Neuroinflammatory reactive astrocyte formation correlates with adverse outcomes in perinatal white matter injury.

Perinatal white matter injury (WMI) is the leading cause of long-term neurological morbidity in infants born preterm. Neuroinflammation during a critical window of early brain development plays a key role in WMI disease pathogenesis. The mechanisms linking inflammation with the long-term myelination failure that characterizes WMI, however, remain unknown. Here, we investigate the role of astrocyte reactivity in WMI. In an experimental mouse model of WMI, we demonstrate that WMI disease outcomes are improved in mutant mice lacking secretion of inflammatory molecules TNF-α, IL-1α, and C1q known, in addition to other roles, to induce the formation of a neuroinflammatory reactive astrocyte substate. We show that astrocytes express molecular signatures of the neuroinflammatory reactive astrocyte substate in both our WMI mouse model and human tissue affected by WMI, and that this gene expression pattern is dampened in injured mutant mice. Our data provide evidence that a neuroinflammatory reactive astrocyte substate correlates with adverse WMI disease outcomes, thus highlighting the need for further investigation of these cells as potential causal players in WMI pathology.

Hybrid cord blood banking in a private-public-partnership: Women's perspectives.

BACKGROUND: The increasing demand for umbilical cord blood (UCB) used in stem cell transplantation led to the establishment of cord blood (CB) banks worldwide. These include public foreign donor banks and private family-directed donor banks. Recently, our department has introduced a third banking model within a private-public-partnership. This hybrid banking allows for storage of family-directed CB units, while also getting Human leukocyte antigen (HLA)-typed and included in the national stem cell donor registry. So if the need arises, the HLA-compatible CB unit can be released to an unrelated recipient as a foreign donor stem cell graft. OBJECTIVES: The aim of this study was to evaluate women's perspectives on the different CB banking options as well as retrospective satisfaction with their decisions. METHODS: We performed a prospective survey study in postpartum women, using a validated questionnaire. RESULTS: A total of 157 women were included in this survey study; 68% of them decided to have their UCB stored or donated. Among those women, 25% of them opted for hybrid storage, 72% of respondents stored UCB publicly, and 3% decided for private family-directed storage. CONCLUSIONS: Our study shows the potential of hybrid banking as an attractive UCB storage option, as an alternative to family-directed banking rather than a substitute for public donation. Hybrid storage potentially combines advantages of family-directed banking as well as unrelated CB donation expanding the number of registered CB units available for transplantation and giving every pregnant woman the possibility to store UCB.

Hybrid umbilical cord blood banking: literature review.

PURPOSE: Interest gaps between public and private umbilical cord blood banks have led to the introduction of hybrid banking options. Hybrid models combine features of private and public banks as well as interests of parents, children and of patients, in order to find an optimized solution. While several different models of hybrid banks exist, there is a lack of literature about this novel model of cord blood stem cell banking. Therefore, the aim of this literature review is to assess different options of umbilical cord blood banking and whether hybrid banking could be a valuable alternative to the existing public and private cord blood banking models. METHODS: We performed a systematic literature search, using five main databases. Five hybrid models regarding their advantages as well as their challenges are discussed in this review. RESULTS: We found that a wealth of literature exists about public cord blood banking, while private and hybrid banking are understudied. Different modalities of hybrid cord blood banking are being described in several publications, providing the basis to assess different advantages and disadvantages as well as practicability. CONCLUSION: Hybrid banks, especially the sequential model, seem to have potential as an alternative to the existing banking models worldwide. A previously conducted survey among pregnant women showed a preference for hybrid banking, if such an option was available. Nevertheless, opinions among stakeholders differ and more research is needed to evaluate, if hybrid banking provides the expected benefits.

First-trimester glycosylated hemoglobin (HbA1c) and maternal characteristics in the prediction of gestational diabetes: An observational cohort study.

INTRODUCTION: This study aimed to investigate the extent to which gestational diabetes mellitus (GDM) can be predicted in the first trimester by combining a marker of growing interest, glycosylated hemoglobin A1c (HbA1c), and maternal characteristics. MATERIAL AND METHODS: This observational study was conducted in the outpatient obstetric department of our institution. The values of HbA1c and venous random plasma glucose were prospectively assessed in the first trimester of pregnancy. We determined maternal characteristics that were independent predictors from the regression analysis and calculated areas under the receiver-operating curves by combining the maternal age, body mass index, previous history of GDM, and first-degree family history for diabetes mellitus. Moreover we investigated the predictive capability of HbA1c to exclude GDM. Patients with a first-trimester HbA1c level of 6.5% (48 mmol/mol) or more were excluded. The study was registered at ClinicalTrials.gov ID: NCT02139254. RESULTS: We included 785 cases with complete dataset. The prevalence of GDM was 14.7% (115/785). Those who developed GDM had significantly higher HbA1c and random plasma glucose values (p < 0.0001 and p = 0.0002, respectively). In addition, they had a higher body mass index, were more likely to have a history of GDM and/or a first-degree family history of diabetes. When these maternal characteristics were combined with the first-trimester HbA1c and random plasma glucose the combined area under the receiver operating characteristics curve was 0.76 (95% CI 0.70-0.81). CONCLUSIONS: Our results indicate that HbA1c and random plasma glucose values combined with age, body mass index, and personal and family history, allow the identification of women in the first trimester who are at increased risk of developing GDM.

The Bern Birth Cohort (BeBiCo) to study the development of the infant intestinal microbiota in a high-resource setting in Switzerland: rationale, design, and methods.

BACKGROUND: Microbiota composition is fundamental to human health with the intestinal microbiota undergoing critical changes within the first two years of life. The developing intestinal microbiota is shaped by maternal seeding, breast milk and its complex constituents, other nutrients, and the environment. Understanding microbiota-dependent pathologies requires a profound understanding of the early development of the healthy infant microbiota. METHODS: Two hundred and fifty healthy pregnant women (≥20 weeks of gestation) from the greater Bern area will be enrolled at Bern University hospital's maternity department. Participants will be followed as mother-baby pairs at delivery, week(s) 1, 2, 6, 10, 14, 24, 36, 48, 96, and at years 5 and 10 after birth. Clinical parameters describing infant growth and development, morbidity, and allergic conditions as well as socio-economic, nutritional, and epidemiological data will be documented. Neuro-developmental outcomes and behavior will be assessed by child behavior checklists at and beyond 2 years of age. Maternal stool, milk, skin and vaginal swabs, infant stool, and skin swabs will be collected at enrolment and at follow-up visits. For the primary outcome, the trajectory of the infant intestinal microbiota will be characterized by 16S and metagenomic sequencing regarding composition, metabolic potential, and stability during the first 2 years of life. Secondary outcomes will assess the cellular and chemical composition of maternal milk, the impact of nutrition and environment on microbiota development, the maternal microbiome transfer at vaginal or caesarean birth and thereafter on the infant, and correlate parameters of microbiota and maternal milk on infant growth, development, health, and mental well-being. DISCUSSION: The Bern birth cohort study will provide a detailed description and normal ranges of the trajectory of microbiota maturation in a high-resource setting. These data will be compared to data from low-resource settings such as from the Zimbabwe-College of Health-Sciences-Birth-Cohort study. Prospective bio-sampling and data collection will allow studying the association of the microbiota with common childhood conditions concerning allergies, obesity, neuro-developmental outcomes , and behaviour. Trial registration The trial has been registered at www. CLINICALTRIALS: gov , Identifier: NCT04447742.

The extended gentle caesarean section protocol-expanding the scope and adding value for the family: a cross-sectional study.

PURPOSE: In Switzerland, about one in three children is born by caesarean section (CS). For many women, this means a restricted birth experience, limited observation of the birth process and a restricted involvement. We evaluated an extended gentle CS protocol, which offered early intraoperative skin-to-skin contact and the possibility of observing the delivery of the baby from the abdomen through a transparent drape. METHODS: This is a cross-sectional study incorporating data from a purposely tailored questionnaire and clinical routine data. The extended gentle CS protocol was compared with the gentle CS, which does not allow the possibility of observing the delivery. Data were collected online and analysed by multivariable regression for quantitative data and content analysis for all text responses to open questions, respectively. RESULTS: 193 women completed the questionnaire. Of these, 154 had a gentle CS and 39 had an extended gentle CS. Multivariable regression did not reveal a statistically significant difference for extended gentle CS with regard to satisfaction with childbirth, mother-to-child bonding, or breastfeeding duration. Nevertheless, early intraoperative skin-to-skin contact was associated with the fulfilment of birth expectations. Furthermore, most women who experienced an extended gentle CS would prefer the same procedure for any potential future CS. CONCLUSIONS: Although our study showed no statistically significant difference in satisfaction from using a transparent drape, most women expressed a preference for this technique. We recommend that the option of an extended gentle CS should be offered to all women for whom CS is indicated.

Use of Polynomial Reference Ranges for Atrioventricular Intervals Assessed by Fetal Echocardiography in Anti-Ro/SSA Antibody-Positive Pregnancies to Exclude Fetal Heart Blocks: A Pilot Study.

INTRODUCTION: Maternal anti-Ro/SSA antibodies can cause fetal atrioventricular blocks (AVB). This pilot study aims to apply previously published echocardiographic reference ranges of the fetal atrioventricular (AV) intervals in the setting of anti-Ro/SSA antibody-positive pregnancies in order to exclude a 1° AVB. MATERIALS AND METHODS: Between January 2018 and September 2022, we included all women with known anti-Ro/SSA antibodies followed up at the prenatal ultrasound department of the University Hospital of Bern. AV intervals were serially measured by two previously reported methods and plotted against previously created reference ranges. RESULTS: We included 23 pregnancies from 17 anti-Ro/SSA antibody-positive women with connective tissue diseases. 443 AV interval measurements were recorded between 16+3 and 38+4 weeks of gestation. 14 (3.2%) AV-intervals measured >150 ms, none measured >170 ms and 8 (1.8%) were found to be >95th percentile. In none of the pregnancies, serial AV-prolongations were noted. The postnatal electrocardiograms demonstrated normal sinus rhythm without AVB in all children. CONCLUSION: AV intervals of pregnancies followed up for anti-Ro/SSA antibodies without neonatal AVB lie within our published polynomial reference ranges. While diagnosing a 1° AVB remains controversial, more data are needed to prove that our reference ranges are helpful exclude a 1° AVB.

Implementing Preeclampsia Screening in Switzerland (IPSISS): First Results from a Multicentre Registry.

INTRODUCTION: The Fetal Medicine Foundation (FMF) London developed a first trimester combined screening algorithm for preterm preeclampsia (pPE) that allows a significantly higher detection of pregnancies at risk compared to conventional screening by maternal risk factors only. The aim of this trial is to validate this screening model in the Swiss population in order to implement this screening into routine first trimester ultrasound and to prescribe low-dose aspirin 150 mg (LDA) in patients at risk for pPE. Therefore, a multicentre registry study collecting and screening pregnancy outcome data was initiated in 2020; these are the preliminary results. METHODS: Between June 1, 2020, and May 31, 2021, we included all singleton pregnancies with pPE screening at the hospitals of Basel, Lucerne, and Bern. Multiple of medians of uterine artery pulsatility index (UtA-PI), mean arterial pressure (MAP), placental growth factor (PlGF), and pregnancy-associated plasma protein A (PAPP-A) as well as risks were analysed as calculated by each centre's software and recalculated on the FMF online calculator for comparative reasons. Statistical analyses were performed by GraphPad Version 9.1. RESULTS: During the study period, 1,027 patients with singleton pregnancies were included. 174 (16.9%) had a risk >1:100 at first trimester combined screening. Combining the background risk, MAP, UtA-PI, and PlGF only, the cut-off to obtain a screen positive rate (SPR) of 11% is ≥1:75. Outcomes were available for 968/1,027 (94.3%) of all patients; 951 resulted in live birth. Fifteen (1.58%) developed classical preeclampsia (PE), 23 (2.42%) developed PE according to the International Society for the Study of Hypertension in Pregnancy (ISSHP) definition. CONCLUSION: First trimester combined screening for PE and prevention with LDA results in a low prevalence of PE. The screening algorithm performs according to expectations; however, the cut-off of >1:100 results in a SPR above the accepted range and a cut-off of ≥1:75 should be considered for screening. More data are needed to evaluate, if these results are representative for the general Swiss population.

Are children born by cesarean delivery at higher risk for respiratory sequelae?

BACKGROUND: Globally, the number of children born by cesarean delivery is constantly increasing. However, hormonal and physiological changes associated with labor and vaginal delivery are considered necessary for lung maturation. OBJECTIVE: We aimed to assess whether the mode of delivery is associated with changes in respiratory and atopic outcomes during infancy and at school age. STUDY DESIGN: We included 578 children, born at ≥37 weeks of gestation, from a prospective birth cohort study. We compared weekly respiratory symptoms throughout the first year of life and infant lung function (tidal breathing and multiple-breath washout) at 5 weeks of age between children born by cesarean delivery (N=114) and those born by vaginal delivery (N=464) after term pregnancy in healthy women. At a follow-up visit conducted at 6 years of age (N=371, of which 65 were delivered by cesarean delivery), we assessed respiratory, atopic, and lung function outcomes (spirometry, body plethysmography, and multiple-breath washout). We performed adjusted regression analyses to examine the association between cesarean delivery and respiratory and atopic outcomes. To account for multiple testing, we used the Bonferroni correction, which led to an adapted significance level of P<.002. RESULTS: During infancy, children born by cesarean delivery did not have more respiratory symptoms than those born by vaginal delivery (median, 4 weeks; interquartile range, 7 weeks vs median, 5 weeks; interquartile range, 7 weeks; adjusted incidence rate ratio, 0.8; 95% confidence interval, 0.6-1.0; P=.02). Infant lung function was similar between the groups. Children born by cesarean delivery did not have a higher incidence of "ever wheezing" (adjusted odds ratio, 0.9; 95% confidence interval, 0.5-1.8; P=.78) or current asthma (adjusted odds ratio, 0.4; 95% confidence interval, 0.0-3.5; P=.42) at school age than those born by vaginal delivery. There was no difference in the lung function parameters between the groups. CONCLUSION: Cesarean delivery was not associated with respiratory symptoms in the first year of life, nor with different respiratory or atopic outcomes at school age, when compared with vaginal delivery. Our results indicate that there are no long-term consequences on the respiratory health of the child associated with cesarean delivery.

Differential Diagnosis and Prognosis of Fetuses with Bilateral Enlarged, Hyperechogenic Kidneys: Renal Volume and Amniotic Fluid Volume with Advancing Gestation.

INTRODUCTION: This study's objective was to identify prenatal criteria helping differential diagnosis of bilateral enlarged, hyperechogenic kidneys, especially looking at development of renal volume and amniotic fluid volume with increasing gestational age. METHOD: Retrospective analysis (single-center database) of all bilateral enlarged, hyperechogenic kidneys between 2000-2018. Renal enlargement was defined as renal volume>90th percentile. Evaluation included development of renal and amniotic fluid volume during pregnancy and fetal outcome. RESULTS: 23 cases fulfilled the inclusion criteria. 12 pregnancies were terminated. For 11 continued pregnancies, longitudinal information on amniotic fluid volume and renal volume were available. 4 cases with oligohydramnios showed a progressive reduction; 6 cases with normal/increased amniotic fluid volume remained stable; in 1 case amniotic fluid volume normalized from initially being oligohydramnios. Regarding renal volume, 4 cases showed exponential enlargement, 3 cases linear progression; in 2 cases renal volume stabilized after initial progression; 2 cases showed initial progression and secondary regression. 4 fetuses survived: 3 autosomal dominant polycystic kidney diseases, 1 Bardet-Biedl syndrome. CONCLUSION: Progressive reduction of amniotic fluid volume with exponential increase of renal volume is highly suggestive for autosomal recessive polycystic kidney disease. Cases of autosomal dominant polycystic kidney disease show a linear progression of renal volume>90th percentile and mostly normal amniotic fluid volume.

Gestational diabetes mellitus affects placental iron homeostasis: Mechanism and clinical implications.

Clinical studies suggest that pregnant women with elevated iron levels are more vulnerable to develop gestational diabetes mellitus (GDM), but the causes and underlying mechanisms are unknown. We hypothesized that hyperglycemia induces cellular stress responses leading to dysregulated placental iron homeostasis. Hence, we compared the expression of genes/proteins involved in iron homeostasis in placentae from GDM and healthy pregnancies (n = 11 each). RT-qPCR and LC-MS/MS analyses revealed differential regulation of iron transporters/receptors (DMT1/FPN1/ZIP8/TfR1), iron sensors (IRP1), iron regulators (HEPC), and iron oxidoreductases (HEPH/Zp). To identify the underlying mechanisms, we adapted BeWo trophoblast cells to normoglycemic (N), hyperglycemic (H), and hyperglycemic-hyperlipidemic (HL) conditions and assessed Fe3+ -uptake, expression patterns, and cellular pathways involving oxidative stress (OS), ER-stress, and autophagy. H and HL induced alterations in cellular morphology, differential iron transporter expression, and reduced Fe3+ -uptake confirming the impact of hyperglycemia on iron transport observed in GDM patients. Pathway analysis and rescue experiments indicated that dysregulated OS and disturbed autophagy processes contribute to the reduced placental iron transport under hyperglycemic conditions. These adaptations could represent a protective mechanism preventing the oxidative damage for both fetus and placenta caused by highly oxidative iron. In pregnancies with risk for GDM, antioxidant treatment, and controlled iron supplementation could help to balance placental OS levels protecting mother and fetus from impaired iron homeostasis.

Obstetrician involvement in planned midwife-led births: a cohort study in an obstetric department of a University Hospital in Switzerland.

BACKGROUND: Healthy women with low risk singleton pregnancies are offered a midwife-led birth model at our department. Exclusion criteria for midwife-led births include a range of abnormalities in medical history and during the course of pregnancy. In case of complications before, during or after labor and birth, an obstetrician is involved. The purpose of this study was 1) to evaluate the frequency of and reasons for secondary obstetrician involvement in planned midwife-led births and 2) to assess the maternal and neonatal outcome. METHODS: We analyzed a cohort of planned midwife-led births during a 14 years period (2006-2019). Evaluation included a comparison between midwife-led births with or without secondary obstetrician involvement, regarding maternal characteristics, birth mode, and maternal and neonatal outcome. Statistical analysis was performed by unpaired t-tests and Chi-square tests. RESULTS: In total, there were 532 intended midwife-led births between 2006 and 2019 (2.6% of all births during this time-period at the department). Among these, 302 (57%) women had spontaneous vaginal births as midwife-led births. In the remaining 230 (43%) births, obstetricians were involved: 62% of women with obstetrician involvement had spontaneous vaginal births, 25% instrumental vaginal births and 13% caesarean sections. Overall, the caesarean section rate was 5.6% in the whole cohort of women with intended midwife-led births. Reasons for obstetrician involvement primarily included necessity for labor induction, abnormal fetal heart rate monitoring, thick meconium-stained amniotic fluid, prolonged first or second stage of labor, desire for epidural analgesia, obstetrical anal sphincter injuries, retention of placenta and postpartum hemorrhage. There was a significantly higher rate of primiparous women in the group with obstetrician involvement. Arterial umbilical cord pH < 7.10 occurred significantly more often in the group with obstetrician involvement, while 5' Apgar score < 7 did not differ significantly. The overall transfer rate of newborns to neonatal intensive care unit was low (1.3%). CONCLUSION: A midwife-led birth in our setting is a safe alternative to a primarily obstetrician-led birth, provided that selection criteria are being followed and prompt obstetrician involvement is available in case of abnormal course of labor and birth or postpartum complications.

Red blood cell transfusion in obstetrics and its implication for patient blood management: a retrospective analysis in Switzerland from 1998 to 2016.

PURPOSE: Peripartum hemorrhage (PPH) remains one of the main causes of maternal mortality worldwide. Treatment includes administration of packed red blood cells (RBC) in severe cases and patient blood management (PBM) may reduce it significantly. In our study, we wanted to retrospectively assess red blood cell administration in PPH to evaluate the impact of PBM in Switzerland. METHODS: Using data from the Swiss obstetric hospital registry (Arbeitsgemeinschaft Schweizer Frauenkliniken, ASF), we included patients with deliveries from 1998 to 2016. We examined available obstetric data as well as blood loss and RBC administration in the acute and subacute peripartal phase. We categorized data into two time intervals: 1998-2011 and 2012-2016, as new PPH guidelines in Switzerland were established in 2012. RESULTS: PPH incidence increased between 1998 and 2016 significantly. The number of vaginal instrumental deliveries and cesarean sections increased as well. Administration of three or more RBC units, as defined in the ASF registry, in the acute and subacute phase in Switzerland has decreased after 2012. Conversely, we saw an increase in the administration of one to two RBC units in the acute and subacute phase. Nevertheless, overall RBC administration has been decreasing from 1998 to 2016. CONCLUSION: The increase of patients obtaining one or two units of RBC for PPH suggests that there may be a potential for effective implication of PBM in obstetrics. Reduction of RBC transfusion in the context of PPH may not only decrease maternal morbidity, but decrease economic costs as well.

Cervico-vaginal placental α-macroglobulin-1 combined with cervical length for the prediction of preterm birth in women with threatened preterm labor.

INTRODUCTION: Preterm birth is a major cause of neonatal morbidity and mortality. There is an urgent need to accurately predict imminent delivery to enable necessary interventions such as tocolytic, glucocorticoid, and magnesium sulfate administration. We aimed to evaluate placental α-macroglobulin-1 as a new diagnostic marker in the prediction of preterm birth. MATERIAL AND METHODS: We performed a prospective observational trial in women with intact membranes between 24+0 and 36+6 weeks of gestation. We included both women with and without threatened preterm labor symptoms. We evaluated the test performance of placental α-macroglobulin-1 measurements in cervicovaginal fluid regarding three different presentation-to-delivery intervals: ≤2, ≤7, ≤14 days. In addition, we calculated placental α-macroglobulin-1 performance in combination with other prognostic factors such as ultrasonographic cervical length measurements. RESULTS: We included 126 women in the study. We detected high specificity (97%-98%) and negative predictive value (89%-97%) for placental α-macroglobulin-1 at all time intervals. We assessed placental α-macroglobulin-1 in combination with cervical length measurements (≤15 mm) in the sub-group of women presenting with threatened preterm labor symptoms (n = 63) and detected high positive predictive values (100%) for 7- and 14-day presentation-to-delivery intervals. CONCLUSIONS: Our study provides evidence that placental α-macroglobulin-1 testing in cervicovaginal fluid, in combination with cervical length measurements, accurately predicts preterm birth in women with preterm labor symptoms. This novel test combination may be used clinically to triage women presenting with threatened preterm labor, avoiding overtreatment and unnecessary hospitalizations.

Patient blood management (PBM) in pregnancy and childbirth: literature review and expert opinion.

PURPOSE: Patient blood management [PBM] has been acknowledged and successfully introduced in a wide range of medical specialities, where blood transfusions are an important issue, including anaesthesiology, orthopaedic surgery, cardiac surgery, or traumatology. Although pregnancy and obstetrics have been recognized as a major field of potential haemorrhage and necessity of blood transfusions, there is still little awareness among obstetricians regarding the importance of PBM in this area. This review, therefore, summarizes the importance of PBM in obstetrics and the current evidence on this topic. METHOD: We review the current literature and summarize the current evidence of PBM in pregnant women and postpartum with a focus on postpartum haemorrhage (PPH) using PubMed as literature source. The literature was reviewed and analysed and conclusions were made by the Swiss PBM in obstetrics working group of experts in a consensus meeting. RESULTS: PBM comprises a series of measures to maintain an adequate haemoglobin level, improve haemostasis and reduce bleeding, aiming to improve patient outcomes. Despite the fact that the WHO has recommended PBM early 2010, the majority of hospitals are in need of guidelines to apply PBM in daily practice. PBM demonstrated a reduction in morbidity, mortality, and costs for patients undergoing surgery or medical interventions with a high bleeding potential. All pregnant women have a significant risk for PPH. Risk factors do exist; however, 60% of women who experience PPH do not have a pre-existing risk factor. Patient blood management in obstetrics must, therefore, not only be focused on women with identified risk factor for PPH, but on all pregnant women. Due to the risk of PPH, which is inherent to every pregnancy, PBM is of particular importance in obstetrics. Although so far, there is no clear guideline how to implement PBM in obstetrics, there are some simple, effective measures to reduce anaemia and the necessity of transfusions in women giving birth and thereby improving clinical outcome and avoiding complications. CONCLUSION: PBM in obstetrics is based on three main pillars: diagnostic and/or therapeutic interventions during pregnancy, during delivery and in the postpartum phase. These three main pillars should be kept in mind by all professionals taking care of pregnant women, including obstetricians, general practitioners, midwifes, and anaesthesiologists, to improve pregnancy outcome and optimize resources.

Different Pharmacological Properties of GLUT9a and GLUT9b: Potential Implications in Preeclampsia.

BACKGROUND/AIMS: Glucose transporter 9 (GLUT9/SLC2A9) is the major regulator of uric acid homeostasis in humans. Hyperuricemia due to impaired regulation by GLUT9 in pregnancy is closely associated with preeclampsia. While GLUT9 is expressed in two alternative splice variants, GLUT9a and GLUT9b, with different subcellular localizations, no functional differences of the two splice variants are known to date. The aim of this study was to investigate the function of both GLUT9 isoforms. METHODS: To characterize the different pharmacological properties of GLUT9a and GLUT9b electrophysiological studies of these isoforms and their modified variants, i.e. NmodGLUT9a and NmodGLUT9b, were performed using a Xenopus laevis oocytes model. Currents were measured by an electrode voltage clamp system. RESULTS: Functional experiments unveiled that uric acid transport mediated by GLUT9a but not GLUT9b is chloride-dependent: Replacing chloride by different anions resulted in a 3.43±0.63-fold increase of GLUT9a- but not GLUT9b-mediated currents. However, replacement by iodide resulted in a loss of current for GLUT9a but not GLUT9b. Iodide inhibits GLUT9a with an IC50 of 35.1±6.7µM. Modification of the N-terminal domain leads to a shift of the iodide IC50 to 1200±228µM. Using molecular docking studies, we identified two positively charged residues H23 and R31 in the N-terminal domain of hGLUT9a which can explain the observed functional differences. CONCLUSION: To the best of our knowledge, this is the first study showing that the N-terminal domain of hGLUT9a has a unique regulatory function and the potential to interact with small negatively charged ions like iodide. These findings may have significant implications in our understanding of hyperuricemia-associated diseases, specifically during pregnancy.

Patient blood management in obstetrics - Review.

Patient blood management (PBM) aims to reduce red blood cell transfusion, minimize preoperative anemia, reduce intraoperative blood loss as well as optimize hemostasis, and individually manage postoperative anemia. Benefits include improved clinical outcome with a reduction in patient morbidity and mortality, but also lower hospital costs and shorter hospital length of stay. To date, it has been successfully implemented in several medical specialties, such as cardiac, trauma and orthopedic surgery. In obstetrics, postpartum hemorrhage (PPH) is one of the leading causes of maternal mortality. PBM has the potential to improve outcome of mother and child. However, pregnancy and childbirth pose a special challenge to PBM, and several adaptations compared to PBM in elective surgery are necessary. To date, awareness of the clinical advantages of PBM among obstetricians and midwifes regarding PBM and its concept in PPH is limited. In the following review, we therefore aim to present the current status quo in PBM in obstetrics and its challenges in the clinical routine.

Shrunken pore syndrome, preeclampsia, and markers of NO metabolism in pregnant women during the first trimester.

Shrunken pore syndrome (SPS) is a condition that manifests itself as the decreased renal clearance of low-molecular-weight proteins but normal clearance of creatinine. Pregnant women with evidence of SPS during the first trimester have an increased risk of developing preeclampsia (PE). The nitric oxide (NO) metabolism markers arginine and ADMA, especially their ratio (Arg/ADMA), are recognized markers of endothelial dysfunction. The aim of this nested case-control study was to establish first-trimester reference intervals (RI) for markers of NO metabolism and to study these markers in women with evidence of SPS at the end of the first trimester. Seventy-four women were stratified in the first trimester according to evidence of SPS (SPS + or SPS-) and the occurrence of PE during subsequent pregnancy (PE + or PE-), as follows: SPS-/PE-, SPS+/PE-, SPS-/PE+, and SPS+/PE+. RIs were determined according to the CLSI EP28-A3c guidelines. Serum Arg and ADMA levels were analyzed. The Arg and ADMA concentrations did not differ among the four groups. However, women in the SPS+/PE + group had a significantly lower Arg/ADMA ratio than those in the other 3 groups (p = .02). In conclusion, we defined the first-trimester RI of Arg, ADMA and the Arg/ADMA ratio as markers of NO metabolism. Our results suggest that SPS in the first trimester predicts a pathophysiological hallmark of subsequent PE, i.e. lower NO production leading to increased vessel tone. Early identification of women at risk for later PE could lead to adaptive prophylactic interventions, such as supplementation with Arg or an NO-donor drug in order to mitigate the risk of developing PE.

Nomograms of the Fetal Sylvian Fissure and Insular Lobe throughout Gestation: A Multicentric, Ultrasonographic Cross-Sectional Study.

INTRODUCTION: Anomalies in cortical development are often associated with an adverse outcome, but prenatal diagnosis is often impeded by the limited knowledge about normal sulci biometries throughout fetal brain development. Our aim was to provide two-dimensional ultrasonographical (2D US) nomograms of the depth of the Sylvian fissure (SF) and insular lobe (IL), as well as of the SF ratio throughout gestation in a large number of fetuses. MATERIALS AND METHODS: This was a prospective cross-sectional study of 329 normal singleton pregnancies. Measurements of the SF, IL, and SF ratio were obtained in a standard transthalamic plane of the fetal head. The SF ratio was defined as SF\SF + IL. All measurements were expressed by regression equations as a function of gestational age (GA) according to the method described by Royston and Wright. The first 38 measurements were repeated twice by 2 examiners to assess the reproducibility through the intraclass correlation coefficient (ICC). RESULTS: A significant correlation was found between GA and SF (r = 0.79; p < 0.0001) as well as IL (r = 0.77; p < 0.0001). Similarly, the SF ratio also showed a significant correlation with GA (r = 0.39; p < 0.0001). When interobserver variability was assessed, ICC was 0.97. CONCLUSIONS: Prenatal 2D US measurements of SF and IL as well as the SF ratio may be feasible and reproducible using a standard view of the fetal head. Our nomograms may be used as a reference for assessing cortical development throughout pregnancy.

The Vermian-Crest Angle: A New Method to Assess Fetal Vermis Position within the Posterior Fossa Using 3-Dimensional Multiplanar Sonography.

BACKGROUND: Normal morphometry of the vermis and its relation to the posterior fossa (PF) rule out most major anomalies of the cerebellum. However, accurate categorization of the position and size of the fetal vermis remains a challenge. OBJECTIVE: Our aim was to test a new method to assess the position and size of fetal vermis on 3-dimensional ultrasound (3D-US). METHODS: We measured the vermian-crest angle (VCA) in normal fetuses using multiplanar 3D-US. We also assessed the diameters (superoinferior, anteroposterior, and horizontal) and volume of the vermis. The Spearman rank test and linear and polynomial regression analyses were used for statistical purposes. RESULTS: We included 126 fetuses. Mean ± SD gestational age (GA) was 26.3 ± 4.6 (range 17-35.5) weeks. Mean ± SD superoinferior, anteroposterior, and horizontal diameters were 16.2 ± 4.9, 11.2 ± 3.6, and 5.6 ± 1.6 mm, respectively. Median (range) vermian volume was 0.50 (0.05-2.9) cm3. The VCA was 64.49° ± 11.45. We found no correlation between GA and VCA (r = 0.15; p = 0.13), a linear correlation between GA and vermian diameters, and a quadratic correlation between GA and vermian volume. CONCLUSIONS: We provide a new method to assess vermian position and size within the PF using 3D-US. The combined information may be of value for screening purposes, particularly to differentiate between the various pathological situations encountered within the PF.