​​英国皇家妇产科协会发表了第63号Scientific Impact Paper。

   现代女性的平均生育年龄逐渐增加，然而女性在35-40岁左右面临生育力急剧下降，不少女性为保留将来生育能力尝试冷冻卵子。冷冻周期卵子数目用于IVF周期占2%以下，而周期需要冷冻卵子的数目更低。随着玻璃化冷冻技术的发展，冷冻卵子的成功率接近于新鲜卵子，但冷冻卵子成功率很大程度上由女性冻卵的年龄决定，35岁以下冻卵成功率更高。为此，英国皇家妇产科学会撰写了第63号Scientific Impact Paper，介绍非医疗因素，女性冻存卵子的背景、有效率、安全性、伦理考量等多方面进行阐述。 

1 Background

The age at which women have their children has been increasing steadily for many years in developed countries. For example, the number of births to women over 35 years in the UK has tripled since 1980 (Appendix 1).1 Societal changes have impacted the time spent in education and establishing financial independence. However, age is the key determinant of female fertility, as the population of non‐growing primordial follicles in the ovaries is established during fetal life and declines progressively until the menopause. In addition, the inability to maintain chromosomal integrity results in a decline in oocyte quality. This double jeopardy results in a fall in the likelihood of conceiving with age, along with an increase in the risk of such a pregnancy resulting in miscarriage. There is clear evidence that provision of fertility education increases fertility awareness about fecundity, infertility, risk factors for reduced fertility and reproductive technologies,2 and that fertility education can advance the timing of births in women with partners.3 Men have similar parenthood aspirations as women, but may have limited knowledge of the impact of age on female fertility.4

The divergence between women’s reproductive ambitions and oocyte biology has led to increasing numbers of women utilising reproductive technology to undergo ovarian stimulation, followed by the recovery and cryopreservation of oocytes (egg freezing), to allow deferment of their reproductive potential. These can then be stored and used if more conventional ways of starting a family do not occur. This procedure is widely known as ‘social egg freezing’, but the term ‘elective egg freezing’ does not have judgemental overtones and is preferred. Current UK legislation allows egg freezing for a maximum of only 10 years in the absence of a medical indication, and eggs must then be discarded.

Egg freezing is also used for fertility preservation for purely medical reasons, e.g. for women with a new cancer diagnosis facing gonadotoxic (i.e. potentially sterilising) therapy. It appears that many more women around the world are currently storing eggs for elective rather than medical reasons, and many are already in their late 30s5 when the efficacy of the procedure is declining.

2 Efficacy of freezing

Freezing to preserve reproductive potential was first achieved with semen storage, and successful pregnancies have been reported using sperm frozen for more than 20 years. Embryo storage followed on the heels of in vitro fertilisation (IVF) and is in widespread use; the success rates achieved are now slightly above fresh embryo transfer.6 Freezing of eggs proved more technically challenging; despite the first report of a live birth in 1986,7 pregnancy rates remained low until the development of vitrification (ultra rapid freezing)8 which transformed success rates and replaced ‘slow freezing’ in most, but not all, IVF laboratories. In a clinic proficient in vitrification, a frozen oocyte has the same developmental potential as a fresh oocyte, thus preventing subsequent age‐related decline.9 The clinical pregnancy rates reported in randomised series using warmed eggs fertilised in vitro are equivalent to fresh IVF treatment,9 however, these are from egg donors who are selected for optimum fertility, and are usually much younger than the recipients, and reflect the expertise of centres with greater and longer term experience of vitrification. This expertise may not be matched by all IVF units, but centre‐specific data are not at present available. Nevertheless, the American Society for Reproductive Medicine (ASRM) changed the status of oocyte vitrification and warming from ‘experimental’ to ‘established’ in 2013.10

The first UK data were reported by the Human Fertilisation and Embryology Authority in 20186 for the period 2014–16. In 2016, there were 1173 egg freezing cycles in the UK, and 519 cycles of treatment using frozen stored eggs (Appendix II), with a live birth rate of 19% per embryo transfer, compared to 21% for fresh IVF treatment in the same period.6 These data do not distinguish between egg donation cycles and women storing their own eggs for medical or elective reasons. Larger series are reported from the US,11 with 8825 cycles for oocyte banking in 2016, although these data are based on voluntary reporting.

The likelihood of future live birth is dependent on the woman’s age at the time of oocyte storage, as well as the number of eggs stored. The number of eggs that are likely to be collected can be indicated by assessing ovarian reserve using follicle stimulating hormone, anti‐müllerian hormone and antral follicle count measurements, often in combination. European data5 indicate high (more than 90%) cumulative live birth rates in women who had electively frozen eggs at 35 years and under, although that required utilising 24 eggs. This demonstrates that increasing the likelihood of a live birth will often require more than one cycle of oocyte storage, even in younger women. Storage of ten eggs gives a cumulative live birth rate of 42.8% compared with 25.2% in women aged 36 years and over at the time of storage.5 Such analyses may represent a ‘best case’ scenario, which individual centres with less than perfect oocyte vitrification techniques may be unable to match. In the UK in 2016, 32% of women freezing their eggs were under 35 years old, and 62% under 38, although how many were egg donors, who must be aged below 36, is not recorded by the HFEA.6 While the technology allows indefinite storage without deterioration, the current UK legal limit of 10 years for duration of elective oocyte freezing has no biological or medical basis and is against the interests of women wishing to freeze eggs at a younger, more effective age.

Freezing of ovarian tissue is also used for medical fertility preservation and could potentially be used for non‐medical reasons; it would allow restoration of endocrine function as well as fertility, but the need for surgical intervention (both to remove tissue and later replace it) is an important consideration. In practice, elective ovarian tissue freezing is not routinely available, and would require licensing by the UK Human Tissue Authority.

3 The context of elective egg freezing

Information from national databases confirm that the numbers of women freezing eggs for non‐medical reasons is increasing6 and we are beginning to understand what is motivating individuals to make this choice. In addition to the well‐recognised demographic forces associated with delaying having a baby, such as education and opportunity in the workplace, rising costs of childbearing, housing factors, workplace inflexibility and the potential wish of men to defer parenthood also contribute to decision making.4 The lack of a current partner is cited by women undergoing elective egg freezing as the most common reason for postponing childbearing.12 Studies of these women show that the majority are university educated, in professional employment, between the ages of 36 and 40 years and not in a relationship at the time of egg freezing. They express the desire to have a baby, ideally when in a committed relationship with a partner and with a genetically connected egg, but many would also consider the use of donor sperm if they were unable to find such a partner.

4 Ethical considerations

The ethics of elective egg freezing has attracted much commentary, focussing on issues such as the medicalisation of reproduction, women’s autonomy and idealisation about the right time to have a baby. It is likely that many women electively freezing eggs will never return to use them; concerns have therefore been expressed about the potential number of unnecessary medical interventions and the exploitation of reproductive anxiety. There is an additional concern that having eggs in storage might give women a false sense of security in the technology, encouraging them to delay parenthood even longer, with no guarantee of a future pregnancy.

Elective egg freezing has been compared with autologous blood storage for elective surgery.13 In both situations:

• there is storage of a tissue to treat possible future health issues
• the person is healthy at the point of intervention
• the procedures are established, with medical and psychological advantages for the patient
• the need for donor material is avoided
• there is no certainty the tissue will ever be used.

All indications for egg freezing should be evaluated using standard ethical perspectives, such as focussing on the balance between benefit and risk/cost, whether women are concerned about the threat to their future fertility from, for example, chemotherapy, or solely increasing age.

The Ethics Committee of the ASRM found elective egg freezing to be ethically permissible, using as main arguments enhancing reproductive autonomy and promoting social equality, although the cost of egg freezing may conversely be socially divisive. A key element of ethical practice involves the honest, accurate counselling of women about what the procedure involves both physically and emotionally, their individual expectation of success when contemplating this procedure, and its long‐term implications, which may include decision‐making about the fate of unused stored eggs. It is essential that this should include both the woman’s age and centre‐specific information. Moreover, women may be doing this alone, hence feelings of isolation, anxiety and, in some cases, stigma may be heightened when seeking advice on egg freezing, and whether or not she decides to proceed, supportive counselling may be required. Marketing the technology as a form of ‘reproductive insurance’ is inappropriate, given the limited success rates in the women most likely to store eggs.

5 Safety of freezing

While the greatest risks to offspring after fertility treatment using frozen eggs are associated with multiple pregnancy and the sequelae of prematurity including cerebral palsy,14 there are no known additional risks specific to freezing. These issues should be considered in women who intend to use their own stored eggs at a later age, especially the risk of multiple pregnancy which is related to age (as an index of egg quality) at storage, and should be minimised by a single embryo transfer strategy. Women embarking on pregnancy at a later age also experience greater obstetric risks, particularly in a first pregnancy, notably pre‐eclampsia, gestational diabetes, and the likelihood of a caesarean birth.

Storing a sufficient number of eggs requires the use of gonadotrophins (injections of follicle stimulating hormone with or without luteinising hormone) to stimulate the ovaries to produce multiple follicular development, and therefore carries the risk of ovarian hyperstimulation syndrome (OHSS), although the refinement of stimulation protocols (for example, the use of a gonadotrophin‐releasing hormone agonist to trigger ovulation instead of the standard human chorionic gonadotrophin) greatly reduces this risk.15 Possible complications from the egg harvest procedure include bleeding, pelvic infection, thrombosis, and the risks of anaesthesia.

There are no long‐term follow‐up studies on children born from frozen eggs.

6 Opinion

• Elective egg freezing provides women who are not in a position to start their family an opportunity to mitigate the inevitable decline in their fertility with increasing age.
• While often perceived (and promoted) as a form of insurance, it is essential that women undertaking egg freezing do so with a full understanding of the likelihood of success, as well as costs and risks.
• Success rates will be limited in women who are already in their mid–late 30s, while younger women are disadvantaged by the current legislated limit of 10 years’ duration of storage, which we feel strongly should be changed.
• An upper limit based on age (for both storage and use) might be more sensible for medical, biological and social reasons, but as it would be difficult to justify a single age that would be appropriate for all situations, a limit specified in primary legislation should be removed.
• The significant costs associated with the procedure and subsequent egg storage preclude many women from being able to consider it, raising issues of equality of access.
• Given that the NHS (or analogous state insurance systems in other countries) will not provide elective egg freezing, this service is provided in the private sector with inevitable commercial implications.
• It seems likely that the future will see increasing numbers of women storing eggs, mostly because they are not in a relationship. There remains a need for societal changes that support women in the workplace to have their family at a biologically optimal age if they so choose, without compromising their career prospects, and with adequate provision for childcare that does not discriminate those women/families at financial disadvantage.
• The increasing recognition of the need to improve public education about age‐related changes in female fertility should highlight the importance of men’s knowledge as well as that of women

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（编译 王伟琳）

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