Women who take ovulation-inducing drugs in conjunction with in vitro fertilization are not at increased risk of developing breast, ovarian or uterine cancer, according to a large Australian cohort study.1 However, women who seek treatment but do not take fertility drugs have more than twice the expected incidence of uterine cancer, and women with unexplained infertility have elevated rates of uterine and ovarian cancer.

The study was based on data on 29,700 women who registered for treatment at 10 in vitro fertilization clinics before January 1, 1994. Clinic records provided background information on the women (including the cause of their infertility) and details about their treatment (including dates and type of treatment, fertility drugs used and number of oocytes collected after each cycle of treatment). By linking clinic records to population-based cancer registries and the national death index, the analysts were able to assess the frequencies of breast, ovarian and uterine cancer in the cohort. They calculated standardized incidence ratios by comparing the frequency of each disease among women seeking infertility treatment with the expected frequency, given rates of cancer in the general population.

About two-thirds of the women underwent treatment involving drugs to induce ovulation; the remainder did not take fertility drugs, predominantly because they received no treatment (although a small proportion were treated without drugs). The median duration of follow-up was seven years for women who had taken drugs and 10 years for those who had not. In both groups, tubal factors were the most common cause of infertility (reported for about two-fifths of women); the cause of infertility could not be explained for about one in seven women in each group.

In all, 143 breast cancers, 13 ovarian cancers and 12 uterine cancers occurred among women in the study. Compared with the general population of Australian women, those who had taken fertility drugs were no more likely to develop these diseases. The frequency of uterine cancer, however, was nearly three times the expected frequency among women who were not treated with drugs (standardized incidence ratio, 2.5). Women with unexplained infertility had elevated frequencies of ovarian and uterine cancer (standardized incidence ratios, 2.6 and 4.6, respectively), and those with tubal infertility experienced a significantly reduced incidence of breast cancer (0.6).

While the frequency of disease was not related to the number of treatment cycles or the type of fertility drug used, the data suggest that it may be associated with a woman's responsiveness to ovarian stimulation. However, the results are based on small numbers and, the researchers comment, require further exploration.

Results of an analysis restricted to the 12 months following the last treatment showed an elevated incidence of breast cancer (2.0) and uterine cancer (5.0). The investigators suggest two possible explanations for these findings: The increases may have been partly attributable to early diagnosis of cancer during clinical management of infertility or related health problems. Alternatively, fertility drugs may promote the development of existing tumors.

As the analysts note, although their study has the advantage of being based on a large cohort, it has several important limitations. For example, 71% of the women had had no more than three treatments with fertility drugs; consequently, the effects of more extensive use of these drugs cannot be assessed from the data. Additionally, with a median follow-up period of only seven years, this study cannot predict the long-term incidence of cancer among women who have taken fertility drugs.

The authors of an editorial accompanying the study, while expanding on these concerns and others, remark that the results nonetheless provide "some reassurance for similarly treated women." They also point out that as symptomless cancers are increasingly detected in the context of treatment for infertility, "the study of cancer risk among women [receiving such treatment] will become increasingly complex."2--D. Hollander


1. Venn A et al., Risk of cancer after use of fertility drugs with in-vitro fertilisation, Lancet, 1999, 354(9190): 1586-1590.

2. Rossing MA and Daling JR, Complexity of surveillance for cancer risk associated with in-vitro fertilisation, editorial, Lancet, 1999, 354(9190):1573-1574.