A study of more than 400,000 women finds medically assisted reproduction is associated with small increases in certain cancers. However, overall cancer risk remains comparable to that of the general population.
Study: Cancer Incidence in Women After Medically Assisted Reproduction. Image credit: Rohane Hamilton/Shutterstock.com
A study published in JAMA Network Open found that women who underwent medically assisted reproduction (MAR) had slightly higher rates of certain cancers, notably uterine and ovarian cancers, although overall cancer incidence after MAR was generally similar to that of the matched general female population. However, the absolute increase in risk was small, amounting to fewer than seven additional cases per 100,000 women per year.
Infertility, treatment, and cancer risk: untangling complex relationships
MAR is becoming more common in wealthy countries, comprising 6.7 % of births in Australia in 2017. It involves treatments such as assisted reproductive technologies (ART), including in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), intrauterine insemination (IUI), and ovulation induction using fertility medications such as clomiphene citrate.
Many of these involve administering hormones or repeatedly puncturing ovarian follicles to retrieve ova. Both of these are potential contributors to cancer development. ART may be linked to increased ovarian cancer risk and lower cervical cancer risk. In other cancers, confounding factors may explain the conflicting findings.
For instance, women who undergo MAR may also have a higher baseline cancer risk because of other factors such as their reproductive history, the use of hormonal contraceptives, infertility-associated conditions such as endometriosis and polycystic ovarian syndrome, and a prior history of cancer that may indicate genetic susceptibility or increased risk due to cancer therapies. Infertility itself has also been associated with elevated risk for some hormonally sensitive cancers.
Protective factors may also be present, including reduced odds of smoking, higher socioeconomic status, and closer medical care before, during, and after MAR that may increase the chances of early diagnosis and treatment.
Australian registry study tracks cancer risk after fertility treatment
The researchers carried out a population-based cohort study of 417,984 Australian women with a history of MAR treatment. They collected data on treatment type, pregnancies, cancer, and death from administrative and registry databases. All women in the study were between 18 and 55 years of age.
Three MAR cohorts were formed according to the exposure:
- ART: 274,676 women (65.7 %), median age at first treatment 34 years
- IUI with ovarian stimulation (IUI/OS): 120,739 women (28.9 %), median age 34 years
- Ovulation induction using clomiphene citrate (clomiphene citrate): 175,510 women (42.0 %), median age 32 years
Women could be in more than one cohort if they underwent multiple types of MAR. Most women lived in major cities and were seeking to have their first baby.
Cancer risks in each cohort were estimated and compared with the general female population by age, geographic location, and year. Because the comparison group was the general population rather than infertile women who did not receive MAR, some observed differences may reflect underlying infertility-related risk factors rather than the treatments themselves.
Small increases seen in specific cancer types
The study shows that all-cancer incidence in women exposed to ART or IUI-OS MAR was similar to the general population risk. It was slightly higher (4 % increase) following clomiphene citrate treatment. However, when analyzed by cancer type, skin melanoma and hormonally sensitive cancers like uterine and ovarian cancers were more common in the MAR group.
Hormonally sensitive cancers
Uterine cancer risk was higher in all treatment groups. Rates were 23 % higher among women who underwent ART, 32 % higher among those who received IUI with ovarian stimulation, and 83 % higher among those treated with clomiphene citrate. Most of the excess cases were type 1 (endometrioid) uterine cancers.
In the clomiphene citrate cohort, the highest incidence occurred in women aged 18-35 years and in the first year from treatment. Interestingly, women who had given birth prior to the use of clomiphene citrate did not show this increase in risk.
Ovarian cancer incidence was higher in women who underwent ART and IUI with ovarian stimulation, increasing by 23 % and 18 %, respectively. The excess cases were confined to the endometrioid and serous subtypes. The highest risk occurred within the first year after MAR and among women who had six or more treatment cycles. The researchers note that this early increase may partly reflect increased medical surveillance after treatment rather than a direct effect of MAR.
Risk patterns also differed by childbirth history. Among women without children, ovarian cancer risk was 48 % to 67 % higher, whereas among women who had given birth, it was 20 % to 37 % lower.
Rates of in situ breast cancer were 24 % higher in women who underwent ART, with the increase appearing about six years after the first treatment. In contrast, invasive breast cancer rates were lower during the first year after MAR. However, risk was higher among women older than 50 years and among those followed for six or more years after their first ART or IUI-OS treatment.
Other cancers
Both in situ and invasive melanoma were more common, by 7 % to 15 %, across cohorts. The highest risk was observed among women who had given birth before treatment. The researchers suggest that differences in healthcare access, increased medical monitoring, and population characteristics such as fairer skin among MAR patients could partly contribute to this pattern.
Thyroid cancer risk was 19 % higher in the clomiphene citrate group, but only in parous women, and only within 3–5 years from first treatment.
In absolute terms, the increases in risk ranged from <1/100,000 person-years to <7 per 100,000 person-years across cohorts. Across all cancers combined, in the clomiphene citrate cohort, this corresponded to about nine additional cancer cases per 100,000 women per year.
Lower cancer incidence
Conversely, cancers of the lung, including the respiratory tree (trachea and bronchi), and of the uterine cervix, were less common in the MAR group. Cervical cancer risk was decreased by 39 % to 48 %, a reduction that has previously been attributed to screening and treatment during infertility investigations rather than a protective effect of MAR itself. Cancers of the respiratory tract were 30 % to 38 % less likely.
Other cancers with lower risks include acute myeloid leukemia, which was reduced across MAR cohorts; chronic myeloid leukemia, which was modestly higher in the ART and IUI-OS groups; pancreatic cancer, which was 25 % lower in the ART and IUI-OS groups; and cancers of the kidney, bladder, and unknown primary site, which were 28 % to 45 % lower in the ART cohort. Overall, decreases in risk ranged from <1 per 100,000 to 5.7 per 100,000 person-years.
The study findings agree in part with prior research, especially the marked increase in uterine cancer risk with clomiphene citrate. These findings indicate the need to pursue further research on cancer risks associated with fertility treatment. Apart from raising awareness among women with a history of MAR who may be at risk, they could be encouraged to modify other risk factors for some of these cancers, such as reducing body fat in cases of overweight or obesity, limiting sun exposure, and quitting smoking.
In addition, the findings may help inform long-term monitoring strategies and future evidence-based guidelines to ensure that such women receive adequate monitoring after treatment.
Strengths and limitations
The study used accurate and reliable data. However, it had multiple limitations. It was observational, limiting causal inferences. It might also be affected by detection bias due to high levels of medical surveillance associated with MAR. The researchers could not stratify by cancer stage. They did not assess cancer incidence in comparison with infertile non-MAR women. The study did not account for poor healthcare access or cancer deaths by cause, and fertility treatment records did not include treatment indication or other risk factors. Follow-up time was relatively short, and many participants had not yet reached the ages at which several cancers become more common, which may have underestimated long-term risks.
Absolute cancer risk increases remain very small
The study establishes a higher incidence of some cancers, but with a marginal elevation above the general population incidence in Australian women who underwent MAR, and a small absolute increase in risk.
The authors suggest that women who undergo MAR may benefit from personalized risk management strategies and stringent follow-up, while emphasizing that the observational design means the study cannot determine whether MAR itself causes these cancers and that underlying infertility or related factors may partly explain the associations.
Download your PDF copy by clicking here.
Novel model expands fertility options for cancer patients