Letrozole versus clomiphene for ovulation induction

Tulandi and colleagues reported on 911 newborns conceived following ovulation induction with clomiphene or letrozole.⁸ Overall, the congenital malformation plus chromosomal abnormality rates associated with letrozole and clomiphene ovulation induction were 2.4% and 4.8%, respectively. The major congenital malformation rate for letrozole was 1.2%, and 3.0% for clomiphene.

Many women with anovulatory infertility and PCOS have a BMI of 30 kg/m² or greater, and some are of advanced maternal age. It is known that women with such a BMI level have an increased risk of congenital malformations, including neural tube defects, spina bifida, septal anomalies, cleft palate, cleft lip, anorectal atresia, hydrocephaly, and limb reduction anomalies.⁹ The risk of gastroschisis is significantly reduced among obese pregnant women.⁹ Women aged 40 or older have an increased risk of having a fetus with cardiac defects, esophageal atresia, hypospadias, and craniosynostosis.¹⁰

Caution women of advanced maternal age with PCOS and a BMI of 30 kg/m² or greater about the increased rate of congenital malformations associated with their age and elevated BMI.

Prioritize letrozole when BMI ≥30 kg/m²
I recommend that clomiphene should remain the first-line ovulation induction agent for women with PCOS and a BMI less than 30 kg/m². This is because, among women with such a BMI level, both clomiphene and letrozole have similar efficacy, and clomiphene is approved by the US Food and Drug Administration for ovulation induction while letrozole is not.

However, for women with PCOS and a BMI of 30 kg/m² or greater—a clinical situation where letrozole is about twice as effective as clomiphene—letrozole may be the preferred agent.

When prescribing letrozole, start with a dose of 2.5 mg daily for cycle days 3 to 7, following a spontaneous menses or progestin-induced bleed. If ovulation occurs, continue with the dose. If ovulation does not occur, increase the dose to 5 mg ­daily for cycle days 3 to 7. The maximal dose is 7.5 mg daily for cycle days 3 to 7. When prescribing letrozole, counsel your patient about the increased rate of congenital anomalies among women with an elevated BMI and the possible teratogenic effects of fertility medications.

The aromatase inhibitor letrozole is an important addition to our options for ovulation induction in women with PCOS. Will you start using letrozole for ovulation induction in your practice?

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