Pregnancy Outcomes Following Letrozole Use in Frozen-thawed Embryo Transfer Cycles: A Systematic Review and Meta-analysis

Abstract

While widely used for ovulation induction in assisted reproductive technology, the clinical efficacy of letrozole for endometrial preparation prior to frozen-thawed embryo transfer (FET) cycles remains yet to be elucidated. We performed a meta-analysis to compare pregnancy outcomes after letrozole use with those of other endometrial preparation protocols in patients undergoing FET. PubMed, Scopus, Embase and the Cochrane Library were searched for eligible studies. Clinical pregnancy rate (CPR), live birth rate (LBR) and birth defect rate (BDR) were analysed using odds ratio (OR) and 95% confidence interval (CI). A total of 10 studies representing 75 968 FET cycles were included. Comparable CPR and LBR were observed when comparing letrozole administration with natural cycle (OR 1.24, 95% CI: 0.69 – 2.24; OR 1.18, 95% CI: 0.60 – 2.32), artificial cycle (OR 1.46, 95% CI: 0.87 – 2.44; OR 1.39, 95% CI: 0.77 – 2.52), and artificial cycle with gonadotropin-releasing hormone agonist suppression (OR 1.11, 95% CI: 0.78 – 1.59; OR 1.18, 95% CI: 0.82 – 1.68). Pooled results of the limited studies comparing letrozole with human menopausal gonadotropin demonstrated a similar CPR between groups (OR 1.46, 95% CI: 0.29 – 7.21, two studies), but the letrozole group had a statistically lower LBR (OR 0.67, 95% CI: 0.52 – 0.86, one study). No increased BDR was observed in the letrozole group compared to natural cycles or artificial cycles (OR 0.98, 95% CI: 0.60 – 1.61; OR 1.39, 95% CI; 0.84 – 2.28). This pooled analysis supports the use of letrozole as an efficacious and safe alternative to mainstream regimens for endometrial preparation in FET cycles.

Letrozole for Female Infertility

“…Letrozole is also used for fertility preservation in women with estrogen-sensitive cancers. Also, studies showed the effectiveness of letrozole in endometrium preparation for frozen-thawed embryo transfer (FET) ( 9 , 10 ). In this mini review, we summarize the mechanism basis and clinical effects of letrozole for female infertility and we aim to provide evidence for the application of letrozole for different settings of infertility treatment.…”

Comparison of Stimulated Cycles with Low Dose r-FSH versus Hormone Replacement Cycles for Endometrial Preparation Prior to Frozen-Thawed Embryo Transfer in Young Women with Polycystic Ovarian Syndrome: A Single-Center Retrospective Cohort Study from China

“… 19 A systematic review and meta-analysis including pooled results of only two studies of PCOS patients found letrozole produces similar CPR, LBR, and birth defect rates as NC and HRC; there were similar CPR and lower LBR in letrozole-stimulated cycle compared to HMG stimulation. 32 Added to Chen et al conclusions, a recent meta-analysis comparing OS using letrozole or HMG with HRT for FET in patients with PCOS found no difference between mild OS cycles and HRT groups for OPR and embryo implantation rate (IR); the letrozole-stimulated cycle may lower the miscarriage rate more than the HRT cycle. 17 , 32 Multiple retrospective cohort studies pointed out a different view, letrozole-stimulated cycle had significantly higher LBR and lower PLR compared with HRT after adjusting for possible confounding factors.…”

“… 32 Added to Chen et al conclusions, a recent meta-analysis comparing OS using letrozole or HMG with HRT for FET in patients with PCOS found no difference between mild OS cycles and HRT groups for OPR and embryo implantation rate (IR); the letrozole-stimulated cycle may lower the miscarriage rate more than the HRT cycle. 17 , 32 Multiple retrospective cohort studies pointed out a different view, letrozole-stimulated cycle had significantly higher LBR and lower PLR compared with HRT after adjusting for possible confounding factors. 33–35 Therefore, whether letrozole has an advantage in preparing FET requires more high-quality researches for confirmation.…”

The impact of estradiol on pregnancy outcomes in letrozole-stimulated frozen embryo transfer cycles

“…There are only a few studies that have investigated the use of LTZ for endometrial preparation before FET, and none have examined the effect of E2 suppression during such preparation. Furthermore, a recent 2020 meta-analysis by Chen et al (47) demonstrated that all LTZ-FET studies were conducted outside the United States, which arguably limits the applicability of such data to patients seeking treatment within the United States. In the largest LTZ-FET study, Tatsumi et al (32) in 2017 compared letrozole with natural and hormone replacement treatment FET cycles; they found that letrozole use improved the clinical pregnancy and live birth rates as well as reduced the miscarriage rates compared with the natural and hormone replacement treatment groups.…”