Drugs to stimulate ovulation have been used to treat subfertility since the early 1960s. There is uncertainty about the safety of these drugs and their potential risk of causing cancer. Moreover, it has already been shown that infertility itself increases the risk of ovarian cancer.
The aim of the review
We aimed with this updated systematic review to summarise current published research on the risk of ovarian cancer in subfertile women treated with fertility drugs compared to the general population and to subfertile women not treated with fertility drugs.
What are the main findings?
Overall, based on 37 studies, which included a total of 4,684,724 women, we did not find enough strong evidence suggesting a potentially higher risk of ovarian cancer in women treated with fertility drugs.
A cumulative analysis of 12 case-control studies from the USA revealed increased risk of ovarian cancer in women using fertility drugs, and this risk was higher in nulliparous women (women who have not given birth) when compared to multiparous women (women who have given birth to more than one child). One of the 37 included studies reported a two-fold increase in development of serous borderline ovarian tumour in women after more than four cycles of progesterone; however the number of cases included in this group was very small. One cohort study also suggested an increased risk of borderline ovarian tumour in infertile women treated with clomiphene citrate when compared to infertile women who did not undergo treatment to conceive.
Quality of the evidence
Studies showing an increase in the risk of ovarian cancer were of low methodological quality, with short follow-up periods and with lack of adjustment for important confounding factors; therefore the results are too unreliable. However, compared with older studies, recent studies have tended to report both the dose and the number of cycles of infertility drugs and have included more contemporary drug regimens; this has made the final results more reliable.
What are the conclusions?
Infertility has been found to be an important risk factor for ovarian cancer. However, the association between infertility drugs and ovarian cancer needs to be addressed with consideration of other factors such as age, body mass index, parity, genetic factors (i.e. family history for ovarian cancer), and aetiology of the infertility, along with longer follow-up times.
Since the last version of this review, only a few new relevant studies have provided additional findings with supporting evidence to suggest that infertility drugs may increase the risk of ovarian cancer slightly in subfertile women treated with infertility drugs when compared to the general population or to subfertile women not treated. The risk is slightly higher in nulliparous than in multiparous women treated with infertility drugs, and for borderline ovarian tumours. However, few studies have been conducted, the number of cancers is very small, and information on the dose or type of fertility drugs used is insufficient.
This is an updated version of the original Cochrane Review published in the Cochrane Library in 2013 (Issue 8) on the risk of ovarian cancer in women using infertility drugs when compared to the general population or to infertile women not treated. The link between fertility drugs and ovarian cancer remains controversial.
To evaluate the risk of invasive ovarian cancer and borderline ovarian tumours in women treated with ovarian stimulating drugs for subfertility.
The original review included published and unpublished observational studies from 1990 to February 2013. For this update, we extended the searches from February 2013 to November 2018; we evaluated the quality of the included studies and judged the certainty of evidence by using the GRADE approach. We have reported the results in a Summary of findings table to present effect sizes across all outcome types.
In the original review and in this update, we searched for randomised controlled trials (RCTs) and non-randomised studies and case series including more than 30 participants.
At least two review authors independently conducted eligibility and 'Risk of bias' assessments and extracted data. We grouped studies based on the fertility drug used for two outcomes: borderline ovarian tumours and invasive ovarian cancer. We conducted no meta-analyses due to expected methodological and clinical heterogeneity.
We included 13 case-control and 24 cohort studies (an additional nine new cohort and two case-control studies), which included a total of 4,684,724 women.
Two cohort studies reported an increased incidence of invasive ovarian cancer in exposed subfertile women compared with unexposed women. One reported a standardised incidence ratio (SIR) of 1.19 (95% confidence interval (CI) 0.54 to 2.25) based on 17 cancer cases. The other cohort study reported a hazard ratio (HR) of 1.93 (95% CI 1.18 to 3.18), and this risk was increased in women remaining nulligravid after using clomiphene citrate (HR 2.49, 95% CI 1.30 to 4.78) versus multiparous women (HR 1.52, 95% CI 0.67 to 3.42) (very low-certainty evidence). The slight increase in ovarian cancer risk among women having between one and three cycles of in vitro fertilisation (IVF) was reported, but this was not clinically significant (P = 0.18). There was no increase in risk of invasive ovarian cancer after use of infertility drugs in women with the BRCA mutation according to one cohort and one case-control study. The certainty of evidence as assessed using GRADE was very low.
For borderline ovarian tumours, one cohort study reported increased risk in exposed women with an SIR of 3.61 (95% CI 1.45 to 7.44), and this risk was greater after treatment with clomiphene citrate (SIR 7.47, 95% CI 1.54 to 21.83) based on 12 cases. In another cohort study, the risk of a borderline ovarian tumour was increased, with an HR of 4.23 (95% CI 1.25 to 14.33), for subfertile women treated with IVF compared with a non-IVF-treated group with more than one year of follow-up. A large cohort reported increased risk of borderline ovarian tumours, with HR of 2.46 (95% CI 1.20 to 5.04), and this was based on 17 cases. A significant increase in serous borderline ovarian tumours was reported in one cohort study after the use of progesterone for more than four cycles (risk ratio (RR) 2.63, 95% CI 1.04 to 6.64). A case-control study reported increased risk after clomiphene citrate was taken, with an SIR of 2.5 (95% CI 1.3 to 4.5) based on 11 cases, and another reported an increase especially after human menopausal gonadotrophin was taken (odds ratio (OR) 9.38, 95% CI 1.66 to 52.08). Another study estimated an increased risk of borderline ovarian tumour, but this estimation was based on four cases with no control reporting use of fertility drugs. The certainty of evidence as assessed using GRADE was very low.
However, although some studies suggested a slight increase in risks of ovarian cancer and borderline ovarian tumour, none provided moderate- or high-certainty evidence, as summarised in the GRADE tables.