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JAMA Pediatrics Aug 2023Little is known about the association between sickle cell disease (SCD) and severe maternal morbidity (SMM). (Comparative Study)
Comparative Study
IMPORTANCE
Little is known about the association between sickle cell disease (SCD) and severe maternal morbidity (SMM).
OBJECTIVE
To examine the association of SCD with racial disparities in SMM and with SMM among Black individuals.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study was a retrospective population-based investigation of individuals with and without SCD in 5 states (California [2008-2018], Michigan [2008-2020], Missouri [2008-2014], Pennsylvania [2008-2014], and South Carolina [2008-2020]) delivering a fetal death or live birth. Data were analyzed between July and December 2022.
EXPOSURE
Sickle cell disease identified during the delivery admission by using International Classification of Diseases, Ninth Revision and Tenth Revision codes.
MAIN OUTCOMES AND MEASURES
The primary outcomes were SMM including and excluding blood transfusions during the delivery hospitalization. Modified Poisson regression was used to estimate risk ratios (RRs) adjusted for birth year, state, insurance type, education, maternal age, Adequacy of Prenatal Care Utilization Index, and obstetric comorbidity index.
RESULTS
From a sample of 8 693 616 patients (mean [SD] age, 28.5 [6.1] years), 956 951 were Black individuals (11.0%), of whom 3586 (0.37%) had SCD. Black individuals with SCD vs Black individuals without SCD were more likely to have Medicaid insurance (70.2% vs 64.6%), to have a cesarean delivery (44.6% vs 34.0%), and to reside in South Carolina (25.2% vs 21.5%). Sickle cell disease accounted for 8.9% and for 14.3% of the Black-White disparity in SMM and nontransfusion SMM, respectively. Among Black individuals, SCD complicated 0.37% of the pregnancies but contributed to 4.3% of the SMM cases and to 6.9% of the nontransfusion SMM cases. Among Black individuals with SCD compared with those without, the crude RRs of SMM and nontransfusion SMM during the delivery hospitalization were 11.9 (95% CI, 11.3-12.5) and 19.8 (95% CI, 18.5-21.2), respectively, while the adjusted RRs were 3.8 (95% CI, 3.3-4.5) and 6.5 (95% CI, 5.3-8.0), respectively. The SMM indicators that incurred the highest adjusted RRs included air and thrombotic embolism (4.8; 95% CI, 2.9-7.8), puerperal cerebrovascular disorders (4.7; 95% CI, 3.0-7.4), and blood transfusion (3.7; 95% CI, 3.2-4.3).
CONCLUSIONS AND RELEVANCE
In this retrospective cohort study, SCD was found to be an important contributor to racial disparities in SMM and was associated with an elevated risk of SMM among Black individuals. Efforts from the research community, policy makers, and funding agencies are needed to advance care among individuals with SCD.
Topics: Adult; Female; Humans; Pregnancy; Anemia, Sickle Cell; Black People; Cohort Studies; Morbidity; Retrospective Studies; United States; Pregnancy Outcome; Pregnancy Complications, Hematologic; White; Health Status Disparities
PubMed: 37273202
DOI: 10.1001/jamapediatrics.2023.1580 -
Cells May 2024Sickle cell disease (SCD) is the most common genetic blood disorder in the United States, with over 100,000 people suffering from this debilitating disease. SCD is... (Review)
Review
Sickle cell disease (SCD) is the most common genetic blood disorder in the United States, with over 100,000 people suffering from this debilitating disease. SCD is caused by abnormal hemoglobin (Hb) variants that interfere with normal red blood cell (RBC) function. Research on SCD has led to the development and approval of several new SCD therapies in recent years. The recent FDA-approved novel gene therapies are potentially curative, giving patients an additional option besides a hematopoietic bone marrow transplant. Despite the promise of existing therapies, questions remain regarding their long-term pharmacological effects on adults and children. These questions, along with the exorbitant cost of the new gene therapies, justify additional research into more effective therapeutic options. Continual research in this field focuses on not only developing cheaper, more effective cures/treatments but also investigating the physiological effects of the current therapies on SCD patients, particularly on the brain and kidneys. In this article, we undertake a comprehensive review of ongoing clinical trials with completion dates in 2024 or later. Our exploration provides insights into the landscape of current therapeutics and emerging novel therapies designed to combat and potentially eradicate SCD, including the latest FDA-approved gene therapies.
Topics: Humans; Anemia, Sickle Cell; Genetic Therapy; Clinical Trials as Topic
PubMed: 38786070
DOI: 10.3390/cells13100848 -
Blood Reviews May 2024Recent advancements in gene editing illuminate new potential therapeutic approaches for Sickle Cell Disease (SCD), a debilitating monogenic disorder caused by a point... (Review)
Review
Recent advancements in gene editing illuminate new potential therapeutic approaches for Sickle Cell Disease (SCD), a debilitating monogenic disorder caused by a point mutation in the β-globin gene. Despite the availability of several FDA-approved medications for symptomatic relief, allogeneic hematopoietic stem cell transplantation (HSCT) remains the sole curative option, underscoring a persistent need for novel treatments. This review delves into the growing field of gene editing, particularly the extensive research focused on curing haemoglobinopathies like SCD. We examine the use of techniques such as CRISPR-Cas9 and homology-directed repair, base editing, and prime editing to either correct the pathogenic variant into a non-pathogenic or wild-type one or augment fetal haemoglobin (HbF) production. The article elucidates ways to optimize these tools for efficacious gene editing with minimal off-target effects and offers insights into their effective delivery into cells. Furthermore, we explore clinical trials involving alternative SCD treatment strategies, such as LentiGlobin therapy and autologous HSCT, distilling the current findings. This review consolidates vital information for the clinical translation of gene editing for SCD, providing strategic insights for investigators eager to further the development of gene editing for SCD.
Topics: Humans; Gene Editing; CRISPR-Cas Systems; Anemia, Sickle Cell; Hemoglobinopathies; Fetal Hemoglobin
PubMed: 38493007
DOI: 10.1016/j.blre.2024.101185 -
Medicina (Kaunas, Lithuania) Dec 2023: Pain management poses a significant challenge for patients experiencing vaso-occlusive crisis (VOC) in sickle cell disease (SCD). While opioid therapy is highly...
: Pain management poses a significant challenge for patients experiencing vaso-occlusive crisis (VOC) in sickle cell disease (SCD). While opioid therapy is highly effective, its efficacy can be impeded by undesirable side effects. Local regional anesthesia (LRA), involving the deposition of a perineural anesthetic, provides a nociceptive blockade, local vasodilation and reduces the inflammatory response. However, the effectiveness of this therapeutic approach for VOC in SCD patients has been rarely reported up to now. The objective of this study was to assess the effectiveness of a single-shot local regional anesthesia (LRA) in reducing pain and consequently enhancing the management of severe vaso-occlusive crisis (VOC) in adults with sickle cell disease (SCD) unresponsive to conventional analgesic therapy. : We first collected consecutive episodes of VOC in critical care (ICU and emergency room) for six months in 2022 in a French University hospital with a large population of sickle cell patients in the West Indies population. We also performed a systematic review of the use of LRA in SCD. The primary outcome was defined using a numeric pain score (NPS) and/or percentage of change in opioid use. : We enrolled nine SCD adults (28 years old, 4 females) for ten episodes of VOC in whom LRA was used for pain management. Opioid reduction within the first 24 h post block was -75% (50 to 96%). Similarly, the NPS decreased from 9/10 pre-block to 0-1/10 post-block. Five studies, including one case series with three patients and four case reports, employed peripheral nerve blocks for regional anesthesia. In general, local regional anesthesia (LRA) exhibited a reduction in pain and symptoms, along with a decrease in opioid consumption post-procedure. : LRA improves pain scores, reduces opioid consumption in SCD patients with refractory pain, and may mitigate opioid-related side effects while facilitating the transition to oral analgesics. Furthermore, LRA is a safe and effective procedure.
Topics: Adult; Female; Humans; Pain Management; Retrospective Studies; Analgesics, Opioid; Volatile Organic Compounds; Pain; Analgesics; Anemia, Sickle Cell
PubMed: 38138299
DOI: 10.3390/medicina59122196 -
Acta Obstetricia Et Gynecologica... Aug 2023Sickle cell trait (SCT) is common in African descendants. Its association with several adverse pregnancy outcomes (APOs) has been reported but remains inconsistent. The...
INTRODUCTION
Sickle cell trait (SCT) is common in African descendants. Its association with several adverse pregnancy outcomes (APOs) has been reported but remains inconsistent. The objectives of this study are to test associations of SCT with APOs in non-Hispanic Black women, including (1) validate the associations of SCT with previously reported APOs, (2) test novel associations of SCT with broad spectrum of APOs, and (3) estimate the attributable risk of SCT for implicated APOs.
MATERIAL AND METHODS
This is a retrospective analysis of a prospectively designed population-based cohort. Women/participants were self-reported non-Hispanic Black women from the UK Biobank (UKB). SCT status was determined based on heterozygous Glu6Val in the HBB gene. Several APOs were studied, including four previously reported SCT-associated APOs (preeclampsia, bacteriuria, pregnancy loss, and preterm delivery), and broad conditions related to pregnancy, childbirth, and the puerperium. APOs were curated by experts' peer review and consensus processes. Associations of SCT with APOs were tested by estimating its relative risk and 95% confidence interval (95% CI), adjusting for number of live births and age at first birth. Attributable risk proportion (ARP) and population attributable risk proportion (PARP) of SCT to APOs were estimated.
RESULTS
Among the 4057 self-reported non-Hispanic Black women with pregnancy records in the UKB, 581 (14.32%) were SCT carriers. For four previously reported SCT-associated APOs, two were confirmed at a nominal P < 0.05; relative risk (RR) was 2.39 (95% CI 1.09-5.23) for preeclampsia, and 4.85 (95% CI 1.77-13.27) for bacteriuria. SCT contributed substantially to these two APOs among SCT carriers, with attributable risk proportion estimated at 61.00% and 68.96% for preeclampsia and bacteriuria, respectively. SCT also contributed substantially to these two APOs in the population (self-reported Black UK women), with population attributable risk proportion estimated at 18.30% and 24.14% for preeclampsia and bacteriuria, respectively. In addition, novel associations were found for seven other APOs (nominal P < 0.05).
CONCLUSIONS
SCT is significantly associated with APOs in this study and contributes substantially to APOs among self-reported Black women in the UK. Confirmation of these findings in independent study populations is required.
Topics: Pregnancy; Infant, Newborn; Humans; Female; Pregnancy Outcome; Sickle Cell Trait; Retrospective Studies; Pre-Eclampsia; Bacteriuria; Risk Factors
PubMed: 37358249
DOI: 10.1111/aogs.14622 -
International Journal of Molecular... Aug 2023Thalassemia is a heterogeneous congenital hemoglobinopathy common in the Mediterranean region, Middle East, Indian subcontinent, and Southeast Asia with increasing... (Review)
Review
Thalassemia is a heterogeneous congenital hemoglobinopathy common in the Mediterranean region, Middle East, Indian subcontinent, and Southeast Asia with increasing incidence in Northern Europe and North America due to immigration. Iron overloading is one of the major long-term complications in patients with thalassemia and can lead to organ damage and carcinogenesis. Hepatocellular carcinoma (HCC) is one of the most common malignancies in both transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT). The incidence of HCC in patients with thalassemia has increased over time, as better chelation therapy confers a sufficiently long lifespan for the development of HCC. The mechanisms of iron-overloading-associated HCC development include the increased reactive oxygen species (ROS), inflammation cytokines, dysregulated hepcidin, and ferroportin metabolism. The treatment of HCC in patients with thalassemia was basically similar to those in general population. However, due to the younger age of HCC onset in thalassemia, regular surveillance for HCC development is mandatory in TDT and NTDT. Other supplemental therapies and experiences of novel treatments for HCC in the thalassemia population were also reviewed in this article.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Thalassemia; Patients; Iron Overload; Iron
PubMed: 37628834
DOI: 10.3390/ijms241612654 -
American Journal of Hematology Oct 2023Sickle cell disease (SCD) remains prevalent because heterozygous carriers (HbAS) are partially resistant to Plasmodium falciparum malaria. Sickle hemoglobin (HbS)...
BACKGROUND
Sickle cell disease (SCD) remains prevalent because heterozygous carriers (HbAS) are partially resistant to Plasmodium falciparum malaria. Sickle hemoglobin (HbS) polymerization in low and intermediate oxygen (O ) conditions is the main driver of HbAS-driven resistance to P. falciparum malaria. However, epidemiological studies have reported mixed malaria morbidity and mortality outcomes in individuals with sickle cell disease (SCD). While maximum-tolerated dose hydroxyurea has been shown to lower malaria incidence, fetal hemoglobin (HbF), an inhibitor of HbS polymerization that is variably packaged in F-erythrocytes, might provide hemoglobin that is accessible to the parasite for feeding.
METHODS
To explore that risk, we examined the effect of variable mean corpuscular fetal hemoglobin (MCHF) on P. falciparum proliferation, invasion, and development in HbSS RBCs.
RESULTS
We found that greater MCHF in HbSS red blood cells (RBCs) is associated with increased P. falciparum proliferation in O environments comparable with the microcirculation. Moreover, both parasite invasion and intracellular growth, the major components of proliferation, occur predominantly in F-erythrocytes and are augmented with increasing MCHF.
CONCLUSIONS
HbF modifies P. falciparum infection in HbSS RBCs, further highlighting the complexity of the molecular interactions between these two diseases. Other inhibitors of HbS polymerization that do not increase HbF or F-erythrocytes should be independently assessed for their effects on P. falciparum malaria proliferation in HbSS RBCs.
Topics: Humans; Anemia, Sickle Cell; Plasmodium falciparum; Malaria, Falciparum; Fetal Hemoglobin; Cell Proliferation; Erythrocytes
PubMed: 37584425
DOI: 10.1002/ajh.27042 -
Blood Advances Dec 2023
Topics: Humans; Anemia, Sickle Cell; Genetic Therapy; Risk Assessment
PubMed: 38085553
DOI: 10.1182/bloodadvances.2023011606 -
PloS One 2023Sickle cell disease (SCD) is an inherited blood disorder in which sickle hemoglobin (HbS) polymerizes, leading to red blood cell sickling and chronic hemolytic anemia,... (Meta-Analysis)
Meta-Analysis
Sickle cell disease (SCD) is an inherited blood disorder in which sickle hemoglobin (HbS) polymerizes, leading to red blood cell sickling and chronic hemolytic anemia, vaso-occlusive crises, and end-organ damage associated with early mortality. Despite standard of care, patients with SCD still experience complications and early mortality, highlighting remaining unmet treatment needs. Voxelotor is a first-in-class HbS polymerization inhibitor approved by the US Food and Drug Administration as a treatment for SCD and by the European Medicines Agency for hemolytic anemia due to SCD. In clinical studies, voxelotor has been shown to increase hemoglobin (Hb) and decrease hemolytic markers in patients with SCD. The objective of this study was to estimate the impact of voxelotor on the burden of SCD in France using a modeling approach, accounting for its anticipated adoption and diffusion over the next 5 years. We designed a sequential multi-cohort model to project and compare the cumulative incidence of SCD complications over a 20-year time horizon in a world with and without voxelotor. A distribution of patients was simulated across various levels of Hb response based on the phase 3 HOPE trial results, and relative risk reduction was adjusted using published meta-analysis results that projected risk reduction due to a 1 g/dL increase in Hb. In 6100 modeled patients with SCD treated with voxelotor, the model projected the number of deaths to decrease by 39.4%, with an increase of 1.8% in life-years gained. The model also projected life expectancy to increase by 15.8%, and incident cases of stroke, pulmonary hypertension, and chronic kidney disease to decrease by 19.8%, 24.5%, and 25.1%, respectively. The model suggests that improving Hb using a treatment such as voxelotor may have a positive public health impact by reducing the burden of SCD for patients and the healthcare system.
Topics: United States; Humans; Public Health; Anemia, Sickle Cell; Benzaldehydes; Hemoglobin, Sickle; France
PubMed: 37703228
DOI: 10.1371/journal.pone.0291211 -
Nature Communications Oct 2023β-thalassemia is a prevalent genetic disorder causing severe anemia due to defective erythropoiesis, with few treatment options. Studying the underlying molecular...
β-thalassemia is a prevalent genetic disorder causing severe anemia due to defective erythropoiesis, with few treatment options. Studying the underlying molecular defects is impeded by paucity of suitable patient material. In this study we create human disease cellular model systems for β-thalassemia by gene editing the erythroid line BEL-A, which accurately recapitulate the phenotype of patient erythroid cells. We also develop a high throughput compatible fluorometric-based assay for evaluating severity of disease phenotype and utilize the assay to demonstrate that the lines respond appropriately to verified reagents. We next use the lines to perform extensive analysis of the altered molecular mechanisms in β-thalassemia erythroid cells, revealing upregulation of a wide range of biological pathways and processes along with potential novel targets for therapeutic investigation. Overall, the lines provide a sustainable supply of disease cells as research tools for identifying therapeutic targets and as screening platforms for new drugs and reagents.
Topics: Humans; beta-Thalassemia; Erythropoiesis; Erythroid Cells; Phenotype
PubMed: 37803026
DOI: 10.1038/s41467-023-41961-9