Natural vs. artificial cycle for frozen embryo transfer: impact on clinical and obstetric outcomes

To compare clinical, obstetric, and neonatal outcomes between natural and artificial endometrial preparation protocols for frozen embryo transfer (FET) in cycles involving single euploid blastocyst transfer.

This retrospective observational study included only single embryo transfers of thawed day 5 or 6 good-quality blastocysts submitted to preimplantation genetic testing for aneuploidy (PGT-A) between January 2022 and May 2024. Patients were allocated to either natural or artificial endometrial preparation groups, and each group was further stratified into three subgroups according to luteal phase support: oral dydrogesterone, vaginal micronized progesterone, or combined treatment. Exclusion criteria were submucosal fibroids, endometrial polyps, intramural fibroids ≥5 cm, and hydrosalpinx detected on transvaginal ultrasound. Clinical pregnancy, live birth, miscarriage, neonatal birth weight, and gestational complications were analyzed using odds ratios (OR), confidence intervals (CI), p-values, generalized linear models, and z test, as appropriate.

The natural cycle group showed significantly better reproductive outcomes, with higher clinical pregnancy rates (OR=0.37; 95%CI: 0.13-1.02; p=0.047) and live birth rates (OR=0.46; 95%CI: 0.24-0.89; p=0.022), whereas the artificial cycle group had a significantly higher miscarriage rate (OR=2.96; 95%CI: 1.51-5.96; p=0.002). Analysis across the six subgroups demonstrated a significant advantage in clinical pregnancy among patients undergoing natural cycles with oral progesterone support. In contrast, miscarriage was significantly more frequent in the artificial cycle subgroup receiving oral progesterone than in the corresponding natural cycle subgroup. Neonatal birth weight was higher in artificial preparation cycles by a mean of 135.81 g, although this difference was not statistically significant (95%CI: -138.29 to 409.90; p=0.326). Among gestational complications, only gestational diabetes differed significantly between groups (z=2.156; p=0.03), while no significant differences were observed for preeclampsia or HELLP syndrome.

True natural cycles were associated with significantly higher clinical pregnancy and live birth rates, as well as lower miscarriage rates, than artificial cycles in euploid frozen embryo transfer cycles.