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BackgroundIn 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.MethodsINTERCOVID-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.FindingsWe 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.InterpretationCOVID-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.FundingNone.

BackgroundThe 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.ObjectiveTo 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 designIn 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.ResultsA 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, P14 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.ConclusionIn 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.

BackgroundAmong nonpregnant individuals, diabetes mellitus and high body mass index increase the risk of COVID-19 and its severity.ObjectiveThis 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 designINTERCOVID 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.ResultsCOVID-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.ConclusionDiabetes 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.

BackgroundIt 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.ObjectiveThis 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 designThis 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.ResultsWe 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.ConclusionCOVID-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.

Aim Methods Results Conclusions The induction of labor before due date has recently been proved to reduce the rate of cesarean sections and is not associated with increased risk of adverse perinatal outcomes as compared to expectant management. Controlled‐release dinoprostone (PGE2) vaginal insert has recently been approved for use in Japan. However, evidence regarding its efficacy in cervical ripening and labor induction before due date remains limited. We aimed to compare the efficacy of PGE2 vaginal inserts and mechanical dilation for labor induction before due date.This retrospective cohort study included 206 mothers at 37, 38, and 39 weeks' gestation delivered at our institution between January 2021 and October 2022. Perinatal outcomes, including the success rate of vaginal delivery, were compared between the PGE2 (n = 46) and metreurynter/laminaria tent (non‐PGE2) (n = 160) groups. The success rate of vaginal delivery was defined as the proportion of women who delivered vaginally within 48 h of initiating oxytocin augmentation.The success rate of vaginal delivery was significantly higher in the PGE2 group (37/49, 80.4%) than in the non‐PGE2 group (106/177, 66.2%). Emergency cesarean section related to non‐reassuring fetal status was performed with none in the PGE2 group and with eight (5.0%) in the non‐PGE2 group.The rate of vaginal delivery was significantly higher in the PGE2 group for elective labor induction between 37 and 39 weeks. The PGE2 vaginal insert could increase the success rate of vaginal delivery for elective induction of labor at 39 weeks. [ABSTRACT FROM AUTHOR]

Birth weight is an important predictor of perinatal complications and long‐term health outcomes of offspring. Fetal programming influenced by maternal obesity, overnutrition, and hyperglycemia has been proposed as the fuel overload hypothesis. Recent investigations related with fetal body composition have revealed that neonatal adiposity can be predicted by fetal fat mass, and that maternal insulin resistance and serum leptin level are indicators of fetal adiposity. Based on the current evidence, the origins of obesity can partly be traced back into the fetal life. Further clarification of the determinants of fetal fat mass may lead to the clinical interventions and treatment strategies for fetal growth and development. This effort potentially leads to the elucidation of pathological conditions related with long‐term health outcomes and the primary prevention of childhood obesity and early onset metabolic syndrome. [ABSTRACT FROM AUTHOR]

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.

BackgroundThe 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.ObjectiveThe 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 designA 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.ResultsNewborn 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

To evaluate perinatal outcomes and risk factors for large for gestational age (LGA; birth weight over 90 percentile) in gestational diabetes diagnosed before 24 gestational weeks and treated with diet therapy alone until delivery (Diet Early gestational diabetes mellitus (Diet Early GDM)), we assessed the maternal characteristics and perinatal outcomes of patients with early GDM (n = 309) and normal glucose tolerance (NGT; n = 309) at Keio University Hospital. The gestational weight gain (GWG) expected at 40 weeks was significantly lower in the Diet Early GDM group than in the NGT group. The Diet Early GDM group exhibited a significantly lower incidence of low birth weight (<2500 g) and higher Apgar score at 5 min than the NGT group. Multiple logistic regression analysis revealed that the pre-pregnancy body mass index and GWG expected at 40 weeks were significantly associated with LGA for Diet Early GDM. No differences were observed in random plasma glucose levels in the first trimester, 75 g oral glucose tolerance test values, and initial increase or subsequent decrease between the two groups. Dietary early GDM did not exhibit a worse prognosis than NGT. To prevent LGA, it might be important to control maternal body weight not only during pregnancy but also before conception. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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). 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. 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). Impaired early phase insulin secretion was associated with GDM onset in underweight women. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Gestational diabetes (GDM) is one of the most common perinatal complications. Of the 264 patients, 104 were diagnosed with COVID-19-GDM and 160 GDM patients diagnosed using the IADPSG criteria were re-classified as COVID-19-NFT. As 65 patients (41%) in the COVID-19-NFT group required insulin during pregnancy, many patients with GDM who should be treated as such, might not be diagnosed when the Japanese GDM diagnostic strategy in the evolving COVID-19 pandemic is used. [Extracted from the article]