Women who undergo medically assisted reproduction (MAR) may have a slightly higher risk of developing certain hormone-related cancers, but a large Australian study suggests much of that increase is likely explained by underlying infertility, greater medical surveillance, and other patient characteristics rather than the fertility treatments themselves.
The findings, published in JAMA Network Open, analyzed data from nearly 1.75 million Australian women and represent one of the largest investigations to date of cancer risk following fertility treatment. Using an emulated target trial design—a statistical approach intended to better approximate the conditions of a randomized clinical trial—the researchers examined whether three common forms of MAR were associated with later cancer diagnoses.
The study included 1,748,927 women aged 18 to 55 years between 1991 and 2018, including 396,661 who had received some form of MAR. Treatments evaluated included assisted reproductive technology (ART), intrauterine insemination (IUI) or ovarian stimulation, and ovulation induction with clomiphene citrate.
Researchers found modest increases in the relative risk of several hormone-related cancers—including breast, ovarian, uterine, thyroid, colorectal cancers, and melanoma—after some fertility treatments. However, the absolute increase in risk was small.
For any individual invasive cancer, the investigators estimated that treated women experienced fewer than 20 additional cancers per 100,000 women per year compared with women who had not undergone MAR.
The authors emphasized that the observed associations should not be interpreted as evidence that fertility treatment causes cancer. “Although we observed increased relative risk for most hormone-related cancers following MAR, this corresponded to only small increases in estimated absolute excess risk,” the authors wrote.
To better distinguish treatment effects from other influences, the investigators incorporated several bias analyses rarely included in previous studies. They calculated E-values to estimate the impact of unmeasured confounding and analyzed cancers not believed to be hormonally driven—including pancreatic, lung, and hematologic cancers—as negative controls.
Those analyses suggested that underlying infertility-related conditions, such as endometriosis and polycystic ovary syndrome, as well as factors including obesity, anovulation, and demographic differences, could account for much of the increased risk observed for ovarian, uterine, and thyroid cancers.
The researchers also found that cancer diagnoses tended to cluster during the first few years after fertility treatment. According to the investigators, “Several emulated trials suggested a greater likelihood of incident cancer shortly after first treatment.” They noted that this pattern could reflect either accelerated growth of preexisting cancers or increased medical monitoring during fertility treatment and pregnancy.
After examining the data, the authors concluded that enhanced surveillance was the more likely explanation. “We believe detection bias is the more likely explanation for these results. This finding is the first empirical indication using a negative control that medical surveillance may be responsible for an increased risk of cancer following MAR,” they wrote.
Women pursuing fertility treatment often undergo repeated medical evaluations and may also be more likely to participate in cancer screening programs, increasing the likelihood that existing cancers are detected earlier than they otherwise would be.
Overall, the researchers concluded that while associations between MAR and hormone-related cancers were observed, the evidence does not support a simple causal relationship.
The investigators said the findings should reassure patients while also encouraging careful counseling and follow-up. They recommend that clinicians discuss the possibility of a small increase in cancer risk but explain that the excess risk “may be partially or fully due to the health and sociodemographic profile of women who receive MAR and increased surveillance during treatment.”
The authors added that routine surveillance after fertility treatment remains appropriate, but they cautioned that observed increases in cancer diagnoses should be interpreted within the broader context of infertility-related health conditions and differences in healthcare utilization rather than being attributed solely to fertility medications themselves.
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