Interpretation
Until now, it remains unclear if estradiol valerate and progesterone harm endometrial receptivity and embryo development. The adverse clinical outcome of AC might be caused by supraphysiological hormone levels during early trophoblast invasion, which could lead to abnormal pregnancy18-20. Estradiol is essential for endometrial and placental development. One historical cohort study indicated elevated serum estradiol levels in AC cycles are associated with lower ongoing pregnancy rate and live birth rate21. Excess estradiol levels in the early stages of pregnancy can have adverse effects on placentation and may in turn cause miscarriage. In vitro study has shown estradiol can cause cell death and inhibit trophoblast invasion in both first-trimester human cytotrophoblast cell line and placental explants22. Studies have indicated preeclampsia in pregnancy is associated with FET23,24. Unfortunately, we have no data on pre-eclampsia. One retrospective study suggested a higher risk of hypertension disorder in women of both singletons and multiples after AC than NC7. The adverse obstetric outcomes of AC for endometrial preparation indicate a possible link between endometrial preparation and placenta-related diseases, which might be caused by supraphysiological hormone levels during early trophoblast invasion. In natural cycles, corpus luteum (CL) is derived from the ovulated follicle. The formation of CL is indispensable for steroid hormone production required to support endometrial receptivity for successful implantation and maintenance of early pregnancy. However, women in the AC cycle do not have CL to produce hormone that is necessary to sustain early pregnancy. Instead, women in the AC cycle were given exogenous estradiol and progesterone and maybe too much or less for individual need. Exogenous endometrial preparation may decrease the ability of embryos selecting the endometrium, which could, in turn, lead to abnormal embryos implantation and miscarriage.
Although we did not find a difference in the live birth rate between two protocols, we did demonstrate a higher miscarriage rate in AC cycles. Miscarriage is a heartbreaking experience for patients and may lead to intrauterine infection or adhesion which could, in turn, have a negative effect on embryo implantation for the next cycle of embryo transfer. Even though AC is convenient for both doctors and patients, a higher miscarriage rate should be considered before making decisions.