Too many embryos: a critical perspective on a global challenge

Abstract

Over the past decade, significant endeavors have been directed toward establishing an optimal oocyte number to maximize the chances for successful in vitro fertilization outcomes. The effectiveness of assisted reproductive technologies has greatly improved, and more good-quality embryos are being created in each cycle. However, many of these embryos remain unused. Notably, in Europe, approximately one-third of couples did not use their surplus cryopreserved embryos. Surplus embryos pose a challenge for patients and clinics. Embryo disposal practices are not the same all over the continent, with embryo donation and embryo discharge not allowed in several countries. In this scenario, limiting the number of surplus embryos by reducing the number of inseminated oocytes, according to couple clinical history, could be a strategy.

Commentary

In a recent study conducted by Zacà and colleagues and published in this journal, the authors reported that limiting the number of injected oocytes in women up to 38 years does not affect the cumulative live birth rate (CLBR) but reduces the number of supernumerary blastocysts [1]. This study holds relevance in the context of human assisted reproductive technologies (ARTs) as it underscores the critical importance of avoiding the accumulation of embryos. Over the past decade, significant endeavors have been directed toward establishing an optimal oocyte number to maximize the chances for successful in vitro fertilization (IVF) outcomes. Several studies showed improved CLBR with a higher number of retrieved and/or injected oocytes [2, 3]. The effectiveness of ART has greatly improved, and more good-quality embryos are being created in each cycle [4]. However, many of these embryos are ultimately not used. Notably, approximately one-third of couples in Europe do not utilize their surplus cryopreserved embryos [5–7]. As pointed out by Zacà and colleagues, prolonged storage of surplus embryos poses challenges for patients and fertility clinics, encompassing economic, logistical, and ethical issues. It has been estimated that 1.2 million frozen embryos are currently in storage in the United States alone [8]. To address the prospect of unused embryos, many clinics ask couples to make dispositional decisions before initiating IVF treatment. Good-quality embryos may be donated to research programs, or other couples facing infertility or discharged [9]. However, embryo disposal practices vary all over the continents, with stringent limitations or outright prohibitions on embryo donation and discharge in certain countries [10]. Indeed, as reported by European registries by ESHRE, embryo donation is not allowed in fourteen European countries [11]. In China, there are still no legal regulations or deadlines for the destruction of cryopreserved embryos at present, and embryo donation to other couples is prohibited [12]. Consequently, unused embryos may persist indefinitely. Additionally, couples’ conceptualization of embryos is complex and may range from picturing embryos as a cohort of cells to considering them as their unborn children, reflecting the patients’ hesitancy to donate their embryos reported by several studies [13, 14]. The undefined moral status of the human embryo remains one of the most significant ethical dilemmas that has surfaced in the world of ART. The moral and legal status of human embryos varies across different cultures, religions, and countries. In Canada, the United States, Australia, and the United Kingdom, the current policy states that human embryos used for fertility treatment have very little or no independent moral status. This is because their legislation considers them to acquire juridic status only at the time of birth [15]. However, in Italy, embryos are believed to be a “person” with their own rights from the moment of conception [16]. In Spain, the constitutional jurisprudence classifies the human embryo as a “new subject” that is neither a person nor a thing [17]. It is constitutionally protected but devoid of the right to life. Recently, the Alabama Supreme Court ruled that blastocysts frozen after in vitro fertilization were to be considered “children” for all intents and purposes and that their destruction could be punished with the penalties provided for the manslaughter of minors [18].

Therefore, the standing variety of disposal protocols may be potentially attributed to moral and ethical perceptions surrounding the preimplantation embryo’s bio-ethical stance. In this context, the issue of surplus unused embryos assumes a global dimension. Recently, Correia and colleagues published an interesting prediction tool based on data from the Society for Assisted Reproductive Technology (SART), to reduce the number of unused embryos [4]. In 66.2% of cycles among patients younger than 38 years, fewer than all retrieved oocytes could be exposed to sperm to minimize the number of unused embryos while optimizing the probability of a live birth. Among cycles recommended to expose fewer than all oocytes, the median numbers recommended for 1 live birth were 7 oocytes [7, 8] for patients aged less than 32 years, 8 [7, 8] for patients aged 32 to 34 years, and 9 [9–11] for patients aged 35 to 37 years [4]. This national model (SART model) has also recently been compared to a clinic-specific model. Like the SART model, among women intending to transfer or freeze a blastocyst, the clinic-specific model recommended that less than all oocytes should be exposed to sperm more often in women younger than 32 years of age (96%) but less often in women older than 42 years [19]. Using the national database, the online platform created can be widely used when patients wish to limit the production of surplus embryos. The approach of Correia and colleagues [4, 19] should be applied to any national data set to reduce the number of supernumerary embryos, particularly in countries where legislation does not offer an alternative to indefinite storage.

The findings from our center align with those reported by Zacà and colleagues. Through a retrospective analysis of the last four years’ activity (2019–2022), we analyzed 611 patients undergoing their first intracytoplasmic sperm injection (ICSI). No restrictions criteria were adopted for maternal age. We divided the cohort into three groups: Group 1 (n = 277, 7–9 injected oocytes), Group 2 (n = 194, 10–12 injected oocytes), and Group 3 (n = 140, 13–15 injected oocytes). We excluded cycles involving preimplantation genetic testing (PGT), gamete donation, cryopreserved oocytes, surgical retrieval, frozen spermatozoa, and cycles with day 3 embryo transfer. The mean maternal age was 35.75 ± 3.7 in Group 1, 35.09 ± 4.05 in Group 2, and 34.61 ± 3.75 in Group 3, p-value = 0.152. The presence of moderate-severe male factor infertility (total sperm motile count < 5 million) was equally represented in each group (Table 1). A multivariate logistic regression was performed, in which Group 2 played the reference role and all other groups were considered as dummy variables. Maternal age, day of transfer, blastocyst quality, and cause of infertility were included as variables potentially affecting CLBR in the regression model. Our results demonstrated a significantly reduced CLBR in Group 1 compared with Group 2 (OR 0.71, 95% CI (0.52–0.97), p-value = 0.02) (Table 1). No significant difference was observed between Group 3 and Group 2 (OR 1.32, 95% CI (0.88–1.98), p-value = 0.173) (Table 1). Conversely, the mean number of blastocysts obtained and surplus blastocysts after live birth achievement increased significantly with the escalating number of injected oocytes (Table 1). Taken together, our results and those of Zacá and colleagues suggest that utilizing more than 10–12 oocytes results in a significant increase in surplus embryos without benefiting the CLBR.

Table 1.

Results among different groups

Variables	Group 1	Group 2	Group 3
Cycles	277	194	140
Maternal age, mean ± SD	35.75 ± 3.70	35.09 ± 4.05	34.61 ± 3.74
Male factor infertility, n (%)	122 (44.04)	83 (42.78)	59 (42.14)
Oocytes inseminated, range	7–9	10–12	13–15
Blastocyst obtained, mean ± SD	3.40 ± 1.55**	4.66 ± 2.02	5.49 ± 2.40**
Cumulative live birth, n (%)	123 (44.40)*	107 (55.15)	85 (60.07)
Supernumerary blastocyst, mean ± SD	2.05 ± 1.70**	3.11 ± 2.13	3.78 ± 2.14**

SD, standard deviation; n, number; *p < 0.05, **p < 0.01, in comparison with Group 2

Another aspect to be scrutinized pertains to the attainment of a second subsequent live birth. In patient achieved a live birth, we calculated the probability of obtaining a second live birth through the following procedure: assigning a value (live-birth probability) to each of the patients’ residual blastocysts based on their day of development and quality, as well as the patient’s age at the time of oocyte retrieval; the values were obtained by retrospectively analyzing the overall data from our center and then attributed to each of the residual blastocysts for the respective patients. The estimated probabilities of achieving a second live birth utilizing the leftover embryos from the first pregnancy were 35.4%, 50.7%, and 54.4% in Groups 1, 2, and 3, respectively. This finding indicates that employing 10–12 oocytes allows a significant number of couples the opportunity to conceive a second child, similar to Group 3 (13–15 oocytes), but reducing the number of surplus embryos. However, it is essential to recognize that the goal of a second pregnancy may not be the primary objective for all couples [20]. We can therefore conclude that using 10–12 oocytes and cryopreserved supernumerary oocytes could be a strategy to increase the cumulative chances without having an exponential increase in surplus embryos. In reducing the number of inseminated oocytes, it is important to consider biological and clinical strategies that can maximize the efficiency of the treatments. Poor outcomes have been associated with insufficient progesterone control, while high progesterone levels on the day of trigger have been linked to a decrease in the quality and percentage of expanded blastocysts on day 5 [21, 22]. Therefore, progesterone should be considered an important indicator in the clinical management of IVF cycles to improve the chances of a successful pregnancy [23]. On the other hand, the male factor is associated with reduced fertilization and blastulation rates [24]; therefore, the number of oocytes to be inseminated should be increased accordingly. It is important to note that the male factor affects blastulation rate but not embryo developmental competence [24, 25]. Another aspect to consider is advanced maternal age; Zaca and colleagues have proposed a limit on maternal age and suggested a maximum of 10 inseminated oocytes for women up to 38 years old [1]. Likewise, Correira has recommended a limit (9–11 oocytes) up to 37 years old [4]. However, beyond these age limits and presence of male factor, it may be reasonable to consider increasing the number of inseminated oocytes.

In the final analysis, the study by Zacà and colleagues represents an opportunity to find a more sustainable balance between the optimal CLBR and supernumerary embryos in ART treatments. However, reducing the number of injected oocytes, according to couple clinical history, and standardizing legislation regarding embryo disposal practices remain a priority.

Firstly, a central part of pre-IVF counseling should be dedicated to informing patients about what they can realistically expect before, during, and after fertility treatment, including the possibility of having surplus embryos and, therefore, the available disposition options. To reduce the global issue of supernumerary embryos, agreements assuming that embryos will be stored unless the couple specifically requests transfer or destruction, expanding options to donate embryos, and simplifying embryo donation for research purposes seem to be mandatory. Although the well-documented difficulties shown by some couples when they need to decide the fate of their embryos [14], the introduction of a carefully constructed informed consent to detail the possible disposition of cryopreserved surplus embryos after a set period seems to be useful whenever possible, according to the different legislation of European countries.

Although most of these embryo disposal practices are not applicable in certain countries, the aim of this commentary is precisely to raise awareness on this topic and to improve shared and standardized policies at least across Europe.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declarations

Conflict of interest

E.P. reported grants and personal fees from MSD; grants from Ferring, IBSA, TEVA, and Gedeon Richter; and grants and personal fees from Merck. The other authors declare no conflict of interest.