This large nationwide cohort study with a median follow-up of 15 years shows that women treated with ovarian stimulation for IVF have a 2-fold increased risk of ovarian malignancies compared with subfertile women not treated with IVF. The excess risk was mostly due to borderline ovarian tumours, but 15 or more years after IVF treatment we also observed a SIR of 3.5 for invasive ovarian cancer.
Surprisingly, we observed that a high proportion (46%) of all ovarian malignancies in the IVF group concerned borderline ovarian tumours, whereas in the general population (below the age of 50 years) borderline ovarian tumours account only for 15–30% (Hart, 2005
) of epithelial ovarian malignancies. So far only few studies examined FD use in relation to risk of borderline ovarian tumours, related to the fact that most population-based cancer registries do not record borderline ovarian tumours. Our cohort study is the first one examining the risk of borderline ovarian tumours following IVF treatment. Strikingly, the few case–control studies that examined the risk of borderline ovarian tumours after FD use found 2- to 4-fold increased risks (Harris et al., 1992
; Rossing et al., 1994
; Shushan et al., 1996
; Parazzini et al., 1998
; Ness et al., 2002
), though based on small numbers. In a case–cohort study (Rossing et al., 1994
) reporting an 11-fold risk increase of ovarian malignancies after 12 or more cycles of clomiphene, 5 of the 11 ovarian tumours were borderline ovarian tumours. Although screening for ovarian tumours in IVF-treated women has never been recommended in the Netherlands, we considered whether the increased risk of borderline ovarian tumours in the IVF group might be due to increased medical surveillance. We sent a questionnaire about diagnostic procedures to the gynaecologists of all case subjects with a borderline ovarian tumour who had given permission to approach their physician (n
= 18). We received information for 14 subjects; in all cases, the diagnosis was made subsequent to complaints for which the woman visited her gynaecologist, rendering surveillance bias an unlikely explanation of our findings. Remarkably, we observed a high proportion of serous borderline ovarian tumours (63%), which was also seen in one case–control study (Ness et al., 2002
). Mucinous borderline ovarian tumours are more frequent in the general population (Verbruggen et al., 2009
Risk of borderline ovarian tumours was particularly strongly elevated in the first year after IVF, which is in line with several case reports of borderline ovarian tumours developing during or shortly after ovarian stimulation treatments (Atlas and Menczer, 1982
; Goldberg et al., 1992
; Nijman et al., 1992
), providing support for speculations that ovarian stimulation may induce growth in existing highly differentiated tumours (Brinton et al., 2005
). We excluded ovarian tumours occurring in the first year after IVF, because of concern that their diagnosis might be related to diagnostic and treatment procedures for infertility. The early increase in risk was followed by a SIR close to unity in the 1–4 year follow-up interval; subsequently, risk of borderline ovarian tumours remained elevated up to more than 15 years after first IVF treatment. Hence, our data suggest that IVF treatment may be causally related to a prolonged increase of the risk of highly differentiated tumours. The natural history of borderline ovarian tumours is unclear and it is unknown which part of borderline ovarian tumours, if undetected, would develop into invasive ovarian cancer (Singer et al., 2003
; Sherman et al., 2004
; Shih and Kurman, 2004
A concerning finding of our study is the increased SIR of invasive ovarian cancer in the IVF group after more than 15 years of follow-up, which was not observed in the non-IVF group. We cannot compare this result with findings from others since our study is the first reporting on cancer risk more than 10 years after IVF treatment. However, Brinton et al. (2004
) followed a large cohort of 12 193 women treated for infertility prior to the IVF era. After 15 or more years of follow-up they reported non-significantly elevated rate ratios of ovarian cancer, 1.48 (95% CI = 0.7–3.2) for clomiphene and 2.46 (95% CI = 0.7–8.3) for gonadotrophins (when compared with never use of these drugs). Sanner et al. (2009)
reported on a Swedish cohort treated for infertility in the 1960s–1970s, with a median follow-up of 33 years. Gonadotrophins were associated with increased risk of invasive ovarian cancer (relative risk = 5.28, 95% CI = 1.70–16.47) but clomiphene was not (when compared with never use of these drugs) (Sanner et al., 2009
). Ovulation stimulating drugs such as clomiphene were introduced in the late 1960s and IVF treatment with gonadotrophins, resulting in much stronger ovarian stimulation, did not become widely available until the late 1980s. Consequently, women exposed to clomiphene have just recently reached the age range at which ovarian cancer frequently occurs (>70 years), while the oldest IVF-treated women have only recently reached their 50s. Since the induction period of ovarian cancer with respect to established risk factors amounts to 25 years or more (Risch, 1998
), much longer follow-up is needed to fully evaluate the effects of gonadotrophins.
If ovarian stimulation were causally related to the risk of ovarian malignancy, we would expect increasing risks with greater number of IVF cycles or number of oocytes harvested. No such dose–response trends emerged. However, numbers in relevant dose categories were small, and data were missing for 17% of subjects, which reduced power for these analyses. In addition, the number of IVF cycles and number of harvested oocytes are only proxies for the number of ovarian punctures, which may have reduced the power to detect a dose–response relationship.
Case–control studies of the association between ovarian cancer risk and FD use have shown inconsistent results, with some studies reporting increased risks for subgroups (e.g. nulliparous women) (Ness et al., 2002
; Rossing et al., 2004
) and some suggesting a dose–response effect for clomiphene (Ness et al., 2002
; Rossing et al., 2004
). Treatment with hMG or FSH, as in IVF, may increase the number of ovulations to approximately six to nine times that of untreated women (Fishel and Jackson, 1989
), which is a much stronger increase than the doubling of ovulations with clomiphene (Glasier, 1990
; Derman and Adashi, 1994
Nationwide cohort studies of IVF-treated women have only been reported from Australia (Venn et al., 1999
), Israel (Lerner-Geva et al., 2003
) and Sweden (Källén et al., 2011
). The first two cohort studies did not show increased risk of ovarian cancer in the IVF group compared with the general population (Venn et al., 1999
; Lerner-Geva et al., 2003
), while the recent Swedish study reported for parous women increased risk of ovarian cancer after IVF, compared with all other Swedish women who gave birth in the study period (HR = 2.09; 95% CI = 1.39–3.12) (Källén et al., 2011
). However, this study had no information on subfertility cause; therefore it is not clear whether the risk increase is attributable to IVF or subfertility. Of all cohort studies including IVF-treated women, our study includes the largest number of ovarian malignancies (n
= 77 versus 13, 3 and 26 cases in the cohort studies from Australia, Israel and Sweden) (Venn et al., 1999
; Lerner-Geva et al., 2003
; Källén et al., 2011
Our study design had several strengths and weaknesses. Advantages include the large size of our cohort and the long-term follow-up. Selection bias can be ruled out since we were able to link 96% of our cohort with the population-based cancer and pathology registries, enabling us to also evaluate the occurrence of borderline ovarian tumours. All ovarian malignancies were histologically confirmed. Furthermore, we collected reproductive variables after IVF directly from the participating women, whereas for the majority of women information on subfertility cause and treatment could be abstracted from the medical files. Our data also include information on FD use prior to IVF, although this was incomplete for 27% of women. A limitation of our study is, however, that the comparison group of women unexposed to IVF treatment was relatively small, and that a proportion of these women (40%), had used FDs (clomiphene) outside the IVF setting (as did 54% of women in the IVF group), thus restricting the power for comparisons with a truly unexposed reference group. However, if multiple ovarian punctures rather than hormonal stimulation would induce ovarian malignancy, potential differences in FD use outside the IVF setting are not relevant.
Unfortunately, the response rate to the questionnaire was lower in the non-IVF group (49 versus 71% in the IVF group). Since we were allowed to link non-responders with the NCR and PALGA, differential non-response could not affect our overall risk estimates. However, the larger proportion of missing values for potential confounders (reproductive factors, cause of subfertility) among controls complicated our multivariable analyses. Adjustment for potential confounders did not materially affect our risk estimates, however.
We wondered whether the increased SIR of invasive ovarian cancer observed in the IVF group after 15 years might be due to less oral contraceptive (OC) use and/or lower parity in IVF-treated women. However, in the non-IVF group no increased SIR after long-term follow-up was seen. The proportion of long-term (≥7 years) OC users was high in our cohort and very similar in the IVF group and the non-IVF group (39.2 and 38.1%, respectively). Dutch women start OC use early and have a late age at first birth (mean 1985–1995: 28 years (Statistics Netherlands; www.cbs.nl
, 2011) and only 19.1% of the IVF group and 22.5% of the non-IVF group never used OC or used them <1 year. Consequently, OC use was not a confounder in our multivariable Cox analysis. IVF-treated women remained more often nulliparous then the non-IVF group (44 versus 35%), but adjustment for parity only affected our results for borderline ovarian tumours, not for invasive ovarian cancer.
Our study is the only IVF cohort including a comparison group of subfertile women not treated with IVF, in addition to a comparison with the general population. Such a comparison group is important since IVF-treated women differ from the general population with respect to several risk factors for ovarian malignancies, e.g. subfertility and nulliparity. We cannot exclude the possibility, however, that the severity of certain causes of subfertility in the IVF group was not the same as in the non-IVF group. Since adjustment for individual causes of subfertility only slightly affected our estimates of the risk associated with IVF (data not shown), residual confounding by severity of certain subfertility causes seems unlikely, however.
Another limitation of our study is that our results are based on IVF treatment protocols used until 1995, prior to the adoption of currently applied milder stimulation regimens.
In conclusion, our results suggest that ovarian stimulation for IVF may increase the risk of ovarian malignancies, especially borderline ovarian tumours. Knowledge about the magnitude of the risks associated with ovarian stimulation is important for women considering starting or continuing IVF treatment, as well as their treating physicians. Clearly, the outcome of weighing a wish to conceive against the potential risks associated with IVF may differ among couples considering fertility treatment. In the Netherlands the cumulative risk of ovarian malignancy (including borderline ovarian tumours) is small, i.e. 0.45% at the age of 55 years. If our results are true, we would estimate a 0.71% risk for women who underwent IVF. It should be explained to women opting for IVF treatment that a borderline ovarian tumour does not constitute a lethal disease, although it may require extensive surgery and cause substantial morbidity. Ovarian cancer, however, is a disease with a high case fatality rate, for which effective screening methods are not available (Hermsen et al., 2007
). Although our findings give reason for some concern, they are still based on rather small numbers, no dose–response relationship was found and the risk increase for invasive ovarian cancer was not statistically significant in multivariable analyses. Even larger prospective cohort studies of IVF-treated women, with prolonged follow-up and a subfertile comparison group not treated with IVF, are needed to confirm or refute our findings and to conduct dose–response analyses with more power.