Clomid vs Letrozole: The Last Words

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Hello Everyone!

Today I will conclude the entries on Letrazol and Clomid, emphasizing the warnings related to letrazole.

“Femara* (the trade name for letrozole) is contraindicated and should not be used in women who may become pregnant, during pregnancy and/or while breastfeeding, because there is a potential risk of harm to the mother and the fetus, including risk of fetal malformations.”

Who says so? Novartis, the company that makes the drug, put out this warning.

There are 2 elements to this statement. First and accurately, the drug has been shown to cause malformations in mice and rats when given in low doses during pregnancy. If is for this reason that we all believe that giving it to pregnant women is not indicated. Clomid also carries a warning that it is not to be used in pregnancy for fear of birth defects, although the potential for defects seems to be lower than for Femara. Nonetheless, Clomid carries a warning.

The second element has to do with taking the drug before pregnancy, as in the case of induction of ovulation. In 2006, the company issued a statement to physicians specifically stating that Femara is not indicated for use in the induction of ovulation.

How did this second statement from Novartis come ot be? In 2005 a very short abstract was presented at a scientific meeting showing the birth defect rate was higher in 150 women who took Femara as compared to the general population. That’s 150 births, not 150 birth defects. Now, no one wants to ignore important birth defect data, however 7 birth defects in 150 women is just too small a group to rely on. Based on this one preliminary study, Novartis quickly issued the warning to physicians.

Soon after the Novartis letter, another physician, Dr Tulandi, examined pregnancy outcome of 911 babies conceived after Clomid or letrozole treatment in infertile women. Here is the data directly quoted from the writings of Dr.Tulandi. “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 of 514) and in the CC group was 3.0% (12 of 397). These differences did not reach statistical significance because of the relatively small sample size.”

Well then, it seems that clomid has a birth defect rate that is at leat equal to that of Femara, and yet Clomid is used much more and without and warnings. The point being that the early small study was not informative enough and Femara seems safe to use, at least as safe as Clomid. Now this second study was not perfect either, but it was bigger and better than the first.

These are not the only studies published on Femara. There have been dozens all showing that the drug can be very effective and none others have shown an increase in birth defects.

Why would the drug company want to sell Femara if there is controversy over its safety?

As we discussed previously, Femara is a medication that blocks estrogen production, which is very helpful for many women with breast cancer. Most women have the type of breast cancer that grows faster in the presence of estrogen. Blocking the body’s ability to produce estrogen using Femara can significantly slow the growth of the tumor. This is why the company produces the drug. Unfortunately, there is a tremendous market for such a product.

On the other hand, the fertility business is comparatively very small and it is associated with very large liability risks. Even if the data relating the drug to birth defects is poor, I can see why the company would want to protect itself from potentially crippling birth defect lawsuits.

The good news is that the drug is available and a licensed MD can prescribe any drug “off label”, as long as there is good evidence that the drug is helpful and there is no harm.

Tons of drugs are used off label. One fertility example is Lupron for endometriosis. This drug is mostly used to treat men with prostate cancer as it lowers testosterone levels which may help restrict tumor growth. Lupron is also used in women with endometriosis because it lowers estrogen levels, and endometriosis needs estrogen to grow. Many women take it and the literature is loaded with scientific articles supporting its use in medical studies. And yet, Lupron it not FDA approved for the treatment of endometriosis. (For those of you thinking ahead, yes Femara is used by some to treat endometriosis). Another example is the use of antiepileptic drugs to treat anxiety and depression. Believe me; the list goes on and on.

So where does this all take us?
1) Femara works for the induction of ovulation.
2) Femara should not be given during pregnancy.
3) Femara does not thin the lining of the uterus as may Clomid
4) Femara is relatively new and associated with more warnings.

It is the last statement that makes doctors understandably nervous about using it, especially when there is a close alternative (Clomid) that has been around since the 1960’s.

As time has gone by, I have used Femara more and more, but still use Clomid first. As more time passes and more studies are done, this may change, and it is possible that Femara may become the first line treatment over Clomid for all fertility doctors. Importantly, no one yet has proven that Femara leads to a higher pregnancy rate than Clomid.

Thanks for reading and don’t forget to read the disclaimer from 5.17.06.

Dr. Licciardi


  • Tulandi T, Martin J, Al-Fadhli R, Kabli N, Forman R, Hitkari J, Librach C, Greenblatt E, Casper RF. Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate. Fertil Steril. 2006 Jun;85(6):1761-5.
  • Fisher SA, Reid RL, Van Vugt DA, Casper RF. A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women. Fertil Steril. 2002 Aug;78(2):280-5.
  • Legro RS, Kunselman AR, Brzyski RG, Casson PR, Diamond MP, Schlaff WD, Christman GM, Coutifaris C, Taylor HS, Eisenberg E, Santoro N, Zhang H; NICHD Reproductive Medicine Network. The Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) trial: rationale and design of a double-blind randomized trial of clomiphene citrate and letrozole for the treatment of infertility in women with polycystic ovary syndrome. Contemp Clin Trials. 2012 May;33(3):470-81.

35 responses to “Clomid vs Letrozole: The Last Words”

  1. Karen says:

    It’s amazing the timing of this post. I’m currently experiencing my third miscarriage in the last year. I have a 6yr old daughter which I carried with no problems. Pregnancy 1 before her was a missed miscarriage and the three this year have all been spontaneous at 5-6wks.

    All blood work,tests, etc show me and my husband are totally fine. The Dr has suggested Letrozole and I’m concerned about using intervention considering that I have been able to get pregnant.

    Will Letrozole actually increase my odds of carrying a baby? I’m guessing it’s because we would know for sure when ovulation occurs and guarantee a long enough luteal phase but I’m not sure.
    I would love more insight on this medication.

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  5. Mel says:

    Any thoughts on Day 5 transfers of Morulas? Thats all we had… and just wondering what to expect. They were both 8 cell on day 3 and “looked good” at that point. Thanks,

  6. Anonymous says:

    One thing you don’t mention is the clearance tome of each medicine. From what my RE said letrozole clears out of the body within days, whereas clomide takes weeks. Thoughts?

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  9. Georgette says:

    How often is clomid your first-line drug for women over 35, vs. Femara?

  10. Georgette says:

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