A Prospective Study on Fertility Preservation in Prepubertal and Adolescent Girls Undergoing Hematological Stem Cell Transplantation

Ida Wikander, Frida E Lundberg, Hanna Nilsson, Birgit Borgström, Kenny A Rodriguez-Wallberg, Ida Wikander, Frida E Lundberg, Hanna Nilsson, Birgit Borgström, Kenny A Rodriguez-Wallberg

Abstract

Background: Hematological stem cell transplantation (HSCT) is an established method which has markedly increased the survival rate of hematologic malignancies since its introduction in the 1980's. The conditioning for HSCT has known gonadotoxic effects and often leads to premature loss of fertility. In this study we have prospectively followed a cohort of girls undergoing HSCT and studied the outcomes of fertility preservation treatments performed before or after HSCT, as well as the long-term reproductive outcome.

Methods: In this one-center prospective study, 39 girls counselled for fertility preservation prior to or after conditioning for HSCT for malignant or benign diseases at childhood or adolescence between 1990 and 2017 were included. The patients were presented with the option to undergo cryopreservation of ovarian tissue or oocytes depending on their age and the time available. Follicle counts of the ovarian tissue and number of oocytes collected before or after HSCT were compared between patients treated for benign and malignant diseases. Hormone measurements post HSCT treatment, including FSH and AMH, reproductive outcomes and overall survival until January 2021 were investigated.

Results: In total, 34 girls and adolescents underwent fertility preservation before or after HSCT. Before HSCT, ovarian tissue was cryopreserved in 15 patients and two patients had oocytes preserved. Thirteen patients cryopreserved ovarian tissue after HSCT and seven patients returned to cryopreserve oocytes. Follicles were present in all tissue samples collected prior to HSCT, and in more than half of the samples collected post-HSCT. Half of the patients had spontaneous menarche or resumed menstruation post HSCT. Overall, 35 patients had survived at end of follow up and 7 patients had achieved parenthood.

Conclusions: Since fertility loss is common following HSCT, fertility preservation should be offered to all patients. Fertility preservation treatments can be performed both before and after HSCT.

Clinical trial registration: https://ichgcp.net/clinical-trials-registry/NCT04602962, identifier NTC04602962.

Keywords: chemotherapy; cryopreservation; fertility preservation; gonadal toxicity; hematological stem cell transplantation; infertility; oocytes; ovarian tissue.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Wikander, Lundberg, Nilsson, Borgström and Rodriguez-Wallberg.

References

    1. Donnez J, Squifflet J, Jadoul P, Demylle D, Cheron AC, Van Langendonckt A, et al. . Pregnancy and Live Birth After Autotransplantation of Frozen-Thawed Ovarian Tissue in a Patient With Metastatic Disease Undergoing Chemotherapy and Hematopoietic Stem Cell Transplantation. Fertil Steril (2011) 95(5):1787.e1–4. 10.1016/j.fertnstert.2010.11.041
    1. Thibaud E, Rodriguez-Macias K, Trivin C, Esperou H, Michon J, Brauner R. Ovarian Function After Bone Marrow Transplantation During Childhood. Bone Marrow Transplant (1998) 21(3):287–90. 10.1038/sj.bmt.1701075
    1. Cohen A, Békássy AN, Gaiero A, Faraci M, Zecca S, Tichelli A, et al. . EBMT Paediatric and Late Effects Working Parties. Endocrinological Late Complications After Hematopoietic SCT in Children. Bone Marrow Transplant (2008) 41(Suppl 2):S43–8. 10.1038/bmt.2008.54
    1. Pfitzer C, Orawa H, Balcerek M, Langer T, Dirksen U, Keslova P, et al. . Dynamics of Fertility Impairment and Recovery After Allogeneic Haematopoietic Stem Cell Transplantation in Childhood and Adolescence: Results From a Longitudinal Study. J Cancer Res Clin Oncol (2015) 141(1):135–42. 10.1007/s00432-014-1781-5
    1. Biasin E, Salvagno F, Berger M, Nesi F, Quarello P, Vassallo E, et al. . Ovarian Tissue Cryopreservation in Girls Undergoing Haematopoietic Stem Cell Transplant: Experience of a Single Centre. Bone Marrow Transplant (2015) 50(9):1206–11. 10.1038/bmt.2015.111
    1. Borgmann-Staudt A, Rendtorff R, Reinmuth S, Hohmann C, Keil T, Schuster FR, et al. . Fertility After Allogeneic Haematopoietic Stem Cell Transplantation in Childhood and Adolescence. Bone Marrow Transplant (2012) 47(2):271–6. 10.1038/bmt.2011.78
    1. Vatanen A, Wilhelmsson M, Borgström B, Gustafsson B, Taskinen M, Sarinen-Pihkala UM, et al. . Ovarian Function After Allogeneic Hematopoetic Stem Cell Transplantation in Childhood and Adolescence. Eur J Endocrinol (2014) 170:211–8. 10.1530/EJE-13-0694
    1. Jadoul P, Anckaert E, Dewandeleer A, Steffens M, Dolmans MM, Vermylen C, et al. . Clinical and Biologic Evaluation of Ovarian Function in Women Treated by Bone Marrow Transplantation for Various Indications During Childhood or Adolescence. Fertil Steril (2011) 96(1):126–33.e3. 10.1016/j.fertnstert.2011.03.108
    1. Forgeard N, Jestin M, Vexiau D, Chevillon F, Ricadat E, Peffault de Latour R, et al. . Sexuality- and Fertility-Related Issues in Women After Allogeneic Hematopoietic Stem Cell Transplantation. Transplant Cell Ther (2021) 27(5):432.e1–6. 10.1016/j.jtct.2021.02.003.
    1. Panasiuk A, Nussey S, Veys P, Amrolia P, Rao K, Krawczuk-Rybak M, et al. . Gonadal Function and Fertility After Stem Cell Transplantation in Childhood: Comparison of a Reduced Intensity Conditioning Regimen Containing Melphalan With a Myeloablative Regimen Containing Busulfan. Br J Haematol (2015) 170(5):719–26. 10.1111/bjh.13497
    1. Rosendahl M, Andersen CY, Ernst E, Westergaard LG, Rasmussen PE, Loft A, et al. . Ovarian Function After Removal of an Entire Ovary for Cryopreservation of Pieces of Cortex Prior to Gonadotoxic Treatment: A Follow-Up Study. Hum Reprod (2008) 23(11):2475–83. 10.1093/humrep/den248
    1. Kristensen SG, Pors SE, Poulsen LC, Andersen ST, Wakimoto Y, Yding Andersen C. Time From Referral to Ovarian Tissue Cryopreservation in a Cohort of Danish Women. Acta Obstet Gynecol Scand (2019) 98(5):616–24. 10.1111/aogs.13575
    1. Rodriguez-Wallberg KA, Marklund A, Lundberg F, Wikander I, Milenkovic M, Anastacio A, et al. . A Prospective Study of Women and Girls Undergoing Fertility Preservation Due to Oncologic and non-Oncologic Indications in Sweden-Trends in Patients' Choices and Benefit of the Chosen Methods After Long-Term Follow Up. Acta Obstet Gynecol Scand (2019) 98(5):604–15. 10.1111/aogs.13559
    1. Cherven B, Meacham L, Williamson Lewis R, Klosky JL, Gilleand Marchak J. Evaluation of the Modified Reproductive Concerns Scale Among Emerging Adult Cancer Survivors. J Adolesc Adult Oncol (2021). 10.1089/jayao.2020.0219.
    1. Rodriguez-Macias Wallberg KA, Keros V, Hovatta O. Clinical Aspects of Fertility Preservation in Female Patients. Pediatr Blood Cancer (2009) 53(2):254–60. 10.1002/pbc.21995
    1. Rodriguez-Wallberg KA, Tanbo T, Tinkanen H, Thurin-Kjellberg A, Nedstrand E, Kitlinski M, et al. . Ovarian Tissue Cryopreservation and Transplantation Among Alternatives for Fertility Preservation in the Nordic Countries – Compilation of 20 Years of Academic Multicentre Experience. Acta Obstet Gynecol Scand (2016) 95(9):1015–26. 10.1111/aogs.12934
    1. Mulder RL, Font-Gonzalez A, Hudson MM, van Santen HM, Loeffen EAH, Burns KC, et al. . Fertility Preservation for Female Patients With Childhood, Adolescent, and Young Adult Cancer: Recommendations From the PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group. Lancet Oncol (2021) 22(2):e45–56. 10.1016/S1470-2045(20)30594-5
    1. Borgström B, Fridström M, Gustafsson B, Ljungman P, Rodriguez-Wallberg KA. A Prospective Study on the Long-Term Outcome of Prepubertal and Pubertal Boys Undergoing Testicular Biopsy for Fertility Preservation Prior to Hematologic Stem Cell Transplantation. Pediatr Blood Cancer (2020) 67(9):e28507. 10.1002/pbc.28507
    1. Rodriguez-Wallberg KA, Anastacio A, Vonheim E, Deen S, Malmros J, Borgström B. Fertility Preservation for Young Adults, Adolescents, and Children With Cancer. Ups J Med Sci (2020) 125(2):1–9. 10.1080/03009734.2020.1737601
    1. Marklund A, Eloranta S, Wikander I, Laczna Kitlinski M, Lood M, Nedstrand E, et al. . Efficacy and Safety of Controlled Ovarian Stimulation Using GnRH Antagonist Protocols for Emergency Fertility Preservation in Young Women With Breast Cancer—a Prospective Nationwide Swedish Multicenter Study. Hum Reprod (2020) 35(4):929–38. 10.1093/humrep/deaa029
    1. Marklund A, Lundberg FE, Eloranta S, Hedayati E, Pettersson K, Rodriguez-Wallberg KA. Reproductive Outcomes After Breast Cancer in Women With vs Without Fertility Preservation. JAMA Oncol (2021) 27(1):86–91. 10.1001/jamaoncol.2020.5957
    1. Dalle JH, Lucchini G, Balduzzi A, Ifversen M, Jahnukainen K, Macklon KT, et al. . State-Of-the-Art Fertility Preservation in Children and Adolescents Undergoing Haematopoietic Stem Cell Transplantation: A Report on the Expert Meeting of the Paediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) in Baden, Austria, 29-30 September 2015. Bone Marrow Transplant (2017) 52(7):1029–35. 10.1038/bmt.2017.21
    1. Jensen AK, Rechnitzer C, Macklon KT, Ifversen MR, Birkebæk N, Clausen N, et al. . Cryopreservation of Ovarian Tissue for Fertility Preservation in a Large Cohort of Young Girls: Focus on Pubertal Development. Hum Reprod (2017) 32(1):154–64. 10.1093/humrep/dew273
    1. Klosky JL, Simmons JL, Russell KM, Foster RH, Sabbatini GM, Canavera KE, et al. . Fertility as a Priority Among at-Risk Adolescent Males Newly Diagnosed With Cancer and Their Parents. Support Care Cancer (2015) 23(2):333–41. 10.1007/s00520-014-2366-1
    1. Young K, Shliakhtsitsava K, Natarajan L, Myers E, Dietz AC, Gorman JR, et al. . Fertility Counseling Before Cancer Treatment and Subsequent Reproductive Concerns Among Female Adolescent and Young Adult Cancer Survivors. Cancer (2019) 125(6):980–9. 10.1002/cncr.31862
    1. Fang T, Su Z, Wang L, Yuan P, Li R, Ouyang N, et al. . Predictive Value of Age-Specific FSH Levels for IVF-ET Outcome in Women With Normal Ovarian Function. Reprod Biol Endocrinol (2015) 13:63. 10.1186/s12958-015-0056-6
    1. Shebl O, Ebner T, Sir A, Schreier-Lechner E, Mayer RB, Tews G, et al. . Age-Related Distribution of Basal Serum AMH Level in Women of Reproductive Age and a Presumably Healthy Cohort. Fertil Steril (2011) 95(2):832–4. 10.1016/j.fertnstert.2010.09.012
    1. Anderson RA, Amant F, Braat D, D'Angelo A, Chuva de Sousa Lopes SM, Demeestere I, et al. . ESHRE Guideline: Female Fertility Preservation. Hum Reprod Open (2020) 2020(4):hoaa052. 10.1093/hropen/hoaa052
    1. McLaughlin M, Albertini DF, Wallace WHB, Anderson RA, Telfer EE. Metaphase II Oocytes From Human Unilaminar Follicles Grown in a Multi-Step Culture System. Mol Hum Reprod (2018) 24(3):135–42. 10.1093/molehr/gay002
    1. Socialstyrelsen . Statistik Om Graviditeter, Förlossningar Och Nyfödda Barn 2019. Stockholm: The National Board of Health and Welfare; (2020).

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