Editorial on infertility and cancer incidence

There are sufficient data demonstrating that a woman’s reproductive history acts as a window for future health. However, it is controversial whether a diagnosis of infertility predisposes women to cancer. Wang et al. (1Wang S. Gaskins A.J. Farland L.V. Zhang D. Birmann B.M. Rich-Edwards J.W. et al.A prospective cohort study of infertility and cancer incidence.Fertil Steril. 2023; 120: 134-142Abstract Full Text Full Text PDF Scopus (1) Google Scholar) attempted to prove that they described a 7% greater risk of certain obesity-related cancers developing in women with a history of infertility compared with the control group without infertility. Specifically, the rate was highest in obesity-related gynecologic cancers (postmenopausal breast, endometrial, and ovarian), with a 17% greater risk after adjusting for various demographic, reproductive, and lifestyle risk factors (1Wang S. Gaskins A.J. Farland L.V. Zhang D. Birmann B.M. Rich-Edwards J.W. et al.A prospective cohort study of infertility and cancer incidence.Fertil Steril. 2023; 120: 134-142Abstract Full Text Full Text PDF Scopus (1) Google Scholar). The association did not differ by body mass index (BMI); even women with a normal BMI at the age of 18 years had a higher risk of developing obesity-related cancer if diagnosed with infertility later in life. This further corroborates 2 hypotheses: pregnancy provides additional benefits to women (aside from reproducing), either through hormonal or immunologic pathways, and infertility may either arise from or contribute to chronic inflammation, which may be a contributing factor to certain cancers. Many studies have examined the risk of gynecologic cancers in women with infertility. Lundberg et al. (2Lundberg F.E. Iliadou A.N. Rodriguez-Wallberg K. Gemzell-Danielsson K. Johansson A.L.V. The risk of breast and gynecological cancer in women with a diagnosis of infertility: a nationwide population-based study.Eur J Epidemiol. 2019; 34: 499-507Crossref PubMed Scopus (24) Google Scholar) demonstrated an increased risk of ovarian and endometrial cancer in a nationwide study of women with infertility; the risk of breast cancer was not increased although. It is reasonable to conclude that endometriosis and anovulation are confounding factors, albeit correlated to their infertility. A meta-analysis by Beebeejaun et al. (3Beebeejaun Y. Athithan A. Copeland T.P. Kamath M.S. Sarris I. Sunkara S.K. Risk of breast cancer in women treated with ovarian stimulation drugs for infertility: a systematic review and meta-analysis.Fertil Steril. 2021; 116: 198-207Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar) also found no increased risk of breast cancer in the infertile population. Wang et al. (1Wang S. Gaskins A.J. Farland L.V. Zhang D. Birmann B.M. Rich-Edwards J.W. et al.A prospective cohort study of infertility and cancer incidence.Fertil Steril. 2023; 120: 134-142Abstract Full Text Full Text PDF Scopus (1) Google Scholar) attempted to mitigate the confounding factors with the use of multivariable Cox models and applying various statistical methods, i.e., causal mediation and sensitivity analyses. They also grouped the obesity-related gynecologic cancers together. However, this makes it difficult for the reader to conceptualize the causative effect. Anovulation is known to predispose women to endometrial cancer, and endometriosis is correlated with ovarian cancer. Thus, it would be appropriate to separate the cancer types. In 2019, the American Cancer Society published an updated report highlighting the strong relationship between obesity and various cancers. According to the American Cancer Society, 11% of cancer cases in women may be attributed to obesity. Obesity predisposes patients to endometrial, ovarian, postmenopausal breast, kidney, brain, and gastrointestinal cancers. Although the investigators aptly adjusted for BMI in their statistical analysis, they did not elucidate clearly whether those patients became overweight or obese at the time of infertility or even later, in their 5th through 7th decades of life. It is well known that women have a longer life expectancy than men, but the effect of pregnancy on longevity remains only theoretical. Women’s prolonged lifespan may be because of lower rates of cancer, as this study demonstrates, or because of other protective effects of pregnancy. Additionally, women who reported infertility at younger ages had higher risks of future cancer development; this suggests that the earlier a woman is exposed to pregnancy, the greater these benefits. What is important to note is that the incidence of cancer in this cohort, 0.3% or 322/100,000 (6925 cases/2,149,385 person-years), was lower than the average population’s risk. According to the National Cancer Institute, the incidence of cancer is 442.4/100,000 person-years. Additionally, the median age at the end of follow-up was only 56, which is another limitation of this study: the median age of a cancer diagnosis in the United States is 66 (4National Cancer Institute. Age and cancer risk. March 5, 2021.https://www.cancer.gov/about-cancer/causes-prevention/risk/age#:∼:text=A%20similar%20pattern%20is%20seen,be%20diagnosed%20at%20any%20ageDate accessed: April 22, 2023Google Scholar). Hence, with a small effect size, there is a greater opportunity to find a statistically significant difference. The risk ratio of cancer in this cohort barely is higher than 1, which calls for an ad hoc hypothesis on why infertility only increases the risk of obesity-related gynecologic cancers. Although there is statistical significance, it would have been prudent to perform a power analysis with an estimated effect size before the study. Moreover, this study found an association between infertility and obesity-related cancers only in women with primary infertility, which begs the question whether there is a disparate etiopathogenesis from secondary infertility. Because our current understanding of the pathophysiologic basis of infertility is limited, further research must be expounded on the physiologic changes of women who experience secondary infertility. The results also corroborate that lower parity and higher age at first pregnancy increase a woman’s risk of cancer. However, the explanation can only be theorized. As the investigators allude to, the theoretic inflammation in women with infertility may be a predisposing factor to cancer. Moreover, the hormonal and immunologic changes that occur during pregnancy may be protective from future development of cancer. This study opens new research avenues for the ongoing controversies on the etiology of infertility and the benefits of pregnancy. Another limitation of the study is the homogeneous patient cohort. The investigators acknowledge this limitation and indicate that 96% of the participants are white, and all are nurses. Nurses often require difficult work schedules that involve working continuous night shift or rotating night shifts. There is substantial evidence that working night shifts predisposes women to breast cancer and shorter lifespans (5Wei F. Chen W. Lin X. Night-shift work, breast cancer incidence, and all-cause mortality: an updated meta-analysis of prospective cohort studies.Sleep Breath. 2022; 26: 1509-1526Crossref PubMed Scopus (6) Google Scholar). A meta-analysis with >9.3 million participants were included, and the investigators concluded that >10 years of exposure to night shift work increased the risk of breast cancer (relative risk, 1.086; 95% confidence interval, 1.032–1.14). The investigators suggest that infertility predisposes women to certain types of cancer. However, this is just an observational study. We caution the readers to avoid asserting any conclusions from an association. Correlation does not imply causation. A prospective cohort study of infertility and cancer incidenceFertility and SterilityVol. 120Issue 1PreviewTo investigate the association between infertility and the incidence of invasive cancer. Full-Text PDF