March 12, 2019
3 min read

Infertility linked to small increased cancer risk

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Photo of Gaya Murugappan
Gayathree Murugappan

Infertile women appeared more likely to develop certain malignancies than women without fertility problems, according to an analysis of a U.S. insurance claims database.

“Although the absolute risks are small, women diagnosed with infertility are at higher relative risk [for] several cancers,” Gayathree Murugappan, MD, a fellow in reproductive endocrinology and infertility at Stanford University School of Medicine, told HemOnc Today. “We were surprised to find several significant risk associations between infertile women and incidence of both gynecologic and nongynecologic malignancies, including leukemia.”

Still, Murugappan emphasized the results should be interpreted with caution.

“The findings of our study are associative and not causative,” she said.

Prior studies showed infertile women are at greater risk for hormone-sensitive cancers. However, limited information about risk for nongynecologic cancers is conflicting, and the effect of pregnancy on risk associations has been established only for a small percentage of malignancies.

“We are evolving toward looking at infertility not just as a specific medical condition, but also as a window to men’s and women’s overall health,” Murugappan said. “Given the increasing prevalence of infertility in the U.S., we need to be asking ourselves what unique issues these men and women face.”

Murugappan and colleagues used the Optum de-identified Clinformatics Data Mart — an administrative health claims database — to conduct their retrospective cohort analysis.

The database included information about more than 57 million individuals from 2003 through 2016.

Investigators compared 64,345 infertile women (mean age, 34 years ± 5.7 years) — identified through infertility diagnosis, testing or treatment — with more than 3.1 million non-infertile women (mean age, 32.7 years ± 7.4 years) who sought routine gynecologic care during the study period.

All women were required to be enrolled in a plan covered by the database for at least 6 months prior to and after the index date.

Those with a prior cancer diagnosis were excluded.

Development of any cancer and specific malignancies as determined by ICD-9 and ICD-10 codes served as the main outcome measures.

Researchers adjusted for index year, age at index date, race, smoking status, obesity, nulliparity, highest level of education and number of visits per year.

Mean follow-up was 3.8 years among the infertile group and 3.9 years among those in the control group. This equated to total follow-up of 246,485 person-years in the infertile group and more than 12.26 million person-years in the control group.

During that time, 1,310 cancers were diagnosed among infertile women and 53,116 were diagnosed among those without fertility problems. Breast cancer was the most common malignancy in each group.


Overall, infertile women demonstrated an 18% higher risk for cancer than women without fertility problems.

However, the absolute risk in both groups was small (2% vs. 1.7%; adjusted HR [aHR] = 1.18; 95% CI, 1.12-1.24). These rates suggest one in 49 infertile women would develop cancer during the follow-up period, compared with one in 59 women in the control group.

Murugappan and colleagues also observed higher risk for specific malignancies among infertile women. These included uterine cancer (aHR = 1.78; 95% CI, 1.39-2.28), ovarian cancer (aHR = 1.64; 95% CI, 1.33-2.01), liver and gallbladder cancers (aHR = 1.59; 95% Ci, 1.11-2.3), leukemia (aHR = 1.55; 95% CI, 1.21-1.98), lung cancer (aHR = 1.38; 95% CI, 1.01-1.88) and thyroid cancer (aHR = 1.29; 95% CI, 1.09-1.53).

Investigators performed a subgroup analysis of women in each cohort who became pregnant and delivered a child during study enrollment. Results showed risk for uterine or ovarian cancers were similar between infertile women and those who did not have fertility problems.

An analysis that excluded women with polycystic ovary syndrome and endometriosis also suggested similar risks for uterine cancer between cohorts.

Murugappan and colleagues acknowledged the need for longer follow-up, noting that — although the total person-years of follow-up was large — the average follow-up for each individual patient was short.

“This is certainly a limitation of the study and inadvertently selects for cancers that present at a young age,” Murugappan told HemOnc Today.

“Our hope is that, in the future, we will be able to understand the etiologies of the risk associations we uncovered,” she added. “For example, is there a common underlying mechanism that can cause cancer and infertility? This will help providers more adequately counsel infertile women about the health risks they face.” – by Mark Leiser


For more information:

Gayathree Murugappan, MD, can be reached at Stanford Department of Reproductive Endocrinology and Infertility, 1195 W. Fremont Ave., Sunnyvale, CA 94087; email:



Murugappan G, et al. Hum Reprod. 2019;doi:10.1093/humrep/dez018.


Disclosures: The authors report no relevant financial disclosures.