Antineoplastic
PREGNANCY RECOMMENDATION: Contraindicated
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
No published reports describing the use of letrozole in human pregnancy have been located.
The animal data suggest risk. However, several reports and reviews have described the use of letrozole for ovulation stimulation, an off-label indication. In a 2005 letter from Novartis to healthcare professionals, the manufacturer warned that the drug should not be used for pregnancy induction because it was teratogenic (Novartis issues breast cancer drug warning. December 1, 2005). Novartis was aware of 13 women exposed to the drug during pregnancy resulting in two spontaneous abortions and two infants with birth defects (no additional details are available). Because the drug inhibits estrogen synthesis in all tissues, it is contraindicated during pregnancy.
FETAL RISK SUMMARY
Letrozole is an aromatase inhibitor indicated for postmenopausal women as (a) adjuvant treatment with hormone receptor positive breast cancer; (b) extended adjuvant treatment of early breast cancer in those who have received prior standard adjuvant tamoxifen therapy; and (c) first- and second-line treatment of those with hormone receptor positive or unknown advanced breast cancer. It also has been used off-label to induced ovulation in infertile women. Letrozole inhibits the aromatase enzyme, resulting in a reduction of estrogen synthesis in all tissues. It is metabolized to inactive metabolites, weakly bound to plasma proteins, and the terminal elimination half-life is about 2 days (1).
Reproduction studies have been conducted in rats and rabbits. In rats, doses during organogenesis that were ≥0.01 times the daily maximum recommended human dose based on BSA (MRHD) caused increased resorptions and 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. Doses that were 0.1 times MRHD caused fetal domed head and cervical/centrum vertebral fusion. In rabbits, doses that were 0.0001–0.00001 times the MRHD caused embryo–fetal toxicity and anomalies that included incomplete ossification of the skull, sternebrae, and fore- and hindlegs (1).
In 2-year studies, letrozole was carcinogenic in mice and rats. The drug was not mutagenic but was a potential clastogen in an in vitro test but not in an in vivo test. In mice, rats, and dogs, letrozole caused sexual inactivity in females and atrophy of the reproductive tract in male and female animals (1).
It is not known if letrozole crosses the human placenta. The molecular weight (about 285), low plasma protein binding, and long terminal elimination half-life suggest that exposure of the embryo and/or fetus will occur.
A number of studies (2–14) and reviews (15–20) have reported the use of letrozole, alone or with gonadotropins, follicle-stimulating hormone, or metformin for ovarian stimulation. The effectiveness of letrozole for this use was comparable to other agents. No increase in the incidence of congenital malformations was observed and pregnancy outcomes were comparable or better than when clomiphene citrate was used.
BREASTFEEDING SUMMARY
No reports describing the use of letrozole during human lactation have been located. Such reports are unlikely because of its indication for breast cancer. Moreover, the molecular weight (about 285), low plasma protein binding, and long terminal elimination half-life (about 2 days) suggest that it will be excreted into breast milk. Women requiring this agent should not breastfeed.
References
1.Product information. Femara. Novartis Pharmaceuticals, 2010.
2.Mitwally MF, Biljan MM, Casper RF. Pregnancy outcome after the use of an aromatase inhibitor for ovarian stimulation. Am J Obstet Gynecol 2005;192:381–6.
3.Thatcher SS, Jackson EM. Pregnancy outcome in infertile patients with polycystic ovary syndrome who were treated with metformin. Fertil Steril 2006;85:1002–9.
4.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;85:1761–5.
5.Dickerson RD, Pinto AB, Putman JM, Lee-Messinger JR. Use of letrozole in polycystic ovary syndrome patients resistant to clomiphene (abstract). Obstet Gynecol 2006;107(Suppl);41S.
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8.Hashim HA, Shokeir T, Badawy A. Letrozole versus combined metformin and clomiphene citrate for ovulation induction in clomiphene-resistant women with polycystic ovary syndrome: a randomized controlled trial. Fertil Steril 2010;94:1405–9.
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10.Badawy A, Elnashar A, Totongy M. Clomiphene citrate or aromatase inhibitors combined with gonadotropins for superovulation in women undergoing intrauterine inseminations: a prospective randomised trial. J Obstet Gynaecol 2010;30:617–21.
11.Zeinalzadeh M, Basirat Z, Esmailpour M. Efficacy of letrozole in ovulation induction compared to that of clomiphene citrate in patients with polycystic ovarian syndrome. J Reprod Med 2010;55:36–40.
12.Akar ME, Johnston-MacAnanny EB, Carrillo AJ, Miller J, Yalcinkaya TM. The pregnancy outcome of retrieved excess eggs collected during selective follicular reduction from patients with three or more preovulatory follicles undergoing controlled ovarian stimulation and IUI. Hum Reprod 2010;25:2931.
13.Wagman I, Levin I, Kapustiansky R, Shrim A, Amit A, Almog B, Azem F. Clomiphene citrate vs. letrozole for cryopreserved-thawed embryo transfer; a randomized, controlled trial. J Reprod Med 2010;55:134–8.
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16.Elizur SE, Tulandi T. Drugs in infertility and fetal safety. Fertil Steril 2008;89:1595–602.
17.Gill SK, Moretti M, Koren G. Is the use of letrozole to induce ovulation teratogenic? Can Fam Physician 2008;54:353–4.
18.Eckmann KR, Kockler DR. Aromatase inhibitors for ovulation and pregnancy in polycystic ovary syndrome. Ann Pharmacother 2009;43:1338–46.
19.Polyzos NP, Tzioras S, Badawy AM, Valachis A, Dritsas C, Mauri D. Aromatase inhibitors for female infertility: a systematic review of the literature. Reprod Biomed Online 2009;19:456–71.
20.Pritts EA. Letrozole for ovulation induction and controlled ovarian hyperstimulation. Curr Opin Obstet Gynecol 2010;22:289–94.