Impact of elevated late-follicular phase serum estrogen and progesterone levels on blastocyst utilization and cumulative live birth rates in freeze-all cycles

Abstract

Study Question: Does elevated late-follicular phase estrogen and progesterone levels have an impact on blastocyst utilization and/or cumulative live birth rates in freeze-all cycles? Summary Answer: High estrogen or progesterone on the day of ovulation trigger is associated with poor blastocyst utilization but comparable cumulative live birth rates in freeze-all cycles. What is Known Already: Several studies suggest impaired clinical outcome in cycles with high estrogen (>3500 pg/ml) or progesterone (>1.5 ng/ml) levels. However, these data were derived from cycles where top-quality embryo(s) were transferred in the fresh cycle and surplus embryos were frozen. These findings might be confounded by alterations in endometrial receptivity. Freeze-all cycles might provide a better model to assess the impact of high late-follicular estrogen or progesterone levels on laboratory and clinical outcome. Study Design, Size, Duration: We performed a retrospective cohort study of all IVF cycles (n = 712) between 2016 and 2018 where the entire cohort of embryos was cryopreserved at the blastocyst stage. After excluding cases with <4 oocytes or preimplantation genetic test, the study group comprised 459 women who had 699 frozen-thawed embryo transfer cycles. Participants/Materials, Setting, Methods: Women were classified into four groups by the indication for freeze-all strategy as elevated progesterone (high P, n = 61), high estrogen (high E, n = 224), elective freezing (elective, n = 114) and tubal-endometrial pathologies (TEP, n = 60). The primary outcome was the cumulative live birth rate in subsequent thaw-transfer cycles and the secondary outcome was the blastocyst utilization rate. Groups were compared using ANOVA and Cox regression analyses to adjust for confounding variables. Main Results and the Role of Chance: The mean age of the study group was 32.8 ± 5.3 years, total number of oocytes and cryopreserved blastocysts were 15.0±7.6 and 4.2±3.0, respectively. The high-E group was younger (31.5 ± 5.2 years) and had higher peak E2 levels (4078.9 ± 588.4 pg/ml), number of oocytes (19.7 ± 7.0), cryopreserved embryos (5.3 ± 3.3) and transfer cycles (2.3 ± 1.4) than the other groups. Blastocyst utilization rate was significantly lower (40.4%) compared to elective freezing (53.6%) and TEP groups (55.7%) (both p = 0.001). The high-P group had higher peak progesterone levels (2.1 ± 0.5 ng/ml, p = 0.001), number of oocytes (14.0 ± 5.2) and frozen embryos (4.1 ± 3.5) compared to elective and TEP groups (both p = 0.04). Blastocyst utilization rate was lower (45.7%) than elective freezing and TEP groups but the difference lacked statistical significance (p = 0.33 and p = 0.21, respectively). Cumulative live birth rates were 42.6% in high-P, 59.8% in high-E, 44.7% in elective freezing and 46.7% in TEP groups. Significant predictors of cumulative live birth were female age (aHR: 0.97, 95%CI:0.95–0.99, p = 0.02) and number of frozen blastocysts (aHR:1.05, 95%CI:1.01–1.10), p = 0.02). When adjusted for these confounders, the cumulative live birth rate was not associated with high-E (aHR: 0.86, 95%CI:0.56–1.31) or high-P (aHR: 0.76,95%CI:0.44–1.32). Limitations, Reasons for Caution: This was a retrospective study with small sample size performed at a single fertility center, which may limit the generalizability of our findings. Wider Implications of the Findings: While lower blastocyst utilization rates are observed in women high late-follicular estradiol or progesterone levels, cumulative live birth rates in subsequent thaw-transfer cycles were not impaired. However, unfavorable outcome parameters observed in women with elevated progesterone deserve further research.