Interleukin-17A stimulation induces alterations in Microglial microRNA expression profiles.

BACKGROUND: Increased maternal interleukin (IL)-17A and activated microglia are pivotal factors contributing to the pathological phenotypes of maternal immune activation (MIA), developing neurodevelopmental disorders in offspring. This study aimed to determine whether IL-17A affects the microglial microRNA (miRNA) profiles. METHODS: The miRNA expression profiles of primary cultured microglia stimulated with recombinant IL-17A were examined comprehensively using miRNA sequencing and validated through qRT-PCR. The expressions of miRNAs target genes identified using bioinformatics, were investigated in microglia transfected with mimic miRNA. The target gene's expression was also examined in the fetal brains of the MIA mouse model induced by maternal lipopolysaccharide (LPS) administration. RESULTS: Primary cultured microglia expressed the IL-17A receptor and increased proinflammatory cytokines and nitric oxide synthase 2 upon treatment with IL-17A. Among the three miRNAs with |log2FC | >1, only mmu-miR-206-3p expression was significantly up-regulated by IL-17A. Transfection with the mmu-miR-206-3p mimic resulted in a significant decrease in the expression of Hdac4 and Igf1, target genes of mmu-miR-206-3p. Hdac4 expression also significantly decreased in the LPS-induced MIA model. CONCLUSIONS: IL-17A affected microglial miRNA profiles with upregulated mmu-miR-206-3p. These findings suggest that targeting the IL-17A/mmu-miR-206-3p pathway may be a new strategy for predicting MIA-related neurodevelopmental deficits and providing preventive interventions. IMPACT: Despite the growing evidence of interleukin (IL)-17A and microglia in the pathology of maternal immune activation (MIA), the downstream of IL-17A in microglia is not fully known. IL-17A altered microRNA profiles and upregulated the mmu-miR-206-3p expression in microglia. The mmu-miR-206-3p reduced autism spectrum disorder (ASD) related gene expressions, Hdac4 and Igf1. The Hdac4 expression was also reduced in the brain of MIA offspring. The hsa-miR-206 sequence is consistent with that of mmu-miR-206-3p. This study may provide clues to pathological mechanisms leading to predictions and interventions for ASD children born to mothers with IL-17A-related disorders.

Antenatal corticosteroids-to-delivery interval associates cord blood S100B levels.

AIM: Antenatal corticosteroids (ACS) are recommended for women at risk of preterm birth before 34 weeks' gestation. However, adverse effects of ACS on the fetal brain have also been reported. The time interval from ACS administration to delivery (ACS-to-delivery interval) might alter the effect of ACS on the fetal brain. This study aimed to evaluate the effect of ACS-to-delivery interval on cord blood S100 calcium-binding protein B (S100B) levels as a biomarker of brain damage. METHODS: Women who delivered between 2012 and 2020 at a tertiary medical center were divided into three groups according to ACS use and ACS-to-delivery interval, retrospectively: non-ACS, ACS ≤7 days, and ACS >7 days. Patients who did not complete the ACS regimen were excluded. The primary outcome was cord blood S100B levels. RESULTS: Cord blood S100B levels were significantly lower in the ACS ≤7 days group than in the non-ACS and ACS >7 days groups. In the multiple regression analysis, birth ≤7 days after ACS showed a significant negative association with S100B level (p < 0.001). CONCLUSIONS: Reduced S100B levels were observed in infants born ≤7 days after ACS but not in infants born >7 days after ACS. These findings suggest the importance of ACS timing to optimize its effects on the fetal brain, although further studies are required to identify these mechanisms.

Antenatal corticosteroids and outcomes of small for gestational age infants born at 24-31 gestational weeks: a population-based propensity score matching analysis.

PURPOSE: To evaluate the effect of antenatal corticosteroid (ACS) treatment on neonatal outcomes in small for gestational age (SGA) infants born at 24-31 gestational weeks compared with non-SGA infants. METHODS: A population-based retrospective study was conducted that analyzed clinical data from the Neonatal Research Network of Japan database, which enrolls neonates born at < 32 gestational weeks and weighing 1500 g or less (n = 22,414). Propensity score matching (with the ratio of ACS to no-ACS groups of 1:1) was performed in SGA (n = 7028) and non-SGA (n = 15,386) infants, respectively. Univariate logistic and interaction analyses were performed to compare the short-term neonatal outcomes of infants with and without ACS treatment in utero. RESULTS: In the SGA and non-SGA infants, ACS treatment significantly reduced in-hospital mortality (odds ratio 0.67 95% confidence interval [0.50-0.88] and 0.62 [0.50-0.78], respectively), respiratory distress syndrome (0.77 [0.69-0.87] and 0.63 [0.58-0.68], respectively), and composite adverse outcomes (0.73 [0.58-0.91] and 0.57 [0.50-0.65], respectively). ACS treatment also significantly reduced intraventricular hemorrhage (grade III/IV), periventricular leukomalacia, and sepsis in the non-SGA infants, but not in the SGA infants. However, interaction analyses revealed no significant differences between the SGA and non-SGA infants in the efficacy of ACS treatment on short-term outcomes except for respiratory distress syndrome. CONCLUSIONS: ACS treatment was associated with beneficial effects on mortality, respiratory distress syndrome, and adverse composite outcomes in extremely and very preterm SGA infants, with similar efficacy on all neonatal outcomes except for respiratory distress syndrome observed in the non-SGA infants.

Severe Congenital Diaphragmatic Hernia With Trisomy 9: A Case Report and Review of the Literature.

Congenital diaphragmatic hernia (CDH) is known to be complicated with various chromosomal abnormalities. However, the grade of pulmonary hypoplasia of CDH complicated by trisomy 9 is not known. This information is essential to the mother who has had a fetus with the same complication. We report a case of severe CDH with trisomy 9. The fetus had fetal growth restriction and multiple anomalies, including severe left CDH (observed/expected lung-to-head ratio 13.7%, liver-up, stomach grade 3 in Kitano classification), mild ventriculomegaly, low-set ear, rocker bottom, and single umbilical artery. Chromosomal test by amniocentesis showed a karyotype of 47,XX,+9. The neonate was born alive at 34 weeks but died 49 minutes after birth. In the literature review, this case and seven cases of complete trisomy 9 had CDH, and four of them were explained as "large" or "severe" CDH. In conclusion, trisomy 9 might be occasionally complicated by severe CDH.

The efficacy of therapeutic cervical cerclage in singleton pregnancies: a retrospective study.

OBJECTIVES: We compared the pregnancy prolongation effect attributable to cervical cerclage to that achieved by conservative management, and determined the cervical length for which cervical cerclage is effective. METHODS: We retrospectively examined medical records of 281 women admitted to our hospital between January 2013 and December 2017 for management of threatened preterm birth at 22-28 weeks of gestation. Obstetricians determined suitability for cervical cerclage, which was performed using the McDonald procedure in all cases. Of the 281 subjects, 71 underwent cervical cerclage (cerclage group); the other 210 received conservative therapy (non-cerclage group). We recorded maternal and neonatal characteristics of all patients. The two groups were compared in terms of length of extension of pregnancy and weeks of gestation at delivery. Multivariate analysis was performed to identify factors associated with extension of time to delivery. RESULTS: Our analyses revealed that the cerclage group was hospitalized earlier in pregnancy than the non-cerclage group (23.7 ± 1.5 weeks vs. 26.4 ± 1.9 weeks, p < .001) and had shorter cervixes (6.0 ± 9.4 mm vs. 16.9 ± 13.0 mm, p < .001). The two groups did not differ significantly in terms of gestational weeks at delivery. Multivariate analysis regarding extension of pregnancy revealed significant differences in extension of pregnancy related with cervical cerclage (26.65 days, 95% CI 17.0 - 36.3, p < .001) and cervical length <10 mm (-27.4 days, 95% CI -36.0--18.8, p < .001). While the time to delivery was extended by cervical cerclage in women with short cervixes (<25 mm), the two groups did not differ when cervical length was ≥15 mm. CONCLUSIONS: Cervical cerclage was a significant positive factor and short cervix was a significant negative factor for elongating pregnancy. In primigravida and multigravida women with no history of preterm birth, when the cervix is short (<10 mm), cervical cerclage should be recommended.

Prenatal diagnosis of distal 13q deletion syndrome in a fetus with esophageal atresia: a case report and review of the literature.

BACKGROUND: Chromosome 13q deletion syndrome shows variable clinical features related to the different potential breakpoints in chromosome 13q. The severely malformed phenotype is known to be associated with the deletion of a critical region in 13q32. However, esophageal atresia is a rare symptom and the relevant region is unknown. Thus, determining the association between accurate breakpoints and new clinical features is essential. CASE PRESENTATION: A 28-year-old Japanese primigravid woman was referred for fetal growth restriction, absence of a gastric bubble, cerebellar hypoplasia, overlapping fingers, and polyhydramnios at 31 weeks gestation. At 38 + 0 weeks, she delivered a 1774 g female infant. The infant presented with isolated esophageal atresia (Gross type A), Dandy-Walker malformation, right microphthalmia, left coloboma, overlapping fingers, pleurocentrum in the thoracic vertebrae, reduced anogenital distance, and hearing loss. Her karyotype was diagnosed as 46,XX,del(13)(q32.1-qter) by amniocentesis, but array comparative genomic hybridization after birth revealed the deletion of 13q31.3-qter. At 48 days after birth, the infant underwent surgery for esophageal atresia and was later discharged from the hospital at 7 months of age. CONCLUSION: This case report and the literature reviews supports the previous findings on the pathological roles of haploinsufficiency of the ZIC2/ZIC5 in Dandy-Walker malformation and the EFBN2 haploinsufficiency in eye malformation and hearing loss. Furthermore, the possible involvement of IRS2, COLA1, and COLA2 in eye malformation were identified. This is the first case of 13q deletion syndrome with esophageal atresia (Gross A), but it may be a symptom of VATER/VACTER association (vertebral defects, anorectal malformations, cardiac defects, tracheoesophageal fistula with or without esophageal atresia, renal malformations, and limb defects), as in the previous cases. These symptoms might also be associated with EFBN2 haploinsufficiency, although further research is required.

Factors associated with intrapartum cesarean section in women aged 40 years or older: a single-center experience in Japan.

Objective: To elucidate the efficacy and safety of attempting a vaginal birth and to understand the factors that contribute to the increased risk of operative delivery in women aged 40 years or older.Methods: A database of the Japanese Red Cross Nagoya Daiichi Hospital was reviewed to identify women aged 40 years or older with singleton, vertex, and vital pregnancies who attempted vaginal delivery at and after 37 + 0 gestational weeks between January 2011 and December 2016.Results: A total of 415 women met the criteria for inclusion in this study, including 372 and 43 women who gave birth by vaginal delivery and by intrapartum cesarean section (CS), respectively. Vaginal delivery was observed in 84.1% (201/239) and 97.2% (171/176) of nulliparous and multiparous women, respectively. In a logistic regression model, nulliparity [odds ratio (OR), 5.18; 95% confidence interval (CI), 1.91-14.00], assisted reproductive technology (OR, 2.83; 95% CI, 1.42-5.62), and admission for induction of childbirth (OR, 2.68; 95% CI, 1.08-6.67) were associated with a higher likelihood of intrapartum CS. Of 372 women who delivered vaginally, 62 women needed operative delivery. Operative delivery was necessary for 25.4% (51/201) and 6.4% (11/171) of nulliparous and multiparous women, respectively. A logistic regression model identified nulliparity (OR, 3.91; 95% CI, 1.89-8.08) and administration of ecbolic (OR, 2.49; 95% CI, 1.21-5.10) as being independent factors associated with vacuum extraction.Conclusions: Maternal age 40 years or older should not be a barrier for attempting a vaginal delivery, and those women should be encouraged to attempt a vaginal delivery.

Evaluation of the risk of umbilical cord prolapse in the second twin during vaginal delivery: a retrospective cohort study.

OBJECTIVE: This study aimed to evaluate the success rate of vaginal delivery, the reasons for unplanned caesarean delivery, the rate of umbilical cord prolapse and the risk of umbilical cord prolapse in twin deliveries. DESIGN: Retrospective cohort study. SETTING: Single institution. PARTICIPANTS: This study included 455 women pregnant with twins (307 dichorionic and 148 monochorionic) who attempted vaginal delivery from January 2009 to August 2018. The following criteria were considered for vaginal delivery: diamniotic twins, cephalic presentation of the first twin, no history of uterine scar, no other indications for caesarean delivery, no major structural abnormality in either twin and no fetal aneuploidy. RESULTS: The rate of vaginal delivery of both twins was 89.5% (407 of 455), caesarean delivery of both twins was 7.7% (35 of 455) and caesarean delivery of only the second twin was 2.9% (13 of 455). The major reasons for unplanned caesarean delivery were arrest of labour and non-reassuring fetal heart rate pattern. The rate of umbilical cord prolapse in the second twin was 1.8% (8 of 455). Multivariate analysis revealed that abnormal umbilical cord insertion in the second twin (velamentous or marginal) was the only significant factor for umbilical cord prolapse in the second twin (OR, 5.05, 95% CI 1.139 to 22.472, p=0.033). CONCLUSIONS: Abnormal umbilical cord insertion in the second twin (velamentous or marginal) was a significant factor for umbilical cord prolapse during delivery. Antenatal assessment of the second twin's umbilical cord insertion using ultrasonography would be beneficial.

Hypertensive disorders of pregnancy and alterations in brain metabolites in preterm infants: A multi-voxel proton MR spectroscopy study.

BACKGROUND: Infants born to mothers with hypertensive disorders of pregnancy (HDP) have adverse neurodevelopmental consequences in later life. Magnetic resonance spectroscopy (MRS) is used to predict subsequent neurodevelopment in the field of perinatology. AIM: We aimed to determine whether exposure to HDP in utero leads to alterations in brain metabolites in preterm infants using multi-voxel proton MRS at term-equivalent age. STUDY DESIGN: Retrospective cohort study. SUBJECTS: A total of 103 preterm infants born before 34 weeks of gestation at Nagoya University Hospital between 2010 and 2018 were eligible. Twenty-seven infants were born to mothers with HDP (HDP group), and 76 were born to mothers without HDP (non-HDP group). OUTCOME MEASURES: The peak area ratios of N-acetylaspartate (NAA)/choline (Cho), NAA/creatine (Cr), and Cho/Cr were evaluated at 10 designated regions of interest (bilateral frontal lobes, basal ganglia, thalami, temporal lobes, and occipital lobes). RESULTS: The peak area ratios of NAA/Cho and NAA/Cr in the bilateral thalami were significantly higher in the HDP group than in the non-HDP group after adjustment for covariates (postmenstrual age at MRS assessment and infant sex). No significant differences were observed in other regions. Preeclampsia, abnormal umbilical artery blood flow, and fetal growth restrictions were significantly associated with increased NAA/Cho and NAA/Cr ratios in the thalami. CONCLUSIONS: Based on the evidence that NAA/Cho and NAA/Cr ratios constantly increase with postmenstrual age in normal brain development, exposure to maternal HDP in utero may accelerate brain maturation and increase neuronal activity in preterm infants.

The impact of the abruption severity and the onset-to-delivery time on the maternal and neonatal outcomes of placental abruption.

Objective: We examined the impact of the abruption severity and the onset-to-delivery time on the maternal and neonatal outcomes of cases of clinically diagnosed placental abruption (PA).Material and methods: We investigated 84 patients who were diagnosed with PA at our hospital from January 2009 to September 2017. We classified the patients with PA into three groups based on the extent of the abruption: (1) mild abruption, <20%; (2) moderate abruption, 20-49%; (3) severe abruption, ≥50%, which was defined by the attending obstetricians at the time of delivery. The neonatal outcome was measured by the umbilical artery pH and the maternal outcome was measured by the obstetric disseminated intravascular coagulation score (DIC score).Results: The rate of hypertensive disorders of pregnancy in the moderate abruption group was significantly lower than that in other groups (p = .010). The umbilical artery pH was below 7.00 in 29 cases. The umbilical artery pH of the severe abruption group (6.92) was the lowest and was significantly lower in comparison to other groups (mild group [7.24], p < .001; moderate group [7.11], p < .05). There was a significant correlation between the onset-to-delivery time and the umbilical artery pH in the moderate group (R = -0.43). The maternal DIC scores in the three groups did not differ to a statistically significant extent.Conclusions: The severity of placental separation is significantly correlated with poor neonatal outcomes and there was a significant negative correlation between the onset-to-delivery time and the umbilical artery pH in moderate abruption.

Ferritin reporter used for gene expression imaging by magnetic resonance.

Magnetic resonance imaging (MRI) is a minimally invasive way to provide high spatial resolution tomograms. However, MRI has been considered to be useless for gene expression imaging compared to optical imaging. In this study, we used a ferritin reporter, binding with biogenic iron, to make it a powerful tool for gene expression imaging in MRI studies. GL261 mouse glioma cells were over-expressed with dual-reporter ferritin-DsRed under beta-actin promoter, then gene expression was observed by optical imaging and MRI in a brain tumor model. GL261 cells expressing ferritin-DsRed fusion protein showed enhanced visualizing effect by reducing T2-weighted signal intensity for in vitro and in vivo MRI studies, as well as DsRed fluorescence for optical imaging. Furthermore, a higher contrast was achieved on T2-weighted images when permeating the plasma membrane of ferritin-DsRed-expressing GL261. Thus, a ferritin expression vector can be used as an MRI reporter to monitor in vivo gene expression.