Sonographic Flow-Mediated Dilation Imaging versus Electronic EndoCheck Flow-Mediated Slowing by VICORDER in Pregnant Women—A Comparison of Two Methods to Evaluate Vascular Function in Pregnancy

The evaluation of endothelial function is gaining interest and importance during pregnancy, since the impaired adaptation in early pregnancy has been associated with an increased risk in preeclampsia and fetal growth restriction. To standardize the risk assessment and to implement the evaluation of vascular function in routine pregnancy care, a suitable, accurate and easy to use method is needed. Flow-mediated dilatation (FMD) of the brachial artery assessed by ultrasound is considered to be the gold standard for measuring the vascular endothelial function. The challenges of the FMD measurement have so far prevented its introduction into clinical routine. The VICORDER ® device allows an automated determination of the flow-mediated slowing (FMS). The equivalence of FMD and FMS has not yet been proven in pregnant women. We collected data of 20 pregnant women randomly and consecutively while they presented for a vascular function assessment in our hospital. The gestational age at investigation was between 22 and 32 weeks of gestation, three had preexisting hypertensive pregnancy disease and three were twin pregnancies. The results for FMD or FMS below 11.3% were considered to be abnormal. Comparing FMD to FMS results in our cohort revealed a convergence in 9/9 cases, indicating normal endothelial function (specificity of 100%) and a sensitivity of 72.7%. In conclusion, we verify that the FMS measurement is a convenient, automated and operator-independent test method of endothelial function in pregnant women

Predictors of treatment requirements in women with gestational diabetes: a retrospective analysis

The diagnosis of gestational diabetes is usually very stressful for pregnant women, especially because they fear that insulin treatment may become necessary. Knowledge about personal risk factors predicting the probability of insulin treatment could therefore help to improve acceptance of the diagnosis and therapy adherence. The aim of this study was to find potential risk factors for insulin dependency and treatment requirements using information available at the time of diagnosis of gestational diabetes during pregnancy. We included 454 singleton pregnancies diagnosed ≥24 weeks of gestation. Multivariate regression analysis was used to evaluate independent associations of metabolic, anthropometric and fetal ultrasound parameters with the general need for insulin treatment and further stratified treatment options: diet ( n = 275), bolus insulin only ( n = 45), basal insulin only ( n = 73) and multiple daily injections ( n = 61). Receiver operator characteristics and cut-off values for independent variables were generated. Treatment groups differed significantly concerning pre-pregnancy weight and BMI as well as fasting glucose and 1 h glucose test values. Significant cut-offs for insulin dependency were HbA1c level of 5.4%, FPG of 5.5 mmol/L and 1 h glucose of 10.6 mmol/L. At time of diagnosis, certain patient characteristics and measurements can help to predict treatment necessities and therefore improve individualized counselling

Contributing factors to perinatal outcome in pregnancies with gestational diabetes: What matters most? A retrospective analysis

The aim of diabetes care of pregnant women with gestational diabetes mellitus (GDM) is to attain pregnancy outcomes including rates of large-for-gestational-age (LGA) newborns, preeclampsia, C-sections (CS) and other neonatal outcomes similar to those of the non-GDM pregnant population. Obesity and excessive weight gain during pregnancy have been shown to also impact perinatal outcome. Since GDM is frequently associated with elevated body mass index (BMI), we evaluated the impact of maternal prepregnancy BMI, development of GDM and gestational weight gain (GWG) during pregnancy on perinatal outcome. We compared 614 GDM patients with 5175 non-diabetic term deliveries who gave birth between 2012 and 2016. Multivariate regression analysis was used to evaluate the independent contribution of each factor on selected perinatal outcome variables. Additionally, subgroup analysis for obese (BMI ≥ 30 kg/m2 ) and non-obese women (BMI < 30 kg/m2 ) was performed. LGA was significantly influenced by BMI, GWG and GDM, while Neonatal Intensive Care Unit (NICU) admission was solely impacted by GDM. Maternal outcomes were not dependent on GDM but on GWG and prepregnancy BMI. These results remained significant in the non-obese subgroup only. Thus, GDM still affects perinatal outcomes and requires further improvement in diabetic care and patient counseling

The relevance of fetal abdominal subcutaneous tissue recording in predicting perinatal outcome of GDM pregnancies: a retrospective study

Guidelines on the management of gestational diabetes (GDM) instruct physicians to involve ultrasound-based monitoring of fetal growth in addition to blood glucose. So far, glucose control besides clinical parameters like maternal body mass index (BMI) and gestational weight gain have been shown to predict neonatal outcome. We aimed to evaluate the discriminative ability of fetal abdominal subcutaneous tissue (FAST) in addition to standard ultrasound parameters like abdominal circumference (AC) and estimated fetal weight (EFW) for perinatal complications like large for gestational age (LGA), hypoglycemia, hyperbilirubinemia, mode of delivery and admission to neonatal intensive care unit (NICU). Ultrasound data and neonatal outcome was collected of 805 GDM cases from 2012 to 2016: 3205 FAST, 3195 AC-measurements and 3190 EFW calculations were included. AC, EFW and FAST increased linear with gestational age. Combining ultrasound and clinical parameters improved predictive power for LGA. In the subgroup where fetuses grow with an AC > 75th additional adding of FAST to standard ultrasound parameters increased predictive power for hypoglycemia. Our results confirm inclusion of ultrasound parameters to be beneficial in monitoring GDM pregnancies. Additional FAST determination revealed to be of potential clinical relevance in the subgroup AC > 75th percentile

Ex vivo perfusion of the human placenta to investigate pregnancy pathologies

Pregnancy pathologies including gestational diabetes, intrauterine fetal growth restriction, and pre-eclampsia are common and significantly increase the risk of poor pregnancy outcomes. Research to better understand the pathophysiology and improve diagnosis and treatment is therefore crucial. The ex vivo placenta perfusion model offers a unique system to study pregnancy pathology without the risk of harm to mother or fetus. The presence of a maternal and fetal circulation and intact villus tree, facilitates investigations into maternal-fetal transfer, altered hemodynamics and vascular reactivity in the human placenta. It also provides a platform to test novel therapeutic agents. Here we review the key studies which have utilized the ex vivo placenta perfusion model to study different aspects of such pregnancy pathologies

Association between antenatal glucocorticoid exposure and the activity of the stress system, cognition, and behavior in 8‐ to 9‐year‐old children: A prospective observational study

Introduction Glucocorticoid (GC) ‐induced fetal programming of the activity of the hypothalamus–pituitary–adrenal axis (HPAA) and its associated cognitive and behavioral consequences in later life have been well characterized in several animal species. However, information on humans is scarce. In this study, we examined HPAA activity markers and associated outcomes at 8 to 9 years of age among children prenatally exposed to GC for suspected preterm birth. Our hypothesis was that antenatal exposure to the betamethasone (BM) is associated with exacerbation of HPAA activity in childhood. Material and methods Prospective observational study in 31 children whose mothers received single ( n = 19) or multiple ( n = 12) courses of BM for threatened preterm birth but born with normal weight appropriate for the gestational age (median 37+ 6 weeks of gestation) compared with 38 non‐exposed, age‐matched children. Primary end point was the activity of the HPAA in response to the Trier Social Stress Test. Secondary end points were changes in autonomic nervous system (ANS) activity, cognitive performance (IQ), attention‐deficit/hyperactivity disorder (ADHD) symptoms, and electrocortical activity (EEG). Results There was no statistically significant difference in HPAA activity markers between antenatal BM exposed and unexposed groups. ANS activity in BM‐exposed children shifted towards a higher parasympathetic tone reflected by a higher overall high‐frequency band power of heart rate variability. IQ scores were within normal limits for both groups; however, BM‐exposed children had lower IQ scores than the unexposed group. BM‐exposed group had marginally more ADHD core symptoms and increased electrocortical activity in the occipital brain region compared with controls. A monotonic dose–response relation between BM exposure and activity of the ANS and IQ was estimated in post‐hoc analyses. Conclusions Antenatal exposure to BM in the context of threatened preterm birth was not associated with changes in HPAA activity in childhood. However, BM exposure may be associated with changes in ANS activity. Antenatal GC prophylaxis is a valuable and often life‐saving therapy, but its prescription may warrant a well‐balanced risk–benefit assessment

Identification of altered miRNAs and their targets in placenta accreta

Placenta accreta spectrum (PAS) is one of the major causes of maternal morbidity and mortality worldwide with increasing incidence. PAS refers to a group of pathological conditions ranging from the abnormal attachment of the placenta to the uterus wall to its perforation and, in extreme cases, invasion into surrounding organs. Among them, placenta accreta is characterized by a direct adhesion of the villi to the myometrium without invasion and remains the most common diagnosis of PAS. Here, we identify the potential regulatory miRNA and target networks contributing to placenta accreta development. Using small RNA-Seq followed by RT-PCR confirmation, altered miRNA expression, including that of members of placenta-specific miRNA clusters (e.g., C19MC and C14MC), was identified in placenta accreta samples compared to normal placental tissues. In situ hybridization (ISH) revealed expression of altered miRNAs mostly in trophoblast but also in endothelial cells and this profile was similar among all evaluated degrees of PAS. Kyoto encyclopedia of genes and genomes (KEGG) analyses showed enriched pathways dysregulated in PAS associated with cell cycle regulation, inflammation, and invasion. mRNAs of genes associated with cell cycle and inflammation were downregulated in PAS. At the protein level, NF-κB was upregulated while PTEN was downregulated in placenta accreta tissue. The identified miRNAs and their targets are associated with signaling pathways relevant to controlling trophoblast function. Therefore, this study provides miRNA:mRNA associations that could be useful for understanding PAS onset and progression

Role of IL-36 Cytokines in the Regulation of Angiogenesis Potential of Trophoblast Cells

IL-36 cytokines (the agonists IL-36α, IL-36β, IL-36γ, and the antagonist IL-36Ra) are expressed in the mouse uterus and associated with maternal immune response during pregnancy. Here, we characterize the expression of IL-36 members in human primary trophoblast cells (PTC) and trophoblastic cell lines (HTR-8/SVneo and JEG-3) and upon treatment with bacterial and viral components. Effects of recombinant IL-36 on the migration capacity of trophoblastic cells, their ability to interact with endothelial cells and the induction of angiogenic factors and miRNAs (angiomiRNAs) were examined. Constitutive protein expression of IL-36 (α, β, and γ) and their receptor (IL-36R) was found in all cell types. In PTC, transcripts for all IL-36 subtypes were found, whereas in trophoblastic cell lines only for IL36G and IL36RN. A synthetic analog of double-stranded RNA (poly I:C) and lipopolysaccharide (LPS) induced the expression of IL-36 members in a cell-specific and time-dependent manner. In HTR-8/SVneo cells, IL-36 cytokines increased cell migration and their capacity to interact with endothelial cells. VEGFA and PGF mRNA and protein, as well as the angiomiRNAs miR-146a-3p and miR-141-5p were upregulated as IL-36 response in PTC and HTR-8/SVneo cells. In conclusion, IL-36 cytokines are modulated by microbial components and regulate trophoblast migration and interaction with endothelial cells. Therefore, a fundamental role of these cytokines in the placentation process and in response to infections may be expected

Perinatal and 2-year neurodevelopmental outcome in late preterm fetal compromise: the TRUFFLE 2 randomised trial protocol

Introduction: Following the detection of fetal growth restriction, there is no consensus about the criteria that should trigger delivery in the late preterm period. The consequences of inappropriate early or late delivery are potentially important yet practice varies widely around the world, with abnormal findings from fetal heart rate monitoring invariably leading to delivery. Indices derived from fetal cerebral Doppler examination may guide such decisions although there are few studies in this area. We propose a randomised, controlled trial to establish the optimum method of timing delivery between 32 weeks and 36 weeks 6 days of gestation. We hypothesise that delivery on evidence of cerebral blood flow redistribution reduces a composite of perinatal poor outcome, death and short-term hypoxia-related morbidity, with no worsening of neurodevelopmental outcome at 2 years. Methods and analysis: Women with non-anomalous singleton pregnancies 32+0 to 36+6 weeks of gestation in whom the estimated fetal weight or abdominal circumference is &lt;10th percentile or has decreased by 50 percentiles since 18-32 weeks will be included for observational data collection. Participants will be randomised if cerebral blood flow redistribution is identified, based on umbilical to middle cerebral artery pulsatility index ratio values. Computerised cardiotocography (cCTG) must show normal fetal heart rate short term variation (≥4.5 msec) and absence of decelerations at randomisation. Randomisation will be 1:1 to immediate delivery or delayed delivery (based on cCTG abnormalities or other worsening fetal condition). The primary outcome is poor condition at birth and/or fetal or neonatal death and/or major neonatal morbidity, the secondary non-inferiority outcome is 2-year infant general health and neurodevelopmental outcome based on the Parent Report of Children's Abilities-Revised questionnaire. Ethics and dissemination: The Study Coordination Centre has obtained approval from London-Riverside Research Ethics Committee (REC) and Health Regulatory Authority (HRA). Publication will be in line with NIHR Open Access policy. Trial registration number: Main sponsor: Imperial College London, Reference: 19QC5491. Funders: NIHR HTA, Reference: 127 976. Study coordination centre: Imperial College Healthcare NHS Trust, Du Cane Road, London, W12 0HS with Centre for Trials Research, College of Biomedical &amp; Life Sciences, Cardiff University. IRAS Project ID: 266 400. REC reference: 20/LO/0031. ISRCTN registry: 76 016 200