Amniotic fluid-derived small extracellular vesicles for predicting postnatal severe outcome of congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) is a life-threatening condition with high morbidity and mortality rates. The survival rate of neonates with severe CDH is reportedly only 10%-15%. However, prenatal prediction of severe cases is difficult, and the discovery of new predictive markers is an urgent issue. In this study, we focused on microRNAs (miRNAs) in amniotic fluid-derived small EVs (AF-sEVs). We identified four miRNAs (hsa-miR-127-3p, hsa-miR-363-3p, hsa-miR-493-5p, and hsa-miR-615-3p) with AUC > 0.8 to classify good prognosis group and poor prognosis group in human study. The AUC for hsa-miR-127-3p and hsa-miR-615-3p, for predicting the poor prognosis, were 0.93 and 0.91, respectively. In addition, in the in vivo study, the miRNA profiles of the lung tissues of CDH rats were different from those of control rats. Additionally, two elevated miRNAs (rno-miR-215-5p and rno-miR-148a-3p) in the lung tissues of CDH rats were increased in the AF-sEVs of CDH rats. Our results suggest that severe CDH neonates can be predicted prenatally with high accuracy using miRNAs contained in AF-sEVs. Furthermore, miRNA profile changes in AF-sEVs reflected the lung status in CDH. Our findings may contribute to the development of advanced perinatal care for patients with CDH.

Prenatal Molecular Hydrogen Administration Ameliorates Several Findings in Nitrofen-Induced Congenital Diaphragmatic Hernia.

Oxidative stress plays a pathological role in pulmonary hypoplasia and pulmonary hypertension in congenital diaphragmatic hernia (CDH). This study investigated the effect of molecular hydrogen (H2), an antioxidant, on CDH pathology induced by nitrofen. Sprague-Dawley rats were divided into three groups: control, CDH, and CDH + hydrogen-rich water (HW). Pregnant dams of CDH + HW pups were orally administered HW from embryonic day 10 until parturition. Gasometric evaluation and histological, immunohistochemical, and real-time polymerase chain reaction analyses were performed. Gasometric results (pH, pO2, and pCO2 levels) were better in the CDH + HW group than in the CDH group. The CDH + HW group showed amelioration of alveolarization and pulmonary artery remodeling compared with the CDH group. Oxidative stress (8-hydroxy-2'-deoxyguanosine-positive-cell score) in the pulmonary arteries and mRNA levels of protein-containing pulmonary surfactant that protects against pulmonary collapse (surfactant protein A) were significantly attenuated in the CDH + HW group compared with the CDH group. Overall, prenatal H2 administration improved respiratory function by attenuating lung morphology and pulmonary artery thickening in CDH rat models. Thus, H2 administration in pregnant women with diagnosed fetal CDH might be a novel antenatal intervention strategy to reduce newborn mortality due to CDH.

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.

A proteome signature of umbilical cord serum associated with congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) is a congenital anomaly characterized by a defect in the diaphragm. Despite the recent improvements in its treatment, CDH is associated with a high rate of neonatal mortality, which is often related to pulmonary hypoplasia (PH) as well as pulmonary hypertension. A better understanding of the underlying pathological mechanisms of PH in CDH could help establish a new treatment to improve its prognosis. In this study, we investigated serum biological profiles in neonates with CDH. For comprehensive investigation, umbilical cord serum samples were collected from isolated CDH cases (n = 4) and matched healthy controls (n = 4). Samples were analyzed using liquid chromatography-tandem mass spectrometry. A total of 697 proteins were detected; of them, 98 were identified as differentially expressed proteins. Among these differentially expressed proteins, complement C1q subcomponent showed the largest fold change, followed by complement C5. In the pathway enrichment analysis, the complement and coagulation cascades expressed the most significant enrichment (p = 2.4 × 10-26). Thus, the complement pathway might play some role in the pathophysiology of CDH.

Adverse effects of endometriosis on pregnancy: a case-control study.

BACKGROUND: Endometriosis is a common disease occurring in 1-2% of all women of reproductive age. Although there is increasing evidence on the association between endometriosis and adverse perinatal outcomes, little is known about the effect of pre-pregnancy treatments for endometriosis on subsequent perinatal outcomes. Thus, this study aimed to evaluate maternal and neonatal outcomes in pregnant women with endometriosis and to investigate whether pre-pregnancy surgical treatment would affect these outcomes. METHODS: This case-control study included 2769 patients who gave birth at Nagoya University Hospital located in Japan between 2010 and 2017. Maternal and neonatal outcomes were compared between the endometriosis group (n = 80) and the control group (n = 2689). The endometriosis group was further divided into two groups: patients with a history of surgical treatment such as cystectomy for ovarian endometriosis, ablation or excision of endometriotic implants, or adhesiolysis (surgical treatment group, n = 49) and those treated with only medications or without any treatment (non-surgical treatment group, n = 31). RESULTS: In the univariate analysis, placenta previa and postpartum hemorrhage were significantly increased in the endometriosis group compared to the control group (12.5% vs. 4.1%, p <  0.01 and 27.5% vs. 18.2%, p = 0.04, respectively). In the multivariate analysis, endometriosis significantly increased the odds ratio (OR) for placenta previa (adjusted OR, 3.19; 95% confidence interval [CI], 1.56-6.50, p <  0.01) but not for postpartum hemorrhage (adjusted OR, 1.14; 95% CI, 0.66-1.98, p = 0.64). Other maternal and neonatal outcomes were similar between the two groups. In patients with endometriosis, patients in the surgical treatment group were significantly associated with an increased risk of placenta previa (OR. 4.62; 95% CI, 2.11-10.10, p <  0.01); however, patients in the non-surgical treatment group were not associated with a high risk (OR, 1.63; 95% CI, 0.19-6.59, p = 0.36). Additionally, other maternal and neonatal outcomes were similar between the two groups. CONCLUSION: Women who have had surgical treatment for their endometriosis appear to have a higher risk for placenta previa. This may be due to the more severe stage of endometriosis often found in these patients. However, clinicians should be alert to this potential increased risk and manage these patients accordingly.

Estrogen producing ovarian fibrosarcoma: A case report.

Fibrosarcoma is an extremely rare malignant sex-cord stromal tumor. Fibrosarcoma is generally unknown as an estrogen producing tumor. This report presents, for the first time, a case of estrogen producing ovarian fibrosarcoma in an 83-year-old female. We performed total hysterectomy, bilateral salpingo-oophorectomy and omentectomy. Histopathologically, the tumor of the left ovary had high cellularity, cellular atypia and 10-15 mitotic counts per 10 high power fields. The tumor contained small components composed of cells that were similar to Sertoli cells. In an effort to examine which component was producing estrogen, we checked aromatase expression; but both components were positive. We could not explain which component was producing estrogen. Postoperative clinical stage was IA. As she was geriatric patient, we did not recommend adjuvant chemotherapy. There were no signs of recurrence or increase in serum estradiol level at two years after the operation.

Observed-to-expected MRI fetal lung volume can predict long-term lung morbidity in infants with congenital diaphragmatic hernia.

OBJECTIVE: Congenital diaphragmatic hernia (CDH) causes pulmonary hypoplasia and pulmonary hypertension, which are associated with long-term respiratory problems in infants. The aim of this study was to establish a marker for predicting lung function at 1 year of age in infants with CDH. MATERIALS AND METHODS: Infants with isolated CDH who were delivered after 35 weeks of gestation from April 2008 to June 2016 at Nagoya University Hospital were registered. Regarding alive infants with CDH, only those who underwent follow-up for at least 1 year were registered. Finally, 48 infants were analyzed in this study. RESULTS: Gestational age at diagnosis, amniotic lamellar body count at birth, observed-to-expected MRI fetal lung volume (percent FLV), liver herniation, and polyhydramnios were found to be significant parameters for predicting mortality in infants with CDH. Regarding alive infants with CDH, percent FLV was the only significant parameter to predict need for oxygen therapy at 1 year of age (p < .05). There was a significant negative correlation between percent FLV and duration of oxygen therapy in infants with CDH (r = .516, p < .001). CONCLUSIONS: Percent FLV is a useful predictor of long-term lung morbidity in infants with CDH.