ORCID Profile
0000-0003-0031-7975
Current Organisations
Australian Academy of Health & Medical Sciences
,
University of New South Wales
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Chemical Engineering | Chemical Engineering Not Elsewhere Classified | Biomaterials | Fluidization And Fluid Mechanics
ANZSRC Socio-Economic Objective (SEO)
Clinical health not specific to particular organs, diseases and conditions | Manufactured products not elsewhere classified | Cancer and related disorders |
Related Links
Publications
Fetal stem cell microchimerism: natural-born healers or killers?
Publisher: Oxford University Press (OUP)
Date: 27-07-2010
Abstract: After four decades of study, the biological role of fetal microchimerism (FMC) remains elusive. Transfer of fetal cells to the mother begins soon after implantation, and increases with gestational age. FMC cells then decline after delivery, but remain detectable for years post-partum. These cells have been implicated in rheumatoid arthritis remission during pregnancy and the prevention of breast cancer by graft-versus-tumor-effects. However, any beneficial effects contrast with their suspected malevolence in triggering of systemic sclerosis after childrearing or their stromal support for tumor formation. Recent evidence that FMC cells participate in disease and tissue repair has stirred controversy on their origin. The detection of FMC cells during early embryogenesis together with the ersity of hematopoietic, mesenchymal and endothelial markers, and plasticity of morphology when integrated into various tissues, provides evidence for their stemness. However, proof of their phenotype in conventional stem cell differentiation assays has been beset with difficulty in isolating and expanding them in culture. Unraveling the function of FMC cells will provide insight into both their engagement in disease and their therapeutic potential.
Potential of Human Fetal Chorionic Stem Cells for the Treatment of Osteogenesis Imperfecta
Publisher: Mary Ann Liebert Inc
Date: 02-2014
Paradoxic Activation of the Renin-Angiotensin System in Twin-Twin Transfusion Syndrome: An Explanation for Cardiovascular Disturbances in the Recipient
Publisher: Springer Science and Business Media LLC
Date: 10-2005
Novel isolation strategy to deliver pure fetal-origin and maternal-origin mesenchymal stem cell (MSC) populations from human term placenta
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.PLACENTA.2014.09.001
Abstract: The placenta is an abundant source of mesenchymal stem/stromal cells (MSC). Although presumed of translationally-advantageous fetal origin, the literature instead suggests a high incidence of either contaminating or pure maternal MSC. Despite definitional criteria that MSC are CD34-, increasing evidence suggests that fetal MSC may be CD34 positive in vivo. We flow sorted term placental digests based on CD34+ expression and exploited differential culture media to isolate separately pure fetal and maternal MSC populations. This method has considerable translational implications, in particular to clinical trials underway with "placental" MSC of uncertain or decidual origin.
The natural caesarean: a woman‐centred technique
Publisher: Wiley
Date: 28-06-2008
Prospective surface marker-based isolation and expansion of fetal endothelial colony-forming cells from human term placenta
Publisher: Oxford University Press (OUP)
Date: 08-10-2013
Abstract: The term placenta is a highly vascularized tissue and is usually discarded upon birth. Our objective was to isolate clinically relevant quantities of fetal endothelial colony-forming cells (ECFCs) from human term placenta and to compare them to the well-established donor-matched umbilical cord blood (UCB)-derived ECFCs. A sorting strategy was devised to enrich for CD45−CD34+CD31Lo cells prior to primary plating to obtain pure placental ECFCs (PL-ECFCs) upon culture. UCB-ECFCs were derived using a well-described assay. PL-ECFCs were fetal in origin and expressed the same cell surface markers as UCB-ECFCs. Most importantly, a single term placenta could yield as many ECFCs as 27 UCB donors. PL-ECFCs and UCB-ECFCs had similar in vitro and in vivo vessel forming capacities and restored mouse hind limb ischemia in similar proportions. Gene expression profiles were only minimally ergent between PL-ECFCs and UCB-ECFCs, probably reflecting a vascular source versus a circulating source. Finally, PL-ECFCs and UCB-ECFCs displayed similar hierarchies between high and low proliferative colonies. We report a robust strategy to isolate ECFCs from human term placentas based on their cell surface expression. This yielded much larger quantities of ECFCs than UCB, but the cells were comparable in immunophenotype, gene expression, and in vivo functional ability. We conclude that PL-ECFCs have significant bio-banking and clinical translatability potential.
Pre- and Postnatal Transplantation of Fetal Mesenchymal Stem Cells in Osteogenesis Imperfecta: A Two-Center Experience
Publisher: Oxford University Press (OUP)
Date: 16-12-2013
Abstract: Osteogenesis imperfecta (OI) can be recognized prenatally with ultrasound. Transplantation of mesenchymal stem cells (MSCs) has the potential to ameliorate skeletal damage. We report the clinical course of two patients with OI who received prenatal human fetal MSC (hfMSC) transplantation and postnatal boosting with same-donor MSCs. We have previously reported on prenatal transplantation for OI type III. This patient was retransplanted with 2.8 × 106 same-donor MSCs per kilogram at 8 years of age, resulting in low-level engraftment in bone and improved linear growth, mobility, and fracture incidence. An infant with an identical mutation who did not receive MSC therapy succumbed at 5 months despite postnatal bisphosphonate therapy. A second fetus with OI type IV was also transplanted with 30 × 106 hfMSCs per kilogram at 31 weeks of gestation and did not suffer any new fractures for the remainder of the pregnancy or during infancy. The patient followed her normal growth velocity until 13 months of age, at which time longitudinal length plateaued. A postnatal infusion of 10 × 106 MSCs per kilogram from the same donor was performed at 19 months of age, resulting in resumption of her growth trajectory. Neither patient demonstrated alloreactivity toward the donor hfMSCs or manifested any evidence of toxicities after transplantation. Our findings suggest that prenatal transplantation of allogeneic hfMSCs in OI appears safe and is of likely clinical benefit and that retransplantation with same-donor cells is feasible. However, the limited experience to date means that it is not possible to be conclusive and that further studies are required.
Occlusion of Arterio-Arterial Anastomosis Manifesting as Acute Twin–Twin Transfusion Syndrome
Publisher: Elsevier BV
Date: 02-2004
Insights into the pathophysiology of twin–twin transfusion syndrome
Publisher: Wiley
Date: 09-2005
DOI: 10.1002/PD.1264
Abstract: Twin-twin transfusion syndrome (TTTS) is attributed to trans-anastomotic transfusion between twins. Anastomoses are ubiquitous in monochorionic (MC) placentae, yet TTTS develops in only 15%. Although ex vivo and in vivo studies fail to identify a unique anastomotic signature, TTTS placentae are typically associated with an imbalance in unidirectional arteriovenous anastomoses with absent bidirectional anastomoses. Doppler detection of an artery-artery anastomosis reduces the chance of TTTS, whereas, in those that develop the disease, it improves stage-independent survival. Selective laser is often curative, but an increasingly recognized risk of persistent or reverse TTTS may be attributable to atypical arteriovenous anastomoses not identifiable from the chorionic plate. Simple dysvolaemia fails to explain several phenotypic features, including haematological concordancy, recipient hypertension, and reversibly absent end diastolic flow in the donor. The renin-angiotensin system is upregulated in the donor and downregulated in the recipient's kidneys, while paradoxically raised renin levels in the recipient may contribute to raised afterload along with endothelin. Although research is limited in humans by therapy and the lack of a suitable experimental model, further studies of placental and vascular pathophysiology may not only refine current treatment modalities but may also, in addition, suggest further avenues for downstream management such as genetic predisposition testing or pharmacological intervention.
Characterisation of deep arterio-venous anastomoses within monochorionic placentae by vascular casting
Publisher: Elsevier BV
Date: 2005
DOI: 10.1016/J.PLACENTA.2004.04.007
Abstract: To characterise arterio-venous anastomoses (AVA) in monochorionic (MC) placentae and determine (i) whether shared cotyledons lie beneath the co-termination of an artery from one twin and a vein to the contralateral twin and (ii) whether all AVA can be detected by visual inspection of the chorionic plate. Vascular casts were made of 15 MC placentae. The number of typical AVAs suspected visually before digestion was compared with the number of AVAs identified after acid digestion. Thirty-three of 67 (49%) suspected typical AVAs were confirmed as typical after casting. There were five false positives and no false negatives. The remainder were classified as atypical AVAs, found in > or =90% of MC placentae. Type I (small vascular connections between two apparently normal cotyledons not seen before casting) and Type II (shared cotyledons arising within larger apparently normal cotyledons) atypical AVAs were found in 53% and 73% of placentae, respectively. Only half the shared cotyledons in MC placentae are characterised by co-termination of an artery and vein on the chorionic plate. We report the existence of deep anastomoses beneath the chorionic plate that cannot be visualised by chorionic plate inspection. These findings have implications for laser treatment of twin-twin transfusion syndrome.
Intracellular trafficking and endocytosis of CXCR4 in fetal mesenchymal stem/stromal cells
Publisher: Springer Science and Business Media LLC
Date: 16-05-2014
Intrauterine transplantation of human fetal mesenchymal stem cells from first-trimester blood repairs bone and reduces fractures in osteogenesis imperfecta mice
Publisher: American Society of Hematology
Date: 02-2008
DOI: 10.1182/BLOOD-2007-08-105809
Abstract: The inherited skeletal dysplasia osteogenesis imperfecta (OI) results in multiple fractures and is currently treated empirically. We transplanted human first-trimester fetal blood mesenchymal stem cells (MSCs) into homozygous oim mice in utero. This resulted in a two-thirds reduction in long bone fractures (P .01), with fewer fractures per mouse (median 1, range 0-2 in mice that received transplants vs median 3, range 1-5 in mice that did not receive transplants by 12 weeks, P .01). Nearly all mice that did not receive transplants had fractures (47 [97.9%] of 48), in contrast to 17 (58.6%) of 29 4- to 12-week-old mice that received transplants (P .01). Transplantation was associated with increased bone strength (P .01), thickness (P .01), and length (P .01), and normalization/reduction of growth plate height in 4- to 12-week-old oim was reduced in mice that underwent transplantion (P .001). More donor cells were found in bone tissues compared with other organs (P .001), with cells clustered in areas of active bone formation and remodeling, and at sites of fracture healing. Donor cells found in the bone expressed osteoblast lineage genes, and produced the extracellular bone structural protein osteopontin. Finally, MSC transplantation decreased bone hydroxyproline content. In conclusion, intrauterine transplantation of fetal MSCs markedly reduced fracture rates and skeletal abnormalities in a mouse model of the intermediate severity type III OI, suggesting a scientific basis for MSC treatment of affected human fetuses.
Systematic analysis of research underfunding in maternal and perinatal health
Publisher: Wiley
Date: 21-01-2009
DOI: 10.1111/J.1471-0528.2008.02027.X
Abstract: Little published evidence supports the widely held contention that research in pregnancy is underfunded compared with other disease areas. To assess absolute and relative government and charitable funding for maternal and perinatal research in the UK and internationally. SEARCH STRATEGY, SELECTION CRITERIA, DATA COLLECTION, AND ANALYSIS: Major research funding bodies and alliances were identified from an Internet search and discussions with opinion leaders/senior investigators. Websites and annual reports were reviewed for details of strategy, research spend, grants awarded, and allocation to maternal and/or perinatal disease using generic and disease-specific search terms. Within the imprecision in the data sets, < or =1% of health research spend in the UK was on maternal erinatal health. Other countries fared better with 1-4% investment, although nonexclusive categorisation may render this an overestimate. In low-resource settings, government funders focused on infectious disease but not maternal and perinatal health despite high relative disease burden, while global philanthropy concentrated on service provision rather than research. Although research expenditure has been deemed as appropriate for 'reproductive health' disease burden in the UK, there are no data on the equity of maternal erinatal research spend against disease burden, which globally may justify a manyfold increase. This systematic review of research expenditure and priorities from national and international funding bodies suggests relative underinvestment in maternal erinatal health. Contributing factors include the low political priority given to women's health, the challenging nature of clinical research in pregnancy, and research capacity dearth as a consequence of chronic underinvestment.
CD34+ cells from first-trimester fetal blood are enriched in primitive hemopoietic progenitors
Publisher: Elsevier BV
Date: 04-2003
DOI: 10.1067/MOB.2003.236
Abstract: The purpose of this study was to investigate whether purified CD34(+) cells from first-trimester fetal blood are a source of primitive and committed hemopoietic progenitors. CD34(+) cells from first-trimester fetal blood and term cord blood were assayed for committed hemopoietic progenitor cells, high proliferative potential colony-forming cells, and long-term culture-initiating cells. First-trimester CD34(+) cells that were compared with cells at term generated fewer hemopoietic progenitor cells and fewer high proliferative potential colony-forming cells with lower recloning efficiency(P <.001). First-trimester CD34(+) cells tended to contain more long-term culture-initiating cells, both in bulk cultures and by limiting dilution analysis. The ratio between committed and primitive progenitors was 3 in the first-trimester and 20 in the term cord blood, respectively. First-trimester fetal blood is enriched in primitive (compared with committed) hemopoietic progenitors and may be an advantageous source of stem cells for prenatal therapy.
Unravelling the Pluripotency Paradox in Fetal and Placental Mesenchymal Stem Cells: Oct-4 Expression and the Case of the Emperor’s New Clothes
Publisher: Springer Science and Business Media LLC
Date: 11-12-2011
DOI: 10.1007/S12015-011-9336-5
Abstract: Mesenchymal stem cells (MSC) from fetal-placental tissues have translational advantages over their adult counterparts, and have variably been reported to express pluripotency markers. OCT-4 expression in fetal-placental MSC has been documented in some studies, paradoxically without tumourogenicity in vivo. It is possible that OCT-4 expression is insufficient to induce true "stemness", but this issue is important for the translational safety of fetal-derived MSC. To clarify this, we undertook a systematic literature review on OCT-4 in fetal or adnexal MSC to show that most studies report OCT-4 message or protein expression, but no study provides definitive evidence of true OCT-4A expression. Discrepant findings were attributable not to different culture conditions, tissue sources, or gestational ages but instead to techniques used. In assessing OCT-4 as a pluripotency marker, we highlight the challenges in detecting the correct OCT-4 isoform (OCT-4A) associated with pluripotency. Although specific detection of OCT-4A mRNA is achievable, it appears unlikely that any antibody can reliably distinguish between OCT-4A and the pseudogene OCT-4B. Finally, using five robust techniques we demonstrate that fetal derived-MSC do not express OCT-4A (or by default OCT-4B). Reports suggesting OCT-4 expression in fetal-derived MSC warrant reassessment, paying attention to gene and protein isoforms, pseudogenes, and antibody choice as well as primer design. Critical examination of the OCT-4 literature leads us to suggest that OCT-4 expression in fetal MSC may be a case of "The Emperor's New Clothes" with early reports of (false) positive expression lified in subsequent studies without critical attention to emerging refinements in knowledge and methodology.
FastFISH: technique for ultrarapid fluorescence in situ hybridization on uncultured amniocytes yielding results within 2 h of amniocentesis
Publisher: Oxford University Press (OUP)
Date: 12-04-2007
Abstract: Rapid aneuploidy detection methods allow prenatal diagnosis results to be released within 48 h, but not on the same day as the invasive test. We aimed to develop a rapid fluorescence in situ hybridization (FISH) method (FastFISH) that releases accurate results on the same day as amniocentesis. FastFISH was optimized to be completed within 2 h of s le collection using CEP and LSI probes for chromosomes 13, 18, 21, X, Y and DiGeorge syndrome (DGS). The technique was tested on 100 consecutive amniotic fluid s les in a blinded study. It was also validated as a 1-day molecular genetic test on three representative fetal tissue s les: chorionic villus, amniotic fluid and fetal blood. In the blinded study, FastFISH results were ready within 2 h of s le collection. Of the 100 amniotic fluid s les, 49 male and 50 female fetuses were identified. One fetus was 47, XXY (Klinefelter syndrome). Three fetuses had trisomy 21. One fetus suspected of DGS by ultrasound was identified as normal. Results of FastFISH analyses in all 100 cases were concordant with their karyotypes (100% accuracy lower 95% CI, 97.05%). In the 1-day test validation, all results were released on the same day and were concordant with their respective karyotypes. FastFISH allows results to be released on the same day as amniocentesis. It represents the necessary development for a 1-day prenatal diagnosis service.
Upregulating CXCR4 in Human Fetal Mesenchymal Stem Cells Enhances Engraftment and Bone Mechanics in a Mouse Model of Osteogenesis Imperfecta
Publisher: Oxford University Press (OUP)
Date: 07-12-2011
Abstract: Stem cells have considerable potential to repair damaged organs and tissues. We previously showed that prenatal transplantation of human first trimester fetal blood mesenchymal stem cells (hfMSCs) in a mouse model of osteogenesis imperfecta (oim mice) led to a phenotypic improvement, with a marked decrease in fracture rate. Donor cells differentiated into mature osteoblasts, producing bone proteins and minerals, including collagen type Iα2, which is absent in nontransplanted mice. This led to modifications of the bone matrix and subsequent decrease of bone brittleness, indicating that grafted cells directly contribute to improvement of bone mechanical properties. Nevertheless, the therapeutic effect was incomplete, attributing to the limited level of engraftment in bone. In this study, we show that although migration of hfMSCs to bone and bone marrow is CXCR4-SDF1 (SDF1 is stromal-derived factor) dependent, only a small number of cells present CXCR4 on the cell surface despite high levels of internal CXCR4. Priming with SDF1, however, upregulates CXCR4 to increase the CXCR4+ cell fraction, improving chemotaxis in vitro and enhancing engraftment in vivo at least threefold in both oim and wild-type bone and bone marrow. Higher engraftment in oim bones was associated with decreased bone brittleness. This strategy represents a step to improve the therapeutic benefits of fetal cell therapy toward being curative.
Ontogeny of foetal exposure to maternal cortisol using midtrimester amniotic fluid as a biomarker
Publisher: Wiley
Date: 13-02-2007
DOI: 10.1111/J.1365-2265.2007.02785.X
Abstract: There is increasing evidence that antenatal stress has long-lasting effects on child development, but there is less accord on the mechanisms and the gestational window of susceptibility. One possible mechanism is by foetal exposure to maternal cortisol. To explore this, we investigated the relationship between cortisol in maternal plasma and amniotic fluid, and any moderating influence of gestational age. Two hundred and sixty-seven women awaiting amniocentesis for karyotyping were studied. S les were collected between 0900 and 1730 h. Gestational age was determined to the nearest day by ultrasound biometry and time of collection noted to the nearest 15 min. Total cortisol was measured by radioimmunoassay in paired amniotic fluid and maternal blood s les (n = 267) [gestation range 15-37 weeks, median 17 weeks (119 days)]. Both maternal and amniotic fluid cortisol levels increased with gestation (r = 0.25, P < 0.001 r = 0.33 P < 0.001, respectively). Amniotic fluid cortisol was positively correlated with time of collection (r = 0.22, P < 0.001) and negatively with maternal age (r =-0.24, P < 0.001). There was a positive correlation between amniotic fluid cortisol with maternal plasma levels (r = 0.32, P < 0.001), which persisted after multivariate analysis controlling for gestation, time of collection and maternal age. The association appeared to be dependent on gestational age, being nonsignificant at 15-16 weeks' gestation and increasing in strength thereafter. This study shows a positive correlation between maternal and amniotic fluid cortisol levels, which becomes robust from 17 to 18 weeks onwards. The results provide support for the hypothesis that alterations in maternal cortisol may be reflected in amniotic fluid levels from this gestation.
A randomized trial of amnioreduction versus septostomy in the treatment of twin-twin transfusion syndrome
Publisher: Elsevier BV
Date: 09-2005
DOI: 10.1016/J.AJOG.2005.01.067
Abstract: Left untreated, severe twin-to-twin transfusion syndrome (TTTS) presenting in the early second trimester of pregnancy is often associated with significant maternal morbidity and almost universal perinatal loss. Removal of excessive amounts of amniotic fluid through serial amniocenteses (amnioreduction) has been the mainstay of therapy. We sought to compare amnioreduction to intentional perforation of the intervening twin membrane (septostomy). Pregnant women with TTTS before 24 weeks' gestation were randomly assigned to serial amnioreduction or septostomy. A single puncture technique under ultrasound guidance was used for the septostomy. The primary outcome measure was survival to neonatal discharge, and was assessed based on the number of pregnancies or the number of fetuses as appropriate. The study was terminated at the planned interim analysis stage after 73 women were enrolled. This was because the rate of survival of at least 1 infant was similar in the amnioreduction group compared to the septostomy group (78% vs 80% of pregnancies, respectively RR=0.94, 95%CI 0.55-1.61 P=.82). Patient undergoing septostomy were more likely to require a single procedure for treatment (64% vs 46% P=.04). Although overall perinatal survival is not enhanced, septostomy offers the advantage of often requiring a single procedure compared to serial amnioreduction in the treatment of severe twin-to-twin transfusion syndrome.
The effects of culture on genomic imprinting profiles in human embryonic and fetal mesenchymal stem cells
Publisher: Informa UK Limited
Date: 2011
Functional intrinsic and extrinsic apoptotic pathways in human fetal mesenchymal stem cells
Publisher: Springer Science and Business Media LLC
Date: 17-06-2005
Comparative osteogenic transcription profiling of various fetal and adult mesenchymal stem cell sources
Publisher: Elsevier BV
Date: 11-2008
DOI: 10.1111/J.1432-0436.2008.00279.X
Abstract: Human mesenchymal stem cells (MSC) from adult and fetal tissues are promising candidates for cell therapy but there is a need to identify the optimal source for bone regeneration. We have previously characterized MSC populations in first trimester fetal blood, liver, and bone marrow and we now evaluate their osteogenic differentiation potential in comparison to adult bone marrow MSC. Using quantitative real-time RT-PCR, we demonstrated that 16 osteogenic-specific genes (OC, ON, BSP, OP, Col1, PCE, Met2A, OPG, PHOS1, SORT, ALP, BMP2, CBFA1, OSX, NOG, IGFII) were expressed in both fetal and adult MSC under basal conditions and were up-regulated under osteogenic conditions both in vivo and during an in vitro 21-day time-course. However, under basal conditions, fetal MSC had higher levels of osteogenic gene expression than adult MSC. Upon osteogenic differentiation, fetal MSC produced more calcium in vitro and reached higher levels of osteogenic gene up-regulation in vivo and in vitro. Second, we observed a hierarchy within fetal s les, with fetal bone marrow MSC having greater osteogenic potential than fetal blood MSC, which in turn had greater osteogenic potential than fetal liver MSC. Finally, we found that the level of gene expression under basal conditions was positively correlated with both calcium secretion and gene expression after 21 days in osteogenic conditions. Our findings suggest that stem cell therapy for bone dysplasias such as osteogenesis imperfecta may benefit from preferentially using first trimester fetal blood or bone marrow MSC over fetal liver or adult bone marrow MSC.
Determinants of flow along arterio-arterial anastomoses in monochorionic placentae by dynamic computer modelling of chorionic plate vasculature
Publisher: Wiley
Date: 2006
DOI: 10.1002/PD.1432
Abstract: To investigate anatomical and physiological determinants of inter-fetal transfusion along arterio-arterial (AA) anastomoses in monochorionic placentae. A computer model of chorionic arterial vasculature was constructed in QuickBASIC using data collected from experimentation and the published literature. After validating the model, the influence of various physiological and anatomical variables on anastomotic flow rates was examined. AA anastomotic flow rates were significantly related to changes in fetal mean arterial pressure (p < 0.0001) and heart rate (p < 0.0005). AA flow rates were also related to the imbalance in number of arterio-venous (AV) anastomoses, to placental territory share, and to the branch number of the AA anastomosis (AAAs) from the chorionic arterial tree. Net blood flow and direction along AA anastomoses are influenced by fetal cardiac output, by the presence of compensatory AV anastomoses, and by the branch number of the chorionic arteries connected by the anastomosis. This study provides insight into the determinants of chronic transfusional imbalance as well as acute inter-fetal transfusion.
First trimester embryo-fetoscopic and ultrasound-guided fetal blood sampling for ex vivo viral transduction of cultured human fetal mesenchymal stem cells
Publisher: Oxford University Press (OUP)
Date: 06-08-2008
Abstract: Intrauterine stem cell transplantation is a promising approach for early onset genetic diseases. However, its utility is limited by the development of the fetal immune system after 14 weeks gestation. An ex vivo gene therapy approach targeting autologous first trimester stem cells to replace the missing or defective gene product should overcome this barrier. We investigated the feasibility of harvesting circulating first trimester human fetal mesenchymal stem cells (hfMSCs) for ex vivo gene therapy. Thin-gauge embryofetoscopic-directed or ultrasound-guided blood s ling (FBS) was performed in 18 pre-termination fetuses at a mean of 10(+0) (range 7(+2) to 13(+4)) weeks gestation through extra-fetal vessels. Harvested blood was plated for isolation of hfMSC and transduced by lentiviruses. FBS was successful in 12/18 procedures (67%). Success rates were comparable in fetoscopic (4/6) and ultrasound-guided (8/12) procedures, but procedural time was shorter in the ultrasound-guided arm (P = 0.01). Fetal bradycardia occurred post-FBS in 33% and 25% of fetoscopic and ultrasound cases, respectively, 5 min post-procedure. hfMSCs were isolated in two-thirds of cases, with high efficiency lentiviral transduction achieved without affecting short-term cell renewal. This phase-one study demonstrates the feasibility of the ex vivo fetal gene therapy approach, in which harvested hfMSCs are genetically manipulated prior to infusion back into the fetus where they should engraft and home to injured tissues. The fetal ex vivo gene therapy paradigm is also of relevance to haemopoietic stem cells to treat inherited haematological diseases. Optimization of stem cell harvest and longer-term safety is required before translation into clinical trials in ongoing pregnancies.
Distant Mesenchymal Progenitors Contribute to Skin Wound Healing and Produce Collagen: Evidence from a Murine Fetal Microchimerism Model
Publisher: Public Library of Science (PLoS)
Date: 05-2013
Fetal cells in the maternal appendix: a marker of inflammation or fetal tissue repair?
Publisher: Oxford University Press (OUP)
Date: 08-07-2008
Abstract: Fetal microchimeric cells that have trafficked into the maternal circulation persist in maternal tissues for years after pregnancy, but their biological role is unclear. We investigated whether fetal cells participate in maternal tissue repair during human pregnancy. Appendix specimens were acquired from women undergoing appendicectomy during (n = 8) or after (n = 1) pregnancy. Fluorescence in situ hybridization (FISH) determined the presence of male presumed-fetal cells, and immunostaining indicated the fetal cell phenotype. Male cells were identified in appendiceal tissues from all women with known present or past male pregnancies (n = 7) and from a woman with a previous spontaneous abortion of undetermined gender (n = 1), but not in one woman with three daughters. One woman was only 6 weeks pregnant at appendicectomy. Male cells were evenly distributed through appendix tissues, in larger numbers where there was a greater degree of inflammation and when the current pregnancy was male. Combined immunostaining and Y-FISH demonstrated male desmin+ muscle cells and CD3+ lymphocytes, suggesting fetal cells had differentiated. Male-presumed fetal cells of haematopoietic and mesenchymal origin were identified in the appendix of all pregnant women who had sons. We suggest that fetal cells are present at sites of maternal tissue injury during pregnancy, and may participate in tissue repair.
Human Mid-Trimester Amniotic Fluid Stem Cells Cultured Under Embryonic Stem Cell Conditions with Valproic Acid Acquire Pluripotent Characteristics
Publisher: Mary Ann Liebert Inc
Date: 02-2013
Abstract: Human mid-trimester amniotic fluid stem cells (AFSC) have promising applications in regenerative medicine, being broadly multipotent with an intermediate phenotype between embryonic (ES) and mesenchymal stem cells (MSC). Despite this propluripotent phenotype, AFSC are usually cultured in adherence in a serum-based expansion medium, and how expansion in conditions sustaining pluripotency might affect their phenotype remains unknown. We recently showed that early AFSC from first trimester amniotic fluid, which endogenously express Sox2 and Klf4, can be reprogrammed to pluripotency without viral vectors using the histone deacetylase inhibitor valproic acid (VPA). Here, we show that mid-trimester AFSC cultured under MSC conditions contained a subset of cells endogenously expressing telomerase, CD24, OCT4, C-MYC, and SSEA4, but low/null levels of SOX2, NANOG, KLF4, SSEA3, TRA-1-60, and TRA-1-81, with cells unable to form embryoid bodies (EBs) or teratomas. In contrast, AFSC cultured under human ESC conditions were smaller in size, grew faster, formed colonies, upregulated OCT4 and C-MYC, and expressed KLF4 and SOX2, but not NANOG, SSEA3, TRA-1-60, and TRA-1-81. Supplementation with VPA for 5 days further upregulated OCT4, KLF4, and SOX2, and induced expression of NANOG, SSEA3, TRA-1-60, and TRA-1-81, with cells now able to form EBs and teratomas. We conclude that human mid-trimester AFSC, which may be isolated autologously during pregnancy without ethics restriction, can acquire pluripotent characteristics without the use of ectopic factors. Our data suggest that this medium-dependant approach to pluripotent mid-trimester AFSC reflects true reprogramming and not the selection of prepluripotent cells.
In Reply
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2013
Microchimeric Fetal Cells Are Recruited to Maternal Kidney following Injury and Activate Collagen Type I Transcription
Publisher: S. Karger AG
Date: 11-12-2010
DOI: 10.1159/000321172
Abstract: Fetal cells enter the maternal circulation from the early first trimester of pregnancy, where they persist in tissue decades later. We investigated in mice whether fetal microchimeric cells (FMCs) can be detected in maternal kidney, and whether they play a role in kidney homeostasis. FMCs were identified in vivo in two models: one an adaptive model following unilateral nephrectomy, the other an injury via unilateral renal ischaemia reperfusion. Both models were carried out in mothers that had been mated with transgenic mice expressing luciferase transgene under the control of collagen type I, and had given birth to either 1 or 3 litters. FMCs were detected by Y-probe fluorescent in situ hybridization (FISH) and bioluminescence, and the cell number quantified by real-time polymerase chain reaction. In the adaptive model, the remaining kidney showed more cells by all 3 parameters compared with the nephrectomized kidney, while ischaemia reperfusion resulted in higher levels of FMC participation in injured compared to contralateral kidneys. Bioluminescence showed that FMCs switch on collagen type I transcription implicating mesenchymal lineage cells. After injury, Y-probe in situ hydridization was found mainly in the tubular epithelial network. Finally, we compared FMCs with bone marrow cells and found similar dynamics but altered distribution within the kidney. We conclude that FMCs (1) are long-term sequelae of pregnancy and (2) are recruited to the kidney as a result of injury or adaptation, where they activate the transcriptional machinery of matrix proteins.
Human Chorionic Stem Cells: Podocyte Differentiation and Potential for the Treatment of Alport Syndrome
Publisher: Mary Ann Liebert Inc
Date: 03-2016
Abstract: Alport syndrome (AS) is a hereditary glomerulopathy caused by a mutation in type IV collagen genes, which disrupts glomerular basement membrane, leading to progressive glomerulosclerosis and end-stage renal failure. There is at present no cure for AS, and cell-based therapies offer promise to improve renal function. In this study, we found that human first trimester fetal chorionic stem cells (CSC) are able to migrate to glomeruli and differentiate down the podocyte lineage in vitro and in vivo. When transplanted into 7-week-old Alport 129Sv-Col4α3(tm1Dec)/J (-/-) mice, a single intraperitoneal injection of CSC significantly lowered blood urea and urine proteinuria levels over the ensuing 2 weeks. In addition, nearly two-thirds of transplanted -/- mice maintained their weight above the 80% welfare threshold, with both males and females weighing more than age-matched nontransplanted -/- mice. This was associated with less renal cortical fibrosis and interstitial inflammation compared to nontransplanted mice as shown by reduction in murine CD4, CD68, and CD45.2 cells. Transplanted CSC homed to glomeruli, where they expressed CR1, VEGFA, SYNAPTOPODIN, CD2AP, and PODOCIN at the RNA level and produced PODOCIN, CD2AP, and COLIVα3 proteins in nontransplanted -/- mice, indicating that CSC have adopted a podocyte phenotype. Together, these data indicate that CSC may be used to delay progression of renal pathology by a combination of anti-inflammatory effects and replacement of the defective resident podocytes.
Mesenchymal stem cells for systemic therapy: Shotgun approach or magic bullets?
Publisher: Wiley
Date: 26-11-2012
Abstract: Given their heterogeneity and lack of defining markers, it is surprising that multipotent mesenchymal stem/stromal cells (MSCs) have attracted so much translational attention, especially as increasing evidence points to their predominant effect being not by donor differentiation but via paracrine mediators and exosomes. Achieving long-term MSC donor chimerism for treatment of chronic disease remains a challenge, requiring enhanced MSC homing/engraftment properties and manipulation of niches to direct MSC behaviour. Meanwhile advances in nanoparticle technology are furthering the development of MSCs as vehicles for targeted drug delivery. For treatment of acute injuries, systemic cell-free exosome delivery may ultimately displace current emphasis on empiric donor-cell transplantation for anti-inflammatory, immunomodulatory and repair-promoting effects. Exploration of potential clinical sources of MSCs has led to increased utilisation of perinatal MSCs in allogeneic clinical trials, reflecting their ease of collection and developmentally advantageous properties.
Infant cortisol response after prolonged antenatal prednisolone treatment
Publisher: Wiley
Date: 22-11-2004
DOI: 10.1111/J.1471-0528.2004.00288.X
Abstract: Prednisolone is widely used to treat medical conditions in pregnancy, despite the lack of long-term safety studies on infants. Animal studies have shown that antenatal glucocorticoid treatment can cause in utero growth restriction and up-regulation of the offsprings' hypathalamic-pituitary-adrenal axis. We recruited women treated antenatally with prednisolone, and followed 12 of the infants up to four months, using routine infant vaccinations as a stressor. Birthweights were similar to controls (n = 289, uncomplicated, singleton term pregnancies), as were infants' baseline and stress-induced cortisol levels. Mothers rated their infants as less difficult and more adaptable than controls. This study provides initial reassurance about the safety of prednisolone in pregnancy.
Pseudo-arterio-arterial anastomoses in twin–twin transfusion syndrome
Publisher: Elsevier BV
Date: 09-2004
Longitudinal Blood Flow in Shared (Arteriovenous Anastomoses) and Non-Shared Cotyledons in Monochorionic Placentae
Publisher: Elsevier BV
Date: 05-2007
DOI: 10.1016/J.PLACENTA.2006.09.001
Abstract: In this study we aimed to quantitate monochorionic twin placental blood flow in vivo through arterio-venous anastomoses (AVA) and corresponding vessels within normal cotyledons. The topography of chorionic plate vasculature was mapped using colour Doppler in ten monochorionic diamniotic twin (MCDA) pregnancies. Cotyledonary flow was derived by insonation of chorionic veins draining normal (n=10) and paired control shared cotyledons (n=10). Venous volume flow was calculated from five determinations of vessel diameter and three of time average mean velocity (TAMV). Measurements were repeated every 2-4 weeks from 18 until 32 weeks' gestation. Blood flow through non-shared and shared cotyledons increased with gestation (p<0.0001). Median flow at 28 weeks through shared cotyledons was 16 ml/min (15-21) (median, interquartile range), lower than in shared cotyledons (31, 25-35) (p<0.001), as was median volume flow across gestation calculated as area under the curve (shared cotyledons 126 (122-167), control cotyledons 269 (214-274), p=0.01). However, velocity was similar, with the difference due to smaller vein diameters draining shared compared to normal cotyledons (mean 3.6mm (SD 0.8) vs. 4.5mm (0.8), p=0.004). Ex vivo quantitation of insonated cotyledons and of all cotyledons confirmed the difference in vein diameter in the placentae studied. Blood flow through shared cotyledons was lower across gestation than through paired normal cotyledons in the placenta studied due to the smaller diameter of the AVA vessels. The size of AVAs rather than simply their presence and direction may contribute to determining transfusional imbalance in monochorionic twins.
Doppler for Artery–Artery Anastomosis and Stage-Independent Survival in Twin–Twin Transfusion
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2004
Increased latency of absent end-diastolic flow in the umbilical artery of monochorionic twin fetuses
Publisher: Wiley
Date: 22-06-2005
DOI: 10.1002/UOG.1900
Abstract: To determine if absent end-diastolic flow (AEDF) in the umbilical artery (UA) has a longer latency in monochorionic (MC) twin fetuses compared to singleton or dichorionic twin (DC) fetuses. One hundred and eight pregnancies with a fetus with AEDF were reviewed: 47 MC and 17 DC twin pregnancies and 44 singletons. Because twin-twin transfusion syndrome (TTTS) is a potential confounder when determining latency, subgroup analysis was also performed on the 21 MC affected pregnancies without TTTS. Latency of AEDF (in days) was defined as the difference between the gestational age at diagnosis of AEDF and gestational age at delivery or intrauterine death. Latency was similar in MC twins (median, 39 days) and DC twins (30 days) but longer compared to singletons (11 days P = 0.0001). After excluding pregnancies with TTTS, latency in non-TTTS MC twins (54 days) was longer than in both singletons and DC twins. This was due to an earlier gestational age at AEDF in non-TTTS MC twins of 20 weeks compared to 27 weeks in both singleton and DC twins because median gestational age at delivery was similar in MC twins, DC twins and singletons. The latency period of UA AEDF is longer in MC twins than in singletons. Our data suggest that in MC twin fetuses without TTTS, AEDF begins earlier and lasts about twice as long as in DC twin fetuses, which is consistent with placental insufficiency not being the sole factor mediating abnormal UA waveforms in MC placentation. This observation is important in counseling and managing twin pregnancies discordant for AEDF.
Maternal anxiety at amniocentesis and plasma cortisol
Publisher: Wiley
Date: 09-05-2006
DOI: 10.1002/PD.1444
Abstract: To assess whether anticipation of amniocentesis is linked with maternal anxiety, and whether this anxiety is associated with increased maternal plasma cortisol. Two hundred and fifty-four women awaiting a morning amniocentesis for karyotyping (gestation range 15-37 weeks, median 17 weeks) completed Spielberger state and trait anxiety inventory (STAI) questionnaires, and provided blood s les immediately before the procedure for cortisol assay. Six hundred and five women at mean gestation of 20 weeks, attending the same hospital for routine ultrasound but not for amniocentesis, also completed Spielberger STAI questionnaires and served as a comparison group for the anxiety ratings. Mean state and trait anxiety scores (+/- SD) in the comparison group of 605 women at mean gestation of 20 weeks were 36.1 +/- 10.2 (range 20-70) and 35.6 +/- 8.9 (range 20-73), respectively. The mean state anxiety score (+/-SD) of 49.8 +/- 14.0 (range 20-77) of the amniocentesis group was considerably higher than the comparison group (p < 0.001), although the mean trait anxiety score in the amniocentesis group was similar at 36.4 +/- 8.6 (range 21-60). The state, but not trait, anxiety correlated with plasma cortisol (r = 0.176, p = 0.005). Maternal cortisol in the amniocentesis group increased with gestational age (r = 0.310, p < 0.001), whereas state anxiety scores showed no significant change with increase in gestational age (r = - 0.042, ns). Multivariate analysis demonstrated that maternal state anxiety was positively correlated with plasma cortisol independent of gestation and time of collection. Women awaiting amniocentesis experience a high state anxiety associated with modestly increased plasma cortisol.
Neo-vascularization and bone formation mediated by fetal mesenchymal stem cell tissue-engineered bone grafts in critical-size femoral defects
Publisher: Elsevier BV
Date: 02-2010
DOI: 10.1016/J.BIOMATERIALS.2009.09.078
Abstract: Tissue-engineered bone grafts (TEBG) require highly osteogenic cell sources for use in fracture repair applications. Compared to other sources of mesenchymal stem cells (MSC), human fetal MSC (hfMSC) have recently been shown to be more proliferative and osteogenic. We studied the functional performance of hfMSC-mediated TEBG in 7 mm rat femoral critical-sized bone defects (CSD). Dynamically-cultured and osteogenically-primed hfMSC seeded onto macroporous poly-epsilon-caprolactone tri-calcium phosphate scaffolds were transplanted into CSDs. After 12 weeks, hfMSC-mediated TEBG induced 2.1x more new bone formation (43.3+/-10.5 vs. 21.0+/-7.4 mm(3), p<0.05), with greater compact and woven bone, and a 9.8x increase in stiffness (3.9+/-1.7 vs. 0.4+/-0.3 mNm/degree, p<0.05) compared to acellular scaffolds, such that only animals transplanted with TEBG underwent full fracture repair of the CSD. Although hfMSC survived for <4 weeks, by 4 weeks they were associated with a 3.9x larger vasculature network in the defect area (35.2+/-11.1 vs. 6.5+/-3.6 mm(3)p<0.05), suggesting an important role for hfMSC in the promotion of neo-vasculogenesis. We speculate that hfMSC-mediated healing of the CSD by stimulating neo-vascularization through as yet undetermined mechanisms. This proof-of-principle study demonstrates the utility of primitive MSC for bone regeneration, and may be of relevance to vascularization in other areas of regenerative medicine.
Transplantation of human fetal blood stem cells in the osteogenesis imperfecta mouse leads to improvement in multiscale tissue properties
Publisher: American Society of Hematology
Date: 20-01-2011
DOI: 10.1182/BLOOD-2010-05-287565
Abstract: Osteogenesis imperfecta (OI or brittle bone disease) is a disorder of connective tissues caused by mutations in the collagen genes. We previously showed that intrauterine transplantation of human blood fetal stem/stromal cells in OI mice (oim) resulted in a significant reduction of bone fracture. This work examines the cellular mechanisms and mechanical bone modifications underlying these therapeutic effects, particularly examining the direct effects of donor collagen expression on bone material properties. In this study, we found an 84% reduction in femoral fractures in transplanted oim mice. Fetal blood stem/stromal cells engrafted in bones, differentiated into mature osteoblasts, expressed osteocalcin, and produced COL1a2 protein, which is absent in oim mice. The presence of normal collagen decreased hydroxyproline content in bones, altered the apatite crystal structure, increased the bone matrix stiffness, and reduced bone brittleness. In conclusion, expression of normal collagen from mature osteoblast of donor origin significantly decreased bone brittleness by improving the mechanical integrity of the bone at the molecular, tissue, and whole bone levels.
Rapid method for growth hormone receptor exon 3 delete (GHRd3) SNP genotyping from archival human placental samples
Publisher: Springer Science and Business Media LLC
Date: 12-06-2015
DOI: 10.1007/S12020-015-0647-1
Abstract: Analysis of archival s les from cohorts of pregnant women may be key to discovering prognosticators of stillbirth and pregnancy erinatal complications. Growth hormone (GH) and its receptor (GHR) are pivotal in feto-placental development and pregnancy maintenance. We report a rapid, optimized method for genotyping the GHR full-length versus exon 3-deleted isoform (GHRd3). TaqMan single nucleotide polymorphism (SNP) genotyping proved superior to standard multiplex polymerase chain reaction (PCR) in allele detection and GHR genotyping from archived s les, including those with poor genomic deoxyribonucleic acid quality/quantity such as formalin fixed, paraffin embedded, blood, and serum. Furthermore, this assay is suitable for high through put 96 or 384-well plate quantitative PCR machines with automated genotype calling software. The TaqMan genotyping assay can increase the data obtained from precious archival human s les.
Reversal of twin–twin transfusion syndrome: frequency, vascular anatomy, associated anomalies and outcome
Publisher: Wiley
Date: 02-2004
DOI: 10.1002/PD.799
Abstract: To determine the frequency of reversal of transfusional gradient and phenotype in a large cohort of prospectively studied cases of twin-twin transfusion syndrome (TTTS) and seek evidence of clinical or placental anastomotic associations. Consecutive cases of TTTS seen over an eight-year period with serial documentation of ultrasonic growth, liquor volume and fetal and placental Doppler studies were reviewed. Postnatal injection studies were inspected. Reversal of TTTS occurred in 5 of 96 affected pregnancies (5%). Two of the five cases had underlying aneuploidy or genetic syndrome, higher than the 2% frequency found in cases without reversal of TTTS (p < 0.05). Placental anastomotic configurations provided no consistent explanation for reversal of phenotype. This study documents the frequency of reversal of the direction of TTTS, and suggests that it is a heterogeneous condition. Reversal of donor-recipient phenotype may be explained by haemodynamic changes secondary to underlying aneuploidy/genetic syndromes, to the presence of multiple anastomoses in either direction or following laser ablation. This series together with previous case reports argues for a high level of suspicion for underlying aneuploidy, genetic syndrome or structural defects where there is reversal of the donor-recipient phenotype.
Distal urinary obstruction
Publisher: Elsevier BV
Date: 09-2003
DOI: 10.1016/S0095-5108(03)00060-5
Abstract: Despite the sound experimental basis and initial promise of early animal models, the results of antenatal intervention have been disappointing, with high rates of misdiagnosis of urethral valves, complications from vesicoamniotic shunting, perinatal mortality, and long-term renal impairment and bladder dysfunction in survivors. The recent development of a cystoscopic approach might obviate some of these problems, but to date the procedure been limited by technical difficulty in negotiating the urethrovesical angle. Overcoming these difficulties through equipment modifications might allow definitive testing of whether or not alleviating distal urinary obstruction in utero is beneficial.
The potential of human fetal mesenchymal stem cells for off-the-shelf bone tissue engineering application
Publisher: Elsevier BV
Date: 03-2012
DOI: 10.1016/J.BIOMATERIALS.2011.12.025
Abstract: Mesenchymal stem cells (MSCs) have become one of the most promising cell sources for bone tissue engineering (BTE) applications. In this review, we first highlight recent progress in the understanding of MSC biology, their in vivo niche, multi-faceted contribution to fracture healing and bone re-modelling, and their role in BTE. A literature review from clinicaltrials.gov and Pubmed on clinical usage of MSC for both orthopedic and non-orthopedic indications suggests that translational use of MSC for BTE indications is likely to bear fruit in the ensuing decade. Last, we disscuss the profound influence of ontological and antomical origins of MSC on their proliferation and osteogenesis and demonstrated human fetal MSC (hfMSC) as a superior cellular candidate for off-the-shelf BTE applications. This relates to their superior proliferation capacity, more robust osteogenic potential and lower immunogenecity, as compared to MSC from perinatal and postnatal sources. Furthermore, we discuss our experience in developing a hfMSC based BTE strategy with the integrated use of bioreactor-based dynamic priming within macroporous scaffolds, now ready for evaluation in clinical trials. In conclusion, hfMSC is likely the most promising cell source for allogeneic based BTE application, with proven advantages compared to other MSC based ones.
Galectin‐1 Induces Skeletal Muscle Differentiation in Human Fetal Mesenchymal Stem Cells and Increases Muscle Regeneration
Publisher: Oxford University Press (OUP)
Date: 08-2006
DOI: 10.1634/STEMCELLS.2005-0564
Abstract: Cell therapy for degenerative muscle diseases such as the muscular dystrophies requires a source of cells with the capacity to participate in the formation of new muscle fibers. We investigated the myogenic potential of human fetal mesenchymal stem cells (hfMSCs) using a variety of stimuli. The use of 5-azacytidine or steroids did not produce skeletal muscle differentiation, whereas myoblast-conditioned medium resulted in only 1%-2% of hfMSCs undergoing muscle differentiation. However, in the presence of galectin-1, 66.1% +/- 5.7% of hfMSCs, but not adult bone marrow-derived mesenchymal stem cells, assumed a muscle phenotype, forming long, multinucleated fibers expressing both desmin and sarcomeric myosin via activation of muscle regulatory factors. Continuous exposure to galectin-1 resulted in more efficient muscle differentiation than pulsed exposure (62.3% vs. 39.1% p < .001). When transplanted into regenerating murine muscle, galectin-1-exposed hfMSCs formed fourfold more human muscle fibers than nonstimulated hfMSCs (p = .008), with similar results obtained in a scid/mdx dystrophic mouse model. These data suggest that hfMSCs readily undergo muscle differentiation in response to galectin-1 through a stepwise progression similar to that which occurs during embryonic myogenesis. The high degree of myogenic conversion achieved by this method has relevance for the development of therapies for muscular dystrophies.
Magnetic Resonance Tracking of Stem Cells with Iron Oxide Particles
Publisher: Springer Netherlands
Date: 2011
A double-blind randomized study of fetal side effects during and after the short-term maternal administration of indomethacin, sulindac, and nimesulide for the treatment of preterm labor
Publisher: Elsevier BV
Date: 04-2003
DOI: 10.1067/MOB.2003.255
Abstract: The purpose of this study was to establish whether nimesulide causes fewer fetal side effects than indomethacin or sulindac after short-term maternal exposure for tocolysis. This was a double-blind, double-dummy prospective randomized study with three drug treatment groups (n = 10 per group) that were comprised of subjects who were at 28 to 32 weeks of gestation with preterm contractions. The subjects were treated in the delivery suites of two busy inner-city teaching hospitals the intervention consisted of 48 hours of treatment and with 72 hours of follow-up observation with indomethacin 100 mg (twice daily), sulindac 200 mg (twice daily), or nimesulide 200 mg (twice daily). The amniotic fluid index, hourly fetal urine production, and ductal Doppler pulsatility index observations were monitored before the treatment and at 4, 24, 48, 72, and 120 hours after the treatment was started. The statistical analysis used repeated measures analysis of variance, Bonferroni test, and Bland-Altman agreement. Significance assumed when the probability value was <.05. Each drug caused a significant reduction in all three observations over the 48-hour treatment period, which recovered to pretreatment levels by 72 hours after treatment. There were no significant differences among drugs for any of these effects. Nimesulide causes similar short-term fetal side effects to indomethacin and sulindac.
Pregnancy-acquired fetal progenitor cells
Publisher: Elsevier BV
Date: 03-2013
DOI: 10.1016/J.JRI.2012.08.004
Abstract: The transfer and persistence of fetal progenitor cells into the mother throughout pregnancy has sparked considerable interest as a trafficking stem cell and immunological phenomenon. Indeed, the intriguing longevity of semi-allogeneic fetal microchimeric cells (FMC) in parous women raises questions over their potential clinical implications. FMC have been associated with both immune-modulatory roles and participation in maternal tissue repair. Although their influence on maternal health is as yet unresolved, FMC selectively home to damaged maternal tissues and often integrate, adopting site-appropriate phenotypes. FMC features, such as plasticity and persistence in their maternal host, suggest that they likely include pluripotent, or various multipotent and committed stem and progenitor cells. Recent efforts to determine what cell types are involved have established that FMC include cells of ectodermal, endodermal, mesodermal, and perhaps trophectodermal lineages. This review details FMC phenotypes and discusses how FMC themselves may be considered a naturally occurring stem cell therapy.
Interstitial laser therapy for fetal reduction in monochorionic multiple pregnancy: loss rate and association with aplasia cutis congenita
Publisher: Wiley
Date: 2008
DOI: 10.1002/PD.2025
Abstract: To evaluate experience with interstitial laser therapy for intrafetal vascular ablation in monochorionic (MC) multiple pregnancy. MC pregnancies that underwent fetal reduction between 1998 and 2007 by interstitial laser therapy were reviewed. Indications were twin reversed arterial perfusion sequence (TRAP) (n = 10), twin-to-twin transfusion (6), discordant abnormality (7) or growth (1) and high-order multiples (6). Thirty pregnancies treated at 15 weeks (median, range: 11 weeks-20 weeks, 5 days) had no technical failures but four manifested procedure-related amniorrhexis. Four of 38 remaining fetuses suffered intrauterine death (IUFD) within 24 h, giving an early procedure-related fetal loss rate of 10% per pregnancy and 11% per fetus. A further five IUFDs occurred within 2 weeks, giving a maximum procedure-related loss rate of 27% per pregnancy and 24% per fetus. Median gestation at delivery was 37 weeks (18 weeks, 1 day-41 weeks, 3 days) for pregnancies continuing > 2 weeks. Perinatal survival was 26 of 38 (68%) in nonreduced fetuses. Two of 26 neonates (8%) were diagnosed with aplasia cutis congenita (ACC). Interstitial laser therapy in complicated MC pregnancies carries significant risks of unintended fetal loss and may be associated with ACC.
The Placenta Contributes to Activation of the Renin Angiotensin System in Twin–Twin Transfusion Syndrome
Publisher: Elsevier BV
Date: 08-2008
DOI: 10.1016/J.PLACENTA.2008.04.010
Abstract: The renin-angiotensin system (RAS) in twin-twin transfusion syndrome (TTTS) is up-regulated in the donor fetus's kidneys, but down-regulated in the recipient's. Ultrasonographic and echocardiographic features suggest that the recipient is also exposed to RAS components. In this study we investigated the role and origin of RAS components in the recipient fetus. Monochorionic diamniotic (MCDA) pregnancies were recruited from a tertiary fetal medicine service. Cord blood was collected from MCDA twins (TTTS and control non-TTTS) at delivery for renin and angiotensin II immunoassays. Placental tissue was flash-frozen for mRNA and protein expression or formalin-fixed for immunohistochemistry. Archival placenta and kidney s les were used for immunohistochemistry and in-situ hybridization. Plasma renin levels were elevated (p<0.05) in recipients (median 201 pg/ml, range 54-315 pg/ml) and donors (125 pg/ml, 25-296) with TTTS compared to controls (2.5 pg/ml, 1.1-1.5 pg/ml). The same was found with angiotensin II with high levels in both recipients (300.5 pg/ml, 86.1-488 pg/ml) and donors (239 pg/ml, 76.6-422) compared to controls (169.5 pg/ml, 89-220 pg/ml, p<0.05). Renin mRNA expression, and protein appeared qualitatively higher in the placental territory of the recipient compared to that of the donor and non-TTTS controls. We conclude that both fetuses in TTTS are exposed to high levels of RAS components these appear to be produced from different sites, namely the kidney of the donor, and the placenta of the recipient. Given the markedly different phenotypes in the genetically identical fetuses with TTTS, we suggest that the source of RAS components may influence their clinical manifestations.
Self-Renewal and High Proliferative Colony Forming Capacity of Late-Outgrowth Endothelial Progenitors is Regulated by Cyclin-Dependent Kinase Inhibitors Driven by Notch Signaling
Publisher: Oxford University Press (OUP)
Date: 06-01-2016
DOI: 10.1002/STEM.2262
Abstract: Since the discovery of endothelial colony forming cells (ECFC), there has been significant interest in their therapeutic potential to treat vascular injuries. ECFC cultures display significant heterogeneity and a hierarchy among cells able to give rise to high proliferative versus low proliferative colonies. Here we aimed to define molecularly this in vitro hierarchy. Based on flow cytometry, CD34 expression levels distinguished two populations. Only CD34 + ECFC had the capacity to reproduce high proliferative potential (HPP) colonies on replating, whereas CD34− ECFCs formed only small clusters. CD34 + ECFCs were the only ones to self-renew in stringent single-cell cultures and gave rise to both CD34 + and CD34− cells. Upon replating, CD34 + ECFCs were always found at the centre of HPP colonies and were more likely in G0/1 phase of cell cycling. Functionally, CD34 + ECFC were superior at restoring perfusion and better engrafted when injected into ischemic hind limbs. Transcriptomic analysis identified cyclin-dependent kinase (CDK) cell cycle inhibiting genes (p16, p21, and p57), the Notch signaling pathway (dll1, dll4, hes1, and hey1), and the endothelial cytokine il33 as highly expressed in CD34 + ECFC. Blocking the Notch pathway using a γ-secretase inhibitor (DAPT) led to reduced expression of cell cycle inhibitors, increased cell proliferation followed by a loss of self-renewal, and HPP colony formation capacity reflecting progenitor exhaustion. Similarly shRNA knockdown of p57 strongly affected self-renewal of ECFC colonies. ECFC hierarchy is defined by Notch signalling driving cell cycle regulators, progenitor quiescence and self-renewal potential.
Human fetal mesenchymal stem cells differentiate into brown and white adipocytes: a role for ERRα in human UCP1 expression
Publisher: Springer Science and Business Media LLC
Date: 26-01-2010
DOI: 10.1038/CR.2010.11
Fetal endothelial and mesenchymal progenitors from the human term placenta: Potency and clinical potential
Publisher: Oxford University Press (OUP)
Date: 13-03-2015
Abstract: Over the last decade, fetal stem cells from a variety of sources have been reported and have shown potential clinical applications. This study briefly reviews recent findings in the fetal stem cell arena, and particularly human term placenta as a robust cell source that harbors large quantities of both fetal and maternal stem cells of various types. It also appraises prospective isolation of large quantities of fetal endothelial progenitor cells and pure preparations of fetal or maternal mesenchymal stromal cells from the same placenta.
Timing of mid-trimester sacral ossification
Publisher: Wiley
Date: 2005
DOI: 10.1002/PD.1053
Characterization of first trimester fetal erythroblasts for non-invasive prenatal diagnosis
Publisher: Oxford University Press (OUP)
Date: 04-2003
Abstract: Isolating fetal erythroblasts from first trimester maternal blood offers a promising non-invasive alternative for prenatal diagnosis. The aim of this study was to characterize the biological properties of first trimester primitive erythroblasts to facilitate their enrichment from first trimester maternal blood. Primitive erythroblasts were the predominant cell type until 12 weeks gestation, after which time their numbers declined steeply 100% were epsilon-globin-positive versus <0.06% definitive erythroblasts. Buoyant densities of first trimester fetal erythroblasts ranged from 1.077 to 1.130 g/ml, and optimal recoveries were obtained with Percoll 1118. Although primitive erythroblasts carried a negative surface charge and were resistant to NH(4)Cl lysis, these properties had only a limited role in fetal cell enrichment. Immunophenotyping showed that primitive, like definitive, erythroblasts were GPA+, CD47+, CD45- and CD35-, whereas CD71 expression was weak/undetectable on primitive erythroblasts but strongly positive on 100% of definitive erythroblasts primitive erythroblasts were also CD36- whereas definitive erythroblasts were CD36+. We therefore used CD45/GPA selection of Percoll 1118-separated cells to demonstrate successful enrichment of male epsilon-globin-positive fetal erythroblasts from model mixtures, and as proof of principle from some first trimester maternal blood s les. Fetal cell enrichment protocols based on first trimester epsilon-globin-positive primitive erythroblasts may allow reliable enrichment of fetal cells from maternal blood for early non-invasive prenatal diagnosis of genetic disorders.
A molecular classification of human mesenchymal stromal cells
Publisher: PeerJ
Date: 24-03-2016
DOI: 10.7717/PEERJ.1845
Abstract: Mesenchymal stromal cells (MSC) are widely used for the study of mesenchymal tissue repair, and increasingly adopted for cell therapy, despite the lack of consensus on the identity of these cells. In part this is due to the lack of specificity of MSC markers. Distinguishing MSC from other stromal cells such as fibroblasts is particularly difficult using standard analysis of surface proteins, and there is an urgent need for improved classification approaches. Transcriptome profiling is commonly used to describe and compare different cell types however, efforts to identify specific markers of rare cellular subsets may be confounded by the small s le sizes of most studies. Consequently, it is difficult to derive reproducible, and therefore useful markers. We addressed the question of MSC classification with a large integrative analysis of many public MSC datasets. We derived a sparse classifier (The Rohart MSC test) that accurately distinguished MSC from non-MSC s les with % accuracy on an internal training set of 635 s les from 41 studies derived on 10 different microarray platforms. The classifier was validated on an external test set of 1,291 s les from 65 studies derived on 15 different platforms, with % accuracy. The genes that contribute to the MSC classifier formed a protein-interaction network that included known MSC markers. Further evidence of the relevance of this new MSC panel came from the high number of Mendelian disorders associated with mutations in more than 65% of the network. These result in mesenchymal defects, particularly impacting on skeletal growth and function. The Rohart MSC test is a simple in silico test that accurately discriminates MSC from fibroblasts, other adult stem rogenitor cell types or differentiated stromal cells. It has been implemented in the www.stemformatics.org resource, to assist researchers wishing to benchmark their own MSC datasets or data from the public domain. The code is available from the CRAN repository and all data used to generate the MSC test is available to download via the Gene Expression Omnibus or the Stemformatics resource.
Superior Osteogenic Capacity for Bone Tissue Engineering of Fetal Compared with Perinatal and Adult Mesenchymal Stem Cells
Publisher: Oxford University Press (OUP)
Date: 2009
DOI: 10.1634/STEMCELLS.2008-0456
Abstract: Mesenchymal stem cells (MSCs) from human adult bone marrow (haMSCs) represent a promising source for bone tissue engineering. However, their low frequencies and limited proliferation restrict their clinical utility. Alternative postnatal, perinatal, and fetal sources of MSCs appear to have different osteogenic capacities, but have not been systematically compared with haMSCs. We investigated the proliferative and osteogenic potential of MSCs from human fetal bone marrow (hfMSCs), human umbilical cord (hUCMSCs), and human adult adipose tissue (hATMSCs), and haMSCs, both in monolayer cultures and after loading into three-dimensional polycaprolactone-tricalcium-phosphate scaffolds.Although all MSCs had comparable immunophenotypes, only hfMSCs and hUCMSCs were positive for the embryonic pluripotency markers Oct-4 and Nanog. hfMSCs expressed the lowest HLA-I level (55% versus 95%–99%) and the highest Stro-1 level (51% versus 10%–27%), and had the greatest colony-forming unit–fibroblast capacity (1.6×–2.0× p & .01) and fastest doubling time (32 versus 54–111 hours p & .01). hfMSCs had the greatest osteogenic capacity, as assessed by von-Kossa staining, alkaline phosphatase activity (5.1×–12.4× p & .01), calcium deposition (1.6×–2.7× in monolayer and 1.6×–5.0× in scaffold culture p & .01), calcium visualized on micro-computed tomography (3.9×17.6× p & .01) and scanning electron microscopy, and osteogenic gene induction. Two months after implantation of cellular scaffolds in immunodeficient mice, hfMSCs resulted in the most robust mineralization (1.8×–13.3× p & .01).The ontological and anatomical origins of MSCs have profound influences on the proliferative and osteogenic capacity of MSCs. hfMSCs had the most proliferative and osteogenic capacity of the MSC sources, as well as being the least immunogenic, suggesting they are superior candidates for bone tissue engineering.
Fetal Microchimeric Cells in a Fetus-Treats-Its-Mother Paradigm Do Not Contribute to Dystrophin Production in Serially ParousmdxFemales
Publisher: Mary Ann Liebert Inc
Date: 10-10-2012
Fetal Stem Cells: Betwixt and Between
Publisher: Georg Thieme Verlag KG
Date: 11-2006
Abstract: Fetal stem cells can be isolated not only from fetal blood and hemopoietic organs in early pregnancy, but from a variety of somatic organs as well as amniotic fluid and placenta throughout gestation. Fetal blood is a rich source of hemopoietic stem cells, which proliferate more rapidly than those in cord blood or adult bone marrow. First-trimester fetal blood, liver, and bone marrow also contain a population of mesenchymal stem cells, which appear to be more primitive with greater multipotentiality than their adult counterparts. Fetal stem cells may thus represent an intermediate cell type in the current debate focusing on dichotomized adult versus embryonic stem cells, and thus prove advantageous as a source for downstream cell therapy applications. They have also been implicated in fetomaternal trafficking in pregnancy, and in long-term microchimerism in postreproductive women.
Exploring cortical subplate evolution using magnetic resonance imaging of the fetal brain
Publisher: S. Karger AG
Date: 13-12-2008
DOI: 10.1159/000109864
Abstract: The subplate is a transient structure essential for normal development of the cortex. We used magnetic resonance imaging of the fetal brain to assess cortical subplate evolution between 20 and 35 weeks gestation. Two-dimensional measures of diameter were obtained for the cortex, subplate and fetal white matter. The subplate was originally seen as a continuous band at early gestations measuring up to 4.5 mm. It became magnetic resonance invisible from approximately 28 weeks initially from the depths of the sulci and then from the tops of the gyri. The disappearance of the subplate was regional, involuting most rapidly in the parietal lobe and remaining prominent in the anterior temporal lobe up to 35 weeks.
Identification of candidate surface antigens for non-invasive prenatal diagnosis by comparative global gene expression on human fetal mesenchymal stem cells
Publisher: Oxford University Press (OUP)
Date: 03-03-2010
Abstract: Transplacental passage of circulating first-trimester fetal mesenchymal stem cells (fMSC) raises the prospect of harvesting fetal cells in maternal blood. Despite high sensitivity in model systems, negative selection and culture strategies yield fMSC only rarely in post-termination maternal blood. The different adhesion molecule profile of fMSC to competitor maternal cell types suggests that improved positive selection strategies may facilitate non-invasive prenatal diagnosis. We aimed to identify surface antigens specific to fMSC and not maternal peripheral blood lymphocytes (PBL), using genome-wide analysis of actively expressed transcripts. Maternal PBL and fMSC cultured from first-trimester blood, liver and bone marrow were assessed for global gene expression by Affymetrix U133Plus2.0 arrays. Data were analysed using Affymetrix GCOS01.2. Transcripts present in all fMSC (n = 9) but absent in all PBL s les (n = 3) were selected for further analysis of cell-surface membrane molecules by RT-PCR and immunocytochemistry. Of 1544 genes expressed in fMSC and not maternal PBL, filtering for cell-surface molecules yielded 159 genes. Of these, 29 had a mean expression ratio of >300 (P < 0.001), which represented 18 unique genes, and their positive expression in all fMSC s les was confirmed by RT-PCR. Candidates for non-invasive prenatal diagnosis were chosen for further analysis by immunocytochemistry. Surface expression of OSMR and COL1 proteins on all fMSC, but no maternal PBL was confirmed. Identification of novel surface antigens on circulating human fMSC and not maternal PBL facilitates positive selection strategies for isolating fMSC for non-invasive prenatal diagnosis.
Vasculogenic and Osteogenesis-Enhancing Potential of Human Umbilical Cord Blood Endothelial Colony-Forming Cells
Publisher: Oxford University Press (OUP)
Date: 20-08-2012
DOI: 10.1002/STEM.1164
Abstract: Umbilical cord blood-derived endothelial colony-forming cells (UCB-ECFC) show utility in neovascularization, but their contribution to osteogenesis has not been defined. Cocultures of UCB-ECFC with human fetal-mesenchymal stem cells (hfMSC) resulted in earlier induction of alkaline phosphatase (ALP) (Day 7 vs. 10) and increased mineralization (1.9× p & .001) compared to hfMSC monocultures. This effect was mediated through soluble factors in ECFC-conditioned media, leading to 1.8–2.2× higher ALP levels and a 1.4–1.5× increase in calcium deposition (p & .01) in a dose-dependent manner. Transcriptomic and protein array studies demonstrated high basal levels of osteogenic (BMPs and TGF-βs) and angiogenic (VEGF and angiopoietins) regulators. Comparison of defined UCB and adult peripheral blood ECFC showed higher osteogenic and angiogenic gene expression in UCB-ECFC. Subcutaneous implantation of UCB-ECFC with hfMSC in immunodeficient mice resulted in the formation of chimeric human vessels, with a 2.2-fold increase in host neovascularization compared to hfMSC-only implants (p = .001). We conclude that this study shows that UCB-ECFC have potential in therapeutic angiogenesis and osteogenic applications in conjunction with MSC. We speculate that UCB-ECFC play an important role in skeletal and vascular development during perinatal development but less so in later life when expression of key osteogenesis and angiogenesis genes in ECFC is lower.
A biomarker‐based mathematical model to predict bone‐forming potency of human synovial and periosteal mesenchymal stem cells
Publisher: Wiley
Date: 28-12-2007
DOI: 10.1002/ART.23143
Abstract: To develop a biomarker-based model to predict osteogenic potency of human mesenchymal stem cells (MSCs) from synovial membrane and periosteum. MSC populations were derived from adult synovium and periosteum. Phenotype analysis was performed by fluorescence-activated cell sorting and real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Telomere lengths were determined by Southern blot analysis. In vitro osteogenesis was assessed quantitatively by measurements of alkaline phosphatase activity and calcium deposits. To investigate bone formation in vivo, MSCs were seeded onto osteoinductive scaffolds and implanted subcutaneously in nude mice. Bone was assessed by histology, and the human origin investigated by in situ hybridization for human Alu genomic repeats. Quantitation was achieved by histomorphometry and real-time RT-PCR for human osteocalcin. Analysis at the single-cell level was performed with clonal populations obtained by limiting dilution. Multiple regressions were used to explore the incremental predictive value of the markers. Periosteal MSCs had significantly greater osteogenic potency than did synovial MSCs inherent to the single cell. Bone was largely of human origin in vivo. Within the same tissue type, there was variability between different donors. To identify predictors of osteogenic potency, we measured the expression levels of osteoblast lineage genes in synovial and periosteal clonal MSCs prior to osteogenic treatment. We identified biomarkers that correlated with osteogenic outcome and developed a mathematical model based on type I collagen and osteoprotegerin expression that predicts the bone-forming potency of MSC preparations, independent of donor-related variables and tissue source. Our findings indicate that our quality-control mathematical model estimates the bone-forming potency of MSC preparations for bone repair.
Microchimeric fetal cells contribute to tissue repair after pregnancy
Publisher: Elsevier BV
Date: 12-2006
Folic Acid Supplementation and Spontaneous Preterm Birth: Adding Grist to the Mill?
Publisher: Public Library of Science (PLoS)
Date: 12-05-2009
Twin-Twin Transfusion Syndrome
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-04-2003
DOI: 10.1161/01.CIR.0000060543.64250.80
Abstract: Background— In twin-twin transfusion syndrome (TTTS), the donor and recipient fetus are exposed to differing volume loads and show discordant intertwin vascular compliance in childhood despite identical genotype. We hypothesized that discordance is prevented by intrauterine endoscopic laser ablation of placental anastomoses, which abolishes intertwin transfusion. We tested this by examining pulse wave velocity (PWV) in brachial arteries of twin survivors of TTTS treated with and without laser therapy. Methods and Results— One hundred children (50 twin pairs, 27 with TTTS) were studied. Group 1 comprised 14 monochorionic (MC) twin pairs with TTTS treated symptomatically group 2 comprised 13 MC twin pairs with TTTS treated by laser. The control groups comprised 12 MC twin pairs without TTTS (group 3) and 11 dichorionic twin pairs (group 4). Fetal cardiovascular data, predictive factors for, and duration of TTTS and cord blood were collected prospectively. We measured blood pressure and PWV photoplethysmographically at a median corrected postnatal age of 11 months (range, 1 week to 66 months). Both TTTS groups showed marked intertwin PWV discordance, unlike MCDA control subjects. The PWV discordance seen in laser treated twin pairs resembled that of dichorionic control subjects (heavier in idual with higher PWV), whereas group 1 showed the opposite (negative) intertwin discordance (ANOVA F (1,45)=4.5, P =0.04). No significant differences in blood pressure or intrauterine growth were observed between TTTS groups. Conclusions— Vascular programming is evident in monozygotic twins with intertwin transfusion and is altered but not abolished by intrauterine therapy to resemble that seen in dichorionic twins.
Abnormalities in the myeloid progenitor compartment in Down syndrome fetal liver precede acquisition of GATA1 mutations
Publisher: American Society of Hematology
Date: 12-2008
DOI: 10.1182/BLOOD-2008-04-152967
Abstract: Down syndrome (DS) children have a high frequency of acute megakaryoblastic leukemia (AMKL) in early childhood. At least 2 in utero genetic events are required, although not sufficient, for DS-AMKL: trisomy 21 (T21) and N-terminal–truncating GATA1 mutations. To investigate the role of T21 in DS-AMKL, we compared second trimester hemopoiesis in DS without GATA1 mutations to gestation-matched normal controls. In all DS fetal livers (FLs), but not marrows, megakaryocyte-erythroid progenitor frequency was increased (55.9% ± 4% vs 17.1% ± 3%, CD34+CD38+ cells P .001) with common myeloid progenitors (19.6% ± 2% vs 44.0% ± 7%) and granulocyte-monocyte (GM) progenitors (15.8% ± 4% vs 34.5% ± 9%) commensurately reduced. Clonogenicity of DS-FL versus normal FL CD34+ cells was markedly increased (78% ± 7% vs 15% ± 3%) affecting megakaryocyte-erythroid (∼ 7-fold higher) and GM and colony-forming unit–granulocyte, erythrocyte macrophage, megakaryocyte (CFU-GEMM) progenitors. Replating efficiency of CFU-GEMM was also markedly increased. These data indicate that T21 itself profoundly disturbs FL hemopoiesis and they provide a testable hypothesis to explain the increased susceptibility to GATA1 mutations in DS-AMKL and DS-associated transient myeloproliferative disorder.
Relative and absolute addressability of global disease burden in maternal and perinatal health by investment in R&D
Publisher: Wiley
Date: 07-04-2011
DOI: 10.1111/J.1365-3156.2011.02778.X
Abstract: Maternal and perinatal disease accounts for nearly 10% of the global burden of disease, with only modest progress towards achievement of the Millennium Development Goals. Despite a favourable new global health landscape in research and development (R&D) to produce new drugs for neglected diseases, R&D investment in maternal erinatal health remains small and non-strategic. Investment in obstetric R&D by industry or the not-for-profit sector has lagged behind other specialties, with the number of registered pipeline drugs only 1-5% that for other major disease areas. Using a Delphi exercise with maternal erinatal experts in global and translational research, we estimate that equitable pharmaceutical R&D and public sector research funding over the next 10-20 years could avert 1.1% and 1.9% of the global disease burden, respectively. In contrast, optimal uptake of existing research would prevent 3.0%, justifying the current focus on health service provision. Although R&D predominantly occurs in high-income countries, more than 98% of the estimated reduction in disease burden in this field would be in developing countries. We conclude that better pharmaceutical and public sector R&D would prevent around 1/3 and 2/3, respectively, of the disease burden addressable by optimal uptake of existing research. Strengthening R&D may be an important complementary strategy to health service provision to address global maternal and perinatal disease burden.
Biphasic recruitment of microchimeric fetal mesenchymal cells in fibrosis following acute kidney injury
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1038/KI.2013.459
Abstract: Fetal microchimeric cells (FMCs) enter the maternal circulation and persist in tissue for decades. They have capacity to home to injured maternal tissue and differentiate along that tissue's lineage. This raises the question of the origin(s) of cells transferred to the mother during pregnancy. FMCs with a mesenchymal phenotype have been documented in several studies, which makes mesenchymal stem cells an attractive explanation for their broad plasticity. Here we assessed the recruitment and mesenchymal lineage contribution of FMCs in response to acute kidney fibrosis induced by aristolochic acid injection. Serial in vivo bioluminescence imaging revealed a biphasic recruitment of active collagen-producing FMCs during the repair process of injured kidney in post-partum wild-type mothers that had delivered transgenic pups expressing luciferase under the collagen type I-promoter. The presence of FMCs long-term post injury (day 60) was associated with profibrotic molecules (TGF-β/CTGF), serum urea levels, and collagen deposition. Immunostaining confirmed FMCs at short term (day 15) using post-partum wild-type mothers that had delivered green fluorescent protein-positive pups and suggested a mainly hematopoietic phenotype. We conclude that there is biphasic recruitment to, and activity of, FMCs at the injury site. Moreover, we identified five types of FMC, implicating them all in the reparative process at different stages of induced renal interstitial fibrosis.
Fetal plasma testosterone correlates positively with cortisol
Publisher: BMJ
Date: 03-2005
Ontological Differences in First Compared to Third Trimester Human Fetal Placental Chorionic Stem Cells
Publisher: Public Library of Science (PLoS)
Date: 04-09-2012
Histomorphometric Characterisation of Shared and Non-shared Cotyledonary Villus Territories of Monochorionic Placentae in Relation to Pregnancy Complications
Publisher: Elsevier BV
Date: 04-2006
DOI: 10.1016/J.PLACENTA.2005.02.020
Abstract: Theoretical estimates and physiological inferences suggest that the structure of a shared cotyledon differs from a non-shared cotyledon. The aim of this study was to characterise the histomorphometry of terminal villi in shared and non-shared cotyledons in monochorionic placentae, both from uncomplicated twins and from those with twin-twin transfusion syndrome (TTTS) or discordant growth restriction (DeltaIUGR). Forty-one monochorionic placentae from Caucasian non-smokers were obtained at caesarean section. Their vascular anatomy and placental territories were ascertained by dye injection. After fixation, full thickness histological blocks were obtained by systematic random s ling from each twin's territory and the shared cotyledons. Fifty randomly selected terminal villi were assessed for: (i) median villus diameter (ii) median villus capillary diameter (iii) median fetomaternal diffusion distance (iv) median no. of capillaries/villus (v) degree of vascularization (median percentage cross-sectional area of terminal villi occupied by capillaries) using a stage micrometer and image analysis programme. The histomorphometric findings were then correlated with birthweight discordance, placental territory discordance and DeltaAVAs (no. of AVAs from smaller twin (donor) to larger twin (recipient) minus no. of AVAs from larger to smaller twin). Histomorphometric variables were similar in shared and non-shared cotyledons of uncomplicated MCDA twins. However, the median diameter of terminal villi in shared cotyledons in DeltaIUGR and TTTS placentae was significantly smaller [51.2 microm (48.2-58.3), p<0.001 and 52.6 microm (53.1-50.4), p<0.001], and had a similar number of smaller capillaries, larger fetomaternal diffusion distance and reduced vascularization compared to non-shared IUGR and TTTS placentae. However, Deltadiameter (defined as the difference between median diameters of terminal villi in large minus small twins' territories) rose with increasing birthweight discordance (Pearson correlation coefficient=0.82, p<0.001). Multiple linear regression analysis revealed that Deltadiameter was influenced by placental territory discordance (p<0.001) and birthweight discordance (p<0.01): log10 Deltadiameter=1.38+(0.01 x birthweight discordance)+(0.56 x log10 placental territory discordance) (R2=0.82, p<0.001), but there was no significant relationship with DeltaAVA and AAA. In the TTTS group, Deltadiameter correlated significantly with DeltaAVA only: log10Deltadiameter=1.44+(0.02 x DeltaAVA) (R2=0.3, p<0.001). This is the first study to characterise the histomorphometry of shared and non-shared cotyledons in MC twins. The findings suggest that abnormal placentation, rather than placental vascular anatomy may be responsible for DeltaIUGR in MC twins, whereas TTTS arises from imbalance in interfetal transfusion with resultant differing terminal villus histomorphometric features in donor, recipient and shared cotyledons.
High frequency of fetal cells within a primitive stem cell population in maternal blood
Publisher: Oxford University Press (OUP)
Date: 31-01-2008
Abstract: During pregnancy, fetal cells enter the maternal bloodstream resulting in fetal cell microchimerism. The fetal cells persist in the mother for decades and colonize a variety of maternal organs. They are associated with maternal autoimmune diseases and may also participate in tissue repair. The identity of the microchimeric cells is not certain but they must be able to persist long-term and have potential for multitissue differentiation. Here we tested the hypothesis that the fetal microchimeric cells are primitive stem cells, represented by CD34+ adherent cells, which have a wide potential for differentiation. We isolated these stem cells from the blood of pregnant females (n = 25) and detected fetal cells of the correct gender, using fluorescence in situ hybridization, in a high proportion (71% male fetuses and 90% female fetuses false positive rate 11%, false negative rate 29%) of cases. By RT-PCR, we demonstrated that the cells express Oct-4, Nanog and Rex-1. No fetal cells were detected in the mononuclear or total CD34+ cell populations but high frequencies (mean 11.8%) of fetal cells were detected in the adherent CD34+ cell population. These results identify adherent CD34+ stem cells as candidate fetal microchimeric cells, which are capable of sustaining the fetal cell population in the long term and have the ability to colonize multiple tissues and organs.
High perinatal survival in monoamniotic twins managed by prophylactic sulindac, intensive ultrasound surveillance, and Cesarean delivery at 32 weeks' gestation
Publisher: Wiley
Date: 26-09-2006
DOI: 10.1002/UOG.3811
Abstract: Increased perinatal mortality in monoamniotic twin pregnancies is attributed to cord accidents in utero and at delivery. We evaluated the following parameters in monoamniotic pregnancies: (1) the incidence of cord entanglement (2) the effect of sulindac on amniotic fluid volume and stability of fetal lie and (3) the perinatal outcome with our current management paradigm. This is a retrospective review of monoamniotic pregnancies of >or=20 weeks' gestation managed with serial ultrasound surveillance, medical amnioreduction and elective Cesarean delivery at 32 weeks' gestation. Mean amniotic fluid index (AFI) and change in AFI in monoamniotic pregnancies managed with oral sulindac was compared with 40 gestation-matched monochorionic-diamniotic controls. Among 44 monoamniotic pregnancies, 20 with two live structurally normal twins at 20 weeks' gestation satisfied the inclusion criteria. All fetuses survived to 28 days postnatally despite early prenatal cord entanglement in all but one case. Whereas AFI remained stable throughout gestation in the controls, the AFI fell in those patients on sulindac from a mean value of 21.0 cm (95% CI, 18.5-23.6 cm) at 20 weeks to a mean of 12.4 cm (95% CI, 10.1-14.6 cm) at 32 weeks (ANOVA P across gestation = 0.001) but mainly remained within normal limits. Fetal lie was stabilized in 11/20 cases in the monoamniotic group compared with 13/40 in the control group (P < 0.0001). Cord entanglement appears unpreventable, as it typically occurs in early pregnancy. Sulindac therapy reduces AFI, leads to more stable fetal lie, and may prevent intrauterine death by diminishing the risk of constricting cords that are already entangled. Perinatal survival in monoamniotic pregnancies managed by a regime of sulindac from 20 weeks' gestation, close ultrasound surveillance and elective abdominal delivery at 32 weeks' gestation seems empirically higher than that in the literature.
Perinatal morbidity and mortality rates in severe twin-twin transfusion syndrome: Results of the International Amnioreduction Registry
Publisher: Elsevier BV
Date: 09-2001
Abstract: Serial aggressive amnioreduction is the most widely used therapy for pregnancies that are complicated by twin-twin transfusion syndrome. Survival rates reported with this therapy are 33% to 83%, the wide range attributable to the small number of patients in these case series. Similarly, data on morbidity in survivors are imprecise. We instituted the international twin-twin transfusion syndrome registry to determine the perinatal survival and morbidity rates and the factors that influence perinatal outcome in patients with twin-twin transfusion syndrome who were treated with serial aggressive amnioreduction from 1990 to 1998. A total of 223 sets of twins who were diagnosed with twin-twin transfusion syndrome before 28 weeks' gestation from 20 fetal medicine referral centers were analyzed, with follow-up data until 4 weeks after birth. Three hundred forty-six twins (78% 182 recipients and 164 donors) were born alive. Two hundred sixty-six twins (60% 144 recipients and 122 donors) were alive 4 weeks after birth. Both fetuses survived to 4 weeks in 108 pregnancies (48.4%), whereas, at least 1 fetus survived in 158 pregnancies (70.8%). The interval between the last amnioreduction and delivery ranged from zero to 138 days (median, 17.5 days). In the infants who survived to 4 weeks after birth, abnormalities on neonatal cranial scan were diagnosed in 24% of recipients and in 25% of donors. Logistic regression analysis indicated that the survival rate was significantly related to gestational age at diagnosis, presence of end-diastolic blood flow in the umbilical artery velocity waveforms, presence of hydrops, mean volume of amniotic fluid removed per week, larger birth weight, and gestational age at delivery. The hemoglobin level difference at birth was the only significant parameter to predict abnormal cranial ultrasonography in newborns. These data document perinatal survival and neonatal morbidity rates in severe twin-twin transfusion syndrome that were treated by serial aggressive amnioreduction. Outcome was influenced by several perinatal risk factors, which may be used to counsel patients before and during therapy.
Systemic delivery of scAAV9 in fetal macaques facilitates neuronal transduction of the central and peripheral nervous systems
Publisher: Springer Science and Business Media LLC
Date: 26-01-2012
DOI: 10.1038/GT.2011.216
Abstract: Correction of perinatally lethal neurogenetic diseases requires efficient transduction of several cell types within the relatively inaccessible CNS. Intravenous AAV9 delivery in mouse has achieved development stage-specific transduction of neuronal cell types, with superior neuron-targeting efficiency demonstrated in prenatal compared with postnatal recipients. Because of the clinical relevance of the non-human primate (NHP) model, we investigated the ability of AAV9 to transduce the NHP CNS following intrauterine gene therapy (IUGT). We injected two macaque fetuses at 0.9 G with 1 × 10(13) vg scAAV9-CMV-eGFP through the intrahepatic continuation of the umbilical vein. Robust green fluorescent protein (GFP) expression was observed for up to 14 weeks in the majority of neurons (including nestin-positive cells), motor neurons and oligodendrocytes throughout the CNS, with a significantly lower rate of transduction in astrocytes. Photoreceptors and neuronal cell bodies in the plexiform and ganglionic retinal layers were also transduced. In the peripheral nervous system (PNS), widespread transduction of neurons was observed. Tissues harvested at 14 weeks showed substantially lower vector copy number and GFP levels, although the percentage of GFP-expressing cells remained stable. Thus, AAV9-IUGT in late gestation efficiently transduces both the CNS and PNS with neuronal predilection, of translational relevance to hereditary disorders characterized by perinatal onset of neuropathology.
Amniotic fluid testosterone: relationship with cortisol and gestational age
Publisher: Wiley
Date: 11-06-2007
DOI: 10.1111/J.1365-2265.2007.02955.X
Abstract: Foetal exposure to testosterone is increasingly implicated in the programming of future reproductive and non-reproductive behaviour. Some outcomes associated with prenatal exposure to testosterone may be predicted from exposure to prenatal stress, suggesting a link between them. The peak serum levels of testosterone in the foetus are thought to be around 14-18 weeks' gestation, and we explored testosterone levels at different gestations. Although best investigated in foetal plasma, this is now difficult because of the decline in frequency of foetal blood s ling in this study, we used amniotic fluid as a biomarker to investigate foetal exposure. To investigate the relationship between amniotic fluid testosterone, amniotic fluid cortisol, foetal gender, and gestational age. Paired amniotic fluid and maternal plasma s les were collected from 264 pregnant women undergoing amniocentesis between 15 and 37 weeks' gestation (median 17 weeks [119 days]). Total testosterone and cortisol in amniotic fluid, and total plasma testosterone (maternal) were measured by radioimmunoassay. Amniotic fluid testosterone levels were higher in male than in female foetuses, with a median (interquartile range) of 0.85 nmol/l (0.60-1.17 nmol/l) and 0.28 nmol/l (0.175-0.45 nmol/l), respectively. No relationship between amniotic fluid testosterone and gestational age was detected in either sex. Amniotic fluid testosterone correlated positively with amniotic fluid cortisol in both sexes (r = 0.30 male foetuses, r = 0.33 female foetuses, P < 0.001 for both), and remained significant in multivariate analysis. Testosterone in amniotic fluid did not change with gestation in the second and third trimester, raising questions about the timing of the reported early peak in the male foetus. The positive correlation between cortisol and testosterone in amniotic fluid suggests that increased foetal exposure to cortisol may also be associated with increased exposure to testosterone.
Intrauterine Bone Marrow Transplantation in Osteogenesis Imperfecta Mice Yields Donor Osteoclasts and Osteomacs but Not Osteoblasts
Publisher: Elsevier BV
Date: 11-2015
An experimental and theoretical study of 4f hybridization across the La1-xCexIn3 series
Publisher: American Chemical Society (ACS)
Date: 06-03-2008
DOI: 10.1021/IC701930J
Abstract: Crystal structures of a series of La(1-x)Ce(x)In(3) (x = 0.02, 0.2, 0.5, or 0.8) intermetallic compounds have been investigated by both neutron and X-ray diffraction, and their physical properties have been characterized by magnetic susceptibility and specific heat measurements. Our results emphasize atypical atomic displacement parameters (ADP) for the In and the rare-earth sites. Depending on the x value, the In ADP presents either an "ellipsoidal" elongation (La-rich compounds) or a "butterfly-like" distortion (Ce-rich compounds). These deformations have been understood by theoretical techniques based on the band theory and are the result of hybridization between conduction electrons and 4f-electrons.
High Incidence of Contaminating Maternal Cell Overgrowth in Human Placental Mesenchymal Stem/Stromal Cell Cultures: A Systematic Review
Publisher: Oxford University Press (OUP)
Date: 25-08-2014
Abstract: Placenta is a readily accessible translationally advantageous source of mesenchymal stem/stromal cells (MSCs) currently used in cryobanking and clinical trials. MSCs cultured from human chorion have been widely assumed to be fetal in origin, despite evidence that placental MSCs may be contaminated with maternal cells, resulting in entirely maternally derived MSC cultures. To document the frequency and determinants of maternal cell contamination in chorionic MSCs, we undertook a PRISMA-compliant systematic review of publications in the PubMed, Medline, and Embase databases (January 2000 to July 2013) on placental and/or chorionic MSCs from uncomplicated pregnancies. Of 147 studies, only 26 (18%) investigated fetal and/or maternal cell origin. After excluding studies that did not satisfy minimal MSC criteria, 7 of 15 informative studies documented MSC cultures as entirely fetal, a further 7 studies reported cultured human chorionic MSC populations to be either maternal (n = 6) or mixed (n = 1), whereas 1 study separately cultured pure fetal and pure maternal MSC from the same placenta. Maternal cell contamination was associated with term and chorionic membrane s les and greater passage number but was still present in 30% of studies of chorionic villous MSCs. Although most studies assume fetal origin for MSCs sourced from chorion, this systematic review documents a high incidence of maternal-origin MSC populations in placental MSC cultures. Given that fetal MSCs have more primitive properties than adult MSCs, our findings have implications for clinical trials in which knowledge of donor and tissue source is pivotal. We recommend sensitive methods to quantitate the source and purity of placental MSCs.
A unique 19F MRI agent for the tracking of non phagocytic cells in vivo
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C8NR00703A
Abstract: We describe the synthesis and characterization of a novel PFPE-based partially fluorinated copolymer for in vivo tracking of MSCs.
Transplantation of human fetal mesenchymal stem cells improves glomerulopathy in a collagen type Iα2‐deficient mouse
Publisher: Wiley
Date: 12-02-2008
DOI: 10.1002/PATH.2325
Abstract: Fetal mesenchymal stem cell (fetal MSC) therapy has potential to treat genetic diseases with early onset, including those affecting the kidney and urinary tract. A collagen type I alpha 2-deficient mouse has a deletion in the alpha2 chain of the procollagen type I gene, resulting in the synthesis of abnormal alpha1(I)(3) homotrimers, which replace normal alpha 1(I)2 alpha 2(I)1 heterotrimers and a glomerulopathy. We first confirmed that col1 alpha 2-deficient homozygous mice show abnormal collagen deposition in the glomeruli, which increases in frequency and severity with postnatal age. Intrauterine transplantation of human MSCs from first trimester fetal blood led postnatally to a reduction of abnormal homotrimeric collagen type I deposition in the glomeruli of 4-12 week-old col1 alpha 2-deficient mice. Using bioluminescence imaging, in situ hybridization and immunohistochemistry in transplanted col1 alpha 2-deficient mice, we showed that the damaged kidneys preferentially recruited donor cells in glomeruli, around mesangial cells. Real-time RT-PCR demonstrated that this effect was seen at an engraftment level of 1% of total cells in the kidney, albeit higher in glomeruli. We conclude that intrauterine transplantation of human fetal MSCs improves renal glomerulopathy in a collagen type I-deficient mouse model. These data support the feasibility of prenatal treatment for hereditary renal diseases.
Can Routine Commercial Cord Blood Banking Be Scientifically and Ethically Justified?
Publisher: Public Library of Science (PLoS)
Date: 22-02-2005
A Molecular Classification of Human Mesenchymal Stromal Cells
Publisher: Cold Spring Harbor Laboratory
Date: 11-08-2015
DOI: 10.1101/024414
Abstract: Mesenchymal stromal cells (MSC) are widely used, isolated from a variety of tissues and increasingly adopted for cell therapy, but the identity of these cells is poorly defined and commonalities between MSC from different tissues sources is controversial. Here we undertook a comprehensive review of all public MSC expression studies to assess whether cells derived from different sources shared any common molecular attributes. In doing so, we discovered an over-arching transcriptional phenotype shared by a wide variety of MSC, freshly isolated or cultured cells, and under a variety of growth conditions. We developed a modified variable selection protocol that included cross platform normalisation, and assessment of the selected gene stability and informativeness. A 16-gene signature classified MSC with % accuracy, discriminating these from fibroblasts, other adult stem rogenitor cell types and differentiated cells. The genes form part of a protein-interaction network, and mutations in more than 65% of this network were associated with Mendelian disorders of skeletal growth or metabolism. The signature and accompanying datasets are provided as a community resource at www.stemformatics.org resource, and the method is available from the CRAN repository.
Fetal stem cells
Publisher: Elsevier BV
Date: 12-2004
DOI: 10.1016/J.BPOBGYN.2004.06.010
Abstract: Fetal stem cells can be isolated from fetal blood and bone marrow as well as from other fetal tissues, including liver and kidney. Fetal blood is a rich source of haemopoietic stem cells (HSC), which proliferate more rapidly than those in cord blood or adult bone marrow. First trimester fetal blood also contains a population of non-haemopoietic mesenchymal stem cells (MSC), which support haemopoiesis and can differentiate along multiple lineages. In terms of eventual downstream application, both fetal HSC and MSC have advantages over their adult counterparts, including better intrinsic homing and engraftment, greater multipotentiality and lower immunogenicity. Fetal stem cells are less ethically contentious than embryonic stem cells and their differentiation potential appears greater than adult stem cells. Fetal stem cells represent powerful tools for exploring many aspects of cell biology and hold considerable promise as therapeutic tools for cell transplantation and ex vivo gene therapy.
Serial aggressive platelet transfusion for fetal alloimmune thrombocytopenia: Platelet dynamics and perinatal outcome
Publisher: Elsevier BV
Date: 04-2002
Abstract: Our purpose was to describe the fetal loss rate and platelet dynamics in fetal alloimmune thrombocytopenia managed by serial platelet transfusions. Retrospective analysis over 10 years of consecutive pregnancies affected by fetal alloimmune thrombocytopenia requiring in utero platelet transfusions. There were 2 perinatal losses in 12 pregnancies managed by 84 platelet transfusions. One was obviously procedure related from exsanguination despite platelet transfusion. The attributable procedure related fetal loss rate was 1.2% per procedure but 8.3% per pregnancy. The median rate of fall in fetal platelet count per day after transfusion was lower at the placental cord insertion (n = 54) 40.5 x 10(9)/L (range, 5.4-96.1 x 10(9)/L) compared with that at the intrahepatic vein (n = 30) 50.9 x 10(9)/L,(range, 29.5-91 x 10(9)/L) (P = .0009). Pooling our results with those previously published yields a cumulative risk of serial weekly transfusions of approximately 6% per pregnancy, indicating the need for development of less invasive approaches.
The case for tocolysis in threatened preterm labour
Publisher: Wiley
Date: 04-2003
Widespread Distribution and Muscle Differentiation of Human Fetal Mesenchymal Stem Cells After Intrauterine Transplantation in Dystrophic mdx Mouse
Publisher: Oxford University Press (OUP)
Date: 21-12-2006
DOI: 10.1634/STEMCELLS.2006-0694
Abstract: Duchenne muscular dystrophy (DMD) is a common X-linked disease resulting from the absence of dystrophin in muscle. Affected boys suffer from incurable progressive muscle weakness, leading to premature death. Stem cell transplantation may be curative, but is h ered by the need for systemic delivery and immune rejection. To address these barriers to stem cell therapy in DMD, we investigated a fetal-to-fetal transplantation strategy. We investigated intramuscular, intravascular, and intraperitoneal delivery of human fetal mesenchymal stem cells (hfMSCs) into embryonic day (E) 14–16 MF1 mice to determine the most appropriate route for systemic delivery. Intramuscular injections resulted in local engraftment, whereas both intraperitoneal and intravascular delivery led to systemic spread. However, intravascular delivery led to unexpected demise of transplanted mice. Transplantation of hfMSCs into E14–16 mdx mice resulted in widespread long-term engraftment (19 weeks) in multiple organs, with a predilection for muscle compared with nonmuscle tissues (0.71% vs. 0.15%, p & .01), and evidence of myogenic differentiation of hfMSCs in skeletal and myocardial muscle. This is the first report of intrauterine transplantation of ontologically relevant hfMSCs into fully immunocompetent dystrophic fetal mice, with systemic spread across endothelial barriers leading to widespread long-term engraftment in multiple organ compartments. Although the low-level of chimerism achieved is not curative for DMD, this approach may be useful in other severe mesenchymal or enzyme deficiency syndromes, where low-level protein expression may ameliorate disease pathology. Disclosure of potential conflicts of interest is found at the end of this article.
Cardiovascular and endocrine responses to cutaneous electrical stimulation after fentanyl in the ovine fetus
Publisher: Elsevier BV
Date: 03-2004
Market Failure and the Poverty of New Drugs in Maternal Health
Publisher: Public Library of Science (PLoS)
Date: 22-01-2008
Molecular Support for Heterogonesis Resulting in Sesquizygotic Twinning
Publisher: Massachusetts Medical Society
Date: 28-02-2019
The Effect of Polyhydramnios on Cervical Length in Twins: A Controlled Intervention Study in Complicated Monochorionic Pregnancies
Publisher: Public Library of Science (PLoS)
Date: 02-12-2008
Transmitted Arterio-arterial Anastomosis Waveforms Causing Cyclically Intermittent Absent/Reversed End-diastolic Umbilical Artery Flow in Monochorionic Twins
Publisher: Elsevier BV
Date: 08-2003
DOI: 10.1016/S0143-4004(03)00114-0
Abstract: To characterize the phenomenon of retrograde transmission of arterio-arterial anastomosis (AAA) interference patterns on umbilical artery (UA) waveform by (a) documenting the periodicity, (b) correlation with in vivo and in vitro demonstration of AAAs and (c) reproducing these patterns by computer modelling. Monochorionic twins (MC) twins underwent placental and umbilical Doppler studies. AAAs were sought by pulse wave Doppler of their bi-directional interference pattern and confirmed by postnatal injection studies. The periodicity of transmitted patterns in the UA was determined. Determinants of the transmitted patterns were ascertained by computer modelling of physiological and fetal variables. Among 83 prospectively studied MC twin pregnancies a transmitted pattern was observed in 6 (7 per cent) patients for 15-114 days. This was found in 20 per cent (6/30) of smaller MC twins discordant for growth restriction but in no appropriately grown twins. It was only observed in association with AAAs validated both in vivo and in ex vivo. Computer modelling demonstrated that this pattern could be reproduced by summating end diastolic flow with a high pulsatility index in the UA in the presence of a large AAA. Consistent with this, MC twins with a transmitted pattern had larger AAAs (median diameter 4.3 mm interquartile range 4.1-5.2) compared to MC twins discordant for intrauterine growth restriction (2.1 mm interquartile range 1.5 to 2.8) (P<0.05) without a transmitted pattern. Perinatal mortality was similar in the fetuses with and without transmitted patterns (0/12 vs. 2/48 P=0.7).
Stable Human FIX Expression After 0.9G Intrauterine Gene Transfer of Self-complementary Adeno-associated Viral Vector 5 and 8 in Macaques
Publisher: Elsevier BV
Date: 11-2011
DOI: 10.1038/MT.2011.107
Noninvasive fetal RHD genotyping by microfluidics digital PCR using maternal plasma from two alloimmunized women with the variant RHD(IVS3+1G>A) allele
Publisher: Wiley
Date: 19-09-2013
DOI: 10.1002/PD.4230
Mesenchymal stem/stromal cells enhance engraftment, vasculogenic and pro-angiogenic activities of endothelial colony forming cells in immunocompetent hosts
Publisher: Springer Science and Business Media LLC
Date: 19-10-2017
DOI: 10.1038/S41598-017-13971-3
Abstract: The clinical use of endothelial colony forming cells (ECFC) is h ered by their restricted engraftment. We aimed to assess engraftment, vasculogenic and pro-angiogenic activities of ECFC in immunocompetent (C57BL/6: WT) or immunodeficient ( rag1 −/− C57BL/6: Rag1) mice. In addition, the impact of host immune system was investigated where ECFC were co-implanted with mesenchymal stem/stromal cells (MSC) from adult bone marrow (AdBM-MSC), fetal bone marrow (fBM-MSC), fetal placental (fPL-MSC), or maternal placental (MPL-MSC). Transplantation of ECFCs in Matrigel plugs resulted in less cell engraftment in WT mice compared to Rag1 mice. Co-implantation with different MSCs resulted in a significant increase in cell engraftment up to 9 fold in WT mice reaching levels of engraftment observed when using ECFCs alone in Rag1 mice but well below levels of engraftment with MSC-ECFC combination in Rag1 recipients. Furthermore, MSCs did not reduce murine splenic T cell proliferation in response to ECFCs in vitro . ECFCs enhanced the murine neo-vascularization through paracrine effect, but with no difference between Rag1 and WT mice. In conclusions, the host adaptive immune system affects the engraftment of ECFCs. MSC co-implantation improves ECFC engraftment and function even in immunocompetent hosts mostly through non-immune mechanisms.
Valproic Acid Confers Functional Pluripotency to Human Amniotic Fluid Stem Cells in a Transgene-free Approach
Publisher: Elsevier BV
Date: 10-2012
DOI: 10.1038/MT.2012.117
High Risk of Unexpected Late Fetal Death in Monochorionic Twins Despite Intensive Ultrasound Surveillance: A Cohort Study
Publisher: Public Library of Science (PLoS)
Date: 28-06-2005
Expandability of haemopoietic progenitors in first trimester fetal and maternal blood: implications for non‐invasive prenatal diagnosis
Publisher: Wiley
Date: 06-2002
DOI: 10.1002/PD.350
Abstract: Selective lification of rare fetal cells in maternal blood is a potential strategy for non-invasive prenatal diagnosis. We assessed the proliferative potential of first trimester fetal progenitors compared to maternal ones. Fetal and maternal haemopoietic progenitors were cultured separately and in two model mixtures: (i) co-cultures of male fetal nucleated cells mixed with maternal nucleated cells and (ii) co-cultures of malefetal CD34+ cells with maternal CD34+ cells. Cell origin was detected by X-Y fluorescence in situ hybridisation (FISH) RESULTS: The frequency of haemopoietic progenitors in first trimester fetal blood (predominantly CFU-GEMM) differed from those in peripheral blood from pregnant women (predominantly BFU-e). First trimester haemopoietic progenitors formed larger colonies (p=0.0001) and their haemoglobinisation was accelerated compared to those of maternal origin (p<0.001). CD34+ fetal haemopoietic progenitor cells could be expanded four times more than their maternal counterparts (median 235.8-fold, range 174.0-968.0 vs 71.9-fold, range 41.1-192.0 p=0.003). While selective expansion of fetal cells was not observed in the mononuclear cell model, the CD34+ cell rare event mixtures produced a 463.2-fold (range 128.0-2915.0) expansion of fetal cells. Selective expansion of first trimester fetal haemopoietic progenitors may be useful for lifying fetal cells from maternal blood.
Management of other complications specific to monochorionic twin pregnancies
Publisher: Elsevier BV
Date: 08-2004
Osterix Induces Osteogenic Gene Expression but not Differentiation in Primary Human Fetal Mesenchymal Stem Cells
Publisher: Mary Ann Liebert Inc
Date: 07-2007
Abstract: The transcription factor osterix (Osx) is a key regulator of osteoblast differentiation and induces bone formation in embryonic but not adult stem cells. We investigated the effect of up-regulating Osx on an intermediate stem cell type, first trimester fetal mesenchymal stem cells (MSCs), which are more expandable than adult MSCs. Human fetal (hf ) MSCs were transduced with a lentiviral vector encoding human Osx. In undifferentiating MSCs cultures, forced expression of Osx stimulated osteopontin and alkaline phosphatase expression. However, Osx did not up-regulate osteocalcin, a late marker of osteoblast differentiation or result in extracellular calcium crystals, indicating that Osx does not directly mediate terminal differentiation in primary hfMSCs. To understand the downstream effects of Osx expression in primary hfMSCs, we next investigated the regulatory relationship between Osx, and the transcription factors Dlx5, Runx2, and Msx2. Osx induced Dlx5 but did not affect Runx2 and Msx2, whereas stealth ribonucleic acid interference of Osx inhibited Dlx5 without affecting expression of Runx2 and Msx2. In conclusion, Osx regulates osteogenic gene expression in hfMSCs but is insufficient to induce terminal osteogenic differentiation.
Pragmatic comparison of β2-agonist side effects within the Worldwide Atosiban versus Beta Agonists Study
Publisher: Elsevier BV
Date: 09-2006
DOI: 10.1016/J.EJOGRB.2006.01.030
Abstract: While beta2-agonists for the acute treatment of preterm labour unequivocally reduce the odds of delivery within 48 h and 7 days, they have been associated with substantial maternal and fetal side effects. We aimed to compare side effect profiles of beta2-agonist tocolytics. Pragmatic comparison of ritodrine, salbutamol and terbutaline from re-analysis of data obtained within three comparator arms of three simultaneous comparable randomised controlled trials of beta2-agonists against atosiban in 742 women in preterm labour. The prevalence of categoric side effects between treatment groups was analysed using a chi2 test. The differences in continuous variables between treatment groups were analysed in analyses of covariance. The prevalence of categoric side effects was similar with the three drugs, with the exception of the subjective symptom of palpitations (ritodrine 24.0%, terbutaline 9.3% and salbutamol 12.3%, P=0.003). There were also some differences in maternal diastolic blood pressure (P<0.001) and serum glucose levels (P<0.001), although these were small (<3 mmHg and < or =2.8 mmol/L, respectively) and clinically unimportant. Side effects were common with all three drugs. Thus, choosing one beta2-agonist over the other to minimise side effects has little rationale, especially now that safer tocolytics are available.
Accurate and Robust Quantification of Circulating Fetal and Total DNA in Maternal Plasma from 5 to 41 Weeks of Gestation
Publisher: Oxford University Press (OUP)
Date: 02-2005
DOI: 10.1373/CLINCHEM.2004.042713
Abstract: Background: Detection of fetal DNA in maternal plasma is achievable at 5 weeks of gestation, but few large-scale studies have reported circulating fetal and maternal DNA across all trimesters. Methods: Blood s les were collected from 201 women between 5 and 41 weeks of pregnancy. Quantitative PCR was used to assess total and fetal DNA concentrations, and allelic discrimination analysis was investigated as a route to detecting specifically fetal DNA. Results: Male fetuses were detectable from 5 weeks amenorrhea with increasing fetal DNA concentrations across gestation. The sensitivity of fetal male gender determination in pregnancies with live birth confirmation was 99%, with 100% specificity. Total DNA concentrations did not correlate with gestational age, but appeared slightly higher in the first and third trimesters than in mid-pregnancy. Analysis of short tandem repeats demonstrated that significant improvements in the detection limit are required for specific detection of fetal DNA. Conclusions: The high sensitivity of PCR-based detection, together with quantification provided by real-time DNA analysis, has clear potential for clinical application in noninvasive prenatal diagnosis. However, accurate quantification using best-fit data analysis, standardization of methods, and performance control indicators are necessary for robust routine noninvasive diagnostics.
Transfusional fetal complications after single intrauterine death in monochorionic multiple pregnancy are reduced but not prevented by vascular occlusion
Publisher: Wiley
Date: 23-04-2009
DOI: 10.1111/J.1471-0528.2009.02128.X
Abstract: To document co-twin death regnancy loss and brain injury after single intrauterine death (sIUD) in monochorionic pregnancies. A total of 135 pregnancies with sIUD were reviewed for co-twin IUD, miscarriage and abnormal antenatal and postnatal neuro-imaging. A tertiary referral fetal medicine unit from 2000 to 2007. All cases referred with a single fetal death in monochorionic pregnancy, including those where sIUD was spontaneous or occurred after fetoscopic laser treatment, or resulted from selective termination by cord occlusion with bipolar diathermy or intrafetal vascular ablation with interstitial laser. Clinical details and ultrasound findings of the study population were retrieved from ultrasound and institutional databases. Delivery and neonatal outcome data were obtained from discharge summaries supplemented by in idual chart review. Co-twin death or pregnancy loss and neurologic injury assessed on antenatal ultrasound and MR-imaging. A total of 81 sIUDs resulted from vascular occlusive feticide (diathermy or interstitial laser), 22 followed placental laser and 32 were spontaneous. In 22 pregnancies (16.8%), the co-twin died in utero and eight pregnancies miscarried (6.1%). Antenatal magnetic resonance (MR) imaging in 76/91 (83.5%) continuing pregnancies detected antenatal brain injury in five (6.6%). Three infants (two not scanned antenatally) had abnormalities detected postnatally. Brain abnormality was detected less often after procedure related (2.6%, 2/77) than spontaneous sIUD (22.2%, 6/27, P = 0.003) and after early compared with late gestation sIUD (3.6%, 4/111 versus 20.0%, 4/20 P = 0.02). We confirm substantial co-twin loss (22.9%) after monochorionic sIUD, but a low risk of antenatally acquired MRI-identified brain injury, suggesting this risk has been overestimated. Procedures restricting inter-twin transfusion reduce, but do not negate risk of brain injury.
Time domain computational modelling of 1D arterial networks in monochorionic placentas
Publisher: EDP Sciences
Date: 07-2003
DOI: 10.1051/M2AN:2003047
Increased Stillbirth in Uncomplicated Monochorionic Twin Pregnancies
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2013
Test amnioinfusion to determine suitability for serial therapeutic amnioinfusion in midtrimester premature rupture of membranes
Publisher: S. Karger AG
Date: 2003
DOI: 10.1159/000069375
Abstract: i Objective: /i To evaluate whether a test amnioinfusion procedure is useful in selecting cases of midtrimester preterm premature rupture of membranes (PPROM) which may benefit from serial amnioinfusions if the initial fluid is retained. i Study Design: /i The Centre for Fetal Care database between 1992 and 2000 was reviewed for women with PPROM weeks who had undergone amnioinfusion. Amniotic fluid index (AFI) was assessed before and after a test amnioinfusion procedure. Those who retained fluid ≧48 h underwent serial AFI assessment with a view to serial amnioinfusion when oligohydramnios recurred. i Results: /i Eighty-five amnioinfusion procedures were performed in 60 women with oligohydramnios. Nineteen of these women presented with confirmed PPROM at a median gestation of 19 (range 15–22) weeks and severe olighohydramnios (median AFI 1, range 0–3 cm), in whom 20 test amnioinfusions were carried out. Two amnioinfusions were abandoned during the procedure because of fetal bradycardia and both mothers opted for termination of pregnancy. Only 4 women retained fluid during the test amnioinfusion, 1 of whom miscarried at 19 weeks before serial amnioinfusion could be started. The remaining 3 underwent a median of 4 (range 1–6) serial amnioinfusion procedures none had evidence of pulmonary hypoplasia. Thirteen (68%) leaked fluid within 48 h within this group there was 1 subsequent miscarriage and 9 pregnancy terminations. The remaining 3 pregnancies resulted in livebirths 2 of which had pulmonary hypoplasia with 1 early neonatal death. Overall survival was poor (4/19), largely attributed to the high incidence of terminations in the presence of persistent severe oligohydramnios. In continuing pregnancies reaching viability survival was 67% (4 of 6). i Conclusion: /i Three quarters of women with mid-trimester PPROM lose fluid at test amnioinfusion and therefore would not be suitable candidates for serial amnioinfusion. However, if infused fluid is retained, this allows subsequent serial amnioinfusion and prolongation of pregnancy in about 75%, with an attendant decrease in the risk of pulmonary hypoplasia. However, even successful serial amnioinfusion remains associated with procedure-related complications (i.e. chorioamnionitis, placental abruption) which themselves may predispose to preterm delivery.
5′ isomiR variation is of functional and evolutionary importance
Publisher: Oxford University Press (OUP)
Date: 23-07-2014
DOI: 10.1093/NAR/GKU656
Small Molecule Mesengenic Induction of Human Induced Pluripotent Stem Cells to Generate Mesenchymal Stem/Stromal Cells
Publisher: Oxford University Press (OUP)
Date: 02-2012
Abstract: The translational potential of mesenchymal stem/stromal cells (MSCs) is limited by their rarity in somatic organs, heterogeneity, and need for harvest by invasive procedures. Induced pluripotent stem cells (iPSCs) could be an advantageous source of MSCs, but attempts to derive MSCs from pluripotent cells have required cumbersome or untranslatable techniques, such as coculture, physical manipulation, sorting, or viral transduction. We devised a single-step method to direct mesengenic differentiation of human embryonic stem cells (ESCs) and iPSCs using a small molecule inhibitor. First, epithelial-like monolayer cells were generated by culturing ESCs/iPSCs in serum-free medium containing the transforming growth factor-β pathway inhibitor SB431542. After 10 days, iPSCs showed upregulation of mesodermal genes (MSX2, NCAM, HOXA2) and downregulation of pluripotency genes (OCT4, LEFTY1/2). Differentiation was then completed by transferring cells into conventional MSC medium. The resultant development of MSC-like morphology was associated with increased expression of genes, reflecting epithelial-to-mesenchymal transition. Both ESC- and iPSC-derived MSCs exhibited a typical MSC immunophenotype, expressed high levels of vimentin and N-cadherin, and lacked expression of pluripotency markers at the protein level. Robust osteogenic and chondrogenic differentiation was induced in vitro in ES-MSCs and iPS-MSCs, whereas adipogenic differentiation was limited, as reported for primitive fetal MSCs and ES-MSCs derived by other methods. We conclude that treatment with SB431542 in two-dimensional cultures followed by culture-induced epithelial-to-mesenchymal transition leads to rapid and uniform MSC conversion of human pluripotent cells without the need for embryoid body formation or feeder cell coculture, providing a robust, clinically applicable, and efficient system for generating MSCs from human iPSCs.
The Basic and Clinical Science of Twin–Twin Transfusion Syndrome
Publisher: Elsevier BV
Date: 05-2009
DOI: 10.1016/J.PLACENTA.2009.02.005
Abstract: Twin-twin transfusion syndrome (TTTS) is a fascinating condition in which fetuses of identical genotype adopt discordant cardiovascular phenotypes, secondary to unbalanced placental inter-twin transfusion. Flow along the primary units of inter-twin transfusion, unidirectional arteriovenous anastomoses, can be as high as litres/day each, and TTTS develops when the placenta has insufficient compensatory counter-transfusional anastomoses. The initial phenotype reflects dysvolaemia, with added contributions from uteroplacental insufficiency in the donor, and raised afterload with diastolic dysfunction secondary to discordant endothelin and placentally derived renin-angiotensin system effectors in the recipient. Endoscopic laser ablation of placental anastomoses has become the primary treatment modality, supported by a randomised trial showing improved survival and short but not long-term neurological morbidity. Its uptake has facilitated comparative pre- and post-laser studies, which provide considerable insight into the pathophysiology. Despite the therapeutic advance, placental laser remains associated with a 25% incidence of fetal death within a week, and a 10% risk each of recurrence and twin anaemia olycythaemia sequence due to residual anastomoses. In Stage I, high rates of non-progression with more conservative management have resulted in therapeutic equipoise as to whether laser is indicated primarily or only for progressive disease. The challenge ahead lies in improving double intact survival rates, which in addition to randomised trials will require technical advances, better understanding of the circulatory pathophysiology and more sophisticated surveillance tools.
Stage I twin–twin transfusion syndrome: rates of progression and regression in relation to outcome
Publisher: Wiley
Date: 15-11-2007
DOI: 10.1002/UOG.5189
Abstract: Twin-twin transfusion syndrome (TTTS) results in high rates of perinatal mortality and neurological morbidity. Fetoscopic laser ablation of placental anastomoses is now established as the treatment of choice for advanced disease. However, there remains controversy about its use in early-stage TTTS, in which laser-related fetal losses need to be balanced against relatively favorable outcomes with more conservative approaches. We investigated rates of progression and regression in Stage I TTTS and determined factors influencing the course of the disease. We undertook a retrospective observational study of all TTTS cases referred to our tertiary referral fetal medicine service from 2000 to 2006. In patients presenting with Stage I TTTS, the following variables were evaluated for their ability to predict the course and progression of the disease: gestational age (GA) at presentation, amniotic fluid index, recipient and donor deepest vertical pool, presence of artery-artery anastomoses, small-sized bladder compared to normal donor bladder and fetal size discordance. Study end-points were disease regression or progression, and neonatal survival at 28 days. Among 132 consecutive cases of TTTS, 46 women presented with Stage I disease. In the majority (69.6%), disease remained stable (28.3%) or regressed (41.3%). Of cases that progressed, 79% did so within 2 weeks and 93% progressed to at least Stage III. No factor was significantly linked with progression or regression, although there was a trend towards the absence of an artery-artery anastomosis (P = 0.10) and the presence of a small rather than normal donor bladder (P = 0.10) influencing progression, and later GA at presentation (P = 0.07) influencing regression. At least one infant survived in 83% of cases and there was double survival in 59%. Perinatal outcome was significantly better in cases that regressed (the rates of at least one survivor and double survival being 89% and 89%, respectively) or remained Stage I (77% and 61%, respectively), compared with those cases that progressed (79% and 14%, respectively). Treatment with amnioreduction at first presentation did not influence progression or regression. This study demonstrates that a high percentage of Stage I TTTS cases regress or remain early stage. Identification of factors predicting progression would facilitate the selection of patients for definitive therapy, while avoiding treatment-related morbidities in mild or transient disease.
Transcriptional ontogeny of first trimester human fetal and placental mesenchymal stem cells: Gestational age versus niche
Publisher: Elsevier BV
Date: 12-2014
Inhibitory effect of erythropoietin on contractility of human chorionic plate vessels
Publisher: Elsevier BV
Date: 2006
DOI: 10.1016/J.AJOG.2005.05.037
Abstract: Placenta is a major source of erythropoietin production in the fetus hypoxia is associated with elevated erythropoietin levels in the fetal circulation. We investigated fetoplacental vascular reactivity after exposure to erythropoietin in vitro. Third-order chorionic plate arteries from human term placentae were incubated in culture medium with or without erythropoietin (3 U/mL) for 24 hours. Vessels were mounted in a myograph for isometric tension recording, and their responses to vasopressors and vasorelaxants were studied. Contractile responses to endothelin-1 and the thromboxane analogue U46619 were decreased in erythropoietin-exposed vessels compared with controls. Relaxant responses to the nitric oxide donor sodium nitroprusside and the phosphodiesterase inhibitor papaverine were not influenced by erythropoietin. Exposure to elevated levels of erythropoietin has an inhibitory effect on contractile responses in human placental chorionic plate arteries. We speculate that this may improve fetoplacental perfusion in hypoxic fetuses with elevated erythropoietin production.
139: A controlled intervention study of the relationship between cervical length and polyhydramnios in complicated monochorionic twin pregnancies
Publisher: Elsevier BV
Date: 12-2007
Stress responses at birth: determinants of cord arterial cortisol and links with cortisol response in infancy
Publisher: Wiley
Date: 17-05-2005
DOI: 10.1111/J.1471-0528.2005.00620.X
Abstract: To investigate (A) the determinants of infant stress response at delivery and (B) test the hypothesis that stress at birth, as reflected by cord arterial cortisol, influences cortisol response to vaccination at two months. Prospective observational study. Tertiary referral maternity hospital. One hundred and seventy-two primiparous women with uncomplicated singleton pregnancies. Women were recruited antenatally. At birth, cord arterial blood and obstetric data were collected. Saliva was collected from infants immediately before and after vaccination at two months. Cortisol was analysed from cord blood and saliva by radio-immunoassay. Stress response at birth, as demonstrated by cord arterial cortisol association with saliva cortisol response to vaccination at two months. Cord arterial cortisol varied with mode of delivery, combined spinal/epidural use and pH. Salivary cortisol response at two months correlated with cord arterial cortisol (r= 0.24, P < 0.05). Infants with the highest and lowest cord arterial cortisol had markedly different cortisol responses at two months (P= 0.017). These groups had different modes of delivery with caesarean rates of <8% in the high cortisol response group and 83% in the low cortisol response group (P < 0.0001). Babies born vaginally mount greater cortisol responses at birth than those delivered by caesarean section. Stress at delivery may influence the infant HPA axis response for up to two months.
Identification of fetal mesenchymal stem cells in maternal blood: implications for non-invasive prenatal diagnosis
Publisher: Oxford University Press (OUP)
Date: 08-2003
Abstract: Strategies for genetic prenatal diagnosis on fetal cells in the maternal circulation have been limited by lack of a cell type present only in fetal blood. However, the recent identification of mesenchymal stem cells (MSC) in first trimester fetal blood offers the prospect of targeting MSC for non-invasive prenatal diagnosis. We developed protocols for fetal MSC enrichment from maternal blood and determined sensitivity and specificity in mixing experiments of male fetal MSC added to female blood, in dilutions from 1 in 10(5) to 10(8). We then used the optimal protocol to isolate fetal MSC from maternal blood in the first trimester, using blood taken after surgical termination of pregnancy as a model of increased feto-maternal haemorrhage. In model mixtures, we could lify one male fetal MSC in 2.5 x 10(7) adult female nucleated cells, yielding a 100% pure population of fetal cells, but not one fetal MSC in 10(8) nucleated cells. Fetal MSC were identified in one of 20 post-termination maternal blood s les and confirmed as fetal MSC by XY fluorescence in-situ hybridization (FISH), immunophenotyping and osteogenic and adipogenic differentiation. We report the isolation of fetal MSC from maternal blood however, their rarity in post-termination blood suggests they are unlikely to have a role in non-invasive prenatal diagnosis. Failure to locate these cells routinely may be attributed to their low frequency in maternal blood, to sensitivity limitations of enrichment technology, and/or to their engraftment in maternal tissues soon after transplacental passage. We speculate that gender microchimerism in post-reproductive maternal tissues might result from feto-maternal trafficking of MSC in early pregnancy.
Derivation of rate of arterio-arterial anastomotic transfusion between monochorionic twin fetuses by Doppler waveform analysis
Publisher: Elsevier BV
Date: 08-2004
Non‐invasive intrapartum fetal ECG: preliminary report
Publisher: Wiley
Date: 07-06-2005
DOI: 10.1111/J.1471-0528.2005.00643.X
Abstract: To obtain fetal heart rate, detailed fetal electrocardiography (fECG) signals and uterine contractions during labour using a single device. Prospective observational study. Delivery suite at a tertiary referral hospital, London, UK. Fifteen patients at median gestation of 39 weeks (range 24-41) were recruited at median cervical dilatation of 4.0 cm (range 0-10) of whom 8/15 (53%) had intact amniotic membranes. Using 12 abdominally sited electrodes, we recorded the composite abdominal signal in pregnancies intrapartum. The recorded data were analysed off-line using a blind signal separation technique. Success of signal separation and fECG time intervals. Successful fECG signal acquisition was achieved in 12/15 (80%) patients and an averaged fECG waveform acquired. In these patients, P and QRS waves were seen in all cases, and T waves in 11/12 (92%). True beat-to-beat heart rate (HR) was displayed and measures of its variability obtained. The mother's ECG and uterine electrical activity, shown to match tocographically recorded uterine contractions, were also separated and displayed. Failure to acquire fECG in three cases was attributed to excessive abdominal muscular activity and electrical interference. This study demonstrates a non-invasive technique that displays detailed intrapartum fECG waveforms, HR variability, maternal ECG and uterine contractions simultaneously, all in a single device and which avoids the potential risks of invasive monitoring with a fetal scalp electrode.
Related Organisations
Royal College Of Obstetricians And Gynaecologists
Location: United Kingdom of Great Britain and Northern Ireland
Royal Australian And New Zealand College Of Obstetricians And Gynaecologists
Location: Australia
Aberdeen Royal Infirmary
Location: United Kingdom of Great Britain and Northern Ireland
Imperial College London
Location: United Kingdom of Great Britain and Northern Ireland
Hammersmith And Queen Charlotte's Special Health Authority
Location: United Kingdom of Great Britain and Northern Ireland
Educational Commission For Foreign Medical Graduates
Location: United States of America
University Of London
Location: United Kingdom of Great Britain and Northern Ireland
University Of Aberdeen
Location: United Kingdom of Great Britain and Northern Ireland
University College London, University Of London
Location: United Kingdom of Great Britain and Northern Ireland
Related Funding Activities
Discovery Projects - Grant ID: DP1095429
Start Date: 2010
End Date: 12-2012
Amount: $400,000.00
Funder: Australian Research Council
View Funded Activity