“Taking fertility drugs does not increase a woman's risk of developing ovarian cancer”, BBC News has reported. It said that a study of over 50,000 women who visited fertility clinics between 1963 and 1998 found no increased risk of the cancer in women who took any of the four types of drugs which were examined.
This study followed 54,362 Danish women who used a variety of treatments for their fertility problems up to an average age of 47 years. Of these, 193 developed ovarian cancer. A main strength of this study is the large number women it looked at. The authors conclude that their study shows no evidence of a link between fertility drugs and an increased risk of ovarian cancer.
The main limitation of this study, as mentioned by the BBC and which the authors acknowledge, is the relatively short duration of follow-up. The average age that women develop ovarian cancer is around 60 years, and so an extended follow-up of women into later age would be valuable.
Where did the story come from?
Allan Jensen and colleagues from the Danish Cancer Society, Institute of Cancer Epidemiology and The Juliane Marie Center, Copenhagen University Hospital, carried out this research. The work was funded by the Danish Cancer Society. The study was published in the (peer-reviewed) British Medical Journal .
What kind of scientific study was this?
This cohort study investigated the effects of different fertility drugs on the overall risk of ovarian cancer. It’s been demonstrated that the risk of ovarian cancer is related to the number of children a woman has, with those without children having the highest risk. However, the association between ovarian cancer, infertility and fertility drugs is less clear.
This study used data from 54,362 Danish women who attended infertility clinics between 1963 and 1998. The data has been used in other studies to examine various associations with infertility, fertility drugs and different cancers. The researchers followed the cohort from the first date they were assessed at the clinics, until death, date of emigration from the area, or to the end of June 2006, whichever came first. They identified cases of cancer by using the women’s civil registry numbers to link them with the Danish Cancer Registry and the Danish Registry of Pathology.
The researchers also used this data to carry out a case-control study. This smaller study compared the characteristics of the women who developed ovarian cancer (156 cases used in the analysis) with 1,241 randomly selected control women. The controls were matched to the cases by the age that they first presented for fertility treatment and the year of entry into the study so that, as a group, the cases and controls were similar to the large cohort.
Medical records were used to collect data for causes of infertility, medical treatments used for infertility, reproductive history and the number of treatment cycles. The risk of ovarian cancer was calculated according to use of fertility drugs and other factors that may affect risk, such as number of children.
What were the results of the study?
The average age of first assessment of infertility was 30 years and the average age of women at the end of follow-up was 47 years. During follow-up, invasive ovarian cancer was diagnosed in 193 women. After excluding women with unspecified histological types of ovarian cancer, those without medical records, and those for whom cause of infertility was sterilisation, 156 women were left for analysis. The average age of cancer diagnosis for these women was 46 years.
Equal proportions of cases (women who developed cancer) and controls had used fertility drugs (49 vs. 50% respectively). Clomifene was the most common drug, used by 37% of cases and 33% of controls, followed by human chorionic gonadotrophins (31 and 33%), gonadotrophins (17 and 15%), and gonadotrophin releasing hormone (10 and 9%).
Compared to having never used fertility drugs, use of any of these four fertility drugs did not increase risk of cancer, and there was also no link with number of cycles of treatment, or duration of time since first use. There was also no association when the researchers looked separately at women who had never had children and those who had. The only positive association was found through an analysis that looked at histological type of ovarian cancer, which found an increased risk of serous ovarian cancer with use of clomiphene compared to never using the drug.
The researchers did find that, compared to having no children, risk of developing ovarian cancer decreased the more children a woman had. Cancer risk was not affected by the women’s age at the birth of their first or last child, their use of oral contraceptives, or their cause of infertility.
What interpretations did the researchers draw from these results?
The researchers conclude that there is ‘no convincing association’ between the use of fertility drugs and the risk of ovarian cancer.
What does the NHS Knowledge Service make of this study?
The main strength of this study is the large size of the cohort; as the researchers say, ‘This potentially represents the largest number of cases of ovarian cancer in any cohort of women with infertility problems to date’. Within this group, the number of women with fertility problems who developed ovarian cancer during follow-up was small (less than 1%). This means that all statistical analyses involved a relatively small number of cases of ovarian cancer (156). This reduces the accuracy of the risk estimate.
The reduction in accuracy is even more pronounced in the smaller sub-analysis by type of fertility drug use and duration of use (only one case and eight controls had used gonadotrophins for 10 or more treatment cycles). The researchers say that the number of ovarian cancer cases in their study is large when compared with other cohorts that have involved much smaller numbers. The study is also strengthened by the fact that loss to follow-up was very small.
An important limitation that should be highlighted is the average age of the women at the end of follow-up. This was only 47 years, which is below the reported peak age of ovarian cancer diagnosis (60 years). Several women may therefore have gone on to develop ovarian cancer after the study was finished. Also, information on other potential risk factors of cause of infertility and oral contraceptive use was only available for a small number of women. The authors suggest that, the increased risk of ovarian cancer in women with fertility problems could be due to factors related to the diagnosis of infertility itself (genetic and medical) rather than fertility drugs.
Further study of women with a longer follow-up would be valuable. This would be able to look at cases of ovarian cancer that develop at an older age.