ArticlesRisk of cancer after use of fertility drugs with in-vitro fertilisation
Introduction
Fertility drugs are routinely used in in-vitro-fertilisation (IVF) treatment to induce multiple folliculogenesis, also known as superovulation. The collection and fertilisation of multiple oocytes increases the chances of pregnancy in a given treatment cycle and allows for excess embryos to be frozen for subsequent pregnancy attempts. The degree of ovarian stimulation achieved in IVF treatment, which exceeds that achieved in patients with chronic anovulation, has led to concerns that treatment may be associated with a long-term increase in risk of breast cancer.
Previous studies of cancer incidence in women who have been exposed to fertility drugs, largely before the introduction of superovulation for IVF, suggested no significant increase in the risk of breast or endometrial cancer compared with untreated infertile women.4, 5, 6, 7 The findings on ovarian cancer have, however, been less consistent. Several studies found no association between exposure to fertility drugs and ovarian tumours,5, 8, 9, 10 but a significant increase in the risk of invasive or borderline ovarian tumours was found in three studies.11, 12, 13 In one of these studies,12 exposure to 12 or more treatment cycles with the fertility drug clomiphene citrate was associated with a relative risk of 11·1 (95% CI 1·5–82·3); the other studies found no dose–response relation.
In 1995, we reported cancer incidence in 10 358 women who had registered with a single IVF clinic.14 The rates of breast and ovarian cancer did not differ significantly from those in the general population for women of the same age. Cancer of the uterus was more common than expected but was not associated with superovulation. Women with unexplained infertility had a higher than expected incidence of ovarian and uterine cancer. Although that study provided some reassurance, it had low statistical power.
This multicentre study was set up to investigate the incidence of cancer in a larger cohort of IVF patients. We aimed to assess rates of cancer according to exposure status to superovulation and by cause of infertility; to examine whether infertility investigations and treatment are associated with higher rates of ascertainment of breast and gynaecological cancers; and to assess whether there are short–term cancer risks associated with exposure to fertility drugs.
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Study population
The cohort consisted of 29 700 women who registered with at least one of ten participating Australian IVF clinics before Jan 1, 1994. 29·7% of the women registered with the clinics before 1986, 39·8% registered between 1986 and 1990, and 30·5% registered after 1990. Participating clinics had to have a minimum dataset from patients' records in electronic format and approval from their institutional ethics committees. We excluded women whose usual residence was outside Australia (n=623), or whose
Results
The characteristics of women in the exposed and unexposed groups are given in table 1, as defined for the follow-up of breast cancer. Fewer women were included in the follow-up of ovarian and uterine cancer (20 583 in the exposed group and 9083 in the unexposed group), but the difference had little effect on the distributions of the characteristics described. Some women who were exposed to superovulation before the end of follow-up for breast cancer were unexposed at the end of follow-up for
Discussion
Overall, the incidence of breast and ovarian cancer in 29 700 women who were referred for IVF was no greater than expected from general-population incidence rates. The rate of uterine cancer was significantly higher than expected among 9083 women who registered for IVF but were not treated. Uterine sarcomas accounted for this increase; these tumours have not, to our knowledge, been associated with infertility in previous studies.18, 19 Ovarian and uterine cancers were more common than expected
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