Infertility and OBGYN professionals across the U.S. and Canada appear to be united in agreeing that there is an undue amount of fear and controversy concerning the use of letrozole (under the trade name Femara) for fertility treatment. Letrozole is a drug that is used for the prevention of recurrence of estrogen-receptor positive breast cancer. Its “off-label” use for ovulation induction is increasingly common, although not approved by the FDA for this application.

In late 2005, Novartis Pharmaceuticals, the Swiss company that developed letrozole for treatment of breast cancer reacted to a single study that showed higher than normal adverse reactions. Novartis sent out a warning letter to infertility clinics asserting that the company does not advocate the use of this medication for infertility treatment. Despite the drug’s successful track record as an alternative to clomid for ovulation induction, at least one Canadian clinic has stopped using it.

As for the background, it started with the presentation of a study conducted by the Montreal Fertility Clinic at the 2005 annual meeting of the American Society for Reproductive Medicine (ASRM). The study reported a much higher rate of serious fetal abnormalities among patients who had been prescribed letrozole. The author’s analysis of only 150 babies born after letrozole therapy revealed a 4.7% rate of major anomalies. This rate was compared to the 1.8% rate of a “control group” of more than 36,000 babies born at a nearby hospital.

Our reading of this study leaves us skeptical about forming any conclusion that letrozole causes an increase in birth defects. First, it is generally agreed that within an unselected population, the background rate of birth defects is 3% for major anomalies and 6% when including minor anomalies. So the background rate in the “control” population seems low. Second, the comparisons between these groups are not indicative of a true controlled study whereby patients of like demographics and health are provided the same treatment protocol, ideally through a double-blind placebo study.

Common sense would remind us that infertility centers treat a higher percentage of women who have delayed childbirth and their older status is typically associated with higher rates of birth defects. The control group in the letrozole study of 36,000 women at a standard hospital would likely include a high percentage of younger women who, by nature, and backed by statistics, have fewer births with congenital anomalies. Indeed, in this study, the mean age of the women treated with letrozole was 35.2 years and the mean age in the control population was 30.5 years. Further, there may be “ascertainment bias” as there may have been under-reporting of defects in the “control” population. Comparing these two groups and drawing a conclusion that sends such alarm through the infertility community is questionable. Lastly, the limited size of the study makes drawing any conclusion very premature.

Novartis has not led any independent studies of its drug with applicability as an infertility medication. But it took the opportunity to analyze its own database with regard to safety. The company claims there were 13 cases involving “adverse reactions” involving letrozole and congenital birth anomalies.

No control groups or comparison to the background rates of congenital anomalies were made. Given this day and age of class action lawsuits, it is understandable for a pharmaceutical company to issue a warning at the hint of any trouble. In light of this, it has been up to the professional associations and communities of medical professionals handling infertility cases to sort through the data carefully, make up their own minds and provide full disclosure to patients.

Just this month, a new study on this subject is appearing in the primary infertility journal of the U.S., Fertility and Sterility. Again from Canada, researchers from Toronto reported on 911 babies conceived with the assistance of either letrozole or clomiphene. In this study, 14 of 514 newborns (2.4%) in the letrozole group and 19 of 397 newborns (4.8%) in the clomiphene group were found to have any congenital anomaly.

For major malformations, the rates were 6/514 (1.2%) for letrozole and 12/397 (3.0%) in the clomiphene group. These rates were not statistically significantly different, and were felt by the authors to be similar to rates of congenital anomalies seen in the general population.

In the field of medicine, there are hundreds of medications that were originally discovered to treat one condition and are subsequently found to be useful for other conditions. Once a drug is approved for a specific indication, most pharmaceutical companies will not go through the trouble and expense to have their drug officially approved for another indication. We at Pacific Fertility have carefully reviewed the data and circumstances around the controversy and we continue to believe that the use of letrozole is appropriate in certain circumstances and with full disclosure. Hundreds of infertility centers and OBGYN clinics worldwide are doing the same.

Although no broad scientific studies have yet established the efficacy of letrozole as the first course standard treatment for treating ovulatory problems, preliminary studies have shown letrozole to be useful, especially for women whose uterine lining may be thinned out by clomiphene (Clomid).

Please see the Science Pulse Extra to learn more about how letrozole works. The only other alternative to clomiphene for ovulation induction is the use of injectable fertility medications (gonadotropins). Use of these drugs in anovulatory women can be tricky, as it is often difficult to induce just one or two eggs to mature with these powerful drugs. So the risks of ovarian hyperstimulation and multiple gestation are significantly higher in anovulatory women on gonadotropins.

We at Pacific Fertility Center carefully explain to those women who might benefit from its treatment the controversy as well as the potential for adverse reactions. Letrozole is generally prescribed to be taken from days 3-7 of the menstrual cycle and has a short life span in the body. There are no traces of the medication in the body by the time an embryo will be implanting.

– Carolyn Givens, MD

Tags: Female Infertility, Medications, Risks of Advanced Reproductive Technologies

This entry was posted on Monday, May 1st, 2006 at 6:17 pm and is filed under Science Pulse. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.