Assessing the effect of medically assisted reproduction on hormone-related cancers in women: an emulated target trial

To determine the risk of hormone-related cancers following medically assisted reproductive treatment. Design Emulated target trial. Setting Australian health registries and administrative datasets. Participants 1,748,927 women enrolled in Medicare, Australia’s universal health insurance scheme, aged 18 to 55 between 1 January 1991 and 31 December 2018. Interventions Three exposures were defined from Medicare records of reimbursement for consultations, procedures and medications: assisted reproduction therapy (ART); intrauterine insemination/ovarian stimulation (IUI/OS); and ovulation induction with Clomiphene Citrate. Main outcome measures Hormone-related invasive cancers included breast, ovarian, uterine, thyroid, colorectal, and melanoma; in-situ cancers included breast and melanoma. Three cancers with no established hormonal links and high incidence – pancreatic, lung, and haematological – were included as negative controls. Flexible parametric survival models ascertained hazard ratios and cumulative marginal differences in incident cancers per 100,000 women. E-values assessed the risk of bias due to unmeasured confounding variables.

Though most hormone-related cancers were elevated after MAR treatment (HRs: 1.09-1.64), E-value analysis suggested confounding due to underlying infertility conditions (endometriosis, polycystic ovarian syndrome) could account for this observed elevation for uterine, ovarian, and thyroid cancers. For any specific invasive cancer, fewer than 20 extra cancers per 100,000 women each year were predicted for treated versus comparator women. Emulated trials on the six hormone-related cancers showed increased cancer risk in the first years after treatment, however this was also observed for pancreatic and haematological cancers, suggesting detection bias. Haematological cancers showed an increased risk after treatment (HRs: 1.19-1.27), indicating uncontrolled confounding by ethnicity may account for the excess risk observed for haematological cancers and melanoma. Lung cancer risk was decreased after some treatments (HRs: 0.73-0.83).

Though MAR showed an association with some hormone-related cancers, the absolute difference in the number of expected cancers was small and may be explained by unmeasured confounding and detection bias. Section 1: What is already known on this topic There is a biologically plausible link between medically assisted reproduction therapies and hormone-related cancers. Current evidence suggests exposure to medically assisted reproduction does not increase the risk of most hormone-related cancers. Assessments of causation in this context are challenging, as women undertaking medically assisted reproduction have a different hormone-related cancer risk profile to those who do not. Section 2: What this study adds This study is one of the largest examinations of women’s cancer risk following medically assisted reproduction and the first to use both the emulated target trial framework and negative control cancers, and to quantify the potential for unmeasured confounding. Most hormone-related cancers show a small elevation in relative and absolute risk following medically assisted reproduction therapies, though this may be due in part or whole to detection bias and unmeasured confounding from infertility-related conditions like endometriosis or polycystic ovary syndrome, anovulation, obesity, and ethnicity. This study provides a comprehensive assessment of the available evidence and guidance for improving future research on medically assisted reproduction and cancer. Competing Interest Statement All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: No support from any organisation for the submitted work. ARW declares that their involvement in this work was supported by employment at UNSW Sydney. CV declares payment to their institution from the National Health and Medical Research Council (APP1164852); research grants from Merck KGaA and Ferring; honoraria from Merk Ltd, Merk Sharpe & Dohme, Ferring, Organon, Gedeon-Richter for being an invited lecturer in scientific meetings/ conferences on multiple occasions as well as member of advisory boards for these companies who have a commercial portfolio in the field of assisted reproduction technology (ART); and speaking fees from IBSA, Vianex, Sonapharm; travel support for their participation in scientific meetings/conferences both nationally and internationally, usually as an invited speaker for the following companies - Merck Ltd, Merck Sharpe & Dohme, Ferring, Organon, Gedeon-Richter; unpaid involvement as a Board member of the Hellenic Society of Fertility and Sterility, Member of the Editorial Board of the journal "Human Reproduction", Senior Deputy of the Coordination Committee of the Special Interest Group "Reproductive Endocrinology" of the European Society for Human Reproduction and Embryology, Member of the Editorial Board of the journal "F&S Reviews", Member of the Editorial Board of the journal "RBM Online", Member of the Editorial Board of the journal "Reproductive Biology & Endocrinology", Member of the Editorial Board of the journal "Frontiers in Endocrinology", and Member of the Editorial Board of the journal "Reproductive Sciences". SO declares that they received payment to their institution from the National Health and Medical Research Council (APP1164852); they received a grant from the European Society for Human Reproduction and Embryology (Open call 2022) including payment to their institution; and that they are a member of the Advisory Board of the Cervical Screening Program in Norway through The Norwegian Institute of Public Health (NIPH), for which they were reimbursed travel expenses to their institution. NH declares payment to their institution from the National Health and Medical Research Council (APP1164852); royalties and licenses for Berek and Hacket's Gynecologic Oncology (Walters Kluwer); royalties and licenses for Hacker and Moore's Essentials of Obstetrics and Gynecology (Elsevier); support for attending the British Gynaecological Cancer Society meeting in Aberdeen, UK, Jun 2023; support for attending the Symposium on Gynaecological Cancer in Budapest, Hungary, Nov 2023; support for attending the International conference of the Rajiv Gandhi Cancer Centre in Delhi, India, Mar 2025; and membership of the Medical Advisory Committee for TruScreen (Australia and New Zealand). MC declares support for Theramex European Society for Human Reproduction and Embryology registration and Fertility Society of Australia and New Zealand registration and accommodation. LJ declares payment to their institution from the National Health and Medical Research Council (APP1164852). CS declares stock or stock options associated with CSL Ltd, Sigma Healthcare Ltd, Resmed Inc, Medical Developments International Ltd, Vitrafy Life Sciences Ltd, Intuitive Surgical, and Steris PLC. GMC declares payment to their institution from the National Health and Medical Research Council (APP1164852). CMV declares payment to their institution from the National Health and Medical Research Council (APP1164852). Clinical Protocols Funding Statement This project was funded by the National Health and Medical Research Council (NHMRC: APP1164852). The funders had no role in the design of the study, the collection, analysis or interpretation of the data, the writing of the manuscript or the decision to submit the manuscript for publication. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by all relevant human research ethics committees (HRECs) including the AIHW HREC (EO2019/5/1061). Data was accessed and used under a waiver of informed consent. Researchers were granted access to linked anonymised data. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability The analyses were based on data from different registries and administrative datasets (Australian Department of Health and Aged Care, State and Territory Health Departments, and the Australian Institute of Health and Welfare). And the data can be made available on request to each of the data custodians after ethical approval from the relevant Human Research Ethics Committees. The statistical analysis plan is available at https://osf.io/rk9n6, and analysis code at https://osf.io/nqkc2/.