13/05/2020

The Art of Social Egg Freezing

Dr Srdjan Saso and his colleagues describe The Art of Social Egg Freezing.

The last 50 years have seen the progression of gender equality and development of women’s rights across the world. Access to family planning, along with greater educational and professional opportunity has enhanced female economic independence and empowerment. Analogous with this, the age of first-time mothers continues to rise, with more women over the age of 40 now giving birth than those under the age of 20 (1).

The ovarian reserve declines with age, from a peak of 6–7 million eggs in utero to below 500 000 by the onset of puberty (2). There is an exponential decrease from the age of 37 years onwards (3), owing to the increased self-death of egg follicles, when just 25 000 eggs remain. Together with a decrease in quantity, egg quality also deteriorates with advancing maternal age, which subsequently increases the risk of genetic issues (3). This manifests clinically with significantly reduced fertility and, in those
who do become pregnant, a dramatically increased risk of miscarriage. This risk increases from approximately 11% in the third decade of life to 93% over the age of 45 (4). The risk of chromosomal disorders such as Down’s syndrome also increases with age from 1 in 1500 at age 20, to 1 in 35 at age 45 (5). When considering this irreversible age-related deterioration in ovarian reserve, it is unsurprising the trend of delaying motherhood has resulted in an increased proportion of women who remain childless involuntarily (6). Furthermore, more women over the age of 45 are using donor eggs rather than their own (7).

The Principles of Egg Freezing

Since its introduction in 1978, an estimated 5 million babies have been born following in vitro fertilization (IVF) worldwide. IVF now accounts for 2% of childbirths in the UK (7). Although IVF can treat infertility secondary to numerous causes, it cannot overcome the irreversible decline in egg quality and quantity associated with advancing age. Egg freezing (technical name: egg cryopreservation) was first reported three decades ago after successful pregnancies were reported following the use of a slow freeze and rapid thaw technique (8).

Electively freezing eggs prior to the physiological decline in egg quality and quantity nullifies future age-related increased risk of miscarriage and congenital abnormality, optimizing the chances of a successful live birth. Referred herein as social egg freezing (SEF), it empowers women with the opportunity to defer their childbearing years, while potentially reducing, but not eliminating, the risk of unintentional permanent childlessness. Cobo et al. recently reported the outcomes of 1382 women who underwent SEF at a mean age of 37.7 years (9). Despite a short follow-up period of 2.2 years, 120 (8.7%) women returned to use their cryopreserved eggs with an oocyte survival rate of 85% and a clinical pregnancy rate of 39% (9). This pregnancy rate is comparable to that achieved by women between the ages of 35 and 37 using fresh embryo transfers (38.7%) (7), despite the mean age of 39.2 at embryo transfer. This exemplifies the potential clinical significance of SEF.

Despite these promising results, utilizing SEF as reproductive insurance is a potentially costly reproductive gamble associated with significant risk. We discuss herein the key multidisciplinary components that underpin SEF, including the obstetric, psychosocial, economic, legal and ethical issues that require consideration.

Obstetric considerations

Although pregnancy rates are superior using eggs frozen at an earlier age, the increased maternal morbidity and mortality associated with advanced maternal age remain. Mortality is increased threefold in women over the age of 40 when compared with women aged 20-24 (10). Not only is there a higher prevalence of chronic medical conditions in women of advanced maternal age (11), but an increased likelihood of maternal and obstetric complications also exists. Women over the age of 40 are at increased risk of blood pressure disorders of pregnancy, with almost twice the risk of developing pre-eclampsia (12). However, given that the use of donor eggs is itself an independent risk factor for pre-eclampsia (13), SEF may be associated with less risk than using donor eggs. Advanced maternal age is also a risk factor for fetal growth restriction (14), stillbirth (15), gestational diabetes, pre-term birth and operative delivery (11).

Regarding neonatal outcomes, although higher neonatal morbidity has previously been implicated in older women, others report that in the context of high-risk antenatal care, similar neonatal outcomes to those of younger mothers can be expected (16). This is applicable even to women at the extremes of reproductive age and, although not advisable, appropriately screened women in their fifties can even expect successful neonatal outcomes (17). Although it is too early to assess the long-term impact on children born following freezing, it is reassuring that congenital abnormality rates are similar to those born following natural conception (18) and child development, at least for the first 3 years, is normal (19).

Social factors

The risk of permanent involuntary childlessness is 6% if childbearing is deferred until the age of 30 years but this increases almost sixfold to 35% if postponed another 10 years (20). The most common indication for SEF is not having a partner (7), which accounts for up to 88% of women undergoing elective oocyte cryopreservation (21). Moreover, in the aforementioned study by Cobo et al (9), of the 79% who were single at the time of cryopreservation, 47% had found a partner by the time they returned to use their eggs, highlighting the potential significance of SEF in single women (9). Other reasons to defer childbearing include seeking high level education, career prioritization or economic uncertainty. There are also potential advantages to postponing parenthood such as greater family stability, higher household income, better quality of living and superior parenting practices (22). It has also been shown to result in better long-term outcomes in offspring, including higher self-sufficiency in adulthood (23), as well as better educational and psychosocial outcomes (24).

Even in populations that have a good understanding of age-related infertility, women continue to defer childbearing (21). In a survey of over 1000 women in the UK and Denmark, 89% considered reproductive planning to be an acceptable indication for SEF (25). These positive attitudes towards SEF are reflected by an almost threefold increase in the number of eggs frozen in the UK, from 2476 in 2008 to 7047 in 2013 (26). Moreover, the number of women freezing eggs for future personal use continues to rise by 25-30% each year and the number of clinics offering egg storage cycles also continues to increase (7). Although these figures include medical reasons in addition to social factors, the majority of cases over the age of 38 cited no partner as the reason for storage, indicating an increasing awareness and demand for SEF.

Economic and legal implications

The highest chance of successful live birth following SEF is when it is performed before the age of 34 years (27). However, owing to the additional expenditure of storing eggs and significant chance of spontaneous conception during these fertile years, the most cost-effective time to achieve a live birth is prior to the age of 38. In women who plan to defer childbearing until over the age of 40, SEF prior to the age of 38 actually reduces the cost of a live birth (28). This figure is based on the US economy but similar cost-effectiveness would be expected in the context of other developed healthcare systems.

From a legal perspective in the UK, Human Fertilisation & Embryology Authority (HFEA) regulations allow the storage of gametes for a standard 10-year period (29). Although this can be extended in circumstances where the individual has or is likely to become prematurely infertile, it may be counterproductive in SEF, particularly in women who cryopreserve at an earlier age to optimize future success. Women who experience physiological age-related fertility decline would therefore be prohibited from extending longer than the current 10-year storage limit, culminating in the destruction of the stored eggs if they are not used.

Conclusion

Spontaneous conception during a woman’s most fertile reproductive years is undoubtedly the safest and most efficacious way to acquire motherhood. However, in the context of a society where the age of motherhood and rates of involuntary childlessness continue to increase, SEF offers the opportunity for women to preserve their reproductive potential if spontaneous conception is not possible.

Women with absolute indications to freeze their eggs, such as those approaching their late thirties who are not in a relationship and want future biologically related children, should consider SEF before their ovarian reserve deteriorates irreversibly. SEF extends the window of opportunity for single women to find a partner, but retains the option to use a sperm donor in the future if they remain single. SEF in women with relative indications to delay childbearing, such as those who decide to focus on their career or prioritize their education, is without question a reproductive gamble. Extensive counselling is paramount to ensure the women are fully informed, including the possibility of unsuccessful treatment in the future with a finite number of stored eggs, as well as the pregnancy-related risks associated with advanced maternal age. Ultimately, each case should be individualized, with consideration of physiological, legal and economic aspects, to optimize timing of oocyte vitrification and determine how many oocytes to store.

References:

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