Reassurance of safety of letrozole and suggested approaches in controlled ovarian hyperstimulation

30 03 2009

To the Editor:

We read the article by Dr. Dickey with interest (1). Although it covers many aspects of ovulation induction and related multiple pregnancies, we believe some points require further comment.

First, referring to a guideline and a review article published over a decade ago, it is stated that clomiphene alone or with intrauterine insemination is the first line treatment for unexplained infertility (2, 3). However, a large randomized controlled trial in couples with unexplained infertility revealed that clomiphene or intrauterine insemination alone does not provide higher cumulative live birth rates as compared to expectant management (4). Based on this study, clomiphene or intrauterine insemination alone is not the first line treatment for these couples.

Second, regarding the safety of letrozole, Dr. Dickey only refers to an abstract presentation that contained many flaws (5). In retrospective analysis of data from five centers in Canada, we have demonstrated that the overall incidence of the congenital malformations and chromosomal abnormalities was similar among children born to women treated with clomiphene  (4.8%) or letrozole (2.4%). Further, the incidence of major malformations was significantly higher after fertility treatment with clomiphene (3% vs. 1.2% in the letrozole group) (6). In another study, Forman et al. compared 112 newborns following letrozole treatment to 271 newborns following clomiphene treatment and 94 newborns following spontaneous pregnancy. The rate of malformations was 0%, 2.6% and 3.2% respectively (7).

Finally, when switching to in vitro fertilization (IVF) is considered as an option for over-stimulated women, concerns should not be limited to additional costs and requirement for an IVF treatment only, but also to the risks of ovarian hyperstimulation syndrome (OHSS). In some women, cancelling the cycle may be preferred over proceeding to IVF with a serious risk of OHSS.

Baris Ata, M.D.
Togas Tulandi, M.D., M.H.C.M.
Department of Obstetrics and Gynecology
McGill University
Montreal, Quebec, Canada

References
1. Dickey RP. Strategies to reduce multiple pregnancies due to ovulation stimulation. Fertil Steril 2009;91:1-17.

2. Royal College of Obstetricians and Gynaecologists. Evidence-based clinical guidelines. The management of infertility in secondary care,. London: RCOG Press, 1998.

3. Guzick DS, Sullivan MW, Adamson GD, Cedars MI, Falk RJ, Peterson EP et al. Efficacy of treatment for unexplained infertility. Fertil Steril 1998;70:207-13.

4. Bhattacharya S, Harrild K, Mollison J, Wordsworth S, Tay C, Harrold A et al. Clomifene citrate or unstimulated intrauterine insemination compared with expectant management for unexplained infertility: pragmatic randomised controlled trial. BMJ 2008;337:a716.

5. Biljan M, Hemmings R, Brassard N. The outcome of 150 babies following the treatment with letrozole or letrozole and gonadotropins. Fertil Steril 2005;84:84 O-231.

6. Tulandi T, Martin J, Al-Fadhli R, Kabli N, Forman R, Hitkari J et al. Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate. Fertil Steril 2006;85:1761-5.

7. Forman R, Gill S, Moretti M, Tulandi T, Koren G, Casper R. Fetal safety of letrozole and clomiphene citrate for ovulation induction. J Obstet Gynaecol Can 2007;29:668-71.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2009.03.103

The author declined to reply.

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