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Preservation of fertility after hematopoietic-cell transplantation (HCT) can have a significant influence on the quality of life of transplant survivors. We describe 178 pregnancies in HCT recipients that were reported to the CIBMTR between 2002 and 2007. There were 83 pregnancies in female HCT recipients and 95 pregnancies in female partners of male HCT recipients. Indications for transplantation included hematologic and other malignancies (N=99) and non-malignant disorders (N=79, of which 75 patients had severe aplastic anemia). The cohort included recipients of autologous HCT (20 women, 13 men), myeloablative allogeneic HCT (12 women, 50 men) and non-myeloablative allogeneic HCT (2 women, 2 men). Age at HCT was <20 years for 50% of women and 19% of men. Conditioning regimens included total body irradiation (TBI) in 16% of women and 19% of men; doses were myeloablative in 10% of women and in 16% of men. Live births were reported in 86% of pregnancies in partners of male transplant patients and 85% of pregnancies in female transplant patients, with most pregnancies occurring 5-10 years after HCT. We conclude that some HCT recipients can retain fertility, including patients who have received TBI and/or myeloablative conditioning. Young patients undergoing HCT should be counseled both before and after HCT about potential loss of fertility, methods for preserving fertility and planning for future pregnancy. Fertility and outcomes of pregnancy after HCT need prospective evaluation in large transplant cohorts.
Long-term survivors of HCT are increasing in number due to improved transplant outcomes and better supportive care. In addition, the expanding indications for transplantation have led to an increase in the number of patients receiving HCT. Hence quality of life after HCT is of greater concern. Among young patients, fertility preservation after transplantation can have a significant influence on quality of life.(1, 2) Infertility is a frequently reported “loss” experienced by HCT recipients, especially by women.(3) HCT recipients may already be at high risk for gonadal damage and infertility from previous exposure to chemotherapy and irradiation during pre-transplant therapies. These risks are further increased by most transplant conditioning regimens.(4-9)
Successful pregnancies have been reported in female HCT recipients and in female partners of male HCT recipients.(4, 10-15) The two largest studies are from the European Group for Blood and Marrow Transplantation (EBMT) and the Bone Marrow Transplant Survivor Study (BMTSS). Salooja et al addressed this issue in the EBMT by sending questionnaires to 199 centers relating to nearly 38,000 transplants (autologous and allogeneic) inquiring about pregnancy rates in their post-transplant patients.(12) They included data on patients who had conceived via assisted reproductive technologies (ART) as well as those who conceived naturally. They reported 312 pregnancies from 232 patients, for an overall conception rate of 0.6%. Overall, the authors found that the frequency of pregnancy complications was much higher in female allograft recipients compared to the normal population, particularly among those receiving total body irradiation (TBI) containing conditioning regimens. These women had higher rates of Caesarean section, preterm delivery and low birth weight infants compared to the normal population. Partners of male HCT recipients had uncomplicated pregnancies. In 2006, the BMTSS reported on pregnancy outcomes of 619 HCT survivors or their partners.(4) Data was collected via a mailed questionnaire to participants in the study and their siblings. There were 54 pregnancies reported from 34 patients (26 male and 8 female), with 46 live births. Compared to their siblings, HCT survivors had a lower prevalence of conception, but if pregnancy did occur, outcome was likely to be favorable. Risk factors for reporting inability to conceive a pregnancy after transplant included female sex of the HCT recipient, age at HCT >30 years, and use of TBI in conditioning.
We report a large case series of pregnancies after autologous and allogeneic HCT that were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Our study describes associations of conditioning regimen, age, and disease with pregnancy after HCT.
Data for this study were obtained from the CIBMTR, which is a voluntary group of more than 500 transplant centers worldwide. Participating centers register basic information on all consecutive HCT’s to a Statistical Center at the Medical College of Wisconsin. Detailed demographic and clinical data are collected on a representative sample of registered patients using a weighted randomization scheme. Patients are followed longitudinally, with yearly follow-up. Observational studies conducted by the CIBMTR during the time period of this study were done with a waiver of informed consent and are compliant with HIPAA regulations as determined by the Institutional Review Board and the Privacy Officer of the Medical College of Wisconsin.
From 2002 to 2007, the CIBMTR requested that centers report whether a transplant recipient or the recipient’s partner became pregnant during post-HCT followup. Patients could have received a transplant at any time prior to 2007. Our study describes disease and transplant characteristics of the HCT recipients who reported a pregnancy during this time period. Data for these analyses were limited to the representative sample of patients on whom CIBMTR requests detailed report forms and we did not contact centers for providing supplemental data about reported pregnancies. The date of conception was not collected on CIBMTR forms and was imputed as the median time point between two successive followup reports submitted before and after pregnancy. This is a descriptive case series only and no comparative statistical analyses were planned for this study.
Our cohort included 178 patients for whom a pregnancy was reported to the CIBMTR during the study period. These included 83 female HCT recipients and female partners of 95 male HCT recipients (Tables 1 and and2).2). In this cohort, 99 patients (34 women and 65 men) were transplanted for a malignant disorder and 79 patients (49 women and 30 men) were transplanted for a non-malignant disorder. The group transplanted for malignancy comprised 97 patients with a hematologic malignancy, primarily acute leukemia (N=35, 10 women and 25 men) and chronic myeloid leukemia (N=25, 3 women and 22 men), as well as 2 patients with solid cancers. The group transplanted for non-malignant disorders included 75 patients with severe aplastic anemia (SAA, 45 women and 30 men) and 4 patients with other conditions (thalassemia, histiocytic disorders, and immune deficiency disorder). Among patients transplanted for malignancy, 33 received an autologous (13 women and 20 men), 62 received a myeloablative allogeneic (12 women and 50 men) and 4 received a non-myeloablative allogeneic (2 women and 2 men) transplant.
Thirty-two patients received TBI, 23 of whom were at myeloablative doses (>800 cGy). Although details regarding dose and duration of radiation treatment prior to HCT were not available, no patient had received craniospinal irradiation. Twelve patients (6 women and 6 men) reported a pregnancy after multiple transplants, including two patients who had received three transplants (one female patient received two autologous HCT followed by a HLA-matched sibling donor HCT for multiple myeloma and a male patient received three HLA-matched sibling donor HCT for CML). For the 6 men whose partners reported pregnancy after multiple transplants, 1 had used cryopreserved sperm to facilitate conception; information on whether cryopreserved sperm was used was missing for the other 5 patients.
Table 3 describes characteristics of recipients for whom a pregnancy was reported to the CIBMTR. Age at the time of pregnancy ranged from 15-40 years in women and 18-55 years among men whose partners became pregnant. Pregnancies were reported to occur as early as within the first year post-HCT. Fifteen men reported use of cryopreserved sperm, but these data were missing in another 26 of 95 men who fathered a child post-HCT. Information regarding use of cryopreserved embryos or donor oocytes in female transplant recipients was not collected on the CIBMTR follow up forms. Centers reported on whether a pregnancy resulted in a ‘live birth’ for 169 patients; 67/79 (85%) of pregnancies in female HCT recipients and 78/91 (86%) of pregnancies in female partners of male HCT recipients resulted in live births. We do not have data on the cause or timing of unsuccessful pregnancies or on pre-, peri- or post-natal maternal or fetal complications.
The distribution of age at transplantation of the cohort with dose of TBI, dose of cyclophosphamide in the conditioning regimen, and diagnosis is shown in Table 4. Forty-two women (50%) and 18 men (19%) had received their transplant before the age of 20 years. Overall, although the majority of pregnancies were reported among women and partners of men who had not received TBI as part of conditioning, some pregnancies did occur, even among patients who had received myeloablative doses of TBI and/or cyclophosphamide.
The median time to pregnancy after autologous HCT was 6 years in women and 7 years in partners of men (Table 3). In both women and partners of men receiving myeloablative HCT for malignancy the median time to pregnancy was 7 years after HCT. The median time to pregnancy among non-myeloablative HCT recipients for malignant disorders was 1 year post-HCT for women and 3.5 years for partners of men. The median time to pregnancy among partners of female recipients and male recipients of HCT for non-malignant diseases was 7 and 9 years, respectively. These time periods are consistent with the observation that spermatogenesis recovers in 20-25% of HCT patients after prolonged follow up, even after TBI based regimens,(16, 17) and thus longer follow up is important when attempting to fully capture fertility and pregnancy.
Among 34 women who received HCT for a malignant disorder, 3 relapsed between HCT and pregnancy (1 autologous, 1 myeloablative allogeneic and 1 non-myeloablative allogeneic HCT); one was in remission and 2 had persistent disease at the time of pregnancy (Hodgkin’s lymphoma and multiple myeloma). No relapse occurred during or after pregnancy in these women. Eight patients (7 men, 1 woman) died following pregnancy. Relapse was the most common cause of death (N=5).
Our study provides further evidence that some autologous and allogeneic HCT recipients have preserved fertility, including patients who receive HCT at age <20 years and those receiving myeloablative doses of TBI and/or cyclophosphamide.
Pregnancy after HCT has been reported previously; the relatively large case series that are published in the literature are summarized in Table 5.(4, 11-13) Taken together, these previous studies and our present study indicate that fertility is most frequently preserved in patients receiving a transplant in the young adult age group (15-30 years), although some patients who received HCT as young as <5 years of age have become pregnant or fathered a child as adults. Among patients whose fertility was maintained, most received a non-TBI based conditioning regimen. However, there were some pregnancies reported by partners of men and by women who received very high doses of TBI and/or cyclophosphamide as part of their HCT conditioning regimens. Pregnancy occurred despite the presence of chronic GVHD, indicating that chronic GVHD and its therapies may not always impair fertility. The majority of reported pregnancies occurred within 5-10 years after transplantation, but some occurred within the first year post-transplant. This observation has clear and potentially unrecognized implications for counseling patients about using contraception even in the immediate post-transplant period.
We could not address the risks of maternal or fetal complications in our study, but the literature (as summarized in Table 5) suggests that these complications may occur at an increased rate in female HCT recipients; hence, post-transplant pregnancies should be considered high risk. Nevertheless, pregnancies in this population are very likely to result in a live birth. Importantly, no increase in the risk of congenital malformations has been observed in other published studies.(4, 10, 12, 13) The frequency of preterm births and of low or very low birth weight infants has been reported as increased in some,(12, 13) but not all prior series.(4) Our study was not able to address this issue.
The effect of non-myeloablative preparative regimens on fertility preservation is unknown. As these regimens were introduced within the last decade, previous studies did not report on pregnancy outcomes in non-myeloablative HCT recipients. Our study included 4 patients who reported pregnancy after non-myeloablative HCT. Although typically used in patients over the age of 40-50, lesser intensity conditioning regimens have been increasingly used among younger patients, especially for those with low grade lymphoid malignancies and non-malignant disorders. Since the effect of chemotherapy and TBI on gonadal function is dose dependent,(7-9) young patients who undergo HCT using a non-myeloablative conditioning regimen may be expected to have a higher likelihood of preserving fertility compared to recipients of conventional myeloablative regimens. On the other hand, any potential advantages to fertility preservation among young patients receiving a non-myeloablative preparative regimen may be offset by extensive prior therapy that may have adversely impacted fertility. With recent data indicating that HCT outcomes may be similar between reduced intensity and myeloablative transplant regimens for certain disorders,(18-20) the possibility of retaining fertility may be a reason to select non-myeloablative conditioning, even in younger patients who typically can withstand myeloablative therapy. The impact of non-myeloablative conditioning on fertility warrants further prospective investigation.
Another noteworthy feature of our study is the large proportion of patients transplanted with non-malignant diseases, specifically SAA which comprised 42% of reported pregnancies. SAA patients generally have not received cytotoxic agents or radiation prior to HCT, and the conditioning regimens used for SAA commonly utilize lower dose of alkylating agents such as cyclophosphamide. Hence, cyclophosphamide as part of conditioning regimen may be relatively less gonadotoxic if the patient has not received any prior alkylator or other gonadotoxic therapies. Again, this observation has particularly important ramifications for contraceptive counseling post-transplantation in these patients.
Options to preserve fertility are available to patients preparing to undergo HCT. For men, cryopreservation of sperm is standard of care and is readily available in most areas. Barriers may include psychological distress and costs. In women, options are fewer, more invasive and mostly investigational. A commonly utilized option is for the patient to undergo oocyte stimulation and retrieval, a semi-invasive surgical procedure, followed by in vitro fertilization and cryopreservation of embryos. This requires either a male partner or a willingness on the patient’s part to fertilize her eggs with donor sperm. Experimental options include oocyte cryopreservation (without fertilization), or removal of all or part of the ovary for cryopreservation and reimplantation at a later date. Oncofertility, or the use of reproductive technology for cancer patients, is a new and rapidly growing area due to the efforts of federal and patient advocacy organizations (e.g. NIH-funded Oncofertility Consortium and Fertile Hope, now part of the Lance Armstrong Foundation). Improving access to both standard and investigational fertility preservation techniques before transplant is an important and increasingly necessary part of pre-transplant counseling which can have a long-lasting impact on quality of life after transplantation.
Our report most likely underestimates the true prevalence of conception and pregnancy after HCT partially due to reporting issues, but also due to early first trimester pregnancy losses that may not be recognized or reported. Pregnancies often occur years after transplantation and patients may no longer be followed primarily by the transplant center, thus limiting the capture than the transplant center. Also, patients may not have reported conceptions that were voluntarily terminated or resulted in a spontaneous abortion. We have no information regarding several important factors such as pre-HCT treatment exposures, pre-HCT fertility preservation techniques (e.g. pelvic shielding during prior radiation or TBI), use of assisted reproductive technology, or maternal and fetal complications. Among men whose partners reported pregnancy, information on whether cryopreserved sperm was used to facilitate conception was missing for 26/95 (27%) patients. Finally, because of lack of understanding about which patients are truly of child bearing age and may be interested in conceiving children, the incidence of preserved fertility cannot be estimated using the current observational data. The European Group for Blood and Marrow Transplantation (EBMT) has reported on pregnancy after HCT in 2001 (12); 39 cases from Europe were included in our study and some of these cases may also have been reported in the previous EBMT study.
Notwithstanding these limitations, our large case series of pregnancies after HCT highlights that fertility may be preserved in selected patients; including patients who were very young at the time of transplant, those who received myeloablative TBI or high-dose alkylator based conditioning, and those who have undergone more than one HCT. We recommend that all patients of reproductive age or younger should be counseled about fertility, contraception, and family planning, both before and after HCT, with particular emphasis on fertility preservation strategies available both routinely and on an investigational basis before transplantation. Fertility and outcomes of pregnancy after HCT need prospective evaluation in large transplant cohorts. The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U01HL069294 from NHLBI and NCI; a contract HHSH234200637015C with Health Resources and Services Administration (HRSA/DHHS); two Grants N00014-06-1-0704 and N00014-08-1-0058 from the Office of Naval Research; and grants from AABB; Aetna; American Society for Blood and Marrow Transplantation; Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Astellas Pharma US, Inc.; Baxter International, Inc.; Bayer HealthCare Pharmaceuticals; Be the Match Foundation; Biogen IDEC; BioMarin Pharmaceutical, Inc.; Biovitrum AB; BloodCenter of Wisconsin; Blue Cross and Blue Shield Association; Bone Marrow Foundation; Buchanan Family Foundation; Canadian Blood and Marrow Transplant Group; CaridianBCT; Celgene Corporation; CellGenix, GmbH; Centers for Disease Control and Prevention; Children’s Leukemia Research Association; ClinImmune Labs; CTI Clinical Trial and Consulting Services; Cubist Pharmaceuticals; Cylex Inc.; CytoTherm; DOR BioPharma, Inc.; Dynal Biotech, an Invitrogen Company; Eisai, Inc.; Enzon Pharmaceuticals, Inc.; European Group for Blood and Marrow Transplantation; Gamida Cell, Ltd.; GE Healthcare; Genentech, Inc.; Genzyme Corporation; Histogenetics, Inc.; HKS Medical Information Systems; Hospira, Inc.; Infectious Diseases Society of America; Kiadis Pharma; Kirin Brewery Co., Ltd.; The Leukemia & Lymphoma Society; Merck & Company; The Medical College of Wisconsin; MGI Pharma, Inc.; Michigan Community Blood Centers; Millennium Pharmaceuticals, Inc.; Miller Pharmacal Group; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Nature Publishing Group; New York Blood Center; Novartis Oncology; Oncology Nursing Society; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Pall Life Sciences; Pfizer Inc; Saladax Biomedical, Inc.; Schering Corporation; Society for Healthcare Epidemiology of America; Soligenix, Inc.; StemCyte, Inc.; StemSoft Software, Inc.; Sysmex America, Inc.; THERAKOS, Inc.; Thermogenesis Corporation; Vidacare Corporation; Vion Pharmaceuticals, Inc.; ViraCor Laboratories; ViroPharma, Inc.; and Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, or any other agency of the U.S. Government.
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