Parenthood Rates and Use of Assisted Reproductive Techniques in Younger Hodgkin Lymphoma Survivors: A Danish Population-Based Study
2Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
3Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
4Unit of Clinical Biostatistics and Epidemiology, Aalborg University Hospital, Aalborg, Denmark
5Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark
6Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
7Department of Hematology, Odense University Hospital, Odense, Denmark
8Department of Hematology, Aarhus University Hospital, Aarhus, Denmark
9Department of Hematology, Zealand University Hospital, Roskilde, Denmark
10Department of Hematology, Copenhagen University Hospital, Herlev, Denmark
11Department of Immunology, Genetics and Pathology, Unit of Oncology, Uppsala University, Uppsala, Sweden
12Department of Hematology, Karolinska University Hospital, Solna, Sweden
13Department of Cardiology, Nordsjællands Hospital, Hillerød, Denmark
14Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
*M.T.S. and T.C.E.-G. share senior authorship.
The majority of young adults with Hodgkin lymphoma (HL) are cured, but chemotherapy-induced infertility can have profound psychosocial consequences. Providing data on parenthood rates and use of assisted reproductive techniques (ARTs) after contemporary HL treatment is important for patient counseling and survivorship care.
All Danish patients with HL diagnosed during 2000-2015 at the ages 18-40 years who achieved remission after first-line therapy were included and matched on age, sex, and parenthood status to five random persons from the general population. Parenthood rates were defined as the rate of first live birth per 1,000 person years, starting 9 months after HL diagnosis. Nationwide birth and patient registers were used to capture parenthood outcomes and ARTs use.
A total of 793 HL survivors and 3,965 comparators were included (median follow-up 8.7 years). Similar parenthood rates were observed for male and female HL survivors when compared with matched comparators (56.2 v 57.1; P = .871 for males and 63.8 v 61.2; P = .672 for females). For male HL survivors, BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) therapy was associated with lower parenthood rates as compared to the matched comparators (28.1 v 60.8; P = .020). Live birth after ARTs were more common for HL survivors than for comparators (males 21.6% v 6.3%; P < .001; females 13.6% v 5.5%; P = .001). There were no differences in gestational age, Apgar score, or newborn measurements between HL survivors and matched comparators.
The parenthood rates for HL survivors who have not experienced relapse were generally similar to the general population. However, ARTs were used more often before the first live birth in HL survivors, which is relevant information when discussing possible long-term side effects and fertility-preserving treatment options.
Chemotherapy- and/or radiotherapy-induced gonadal toxicities leading to reduced fertility may be a source of significant concern among younger patients with cancer, in particular those without children.1-3 This is a situation likely to become more common in the Western world, as the parental age at first childbirth has been increasing resulting in a growing patient population with cancer before parenthood.4 Medical advances in assisted reproductive techniques (ARTs) may offset some of the impact of cancer therapies on fertility, either by preserving fertility or overcoming the consequences of reduced fertility after therapy.5,6 Hodgkin lymphoma (HL) is a rare malignancy, but among the most frequent types in younger individuals with first incidence peak between 18 and 30 years of age.7,8 The two commonly used chemotherapy regimens, ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) and BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone), cure > 80% of patients with HL regardless of stage disease.9-12 Therefore, the prevalence of HL survivors in childbearing age is high despite low incidence of the disease.13 All types of chemotherapy and radiotherapy (if radiation field includes gonads) have been associated with infertility, but higher doses of chemotherapy, in particular alkylating agents, may be particularly harmful. The BEACOPP regimen has been shown to confer higher risk of premature ovarian failure, secondary amenorrhea as well as long-term azoospermia and consequently a lower parenthood rate in clinical studies.14-19 Much of existing knowledge about fertility in HL survivors is derived from secondary analyses of clinical trials, where there is a considerable number of nonresponders (respondent rate approximately 50%), the observation time is limited (median 42-48 months), and collection of key outcomes rely on questionnaire surveys with risk of bias and incomplete information.15,17 There are no studies to date addressing the fertility and use of ARTs in woman and in men after modern HL treatment in a population-based setting using complete and prospectively collected data and with long observation time. In this study based on the entire Danish population with long and complete follow-up from registry data, we investigated parenthood rates, use of ARTs, and pregnancy outcomes in young HL survivors treated after the year 2000.
The objective was to investigate the parenthood rates (rate of first live birth after diagnosis) and the use of assisted reproductive techniques (ARTs) in relapse-free young Hodgkin lymphoma (HL) survivors relative to the Danish background population.
This population-based registry study demonstrated that HL survivors generally had parenthood rates comparable to the background population. An exception was lower parenthood rate in BEACOOP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone)-treated male survivors. However, a significantly higher use of ARTs among all HL survivors suggests that contemporary HL therapy generally does have adverse long-term impact on fertility. Prior HL treatment did not increase the risk of adverse pregnancy outcomes in terms of malformations or birth weight.
Relevance (J.W. Friedberg)
Younger patients with HL can be informed that their parenthood potential may not be not compromised significantly, particularly with ARTs. Fertility preservation should remain a focus and may affect choice of dose-dense regimens like BEACOPP.*
*Relevance section written by JCO Editor Jonathan W. Friedberg, MD.
Patients with lymphoma diagnosed at hematologic departments in Denmark are registered in the Danish National Lymphoma Registry (LYFO).20 Data in LYFO include patient characteristics at diagnosis (eg, Eastern Cooperative Oncology Group [ECOG] performance score and presence of B symptoms), disease characteristics (eg, subtype and stage), treatment information, and treatment outcomes. Patients fulfilling the following inclusion criteria were selected: (1) diagnosed with classical or lymphocyte-predominant HL between January 1, 2000, and December 31, 2015, (2) aged between 18 and 40 years at diagnosis, (3) in complete remission or complete remission unconfirmed or partial remission following first-line treatment, and (4) alive without relapse 9 months after diagnosis. Follow-up started 9 months after the HL diagnosis (index date) as all patients were expected to have completed therapy at this time point.
Matched comparators were identified using the Danish Civil Registration System.21,22 Five random comparators with no prior history of HL were matched to each HL survivor (incidence density matching) based on sex, age (year and month of birth), and parenthood status at inclusion (children or no children at inclusion).
The primary outcome of the study was time to first live birth after the index date and the differences in parenthood rates between HL survivors and matched comparators. Key secondary outcomes were impact of chemotherapy regimen and disease-related features on parenthood rates, the use of ARTs among HL survivors, the total number of children after HL, and the pregnancy outcomes.
The Danish National Patient Registry holds data on all inpatient, outpatient, and emergency department contacts at Danish hospitals and was used to calculate the Charlson Comorbidity Index at the time of HL diagnosis.23,24 To capture all live births, the Danish Fertility Database and the Danish Medical Birth Register were used. These databases include data on childbirth outcomes, stillbirths, and parents.25,26 Registration of ARTs in the Danish In Vitro Fertilization Register is mandatory by Danish law.26 Linkages between the various data sources used in this study were possible using the unique ten-digit personal identification number given to all Danish citizens.
Proportions are provided for categorical variables and differences were tested using the chi square test. Median and interquartile range (IQR) are provided for continuous variables, and differences between groups were tested using the Mann-Whitney U test. All analyses were done separately for males and females.
Follow-up was defined as the time from index date until first live birth, death, relapse, emigration, end of follow-up (August 31, 2018), or 10 years after index date. The cumulative incidence of first live birth after index date was calculated using the Aalen-Johansen method with death and relapse as competing events.27 Parenthood rates were computed as the number of first live birth during the first 10 years after the index date divided by the total follow-up time, and reported per 1,000 person years (py), irrespective of prior parenthood status. Poisson regression was used to estimate incidence rate ratios (IRRs), 95% CIs for the parenthood rates and IRRs, and to test for differences in rates. A sensitivity analysis of the parenthood rates including all child births after index date was conducted to see if total number of births was lower. Time-varying parenthood rates and IRRs were calculated using the spline-based Poisson regression approach of Carstensen.28 The follow-up time was split into smaller intervals (6 months) and natural cubic splines with five knots were used to smooth the time-varying incidence rates.
All analyses were conducted in SAS (SAS Institute Inc, Gary, NC) and R version 3.6.1 (R foundation for Statistical Computing, Vienna, Austria). The study was approved by the Danish Data Protection Agency (internal ID No. 2018-88).
In total, 793 HL survivors were included (Appendix Fig A1, online only, flow diagram). Detailed characteristics of HL survivor by sex are provided in Table 1. The median follow-up (reverse Kaplan-Meier method) was 8.7 years for HL survivors. The 5-year progression-free survival from index date was 90.6% (95% CI, 87.9 to 93.5) for male HL survivors and 89.4% (95% CI, 86.2 to 92.6) for female HL survivors (of note, all HL survivors included in this study were in remission 9 months after diagnosis).
The 10-year cumulative incidence of first live birth was 38.3% (95% CI, 32.7 to 43.9) in male HL survivors and 39.9% (95% CI, 37.4 to 42.4) in the matched comparators. For females, the 10-year cumulative incidence was 42.0% (95% CI, 35.9 to 48.2) in HL survivors and 43.3% (95% CI, 40.5 to 46.0) in the matched comparators (Fig 1).
Sex-specific parenthood rates for HL survivors and the matched comparators are provided in Table 1. The parenthood rates for male HL survivors (56.2 per 1,000 py; 95% CI, 47.4 to 66.1) and female HL survivors (63.8 per 1,000 py; 95% CI, 53.5 to 75.3) were like those of male comparators (57.1 per 1,000 py; 95% CI, 40.3 to 80.7; P = .871) and female comparators (61.2 per 1,000 py males; 95% CI, 42.8 to 87.4; P = .672; Table 1). Further analysis of the parenthood rates including all live births showed similar results (Appendix Table A1, online only). Consistently, the time-varying parenthood rates for relapse-free male and female HL survivors were like those of matched comparators during the first 10 years of follow-up (Appendix Fig A2, online only).
No clinicopathologic variables were significantly associated with lower parenthood rates (Table 1), but male HL survivors treated with 6-8 cycles of BEACOPP (n = 62) had lower parenthood rates than matched comparators (28.1 v 60.8 per 1,000 py; P = .020) (Table 1 and Appendix Fig A3, online only). On the contrary, parenthood rates for female HL survivors treated with 6-8 cycles of BEACOPP (n = 26) were similar to matched comparators (61.2 v 62.5 per 1,000 py; P = .956, Table 1 and Appendix Fig A4, online only).
Parenthood rates were significantly higher in HL survivors with secondary or tertiary educational level as compared to the HL survivors with primary educational level after adjusting for age and parenthood status (male HL survivors—IRR 2.31, P ≤ .001; female HL survivors—IRR 2.26, P ≤ .001; Appendix Table A2, online only). Male HL survivors treated with 6-8 cycles of BEACOPP had a lower IRR than male HL survivors treated with 6-8 cycles of ABVD (IRR, 0.47; P = .029) after adjusting for age and parenthood status, but this was not the case for females (P = .891), although the number of females was too small to draw firm conclusions. IRRs for male and female HL survivors after 2-4 cycles of ABVD were similar to those after 6-8 cycles of ABVD (P = .764 for males; P = .303 for females).
Among HL survivors with a live birth after index date, a total of 21.6% of male and 13.6% of female HL survivors had their first live birth after ARTs as compared to 6.3% of male comparators (P < .001 v male HL survivors) and 5.5% of female comparators (P = .001 v female HL survivors) (Table 2). ARTs in male HL survivors were mainly explained by reduced male fertility (50.0%), which was higher than for comparators (22.9%; P < .001). ARTs treatment was used because of reduced female fertility in 50% for both female HL survivors and their comparators.
The 10-year cumulative incidence of ARTs among male HL survivors was 5.6% (95% CI, 0.2 to 11.0) after treatment with 2-4 cycles of ABVD, 8.6% (95% CI, 3.0 to 14.2) after treatment with 6-8 cycles of ABVD, and 29.3% (95% CI, 13.0 to 45.6) after treatment with 6-8 cycles of BEACOPP (Fig 2). No differences in the 10-year cumulative incidence of ARTs treatment were observed for different treatment categories among female HL survivors (2-4 ABVD, 8.2%; 6-8 ABVD 9.8%; 6-8 cycles of BEACOPP, 6.2% [95% CI, 0.0 to 18.0]).
Gestational age, Apgar score, newborn measurements (eg, weight), and rate of child malformation were similar for HL survivors and comparators (Table 2).
This Danish nationwide study demonstrated that relapse-free HL survivors had parenthood rates similar to that of the general population. Consistent with this finding, the analysis of the total number of live births confirmed that HL survivors did not have fewer children than the general population (Appendix Table A1). The absence of significant impact on parenthood rates for the majority of HL may be at least partially explained by the medical advances in ARTs technologies. The higher use of ARTs among HL survivors relative to the general population suggests more frequent problems with conception despite the fact that ABVD, the most commonly used regimen, has been shown to have limited impact on hormonal balance.15,17,19 Male HL survivors treated with 6-8 BEACOPP was the only subgroup where significantly lower parenthood rates were observed. The finding was consistent in several separate analyses—male HL survivors treated with BEACOPP had lower parenthood rates than their comparators, they had lower parenthood rates than those treated with 6-8 cycles of ABVD, and they had higher use of ARTs. Only 26 females received BEACOPP treatment in the observation period, a number too small to draw any firm conclusions on the impact of this regimen on female fertility. We also observed that parenthood rates adjusted for age and parenthood status were lower for HL survivors with lower educational level compared to those with higher educational level. Our data suggest that a possible explanation might be differences in the use of ARTs, as HL survivors with lower educational level had lower use of ARTs (results not shown).29,30 Finally, previous treatment for HL did not have negative impact on pregnancy outcomes.
In a study of fertility rates in Swedish relapse-free female HL survivors (n = 449, aged 18-40 years, diagnosed in 1992-2009), birthrates were similar to those observed in a matched Swedish background population from 3 years after diagnosis and onward.31 Birthrates increased over time, as women diagnosed with HL in 2004-2009 had higher likelihood of childbirth after diagnosis as compared to women diagnosed with HL in 1992-2004. Birthrates were lower in female HL survivors treated with 6-8 cycles of BEACOPP in the first 3 years, but normalized to the matched general population after 3 years.31 This study did not confirm lower birthrates among female HL survivors early but there were important differences between the studies, mainly inclusion of earlier periods in the Swedish study where ARTs were less developed. Moreover, we did not identify a lower parenthood rate among female BEACOPP treated HL survivors, but this may be because of slightly higher use of ARTs in Denmark32 and the lack power (n = 26). Lower parenthood rates were also observed by Stensheim et al33 in 1,234 Norwegian HL survivors treated between 1967 and 2004; HL survivors had lower birthrates than the Norwegian general population (hazard ratio [HR] 0.79, 95% CI, 0.69 to 0.92 for males; HR 0.61, 95% CI, 0.51 to 0.73 for females). A Canadian study of 204 female HL survivors treated between 1992 and 1999 showed consistent results with an HR of 0.57 (95% CI, 0.36 to 0.91) for childbirth.34 Finally, a register study showed lower parenthood rates in cancer survivors, including 656 HL survivors, treated between 1971 and 1997 at a Norwegian hospital.35 The explanations behind the discrepancies between these studies and this study are likely the significant changes in HL treatment, cryopreservation techniques, and increased availability of ARTs.33,36-38 Outdated treatments with more heavy use of alkylating agents (eg, nitrogen mustard, vincristine, procarbazine, and prednisone) and extensive field radiation therapy (eg, inverted Y field radiation) were not relevant in the surveyed period of this study.39 Thus, the present study results reported apply more to patients with HL treated with contemporary therapies. In particular, moving away from extensive radiotherapy field has reduced late toxicities in HL survivors.40
It is possible that positron emission tomography-computed tomography (PET-CT)-guided therapy has even less impact on fertility. The HD-18 study from showed that four cycles of escalated BEACOPP was associated with similar outcomes as six cycles in high-risk HL in the 51.7% of patients with HL who are PET-negative after the first two cycles.11 Whether less BEACOPP will result in higher parenthood rates in high-risk HL survivors is to be proven, but less gonadotoxicity is likely. In countries adopting the RATHL approach, the use of BEACOPP in high-risk patients has been substantially reduced to patients with a positive interim PET-CT (15.2% in the RATHL study).10 Thus, the implementation of PET-CT–guided de-escalation and escalation strategies already spares a large group of patients with HL from prolonged exposure to the most intensive regimens. Although this could theoretically limit the need for cryopreservation of ovaries in patients with HL, this would be difficult to implement in clinical practice since pretherapy identification of patients who will be candidates for treatment escalations is not possible.
To our knowledge, this is the first nationwide register-based study to investigate the use of ARTs in male and female HL survivors based on data retrieved from nationwide registers. This study capitalized on prospectively registered data with high degree of completeness because of mandatory registration by law. Therefore, the study is not influenced by selection bias from only including subsets of patients with registrations or willingness to participate and recall bias when relying on patient questionnaires. Van der Kaaij et al41 conducted a questionnaire-based study in French and Dutch HL survivors treated in 1964-2004 showing that male HL survivors more often had children after ARTs treatment (14%) compared with female HL survivors (2%), a difference also observed in this study. However, this study showed a much higher use of ARTs among female HL survivors (11.4%). The difference may reflect broader availability of ARTs and a lower threshold to use them today, but also possible underreporting in the study by Van der Kaaij et al.
The use of Danish, nationwide population-based administrative registries is a strength of this study because the registries have high degree of completeness and quality. The data in the registries are collected prospectively, and the structure of data collection ensures complete follow-up with exception of rare cases of emigration from Denmark. However, the register-based nature of this study is also a limitation in other areas, as it was not possible to determine the actual number of couples who tried to conceive but were unsuccessful in the surveyed period. However, this problem would be similar for HL survivors and comparators. Van der Kaaij et al showed that of the 40% of HL survivors who tried to conceive after diagnosis, 77% (31% of all HL survivors) had a child spontaneously (69%) or after ARTs (8%).41 Second, we showed that male HL survivors treated with 6-8 cycles of BEACOPP had lower parenthood rates than those receiving ABVD, but the included cohort of BEACOPP-treated survivors was small, and more studies are warranted to determine whether PET-response adapted therapies have changed this. Formal adjustments for multiple comparisons were not conducted, as we used well-defined and commonly accepted grouping of treatments. Conservative P value adjustments would reduce false-positive findings, but also increase false-negative conclusions. The negative impact of BEACOPP on fertility in male survivors was shown consistently across several analyses; lower parenthood rates were observed after BEACOPP versus ABVD, and BEACOPP-treated male HL survivors had lower parenthood rates than their comparators. The higher ARTs use among BEACOPP-treated male survivors could not offset the adverse impact of BEACOPP on fertility. This observation is supported by a study of fertility in 38 male patients treated with BEACOPP in the HD9 and HD12 clinical trials; azoospermia was observed in 89% of the patients after treatment.18
In this nationwide, population-based study with long and complete follow-up of patients treated with contemporary first-line regimens for HL, parenthood rates among female and male HL survivors were generally similar to that of matched comparators, with the possible exception of BEACOPP-treated male HL survivors. Further studies on the effect of PET-adapted therapies on parenthood rates in HL survivors are planned in an upcoming Nordic collaborative study. Despite the observation of similar parenthood rates, the higher use of ARTs before first child among HL survivors suggest that fertility is impacted and the focus on fertility preservation remains critical. Overall, the results of this study are positive and encouraging for young patients with HL—the negative consequences of HL therapy on fertility are limited for the majority of patients who have access to modern ARTs.
Listen to the podcast by Dr Morton at jcopodcast.libsynpro.com
Presented in part as a poster at the 61st American Society of Hematology Annual Meeting and Exposition, Orlando, FL, December 7-10, 2019.
Supported by the Danish Lymphoma Group and A.P. Møller Fonden (Lægefonden)(A.K.Ø), the Danish Cancer Society and Aalborg University (T.C.E.-G), and the Nordic Cancer Union (T.C.E.-G., L.H.J., I.G., S.E., and K.E.S).
Conception and design: Andreas K. Øvlisen, Ingrid Glimelius, Karin E. Smedby, Tarec C. El-Galaly
Financial support: Tarec C. El-Galaly
Administrative support: Kristian H. Kragholm, Marianne T. Severinsen, Tarec C. El-Galaly
Provision of study materials or patients: Martin Hutchings, Danny Stoltenberg
Collection and assembly of data: Andreas K. Øvlisen, Peter Kamper, Rasmus Bo Dahl-Sørensen, Danny Stoltenberg, Christian Torp-Pedersen, Tarec C. El-Galaly
Data analysis and interpretation: Andreas K. Øvlisen, Lasse H. Jakobsen, Sandra Eloranta, Kristian H. Kragholm, Martin Hutchings, Henrik Frederiksen, Rasmus Bo Dahl-Sørensen, Caroline E. Weibull, Joshua P. Entrop, Ingrid Glimelius, Karin E. Smedby, Christian Torp-Pedersen, Marianne T. Severinsen, Tarec C. El-Galaly
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
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Andreas K. Øvlisen
Travel, Accommodations, Expenses: Pfizer, AbbVie
Lasse H. Jakobsen
Research Funding: Janssen
Other Relationship: Janssen
Consulting or Advisory Role: Takeda, Roche, Genmab, Janssen
Research Funding: Celgene, Genmab, Roche, Takeda, Novartis, Janssen
Consulting or Advisory Role: AbbVie, Novartis
Research Funding: AbbVie, Gilead Sciences
Travel, Accommodations, Expenses: Roche, AbbVie
Rasmus Bo Dahl-Sørensen
Travel, Accommodations, Expenses: Takeda
Caroline E. Weibull
Research Funding: Janssen
Speakers' Bureau: Jansen Cilag
Karin E. Smedby
Research Funding: Janssen-Cilag
Research Funding: Bayer, Novo Nordisk
Tarec C. El-Galaly
Consulting or Advisory Role: Roche
Other Relationship: Roche
No other potential conflicts of interest were reported.
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