Despite significant advancements in in vitro fertilisation (IVF) technology, managing women with a low prognosis remains a persistent challenge. The POSEIDON criteria define low prognosis as retrieving nine or fewer oocytes or having a poor ovarian reserve, indicated by an antral follicle count below five or anti-Müllerian hormone (AMH) levels under 8.6 pmol/L.

Nearly 40% of women undergoing IVF fall into this category, and they experience a 50% lower cumulative live birth rate than those with a normal prognosis. Enhancing live birth rates in this population is now a key focus in medically assisted reproduction research. The primary challenge in treating women with a low prognosis is their reduced ovarian response to stimulation, leading to fewer oocytes and, consequently, a lower number of viable embryos available for transfer. The limited embryo availability restricts the options for selection and increases the pressure to maximise the success rate per cycle.

Another complicating factor is the unpredictability of embryo quality. Even when embryos are successfully retrieved and fertilised, the implantation rates in low prognosis women tend to be lower than in those with normal ovarian reserves. This reduced implantation potential raises important considerations regarding the most effective embryo transfer strategy to employ.

Low Prognosis Women

There are two primary embryo transfer strategies: fresh embryo transfer (ET) and frozen embryo transfer (FET). In fresh ET, embryos are transferred immediately after retrieval and fertilisation, whereas in FET, embryos are cryopreserved for transfer in a later cycle. The freeze-all strategy has gained popularity in recent years as a method to enhance pregnancy outcomes and minimise ovarian hyperstimulation risks.

Fresh embryo transfer is often favoured due to the minimal handling of embryos and the avoidance of potential damage from the cryopreservation process. It enables the embryos to develop within the natural reproductive cycle of the patient, reducing the risks associated with freezing and thawing. On the other hand, frozen embryo transfer allows for better endometrial preparation and synchronisation, which some evidence suggest can improve implantation rates. However, this potential advantage does not appear to extend to women with a low prognosis, who may benefit more from fresh transfers.

Concerns of Freeze-All Strategy

The rationale behind the freeze-all approach is to avoid the adverse effects of supraphysiological steroid hormones on endometrial receptivity in fresh cycles. In conventional IVF cycles, the use of gonadotropins can lead to elevated oestrogen levels, which may negatively impact the endometrial lining, making it less receptive to embryo implantation. By freezing all embryos and delaying transfer, the endometrial environment can be better optimised in subsequent cycles with more natural hormone levels.

However, despite its theoretical benefits, this strategy also presents concerns. The processes of freezing and thawing may cause embryo injury, potentially reducing implantation success rates. The structural integrity and metabolic activity of embryos may be altered during the cryopreservation process, which can contribute to lower success rates when compared to fresh transfers. Furthermore, studies suggest that the potential benefits of freeze-all cycles may not be as pronounced in women with low prognosis as they are in women with normal ovarian response.

Comparing Fresh and Frozen Embryo Transfers

Unlike women with a normal prognosis, research indicates that FET results in a lower live birth rate for low prognosis patients. Additionally, the cumulative live birth rate within a year is also reduced in the frozen embryo group compared to the fresh embryo group. However, no significant differences have been observed in healthy singleton live birth rates, birth weights, or maternal and neonatal complications such as pre-eclampsia.

This suggests that for low prognosis women, the detrimental effects of embryo cryopreservation may outweigh the benefits of improved endometrial receptivity in frozen cycles. Since these women already produce fewer oocytes, preserving the quality of each viable embryo is critical, and any damage sustained during the freezing and thawing process could significantly impact their chances of achieving a successful pregnancy.

Potential Interpretation of Findings

One possible explanation is that women with a low prognosis may have more physiologically favourable endometrial conditions in fresh cycles due to lower ovarian steroid levels. Since they produce fewer follicles, their oestrogen levels tend to be lower than those in high responders, meaning that their endometrium may not experience the same level of hormonal disruption seen in women with a normal prognosis. This could make fresh embryo transfers more suitable for them.

Additionally, the potential damage embryos sustain during cryopreservation could outweigh the benefits of avoiding a compromised endometrial environment in fresh cycles. Cryopreservation has been associated with structural and metabolic alterations in embryos, potentially leading to lower implantation rates.

This aligns with findings from a study on oocyte donor recipients, who also demonstrated better outcomes with fresh embryo transfers. Some evidence further suggests that vitrification and thawing may induce epigenetic dysregulation, cell loss, or metabolic changes in embryos, contributing to lower success rates with FET. These factors signify the need for individualised treatment plans based on ovarian response and embryo quality.

Impact of Gonadotropin Doses on IVF Outcomes

The role of gonadotropin doses in IVF outcomes has also been explored. High doses exceeding 2500 IU have been suggested to negatively impact endometrial receptivity. Previous studies indicated better live birth rates after FET in women who received high gonadotropin doses. However, the latest trial did not confirm a strong detrimental effect of high gonadotropins on fresh ET outcomes, suggesting that fresh transfer may still be a viable option regardless of stimulation intensity.

While excessive gonadotropin doses may impair endometrial function, low prognosis women often require higher doses to obtain a sufficient number of oocytes. Balancing optimal ovarian stimulation while preserving endometrial receptivity is a crucial consideration in determining the best embryo transfer strategy.

Strengths and Limitations

One of the key strengths of this research is its focus on women with low prognosis, a group that is frequently overlooked in prior trials. The findings provide crucial insights that can help refine treatment strategies personalised specifically for this subgroup. However, certain limitations must be acknowledged.

The study was conducted as a pragmatic trial without standardised stimulation protocols, potentially introducing variability in results. Additionally, differences in the number and stage of embryos transferred between fresh and frozen groups could have influenced outcomes. A small proportion of women also discontinued or delayed treatment after embryo freezing, impacting the final results. Furthermore, the trial was not designed to detect obstetric or neonatal complications, necessitating further research.

Future Research

To optimise IVF outcomes for low prognosis women, further studies should focus on identifying clinical and biological markers that can guide the selection of the most effective embryo transfer strategy. Additionally, research should explore the optimal number and developmental stage of embryos for fresh transfer in this population.

Investigating the potential benefits of natural ovulation regimens in frozen embryo transfers is another promising area of study. Furthermore, evaluating the impact of embryo accumulation and preimplantation genetic testing could provide valuable insights into improving success rates for these patients.

Conclusion

Fresh embryo transfer appears to be the preferred option for women with a low prognosis in terms of live birth rates. The freeze-all strategy, while beneficial in certain cases such as embryo accumulation or genetic testing, requires further evaluation before being widely recommended for this subgroup.

IVF treatment should be individualised, taking into account ovarian response, embryo viability, and the potential risks associated with different transfer strategies. By refining these approaches, the goal of improving reproductive outcomes for women with low prognosis can become more achievable. Continued research and clinical advancements are essential in ensuring that every patient receives the most effective and personalised care possible.