Comparing endometrial preparation protocols and clinical outcomes: lessons learned from 3507 vitrified-warmed euploid transfers

Purpose: To evaluate whether artificial endometrial preparation using hormone replacement therapy (HRT) influences clinical and neonatal outcomes compared with modified natural cycles (mNC) in single euploid vitrified-warmed blastocyst transfers. Methods: This retrospective cohort study analyzed single euploid vitrified-warmed blastocyst transfers performed at a single IVF center over an 11-year period. Endometrial preparation was conducted either through HRT or mNC. Clinical and neonatal outcomes were compared between groups. Statistical analyses included multivariable logistic regression models, adjusted for relevant confounders, with generalized estimating equations to account for repeated embryo transfers (ETs) within patients. Results: A total of 3507 ETs were conducted in 2257 patients. Mean age was 37.5 ± 3.2 years at oocyte pick-up and 37.8 ± 3.3 years at ET. HRT was associated with a higher miscarriage rate (N = 167/1034, 16.2% vs N = 70/700, 10%; OR 1.72, 95% CI 1.27-2.33) and a lower live birth rate (N = 867/2129, 40.7% vs N = 630/1378, 45.7%; OR 0.83, 95% CI 0.72-0.96) than mNC. Additionally, HRT was associated with a higher prevalence of large for gestational age newborns. Conclusions: mNC endometrial preparation may show some clinical benefit compared to HRT. The latter remains necessary in specific cases, such as hypothalamic amenorrhea (excluded in this study), but mNC protocols should be preferred whenever possible. Randomized controlled trials in Preimplantation Genetic Testing for Aneuploidy (PGT-A) cycles are essential to confirm these findings.