A large, randomized study has shown that using a natural cycle to prepare the endometrium for frozen-thawed embryo transfer in women undergoing in vitro fertilization leads to better outcomes than hormone replacement therapy.
The trial involved 902 women with regular menstrual cycles and compared two commonly used approaches for endometrial preparation: natural cycle monitoring and hormone therapy using estradiol and progesterone. All participants were scheduled for frozen-thawed embryo transfer (FET) and had no ovulation disorders.
Participants were randomly assigned to either natural cycle (NC) or hormone replacement therapy (HRT). In the NC group, ovulation was tracked using ultrasound and hormone testing. In the HRT group, synthetic hormones were used to simulate a menstrual cycle. Some participants crossed over to the other protocol due to clinical needs, primarily due to lack of ovulation or spontaneous follicular development.
The primary outcome, live birth rate, was significantly higher in the NC group at 54.0% compared with 43.0% in the HRT group. The risk ratio was 1.26 (95% confidence interval [CI], 1.10 to 1.44), indicating a 26% higher likelihood of live birth with NC preparation.
Secondary outcomes also favored the NC approach. Women in this group had higher clinical and ongoing pregnancy rates and a lower miscarriage rate (13.0% vs 21.4%). Antepartum hemorrhage occurred less frequently in the NC group (14.5% vs 23.1%).
Neonatal outcomes—including birth weight, incidence of low birth weight, large or small for gestational age, congenital anomalies, and NICU admission—did not differ significantly between groups. No perinatal deaths were reported.
The NC group also had slightly thicker endometrial linings and more biochemical pregnancies. The trial permitted crossovers: 101 participants in the NC group switched to HRT due to anovulation, while 29 in the HRT group switched to NC following spontaneous ovulation. An instrumental variable analysis accounting for these crossovers found a 15.6% adjusted increase in live birth probability with the NC strategy.
There were no significant differences in rare pregnancy complications such as hypertensive disorders or gestational diabetes between protocols. Sensitivity and per-protocol analyses confirmed the main findings.
Investigators noted that natural cycle preparation may better reflect physiological hormonal conditions and reduce potential risks associated with synthetic hormone exposure, especially in ovulatory women.
These results support the use of natural cycle protocols for endometrial preparation in IVF patients undergoing FET. Further studies may be needed to evaluate outcomes in older or anovulatory populations.
Full disclosures can be found in the study.
Source: PLOS