High serum estradiol levels on the day of frozen blastocyst transfer are associated with increased early miscarriage rates in artificial cycles using transdermal estrogens

Do serum estradiol (E2) levels on the day of frozen blastocyst transfer (FBT) affect pregnancy outcomes in hormonal replacement therapy (HRT) cycles using transdermal estrogens? E2 levels ≥313 pg/ml on the day of FBT are associated with increased early miscarriage rates (EMRs), but do not significantly impact the live birth rate (LBR). E2 plays a crucial role in endometrial receptivity and placentation. The effect of serum E2 levels measured around the time of FBT in HRT cycles remains debated, with some studies indicating a negative impact of high E2 levels and others finding no significant difference. Currently, no studies focus exclusively on HRT cycles using transdermal estrogens, which are considered safer regarding thromboembolic complications. This retrospective cohort study analyzed 2364 patients undergoing HRT-FBT cycles at a university hospital between January 2019 and December 2022. Each patient was included only once during the study period. The study involved patients undergoing single autologous FBT under HRT with transdermal estrogens and vaginal micronized progesterone. Serum E2 levels were measured in the morning of the FBT at a single laboratory. Primary outcomes included the LBR, with secondary outcomes encompassing clinical pregnancy rates, EMRs, and neonatal outcomes (birth weight and term of delivery). Patients were categorized into three groups based on E2 levels: <25th centile (<122 pg/ml), between 25th and 75th centile (122-312 pg/ml), and >75th centile (≥313 pg/ml), and analyzed using univariate and multivariate logistic regression models. Of the 2364 patients, 590 were in the '<122 pg/ml' group, 1184 in the '122-312 pg/ml' group, and 590 in the '≥313 pg/ml' group. The median (interquartile range) E2 level in the entire study population was 195.3 pg/ml (122.1-312.8). The LBRs across the E2 level groups were 33.7%, 31.6%, and 31.0%. Crude and adjusted odds ratios (ORs) showed no significant differences in LBR between the '<122 pg/ml' and '≥313 pg/ml' groups compared to the '122-312 pg/ml' reference group (adjusted OR 0.9, 95% CI 0.72-1.14 and 0.9, 95% CI 0.69-1.09, respectively). The EMRs for the groups were 25.5%, 24.6%, and 30.3%, respectively. While crude analysis showed no differences between the groups, the multivariable analysis indicated that the '≥313 pg/ml' group had a significantly higher risk of early miscarriage compared to the reference group (adjusted OR 1.5, 95% CI 1.06-2.18). No significant differences were observed in clinical pregnancy rates or neonatal outcomes. The primary limitation is the study's retrospective design, which introduces risks of selection and confusion bias, although multivariable analysis was employed to mitigate these issues. Managing high serum E2 levels on the day of the FBT may enhance ART outcomes. Future research should aim to define optimal E2 thresholds for HRT-FBT cycles and develop personalized treatment protocols that account for individual patient variability. No funding was received. The authors have no conflicts of interest. N/A.