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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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