Clinical management of patients with a low prognosis for success in in vitro fertilization (IVF) remains a challenge despite advances in technology over the last several decades. Current criteria defining low prognosis include patients with 9 or fewer oocytes retrieved or poor ovarian reserve, and the prevalence of patients who meet these criteria is nearly 40% in IVF patients. Low prognosis is associated with a 50% lower cumulative live birth rate on average compared with patients with a normal prognosis. A new strategy in IVF of freezing all embryos and then proceeding with a planned frozen embryo transfer has been adopted in the last few years in the hope of avoiding unfavorable endometrial conditions due to the treatments necessary for oocyte retrieval. Previous trials have found that compared with fresh embryo transfer, this strategy yielded comparable or higher live birth rates in patients with normal or good prognosis, but there is little prospective data surrounding the implementation of this strategy in patients with low prognosis. This study aims to address this gap. This was a prospective randomized controlled trial conducted at 9 sites in China. Inclusion criteria were patients undergoing their first or second IVF cycle with or without intracytoplasmic sperm injection (ICSI) with low prognosis as defined previously. Exclusion criteria were conditions that were unsuitable for fresh embryo transfer, natural cycles for oocyte retrieval, and diagnosis of polycystic ovary syndrome, hydrosalpinx, malformed uterus, or a history of intrauterine adhesions or recurrent clinical pregnancy loss. Randomization was performed in a 1:1 ratio on the day of oocyte retrieval. Standard IVF protocols were used at the discretion of clinicians for each patient. The primary outcome for this study was live birth after first embryo transfer, defined as delivery of a neonate with heartbeat and respiratory activity at 28 weeks of gestation or later. Secondary outcomes included clinical pregnancy, singleton or twin pregnancy, pregnancy loss, ectopic pregnancy, singleton or twin live birth, birth weight, maternal complications, neonatal complications, healthy singleton live birth, and cumulative live birth of embryo transfers within 1 year of randomization. Final analysis included 838 patients, with 419 randomized to each group. A total of 62 patients who were randomized to the frozen transfer group were given fresh embryo transfers at patient request, and 31 patients who were randomized to the fresh transfer group were given frozen embryo transfers due to asynchronous development and other factors. In addition, 22 patients in the frozen embryo transfer group and 2 patients in the fresh transfer group had not undergone embryo transfer within 1 year of randomization. Intention-to-treat analysis showed a live birth rate of 40% in the fresh embryo transfer group compared with 32% in the frozen transfer group ( P = 0.009). Rates of twin live birth were also lower in the frozen transfer group, at 5% versus 9% ( P = 0.01), as was the rate of clinical pregnancy (39% vs. 47%, P = 0.02). Pregnancy loss was also more common in the frozen transfer group (31% vs. 23%, P = 0.05). No significant difference was reported in mean birth weight of singletons or twins, rates of healthy singleton live birth, obstetric or neonatal complications, congenital anomalies, or other adverse events. The cumulative live birth rate of embryo transfers within 1 year of randomization was 44% in the frozen transfer group and 51% in the fresh transfer group ( P = 0.04). Per protocol analyses showed similar results. These results indicate an overall lower success rate of IVF for patients with low prognosis undergoing frozen embryo transfer compared with fresh embryo transfer. This directly contrasts with results of previous studies in patients with normal or good prognosis. Mechanisms underlying these findings are unclear. Future research should attempt to elucidate mechanisms underlying this difference in outcomes between fresh and frozen embryo transfers in patients with low prognosis, as well as evaluating the effect of fresh versus frozen transfers in patients with other comorbid conditions. In addition, future studies should attempt to identify biomarkers that could predict the best choice of transfer strategy for each patient as well as the best number and stage of embryos to transfer in patients with low prognosis. (Summarized from Wei D, Sun Y, Zhao H, et al. Frozen versus fresh embryo transfer in women with low prognosis for in vitro fertilisation treatment: pragmatic, multicentre, randomised controlled trial. BMJ . 2025;388:e081474. doi:10.1136/bmj-2024-081474)
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