COMMENTARY

Game Changers in Obstetrics & Gynecology: 2011

Peter Kovacs, MD, PhD

Disclosures

November 23, 2011

In This Article

Risk for Ovarian Tumors After Ovarian Stimulation for IVF

The OMEGA study[1] is a large cohort study that evaluated the effect of fertility drug use on ovarian cancer risk. Women (N = 19,146) who received at least 1 cycle of in vitro fertilization (IVF) between 1983 and 1995 were identified. The control group consisted of women (n = 6006) with subfertility who did not receive IVF treatment. Data from the general fertile population were also available for comparison. The median follow-up period was 16.4 years in the non-IVF and 14.3 years in the IVF group. Compared with the general population, the risk for ovarian malignancy was increased in the IVF group (standardized incidence ratio [SIR], 1.59; 95% confidence interval [CI], 1.21-2.04) but not in the non-IVF group. When analyzed separately, the risk for invasive cancer was not significantly different from that of the general population in either the IVF (SIR: 1.35; 95% CI: 0.91-1.92) or the non-IVF group (SIR, 1.24; 95% CI, 0.64-2.17). The risk for borderline ovarian tumors was, however, higher in the IVF group (SIR, 1.93; 95% CI, 1.31-2.73), but no effect was seen in the non-IVF cohort. The greatest increase in risk for invasive ovarian cancer was after 15 years of follow-up in the IVF group (SIR, 3.54; 95% CI, 1.62-6.72). The number of IVF attempts and the dose of gonadotropin did not appear to be independent risk factors. When compared with the non-IVF group, the risk for ovarian malignancy was increased in the IVF group (SIR, 2.14; 95% CI, 1.07-4.25). The risk for invasive ovarian cancer was not higher when analyzed separately, but the risk for borderline ovarian tumors was increased in the IVF group (SIR, 4.23; 95% CI, 1.25-14.33).

The investigators concluded that stimulation may increase the risk for ovarian malignancies, especially borderline tumors. They observed a significant increase in the first year following stimulation, which suggests that stimulation promotes the growth of already existing small tumors. They also point out that although their follow-up was relatively extended, even longer follow-up is required because the induction of ovarian cancer could take decades. In the study population, women undergoing IVF were more likely to remain nulliparous than women in the control group, and therefore were less likely to use oral contraception (which lowers the risk): a factor that must be considered when the results are interpreted. Finally, they pointed out that the overall risk (even if increased) is small as a result of the relatively low frequency of ovarian cancer (0.5%). They also mentioned that the long-term outcome of borderline ovarian cancers is significantly more favorable than that of invasive cancer. Still, the findings of this study should be shared with couples planning to undergo infertility treatment, and the importance of lifelong gynecologic follow-up must be stressed.

Why Is This a Game Changer?

IVF has been successfully practiced for more than 3 decades. Over the years it is estimated that 4 million babies have been born, and in the developed world 2%-4% of all deliveries occur after IVF treatments. When IVF was introduced, no one knew what effect the treatment would have on mothers and their offspring; therefore, ongoing data collection about potential short- and long-term complications has been very important.

The problem of excess risk for ovarian cancer was raised because multiple ovulations and the potential negative impact of the mechanical trauma induced at egg retrieval are believed to play roles in malignant transformations. Evidence for cancer risk has been reassuring so far, with only a few studies suggesting an increased risk on the basis of a small number of cases and relatively short follow-up.[2,3,4] This study provides data from a large cohort of patients after an average of 15 years' follow-up. Ovarian cancer is known to have a long induction time; therefore, sufficiently long follow-up is needed to assess the impact of stimulation and egg retrieval.[5]

Numerous risk factors for ovarian cancer are known (early menarche, late menopause, nulliparity, late first birth, no use of contraceptive pills, endometriosis, ovulatory defect) with infertility being among them. As a result, it is important to have the proper comparison group, as in this study, in which comparisons were made with the general population as well as with the infertile population.

The findings of this study are important because the investigators made a good effort to control for known confounders and even assessed the impact of contraceptive pill use. Even after these adjustments, an increased risk was found for the entire study cohort when compared with the general population. This is not surprising because infertility is a risk factor for ovarian cancer. However, this cohort study also found an increased risk for borderline ovarian tumors in the IVF group when compared with infertile women who were not exposed to IVF.

Women who undergo IVF may differ from those who are infertile but are not exposed to IVF. They may be less likely to achieve a pregnancy in the end. They may have a different etiology for their infertility. They are likely to use more medications because of their treatments. Women who are not participating in IVF are not exposed to the mechanical trauma of the ovary associated with egg retrieval.

As a result of the relatively low incidence of ovarian cancer, the overall risk is still not very high, but this information must be shared with women requesting fertility treatment. Women should be informed about the need for long-term follow-up and screening, although the available screening tools are not very effective. More research is warranted to determine what happens to women who receive conservative treatment for borderline tumors and their long-term outcomes. In addition, the benefit of oophorectomy upon successful treatment should be discussed. IVF is still considered an effective and safe fertility treatment, but women who receive this treatment need long-term gynecologic follow-up and should be encouraged to receive the recommended screening tests.

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