All but Small: miRNAs from Wharton's Jelly-Mesenchymal Stromal Cell Small Extracellular Vesicles Rescue Premature White Matter Injury after Intranasal Administration.

White matter injury (WMI) is a common neurological issue in premature-born neonates, often causing long-term disabilities. We recently demonstrated a key beneficial role of Wharton's jelly mesenchymal stromal cell-derived small extracellular vesicles (WJ-MSC-sEVs) microRNAs (miRNAs) in WMI-related processes in vitro. Here, we studied the functions of WJ-MSC-sEV miRNAs in vivo using a preclinical rat model of premature WMI. Premature WMI was induced in rat pups through inflammation and hypoxia-ischemia. Small EVs were purified from the culture supernatant of human WJ-MSCs. The capacity of WJ-MSC-sEV-derived miRNAs to decrease microglia activation and promote oligodendrocyte maturation was evaluated by knocking down (k.d) DROSHA in WJ-MSCs, releasing sEVs containing significantly less mature miRNAs. Wharton's jelly MSC-sEVs intranasally administrated 24 h upon injury reached the brain within 1 h, remained detectable for at least 24 h, significantly reduced microglial activation, and promoted oligodendrocyte maturation. The DROSHA k.d in WJ-MSCs lowered the therapeutic capabilities of sEVs in experimental premature WMI. Our results strongly indicate the relevance of miRNAs in the therapeutic abilities of WJ-MSC-sEVs in premature WMI in vivo, opening the path to clinical application.

First Trimester Contingent Screening for Aneuploidies with Cell-Free Fetal DNA in Singleton Pregnancies - a Swiss Single Centre Experience.

Introduction: Switzerland was amongst the first countries to offer cell-free fetal DNA (cffDNA) testing covered by the health insurance to pregnant women with a risk ≥ 1:1000 for trisomies at first trimester combined screening (FTCS). The aim of this study is to evaluate the implementation of this contingent model in a single tertiary referral centre and its effect on gestational age at diagnosing trisomy 21. Materials and Methods: Between July 2015 and December 2020 all singleton pregnancies at 11-14 weeks of gestation without major fetal malformation were included and stratified according to their risk at FTCS. Statistical analysis was performed by GraphPad Version 9.1 for Windows. Results: 4424 pregnancies were included. Of 166 (3.8%) pregnancies with a NT ≥ 3.5 mm and/or a risk ≥ 1:10 at FCTS, 130 (78.3%) opted for direct invasive testing. 803 (18.2%) pregnancies had an intermediate risk, 692 (86.2%) of them opted for cffDNA first. 3455 (78.1%) pregnancies had a risk < 1:1000. 63 fetuses were diagnosed with trisomy 21, 47 (74.6%) directly by invasive procedures after FTCS, 16 (25.4%) by cffDNA first. Conclusions: Most women choose cffDNA or invasive testing as second tier according to national guidelines. Despite the delay associated with cffDNA testing after FCTS, 75% of all trisomy 21 are still diagnosed in the first trimester with this contingent screening model.

Introducing Artificial Intelligence in Interpretation of Foetal Cardiotocography: Medical Dataset Curation and Preliminary Coding-An Interdisciplinary Project.

Artificial intelligence (AI) is gaining increasing interest in the field of medicine because of its capacity to process big data and pattern recognition. Cardiotocography (CTG) is widely used for the assessment of foetal well-being and uterine contractions during pregnancy and labour. It is characterised by inter- and intraobserver variability in interpretation, which depends on the observers' experience. Artificial intelligence (AI)-assisted interpretation could improve its quality and, thus, intrapartal care. Cardiotocography (CTG) raw signals from labouring women were extracted from the database at the University Hospital of Bern between 2006 and 2019. Later, they were matched with the corresponding foetal outcomes, namely arterial umbilical cord pH and 5-min APGAR score. Excluded were deliveries where data were incomplete, as well as multiple births. Clinical data were grouped regarding foetal pH and APGAR score at 5 min after delivery. Physiological foetal pH was defined as 7.15 and above, and a 5-min APGAR score was considered physiologic when reaching ≥7. With these groups, the algorithm was trained to predict foetal hypoxia. Raw data from 19,399 CTG recordings could be exported. This was accomplished by manually searching the patient's identification numbers (PIDs) and extracting the corresponding raw data from each episode. For some patients, only one episode per pregnancy could be found, whereas for others, up to ten episodes were available. Initially, 3400 corresponding clinical outcomes were found for the 19,399 CTGs (17.52%). Due to the small size, this dataset was rejected, and a new search strategy was elaborated. After further matching and curation, 6141 (31.65%) paired data samples could be extracted (cardiotocography raw data and corresponding maternal and foetal outcomes). Of these, half will be used to train artificial intelligence (AI) algorithms, whereas the other half will be used for analysis of efficacy. Complete data could only be found for one-third of the available population. Yet, to our knowledge, this is the most exhaustive and second-largest cardiotocography database worldwide, which can be used for computer analysis and programming. A further enrichment of the database is planned.

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.

A Retrospective before and after Assessment of Multidisciplinary Management for Postpartum Hemorrhage.

Postpartum hemorrhage (PPH) remains a major cause of maternal morbidity and mortality. While PPH treatment guidelines exist, data on their effect on reduction in red blood cell (RBC) transfusions and use of hemostatic products are scarce. Continuous evaluation of PPH management is important to assess potential pitfalls and incorporate new treatment options. We retrospectively compared PPH management and administration of RBC and hemostatic products before and after international guideline implementation. The primary endpoint was RBC administration for PPH. Secondary endpoints were hemoglobin trigger for RBC administration, administration of hemostatic products and surgical therapies. In total 235 patients had a PPH, 59 in 2011 and 176 in 2018. In 2018, fewer patients received RBC within 24 h (2018: 10% vs. 2011: 32%, p < 0.001) and 24 h after delivery (2018: 4.5% vs. 2011: 37%, p < 0.001). The number of RBC units transfused per case was significantly lower in 2018 (two vs. four units in 2011, p = 0.013). A significantly reduced transfusion of fresh frozen plasma and platelets was observed in 2018 (p < 0.001 and p = 0.002, respectively). In 2011, additional surgeries for PPH in both the acute and subacute phase were performed more frequently. Local implementation of multidisciplinary PPH guidelines is feasible and was associated with a significant reduction in transfused blood products.

Bacterial Vaginosis: Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry No. 015/028, June 2023).

Aim This official guideline was coordinated and published by the DGGG, OEGGG and SGGG with the involvement of additional professional societies. The aim of the guideline is to evaluate the relevant literature and use it to provide a consensus-based overview of the diagnosis and management of bacterial vaginosis. Methods This S2k-guideline was developed by representative members from different medical professional societies on behalf of the guidelines commission of the above-listed societies using a structured consensus process. Recommendations This guideline provides recommendations on the diagnosis, management, counselling, prophylaxis, and other aspects related to bacterial vaginosis.

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.

Correction: Prevention and Therapy of Preterm Birth. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry Number 015/025, September 2022) - Part 1 with Recommendations on the Epidemiology, Etiology, Prediction, Primary and Secondary Prevention of Preterm Birth.

[This corrects the article DOI: 10.1055/a-2044-0203.].

Correction: Prevention and Therapy of Preterm Birth. Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Registry Number 015/025, September 2022) - Part 2 with Recommendations on the Tertiary Prevention of Preterm Birth and on the Management of Preterm Premature Rupture of Membranes.

[This corrects the article DOI: 10.1055/a-2044-0345.].

MicroRNA Cargo in Wharton's Jelly MSC Small Extracellular Vesicles: Key Functionality to In Vitro Prevention and Treatment of Premature White Matter Injury.

Preterm birth is the leading cause of childhood morbidity and mortality and can result in white matter injury (WMI), leading to long-term neurological disabilities with global health burden. Mesenchymal stromal cell-derived small extracellular vesicles (MSC-sEV) are a promising therapeutic agent for treating perinatal neurological injury. They carry microRNAs (miRNAs) predicted to be involved in the onset of premature WMI. We hypothesize that miRNAs have a key function in the beneficial effects of MSC-sEV. We isolated MSC from umbilical cord tissue, the Wharton's jelly (WJ), and purified small extracellular vesicles (sEV) from WJ-MSC culture supernatant by ultracentrifugation and size exclusion chromatography. The miRNA content was quantified by real-time polymerase chain reaction. A luciferase gene assay validated silencing of TP53 and TAOK1, which we previously identified as predicted target genes of MSC-sEV miRNAs by Next Generation Sequencing and pathway enrichment analysis. The impact of sEV miRNAs on oligodendroglial maturation and neuronal apoptosis was evaluated using an in vitro oxygen-glucose deprivation model (OGD/R) by knocking-down DROSHA in WJ-MSC, which initiates miRNA processing. WJ-MSC-sEV contained miRNAs involved in WMI, namely hsa-miR-22-3p, hsa-miR-21-5p, hsa-miR-27b-3p, and the hsa-let-7 family. The luciferase assay strongly indicated an inhibitory effect of sEV miRNAs on the gene expression of TP53 and TAOK1. Small EV initiated oligodendrocyte maturation and reduced OGD/R-mediated neuronal apoptosis. Knocking-down DROSHA in WJ-MSC reduced the expression of sEV miRNAs and led to the loss of their beneficial effects. Our in vitro study strongly indicates the key function of miRNAs in the therapeutic potential of WJ-MSC-sEV in premature WMI.

Diverse mechanisms underlying the fetal growth course in gastroschisis and omphalocele.

BACKGROUND: Gastroschisis and omphalocele are the 2 most common congenital fetal abdominal wall defects. Both malformations are commonly associated with small-for-gestational-age neonates. However, the extent and causes of growth restriction remain controversial in both gastroschisis and omphalocele without associated malformations or aneuploidy. OBJECTIVE: This study aimed to examine the role of the placenta and the birthweight-to-placental weight ratio in fetuses with abdominal wall defects. STUDY DESIGN: This study included all cases of abdominal wall defects examined at our hospital between January 2001 and December 2020, retrieving the data from the hospital's software. Fetuses with any other combined congenital anomalies, known chromosomal abnormalities, or lost to follow-up were excluded. Overall, 28 singleton pregnancies with gastroschisis and 24 singleton pregnancies with omphalocele met the inclusion criteria. Patient characteristics and pregnancy outcomes were reviewed. The primary outcome was to investigate the association between birthweight and placental weight in pregnancies with abdominal wall defects as measured after delivery. To correct for gestational age and to compare total placental weights, ratios between the observed and expected birthweights for the given gestational age in singletons were calculated. The scaling exponent ß was compared with the reference value of 0.75. Statistical analysis was performed using GraphPad Prism (version 8.2.1; GraphPad Software, San Diego, CA) and IBM SPSS Statistics. A P value of <.05 indicated statistical significance. RESULTS: Women pregnant with a fetus with gastroschisis were significantly younger and more often nulliparous. In addition, in this group, the gestational age of delivery was significantly earlier and almost exclusively for cesarean delivery. Of 28 children, 13 (46.7%) were born small for gestational age, only 3 of them (10.7%) had a placental weight <10th percentile. There is no correlation between birthweight percentiles and placental weight percentiles (P=not significant). However, in the omphalocele group, 4 of 24 children (16.7%) were born small for gestational age (<10th percentile), and all children also had a placental weight <10th percentile. There is a significant correlation between birthweight percentiles and placental weight percentiles (P<.0001). The birthweight-to-placental weight ratio differs significantly between pregnancies diagnosed with gastroschisis and pregnancies diagnosed with omphalocele (4.48 [3.79-4.91] vs 6.05 [5.38-6.47], respectively; P<.0001). Allometric metabolic scaling revealed that placentas complicated by gastroschisis and placentas complicated by omphalocele do not scale with birthweight. CONCLUSION: Fetuses with gastroschisis displayed impaired intrauterine growth, which seemed to differ from the classical placental insufficiency growth restriction.

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.

Prevention and Therapy of Preterm Birth. Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Registry Number 015/025, September 2022) - Part 2 with Recommendations on the Tertiary Prevention of Preterm Birth and on the Management of Preterm Premature Rupture of Membranes.

Aim The revision of this guideline was coordinated by the German Society for Gynecology and Obstetrics (DGGG), the Austrian Society for Gynecology and Obstetrics (OEGGG) and the Swiss Society for Gynecology and Obstetrics (SGGG). The aim of the guideline is to improve the prediction, prevention and management of preterm birth based on evidence from the current literature, the experience of members of the guidelines commission, and the viewpoint of self-help organizations. Methods The members of the contributing professional societies and organizations developed recommendations and statements based on international literature. The recommendations and statements were presented and adopted using a formal process (structured consensus conferences with neutral moderation, written Delphi vote). Recommendations Part 2 of this short version of the guideline presents statements and recommendations on the tertiary prevention of preterm birth and the management of preterm premature rupture of membranes.

Prevention and Therapy of Preterm Birth. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry Number 015/025, September 2022) - Part 1 with Recommendations on the Epidemiology, Etiology, Prediction, Primary and Secondary Prevention of Preterm Birth.

Aim This revised guideline was coordinated by the German Society for Gynecology and Obstetrics (DGGG), the Austrian Society for Gynecology and Obstetrics (OEGGG) and the Swiss Society for Gynecology and Obstetrics (SGGG). It aims to improve the prediction, prevention, and management of preterm birth, based on evidence from the current literature, the experience of members of the guidelines commission, and the viewpoint of self-help organizations. Methods The members of the contributing professional societies and organizations developed recommendations and statements based on international literature. The recommendations and statements were presented and adopted using a formal process (structured consensus conferences with neutral moderation, written Delphi vote). Recommendations Part 1 of this short version of the guideline presents statements and recommendations on the epidemiology, etiology, prediction, and primary and secondary prevention of preterm birth.

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.

Artificial intelligence and machine learning in cardiotocography: A scoping review.

INTRODUCTION: Artificial intelligence (AI) is gaining more interest in the field of medicine due to its capacity to learn patterns directly from data. This becomes interesting for the field of cardiotocography (CTG) interpretation, since it promises to remove existing biases and improve the well-known issues of inter- and intra-observer variability. MATERIAL AND METHODS: The objective of this study was to map current knowledge in AI-assisted interpretation of CTG tracings and thus, to present different approaches with their strengths, gaps, and limitations. The search was performed on Ovid Medline and PubMed databases. The Preferred Reporting Items for Systematic Reviews and meta-Analysis for Scoping Reviews (PRISMA-ScR) guidelines were followed. RESULTS: We summarized 40 different studies investigating at least one algorithm or system to classify CTG tracings. In addition, the Oxford Sonicaid system is presented because of its wide use in clinical practice. CONCLUSIONS: There are several promising approaches in this area, but none of them has gained big acceptance in clinical practice. Further investigation and refinement of the algorithms and features are needed to achieve a validated decision-support system. For this purpose, larger quantities of curated and labeled data may be necessary.

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.

A Novel Murine Multi-Hit Model of Perinatal Acute Diffuse White Matter Injury Recapitulates Major Features of Human Disease.

The selection of an appropriate animal model is key to the production of results with optimal relevance to human disease. Particularly in the case of perinatal brain injury, a dearth of affected human neonatal tissue available for research purposes increases the reliance on animal models for insight into disease mechanisms. Improvements in obstetric and neonatal care in the past 20 years have caused the pathologic hallmarks of perinatal white matter injury (WMI) to evolve away from cystic necrotic lesions and toward diffuse regions of reactive gliosis and persistent myelin disruption. Therefore, updated animal models are needed that recapitulate the key features of contemporary disease. Here, we report a murine model of acute diffuse perinatal WMI induced through a two-hit inflammatory-hypoxic injury paradigm. Consistent with diffuse human perinatal white matter injury (dWMI), our model did not show the formation of cystic lesions. Corresponding to cellular outcomes of dWMI, our injury protocol produced reactive microgliosis and astrogliosis, disrupted oligodendrocyte maturation, and disrupted myelination.. Functionally, we observed sensorimotor and cognitive deficits in affected mice. In conclusion, we report a novel murine model of dWMI that induces a pattern of brain injury mirroring multiple key aspects of the contemporary human clinical disease scenario.

Hyperuricemia during Pregnancy Leads to a Preeclampsia-Like Phenotype in Mice.

Hyperuricemia is a common feature in pregnancies compromised by pre-eclampsia, a pregnancy disease characterized by hypertension and proteinuria. The role of uric acid in the pathogenesis of pre-eclampsia remains largely unclear. The aim of this study was to investigate the effect of elevated uric acid serum levels during pregnancy on maternal blood pressure and neonatal outcome using two different murine knockout models. Non-pregnant liver-specific GLUT9 knockout (LG9KO) mice showed elevated uric acid serum concentrations but no hypertensive blood pressure levels. During pregnancy, however, blood pressure levels of these animals increased in the second and third trimester, and circadian blood pressure dipping was severely altered when compared to non-pregnant LG9KO mice. The impact of hyperuricemia on fetal development was investigated using a systemic GLUT9 knockout (G9KO) mouse model. Fetal hyperuricemia caused distinctive renal tissue injuries and, subsequently an impaired neonatal growth pattern. These findings provide strong evidence that hyperuricemia plays a major role in the pathogenesis of hypertensive pregnancy disorders such as pre-eclampsia. These novel insights may enable the development of preventive and therapeutic strategies for hyperuricemia-related diseases.