Published papers

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.

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.

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.

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.

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.

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.

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.

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.

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.

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)

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)

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)

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)

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.

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.

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.

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.