The Basics about Egg-Freezing
What every woman considering delaying her pregnancies into older age should be aware of before committing to a first cycle
SÓNIA GAYETE LAFUENTE, MD, PhD, is a Foundation for Reproductive Medicine Research Fellow and regular contributor to THE REPRODUCTIVE TIMES.
September 9, 2024. Revised from the CHR VOICE.
Female infertility increases with advancing age. Increasing demand for fertility preservation into older ages created a booming “egg-freezing industry,” with most businesses no longer owned by physicians but investors. Even after using “egg-freezing parties” and other marketing tools to entice young women to freeze their eggs, clinics established exclusively for “egg-freezing” proved economically unsustainable, and either quickly shut down or converted to more general infertility practices. Egg-freezing cycles, therefore, are currently offered by full-service clinics which offer egg-freezing as part of a comprehensive infertility treatment program and by clinics that started out as “egg-freezing factories” but now also offer more general fertility services. A patient’s choice of clinic is important.
Some general background
As women are born with all of their eggs, two negative things occur in both ovaries to their original egg-pool as they age. First, it shrinks in size, as eggs are constantly recruited out of this pool—biologically speaking, going to waste. Second, eggs not recruited remain in the ovaries but age with the female and lose pregnancy potential. The egg of a healthy 25-year-old, for example, offers at least a 35% pregnancy chance, while the egg of a 45-year-old woman offers only approximately a 5% pregnancy chance. In parallel, with advancing age poorer egg quality also means more chromosomal abnormalities in eggs and embryos and, therefore, more miscarriages.
The principal idea of egg-freezing, therefore, is to interrupt this biological “double-whammy” of fewer and poorer quality eggs during older age by freezing eggs at a relatively young age in sufficiently large numbers so that later in life —with a somewhat foreseeable probability — the woman can conceive one or more children, even if her egg-pool at that age no longer permits pregnancy.
Once frozen, eggs preserve their pregnancy potential at the woman’s age at which they were cryopreserved.
So, who then may benefit from egg-freezing at young ages?
First, we must differentiate between women at risk to lose their fertility because their ovaries need to be surgically removed and/ or who, because of cancer or other diseases, must be treated with gonadotoxic medications which will wipe out most or all of their eggs (this is called medically indicated egg cryopreservation) and those who wish to freeze their eggs to preserve their ability to conceive into older ages (called non-medical or social egg-freezing). This latter group is made up of only two potential clinical scenarios:
§ Biological females planning on undergoing gender-affirmative treatments who want to maintain the option of later producing biological children themselves or using their eggs in creating embryos carried by a female partner.
§ Women who consciously choose to delay motherhood for personal reasons. Pursuit of a professional career was long widely believed to represent the major motivation. Recent research, however, has demonstrated that the most frequent motivation appears to be a woman’s inability to find her “right” partner.
It is this second scenario we are addressing here. What, then, are the most important issues to consider for women who choose to freeze their eggs because they consciously wish to secure their ability at some future time to achieve pregnancy with their own eggs?
Questions that should always be asked
Questions to be asked include, should I freeze my eggs or is it not necessary? The so-called ovarian reserve (OR) gradually diminishes over time, with a notable acceleration between the ages of 37 to 40 years. Women reach menopause on average at age 51. Concurrently, egg competence also diminishes, a process accelerating from approximately age 35, and more significantly from ages 37-40. Variability can, however, be substantial. During their late thirties and beyond, declines in egg quantity and quality are the primary factors contributing to decreasing female fertility.
If surviving thawing, eggs retain their reproductive potential at the age a woman was when her eggs were frozen. This, however, does not necessarily mean over all age-ranges that the younger the eggs are frozen, the better. Recent data, indeed, indicate that elective freezing should likely not be done before age 23. Moreover, optimal timing should not only take into consideration the female’s OR (a factor often not even assessed in primary egg-freezing clinics) but also social factors characteristic of the patient (and, yes, egg-freezing should not be viewed as just a social interaction, but—very definitely—as a medical procedure).
Social factors deserving attention include transparently the expected costs for not only one retrieval cycle (as patients only too often are quoted) but for all cycles she will likely need to obtain a large enough frozen oocyte pool to meet her expectation for one or more deliveries at a later point.
Of similar importance is an assessment (as uncertain as it may be) of whether the patient likely will or will not return to use her frozen eggs. In some cases, even psychological evaluations may be indicated before committing young patients to these costly interventions (once again, rarely a concern expressed in clinics primarily serving as egg-freezing providers).
Freezing eggs in the 20s may be biologically highly efficient but, at the same time, can be expected to lag in cost-effectiveness, since later utilization of frozen eggs will likely be low. In comparison to older counterparts, young women, of course, will still have excellent chances of completing their families through spontaneous conceptions. Cost-effectiveness of egg-freezing, therefore, achieves a maximal peak at ages 37-38 years. Under age 30, the mean number of eggs obtained per retrieval remains similar; but after 35 years the number starts significantly declining. Moreover, in non-infertile individuals, fertilization and pregnancy rates obtained from the eggs of women in their late twenties or early thirties are comparable to those obtained in early twenties, and better than eggs of younger women below ages 22-23.
The best OR, therefore, can be expected between approximately the mid- to late-20s until the mid-30s. Considerations, however, change dramatically if women at younger ages already demonstrate evidence of low OR, a diagnosis called premature ovarian aging (POA). The recommendation then is straightforward: get pregnant as soon as possible or, if that is not possible, start egg-freezing at a good IVF clinic immediately. The poorer a patient’s OR, the more important the quality of the clinic where the egg-freezing cycle is performed.
These recommendations are supported by several arguments. First, medicine has not yet learned to arrest POA and POA is, of course, a progressive condition. Second, even though POA in a large majority of cases only progresses slowly, in a small subgroup of women deterioration can occur very quickly and to date we have not learned to predict who falls into this small subgroup. Consequently, all POA patients need to be prudently approached assuming a poor case-scenario of quick OR loss.
How egg-freezing works
Like in a regular in vitro fertilization (IVF) cycle, egg freezing requires that a woman goes through ovarian stimulation with injectable fertility drugs called gonadotropins. But there should not be a uniform protocol for every patient (as is unfortunately often the case in clinics where egg-freezing is the most-performed IVF cycle). Instead, understanding egg-freezing as the complex medical procedure it really is, every patient should beforehand have a highly individualized assessment and, accordingly, a personalized and tailored ovarian stimulation plan. And, as with all IVF cycles, this requires close monitoring of the patient over an average of 10-14 days, during which time patients should be seen frequently, not only by support staff, but by a responsible physician who is experienced in assessing hormone levels and pelvic ultrasounds, both essential components of monitoring a cycle’s progress.
Ovarian stimulation occurs through self-injection of sub-cutaneous gonadotropins (FSH, LH, or both in combination). During a natural menstrual cycle, these hormones are secreted by the pituitary gland at only low amounts and produce only one or two growing follicles (the small cystic spaces in which eggs live, Figure 1). But under external and much higher-dosed amounts of hormone, ovaries, especially in younger women, will produce much larger numbers of follicles and eggs. Though not every follicle yields an egg, some younger women–and even older women with PCOS–can easily produce over 20 eggs. Since the goal of egg-freezing is to get a certain minimum number of eggs, there always exists the risk that ovaries are hyper-stimulated. In extreme cases that can lead to ovarian hyperstimulation syndrome (OHSS), a potentially dangerous complication of ovarian stimulation which can sometimes even be life-threatening. Fortunately, OHSS in experienced hands has by now become an extremely rare event.
At the end of ovarian stimulation, when leading follicles reach the appropriate diameter, a “trigger” injection for final follicular maturation is administered, and eggs are collected 34-36 hours later. With the patient asleep, eggs are aspirated with a long needle under ultrasound control. Using this technology, the operating physician can carefully lead the needle tip, which is clearly visible on ultrasound.
Women almost universally tolerate (careful) ovarian stimulation and egg retrievals well, with the latter done under conscious sedation of the patient which should be administered by an anesthesiologist. The process may cause mild bloating and abdominal cramping, but most women do not report additional symptoms. The length of the procedure depends, of course, on the number of follicles, but rarely lasts more than 15 minutes. Patients are then discharged from recovery in about one hour.
How many eggs should be frozen?
Since not all retrieved oocytes are mature and will successfully fertilize, develop into viable embryos, implant in the uterus, and result in a pregnancy and, ultimately, a live birth, how many oocytes a woman who decides to pursue egg-freezing should cryopreserve is likely the most important—but also the most difficult—question to answer. And yet, it is the one question that should be answered at the very beginning of the decision-making process because it ultimately determines how many retrieval cycles will be needed and at what cost.
Figure 1. Vaginal ultrasound of the right ovary demonstrating follicles of several sizes during an IVF cycle
The answer is so difficult because it depends on so many varying factors: The female’s age and her OR are obviously the two most important ones, but one should not forget to find out how many children the patient may ultimately want with help of her frozen eggs. To make a recommendation to a patient, therefore, is always only an educated guess because what cannot be predicted with certainty is how well (or poorly) the frozen eggs will thaw out, since this depends to a large degree on the inherent quality of those oocytes which at the time of freezing is not always obvious.
Moreover–in a circular pattern–egg quality declines with advancing female age, but also with declining OR, even if such declines happen prematurely in younger women. Consequently, superficial patient evaluations (especially in younger women) are often wrong because they automatically (and falsely) are assumed to have good quality eggs. Hence, young women before stimulation should be investigated with the same detail as older women.
Assuming no unusual findings in a patient, the literature suggests that, up to age 35, at least 8-12 mature oocytes should be cryopreserved (note the wide range!) per desired child, with likelihood of success, of course, increasing with more stored eggs. In other words, to determine how many eggs a woman should freeze per desired child also greatly depends on the coveted level of certainty for the prediction given: 8-12 mature oocytes, therefore, likely offer an approximately 75-80% probability, which still means that 20-25% of women with that (wide) range of eggs will not have enough eggs frozen to achieve even just one live birth.
And, as already noted above, achieving pregnancy cannot be equated with achieving healthy live birth, as pregnancies can be lost for a variety of reasons which, again, are highly patient-dependent. Miscarriages and practically all other pregnancy complications increase with age, and so do all potential medical problems a patient may have that may affect pregnancy, again pointing out the importance of a proper and detailed medical evaluation of every woman planning on freezing eggs.
Once an estimate has been made of how many eggs a woman should freeze to meet her expectations, the next big question arises: how many stimulation cycles will the patient require to achieve this goal? And the answer, once again especially in first cycles, can only be a crude estimate. Therefore, unfortunately, insufficiently informed women often start their egg-freezing experience believing that all they will need is one cycle of oocyte preservation. When after that cycle they learn that not enough eggs were retrieved and they need one or more additional cycles, they often are surprised and unable to afford them. Consequently, they find themselves in limbo, with only an insufficient number of frozen eggs, leaving them far from meeting their desired probability of success.
Does egg-freezing adversely affect fertility?
A question frequently asked is whether egg-freezing reduces a woman’s remaining egg pool (her OR). And the answer is a categorical no! The reason is simple: no additional eggs are lost that the patient would not have lost in this month anyhow. What so-called fertility drugs do is not recruit more eggs; the egg recruitment process is naturally going on all the time uninterrupted. Fertility drugs prevent some of those steadily recruited eggs from degenerating. In other words, the eggs obtained in an egg-freezing cycle (or in a regular IVF cycle) are saved from otherwise being lost. Consequently, there is no impact on the remaining OR, nor is the timing of menopause affected.
What happens after the retrieval?
You will very likely resume your usual menstrual cycle pattern within one to two months. Your frozen eggs will remain stored until you wish to use them. At many clinics, eggs are shipped out into long-term storage facilities. Storage facilities routinely bill for storage quarterly.
What happens if the frozen eggs are used or never needed? Whenever frozen eggs are used, moved, or discarded, storage costs end. Storage costs also automatically end if eggs are anonymously or openly donated to an infertile woman under treatment or for research. While donations for academic purposes seem to have become the most popular option in recent years, most data suggest that disposition decisions often evolve throughout a woman’s fertility journey, highlighting the importance of ongoing contact between clinic and patient, as intentions and plans can change over time.
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