Sickle cell disease and infertility risks: implications for counseling and care of affected girls and women.

INTRODUCTION: Sickle cell disease (SCD), its treatments and cures present infertility risks. Fertility counseling is broadly indicated for affected girls and women and fertility preservation may appeal to some. Several streams of evidence suggest that the reproductive lifespan of women with SCD is reduced. Pregnancy is associated with high miscarriage rates. There are enduring questions about the effects of highly effective hydroxyurea treatment on female fertility. Current conditioning regimens for gene therapy or hematopoietic stem cell transplant are gonadotoxic. Fertility preservation methods exist as non-experimental standards of care for girls and women. Clinicians are challenged to overcome multifactorial barriers to incorporate fertility counseling and fertility preservation care into routine SCD care. AREAS COVERED: Here we provide a narrative review of existing evidence regarding fertility and infertility risks in girls and women with SCD and consider counseling implications of existing evidence. EXPERT OPINION: Addressing fertility for girls and women with SCD requires engaging concerns that emerge across the lifespan, acknowledging uncertainty and identifying barriers to care, some of which may be insurmountable without public policy changes. The contemporary SCD care paradigm can offer transformative SCD treatments alongside comprehensive counselling that addresses fertility risks and fertility preservation opportunities.

Managing sickle cell disease and related complications in pregnancy: results of an international Delphi panel.

ABSTRACT: Data to guide evidence-based management of pregnant people with sickle cell disease (SCD) are limited. This international Delphi panel aimed to identify consensus among multidisciplinary experts for SCD management during pregnancy. The 2-round Delphi process used questionnaires exploring 7 topics (antenatal care, hydroxyurea use, transfusion, prevention of complications, treatment of complications, delivery and follow-up, and bottlenecks and knowledge gaps) developed by a steering committee. Thirteen panelists (hematologists, physiologists, obstetricians, maternal fetal medicine, and transfusion medicine physicians) from the United States, the United Kingdom, Turkey, and France completed the first survey; 12 panelists completed the second round. Anonymized responses were collected and summarized by a contract research organization (Akkodis Belgium). Consensus and strong consensus were predefined as 75% to 90% (9-10 of 12) and >90% (≥11 of 12) of panelists, respectively, agreeing or disagreeing on a response to a predefined clinical scenario or statement. In several areas of SCD management, consensus was achieved: experts recommended performing at least monthly multidisciplinary antenatal follow-up, administering prophylactic aspirin for preeclampsia prevention between gestational weeks 12 and 36, initiating prophylactic transfusion therapy in certain cases, or choosing automated red blood cell exchange over other transfusion methods for patients with iron overload or severe acute chest syndrome. No consensus was reached on several topics including the prophylactic aspirin dose, indications for starting infection prophylaxis, routine use of prophylactic transfusions, or use of prophylactic transfusions for preventing fetal complications. These recommendations could inform clinical care for patients with SCD who are pregnant in the absence of large clinical trials involving this population; the identified knowledge gaps can orient future research.

Psychiatry referral and appointment attendance in a clinic for young adults with sickle cell disease.

Mental illness is a common sickle cell disease (SCD) comorbidity. This observational study evaluated psychiatry appointment attendance among 137 young adults with SCD. In their first year of adult SCD care, 43% of subjects were referred to psychiatry. Referral was associated with chronic transfusion therapy. Twenty-four percent of subjects attended a psychiatry appointment; attendance was associated with the appointment being scheduled within 6 weeks of referral and no subject characteristics. Ninety-one percent of subjects attending psychiatry appointments had a psychiatric disorder. Among young adults with SCD, psychiatric morbidity is high. Psychiatric services are, therefore, essential for this patient population.

Blood pressure thresholds for the diagnosis of hypertensive disorders of pregnancy in sickle cell disease.

In this retrospective cohort study of singleton pregnancies in people with sickle cell disease (SCD) delivered at two academic centres between 1990 and 2021, we collected demographic and SCD-related data, pregnancy outcomes, and the highest systolic and diastolic blood pressure (SBP and DBP) at seven time periods. We compared the characteristics of subjects with new or worsening proteinuria (NWP) during pregnancy to those without. We then constructed receiver operating characteristic (ROC) curves to determine the blood pressure (BP) that best identifies those with NWP. The SBP or DBP thresholds which maximized sensitivity and specificity were 120 mmHg SBP (sensitivity: 55.2%, specificity: 73.5%) and 70 mmHg DBP (sensitivity: 27.6%, specificity: 67.7%). The existing BP threshold of 140/90 mmHg lacked sensitivity in both genotype groups (HbSS/HbSß0 : SBP = 21% sensitive, DBP = 5.3% sensitive; HbSS/HbSß+ : SBP = 10% sensitive, DBP = 0% sensitive). Finally, percent change in SBP, DBP and MAP were all poor tests for identifying NWP. Existing BP thresholds used to diagnose hypertensive disorders of pregnancy (HDP) are not sensitive for pregnant people with SCD. For this population, lowering the BP threshold that defines HDP may improve identification of those who need increased observation, consideration of early delivery and eclampsia prophylaxis.

How young adults with sickle cell disease define "being a good patient" in the adult healthcare system.

BACKGROUND: Young adulthood brings new challenges for managing sickle cell disease. There are fewer adult specialists, sickle cell disease morbidities accumulate, and mortality increases. Developmental changes in roles and responsibilities also affect management. This study explores how young adults with sickle cell disease experience their role as a patient. METHODS: In this mixed-methods study at a sickle cell center, young adult participants completed the Sickle Cell Self Efficacy Survey, the Measures of Sickle Cell Stigma, and the Adult Sickle Cell Quality of Life Measurement Short-Forms. Semi-structured interviews on the patient role were conducted, transcribed, and then analyzed using thematic analysis. RESULTS: Twenty-four participants aged 19-25 years defined expectations of being a "good patient." Five definitional themes emerged: health maintenance, emotion regulation, self-advocacy, honest communication, and empathy for clinicians. Participants identified support from families and clinicians are important facilitators of role fulfillment. DISCUSSION: How young adult patients with sickle cell disease define being a "good patient" has implications for the transition of care for both pediatric and adult medicine practices. This understanding can inform healthcare system designs and programs aimed at supporting patients and families.

Natural history of blood pressure in sickle cell disease pregnancy.

In this retrospective cohort study of singleton pregnancies in people with sickle cell disease (SCD) delivered at two academic centres between 1990 and 2021, we collected demographic and SCD-related data, pregnancy outcomes, and the highest systolic and diastolic blood pressure (SBP and DBP) at seven time periods. We compared blood pressure values and trajectories in the composite cohort and in each genotype group to control values in a non-SCD pregnancy dataset. There were 290 pregnancies among 197 patients with SCD. Sixteen per cent (n = 47) of pregnancies had a hypertensive disorder of pregnancy (HDP); the rates did not differ by genotype. The mean SBP and DBP were lower in the HbSS/HbSß0 group than in the non-SCD control group at all timepoints. Mean SBP and DBP trajectories were similar between the HbSS/HbSß0 group and non-SCD controls, whereas the mean SBP and DBP in the HbSC/HbSß+ group decreased between the first and second trimesters and plateaued between the second and third trimesters. There were no differences in blood pressure trajectory by haemoglobin >/< 10 gm/dL or by chronic transfusion status. Overall, pregnant people with SCD have lower blood pressure than unaffected pregnant people, raising the possibility that HDP are underdiagnosed, particularly in people with HbSS/HbSß0 .

"Buprenorphine, It Works so Differently": Adults with Sickle Cell Disease Describe Transitioning to Buprenorphine for Treatment of Chronic Pain.

A growing body of literature describes the use of buprenorphine for the treatment of chronic pain in people with sickle cell disease. The experiences of people with sickle cell disease who have tried buprenorphine have not yet reported. This qualitative descriptive study was conducted to explore perspectives on buprenorphine for chronic pain in sickle cell disease. We interviewed 13 participants with sickle cell disease who had been prescribed buprenorphine and had a clinic visit between December 1, 2020, and April 2022 in our Sickle Cell Center for Adults. Interviews were recorded, transcribed, and analyzed using thematic analysis. Eleven out of 13 participants were taking buprenorphine at the time of the interview, with a mean treatment duration of 33 months (SD 18, range 7-78 months). Five major themes were identified: 1) dissatisfaction with full agonist opioids; 2) navigating uncertainty with autonomy in deciding to try buprenorphine; 3) functional and relational changes after starting buprenorphine, 4) enduring systemic barriers to pain treatment, and 5) trusting treatment relationships are necessary when approaching patients about buprenorphine. The experience of adulthood living with sickle cell disease before and after starting buprenorphine is qualitatively different with significant improvements in social functioning. PERSPECTIVE: This study examined the experience of adults with sickle cell disease and chronic pain transitioning from full agonist opioids to buprenorphine. It is the first qualitative study of buprenorphine in people with sickle cell disease, contributing to a small but growing literature about buprenorphine and sickle cell disease.

Sickle cell disease, pregnancy, and COVID-19 in France: plus ça change.

Not available.

"The Patient Should Have a Choice": Adults with Sickle Cell Disease Advise Integration of Telemedicine into the Comprehensive Sickle Cell Disease Care Model.

BACKGROUND: Adults with sickle cell disease (SCD) constitute a unique and vulnerable patient population with complex healthcare needs including routine follow-up visits and acute care evaluations. The COVID-19 pandemic accelerated healthcare systems' transition to providing telemedicine care. The purpose of this qualitative study was to elicit the perspectives of adults with SCD about their experience with telemedicine during the COVID-19 pandemic and to understand their preferences with respect to future telemedicine care. METHODS: Adults with SCD who had a telemedicine visit between March August 2020 and were cared for at our SCD center were eligible to participate in a one-time interview. Interviews were audio taped, transcribed, and analyzed using NVIVO software. RESULTS: Among 30 interviewed subjects, 28 transcripts were available for analysis. Analysis identified that participants compared telemedicine to in-person care across several domains including (a) how time is used, (b) personal safety, (c) pain management, and (d) maintaining caring relationships. Participants agreed that telemedicine care was most appropriate for follow-up care and less useful for painful crises or urgent needs. They expressed concerns about the need to expand telemedicine to other specialities and to ensure that privacy and technical support are provided. CONCLUSIONS: Telemedicine appeals to adults with SCD for maintenance SCD care. Decisions about in-person or telemedicine care need to be made in discussion with the patient with particular attention to pain management preferences. Ultimately, telemedicine is an option that adults with SCD would like to see continue and that has the potential to expand access to care to more geographically distant regions.

Alpha globin gene copy number and incident ischemic stroke risk among Black Americans.

Introduction: People 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. Methods: We 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 determine HBA copy number. Multivariable Cox proportional hazards regression was used to estimate the hazard ratio (HR) of HBA copy number on time to first ischemic stroke. Results: Four-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. HBA copy 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 (<1%) ααα/ααα. The adjusted HR of ischemic stroke with HBA copy number was 1.04; 95%CI 0.89, 1.21; p = 0.66. Conclusions: Although a reduction in HBA copy number is expected to increase endothelial nitric oxide signaling in the human vascular endothelium, HBA copy number was not associated with incident ischemic stroke in this large cohort of Black Americans.

Family planning needs of young adults with sickle cell disease.

Sexual and reproductive healthcare standards for adolescents and young adults with sickle cell disease (SCD) are not established. A total of 50 young adults entering adult SCD care completed a Family Planning Survey assessing sexual and reproductive health needs from March 2019 to July 2020. Clinical data were abstracted from respondents' electronic medical records. Linear and logistic regression was applied to explore associations between clinical characteristics and survey results. Few respondents (8%) wished to be pregnant in the coming year, and 46% answered yes to at least one of four needs assessment questions. Those who were not employed full time were more likely to endorse needing help with getting sickle cell trait testing for a partner (ORadj = 9.59, p-value = 0.05). Contraceptive use was associated with having an obstetrician-gynecologist (OR = 6.8, p-value = 0.01). Young adults with SCD entering adult care have diverse reproductive health needs, highlighting opportunities to provide multidisciplinary, SCD-specific reproductive healthcare.

Knowledge of fertility and perception of fertility treatment among adults with sickle cell disease (KNOW FERTILITY).

Introduction: This study assessed fertility knowledge in adults with sickle cell disease using the Cardiff Fertility Knowledge Scale and Fertility Treatment Perception Survey and compared knowledge scores in respondents with sickle cell disease to previously reported unaffected cohorts. Methods: This cross-sectional study surveyed adults over age 18 with sickle cell disease at an adult sickle cell disease center using a 35-question survey addressing infertility risk factor knowledge and perceptions of fertility treatment. Analyses included summary statistics for continuous and categorical variables, univariate linear regression, and Mann-Whitney U tests for group comparisons of Fertility Knowledge Scale scores. Fertility Treatment Perception Survey scores were measured by medians of the two positive statements and four negative statements to generate separate positive and negative treatment belief scores. Statistical significance was set at p < 0.05 for all analyses. Results: Ninety-two respondents (71 female, 21 male) with median age of 32 years (IQR: 25.0, 42.5) completed the survey between October 2020-May 2021. Sixty-five percent of respondents reported taking sickle cell disease treatment and 18% reported refusing at least one sickle cell disease treatment due to fertility concerns. The mean Fertility Knowledge Score was 49% (SD: 5.2), lower than reported in an international cohort (57% vs. 49%, p = 0.001), and higher than in a cohort of reproductive-aged Black women in the USA (49% vs. 38%, p = 0.001). Less than 50% of respondents correctly identified common infertility risk factors including sexually transmitted infections, advanced age, and obesity. Mean positive fertility perception score was 3 (IQR 3, 4), and negative fertility perception score was 3.5 (IQR 3, 4). Factors associated with agreement with negative fertility perception statements included: trying to conceive, refusing sickle cell disease treatment, and undergoing fertility treatment. Discussion: Opportunities exist to improve knowledge of infertility risk factors among adults with sickle cell disease. This study raises the possibility that nearly one in five adults with sickle cell disease refuse SCD treatment or cure due to infertility concerns. Education about common infertility risks factors needs to be addressed alongside disease- and treatment- associated fertility risks.

Alpha globin gene copy number and incident ischemic stroke risk among Black Americans.

Introduction: People 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. Methods: We 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 determine HBA copy number. Multivariable Cox proportional hazards regression was used to estimate the hazard ratio (HR) of HBA copy number on time to first ischemic stroke. Results: Four-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. HBA copy 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 (<1%) ααα/ααα. The adjusted HR of ischemic stroke with HBA copy number was 1.04; 95%CI 0.89, 1.21; p = 0.66. Conclusions: Although a reduction in HBA copy number is expected to increase endothelial nitric oxide signaling in the human vascular endothelium, HBA copy number was not associated with incident ischemic stroke in this large cohort of Black Americans.

Severe Maternal Morbidity and Mortality in Sickle Cell Disease in the National Inpatient Sample, 2012-2018.

Importance: Pregnancy 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. Objective: To 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 Participants: This 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. Exposures: SCD, racial disparities. Main Outcomes and Measures: Severe 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. Results: The 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 < .001), especially cerebrovascular events (aOR, 22.00; 95% CI, 15.25-31.72; P < .001) and thromboembolism (aOR, 17.34; 95% CI, 11.55-26.03; P < .001). Racial disparities explained a median (IQR) 28.9% (21.2%-33.1%) of the increased risk in deliveries to people with SCD and between 40% and 50% of the increased risk for acute kidney failure (excess risk [ER], 56.9%; 95% CI, 54.3%-59.3%), intrauterine fetal demise (ER, 47.8%; 95% CI, 46.6%-49.1%), and eclampsia (ER, 42.1%; 95% CI, 37.9%-46.1%). Conclusions and Relevance: In 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.

Comparisons of Severe Maternal Morbidity and Other Adverse Pregnancy Outcomes in Pregnant People With Sickle Cell Disease vs Anemia.

Importance: Pregnancy 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. Objective: To 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 Participants: This 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. Exposures: Prenatal anemia and SCD. Main Outcomes and Measures: SMM 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. Results: Among 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 Relevance: This 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.