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.

Predicting preterm birth within 2 weeks in asymptomatic women with a short cervix: Combined effects of cervicovaginal fluid cytokine levels and fetal fibronectin test.

AIMS: To predict preterm birth (PTB) accurately, we conducted a comprehensive cytokine assay using cervicovaginal fluid (CVF) and evaluated the additive effects of cytokine levels on the fetal fibronectin (fFN) test. METHODS: A total of 645 CVF samples were collected from 256 asymptomatic pregnant women between 24 and 35 weeks gestation, exhibiting short cervix. After selection based on specific criteria, 17 cytokines in 105 CVF samples were simultaneously measured using multiplex assay. Multivariate logistic regression analysis was performed to evaluate the association between cytokine levels and impending PTB, which is defined as PTB within 2 weeks after CVF collection. Moreover, receiver operating characteristic (ROC) analysis was performed in women with positive fFN results, which was validated using another set of 65 CVF samples. RESULTS: In positive fFN women, the CCL2 level was significantly higher in the impending PTB group than the other group (p < 0.01) and a predictor of impending PTB (adjusted odds ratio 1.020, 95% confidence interval [95% CI] 1.003-1.038, p = 0.020). The cutoff value of CCL2 was 64.8 pg/mL (are under the curve 0.726, p = 0.004, 95% CI 0.593-0.859, sensitivity 45.2%, specificity 91.7%). Additionally, the reliable classification performance of proposed ROC model could be validated. However, measuring cytokine levels could not help in predicting impending PTB in women with negative fFN or normal labor onset in healthy-term women. CONCLUSION: Comprehensive analysis of CVF cytokines revealed that the CCL2 level significantly improves the prediction of impending PTB in asymptomatic fFN-positive women with a short cervix, which may contribute to better clinical management.

Intrauterine exposure to chorioamnionitis and neuroanatomical alterations at term-equivalent age in preterm infants.

PURPOSE: Infants born to mothers with chorioamnionitis (CAM) are at increased risk of developing adverse neurodevelopmental disorders in later life. However, clinical magnetic resonance imaging (MRI) studies examining brain injuries and neuroanatomical alterations attributed to CAM have yielded inconsistent results. We aimed to determine whether exposure to histological CAM in utero leads to brain injuries and alterations in the neuroanatomy of preterm infants using 3.0- Tesla MRI at term-equivalent age. METHODS: A total of 58 preterm infants born before 34 weeks of gestation at Nagoya University Hospital between 2010 and 2018 were eligible for this study (CAM group, n = 21; non-CAM group, n = 37). Brain injuries and abnormalities were assessed using the Kidokoro Global Brain Abnormality Scoring system. Gray matter, white matter, and subcortical gray matter (thalamus, caudate nucleus, putamen, pallidum, hippocampus, amygdala, and nucleus accumbens) volumes were evaluated using segmentation tools (SPM12 and Infant FreeSurfer). RESULTS: The Kidokoro scores for each category and severity in the CAM group were comparable to those observed in the non-CAM group. White matter volume was significantly smaller in the CAM group after adjusting for covariates (postmenstrual age at MRI, infant sex, and gestational age) (p = 0.007), whereas gray matter volume was not significantly different. Multiple linear regression analyses revealed significantly smaller volumes in the bilateral pallidums (right, p = 0.045; left, p = 0.038) and nucleus accumbens (right, p = 0.030; left, p = 0.004) after adjusting for covariates. CONCLUSIONS: Preterm infants born to mothers with histological CAM showed smaller volumes in white matter, pallidum, and nucleus accumbens at term-equivalent age.

Trend changes in age-related body mass index gain after coronavirus disease 2019 pandemic in Japan: a multicenter retrospective cohort study.

BACKGROUND: Accumulating studies suggest that strict lockdown with enforcement including segregation to control the coronavirus disease 2019 (COVID-19) pandemic is associated with excess weight gain, but the such lockdown was not practiced in Japan. We aimed to compare the age-related weight gain before and after the COVID-19 pandemic in Japan where achieved epidemic control based on individual voluntary action. METHODS: This multicenter retrospective cohort study used electronic data from annual health checkups for workers from January 2015 to December 2021 at four facilities belonging to the Central Clinic Group, Aichi, Japan. We defined pre-pandemic and post-pandemic periods as January 2015-December 2019 and January 2020-December 2021, respectively. Participants were grouped by sex, age, and body mass index (BMI) stratus as of 2015, and the pre-pandemic and post-pandemic age-related BMI changes in overall individuals and each specific group were compared using a paired t-test. RESULTS: The total number of eligible participants was 19,290. During the pre-pandemic period, the mean BMI increased linearly in every group. The mean age-related BMI changes in females' pre-pandemic and post-pandemic periods were + 0.11 and + 0.02 kg/m2/year, respectively. This significant decrease was also shown in males, + 0.11 in the pre-pandemic and - 0.02 kg/m2/year in the post-pandemic periods. The reduction was consistently observed in all age strata. Furthermore, a significant reduction was also observed in the normal-weight females of reproductive ages aged 15-44 years. CONCLUSIONS: This is the first report showing that age-related weight gain was reduced after the COVID-19 pandemic in Japan, which could affect the reproductive age of females.

Sex-specific differences in head circumference of term singletons after assisted reproductive technology: a multicentre study in Japan.

RESEARCH QUESTION: Does fertility treatment, specifically assisted reproductive technology (ART), affect head circumference in term singletons? DESIGN: A total of 32,651 women who delivered at term at 12 maternity hospitals in Japan between 2010 and 2018 were included in the analysis; of these, 1941 (5.9%) and 2984 (9.1%) women conceived through ART and non-ART fertility treatments (timed intercourse, ovulation induction or artificial insemination), respectively. The study evaluated the adjusted odds ratios of head circumference ≥90th percentile stratified by infant sex and type of ART procedure after adjusting for covariates, with natural conception as the reference group. RESULTS: ART significantly increased the risk of head circumference ≥90th percentile (adjusted odds ratio 1.56 [95% confidence interval 1.25-1.96]), whereas non-ART fertility treatment did not increase the risk (1.14 [0.92-1.42]). This increased risk of head circumference ≥90th percentile was observed exclusively in male neonates (1.73 [1.33-2.26]) and not in female neonates (1.18 [0.76-1.85]) in the ART group. Frozen embryo transfer (FET), FET in a hormone replacement cycle (HRC-FET) and blastocyst-stage embryo transfer were significantly associated with head circumference ≥90th percentile (1.60 [1.26-2.02], 1.70 [1.30-2.22] and 1.72 [1.33-2.24], respectively). CONCLUSIONS: The use of ART, particularly FET, HRC-FET or blastocyst-stage embryo transfer, was linked with a heightened risk of head circumference ≥90th percentile compared with non-ART fertility treatment or natural conception. The increased risk was observed only in male neonates.

Comparison of the efficacy between controlled-release dinoprostone delivery system (PROPESS) and Cook's double balloon catheter plus oxytocin: A retrospective single-center study in Japan.

AIMS: To compare the efficacy of the controlled-release dinoprostone delivery system (PROPESS) and Cook's double balloon catheter (DBC) plus oxytocin as induction treatment. METHODS: A total of 197 term pregnant women with unfavorable cervix were admitted for scheduled induction and enrolled retrospectively (PROPESS, 113; Cook's DBC plus oxytocin, 84). The main birth outcomes were cervical ripening at the treatment-end and 24 h after the treatment-start, and rate of vaginal birth. Logistic regression and propensity score matching analyses were performed to evaluate the association between the outcomes and clinical characteristics including which treatment was selected. RESULTS: The choice of PROPESS was associated with the success of cervical ripening at 24 h after (adjusted odds ratio (OR) 2.17, 95% confidence interval (CI) 1.11-4.26, p = 0.024) and increased the rate of vaginal birth (adjusted OR 2.03, 95% CI 1.04-3.98, p = 0.039). Similar trends in the association between PROPESS and birth outcomes were maintained after adjusting for propensity scores (p = 0.072 and p = 0.163, respectively). However, some of the women with gestational age of early 39 weeks and low Bishop scores could achieve cervical ripening at 24 h after using Cook's DBC plus oxytocin, and none by PROPESS. CONCLUSION: Our findings suggest the possibility of slight advantages of PROPESS for scheduled induction of labor. In women with early term and extremely low Bishop scores, Cook's DBC plus oxytocin may be a superior or alternative treatment to PROPESS. Therefore, the optimal choice of induction treatment should be managed on an individual basis.

Clinical significances of Bishop score and vaginal bleeding to controlled-release dinoprostone delivery system (PROPESS) efficacy for cervical ripening: A retrospective single-center study in Japan.

AIMS: To evaluate the effect of vaginal bleeding on the efficacy of controlled-release dinoprostone delivery system (PROPESS) for cervical ripening and the factors affecting the PROPESS efficacy in a Japanese clinical setting. METHODS: A total of 100 term pregnant women in whom PROPESS was used due to an unfavorable cervix (Bishop score ≤ 6) were enrolled. We retrospectively investigated which factors, including vaginal bleeding, were associated with the success of cervical ripening using logistic regression analysis. Moreover, the effect of vaginal bleeding on vaginal acidity was examined in 24 selected cases (control, 11; rupture of membrane, 4; and vaginal bleeding, 8). RESULTS: A 25 women successfully ripened the cervix (effective group), and 75 were unsuccessful (noneffective group). Bishop score at insertion (adjusted odds ratio: 1.87; 95% confidence interval: 1.23-2.86; p = 0.004), and vaginal bleeding at PROPESS insertion (adjusted odds ratio 6.63; 95% confidence interval 1.21-36.36; p = 0.029) affected cervical ripening success. The cases with vaginal bleeding showed a significantly higher vaginal pH than the control cases (median value: 6.75 and 5.0, respectively). We identified no obvious adverse outcomes, such as tachysystole, fetal heart rate abnormality, or low Apgar/pH, associated with vaginal bleeding at insertion. CONCLUSIONS: Our findings suggest that the PROPESS efficacy depends on Bishop score at insertion and that vaginal bleeding at PROPESS insertion might have a significantly positive effect on cervical ripening in term pregnant women.

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 prediction models for outcomes of extremely and very preterm infants based on machine learning.

PURPOSE: Predicting individual risks for adverse outcomes in preterm infants is necessary for perinatal management and antenatal counseling for their parents. To evaluate whether a machine learning approach can improve the prediction of severe infant outcomes beyond the performance of conventional logistic models, and to identify maternal and fetal factors that largely contribute to these outcomes. METHODS: A population-based retrospective study was performed using clinical data of 31,157 infants born at < 32 weeks of gestation and weighing ≤ 1500 g, registered in the Neonatal Research Network of Japan between 2006 and 2015. We developed a conventional logistic model and 6 types of machine learning models based on 12 maternal and fetal factors. Discriminative ability was evaluated using the area under the receiver operating characteristic curves (AUROCs), and the importance of each factor in terms of its contribution to outcomes was evaluated using the SHAP (SHapley Additive exPlanations) value. RESULTS: The AUROCs of the most discriminative machine learning models were better than those of the conventional models for all outcomes. The AUROCs for in-hospital death and short-term adverse outcomes in the gradient boosting decision tree were significantly higher than those in the conventional model (p = 0.015 and p = 0.002, respectively). The SHAP value analyses showed that gestational age, birth weight, and antenatal corticosteroid treatment were the three most important factors associated with severe infant outcomes. CONCLUSION: Machine learning models improve the prediction of severe infant outcomes. Moreover, the machine learning approach provides insight into the potential risk factors for severe infant outcomes.

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.

Pre-pregnancy sleep duration and postpartum depression: a multicenter study in Japan.

Postpartum depression (PPD) is as a major public health issue and clinical priority worldwide. This study aimed to investigate the association between pre-pregnancy sleep duration and PPD. A multicenter retrospective study was conducted using clinical data of women who delivered at term between 2014 and 2018 at 12 maternity care hospitals in Japan. A total of 15,314 women were stratified into five groups according to their pre-pregnancy sleep duration: < 6, 6-7, 7-8, 8-9, and ≥ 9 h. Univariate and multivariate regression analyses were conducted to determine whether pre-pregnancy sleep duration affects the Edinburgh Postnatal Depression Scale (EPDS) scores at 1 month postpartum. We also evaluated whether the risk for PPD differs between primipara and multipara women classified according to pre-pregnancy sleep duration. The adjusted odds ratio for high EPDS scores (≥ 9) among women who slept for < 6 h and 6-7 h was 2.08 (95% confidence interval [CI]: 1.60-2.70) and 1.41 (95% CI: 1.18-1.68), respectively, relative to that in women with 7-8 h of sleep as the reference group. A 1-h increase in sleep duration was associated with an approximately 14% reduction in the risk for high EPDS scores. The association between short sleep duration and high EPDS scores was more remarkable in multipara women than in primipara women. Short pre-pregnancy sleep duration is associated with high EPDS scores, and this association is more significant in multipara women than in primipara women. Our findings emphasize the importance of collecting information on pre-pregnancy sleep duration to identify women at a high risk for PPD.

Reassessing the duration of each stage of labor and their relation to postpartum hemorrhage in the current Japanese population.

AIM: To reassess the normal duration of each stage of labor in a contemporary Japanese cohort, and to determine whether prolongation of each stage of labor increases the rate of postpartum hemorrhage (PPH) in vaginal deliveries. METHODS: Clinical data of women who delivered at term at 12 facilities between 2012 and 2018 were retrospectively collected. A total of 31 758 women were subdivided into three or four subgroups according to the duration of each stage of labor and parity. Univariate and multivariate logistic regression analyses were performed to estimate crude and adjusted odds ratios (ORs) of PPH (blood loss ≥ 1000 mL) in each subgroup, with women with the shortest durations in each subgroup used as the reference group. RESULTS: The reference range of each stage of labor was found to be shorter than that previously reported. Women with prolonged second (primiparity, adjusted OR: 1.15-1.78; multiparity, adjusted OR: 1.14-1.74) and third (primiparity, adjusted OR: 1.39-4.95; multiparity, adjusted OR: 1.46-3.80) stages of labor showed an increased risk of PPH, whereas those with prolonged first stage did not. A significantly increased risk of PPH was found both in primiparous and multiparous women with third stages of labor ≥ 5 min. CONCLUSIONS: The normal duration of each stage of labor in the Japanese population needs to be revised and well-recognized by obstetric care providers. A prolonged third stage of labor was a more important contributing factor to PPH than prolonged first or second stages.

Assessment of placental abruption with diffusion-weighted imaging.

AIM: To investigate whether placental abruption without fetal distress could be assessed by apparent diffusion coefficient (ADC) values in magnetic resonance imaging (MRI). METHODS: We conducted a retrospective case-control study at a single center. ADC values at the lesions of placental abruption in the abruption group (n = 8) were compared to those in the control group (n = 32). In the abruption group, ADC values at the sites of abruption were also compared to those at the nonabruption sites within the same placenta. RESULTS: The ADC values in the placental area above the abruption site in the abruption group showed lower values than those in the control group when the slice containing the umbilical cord insertion site was set as the reference, and those values were compared in each corresponding slice. Compared with average ADC values, those above the abruption site in the abruption group were also significantly lower than those in the control group (p < 0.001). Furthermore, ADC values at the area above abruption were lower than those at the nonabruption area of all planes in the abruption group. CONCLUSIONS: ADC values at the lesions above the placental abruption site were reduced compared to those in the normal placenta and those in the nonabruption area. Thus, it would be helpful to understand the pathophysiology of placental abruption in expectant management, although further investigations would be needed.

Machine learning prediction models for postpartum depression: A multicenter study in Japan.

AIM: Postpartum depression (PPD) and perinatal mental health care are of growing importance worldwide. Here we aimed to develop and validate machine learning models for the prediction of PPD, and to evaluate the usefulness of the recently adopted 2-week postpartum checkup in some parts of Japan for the identification of women at high risk of PPD. METHODS: A multicenter retrospective study was conducted using the clinical data of 10 013 women who delivered at ≥35 weeks of gestation at 12 maternity care hospitals in Japan. PPD was defined as an Edinburgh Postnatal Depression Scale score of ≥9 points at 4 weeks postpartum. We developed prediction models using conventional logistic regression and four machine learning algorithms based on the information that can be routinely collected in daily clinical practice. The model performance was evaluated using the area under the receiver operating characteristic curve (AUROC). RESULTS: In the machine learning models developed using clinical data before discharge, the AUROCs were similar to those in the conventional logistic regression models (AUROC, 0.569-0.630 vs. 0.626). The incorporation of additional 2-week postpartum checkup data into the model significantly improved the predictive performance for PPD compared to that without in the Ridge regression and Elastic net (AUROC, 0.702 vs. 0.630 [p < 0.01] and 0.701 vs. 0.628 [p < 0.01], respectively). CONCLUSIONS: Our machine learning models did not achieve better predictive performance for PPD than conventional logistic regression models. However, we demonstrated the usefulness of the 2-week postpartum checkup for the identification of women at high risk of PPD.

The Possible Effects of Zinc Supplementation on Postpartum Depression and Anemia.

Background and Objectives: The effects of postpartum zinc supplementation are still unclear. Our purpose in this study is to investigate the association between Zn supplementation and postpartum depression, defined by an Edinburgh Postnatal Depression Scale (EPDS) score ≥ 9, and the effect on the hematological status of postpartum women. Materials and Methods: We first investigated whether zinc supplementation affected the perioperative levels of zinc, hemoglobin, and hematocrit in 197 cases who underwent cesarean section and had postpartum anemia. Next, logistic regression analyses were performed on 148 eligible cases to determine the association between zinc supplementation and postpartum depression. Results: Postpartum zinc supplementation significantly improved the status of maternal blood zinc levels and reduced the risk of developing postpartum depression (adjusted odds ratio: 0.249; 95% confidence interval: 0.062-0.988; p = 0.048). Iron supplementation is a standard and effective strategy for treating anemia; however, the combination of oral iron plus zinc supplementation resulted in slightly significant negative effects on postpartum hemoglobin and hematocrit compared to oral iron supplementation only. Conclusions: Postpartum zinc supplementation causes a significant positive effect on postpartum depression (EPDS score ≥ 9). Zinc supplementation had a negative but transient influence on the hematological status in women with postpartum anemia treated with oral iron supplementation; however, the differences were not clinically significant. Thus, we did not regard it as an adverse effect to be considered, and postpartum zinc supplementation may be viewed as beneficial in postpartum women.

Multiple cytokine analysis in gastroschisis: Association with adverse outcomes including fetal brain damage.

OBJECTIVES: To investigate the distribution of multiple cytokines in gastroschisis and reveal its association with clinical outcomes, including gastrointestinal disorders and fetal brain damage caused by chronic inflammation in gastroschisis. METHODS: We obtained amniotic fluid and arterial cord blood from 10 patients with gastroschisis, and evaluated the profile of 40 cytokines via multiplex immunoassay. The possible relationship of the cytokines with the time taken to attain full enteral nutrition and cord S100B, a surrogate marker of brain damage, was estimated. Associations among the relevant cytokines were also assessed. RESULTS: Although clinical characteristics in our cohort had no relevance, several cytokines in cord blood, especially IL-2, IL-8, CCL1, CCL7, CXCL1, CXCL2, and CXCL6, were clearly elevated in patients who took a longer time to attain full enteral nutrition, whereas only IL-16 in cord blood was significantly related to cord S100B and strongly correlation with cord S100B levels. Moreover, our data indicated that IL-16 was considerably less correlated with the other cytokines associated with adverse outcomes. CONCLUSIONS: We investigated the cytokine characteristics of both amniotic fluid and cord blood in gastroschisis, and found that certain cytokines could affect the adverse outcomes, including fetal brain damage. These findings provide important information that could further clarify the pathophysiology of gastroschisis and propose a novel clinical implication of gastroschisis that could be used to predict adverse outcomes, especially neurodevelopmental disorders.

Postpartum alterations following inflammation in rat pregnancy: a discovery proteomic analysis.

Women with a history of preeclampsia have an increased risk of subsequent cardiovascular and metabolic disease. While aberrant inflammation during pregnancy is associated with the development of preeclampsia, whether maternal inflammation increases the risk of disease later in life is unclear. Using a rat model we determined whether aberrant inflammation in pregnancy alters the levels of plasma proteins associated with cardiovascular and metabolic disease risk in the postpartum period. Pregnant rats were administered lipopolysaccharide (LPS) or saline on gestational days 13.5-16.5 to induce inflammation. Non-pregnant controls consisted of age-matched female rats subjected to similar administration of LPS or saline. Examination of the proteomic profile of plasma collected 16 weeks after delivery or from non-pregnant controls using liquid chromatography-tandem mass spectrometry revealed 100 differentially expressed proteins. Moreover, we identified 188 proteins in pregnant rats, of which 49 were differentially expressed in saline- vs LPS-treated dams. Of the 49 proteins regulated by LPS, 28 were pregnancy specific. PANTHER classification software, DAVID database and Ingenuity Pathways analysis revealed that the differentially expressed proteins in pregnant saline vs LPS-treated rats are associated with alterations in lipid and glucose metabolism and atherosclerosis, all of which may contribute to cardiovascular and metabolic disease risk. Results from proteomic and pathway analyses were validated by immunoassay of three serum proteins selected a priori and by assessment of serum metabolites. This discovery study demonstrates that aberrant inflammation during pregnancy results in long-lasting postpartum physiological alterations known to be associated with metabolic and cardiovascular disease.

Vitamin D improves pulmonary function in a rat model for congenital diaphragmatic hernia.

A congenital diaphragmatic hernia (CDH) is an anomaly caused by defects in the diaphragm; the resulting limited thorax cavity in turn restricts lung growth (pulmonary hypoplasia). This condition is related to pulmonary hypertension. Despite advances in neonatal CDH therapy, the mortality for severe pulmonary hypoplasia remains high. Therefore, it is essential to establish prenatal therapeutic interventions. Vitamin D was reported to have beneficial effects on adult pulmonary hypertension. This study aims to evaluate the efficacy of prenatal vitamin D administration for CDH. First, serum 25-hydroxyvitamin D [25(OH)D] levels in umbilical cord blood were evaluated among CDH newborns. Second, Sprague Dawley rat CDH models were exposed to nitrofen on embryo day 9 (E9). Randomly selected rats in the nitrofen-treated group were infused with calcitriol from E9 to E21. Samples from CDH pups diagnosed after birth were used for lung weight measurements, blood gas analysis, and immunohistochemical analysis. Third, microarray analysis was performed to examine the effect of vitamin D on gene expression profiles in CDH pulmonary arterial tissues. Serum 25(OH)D levels in the umbilical cord blood of newborns who did not survive were significantly lower than those who were successfully discharged. Prenatal vitamin D showed no significant effect on CDH incidence or lung weight but attenuated alveolarization and pulmonary artery remodeling accompanied the improved blood gas parameters. Vitamin D inhibited several gene expression pathways in the pulmonary arteries of CDH rats. Our results suggest that prenatal vitamin D administration attenuates pulmonary vascular remodeling by influencing several gene pathways in CDH.

Antenatal prediction models for short- and medium-term outcomes in preterm infants.

INTRODUCTION: In extremely and very preterm infants, predicting individual risks for adverse outcomes antenatally is challenging but necessary for risk-stratified perinatal management and parents' participation in decision-making about treatment. Our aim was to develop and validate prediction models for short-term (neonatal period) and medium-term (3 years of age) outcomes based on antenatal maternal and fetal factors alone. MATERIAL AND METHODS: A population-based study was conducted on 31 157 neonates weighing ≤1500 g and born between 22 and 31 weeks of gestation registered in the Neonatal Research Network of Japan during 2006-2015. Short-term outcomes were assessed in 31 157 infants and medium-term outcomes were assessed in 13 751 infants among the 31 157 infants. The clinical data were randomly divided into training and validation data sets in a ratio of 2:1. The prediction models were developed by factors selected using stepwise logistic regression from 12 antenatal maternal and fetal factors with the training data set. The number of factors incorporated into the model varied from 3 to 10, on the basis of each outcome. To evaluate predictive performance, the area under the receiver operating characteristics curve (AUROC) was calculated for each outcome with the validation data set. RESULTS: Among short-term outcomes, AUROCs for in-hospital death, chronic lung disease, intraventricular hemorrhage (grade III or IV) and periventricular leukomalacia were 0.85 (95% CI 0.83-0.86), 0.80 (95% CI 0.79-0.81), 0.78 (95% CI 0.75-0.80), and 0.58 (95% CI 0.55-0.61), respectively. Among medium-term outcomes, AUROCs for cerebral palsy and developmental quotient of <70 at 3 years of age were 0.66 (95% CI 0.63-0.69) and 0.72 (95% CI 0.70-0.74), respectively. CONCLUSIONS: Although the predictive performance of these models varied for each outcome, their discriminative ability for in-hospital death, chronic lung disease, and intraventricular hemorrhage (grade III or IV) was relatively good. We provided a bedside prediction tool for calculating the likelihood of various infant complications for clinical use. To develop these prediction models would be valuable in each country, and these risk assessment tools could facilitate risk-stratified perinatal management and parents' shared understanding of their infants' subsequent risks.

Manual removal of the placenta and postpartum hemorrhage: A multicenter retrospective study.

AIM: In postpartum women, retained placenta is diagnosed in the absence of signs of placental separation and expulsion, and requires manual removal of the placenta (MROP). MROP may lead to massive hemorrhage, hemodynamic instability, and the need for emergency interventions including blood transfusion, interventional radiology, and hysterectomy. In this study, we aimed to identify the risk factors for retained placenta requiring MROP after vaginal delivery and postpartum hemorrhage (PPH) following MROP. METHODS: A multicenter retrospective study was performed using data from women who delivered at term between 2010 and 2018 at 13 facilities in Japan. Of 36 454 eligible women, 112 women who required MROP were identified. Multivariate logistic regression analyses were conducted to evaluate the risk factors for retained placenta and PPH following MROP. RESULTS: A history of abortion, assisted reproductive technology (ART), instrumental delivery, and delivery of small-for-gestational-age infant were independent risk factors for MROP (adjusted odds ratios [95% confidence intervals]: 1.93 [1.28-2.92], 8.41 [5.43-13.05], 1.80 [1.14-2.82], and 4.32 [1.97-9.48], respectively). ART was identified as an independent risk factor for PPH (adjusted odds ratio [95% confidence interval]: 6.67 [2.42-18.36]) in patients who underwent MROP. CONCLUSION: ART pregnancies significantly increased the risk of retained placenta requiring MROP and PPH. Our results suggest that clinicians need consider patient transfer to a higher-level facility and preparation of sufficient blood products before initiating MROP in cases of ART pregnancies. Our study may assist in identifying high-risk women for PPH before MROP and in guiding treatment decisions, especially in facilities without a blood bank.