Concern has been expressed that exposure to fertility drugs might be associated with a risk of ovarian cancer. In particular, pooled analysis of three case-controlled studies by Whittemore et al. (75) suggested an odds ratio of 2.8 (95% CI 1.3-6.1) for invasive ovarian cancer infertile women treated with fertility drugs compared with women with no diagnosis of infertility or infertility drug treatment. This study, suggesting an apparent trebling of risk in infertile women treated with fertility drugs, has been controversial and widely criticized for various biases in the study design.
In 1994, Rossing et al. undertook a study that yielded the best data, to this time, examining the role of clomiphene citrate and ovarian cancer. Rossing et al. used record linkage with a population-based cancer register. They identified an increased incidence of ovarian cancer comprising both borderline malignant tumors and invasive disease. They found a standardized incidence rate (SIR) of 2.5 with 95% confidence intervals (1.3-4.7) in a cohort of infertile women compared with age-standardized general population rates (76). This, of course, is a similar rate of increase found by Whittemore et al. in the previously mentioned study. In the Rossing data, an increased relative risk was also found in women who had been treated with clomiphene citrate for more than 1 year when compared with infertile women who had not taken clomiphene citrate. This increased risk of ovarian cancer was seen regardless of whether the patients did or did not have diagnosed ovarian abnormalities and were treated with clomiphene citrate. There was no increased risk when patients were prescribed clomiphene citrate for less than 1 year.
There are significant clinical differences between the prescription of clomiphene citrate to a U.S. population of women compared with the administration of clomiphene citrate in other parts of the world. In Australia, e.g., clomiphene citrate is only available on prescription from specialist gynecologists and obstetricians rather than from general practitioners as in the United States. Furthermore, clomiphene citrate can only be prescribed in Australia for patients with polycystic ovary syndrome or related disorders and not for women who are infertile but who are spontaneously ovulating. Moreover, our general advice is to use clomiphene citrate in order to achieve four to six ovulatory cycles but not more in the treatment of an infertile woman with polycystic ovary syndrome and chronic anovulation. The use of clomiphene citrate for more than 1 year in an infertile woman would be highly usual and not recommended in our experience.
Previous studies of cancer after infertility have been limited by low statistical power and difficulties in distinguishing possible effects of fertility drug exposure from the underlying ovulation disorder they were used to treat. We have completed a large study looking at the incidence of breast and ovarian cancer after infertility and IVF (77). The great majority of these patients received HMG or ovarian stimulation for IVF. In this study, we examined the incidence of breast and ovarian cancer and a cohort of 10,358 women referred for IVF treatment in Victoria, Australia, between 1978 and 1992.
The exposed group (n = 5564) had ovarian stimulation to induce multiple folliculogenesis for IVF. The unexposed group (n = 4794) had been referred for IVF but were untreated or had a natural cycle treatment without ovarian stimulation. The duration of follow-up in both groups ranged from 1 to 15 years.
Cases of cancer were determined by record linkage with data from population-based cancer registries. We observed 34 cases of invasive breast cancer and six cases of invasive ovarian cancer. A comparison with the expected numbers derived by applying age-standardized general population rates to the cohort gave SIR for breast cancer of 0.89 (95% CI 0.62-1.56) in the unexposed group. For ovarian cancer, the SIRs were 1.70 (0.55-5.27) and 1.62 (0.52-5.02), respectively. In this large study, we were able to look at the rates of all cancers in these two groups of individuals and not only their rates of breast and ovarian cancers. The rates of all cancers in these two groups of women were not significantly different from the general population rates in Victoria, Australia.
We found that the risk of cancer of the body of the uterus, particularly endometrial adenocarcinoma, was increased in both these groups of infertile women combined [SIR 2.84 (1.18-6.18)]. Women with unexplained infertility, regardless of whether they had gonadotropin treatment for IVF or not, also had a significantly increased risk of ovarian cancer [RR = 19.19 (2.23-165.0)] and cancer of the uterus [RR = 6.34 (1.06-38.0)] compared with women with known causes of infertility.
This relatively short-term follow-up of patients after HMG treatment for IVF indicates that ovarian stimulation with gonadotropins is not associated with any increased risk of breast cancer. We also found no significant increased risk of ovarian cancer after ovarian stimulation for IVF with gonadotropins. However, the small number of cases limits the conclusions that can be drawn. Longer-term follow-up of large cohorts of women who have been prescribed gonadotropins for ovulation induction or IVF programs will be necessary. NICE guidelines suggest that medical practitioners should confine the use of ovulation induction agents to the lowest effective dose and shortest duration of use (78).
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A Beginner's Guide to Healthy Pregnancy. If you suspect, or know, that you are pregnant, we ho pe you have already visited your doctor. Presuming that you have confirmed your suspicions and that this is your first child, or that you wish to take better care of yourself d uring pregnancy than you did during your other pregnancies; you have come to the right place.