Despite advancements in in vitro fertilization (IVF) technology, managing women with a poor prognosis remains a critical challenge. The POSEIDON criteria define low-prognosis patients as those who retrieve ≤9 oocytes or have poor ovarian reserve indicators. This accounts for almost 40% of IVF patients, who experience a 50% reduction in cumulative live birth rates compared to those with a normal prognosis. An international Delphi consortium aimed to improve live birth rates in these women.
A growing strategy in IVF is the freeze-all approach, in which all embryos are frozen and transferred in a subsequent frozen embryo transfer cycle. This method aims to improve pregnancy outcomes and reduce the risk of ovarian hyperstimulation syndrome by avoiding the negative effects of elevated hormone levels during fresh cycles.
This multicenter, randomized clinical trial was conducted at nine study sites in China, which obtained ethical approval and ensured patient consent. Women undergoing their first or second IVF cycle, either with or without intracytoplasmic sperm injection (ICSI), and who had a low prognosis according to the POSEIDON criteria, were selected for the study. Women were excluded if they had conditions that would make them unsuitable for fresh embryo transfer. These conditions included specific ovarian stimulation protocols, premature progesterone rises, uterine abnormalities, or reproductive health issues such as intrauterine adhesions or polycystic ovarian syndrome (PCOS).
Patients were randomly assigned in a 1:1 ratio, to either fresh or frozen embryo transfer on the oocyte retrieval day. The study design allowed for discretion by doctors regarding stimulation protocols and transfer strategies. There were no limitations regarding gonadotrophin-releasing hormone (GnRH) antagonist and agonist protocols, oocyte retrieval took place between 34-36 hours of hormone administration. Fresh embryo transfer occurred on Day 3 or 5 post-retrieval, while frozen embryos were stored and transferred in a later cycle.
In the intention-to-treat analysis, the frozen embryo transfer group had a lower live birth rate compared with the fresh embryo transfer group (32% [132/419] vs. 40% [168/419]; relative ratio 0.79 [95% confidence interval (CI) 0.65-0.94]; P = 0.009). The clinical pregnancy rate for frozen embryo transfer is also relatively lower than that of the fresh group (39% [164/419] vs. 47% [197/419]; relative ratio 0.83 [95% CI 0.71-0.97]). Even more significantly, cumulative live birth rates were lower for frozen embryos compared with fresh transfers (44% [185/419] vs. 51% [215/419]; relative ratio 0.86 [95% CI 0.75-0.99]). However, no significant differences were found between the fresh and frozen embryo transfer groups in terms of birth weight, obstetric complications, or neonatal morbidity.
Ovarian stimulation uses gonadotrophins, followed by human chorionic gonadotropins (hCG) or GnRH agonists to trigger oocyte maturation. Embryos were assessed using Puissant and Gardner criteria and transferred fresh or frozen, with up to two good-quality embryos per patient. Progesterone-based luteal support was started on retrieval day for fresh transfers. If no had blastocyst formed by day 5, the fresh transfer was canceled due to embryo-endometrial asynchrony.
The primary outcome reported was the live birth rate after the first transfer of the embryo, which is defined as giving birth to a neonate at 28 weeks of gestation with heartbeat and breathing. The secondary outcomes included clinical pregnancy rates, pregnancy losses, maternal and neonatal complications, birth weights, and cumulative live birth rates within one year after randomization.
The results further showed a reduced live birth rate among women with low prognosis following frozen embryo transfer compared to fresh transfer. Cumulative live birth rates over one year were also reduced among women in the frozen embryo transfer group.
However, there was no significant difference between the groups in singleton live birth rates, birth weight, maternal or neonatal complications, or the risk of pre-eclampsia. The results were consistent across intention-to-treat, per-protocol, and per-treatment analyses.
References: Wei D, Sun Y, Zhao H, et al. Frozen versus fresh embryo transfer in women with low prognosis for in vitro fertilization treatment: pragmatic, multicentre, randomized controlled trial. BMJ. 2025;388:e081474. doi:10.1136/bmj-2024-081474
