For years, infertility specialists have insisted in scientific and public arenas that a key IVF procedure known as ovarian stimulation—chemically goosing women’s ovaries to ripen multiple eggs in a single menstrual cycle—poses little or no long-term cancer risk for those undergoing it.

Like so many other safety claims advanced by researchers and clinicians since the early days of reproductive medicine, this assertion has been made on the basis of virtually no solid evidence, and those who have accepted it can only have done so on the basis of faith: Over the last two decades, the two dozen or so scientific follow-up studies of women who have undergone ovarian stimulation have yielded conflicting results and have been largely unconvincing because they have looked at relatively small numbers of women, have collected a limited range of medical information, and have not tracked their subjects over a long period of time.

That said, a dozen or so previous studies pointed to an increased risk for both ovarian cancer and borderline ovarian tumors, malignancies that are usually self-contained and operable and have higher survival rates than full-blown ovarian cancers.

Now an impressively large and comprehensive study out of the Netherlands has confirmed the disquieting findings of those studies while affording a much sharper picture of the risks posed by exposure to fertility drugs like clomiphene citrate, synthetic gonadotropin releasing hormone analogs, and other stand-ins for the naturally circulating hormones that, in fertile women, cause eggs to ripen and be released. The article, published in the online version of Human Reproduction on October 26, concludes that among the population of women in the study, exposure to fertility drugs significantly heightened the chances of borderline and invasive ovarian malignancies.

The 18-member team, led by epidemiologist F. E. van Leeuwen of the Netherlands Cancer Institute in Amsterdam, went to exhaustive lengths to assemble a longitudinal study that would have a high degree of statistical power.  Aided by extremely detailed records from Dutch IVF clinics, the team identified an initial cohort of 19,861 women who had been treated at least once with fertility drugs between 1983 and 1995, as well as a comparison group of 6604 other women who were diagnosed as being subfertile during that same period but had not received such treatment.

Ultimately, a total of 25,152 women were represented in the final study, 19,146 in the IVF cohort and 6006 in the control group, and their medical histories from 1 January 1989 to June 2007 examined. The researchers corrected for failings of earlier studies by gathering information from both clinics and participants about whether they had children or had experienced difficulty conceiving, because both the lack of children and subfertility itself have been posited as risk factors for ovarian cancer.  They drew in data on the women’s family histories and lifestyle factors and, for the women who had undergone IVF or artificial insemination, obtained details on the date, dosage, and type of fertility drugs received.  Then, the team linked these women to a national registry with computerized records from all pathology labs in the country, which gave them great certainty concerning ovarian cancer diagnoses and deaths.  They made multiple other adjustments to ensure the validity of their findings.

They found that “women treated for ovarian stimulation for IVF have a 2-fold increased risk of ovarian malignancies compared with subfertile women not treated with IVF.”  In addition, the type of tumor that appeared most frequently—known as serous—is thought to originate specifically from the layer of cells covering the ovaries and occurs less frequently in general than the other type, called mucinous.

Although the overall incidence of ovarian cancer in the Netherlands is low, there, as elsewhere, the mortality rate is disproportionately high, most likely because ovarian cancer is often asymptomatic until very late stages.  In the U.S., according to the most recent Centers for Disease Control and Prevention statistics, 20,749 women were diagnosed with ovarian cancer in 2007, while 14,621 died from it.  Although ovarian cancer was only the 8th most common cancer among women, striking 12 out of 100,000 females, it was the fifth most common cause of cancer death. Consequently, a two-fold increase in risk is reason for concern.

With treatment for IVF on the rise globally, and births via egg donation also on the rise, it would seem imperative that the industry amend its safety claims regarding exposure to fertility drugs.  Most of the young women who took my “Women’s and Gender Studies” course this semester were quite familiar with the advertisements run in the student newspaper and elsewhere for egg donation, and knew about the bank account benefits of the procedure.  None had heard, coming into the course, about any possible down side.  

Certainly, the American Society for Reproductive Medicine (ASRM) should consider doing more than it has done to date to advertise the risks.  If one goes to the ASRM website page on “The Risks and Benefits of Donating Your Eggs,” which claims to have been updated December 16, 2011, one is sent to an article on the website i09, “a daily publication that covers science, science fiction, and the future,” albeit with the disclaimer: WARNING! THE ASRM HAS NOT REVIEWED THE CONTENTS OF THE EXTERNAL WEB SITES LISTED ON THIS PAGE, NOR CAN WE ENDORSE THEM OR THE VIEWS EXPRESSED WITHIN.

Why an organization whose mission statement asserts that it “is committed to facilitating and sponsoring educational activities for the lay public” would link to information that it has not bothered to review is a matter for another blog, but, for the record, the i09 article is happy to explain that:

Accelerated cancer proliferation is suggested in rare cases due to the increase in hormone levels, but this is far from an established correlation. Premature menopause and infertility are often linked to egg donors, but we will not know if a correlation is present until decades pass and more data is collected. The only confirmed positive or negative effects of egg donation are psychological ones, with most women benefiting from the joy of helping a couple in need.

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