Fertility Treatment and Cancers - The Eternal Conundrum: A Systematic Review and Meta-analysis

Given the increased risk of ovarian, breast, and endometrial cancers associated with nulliparity, there is a higher inherent cancer risk among patients pursuing fertility treatment (FT) than the general population. Endometrial and breast are hormone-sensitive cancers that carry elevated risk associated with estrogen predominant states including ovarian stimulation. Repeated ovulation causing disruption of ovarian epithelium may partially explain the elevated risk of ovarian cancer incurred by nulliparity. The rise in prevalence of FT has prompted the need for comprehensive evaluation of the association between FT and malignancy. This meta-analysis aimed to assess whether exposure to FT through ovulation induction, ovarian stimulation, and in vitro fertilization (IVF) increased risk of breast, ovarian, endometrial, or cervical cancer diagnosis. Several databases were queried up to December 2019 to identify articles comparing the incidence of endometrial, cervical, ovarian, and breast cancer among infertile patients that had undergone FT (FT cohort) to those that had not (control cohort). Peer-reviewed original studies published in English that defined the incidence of malignancy in treatment and control groups and FT including the use of clomiphene citrate, hMG, GnRH, gonadotrophins, and progestogens in various combinations were included. The primary study outcome was cancer incidence, both overall and per organ, in the FT group compared with the control group. The meta-analysis was performed according to MOOSE and PRISMA guidelines. The final meta-analysis included 29 retrospective studies of which 17 studies included multiple cancers, 19 studies investigated breast cancer, 19 studies investigated ovarian cancer, 15 studies investigated endometrial cancer, and 13 studies investigated cervical cancer. The total study population included 875,956 in the FTcohort and 20,194,381 in the control cohort, and when all patients were included, the difference in overall cancer diagnosis was not shown to be statistically significant (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.82-1.10). There was not found to be a statistically significant difference between FT and breast cancer incidence (OR, 0.86; 95% CI, 0.73-1.01), ovarian cancer incidence (OR, 1.28; 95% CI, 0.92-1.79), or endometrial cancer incidence (OR, 1.28; 95%CI, 0.92-1.79). The difference in cervical cancer incidence between the FTand control cohort was statistically significant favoring the FT group (OR, 0.68; 95% CI, 0.46-0.99). Subgroup analysis of borderline ovarian cancers (OR, 1.69; 95% CI, 1.27-2.25), ovarian cancer among IVF-only FT patients (OR, 1.32; 95% CI, 1.03-1.69), and among clomiphene citrate-only FT patients (OR, 1.40; 95% CI, 1.10-1.77) did reveal a statistically significant increase in risk among the FTcohort. Subgroup analysis of IVF-only FT patients revealed a decrease in breast (OR, 0.75; 95% CI, 0.61-0.92) and cervical (OR, 0.58; 95% CI, 0.38-0.89) cancer risk. The results of this study indicate that FT exposure has no association with an increased risk of developing breast, endometrial, ovarian, or cervical cancer and may in fact be associated with a reduction in cervical cancer incidence compared with those that have not undergone FT.