P-689 Reproductive outcomes in letrozole-stimulated vs artificial frozen-thawed embryo transfer cycles in women with PCOS and/or oligo-anovulation: a systematic review and meta-analysis.
Authors: Søderhamn Bülow N , Wissing M L , Pinborg A , Løssl K 
Published: June 2023

Abstract

Study question
Does stimulation with letrozole improve reproductive outcomes compared to artificial endometrial preparation before frozen-thawed embryo transfer (FET) in women with PCOS and/or oligo-anovulation?

Summary answer
Live birth rate (LBR) was significantly improved with letrozole stimulation compared to artificial endometrial preparation before FET in PCOS and oligo-anovulatory women.

What is known already
Letrozole, an aromatase inhibitor reducing oestradiol levels, has been shown to increase live LBR compared to clomiphene citrate in PCOS/anovulatory women before intrauterine insemination. There is now growing interest in its potential value in improving LBR in FET cycles as well. Furthermore, recent studies indicate an increased risk of hypertensive disorders in pregnancies that have arisen following FET cycles in the absence of a corpus luteum. Letrozole stimulation offers an alternative approach compared to artificial cycle FET with oestradiol and progesterone in women with oligo-anovulation and preserved ovarian reserve, ensuring a corpus luteum, which may improve reproductive outcomes.

Study design, size, duration
A systematic review of studies published in PubMed or the Cochrane library up until the 14th of October 2022. Randomised controlled trials and cohort studies comparing letrozole-stimulated FET and artificial cycle FET were included. Screening, data extraction, and quality assessment was done independently by two reviewers using the Robins-I tool and Cochrane Handbook. The study is registered in PROSPERO, and data collection and reporting followed the PRISMA guidelines.

Participants/materials, setting, methods
Women with PCOS according to the Rotterdam Criteria and/or oligo-anovulation disorders and FET cycles were included. Letrozole-stimulated FET cycles with or without adjuvant gonadotrophins and/or luteal phase support were included in comparison to artificial endometrial preparation for FET. Random-effect meta-analyses were conducted with Review Manager. Dichotomous variables were summarised using the Mantel-Haenszel risk ratio, and heterogeneity was evaluated with Forest plots and I2-statistic. Funnel plots were used to assess publication bias for all outcomes.

Main results and the role of chance
The systematic search identified 62 studies, 23 relevant full-text studies were scrutinized, and a total of 10 studies fulfilled inclusion criteria with an appropriate control group. Five observational studies of women with oligo/anovulation, and one randomised controlled trial and four observational studies of women with PCOS according to the Rotterdam criteria, but no further information on ovulation pattern. Except three studies, adjuvant gonadotrophins were used as a standard or if the follicular response to letrozole was poor. In all the studies letrozole-stimulated women received luteal phase support. The live birth rate (LBR) was 7% higher in the letrozole vs artificial FET cycle groups (95% CI: (3%;10%), I2= 56%, P=0.0001) with similar effects in the subgroup analysis (7 studies, n = 3931 letrozole-treated women). Furthermore, the ongoing pregnancy rate increased by 10% (95% CI: (4%;16%), I2= 1%, P=0.001) in women with PCOS and/or oligo-anovulation (4 studies, n = 297 letrozole-treated women). Definition criteria of miscarriage and biochemical pregnancy loss varied to an extent where a meta-analysis could not be performed. Nevertheless, seven studies reported on miscarriage rate, six showed similar rates and one significantly lower miscarriage rate with letrozole. No outcomes raised concerns of publication bias in the funnel plots.

Limitations, reasons for caution
Most included studies were observational studies with a high risk of bias, and substantial heterogeneity was observed amongst the studies, which could dilute the evidence. Some studies included women with PCOS without clarifying if ovulatory or anovulatory. The funnel plot of each outcome raised no suspicion of publication bias.

Wider implications of the findings
Letrozole stimulation FET in PCOS and/or oligo-anovulatory women significantly improves LBR and ongoing-pregnancy-rate compared to artificial endometrial preparation. However, robust evidence is lacking and RCTs restricted to women with oligo-anovulatory women are urgently needed. The evidence is insufficient to conclude whether luteal phase support is required after letrozole stimulation

Trial registration number
Not applicable