Comment on “Natural Ovulation Versus Programmed Regimens Before Frozen Embryo Transfer in Ovulatory Women: Multicentre, Randomized Clinical Trial”

Vollständiger Abstract

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Frozen embryo transfer in in vitro fertilization (IVF) treatments has now surpassed fresh embryo transfer in the annual number of cycles due to increases in the use of preimplantation genetic testing and the freeze-all strategy. In frozen transfer cycles, the endometrium requires preparation to receive the embryo, and the most common regimens are a natural ovulation regimen and a programmed regimen using exogenous estrogen and progesterone. Great controversy surrounds the issue of which regimen provides better safety and efficacy; previous studies have focused on pregnancy and live birth rate, but have not been powered to detect differences in obstetric or neonatal complications. This study was designed to assess the association of natural ovulation regimens with healthy live birth, preeclampsia, and eclampsia compared with a programmed regimen. This was a 2-arm, assessor-blinded, multicentre, randomised controlled trial that included 24 study sites in China. Inclusion criteria were patients aged 20 to 40 with regular menstrual cycles undergoing a frozen single blastocyst transfer after IVF or intracytoplasmic sperm injection cycles after preimplantation genetic testing. Exclusion criteria were blastocysts derived from oocyte donation, frozen oocytes, or blastocysts that had been thawed and refrozen; patients who did not achieve pregnancy after 2 or more previous embryo transfers; patients who had previously canceled cycles due to endometrial thickness; and patients with a history of intrauterine adhesions, untreated submucosal uterine fibroids, or untreated hydrosalpinx. Randomization occurred in a 1:1 ratio between a natural ovulatory regimen and a programmed regimen. The primary outcome for this study was healthy live birth defined as a singleton liveborn infant delivered at 37 weeks of gestation or after and weighing between 2500 and 4000g without major congenital anomalies. An additional primary outcome was diagnosis of preeclampsia or eclampsia. Secondary outcomes included cancellation of the transfer cycle, biochemical pregnancy, clinical pregnancy, ongoing pregnancy, pregnancy loss, ectopic pregnancy, live birth, birth weight, and maternal, fetal, and neonatal complications. Final analysis included 4376 patients, with final follow-up concluded on January 31, 2025. Baseline characteristics were similar between groups. A total of 56 patients in the natural ovulation group and 41 in the programmed group had not had an embryo transfer within a year of randomization; 72 patients in the programmed group and 64 in the natural ovulation group had 2 embryos transferred or cleavage stage embryos, and 222 in the programmed group and 183 in the natural ovulation group received different endometrial preparation regimens than planned. In addition, 19 patients were discovered to be ineligible after randomization and were excluded. Intention-to-treat analysis showed that 910 patients in the natural ovulation group and 890 in the programmed group had healthy live births (41.6% and 40.6%, respectively), with no significant difference between groups. Patients in the natural ovulation group had a lower risk of preeclampsia ( P = 0.02), and there were no instances of eclampsia. Patients who had natural ovulation cycles also had a decreased risk of first-trimester pregnancy loss ( P = 0.02), vaginal bleeding ( P < 0.001), hypertensive disorders of pregnancy ( P = 0.004), and placenta accreta ( P = 0.005). Cesarean delivery was also less common ( P = 0.001), as was postpartum hemorrhage ( P < 0.001). Other outcomes were not significantly different between groups. Per protocol analysis showed similar results. These results indicate that a natural ovulation regimen for frozen embryo transfer was as effective as a programmed regimen for achieving healthy live birth, with the additional benefit of reduced risk for certain obstetric complications. This is consistent with previous studies focusing on live birth, but adds the element of assessing safety for mothers and neonates. Future research should focus on serum and endometrial biomarkers and maternal-fetal interactions that may explain the mechanisms for the findings of this study. (Summarized from Wei D, Qin Y, Sun Y, et al Natural ovulation versus programmed regimens before frozen embryo transfer in ovulatory women: multicentre, randomised clinical trial. BMJ . 2026; 392:e087045. doi:10.1136/bmj-2025-087045)