RESUMO
INTRODUCTION: Severe osteogenesis imperfecta (OI) is a debilitating disease with no cure or sufficiently effective treatment. Mesenchymal stem cells (MSCs) have good safety profile, show promising effects and can form bone. The Boost Brittle Bones Before Birth (BOOSTB4) trial evaluates administration of allogeneic expanded human first trimester fetal liver MSCs (BOOST cells) for OI type 3 or severe type 4. METHODS AND ANALYSIS: BOOSTB4 is an exploratory, open-label, multiple dose, phase I/II clinical trial evaluating safety and efficacy of postnatal (n=15) or prenatal and postnatal (n=3, originally n=15) administration of BOOST cells for the treatment of severe OI compared with a combination of historical (1-5/subject) and untreated prospective controls (≤30). Infants<18 months of age (originally<12 months) and singleton pregnant women whose fetus has severe OI with confirmed glycine substitution in COL1A1 or COL1A2 can be included in the trial.Each subject receives four intravenous doses of 3×106/kg BOOST cells at 4 month intervals, with 48 (doses 1-2) or 24 (doses 3-4) hours in-patient follow-up, primary follow-up at 6 and 12 months after the last dose and long-term follow-up yearly until 10 years after the first dose. Prenatal subjects receive the first dose via ultrasound-guided injection into the umbilical vein within the fetal liver (16+0 to 35+6 weeks), and three doses postnatally.The primary outcome measures are safety and tolerability of repeated BOOST cell administration. The secondary outcome measures are number of fractures from baseline to primary and long-term follow-up, growth, change in bone mineral density, clinical OI status and biochemical bone turnover. ETHICS AND DISSEMINATION: The trial is approved by Competent Authorities in Sweden, the UK and the Netherlands (postnatal only). Results from the trial will be disseminated via CTIS, ClinicalTrials.gov and in scientific open-access scientific journals. TRIAL REGISTRATION NUMBERS: EudraCT 2015-003699-60, EUCT: 2023-504593-38-00, NCT03706482.
Assuntos
Transplante de Células-Tronco Mesenquimais , Osteogênese Imperfeita , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Gravidez , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Células-Tronco Fetais/transplante , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais , Estudos Multicêntricos como Assunto , Osteogênese Imperfeita/terapia , Resultado do TratamentoRESUMO
OBJECTIVE: To investigate the maternal and fetal safety of In utero stem cell transplantation (IUSCT). METHODS: Medline®, Embase and Cochrane library (1967-2023) search for publications reporting IUSCT in humans. Two reviewers independently screened abstracts and full-text papers. RESULTS: Sixty six transplantation procedures in 52 fetuses were performed for haemoglobinopathies (n = 14), red cell/bleeding disorders (n = 4), immunodeficiencies (n = 15), storage disorders (n = 7), osteogenesis imperfecta (n = 2) and healthy fetuses (n = 10). The average gestational age was 18.9 weeks; of procedures reporting the injection route, cells were delivered by intraperitoneal (n = 37), intravenous (n = 19), or intracardiac (n = 4) injection or a combination (n = 3); most fetuses received one injection (n = 41). Haematopoietic (n = 40) or mesenchymal (n = 12) stem cells were delivered. The cell dose was inconsistently reported (range 1.8-3.3 × 109 cells total (n = 27); 2.7-5.0 × 109 /kg estimated fetal weight (n = 17)). The acute fetal procedural complication rate was 4.5% (3/66); the acute fetal mortality rate was 3.0% (2/66). Neonatal survival was 69.2% (36/52). Immediate maternal and pregnancy outcomes were reported in only 30.8% (16/52) and 44.2% (23/52) of cases respectively. Four fetal/pregnancy outcomes would also classify as ≥ Grade 2 maternal adverse events. CONCLUSIONS: Short-, medium-, and long-term maternal and fetal adverse events should be reported in all IUSCT studies.
Assuntos
Resultado da Gravidez , Cuidado Pré-Natal , Gravidez , Recém-Nascido , Feminino , Humanos , Lactente , Feto , Idade GestacionalRESUMO
OBJECTIVE: To evaluate long-term neurodevelopment in children born after low-or mid-station vacuum-assisted delivery (VAD) compared with children delivered by second-stage caesarean delivery (SSCD) or spontaneous vaginal delivery (SVD). DESIGN: Cross-sectional cohort study. SETTING: Two delivery wards, Karolinska University Hospital, Sweden. PATIENTS: 253 children born by low-station or mid-station VAD, 247 children born after an SVD, and 86 children born via an SSCD accepted to participate. INTERVENTIONS: The Five-to-Fifteen questionnaire was used as a validated screening method for neurodevelopmental difficulties, assessed by parents. MAIN OUTCOMES MEASURES: Results in the Five-to-Fifteen questionnaire. In addition, registered neurodevelopmental ICD-10 diagnoses were collected. Regression analyses estimated associations between delivery modes. RESULTS: Children born after VAD exhibited an increased rate of long-term neurodevelopmental difficulties in motor skills (OR 2.2, 95% CI 1.3 to 3.8) and perception (OR 1.7, 95% CI 1.002 to 2.9) compared with SVD. Similar findings were seen in the group delivered with an SSCD compared with SVD (motor skills: OR 3.3, 95% CI 1.8 to 6.4 and perception: OR 2.3, 95% CI 1.2 to 4.4). The increased odds for motor skills difficulties after VAD and SSCD remained after adjusting for proposed confounding variables. There were significantly more children in the VAD group with registered neurodevelopmental ICD-10 diagnoses such as attention deficit/hyperactivity disorders. CONCLUSIONS: The differences in long-term neurodevelopmental difficulties in children delivered with a VAD or SSCD compared with SVD in this study indicate the need for increased knowledge in the field to optimise the management of second stage of labour.
Assuntos
Cesárea , Parto Obstétrico , Gravidez , Feminino , Humanos , Criança , Estudos de Coortes , Estudos Transversais , Parto Obstétrico/efeitos adversos , Cesárea/efeitos adversos , Vácuo-Extração/efeitos adversosRESUMO
INTRODUCTION: During the second stage of labor, vacuum-assisted delivery is an alternative to forceps delivery and emergency cesarean section. Extensive research concerning perinatal outcomes has indicated that the risk of complications, although rare, is higher than with a spontaneous vaginal delivery. An important factor related to perinatal outcomes is the traction force applied. Our research group previously developed a digital extraction handle, the Vacuum Intelligent Handle-3 (VIH3), that measures and records traction force. The objective of this study was to compare traction force profiles in children with and without severe perinatal outcomes delivered with the digital handle. A secondary aim was to establish a safe force limit. MATERIAL AND METHODS: This was an observational case-control study at the delivery ward at Karolinska University Hospital, Sweden. In total, 573 children delivered with the digital handle between 2012 and 2018 were included. Cases were defined as a composite of severe perinatal outcomes, including subgaleal hematoma, intracranial hemorrhage, hypoxic ischemic encephalopathy 1-3, seizures or death. The cases in the cohort were matched 1:3 based on five matching variables. Traction profiles were analyzed using the MATLAB® software and conditional logistic regression. RESULTS: The incidence of severe perinatal outcomes was 2.3%. The 13 cases were matched with three controls each (n = 39). A statistically significant increased odds for higher total traction forces was seen in the case group (odds ratio [OR] 1.004; 95% confidence interval [CI] 1.001-1.007) and for the peak force (OR 1.022; 95% CI 1.004-1.041). Several procedure-related parameters were significantly increased in the case group. As expected, some neonatal characteristics also differed significantly. An upper force limit of 343 Newton minutes (Nmin) revealed an 86% reduction in severe perinatal outcomes (adjusted OR 0.14; 95% CI 0.04-0.5). CONCLUSIONS: Children with severe perinatal outcomes had traction force profiles with significantly higher forces. The odds for severe perinatal outcomes increased for every increase in Nmin and Newton used during the extraction procedure. A calculated total force level of 343 Nmin is suggested as an upper safety limit, but this must be tested prospectively to provide validity.
Assuntos
Cesárea , Vácuo-Extração , Recém-Nascido , Criança , Gravidez , Humanos , Feminino , Vácuo-Extração/métodos , Cesárea/métodos , Estudos de Casos e Controles , Tração , Parto Obstétrico , Estudos RetrospectivosRESUMO
OBJECTIVE: Adverse event (AE) monitoring is central to assessing therapeutic safety. The lack of a comprehensive framework to define and grade maternal and fetal AEs in pregnancy trials severely limits understanding risks in pregnant women. We created AE terminology to improve safety monitoring for developing pregnancy drugs, devices and interventions. METHOD: Existing severity grading for pregnant AEs and definitions/indicators of 'severe' and 'life-threatening' conditions relevant to maternal and fetal clinical trials were identified through a literature search. An international multidisciplinary group identified and filled gaps in definitions and severity grading using Medical Dictionary for Regulatory Activities (MedDRA) terms and severity grading criteria based on Common Terminology Criteria for Adverse Event (CTCAE) generic structure. The draft criteria underwent two rounds of a modified Delphi process with international fetal therapy, obstetric, neonatal, industry experts, patients and patient representatives. RESULTS: Fetal AEs were defined as being diagnosable in utero with potential to harm the fetus, and were integrated into MedDRA. AE severity was graded independently for the pregnant woman and her fetus. Maternal (n = 12) and fetal (n = 19) AE definitions and severity grading criteria were developed and ratified by consensus. CONCLUSIONS: This Maternal and Fetal AE Terminology version 1.0 allows systematic consistent AE assessment in pregnancy trials to improve safety.
Assuntos
Complicações na Gravidez/classificação , Terminologia como Assunto , Feminino , Feto/anormalidades , Feto/diagnóstico por imagem , Humanos , Gravidez , Padrões de ReferênciaRESUMO
The aim of this study was to provide a brief overview on the background and rationale on treating fetuses and children suffering from osteogenesis imperfecta (OI) with mesenchymal stem cells (MSCs). MSCs ability to migrate, engraft, and differentiate into bone cells and to act via paracrine effects on the recipient's tissues makes these cells promising candidates as a clinical therapy for OI. Animal work and limited clinical studies in humans support the use of MSC in treating OI. Off-the-shelf MSC have a good safety profile and exhibit multilineage differentiation potential and a low immunogenic profile and thereby may enable this potential therapy to become widely available. MSC transplantation before and after birth to treat OI is an experimental therapy that is currently tested in the international multicentre phase I/II clinical trial BOOSTB4 that aims to assess the safety and efficacy of fetal MSC transplantation for the treatment of severe types of OI.
Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Osteogênese Imperfeita , Animais , Diferenciação Celular , Feto , Humanos , Osteogênese Imperfeita/terapiaRESUMO
OBJECTIVE: The aim was to explore the potential role of the placenta for the risk of stillbirth at term in pregnancies of obese women. METHODS: This was a case-control study comparing placental findings from term stillbirths with placental findings from live born infants. Cases were singleton term stillbirths to normal weight or obese women, identified in the Stockholm stillbirth database, n = 264 and n = 87, respectively. Controls were term singletons born alive to normal weight or obese women, delivered between 2002-2005 and between 2018-2019. Placentas were compared between women with stillborn and live-born infants, using logistic regression analyses. RESULTS: A long and hyper coiled cord, cord thrombosis and velamentous cord insertion were stronger risk factors for stillbirth in obese women compared to normal weight women. When these variables were adjusted for in the logistic regression analysis, also adjusted for potential confounders, the odds ratio for stillbirth in obese women decreased from 1.89 (CI 1.24-2.89) to 1.63 (CI 1.04-2.56). CONCLUSION: Approximately one fourth of the effect of obesity on the risk of stillbirth in term pregnancies is explained by umbilical cord associated pathology.
Assuntos
Obesidade Materna/patologia , Placenta/patologia , Complicações na Gravidez/patologia , Natimorto , Adulto , Estudos de Casos e Controles , Bases de Dados Factuais , Feminino , Humanos , Nascido Vivo , Gravidez , Fatores de Risco , Cordão Umbilical/patologiaRESUMO
BACKGROUND: Low and mid station vacuum assisted deliveries (VAD) are delicate manual procedures that entail a high degree of subjectivity from the operator and are associated with adverse neonatal outcome. Little has been done to improve the procedure, including the technical development, traction force and the possibility of objective documentation. We aimed to explore if a digital handle with instant haptic feedback on traction force would reduce the neonatal risk during low or mid station VAD. METHODS: A two centre, randomised superiority trial at Karolinska University Hospital, Sweden, 2016-2018. Cases were randomised bedside to either a conventional or a digital handle attached to a Bird metal cup (50 mm, 80 kPa). The digital handle measured applied force including an instant notification by vibration when high levels of traction force were predicted according to a predefined algorithm. Primary outcome was a composite of hypoxic ischaemic encephalopathy, intracranial haemorrhage, seizures, death and/or subgaleal hematoma. Three hundred eighty low and mid VAD in each group were estimated to decrease primary outcome from six to 2 %. RESULTS: After 2 years, an interim analyse was undertaken. Meeting the inclusion criteria, 567 vacuum extractions were randomized to the use of a digital handle (n = 296) or a conventional handle (n = 271). Primary outcome did not differ between the two groups: (2.7% digital handle vs 2.6% conventional handle). The incidence of primary outcome differed significantly between the two delivery wards (4% vs 0.9%, p < 0.05). A recalculation of power revealed that 800 cases would be needed in each group to show a decrease in primary outcome from three to 1 %. This was not feasible, and the study therefore closed. CONCLUSIONS: The incidence of primary outcome was lower than estimated and the study was underpowered. However, the difference between the two delivery wards might reflect varying degree of experience of the technical equipment. An objective documentation of the extraction procedure is an attractive alternative in respect to safety and clinical training. To demonstrate improved safety, a multicentre study is required to reach an adequate cohort. This was beyond the scope of the study. TRIAL REGISTRATION: ClinicalTrials.gov NCT03071783 , March 1, 2017, retrospectively registered.
Assuntos
Traumatismos do Nascimento/epidemiologia , Hipóxia-Isquemia Encefálica/epidemiologia , Hemorragias Intracranianas/epidemiologia , Resultado da Gravidez/epidemiologia , Vácuo-Extração/efeitos adversos , Adulto , Traumatismos do Nascimento/etiologia , Feminino , Humanos , Hipóxia-Isquemia Encefálica/etiologia , Recém-Nascido , Hemorragias Intracranianas/etiologia , Gravidez , Resultado do TratamentoRESUMO
BACKGROUND: Fetal anemia is associated with a hyperdynamic circulation and cardiac remodeling. Rapid intrauterine transfusion (IUT) of blood with high hematocrit and viscosity into the umbilical vein used to treat this condition can temporarily further affect fetal heart function. The aim of this study was to evaluate the short-term changes in fetal myocardial function caused by IUT using automated analysis of cine-loops of the fetal heart obtained by color tissue Doppler imaging (cTDI). METHODS: Fetal echocardiography was performed before and after IUT. cTDI recordings were obtained in a four-chamber view and regions of interest were placed at the atrioventricular plane in the left ventricular (LV), right ventricular (RV) and septal walls. Myocardial velocities were analyzed by an automated analysis software to obtain peak myocardial velocities during atrial contraction (Am), ventricular ejection (Sm), rapid ventricular filling (Em) and Em/Am ratio was calculated. Myocardial velocities were converted to z-scores using published reference ranges. Delta z-scores (after minus before IUT) were calculated. Correlations were assessed between variables and hemoglobin before IUT. RESULTS: Thirty-two fetuses underwent 70 IUTs. Fourteen were first time transfusions. In the LV and septal walls, all myocardial velocities were significantly increased compared to normal values, whereas in the RV only Sm was increased before IUT (z-scores 0.26-0.52). In first time IUTs, there was a negative correlation between LV Em (rho = - 0.61, p = 0.036) and LV Em/Am (rho = - 0.82, p = 0.001) z-scores and hemoglobin before IUT. The peak myocardial velocities that were increased before IUT decreased, whereas LV Em/Am increased significantly after IUT. CONCLUSIONS: This study showed that peak myocardial velocities assessed by cTDI are increased in fetuses before IUT reflecting the physiology of hyperdynamic circulation. In these fetuses, the fetal heart is able to adapt and efficiently handle the volume load caused by IUT by altering its myocardial function.
Assuntos
Anemia/terapia , Transfusão de Sangue Intrauterina , Coração Fetal/diagnóstico por imagem , Coração Fetal/fisiopatologia , Ultrassonografia Doppler em Cores , Adulto , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Gravidez , Ultrassonografia Pré-NatalRESUMO
INTRODUCTION: Traction force is a possible risk factor for adverse neonatal outcome in vacuum extraction delivery, but the knowledge is scarce and further investigation is needed. Our hypothesis was that high-level traction force increases the risk of admission to the neonatal intensive care unit. MATERIAL AND METHODS: The study was a hospital-based prospective cohort study on low- and mid-vacuum extractions at the labor and delivery ward, Karolinska University Hospital, Huddinge, Sweden. Traction forces were measured in 331 women. An electronical handle was used to measure and register traction force. The main exposure variable was high-level traction force (≥75th percentile) during the first three pulls and the primary outcome was admission to the neonatal intensive care unit. Logistic regression was used to estimate the adjusted risk. RESULTS: Among the exposed, 14/84 (16.7%) were admitted to neonatal intensive care, and among the unexposed 10/247 (4%). The crude odds ratio (OR) of admission to the neonatal intensive care unit when exposed to high-level traction force was 4.7, and the adjusted (birthweight, gestational length, cup detachment, number of pulls, duration, duration >15 minutes, mid-cavity fetal head station, failed extraction, indication and parity) OR was 2.85 (95% confidence interval [CI] 1.09-7.48). No significant effect was seen in Apgar scores <7 at 5 minutes or pH <7.1. CONCLUSIONS: High-level traction force may be a risk factor for neonatal complications. Although these results do not mandate any alterations in clinical guidelines, perioperative feedback on traction force may be useful to alert the obstetrician to a timely conversion to cesarean section. To study plausible traction force specific outcomes such as head traumas, a larger sample size is required.
Assuntos
Traumatismos do Nascimento , Complicações do Trabalho de Parto , Tração/efeitos adversos , Vácuo-Extração , Adulto , Traumatismos do Nascimento/diagnóstico , Traumatismos do Nascimento/epidemiologia , Traumatismos do Nascimento/etiologia , Traumatismos do Nascimento/prevenção & controle , Cesárea/métodos , Tomada de Decisão Clínica , Feminino , Humanos , Recém-Nascido , Unidades de Terapia Intensiva Neonatal/estatística & dados numéricos , Complicações do Trabalho de Parto/epidemiologia , Complicações do Trabalho de Parto/etiologia , Complicações do Trabalho de Parto/prevenção & controle , Gravidez , Risco Ajustado/métodos , Fatores de Risco , Suécia/epidemiologia , Tempo para o Tratamento , Tração/métodos , Vácuo-Extração/efeitos adversos , Vácuo-Extração/métodos , Vácuo-Extração/estatística & dados numéricosRESUMO
INTRODUCTION: The prevalence of obesity in pregnancy is increasing worldwide. Maternal obesity increases risks of severe fetal and neonatal complications. The underlying pathophysiological mechanisms are unclear. One possible contributing factor could be chronic fetal hypoxia. The aim of this study was to compare placentas from women with and without obesity with respect to placental lesions, which could reflect compensatory mechanisms in response to chronic fetal hypoxia as well as lesions possibly leading to chronic fetal hypoxia. In addition, levels of erythropoietin in cord blood were compared between offspring of lean and obese women. MATERIAL AND METHODS: This cohort study included 180 women with uneventful, full-term, singleton pregnancies, out of which 91 lean women had a body mass index (BMI) of 18.5-24.9 kg/m2 and 89 women had obesity (BMI ≥30 kg/m2 ). Women were recruited at Södersjukhuset between 16 October 2018 and 2 December 2019. Placentas were investigated by two senior perinatal pathologists, who were blinded for maternal BMI. Cord blood was analyzed for levels of erythropoietin. RESULTS: Levels of erythropoietin in cord blood increased with maternal BMI (P = .01, ß = 0.97, 95% CI 0.27-1.68). There was no difference between placentas of obese and lean women in number of placental lesions reflecting chronic fetal hypoxia or in lesions that could possibly lead to chronic fetal hypoxia. CONCLUSIONS: This study of term and uneventful pregnancies demonstrated a positive association between maternal obesity and concentrations of erythropoietin in cord blood at birth. This finding supports the hypothesis of chronic fetal hypoxia as a risk factor for complications in the pregnancies of obese women. There were no differences in lesions associated with hypoxia between placentas of obese and lean women.
Assuntos
Eritropoetina/sangue , Hipóxia Fetal , Obesidade Materna , Placenta/patologia , Adulto , Índice de Massa Corporal , Estudos de Coortes , Correlação de Dados , Feminino , Sangue Fetal , Hipóxia Fetal/sangue , Hipóxia Fetal/diagnóstico , Hipóxia Fetal/epidemiologia , Hipóxia Fetal/etiologia , Humanos , Obesidade Materna/complicações , Obesidade Materna/diagnóstico , Obesidade Materna/epidemiologia , Gravidez , Resultado da Gravidez , Fatores de Risco , Suécia/epidemiologiaAssuntos
Infecções por Coronavirus , Pandemias , Pneumonia Viral , Complicações Infecciosas na Gravidez , Infecção Puerperal , Adulto , Betacoronavirus/isolamento & purificação , COVID-19 , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/terapia , Cuidados Críticos/métodos , Cuidados Críticos/estatística & dados numéricos , Feminino , Humanos , Mortalidade Materna , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Pneumonia Viral/fisiopatologia , Pneumonia Viral/terapia , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Complicações Infecciosas na Gravidez/fisiopatologia , Complicações Infecciosas na Gravidez/terapia , Complicações Infecciosas na Gravidez/virologia , Infecção Puerperal/epidemiologia , Infecção Puerperal/fisiopatologia , Infecção Puerperal/terapia , Infecção Puerperal/virologia , Respiração Artificial/métodos , Medição de Risco , Fatores de Risco , SARS-CoV-2 , Índice de Gravidade de Doença , Suécia/epidemiologiaRESUMO
INTRODUCTION: Cardiotocography (CTG) is currently the most commonly used method for intrapartum fetal monitoring during labor. However, a high false-positive rate of fetal acidosis indicated by CTG leads to an increase in obstetric interventions. We developed a microdialysis probe that is integrated into a fetal scalp electrode allowing continuous measurement of lactate subcutaneously, thus giving instant information about the oxygenation status of the fetus. Our aim was to establish proof of concept in an animal model using a microdialysis probe to monitor lactate subcutaneously. MATERIAL AND METHODS: We performed an in vivo study in adult male wild-type Wistar rats. We modified electrodes used for CTG monitoring in human fetuses to incorporate a microdialysis membrane. Optimum flow rates for microdialysis were determined in vitro. For the in vivo experiment, a microdialysis probe was inserted into the skin on the back of the animal. De-oxygenation and acidosis were induced by lowering the inspiratory oxygen pressure. Oxygenation and heart rate were monitored. A jugular vein cannula was inserted to draw blood samples for analysis of lactate, pH, pco2 , and saturation. Lactate levels in dialysate were compared with plasma lactate levels. RESULTS: Baseline blood lactate levels were around 1 mmol/L. Upon de-oxygenation, oxygen saturation fell to below 40% for 1 h and blood lactate levels increased 2.5-fold. Correlation of dialysate lactate levels with plasma lactate levels was 0.89 resulting in an R2 of .78 in the corresponding linear regression. CONCLUSIONS: In this animal model, lactate levels in subcutaneous fluid collected by microdialysis closely reflected blood lactate levels upon transient de-oxygenation, indicating that our device is suitable for subcutaneous measurement of lactate. Microdialysis probe technology allows the measurement of multiple compounds in the dialysate, such as glucose, albumin, or inflammatory mediators, so this technique may offer the unique possibility to shed light on fetal physiology during the intrapartum period.
Assuntos
Monitorização Fetal/instrumentação , Lactatos/análise , Membranas Artificiais , Microdiálise , Tela Subcutânea/química , Acidose/diagnóstico , Animais , Feminino , Doenças Fetais/diagnóstico , Monitorização Fetal/métodos , Modelos Animais , Oximetria , Gravidez , Ratos WistarRESUMO
Imagine the profits in quality of life that can be made by treating inherited diseases early in life, maybe even before birth! Immense cost savings can also be made by treating diseases promptly. Hence, prenatal stem cell therapy holds great promise for developing new and early-stage treatment strategies for several diseases. Successful prenatal stem cell therapy would represent a major step forward in the management of patients with hematological, metabolic, or immunological disorders. However, treatment before birth has several limitations, including ethical issues. In this review, we summarize the past, the present, and the future of prenatal stem cell therapy, which includes an overview of different stem cell types, preclinical studies, and clinical attempts treating various diseases. We also discuss the current challenges and future strategies for prenatal stem cell therapy and also new approaches, which may lead to advancement in the management of patients with severe incurable diseases.
Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco/métodos , Condicionamento Pré-Transplante/métodos , Feminino , Humanos , GravidezRESUMO
Postpartum hemorrhages with blood transfusions are increasing in many high-resource countries. Currently, up to 3% of all women receive blood transfusion postpartum. Most blood transfusions are safe and, in many cases, are lifesaving, but there are significant concerns about adverse reactions. Pregnancy is associated with higher levels of leukocyte antibodies and has a modulating effect on the immune system. Our objective was to investigate whether blood transfusions postpartum are accompanied by an increased risk for transfusion reactions (TRs) compared with transfusions given to nonpregnant women. We included all women who gave birth in Stockholm County, Sweden between 1990 and 2011. Data from the Swedish National Birth Registry were linked to the Stockholm Transfusion Database and included information on blood components administered and whether a TR occurred in women who received blood transfusions postpartum. Background controls were nonpregnant women who received blood transfusions during the study period. The study cohort consisted of 517 854 women. Of these, 12 183 (2.4%) received a blood transfusion. We identified 96 events involving a TR postpartum, giving a prevalence of 79 per 10 000 compared with 40 per 10 000 among nonpregnant women (odds ratio, 2.0; 95% confidence interval, 1.6-2.5). Preeclampsia was the single most important risk factor for TRs (odds ratio, 2.1; 95% confidence interval, 1.7-2.6). We conclude that special care should be taken when women with preeclampsia are considered for blood transfusion postpartum, because our findings indicate that pregnancy is associated with an increased risk for TRs.
Assuntos
Transfusão de Sangue , Reação Transfusional/epidemiologia , Reação Transfusional/etiologia , Adulto , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Razão de Chances , Hemorragia Pós-Parto/terapia , Medição de Risco , Fatores de Risco , Adulto JovemRESUMO
There is a need for effective therapy with few side effects for severe acute graft-versus-host disease (GVHD). The placenta protects the fetus from the mother's haploidentical immune system during pregnancy. We found that maternal stromal cells from the fetal membrane, so-called decidua stromal cells (DSCs), are more immunosuppressive than other sources of stromal cells. We prospectively treated 21 patients (median age, 49 years; range, 1.6 to 72 years) for grade II-IV acute GVHD. All 21 patients had biopsy-proven gastrointestinal GVHD. The majority of patients were either steroid-refractory or had progressive GVHD, 11 patients after >7 days or with progression after 3 days, and 10 were refractory to steroids after >3 days. We used an improved protocol in which DSCs were thawed and infused in a buffer with 5% human albumin. DSCs were given at a median dose of 1.2 (range, 0.9 to 2.9)â¯×â¯106 cells/kg body weight with a median of 2 (range, 1 to 6) doses, given 1 week apart. The median viability of thawed DSCs was 93% (range, 69% to 100%), and the median cell passage number was 4 (range, 2 to 4). Complete resolution of GVHD was seen in 11 patients, with a partial response in the other 10. The cumulative incidence of chronic GVHD was 52%. GVHD was mild in 6 patients, moderate in 4 patients, and severe in 1 patient based on National Institutes of Health chronic GVHD severity scoring. Nine patients died, including 3 from relapse and 1 each from acute GVHD and septicemia, Zygomycetes infection, liver insufficiency, cerebral hemorrhage, multiple organ failure, and chronic GVHD with obstructive bronchiolitis. Four-year transplantation-related mortality was 28.6%, and overall survival was 57%. Survival was similar (Pâ¯=â¯.33) to that for all 293 patients who underwent allogeneic hematopoietic cell transplantation during the same period (2012 to 2015), with 66% overall survival. DSC infusion is a novel therapy for acute GVHD grade II-IV, and a randomized trial is currently underway (ClinicalTrials.gov NCT02172937).
Assuntos
Decídua/metabolismo , Doença Enxerto-Hospedeiro/genética , Placenta/metabolismo , Células Estromais/metabolismo , Doença Aguda , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Gravidez , Estudos Prospectivos , Análise de Sobrevida , Adulto JovemRESUMO
OBJECTIVE: To study if children of women exposed to organic particles and combustion products at work during pregnancy, have an increased risk of low birth weight, preterm birth or small for gestational age. METHODS: A nationwide cohort of all occupationally active mothers and their children from single births during 1994 to the end of 2012 (1 182 138 observations) was formed. Information on birth outcome was obtained from the medical birth register. Information on absence from work, education, occupation, age, nationality and smoking habits was obtained from national registers. A job exposure matrix (FINJEM) was used to assess the exposure. RESULTS: Pregnant women with low absence from work and high (>50th percentile) exposure to organic particles had an increased risk of giving birth to children with low birth weight (OR=1.19; 95% CI: 1.07 to 1.32), small for gestational age (OR=1.22; 95% CI: 1.07 to 1.38) or preterm birth (OR=1.17; 95% CI: 1.08 to 1.27). Subgroup analyses showed an increased risk of small for gestational age in association with exposure to oil mist. Exposure to oil mist and cooking fumes was associated with low birth weight. Paper and other organic dust was associated with preterm birth. Exposure to combustion products showed an increased risk of small for gestational age (OR=1.40; 95% CI: 1.15 to 1.71). CONCLUSIONS: The results indicate that occupational exposure to organic particles or combustion products during pregnancy is associated with restriction of fetal growth and preterm birth. More studies are needed to confirm a casual association.
Assuntos
Recém-Nascido de Baixo Peso , Recém-Nascido Pequeno para a Idade Gestacional , Exposição Materna/efeitos adversos , Exposição Ocupacional/efeitos adversos , Material Particulado/efeitos adversos , Hidrocarbonetos Policíclicos Aromáticos/efeitos adversos , Nascimento Prematuro/epidemiologia , Adulto , Poluentes Ocupacionais do Ar/efeitos adversos , Estudos de Coortes , Culinária , Feminino , Humanos , Recém-Nascido , Óleos/efeitos adversos , Gravidez , Suécia/epidemiologiaRESUMO
Here, we present a method for in-depth human plasma proteome analysis based on high-resolution isoelectric focusing HiRIEF LC-MS/MS, demonstrating high proteome coverage, reproducibility and the potential for liquid biopsy protein profiling. By integrating genomic sequence information to the MS-based plasma proteome analysis, we enable detection of single amino acid variants and for the first time demonstrate transfer of multiple protein variants between mother and fetus across the placenta. We further show that our method has the ability to detect both low abundance tissue-annotated proteins and phosphorylated proteins in plasma, as well as quantitate differences in plasma proteomes between the mother and the newborn as well as changes related to pregnancy.