnancy to explore mechanisms underlying gestational diabetes mellitus (GDM). We reviewed a total of 62 pregnant Japanese women who underwent a 75g oral glucose tolerance test (OGTT) twice during pregnancy (median: early, 13; late, 28 weeks' gestation) because of positive GDM screening. All showed normal OGTT results in early pregnancy. Based on late OGTT, 15 had GDM (late- onset GDM) and 47 normal glucose tolerance (NGT). In early pregnancy, there were no significant differences in insulin sensitivity (insulin sensitivity index derived from OGTT [ISOGTT] and homeostasis model assessment for insulin resistance [HOMA-IR]) and insulin secretion (a ratio of the total area-under-the-insulin-curve to the total area-under-the-glucose-curve [AUCins/glu] and insulinogenic index [IGI]) between the NGT and late-onset GDM groups. In each group, insulin sensitivity significantly decreased from early to late pregnancy, most in the late-onset GDM group (each p < 0.05). The insulin secretion showed no significant changes with advancing pregnancy in both of the groups, although late-onset GDM showed significantly lower IGI compared with NGT in late OGTT (p < 0.05). When assessed beta cell function by OGTT-derived disposition index (i.e. Insulin Secretion-Sensitivity Index-2 and IGI/fasting insulin), the indices significantly decreased from early to late pregnancy in the both groups (each p < 0.05). Women with late-onset GDM showed significantly lower indices compared with NGT (each p < 0.05). The failure of beta cell to compensate for decreased insulin sensitivity could contribute to the development of the late-onset GDM. © The Japan Endocrine Society.

Antenatal management of recurrent fetal goitrous hyperthyroidism associated with fetal cardiac failure in a pregnant woman with persistent high levels of thyroidstimulating hormone receptor antibody after ablative therapy

Matsumoto T., Miyakoshi K., Saisho Y., Ishii T., Ikenoue S., Kasuga Y., Kadohira I., Sato S., Momotani N., Minegishi K., Yoshimura Y.

Endocrine Journal （Endocrine Journal） 60 （ 12 ） 1281 - 1287 2013年

ISSN 0918-8959

High titer of maternal thyroid-stimulating hormone receptor antibody (TRAb) in patients with Graves' disease could cause fetal hyperthyroidism during pregnancy. Clinical features of fetal hyperthyroidism include tachycardia, goiter, growth restriction, advanced bone maturation, cardiomegaly, and fetal death. The recognition and treatment of fetal hyperthyroidism are believed to be important to optimize growth and intellectual development in affected fetuses. We herein report a case of fetal treatment in two successive siblings showing in utero hyperthyroid status in a woman with a history of ablative treatment for Graves' disease. The fetuses were considered in hyperthyroid status based on high levels of maternal TRAb, a goiter, and persistent tachycardia. In particular, cardiac failure was observed in the second fetus. With intrauterine treatment using potassium iodine and propylthiouracil, fetal cardiac function improved. A high level of TRAb was detected in the both neonates. To the best of our knowledge, this is the first report on the changes of fetal cardiac function in response to fetal treatment in two siblings showing in utero hyperthyroid status. This case report illustrates the impact of prenatal medication via the maternal circulation for fetal hyperthyroidism and cardiac failure. ©The Japan Endocrine Society.

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当院における新診断基準導入後の妊娠糖尿病の臨床像に関する検討

池ノ上学, 宮越敬, 税所芳史, 春日義史, 門平育子, 松本直, 峰岸一宏, 吉村泰典

糖尿病と妊娠（(一社)日本糖尿病・妊娠学会） 13 （ 1 ） 80 - 83 2013年

ISSN 1347-9172

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)

Beta cell dysfunction and its clinical significance in gestational diabetes

Saisho Yoshifumi, Miyakoshi Kei, Tanaka Mamoru, Shimada Akira, Ikenoue Satoru, Kadohira Ikuko, Yoshimura Yasunori, Itoh Hiroshi

Endocrine Journal （JAPAN ENDOCRINE SOC） 57 （ 11 ） 973 - 980 2010年

ISSN 0918-8959

The aim of this study is to explore beta cell dysfunction and its clinical significance in gestational diabetes mellitus (GDM). We assessed insulin sensitivity and insulin secretion in a total of 277 Japanese women between 24 and 27 weeks of pregnancy who underwent a 2 h, 75 g oral glucose tolerance test (OGTT) because of an abnormal result on a 1 h 50 g oral glucose challenge conducted as part of a standard screening for GDM. Insulin sensitivity was evaluated by an insulin sensitivity index derived from OGTT (IS_OGTT), whereas insulin secretion was calculated as a ratio of the total area under the insulin curve to the total area under the glucose curve (AUC_ins/glu). Beta cell function in relation to insulin sensitivity (i.e. disposition index) was derived from the product of insulin sensitivity and insulin secretion (i.e. AUC_ins/glu × IS_OGTT). In women diagnosed with GDM (n=57), the disposition index was significantly lower than that in those without GDM, irrespective of obesity. The disposition index in women with GDM was significantly correlated with levels of fasting and mean preprandial capillary glucose and HbA1c before initiating insulin therapy (r = -0.45, -0.38, -0.49, respectively). Furthermore, there was a significant correlation between the disposition index and total insulin dosage to achieve glycemic goal (r = -0.41). In conclusion, we demonstrated beta cell dysfunction in Japanese women with GDM irrespective of obesity. The level of beta cell dysfunction in GDM was associated with the severity of glucose intolerance and total insulin dosage required. These findings underpin clinical significance of beta cell dysfunction in GDM.

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