O-024 The impact of endometrial preparation on pregnancy loss in vitrified-thawed euploid blastocyst transfer cycles: A randomized controlled trial

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Abstract Study question Does artificial cycle (AC) endometrial preparation result in increased pregnancy loss rates in patients undergoing vitrified-thawed euploid blastocyst transfer (FET)? Summary answer Artificial cycle endometrial preparation is associated with higher pregnancy loss rates compared to true natural cycle preparation (tNC-FET). What is known already The increased use of FET cycles has fueled discussion regarding the optimal endometrial preparation method. While earlier reviews found no significant differences in pregnancy outcomes between preparation strategies, recent studies suggest that artificial preparation may be associated with higher pregnancy loss rates and, more recently with hypertensive disorders of pregnancy. However, these findings were not confirmed in a recent RCT using genetically untested embryos. Since up to 70% of early pregnancy losses are attributed to genetic anomalies in the embryo, analyzing FET of euploid embryos provides a more accurate evaluation of the impact of endometrial preparation on pregnancy loss. Study design, size, duration A randomized controlled trial was conducted in a university hospital (May 2019-May 2024) investigating the impact of endometrial preparation on pregnancy loss in FET. A power calculation based on internal data determined that 261 patients per arm were needed to detect an increase in pregnancy loss from 9.9% in tNC-FET to 18.4% in AC-FET (80% power, 5% significance). Due to safety concerns regarding hypertensive disorders following AC-FET, the trial was discontinued after enrolling 354 patients. Participants/materials, setting, methods Patients under 42years with regular menstrual cycles undergoing their first FET after up to three ICSI cycles were randomized 1:1 to tNC-FET (no ovulation trigger or luteal phase support) or AC-FET (estradiol valerate and micronized vaginal progesterone without luteal phase progesterone measurement). Preimplantation genetic testing combined with aneuploidy screening was performed. The primary outcome was pregnancy loss rate before 8 weeks of gestation. Secondary outcomes included live birth rate, biochemical pregnancy rate, and obstetrical outcomes. Main results and the role of chance A total of 354 patients were randomized to tNC-FET or AC-FET. In order to account for cancellations, protocol deviations, or other reasons, both intention-to-treat (ITT) and per-protocol (PP) analyses were performed, with the latter including 328 patients. Demographic characteristics were comparable between groups, with a mean age of 32 years, BMI of 24 kg/m², and AMH levels averaging 2.5 ng/mL. Preimplantation genetic testing for monogenic disorders was the main indication for genetic testing in both groups. The primary outcome, pregnancy loss rate before 8 weeks of gestation per positive hCG, was significantly higher in AC-FET than in tNC-FET in both ITT (21.6% vs. 9.0%; p = 0.005) and PP analyses (21.6% vs. 9.0%; p = 0.006). While biochemical pregnancy rates did not differ significantly (ITT: 75.3% in tNC-FET vs. 65.9% in AC-FET; p = 0.053), live birth rates were significantly higher in tNC-FET (ITT: 66.9% vs. 47.2%; p < 0.001). Obstetrical outcomes, including birth weight (tNC-FET: 3300.2g ± 505.8g vs. AC-FET: 3364.2g ± 585.0g; p = 0.41), gestational age at birth (tNC-FET: 39.0weeks ± 1.9weeks vs. AC-FET: 38.9weeks ± 2.3weeks; p = 0.60), and rates of hypertensive disorders of pregnancy (7.6% vs. 10.8% for respectively tNC-FET and AC-FET; p = 0.43), were not significantly different between groups. Limitations, reasons for caution Although this randomized study achieved the estimated difference in the primary outcome, the premature cessation necessitates cautious interpretation. Additionally, the absence of luteal phase progesterone measurements in both groups may represent a limitation. Nevertheless, these findings offer valuable insights for counseling patients on the optimal FET preparation method. Wider implications of the findings The results of this RCT reinforce concerns regarding AC-FET cycles. In addition to previously reported higher obstetrical complications, an increased risk of pregnancy loss was associated with AC-FET cycles. This protocol should therefore preferentially be used in patients with (premature) ovarian insufficiency or those resistant to ovulation induction agents. Trial registration number Yes

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