ALBERT

Description: Sickle cell trait (SCT) is unique among the carrier states that are identified during newborn screening. Unlike other heterozygous states for rare recessive diseases, SCT is exceedingly prevalent throughout regions of the world, making sickle cell disease one of the most common monogenetic diseases worldwide. Because of this high frequency, reproductive counseling is of paramount importance. In addition, unlike other carrier states, SCT seems to be a risk factor for several clinical complications, such as extreme exertional injury, chronic kidney disease, and venous thromboembolism. Increasing knowledge about these clinical outcomes can help inform genetic counseling recommendations. Expanding research and clinical efforts are needed to ensure that the promises of modern and precision medicine can be delivered to the millions of SCT carriers and their children.

Description: Introduction: Whether sickle cell disease (SCD) or its primary treatment, hydroxyurea (HU), limits reproductive potential in affected women is unknown. Females are born with a finite number of eggs. Anti-Mullerian Hormone (AMH), produced by immature ovarian follicles, is an established method to measure ovarian reserve. Two studies of AMH, one in adolescents with SCD and another in adult women with SCD exist, but neither normal AMH values nor the effect of HU on AMH are established in girls and women with SCD. The purpose of this study is to evaluate AMH levels in women who participated in the seminal study that led to FDA-approval for HU in adults with SCD, the Multi-Center Study of Hydroxyurea (MSH). Methods: The MSH was a randomized placebo-controlled trial (RCT) of HU. The RCT demonstrated HU's efficacy, so a 10-year MSH extension study was conducted to assess HU's potential for "mutagenesis, teratogenesis and oncogenesis". Although no samples from the RCT remain, serum samples (n=285) were available for many women in the follow-up study (n=93). We measured AMH in these samples using the CLIA-certified electrochemiluminescence assay in clinical use at our institution (Esoterix Labs, Calabasas Hills, CA). The assay's reference median AMH in women ages 26 - 30 years is 4.20 ng/mL, and in women 36 - 40 years is 1.69 ng/mL. The assay's lower limit of detection is 0.015ng/mL. Samples with AMH levels beneath the detection limit were run in duplicate when sufficient sample existed; this did not change any results. Here, we report AMH levels in female subjects (n=57) with a serum sample from the first annual follow-up visit (AV01). Descriptive statistics with median values reported for non-parametric variables (Mann Whitney U Test) were performed. AMH 〈 1 is associated with diminished ovarian reserve, a risk factor for shortened reproductive lifespan, infertility and poor outcomes with assisted reproductive technology. Therefore, we categorized AMH as normal (〉/= 1 ng/ml) and low (

Description: Introduction: In addition to forming hemoglobin in red blood cells, alpha globin (HBA) has non-erythroid effects and is expressed in vascular endothelial cells where it interacts with endothelial nitric oxide (NO) synthase (eNOS) to limit nitric oxide diffusion across the myoendothelial junction. Reduced expression of HBA or disruption of HBA/eNOS interactions increases endothelial nitric oxide signaling. Humans have 0 to 3 copies of HBA per chromosome and Black individuals have increased variation in HBA allele count. Moreover, Black individuals are more likely to develop end-stage kidney disease (ESKD) and unexplained genetic factors may contribute to racial disparities in kidney disease not attributable to socioeconomic factors. Given that decreased endothelial NO signaling accelerates renal disease in mouse models, we hypothesized that lower HBA gene copy number would be associated with lower risk of kidney disease among Black individuals. Methods: We used droplet digital PCR to measure HBA copy number in Black individuals enrolled in the REasons for Geographic and Racial Differences in Stroke cohort. This national, prospective observational study enrolled 30,239 men and women 〉45 years of age from the 48 contiguous United States. Prevalent chronic kidney disease (CKD) was defined as eGFR

Description: 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

Description: 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.