Factors Associated With Quality of Life Among Adolescent With Beta Thalassemia in Indonesia: A Cross-Sectional Study.

Introduction: Thalassemia is a hereditary condition that causes chronic anemia and is a serious public health concern globally. Quality of life is a concept to help healthcare professional understand the impact of disease or treatment of life. While many quality of life studies have been performed to improve patient care in developed countries, such research and their practical implementation are limited in developing countries such as Indonesia. Objective: This study aimed to assess the quality of life in adolescent with thalassemia in Indonesia, and determining its main clinical and demographic correlations. Methods: This was a cross-sectional study. Data were collected between December 2020 and May 2021 from patients diagnosed with beta thalassemia in Indonesia. The study involved adolescent diagnosed with thalassemia major and had been officially recorded in the thalassemia association records at least three months prior data collection. TranQOL was used to measure quality of life. Linear regression with enter method was used to determine factors associated with quality of life. Results: showed that 63% of thalassemic adolescents were aged at 10 to 15 years old and 76% of them had diagnosed with beta thalassemia at aged less than one year old. About 54% (n = 130) of the sample were boy and 45% (n = 108) were junior high school. The highest mean score was reported for physical health (58.3 ± 14.8) and the lowest score was reported for the school and career functioning (52.6 ± 14.3). Age, gender, comorbidity, and hemoglobin concentration explained 10.5% of the variances in the total quality of life. Conclusions: The results of this study that thalassemia has a detrimental impact on the quality of life of Indonesian adolescents. Healthcare providers must expand their access to information and abilities in order to fulfill new nursing responsibilities as genetic educators and counselors.

Noninvasive Prenatal Genetic Screening of Cell-Free Fetal DNA for Early Prediction of ß-Thalassemia Using Fiber Optic Nanogold-Linked Sorbent Assay.

ß-Thalassemia is a prevalent type of severe inherited chronic anemia, primarily identified in developing countries. The identification of single nucleotide polymorphisms (SNPs) plays a vital role in the early diagnosis of genetic diseases. Here, we reported the development of an amplification-free fiber optic nanogold-linked sorbent assay method using a fiber optic particle plasmon resonance (FOPPR) biosensor for rapid and ultrasensitive detection of SNPs. Herein, MutS protein was selected as the biorecognition capture probe and immobilized on the sensing region to capture the target mutant DNA, which was hybridized with a single-base mismatched single-stranded DNA labeled by a gold nanoparticle (AuNP). The AuNP acts as a signaling agent to be detected by the FOPPR biosensor when it is bound on the fiber core surface. The method effectively differentiates mismatched double-stranded DNA by MutS protein from perfectly matched/complementary dsDNA. It exhibits an impressively low detection limit for the detection of SNPs at approximately 10-16 M using low-cost sensor chips and devices. By determination of the ratio of mutant DNA to normal DNA in cell-free genomic DNA from blood samples, this method is promising for diagnosing ß-thalassemia in fetuses without invasive testing techniques.

Advances in Hemoglobinopathies and Thalassemia Evaluation.

Hemoglobin (Hb) disorders are among the most prevalent inherited diseases. Despite a limited number of involved genes, these conditions represent a broad clinical and prognostic spectrum. The menu of laboratory tests is extensive. From widely available modalities, for example, complete blood count to rather sophisticated molecular technologies, the investigation of Hb disorders recapitulates an increasing complexity of laboratory workup in other medical fields. This review highlights a current state of biochemical and molecular investigation of Hb disorders and offers a glimpse on technologies that are yet to be fully embraced in clinical practice.

Dominant Beta Thalassemia: A Very Rare Cause of Thalassemia in a Mediterranean Country.

Beta thalassemia is one of the monogenic disorders characterized by decreased production of ß-globin chains and various types of mutations have been reported to cause thalassemia phenotype. On the other hand, rare mutations also affect and diversify the disease spectrum. Herein, we present an anemic patient from Turkey diagnosed with dominant ß thalassemia due to a heterozygous mutation in exon 3 of the HBB gene.

Thalidomide and Hydroxyurea in Transfusion-Dependent Thalassemia: Efficacy, Safety Profile and Impact on Quality of Life.

Transfusion-dependent thalassemia (TDT) is a major public health concern in India, requiring regular transfusions for survival. There is also significant morbidity caused by iron overload and transfusion related infections. Novel therapies targeting fetal hemoglobin induction are the need of the hour in resource-poor institutions for patients where transplant is not feasible for various reasons. This single arm, non-randomised prospective trial evaluated the efficacy and safety of a combination of low dose thalidomide and hydroxyurea in TDT along with the impact on quality of life (QoL). It included 41 TDT patients, who failed a reasonable trial of hydroxyurea. Complete response (CR) was defined as transfusion independence and partial response (PR) denoted at least a 50% reduction in transfusion requirement. The rest were defined as non-responders (NR). The mean age of the cohort was 20.78 years (range 12-45 years). There were 13 males and 28 females. Nineteen (46.3%), 7 (17.1%), and 15 (36.6%) patients achieved CR, PR, and no response respectively. The overall response rate (CR + PR) was 63.4%. There was a significant increase in hemoglobin levels with decrement in transfusion burden and ferritin levels. There were no significant adverse reactions. No significant predictors of response were found including amongst genetic modifiers. It improved the health related QoL amongst responders. The combination of thalidomide and hydroxyurea appear safe and effective in the reduction in transfusion requirement of TDT patients. The judicious use of these drugs can improve the quality of life and pave the way for patients not eligible for a stem cell transplant.

Radiological Features of Extramedullary Hematopoiesis in a Young Male With Beta-Thalassemia: A Case Report.

The formation of the blood elements and their maturation is called hematopoiesis. In adults, this typically takes place in the bone marrow of vertebrae, ribs, and long bones. In contrast, during fetal development, the primary sites of hematopoiesis are the spleen, liver, and the yolk sac. This process of hematopoiesis, when it occurs in sites other than the bone marrow, is called the extramedullary hematopoiesis (EMH). Extramedullary hematopoiesis usually happens in patients with blood disorders like sickle cell disease and thalassemia, where there is failure of hematopoiesis in the primary sites. Here, we present a young male with beta-thalassemia who presented with shortness of breath and palpitations for one month. This manuscript discusses the imaging findings of the EMH in our patient.

Global and regional cardiac magnetic resonance feature tracking left ventricular strain analysis in assessing early myocardial disease in ß thalassemia major patients.

BACKGROUND: Cardiac magnetic resonance imaging (CMR) is the modality of choice for quantification of myocardial iron overload in ß-thalassemia major patients using the T2* sequence. CMR feature tracking (FT) is a recent magnetic resonance imaging tool that gives an idea about myocardial fibers deformation; thus, it can detect early impairment in myocardial function even before the reduction in ejection fraction. METHODS: This study aims to assess the ability of left ventricular CMR-FT in the early detection of systolic dysfunction in ß thalassemia major patients and to correlate it with the degree of myocardial iron overload measured by CMR T2*. This prospective study enrolled 57 ß thalassemia major patients who received long-term blood transfusion and 20 healthy controls. CMR was used to evaluate left ventricular volumes, ejection fraction, and the amount of myocardial T2*. A two-dimensional left ventricular FT analysis was performed. Both global and segmental left ventricular strain values were obtained. RESULTS: The mean global circumferential strain (GCS) and global radial strain (GRS) values were significantly lower in patients compared to control (P = 0.002 and P = 0.006, respectively). No correlation was found between T2* values and ejection fraction; however, there was a significant correlation between T2* values and GCS and GRS (P = 0.012 and P = 0.025, respectively) in thalassemia patients. Regional strain revealed significantly lower values of GCS and GRS in basal regions compared to apical ones (P = 0.000). CONCLUSIONS: Our study revealed that CMR-FT can play a role in the early detection of systolic impairment in thalassemia patients.

Skin complications during iron chelation therapy for beta-thalassemia: overview and treatment approach.

Thalassemia is an inherited genetic disorder of hemoglobin that affects a large population worldwide, and it is estimated that between 50,000 and 60,000 infants with thalassemia are born each year. The most common treatment for thalassemia is blood transfusion, which leads to iron overload. This in itself is a serious clinical condition, and is commonly managed with iron chelation therapy. However, iron chelators can cause various skin complications, including hyperpigmentation, skin rash, itching, and photosensitivity. These skin side effects can impact patients' quality of life. Therefore, this article provides a comprehensive overview of skin complications caused by iron chelators, along with a proposed comprehensive approach to their management in patients with beta-thalassemia. Key strategies include patient education, regular skin assessment, sun protection measures, symptomatic relief with topical corticosteroids and antihistamines, and consideration of treatment modification if severe complications occur. Collaboration between hematologists and dermatologists, along with psychological support and regular follow-up, is an essential component of this multidisciplinary approach. By implementing these strategies, healthcare providers can optimize skin care for patients with beta-thalassemia treated with iron chelators and improve their quality of life.

A Novel Frameshift Mutation of HBB Causing Dominant ß-Thalassemia in a Chinese Individual.

We reported a rare ß-thalassemia patient, a 41-year-old Chinese male with small cell hypopigmentation anemia, jaundice and splenomegaly as the main clinical symptoms. By using Next-Generation Sequencing (NGS), we identified a novel de novo HBB mutation(c.358_365dup, p.Phe123Alafs*39) which resulted in an abnormally prolonged ß-globin chain comprising 159 amino acid residues. The secondary and three-dimensional structures of the ß-globin predicted that the novel prolonged ß-globin chain has a considerable risk of instability in the hemoglobin, and leads to clinical phenotype. This study contributes to the enrichment of the genetic pathogenic mutation database for thalassemia and underscores the significance of NGS in the screening of mutations for thalassemia families.

Correlation between plasma biochemical parameters and cardio-hepatic iron deposition in thalassemia major patients.

INTRODUCTION: Major Thalassemia patients suffer from iron overload and organ damage, especially heart and liver damage. Early diagnosis and treatment with a chelator can reduce the complications and mortality of iron overload. Therefore, we aimed to investigate the biochemical and hematological predictors as an alternative and indirect indicator of iron deposition in heart and liver cells in comparison with the MRI T2* method as the gold standard. MATERIAL AND METHOD: MRI T2* was evaluated in the heart and liver tissues of 62 major beta-thalassemia patients undergoing regular transfusion and chelator therapy. Biochemical and hematological factors were also measured, including serum ferritin, serum electrolytes, liver enzymes, hemoglobin, blood glucose, and serum magnesium. The correlation between these factors was assessed using statistical evaluations. RESULT: Serum ferritin had a positive and significant correlation with liver siderosis based on MRI T2* (p-value = .015), and no significant association was observed with cardiac siderosis (p-value = .79). However, there was a significant positive correlation between cardiac iron deposition and fasting blood sugar level (p-value = -.049), and plasma level of liver enzymes (alanine aminotransferase (ALT) (p-value = .001), aspartate aminotransferase (AST ((p-value = .01)). Moreover, there was a significant negative correlation between cardiac iron overload and plasma magnesium level (p-value = .014). According to MRI T2*, there was no significant correlation between cardiac and hepatic iron overload (p value = .36). CONCLUSION: An increase in blood sugar or liver enzymes and a decrease in serum magnesium was associated with an increase in cardiac iron overload based on MRI T2*. Liver iron overload based on MRI T2* had a significant correlation with serum ferritin.

Genetic Correlation of HBB, HFE and HAMP Genes to Endocrinal Complications in Egyptian Beta Thalassemia Major Patients.

Iron loading is regarded as the primary cause of endocrine abnormalities in thalassemia major patients. Thus, the purpose of the current research was to explore the impact of thalassemia genotypes, hepcidin antimicrobial peptide (HAMP) and hereditary hemochromatosis (HFE) gene variants, and hepcidin expression on serum ferritin and endocrinal complications in thalassemia patients. The study comprised fifty beta-thalassemia cases and fifty age- and sex-matched controls. Genotyping of the Beta-globin gene (HBB), HAMP, and exon 2 of the HFE gene was performed using Sanger sequencing. C282Y (c.845G > A) variant of the HFE gene was determined by PCR-RFLP. Hepcidin mRNA expression was assessed by qRT-PCR. Biochemical and hormonal studies were done for all patients. Hypogonadism and short stature were found in 56% and 20% of the investigated cases, respectively. Molecular studies reported a statistically higher frequency of the HAMP variant c.-582A > G in thalassemic patients than controls. Significant downregulation of hepcidin expression was found in cases compared to healthy subjects that was significantly associated with short stature. Considering the thalassemia alleles, the IVSI.1G > A (ß0) allele was statistically related to hypogonadism. Our results proposed that thalassemia genotypes and downregulated hepcidin expression were the potential risk factors for endocrinopathies in our cases. We also demonstrated an increased incidence of the HAMP promoter variant c.- 582A > G that might have a role in the pathogenesis of iron overload in thalassemic cases. Significant downregulation of hepcidin expression, that contributes to increased iron burden, could be used as a future therapeutic target in these patients.

Red Cell Alloimmunisation Among Sickle Cell Disease and Thalassemia Patients Following Rh- and K-Matched Red Cell Transfusion in Southwestern Saudi Arabia: A Multicenter Study.

Background: Alloimmunisation remains a major consequence of blood transfusion among sickle cell disease (SCD) and thalassemia patients due to the exposure to non-self-red blood cell (RBC) antigen. The complication is associated with transfusion reactions and delayed transfusion procedure because of the difficulty of finding compatible blood. This study aims to determine the prevalence of alloimmunisation to RBC and alloantibody specificities among SCD and thalassemia patients in, an endemic area of SCD and thalassemia, Jazan province of Saudi Arabia, from three major hospitals. Methods: This is a retrospective, multicenter cross-sectional study conducted on 1027 patients with SCD and thalassemia, which received Rh/K matched transfusions in 2019 in the three centers. Demographic data and medical records of participants from three transfusion institutions were collected and analysed. Results: A total of 1027 were enrolled in the cohort; 906 (88.2%) and 121 (11.8%) patients with SCD and thalassemia, respectively. There were 483 (47%) males and 544 (53%) females with median age of 15 (range 1-48). Among the studied population, 78 were alloimmunised with an overall alloimmunisation rate of 7.6%. These patients developed a total of 108 alloantibodies, and anti-E was the most detected antibody (25.9%) followed by anti-K (24.1%). Conclusion: The overall rate of alloimmunisation to RBC antigen among the studied population in Jazan was low compared to other areas in the country. Most alloantibodies detected were against E and K antigens. The knowledge of most encountered alloantibodies in our population will aid in selecting the most appropriate antigen-negative red cells. Further research, however, is needed to explore factors associated with residual risk of alloimmunisation in these patients.

Prevalence of HIV, hepatitis B and hepatitis C infections among patients with thalassemia attending a tertiary care (rural) hospital.

Introduction: The Sunderban area of West Bengal is home to tribal and religious minorities inhabiting various islands. There is a high prevalence of thalassemia among poverty-stricken residents of this region living with meagre health care facilities. This work was planned to determine the proportion of four viral transfusion-transmitted infections (TTIs): HIV-1, HIV-2, hepatitis B virus (HBV) and hepatitis C virus (HCV) among thalassemia patients attending the sole rural medical college in the region. Materials and Methods: Thalassemia patients (n = 359, age ranging from 1 year to 60 years) attending the thalassemia clinic or being admitted to the indoor facilities for better management were included in the study. Only patients diagnosed with high-performance liquid chromatography (HPLC) and with classical clinical features were included in the study. Blood samples of these patients were tested for HIV as per NACO protocol. For HBV and HCV, samples were first tested serologically; reactive samples were collected and sent in the cold chain to a higher centre for nucleic acid amplification testing (NAAT) for qualitative and quantitative estimation. Clinical and laboratory data was collected, patients were followed up for complications and hospitalisation during the study period, and statistical analysis was performed. Results: Majority of our patients had E-beta-thalassemia (245, 59.81%), followed by beta-thalassemia major (102, 28.30%). NAAT-confirmed HCV infection (14.21%) infection was the most common, followed by HBV (2.51%), and lastly by HIV-1 (0.58%) infection. Among infected thalassemia patients, the mean HCV RNA was 741063 ± 438514.67 IU/ml while the mean HBV DNA level was 4082863 ± 7298514 IU/ml. Co-infections of HIV-1 and HCV and that of HBV and HCV were noted in one patient each (0.28%). HCV-related liver disease (14.21%) and growth retardation (10.31%) were the most typical complication noted, and death occurred in five patients (1.39%) during the study period. Conclusion: Primary care physicians should know HCV infection is the most common TTI among thalassemia patients in rural eastern India.

A Novel ß-Globin Variant, Hb Odder [HBB: C.316C > G; CD105 (Leu > Val)].

We report the discovery of a novel ß-globin gene variant, Hb Odder, characterized by a single nucleotide substitution; HBB:c.316C > G; CD105 (Leu > Val). This variant emerged incidentally during routine HbA1c measurements for diabetes monitoring. The patient exhibited no clinical or biochemical evidence of anemia or hemolysis. Our data on this variant suggest that Hb Odder is benign, regrettably limitations in our data make formal evaluations of stability and oxygen affinity impossible; additionally this emphasizes the importance of considering hemoglobin variants in the differential diagnosis of abnormal Hb A1c levels and suggest that laboratories should use alternative methods for the correct measurement of Hb A1c when hemoglobin variants interfere with diabetes monitoring. Notably, three other mutations have been described at codon 105 of the ß globin chains and correspond to three Hb variants with different characteristics: Hb South Milwaukee, Hb Bellevue IV and Hb St. George.

The German sickle cell disease registry reveals a surprising risk of acute splenic sequestration and an increased transfusion requirement in patients with compound heterozygous sickle cell disease HbS/ß-thalassaemia and no or low HbA expression.

Patients with sickle cell disease (SCD) in Germany exhibit a substantial genetic diversity in the ß-globin genotype. Data collected by the national German SCD registry reflect this diversity and allowed us to analyze the phenotypes associated with different SCD genotypes. Our study focused on 90 patients with HbS/ß-thalassaemia (HbS/ß-thal) and compared these to patients with HbSS and HbSC. Patients with HbS/ß-thal were classified into three groups: HbS/ß0-thal (no HbA), HbS/ß+-thal (HbA < 14%), and HbS/ß++-thal (HbA≥14%). In comparison to HbSS, patients with HbS/ß++-thal had higher Hb-levels, lower hemolytic activity and rarely required red blood cell transfusions. HbS/ß0-thal and HbS/ß+-thal closely resembled each other and are jointly referred to as HbS/ß0/+-thal. Compared to HbSS, patients with HbS/ß0/+-thal experienced a similar frequency of vasoocclusive crises and degree of hemolysis. However, the frequency of red blood cell transfusions (0.6 vs. 0.39/year, p = .0049) and splenic sequestration crises (42.4 vs. 15.5% of patients, p = 3.799e-05) was higher in HbS/ß0/+-thal than in HbSS, but close to zero in HbS/ß++-thal. In conclusion, the level of HbA expression determines the phenotype of HbS/ß+-thal. HbS/ß-thal expressing no or little HbA is hematologically similar to HbSS, but causes a previously unknown high risk of splenic sequestration.

Evaluation of microstructural changes in the brain in transfusion dependent thalassemia patients with advanced magnetic resonance imaging techniques.

PURPOSE: Transfusion-dependent thalassemia (TDT) is associated with iron accumulation in the body and an increased tendency for thrombosis. With the increased life expectancy in these patients, the detection of neurocognitive complications has gained importance. This study investigates the microstructural changes in TDT patients using advanced diffusion MRI techniques and their relationship with laboratory parameters. METHODS: The study included 14 TDT patients and 14 control subjects. Tract-based spatial statistics (TBSS) were used to examine differences in DTI parameters such as fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) in thalassemia patients using multi-shell DWI images. The mean kurtosis (MK) difference was investigated using diffusion kurtosis imaging. Fiber density (FD), fiber cross-section (FC), and fiber density and cross-section (FDC) differences were examined using fixel-based analysis. In the patient group, correlative tractography was used to investigate the relationship between DTI parameters and platelet (PLT) and ferritin levels. RESULTS: Increase in RD and MD was observed, particularly in the white matter tracts of the corona radiata in patient group. Additionally, an increase in AD was detected in a limited area. Correlative tractography in thalasemia patients showed a positive correlation between increases in RD, MD, and AD with PLT and ferritin. Fixel-based analysis demonstrated a dispersed distribution in white matter fibers, with a more pronounced decrease in FD, FC, and FDC in the internal capsule. CONCLUSION: There is widespread involvement in the white matter and fiber tracts in thalassemia patients, which is highly correlated with thrombotic parameters.

Association of serum ferritin trends with liver enzyme patterns in ß-thalassemia major: A longitudinal correlational study.

Background: ß-Thalassemia major patients require lifelong blood transfusions, leading to iron overload and liver injury. This study examines the longitudinal association between serum ferritin and liver function over 5 years in pediatric patients. Methods: This retrospective study included 582 transfusion-dependent thalassemia patients aged 1-18 years. Serum ferritin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and albumin were measured annually. Correlation and linear regression analyses assessed associations between ferritin trajectories and liver enzymes. Results: Mean ferritin rose from 1820 ± 960 ng/mL at baseline to 4500 ± 1900 ng/mL at year 5, indicating worsening iron overload. AST and ALT levels also steadily climbed over follow-up, whereas albumin declined slightly. Ferritin correlated positively with AST (r = 0.675, P < 0.01) and ALT (r = 0.607, P < 0.01), but not with albumin (r = -0.143, P = 0.153) annually. The regression interaction term showed within-patient ferritin increases over time were independently associated with escalating AST and ALT (P < 0.05), after adjusting for confounders. Conclusion: Rising ferritin levels predict progressive liver injury in regularly transfused pediatric thalassemia patients. Tighter control of iron overload may help preserve hepatic function.

Assessing NESTROFT as a preliminary screening tool for thalassemia in the Malayali tribes of Dharmapuri district, Tamil Nadu, India.

Background: Mutations affecting transcription, translation, or beta-globin stability, among other stages of beta-globin production, cause beta-thalassemia. Methods: Beta-thalassemia results in a high red blood cell count with a low mean corpuscular volume (60-70fl) and mean corpuscular hemoglobin (19-23pg), and Naked Eye Single Tube Red Cell Osmotic Fragility Test (NESTROFT) is recommended for mass screening of populations. Among tribals in Dharmapuri district, this cross-sectional analysis evaluated the efficacy of RBC and NESTROFT against HPLC, regarded as the gold standard, in a study involving 484 subjects. Results: Findings indicated that out of the 484 samples, 73 tested positive for the beta-thalassemia trait through HPLC. The NESTROFT test demonstrated 87% sensitivity, 98.5% specificity, a positive predictive value of 99.3%, and a negative predictive value of 73.3%. In the multivariate analysis, NESTROFT and hemoglobin showed high significance with P values of 0.003 and 0.000, respectively. Conclusion: NESTROFT's high sensitivity is particularly noteworthy due to the absence of research among the Malayali tribes in the Dharmapuri district. Adoption of this preliminary test shows promise in detecting the disease at the local level, providing important information for early detection, especially considering the sizeable tribal population.

Effects of thalassemia minor on umbilical artery blood flow and perinatal outcomes in pregnancy: A retrospective cohort study.

OBJECTIVE: The aim of the present study was to compare the fetal umbilical artery blood flow parameters in the third trimester and perinatal outcomes between pregnant women with and without thalassemia minor in South China. METHODS: This was a retrospective cohort study. Doppler ultrasound was used to detect fetal umbilical artery hemodynamics in pregnant women with or without thalassemia minor during the third trimester. The main parameters assessed were umbilical artery peak systolic flow velocity/end-diastolic flow velocity (S/D), resistance index (RI), pulsation index (PI), and relevant perinatal outcomes. RESULTS: This study included 540 pregnant women, 180 with thalassemia minor and 360 being healthy controls. In the third trimester, the thalassemia minor group had higher umbilical artery S/D (P = 0.002), RI (P = 0.002), and PI (P = 0.012) than healthy pregnant women, as well as lower levels of hemoglobin (Hb) (P < 0.001) and higher ferritin levels (P < 0.001). Compared to the non-thalassemia group, neonatal body weight in the thalassemia minor group was significantly lower (P = 0.001). Additionally, the incidence of maternal anemia (odds ratio [OR] 3.92; 95% confidence interval [CI]: 2.57-5.99, P < 0.001), low birth weight (OR 15.35; 95% CI: 1.71-137.93, P = 0.015), fetal distress (OR 2.18; 95% CI: 1.12-4.26, P = 0.023), neonatal asphyxia (OR 12.81; 95% CI: 1.40-117.33, P = 0.024), oligohydramnios (OR 18.25; 95% CI: 2.21-150.36, P = 0.007) and Apgar score <7 at 1 min after birth (OR 7.97; 95% CI: 1.53-41.54, P = 0.014) was significantly higher in the thalassemia minor group. CONCLUSION: Pregnant women with thalassemia minor have higher umbilical artery S/D, RI and PI during the third trimester and a higher risk of adverse perinatal outcomes.

Casgevy: Innovative Medicinal Products Require Innovative Approaches to Regulatory Assessment.

Casgevy (exa-cel) is an autologous cellular therapy modified ex vivo by a CRISPR-Cas9-mediated gene-editing technology. For Casgevy to be granted the indication in transfusion-dependent ß-thalassemia, one single-arm trial was submitted which was not amenable to conventional statistical analysis of 'effect of cause'. Therefore, an analysis was conducted on the basis of 'cause of effect' making use of the scheme described by Toulmin coupled to an analysis of causal inference. Based on the current data within the submitted study: subjects with transfusion-dependent ß-thalassemia no longer needed a red blood cell transfusion with a 93-percent probability if and only if administered Casgevy; PNS = 93%. It is acknowledged that unknown elements of safety may yet be revealed by long-term follow-up of recipients of Casgevy. Its durability of efficacy is, at present, also an unknown that may also be ascertained by long-term follow-up of recipients. The limitations of a causal analysis are related to assumptions of the proposed causal structure which may not capture the complexity of the real world. Overall, the claim that Casgevy is indicated to treat people with transfusion-dependent ß-thalassemia is considered to be supported by the results of the submitted study; the benefit-risk evaluation of Casgevy is found to be positive.