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IVF Ovarian Stimulation Linked to 'Borderline' Ovarian Tumors

As Giuiliana Rancic’s breast cancer diagnosis has raised questions about a link between in vitro fertilization (IVF) and breast cancer (there is no conclusive link between the two), researchers from the Netherlands have found a link between the fertility drugs used to stimulate the ovaries to produce more eggs for IVF and the increased risk of ovarian tumors later in life.

Women undergoing IVF should not be deterred by the study, according to Eric Widra, M.D., a fertility doctor with Shady Grove Fertility in Maryland. "This is a very small difference in risk of an ovarian tumor — 0.45 percent v 0.71 percent," he says. "Further, these are borderline or low-malignant potential (LMP) tumors. Yes, they can require one or more surgeries, but do not require chemotherapy and are non-fatal."

The Dutch Study

The study, published online in the journal Human Reproduction found that the long-term risk for borderline ovarian tumors is twice high as among women who undergo ovarian stimulation for IVF compared with subfertile women not treated with IVF. However, the overall risk for malignant (invasive) ovarian cancer was not significantly increased in this group of subfertile women treated with IVF. The researchers used data from the OMEGA study, a large nationwide observational study examining the late-effects of hormone stimulation in women diagnosed with subfertility problems from all 12 IVF clinics in The Netherlands between 1980 and 1995.

"This study, with 15 years of follow-up, is the first to include a comparison group of subfertile women not treated with IVF,” said lead researcher Professor Flora van Leeuwen, Head of the Department of Epidemiology in The Netherlands Cancer Institute. “This is particularly important because IVF-treated women are different from the general population due to the fact that difficulty conceiving or never having been pregnant are known risk factors for an increased risk of developing ovarian malignancies. Women who were unable to conceive after one or more years of frequent unprotected sexual intercourse were considered to be subfertile, and the main causes of subfertility observed in this study population were fallopian tube problems, male subfertility, unexplained infertility and endometriosis."

The investigators looked at 19,146 subfertile women who received at least one IVF ovarian stimulation treatment and 6,006 subfertile women who were not treated with IVF. They found that of the 25,152 subfertile women included in the study, 77 had ovarian tumors, and 61 of those women were in the IVF treatment group . Of those 61, 31 had borderline ovarian cancer and 30 had invasive ovarian cancer.

“This proportion of ovarian borderline tumors was unusually high,” says Prof van Leeuwen. “Borderline ovarian tumors are tumors with a low malignancy potential, which means that they are not fatal, but would require extensive surgery and cause substantial morbidity."

The researchers adjusted for factors that could affect the results, such as age, number of children (if any) and the cause of subfertility. They found the following:

  • The long-term risk for ovarian malignancies and borderline ovarian tumors was significantly elevated in the IVF treatment group compared with the subfertile non-IVF group.
  • There was a two-fold risk of ovarian malignancies overall and a four-fold risk for borderline ovarian cancer.
  • The risk of invasive ovarian cancer was slightly increased in the IVF treatment group, but it was not statistically significant.

"The individual risk of developing ovarian cancer or a borderline ovarian tumor is very low. In The Netherlands the cumulative risk of ovarian malignancies (including borderline ovarian tumors) before the age of 55 is 0.45 percent in the general population. The results of our analysis suggest this risk increases to about 0.71 percent for women who undergo IVF, with the increase being due to borderline tumors of the ovary," Prof van Leeuwen says.

Should Women Undergoing IVF Worry?

Dr. Widra explains that the study does not indicate a dose-response relationship between IVF and tumors. "It does not seem reasonable that one cycle is equivalent to six in their model," he says. "This also contradicts the prior studies demonstrating a link between number of treatment cycles and risk." In addition, the study group and the control group are from different time-periods and may have had different exposures other than IVF.

Dr. Widra also points out that when the data are broken down, only the group of women who had never had children had an increased risk of low malignancy potential tumors. "This could suggest that the patients refractory [resistant] to IVF may have different risks," he says. "More likely, this demonstrates the protective effect of pregnancy against ovarian cancer. Given the modest success rates of IVF in the study period, one could conclude that with improving pregnancy rates and more pregnancies over time, that the risk, if any, would diminish."

The Dutch researchers plan to continue the study and expand the study population to investigate whether the number of IVF treatment cycles has an effect.

Dr. Widra of Shady Grove says further studies are warranted. "We must remain watchful for long-term consequences of all medical treatments, including IVF."


Comments (1)

The American Fertility Association did an in depth analysis of the data reported in this study and came up with a very different conclusion. We turned to physicians Dan Potter M.D. and Alan Penzias M.D. for their opinions as well, as we believe that the study's conclusive remarks are misleading. Patients truly deserve the truth about the data, for full information please click here:

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