Letrozole (marketed as Femara in the U.S.) is a drug that is approved for the treatment of breast cancer after surgery. It is also used (“off label”) for ovulation induction. I have discussed its mechanism of action and success rates in a previous blog, as well as use of Letrozole versus Clomid for patients with PCOS. Despite its obvious advantages, Letrozole is used infrequently by fertility specialists in the U.S. A major reason for this is a controversy about the use of Letrozole and birth defects in the resultant children.
Does Letrozole increase the risk of birth defects? Requena et al. and the Reproductive Endocrinology Interest Group of the Spanish Society of Fertility addressed this question in a systematic review (Human Reproduction Update, Vol. 14, No. 6 pp. 571-582, 2008). Here is a summary of their review.
Letrozole, however, has a relatively short half-life (~ 45 hours). It is therefore cleared quickly from the body. It is therefore extremely unlikely that a drug that is given from days 3 – 7 of the cycle (at least a week before ovulation) can cause birth defects.
However, Letrozole should NOT be given to pregnant women. A pregnancy test is usually recommended prior to starting Letrozole (especially in a patient who is not getting menses).
How the Letrozole / Birth Defects Controversy Started
A small Canadian study presented at the 2005 American Society for Reproductive Medicine meeting (Biljan B. et al.) suggested that letrozole could cause serious fetal anomalies when used off-label for ovulation induction. This group from the Montreal Fertility Center, found a malformation rate of 4.7% among 150 babies born after the use of letrozole, compared with a rate of just 1.8% in a database of 36,050 normal conceptions.
An identical number of birth defects in each group was reported, but the incidence of cardiac malformations and malformation of the musculoskeletal system was significantly higher in letrozole- treated group. As a result, the pharmaceutical company (Novartis), which markets the drug as Femara for the treatment of breast cancer, issued global warnings to healthcare professionals about the potential for letrozole to cause embryo and fetus toxicity in premenopausal women, and that the drug should only be used for its primary indication—as breast cancer therapy for post- menopausal women.
That warning was probably premature as this particular study had several methodological problems. The main criticism was that the controls were normal deliveries, which are known to have a lower risk of malformations than babies born to women needing assistance to ovulate. The study group had women that were older (35.2 y vs. 30.5 y in the control group). Moreover, cardiac and possibly skeletal abnormalities are likely to be diagnosed before birth, and the mothers transferred to a tertiary care hospital for delivery. Therefore, it is possible that such abnormalities were underrepresented in the control cohort. In addition, only 110 women treated with letrozole gave birth to singleton infants, and it is well known that congenital malformations are more common in twin births than in singletons.
Have Other Studies Confirmed a Letrozole – Birth Defects Connection?
No. Since that preliminary report, other studies have shown no increase in birth defects. Mitwally and co-workers in 2005 compared the outcome of pregnancies achieved after letrozole and other ovarian stimulation treatments with a control group of pregnancies spontaneously conceived without ovarian stimulation. There were 394 pregnancy cycles in 345 infertile couples (63 pregnancies with 2.5 mg of letrozole alone or with gonadotrophins, 70 pregnancies with 5.0 mg of letrozole, 113 pregnancies with clomiphene alone or with gonadotrophins, 110 pregnancies with gonadotrophins alone and 38 pregnancies achieved without ovarian stimulation). Pregnancies conceived after letrozole treatments were associated with similar miscarriage and ectopic pregnancy rates compared with all other groups.
In a large retrospective study conducted in five fertility centers in Canada (Tulandi et al., 2006), the incidence of congenital malformations among children of mothers who conceived with CC (n = 397) or with letrozole (n = 514) treatment for infertility was assessed. Overall, congenital malformations and chromosomal abnormalities were found in 14 of 514 newborns in the letrozole group (2.4%) and in 19 of 397 newborns in the CC group (4.8%). The major malformation rate in the letrozole group was 1.2% (6/514) and in the CC group was 3.0% (12/397). In addition, the rate of all congenital cardiac anomalies was significantly higher in the CC group (1.8%) compared with the letrozole group (0.2%) (P = 0.02).
On the basis of these data, the concern that letrozole use for ovulation induction could be teratogenic is unfounded.
At InVia Fertility Specialists, we usually use clomiphene citrate for ovulation induction. In patients who do not respond to clomiphene citrate, we may try adding dexamethasone to induce ovulation. Another option would be to switch to Letrozole. This would also be considered in patients that develop a thin lining on clomiphene citrate. We use letrozole in IVF cycles only for patients with estrogen dependent cancers (to avoid high estrogen levels).
Dr. Karande is Board Certified in the specialty of Obstetrics and Gynecology as well as the subspecialty of Reproductive Endocrinology and Infertility. He is a Fellow of the American College of Obstetricians and Gynecologists and Member of the American Society for Reproductive Medicine.