Assisted reproductive technologies for fertility preservation and fertility treatment in young women with cancer

Loss of fertility as a potential side effect of anti-neoplastic treatments may have a significant negative impact on the survivors’ quality of life. Assisted reproductive technologies (ART) have been adapted and further developed for fertility preservation (FP) and fertility treatments in young women with cancer. The last three decades have seen impressive achievements in this field, with the rapid introduction and development of methods in clinical practice. Still, the data on outcomes and safety of FP are scarce, and numerous questions await answering.

The four studies included in this thesis aimed to investigate: if a history of cancer may increase the risk of adverse perinatal outcomes in pregnancies achieved with donor oocytes (Study I), if return rates and utilization rates differ in patients with oncologic and nononcologic indications for FP, and if the trends in decisions regarding preferred FP-methods have changed over time (Study II), if current approaches to controlled ovarian stimulation aimed at FP in women with breast cancer are efficacious and safe (Study III) and if longterm reproductive outcomes after breast cancer differ in women with and without FP (Study IV).

Study I was a single-center cohort study, including 25 live births in 20 women with a history of cancer and 244 live births in 212 women without a history of cancer, all after treatments with donor oocytes. Higher rates of pre-eclampsia (adjusted odds ratio (aOR) 2.79, 95% CI 1.07-7.34) and preterm birth (aOR 5.54, 95% CI 2.01-15.31) were observed in women with a history of cancer. Study II included data on 1254 women that underwent FP counseling due to oncologic and non-oncologic indications at Karolinska University Hospital during a 20-year long period (1998-2018). Oncologic indication for FP was associated with a slightly lower likelihood of returning for counseling (OR 0.72, 95% CI 0.51-1.0) and a significantly lower likelihood of returning for pregnancy attempt (OR 0.41, 95%CI 0.27-0.62), when compared to nononcologic FP indication. Among different FP methods, cryopreservation of unfertilized oocytes has become the preferred one in recent years, both by adult women (with or without partners) and by post-menarchal girls. Study III was a multicenter study including data on FP counseling (n=610) and FP treatments (n=468) of women with breast cancer at six Swedish University Hospitals with programs for FP. In this study 380 cycles of controlled ovarian stimulation (COS) in gonadotropin-releasing hormone (GnRH) antagonist protocol were available for the final analysis. Three recently introduced approaches to COS in women with cancer aiming to increase the safety of the procedures were investigated: 1) the concurrent use of letrozole, 2) the random start initiation of stimulation, and 3) the use of gonadotropin-releasing hormone agonist (GnRHa) for ovulation trigger instead of hCG trigger. The efficacy of these approaches, measured as the number of cryopreserved oocytes and embryos, was observed to be at least non-inferior compared to the standard GnRH antagonist protocols. Overall survival did not differ between women with versus without FP, and women in letrozole versus non-letrozole group. Study IV, a register-based nationwide cohort study, included 425 women with and 850 women without FP history, all of them diagnosed with breast cancer at reproductive age. Rates of live births (aHR: 2.3, 95%CI: 1.6-3.3) and ART-treatments (aHR: 4.8, 95%CI: 2.2-10.7) after breast cancer were higher among women that had undergone FP when compared to women without FP. FP exposure was not associated with any decrease in overall survival in this cohort.

In conclusion, the findings suggest that the use of ART for FP and fertility treatment in eligible young women with cancer seems to be both safe and efficacious. Yet, some caution is warranted when interpreting the findings, since these studies were not randomized and women with cancer who undergo FP might be healthier, on average, than the women who do not (“healthy FP effect”). In women with a previous history of cancer that achieve pregnancy with donor oocytes, individual assessment of pregnancy risks and potential increased obstetric surveillance may be indicated. Further research investigating the risk of breast cancer-relapse in women undergoing FP, with additional measures taken to overcome a possible “healthy FP effect”, is of utmost importance.

List of scientific papers

I. Marklund A, Nasiell J, Berger AS, Fagerberg A, Rodriguez-Wallberg KA. Pregnancy Achieved Using Donor Eggs in Cancer Survivors with Treatment-Induced Ovarian Failure: Obstetric and Perinatal Outcome. J Womens Health (Larchmt). 2018;27(7):939-945.
https://doi.org/10.1089/jwh.2017.6703

II. Rodriguez-Wallberg KA, Marklund A, Lundberg F, Wikander I, Milenkovic M, Anastacio A, Sergouniotis F, Wånggren K, Ekengren J, Lind T, Borgström B. 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 longterm follow up. Acta Obstet Gynecol Scand. 2019;98(5):604-615.
https://doi.org/10.1111/aogs.13559

III. Marklund A, Eloranta S, Wikander I, Kitlinski ML, Lood M, Nedstrand E, Thurin-Kjellberg A, Zhang P, Bergh J, Rodriguez-Wallberg KA. 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):929-938.
https://doi.org/10.1093/humrep/deaa029

IV. 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. 2020. [Accepted]
https://doi.org/10.1001/jamaoncol.2020.5957