Go the Distance: Reproductive healthcare for people with sickle cell disease

Abstract

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.

Overview

Many people with sickle cell disease (SCD) around the globe are surviving well into their reproductive years^1–4. SCD, its therapies, and cures affect many dimensions of reproductive and sexual health⁵. These needs can be complex as information is entwined with decisions about disease treatment and cure⁶ and care is often multidisciplinary (Table 1). Provision of reproductive and sexual health care will be enhanced by the continuing development of comprehensive SCD care models that include dedicated staff to attend to patient and family counseling, care, and, because referrals to additional specialists may be required, care coordination⁷.

Table 1.

Basic reproductive & sexual healthcare concerns for people with SCD & their families

Pre-Pubertal Pediatric   • Family planning for parents of affected child   • Pubertal development, often delayed   • SCD & therapies risks for future fertility

Peri & Post Pubertal Pediatric & Early Adulthood   • Menstruation-associated painful crisis   • Priapism   • Sexual health   • Family planning: contraception, pregnancy & genetic counseling

Older Adult   • Sexual health concerns   • Menopause symptoms & treatment

Several themes emerge in this review.

• Evidence limitations affect most domains of sexual and reproductive health in SCD. This review is clinically oriented. Wherever possible, we provide citations to guide the interested reader to more detailed information. Citations provide further insights regarding mechanisms and, in some cases, genotype-specific considerations.

• Sexual and reproductive health complications of SCD are ubiquitous (Table 1). These complications require clinicians to use, with sensitivity, screening questions, as patients may not volunteer information about, for example, erectile dysfunction or menstrual pain. People may not indicate that they need help obtaining pre-marital or preconception genetic testing or that they have questions about the inheritance pattern of SCD, but do not know how to ask.

• Encouraging people with SCD to develop a reproductive life plan (Table 2) can enable far-sighted guidance regarding many aspects of SCD treatment and care. Since, for example, preconception planning and pregnancy introduce complicated needs, advanced discussion can help inform future decision making and individualize the structure and content of often busy clinic visits.

• Survival is a precondition for reproductive and sexual health care concern relevancy. Disease modifying therapy is therefore fundamental to SCD care. However, the effects of disease modifying SCD therapies on reproductive health outcomes need consideration. Reproductive and sexual health concerns affect referral and selection of SCD treatment and curative options (Table 3A, 3B)⁶.

• Understandings of how SCD genotype and genetic polymorphisms affect sexual and reproductive health are extremely limited ^8–12.

Table 2.

Basic Questions in a Reproductive Lifeplan²¹

Do you plan to have a(nother) child in the future?
Yes	• How many children would you like to have?
	• How long would you like to wait until you (or your partner) become pregnant?
	• What form of family planning do you plan to use until you (or your partner) are ready to become pregnant?
	• How sure are you that you will be able to use this method of family planning without any problems?
	• Has your partner been tested for sickle cell disease or thalassemia trait? If yes, what form of testing was performed (how do you know)?
No	• What method of family planning will you use to avoid pregnancy?
	• How sure are you that you will be able to use this method of family planning without any problems?
	• Plans can change. Might you or your partner ever decide to pursue pregnancy?

Table 3A.

Reproductive & sexual health considerations for disease modifying therapy for SCD in women

Hydroxyurea	• Improved symptoms and global function, improves childhood social experiences, educational opportunities; impact on growth and development unclear29
	• May improve SCD pain with menstruation
	• Contraindicated during pregnancy due to teratogenicity; preconception approach varies
	• Use during breastfeeding requires shared decision making81
	• Associated with diminished ovarian reserve
	• Impact on, and need for discontinuation of, prior to fertility preserving interventions is unclear
Chronic Transfusion	• Improves symptoms and global function, improves childhood social life and educational opportunities
	• May improve SCD pain with menstruation
	• Only available treatment for SCD during pregnancy64
	• Associated iron overload seems not to cause central hypogonadism; primary gonadal effects are unknown
	• Use before fertility preservation may be indicated for procedural risk mitigation79
Voxelotor	• Little evidence to address risks or benefits; theoretically might improve growth & development by raising hemoglobin, not FDA approved in young children
	• Discontinue at conception attempt or once pregnant
Crizanlizumab	• Little evidence to address risks or benefits; theoretically might improve development by preventing hospitalizations, not FDA approved in young children
	• Possibly improves SCD pain associated with menstruation
	• Discontinue at conception attempt or once pregnant
L-glutamine	• Little evidence to address risks or benefits
	• Possibly improves SCD pain associated with menstruation
	• Discontinue at conception attempt or once pregnant

Table 3B.

Reproductive & sexual health considerations for disease modifying therapy for SCD in men

Hydroxyurea	• Reducing symptoms, improving growth and enhanced global function improves childhood social experiences, educational opportunities
	• Reduced mortality and morbidity and improvement in quality-of-life and function may ensure the opportunity to pursue reproductive lifegoals.
	• Early initiation may reduce future priapism risk, inconsistent benefit in men already experiencing priapism
	• Contraindicated during attempts to conceive due to teratogenicity, effects on sperm
	• Discontinue before fertility preserving interventions
Chronic Transfusion	• Reducing symptoms, improving growth and enhanced global function improves childhood social experiences, educational opportunities
	• May reduce priapism onset and frequency
	• Associated iron overload seems not to cause central hypogonadism; primary gonadal effects not established
Voxelotor	• Little evidence to address risks or benefits (i.e., teratogenicity, effects on sperm, priapism); theoretically might improve growth & development by raising hemoglobin, not FDA approved in young children
Crizanlizumab	• Little evidence to address risks or benefits (i.e., teratogenicity, effects on sperm); theoretically might improve development by preventing hospitalizations, not FDA approved in young children
	• Under investigation to reduce priapism
L-glutamine	• Little evidence to address risks or benefits (teratogenicity, effects on sperm, priapism)

Inviting discussion of these topics in clinic creates opportunities to address misconceptions and realities, to share information, however limited, and to encourage patients to share their vision for their future. Addressing these topics head-on is not just part of high-quality care, it is also trust-building and treatment informing.

Authors’ notes on language:

Sex as the biologic factor assigned at birth and gender as a socio-cultural identity are not synonymous for everyone. We use “girls and women” to refer to people with ovaries and “boys and men” to refer to people with testes. We acknowledge the non-binary nature of gender and that not all individuals with SCD born with ovaries identify as girls or women as not all individuals born with testes identify as boys or men¹³. In clinical care, we invite patients to identify their preferred gender and sexual identity, which may be dynamic especially in adolescent and early adulthood.

Lifespan Approach to Identify & Organize Sexual & Reproductive Healthcare Needs in SCD

To organize clinical approaches and thinking about sexual and reproductive health, we assume a lifespan approach, which recognizes that the personal and clinical salience of sexual and reproductive healthcare changes with age, developmental stage, and individual values and preferences. This approach does not always align with healthcare system organization: the sexual and reproductive healthcare concerns of late-adolescences and early adulthood have significant overlap. Usually, transition from pediatric to adult SCD care occurs in deference to medical structures, not patients’ developmental needs. However, some centers are evolving patient-centered care models that identify emerging adulthood as a unique lifestage^14–16. Emerging adulthood is a particularly important and vulnerable time, both as sexual and reproductive health concerns gain new salience for patients and as SCD morbidity and mortality rises. Ultimately, the topics have relevance for both pediatric and adult clinicians, as acknowledged by the recently updated American Society of Hematology Clinical Summary transition form for SCD¹⁷.

Several national guidelines, including the National Heart Lung and Blood Institute’s SCD Guidelines state that all people with SCD should be offered the opportunity to develop a reproductive life plan (Table 2)^18–20. A reproductive life plan can help people with SCD of reproductive age consider if and when in their lives they would like to build a family, and this can guide individualized counseling and care.²¹ Several U.S. states have developed freely available reproductive life plan tools. Another approach that we sometimes use is the One Key Question. The Question is an approach that encourages asking women of reproductive age the question, “would you like to become pregnant in the next year?”²² Although this question is studied for use in women, for men with SCD, a modified version of this question may be useful. For both men and women, the answer helps individualize patient counseling and care. A resource to align pregnancy intention and behavior for young adults with SCD is under investigation (NCT05292781).

Sexual & Reproductive Healthcare for People with Ovaries

Gonadal function

Puberty:

Constitutional delay of puberty occurs in girls with SCD and is partly attributable to the high metabolic rate of people with SCD^23–26. A study that matched children with SCD to peers without SCD by Tanner Stage, identified that age of onset of each Tanner stage lagged unaffected children by 2 – 4 years²⁷. Early initiation of hydroxyurea therapy helps reduce early mortality²⁸ and normalize growth parameters²⁹. Hormone deficiencies occur³⁰. Thus, children with SCD often appear younger than their peers. This developmental delay understandably worries parents, creates social challenges, and is a risk for poorer mental health³¹. Clinicians should be mindful of unresolved developmental delays during the transition from pediatric to adult care and ensure continued care by an expert adult endocrinologist.

Menstruation:

Girls with SCD are expected to menstruate with regular cycles. Women with SCD differentiate dysmenorrhea from SCD pain during menstruation. Thirty percent of women with SCD report painful crisis pain associated with menstruation^32,33. In addition, some women with SCD report heavy menstrual bleeding; this is also associated with reduced quality of life³⁴. The full effect of this pain on quality of life may be underappreciated as women with SCD report that some clinicians are dismissive of this concern³⁵. The extent to which disease modifying therapies for SCD or menstrual-suppressing contraception modify the experience of menstrual pain in SCD is not established⁸, but deserves reasonable consideration for patients experiencing diminished quality of life or pain interference from menstruation. As not all people with SCD will volunteer that they are experiencing menstruation-associated symptoms, systematic anticipatory guidance at the onset of menstruation and regular screening is indicated.

Menopause:

A dearth of evidence exists to address menopause in women with SCD³⁶. This may be partly attributed to the difficult reality that menopause onset may occur after the median age of death in SCD². Concerns about menopause include changes, possibly beneficial, in SCD symptoms with decline in estrogen levels and the use of transdermal estrogen for peri-menopausal symptom relief. Of note, transdermal estrogen preparations are distinct from those used in combined oral contraception and are not a thrombophilic risk¹³. Patients with SCD often have below average bone mineral density and requires additional care, preferably by an expert endocrinologist in bone health, after menopause onset^37,38.

Family Planning

Hormonal contraception:

Progesterone-only forms of hormonal contraception are first line for women with SCD due to the increased thrombotic risk associated with estrogen-containing contraception^20,39,40. These preparations include progesterone-only pills, medroxyprogesterone intramuscular injections, and hormone-eluting intrauterine devices and/or implants. Contraception recommendations balance pregnancy risks against contraceptive risks. In situations where pregnancy is deemed riskier than the thrombotic risk with estrogen-containing contraception, this approach may be justified. However, many SCD comorbidities are firm contraindications to estrogen containing contraception. This includes a history of overt stroke, thrombosis, migraine with aura, retinopathy, neuropathy and nephropathy⁴¹. Girls and women with SCD from many countries report low uptake of highly reliable forms of birth control^42–46. Interventions that are effective at improving use of contraception consistent with life and family planning goals in the general population are not yet studied for people with SCD⁴⁷. As described below, pregnancy in people with SCD is high risk. Thus, further studies defining the barriers and facilitators of hormonal contraceptive uptake for this population are needed; colocalization of gynecology care in the comprehensive SCD care model may help.

Sexual Health:

Sexual health is affected by SCD^48,49. Sexual excitement and/or activity may be associated with painful crises and the disease may affect many domains of sexual function. Dyspareunia occurs and is associated with chronic pain in adults⁵⁰.

Preconception Care:

Pregnancy plans should be addressed with all women of reproductive age at least annually⁵¹. Initial topics that may be addressed in advance of pregnancy are that (1) pregnancy in women with SCD is high risk and requires specialty high-risk obstetric care, (2) medication changes are required for many women with SCD including (but not limited to) discontinuing hydroxyurea, novel disease modifying therapies such as voxelotor and crizanlizumab, chelating agents and non-steroidal anti-inflammatory agents, and initiating a prenatal vitamin and possibly chronic transfusions (Table 3A), and (3) genetic counseling referral is offered universally along with partner testing with biochemical testing, which includes CBC, hemoglobin electrophoresis, capillary zone electrophoresis, high performance liquid chromatography, and/or molecular testing to help the information shared during counseling. Many patients benefit from support in ensuring that partners have the correct test performed and interpreted; when testing indicates the chance that a patient may have a child with SCD, care becomes more complex and includes a discussion of in vitro fertilization with preimplantation genetic testing^8,52. An existing patient education material can help guide this care⁵³.

As patients move from contemplating to pursuing pregnancy, additional concerns arise. This includes baseline end-organ assessments. We pay particular attention to cardiopulmonary and renal function, but all SCD end-organs may have progressive injury during pregnancy and musculoskeletal injury that accumulates in adults with SCD can be especially painful during pregnancy. Preconception end organ assessments can be considered on a case-by-case basis⁵¹. Baseline blood pressure is necessary as pregnancy is associated with increased preeclampsia risk and this diagnosis is partly conditioned on blood pressure. Finally, active discontinuation of hydroxyurea for those on therapy with a transition to chronic transfusions as an alternative therapy for some^54,55.

Pregnancy:

Maternal morbidity and mortality is high in women with SCD^56,57. However increasing evidence from diverse regions of the world supports the hypothesis that some of this morbidity and mortality is related to care delivery; centers with combined hematology and obstetric expertise in SCD have improved outcomes^56–58. Improvements are gravely needed as the risk of death, venous thromboembolism, preeclampsia, eclampsia, stillbirth, preterm delivery, and small for gestational age are significantly increased in SCD^{56,57,59–61}. Care needs can be addressed with trimester-specific considerations^51,62. Not all SCD complications occur equally in people with sickle cell anemia and those with compound heterozygous forms of SCD⁶³, but severe complications of pregnancy can occur in women with all forms of SCD⁵⁶. Experience with SCD related complications such as painful events before pregnancy does not necessarily predict the frequency and severity of such complications during pregnancy.

The following list captures the dimensions of pregnancy care needs. Once pregnancy occurs care needs include:

1. Referral for co-management with high-risk obstetrician and/or maternal-fetal medicine specialist. Where geography precludes regular high-risk obstetric care, consider interval consultations and ideally plan for delivery at center with SCD expertise and high-risk obstetric care.

2. Intrapartum monitoring of hemoglobin, blood pressure, oxygen saturation, urine protein/creatinine and markers of renal and hepatic function.

3. Individualize SCD treatment considerations and consider transfusion for women with SCA. The criteria for transfusion during pregnancy in the American Society of Hematology Guidelines is broad and many if not most women with SCA will meet criteria to at least consider chronic transfusions during pregnancy⁶⁴. Pain and acute chest syndrome occur in pregnancy. Transfusion may reduce these risks, but fetal protection with this intervention is unclear and there is a risk of alloimmunization^65,66.

4. Provide prenatal vitamins and particular attention to potentially increased needs for vitamin D and folate⁵¹. For patients with iron overload, avoid iron-containing prenatal vitamins as iron has unpleasant gastrointestinal side effects in many pregnant women and is not indicated for a person with an established iron surplus.

5. Between 9- and 12-weeks gestational age, initiation of a baby aspirin to reduce preeclampsia risk is considered^18,20,51.

6. Intrapartum venous thromboembolism prophylaxis with low molecular weight heparin is considered on a case-by-case basis and with recognition that the risk of thrombotic events in pregnancy is high in women with SCD⁶⁰.

7. Opioid use may be reasonably required during pregnancy as acetaminophen is the only other analgesic safe in pregnancy. The use of opioids during pregnancy, especially at high doses, poses a risk for neonatal abstinence syndrome and other complications in offspring^67–69. However, these risks must be realistically and compassionately balanced with the antenatal care needs of the mother.

8. Anticipate delivery planning needs which includes assessment of hips as avascular necrosis may impede vaginal delivery, plan to discontinue aspirin and/or anticoagulation, and establishing indications for induction of labor as intrauterine growth restriction and fetal demise are increased in this population.

The developmental effects of fetal exposure to maternal SCD and associated therapies is not established. In the lone study addressing this issue, ADHD and obesity risks are increased in children born to women with SCD compared to matched controls, but whether this reflects aspects of the home environment as opposed to intra uterine exposures is not established⁷⁰.

Clinicians who are caring for women with SCD are advised that national SCD pregnancy guidelines from Canada¹⁹, the United Kingdom⁵¹, the United States²⁰ and Nigeria⁷¹ can be used to inform context-specific care.

Infertility Risks:

Concerns that fertility is reduced in women with SCD, particularly in SCA, are over fifty-years old⁷². There are many plausible mechanisms including SCD pathophysiology, symptoms, palliative, and disease modifying treatments and cures^6,73. Infertility is a clinical diagnosis defined in heterosexual women under 35 years of age as not conceiving after one year of unprotected intercourse. Women over 35 years have 6-months to conceive⁷⁴. Ovarian reserve declines more quickly in women with SCD compared to unaffected women, suggesting that the reproductive lifespan of women with SCD may be reduced^1,75,76. In three small studies, approximately 25% of young women (18 – 30 years) with SCD and no history of hematopoietic stem cell transplant (HSCT), had diminished ovarian reserve, a risk factor for miscarriage and infertility⁵⁵. Additional risks for infertility include that woman may have fewer opportunities for intercourse due to pain or other SCD-associated symptoms⁵⁰. Anticipatory guidance and referral to care at 6 rather than 12 months in women under 35 years is conservative. This approach deserves consideration in countries like the U.S.A. where barriers to care cause delays that disproportionately affect Black women and those who lack adequate insurance coverage or personal wealth to cover treatments⁷⁷.

Fertility Preservation: Fertility Preservation:

At present, anticipation of HSCT or gene therapy/editing are the strongest established indication for fertility preservation for girls and women with SCD⁶. Some young women with SCA develop diminished ovarian reserve, a risk factor for infertility and poorer outcomes with in vitro fertilization. Diminished ovarian reserve is associated with hydroxyurea, causality is not established⁵⁵. These findings led several to recently conclude that fertility services be included as standard clinical care for girls and women along with disease-modifying therapy, highlighting the need to integrate fertility care into existing care models.⁷⁸

Fertility preservation strategies for girls and women exist as standards of care⁶: limited outcomes of oocyte or embryo cryopreservation and ovarian tissue cryopreservation are described^6,79,80. In a small study of ovarian tissue from girls with sickle cell anemia before HSCT, ovarian follicle density was normal⁸⁰. Collaboration between reproductive endocrinology/infertility, anesthesiologists, and SCD experts is necessary to optimize SCD management and to mitigate risks during controlled ovarian hyperstimulation and oocyte harvest or ovarian tissue cryopreservation⁷⁹.

Sexual & Reproductive Healthcare for People with Testes

Gonadal function

Puberty:

Constitutional delay of puberty also occurs in boys with SCD and is partly attributable to the high metabolic rate of people with SCD^24,27. Boys with SCD reach Tanner Stages 2 – 5 at later ages than Tanner-Stage matched peers²⁷. Thus, children with SCD often appear younger than their peers. This developmental delay understandably worries parents, creates social challenges and is a risk for poorer mental health³¹. Patients with unresolved issues of pubertal or constitutional growth delay at the end of pediatric care should transition to an expert adult endocrinologist to continue care.

Hypogonadism:

SCD pathophysiology damages the testes which are damaged by cycles of infarction and hypoxia; approximately 25% of men with SCD have testosterone deficiency making it two to three times more common than in unaffected men⁸². Testosterone is important for physical development, bone health, sexual function, fertility, and socioemotional and cognitive function. Exogenous testosterone replacement is associated with side effects that limit use in SCD⁸². Meanwhile, stimulating endogenous testosterone production is ineffective in the setting of primary testicular failure.

Priapism:

Between 30 and 50% of men with SCD experience priapism, a prolonged, painful, often unwanted, and unstimulated penile erection^4,82. Recurrent episodes of priapism can lead to irreversible damage to the penis and erectile dysfunction. Described triggers include a full bladder at night, infection, emotional and physical stressors. As these episodes often coincide with nocturnal tumescence, they can be profoundly disruptive of sleep. It is unsurprising that quality of life is adversely affected, as mental health and intimate sexual relationships are often negatively affected. Priapism often coincides with puberty onset and treatments are limited. Priapism is an SCD emergency. Patients should be counseled to present promptly for care within 3 hours of priapism onset if home remedies with pain relief, vigorous exercise, hot baths or showering (to induce a “steal syndrome”), ejaculation and/or alpha agonists such as etilefrine or pseudoephedrine fail to resolve symptoms. Consultation to urology for surgical drainage and/or creation of shunts, and to address potential treatment options, such as dutasteride and phosphodiesterase 5 inhibitors is fundamental. Recurrent priapism is an inclusion criterion for some HSCT trials (i.e., NCT03279094, NCT03421756). In the U.S.A., an investigation of crizanlizumab for priapism is ongoing (NCT03938454), and in Nigeria, a randomized double-blind, placebo control trial comparing hydroxyurea to hydroxyurea and tadalafil in men with recurrent priapism is underway (NCT05142254).

Family Planning

Sexual health:

As described above, hypogonadism and priapism with or without consequent erectile dysfunction affect sexual health in men with SCD. Compared to men without SCD, men with SCD report lower overall sexual satisfaction and sexual desire⁴.

Contraception:

Boys and men with SCD need affirming care that reminds them that if not using contraception with a female partner, pregnancy is possible even if sperm counts are compromised by SCD or by hydroxyurea.

Abortion and miscarriage:

Abortion care may be safely provided to women with SCD. When sedation is required, pre-procedure transfusion may be indicated for some patients. However, Pregnancy in women with SCD is high risk and for women who wish or need to end a pregnancy or who require miscarriage management, delays in care should be minimized. After therapeutic abortion or miscarriage, consider post-partum thromboprophylaxis and provide close follow-up care. We note that since abortion rights are no longer federally protected in the United States, abortion care is increasingly complicated by insurance coverage and care location. Local and national abortion funds (abortionfunds.org) and organizations like the Brigid Alliance (BrigidAlliance.org) may help patients obtain indicated care.

Preconception care:

Anticipatory preconception care for men with SCD who are pursuing pregnancy with a partner includes addressing the effects of SCD and its treatments on sperm (see Infertility risks below). As discussed, SCD inheritance and partner testing for SCD with a CBC and hemoglobin electrophoresis is also needed. We offer similar support to men in getting their partner tested as for women and we also refer for genetic counseling.

Infertility Risks:

Men with SCD have multiple infertility risks including impaired sexual development, hypogonadism, and semen abnormalities, such as decreased ejaculate volume, oligospermia, decreased motility/density, and sperm morphologic abnormalities⁸². Hydroxyurea is an additional infertility risk as treatment in men is associated with further reduction in sperm counts^83,84. Evidence is suggestive but does not yet definitively address whether decades of hydroxyurea use in infancy affects the spermatogonial pool and fertility in adulthood⁸⁵. This is not currently an indication for offering fertility preservation especially since testicular cryopreservation is experimental. Treatment is often discontinued in the preconception setting due to concerns for teratogenicity and to allow sperm to recover^6,54. There is not yet a standardized approach to conducting semen analyses in SCD. Some patients prefer a baseline sperm analysis prior to initiating on hydroxyurea and, where resources permit, this approach helps define semen analysis parameters that may be affected by SCD. This care is complex due to the need for masturbation to collect sample and the unclear implications for findings on semen analysis outside the setting of pursuing pregnancy or fertility preservation before HSCT.

Fertility Preservation:

Unlike experimental testicular tissue cryopreservation, sperm cryopreservation is an established method for preserving fertility⁸⁶. Although sample collection is less onerous, in treated men hydroxyurea may need to be discontinued for at least three months to allow sperm recovery. Anticipatory guidance regarding the clinical definition of infertility is also warranted for men with SCD and may be affected by the age of the female partner.

Additional considerations for all people with SCD

Parenthood:

SCD is a complex chronic illness which may meaningfully impact parenting. In the absence of meaningful published information about parenting with SCD, local support groups for affected individuals may be the best resource for patients seeking more information.

Transgender care:

Transgender people with SCD may require special consideration when cross-sex hormone therapy is being considered¹³. People with SCD and a history of cerebrovascular disease or thrombosis are a special subgroup since exogenous hormone administration poses at least theoretical risks. Having SCD and being transgender presents complex layered stigma and vulnerability. Collaborating with experts in transgender care is essential. We often choose risk mitigation strategies that can help retain patients in care, build trust and assist them in their goals of gender transition. For example, collaborating with transgender experts in the titration of testosterone therapy to reduce painful episodes or initiation of thromboprophylaxis.

Reproductive health & mental health:

Reproductive and sexual complications pose risks for reduced quality of life and low mood^{4,32,34,50,87–89}.

Reproductive healthcare in the sickle cell disease care paradigm

Over fifty years ago, SCD medical leaders recognized the overlap of sickle cell trait and diagnosis testing with fears about racial disparities in the provision of non-coercive, non-judgmental reproductive healthcare^90–92. Meanwhile, the late effects of childhood SCD and its therapies are increasingly relevant as global improvements in childhood SCD care shift SCD morbidity and mortality into adulthood. This reality frames the need for an SCD care paradigm that is structured to address sexual and reproductive healthcare concerns across the lifespan of people with SCD and that occurs with respect for health literacy and care preferences and in support of SCD treatment and care goals^5,6,93,94. These concerns span the transition from pediatric to adult care and are affected not just by disparities in SCD research, but also in well documented disparities in reproductive and sexual healthcare for people of color^77,95–97. Specific evidence and care possibilities will vary based on care context.

Reproductive autonomy and access to comprehensive SCD care are the sine qua non of high quality sexual and reproductive healthcare for people with SCD. Both are unrealized for people with SCD. Going the distance for people with sickle cell disease requires making efforts to address the reproductive healthcare concerns discussed here. A proactive approach to this clinical care can change lives.

Abbreviations

SCD

Sickle cell disease

IVF+PGT

In vitro fertilization + Preimplantation Genetic Testing

SCT

Sickle Cell Trait