Reproduction patterns among non-Hodgkin lymphoma survivors by subtype in Sweden, Denmark and Norway: A population-based matched cohort study.

Previous studies concerning reproductive patterns among non-Hodgkin lymphoma (NHL) survivors are scarce and those available have reported conflicting results. Treatment regimens vary considerably between aggressive and indolent NHL and studies of reproductive patterns by subtypes are warranted. In this matched cohort study, we identified all NHL patients aged 18-40 years and diagnosed between 2000 and 2018 from the Swedish and Danish lymphoma registers, and the clinical database at Oslo University Hospital (n = 2090). Population comparators were matched on sex, birth year and country (n = 19 427). Hazard ratios (HRs) were estimated using Cox regression. Males and females diagnosed with aggressive lymphoma subtypes had lower childbirth rates (HRfemale : 0.43, 95% CI: 0.31-0.59, HRmale : 0.61, 95% CI: 0.47-0.78) than comparators during the first 3 years after diagnosis. For indolent lymphomas, childbirth rates were not significantly different from comparators (HRfemale : 0.71, 95% CI: 0.48-1.04, HRmale : 0.94, 95% CI: 0.70-1.27) during the same period. Childbirth rates reached those of comparators for all subtypes after 3 years but the cumulative incidence of childbirths was decreased throughout the 10-year follow-up for aggressive NHL. Children of NHL patients were more likely to be born following assisted reproductive technology than those of comparators, except for male indolent lymphoma patients. In conclusion, fertility counselling is particularly important for patients with aggressive NHL.

Reproduction patterns among classical Hodgkin lymphoma survivors treated with BEACOPP and ABVD in Sweden, Denmark and Norway-A population-based matched cohort study.

Childbirth rates in classical Hodgkin lymphoma (cHL) survivors have historically been reduced compared to the general population. Understanding if contemporary treatment protocols are associated with reduced fertility is crucial as treatment guidelines shift toward more liberal use of intensive chemotherapy. We identified 2834 individuals aged 18-40 years with cHL in Swedish and Danish lymphoma registers, and in the clinical database at Oslo University Hospital diagnosed 1995-2018, who were linked to national medical birth registers. Cox regression adjusted for stage, performance status, year, and age at diagnosis was used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) contrasting time to first childbirth by treatment groups (ABVD, 2-4 BEACOPP, 6-8 BEACOPP) up to 10 years after diagnosis. Overall, 74.8% of patients were treated with ABVD, 3.1% with 2-4 BEACOPP and 11.2% with 6-8 BEACOPP. Adjusted HRs comparing childbirth rates in individuals treated with 6-8 BEACOPP, and 2-4 BEACOPP to ABVD were 0.53 (CI: 0.36-0.77) and 0.33 (CI: 0.12-0.91) for males, and 0.91 (CI: 0.61-1.34) and 0.38 (CI: 0.12-1.21) for females. Cumulative incidence of childbirths after 10 years was 19.8% (CI: 14.5%-27.0%) for males and 34.3% (CI: 25.8%-45.6%) for females treated with 6-8 BEACOPP. Proportions of children born after assisted reproductive technique (ART) treatments were 77.4% (CI: 60.2-88.6%) for males following 6-8 BEACOPP, and <11% for females. Among ABVD treated patients the corresponding proportions were 12.2% (CI: 8.5%-17.3%) and 10.6% (CI: 7.4%-14.9%). BEACOPP treatment is associated with decreased childbirth rates compared to ABVD in male, but not female, cHL patients, despite widespread access to ART in the Nordics.

Relapse Rates and Disease-Specific Mortality Following Procedures for Fertility Preservation at Time of Breast Cancer Diagnosis.

Importance: Breast cancer (BC) is the most common indication for fertility preservation (FP) in women of reproductive age. Procedures for FP often include hormonal stimulation, but current data are scarce regarding whether using hormonal stimulation for FP is associated with any deterioration in BC prognosis. Objective: To investigate the risk of disease-specific mortality and relapse in women who underwent FP with or without hormonal stimulation compared with women who did not at time of BC diagnosis. Design, Setting, and Participants: This Swedish nationwide prospective cohort study was conducted to assess the safety of hormonal and nonhormonal FP procedures indicated by BC in Sweden from January 1, 1994, through June 30, 2017. Women were identified from any of the regional FP programs located at Swedish university hospitals. A total of 425 women were found to have undergone FP, and 850 population comparators who had not undergone FP were sampled from regional BC registers and matched on age, calendar period of diagnosis, and region. Relapse-free survival was assessed in a subcohort of 241 women who underwent FP and 482 women who had not, with complete data. Nationwide demographic and health care registers provided data on outcome, disease- and treatment-related variables, and socioeconomic characteristics. Data analyses were performed between November 2021 and March 2022 and completed in June 2022. Main Outcomes and Measures: Relapse and disease-specific mortality after a diagnosis of BC. Results: The final study population included 1275 women (mean [SD] age, 32.9 [3.8] years) at the time of BC diagnosis. After stratification by the matching variables age, calendar period, and region, and adjustment for country of birth, education, parity at diagnosis, tumor size, number of lymph node metastases, and estrogen receptor status, disease-specific mortality was similar in women who underwent hormonal FP (adjusted hazard ratio [aHR], 0.59; 95% CI, 0.32-1.09), women who underwent nonhormonal FP (aHR, 0.51; 95% CI, 0.20-1.29), and women who were not exposed to FP (reference). In a subcohort with detailed data on relapse, adjusted rate of disease-specific mortality and relapse were also similar among the groups who underwent hormonal FP (aHR, 0.81; 95% CI, 0.49-1.37), underwent nonhormonal FP (aHR, 0.75; 95% CI, 0.35-1.62), and were not exposed to FP (reference). Conclusions and Relevance: In this cohort study, FP with or without hormonal stimulation was not associated with any increased risk of relapse or disease-specific mortality in women with BC. Results of this study provide much needed additional evidence on the safety of FP procedures in women with BC and may influence current health care practice to the benefit of young women with BC who wish to preserve their fertility.

Hot Topics on Fertility Preservation for Women and Girls-Current Research, Knowledge Gaps, and Future Possibilities.

Fertility preservation is a novel clinical discipline aiming to protect the fertility potential of young adults and children at risk of infertility. The field is evolving quickly, enriched by advances in assisted reproductive technologies and cryopreservation methods, in addition to surgical developments. The best-characterized target group for fertility preservation is the patient population diagnosed with cancer at a young age since the bulk of the data indicates that the gonadotoxicity inherent to most cancer treatments induces iatrogenic infertility. Since improvements in cancer therapy have resulted in increasing numbers of long-term survivors, survivorship issues and the negative impact of infertility on the quality of life have come to the front line. These facts are reflected in an increasing number of scientific publications referring to clinical medicine and research in the field of fertility preservation. Cryopreservation of gametes, embryos, and gonadal tissue has achieved quality standards for clinical use, with the retrieval of gonadal tissue for cryopreservation being currently the only method feasible in prepubertal children. Additionally, the indications for fertility preservation beyond cancer are also increasing since a number of benign diseases and chronic conditions either require gonadotoxic treatments or are associated with premature follicle depletion. There are many remaining challenges, and current research encompasses clinical health care and caring sciences, ethics, societal, epidemiological, experimental studies, etc.

Reproductive Outcomes After Breast Cancer in Women With vs Without Fertility Preservation.

IMPORTANCE: The practice of fertility preservation (FP) in women with breast cancer (BC) is spreading, but long-term reproductive outcomes after FP are largely unknown. OBJECTIVE: To investigate the long-term reproductive outcomes in women who did or did not undergo FP at the time of BC diagnosis. DESIGN, SETTING, AND PARTICIPANTS: A Swedish nationwide cohort study was conducted to investigate the long-term reproductive outcomes of women with BC receiving FP at 1 of the regional FP programs from 1994 to 2017 (n = 425). Population comparators with BC but without history of FP (n = 850) were sampled from regional BC registers, matched on age, calendar period of diagnosis, and county. Data on live births, assisted reproductive technology (ART) use, and mortality were retrieved from population-based registers. Data analysis was performed from January to September 2020. EXPOSURES: History of having received FP compared with no history of FP (unexposed). MAIN OUTCOMES AND MEASURES: The primary outcome was hazard ratios (HRs) of live births and ART treatments following BC in women with vs without FP and the cumulative incidence of these events in the presence of the competing risk of death. RESULTS: Women who had undergone FP (n = 425) had lower parity (302 [71.1%] were nulliparous compared with 171 [20.1%] in the unexposed group), were younger (mean [SD] age, 32.1 [4.0] vs 33.3 [3.6] years), more often had estrogen receptor-positive tumors (289 [68.0%] vs 515 [60.6%]), and were more often scheduled for chemotherapy (399 [93.9%] vs 745 [87.7%]). Of 425 women exposed to FP, 97 (22.8%) had at least 1 post-BC live birth (mean follow-up, 4.6 years), compared with 74 of 850 women (8.7%) unexposed to FP (mean follow-up, 4.8 years). Overall, live birth rates after BC were significantly higher among women with FP (adjusted hazard ratio [aHR], 2.3; 95% CI, 1.6-3.3). The 5-year and 10-year cumulative incidence of post-BC live births was 19.4% and 40.7% among FP-exposed women vs 8.6% and 15.8% among comparators, respectively. Rates of ART use were also higher in the FP group (aHR, 4.8; 95% CI, 2.2-10.7). The all-cause mortality rate was lower in women exposed to FP (aHR, 0.4; 95% CI, 0.3-0.7), with 5-year cumulative incidence of death of 5.3% (95% CI, 3.1%-9.0%) vs 11.1% (95% CI, 8.7%-14.1%) for women with vs without FP. CONCLUSIONS AND RELEVANCE: In this cohort study of Swedish women after a BC diagnosis, successful pregnancy after BC was possible both in women with and without FP at the time of diagnosis, but a significantly higher likelihood of post-BC live births and ART treatments was observed in women who underwent FP, without any negative association with all-cause survival. This information is valuable for health care clinicians responsible for oncologic treatment and reproductive counseling of women diagnosed with breast cancer at reproductive age.

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.

STUDY QUESTION: How efficacious and safe are the current approaches to controlled ovarian stimulation (COS) aimed at fertility preservation (FP) in women with breast cancer (BC)? SUMMARY ANSWER: In women with BC undergoing COS aiming at egg/embryo cryopreservation, letrozole-based protocols and those randomly started were equally effective compared with conventional COS, and the overall survival was similar between the women that proceeded to FP and those who did not. WHAT IS KNOWN ALREADY: Cryopreservation of oocytes and embryos is an established method for FP in women with BC. Recent improvements to COS protocols include concomitant use of letrozole, random-cycle start day of stimulation and the use of GnRHa for the egg maturation trigger. To date, limited sample size of the available studies has not allowed investigation of differences in the efficacy of the different approaches to COS for FP in this patient population. STUDY DESIGN, SIZE, DURATION: A prospective multicenter study with national coverage including 610 women with BC counseled between 1 January 1995 and 30 June 2017 at six Swedish FP regional programs. PARTICIPANTS/MATERIALS, SETTING, METHODS: After counseling, 401 women elected to undergo COS. Treatments differed in the use or not of concomitant letrozole, a conventional or random-cycle day COS initiation and the use of hCG versus GnRHa trigger for oocyte maturation. Numbers of cryopreserved oocytes and embryos were defined as primary outcome. Pregnancy attempts, reproductive outcomes and long-term survival, investigated by the linking of individuals of the cohort to the total population register of the Swedish Tax Agency (up to 25 November 2018), were evaluated. MAIN RESULTS AND THE ROLE OF CHANCE: Using letrozole or not resulted in similar numbers of oocytes and embryos cryopreserved (meanoocytes = 9.7 versus 10 and meanembryos 4.0 versus 5.3, respectively), similar to COS with random versus conventional start (meanoocytes 9.0 versus 10.6 and meanembryos 4.8 versus 4.8). In COS with letrozole, a GnRHa trigger was associated with a higher number of oocytes retrieved (P < 0.05) and embryos cryopreserved (P < 0.005), compared with conventional hCG trigger. Of 99 women who returned to fertility clinics after cancer treatment, 32 proceeded to thawing of oocytes or embryos and 10 of them had live births. The all-cause survival between the women that underwent COS and those who did not was similar and did not differ between the two groups. LIMITATIONS, REASONS FOR CAUTION: Data on tumor characteristics and estrogen receptor (ER) status were not known for all women at the time of FP counseling and planning of COS, thus protocols with letrozole have been used for both estrogen-sensitive and non-estrogen-sensitive BC. For the same reason, subsequent adjustment for ERs in the BC or tumor characteristics as potential confounders were not performed as these parameters were not available and did not influence the provision of FP through COS. WIDER IMPLICATIONS OF THE FINDINGS: The results of our study support the premise that recently introduced potential improvements to COS protocols for FP in women with BC are efficacious and safe. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by research grants from the Swedish Cancer Society, the Stockholm County Council, the Percy Falk Stiftelsen, Radiumhemmets Forskningsfonder, The Swedish Breast Cancer Association and Karolinska Institutet to K.A.R.W. J.B. reports grants from Amgen, AstraZeneca, Pfizer, Roche, Sanofi-Aventis and Merck, outside the submitted work, and payment from UpToDate to Asklepios Medicine HB for a chapter on BC prediction and prognostication. All the other authors have no competing interests to report.

Endometriosis, the great imitator - a successful case of fertility preservation in a woman receiving sterilizing treatment due to a diagnosis of rectosigmoid carcinoma.

Bowels are the most common site of extrapelvic endometriosis. Still, colonic endometriosis often presents a diagnostic challenge, mimicking a broad spectrum of diseases including primary colonic malignancy. For women of fertile age, the consequences of endometriosis being misdiagnosed as colorectal cancer may include loss of fertility. We hereby present a case of endometriosis mimicking rectosigmoid adenocarcinoma in a young woman, where fertility preservation prior to the start of antineoplastic treatments turned out to be of crucial importance for the woman's future attempts to achieve a pregnancy and livebirth.

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.

INTRODUCTION: In Scandinavian countries, programs for fertility preservation are offered free of charge at tertiary-care university hospitals to all patients facing treatments with risk of subsequent sterility. In this prospective study we aimed to investigate trends in female patients' choices after counseling and fertility preservation outcomes during follow up in relation to benign vs malignant indications. MATERIAL AND METHODS: Data on 1254 females including 1076 adults and 178 girls who received fertility preservation counseling for either oncologic (n = 852) or benign indications (n = 402) at Karolinska University Hospital, Stockholm, between 1 October 1998 and 1 December 2018 were analyzed. As appropriate, t tests and chi-square tests were used to compare groups. Logistic regression was used to compare outcomes among groups depending on indications. RESULTS: Adult women generally elected to undergo oocyte retrieval after controlled ovarian stimulation for cryopreservation of embryos or oocytes (n = 538, 73%), whereas a minor proportion opted for cryopreservation of ovarian tissue retrieved through laparoscopy (n = 221, 27%). More than half of the women with a partner chose either not to fertilize their oocytes aiming at cryopreservation of oocytes or to share obtained oocytes attempting both cryopreservation of oocytes and cryopreservation of embryos. All pre-pubertal (n = 48) and 73% of post-pubertal girls (n = 66) elected cryopreservation of ovarian tissue. In recent years, an increasing number of teenagers have opted for controlled ovarian stimulation aiming at cryopreservation of oocytes, either before (n = 24, 17%) or after completion of cancer treatment (n = 15, 10%). During follow up, 27% of the women returned for a new reproductive counseling, additional fertility preservation or to attempt pregnancy. Utilization rates among individuals who were alive and of childbearing age by December 2018 indicated 29%, 8% and 5% for embryos, oocytes and ovarian tissue with live birth rates of 54%, 46% and 7%, respectively. Women with benign indications were significantly younger than women with previous malignant indications at the time of attempting pregnancy. Although the pregnancy rates were similar among both groups, the live birth rate was significantly higher in women with benign vs previous malignant indications (47% vs 21%, P = .002). CONCLUSIONS: Trends in fertility preservation choices have changed over time. Women with previous malignancy had lower live birth rates than women with benign fertility preservation indications.

Pregnancy Achieved Using Donor Eggs in Cancer Survivors with Treatment-Induced Ovarian Failure: Obstetric and Perinatal Outcome.

BACKGROUND: Egg donation is a common fertility treatment in female cancer survivors with reproductive wish and iatrogenic ovarian failure. We examined whether women previously treated for cancer have a higher risk of pregnancy complications after egg donation treatments when compared to women without cancer history. METHODS: In this prospective cohort treated during 2003-2015 at a single center, 31 women with previous history of cancer achieved 25 deliveries and 212 women without cancer history achieved 244 deliveries. All egg donor treatments were performed with a strict policy of single embryo transfer to reduce pregnancy and perinatal complications. Data were analyzed using logistic regression with adjustment for relevant confounders, to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for perinatal and obstetric outcomes. Women without previous history of cancer were used as the reference group in the regression models. RESULTS: Women with a history of cancer presented with a significantly increased risk of pregnancy complications, including preterm birth (aOR 5.54, 95% CI 2.01-15.31) and preeclampsia (aOR 2.79, 95% CI 1.07-7.34), compared to women without cancer history. CONCLUSIONS: The findings of this study suggest that the risks of preterm birth and preeclampsia in women with prior cancers who become pregnant by egg donor treatment significantly exceed those of women without cancer history undergoing similar treatments. As pregnancies using donor eggs are already acknowledged of higher risk for hypertensive pathologies, this study alerts toward characterization of specific increased risks in women who are cancer survivors to provide adapted pregnancy monitoring.