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IntroductionPeople with African ancestry have greater stroke risk and greater heritability of stroke risk than people of other ancestries. Given the importance of nitric oxide (NO) in stroke, and recent evidence that alpha globin restricts nitric oxide release from vascular endothelial cells, we hypothesized that alpha globin gene (HBA)deletion would be associated with reduced risk of incident ischemic stroke.MethodsWe evaluated 8,947 participants self-reporting African ancestry in the national, prospective Reasons for Geographic And Racial Differences in Stroke (REGARDS) cohort. Incident ischemic stroke was defined as non-hemorrhagic stroke with focal neurological deficit lasting ≥ 24 hours confirmed by the medical record or focal or non-focal neurological deficit with positive imaging confirmed with medical records. Genomic DNA was analyzed using droplet digital PCR to determineHBAcopy number. Multivariable Cox proportional hazards regression was used to estimate the hazard ratio (HR) ofHBAcopy number on time to first ischemic stroke.ResultsFour-hundred seventy-nine (5.3%) participants had an incident ischemic stroke over a median (IQR) of 11.0 (5.7, 14.0) years’ follow-up.HBAcopy number ranged from 2 to 6: 368 (4%) -α/-α, 2,480 (28%) -α/αα, 6,014 (67%) αα/αα, 83 (1%) ααα/αα and 2 (HBAcopy number was 1.04; 95%CI 0.89, 1.21; p = 0.66.ConclusionsAlthough a reduction inHBAcopy number is expected to increase endothelial nitric oxide signaling in the human vascular endothelium,HBAcopy number was not associated with incident ischemic stroke in this large cohort of Black Americans.

Growing recognition that the ovary is an end organ in sickle cell disease (SCD), advances in SCD treatment and cure, and innovations in assisted reproductive technologies invite progressive challenges in fertility care for women with SCD. The reproductive life span of women with SCD may be reduced because ovarian reserve declines more rapidly in people with SCD compared to unaffected people. Some young women have diminished ovarian reserve, a risk factor for infertility. Referrals for fertility preservation may be offered and anticipatory guidance about when to seek infertility care provided. For a subset of people with SCD, this information is also applicable when pursuing in vitro fertilization with preimplantation genetic testing to avoid implantation of an embryo with SCD. Here we explore the dimensions of SCD-related fertility care illustrated by the case of a 28-year-old woman with hemoglobin SS disease who initially presented for a hematology consultation for preconception counseling. This case highlights the complexity of preconception SCD management and care and the need to partner with patients to help align pregnancy hopes with SCD treatment and the many associated uncertainties.

Background High rates of unplanned pregnancy and low rates of contraception use are reported among women with sickle cell disease (SCD). Pregnancy in women with SCD is high risk and unintended pregnancies limit opportunities to provide indicated preconception care and counseling. Contraceptive use in women with SCD is complicated by a lack of disease-specific data about treatment risks and benefits. The purpose of this study was to describe, for the first time in the U.S. context, contraceptive use, knowledge and preferences in adult cohort of women with SCD. Materials and Methods A single-center survey study of women with SCD of reproductive age from our Center's adult and pediatric sickle cell centers. Results Seventy-eight women ages 28-65 years (median 33.5 years, IQR 16) completed surveys. Seventy-three percent of respondents had an average of 2.5 pregnancies (S.D. 1.22) and of these, 58% reported being pregnant when they did not want to be pregnant at least once. The most common forms of contraception used were condoms (87%), birth control pills (46%), medroxyprogesterone (44%) and withdrawal (44%). Twenty-two percent of subjects reported using a long-acting reversible form of contraception and 21% reported a tubal ligation or partner vasectomy. Respondents demonstrated low knowledge of the efficacy of contraceptive options and over-estimated the risk of pregnancy with the IUD, implant. Contraceptive priorities included pregnancy prevention, decreasing HIV transmission and effects on SCD symptoms. Conclusions Women with SCD have high rates of unintended pregnancy, low knowledge of contraceptive efficacy and low use of long-acting reversible contraception.

This review provides an overview of reproductive and sexual healthcare concerns for individuals with SCD and their families. Reproductive and sexual health care are fundamental concerns for individuals with sickle cell disease (SCD) and their families and should be so for their clinical care teams. This care is often complex, inherently multidisciplinary, and often requires clinician-initiated discussion as patients may not volunteer their intimate reproductive healthcare questions or problems. Reproductive health care is central to SCD as the disease is associated with delayed onset of puberty, sickle pain during menstruation, disease-specific contraceptive considerations, high-risk pregnancy, priapism and erectile dysfunction, and offspring certain to inherit a hemoglobinopathy trait from their affected parent. These underrecognized, undertreated, and understudied reproductive health considerations need attention in general pediatrics, in internal medicine clinics and in SCD, urology, and obstetrics and gynecology clinics.

Background Adults with sickle cell disease (SCD) on chronic transfusion therapy are exposed to a large volume of blood products, thus increasing their risk of transfusion-associated human immunodeficiency virus (HIV), hepatitis C (HCV), and hepatitis B (HBV). Methods We performed a systematic chart review of chronically transfused SCD subjects at the Johns Hopkins Sickle Cell Center for Adults between October 2014 and September 2019 to determine our Center's adherence to the 2014 National Heart, Lung and Blood Institute (NHLBI) SCD guidelines for annual screening for Transfusion Transmitted infections (TTI) and assessed HBV immunity and HBV vaccination rates. Results The study included 85 subjects with a median age of 34 years (23-63); 52% were female. No subject received annual screening; 68 subjects (80%) were screened for HIV, 60 subjects (71%) for HCV and 53 subjects (62%) for HBV infections at least once in the study period. Of those screened, one patient was newly diagnosed with HCV infection, and none with HIV or HBV infection. Among 31 subjects tested for anti-Hepatitis B surface antibody, 16 subjects (52%) tested negative. Nineteen (20%) subjects had HBV vaccination documented. Conclusions Low adherence to the NHLBI TTI screening guidelines, especially for HBV, highlights the resource intensiveness of this patient population. The low rates of anti-Hepatitis B surface antibody positivity highlight the need to confirm vaccination, provide boosters as indicated, and investigate the adults with SCD's immune response to HBV vaccination.

Introduction Opioids are used for acute and chronic pain in patients with sickle cell disease. How outpatient opioid regimens relate to acute care visits is of interest given the risks of high opioid doses and high hospital utilization. A prior study by our group suggested that outpatient opioid treatment for chronic pain could contribute to a vicious cycle of treatment-refractory acute pain, greater acute care utilization, and escalating opioid doses. The present larger naturalistic observational study was undertaken to determine whether the results were reliable across multiple acute care settings. Methods One year of clinical data on patients (n = 291) followed in the Sickle Cell Center for Adults (August 2018 to July 2019) were extracted, including visits to the emergency department, visits to the infusion center, and inpatient admissions. Outpatient opioid dosage was used to predict acute care treatment in generalized linear models that were controlled for patient, disease, and treatment characteristics. Results Outpatient opioid dosage predicted dosage during visits but did not predict visit length or pain relief. Higher outpatient opioid dosage was associated with greater number of visits. However, in post hoc analyses, this relationship was nonlinear, with a clear positive association only for those prescribed the lowest 50% of dosages. Discussion Higher outpatient opioid dosage predicted higher dosages during acute care visits to achieve the same pain score improvement, which is more consistent with opioid tolerance than with treatment-refractory pain. The relationship of outpatient opioid dosage with number of acute care visits was more complex, which suggests that opioid consumption at lower levels is driven by intermittent acute pain and opioid consumption at higher levels is driven by chronic pain.

Sickle cell disease is an umbrella term for a group of hemoglobinopathies characterized by the presence of 2 β-globin gene mutations or deletions, at least 1 of which is the point mutation that leads to the production of hemoglobin S. Sickle cell disease is associated with hemolytic anemia, significant chronic end-organ damage, and early death. In high-income countries, at least 95% of children with the disease survive into adulthood, resulting in a growing population of affected adults with significant comorbidities, complex medical issues, and not enough specialists to provide care. Hydroxyurea is the primary therapy, and recent advances in understanding disease pathophysiology have led to new therapies; progress in bone marrow transplant and gene editing has resulted in cure in some patients. The purpose of this review is to provide an overview of the diagnosis, common acute and chronic clinical manifestations, and best practices for management of sickle cell disease.

1. Lindy Zhang, MD*,† 2. Caroline DeBoer, MD†† 3. Alejandra Ellison-Barnes, MD‡ 4. Jessica Berger, MD‡‡ 5. Courtney E. Lawrence, MD*,¶ 6. Rosalyn W. Stewart, MD MS MBA‡,§ 7. Lydia H. Pecker, MD** 1. *Departments of Pediatric Hematology, 2. †Pediatric Oncology, 3. ‡Internal Medicine, and 4. §Pediatrics and 5. ¶Division of Transfusion Medicine, Department of Pathology, and 6. **Division of Hematology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD; 7. ††Advocate Aurora Healthcare, Milwaukee WI; 8. ‡‡Department of Anesthesiology and Critical Care Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 1. Address correspondence to Lindy Zhang, MD, Charlotte R. Bloomberg Children’s Center, Johns Hopkins Hospital, 1800 Orleans St, Baltimore, MD 21287. E-mail: lindyzhang{at}jhmi.edu A term boy was born via elective, repeat cesarean delivery to a mother whose prenatal laboratory tests were positive for group B Streptococcus genital infection and negative for human immunodeficiency virus, syphilis, gonorrhea, and chlamydia infections, and showed immunity for rubella. He was the third child born to this mother. The mother had no other diagnosed illnesses, including autoimmune diseases. The cesarean delivery was complicated by extensive adhesions from previous deliveries, but the delivery was atraumatic for the infant. The infant weighed 3.81 kg (82nd percentile for age), and had ABO mismatch with his mother (mother’s blood type was O+, infant’s blood type was A+). By 20 hours of age, the infant developed indirect hyperbilirubinemia (total bilirubin, 7.9 mg/dL). This elevation in bilirubin levels was attributed to ABO isoimmunization. He received 12 hours of phototherapy delivered by a fiberoptic mattress and fluorescent bulbs on an overhead lamp. On postnatal day 2, he had a circumcision, which was complicated by bleeding and required cauterization with silver nitrate. The remainder of his hospital course was uneventful. He was discharged without any ongoing evidence of easy bruising or bleeding and was scheduled for close follow-up with his pediatrician. On postnatal day 6, the infant was presented for his first newborn visit to his pediatrician with jaundice. His total bilirubin level was 19.3 mg/dL. The pediatrician sent the infant to the emergency department for additional evaluation and treatment. There, the infant was found to have severe thrombocytopenia (platelet count, 35 K/mm3) and indirect hyperbilirubinemia (total bilirubin, 20.2 mg/dL; direct bilirubin, 0.3 mg/dL). Mild anemia was present (hemoglobin, 13.8 …

Adults with sickle cell disease (SCD) are at risk for cognitive impairment, which causes significant morbidity. Guidelines support routine cognitive screening, but no screening test is validated in this population. We explored the Montreal Cognitive Assessment (MoCA) as a possible screening test in SCD. We administered the MoCA; a literacy test, the Wide Range Achievement Test, fourth edition (WRAT-4); and a health literacy test, the Shortened Test of Functional Health Literacy in Adults (S-TOFHLA) to adults with SCD and gathered clinical variables through chart review. Spearman's rho, Mann-Whitney, and Kruskal-Wallis tests and quantile regression models were used. Among our sample of 49 adults with SCD, the median MoCA score was 25.0 [interquartile range (IQR) 22.0-28.0]. Higher educational attainment was associated with MoCA scores (p = 0.001). In multivariable models, MoCA scores were associated with S-TOFHLA (p = 0.001) and WRAT-4 Reading (p = 0.002) scores, and overt stroke (p = 0.03) at the median. This pilot study adds to the limited literature of cognitive screening tests in adults with SCD and demonstrates a relationship between MoCA scores and measures of literacy and health literacy. The MoCA is a promising option for briefly screening for cognitive impairment in adults with SCD, though further study is needed to confirm its validity.

The application of modern ovarian reserve measures to women with sickle cell disease (SCD) may help answer longstanding questions about whether SCD or hydroxycarbamide (HC; also known as hydroxyurea) affect women's reproductive lifespan. Anti-Müllerian hormone (AMH), an established marker of ovarian reserve, is used to assess the ovarian follicle pool. We used a standard clinical assay to measure AMH in 285 banked samples from 93 female subjects with haemoglobin SS from the historic Multicenter Study of Hydroxyurea (MSH), which led to the United States Food and Drug Administration approval of HC for adults with SCD. No samples from the randomised portion of the MSH remain, so samples from the decade-long MSH follow-up studies were analysed. Most subjects were exposed to HC (86/93). The median AMH levels were lower in study subjects than in age- and sex-matched reference values. The median AMH levels consistent with diminished ovarian reserve, a risk factor for infertility, occurred in subjects starting at the age of 25-30 years; in healthy women, this occurs after the age of 40 years. In multivariate analysis, taking HC was independently associated with a low AMH (β = 0·001, 95% confidence interval -0·002 to 0·000; P = 0·006). These results suggest that ovarian reserve is prematurely reduced in women with haemoglobin SS and raise the possibility that HC contributes to this finding.

Women with sickle cell anemia (SCA) have higher rates of diminished ovarian reserve (DOR) than age-matched controls. Pecker et al report a small study of patients with SCA that compares ovarian reserve in patients after stem cell transplant, on therapy with hydroxyurea (HU), and on supportive care. As expected, patients who received transplants have severe DOR. About one-third of patients on HU have DOR, while DOR was absent in patients on supportive care. Whether this reflects an impact of HU or is a biomarker of severe disease remains to be established in a larger study.

BACKGROUND: α-Globin is expressed in endothelial cells of resistance arteries, where it limits endothelial nitric oxide signaling and enhances α-adrenergic–mediated vasoconstriction. α-Globin gene (HBA) copy number is variable in people of African descent and other populations worldwide. Given the protective effect of nitric oxide in the kidney, we hypothesized that HBA copy number would be associated with kidney disease risk. METHODS: Community-dwelling Black Americans aged ≥45 years old were enrolled in a national longitudinal cohort from 2003 through 2007. HBA copy number was measured using droplet digital PCR. The prevalence ratio (PR) of CKD and the relative risk (RR) of incident reduced eGFR were calculated using modified Poisson multivariable regression. The hazard ratio (HR) of incident ESKD was calculated using Cox proportional hazards multivariable regression. RESULTS: Among 9908 participants, HBA copy number varied from 2 to 6. In analyses adjusted for demographic, clinical, and genetic risk factors, a one-copy increase in HBA was associated with 14% greater prevalence of CKD (PR, 1.14; 95% CI, 1.07 to 1.21; P

ImportancePregnancy outcomes are historically poor among people with sickle cell disease (SCD) in the US, most of whom have Black race. Whether outcomes have improved is unknown.ObjectiveTo tabulate adverse pregnancy outcomes among patients with SCD, comparing outcomes of deliveries among Black people with SCD with those of Black people without SCD and a control non-Black population, and to measure the association of racial disparities with adverse outcomes in SCD pregnancies.Design, Setting, and ParticipantsThis cross-sectional study was a secondary analysis involving data from National Inpatient Sample, a nationally representative sample of 20% of acute hospital admissions in the US, between 2012 and 2018. The data set included all admissions with codes for delivery of a pregnancy among people aged 11 to 55 years. Data were analyzed from September 2021 to August 2022.ExposuresSCD, racial disparities.Main Outcomes and MeasuresSevere maternal morbidity (SMM) as measured by the US Centers for Disease Control and Prevention’s index alongside other outcomes; multiple logistic regression was used to compare the odds for adverse pregnancy outcomes.ResultsThe sample included 5 401 899 deliveries, including 3901 deliveries among people with SCD and 742 164 deliveries among people with Black race. Compared with the non-Black control group, patients with SCD and Black patients were younger (mean [SD] age: SCD, 27.2 [5.9] years; Black, 27.1 [6.1] years vs 28.7 [5.9] years) and more likely to have public insurance (SCD, 2609 deliveries [67.3%]; Black, 496 828 deliveries [65.4%] vs 1 880 198 deliveries [40.8%]). The maternal mortality rate in deliveries among people with SCD was 26 times greater than in the non-Black control group and more than 10 times greater than among Black pregnant people without SCD (Per 10 000 deliveries: SCD 13.3; 95% CI, 5.7-31.2; Black race, 1.2; 95% CI, 1.0-1.5; non-Black control 0.5; 95% CI, 0.5-0.6). Compared with the control group, SCD deliveries had higher odds of SMM (adjusted odds ratio [aOR], 7.22; 95% CI, 6.25-8.34; P P P Conclusions and RelevanceIn this large cross-sectional study of pregnancy outcomes in people with SCD, the risk for SMM was higher compared with deliveries among people without SCD, especially for thrombotic events, organ failure, and death. Racial disparities were associated with adverse outcomes. Our findings compel scientific, clinical, and political effort to improve outcomes for pregnant people with SCD.

ImportancePregnancy in sickle cell disease (SCD) is high risk, but whether prenatal anemia, which is treatable with red blood cell transfusions, is a mediator associated with adverse pregnancy outcomes (APOs) is not known.ObjectiveTo compare rates and odds of severe maternal morbidity (SMM) and other APOs in pregnancies among individuals with SCD vs those without SCD but with prenatal anemia.Design, Setting, and ParticipantsThis cross-sectional study was conducted using data from 2012 to 2018 from the National Inpatient Sample, a nationally representative sample of 20% of acute hospital admissions in the United States. All admissions with codes for delivery of a pregnancy among people aged 11 to 55 years were included. Only admissions coded with Black race were included. Data were analyzed from September 2021 through August 2022.ExposuresPrenatal anemia and SCD.Main Outcomes and MeasuresSMM was tabulated per the Center for Disease Control and Prevention SMM Index alongside other APOs. Multiple logistic regression was used to compare the odds for APOs and risk ratios (RRs) to compare rates of APOs.ResultsAmong 764 455 total delivery admissions among patients identified as Black (mean [SD] age at delivery, 27.00 [6.08] years), 3200 deliveries were coded with maternal SCD, 34 808 deliveries were coded with maternal anemia, and 726 447 deliveries were control. Most patients were publicly insured (499 060 [65.4%]). For most outcomes, including SMM and mortality per 10 000 deliveries, the SCD group had higher rates (SMM: 5.9%; 95% CI, 5.1%-6.8%; maternal mortality: 13.0 deaths; 95% CI, 4.9 to 35.0 deaths) than anemia (SMM: 2.1%; 95% CI, 2.0%-2.3%; maternal mortality: 0.9 deaths; 95% CI, 0.3 to 2.8 deaths) or control groups (SMM: 1.1%; 95% CI, 1.0%-1.1%; maternal mortality: 1.2 deaths; 95% CI, 1.0 to 1.5 deaths). SCD (adjusted odds ratio [aOR], 5.51; 95% CI, 4.71-6.45) and anemia groups (aOR, 2.00; 95% CI, 1.84-2.17) had higher adjusted odds of SMM compared with the control group. However, for many complications associated with ischemia or abnormal placentation, CIs of aORs for SCD and anemia groups overlapped (eg, eclampsia: aOR, 2.74; 95% CI, 1.51-4.96 vs aOR, 1.40; 95% CI, 1.08-1.81). For these complications, RRs for SCD vs anemia were between 1.0 and 2.1 (eg, eclampsia: 1.76; 95% CI, 0.93-3.32). For complications associated with thrombosis or SCD-specific pathologies, rates and aORs were greater for the SCD vs anemia group. For these complications, RRs were between 3.70 and 10.90. For example, rates of acute respiratory distress syndrome, including acute chest syndrome, were 56 of 3144 deliveries (1.8%) vs 122 of 34 686 deliveries (0.4%), and the RR was 4.99 (95% CI, 3.65-6.84).Conclusions and RelevanceThis study found that risks associated with prenatal anemia and SCD were similar for many APOs, especially those associated with ischemia and abnormal placentation, suggesting that prenatal anemia may be a mediator associated with pregnancy risk in individuals with SCD.

In this Ethics Rounds we present a conflict regarding discharge planning for a febrile infant in the emergency department. The physician believes discharge would be unsafe and would constitute a discharge against medical advice. The child’s mother believes her son has been through an already extensive and painful evaluation and would prefer to monitor her well-appearing son closely at home with a safety plan and a next-day outpatient visit. Commentators assess this case from the perspective of best interest, harm-benefit, conflict management, and nondiscriminatory care principles and prioritize a high-quality informed consent process. They characterize the formalization of discharge against medical advice as problematic. Pediatricians, a pediatric resident, ethicists, an attorney, and mediator provide a range of perspectives to inform ethically justifiable options and conflict resolution practices.

PURPOSE: People with sickle cell disease (SCD) or trait have many reproductive options, some of which decrease the chance of passing SCD to children, including in vitro fertilization with preimplantation genetic testing (IVF + PGT). Few are aware of these options, and educational materials are needed. This study aimed to develop an accessible, non-directive patient education material about reproductive options for those with SCD or trait via a process that incorporated stakeholders from the SCD community. METHODS: Multidisciplinary stakeholders guided development and revision of a novel pamphlet. Researchers applied health literacy scales to measure pamphlet understandability. We interviewed nine patients with SCD and six multidisciplinary clinicians to evaluate the pamphlet. Interviews were recorded, transcribed, and coded by a five-member team who developed a codebook and proposed themes that were revised by all research team members. Feedback was incorporated into a revised pamphlet. RESULTS: A two-page pamphlet describing reproductive options for people with SCD including IVF + PGT was acceptable to key stakeholders, including people with SCD. Material about this complex topic met health literacy standards, including being written at a 5th grade level. Patients reported feeling hopeful after reviewing the pamphlet, and participants considered the pamphlet useful, clear, and appropriate for distribution in clinics and online. CONCLUSIONS: Though awareness of reproductive options for those with SCD or trait is low, patients and providers find a novel pamphlet about this topic acceptable and useful. Educational materials about complex topics including IVF + PGT can be written at a level understandable to the average American. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10815-021-02358-z.

There is an immediate need to address long-standing questions about the reproductive health of girls and women with sickle cell disease (SCD). There are many SCD-related reproductive risks and uncertainties across girls' and women's reproductive life span, with particularly outstanding concerns about menstruation, contraception, fertility and pregnancy. Extant literature addressing women's reproductive health topics is mostly descriptive; there are few high-quality interventional studies. In 2020, the Centers for Disease Control and Prevention and the Foundation for Women and Girls with Blood Disorders convened an expert panel to assess the knowledge gaps in women's reproductive health in SCD. The panel identified significant limitations to clinical care due to the need for research. The panel also identified prominent barriers to research and care. In this report, we frame these issues, providing a roadmap for investigators, funding agencies, and policy makers to advance care for girls and women with SCD.

Psychosocial and affective comorbidities are common in sickle cell disease (SCD) and can strongly influence disease outcomes, especially those related to pain such as frequency and intensity of pain, use of emergency- and hospital-based care and opioid use. Depression, anxiety, sleep disorders, and substance use challenges are among the common comorbidities that inform the patient experience of SCD. Underlying neurocognitive changes may also contribute to the expression of affective disorders in people with SCD. The neurobiological basis of these comorbidities in SCD is being investigated. In this mini-review, we discuss psychosocial and affective disorders that can coexist in children and adults with SCD and highlight how these common psychological pathologies may interact with complications associated with SCD. Patients with SCD should be screened for these comorbidities using standardized screening tools and managed appropriately to improve outcomes.

Sickle cell disease (SCD) is a monogenic disorder that afflicts approximately 100,000 Americans and millions of people worldwide. It is characterized by hemolytic anemia, vaso-occlusive crises, relentless end-organ injury, and premature death. Currently, red blood cell transfusion and hydroxyurea are the major disease-modifying therapies available for SCD. Hematopoetic stem cell transplant is curative, but barriers to treatment are substantial and include a lack of suitable donors, immunologic transplant rejection, long-term adverse effects, prognostic uncertainty, and poor end-organ function, which is especially problematic for older patients. Gene therapy to correct the βs point mutation is under investigation as another curative modality. Deeper insights into the pathophysiology of SCD have led to the development of novel agents that target cellular adhesion, inflammation, oxidant injury, platelets and/or coagulation, vascular tone, and hemoglobin polymerization. These agents are in preclinical and clinical trials. One such agent, L-glutamine, decreases red blood cell oxidant injury and is recently US Food and Drug Administration approved to prevent acute pain episodes of SCD in patients 5 years of age or older. The purpose of this review is to describe the currently established therapies, barriers to curative therapies, and novel therapeutic agents that can target sickle cell hemoglobin polymerization and/or its downstream sequelae. A PubMed search was conducted for articles published up to May 15, 2018, using the search terms sickle cell disease, novel treatments, hematopoietic stem cell transplantation, and gene therapy. Studies cited include case series, retrospective studies, prospective clinical trials, meta-analyses, online abstracts, and original reviews.

BackgroundAlpha globin gene (HBA)copy number is variable among people of African descent.HBAlimits endothelial nitric oxide signaling and variation in gene copy number could modify kidney disease risk in this population.ObjectiveTo examine the association ofHBAcopy number with chronic kidney disease (CKD) and end-stage kidney disease (ESKD). We hypothesized that higherHBAcopy number would be associated with greater CKD prevalence and ESKD incidence.DesignProspective, longitudinal cohort from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study which enrolled participants from 2003 through 2007 and conducted follow-up through June 2014. Data were analyzed from January 2018 through January 2021.SettingCommunity-dwelling participants enrolled throughout the contiguous United StatesParticipantsBlack Americans age 45 years and olderMeasurementsHBAcopy number was measured using droplet-digital PCR on genomic DNA; copy number ranged from 2 to ≥ 5 copies. The prevalence ratio (PR) of CKD and relative risk (RR) of incident reduced estimated glomerular filtration rate (eGFR) were calculated using modified Poisson multivariable regression employing a log-linear effect ofHBAallele count. The hazard ratio (HR) of incident ESKD was calculated using Cox proportional hazards multivariable regression.ResultsAmong 9,918 participants,HBAgene copy number frequencies were 4%, 28%, 67%, and 1% for 2, 3, 4, and ≥5 copies, respectively. After adjusting for demographic, clinical, and genetic risk factors, each additional copy ofHBAwas associated with 14% greater prevalence of CKD (PR = 1.14, 95% CI 1.07 to 1.21;P< 0.0001). While there was no significant association with incident reduced eGFR (RR = 1.06, 95% CI 0.94 to 1.18; p = 0.36), the hazard of incident ESKD was 28% higher for each additional copy ofHBA(HR = 1.28, 95% CI 1.01 to 1.61;P= 0.04).LimitationsThis study did not identify the mechanism by whichHBAcopy number modifies kidney disease risk. This study focused on Black Americans, a population with a high frequency of the 3.7 kb gene deletion; it is unknown whetherHBAmodifies kidney disease risk in other populations with the 3.7 kb deletion.ConclusionsIncreasingHBAcopy number was associated with greater prevalent CKD and incident ESKD in a national longitudinal study of Black Americans.Funding SourceNational Institutes of Health

Withdrawal: Primary prevention of sickle cell disease using preimplantation genetic testing and in vitro fertilization is cost-effective. The above article, published online on 20 August 2020 in Wiley Online Library (wileyonlinelibrary.com) as an Accepted Article, has been withdrawn by agreement between the authors, the journal Editor in Chief, and John Wiley & Sons Ltd. The article has been withdrawn after the accepted article was posted online, the authors received independent feedback that has prompted them to review their analysis in the article to ensure that the original conclusions are accurate.

BACKGROUND: Patients with Sickle cell disease (SCD) experience high rates of chronic pain, and have a high burden of mental health comorbidities shown to negatively influence health. There is limited research on substance use among individuals with SCD. OBJECTIVE: The aim of this study is to measure the prevalence of substance use in patients with SCD and determine whether psychosocial or clinical risk factors are associated with substance use. METHODS: This study was conducted as part of an observational study of patients with SCD at two academic medical centers. We asked participants (ages 15 and older) about lifetime use of heroin, cocaine, amphetamines, and marijuana/cannabis. We measured stigma, depression, urban life stress, pain catastrophizing, and asked about a brief pain inventory. RESULTS: Of 258 participants, 24.9% (n=71) reported substance use. Marijuana was most common substance used (22.5%; n=65). The mean depressive score met criteria for positive screen amongst individuals who reported a history of substance use (mean 10.7(5.76)). Adjusting for age, sex, yearly family income, and education level, odds of substance use increased with higher levels of internalized stigma (aOR:1.38;95% CI: 1.07,1.77;p=0.012); higher urban life stress scores (aOR1.06; 95%CI:1.01,1.12;p=0.017) and higher pain catastrophizing scores (aOR:1.03;95% CI:1.01,1.06;p=0.008). CONCLUSIONS: Among individuals with SCD who endorse substance use, there was markedly more stress and distress with higher rates of depression and poorer quality of life. Interventions focusing on improving distress tolerance and coping to not only pain, but also social stressors, might reduce substance use.

IntroductionAs marijuana use becomes more common, it is essential clinicians understand the relationship between marijuana use and health behaviors.MethodsUsing a retrospective cohort of adolescents and adults with sickle cell disease (SCD) stratified into a young ( = 25 years), we conducted multiple linear regression examining relationship of marijuana use (independent variable) on each dependent variable (SCD self-management score and pain management).ResultsAmong young cohort, 16.9% used marijuana compared to 21.8% of older cohort. The younger cohort reporting marijuana use had lower mean self-care scores (β = -2.74;p = 0.009) and were more likely to have admissions to the hospital for pain (β = 0.87;p = 0.047) compared to non-users. In contrast, the older cohort reporting marijuana use had more days treating pain at home (β = 0.44;p = 0.035).ConclusionsOnly a minority of patients with SCD reported lifetime marijuana use. Among those reporting marijuana use, there were different associations with self-care and health-related behaviors by age. The older cohort who endorsed marijuana use reported more days of treating pain at home, although this did not translate into increased acute care visits for pain crisis. Among youth, endorsing marijuana use was associated with worse SCD self-care.

PURPOSE: In vitro fertilization with preimplantation genetic testing (IVF+PGT-M) reduces the risk of having a child affected by a heritable condition, yet only one-third of eligible patients are aware of this reproductive option. Access to education materials written at appropriate literacy levels could raise patients’ awareness, but there is a mismatch between patient reading ability and the literacy demand of most materials. This study aimed to systematically identify written education materials on IVF+PGT-M and evaluate their literacy levels. We hypothesized that materials would fail to meet standards set by the Joint Commission and Centers for Disease Control and Prevention (CDC). METHODS: To identify patient education materials about IVF+PGT-M from academic databases and public-facing sources, an environmental scan was performed. Materials were analyzed using three validated scales: Simple Measure of Gobbledygook, Patient Education Materials Assessment Tool, and Clear Communication Index. RESULTS: Seventeen patient education materials about IVF+PGT-M were identified from patient education databases, a consumer search engine, and professional organizations. The median reading level was 14.5 grade, median understandability was 74.2%, and median comprehensibility was 73.3%. CONCLUSIONS: For most American adults, materials about IVF+PGT-M are not readable, understandable, or clear. The Joint Commission requires patient education materials be written at or below 5th grade reading level and the CDC recommends a 90% minimum score for comprehensibility. No evaluated material met these guidelines. Patient education materials that exceed average American literacy skills may perpetuate disparities in the utilization of IVF+PGT-M. Materials that communicate this complicated subject at an understandable level are needed.

A large proportion of the morbidity and almost all of the mortality of sickle cell disease (SCD) now occurs in adulthood. Children with SCD underuse disease-modifying and curative treatments, in part because of how patients/parents understand SCD morbidity and mortality. Whether practitioners provide prognostic information to families is unknown. We emailed a 31-item survey to 1,149 pediatric hematologist-oncologists and analyzed 96 responses. Most said discussing prognosis would change patient/parent willingness to start hydroxyurea, but fewer actually discuss prognosis when they want to start hydroxyurea (91% vs. 75%, p=.001). Similarly, most said discussing prognosis would change adherence to therapy, but fewer actually discuss prognosis to motivate adherence (78% vs 31%, plt;.001). Most (77%) addressed prognosis when the "patient or their parent bring it up." Respondents reporting frequent life expectancy discussions were more likely to report a pathway for such discussions (p=.017). Pediatric hematologists may not conduct prognostic discussions without prompting, although these conversations may be important for shared, informed decision-making.

Introduction: Sickle cell disease (SCD), a common genetic disease involving red blood cell structure and function, is associated with cerebral vasculopathy and increased risk of ischemic events that may also affect the inner ear. Individuals with SCD are at increased risk for hearing loss; however, little is known regarding the effects of SCD on the vestibular system or the relationship between hearing loss and vestibular symptoms in these patients. Vestibular dysfunction affects 15-20% of the general population can lead to significant morbidity through falls, fall-related injuries, missed work, and overall reduction in quality of life. Methods: To assess the burden of vestibular dysfunction amongst individuals with SCD, we surveyed individuals with SCD who answered questions about symptoms of dizziness, imbalance, and hearing loss. The survey also captured demographic information, current symptoms of dizziness/imbalance, symptoms of hearing loss, and history of falls. Fisher's exact test was performed to test for associations between clinical characteristics including SCD genotype, hearing loss, dizziness or imbalance, and headache history. Results: Twenty-six participants, ages 20 to 73 years (median 37.5 years) completed the survey. All participants were Black or African-American. Five participants (19.2%) were male, 15 (58%) had hemoglobin SS, 8 (32%) hemoglobin SC, and 3 (12%) S-β + thalassemia. Three (11.5%) participants reported hearing loss. Twelve (46.2%) participants reported dizziness or imbalance, of which 8 (66%) reported recent falls. Of the 12 participants experiencing dizziness, 9 (75%) reported having dizziness for 1 to 3 days a month, 2 reported having dizziness for 4 to 9 days a month, and 1 reported having dizziness for more than 15 days a month. Three participants reported their dizziness symptoms resolved within seconds, 7 within minutes, and 2 within hours. Eleven (42.3%) participants reported headaches. Self-reported dizziness or imbalance was not associated with hearing loss (X 2=0.57; p=0.45), SCD genotype (X 2=0.75; p=0.68), or sex (X 2=0.09; p=0.76). Headache history was associated with dizziness or imbalance (X 2=9.76; p=0.002). Conclusions: In this small pilot study, 46% of individuals with SCD reported dizziness or imbalance, which is twice the rate reported amongst the general population. Headache history is associated with dizziness and imbalance amongst individuals with SCD. Further investigation is warranted to determine the specific effects of SCD on the vestibular end-organs. Disclosures Lanzkron: Imara: Research Funding; Pfizer: Current holder of individual stocks in a privately-held company; GBT: Research Funding; Shire: Research Funding; Teva: Current holder of individual stocks in a privately-held company; Novartis: Research Funding; Novo Nordisk: Consultancy; Bluebird Bio: Consultancy; CSL Behring: Research Funding. Lance: Novartis: Other: participated in research advisory board in 2020.

Background Adults with sickle cell disease (SCD) face unique fertility risks due to SCD and use of disease modifying therapies (DMTs). Concerns about compromising fertility may inform patients' therapy choices, but little is known about fertility knowledge in adults with SCD. The Cardiff Fertility Knowledge Scale (CFKS) and Fertility Treatment Perception Survey have been studied in international and national cohorts 1,2. The purpose of this study was to administer these surveys to adults with SCD and compare responses to previously studied populations. Methods Our IRB approved this cross-sectional study of adults with SCD (≥18YO) cared for at our Sickle Cell Center for Adults. Due to the COVID-19 pandemic, eligible subjects were recruited during routine telemedicine clinic visits and by invitation via electronic medical record. We collected demographic information (sex, age (≥/< 31YO), educational attainment, and use of DMTs). The CFKS is a 13-question survey that measures knowledge of causes of reduced fertility, common misconceptions about fertility, and infertility facts. Questions are answered True/False/Don't know and equally weighted; the cumulative score is 0-100%. We compared the mean CFKS scores to the scores from two published cohorts 1,2. The fertility treatment perception survey consists of two positive and four negative statements about fertility treatment with responses given on a five-point Likert scale (1= strongly disagree to 5= strongly agree). Responses are calculated by number of respondents with an agreement score of 4 and/or 5 divided by total number of respondents per sub-group; higher scores indicate stronger agreement. Analysis included summary statistics with means and standard deviations and independent student's T-test to compare the mean fertility knowledge scores. Results We contacted 435 subjects; 91 respondents were enrolled (21% response rate). Respondents were 77% female [median age 33 years (IQR 23, 50)]. 51% completed high school or less and 18% used one or more DMTs, with 65% taking hydroxyurea. Table 1 shows the CFKS results. The average CFKS score was 50%, lower than the international cohort (50% vs. 57%, p Conclusion In this study, we identify that higher educational attainment in adults with SCD is associated with better fertility knowledge. All subjects had low knowledge of sexually transmitted infections, weight gain, and older age as infertility risks. Although there is concern that hydroxyurea may compromise fertility, its use was not associated with greater fertility knowledge in this study. Given concerns about fertility in the SCD community, we identify an opportunity to support patients concerned about fertility by contextualizing real or theorized SCD-specific fertility risks within a broader set of established fertility risks. References: 1. Bunting L, Tsibulsky I, Boivin J. Fertility knowledge and beliefs about fertility treatment: findings from the International Fertility Decision-making Study. Hum Reprod. 2013 Feb;28(2):385-97. doi: 10.1093/humrep/des402. Epub 2012 Nov 25. PMID: 23184181. 2. Wiltshire A, Brayboy LM, Phillips K, et al. Infertility knowledge and treatment beliefs among African American women in an urban community. Contracept Reprod Med. 2019 Sep 24;4:16. doi: 10.1186/s40834-019-0097-x. PMCID: PMC6757383. Figure 1 Figure 1. Disclosures Lanzkron: Shire: Research Funding; GBT: Research Funding; Novo Nordisk: Consultancy; CSL Behring: Research Funding; Pfizer: Current holder of individual stocks in a privately-held company; Teva: Current holder of individual stocks in a privately-held company; Novartis: Research Funding; Bluebird Bio: Consultancy; Imara: Research Funding.

Background: Sickle cell disease (SCD) and cystic fibrosis (CF) are associated with an increased risk of venous thromboembolism (VTE). VTE prophylaxis non-administration is a risk factor for VTE. Since many patients with SCD or CF experience frequent hospitalizations, we hypothesized that missed doses of VTE prophylaxis may be common in these populations. The purpose of this study was to characterize VTE prophylaxis non-administration among patients with SCD or CF compared to medically ill patients without SCD or CF. Methods: We conducted a single-center retrospective cohort study of patient admissions from July 1 st, 2016 to December 31 st, 2019 who were prescribed at least 2 doses of pharmacologic VTE prophylaxis. Three adult inpatient cohorts were defined: patients with SCD, patients with CF, and medically ill patients without SCD or CF. We excluded patients on pediatric and surgical units, and excluded doses received while in intensive care units or prescribed as once doses. The primary outcome was the proportion of missed doses of VTE prophylaxis by cohort. Secondary outcomes included the proportion of patients who missed at least one dose by cohort, the proportion of missed doses by medication and frequency, and the proportion of missed doses in patients with more than one admission during the study period. Multivariable logistic regression was used to identify characteristics associated with non-administration. Results: The 13,316 subjects included 246 with SCD, 89 with CF, and 12,981 medically ill. Subjects with SCD and CF were younger than medically ill patients [median (IQR) age 31 (16) and 30 (11) years, respectively versus 58 (24) years, p Conclusion: Patients with SCD or CF missed a larger proportion of pharmacologic VTE prophylaxis compared to medically ill patients. Factors independently associated with increased odds of non-administration include age < 30 years and multiple hospital admissions. Black race and once daily administration were associated with decreased odds of non-administration. These findings suggest that targeted education or once-daily dosing may improve VTE prevention in high-risk lifelong disorders such as SCD and CF. Figure 1 Figure 1. Disclosures Naik: Rigel: Research Funding. Lanzkron: GBT: Research Funding; Shire: Research Funding; Novo Nordisk: Consultancy; Teva: Current holder of individual stocks in a privately-held company; Pfizer: Current holder of individual stocks in a privately-held company; Imara: Research Funding; CSL Behring: Research Funding; Novartis: Research Funding; Bluebird Bio: Consultancy. Dane: Sanofi Genzyme: Honoraria; Janssen: Honoraria; Alexion: Honoraria.

Introduction The 2014 NHLBI Sickle Cell Expert Panel recommends that young adults with sickle cell disease (SCD) be supported to develop a reproductive life plan, but little data about implementing this recommendation exists and reproductive health behaviors or knowledge is not assessed in existing SCD transition readiness forms. Young adults with SCD confront typical age-related reproductive challenges and require additional support due to SCD-related complexities. For men and women, there are questions about the effect of SCD and its treatments on fertility and reproductive lifespan and the problem of genetic risk for SCD in offspring. For men, priapism and erectile dysfunction may be problems, while women face contraception choices and complicated pregnancy care. In our young adult clinic, we assess young adults' reproductive history, intentions and knowledge using a clinical survey and standard intake questions. The purpose of this study was to describe young adult responses to our family planning survey. Methods This is a retrospective analysis of patients who established care at the Johns Hopkins Sickle Cell Center for Adults' Young Adult Clinic (YAC), which serves young adults with SCD Results Fifty patients who established care in the YAC over its first 15 months (April 2019-July 2020) completed the survey. They were 66% female with a median age of 23.5 (IQR 21,25). Most (74%) had sickle cell anemia (SCA); 60% had education beyond high school. Most (78%) were either students (34%) or employed full time (44%). Forty-two percent lived with a parent. Most (68%) were sexually active, and 45% reported contraception use. Condoms were commonly used by both sexes (41%); forty percent of women used depot-medroxyprogesterone acetate (DMPA). Half of women (58%) had a gynecologist. One third of women reported dysmenorrhea. Forty-one percent of men reported priapism. Twenty-four percent of respondents had a history of pregnancy or of impregnating a partner and 14% had children. The median age of parents at the birth of the first child was 21 (IQR 16,22). Survey results are in Table 1. The response rate was 98% for eight questions and 50% for two questions. Few (8%) reported desire to have a child in the next year, and 27% wished to discuss contraception. Among sexually active respondents, 29% knew their partner's sickle cell trait status and 35% of them wanted testing. Few respondents wanted to meet with a genetics counselor (12%) or reported knowledge of preimplantation genetic testing (PGT) (11%). Thirty-eight percent of respondents were interested in learning how to identify if a fetus has SCD. Ninety-two percent of respondents indicated they do not desire pregnancy in the next year, and 38% of them were using contraception - 33% used condoms, 22% used DMPA, and 11% had an intrauterine device (IUD). Those interested in contraception were young (68% under 26), female (77%), and, of those women, most did not have a gynecologist (60%). Most women with dysmenorrhea (63%) were not interested in discussing contraception. Of the 14% of respondents with children, 29% knew their partner's trait status; and of those who did not, 20% wanted testing. Among 10 patients interested in genetic counseling or who knew of PGT, half had more than high school education; most (70%) were women with SCA who had never been pregnant. Among 82% who had not heard of PGT, 17% identified interest in more information. Most (70%) of this group was 22-25 years old, 14% wanted a child in the next year, all were either students (43%) or employed full time (57%); most (57%) had education beyond high school. Conclusions Clinic administration of a family planning survey is feasible. Many young adults transition to adult care and are parents or interested in becoming parents. Ninety-two percent of respondents do not desire pregnancy in the near future but 67% of them are not using reliable birth control. Genetic counseling interest, knowledge of PGT, and knowledge of partner sickle trait status is low. Current transition readiness documents for SCD do not adequately address reproductive health. These results suggest a discordance between the reproductive health priorities of young adults with SCD and providers that should be further examined. Disclosures Stewart: HRSA: Research Funding. Lanzkron:GBT: Research Funding; HRSA: Research Funding; Ironwood: Research Funding; NHLBI: Research Funding; PCORI: Research Funding; Pfizer: Research Funding; Pharmacy Times Continuing Education: Honoraria; Prolong: Research Funding. Pecker:Forma Therapeutics: Consultancy.

Introduction: Females are born with a set number of ovarian follicles. Ovarian reserve, defined by the number of primordial follicles, decreases with age. Diminished ovarian reserve (DOR) is a risk factor for shortened reproductive lifespan, infertility and poor assisted reproductive technology outcomes. Young women with sickle cell anemia (SCA) are at risk for DOR1,2. Whether hydroxyurea (HU) use contributes to this risk is not established. Antimullerian hormone (AMH), a biomarker of the ovarian follicle pool, is used with antral follicle count (AFC) and follicle stimulating hormone (FSH), to estimate ovarian reserve. The extent to which AMH corresponds with visualized AFC in SCA, and thus serves as a reasonable surrogate biomarker, is unknown. The purpose of this study was to test the hypothesis that young women with SCA have lower AMH than age and race matched controls and that HU exposure is a risk for DOR. Methods: Subjects from our Adult Sickle Cell Center had ovarian reserve measured on day 3-5 of the menstrual cycle or at any time if on menses-suppressing contraception. We measured serum AMH, FSH, estradiol and AFC by ultrasound. Subjects' demographic, reproductive and SCA treatment history were obtained. HU exposure variables included (1) age at first exposure, (2) use at time of study visit, (3) markers of adherence (MCV and ANC), and (4) refill data. Ferritin was used to assess iron overload. We compared AMH levels in subjects ages 19-25 and 26-31 years to AMH levels in age-matched African American women controls with tubal factor infertility and no chemotherapy exposure, and age-matched levels from the historic Multicenter Study of Hydroxyurea (MSH) cohort2. We then compared subject characteristics by the presence of DOR (AMH 10 - 40IU) or primary ovarian insufficiency (POI), (AMH < 1.1ng/mL and FSH ≧ 40IU). The chi-squared and Mann Whitney U test was used for categorical and continuous variables, respectively, to determine associations with DOR. Results: Sixteen women with SCA participated with a median age of 25.5 years (IQR 21,29), hemoglobin 8.8g/dL (IQR 8,9.2), MCV 96.9fL (IQR 88.6, 101.1), ANC 5.7K/mcl (IQR 3.4, 8.4), and ferritin 857ng/mL (IQR 246, 1957). All had prior HU exposure. The median age at first HU exposure was 17.5 years (IQR 14.5, 21), median months of HU exposure was 23 (IQR 2.8, 38.5). Twelve subjects were taking HU at the study visit and, by refills, 7 took continuous HU in the previous 6-months, median dose 1715mg (IQR 1000, 2000). Lower AMH and AFC was observed in older subjects as expected. AMH was lower in study subjects compared to controls in both age groups: 19 - 25 years [2.48ng/mL (IQR 1.7, 3.4) vs 7.45ng/mL (IQR 6.5, 10.7), p0.05)1. Younger women (19-25yo) had higher median AFC than older women (26-31yo), a difference that was not statistically significant (14(IQR 8, 35) vs 9(IQR 7,12) follicles). Four of 16 subjects had DOR; all four were taking HU and >25yo. In those with or without DOR, there was no difference in median BMI (21.1(20.7, 22.4) vs 24.7 (IQR 20.8, 26.2), hemoglobin (8.7 (IQR 8.4, 8.9) vs 8.8 (7.9, 9.8) g/dL), or ferritin (602 (IQR 131, 1529) vs 875 (IQR 303, 1975). DOR was associated with a lower median AFC (5.5(IQR 4, 7) vs 12 (IQR 9,24) oocytes p=0.04) and higher MCV (112 vs 92fL, p=0.02). Table 1 compares DOR and HU exposure our cohort, the MSH2 and a pediatric cohort1. In all cohorts, some young women exposed to HU have DOR. Conclusions In this pilot study of ovarian reserve in young adult women with SCA, AMH is significantly lower in age- and race-matched controls and levels are similar to an historic SCA cohort. AMH and AFC were both lower in older subjects, suggesting that AMH is a reasonable ovarian reserve marker in SCA. No women had POI. DOR was associated with lower AFC and higher MCV. In young adult women of reproductive age with SCA, taking HU may be a risk for DOR. This data forms the basis for ongoing research on the pathobiological mechanisms and clinical significance of DOR in women with SCA. References 1Pecker, LH et al. Hydroxycarbamide and ovarian reserve in the Multicenter Study of Hydroxycarbamide. British Journal of Haematology. 2020. 2Elchuri, SV et al. The effects of hydroxyurea and bone marrow transplant on AMH levels in females with SCA. Blood Cells Mol Dis. 2015. Disclosures Pecker: Forma Therapeutics: Consultancy. Lanzkron:GBT: Research Funding; HRSA: Research Funding; Ironwood: Research Funding; NHLBI: Research Funding; PCORI: Research Funding; Pfizer: Research Funding; Pharmacy Times Continuing Education: Honoraria; Prolong: Research Funding.

A previously healthy 16-year-old adolescent boy presented with pallor, blurry vision, fatigue, and dyspnea on exertion. Physical examination demonstrated hypertension and bilateral optic nerve swelling. Laboratory testing revealed pancytopenia. Pediatric hematology, ophthalmology and neurology were consulted and a life-threatening diagnosis was made.

The prognosis for homozygous α-thalassemia is changing. Prenatal diagnosis and intrauterine transfusions (IUT) reduce maternofetal morbidity and mortality; hematopoietic stem cell transplant (HSCT) is curative. Empiric evidence to support IUT and HSCT to treat homozygous α-thalassemia is lacking. The first case of curative HSCT for homozygous α-thalassemia was reported in 1997. Nearly 20 years later, five additional reports are published. We review the literature and report an institutional experience with three homozygous α-thalassemia patients. The first died shortly after birth. The second underwent HSCT after years of chronic transfusion therapy. The third benefited from IUT and HSCT. These cases exemplify the varied outcomes associated with this condition.