Fertility treatment and cancers—the eternal conundrum: a systematic review and meta-analysis

Abstract

STUDY QUESTION Does fertility treatment (FT) significantly increase the incidence of breast, ovarian, endometrial or cervical cancer? SUMMARY ANSWER Overall, FT does not significantly increase the incidence of breast, ovarian or endometrial cancer and may even reduce the incidence of cervical cancer. WHAT IS KNOWN ALREADY Infertility affects more than 14% of couples. Infertility and nulliparity are established risk factors for endometrial, ovarian and breast cancer, yet the association with FT is more contentious. STUDY DESIGN, SIZE, DURATION A literature search was carried out using Cochrane Library, EMBASE, Medline and Google Scholar up to December 2019. Peer-reviewed studies stating cancer incidence (breast, ovarian, endometrial or cervical) in FT and no-FT groups were identified. Out of 128 studies identified, 29 retrospective studies fulfilled the criteria and were included (n = 21 070 337). PARTICIPANTS/MATERIALS, SETTING, METHODS In the final meta-analysis, 29 studies were included: breast (n = 19), ovarian (n = 19), endometrial (n = 15) and cervical (n = 13), 17 studies involved multiple cancer types and so were included in each individual cancer meta-analysis. Primary outcome of interest was cancer incidence (breast, ovarian, endometrial and cervical) in FT and no-FT groups. Secondary outcome was cancer incidence according to specific fertility drug exposure. Odds ratio (OR) and random effects model were used to demonstrate treatment effect and calculate pooled treatment effect, respectively. A meta-regression and eight sub-group analyses were performed to assess the impact of the following variables, maternal age, infertility, study size, outliers and specific FT sub-types, on cancer incidence. MAIN RESULTS AND THE ROLE OF CHANCE Cervical cancer incidence was significantly lower in the FT group compared with the no-FT group: OR 0.68 (95% CI 0.46–0.99). The incidences of breast (OR 0.86; 95% CI 0.73–1.01) and endometrial (OR 1.28; 95% CI 0.92–1.79) cancers were not found to be significantly different between the FT and no-FT groups. Whilst overall ovarian cancer incidence was not significantly different between the FT and no-FT groups (OR 1.19; 95% CI 0.98–1.46), separate analysis of borderline ovarian tumours (BOT) revealed a significant association (OR 1.69; 95% CI 1.27–2.25). In further sub-group analyses, ovarian cancer incidence was shown to be significantly higher in the IVF (OR 1.32; 95% CI 1.03–1.69) and clomiphene citrate (CC) treatment group (OR 1.40; 95% CI 1.10–1.77), respectively when compared with the no-FT group. Conversely, the incidences of breast (OR 0.75; 95% CI 0.61–0.92) and cervical cancer (OR 0.58; 95% CI 0.38–0.89) were significantly lower in the IVF treatment sub-group compared to the no-FT group. LIMITATIONS, REASONS FOR CAUTION The large, varied dataset spanning a wide study period introduced significant clinical heterogeneity. Thus, results have to be interpreted with an element of caution. Exclusion of non-English citations, unpublished work and abstracts, in order to ensure data accuracy and reliability was maintained, may have introduced a degree of selection bias. WIDER IMPLICATIONS OF THE FINDINGS The results for breast, ovarian, endometrial and cervical cancer are reassuring, in line with previously published meta-analyses for individual cancers but the association between IVF and CC treatment and an increase in ovarian cancer incidence requires additional work to understand the potential mechanism driving this association. In particular, focusing on (i) discriminating specific treatments effects from an inherent risk of malignancy; (ii) differential risk profiles among specific patient sub-groups (refractory treatment and obesity); and (iii) understanding the impact of FT outcomes on cancer incidence. STUDY FUNDING/COMPETING INTEREST(S) This study did not receive any funding. The authors have no financial, personal, intellectual and professional conflicts of interest to declare. PROSPERO REGISTRATION NUMBER CRD42019153404.

Age-related fertility decline: is there a role for elective ovarian tissue cryopreservation?

“…In one of the largest longitudinal cohort studies including a 15-year follow-up of over 19 000 women receiving IVF, the risk of BOT was significantly increased amongst the IVF group, compared to the general population ( van Leeuwen et al , 2011 ). This is consistent with a recent systematic review which confirmed that BOTs are significantly associated with fertility treatment ( Barcroft et al , 2021 ). The risk of invasive ovarian cancer associated with fertility treatment is less consistent.…”

“…The risk of invasive ovarian cancer associated with fertility treatment is less consistent. In subgroup analyses, an observed increased incidence amongst IVF groups has been demonstrated ( van Leeuwen et al , 2011 ; Barcroft et al , 2021 ), although other studies have also not identified a significant association ( Cobo et al , 2016 ). Interestingly, the incidence of cervical and breast cancer is significantly lower in IVF treatment subgroups when compared with those who have not undergone IVF ( Barcroft et al , 2021 ).…”

Potential Role of Quercetin in Polycystic Ovary Syndrome and Its Complications: A Review

“…It mainly manifests as ovarian cystic enlargement, capillary permeability increases and systemic edema, which is one of the critical gynecological diseases. Long-term use of clomiphene also increases the risk of ovarian cancer, but the mechanism is unclear and may be related to increased FSH [ 7 ]. It can be seen that the current treatment drugs can only target a certain pathological link of PCOS, and there are certain limitations.…”

Achievement of live birth after overcoming two gynecological malignancies treated with radical trachelectomy and medroxyprogesterone acetate therapy

“…Although several reports on the oncological and obstetrical outcomes of fertility-preserving treatments such as RT for cervical cancer 410 and MPA therapy for EC and AEH have been reported, 11 this is the first reported case of a patient with both cervical cancer and AEH who underwent two fertility-preserving treatments and achieved a live birth. The risk factors of AEH are obesity, hypertension, diabetes mellitus, irregular menstruation, and long-term use of estrogen preparations, 12 while the risk factor of cervical cancer is high-risk HPV infection. As these two diseases do not share any risk factors, 12 co-occurrence of the two diseases is theoretically possible, but only few cases have been reported.…”

“…The risk factors of AEH are obesity, hypertension, diabetes mellitus, irregular menstruation, and long-term use of estrogen preparations, 12 while the risk factor of cervical cancer is high-risk HPV infection. As these two diseases do not share any risk factors, 12 co-occurrence of the two diseases is theoretically possible, but only few cases have been reported. According to a study that evaluated the incidence rate of other cancers with endometrial and ovarian cancers using an autopsy database in Japan, the frequency of coexistence between corpus and cervical cancers is low (odds ratio [OR], 0.5 [range, 0.22-1.13]).…”