Insights: Letrozole and Early Miscarriage Management

Written by Kenya Lyons, MD

The administration of mifepristone followed by misoprostol is a highly effective regimen for the management of first-trimester miscarriage and medication abortion.1 However, even prior to the onset of legal challenges to mifepristone, including FDA v. Alliance for Hippocratic Medicine, the search for alternative therapies existed. This has been driven by barriers to mifepristone use, including expense, lack of availability in certain countries, and the current FDA Risk Evaluation and Mitigation Strategy (REMS) requirements for prescribers in the United States.2-3

Letrozole, an oral aromatase inhibitor used in ovulation induction and breast cancer treatment, has been explored as one possible alternative to mifepristone. Letrozole’s mechanism of action lies in its inhibition of aromatase, suppression of estrogen levels, and modification of progesterone receptor concentration.4 It is less costly than mifepristone and is available in more than 100 countries.5 Common side effects of the medication include nausea, vomiting, diarrhea, and chills; patients administered letrozole experience significantly more nausea and vomiting than those given mifepristone.2

A 2023 randomized controlled trial by Du compared the outcomes of patients with missed miscarriage pre-treated with 10 mg of oral letrozole once daily for three days to those provided with mifepristone 200 mg once. Following pre-treatment, both groups received 800 mcg misoprostol vaginally, either 24-48 hours after mifepristone, or on the last day of letrozole. Complete expulsion not requiring surgical intervention was comparable between the groups (p ≤ 0.001 for non-inferiority), though the mean time to expulsion was longer in the letrozole group (15.4 vs. 9.0 hours). Adverse events, pain scores, duration of vaginal bleeding, and the number of doses of misoprostol required did not significantly differ between the groups.5 However, a 2023 study by Shochet found that a single dose of letrozole 30 mg followed two days later by misoprostol 800 mcg buccally only resulted in complete abortion without further intervention 74% of the time.6 This regimen was found to be inferior to both misoprostol-only and mifepristone-misoprostol regimens.

The World Health Organization recommends for individuals less than 12 weeks, a letrozole-misoprostol protocol should combine 10mg of oral letrozole daily for 3 days, with 800μg of misoprostol administered sublingually on the fourth day.7 Further evidence is needed to determine the safety and effectiveness of the letrozole-misoprostol combined regimen at gestational ages past 12 weeks.7 As mentioned above, it is important to recognize that this regimen was overall found to have a longer time to expulsion with more nausea and vomiting than the misoprostol-only regimen and the combined mifepristone-misoprostol regimen, providers may want to consider its use in the setting of lack of access to mifepristone, and not where mifepristone is accessible and feasible. Although, if mifepristone is inaccessible the misoprostol-only regimen is still considered to be the more effective alternative over the letrozole-misoprostol regimen.

RHAP Resources:

Protocol for Medication Management of Early Pregnancy Loss: Mifepristone and Misoprostol

Early Pregnancy Loss (Miscarriage) Treatment: Medication Management with Mifepristone and Misoprostol


1. Macnaughton H, Nothnagle M, Early J. Mifepristone and Misoprostol for Early Pregnancy Loss and Medication Abortion. Am Fam Physician. 2021 Apr 15;103(8):473-480. PMID: 33856168.

2. Torky HA, Marie H, ElDesouky E, Gebreel S, Raslan O, Moussa AA, Ahmad AM, Zain E, Mohsen MN. Letrozole vs. Placebo Pretreatment in the Medical Management of First Trimester Missed Miscarriage: a Randomized Controlled Trial. Geburtshilfe Frauenheilkd. 2018 Jan;78(1):63-69. doi: 10.1055/s-0043-122499. Epub 2018 Jan 22. Erratum in: Geburtshilfe Frauenheilkd. 2018 Jan;78(1):e2-e3. PMID: 29375147; PMCID: PMC5778197.

3. “Understanding the Practical Implications of the FDA’s December 2021 and January 2023 Mifepristone REMS Decisions.” ACOG. 2023 Dec 4.

4. World Heath Organization. Medical management of induced abortion: recommendations 27-30 (3.4.2) – Abortion care guideline [Internet]. 2021 [accessed June 14th, 2022]. Available from:

5. Du L, Li HWR, Gemzell-Danielsson K, Zhang Z, Du Y, Zhang W, Xu B, Wang X, Wang Y, Wan W, Chang Y, Diao W, Wang Y, Zhang L, Ho PC. Comparing letrozole and mifepristone pre-treatment in medical management of first trimester missed miscarriage: a prospective open-label non-inferiority randomised controlled trial. BJOG. 2024 Feb;131(3):319-326. doi: 10.1111/1471-0528.17646. Epub 2023 Sep 5. PMID: 37667661.

6. Shochet T, Turok D, Frye LJ, Sexsmith CD, Gawron LM, Kaiser JE, Winikoff B. Single dose letrozole and misoprostol for termination of pregnancy through 63 days’ gestation: A pilot study. Contraception. 2023 Apr;120:109924. doi: 10.1016/j.contraception.2022.109924. Epub 2022 Dec 15. PMID: 36529240.

7. Recommendations Combination Regimen a Misoprostol-Only. World Health Organization; 2022.

Pharma-free: The Reproductive Health Access Project does not accept funding from pharmaceutical companies. We do not promote specific brands of medication or products. The information in the Insights is unbiased, based on science alone.

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