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The Cochrane Database of Systematic... Apr 2021Thalassaemia is an autosomal recessive blood disorder, caused by mutations in globin genes or their regulatory regions, resulting in a reduced rate of synthesis of one...
BACKGROUND
Thalassaemia is an autosomal recessive blood disorder, caused by mutations in globin genes or their regulatory regions, resulting in a reduced rate of synthesis of one of the globin chains that make up haemoglobin. In β-thalassaemia there is an underproduction of β-globin chains combined with excess of free α-globin chains. The excess free α-globin chains precipitate in red blood cells, leading to their increased destruction (haemolysis) and ineffective erythropoiesis. The conventional treatment is based on the correction of haemoglobin through regular red blood cell transfusions and treating the iron overload that develops subsequently with iron chelation therapy. Although, early detection and initiations of such supportive treatment has improved the quality of life for people with transfusion-dependent thalassaemia, allogeneic hematopoietic stem cell transplantation is the only widely available therapy with a curative potential. Gene therapy for β-thalassaemia has recently received conditional authorisation for marketing in Europe, and may soon become widely available as another alternative therapy with curative potential for people with transfusion-dependent thalassaemia. This is an update of a previously published Cochrane Review.
OBJECTIVES
To evaluate the effectiveness and safety of different types of hematopoietic stem cell transplantation, in people with transfusion-dependent β-thalassaemia.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched online trial registries. Date of the most recent search: 07 April 2021.
SELECTION CRITERIA
Randomised controlled trials and quasi-randomised controlled trials comparing hematopoietic stem cell transplantation with each other or with standard therapy (regular transfusion and chelation regimen).
DATA COLLECTION AND ANALYSIS
Two review authors independently screened trials and had planned to extract data and assess risk of bias using standard Cochrane methodologies and assess the quality using GRADE approach, but no trials were identified for inclusion in the current review.
MAIN RESULTS
No relevant trials were retrieved after a comprehensive search of the literature.
AUTHORS' CONCLUSIONS
We were unable to identify any randomised controlled trials or quasi-randomised controlled trials on the effectiveness and safety of different types of hematopoietic stem cell transplantation in people with transfusion-dependent β-thalassaemia. The absence of high-level evidence for the effectiveness of these interventions emphasises the need for well-designed, adequately-powered, randomised controlled clinical trials.
Topics: Hematopoietic Stem Cell Transplantation; Humans; beta-Thalassemia
PubMed: 33880750
DOI: 10.1002/14651858.CD008708.pub5 -
Ultrasound in Obstetrics & Gynecology :... Oct 2021To determine the incremental yield of exome sequencing (ES) over chromosomal microarray analysis (CMA) or karyotyping in prenatally diagnosed non-immune hydrops fetalis... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To determine the incremental yield of exome sequencing (ES) over chromosomal microarray analysis (CMA) or karyotyping in prenatally diagnosed non-immune hydrops fetalis (NIHF).
METHODS
A prospective cohort study (comprising an extended group of the Prenatal Assessment of Genomes and Exomes (PAGE) study) was performed which included 28 cases of prenatally diagnosed NIHF undergoing trio ES following negative CMA or karyotyping. These cases were combined with data from a systematic review of the literature. MEDLINE, EMBASE, CINAHL and ClinicalTrials.gov databases were searched electronically (January 2000 to October 2020) for studies reporting on the incremental yield of ES over CMA or karyotyping in fetuses with prenatally detected NIHF. Inclusion criteria for the systematic review were: (i) at least two cases of NIHF undergoing sequencing; (ii) testing initiated based on prenatal ultrasound-based phenotype; and (iii) negative CMA or karyotyping result. The incremental diagnostic yield of ES was assessed in: (i) all cases of NIHF; (ii) isolated NIHF; (iii) NIHF associated with an additional fetal structural anomaly; and (iv) NIHF according to severity (i.e. two vs three or more cavities affected).
RESULTS
In the extended PAGE study cohort, the additional diagnostic yield of ES over CMA or karyotyping was 25.0% (7/28) in all NIHF cases, 21.4% (3/14) in those with isolated NIHF and 28.6% (4/14) in those with non-isolated NIHF. In the meta-analysis, the pooled incremental yield based on 21 studies (306 cases) was 29% (95% CI, 24-34%; P < 0.00001; I = 0%) in all NIHF, 21% (95% CI, 13-30%; P < 0.00001; I = 0%) in isolated NIHF and 39% (95% CI, 30-49%; P < 0.00001; I = 1%) in NIHF associated with an additional fetal structural anomaly. In the latter group, congenital limb contractures were the most prevalent additional structural anomaly associated with a causative pathogenic variant, occurring in 17.3% (19/110) of cases. The incremental yield did not differ significantly according to hydrops severity. The most common genetic disorders identified were RASopathies, occurring in 30.3% (27/89) of cases with a causative pathogenic variant, most frequently due to a PTPN11 variant (44.4%; 12/27). The predominant inheritance pattern in causative pathogenic variants was autosomal dominant in monoallelic disease genes (57.3%; 51/89), with most being de novo (86.3%; 44/51).
CONCLUSIONS
Use of prenatal next-generation sequencing in both isolated and non-isolated NIHF should be considered in the development of clinical pathways. Given the wide range of potential syndromic diagnoses and heterogeneity in the prenatal phenotype of NIHF, exome or whole-genome sequencing may prove to be a more appropriate testing approach than a targeted gene panel testing strategy. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
Topics: Female; High-Throughput Nucleotide Sequencing; Humans; Hydrops Fetalis; Karyotyping; Microarray Analysis; Predictive Value of Tests; Pregnancy; Prenatal Diagnosis; Prospective Studies; Exome Sequencing
PubMed: 33847422
DOI: 10.1002/uog.23652 -
Genetics in Medicine : Official Journal... Jan 2021Hydrops fetalis (HF), accumulation of fluid in two or more fetal compartments, is life-threatening to the fetus. Genetic etiologies include many chromosomal and...
Hydrops fetalis (HF), accumulation of fluid in two or more fetal compartments, is life-threatening to the fetus. Genetic etiologies include many chromosomal and monogenic disorders. Despite this, the clinical workup typically evaluates limited genetic targets. To support broader molecular testing of pregnancies with HF, we cataloged the spectrum of monogenic disorders associated with nonimmune hydrops fetalis (NIHF). We performed a systematic literature review under PROSPERO tag CRD42018099495 of cases reporting NIHF meeting strict phenotypic criteria and well-defined genetic diagnosis. We ranked the evidence per gene based on number of reported cases, phenotype, and molecular/biochemical diagnosis. We identified 131 genes with strong evidence for an association with NIHF and 46 genes with emerging evidence spanning the spectrum of multisystem syndromes, cardiac disorders, hematologic disorders, and metabolic disorders. Several genes previously implicated with NIHF did not have any reported cases in the literature with both fetal hydrops and molecular diagnosis. Many genes with strong evidence for association with NIHF would not be detected using current sequencing panels. Nonimmune HF has many possible monogenic etiologies, several with treatment implications, but current diagnostic approaches are not exhaustive. Studies are needed to assess if broad sequencing approaches like exome sequencing are useful in clinical management of HF.
Topics: Female; Fetus; Humans; Hydrops Fetalis; Pregnancy; Prenatal Care; Exome Sequencing
PubMed: 33082562
DOI: 10.1038/s41436-020-00967-0 -
The Cochrane Database of Systematic... Aug 2019Thalassaemia is a quantitative abnormality of haemoglobin caused by mutations in genes controlling production of alpha or beta globins. Abnormally unpaired globin chains...
BACKGROUND
Thalassaemia is a quantitative abnormality of haemoglobin caused by mutations in genes controlling production of alpha or beta globins. Abnormally unpaired globin chains cause haemolytic anaemia by causing membrane damage and cell death within organ systems and destruction of erythroid precursors in the bone marrow. The life-long management of the general health effects of thalassaemia in affected individuals is a highly challenging issue in and of itself; and failure to deal with dental and orthodontic complications in people with thalassaemia exacerbates the public health, financial and personal burden posed by the condition. There exists a lack of evidence-based guidelines for care-seekers and providers to best deal with such dental and orthodontic complications in thalassaemia, which this review seeks to address.
OBJECTIVES
The main objective of this review was to assess different methods to treat dental and orthodontic complications in people with thalassaemia.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We searched the reference lists of relevant articles and reviews.Date of last search: 01 August 2019.We also searched nine online databases (PubMed, Google Scholar, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Literature in the Health Sciences in Latin America and the Caribbean database, African Index Medicus, Index Medicus for South East Asia Region, Index Medicus for the Eastern Mediterranean Region, Indexing of Indian Medical Journals). We searched the reference lists of relevant articles and reviews and contacted haematologists, experts in fields of dentistry, organizations, pharmaceutical companies and researchers working in this field.Date of last search: 22 July 2019.
SELECTION CRITERIA
We searched for published or unpublished randomised controlled trials for treatment of dental and orthodontic complications in individuals diagnosed with thalassaemia, irrespective of phenotype, severity, age, gender and ethnic origin.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened 35,202 titles from search results. We identified four unique randomised controlled trials, of which one seemed potentially relevant. Based on closer inspection, the trial was found not to be eligible for inclusion.
MAIN RESULTS
We did not find any relevant trials for inclusion in the review.
AUTHORS' CONCLUSIONS
We were unable to draw any conclusions due to the lack of available data and trials. This review highlights the need for conducting and appropriate reporting, of high-quality randomised controlled trials investigating the effectiveness of various treatment modalities for dental and orthodontic complications in people with thalassaemia.
Topics: Humans; Malocclusion; Randomized Controlled Trials as Topic; Thalassemia; Tooth Diseases
PubMed: 31425614
DOI: 10.1002/14651858.CD012969.pub2 -
Ultrasound in Obstetrics & Gynecology :... Apr 2020To report the perinatal outcome of singleton pregnancies complicated by placental chorioangioma diagnosed on prenatal ultrasound. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To report the perinatal outcome of singleton pregnancies complicated by placental chorioangioma diagnosed on prenatal ultrasound.
METHODS
MEDLINE, EMBASE, CINAHL and ClinicalTrials.gov databases were searched for studies reporting the outcome of pregnancies complicated by placental chorioangioma. Inclusion criteria were singleton pregnancy diagnosed with placental chorioangioma on prenatal ultrasound, with no other associated structural anomaly. The primary outcome was perinatal mortality. Secondary outcomes included associated non-structural anomalies detected on prenatal ultrasound (including fetal hydrops, anemia, polyhydramnios, signs of hyperdynamic circulation and small-for-gestational-age (SGA) fetus), SGA at birth, composite neonatal morbidity and preterm birth. Outcome was assessed separately in pregnancies undergoing and those not undergoing fetal therapy. Subanalyses were performed according to the presence of hydrops and the size of the tumor in all pregnancies diagnosed with chorioangioma. Random-effects meta-analyses of proportions were used to analyze the data.
RESULTS
Twenty-eight studies (161 pregnancies) were included. In pregnancies complicated by chorioangioma that did not undergo intervention, intrauterine death occurred in 8.2% (95% CI, 3.8-15.0%), while neonatal death and perinatal death occurred in 3.8% (95% CI, 1.0-8.1%) and 11.1% (95% CI, 5.0-19.4%), respectively. SGA at birth was present in 24.0% (95% CI, 13.5-36.5%) of cases, while preterm birth < 37 weeks complicated 34.1% (95% CI, 21.1-48.3%) of pregnancies. Composite neonatal morbidity occurred in 12.0% (95% CI, 4.5-22.3%) of cases. On ultrasound, signs of fetal hyperdynamic circulation were present in 21.0% (95% CI, 9.6-35.3%) of cases, while peak systolic velocity in the fetal middle cerebral artery was increased in 20.6% (95% CI, 10.9-32.3%). Subanalysis according to the size of chorioangioma, including both pregnancies that did and those that did not undergo intervention, showed a progressive increase in the occurrence of most of the outcomes explored with increasing size of the tumor. Furthermore, the prevalence of adverse perinatal outcome was high in pregnancies complicated by chorioangioma presenting with fetal hydrops. There was no randomized controlled trial comparing intervention vs expectant management in pregnancies complicated by chorioangioma with signs of fetal compromise (hydrops or hyperdynamic circulation). Overall, perinatal mortality occurred in 31.2% (95% CI, 18.1-46.1%) of fetuses undergoing in-utero therapy, and 57.3% (95% CI, 39.2-74.4%) had resolution of hydrops or hyperdynamic circulation after treatment.
CONCLUSIONS
Placental chorioangioma is associated with adverse perinatal outcome. The size of the mass and presence of fetal hydrops are likely to be the main determinants of perinatal outcome in affected pregnancies. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.
Topics: Adult; Female; Hemangioma; Humans; Hydrops Fetalis; Infant, Newborn; Perinatal Death; Perinatal Mortality; Placenta Diseases; Pregnancy; Pregnancy Complications, Neoplastic; Pregnancy Outcome; Ultrasonography, Prenatal
PubMed: 31034661
DOI: 10.1002/uog.20304