Optimal Endometrial Preparation Protocols for Frozen-thawed Embryo Transfer Cycles by Maternal Age

This retrospective cohort study aimed to explore the optimal endometrial preparation protocols among different maternal age groups. A total of 16,867 frozen-thawed embryo transfer (FET) cycles were categorized into three groups based on endometrial preparation protocols: Natural cycle (NC n = 3893), artificial cycles (AC, n = 11456) and AC with GnRH-a pretreatment (AC+GnRH-a, n = 1518). To account for repeat cycles, a generalized estimating equation (GEE) method was applied to examine the associations between cycle regimens and pregnancy outcomes. Subgroup analyses were conducted to evaluate the best preparation methods for different maternal age groups. Primary outcomes were live birth and early miscarriage rates. After completing GEE, in overall population, the live birth rate [(NC as reference; AC: adjusted odds ratio (aOR) = 0.837, 95% confidential interval (CI) 0.771-0.908; AC+GnRHa: aOR = 0.906, 95%CI 0.795-1.031)] in NC was significantly higher than that in AC, while comparable that in AC+GnRH-a. The early miscarriage rate (AC: aOR = 1.420, 95%CI 1.225-1.646; AC+GnRHa: aOR = 1.545, 95%CI 1.236-1.931) was significantly lower in NC compared to either AC group. Subgroup analysis showed that in younger women, the incidences of live birth (AC: aOR = 0.900, 95%CI 0.804-1.007; AC+GnRHa: aOR = 1.091, 95%CI 0.904-1.317) were equivalent between groups, with a slightly higher in AC+GnRH-a. Early miscarriage rate (AC: aOR = 1.462, 95%CI 1.165-1.835; AC+GnRHa: aOR = 1.137, 95%CI 0.948-1886) was only significantly lower in NC compared to that in AC. In older women, the live birth rate (AC: aOR = 0.815, 95%CI 0.722-0.920; AC+GnRHa: aOR = 0.759, 95%CI 0.627-0.919) was significantly higher, and early miscarriage rate (AC: aOR = 1.353, 95%CI 1.118-1.638; AC+GnRHa: aOR = 1.704, 95%CI 1.273-2.280) was significantly lower in NC compared to either AC group. Our study demonstrated that NC is associated with lower early miscarriage late in overall IVF population. There is a mild favor of AC+GnRH-a in younger women, while the priority of NC is remarkable in older women. Maternal age should be a considerable factor when determining endometrial preparation method for FET.