O-126 Impact of letrozole cO-treatment during ovarian stimulation on the oocyte yield, embryo development, and live birth rate – a randomised controlled trial (RIOT)
Authors: Søderhamn Bülow N , Warzecha A.K , Villads Nielsen M , Yding Andersen C , Dreyer Holt M , Rønn Petersen M , Sopa N , Zedeler A , Englund A.L , Pinborg A , Macklon N.S , Grøndahl M.L , Skouby S.O 
Published: June 2022

Abstract

Study question
Does letrozole co-treatment during ovarian stimulation for in vitro fertilization (IVF) impact oocyte yield, embryo development, and live birth rate (LBR) in expected normal responders?

Summary answer
Letrozole co-treatment leads to similar oocyte yield, embryo- development and utilisation rate, and live birth rate after transfer in the fresh cycle.

What is known already
Letrozole reduces oestradiol levels by inhibiting the aromatization of androgens, this diminishes pituitary suppression and increases endogenous gonadotrophin release. These effects are utilized in ovulation induction in PCOS patients and may benefit certain patients during IVF treatment. In addition, we have recently reported in an RCT that co-treatment with letrozole increases luteal phase progesterone levels and, consistent with previous studies, no significant effect on pregnancy rates was observed. However, the impact of the changes in the endocrine milieu caused by letrozole co-treatment on the developing oocytes and embryos remains unclear as most published studies are retrospective and lack appropriate control-groups.

Study design, size, duration
A multicentre double-blinded randomised placebo-controlled trial was conducted in four fertility clinics at University Hospitals in Denmark from August 2016 to November 2018. 159 women were randomised, 129 women received single embryo (cleavage stage or blastocyst) transfer in the fresh cycle, and the surplus 257 embryos were vitrified. The study was conducted following the Helsinki Declaration and the ICH-Good-Clinical-Practice. Data collection and reporting followed the guidelines of CONSORT to achieve transparent reporting of trials.

Participants/materials, setting, methods
Women with expected normal ovarian response received an antagonist protocol with fixed-dose FSH. Co-treatment consisted of 5mg letrozole or placebo from the start of stimulation until the day of triggering final oocyte maturation with hCG. Standardized morphological evaluation was performed at all centres (applying the Istanbul consensus and Gardner-score). A sub-cohort of the embryos were cultured in an EmbryoScope incubator and further assessed by morphokinetic annotation and reported with.KIDScoreD3. Ongoing pregnancies were followed until birth.

Main results and the role of chance
A total of 1268 oocytes were retrieved from 154 women, leading to development of 386 usable embryos that were either transferred or vitrified. Utilisation rate (the proportion of usable embryos to oocytes) was similar in the letrozole group and placebo group with 0.31 vs. 0.36 (mean difference (MD): -0.05, 95% CI[-0.03;0.12], P = 0.25). Morphologically grading the embryos as “good”, “fair”, and “poor” quality showed similar results, the odds of having a higher quality were 0.78 times higher in the letrozole- vs. placebo group (CI[0.5;1.1], P = 0.2). Morphokinetic annotations (n = 302 embryos) showed similar results with the odds of having a high KIDScore3 1.3 times higher in the letrozole – vs. placebo group (CI[0.9;2.1], P = 0.2). The endometrial thickness at transfer was thinner in the letrozole compared to the placebo group with 8.5 vs. 9.5 mm (MD 1.0, 95% CI[0.4;1.6], P = 0.001) but with the same ultrasonic echogenicity and a preovulatory three-layer appearance. After embryo transfer in the fresh cycle (n = 129), no differences were seen in the pregnancy outcomes: positive serum hCG, ongoing pregnancy rate, early miscarriage rate, foetal miscarriage rate, or LBR. LBR per initiated cycle were similar as well (n = 159): 23.8% vs. 29.1% (MD of -5,3%, CI[-20.3%;9.6%], P = 0.48) in letrozole vs. placebo group, respectively.

Limitations, reasons for caution
Four clinics participating could lead to interobserver variability. However, bias was reduced by block-randomised design. All data are derived from an RCT, the primary endpoint of which, preovulatory progesterone, was the basis of the sample size calculation. The study may have been underpowered to show a significant impact on LBR.

Wider implications of the findings
Letrozole co-treatment during ovarian stimulation with gonadotrophins did not have an impact on the oocyte yield and embryo development. These data suggest that letrozole co-treatment is unlikely to compromise outcomes in its growing indications: ovulation induction, IVF in poor responders, and fertility preservation in breast cancer patients.

Trial registration number
NCT02946684