Sickle cell, BMT and fertility preservation – Part 2

Last week, I began a two-part series discussing women living with sickle cell disease, the possibility of undergoing a bone marrow transplant, and the importance of considering fertility preservation.

Sickle cell disease itself can affect ovarian function, and the curative therapies involved in BMT further increase the risk of infertility. Today, we’ll continue from where we left off and explore these and other issues further.

Sickle cell disease can significantly impact a woman’s reproductive health in several ways.

Impaired blood flow to the ovaries: The sickle-shaped red blood cells characteristic of SCD can block small blood vessels, including those that supply blood to the ovaries.
When the ovaries do not receive enough oxygen-rich blood, their function can be compromised, leading to a decrease in the number and quality of viable eggs. Over time, this reduced blood flow can lead to earlier ovarian failure, causing early menopause, reduced fertility, and an increased risk of miscarriage.

Chronic inflammation and organ stress: SCD causes chronic inflammation and oxidative stress in the body, which can also affect the ovaries. Prolonged exposure to inflammation can damage ovarian tissue, further reducing the ovarian reserve and accelerating reproductive ageing.

Blood vessel clogging: The sickle-shaped cells associated with SCD can clog the small blood vessels that supply the ovaries, potentially causing them to stop functioning earlier than expected.
Medication: Medications commonly used to manage SCD, such as nonsteroidal anti-inflammatory drugs, such as naproxen or ibuprofen, which are commonly used to manage pain in SCD, may make it more difficult for women to ovulate as they interfere with ovulation. Chronic use of pain medications also can contribute to infertility. Opioids decrease the overall fertility rate in women.

Bone marrow transplants: Women who undergo bone marrow transplants to treat SCD are exposed to radiation and chemotherapy, both of which can severely damage the ovaries. The radiation and chemotherapy used as part of the preparation for a bone marrow transplant further diminishes ovarian reserve and increases the risk of infertility and early menopause.

During hematopoietic stem cell transplant, candidate patients face gonadotoxic therapy akin to those used to fight neoplasia. These treatments, such as the use of alkylating agents and irradiation, are well known to impair future fertility by damaging ovarian reserve.

Hydroxyurea: Small studies suggest that hydroxyurea, a chemotherapy drug used to manage SCD, may impair ovarian function, by affecting egg production and quality. However, more research is needed to confirm this.

Iron overload: Many women with SCD require chronic blood transfusions, which can lead to iron overload. Women who undergo chronic transfusion therapy to manage SCD can experience iron overload, which may lead to infertility over time. Excessive iron in the body can accumulate in various organs, including the ovaries, potentially impairing their function and reducing fertility.

Despite the challenges, fertility preservation strategies are available for women with sickle cell disease. Options such as ovarian tissue cryopreservation, embryo or oocyte cryopreservation, and egg freezing allow women to take proactive steps in preserving their fertility.
For severely ill patients with Sickle Cell Anemia, hematopoietic cell transplantation may offer a cure. However, the gonadotoxic pretreatment required for this disease-altering therapy often results in sterility. Given the complexity and difficulty of HCT, it is typically only offered to those suffering the most from SCA, particularly those with clinically significant end-organ damage. Additionally, SCA and its associated comorbidities can complicate both ovarian stimulation and the oocyte retrieval process.
Gonadotoxic therapy refers to medical treatments that can cause permanent damage to reproductive function and lead to infertility. This is a significant concern for SCA patients undergoing HCT, given how ill this subpopulation typically is.

Reports underscore the severity of illness in these patients, who represent an extreme group, as only the most severely affected individuals are candidates for HCT. If HCT treatments were to become less toxic, they could be offered to healthier patients, expanding the candidate pool for fertility preservation. This shift could provide candidates who are less vulnerable to the complications associated with fertility preservation treatments.

Sickle cell anaemia, which includes haemoglobin SS and haemoglobin Sb0 genotypes, is a life-limiting disease characterised by haemolytic anaemia, vascular dysfunction, chronic end-organ injury, and premature death.

An increasing number of patients with SCA are pursuing hematopoietic stem cell transplants as a potential cure for their condition. However, recipients of HSCT are exposed to gonadotoxic therapies, such as alkylating agents like cyclophosphamide and busulfan, as well as total body irradiation. These treatments are associated with up to an 80% risk of premature ovarian failure.

Patients with SCD who undergo hematopoietic cell transplantation face a particularly high risk of subfertility and infertility due to the use of alkylating agents and radiation in pretransplant conditioning regimens. However, early data indicate that fertility-preserving treatments can be effective for this population.

Despite this, due to under-counselling and limited access to assisted reproductive technology, this group faces an increased need for fertility treatments but decreased access to them.

The combined impacts of SCD, HCT, and infertility significantly affect the quality of life and mental health, though no studies have specifically addressed the ramifications of this combination. While other effects of HCT are undoubtedly important to the overall quality of life, fertility issues have received relatively less attention and are particularly impactful for the SCD community.
Although research specific to SCD patients’ access to ART before HCT is lacking, there is ample evidence of these patients’ overall inadequate access to care, including challenges in finding providers with sufficient knowledge of SCD treatment.

Given the risks, we strongly recommend that all women with SCD be referred to a reproductive endocrinologist before undergoing HSCT or gene therapy. This ensures that fertility preservation and surrogacy options can be discussed in advance, providing women with the opportunity to make informed decisions.

Until next time.

If you would like to get in touch with me about sickle cell, do so, via my email address: [email protected]. And do check out my blog: https://www.dailylivingwithsicklecell.com/  My book on Sickle Cell – HOW TO LIVE WITH SICKLE CELL and my other books are available for purchase on www.amazon.com.