Anupama Rambhatla1,2, Michael R Strug3,4, Jessica Garcia De Paredes3,4, Marcos I Cordoba Munoz3,5, Mili Thakur6,7,8. 1. Camran Nezhat Institute, Center for Minimally Invasive & Robotic Surgery, Palo Alto, CA, USA. 2. Stanford University Medical Center, Palo Alto, CA, USA. 3. Department of Obstetrics, Gynecology and Women's Health, Spectrum Health Medical Group, Grand Rapids, MI, USA. 4. Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA. 5. Division of Maternal Fetal Medicine, Department of Obstetrics, Gynecology and Women's Health, Spectrum Health Medical Group, Grand Rapids, MI, USA. 6. Department of Obstetrics, Gynecology and Women's Health, Spectrum Health Medical Group, Grand Rapids, MI, USA. tfcgenetics@mrivf.com. 7. Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA. tfcgenetics@mrivf.com. 8. Reproductive Genomics Program, The Fertility Center, 3230 Eagle Park Dr. NE, Suite 100, Grand Rapids, MI, 49525, USA. tfcgenetics@mrivf.com.
Abstract
PURPOSE: To review the impact of tyrosine kinase inhibitors (TKIs) on fertility in men and women, embryo development, and early pregnancy, and discuss considerations for fertility preservation in patients taking TKIs. METHODS: A comprehensive literature search using the PubMed database was performed through February 2021 to evaluate the current literature on imatinib, nilotinib, dasatinib, and bosutinib as it relates to fertility and reproduction. Published case series were analyzed for pregnancy outcomes. RESULTS: TKIs adversely affect oocyte and sperm maturation, gonadal function, and overall fertility potential in a self-limited manner. There are insufficient studies regarding long-term consequences on fertility after discontinuation of TKIs. A total of 396 women and 236 men were on a first- or second-generation TKI at the time of conception. Of the women with detailed pregnancy and delivery outcomes (n = 361), 51% (186/361) resulted in a term birth of a normal infant, 4.3% (16/361) of pregnancies had a pregnancy complication, and 5% (20/361) of pregnancies resulted in the live birth of an infant with a congenital anomaly. About 22% of pregnant women (87/396) elected to undergo a termination of pregnancy, while 16% (63/396) of pregnancies ended in a spontaneous abortion. In contrast, of the 236 men, 87% conceived pregnancies which resulted in term deliveries of normal infants. Elective terminations, miscarriage rate, pregnancy complication rate, and incidence of a congenital malformation were all less than those seen in females (4%, 3%, 2%, and 2.5%, respectively). CONCLUSION: Women should be advised to avoid conception while taking a TKI. Women on TKIs who are considering pregnancy should be encouraged to plan the pregnancy to minimize inadvertent first trimester exposure. In women who conceive while taking TKIs, the serious risk of relapse due to discontinuation of TKI should be balanced against the potential risks to the fetus. The risk of teratogenicity to a fathered pregnancy with TKI use is considerably lower. Fertility preservation for a woman taking a TKI can be considered to plan a pregnancy with a minimal TKI-free period. With careful monitoring, providers may consider a TKI washout period followed by controlled ovarian stimulation to cryopreserve oocytes or embryos, with a plan to resume TKIs until ready to conceive or to transfer an embryo to achieve pregnancy quickly. Fertility preservation is also indicated if a patient on TKI is requiring a gonadotoxic therapy or reproductive surgery impacting fertility.
PURPOSE: To review the impact of tyrosine kinase inhibitors (TKIs) on fertility in men and women, embryo development, and early pregnancy, and discuss considerations for fertility preservation in patients taking TKIs. METHODS: A comprehensive literature search using the PubMed database was performed through February 2021 to evaluate the current literature on imatinib, nilotinib, dasatinib, and bosutinib as it relates to fertility and reproduction. Published case series were analyzed for pregnancy outcomes. RESULTS: TKIs adversely affect oocyte and sperm maturation, gonadal function, and overall fertility potential in a self-limited manner. There are insufficient studies regarding long-term consequences on fertility after discontinuation of TKIs. A total of 396 women and 236 men were on a first- or second-generation TKI at the time of conception. Of the women with detailed pregnancy and delivery outcomes (n = 361), 51% (186/361) resulted in a term birth of a normal infant, 4.3% (16/361) of pregnancies had a pregnancy complication, and 5% (20/361) of pregnancies resulted in the live birth of an infant with a congenital anomaly. About 22% of pregnant women (87/396) elected to undergo a termination of pregnancy, while 16% (63/396) of pregnancies ended in a spontaneous abortion. In contrast, of the 236 men, 87% conceived pregnancies which resulted in term deliveries of normal infants. Elective terminations, miscarriage rate, pregnancy complication rate, and incidence of a congenital malformation were all less than those seen in females (4%, 3%, 2%, and 2.5%, respectively). CONCLUSION: Women should be advised to avoid conception while taking a TKI. Women on TKIs who are considering pregnancy should be encouraged to plan the pregnancy to minimize inadvertent first trimester exposure. In women who conceive while taking TKIs, the serious risk of relapse due to discontinuation of TKI should be balanced against the potential risks to the fetus. The risk of teratogenicity to a fathered pregnancy with TKI use is considerably lower. Fertility preservation for a woman taking a TKI can be considered to plan a pregnancy with a minimal TKI-free period. With careful monitoring, providers may consider a TKI washout period followed by controlled ovarian stimulation to cryopreserve oocytes or embryos, with a plan to resume TKIs until ready to conceive or to transfer an embryo to achieve pregnancy quickly. Fertility preservation is also indicated if a patient on TKI is requiring a gonadotoxic therapy or reproductive surgery impacting fertility.
Authors: Arnel Pallera; Jessica K Altman; Ellin Berman; Camille N Abboud; Bhavana Bhatnagar; Peter Curtin; Daniel J DeAngelo; Jason Gotlib; R Tanner Hagelstrom; Gabriela Hobbs; Madan Jagasia; Hagop M Kantarjian; Patricia Kropf; Leland Metheny; Joseph O Moore; Evelena Ontiveros; Enkhtsetseg Purev; Albert Quiery; Vishnu V B Reddy; Michal G Rose; Neil P Shah; B Douglas Smith; David S Snyder; Kendra L Sweet; Raoul Tibes; David T Yang; Kristina Gregory; Hema Sundar; Michael Deininger; Jerald P Radich Journal: J Natl Compr Canc Netw Date: 2016-12 Impact factor: 11.908