An umbrella review of meta-analyses regarding the incidence of female-specific malignancies after fertility treatment

Importance: Understanding the potential risks associated with fertility treatments (FTs) can guide clinical decision and patient counseling. Objective: To investigate the validity of the association between the development of female-specific malignancies including ovarian, endometrial, breast, and cervical cancer after FT. Data Sources: A search of systematic reviews and meta-analyses was performed from inception to April 2022 within several databases: Cochrane Database of Systematic Reviews, EMBASE, Google Scholar, and PubMed. Study Selection and Synthesis: The inclusion criteria required the incidence of each cancer subgroup to be stated in both the defined treatment group (controlled ovarian stimulation and/or in vitro fertilization [IVF] or intracytoplasmic sperm injection) and the control group (no-FT, general population). From 3,129 identified publications, 11 meta-analytical reviews consisting of 188 studies were selected for synthesis. Main Outcome: The primary outcome of interest was incidence of each subgroup of cancer in the “FT” group compared with the “no-FT” group. Results: A statistically significant increase in incidence of ovarian (1,229/430,611 in FT group vs. 27,358/4,263,300 in no-FT group) cancer (odds ratio [OR], 1.21; 95% confidence interval [CI], 1.00–1.45) and borderline ovarian tumors (117/414,729 in FT group vs. 934/2,626,324 in no-FT group) (OR, 1.87; 95% CI, 1.18–2.97) was observed. The incidence of ovarian cancer was higher with FT and IVF specifically (OR, 1.65; 95% CI, 1.07–2.54). For borderline ovarian tumors, the incidence was higher, not only with FT overall and IVF, but also according to the fertility drug regimen applied: clomiphene citrate (CC) only (OR, 1.99; 95% CI, 1.02–3.87), human menopausal gonadotropin only (OR, 3.46; 95% CI, 1.39–8.59), and CC and human menopausal gonadotropin combined (OR, 3.79; 95% CI, 1.47–9.77). When using the threshold for statistical significance, the meta-analyses relevant to ovarian cancers remained statistically significant (random-effects method). However, none of the examined associations could claim either strong or highly suggestive evidence. Conclusion and Relevance: An observed association between ovarian cancer (including borderline ovarian tumors) and FT has been demonstrated. The association between FT and female-specific malignancy remains a contentious topic because there have been contradictory outcomes among meta-analyses. This umbrella review interrogates existing systematic reviews and meta-analyses on this topic and concludes that a statistically significant increase in the incidence of ovarian cancer and borderline ovarian tumors is associated with FT. These findings have a significant clinical impact because it helps to inform and provide effective counseling for patients undergoing FT.