Defining trophoblast injury patterns in the transcriptomes of dysfunctional placentas.

Trophoblast injury is central to clinically relevant placenta dysfunction. We hypothesized that the mRNA of primary human trophoblasts, exposed to distinct injuries in vitro, capture transcriptome patterns of placental biopsies obtained from common obstetrical syndromes. We deployed a CIBERSORTx deconvolution method to correlate trophoblastic RNAseq-based expression matrices with the transcriptome of omics-defined placental dysfunction patterns in vivo. We found distinct trophoblast injury patterns in placental biopsies from women with fetal growth restriction and a hypertensive disorder, or in biopsies clustered by their omics analysis. Our RNAseq data are useful for defining the contribution of trophoblast injuries to placental dysfunction syndromes.

The impact of opioids on the transcriptional landscape of human villous trophoblasts.

INTRODUCTION: Opioid use disorder (OUD) is implicated in major obstetrical diseases such as fetal growth restriction. Whether or not opioids directly impact placental trophoblast development and function remains unclear. We sought to examine the expression of opioid receptors (OPRs) in villous trophoblasts and the effect of opioids on placental transcriptomics. METHODS: Trophoblast stem (TS) cells and primary human trophoblast (PHT) cells from healthy term placentas were used to assess OPR expression in conditions that enhance trophoblast stemness vs differentiation. Placental RNAseq was conducted using our retrospective cohorts of pregnant people with OUD vs controls, both without major obstetrical complications. RT-qPCR was used to determine the effect of fentanyl on the expression of putative opioid targets and stemness or differentiation-associated genes in TS and PHT cells. RESULTS: Three main OPRs, including OPRM1, OPRD1, and OPRK1 were expressed in term PHT cells cultured in the stemness medium, whereas only OPRD1 and OPRK1 were expressed in TS cells. Interestingly, upon induction of differentiation, the expressed OPR mRNAs in TS or in PHT cells were downregulated. We found 286 differentially expressed long RNAs in placentas from the OUD participants vs controls. While three putative opioid targets differed their expression in stemness vs differentiation states of trophoblasts, fentanyl had no effect on their expression or the expression of major stemness or differentiation-relevant genes in TS and PHT cells. DISCUSSION: Trophoblastic expression of OPRs and opioid RNA targets is impacted by cell differentiation, suggesting differential susceptibility of villous trophoblasts to the effect of opioids.

Integrated unbiased multiomics defines disease-independent placental clusters in common obstetrical syndromes.

BACKGROUND: Placental dysfunction, a root cause of common syndromes affecting human pregnancy, such as preeclampsia (PE), fetal growth restriction (FGR), and spontaneous preterm delivery (sPTD), remains poorly defined. These common, yet clinically disparate obstetrical syndromes share similar placental histopathologic patterns, while individuals within each syndrome present distinct molecular changes, challenging our understanding and hindering our ability to prevent and treat these syndromes. METHODS: Using our extensive biobank, we identified women with severe PE (n = 75), FGR (n = 40), FGR with a hypertensive disorder (FGR + HDP; n = 33), sPTD (n = 72), and two uncomplicated control groups, term (n = 113), and preterm without PE, FGR, or sPTD (n = 16). We used placental biopsies for transcriptomics, proteomics, metabolomics data, and histological evaluation. After conventional pairwise comparison, we deployed an unbiased, AI-based similarity network fusion (SNF) to integrate the datatypes and identify omics-defined placental clusters. We used Bayesian model selection to compare the association between the histopathological features and disease conditions vs SNF clusters. RESULTS: Pairwise, disease-based comparisons exhibited relatively few differences, likely reflecting the heterogeneity of the clinical syndromes. Therefore, we deployed the unbiased, omics-based SNF method. Our analysis resulted in four distinct clusters, which were mostly dominated by a specific syndrome. Notably, the cluster dominated by early-onset PE exhibited strong placental dysfunction patterns, with weaker injury patterns in the cluster dominated by sPTD. The SNF-defined clusters exhibited better correlation with the histopathology than the predefined disease groups. CONCLUSIONS: Our results demonstrate that integrated omics-based SNF distinctively reclassifies placental dysfunction patterns underlying the common obstetrical syndromes, improves our understanding of the pathological processes, and could promote a search for more personalized interventions.

Prediabetes in pregnancy - follow-up, treatment, and outcomes compared to overt pregestational diabetes.

OBJECTIVE: There are limited data on follow-up, treatment, and maternal and fetal outcomes in women with prediabetes before or at the beginning of pregnancy. The aim of this study was to comprehensively characterize women with prediabetes compared to women with type 2 diabetes mellitus. STUDY DESIGN: This was a retrospective cohort data from a single medical center treating women with pregestational prediabetes mellitus (PDM). Women were compared to pregestational overt type 2 diabetes mellitus (T2DM). RESULTS: Data were collected from 120 women in the PDM group and 86 women in the T2DM group. Baseline characteristics were comparable, albeit women in the PDM group arrived at medical attention significantly later, 55% after 15 weeks gestation. Women with PDM needed significantly less treatment to achieve glycemic control and glycated hemoglobin remained lower throughout pregnancy. Maternal and fetal outcomes were similar between groups, although significantly higher rates of macrosomia and neonatal jaundice were observed in the T2DM group. CONCLUSIONS: The lack of clear guidelines causes a delay in the first prenatal visit of women with PDM. Comparable pregnancy outcomes may tip the balance toward acceptance of early treatment. Establishing clear guidelines will enable primary caregivers to refer prediabetic women sooner for lifestyle modifications and treatment if needed.

The association between an oral glucose tolerance test performed at term pregnancy and obstetric outcomes.

Aims: Assessing the value of oral glucose tolerance test performed at term pregnancy in identifying obstetric complications. Methods: Retrospective cohort study of women with a normal 50 g glucose challenge test who also had an oral glucose tolerance test at term (defined as at or after 37 weeks of gestation). Comparison between the pathological and normal oral glucose tolerance test groups was performed. Results: The mean glucose in the glucose challenge test of women in the normal oral glucose tolerance test (n = 256) group was lower than that in the pathological oral glucose tolerance test (N = 16) group (105 ± 17 mg/dl (5.8 ± 0.9 mmol/l) vs 117 ± 13 mg/dl (6.5 ± 0.7 mmol/l), p = 0.007). Relevant obstetrical complications did not differ significantly between the groups. Of note, in the pathological oral glucose tolerance test group only one woman delivered a macrosomic infant. Conclusions: A pathological oral glucose tolerance test performed at term was unable to identify women at risk for impaired glucose metabolism-related obstetric complications and is therefore of limited clinical value and seems to be unjustified.

The Challenges of Treating Glucokinase MODY during Pregnancy: A Review of Maternal and Fetal Outcomes.

Background: The optimal treatment strategy for the follow-up and management of women with glucokinase maturity-onset diabetes of the young (GCK−MODY)during pregnancy remains unknown. Data regarding maternal and fetal outcomes are lacking. Aim: This paper summarizes the existing literature regarding the maternal and fetal outcomes of women with glucokinase MODY to guide future treatment strategy. Methods: A literature search was conducted in Pubmed, Embace, and Cochrane library with citation follow-up using the terms: glucokinase, MODY, diabetes, pregnancy, gestation, and outcomes. We searched for articles with known fetal mutational status. Relevant outcomes included: birthweight, large for gestational age (LGA), small for gestational age (SGA), macrosomia, cesarean delivery (CD), shoulder dystocia, congenital anomalies, miscarriages, preterm births, and long-term outcomes. Results: Fourteen relevant manuscripts were identified describing maternal and fetal outcomes. The percentage of LGA and macrosomia in 102 glucokinase -unaffected offspring (GCK−) was significantly higher than in the glucokinase -affected offspring (GCK+) (44% vs. 10%, p < 0.001 and 22% vs. 2%, p < 0.001, respectively). Among the 173 GCK(+) offspring, only 5% were SGA, which can be expected according to the normal distribution. We observed higher rates of CD and shoulder dystocia in the GCK(−) offspring. Conclusions: GCK(−) offspring have significantly higher birthweights and more birth complications. The optimal treatment strategy to guide management should take into consideration multiple variables other than fetal mutational status.

Can assessing the angle of progression before labor onset assist to predict vaginal birth after cesarean?: A prospective cohort observational study.

OBJECTIVE: To assess whether pre-labor measurement of the angle of progression (AOP) can assist in predicting a successful vaginal birth after cesarean in women without a previous vaginal birth. METHODS: A prospective observational cohort study performed in a single tertiary center including women at term with a single previous cesarean delivery (CD), without prior vaginal births, who desire a trial of labor. Transperineal ultrasound was used to measure the AOP before the onset of labor. The managing staff in the delivery suite was blinded to the ultrasound measurements. Clinical data and delivery outcome were retrieved from medical records. The study was approved by the institutional ethics committee (KMC 0117-10). RESULTS: Of the 111 women included in the study, 67 (60.4%) had a successful vaginal birth after CD. Women were sonographically assessed at a median of 3 days [interquartile range (IQR) 1-3 days] prior to delivery. The median AOP was significantly narrower in women who eventually underwent a CD than in those who delivered vaginally (88°, IQR 78-96° vs. 99°, IQR 89-107°, respectively; p < .001). An AOP >98° (derived from a receiver operating characteristic curve) was associated with a successful vaginal birth after CD in 87.5% of women. Multivariable regression analysis demonstrated that each additional 1° in the AOP increases the chance for a successful vaginal birth after CD by 6%. CONCLUSIONS: Pre-labor AOP may be a useful sonographic tool for predicting vaginal birth after CD and can assist in consulting primiparous women with a prior CD opting for a trial of labor.

RNA Network Interactions During Differentiation of Human Trophoblasts.

In the human placenta, two trophoblast cell layers separate the maternal blood from the villous basement membrane and fetal capillary endothelial cells. The inner layer, which is complete early in pregnancy and later becomes discontinuous, comprises the proliferative mononuclear cytotrophoblasts, which fuse together and differentiate to form the outer layer of multinucleated syncytiotrophoblasts. Because the syncytiotrophoblasts are responsible for key maternal-fetal exchange functions, tight regulation of this differentiation process is critical for the proper development and the functional role of the placenta. The molecular mechanisms regulating the fusion and differentiation of trophoblasts during human pregnancy remain poorly understood. To decipher the interactions of non-coding RNAs (ncRNAs) in this process, we exposed cultured primary human trophoblasts to standard in vitro differentiation conditions or to conditions known to hinder this differentiation process, namely exposure to hypoxia (O2 < 1%) or to the addition of dimethyl sulfoxide (DMSO, 1.5%) to the culture medium. Using next generation sequencing technology, we analyzed the differential expression of trophoblastic lncRNAs, miRNAs, and mRNAs that are concordantly modulated by both hypoxia and DMSO. Additionally, we developed a model to construct a lncRNA-miRNA-mRNA co-expression network and inferred the functions of lncRNAs and miRNAs via indirect gene ontology analysis. This study improves our knowledge of the interactions between ncRNAs and mRNAs during trophoblast differentiation and identifies key biological processes that may be impaired in common gestational diseases, such as fetal growth restriction or preeclampsia.

Does therapy with biological drugs influence COVID-19 infection? Observational monocentric prevalence study on the clinical and epidemiological data of psoriatic patients treated with biological drugs or with topical drugs alone.

Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, there has been an open debate on the impact of biological drugs used in the treatment of psoriasis. To define whether patients under treatment with biologics suffer from increased morbidity and mortality from COVID-19, compared to psoriatic patients treated only with topical drugs, we designed an observational monocentric prevalence study recording the personal and clinical data of psoriatic patients, with focus on the presentation of signs and symptoms related to COVID-19 in the period of time ranging from 1 January 2020 to 31 May 2020. A total of 180 patients were enrolled into two groups: 100 patients in the topical therapy group and 80 patients in the biological therapy group. No statistically significant difference was found between the groups regarding the prevalence of COVID-19 infection and symptoms at a bivariable analysis with adjustment for confounders. In conclusion, psoriatic patients under treatment with biologics do not seem to be more susceptible to COVID-19 compared to other psoriatic patients and we suggest not interrupting treatment with biological drugs, even in areas suffering from active outbreaks of the disease.

Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection.

Obesity, diabetes, and related manifestations are associated with an enhanced, but poorly understood, risk for mucosal infection and systemic inflammation. Here, we show in mouse models of obesity and diabetes that hyperglycemia drives intestinal barrier permeability, through GLUT2-dependent transcriptional reprogramming of intestinal epithelial cells and alteration of tight and adherence junction integrity. Consequently, hyperglycemia-mediated barrier disruption leads to systemic influx of microbial products and enhanced dissemination of enteric infection. Treatment of hyperglycemia, intestinal epithelial-specific GLUT2 deletion, or inhibition of glucose metabolism restores barrier function and bacterial containment. In humans, systemic influx of intestinal microbiome products correlates with individualized glycemic control, indicated by glycated hemoglobin levels. Together, our results mechanistically link hyperglycemia and intestinal barrier function with systemic infectious and inflammatory consequences of obesity and diabetes.

The Routine Use of Intrapartum Ultrasound in Clinical Decision-Making during the Second Stage of Labor - Does It Have Any Impact on Delivery Outcomes?

BACKGROUND/AIMS: The study aimed to assess whether the use of intrapartum transperineal ultrasound (US) can reduce the rate of failed vacuum extraction (VE). METHODS: This is a retrospective cohort study including all women delivering at term with the diagnosis of protracted second stage of labor. The mode of delivery and rate of failed VE were compared between women who underwent a US examination prior to the decision on obstetrical interventions ("+US" group) and those in whom clinical decisions were based upon digital assessment only ("no-US" group). RESULTS: The study included 635 women. Among the "no-US" group (536), there were 13 failed VE attempts (3.6%) vs. none in the "+US" group (99, p = 0.1). There was a significant difference between the groups regarding mode of delivery (p = 0.001), with a lower cesarean section (CS) rate (20.2 vs. 27.8%) among the "+US" group. Maternal age, body mass index, nulliparity, gestational age at delivery, and birth weight, as well as neonatal short-term outcome did not differ significantly between the 2 groups. CONCLUSIONS: We demonstrate that among women who had the addition of intrapartum US during the second stage of labor there was a trend toward a lower rate of failed VE (although not reaching statistical significance), with a lower rate of CS but not affecting neonatal outcome.