Anna David
University College London, Institute for Womens Health, Faculty Member
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Research Interests: Biology, Treatment Outcome, Medicine, Humans, Genetic Enhancement, and 14 moreMedical Biotechnology, Female, Animals, Gene transfer techniques, Male, Adeno-associated virus, Clinical Sciences, Fetus, Gestation, Hemophilia B, Gene Expression Regulation, Genetic Therapy, Medical biochemistry and metabolomics, and In Utero
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To review the potential of stem cells derived from amniotic fluid and applications in prenatal and postnatal therapy. We have recently described that pluripotent stem cells can be isolated from amniotic fluid defined as amniotic fluid... more
To review the potential of stem cells derived from amniotic fluid and applications in prenatal and postnatal therapy. We have recently described that pluripotent stem cells can be isolated from amniotic fluid defined as amniotic fluid stem (AFS) cells by selection for expression of the membrane stem cell factor receptor c-Kit. AFS cells maintained for over 250 population doublings retained long telomeres and normal karyotype. Clonal human lines verified by retroviral marking were induced to differentiate into cell types representing each embryonic germ layer, including adipogenic, osteogenic, myogenic, endothelial, neuronal, and hepatic lineages. Rat AFS cells have been able to improve the repair of damaged smooth muscle in cryoinjury bladders. Furthermore, AFS cells could be differentiated toward cardiomyogenic lineages, when co-cultured with neonatal cardiomyocytes and have potential to generate hematopoietic lineages both in vitro and in vivo. These cells have been applied into fetal therapy, and widely used for tissue repair in animal models. Finally, we demonstrated a feasible way to do in-utero autologous AFS transplantation in sheep. Stem cells derived from amniotic fluid are a relatively new source of cells that could have a therapeutic value in various diseases prenatally and/or postnatally.
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Response to Moldenhauer, Johnson & Van Mieghem ISPD 2022 DEBATE: There should be formal accreditation and ongoing quality assurance/review for units offering fetal therapy that includes public reporting of outcomes. MFAET, an international standardised medical terminology to support quality a...more
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ObjectiveTo determine the incidence and characterise corpus callosum (CC) abnormalities in fetuses with spina bifida aperta (SBA) between 18 and 26 weeks of gestation.MethodsThis was a retrospective study on fetuses with isolated SBA and... more
ObjectiveTo determine the incidence and characterise corpus callosum (CC) abnormalities in fetuses with spina bifida aperta (SBA) between 18 and 26 weeks of gestation.MethodsThis was a retrospective study on fetuses with isolated SBA and who were assessed for fetal surgery. Digitally stored ultrasound images of the brain were reviewed for the presence/absence of the CC, and the length and diameter of its constituent parts (rostrum, genu, body and splenium). We used regression analysis to determine the relationship between CC abnormalities and gestational age, head circumference, ventricle size, lesion level and lesion type.ResultsNearly three-quarters of fetuses with isolated SBA had an abnormal CC (71.7%, 76/106). Partial agenesis was most common in the splenium (18.9%, 20/ 106) and the rostrum (13.2%, 14/106). The most common abnormal pattern was of a short CC with normal diameter throughout. Of note, 20.8% (22/106) had a hypoplastic genu and 28.3% (30/106) had a thick body part. Larger lateral ventricle size was associated with partial agenesis of the CC (odds ratio [OR]: 0.14, p < 0.001) and inversely associated with a shorter CC (OR: 2.60, p < 0.01).ConclusionAn abnormal CC is common in fetuses with isolated SBA who are referred for fetal surgery.
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Prenatal gene therapy aims to deliver genes to cells and tissues early in prenatal life, allowing correction of a genetic defect, before long‐term tissue damage has occurred. In contrast to postnatal gene therapy, prenatal application can... more
Prenatal gene therapy aims to deliver genes to cells and tissues early in prenatal life, allowing correction of a genetic defect, before long‐term tissue damage has occurred. In contrast to postnatal gene therapy, prenatal application can target genes to a large population of dividing stem cells, and the smaller fetal size allows a higher vector‐to‐target cell ratio to be achieved. Early‐gestation delivery may allow the development of immune tolerance to the transgenic protein which would facilitate postnatal repeat vector administration if needed.Targeting particular organs will depend on manipulating the vector to achieve selective tropism and on choosing the most appropriate gestational age and injection method for fetal delivery. Intra‐amniotic injection reaches the skin, and other organs that are bathed in the fluid however since gene transfer to the lung and gut is usually poor more direct injection methods will be needed. Delivery to the liver and blood can be achieved by systemic delivery via the umbilical vein or peritoneal cavity. Gene transfer to the central nervous system in the fetus is difficult but newer vectors are available that transduce neuronal tissue even after systemic delivery. Copyright © 2011 John Wiley &amp; Sons, Ltd.
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Research Interests: Computer Science, Artificial Intelligence, Computer Vision, Neuroimaging, Magnetic Resonance Imaging, and 11 moreMedicine, Super resolution, Superresolution, Deep Learning, Segmentation, Neuroimage, Fetal MRI, Convolutional Neural Network, Psychology and Cognitive Sciences, Medical and Health Sciences, and Brain Localization
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ObjectiveFetal surgery for spina bifida aperta (SBA) by open hysterotomy typically repairs anatomical native tissue in layers. Increasingly, fetoscopic repair is performed using a dural patch followed by skin closure. We studied the host... more
ObjectiveFetal surgery for spina bifida aperta (SBA) by open hysterotomy typically repairs anatomical native tissue in layers. Increasingly, fetoscopic repair is performed using a dural patch followed by skin closure. We studied the host response to selected commercially available patches currently being used in a fetal rabbit model for spina bifida repair.MethodsSBA was surgically induced at 23–24 days of gestation (term = 31 days). Fetal rabbits were assigned to unrepaired (SBA group), or immediate repair with Duragen™ or Durepair™. Non‐operated littermates served as normal controls. At term, spinal cords underwent immunohistochemical staining including Nissl and glial fibrillary acidic protein. We hypothesized that spinal cord coverage with a dural patch and skin closure would preserve motor neuron density within the non‐inferiority limit of 201.65 cells/mm2 and reduce inflammation compared to unrepaired SBA fetuses.ResultsMotor neuron density assessed by Nissl staining was conserved both by Duragen (n = 6, 89.5; 95% CI −158.3 to −20.6) and Durepair (n = 6, 37.0; 95% CI −132.6 to −58.5), whereas density of GFAP‐positive cells to quantify inflammation was lower than in unrepaired SBA‐fetuses (SBA 2366.0 ± 669.7 cells/mm2 vs. Duragen 1274.0 ± 157.2 cells/mm2; p = 0.0002, Durepair 1069.0 ± 270.7 cells/mm2; p &lt; 0.0001).ConclusionsCovering the rabbit spinal cord with either Duragen or Durepair followed by skin closure preserves motor neuron density and reduces the inflammatory response.
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Spontaneous preterm births (< 37 weeks gestation) are frequently associated with infection. Current treatment options are limited but new therapeutic interventions are being developed in animal models. In this PROSPERO-registered... more
Spontaneous preterm births (< 37 weeks gestation) are frequently associated with infection. Current treatment options are limited but new therapeutic interventions are being developed in animal models. In this PROSPERO-registered preclinical systematic review, we aimed to summarise promising interventions for infection/inflammation-induced preterm birth. Following PRISMA guidance, we searched PubMed, EMBASE, and Web of Science using the themes: “animal models”, “preterm birth”, “inflammation”, and “therapeutics”. We included original quantitative, peer-reviewed, and controlled studies applying prenatal interventions to prevent infection/inflammation-induced preterm birth in animal models. We employed two risk of bias tools. Of 4020 identified studies, 23 studies (24 interventions) met our inclusion criteria. All studies used mouse models. Preterm birth was most commonly induced by lipopolysaccharide (18 studies) or Escherichia coli (4 studies). Models varied according to infectio...
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Mechanical and inflammatory signals in the fetal membrane play an important role in extracellular matrix (ECM) remodelling in order to dictate the timing of birth. We developed a mechanical model that mimics repetitive stretching of the... more
Mechanical and inflammatory signals in the fetal membrane play an important role in extracellular matrix (ECM) remodelling in order to dictate the timing of birth. We developed a mechanical model that mimics repetitive stretching of the amniotic membrane (AM) isolated from regions over the placenta (PAM) or cervix (CAM) and examined the effect of cyclic tensile strain (CTS) on mediators involved in mechanotransduction (Cx43, AKT), tissue remodelling (GAGs, elastin, collagen) and inflammation (PGE2, MMPs). In CAM and PAM specimens, the application of CTS increased GAG synthesis, PGE2 release and MMP activity, with concomitant reduction in collagen and elastin content. Co-stimulation with CTS and pharmacological agents that inhibit either Cx43 or AKT, differentially influenced collagen, GAG and elastin in a tissue-dependent manner. SHG confocal imaging of collagen fibres revealed a reduction in SHG intensity after CTS, with regions of disorganisation dependent on tissue location. CTS ...
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ObjectiveTo establish maternal complication rates for fetoscopic or open fetal surgery.MethodsWe conducted a systematic literature review for studies of fetoscopic or open fetal surgery performed since 1990, recording maternal... more
ObjectiveTo establish maternal complication rates for fetoscopic or open fetal surgery.MethodsWe conducted a systematic literature review for studies of fetoscopic or open fetal surgery performed since 1990, recording maternal complications during fetal surgery, the remainder of pregnancy, delivery, and after the index pregnancy.ResultsOne hundred sixty‐six studies were included, reporting outcomes for open fetal (n = 1193 patients) and fetoscopic surgery (n = 9403 patients). No maternal deaths were reported. The risk of any maternal complication in the index pregnancy was 20.9% (95%CI, 15.22‐27.13) for open fetal and 6.2% (95%CI, 4.93‐7.49) for fetoscopic surgery. For severe maternal complications (grades III to V Clavien‐Dindo classification of surgical complications), the risk was 4.5% (95% CI 3.24‐5.98) for open fetal and 1.7% (95% CI, 1.19‐2.20) for fetoscopic surgery. In subsequent pregnancies, open fetal surgery increased the risk of preterm birth but not uterine dehiscence o...
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Fetal growth restriction (FGR) is a common and potentially severe pregnancy complication. Currently there is no treatment available. The guinea pig is an attractive model of human pregnancy as placentation is morphologically very similar... more
Fetal growth restriction (FGR) is a common and potentially severe pregnancy complication. Currently there is no treatment available. The guinea pig is an attractive model of human pregnancy as placentation is morphologically very similar between the species. Nutrient restriction of the dam creates growth-restricted fetuses while leaving an intact uteroplacental circulation, vital for evaluating novel therapies for FGR. Growth-restricted fetuses were generated by feeding Dunkin Hartley guinea pig dams 70% of ad libitum intake from four weeks before and throughout pregnancy. The effect of maternal nutrient restriction (MNR) on dams and fetuses was carefully monitored, and ultrasound measurements of pups collected. There was no difference in maternal weight at conception, however by five weeks post conception MNR dams were significantly lighter (P < 0.05). MNR resulted in significantly smaller pup size from 0.6-0.66 gestation. Ultrasound is a powerful non-invasive tool for assessing...
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Research Interests: Andrology, Stem Cell, Medicine, Biological Sciences, Mesenchymal stem cells, and 15 morePregnancy, Sheep, Female, Animals, Cell, Amniotic Fluid, Mesenchymal Stem Cell, Cell Transplantation, Amniocentesis, Fetus, Gestational Age, Congenital abnormalities, Mesenchymal Stromal Cells, Medical and Health Sciences, and In Utero
ABSTRACTDespite advances in prenatal diagnosis, it is still difficult to predict severity and outcomes of many congenital malformations. New patient-specific prenatal disease modelling may optimise personalised prediction. We and others... more
ABSTRACTDespite advances in prenatal diagnosis, it is still difficult to predict severity and outcomes of many congenital malformations. New patient-specific prenatal disease modelling may optimise personalised prediction. We and others have described the presence of mesenchymal stem cells in amniotic fluid (AFSC) that can generate induced pluripotent stem cells (iPSCs). The lengthy reprogramming processes, however, limits the ability to define individual phenotypes or plan prenatal treatment. Therefore, it would be advantageous if fetal stem cells could be obtained during pregnancy and expanded without reprogramming. Using single cell analysis, we characterised the cellular identities in amniotic fluid (AF) and identified viable epithelial stem/progenitor cells of fetal intestinal, renal and pulmonary origin. With relevance for prenatal disease modelling, these cells could be cultured to form clonal epithelial organoids manifesting small intestine, kidney and lung identity. To conf...
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This Review depicts the evolving role of MRI in the diagnosis and prognostication of anomalies of the fetal body, here including head and neck, thorax, abdomen and spine. A review of the current literature on the latest developments in... more
This Review depicts the evolving role of MRI in the diagnosis and prognostication of anomalies of the fetal body, here including head and neck, thorax, abdomen and spine. A review of the current literature on the latest developments in antenatal imaging for diagnosis and prognostication of congenital anomalies is coupled with illustrative cases in true radiological planes with viewable three-dimensional video models that show the potential of post-acquisition reconstruction protocols. We discuss the benefits and limitations of fetal MRI, from anomaly detection, to classification and prognostication, and defines the role of imaging in the decision to proceed to fetal intervention, across the breadth of included conditions. We also consider the current capabilities of ultrasound and explore how MRI and ultrasound can complement each other in the future of fetal imaging.
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ABSTRACTFetal gene therapy has the potential to treat inherited genetic diseases in utero before significant organ damage has occurred. Rapidly expanding stem cell populations may be targeted and the introduction of transgenes to the... more
ABSTRACTFetal gene therapy has the potential to treat inherited genetic diseases in utero before significant organ damage has occurred. Rapidly expanding stem cell populations may be targeted and the introduction of transgenes to the fetus during development of the immune system could result in immune tolerance and facilitate repeat treatment postnatally. Genetic diseases such as cystic fibrosis, which are life-threatening and for which there are no currently acceptable treatments available, are suggested targets for this therapy.Ultrasound may be a safe method of delivering a therapeutic gene into the fetus, although most studies have used more invasive techniques, even in large animal models. Viral vectors currently offer the most potential. Adenovirus-based vectors are stable, independent of host cell replication, efficient at tissue infection and have been used as a ‘pathfinder’ to test routes of administration. Unfortunately, they are also highly immunogenic and other systems based on retrovirus or a...
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ObjectiveTo quantify the risks of mortality, morbidity and postnatal characteristics associated with extreme preterm fetal growth restriction (EP-FGR).DesignThe EVERREST (Doesvascular endothelial growth factor gene therapy safely improve... more
ObjectiveTo quantify the risks of mortality, morbidity and postnatal characteristics associated with extreme preterm fetal growth restriction (EP-FGR).DesignThe EVERREST (Doesvascular endothelial growth factor gene therapy safely improve outcome in severeearly-onset fetal growth restriction?) prospective multicentre study of women diagnosed with EP-FGR (singleton, estimated fetal weight (EFW) &lt;3rd percentile, &lt;600 g, 20+0–26+6weeks of gestation). The UK subgroup of EP-FGR infants (&lt;36 weeks) were sex-matched and gestation-matched to appropriate for age (AGA) infants born in University College London Hospital (1:2 design, EFW 25th−75th percentile).SettingFour tertiary perinatal units (UK, Germany, Spain, Sweden).Main outcomesAntenatal and postnatal mortality, bronchopulmonary dysplasia (BPD), sepsis, surgically treated necrotising enterocolitis (NEC), treated retinopathy of prematurity (ROP).ResultsOf 135 mothers recruited with EP-FGR, 42 had a stillbirth or termination of pregnancy (31%) and 93 had live births (69%). Postnatal genetic abnormalities were identified in 7/93 (8%) live births. Mean gestational age at birth was 31.4 weeks (SD 4.6). 54 UK-born preterm EP-FGR infants (&lt;36 weeks) were matched to AGA controls. EP-FGR was associated with increased BPD (43% vs 26%, OR 3.6, 95% CI 1.4 to 9.4, p=0.01), surgical NEC (6% vs 0%, p=0.036) and ROP treatment (11% vs 0%, p=0.001). Mortality was probably higher among FGR infants (9% vs 2%, OR 5.0, 95% CI 1.0 to 25.8, p=0.054). FGR infants more frequently received invasive ventilation (65% vs 50%, OR 2.6, 95% CI 1.1 to 6.1, p=0.03), took longer to achieve full feeds and had longer neonatal stays (median difference 6.1 days, 95% CI 3.8 to 8.9 and 19 days, 95% CI 9 to 30 days, respectively, p&lt;0.0001).ConclusionsMortality following diagnosis of EP-FGR is high. Survivors experience increased neonatal morbidity compared with AGA preterm infants.Trial registration numberNCT02097667.
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The first human gene therapy trials began over 10 years ago, but in spite of continuous technological progress most clinical results have been disappointing. The reasons for this include difficulties in targeting the appropriate organ, a... more
The first human gene therapy trials began over 10 years ago, but in spite of continuous technological progress most clinical results have been disappointing. The reasons for this include difficulties in targeting the appropriate organ, a robust immune response to the therapy in adults and low level expression of the therapeutic gene product. Applying the therapy before birth may avoid these difficulties, and recent pre-clinical work has shown proof-of-principle for phenotypic cure of congenital disease in animal models using this approach. Selecting the right diseases for therapeutic intervention will be critical for clinical translation. Perinatal application of gene therapy has been proposed to be appropriate for life-threatening disorders, in which prenatal gene delivery maintains a clear advantage over cell transplantation or postnatal gene therapy and for which there are currently no satisfactory treatments available. Gene therapy could be applied directly to the fetus in utero. In the case of maternal pathology affecting the fetus such as occurs in uteroplacental insufficiency, a major cause of fetal growth restriction, gene therapy could be given to the mother. Combining stem cell transplantation (SCT) and gene therapy by transplanting the fetus with gene corrected autologous stem cells is an attractive proposition. This would avoid some of the issues of safety with regard to direct fetal vector injection, in particular the potential for germline gene transfer and untargeted fetal systemic vector delivery.
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INTRODUCTION Severe fetal growth restriction (FGR) affects 1:500 pregnancies, is untreatable and causes serious neonatal morbidity and death. Reduced uterine blood flow (UBF) and lack of bioavailable VEGF due to placental insufficiency is... more
INTRODUCTION Severe fetal growth restriction (FGR) affects 1:500 pregnancies, is untreatable and causes serious neonatal morbidity and death. Reduced uterine blood flow (UBF) and lack of bioavailable VEGF due to placental insufficiency is a major cause. Transduction of uterine arteries in normal or FGR sheep and guinea pigs using an adenovirus (Ad) encoding VEGF isoforms A (Ad.VEGF-A165) and a FLAG-tagged pre-processed short form D (DΔNΔC, Ad.VEGF-DΔNΔC-FLAG) increases endothelial nitric oxide expression, enhances relaxation and reduces constriction of the uterine arteries and their branches. UBF and angiogenesis are increased long term, improving fetal growth in utero. For clinical trial development we compared Ad.VEGF vector transduction efficiency and function in endothelial cells (ECs) derived from different species. OBJECTIVE To compare the transduction efficiency and function of the pre-clinical study Ad. constructs (Ad.VEGF-A165, Ad.VEGF-DΔNΔC-FLAG) with the intended clinical trial construct (Ad.VEGF-DΔNΔC) where the FLAG tag is removed. METHODS We infected ECs from human umbilical vein, pregnant sheep uterine artery, pregnant guinea pig aorta and non-pregnant rabbit aorta, with increasing multiplicity of infection (MOI) for 24 or 48 hours of three Ad.VEGF vectors, compared to control Ad. containing the LacZ gene (Ad.LacZ). VEGF supernatant expression was analysed by ELISA. Functional assessment used tube formation assay and Erk-Akt phosphorylation by ELISA. RESULTS VEGF expression was higher after Ad.VEGF-DΔNΔC-FLAG and Ad.VEGF-DΔNΔC transduction compared to Ad.VEGF-A165 in all EC types (*p<0.001). Tube formation was higher in ECs transduced with Ad.VEGF-DΔNΔC in all species compared to other constructs (***p<0.001, *p<0.05 with rabbit aortic ECs). Phospho-Erk and phospho-Akt assays displayed no differences between the three vector constructs, whose effect was, as in other experiments, higher than Ad.LacZ (***p<0.001). CONCLUSION We observed high transduction efficiency and functional effects of Ad.VEGF-DΔNΔC vector with comparability in major pathway activation to constructs used in pre-clinical studies, supporting its use in a clinical trial.
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We are living in a golden age of medicine in which the availability of prenatal diagnosis, fetal therapy, and gene therapy/editing make it theoretically possible to repair almost any defect in the genetic code. Furthermore, the ability to... more
We are living in a golden age of medicine in which the availability of prenatal diagnosis, fetal therapy, and gene therapy/editing make it theoretically possible to repair almost any defect in the genetic code. Furthermore, the ability to diagnose genetic disorders before birth and the presence of established surgical techniques enable these therapies to be delivered safely to the fetus. Prenatal therapies are generally used in the second or early third trimester for severe, life‐threatening disorders for which there is a clear rationale for intervening before birth. While there has been promising work for prenatal gene therapy in preclinical models, the path to a clinical prenatal gene therapy approach is complex. We recently held a conference with the University of California, San Francisco–Stanford Center of Excellence in Regulatory Science and Innovation, researchers, patient advocates, regulatory (members of the Food and Drug Administration), and other stakeholders to review th...
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This workbook contains anonymised data from the study Quantitative fetal fibronectin to improve decision making in women with signs and symptoms of preterm birth (QUIDS): Spontaneous preterm birth within 7 days risk predictor.
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Incomplete lung development, also known as pulmonary hypoplasia, is a recognized cause of neonatal death and poor outcome for survivors. To date, there is no effective treatment that promotes fetal lung growth and maturation. Herein, we... more
Incomplete lung development, also known as pulmonary hypoplasia, is a recognized cause of neonatal death and poor outcome for survivors. To date, there is no effective treatment that promotes fetal lung growth and maturation. Herein, we describe a novel stem cell-based approach that enhances fetal lung development via the administration of extracellular vesicles (EVs) derived from amniotic fluid stem cells (AFSCs). In experimental models of pulmonary hypoplasia, administration of AFSC-EVs promoted lung branching morphogenesis and alveolarization, and stimulated pulmonary epithelial cell and fibroblast differentiation. This regenerative ability was confirmed in two models of injured human lung cells, where human AFSC-EVs obtained following good manufacturing practices restored pulmonary epithelial homeostasis. AFSC-EV beneficial effects were exerted via the release of RNA cargo, primarily miRNAs, that regulate the expression of genes involved in fetal lung development. Our findings s...
Research Interests: Biology, Cell Biology, Stem Cell, Medicine, Embryonic Stem Cell, and 3 moreAmniotic Fluid, Lung, and Fetus
Background The diagnosis of preterm labour is challenging. False-positive diagnoses are common and result in unnecessary, potentially harmful treatments (e.g. tocolytics, antenatal corticosteroids and magnesium sulphate) and costly... more
Background The diagnosis of preterm labour is challenging. False-positive diagnoses are common and result in unnecessary, potentially harmful treatments (e.g. tocolytics, antenatal corticosteroids and magnesium sulphate) and costly hospital admissions. Measurement of fetal fibronectin in vaginal fluid is a biochemical test that can indicate impending preterm birth. Objectives To develop an externally validated prognostic model using quantitative fetal fibronectin concentration, in combination with clinical risk factors, for the prediction of spontaneous preterm birth and to assess its cost-effectiveness. Design The study comprised (1) a qualitative study to establish the decisional needs of pregnant women and their caregivers, (2) an individual participant data meta-analysis of existing studies to develop a prognostic model for spontaneous preterm birth within 7 days in women with symptoms of preterm labour based on quantitative fetal fibronectin and clinical risk factors, (3) exter...
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BackgroundPregnant women have been identified as a potentially at‐risk group concerning COVID‐19 infection, but little is known regarding the susceptibility of the fetus to infection. Co‐expression of ACE2 and TMPRSS2 has been identified... more
BackgroundPregnant women have been identified as a potentially at‐risk group concerning COVID‐19 infection, but little is known regarding the susceptibility of the fetus to infection. Co‐expression of ACE2 and TMPRSS2 has been identified as a prerequisite for infection, and expression across different tissues is known to vary between children and adults. However, the expression of these proteins in the fetus is unknown.MethodsWe performed a retrospective analysis of a single cell data repository. The data were then validated at both gene and protein level by performing RT‐qPCR and two‐colour immunohistochemistry on a library of second‐trimester human fetal tissues.FindingsTMPRSS2 is present at both gene and protein level in the predominantly epithelial fetal tissues analysed. ACE2 is present at significant levels only in the fetal intestine and kidney, and is not expressed in the fetal lung. The placenta also does not co‐express the two proteins across the second trimester or at ter...
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Administration of extracellular vesicles derived from amniotic fluid stem cells regenerates underdeveloped fetal lungs in rodents.