Fertility Issues Following Hematopoietic Stem Cell Transplantation

André Tichelli; Alicia Rovó


Expert Rev Hematol. 2013;6(4):375-388. 

In This Article

Patients' & Doctors' Attitudes Towards Fertility Issues After HSCT

Fertility preservation is of great importance to many patients treated with HSCT. Infertility resulting from treatment is associated with significant psychologic distress, with levels of depression twice that of the normal population and impaired quality of life. Infertility also means stress for the partner and, in case of the patient is a child, for the parents. The lack of information and the uncertainty on impact of the cancer treatment on fertility (not knowing for sure) are factors involved in fertility concerns. Cancer survivors that were reported to be infertile after treatment were significantly more likely to report poorer mental health, cancer-specific distress and lower psychological well-being.[59] Even for persons who may not have planned to have children, the threat of infertility can result in a deep sense of loss and anger.[6,37,51,60] On the other hand, male patients having banked sperm considered it a positive factor in coping emotionally with cancer, even when the sperm were never used.[61]

Although transplant survivors can become parents through options such as adoption and third-party reproduction, most prefer to have a biological offspring. Often cancer survivors and couples decide to adopt after a series of failed attempts to conceive by assisted reproductive technology. There are reasons why cancer and transplant survivors may prefer adoption to assisted reproductive technology: refusal to undergo an invasive treatment, wish to adopt a biogenetically unrelated child and lack of sufficient funds.[62] Unfortunately, cancer survivors, because of their diagnosis, may face discrimination in domestic and international adoption agencies. Indeed, many countries and adoption agencies underestimate the chance for cure of cancer survivors and exclude them from adoption programs.[63]

Limited research has examined the barriers and facilitators of fertility discussion with survivors of cancer treatment and HSCT. Barriers are mainly related with the lack of patients' information on infertility issues, and the clinician's reservation to speak about infertility and fertility preservation.

Patient's Attitude Toward Fertility Issues

Given the high risk of infertility associated with HSCT, patients have to be aware about the risk of treatment-related infertility and the possibilities for fertility preservation. In recent surveys, only 30−60% of male and female cancer survivors of reproductive age remembered about a discussion of fertility at time of treatment.[64–66] It is possible that long-term survivors no longer recall information provided years ago. Therefore, patients need to be repeatedly informed about fertility issues, before cancer treatment for patients with malignant diseases, but also before HSCT and repeatedly during long-term follow-up. In a questionnaire-based study on 196 female patients treated with HSCT, 38% reported that they had discussed fertility-related issues with health care providers since their diagnosis and 54% had discussed menopause-related issues. After transplantation, the participants considered receiving information on menopause was more important than information on fertility. Fertility issues seemed of particular importance for patients younger than 40 years, desiring to bear children in the future and having a high score on anxiety.[67] In a single center study uptake and outcome of assisted reproductive medicine was evaluated in long-term survivors after HSCT. The rate of patients recalled being counseled about infertility before HSCT increased from 42 to 86% when transplantation was performed before and after 1990, respectively. The rates of male patients who were offered sperm banking (71%) was higher compared to rates of female patients who were offered embryo banking (46%). Eventually, in 53% of male patients and 36% of female patients the offer of banking was taken up.[34]

In a pilot survey of survivors' attitude and experiences, the majority of younger cancer survivors saw their cancer experience as potentially making them better parents. Those who were childless wanted to have children in the future. However, many of them had significant anxieties and insufficient information about reproductive issues.[65] For some patients of childbearing age, a loss of fertility was reported to be almost as painful as confronting the cancer itself.[6] A total of 29% of young women with breast cancer reported that concern about fertility impacted on their treatment decision.[68] However, conclusions drawn from breast cancer studies cannot be extrapolated to patients undergoing HSCT. The impact of a patient's knowledge about the risk of treatment-related infertility on his decision of HSCT is still unexplored. Transplant physicians recognize that patients are interested in learning about the impact of transplant on fertility.[56]

The issue of fertility preservation in children is even more complex. Fertility preservation methods are limited for prepubertal children. Furthermore, the parents have to decide and provide consent of fertility preservation for their child. However, parental decisions may not always reflect the patients' wishes later in life.[53] There are two separate aspects to consider in decision making on fertility issues of children: first, the decision to store material for fertility preservation. This has to be done immediately, before initiation of therapy; secondly, the information of the patient on fertility and fertility preservation. This information can be postponed to the time when the child has become a young adult survivor. Cancer-related infertility often comes as a surprise to young survivors.[65] Actually, about 60% of young adult survivors of childhood cancer are uncertain about their fertility. Parents refusing to allow the information to be given, or neglecting to pass it on at an appropriate age may account for the large proportion of lack of knowledge.[69] The decision-making process regarding fertility preservation among adolescent cancer patients is even more complicate. A review of 29 articles published between 1999 and 2009 focusing on decision making in teens with cancer showed that adolescents have a strong desire to participate in decision related to the cancer treatment. Most teenagers rely on their parents to interpret and process information regarding health issues. However, they may be more selective about whom they wish to discuss fertility issues with. Teenagers have concerns regarding their future fertility and want to be informed. Nevertheless, they are often apprehensive to discuss fertility preservation with their parents, particularly if as a child they had not previously discussed sexuality with their parents.[70]

Clinician's Attitude Toward Fertility Issues

Despite the interest in fertility issues, the physicians face a number of barriers responsible for low rates of discussion with their cancer patients and of referrals to a fertility preservation center.[71–73] The most common reasons given for not offering information on fertility and fertility preservation include the lack of knowledge about fertility preservation, lack of awareness of appropriate referral site for fertility preservation, concerns about potential treatment delays due to fertility preservation efforts, unresolved financial costs involved in fertility preservation and the lack of time to discuss the issue.[66,74,75] Oncologists may not discuss fertility preservation options with their patients because they doubt the success of such methods. They may not be aware of recent medical advances in fertility preservation. In a survey of health care providers from a pediatric hematology/oncology department, 34.4% of the participants estimated the success rate of infertility treatment too low to justify a treatment.[74] Most data on clinicians' attitude toward fertility issues concern cancer treatment; comparable studies in the HSCT setting are spare. In a recent study, transplant clinicians from the USA were evaluated for fertility preservation technology knowledge, practices, perception and barriers. Physicians were generally interested in discussing fertility issues, but only 55% of them referred patients to a specialist in fertility preservation and about two thirds of them considered that there is a lack of educational materials. The main barriers mentioned were the common impression that their patients were already infertile due to prior treatment, the lack of access to specialists in fertility preservation, time constraints as well as the ability to afford fertility preservation and insurance coverage.[76] A regular collaboration between the transplant center and the infertility programs would help to overcome some of these barriers. In women aged 18 years or older, pretreatment infertility counseling by a fertility specialist together with an oncologist resulted in lower regret than counseling by an oncologist alone.[77] However not all centers have such resources. It remains therefore the responsibility of the transplant team to counsel patients and to make referrals where appropriate.[78]

Time constraints are an often-cited barrier to fertility discussion. There is an increasing pressure to see more patients within defined periods of time. During the visit prior to cancer treatment providers are challenged to discuss all cancer treatment options available. At that time, adding a discussion on potential threats to fertility may seem inappropriate. Specialized nurses and social workers could be appointed to provide much of the counseling on fertility issues. Furthermore, innovative strategies of direct patient education could be helpful, including use of computerized media, peer counseling or special education modules.[79] For patients prepared to receive HSCT additional time constraints have to be taken into account: coordination of the transplant preparative regimen together with the availability of the stem cell donor, the radiotherapist and the TBI instruments if TBI is going to be used and the availability of a transplant bed in the division. Time and efforts needed in finding and in organizing banking sperm or ovarian tissue need to be added in case that the patient agrees on fertility preservation.[74] Of particular concern are the patients with aggressive disease requiring a rapid initiation of treatment. The clinician may consider that a fertility preservation procedure could represent a disproportionate risk due to the delay in the cancer treatment. Today, time constraints are no longer an argument to deny fertility preservation in male patients. In women, some methods of fertility preservation require time and timing with the menstrual cycle to collect satisfactory material.

Health care providers may wrongly discuss fertility preservation with only selected groups of patients based on the perception that parenthood is only acceptable for a subgroup of patients. Disease and stage of the disease may impact whether fertility issues are discussed. Some physicians may neglect to speak about fertility issues because of the poor prognosis of the malignant disease. However, it is impossible to know which patient will survive. Patient's characteristics may be mentioned as well for neglecting to approach the fertility issue.[80] Following factors are associated with patients' concern regarding infertility: desire for children at time of diagnosis, number of previous pregnancies in women and previous infertility. Characteristics such as financial status, marital status or age are not associated with interest on fertility information.[68] Therefore, the safest and most equitable approach is to raise fertility issues with every patient of childbearing age. Adoption issues have also to be considered as an option.

The costs for fertility preservation are covered by insurance in only a limited number of countries. The main reasons for excluding assisted preservation technology from health insurance coverage were because it was considered for long an experimental technology, and later, because infertility is not considered a disease, nor a medical necessity.[81] Therefore, patients and their family become responsible for all or part of the costs. Fertility preservation options are costly and annual storages fees may be added for cryopreserved material. Although costs vary widely between countries, some estimation has been done for centers in the USA. Sperm banking for three samples cost approximately US$1000, testicular tissue freezing $500–2000, and, embryo or egg freezing $12,000 per cycle. The average yearly fee for storage is approximately $500.[78] Assuming that the survivor, or his partner in the case of a male recipient, will attempt pregnancy after HSCT, the costs will include tissue thawing and the fertilization procedure. Although the need for in vitro fertilization (IVF) is similar from country to country, the availability and cost of IVF are highly variable. In 2002, the average cost per IVF cycle was about two- to three-times higher in the USA, as compared to 25 other countries. For a couple the costs would range between 10% of annual household expenditures in many European countries to 25% in Canada and the USA. For some countries of other regions the costs were >50% of annual household expenditures. A decrease of 10% of the IVF costs would probably generate a 30% increase in utilization.[82] Therefore, physicians concerns regarding costs are not unfounded. However, they may overestimate the deterrent effect of the costs on the patient. Indeed, in a companion survey of young men, only 7% of male patients cited financial reasons for not banking sperm.[66] Therefore, concerns about costs on fertility preservation should not be a reason to withhold information to the patient. Several non-profit organizations are offering financial aid for infertility treatment to assist couples unable to pay. A list of organizations supporting grant founding for couples in need in the Unites States can be found online.[101,102]

A report by the President's Cancer Panel and the American Society of Clinical Oncology recommends that all patients of reproductive age should be informed about the possibility of treatment related infertility.[83] Considering clinician role in treatment decision and communication of treatment side-effects, both the American Society of Clinical Oncology (ASCO) and the American Society of Reproductive Medicine provided guidelines highlighting the role of the oncologist as the main communicator of fertility related information.[83,84] Table 2 provides guidance to clinicians in initial discussion, with points of discussion between the patients and the physician.[83]

Any clinical transplant program needs a quality assessment program in order to fulfill international standards promoting improvement and progress in cellular therapy, such as Joint accreditation committee ISCT-EBMT or Foundation for the Accreditation of Cellular Therapy. According to the accreditation guidelines, a transplant center needs to have access to certified and trained consulting specialists, able to counsel patients and transplant physicians on fertility issues before and after HSCT and to assist long-term survivors in fertility preservation technology.