Ovarian Cancer and Fertility Medications: A Critical Appraisal

S. Kashyap, M.D., F.R.C.S.(C), O.K. Davis, M.D., F.A.C.O.G.


Semin Reprod Med. 2003;21(1) 

In This Article

Abstract and Introduction

Ovarian cancer is the fifth most common cancer in the Western world. Infertility and nulliparity are independent risk factors for this disease. The possible link between fertility drugs and ovarian cancer remains controversial. Despite concern regarding increasing use of fertility therapy, the incidence of ovarian cancer in the Western world has remained stable for several decades. Evaluation of the literature requires assessment of the validity, importance, and applicability of the study to your particular patient. The following article demonstrates how to conduct such an assessment. The data to date do not support a causal relationship between fertility drugs and ovarian cancer. In fact, infertility therapy may confer protection for those patients who conceive. Further prospective, long-term data are needed to further delineate this relationship.

We were recently asked by a 35-year-old G0 patient about the risk of ovarian cancer following in vitro fertilization (IVF) therapy. This is a frequently encountered question in reproductive medicine. Attempts to answer this question have resulted in conflicting opinions. Evaluation of the literature requires a systematic approach that assesses the study's validity, importance, and applicability to your particular patient.[1] We will present the analysis of such a question here.

Several reports have attempted to delineate an association between ovulation induction and the occur-rence of ovarian cancer. The nature of the association does not permit randomized controlled clinical trials. Whittemore et al published the first pooled analysis of 12 case control studies in 1992. This article suggested that women treated with infertility drugs were at higher risk than the general population for ovarian cancer.[2] This article ignited much controversy, engendering criticism from both the reproductive medicine and epidemiology communities. Specific concerns included the following: Information on the specific type of infertility treatment was available in only 3 of the 12 studies (12 cases and 1 control exposed to infertility treatment); for the majority of the period of study, currently prescribed fertility medications were not available, and the specific type of medication, dosages, and duration were not described. In fact, a later publication revealed that the medications used in these studies were, for the most part, irrelevant today.[3] The studies had high rates of nonresponders who were not characterized. Lead time bias, selection bias, recall bias, and inability to control for confounding factors were not adequately addressed. Infertility diagnoses and outcomes of therapy were not characterized. The use of general population controls is not appropriate given the elevated risk of cancer in nulliparous and infertile patients.

Nevertheless, in the absence of definitive data, numerous reviews and editorials have been published. Spirtas et al suggested that the data is not sufficient to change practice. However, they did suggest that counseling of infertile patients, in view of a nonsignificant trend toward increased risk, might be accordingly modified to incorporate this information. They also suggested that egg donors, who derive no personal reproductive benefit from ovarian stimulation, might reconsider participation if given this information.[4] Rosen et al attempted to evaluate the perceived risk versus benefit in infertile women. They found that 40% of women would accept a lifetime risk for ovarian cancer of > 4% (greater than twice the general population lifetime risk) for the enhanced chance to conceive. Fewer than 10% would not accept any increased risk, and the remainder indicated that they would accept a 2 to 4 % lifetime risk for the chance to have children.[5]

To establish cause and effect, a study must fulfill the following requirements:

  1. assessment of the strength of association,

  2. biologic credibility,

  3. consistency with other investigations,

  4. time sequence/temporality, and

  5. dose-response relationship.

Observational data are by definition "hypothesis generating." Nevertheless, in the evaluation of adverse effects from treatment, observational data is usually the only tool we have. It would be considered unethical to randomize patients into treatment versus nontreatment groups for the sole purpose of establishing causation of harm. Therefore, large prospective cohort studies often provide the most reasonable solution to establish an association between exposure and harm.


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