In 2005, research published at the annual American Society of Reproductive Medicine conference sparked controversy.  This research, published by Marinko Biljan M.D., found that the use of Femara (letrozole) during pregnancy was associated with an increased risk for birth defects.  Biljan found that among 150 pregnancies in women who used Femara, 4.7% of children were born with a congenital malformation, compared to 1.8% in 36,050 control subjects from the general population.  Femara  is a drug used to treat breast cancer, intended for women who have already gone through menopause, and is Pregnancy Category X – unsafe for a developing fetus.  Some women used Femara before menopause and became pregnant, and Biljan aimed to determine the frequency of birth defects after in utero letrozole exposure.

The Biljan (2005) team, however, made a considerable mistake and therefore their research must be thrown out, considered utterly meaningless.  Biljan compared the frequency of birth defects among women who used Femara during pregnancy to women who did not use Femara, and though this may sound like a fruitful comparison, it is absolutely not.  Women who need to use drugs like Femara are more likely to have offspring with a congenital malformation than women in the general population, whether they end up using the drug or not.  Therefore, Biljan should have compared the rate of birth defects among Femara users to similar women who did not use the drug to determine the increased risk for birth defects associated with Femara specifically.

Later, in 2006, a team of researchers led by T. Tulandi published research in Fertility and Sterility titled “Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate” that also reported an increased risk for congenital malformations among women who used Femara during pregnancy, but faced similar concerns.

Several reviews published by other prominent researchers purport the findings of these research teams are unfounded, and these reviews make good points: the Tulandi and Biljan reports are flawed, and their research does not in fact demonstrate that Femara causes birth defects.

However, it is probably only a matter of time until research is published illuminating a connection between Femara and birth defects.  As it currently stands, – a highly respected pharmaceutical information database – states that “Femara may cause fetal harm”, and that “Femara caused adverse pregnancy outcomes, including congenital malformations, in rats and rabbits at doses much smaller than the daily maximum recommended human dose”, and that adverse pregnancy outcomes observed in animals “included increased post-implantation pregnancy loss and resorptions, fewer live fetuses, and fetal malformations affecting the renal and skeletal systems. Animal data and letrozole’s mechanism of action raise concerns that letrozole could be a human teratogen as well.” (Click here for the full report on Femara and pregnancy)

Further, the Femara warning guide provided by Novartis (the manufacturer of Femara) available through the United States Food and Drug Administration states clearly that Femara was associated with an increased rate of birth defects in lab animals and “may cause fetal harm.”  Below is an excerpt from that document.  For clarity, a “teratogenic” drug is a drug that has been found to cause birth defects.

“Femara® (letrozole tablets)may cause fetal harm when administered to pregnant women. Studies in rats at doses equal to or greater than 0.003 mg/kg (about 1/100 the daily maximum recommended human dose on a mg/m2 basis) administered during the period of organogenesis, have shown that letrozole is embryotoxic and fetotoxic, as indicated by intrauterine mortality, increased resorption, increased postimplantation loss, decreased numbers of live fetuses and fetal anomalies including absence and shortening of renal papilla, dilation of ureter, edema and incomplete ossification of frontal skull and metatarsals. Letrozole was teratogenic in rats. A 0.03 mg/kg dose (about 1/10 the daily maximum recommended human dose on a mg/m2 basis) caused fetal domed head and cervical/centrum vertebral fusion.  Letrozole is embryotoxic at doses equal to or greater than 0.002 mg/kg and fetotoxic when administered to rabbits at 0.02 mg/kg (about 1/100,000 and 1/10,000 the daily maximum recommended human dose on a mg/m2 basis, respectively). Fetal anomalies included incomplete ossification of the skull, sternebrae, and fore- and hindlegs.” (emphasis added)

So, while studies with human subjects demonstrating the teratogenicity of Femara have been lacking in the past, it is well known that Femara is dangerous for a fetus and that Femara causes birth defects in lab animals.  Even the manufacturer of Femara admits that.

If you or a loved one uses Femara, it is important to understand that the safety of this drug for a developing fetus is at the very least, questionable.  Another important thing to consider is that reviews purporting that the findings of other researchers are unfounded do not necessarily prove that a drug is safe, rather only demonstrate that a drug was not sufficiently demonstrated to be dangerous.  Absence of evidence of risk is not evidence of absence of risk.