One’s expectations for normality

In this issue of Blood, Sockel et al report a comprehensive analysis of pregnancy and birth rates in 2654 women, aged 18 to 40 years, after allogeneic hematopoietic cell transplantation in Germany from 2003 to 2018. The annual first live birth rate after allogeneic hematopoietic cell transplantation was compared with the annual first birth rate of women, aged 18 to 40 years, in Germany in 2019 obtained from the German Bureau of Statistics.¹ This report concluded that the annual first birth rate of the general German population was >6 times higher than among women after allogeneic hematopoietic cell transplantation.¹ 

With improvements in survival after hematopoietic cell transplantation,² young adults are likely to express a desire to have children in their goal for normal health and social functioning. The current report¹ extends the findings noted in earlier studies on fertility after hematopoietic cell transplantation.^3,4 Adverse risks on fertility included older age (>25 years), transplantation for a nonmalignant disease, and a myeloablative regimen with cumulative total body irradiation ≥8 Gy.¹ In a subset with information on conception, antenatal complications, and fetal outcomes, observations support a favorable outcome.¹ An unexpected observation was the spontaneous occurrence of pregnancy in ∼70% of those who conceived. It is plausible with appropriate counseling before start of gonadotoxic therapy and with extended use of assisted reproductive technology, there could be further improvements in fertility rates after hematopoietic cell transplantation. Others have shown in survey data from male and female transplant recipients and their partners that female recipients reported a higher rate of no conception than male recipients.³ A limitation of the study design of Sockel et al is that men were excluded. It is plausible that had the study design included men who fathered offspring, the annual first live birth after hematopoietic cell transplantation may have been higher.

How can the findings of Sockel et al inform clinical management and future research efforts regarding infertility after hematopoietic cell transplantation?

First, fertility counseling should be offered early, with the gold standard being soon after diagnosis and before any gonadotoxic therapy.⁵ All health care providers should be prepared to discuss infertility as a potential risk of therapy with the discussion taking place as soon as a cancer diagnosis is made and occurring in parallel with staging and formulation of a treatment plan. In the setting of transplantation for nonmalignant diseases, a transplant physician should initiate discussions regarding infertility and its preservation in parallel with donor search for transplantation.

Second, health care providers should incorporate evidence-based practice guidelines into their clinical practice on fertility preservation for men and women. The American Society of Clinical Oncology has provided evidence-based clinical practice guidelines on fertility preservation since 2006, with the most recent guideline update in 2018.⁵ Summary of the recommendations includes the following: (1) health care providers should address the possibility of infertility as early as possible before treatment starts, (2) patients who express an interest and those who are ambivalent should be referred to reproductive specialists for consultation, and (3) to preserve the full range of options that are available, fertility preservation approaches must to be discussed before treatment starts and continued during follow-up visits after completion of treatment if there is a desire to have offspring. The recommended option for postpubertal men is sperm cryopreservation.⁵ Hormonal gonadoprotection in men is not successful in preserving fertility; and other methods, such as testicular tissue cryopreservation, should only be offered as part of a clinical trial or an approved experimental protocol. Recommendations for postpubertal women of childbearing age include established fertility preservation methods by the American Society for Reproductive Medicine, specifically embryo cryopreservation, cryopreservation of unfertilized oocytes, and ovarian tissue cryopreservation.^5,6 Ovarian transposition (oophoropexy), conservative gynecologic surgery, and ovarian suppression should not be used in place of proven fertility preservation methods. Children require special consideration. The established methods described above are recommended for postpubertal children, with patient assent and parent or guardian consent.⁵ For prepubertal children, the only fertility preservation options are ovarian and testicular cryopreservation.⁶ 

Third, over the past 3 decades, there have been many advances in gene therapy to correct inherited blood disorders.⁷ Inherited blood disorders that have and continue to benefit from gene therapy include hemoglobinopathy (sickle cell disease and thalassemia), inborn errors of immunity, lysosomal storage disorders, leukodystrophies affecting tissue-resident macrophages and brain microglial cells, and Fanconi anemia.⁷ 

Gene therapy requires collection of the patient’s own hematopoietic stem cells (autologous) that are gene corrected by either adding a normal copy of the inherited defective gene with an integrating vector or editing the defective gene to restore its function. With the exception of Fanconi anemia, conditioning chemotherapy with busulfan (one of the most gonadotoxic agents) is needed to attain engraftment of the genetically modified autologous cells.⁸ Although there are no evidence-based practice guidelines that have been developed for preserving fertility after gene therapy, it would be prudent to adopt the recommendations for patients with cancer.^5,6 Fertility preservation is further complicated by the fact that several of the inherited blood disorders require correction at a young age, an age group that has proven to be challenging to preserve fertility.⁶ 

Last, Sockel et al have acknowledged the challenges of collecting comprehensive information from adults of childbearing age, a necessity for a comprehensive study on reproductive health. It is conceivable for transplant registries to seek consent for direct engagement with those who are willing to consent to collect pretransplant and longitudinal data prospectively on reproductive health, in men and women. Pertinent pretransplant questions should seek information on whether fertility preservation was discussed before gonadotoxic therapy was initiated, access to a fertility preservation program, method of preservation undertaken, monetary challenges, psychologic burden, and support from health care providers posttransplantation in achieving their goal toward pregnancy, including men who wish to father offspring. Only through systematic data collection can the medical community begin to identify obstacles and mitigate the challenges of infertility associated with allogeneic and autologous hematopoietic cell transplantation.

Conflict-of-interest disclosure: The author declares no competing financial interests.