The Impact Of Supraphysiologic Estradiol During COH On The Clinical Outcomes Of In Vitro Fertilization And Embryo Transfer

Introduction:In vitro fertilization and embryo transfer?IVF-ET?is the most effective method for infertility treatment,and thus has been widely used throughout the world.Previous studies have demonstrated that IVF-ET has negative impact on the perinatal outcomes and short and long time health of offspring.Controlled ovarian hyperstimulation?COH?is the first step of the IVF technology which can induce supraphysiologic maternal serum estradiol?E2?.However,the conclusions from different studies focusing on the impact of supraphysiologic E2 on birth weight remain inconsistent.Additionally,the impact of supraphysiologic E2 on cumulative live birth rate?cLBR?has been rarely investigated.Only a retrospective cohort study with a small sample size suggested that when the peak E2 level was higher than 5000 pg/ml,the cLBR significantly decreased whilst the miscarriage rate significantly increased.Therefore,investigating the impact of supraphysiologic E2 during COH on the clinical outcomes of IVF and on the health of IVF offspring is of considerable significance.Objective:?1?To explore the relationship between the supraphysiological E2 during COH and the cLBR,miscarriage rate and preterm delivery rate;?2?To explore the relationship between the supraphysiological E2 during COH and the birth weight in full term singletons born from FET;?3?To primarily explore the molecular mechanism of the impact of COH on the birth weight.Material and method:?1?Patients came to our center for the sake of infertility treatment between Jan.1^st.2016 to Dec.31^st,2016 were screened for the retrospective cohort study.Statistic method,such as multivariable analysis,smooth curve fitting,trend test,interaction test and so on were applied to estimate the relationship between the supraphysiological E2 during COH and the cLBR,miscarriage rate and preterm delivery rate and the relationship between the supraphysiological E2 during COH and the birth weight in full term singletons born from FET;?2?PMSG+HCG were injected into abdominal cavity of ICR mouse to establish the COH mice model.Molecular biologic techniques such as western-blot,qRT-PCR,HE staining and so on were used to investigate the molecular mechanisms of the impact of COH on birth weight;Outcomes:?1?One thousand one hundred and forty-one non-PCOS infertile women who underwent the first ovarian stimulation cycle were included in the present cohort.The mean level of peak E2 and the mean cLBR was 3911.02±1302.93 pg/ml and 66.9%,respectively.The results of multivariable analysis and the smooth curve fitting indicated that when the peak E2 was lower than 2185 pg/ml,the cLBR increased about 12%with 100 pg/ml increasing of the peak E2.When the peak E2 was higher than 6136 pg/ml,the cLBR decreased about10%with 100 pg/ml increasing of the peak E2.There was no influence of the peak E2 on the miscarriage rate and the preterm delivery rate in general or subgroup populations.?2?Four hundred and thirty one patients with full term singleton newborns from FET were finally included in the cohort.The mean peak E2 level was 4186.6±1215.0 pg/ml,the mean number of oocytes retrieved was 11.5±5.4,the mean length of ovarian stimulation was 11.3±2.1 days and the mean birth weight was 3441.8±466.1 g in this cohort.The result indicated that the peak E2 level was negatively correlated with the birth weight in full term singletons born after FET[adjusted?-5.0,95%CI?-9.2,–0.7?].The effect value represented that for every 100 pg/ml increase of peak E2,birth weight decreased by 5.0 g.P for trend test was 0.038.?3?Study with mice model showed that the birth weight and the ratio of birth weight to placenta weight was significantly lower in COH group than those in the naturally conceived group?P<0.05?;The tissue structure and the glycogen deposition were disturbed in the placentas from COH mouse.Protein and mRNA expression of CLUT4were significantly unregulated in COH placentas.The expression of maternal imprinting genes in COH placentas was abnormal when compared to the control group,while the expression of paternal imprinting gene plagl1 was unaffected by COH.Conclusion:?1?The peak E2 level on hCG trigger day was associated with the cLBR in a segmental pattern.The peak E2 level had a negative impact on the cLBR in patients with unexplained infertility probably due to the impaired ovarian reserve and poor oocyte quality.The miscarriage rate didn't change with peak E2 in general population or subgroup population with normal ovarian response.?2?Peak serum E2 during COH is negatively associated with birth weight.This model proposes a novel concept as well as new evidence that the effect on birth weight is due to the primary influence of high E2 on oocytes during COH.?3?The outcome of animal study indicated that the abnormal glucose metabolism and the disturbed expression of maternal imprinting genes within placenta might play key roles in the molecular mechanisms regarding the impact of the COH on the birth weight of newborns.