Project Summary Estrogen-containing hormonal contraception and injectable progestin-only contraception have been associated with venous thromboembolism (VTE) and stroke in the general population. However, little is known about the safety of these contraceptive methods among people with sickle cell disease (SCD) even though around 25% of people with SCD experience VTE with a mean age at diagnosis early in the reproductive lifespan. This critical gap in knowledge affects contraceptive counseling from both the clinician and patient’s perspectives. In fact, unplanned pregnancy is more common among people with SCD than the general population suggesting this population faces multifaceted impediments to contraceptive access. Further, the burden of having a serious chronic disease is compounded by the fact that, in the United States, SCD disproportionately affects people with African ancestry (1 in 365 births) and the responsibility of contraception largely falls on women. Thus, people with SCD are more likely to experience a high burden of social stressors, socioeconomic disadvantage, and poor quality of life; all of which may contribute to sub-optimal contraception use. Our overarching goal is to improve the quality of care for people with SCD by assessing the safety of different hormonal contraceptive methods in this population and by holistically evaluating patient and provider factors that affect the use of different contraceptive options. To address this goal, we will leverage health system data from Kaiser Permanente Mid-Atlantic States, which includes approximately 1,642 women with SCD enrolled from 2001-2022. We will augment these data with patient surveys and semi-structured interviews of their providers. Our research will be guided by a Patient Advisory Board. Aim 1 will use health system data to compare the risk of SCD complications (VTE, stroke, myocardial infarction, and SCD pain crisis) for people initiating estrogen-containing contraception versus progestin-only contraception. We will use the state-of-the- art target trial emulation framework to compare people initiating different contraceptives methods (new user- active comparator design). Aim 2 will evaluate which patient characteristics are associated with the use of different types of hormonal contraception using health system data and patient survey data (n=250) that address the knowledge and attitudes of people with SCD towards different contraceptive methods. Aim 3 will use semi-structured interviews, informed by a mixed-methods sequential explanatory design, to evaluate the knowledge and beliefs of clinicians (n=25) regarding hormonal contraception for people with SCD. Impact: This work addresses the NICHD priority Effects of Long-Term Contraceptive Use on Health with a special focus on racial minorities and people with chronic conditions by directly assessing the safety of different contemporary contraceptive methods in an historically understudied population. Further, by examini...