A Retrospective Cohort Study On The Effect Of Superphysiological Estradiol Exposure On Adverse Perinatal Outcomes During Frozen-Thrawed Embryo Transfer

Objective:To explore possible factors affecting maternal response to controlled ovarian stimulation.To explore the impact of exposure of high serum estradiol levels to oocytes during COH on adverse pregnancy and neonatal outcomes after frozen-thawed embryo transfer.To provide evidence for optimizing assisted reproductive technology procedures.Methods:This single centre,retrospective cohort study included all FET cycles between January 2014 and September 2017 at the Assisted Reproductive Unit of International Peace Maternity and Child Health Hospital.All FET cycles were categorized into three groups according to the E2 level on the day of the hCG trigger?Group I:<10000 pmol/L;Group II:10000-15000 pmol/L;Group III:>15000 pmol/L?.Information of social background,COH protocols,process of insemination and embryo transfer was collected.Differences of continuous variables among groups were tested by one-way analysis of variance or the Kruskal-Wallis test.Differences of categorical variables were detected by Cochran-Mantel-Haenszel?2 test or Fisher's exact test.The odds ratios and 95%confidence intervals calculated by multiple logistic regression analysis were used to estimate the relationships between supraphysiological E2 exposure during ovarian stimulation and pregnancy outcomes following FET.Results:A total of 10,581 FET cycles were included in the analysis?3695 cycles in Group I,2565 cycles in Group II,and 4321 cycles in Group III?.Social background of patients were similar among three groups.However,patients with higher E2level on the day of hCG trigger were more likely to have experienced GnRH-agonist protocol,while those with lower E2 level were more likely to have experienced microflare protocol.The number of oocytes retrieved trended to increase with E2 level increased on the day of hCG trigger?p<0.001?.Transferred embryos with higher E2 level during COH showed a lower rate of chemical pregnancy(p_{for trend}<0.001),clinical pregnancy(p_{for trend}=0.009),ongoing pregnancy(p_{for trend}<0.001),live birth(p_{for trend}=0.005)as well as an increased rate of early miscarriage(p_{for trend}=0.023).Exposure to higher levels of E2 during COH was associated with an increased risk of preterm birth among singleton deliveries.In addition,compared to participants with relative lower level of E2 during COH,an increased risk of LBW and SGA were found in those with higher E2 level in both singletons and multiples.There was no evidence of an effect of E2 levels on the risk of macrosomia or LGA population.Conclusions:Increased E2 level during COH is associated with a decreased pregnancy rate and an increased rate of early miscarriage.Pregnancies conceived from frozen-thawed embryos with supraphysiological E2 exposure during COH may also be at increased risk of preterm birth,LBW and SGA.In patients undergoing FET cycles,milder COH protocols should be adopted to avoid supraphysiological hormone levels.