Frozen versus fresh embryo transfer in women with low prognosis for in vitro fertilisation treatment: pragmatic, multicentre, randomised controlled trial
BMJ 2025; 388 doi: https://doi.org/10.1136/bmj-2024-081474 (Published 29 January 2025) Cite this as: BMJ 2025;388:e081474Linked Editorial
IVF in women with low ovarian reserve or response
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Dear Editor
A recent pragmatic trial published in the BMJ has advocated the benefit of ‘fresh’ IVF cycles compared to frozen embryo cycles for patients with a poor prognosis due to superior pregnancy rates in the fresh cycles (1). This recommendation deserves analysis as it is based on unequal medical practices between study groups with respect to patient safety. Firstly, there was less adherence to the protocol in the frozen protocol such that there were fewer embryo transfers than in the fresh cycle, and more protocol deviations (88 vs 33). As a consequence, multiple pregnancy rates were 4.8% in the frozen vs 9.1% in fresh cycles. This may reflect more cancelled cycles in the frozen cycles, observed as a higher proportion of single blastocyst transfers. Whilst the pregnancy and live birth rate were higher in the fresh cycles, it is apparent that this benefit is mediated through multiple embryo transfer, as twinning is higher.
It is now established that iatrogenic twinning is intrinsically unsafe and there is no clinical basis for multiple embryo transfer during IVF (2).
In vitro fertilisation (IVF) is evolving rapidly in terms of scale, technology, treatment options, and effectiveness. However, response to treatment is variable, and many, perhaps the majority, of patients may leave a course of care without a child (3). Balancing medical risk and the desired outcome of a healthy and happy family has remained a constant theme for infertility treatment (4). The early years from the first IVF birth in1978 were experimental with high effort and cost for low birth rates. In 1984, pregnancy rates remained in the low single digits, which resulted in advocacy for multiple embryo transfer (5). However, as laboratory techniques improved, so did implantation rates, resulting in an exponential rise of iatrogenic multiple pregnancies, which are by definition, high risk for mother and child. This is undesirable as IVF twinning (as is natural twinning) is associated with increased risk of preeclampsia, miscarriage, stillbirth, neonatal death, low birth weight, preterm birth, admissions to neonatal care and total costs in the first year of life (6, 7).
After over 20 years of escalating multiple pregnancy rates, implementing single embryo transfer to reduce multiple pregnancies has been transformative for reducing the risk of adverse effects from twinning and higher order pregnancies (8).
Cryopreservation of the surplus embryos from the initial ovarian hyperstimulation cycle has enabled sequential single embryo freeze-thaw cycles. The resulting cumulative birth rates are comparable to aggressive fresh cycles that result in high multiple rates but with far safer outcomes (9).
The present paper therefore over-emphasises the potential benefit of fresh cycles in poorly responding patients by comparing treatments with different risk profiles. However, fresh cycles do not inevitably result in twinning if clinicians adopt single embryo transfer during fresh cycle IVF, or monitor ovulation by ultrasound and cancel cycles during intra-uterine insemination cycles (9). I suggest a comparison between groups with comparable cancellation and multiple rates might be more informative.
References
1. Wei D, Sun Y, Zhao H, Yan J, Zhou H, Gong F, 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.
2. Transfer EGGotNoEt, Alteri A, Arroyo G, Baccino G, Craciunas L, De Geyter C, et al. ESHRE guideline: number of embryos to transfer during IVF/ICSI†. Human reproduction. 2024;39(4):647-57.
3. Chen D, Shen X, Wang L, Kuang Y. Cumulative live birth rates for low-prognosis women over 5 years or 9 frozen-thawed embryo transfer cycles. BMC pregnancy and childbirth. 2022;22(1):233.
4. Davies MJ, Wang JX, Norman RJ. What is the most relevant standard of success in assisted reproduction? Assessing the BESST index for reproduction treatment. Hum Reprod. 2004;19(5):1049-51.
5. Wood C, Downing B, Trounson A, Rogers P. Clinical implications of developments in in vitro fertilisation. Br Med J (Clin Res Ed). 1984;289(6450):978-80.
6. Marino JL, Moore VM, Willson KJ, Rumbold A, Whitrow MJ, Giles LC, Davies MJ. Perinatal outcomes by mode of assisted conception and sub-fertility in an Australian data linkage cohort. PloS one. 2014;9(1):e80398.
7. Lemos EV, Zhang D, Van Voorhis BJ, Hu XH. Healthcare expenses associated with multiple vs singleton pregnancies in the United States. Am J Obstet Gynecol. 2013;209(6):586.e1-.e11.
8. Henningsen AA, Gissler M, Skjaerven R, Bergh C, Tiitinen A, Romundstad LB, et al. Trends in perinatal health after assisted reproduction: a Nordic study from the CoNARTaS group. Hum Reprod. 2015.
9. Mancuso AC, Boulet SL, Duran E, Munch E, Kissin DM, Van Voorhis BJ. Elective single embryo transfer in women less than age 38 years reduces multiple birth rates, but not live birth rates, in United States fertility clinics. Fertility and sterility. 2016;106(5):1107-14.
Competing interests: No competing interests
Lack of Blinding: A Critical Source of Performance Bias
Dear Editor,
Wei et al.’s RCT on fresh versus frozen embryo transfer in women with a low prognosis undeniably advances our understanding of IVF practice.¹ Yet it is important to note that, from the time of oocyte collection, both participants and clinicians were informed of which arm the patient had been randomised to (fresh or frozen). This lack of blinding is widely recognised, including by the Cochrane Collaboration,² as a key source of performance bias in randomised trials. Even for an apparently objective outcome such as live birth, if knowledge of the allocated arm leads to systematically different care (for example, transferring two cleavage-stage embryos more readily in the fresh group), the reported effect size may be artificially magnified.²
Crucially, knowing in advance that an embryo would be transferred fresh can shape not only the day of embryo transfer but also the number of embryos to transfer. In this study, the fresh-transfer group saw a notably greater tendency for double cleavage-stage transfers (58.8% in the fresh arm vs 49.6% in the frozen arm), whereas the frozen arm had proportionally more single blastocyst transfers (29.3% vs 18.9%).¹ Such differences are plausibly driven by clinicians’ and patients’ decisions in light of their assigned arm—if everyone knows it is a “fresh” scenario, they may transfer more aggressively or earlier. This dynamic is especially relevant in low responders, who are already thought to experience low success and may be more inclined to opt for double embryo transfers in an effort to secure at least one successful implant.
This phenomenon underscores how performance bias can arise in open-label trials: once people are unblinded to which group they are in, their subsequent management decisions can be skewed. The reported difference in live birth rates (40.1% fresh vs 31.5% frozen)¹ could thus be partly attributed to these varied transfer decisions rather than any inherent advantage of fresh over frozen. Observational data from Han et al.³ indicating that double cleavage-stage transfers can yield higher birth rates than single blastocyst transfers further supports the notion that more proactive transfer practices might inflate outcomes in the fresh arm.
Although the trial was labelled “pragmatic,” which implies minimal interference with routine care, the risk is that open-label approaches make it difficult to isolate the true effect of fresh versus frozen per se. Pragmatism does not necessarily exclude concealing assignment until the last possible point or standardising certain protocols around transfer decisions. Doing so would help address performance bias by minimising the likelihood that knowledge of the assigned arm influences clinicians’ and patients’ choices, particularly in low-prognosis populations where any perceived opportunity for success can prompt more aggressive decisions.
In summary, while Wei et al.’s findings provide invaluable clinical insights, the unblinded design likely affected embryo-transfer practices in each arm. That possibility should temper our interpretation of the magnitude of difference observed. Future IVF trials on this question could strengthen their conclusions by adopting later or more rigorous concealment of assignment, ensuring that the core decisions regarding embryo transfer are not systematically altered by knowledge of which group a patient has been randomised to.
References
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
Higgins JPT, Thomas J, Chandler J, et al., eds. Cochrane handbook for systematic reviews of interventions. Version 6.3 (updated February 2022). Cochrane, 2022.
Han Y, Deng X, Cai J, et al. Trade-off between double cleavage-stage embryo transfer and single blastocyst-stage embryo transfer in patients with few good quality embryos in antagonist cycles: a retrospective study using a propensity score matching analysis. BMC Pregnancy Childbirth 2024;24:339.
Competing interests: No competing interests