Gonadotropin Releasing Hormone agonist (GnRHa) during chemotherapy and post-cancer childbirths - a Nationwide population-based cohort study of 24,922 women diagnosed with cancer in Sweden

Kenny A Rodriguez-Wallberg; Helle Kieler; Theodoros Foukakis; Jiong Li; Mika Gissler; Anna Sara Oberg; Jonas Bergh; Frida E Lundberg

doi:10.1016/j.eclinm.2023.102335

Gonadotropin Releasing Hormone agonist (GnRHa) during chemotherapy and post-cancer childbirths - a Nationwide population-based cohort study of 24,922 women diagnosed with cancer in Sweden

EClinicalMedicine. 2023 Dec 7:67:102335. doi: 10.1016/j.eclinm.2023.102335. eCollection 2024 Jan.

Authors

Kenny A Rodriguez-Wallberg^{1

2

3}, Helle Kieler⁴, Theodoros Foukakis^{1

5}, Jiong Li⁶, Mika Gissler^{7

8

9}, Anna Sara Oberg¹⁰, Jonas Bergh^{1

5}, Frida E Lundberg^{1

10}

Affiliations

¹ Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
² Division of Gynecology and Reproduction, Department of Reproductive Medicine, Karolinska University Hospital, Stockholm, Sweden.
³ Laboratory of Translational Fertility Preservation, BioClinicum, New Karolinska University Hospital, Stockholm, Sweden.
⁴ Department of Medicine, Centre for Pharmacoepidemiology (CPE), Karolinska Institutet, Stockholm, Sweden.
⁵ Breast Cancer Center, Theme Cancer, Karolinska Comprehensive Cancer Center, Karolinska University Hospital, Stockholm, Sweden.
⁶ Department of Clinical Medicine-Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.
⁷ Department of Knowledge Brokers, THL Finnish Institute for Health and Welfare, Helsinki, Finland.
⁸ Region Stockholm, Academic Primary Health Care Centre, Stockholm, Sweden.
⁹ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
¹⁰ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Abstract

Background: Worldwide, an increasing number of women with cancer are receiving Gonadotropin Releasing Hormone agonist (GnRHa) co-treatment during chemotherapy aiming at ovarian protection. There is divergence among guidelines, and some have recommended GnRHa co-treatment for women with breast cancer, however, the effect of GnRHa on future fertility is uncertain.

Methods: In this population-based cohort study we included all women diagnosed with cancer at ages 15-45 between July 2005 and March 2017 in Sweden, identified in the Swedish Cancer Register. Exposure to GnRHa co-treatment was captured using the Prescribed Drug Register. Post-cancer childbirth, extracted from the Medical Birth Register, was the main outcome. Secondary outcomes included childbirths achieved through natural conception (NC), infertility diagnosis and cancer mortality. For each outcome, adjusted hazard ratios (aHR) and 95% confidence intervals (CI) were estimated using delayed-entry Cox models, stratified by age and cancer site.

Findings: Among 24,922 women diagnosed with cancer, 1.5% had GnRHa co-treatment. Breast cancer diagnoses were found in 80.2% of GnRHa exposed women and the GnRHa exposure was not associated with higher rates of childbirth (aHR 1.23, 95% CI 0.80-1.89), or NC childbirth (aHR 1.02, 95% CI 0.62-1.67), whereas the rate of infertility was significantly higher (aHR 2.42, 95% CI 1.44-4.08). In women with lymphoma and other cancers, GnRHa exposure was not associated with higher rates of childbirth, NC childbirth or infertility. GnRHa exposure was not associated with higher cancer mortality for any cancer type.

Interpretation: We did not find evidence of improved or maintained fertility, estimated as childbirth rates post-cancer, in women who received GnRHa during cancer treatment.

Funding: This study was financed by research grants from The Swedish Cancer Society (CAN 2017/704; 190249Pj, 200170F), The Swedish Research Council (Dnr 2019-00446), the Nordic Cancer Union NCU (Grant 2017), The Swedish Childhood Cancer Fund (KP2016-0031), Radiumhemmets Forskningsfonder (Dnr: 201313), Stockholm County Council (FoUI-953912) and Karolinska Institutet (Dnr 2020-01963).

Keywords: Breast cancer; Cancer treatment; Female; Fertility preservation; GnRHa; Gonadal toxicity; Iatrogenic infertility; Live birth; Lymphoma; Ovarian suppression.