This analysis included 792 women and 228 live birth singletons with the following outcomes: 45.1% clinical pregnancy rate, 36.4% live birth rate (288 live birth including singletons and twins). There were 324 patients who were given oral and vaginal estradiol (OVE group), and 468 patients who were given oral estradiol (OE group). Baseline demographics and characteristics were compared between patients with different estrogen regimens (Table 1). Among the 792 women, no significant difference of maternal age, BMI, fraction of patients with at least one good quality embryo transferred, progesterone route, E2 level at 14th day after embryo transfer and P level at progesterone starting day, was revealed between two groups. There were more patients with estradiol treatment days over 21 days in OVE group than in OE group. Serum E2 level at progesterone starting day in OVE group was significantly higher than that in OE group. Endometrium thickness at progesterone starting day in OVE group was smaller than that in OE group. Meanwhile, endometrium thickness at trigger day in COS of OVE group was also smaller than that of OE group. No significant difference of live birth rate (Crude OR 1.229, 95%CI 0.917, 1.649) and clinical pregnancy rate (Crude OR 1.260, 95%CI 0.948, 1.675) was found between OVE and OE group (Table 2). Controlling for maternal age, BMI, whether estradiol duration was longer than 21 days, whether there was at least one good quality embryo transferred, progesterone route, endometrium thickness at progesterone starting day, estradiol administered regimen did not modify the odds of achieving live birth (Adjusted OR 1.327, 95%CI 0.982, 1.794, p = 0.066) or clinical pregnancy (Adjusted OR 1.278, 95%CI 0.937, 1.743, p = 0.121) (Table 2). Endometrium thickness at progesterone starting day positively influenced the clinical pregnancy (Adjusted 1.184, 95%CI 1.026, 1.365, p = 0.021) but with no impact on live birth rate (Adjusted OR 1.119, 95%CI 0.968, 1.295, p = 0.130) (Supplementary Figure 1 & 2). Maternal age and at least one good quality embryo transferred were the independent factors positively correlated to the live birth rate and clinical pregnancy rate (Supplementary Figure 1&2).
To further explore the estrogen regimen impact on birthweight and gestational age, a cohort of 228 live birth singletons from 792 patients was further investigated. The singletons were divided in two groups which were OVE group, and OE group. Baseline demographic and cycle characteristics were presented in Table 3. Comparison between the two groups did not reveal any significant difference for maternal age, BMI, whether there was at least one good quality embryo transferred or progesterone route. OVE group from 228 singletons cohort had more percentage of patients with longer days of estradiol treatment, thinner endometrium and higher serum E2 level at progesterone starting day than OE group, as the same with the 792 cohort (Table 3).
Neonatal outcomes stratified by the regimen of estradiol administered were also presented in Table 3. Preterm delivery rate, mean birthweight and Z-scores were not different across two groups (Table 3). Given that gestational age at delivery is an important determinant for newborn birthweight, a subgroup analysis was conducted stratified by term delivery. The analysis of preterm delivery singletons was not performed because the number in this category was too small. As shown in Table 3, among the term singletons, newborn gender, mean birthweight, LGA rate and SGA rate were not different across the two groups.
In multivariate analyses (Table 4), the risk of preterm delivery (Adjusted OR 0.969, 95%CI 0.292, 3.214, p = 0.959) and the risk of LGA (Adjusted OR 1.165, 95%CI 0.545, 2.490, p = 0.694), SGA in term delivery (Adjusted OR 0.569, 95%CI 0.096, 3.369, p = 0.535) were not significantly different between two groups after adjusting for maternal age, BMI, whether embryo transfered with at least one good quality embryo, whether estrogen administration lasted more than 21 days, endometrium thickness at progesterone starting day, progesterone route and newborn gender. The multivariate analysis of LGA and SGA rate for preterm delivery singletons was not performed because the number in this category was too small. After correction for a number of potential confounders, estradiol route was not correlated with infant birthweight (β = -30.962, SE = 68.723, p = 0.653) (Table 5).