History of Infertility and Risk of Colorectal Cancer.

Among 2,014,029 person-years, there were 2,680 cases of colorectal cancer (invasive n=2,223), and 715 colorectal cancer deaths. No association was observed between infertility and risk of incident colorectal cancer (RR: 0.97, 95% CI: 0.87–1.08), invasive colorectal cancer (RR:0.99, 95% CI: 0.88–1.10), or colorectal cancer mortality (RR: 0.89, 95% CI: 0.71–1.12) ( Table 1 ). No associations were observed when outcomes were assessed by specific infertility diagnoses, however there were small samples sizes for some specific infertility diagnoses ( Table 2 ).

The WHI has been described in detail previously ( 1 ). Briefly, postmenopausal women aged 50–79 years were enrolled between 1993–1998 into either one of three randomized trials or an observational study. Participants have been followed subsequently as part of the original study and subsequent extensions. For this analysis, we excluded participants with missing data on infertility (n=1,644) or cancer (n=1,153), or who had prevalent cancer at baseline other than non-melanoma skin cancer (n=14,151). This study was reviewed and approved by the IRB of the Fred Hutchinson Cancer Center (approval number: 3467-EXT) and this analysis was approved by the University of Arizona IRB (Protocol number: 2011237760). At baseline, participants were asked whether they had ever tried to become pregnant for more than one year without becoming pregnant, which is considered the epidemiologic standard for diagnosing infertility ( 2 ). Participants were also asked whether they visited a doctor or clinic because they could not get pregnant and whether a reason was identified (ovulatory, tubal or uterine, endometriosis, male, other, not known). In order to be classified as infertile you had to have been trying to become pregnant, therefore, to reduce misclassification we restricted the reference group of fertile women, to parous women without a history of infertility. Participants completed self-reported questionnaires which collected information on incident colorectal cancer. Reported cancer was verified by the WHI adjudication committee or trained physician adjudicators who obtained medical records and coded cases according to the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) guidelines. Cox proportional hazards models stratified by age (months) were used to calculate the hazard ratios (HR) and 95% confidence intervals (CI) of colorectal cancer (Model 1). Multivariable models further adjusted for baseline education, oral contraceptive use history, age at menarche, body mass index (BMI), smoking status, marital status, physical activity, alcohol use, WHI trial arm, and menstrual cycle irregularity. Sensitivity analyses using Cox proportional hazard multivariable models examined specific infertility diagnoses separately and looked at invasive colorectal cancer and colorectal cancer mortality. Data are available through the WHI online resource, ( https://www.whi.org/datasets ), while the WHI remains funded and indefinitely through BioLINCC, ( https://biolincc.nhlbi.nih.gov/studies/whi_ctos/ ).

In our large, prospective cohort of postmenopausal women, we did not observe an association between history of infertility and risk of colorectal cancer. The influence of hormonal factors on colorectal cancer has not been consistent and there has been limited prior research on infertility, which can influence exposure to hormones across the reproductive lifespan, and risk of colorectal cancer. An early UK study among patients undergoing fertility treatment observed an elevated colorectal cancer incidence in their population compared to the expected age-standardized cancer incidence ( 3 ). A similar pattern was observed in US data; compared to the general SEER population, women with a history of infertility were observed to have a 1.7-fold increased risk of developing colon cancer ( 4 ). However, some studies have only observed associations among specific subgroups such as gravid women with tubal factor infertility (HR:2.11) ( 5 ). Other studies have observed no association with infertility and colorectal cancer ( 6 , 7 ). While this study has strengths, including its large sample size with ample statistical power to identify associations, adjudicated endpoints, and longitudinal follow-up, there are limitations. To be defined as infertile, a woman must have been trying to become pregnant and been unsuccessful for 12 months, which may be prone to misclassification; however, to reduce misclassification, our comparison group of fertile women was parous women who never reported infertility. The results of this study may not be generalizable to risk of all colorectal cancer given enrollment criteria or to women undergoing modern fertility treatments (in vitro fertilization) given the study population’s birth cohort. There was limited information on colorectal cancer site or subtype which should be investigated in further analyses. Future research should incorporate information on modern fertility treatments in addition to fertility history and diagnoses.

Infertility is a common condition affecting nearly 13–18% of women. Different biologic mechanisms may cause distinct types of infertility. Few studies have investigated the role of infertility on colorectal cancer incidence. Therefore, we used the Women’s Health Initiative (WHI), a cohort of postmenopausal women, to investigate the association between history of infertility and risk of post-menopausal colorectal cancer.