Women who underwent medically assisted reproduction had higher observed rates of several hormone-related cancers in a large Australian cohort study, although the absolute excess risk was small and the associations may be partially or fully explained by underlying infertility-related conditions, unmeasured confounding, and detection bias rather than the treatments themselves.
Researchers conducted a retrospective cohort study using an emulated target trial design based on linked Australian national registries and administrative datasets. The study included 1,748,927 women aged 18 to 55 years between 1991 and 2018, including 396,661 who underwent medically assisted reproduction (MAR). Treatment exposure included assisted reproductive technology (ART), intrauterine insemination or ovarian stimulation (IUI/OS), and ovulation induction with clomiphene citrate. Main outcomes included incident hormone-related invasive cancers, including breast, ovarian, uterine, thyroid, colorectal, and melanoma, with in situ breast cancer and melanoma also evaluated; pancreatic, lung, and hematologic cancers were included as negative controls. Patients were followed through cancer diagnosis, death, or December 31, 2019.
Overall, most hormone-related cancers were associated with modest increases in observed risk following MAR. Hazard ratios generally ranged from 1.09 to 1.64, although for any individual invasive cancer the estimated excess amounted to fewer than 20 additional cancers per 100,000 treated women annually compared with matched comparator groups.
Several cancer-treatment comparisons showed higher risks during the first years following MAR that decreased over time, often reaching little or no excess risk after approximately 10 years. Similar patterns for the negative-control pancreatic and hematologic cancers supported the investigators’ interpretation that increased medical surveillance and earlier cancer detection may contribute to the observed associations.
Additional analyses suggested that underlying infertility-related conditions may account for several observed associations. The investigators noted that underlying causes of infertility, including endometriosis and polycystic ovary syndrome, together with associated obesity and diabetes, could account for all or a substantial proportion of the observed associations with ovarian, uterine, and thyroid cancers. Increased hematologic cancer risk despite no established biologic mechanism and lower lung cancer risk following ART and IUI/OS further supported the likelihood of residual confounding and differences in patient characteristics rather than treatment effects.
The investigators acknowledged several limitations. Because of the observational design, the study cannot establish causality. Important confounders—including the underlying cause of infertility, smoking, family history of cancer, race and ethnicity, oral contraceptive use, and other patient characteristics—were unavailable in the linked datasets. In addition, the findings reflect Australia’s subsidized MAR system and may not be generalizable to other health care settings.
Overall, the findings suggest that any excess risk of hormone-related cancer following medically assisted reproduction was small and should be interpreted cautiously because much of the observed association may reflect underlying patient characteristics and increased medical surveillance rather than the treatments themselves.
“Clinicians and patients should be aware that a small excess risk of cancer following MAR treatment may exist, but this excess risk may be partially or fully due to the health and sociodemographic profile of women who receive MAR and increased surveillance during treatment,” wrote Adrian Raymond Walker, PhD, of the Centre for Big Data Research in Health, University of New South Wales, Sydney, Australia, and colleagues.
Disclosures: The study was funded by the Australian National Health and Medical Research Council. Several authors reported grants, personal fees, editorial roles, and other relationships outside the submitted work.
Source: JAMA Network Open
