Women who have undergone in vitro fertilization appear to have a twofold risk of ovarian malignancies later in life, compared with women with fertility problems who never used IVF.
However, the risk of invasive ovarian cancer was not significantly increased in IVF-treated women until 15 years after IVF treatment, the results of the study found.
Results from a large Dutch cohort study of 25,152 women using linked medical records to identify women who had been seen for infertility and/or treated with IVF from 1983 to 1995 showed that borderline ovarian tumors accounted for most of the increase in risk after a median 15 years of follow-up. Most of the women were in their late 40s at the study end point.
The investigators of the study, which was published Oct. 26 in Human Reproduction, compared the 19,146 IVF-treated women in the cohort with a control group of 6,006 women who had been seen for fertility problems but had not undergone IVF (although they may have received other forms of treatment, including drugs). The investigators also looked at rates of ovarian malignancies in the general population (Hum. Reprod. 2011 [doi:10.1093/humrep/der322]).
Having subfertile controls was important, the investigators said, because women with infertility have a different risk profile for ovarian malignancies than do women in the population at large. Causes of infertility in the study included fallopian tube disorders, subfertility of a male partner, cervical factor, and endometriosis.
The investigators, led by Flora E. van Leeuwen, Ph.D., of the Netherlands Cancer Institute in Amsterdam, noted that the findings of a risk increase for ovarian malignancies confirmed older findings from smaller cohort studies. Borderline tumors are considered to have a low malignancy potential, and not much is known about which will become invasive, but these tumors do require treatment.
Nearly half of the 61 malignancies detected in the IVF-treated women were borderline tumors, while in the general population of women under age 50 years, these normally account for 15%-30% of malignancies, Dr. van Leeuwen and her colleagues found. A high proportion – 63% – of the borderline tumors seen in the IVF-treated group were serous, while mucinous tumors are more frequent in the general population.
After the researchers adjusted for such potential confounding factors as age, parity, and causes of infertility, IVF-treated women saw a significantly elevated risk for borderline ovarian tumors, compared with subfertile controls (hazard ratio 4.23) and for all ovarian malignancies combined, compared with controls (HR 2.14).
Risk of invasive ovarian cancer was not seen as significantly increased in the IVF-treated women, compared with controls (HR 1.51). However, compared with the general population, the IVF-treated women’s risk of developing invasive ovarian cancer was higher 15 years after IVF treatment, with a standard incidence ratio of 3.54. No increased risk was reported for non-IVF controls, compared with the general population.
Dr. van Leeuwen and her colleagues noted that they did not find evidence that repeated cycles of IVF increased the risk of malignancies, as might be expected. However, they wrote, the powers of their analyses were reduced by missing data and small numbers of women in the subgroups. In the IVF group, 40% of women had one to two stimulated IVF cycles, 39% had three to four cycles, and 21% received five or more cycles.
The type of infertility treatments were as follows: clomiphene/hMG (human menopausal gonadotropins) or FSH (follicle stimulating hormone)/hMG stimulation protocols were used until 1988-1989, whereas stimulation with GnRH (gonadotropin-releasing hormone) agonists became common after 1990 (from 20% in 1986 to about 90% after 1990), the investigators said.
Dr. van Leeuwen and her colleagues cited the large cohort size and long follow-up period as strengths of their study, as well as linkages to population-based cancer and pathology registries, which enabled the investigators to also evaluate the occurrence of borderline ovarian tumors.
They noted as a weakness of their study the fact that their group of subfertile controls was relatively small and that 40% of controls had been prescribed clomiphene, meaning that they were not truly unexposed if the cause of the malignancies was drug related and not related to ovarian puncture. The study was based on IVF treatment protocols through 1995 only, they added.
Still, the researchers concluded that they had demonstrated sufficient risk for women and their physicians to consider when deciding whether to start or continue IVF treatment.
The study was funded by the Dutch Ministry of Health, the Health Research and Development Counsel, and the Netherlands Cancer Institute. J.L.H. Evers declared that he works in a department that has received unrestricted research grants from Merck and Ferring. Neither Dr. van Leeuwen nor any other of her colleagues declared any relevant financial disclosures.