Enucleated oocyte donation: first for infertility treatment, then for mitochondrial diseases

Abstract

There seems to be a consensus that enucleated oocyte donation (EOD) should only be used to reduce the risk of having a child with mitochondrial disorders. However, this paper argues that in the initial phase in which we are at the moment, EOD should first be used to remedy infertility caused by poor oocyte quality or poor embryonic development. That learning period will allow researchers to improve their technical skills and the knowledge of the best procedure before starting on high-risk cases. Mitochondrial carryover of pathologic mtDNA is the main cause of concern for the offspring. That risk does not exist in infertility cases. The application of EOD to treat infertility should at present be performed in a clinical research setting to obtain more evidence about efficacy and safety.

Introduction

In 2015, the UK approved the application of enucleated oocyte donation (EOD) for mitochondrial disorders. This technique, commonly misnomed mitochondrial donation, consists in the use of a donor oocyte of which the nucleus has been replaced by the oocyte nucleus of the intended mother. No data has been released to date by the one clinic in Newcastle that has been granted a license to apply EOD. This paper will consider a position that is apparently taken for granted in this debate: EOD is only acceptable when applied for the prevention of mitochondrial disease in the offspring and not for infertility treatment.

EOD only for mitochondrial diseases

In the documents of the Human Fertilisation and Embryology Authority (HFEA) regarding the permissibility of EOD, it was explicitly mentioned that EOD should only be used ‘for a specific and defined group of patients whose offspring may have severe or lethal genetic disease, due to mutations in mtDNA, and who have no other option of having their own genetic child’ [1]. To be fair, when the HFEA formulated its policy, very little information was available on the possible useability of EOD for female infertility. Also in the new Australian Mitochondrial Donation Law Reform (Maeve’s Law) Bill 2021 that is about to be voted, the application is limited to mitochondrial diseases. EOD might enable couples with a mother carrying a mitochondrial mutation to have a genetically related child without a serious genetic condition. The only technique that allows them to reach the same goal would be preimplantation genetic testing for monogenic disorders (PGT-M) to select embryos with a low load of the mtDNA mutation. Donor oocytes would be much safer, much simpler and much more effective but that solution does not allow the couples to have a genetically related child. This shows that it is not only about having healthy children but also (or mainly) about having genetically related children.

Let us assume that there are two possible settings in which a new technique can be introduced: setting A in which some harm may be caused by the application of the technique but, based on the preclinical research, the harm will likely be small. Or setting B in which some harm may be caused by the application of the technique but in which in addition there is a high risk of serious harm related to another cause. Most people would conclude that, given the moral duty to minimize harm, one should start in setting A. In contrast, the HFEA decided that the technique should be initiated, practiced on and limited to those cases where there is a high risk of a serious and/or lethal genetic disease related to mtDNA mutations. In all studies, the carryover rate of mtDNA is mentioned as the main concern for the technique’s safety. This concern can be explained by the difficulty of transferring the nuclear material into the donor oocyte without taking any pathogenic mitochondria along. The higher the carryover levels, the higher the risk for the child to develop the mitochondrial disease. In the only published case of maternal spindle transfer described in the literature, the average level of mtDNA mutation in the blastocyst was 5.73% [2]. Moreover, due to a transmission mechanism unique to mtDNA, there is a risk of reversion to the disease-causing mtDNA type even when the carryover level is very low (< 1%) [3–5]. This reversion has been found in stem cell lines derived from embryos in which mitochondria were replaced [3–5]. There have been several reviews of the mtDNA carryover rate with different transfer methods (germinal vesicle, maternal spindle, pronuclear, polar bodies) [6–8]. The carryover rate for all techniques was low (< 6%) (apart from germinal vesicle transfer for which no data is available in humans). The carryover rate of pronuclear transfer seems to be slightly higher than for maternal spindle transfer but the evidence is insufficient to definitely opt for one rather than the other [7]. The same applies to polar body transfer which has minimal carryover rates but this technique has not been employed by many so the evidence is limited [6, 7]. Further research is needed. An important point related to the carryover rate is that after PGT-M, the commonly accepted threshold for embryo replacement is a mutant load < 18% [9]. No explanation could be found for the difference in safety standards. If the risk for the child is mainly correlated with the mutation load and no other mechanism increases the risk of reversion, EOD would be safer than PGT-M.

One can expect on the basis of the unavoidable learning curve that the application of the technique will not be perfect in the initial phase. By applying the technique first in infertility cases, practitioners could not only learn more about the risks of applying the technique itself but they would also be more experienced (moving along the learning curve) by the time they would start practicing the technique on high-risk cases. Trials could be set up to find out which procedure results in the lowest carryover rate. If these methods are applied in patients with low-quality oocytes, possible changes and adaptations to the protocol could be tested without creating high risks for the offspring since the mtDNA of the donor is not pathogenic. Already in the short period of application of the technique, optimization of the procedure has led to the reduction of the mtDNA carryover [3]. Such optimization will undoubtedly continue in the future, leading to a more standardized protocol. There will still be risks involved, for instance because of the uncertainty about the effects of heteroplasmy even with two types of non-pathogenic mtDNA or because of a mismatch between the nuclear genome of the recipient and the mtDNA of the donor [5]. However, the HFEA has already decided that the risks linked to the application of the technique itself are acceptable since this risk is the same regardless of the indication for the application. The HFEA’s position resembles that of the American Society for Reproductive Medicine (ASRM) in 2012 when they stated that oocyte freezing was acceptable for medical but not for social indications [10]. The Practice Committee of the ASRM explained the difference in attitude ‘on the grounds that there were insufficient data on the ‘‘safety, efficacy, ethics, emotional risks, and cost-effectiveness’’ for that indication’ [11]. But why only for that indication? The lack of data surely also applied to applications of oocyte vitrification for medical reasons. All women, regardless of the indication, wanted to preserve their fertility in the future.

The underlying reason for the distinction seems to be risk reduction [12]. Further analysis of the reasoning reveals some dubious underlying arguments. First, there can only be risk reduction if there is a risk, and, presumably, a higher than normal risk. This is the case for women carrying disease-causing mtDNA mutations. So, people with a high genetic risk can use a technique while people with a (presumed) low genetic risk cannot, although they both need the technique to increase their chances of having a healthy genetically related child. Moreover, the acceptability seems to be based on the reduction of the risk compared to natural reproduction. When a couple with a mitochondrial disease tries to have a child naturally, they have a high risk of having an affected child. This reasoning assumes that couples with a high genetic risk will try to have a child naturally. Many people would argue that parents who know that they have a high risk of a child with a serious disease should refrain from reproducing naturally [13, 14]. If the parents would do the right thing (i.e. refrain from reproducing naturally), there is no risk reduction. Moreover, even after the application of EOD, the risk for the child will be higher in the mitochondrial disease cases than in the infertility cases.

EOD for infertility treatment

EOD could also be used as a technique for the sole purpose of allowing people to have children with whom they share a genetic link. Like ICSI has turned out to be a solution for male infertility, EOD could be a solution for some female-related infertility. Poor oocyte quality is characterized by impaired nuclear and/or cytoplasmic maturity. Mitochondrial dysfunction or low mitochondrial count is linked to oocyte competence [15]. These problems show themselves in ‘premature ovarian failure, unexplained infertility, poor ovarian response to stimulation, failed fertilisation, repeated implantation failure and early pregnancy loss due to poor embryo development’ [16]. When EOD is considered for infertility treatment, the standard steps of introducing an innovative technique should be applied. These steps (animal and preclinical research) have already been made satisfactorily, at least according to the regulatory authorities of the UK and Australia. Obviously, in order to be recognized as an infertility treatment, its effectiveness and safety should be demonstrated.

According to the HFEA, EOD should not be used for fertility problems ‘because a strong causal link between infertility and impaired mitochondrial function has not been made’ [12]. The selection of patients for whom the technique would be used should be based on scientific evidence indicating a causal link between infertility and the mitochondria. However, such link would be needed if only mitochondria would be transferred but, as the term ‘EOD’ clearly indicates, this is not the case. In fact, the whole oocyte with the exception of the nucleus is used. That includes many other parts of the oocyte (several RNAs, proteins, energy-producing components, mitochondria, and many other yet unknown factors) that may affect oocyte maturation, fertilization and embryo development [15]. In recent years, much progress has been made in identifying mutations that are involved in female infertility and more specifically embryo developmental arrest and diminished ovarian reserve [17, 18]. Patients carrying such mutations could be helped by EOD as demonstrated in a mouse model [19, 20]. Also in humans, promising results were obtained for patients with arrested embryos after IVF and patients with failed fertilization after ICSI [21, 22]. In order to maintain the highest balance of risks and benefits, the technique should only be tried in people who have a history of failed IVF cycles. In that case, they, exactly like the women considered by the HFEA, ‘have no other option of having their own genetic child’. The evidence of its effectiveness is very limited at the moment. One pilot trial has started in Greece in 2018 [23]. The preliminary results of a study in Greece in 25 patients with poor oocyte quality resulted in 6 live births after 25 maternal spindle transfer cycles. These women had a mean number of failed IVF attempts of 4.9. The mtDNA carryover levels were below 1% and almost undetectable in the children, apart from one child who carried up to 60% of the maternal haplotype in different tissues at the age of 6 months [24, 25]. This reversion would have been very worrisome if it would have happened in patients with mitochondrial disease. Further follow-up of the children will tell us more about their health.

Like many other techniques in infertility treatment, EOD illustrates a trial and error approach: an element of the process is changed and one hopes that it is effective and does not cause harm. Whether or not it is effective and safe should be shown through application in a research setting. Other techniques, generally captured under the header of ‘add-ons’, are applied in infertility treatment without proven effectiveness and safety. This fact is, at least for most people, an argument against these techniques. Still, they are widely used and offered mainly for commercial purposes [26]. The regulatory authorities in general restrict themselves to a recommendation not to use these techniques and in some cases to a condemnation without sanctions. However, the reaction to EOD in the UK and Australia is much stronger: the application for infertility treatment is forbidden by law. It is unclear why the technique cannot be tested as an innovative technique within a clinical research setting, given the reassuring data from animal and preclinical stem cell research [27]. The absence of evidence for effectiveness and safety is an argument against the use of EOD in clinical practice as an established treatment but it is not an argument against its use in research. Moreover, if lack of a strong causal link is sufficient to forbid a technique, all add-ons with a red light should also be forbidden. Still, the many concerns regarding the technique may justify additional precautionary restrictions beside the requirements of a research setting including ethics committee approval. Such measures may be strict regulatory oversight, limiting application to licensed centres and reporting of outcomes and follow-up to an international registry [16].

Conclusion

The applications of EOD should be considered as two distinct categories, each with their own criteria. EOD should be evaluated as an infertility treatment when applied for low oocyte quality and as a technique for the prevention of genetic risks when applied for mitochondrial diseases. The technique should be applied first for infertility treatment because the risks for the offspring, especially at the start of the learning curve, are much lower. When the technique has been brought to perfection (i.e. knowing what should be done when and how), it can be applied to the more risky group of couples with mitochondrial disorders. The use for infertility treatment should at the start only be used in an appropriate research setting to obtain information on efficacy and safety.

Availability of data

No data was generated for this paper.

Declarations

Conflict of interest

The author declares no competing interests.