A Cochrane review included 11 case-control studies and 14 cohort studies with a total of 182 972 women. 7 cohort studies showed no evidence of an increased risk of invasive ovarian cancer in subfertile women treated with any drug compared with untreated subfertile women. 7 case-control studies showed no evidence of an increased risk, compared with control women of a similar age. 2 cohort studies reported an increased incidence of invasive ovarian cancer in subfertile women treated with any fertility drug compared with the general population. One of these reported a standardised incidence ratio (SIR) of 5.0 (95% confidence interval (CI) 1.0 to 15), based on 3 cancer cases, and a decreased risk when cancer cases diagnosed within one year of treatment were excluded from the analysis (SIR 1.67, 95% CI 0.02 to 9.27). The other cohort study reported an OR of 2.09 (95% CI 1.39 to 3.12), based on 26 cases. For borderline ovarian tumours, exposure to any fertility drug was associated with a 2 to 3-fold increased risk in two case-control studies. One case-control study reported an OR of 28 (95% CI 1.5 to 516), which was based on only 4 cases. In one cohort study, there was more than a 2-fold increase in the incidence of borderline tumours compared with the general population (SIR 2.6, 95% CI 1.4 to 4.6) and in another the risk of a borderline ovarian tumour was HR 4.23 (95% CI 1.25 to 14.33) for subfertile women treated with in vitro fertilisation (IVF) compared with a non-IVF treated group with more than one year of follow-up. There was no evidence of an increased risk in women exposed to clomiphene alone or clomiphene plus gonadotrophin, compared with unexposed women. One case-control study reported an increased risk in users of human menopausal gonadotrophin (HMG)(OR 9.4, 95% CI 1.7 to 52). However, this estimate is based on only 6 cases with a history of HMG use.
Another Cochrane review included 19 observational studies with a total of 1 937 880 participants. Overall, the quality of evidence was very low. Subfertile women with exposure to any ovary-stimulating drug did not have an increased risk of endometrial cancer compared with subfertile women without the exposure . An increased risk was found after exposure to any ovary-stimulating drug compared with general population without an exposure .
| Outcome in all: Endometrial cancer Treatment and comparison | Relative effect RR (95% CI) | Risk with no treatment | Risk with intervention (95% CI) | № of participants (studies) |
|---|---|---|---|---|
| Any ovary-stimulating drug for subfertility Comparison: Untreated subfertile women | RR 0.96 (0.67 to 1.37) | 111 per 100 000 | 109 per 100,000 (74 to 163) | 156 774 (6) |
| Any ovary-stimulating drug for subfertility Comparison: General population | RR 1.75 (1.18 to 2.61) | 53 per 100 000 | 92 per 100 000 (62 to 138) | 1 762 829 (15) |
| Clomiphene citrate for subfertility Comparison: Untreated subfertile women | RR 1.32 (1.01 to 1.71) | 524 per 100 000 | 691 per 100 000 (530 to 894) | 92 849 (5) |
| Clomiphene citrate for subfertility Comparison: General population | RR 1.87 (1.00 to 3.48) | 284 per 100 000 | 529 per 100 000 (284 to 980) | 19 614 (4) |
| Gonadotropins for subfertility Comparison: Untreated subfertile women | RR 1.55 (1.03 to 2.34) | 1291 per 100 000 | 1987 per 100 000 (1329 to 2970) | 17 769 (4) |
| Gonadotropins for subfertility Comparison: General population | RR 2.12 (0.79 to 5.64) | 542 per 100 000 | 1148 per 100 000 (428 to 3054) | 1 595 (2) |
| Clomiphene citrate and gonadotropins for subfertility Comparison: Untreated subfertile women | RR 1.18 (0.57 to 2.44) | 490 per 100 000 | 579 per 100 000 (279 to 1196) | 6 345 (2) |
| Clomiphene citrate and gonadotropins for subfertility Comparison: General population | RR 2.99 (1.53 to 5.86) | 76 per 100 000 | 245 per 100 000 (150 to 401) | 7 789 (3) |
| GnRH analogues for subfertility Comparison: Untreated subfertile women | RR 1.21 (0.65 to 2.27) | 458 per 100 000 | 554 per 100 000 (297 to 1039) | 42 558 (2) |
Comment: The quality of evidence is downgraded by study quality.