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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]

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]

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. [ABSTRACT FROM AUTHOR]

• The use of hAFSCs in applications of cell sheet technology remains limited. • hAFSC sheets implanted on wound in mice exerted anti-fibrotic properties. • hAFSC sheets implanted on wound in mice did not delay wound closure. 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. [ABSTRACT FROM AUTHOR]

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