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

Abstract

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 counselling 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.

1. Introduction

Sickle cell disease (SCD) is an autosomal recessive blood disease associated with acute crises, relentless end-organ injury, and early death¹. The arrival of gene therapy as a SCD treatment standard is drawing attention to the infertility care needs for individuals with SCD: current conditioning regimens for transformative therapies are frankly gonadotoxic². Yet even in the absence of exposure to therapies intended to cure SCD, girls and women with SCD face increased infertility risks. Twenty-three percent of women surveyed in the Sickle Cell Disease Implementation Consortium Study reported infertility, nearly twice the U.S. infertility rate^3,4. A survey of 100 women with SCD in London identified a lower-than-expected unintended pregnancy rate⁵. As evidence about infertility risk factors emerge and fertility preservation approaches exist, an updated clinical care paradigm is needed^6,7.

Addressing infertility with girls and women with SCD is complex^2,8–13 and is among the population’s dynamic sexual and reproductive health concerns. In high income settings, the preconditions for routinely addressing these concerns are achieved. First, survival to reproductive age is a near-universal reality for people with SCD¹⁴. Second, the disease clearly affects menstruation^15,16, contraception^17–19, sexual function^20,21, fertility/infertility^6,8,22,23, pregnancy^24,25 and, likely, menopause^9,11,13,26. Third, there are specialists who can evaluate and manage gonadal function, fertility preservation, high-risk pregnancy, and exogenous hormone administration. These specialists include pediatric endocrinologists, reproductive endocrinologists, gynecologists, and maternal fetal medicine experts. Integrating these specialists into lifespan SCD care systems is both possible and critically necessary. Finally, secular changes in family building timelines may be reasonably understood to affect individuals with SCD. Globally, women are postponing childbearing to pursue educational and professional goals. Advances in SCD care enable speculation that this trend is likely also among individuals with SCD.

The purpose of this review is to support clinicians in providing counselling about fertility and infertility risks to girls and women with SCD and their families. The impact of SCD and SCD-treatment on the function of the ovaries and future fertility is reviewed. We performed a narrative review to synthesize existing evidence on fertility and infertility in girls and women with SCD and integrate what is known with a proposed counselling approach for patients and families²⁷. Keywords and MeSH terms used included, but were not limited to: sickle cell disease, infertility, pregnancy, menstruation, ovary, and hydroxyurea. This review included studies from Nigeria, Ghana, USA, Jamaica, France, Denmark and the United Kingdom.

Both ovarian tissue cryopreservation and oocyte or embryo cryopreservation are options for fertility preservation to be addressed with girls and women with SCD^28,29. The universal use of alkylating agents renders conditioning regimens for hematopoietic stem cell transplantation (HSCT) and gene therapy high risk for infertility and premature ovarian insufficiency. Until conditioning regimens are fertility sparing³⁰, these therapies are an absolute indication for fertility preservation consultation for girls and women with SCD. In the absence of that indication, counselling about when to pursue fertility preservation is complex. Counseling requires addressing indications, timing, and outcomes of fertility preservation in the absence of strong evidence. It requires balancing patient- and family-centred short- and long-term goals and interacts with overlapping social, biomedical, and reproductive spheres. Individuals with SCD and their families receive care across their developmental stages and in diverse geographies with variable cultural value, legal protections, and financial supports for fertility care⁸. Counseling may need to acknowledge profound barriers to obtain indicated SCD and reproductive healthcare^8,10,31–33.

2. Overview of sexual and reproductive health concerns in girls and women with SCD

For clinicians caring for girls and women with SCD and their families, knowledge of overall sexual and reproductive outcomes can enrich and shape counselling. This section provides a review of fertility-related considerations for girls and women with SCD. Knowledge of reproductive lifespan, menstruation, sexual function, contraception, high-risk pregnancy, and fertility preservation approaches can help clarify and focus counselling about fertility and infertility concerns.

2.1. SCD and the reproductive lifespan: ovarian reserve

The ovaries are a SCD end-organ and ovarian follicle count one measure of their health. Understanding normal ovarian function can inform counselling in the unique setting of SCD (Table 1).

Table 1.

Measures of gonadal function

Measure	Clinical Significance Women	Limitations
Follicle Stimulating Hormone (FSH)	• Pituitary hormone that binds to ovarian granulosa cells where androgens are converted to estrogens • Stimulates folliculogenesis • Ovarian reserve marker • ≥25–40 IU ×2, POI diagnosis	• Fluctuates with menstrual cycle • May return to normal with time after chemoradiation
Luteinizing Hormone (LH)	• Pituitary hormone that stimulates progesterone and androgen production within ovarian theca cells • Oocyte maturation—progresses from arrested prophase I to metaphase II (state required for fertilization)	• Fluctuates with menstrual cycle
Estradiol	• Produced from testosterone via aromatase in granulosa cells • Breast and uterine development during puberty • Uterine endometrial lining growth to prepare for embryo implantation • Maintain bone mineral density • Measure of ovarian function	• Fluctuates with menstrual cycle • May return to normal with time after chemoradiation
Progesterone	• Stabilizes and maintains uterine lining for pregnancy • Decline induces menses	• Fluctuates with menstrual cycle
Testosterone	• Hormone precursor for estradiol	• N/A
Antimullerian Hormone (AMH)	• Ovarian reserve marker • Helps predict ovarian response to IVF medications • <1.1 ng/mL may indicate diminished ovarian reserve	• Variable depending on age • Large range of normal • Only reflects pool of growing follicles • May not reflect number of dormant primordial follicles • May increase with time after chemoradiation
Antral Follicle Count (AFC)	• Ovarian reserve marker • Helps predict ovarian response to IVF medications and pregnancy rate	• Inter and intra cycle variation • Prone to observer bias
Inhibin B	• Secreted by granulosa cells • Negative feedback on FSH • Possible marker of ovarian reserve	• Abnormalities may signal dysfunction in the HPA axis • Role in women remains unclear and controversial

POI = premature ovarian insufficiency, HPA axis = hypothalamic-pituitary-adrenal axis

Adapted from ²Nickel et al, Fertility after Curative Therapy for Sickle Cell Disease, J Clin Med

The biological reproductive lifespan captures women’s childbearing years and is defined as the time between menarche and menopause³⁴. Ovarian reserve refers to the primordial follicle pool in the ovaries at any given time. People are born with a fixed number of ovarian follicles that decline over time. Primordial follicle count peaks at 10 million at about 20-weeks’ gestation, atresia then begins and proceeds continuously, such that at puberty onset, about 500,000 follicles remain and at menopause onset, fewer than 1,000 remain³⁵. Ovarian aging depends on follicle loss from the finite gonadal pool. Quantifying primordial follicles helps define reproductive potential in women. Several biomarkers are used clinically as proxy measures of the ovarian primordial follicle pool. Anti-mullerian hormone (AMH) is a glycoprotein hormone produced by small ovarian follicles; serum concentrations are used to quantify ovarian reserve. Ultrasonographic measurement of antral follicle count (AFC) is the sum of antral follicles directly counted in both ovaries and is as sensitive as AMH³⁶.

Two clinical terms define low ovarian reserve for age. First, diminished ovarian reserve (DOR) is generally accepted to mean ovarian follicular depletion and diminished oocyte quality. DOR is not the inability to conceive³⁷. However, DOR is predictive of response to, success of fertility preservation interventions and an indication for offering fertility preservation. Second, premature ovarian insufficiency (POI) is the near complete depletion of the follicular pool and is clearly associated with infertility due to complete loss of ovarian function.

There is growing evidence to support the claim that in SCD, the reproductive lifespan is reduced. This is best substantiated for those with hemoglobin SS or hemoglobin Sβ⁰-thalassemia (Figure 1). Multiple lines of evidence support this generalization. First, for girls with SCD, menarche occurs later than in the general population. Second, as might be expected in a disease of accelerated aging, there is accelerated decline in ovarian reserve compared to unaffected individuals^6,23,38–40. POI appears to be uncommon in SCD^{6,23,38,40,41}. However, DOR occurs in about 25% adolescent and young adults with SCD before age 31 years^6,23,38–40. Identifying these individuals may potentially change practice because the presence of DOR is an indication for offering fertility preservation^8,42. Finally, menopause onset may be sooner than in the general population²⁶. While clinical infertility is not yet definitively associated with these findings, rates of self-reported infertility are high in women with SCD^5,22,43. For this reason, we offer fertility preservation consultations (discussed below), and offer referral for infertility evaluations starting at 6-months of trying to conceive for heterosexual women with SCD.

Figure 1.

Antimullerian hormone in women with hemoglobin SS disease who participated in the Multi-Center Study of Hydroxyurea

Adapted from ³⁷Pecker et al, Hydroxycarbamide exposure and ovarian reserve in women with sickle cell disease in the Multicenter Study of Hydroxycarbamide, Brit J Haematol

2.2. Menstruation, contraception, and sexual function

Menstruation is associated with SCD pain for about a third of girls and women with SCD^15,44. Sexual function is also affected. Compared to matched controls, married Nigerian women with SCD have much poorer sexual function and marital satisfaction²¹, and chronic SCD pain is a risk factor for dyspareunia⁴⁵. Data is suggestive that hormonal contraception and/or SCD modifying therapies alters menstruation associated SCD pain and may improve sexual function, but this is not established^15,16,46. In general, girls and women spend a significant amount of their life not wanting to be pregnant. The Centers for Disease Control and Prevention will soon issue updated guidance on SCD and hormonal contraception. We expect this guidance to account for the reality that SCD poses a thrombosis risk akin to high risk thrombophilias such as antithrombin deficiency⁴⁷ and that thrombosis is a mortality risk factor in SCD⁴⁸. This may make estrogen-containing contraception contraindicated in SCD and affect recommendations for medroxyprogesterone^19,49. Some may express concern that hormonal contraception cause infertility. Clinicians can offer reassurance that reversible forms of hormonal contraception do not cause infertility^50,51.

2.3. High-risk pregnancy

The incidence of infertility in people with SCD is not yet established; many people become pregnant. We counsel pre-menopausal, heterosexual, sexually active women with SCD who are not using contraception that they are at risk for pregnancy. Like the ovaries, the uterus, placenta and fetus are incompletely considered SCD end-organs. SCD pregnancy is high risk and advanced planning presents many opportunities for high stakes decision making¹¹. SCD pregnancy outcomes in high- and middle-income countries including the United States and Jamaica have not changed for over 20 years^24,52,53. While the absolute individual risk of maternal mortality is low, the risk compared to unaffected populations is high. In the U.S., the risk of death of Black women with SCD is 10-times greater than unaffected Black women and 26-times greater than unaffected White women²⁴. Racial disparities, deficiencies in care systems, and disease pathophysiology affect these outcomes^24,54–56. Miscarriage, severe maternal morbidity and small for gestational age infants are common. Unsurprisingly given the panoply of in utero exposures, children born to women with SCD may have some developmental risks⁵⁷. All pregnant people with SCD require multidisciplinary care that ideally includes at least SCD and maternal-fetal medicine specialists⁵⁸.

2.4. SCD therapies and infertility risks

Studying the fertility risks of SCD and its treatment is difficult because ‘fertility’ is a difficult outcome to measure. An individual’s fertility is contingent upon many variables which include the availability of an opposite sex, fertile partner, and an intention to conceive. To calculate a true infertility rate, the denominator must include individuals attempting to conceive. Existing studies on SCD pregnancy rates in the context of chronic disease or post-HSCT events do not use the correct, if any, denominator⁵⁹. The gold standard epidemiologic method to study fertility is to conduct prospective “time to pregnancy” studies. These studies have not been performed in SCD.

Chronic SCD therapies and treatments intended to cure SCD may constrain the reproductive lifespan or cause infertility (Table 2). Hydroxyurea is associated with lower ovarian reserve in a growing number of studies, but this risk is not currently associated with pregnancy^6,38,40,41. Whether hydroxyurea causes lower ovarian reserve is not firmly established^7,8; treatment is a marker of baseline disease severity. In limited data, chronically transfused individuals with SCD have preserved ovarian reserve^6,40. Pituitary iron deposition in beta thalassemia presents infertility risks due to hypothalamic-pituitary-ovarian axis suppression; this manifestation of iron overload is uncommon in SCD. Ovarian iron deposition is plausible but understudied. There is no data regarding the effects of l-glutamine, crizanlizumab or voxelotor on ovarian reserve. Experimental therapies, like decitabine/tetrahydrouridine⁶⁰, will need study as will studies of oocyte quality to augment quantitative measures of ovarian reserve.

Table 2.

Putative infertility risks associated with sickle cell disease and its treatments and cures.

Few infertility risks are universal features of SCD, so fertility care must account for age, sex, genotype, disease complications and measures of treatment dose, duration and adherence. Uncertainties related to infertility risks can be incorporated into information sharing about disease complications and treatment benefits.

	People with ovaries
Untreated sickle cell disease	Ovarian reserve decline is accelerated in adulthood; some adolescents and young adults have diminished ovarian reserve
	Pregnancy is high-risk for maternal and fetal morbidity & mortality
Disease modifying therapies	Hydroxyurea: associated with diminished ovarian reserve; concern for early embryonal developmental changes, teratogenesis
	Red cell transfusions: ovarian follicle iron deposition possible, pituitary iron overload uncommon, chelators are teratogenic
	L-glutamine, crizanlizumab, voxelotor: no data
Curative/HSCT preparative regimens	Alkylating Agents: gonadal toxicity and infertility
	Total Body Irradiation: Reduced ovarian reserve, infertility, uterine damage reducing future blastocyst implantation

HSCT = hematopoietic stem cell transplantation

Adapted from ⁸Pecker et al, Expecting More, Lancet Heme

Therapies intended to cure SCD currently require the use of alkylating agents and sometimes total body irradiation. This renders them high risk for causing POI and infertility. For individuals pursing these therapies, there is an absolute indication for fertility preservation consultation^2,61.

3. Assisted reproductive technologies for fertility preservation

Assisted reproductive technologies (ART) can support achievement of reproductive goals for individuals facing reproductive toxicity. ART care may be indicated for carriers of sickle cell trait, among them parents of children with SCD, and individuals with SCD⁶². ART includes fertility preservation, use of in vitro fertilization to treat infertility, use of in vitro fertilization with preimplantation genetic testing for monogenetic disorders (IVF+PGT-M) or to determine if embryos might become a potential matched sibling donor for an affected child^8,13. Few reports exist on outcomes from IVF use to treat infertility in women with SCD or on the use of IVF+PGT-M⁶³ for women with SCD. Unfortunately, the Centers for Disease Control and Prevention’s mandatory IVF reporting system does not capture disease-specific information⁶⁴.

3.1. Fertility preservation

Ovarian tissue cryopreservation (OTC) is the only fertility preservation technique available for prepubescent girls. OTC requires undergoing a brief laparoscopic surgery with an abdominal incision to remove either ovarian cortical tissue or one whole ovary for dissection into cortical strips for cryopreservation. The ovarian tissue strips can subsequently be thawed and implanted later if they are needed in the setting of POI from SCD or SCD-related treatment. Globally, there have been over 200 live births from frozen-thawed autologous ovarian tissue transplantation. There is an experimental alternative to ovarian tissue reimplantation is to extract follicles from ovarian tissue. Extracted follicles can then be matured in vitro and these mature oocytes can be fertilized with mature embryo(s) subsequently transferred to the uterus if pregnancy is desired. This follicle extraction approach has not yet resulted in live births in human, but studies are humans are underway. Uncertainties with OTC include defining normal ovarian follicle density. This may be important to predict outcomes. In children with SCD follicular density may not be reduced^29,65. In general, OTC presents risk for hypoxic-ischemic tissue damage at harvest or reimplantation leading to graft failure, the potential for in vitro fertilization to become pregnant and the possibility that removing ovarian tissue may contribute to POI. The extent to which these risks are exacerbated by SCD or mitigated by curative therapies is not established. SCD-specific pregnancy rates with OTC are needed.

Embryo cryopreservation is the longest-standing fertility preservation method. In people with infertility, there is a predictable likelihood of future pregnancy based on the number and quality of embryos cryopreserved. Embryo cryopreservation is available to post-pubertal women who either have a committed partner or are prepared to use donor sperm. Embryo cryopreservation requires approximately two weeks of ovarian stimulation with exogenous gonadotropins, then surgically retrieving oocytes from the ovaries and inseminating them with sperm and then culturing any resulting embryos for 2-7 days with subsequent cryopreservation. Genetic testing, for aneuploidy or monogenetic conditions such as SCD, can also be performed before or after cryopreservation. In studies of people without SCD, embryo cryopreservation can then have a success rate of 30-50% per subsequent embryo transfer. This may not be a realistic approach for girls and young single women⁶⁶.

Mature oocyte cryopreservation is another option for post-pubertal women and does not require a sperm source at the time of fertility preservation. Like embryo cryopreservation, oocyte cryopreservation requires approximately two weeks of ovarian stimulation with exogenous gonadotropins and then transvaginal, surgical extraction of oocytes from the ovaries. Cryopreserved oocytes may be used for future fertilization, for instance with a future partner, enabling additional reproductive autonomy. Age at vitrification and number of oocytes cryopreserved are predictors of future pregnancy success, however this data is more limited than for embryo cryopreservation, and clinic-specific success rates should be used to counsel patients whenever possible.

Ovarian stimulation presents disease-specific risks for women with SCD²⁸. Oocytes are usually removed from the ovaries using an ultrasound-guided needle that passes through the posterior vaginal fornix directly into the ovary. This may be done with monitored anesthesia care with deep sedation. Ovarian hyperstimulation also causes hyperestrogenemia and is consequently associated increased thrombosis risk, a risk already present in individuals with SCD. Corticosteroids are often (but unnecessarily) used as post-procedure anti-emetic^28,67. Since corticosteroids are associated with painful crises and other adverse outcomes in SCD, they should be avoided for this indication⁶⁷. Ovarian hyperstimulation syndrome (OHSS) is a relatively uncommon complication (1-2%) but may be particularly perilous for those with SCD. OHSS is a capillary leak syndrome that occurs on a spectrum from mild fluid overload to ileus, ascites, and acute renal failure. While potentially a cause of severe morbidity, reproductive endocrinologists assess and reduce risk with preventive measures such as reduced gonadotropin doses and other adjunct medications. Finally, SCD complications are reported and cycles have been disrupted due to pain or acute chest syndrome. Because of the potential for disrupted cycles, we implemented a protocol that includes exchange transfusion, individual evaluation for anticoagulation, discussing pain management and avoiding routine use of corticosteroids as an antiemetic (Figure 2).

Figure 2.

Proposed algorithm for reproductive endocrinologists managing ovarian stimulation and retrieval in girls and women with sickle cell disease (SCD).

Adapted from ²⁷Pecker et al, Risks associated with fertility preservation for women with sickle cell anemia, Fertil Steril

3.2. Pregnancy outcomes from fertility preservation techniques

Very limited data exists on outcomes from embryo or oocyte cryopreservation in patients with SCD. Adults with SCD may have very variable oocyte harvest yields²⁸. Beyond oocyte quantity, SCD is a disease of accelerated aging thus it is possible that cryopreserved oocytes behave as biologically older gametes than an individual’s stated age though this has not been examined. Case series and reports (i.e. anecdote) identify positive pregnancy outcomes using cryopreserved gametes among women with SCD. Some pregnancies to individuals with SCD using OTC or cryopreserved games are reported²⁹. While we are optimistic about fertility preservation as a hopeful intervention for the SCD community, systematic evidence needs to be collected that not only identifies when pregnancy occurs but also when pregnancy fails to occur⁵⁹. Currently, the extent of the literature on fertility in individuals with SCD exposed to HSCT is marked by significant reporting bias: pregnancy, but not infertility is most often reported^2,68.

4. Counseling considerations

Existing conditioning regimens for therapies intended to cure SCD carry an absolute indication to offer fertility preservation counseling^2,10,61. In most other scenarios, discussing fertility is challenging because this counselling involves complex practical, emotional, and social dimensions, and includes identifying patient and family values, integrating diverse evidence streams to provide coherent counsel, and acknowledging uncertainty⁶⁹. Clinicians may be hesitant to initiate such conversations, citing reasons such as insufficient knowledge, lack of time, patient lack of access, or concerns about the SCD-specific risks associated with fertility preservation. In people with cancer, counselling by a fertility specialist results in less regret, regardless of whether fertility preservation was ultimately pursued^70,71. Since SCD and its treatment and cures may affect ovarian reserve and future fertility, until there are criteria that enable clinical discernment, liberal referral to a reproductive endocrinology for fertility preservation counselling may be prudent.

In this section, we focus on approaching individuals and families considering chronic, rather than curative, SCD interventions where indications for fertility preservation are emerging⁷. We especially focus on hydroxyurea, the best chronic SCD therapy which is a chemotherapeutic agent initiated in 9-month-olds because of the profound benefits of treatment^72–75. We have encountered significant and understandable anguish among clinicians who worry they will deter use of this transformative therapy if they share uncertainties about hydroxyurea and its relationship with ovarian reserve, and infertility risks^{6,22,38,40,41,76}. Four principles inform our multi-disciplinary counselling of girls and women with SCD regarding fertility and infertility. They are, (1) listen to patients and families as they identify their concerns and priorities around reproductive topics, (2) build a multi-disciplinary village to counsel and care, (3) claim solid ground regarding evidence, where it exists, and (4) embrace uncertainty.

4.1. Invite discussion to identify patient and family concerns

Clinicians can proactively assess whether parents, adolescents, or adults with SCD have questions about the heritability of SCD, infertility associated with SCD or its therapies, know about in vitro fertilization with preimplantation genetic testing, or have other, specific reproductive health concerns. In our Young Adult Clinic, these queries are embedded in standard review of systems in our electronic medical record⁷⁷. Some of these issues may be pressing. For example, the parents of a child with SCD may be unaware of opportunities to perform fetal testing for SCD with cell-free DNA using a commercially available maternal blood test^78,79, to build their family with IVF+PGT-M⁸⁰ or, to test whether embryos might be a future matched sibling donor for HSCT⁸. Parents may refuse transformative hydroxyurea treatment for their infant due to concerns for future infertility⁸¹. A patient or family may need to identify financial resources to pursue fertility preservation before scheduled, transformative HSCT or gene therapy. Another may have had years of unprotected intercourse without conceiving^22,59,82. These issues may not need to be addressed at every clinic visit; however, clinicians can initiate conversations about these intensely private and life-altering reproductive concerns.

4.2. It takes a village: build a care team

Family and friends, genetic counsellors, pediatric endocrinologists, adolescent medicine specialists, reproductive endocrinologists, maternal fetal medicine specialists, stem cell transplanters, psychiatrists, community-based organization staff, and mental health care providers may all be called upon during highly consequential decisions regarding treatment, infertility risks and decisions to pursue, or not, fertility preserving interventions or pregnancy. As these specialists become clinical collaborators, opportunities for knowledge exchanges emerge with the potential to improve fertility preservation and pregnancy outcomes^28,56. We offer referrals to sub-specialists, community-based organizations and occasionally (with permission) connect families with shared concerns to one another. SCD is both stigmatizing and immensely isolating for many affected individuals and their families^83,84. Multi-disciplinary care helps alleviate some of this burden and supports individuals’ and their families in clarifying values and preferences in making highly consequential treatment decisions.

4.3. Claim solid ground

Evaluation of a decision aid for hydroxyurea initiation highlights that parents of children with SCD view this treatment decision as complex⁸⁵. Extant literature suggests that a minority of individuals reject hydroxyurea because of concern that treatment causes infertility^81,86,87. While a growing number of papers show an association with lower AMH in hydroxyurea-exposed women, this is (1) not yet clearly associated with infertility, nor (2) an established, causal relationship. Further studies are needed to clarify whether lower AMH in hydroxyurea-treated individuals with SCD is associated with infertility, a marker of disease severity or a consequence of treatment exposure.

In addition to clearly addressing what is unknown about SCD, hydroxyurea and fertility, there is information to share about what is known. We approach this conversation with the following information in mind:

• Affirm that infertility risks from SCD and its treatments are long-standing SCD community concerns that are inadequately addressed with existing data ^88–90. Knowledge gaps around fertility and infertility are manifestations of global failures to invest in SCD research and care^59,91–94 and the neglect of reproductive healthcare concerns for affected girls and women^7,9. Genotype-specific nuance can be offered and clinicians can acknowledge that most evidence addresses ovarian reserve and infertility risks in girls and women with hemoglobin SS or hemoglobin Sβ⁰ thalassemia; as in other dimensions of SCD research and care, hemoglobin SC and other compound heterozygous states are neglected⁹⁵.

• Do not equivocate: hydroxyurea is a transformative treatment for children with SCD^96–98. Treatment results in fewer hospitalizations, transfusions, prevents painful crises, acute chest syndrome, improves neurocognition, reduces cardiac dysfunction, prevents conversion to abnormal transcranial doppler, reduces stroke risk, improves kidney function, and prolongs life. These benefits reasonably translate into fewer missed school and workdays, and higher educational attainment. These benefits should also help optimize young people’s physical well-being when they enter adult care. Even if hydroxyurea is causally associated with lower ovarian reserve, this does not yet translate into clear infertility risk and it may be paradoxically protective of future fertility by protecting end-organs, reducing pain, and indirectly enabling adult relationships where family planning concerns can become a priority.

• For children, one critical goal is to enter adulthood with the least possible accumulated SCD morbidity. Translating the impact of end-organ protection with SCD treatments into clinically relevant outcomes may feel challenging; the progressive end-organ injury from SCD can be insidious with clinical effects manifesting only in adulthood. Yet we know that many adults with SCD lead very difficult lives^33,99–101. Normative realities include high rates of complex chronic pain, progressive end-organ decline, neurocognitive dysfunction, psychiatric co-morbidities, poor health related quality of life, low educational attainment, impaired social function, and high reliance on health care systems that are largely lacking in compassion and experts to provide care^83,84,102. There are not enough adult SCD doctors to care for adults with SCD. We do not propose that these harsh realities be shared with families on their first visit to the pediatric hematologist. Yet neither can they be completely glossed over as patients and parents weigh highly consequential treatment decisions.

• Many women with SCD certainly become pregnant; we have less information on those who do not. Plausibly, reducing pain in SCD enables the social interactions and physical intimacy required for intercourse^21,45. Women with SCD pursuing pregnancy can be conservatively counselled that if they are not pregnant after 6-months of unprotected heterosexual intercourse, it is reasonable to pursue an infertility consultation; certainly, this referral is indicated if conception is not achieved after 12-months of trying¹¹.

• Finally, fertility preservation opportunities exist. As is standard for individuals with cancer, we can offer opportunities to preserve fertility in pre -pubescent and menstruating girls and women with SCD alongside chemotherapy that transforms outcomes^7,103. About 25% of adult women for whom hydroxyurea is indicated (whether taking it or not) have DOR, an indication for offering fertility preservation (Table 3)⁶. Thus, families may be offered opportunities to meet with reproductive endocrinologists to learn about embryo, oocyte, and ovarian tissue cryopreservation. Post-pubertal adolescent girls can participate in decisions about preserving fertility and, of course, young adults may make these decisions independently.

Table 3.

Diminished ovarian reserve (DOR) is associated with hydroxyurea use in 3 independent cohorts of young women with sickle cell anemia, all subjects with DOR were exposed to hydroxyurea Elchuri et al described DOR in adolescents with SCA taking hydroxyurea in their study⁴⁰. Pecker et al described DOR in adult women with SCA in the Multi-Center Study of Hydroxyurea³⁷. The Multi-Center Study of Hydroxyurea dataset precluded the possibility of determining whether hydroxyurea was being used at the time the samples used to measure AMH were procured, but data did identify who ever took hydroxyurea (“Ever took”).

	Currently taking hydroxyurea				“Ever took” hydroxyurea
	Elchuri40*		Pecker6a		Hopkins6b		Multi-Center Study of Hydroxyurea37
Age Range Median (IQR)	10 - 21 14.5 (2.5)**		19 - 30 24 (22, 28)		19 – 30 24 (22, 28)		20 – 30 29 (25, 29)
	HU	No HU	HU	No HU	Ever HU	No HU	Ever HU	No HU
DOR	8	0†	5	0†	5	0†	14	0†
No DOR	25	14	10	11	19	2	13	2
Risk difference (95% CI)	0.24 (0.096,0.39)		0.33 (0.095,0.57)		0.21 (0.046,0.37)		0.52 (0.33,0.71)
Number to Harm (95% CI)	4.1 (2.6, 10.4)		3.0 (1.7, 10.6)		4.8 (2.7, 21.8)		1.9 (1.4, 3.0)

To enable comparison to previous studies, Pecker et al⁶ (“Hopkins” below) compared subjects with HbSS < 31 years of age and categorized subjects a currently taking^a or ever taking (“ever took”) hydroxyurea^b. No subjects without hydroxyurea exposure had DOR.

^*Elchuri et al⁴⁰ measured AMH using Beckman-Coulter AMH Gen II ELISA and defined abnormally low AMH (“DOR”) as <5^th percentile for age. Pecker et al³⁷ measured AMH using Esoterix (LabCorp) assay and defined DOR as AMH < 1.1ng/mL. Pecker at al⁶ measured AMH using the Beckman Coulter Access 2 assay and defined DOR as AMH <1.1ng/mL.

^**Mean values with standard deviation are reported

^†All subjects with DOR had hydroxyurea exposure. Conversely, there was no one without hydroxyurea exposure who had DOR.

Adapted from ⁶Pecker et al, Diminished ovarian reserve in young women with sickle cell anemia, Blood, 2022

4.4. Embrace uncertainty, imagine the future

Despite all that is unknown, we can proactively initiate discussions about present or future fertility. Withholding information that exists risks perpetuating structures of reproductive injustice that have disproportionately harmed Black communities in the U.S.A.^8,32. Individuals with SCD and their families face significant clinical uncertainties, a dynamic treatment landscape and many barriers to comprehensive high-quality care. Transparently acknowledging this uncertainty is trust-building¹⁰⁴. Outside of curative therapies, we do not know definitively when to offer fertility preservation, but standard options exist and the benefits of a consultation are well-established; we do not know what the precise risk of infertility is in adult women with SCD, but we know the risk is present; we do not know whether DOR is associated with infertility in individuals with SCD, but we know it is an indication to offer fertility preservation.

Expert Opinion

To determine how to approach conversations about fertility, SCD and SCD treatments, parsing patient and family communication needs can be critical. Communication strategies that honor patient interests and wishes are critical. However, even patients and families who are not explicitly asking questions about this topic deserve counselling regarding contemporary existing evidence. The lack of access to standard fertility preservation interventions can make clinicians feel like this counselling is at odds with what is possible. The availability of standard of care fertility preservation interventions and the presence of elevated infertility risks in at least some people with SCD changes this dimension of SCD care. An updated treatment paradigm that coordinates optimizing SCD treatment with fertility care is indicated^6,7.

Stronger evidence and access to fertility care would meaningfully shift the significant burden on clinicians tasked with counselling patients and families with SCD about fertility preservation and infertility risks. Robust data addressing significant questions about menstruation, contraception, pregnancy, infertility, menopause and how these issues are affected by genotype and SCD therapies would allow clinicians to claim more solid ground and clarify recommendations^8,9. Obviously, access to assisted reproductive technologies would ensure that patients can actually pursue the opportunities afforded through these interventions^8,32. Counseling alone about the existence of standard assisted reproductive technology interventions does not ensure uptake. In the USA, a mosaic of largely inadequate state and federal policy inform access to care^8,32. Most states have no requirement for coverage for infertility or fertility preservation care and some states are imposing severe policies that threaten assisted reproductive technology care even for those with insurance coverage or independent wealth to afford the expense. The Centers for Medicaid and Medicare Services identified the lack of access to fertility preservation as a barrier to uptake for newly approved SCD gene therapy¹⁰⁵. In sub-Saharan Africa, where SCD is most prevalent and infertility in general is also a significant public health concern, major investments in clinical workforce and infrastructure and funding for care will be needed to realize fertility preservation and infertility care for all people, including those with SCD. This reality underscores the need for transformative SCD therapies that are not gonadotoxic.

Our patients and their families are acutely aware of the unpredictable dimensions of SCD and inequalities SCD. We invite discussion because we cannot assume to know what information will be most salient to any one individual or family. We expect that different kinds of fertility-related information will be important across developmental life stages, as disease complications arise, and as new evidence or interventions for SCD or fertility become available. Information shared might inform how families plan their financial futures, saving money to store gametes harvested through fertility preservation. Information shared may inform where individuals decide to live – proximal to SCD centers or, in the USA, in states with better insurance coverage for infertility and fertility preservation treatments or with lower maternal mortality rates. Families and relatives might even choose to join local community groups or advocacy days to urge policy makers to address deficiencies in SCD care, including the need for access to standard of care fertility preserving interventions.

Children with SCD are surviving to adulthood and many have dreams of pursuing parenthood. These dreams are entirely consistent with the significance and value of biological parenthood in most societies. SCD affects most of the body’s organs including the ovaries, uterus, placenta, and fetus. The disease affects social development, intimate relationships, health related quality of life and mood. Chronic treatments and therapies intended to cure SCD may reduce clinical complications and improve physical and social function but can present independent infertility risks. SCD, too, poses infertility risks. Standard of care fertility preserving options for girls and women exist and can be offered along with SCD treatment. We must work to reduce the significant barriers to deliver fertility care to our community. While we do so, we can partner with patients and their families to address what we do and do not know and share hope for what the future may hold.

Article Highlights.

• Survival into adulthood is a near-univeral outcome for children with sickle cell disease in high income settings.

• Infertility risks are a consequence of sickle cell disease, and its chronic and curative therapies.

• A treatment paradigm that acknowledges the risks of untreated sickle cell disease, the benefits of treating sickle cell disease, and the potential for compromised fertility in the future is warranted.

• Non-experimental fertility preservation interventions exist for pre-pubescent girls and pubescent girls and women with sickle cell disease. These interventions have disease-specific risks.

• Access to assisted reproductive technologies including fertility preservation, in vitro fertilization and preimplantation genetic testing are inaccessible to many due to inadequate insurance, lack of experts and high cost.

• We suggest a counselling regarding infertility risks that (1) invites discussion with patients and families, (2) involves a care team with fertility preservation experts, (3) claims solid ground where evidence exists to inform care, and (3) embrace uncertainty as there is much that remains unknown.

Abbreviations

SCD

Sickle cell disease

HSCT

Hematopoietic stem cell transplantation

AMH

Anti-Mullerian hormone

AFC

Antral follicle count

POI

Premature ovarian insufficiency

DOR

Diminished ovarian reserve

ART

Assisted reproductive technologies

OTC

Ovarian tissue cryopreservation

IVM

Matured in vitro

OHSS

Ovarian hyperstimulation syndrome