Freeze all for all- is it justified?

The choice between freeze-all and fresh embryo transfer in IVF has been a longstanding topic of interest within reproductive medicine. Reproductive Biology and Endocrinology has consistently contributed valuable studies to this ongoing debate. In a previous editorial meeting, we had planned to dedicate a special collection of articles to explore this subject in depth. Although this project was not carried out, we decided to write an editorial, aiming to summarize the topic and shine a light on the key challenges and controversial aspects surrounding it.

In recent years, there has been a rise in the practice of elective freezing of all good quality embryos followed by transfer in subsequent frozen embryo transfer (FET) cycles. This paradigm shift is largely attributed to advancements in cryopreservation techniques (vitrification), as well as the widespread implementation of gonadotropin-releasing hormone (GnRH) agonist triggers, preimplantation genetic testing for aneuploidy (PGT-A), and the routine adoption of elective single embryo transfer (SET). Collectively, these developments have led to a greater number of embryos being cryopreserved and utilized in FET cycles.

There is broad consensus that specific clinical scenarios encountered at the start or during ovarian stimulation (OS) warrant a freeze-all approach. These include the presence of intrauterine pathology (e.g., endometrial polyps, intrauterine fluid accumulation), suboptimal endometrial development, hydrosalpinx, premature progesterone elevation, and a high risk of severe ovarian hyperstimulation syndrome (OHSS) [1]. While numerous studies have evaluated the efficacy of the freeze-all strategy in IVF, current evidence suggests limited benefit for patients with low [2–4] or normal ovarian response [5]. However, for high responders, the data remain inconsistent, and further investigation is warranted. From a safety perspective, elective FET is associated with a significantly reduced risk of moderate to severe OHSS, offering a compelling advantage in high responders. Nonetheless, this benefit must be weighed against emerging evidence linking frozen transfer cycles to increased risks of obstetric complications, including pre-eclampsia and fetal overgrowth (e.g., macrosomia) [6].

The remaining question is whether elective FET offers improved reproductive outcomes compared to fresh embryo transfer in high-responder patients undergoing IVF/ICSI, taking into account both efficacy and safety.

A comprehensive review of the literature identified two randomized controlled trials (RCTs) from the same group [7, 8], along with three large-scale retrospective studies analyzing data from the Society for Assisted Reproductive Technology (SART) [2], the National Assisted Reproductive Technology (ART) Surveillance System [9], and a population-based cohort study utilizing data from the Victorian Assisted Reproductive Treatment Authority [3].

The two RCTs evaluated elective freeze-all versus fresh embryo transfer in well-defined high responder populations. The first randomized women with polycystic ovary syndrome (n = 746 vs. 762) [7], and the second included ovulatory high responder women (n = 825 vs. 825) [8], with peak high estradiol concentrations at the time of hCG trigger (4141 ± 2159 pg/mL and 3362 ± 1762 pg/mL, respectively). In both trials, the freeze-all strategy was associated with higher live birth rates (LBR) compared to fresh embryo transfer. Moreover, the incidence of moderate to severe OHSS was reportedly lower in the freeze-all arms (0.5–1.3% vs. 1.0–7.1%, respectively). However, these exceptionally low OHSS rates, particularly in high-risk populations triggered by hCG, raise concerns regarding case definitions, underreporting, or potential selection bias, and merit further scrutiny. Additionally, the LBRs reported in these studies—as well as in the same group’s RCT involving poor prognosis patients (POSEIDON classification) [4] appear surprisingly comparable (ranging from 40 to 42%), especially when considering variability in embryo transfer protocols, patient characteristics, and clinical practice settings across trials. Such discrepancies suggest that the generalizability of these findings may be limited.

Among the retrospective analyses, the SART registry study encompassing 82,935 cycles demonstrated higher LBRs in freeze-all cycles compared with fresh transfer cycles in high responders (n = 7,337 vs. 24,174, respectively) [2]. In contrast, a retrospective cohort study using data from the National ART Surveillance System analyzed outcomes among 44,750 young women (aged 20–35 years) undergoing their first oocyte retrieval. Despite a high mean oocyte yield (17.7–22.4), no statistically significant difference in singleton LBR was found between frozen and fresh elective single embryo transfers (n = 2,318 vs. 6,324, respectively) after adjustment using log-linear models and propensity score analyses [9].

Similarly, a population-based cohort study conducted in Australia evaluated 14,331 women undergoing their first stimulated ART cycle. Among high responders (> 15 oocytes retrieved), cumulative LBRs were comparable between the freeze-all group and the fresh transfer group (n = 1,942 vs. 5,021, respectively) [3].

In summary, while the two RCTs and one large U.S.-based retrospective study (SART) [2, 7, 8] suggest a potential benefit of the freeze-all strategy in high responders, these findings must be interpreted with caution due to questions about data accuracy, patient selection, and real-world applicability in the two RCTs. Conversely, two other robust retrospective cohort studies—one from the U.S. national surveillance system [9] and another from an Australian registry [3] found no clear advantage of freeze-all over fresh transfer in this population.

Together, this body of evidence underscores the need for further well-powered, stratified RCTs and real-world data analyses to determine whether elective freeze-all policies should be routinely recommended for high responder patients, or reserved for specific clinical indications. Moreover, let’s not forget the additional costs of the freeze–all strategy, the laboratory workload, and the delay time-to-pregnancy. Resource-limited settings may benefit more from fresh ET where feasible and safe.

Author’s contributions

R.O. wrote the first paper draft; contributed to conception and design, drafted and revised the article critically for important intellectual content, and final approved the version to be published.

Funding

The author received no financial support for the research, authorship, and/or publication of this article.

Data availability

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Competing interests

R.O declares no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. R.O. is Co-Editor-in-Chief of Reproductive Biology and Endocrinology.