Elsevier

The Lancet

Volume 354, Issue 9190, 6 November 1999, Pages 1586-1590
The Lancet

Articles
Risk of cancer after use of fertility drugs with in-vitro fertilisation

https://doi.org/10.1016/S0140-6736(99)05203-4Get rights and content

Summary

Background

We investigated the incidence of invasive cancer of the breast, ovary, and uterus in a cohort of patients who had undergone in-vitro-fertilisation (IVF) treatment and examined whether cause of infertility or exposure to fertility drugs to induce superovulation was associated with an increased cancer risk.

Methods

Ten Australian IVF clinics provided data for women who had been referred for IVF before Jan 1, 1994. The frequencies of invasive breast, ovarian, and uterine cancer were assessed by record linkage to population-based cancer registries and the national death index. The observed number of cancers was compared with the expected number calculated by application of age-standardised generalpopulation cancer rates to the cohort. Standardised incidence ratios (SIRs) were derived from the ratio of observed to expected cases.

Findings

The cohort consisted of 29 700 women: 20 656 were exposed to fertility drugs and 9044 were not. 143 breast cancers, 13 ovarian cancers, and 12 cancers of the uterus occurred among these women. For breast and ovarian cancer the incidence was no greater than expected (SIR 0·91 [95% CI 0·741–1·13] for breast cancer and 0·88 [0·42–1·84] for ovarian cancer in the exposed group and 0·95 [0·73–1·23] for breast cancer and 1·16 [0·52–2·59] for ovarian cancer in the unexposed group). The incidence of uterine cancer was no higher than expected in the exposed group (1·09 [0·45–2·61]) but was significantly higher in the unexposed group (2·47 [1·18–5·18]). Women with unexplained infertility had significantly more cancers of the ovary and uterus than expected (2·64 [1·10–6·35] and 4·59 [1·91–11·0], whole cohort). Analysis of cancer incidence within 12 months of exposure to fertility drugs with IVF showed that incidence was significantly higher than expected for breast and uterine cancer (1·96 [1·22–3·15] and 4·96 [1·24–19·8]).

Interpretation

Women who have been exposed to fertility drugs with IVF seem to have a transient increase in the risk of having breast or uterine cancer diagnosed in the first year after treatment, though the incidence overall is no greater than expected. Unexplained infertility was associated with an increased risk of a diagnosis of ovarian or uterine cancer.

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.

Section snippets

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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