Abstract
Objectives: Natural cycle frozen embryo transfer (FET) has become an increasingly preferred approach for endometrial preparation in ovulatory women. Whether modified natural cycle (mNC) protocols incorporating human chorionic gonadotropin (hCG) for ovulation triggering provide any reproductive advantage over true natural cycle (tNC) protocols remains controversial. This study aimed to compare pregnancy and live birth outcomes between mNC-FET and tNC-FET cycles. Methods: This retrospective cohort study analysed 256 frozen–thawed embryo transfer cycles in ovulatory women at a single tertiary centre between January 2014 and December 2024. Of these, 91 cycles used an mNC protocol (mNC-FET group) and 165 cycles used a tNC protocol (tNC-FET group). All transfers involved a single day-5 good-quality or top-quality blastocyst, with identical luteal phase support. Baseline demographic and clinical characteristics, ovarian reserve markers, and embryological parameters were compared between groups. Multivariable logistic regression was performed to identify independent predictors of live birth. Results: The mNC-FET and tNC-FET groups were comparable with respect to age (29.88 ± 4.28 vs. 29.96 ± 3.78 years, p = 0.880), body mass index (24.86 ± 5.27 vs. 23.73 ± 4.58 kg/m2, p = 0.145), anti-Müllerian hormone concentration (3.28 ± 2.86 vs. 3.05 ± 1.88 ng/mL, p = 0.850), and endometrial thickness (9.76 ± 1.55 vs. 9.32 ± 2.18 mm, p = 0.065). The mean number of cryopreserved embryos was slightly higher in the mNC-FET group (5.79 ± 3.47 vs. 5.00 ± 3.47, p = 0.050). Embryo quality distribution did not differ significantly between groups (top-quality blastocysts: 69.2% vs. 70.3%, p = 0.858). Clinical pregnancy rates were 58.2% (53/91) in the mNC-FET group and 55.2% (91/165) in the tNC-FET group (odds ratio [OR] 1.13, 95% confidence interval [CI] 0.68–1.90; p = 0.633). Live birth rates were 46.2% (42/91) in the mNC-FET group and 37.0% (61/165) in the tNC-FET group, without a statistically significant difference (OR 1.46, 95% CI 0.87–2.46; p = 0.151). Women who achieved live birth had a significantly higher number of cryopreserved embryos than those who did not (5.91 ± 3.68 vs. 4.86 ± 3.29, p = 0.024). In multivariable logistic regression, endometrial preparation protocol was not independently associated with live birth (OR 1.27, 95% CI 0.74–2.19, p = 0.394). Conclusions: True natural cycle and modified natural cycle protocols did not differ significantly in clinical pregnancy or live birth rates in ovulatory women undergoing single frozen–thawed day-5 good-quality or top-quality blastocyst transfer. hCG-triggered ovulation did not confer a significant reproductive advantage over spontaneous ovulation. However, this does not prove that the two protocols are equivalent, and larger, adequately powered studies are needed given the relatively small sample size.