Knowledge gaps in reproductive and sexual health in girls and women with sickle cell disease.

Studies of sex hormone therapies for individuals with SCD are limited. Whether sex-steroid deficiency or supplementation affects polymerization of sickle haemoglobin is not established( 73 – 75 ). Sex hormone therapies may be used to prevent dysmenorrhea and SCD-pain associated with menstruation, as contraception, for symptomatic menopausal women and for transgender individuals. Two significant concerns raised by treatment with sex hormones are the risk of 1) exacerbating existing hypercoagulability with the administration of exogenous oestrogens( 6 ) and 2) further compromising bone health( 76 , 77 ). Studies are warranted to generate sufficient data to guide the risk-benefit ratio of long-term sex hormone therapies in women with SCD. The increased pregnancy and menstruation-related morbidities of SCD and the potential teratogenicity of disease-modifying therapies make counselling about contraception therapy essential. Combined hormonal contraception and high-dose progestin contraception is associated with increased cardiovascular and thrombotic risk in the general population. Individuals with SCD are at increased risk of thrombotic events, a complication that is associated with poor clinical outcomes( 78 ). Girls and women with SCD in many countries report varied hormonal and non-hormonal contraception use, with infrequent use of long-acting reversible contraception ( 9 , 10 , 48 , 79 , 80 ). Interest in and use of tubal ligation are not established. Further studies are warranted to establish risks and benefits of contraceptive methods and to determine the factors that influence contraception choice, the short- and long-term sequelae of these decisions with respect to their overall health, SCD-related complications, desire for fertility, and quality of life. Data regarding menopausal symptoms in women with SCD are limited ( 15 ). Whether the principles of hormone therapy for unaffected women are generalizable to women with SCD needs study, particularly because SCD is a hypercoagulable condition and the thrombogenicity of oestrogen preparations varies( 81 , 82 ). Research is needed to best characterize the components needed to optimize shared decision-making around hormonal therapy in perimenopausal women with SCD. Transgender individuals with SCD requesting cross sex hormone therapy face theoretical risks with exogenous testosterone (hyperviscosity) or oestrogen (thrombosis). Withholding treatment may have grave consequences, and disease-specific evidence identifying optimal hormone preparations and concurrent SCD treatments is needed( 83 ). Future studies will help define whether these hormonal therapies affect acute and chronic pain or other SCD complications.

Whether and how SCD modifies women’s risk for breast cancer or fibrocystic breast disease, and for common gynaecological problems such as polycystic ovarian syndrome, endometriosis, and heavy menstrual bleeding is not established. Sexual health concerns, like dyspareunia, might be anticipated in a population with high rates of complex chronic pain, psychiatric co-morbidities, and disproportionately low socioeconomic status, but this topic is largely unexplored ( 84 ).

SCD affects all aspects of reproductive health for girls and women, but few quality-of-care indicators are established. Studies focused on implementing existing recommendations for reproductive life planning, preconception counselling and pregnancy care are needed. Studies on the organization of optimal comprehensive, multidisciplinary clinical care for individuals living with SCD should include attention to sex- and gender-specific healthcare needs and address how genetic counselling, and obstetrics and gynaecology care can be included in proposed care systems ( 85 ). A successful model within haematology is established: multidisciplinary clinics that include haematologists and obstetrician-gynaecologists who provide high quality care for women and girls with bleeding disorders. Benchmarks related to reproductive health knowledge and decisions need to be integrated into transition assessments, planning and integration into adult care( 86 ). Interventions to optimize communication and persistence of genetic information about SCD and sickle trait status in the medical record are overdue. Appropriate use of this information to generate testing protocols and recommendations to inform couples of their risk of having a child with SCD require further study. Finally, ordering the correct kind of screening testing for pregnant women with SCD and their partners is an ongoing health inequity that needs attention.

In 2020, the Centers for Disease Control and Prevention (CDC) convened an expert panel to discuss gaps in the care of girls and women with SCD. Working group participants included five manuscript co-authors (LHP, CH, MJP, AJ, KSW). The Foundation for Women and Girls with Blood Disorders (FWGBD) then convened a second public gathering to discuss the working group’s findings. This gathering included paediatric and adult haematologists and a physician assistant who collectively represented eleven academic medical centres in the U.S.A. Participants from the CDC included health policy analysts, epidemiologists, research biologists and policy directors. Finally, members of the Sickle Cell Disease Foundation of California, a prominent community-based organization, attended this meeting. Additional leaders of the FWGBD’s SCD Learning Action Network (KSW, DS, REW, AN) contributed to this report. Table 2 and Table 3 summarize our findings, providing reproductive health research priorities and framing reproductive health questions about SCD treatments and curative therapies. In each domain, patient characteristics such as age, genotype, and geographic location need to be considered to define best practices, inform research approaches and interpret data. The issues identified apply to all or most SCD treatment modalities.

Most aspects of this care intersect with or are complicated by having SCD in some way. Consequently, girls and women with SCD need developmentally appropriate reproductive health care across their lifespan. The 2014 National Heart, Lung, and Blood Institute Sickle Cell Disease Guidelines suggest that all individuals with SCD implement a reproductive life plan ( 14 ). Even though reproductive life planning is an overlapping concern between paediatric and adult care, and indeed some young women are already mothers when they transition to adult care, reproductive life planning and reproductive healthcare it is not a standard component of existing SCD transition planning documents. The Working Group takes a lifespan approach to considering reproductive healthcare concerns in girls and women with SCD and recognizes that the responsibility for this healthcare, although closely intertwined with SCD care, may not be perceived as the domain of paediatric or adult SCD specialist.

Limitations in current reproductive healthcare for girls and women with SCD are bound to intersectional disparities in reproductive health care for Black women. Structural racism and racist mythologies both contribute to disparities in Black women’s reproductive outcomes( 87 , 88 ). Differences in the broad distribution of health care resources, the availability of SCD experts and insurance coverage contribute to profound limitations to SCD-related reproductive healthcare. In the USA, adults with SCD lack specialists to provide care( 85 ), unintended pregnancy is more common than in Europe( 89 ), and access to comprehensive reproductive healthcare is limited by geography and health insurance status( 90 – 93 ). European nations differ in approaches to newborn screening for SCD, the availability of SCD expertise and access to comprehensive reproductive health care that includes fertility preservation ( 94 , 95 ). Of course, most girls and women with SCD live in sub-Saharan Africa and India where access to fundamental SCD diagnostics and treatments are profound public and personal health problems( 96 ). In this setting too, the reproductive consequences of SCD and its treatments are needed( 97 – 99 ). Healthcare policies that build access to reproductive healthcare are required to fully optimize outcomes for girls and women with SCD.

Fertility preservation for girls and women with SCD needs is increasingly important because of improved survival, the increased use of treatments that may compromise fertility and existence of approaches to preserve fertility in pre- and post-menarchal girls and women. At present, ovarian reserve testing is not universally offered to women with SCD. Exposure to gonadotoxic preparative regimens before HSCT or gene therapy is the only indication for fertility preservation in affected girls or women ( 19 , 20 ). Recent evidence suggests women with SCD have a reduced reproductive lifespan as indicated by accelerated decline in ovarian reserve starting in 25 – 30-year-olds ( 15 , 21 , 22 ). Direct end-organ injury to the ovaries from SCD, possibly from ovarian sickling ( 23 ), may drive the premature decline in ovarian reserve. Secondary hypopituitarism is described in girls with thalassemia, but girls with SCD usually have intact endocrine function, even in the presence of iron overload ( 24 ). There is limited data about whether transfusional iron overload affects oocyte quality and/or quantity ( 24 , 25 ) and none about SCD treatments approved over the last few years (crizanlizumab, l-glutamine and voxelotor). Several studies raise the possibility that hydroxyurea accelerates the decline of ovarian reserve in some girls and women ( 15 , 22 , 26 , 27 ). With limited data, clinicians are confronted by how and if to address open questions about hydroxyurea and future fertility during shared decision-making conversations about treatment. This concern must be understood in the context of strong evidence that hydroxyurea has profound clinical benefit for children around the globe ( 28 – 30 ). Whether addressing uncertainty about effects on fertility will dissuade parents from accepting treatment for their affected children is not established ( 31 ). Comparing the long-term fertility effects of existing and emerging treatment options may help guide counselling. The Sickle Cell Transplant Evaluation of Long-Term and Late Effects Registry will compare the fertility effects of hydroxyurea and HSCT (OTA HL152762 ). Both ovarian tissue and oocyte or embryo cryopreservation are standards of care to preserve fertility in at-risk populations ( 32 ) and their use is reported in girls and women with SCD, usually before HSCT ( 25 , 33 , 34 ). However, SCD fertility research lags significantly behind oncofertility research as indicated by the presence of oncofertility guidelines and communication standards for individuals with cancer, but their absence for individuals with SCD ( 35 , 36 ). As with oncofertility research, early studies in SCD fertility focused on boys and men. The effects of hydroxyurea on sperm is more substantively addressed than is the effect of hydroxyurea on oocytes ( 22 , 26 , 37 – 44 ). Systematic studies are needed to define indications for fertility preservation, peri-procedural risks and risk mitigation strategies during fertility preservation, and outcomes relating to immediate fertility preservation and pregnancy when cryopreserved oocytes or ovarian tissue are used ( 33 ). How existing fertility preserving approaches should influence clinical practice is unresolved due to insufficient research and because of inequitable access to fertility preservation for girls and women with SCD. This is a meaningful barrier to optimizing SCD care ( 45 , 46 ). In the United States, no federal law ensures that individuals with SCD, will have access to fertility preserving care or artificial reproductive technologies. Access to fertility preservation in European countries varies. Funding for longitudinal, cooperative studies will inform optimal approaches and indications for fertility preservation, but this work will be inadequate in the absence of policies to address this financial toxicity of SCD and ensure access to care ( 47 ).

Women with SCD are at risk for significant pregnancy related morbidity and mortality ( 52 , 53 ). Studies are needed to identify risk factors for adverse outcomes for mother and foetus, evaluate SCD treatments for safety and efficacy when used in pregnancy, and to optimize pregnancy management and outcomes ( 58 , 59 ). The extent to which established risk factors for poor pregnancy outcomes in the general population affect women with SCD is incompletely addressed by the existing literature. Pressing research needs include: defining the necessary preconception evaluations of end-organ function, treatment optimization, timing or need for treatment modification (both pre- and post-conception) and whether findings and interventions modify pregnancy risks, rigorously studying interventions for pregnant women that reduce maternal and foetal morbidity and mortality, clarifying breastfeeding contraindications, and counselling and implementation of postpartum contraception ( 52 , 53 , 58 , 60 ). Existing technologies can determine whether a foetus is affected by SCD. However novel, non-invasive foetal genetic testing methods that isolate foetal DNA from maternal blood ( 61 ) or the cervix( 62 ), need further evaluation in the SCD population. In addition, research that furthers our understanding of how women with SCD make reproductive decisions and experience parenthood is needed ( 63 – 65 ). In high income countries, the use of artificial reproductive technologies for family building is increasing. Women with SCD may pursue artificial reproductive technologies due to infertility, with cryopreserved ovarian tissue, oocytes or embryos, or in conjunction with pre-implantation genetic testing. In vitro fertilization with preimplantation genetic testing (IVF+PGT) is relevant for some women with sickle cell disease and sickle cell trait because it provides opportunities to conceive children unaffected by SCD( 66 , 67 ), and to select embryos for implantation that may be a match for HSCT in an affected child. In the United Kingdom, the National Health System makes IVF + PGT-M available to all couples at risk for having a child with SCD. A contemporary case series of 60 treated couples in London identified use by couples with diverse economic backgrounds and successful outcomes, including in three women with SCD ( 67 ). Significant barriers to uptake of this reproductive technology include that couples may be unaware of its existence ( 68 , 69 ) and may lack insurance coverage. Data about outcomes, regardless of indication, are needed. In the U.S.A., systematic data reporting on artificial reproductive technologies is federally mandated, but sickle-cell related variables are not collected. A recent report identified 16.5% of embryos created for the purpose of having an HLA-matched sibling were suitable for transfer( 70 ). Patient education and counselling that address complex risks and benefits of treatment. Existing patient education materials about IVF+PGT-M exceed the reading levels of most Americans ( 71 ), highlighting the value of genetic counsellors and others trained to provide accessible education on complex genetic and reproductive concepts. The cost of IVF + PGT-M to prevent SCD or to implant HLA-matched embryo to produce a matched sibling donor need further study and might inform compassionate policy solutions for care ( 70 , 72 ).

The survival of children with sickle cell disease (SCD) well into their reproductive years creates the necessary precondition to address long-standing questions about the reproductive health of affected girls and women( 1 – 4 ). Girls and women with SCD are at risk for having SCD pain with menses and thrombotic complications with oestrogen-containing contraception ( 5 , 6 ). Adolescent and young women with SCD look forward to having biologically related children ( 7 ), but anticipatory guidance and preconception counselling is complex for many reasons. In addition, unplanned pregnancy is common, highlighting the need for proactive rather than reactive reproductive health care ( 8 – 11 ). A summary of important publications addressing reproductive health concerns for girls and women with SCD is summarized in Table 1 . Reproductive healthcare for girls and women with SCD is limited by the absence of practice standards, the lack of clearly delineated responsibilities among specialties, and inadequate research to address pressing concerns. Research is hampered by a lack of prioritization of reproductive health research among specialists caring for individuals with SCD and the need to 1) optimize methods for conducting women’s health research; 2) establish infrastructure for multi-centre and multi-disciplinary collaboration; and 3) ensure funding to support this research agenda ( 12 , 13 ). The purpose of this paper is to provide a roadmap for investigators and funding agencies to advance reproductive healthcare for girls and women with SCD.

Women with SCD are surviving into and beyond their reproductive years. Even in the absence of high-quality evidence that is specific to adolescent and adult women living with SCD, we can do more with what we know now to advance reproductive healthcare for this population. There are opportunities to improve their medical care through healthcare policy reform, advocacy, and implementation of preventative care models. These initiatives are important and underutilized, but they are no substitute for long-neglected, hypothesis-driven, patient-oriented studies. Rigorous research studies will bolster the limited evidence available to care for girls and women with SCD. The SCD community – patients, families, and providers – deserves more. The SCD research community and funding agencies must rise to meet this challenge.

Girls with SCD achieve sexual development milestones later than their unaffected peers; the extent to which SCD therapies modify the onset of menses is not established (Smith-Whitley, 2014; Alleyne et al , 1981; Queiroz et al , 2020). Studies of menopause are challenging because onset coincides with the median age of death for affected women ( 1 , 15 ). Menstruation-related morbidity is underappreciated, undertreated, and associated with poor quality of life ( 16 ). No evidence-based recommendations guide management. In the historic Cooperative Study of Sickle Cell Disease, women had higher rates of SCD-related pain than men; this difference was most notable during women’s reproductive years which raises the possibility that menses-triggered pain contributed to this finding ( 17 ). Women differentiate SCD-related menstrual pain from dysmenorrhea. One-third report SCD-related pain in the week before or during their menstrual cycles ( 5 ). Women with SCD indicated that male providers are dismissive of concerns about menstruation associated SCD pain ( 18 ). Studies are needed to understand the biological mechanisms that drive SCD-related pain during menstruation and to define evidence-based interventions for management and prevention of this common complication.

Preconception counselling is sub-optimal for women with SCD and unintended pregnancies are common ( 9 , 48 , 49 ). Preconception counselling is resource intensive as it includes: Need for partner testing and genetic counselling to provide accurate information about the chance of having a child with SCD ( 50 ); Discontinuing and discussing commonly used medications with established or potential teratogenicity in individuals with SCD ( 3 , 51 ); Pre-conception end-organ assessments (retinopathy, echocardiogram, pulmonary function tests, renal function); Risk and benefit of SCD treatment in pregnancy hampered by a lack of definitive interventions to alter the trajectory of high-risk pregnancy ( 52 – 54 ); Outstanding questions about whether SCD and its treatments compromise fertility ( 22 , 26 ); Inequitable access to fertility preservation ( 45 ). Need for partner testing and genetic counselling to provide accurate information about the chance of having a child with SCD ( 50 ); Discontinuing and discussing commonly used medications with established or potential teratogenicity in individuals with SCD ( 3 , 51 ); Pre-conception end-organ assessments (retinopathy, echocardiogram, pulmonary function tests, renal function); Risk and benefit of SCD treatment in pregnancy hampered by a lack of definitive interventions to alter the trajectory of high-risk pregnancy ( 52 – 54 ); Outstanding questions about whether SCD and its treatments compromise fertility ( 22 , 26 ); Inequitable access to fertility preservation ( 45 ). Finally, partner testing to determine hemoglobinopathy carrier status is indicated. This testing may be used to provide counselling on the foetal risk for SCD and opportunity for in vitro fertilisation with preimplantation genetic testing. In some countries partner testing is systematically available ( 50 ). In the U.S.A. several barriers to partner testing persist. First, despite universal newborn screening for SCD, which also identifies individuals with SCT, this information is not systematically shared with families or retained in medical records. Second, unintended pregnancy is common and limits preconception counselling. Third, access to testing may be compromised based on insurance coverage ( 50 , 55 ). Finally, providers may not follow testing guidelines and even order the wrong screening test( 56 , 57 ). Evidence-based communication tools are needed to standardize comprehensive and complex counselling about fertility risks, contraception choices, and family planning in the context of pregnancy and postpartum risks for individuals with SCD. Incentives for research collaboration across subspecialties should be encouraged to improve partnerships among haematologists, high-risk obstetricians, reproductive endocrinologists, psychologists, and genetic counsellors.