miR-15b-5p promotes expression of proinflammatory cytokines in human placenta by inhibiting Apelin signaling pathway.

INTRODUCTION: The timing of parturition at end of human gestation may be controlled by fetal signals. The signaling molecules contributing to activation of human labor may be mediated by fetal exosomes. In this study, we focused on investigation of the role of microRNAs (miRNAs) derived from fetal exosomes in the regulation of human placental gene expression. METHODS: Using immunofluorescent labeling, array-based miRNA profiling assay, target prediction analysis, and conducting a variety of biochemical approaches including miRNA mimics, dual-luciferase, siRNA-mediated gene silencing, and immunohistochemical staining assay in primary trophoblast culture and formalin-fixed paraffin-embedded placental tissues, we examined whether fetal exosomal miRNAs can stimulate expression of proinflammatory mediators in human placenta. RESULTS: We showed placental uptake of exosomes derived from the umbilical artery, and found that 9 fetal exosomal miRNAs: let-7i-5p, miR-185-5p, miR-15b-5p, miR-376c-3p, miR-548d-5p, miR-92b-3p, miR-16-5p, and miR-1301-3p were significantly increased in placentas of women delivering following term labor compared to those delivering by Cesarean section in the late preterm period. Target prediction analysis identified miR-15b-5p of particular interest, because one of its predicted targets is Apelin, a potent inhibitor of proinflammatory mediators. We further found that miR-15b-5p repressed Apelin protein levels and activated pro-labor hormones and cytokines including IL-1, IL-6, IL-8, and TNF-α. DISCUSSION: These data suggest a potential fetal-to-placental signal that could play a role in the length of human gestation and onset of human labor.

Smith-Lemli-Opitz's Syndrome as a Possible Cause of Recurrent Pregnancy Loss: A Case Report.

Based on the known carrier frequency of Smith-Lemli-Opitz's syndrome (SLOS), the prevalence of this disease should be significantly higher than what is observed in the population. This may be due to a higher rate of pregnancy loss in affected embryos. Here, we present the case of a couple who underwent expanded carrier screening (ECS) after experiencing three first trimester pregnancy losses. Both parents were found to be carriers of SLOS mutations, and DNA analysis of the fetal remains of the third loss revealed the aborted fetus had inherited both the maternal and paternal mutations. This suggests SLOS as a reason for this patient's recurrent pregnancy loss (RPL), and therefore, ECS should be considered as part of the RPL work-up.

Changes in the Prevalence of Chronic Hypertension in Pregnancy, United States, 1970 to 2010.

We estimated changes in the prevalence of chronic hypertension among pregnant women and evaluated the extent to which changes in obesity and smoking were associated with these trends. We designed a population-based cross-sectional analysis of over 151 million women with delivery-related hospitalizations in the United States, 1970 to 2010. Maternal age, year of delivery (period), and maternal year of birth (birth cohort), as well as race, were examined as risk factors for chronic hypertension. Prevalence rates and rate ratios with 95% CIs of chronic hypertension in relation to age, period, and birth cohort were derived through age-period-cohort models. We also examined how changes in obesity and smoking rates influenced age-period-cohort effects. The overall prevalence of chronic hypertension was 0.63%, with black women (1.24%) having more than a 2-fold higher rate than white women (0.53%; rate ratio, 2.31; 95% CI, 2.30-2.32). In the age-period-cohort analysis, the rate of chronic hypertension increased sharply with advancing age and period from 0.11% in 1970 to 1.52% in 2010 (rate ratio, 13.41; 95% CI, 13.22-13.61). The rate of hypertension increased, on average, by 6% (95% CI, 5-6) per year, with the increase being slightly higher among white (7%; 95% CI, 6%-7%) than black (4%; 95% CI, 3%-4%) women. Adjustments for changes in rates of obesity and smoking were not associated with age and period effects. We observed a substantial increase in chronic hypertension rates by age and period and an over 2-fold race disparity in chronic hypertension rates.

The effect of paternal cues in prenatal care settings on men's involvement intentions.

A father's involvement in prenatal care engenders health benefits for both mothers and children. While this information can help practitioners improve family health, low paternal involvement in prenatal care remains a challenge. The present study tested a simple, easily scalable intervention to promote father involvement by increasing men's feelings of comfort and expectations of involvement in prenatal settings through three randomized control trials. Borrowing from social psychological theory on identity safety, the three studies tested whether the inclusion of environmental cues that represent men and fatherhood in prenatal care offices influenced men's beliefs and behavioral intentions during the perinatal period. Men in studies 1 and 3 viewed online videos of purported prenatal care offices, while men in study 2 visited the office in person. Those who viewed or were immersed in a father-friendly prenatal care office believed that doctors had higher expectations of father involvement compared to treatment-as-usual. This perception predicted greater parenting confidence, comfort, and behavioral intentions to learn about the pregnancy and engage in healthy habits, such as avoiding smoking and alcohol during their partner's pregnancy. Study 3 replicated these studies with an online sample of expectant fathers. The results suggest that shifting environment office cues can signal fathering norms to men in prenatal settings, with healthier downstream behavior intentions.

Fetal lung C4BPA induces p100 processing in human placenta.

The non-canonical NF-κB signaling may be a central integrator of a placental clock that governs the length of human pregnancy. We sought to identify fetal signals that could activate this NF-κB pathway in the placenta, and in turn, contribute to the onset of labor. Proteomics analysis of exosomes purified from fetal cord arterial blood revealed a total of 328 proteins, among which 48 were more significantly abundant (p < 0.01) in samples from women who delivered following elective Cesarean-section at term (39 to 40 weeks of estimated gestational age, EGA) compared to those who had elective Cesarean deliveries near term (35 to 36 weeks of EGA). Computational, crystal structural, and gene functional analyses showed that one of these 48 proteins, C4BPA, binds to CD40 of placental villous trophoblast to activate p100 processing to p52, and in turn, pro-labor genes. These results suggest that fetal C4BPA-induced activation of non-canonical NF-κB in human placenta may play a critical role in processes of term or preterm labor.

Whole exome sequencing for prenatal diagnosis in cases with fetal anomalies: Criteria to improve diagnostic yield.

Whole exome sequencing (WES) for prenatal diagnosis has a reported diagnostic yield of 6.2%-57%. Our aim was to identify patients with a high likelihood of genetic diagnosis using WES in cases with fetal ultrasound anomalies. This is a series of five selected cases for prenatal WES at our institution. Pregnant couples were initially identified due to fetal ultrasound anomalies. Candidates for WES for fetal diagnosis had a normal fetal karyotype and negative microarray with at least one of the following: parental consanguinity, large regions of homozygosity on fetal microarray, or high likelihood of single gene disorder based on ultrasound findings. All trios underwent sequencing of parental and fetal samples. WES was diagnostic in four of the five cases (80%). We identified two recessive conditions and two de novo mutations. Four couples consented to secondary findings and in one case, the father was found to have an MSH2 mutation associated with Lynch syndrome. The use of specific selection criteria for WES increased diagnostic yield to 80%. This is higher than previously reported. Wide application of our criteria can help identify those who may benefit most from this testing in prenatal diagnosis.

Top-cited articles in the Journal: a bibliometric analysis.

BACKGROUND: The Journal has had a profound influence in nearly 150 years of publishing. A bibliometric analysis, which uses citation analyses to evaluate the impact of articles, can be used to identify the most impactful papers in the Journal's history. OBJECTIVE: The objective was to identify and characterize the top-cited articles published in the Journal since 1920. STUDY DESIGN: We used the Web of Science and Scopus databases to identify the most frequently cited articles of the Journal from 1920 through 2018. The top 100 articles from each database were included in our analysis. Articles were evaluated for several characteristics including year of publication, article type, topic, open access, and country of origin. Using the Scopus data, we performed an unadjusted categorical analysis to characterize the articles and a 2 time point analysis to compare articles before and after 1995, the median year of publication from each database list. RESULTS: The top 100 articles from each database were included in the analysis. This included 120 total articles: 80 articles listed in both and 20 unique in each database. More than half (52%) were observational studies, 9% were RCTs, and 75% were from US authors. When the post-1995 studies were compared with the articles published before 1995, articles were more frequently cited (median 27 vs 13 citations per year, P < .001), more likely to be randomized (14.0% vs 4.8%, P = .009), and more likely to originate from international authors (33.3% vs 17.5%, P = .045). CONCLUSION: Slightly more than half of the top-cited papers in the Journal since 1920 were observational studies and three quarters of all papers were from US authors. Compared with top-cited papers before 1995, the Journal's top-cited papers after 1995 were more likely to be randomized and to originate from international authors.

Vitamin D stimulates multiple microRNAs to inhibit CRH and other pro-labor genes in human placenta.

Maternal vitamin D deficiency is linked to adverse pregnancy outcomes including spontaneous preterm birth (SPB). Placental corticotropin-releasing hormone (CRH) has been proposed to be part of a clock that governs the length of gestation in humans, with elevated maternal serum levels predicting early delivery. In this study, we test the hypothesis that vitamin D could contribute to the prevention of preterm labor by inhibiting CRH and other pro-labor mediators. The biological activity of vitamin D occurs via two pathways: non-genomic and genomic responses, both of which involve binding of 1,25-dihydroxyvitamin D (1,25(OH)2D), the active metabolite of vitamin D binding to the vitamin D receptor (VDR). By using chromatin immunoprecipitation followed by sequencing (ChIP-seq), we found that 1,25(OH)2D stimulates association of VDR with a number of miRNA genes including MIR181B2 and MIR26B, and their mature products miR-181b-5p and miR-26b-5p are predicted to target CRH and cyclooxygenase-2 (COX-2) mRNA at 3'-untranslated region (UTR), respectively. We performed RT-qPCR analysis to validate that expression of mature miR-181b-5p and miR-26b-5p in term human syncytiotrophoblast increased in response to treatment with 1,25(OH)2D. miR-181b-5p- or miR-26b-5p-mediated inhibition of CRH or COX-2 was further assessed by the use of miRNA mimics/inhibitors and a luciferase reporter assay. Taken together, this study has identified novel mechanisms by which vitamin D downregulates pro-labor genes and could lower the risk of preterm delivery.