EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Autologous hematopoietic stem cell transplant has become a successful treatment option in aggressive autoimmune diseases. Young women who are consulted before this treatment are faced with an absence of data on the transplant’s effect on their fertility. The aim of our study was to analyze information on menstruation recovery after autologous hematopoietic stem cell transplant for autoimmune diseases.

Materials and Methods: An anonymous online questionnaire was distributed among members of an international Web forum of patients who had autologous hematopoietic stem cell transplant for autoimmune disease. Data were collated and analyzed.

Results: We obtained responses from 28 female patients to the questionnaire. The conditioning regimens used in this population were cyclophosphamide ± antibodies or BCNU (carmustine), etoposide, Ara-C (cytarabine), and melphalan chemotherapy. All patients who were transplanted at the age of 32 years or younger showed restored menstruation after an average (standard deviation) of 5.38 months (5.34 mo). In patients aged 33 to 41 years, menstruation was restored in 38%. We found that 73% of patients already had children before autologous hematopoietic stem cell transplant, and only 15% of responders declared desire for pregnancy after transplant.

Conclusions: Our online analysis showed feasibility as a questionnaire for assessing fertility after autologous hematopoietic stem cell transplant. The results show that menstruation is restored in all patients of 32 years of age or younger, regardless of the conditioning regimen. Many of these women are likely to maintain fertility and may eventually become pregnant. However, a significant number of responders who underwent autologous hematopoietic stem cell transplant for autoimmune diseases already had children before transplant and indicated no desire for pregnancy after transplant; the data on pregnancy occurrence in this group should be interpreted in this context.

Key words : Fertility, Online questionnaire, Multiple sclerosis, Stem cell therapy

Autologous hematopoietic stem cell transplant (AHSCT) in autoimmune diseases has recently gained international attention due to multiple publications of randomized trials showing advantages of this form of treatment over standard therapies in multiple sclerosis,^1,2 systemic sclerosis,^3,4 and Crohn disease.⁵ With the growing numbers of patients with autoimmune diseases in which AHSCT can be considered as a therapy option, consulting physicians face the common question of the posttransplant effect on gonadal function and fertility. This question is particularly important in young women undergoing this procedure. Well-established risk factors of gonadal malfunction after hematopoietic stem cell transplant for traditional indications are age at transplant > 30 years, postpuberty status at transplant, male sex, use of radiotherapy, multiple doses of chemotherapy before hematopoietic stem cell transplant, inclusion of alkylating agents in the conditioning regimen before transplant, and type of transplant (allogeneic > autologous).⁶ However, these results are from studies on patients who have autologous and allogeneic hematopoietic stem cell transplant as a standard hematologic treatment for currently established indications (mainly malignancies), that is, diseases and patients who are different from patients with autoimmune diseases. So far, there are only a few studies that have focused on outcomes of pregnancy after AHSCT but none on its effect on menstruation.⁷ Studies that include larger populations can be difficult to perform due to the need to coordinate between many international treatment centers with few patients scattered among them and the requirement to monitor patients over an extended period after treatment completion.

To overcome these limitations, we designed an online study that could access the largest international online forum of patients who had received AHSCT at multiple international treatment centers. This online forum, which also included patients who were interested in AHSCT as a treatment option,8 consisted of over 1700 users at the time of the initiation of our study. The online questionnaire addressed the 2 most important questions in female patient counseling: menstruation recovery after AHSCT and chances for successful pregnancy in women who desired it.

Materials and Methods

This study was designed as an anonymous, voluntary, online questionnaire published on an international Web forum for patients who underwent or had plans to undergo AHSCT for autoimmune disease. The protocol of the study conformed to the ethical guidelines of the 1975 Helsinki Declaration and was approved by the local bioethics committee before the initiation of the study. All patients involved in the study gave informed consent for use of data for this analysis. Inclusion criteria were female sex, completion of AHSCT for autoimmune disease, and age over 18 before AHSCT. Responders were asked about their basic personal data, underlying diseases, details of the AHSCT procedure (including age during procedure and conditioning regimen used), fertility issues (including menstruation before and after AHSCT), and pregnancies and deliveries before and after AHSCT. The questionnaire could be accessed online.⁹ The questionnaire was made available between February 14 and March 14, 2014, on the international social forum to gain access to a possibly wider number of patients who already received such treatment over an extended period of time and at multiple international treatment centers.

Responders
Twenty-eight women responded to the questionnaire, with 2 excluded from further analyses due to being menopausal before transplant (age related). Mean age of responders was 40 years old (range, 20-56 y). Responders had various autoimmune diseases, including 20 patients (77%) with multiple sclerosis, 3 (11%) with systemic scleroderma, 2 (8%) with chronic inflammatory demyelinating polyneuropathy, and 1 patient (4%) with type 1 diabetes. Time from diagnosis to AHSCT varied from 2 months to 16 years. All women in the study were postpubertal before treatment. Of those who responded, 73% (19 patients) reported to have at least 1 child before AHSCT (Figure 1). Three patients (11%) had ovarian cryopreservation performed before transplant.

Hematopoietic stem cell transplant
The most common conditioning regimens used for AHSCT in this population of patients were cyclophosphamide-rituximab (27% of patients, n = 7); cyclophosphamide alone (23%, n = 6); BCNU (carmustine), etoposide, Ara-C (cytarabine), and melphalan chemotherapy (15%, n = 4); and cyclophosphamide-antithymocyte globulin (8%, n = 2). The treatment results of AHSCT varied. Ten patients reported improvement of underlying disease, with improvement defined as milder symptoms and reduction of lesions compared with before therapy. Full remission of disease activity and associated symptoms was reported by 7 patients (27%). Stabilization (no new symptoms and lesions after the treatment) was reported by 7 patients (27%). One patient (4%), after nonmyeloablative conditioning, reported progression of disease after AHSCT.

Menstruation
Seventeen patients (65%) experienced amenorrhea during or after conditioning and went into menopause. Their mean (standard deviation) age was 45 (6.2) years old. Of the 9 patients (35%) who spontaneously recovered menstruation after completion of treatment, the mean age was 29 (6.5) years, with median recovery time of 4 months from transplant completion (range, 0-16 mo) (Figure 2). All women who were 32 years old and younger at the time of transplant recovered menstruation, regardless of conditioning. The maximum age that a responder noted menstruation recovery after treatment was 41 years of age.

Pregnancy desire
A significant number of responders had already fulfilled their reproductive needs and declared no further desire to be pregnant (73% of women in the study had children before AHSCT). Pregnancy desire after AHSCT was only declared by 15% of women in the study. Mean age of responders declaring pregnancy desire was 29 years. All of them experienced amenorrhea after conditioning but spontaneously recovered menstruation. Half of these women did not have any children before treatment. The remaining had at least 1 child, with uncomplicated pregnancy after natural conception. One patient (3.85%) reported pregnancy after AHSCT.

Key results
Our study shows that online questionnaires are a good tool for assessing data on fertility in patients after transplant. Unfortunately, not many patients used the questionnaire, perhaps due to the low actual number of patients who were registered in that particular online forum. The questionnaire could be used more easily by patients in follow-up care at an institution, for example, while waiting for their appointment. We plan to approach patients and use this questionnaire at our center and at our collaborating institutions.

From the questionnaires that were collected, we noted that gonadal function is likely to be maintained in women after AHSCT for autoimmune diseases. In our evaluated group, gonadal function was preserved in all women who were 32 years of age and younger. Moreover, the women up to 41 years of age at transplant showed recovery of menstruation, an age significantly higher than 30 years of age reported in hematopoietic stem cell transplant for hematological malignancies.⁶

Although our study involved a small pool of patients, the results provide an interesting observation that gives a new perspective to the previously reported 4.6% of patients with pregnancies after AHSCT treatment for autoimmune disease (who were a part of the European-wide European Blood and Marrow Transplantation study).⁷ A significant number of responders in our study had already fulfilled their reproductive needs and did not wish to become pregnant again, with 73% of women having children before AHSCT. Therefore, the percentage of pregnancies in the entire population may not be as important as percentage of pregnancies among the women who declare pregnancy desire, and this should be explored in further studies. A similar question could be asked for all patients after hematopoietic stem cell transplant, as no cited publications have reported data on percentage of women who had children before hematopoietic stem cell transplant and who are likely not to want further pregnancies. In our study, only 15% of women undergoing AHSCT expressed desire to become pregnant after the procedure. In comparison with the European Blood and Marrow Transplantation data, we can speculate that the percent of successful conceptions after AHSCT in this group of patients would be probably significantly higher among women with pregnancy desire. These data could also relate to other transplants. The mean age of women interested in having children after AHSCT in our study (at the time of responding to the questionnaire) was 29 years; thus there is a possibility of further pregnancies among these women.

In contrast, women who were above 41 years of age in our group did not recover menstruation, with menopause most likely induced in this patient population.

Limitations of the study
The major limitation of this survey was the small number of responders. Therefore, our data should be viewed as preliminary and the results may not be accurate, especially regarding pregnancy occurrence as we had only 1 reported case of post-AHSCT pregnancy in our group. On the other hand, patients who have AHSCT for autoimmune diseases constitute a small, unique group of internationally dispersed patients, and extended posttransplant follow-up may be difficult. Also, there are many treatment centers where the total female population of post-AHSCT for autoimmune diseases is smaller than the one in this study. It seems that the more optimal way to use such a questionnaire would be by direct contact with patients in few participating centers. This approach could possibly increase the studied population.

Moreover, our group tried to design an easy to complete, short, and uncomplicated questionnaire; however, because it was addressed to patients themselves and not to their physicians, the medical data obtained may not be accurate. If the patient fills the questionnaire before a visit, a physician could check the data, increasing the quality for further studies. We will use this approach during further studies on this topic.

The likeliness to maintain menstruation after transplant may also be affected by the type of underlying disease, conditioning regimen, patient’s education, access to contraception or assisted conception, quality of posttransplant follow-up, and gynecologic care. Because some patients recover menstruation as early as 1 month after AHSCT, the physicians should advise patients on contraception after AHSCT. We cannot be sure that all of the women who recovered menstruation will be able to conceive a child, but we can be sure that without menstruation recovery there is no possibility for pregnancy.

Female patients of reproductive age and with yet unfulfilled reproductive desires should be consulted before the decision to undergo AHSCT for autoimmune diseases. One of the greatest concerns expressed by this group was the posttransplant effects on gonadal function and fertility. The transplant physicians are usually faced with certain questions; first, what are the chances of menstruation recovery? Despite obvious limitations, our preliminary results suggest that most women who are 32 years of age or younger will most likely resume menstruation after AHSCT at a mean average of 4 months after treatment. Second, what are the chances of becoming pregnant if they desire pregnancy after AHSCT? Because only 15% of our patients desired to become pregnant after AHSCT and the general pregnancy occurrence seen in wider studies is roughly 4% to 6%, the chances of becoming pregnant could be as high as 25% among patients who wish to become pregnant. This rate is probably one of the highest for any type of hematopoietic stem cell transplant patient group.⁷

With all points considered, this study provides helpful guidance to practitioners counselling patients in making an informed decision before undergoing AHSCT for autoimmune diseases. Such an online questionnaire could be an easy tool for data gathering and follow-up of patients after treatment for rare diseases, especially in outpatient units as part of long-term follow-up. Larger, European-wide studies, directly assessing the gonadal function issues after AHSCT as treatment of severe autoimmune diseases, could be of great value for practitioners counselling patients considering this treatment. Pregnancy occurrence has to be further analyzed in wider studies, concentrating on patients declaring pregnancy desire versus whole populations undergoing AHSCT for autoimmune diseases.

Volume: 14 Issue: 6 December 2016

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