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27. Oocyte Cryopreservation at an Earlier Age
Keywords
Oocyte cryopreservationFertility preservationOncofertilityAge-relatedPreventive medicineInfertility27.1 Brief History of Oocyte Cryopreservation
The idea to preserve items for future use dates back to the early humans, who learned to preserve food in order to travel larger distances and to help survive famine [1]. Over time, a variety of ways to preserve items of importance have been developed, such as the use of preservatives/desiccants, dehydration, and freezing [1]. The first reports of successfully preserving human gametes involved sperm, and in 1953, the first human was born from a frozen sperm sample [1, 2]. The first birth from a frozen oocyte did not occur until 1986, 33 years later [3]. This was two years after the first live birth from a cryopreserved embryo [2]. Furthermore, another live birth from a frozen oocyte was unable to be replicated for several more years [1]. The original patients possibly benefiting from oocyte cryopreservation were those diagnosed with cancer, who did not have a partner, or had ethical reasons for why they did not feel comfortable cryopreserving embryos [4].
Why was the cryopreservation and thaw of an oocyte more difficult than either for sperm or embryos? The meiotic spindles of oocytes are very sensitive to temperature changes, and oocytes have a large volume to surface ratio, significant water content, and a single membrane [5, 6]. Slow-freezing was the original method of oocyte cryopreservation, which involved placing embryos in the presence of low concentrations of cryoprotectant agents and slowly lowering the temperature until frozen [7]. The water content in the ooplasm forms ice crystals during this procedure, which may physically interrupt the meiotic spindle. Different recipes for various cryoprotectants and protocols for freezing and thawing did not help improve the overall efficiency of the slow-freeze method; there is only a 2% live birth rate per oocyte [8]. Vitrification was then discovered, which involves exposure of the oocyte to higher concentrations of cryoprotectants in very small volumes followed by plunging in liquid nitrogen to maximize the rapidity of cooling [2, 7]. This freezes oocytes in a state that has been described as “glass-like,” minimizes ice crystal formation, and improves oocyte survival and pregnancy rates [1, 2, 7, 9]. Due to the higher rates of success by vitrification, oocyte cryopreservation was no longer considered experimental, starting in 2012 [1, 2, 6, 7]. The number of cycles to cryopreserve oocytes has been on the rise ever since. Women may cryopreserve oocytes for several reasons, including in the setting of imminent gonadotoxic treatments such as chemotherapy or for banking in the setting of aging without a partner.
27.2 Rationale of Cryopreserving Oocytes in a Young Patient
27.2.1 “Need-Based”
Women of reproductive age may find themselves in a situation where a gonadotoxic agent (such as an alkylating agent-based chemotherapy or pelvic radiation) may be recommended for treatment of a number of disease states, including cancers. In the United States, approximately 70,000 men and women ages 15 to 39 are diagnosed with cancer every year [10]. Some of these individuals might not have children or may not have completed their families. This can increase the stress and devastation a new diagnosis such as cancer can have on a patient, even if the disease, with treatment, has an otherwise good prognosis [11]. The most commonly applied technique to safeguard a woman’s reproductive potential after a course of gonadotoxic treatment is controlled ovarian stimulation with oocyte retrieval in order to cryopreserve oocytes or embryos for later use [12]. This is ideally done before any gonadotoxic treatment is administered and can be performed by any modern Assisted Reproductive Technology (ART) Center. Other methods, such as ovarian tissue cryopreservation and sole use of GnRH agonists before and during gonadotoxic treatment to protect oocytes in situ, are still considered experimental or controversial and are outside the scope of this chapter.
Since fertility preservation for women became available, both the occurrence of counseling and the numbers of patients undergoing these procedures have increased over time [13]. A study of over 5000 patients revealed that most women counseled for fertility preservation had been diagnosed with breast cancer (41%), followed by lymphoma (28%) [13]. Only 7% of the patients had a benign disease that required a gonadotoxic therapy [13]. Of the benign diseases, the most common one was systemic lupus erythematosus, at 24.8% [13].
A study published by Quinn et al. in 2017 found that baseline antral follicle counts and outcomes of ovarian stimulation in regard to mature oocyte numbers were similar between age-matched patients with breast cancer and healthy women who were undergoing planned oocyte cryopreservation [14]. Another, larger study evaluated a number of other malignancies, including sarcomas, Hodgkin’s and non-Hodgkin’s lymphomas, gastrointestinal, cerebral, gynecological cancers, and a group of remaining malignancies in comparison to breast cancer patients to determine if oocyte yield was decreased [13]. They discovered that oocyte yield was not affected by malignancy type (other than ovarian cancer) but by maternal age in their group of patients [13]. This has been shown in several other studies as well [15–17].
Treatments most associated with decreased fertility include alkylating agent-based chemotherapies such as cyclophosphamide, pelvic radiation therapy (mostly due to effects on the ovaries rather than the uterus), and high-dose cranial radiation therapy (impairs pituitary function) [10]. The effects are typically dependent on dose and also on the age of the female undergoing the therapy [18]. Higher dosing and older women tend to have worse outcomes. However, even if a woman maintains her fertility after her cancer treatment, her pregnancy and live birth rates are typically lower than that of an average woman of the same age [18]. When a woman presents for discussion of oocyte cryopreservation, it is important to have an open discussion with the medical team that includes the oncologist and reproductive endocrinologist, regarding the plan for cancer treatment, if the treatment can be reasonably delayed to allow for an ovarian stimulation cycle and oocyte retrieval, as well as the likelihood of effects on fertility at the end of treatment.
27.2.2 Planned Oocyte Cryopreservation (“Anticipated Gamete Exhaustion,” “Elective,” “Social”)
Teenage pregnancies in the United States have decreased by 51% from 2007 to 2016 [19]. The birth rate for women in their 20s decreased by 4% in just 1 year (2015 to 2016) and has been declining steadily each year since 2006 [19]. The birth rates for these two age groups have been at record lows, while birth rates for women in their 30s and 40s are at their highest since the 1960s [19]. As a result, the general fertility rate has been declining from 2007 to 2013 and continuing in 2015 and 2016 [19]. The average age of a first-time mother in the United States is now 26.6, a record high for this country [19].
What is influencing the trend toward delaying childbirth? It is likely multifactorial. In part, it may be due to improved contraceptive methods and improved access to these methods [20]. It may also be affected by the decision to delay childbearing until after certain educational, financial, or career goals are met [20–23]. However, most women state that they are waiting for the right partner before pursuing pregnancy [22–24]. With the rate of marriage on the decline in the United States and the rate of births by unmarried women declining as well, this is not surprising [19, 25]. As women are often delaying childbirth for reasons outside of their control, there is a push to move away from terminology suggesting that planned oocyte cryopreservation is “elective,” “social,” or “non-medical,” but rather as possible preventative medicine for anticipated gamete exhaustion [26]. It has been argued that women protecting their gametes by cryopreservation prior to gonadotoxic therapies are undergoing preventive medicine and those women protecting their gametes from the threat of time are doing the same thing- possibly preventing infertility in the future [26]. Fertility preservation without a “medical indication/necessity” has been available for men for several decades, and with the streamlining of oocyte cryopreservation, it appears to be the time for this to be an option available for women as well.
27.3 Are There Limitations for Offering Oocyte Cryopreservation?
27.3.1 Lower Age Limit?
A lower age limit for oocyte cryopreservation becomes important when a patient is planned to undergo a gonadotoxic therapy at a very young age. As discussed in a previous section, there are several treatments for fertility preservation that are under investigation, such as ovarian tissue cryopreservation and in vitro maturation of oocytes, which may be useful in the future for pre-pubertal females [27, 28]. As of the time of this writing, the accepted methods of controlled ovarian hyperstimulation, oocyte retrieval, and vitrification are used for females who have already undergone puberty. Treatments for females who have not yet gone through puberty are considered experimental [29]. If a young patient has recently gone through puberty and is interested in oocyte preservation, discussion with the patient and her parents is warranted to review what is involved in the process, including injections, blood tests, and ultrasounds. Depending on the patient’s body habitus, it may be possible to perform follicular monitoring abdominally, but still perform transvaginal oocyte retrieval while the patient is sedated for decreased discomfort. For religious, cultural or other reasons, families may not be supportive of a vaginal ultrasound or pelvic examination at any point in the process, and it is best to discuss these issues ahead of the treatment so alternative options can be explored.
27.3.2 Upper Age Limit?
Is there an upper age threshold, where a practitioner should not recommend or allow a patient to undergo oocyte cryopreservation? The American Society for Reproductive Medicine (ASRM) prefers that those who wish to be oocyte donors donate between the ages of 21 and 34, to decrease the cytogenetic risks associated with oocyte age [30]. There are no recommendations from ASRM regarding an upper age limit for patients attempting to use or cryopreserve their own oocytes, although counseling regarding the risks of doing so should be provided [31]. Success rates have been shown to be higher when patients have cryopreserved oocytes at ≤35 years of age [4]. However, cryopreservation of oocytes at age 38 that are then used at age 40 may be more successful than attempts at natural pregnancy or with assisted reproduction at age 40 [4]. Providers in the United States are varied in their practice, and each clinic may have its own age threshold for women to proceed with their own eggs [31]. It may be reasonable to assess a patient’s ovarian reserve and then counsel her accordingly, to see if the possible benefits would outweigh the risks and costs of undergoing stimulation, retrieval, and storage [9, 32].
If the opportunity arises, patients should be encouraged to proceed with oocyte cryopreservation at a younger age, to avoid the risks of genetic abnormalities in older oocytes, as well as the risk of diminished ovarian reserve with age and the lower likelihood of a live birth with fewer cryopreserved oocytes, probably also with lower quality [32]. Unfortunately, the average age of a female inquiring about planned oocyte preservation is between 36 and 38 years old [20, 24]. It is important to continue the education of females about the age-related decline in fertility while giving honest facts about the success rates of oocyte cryopreservation resulting in a live birth at a later time point in their lives. Any woman considering oocyte cryopreservation should also be informed about the timeline for embryo transfer and the maximum age that the individual reproductive center would offer an embryo transfer based on obstetric and other risks associated.
27.4 Ovarian Stimulation Protocol Considerations
When a woman is undergoing oocyte cryopreservation, providers do not have to be concerned about how the stimulation will affect the endometrial lining or pregnancy in a fresh cycle. In addition, women undergoing oocyte cryopreservation are more likely to be high responders, as they are not in the clinic for infertility and may be at higher risk of ovarian hyperstimulation syndrome (OHSS). Strategies such as the use of GnRH antagonist protocols with agonist-only triggers to reduce the risks of OHSS should be considered in individuals with good ovarian reserve.
In situations where time is of the essence, such as in oocyte cryopreservation cases for cancer, consideration can be given to some of the newer strategies for ovarian stimulation, such as random-start and double stimulation cycles. These strategies take advantage of the theory that follicular growth occurs in waves and that two or more cohorts of follicles can grow and provide oocytes without unnecessary delay [33].
In a random-start stimulation cycle, stimulation is started without regard given to where the patient is in her menstrual cycle. This reduces the possibility of potential delay for controlled ovarian stimulation and consequently the delay in gonadotoxic treatment. This may allow an additional number of patients that may be able to take advantage of oocyte cryopreservation as the delay to cancer treatment can be significantly shorter. One study comparing random-start cancer patients matched with women undergoing conventional ovarian stimulation due to male, tubal, or uterine factor infertility revealed that the duration of stimulation was one day longer in the random-start patients, but the total number of oocytes and total mature oocytes were higher [34]. In a study comparing cancer patients undergoing random-start versus early follicular phase start stimulations, oocyte and embryo numbers were similar between the groups [35]. A 2017 systematic review of 19 publications also suggested that random-start ovarian stimulation is an effective option for cancer patients given similar outcomes as traditional protocols but with a shorter duration [36].
In a double stimulation cycle, a patient undergoes two stimulations and two oocyte retrievals within one 28-day “cycle” or time frame. This could potentially increase the total number of oocytes or embryos obtained in the same time period as a conventional stimulation cycle. A 2018 study compared follicular phase stimulation with immediate subsequent luteal phase stimulation in women with diminished ovarian reserve to see if the oocyte and embryo quantity and quality were comparable between the phases and if it would increase the total number of oocytes and embryos obtained [37]. The oocyte and embryo quality was found to be similar between the phases and more oocytes and embryos were obtained in the time period than if only a single stimulation had occurred [37]. This result has been shown in previous smaller studies as well [38, 39]. This protocol was utilized in a small study of ten cancer patients undergoing oocyte cryopreservation, and there were no delays in treatment or diagnoses of OHSS [40]. The use of the double stimulation protocol has been mostly studied in poor responders. Additional studies reviewing the safety in cancer patients given their typically normal ovarian reserve are needed.
27.5 Reported Recovery Rates and Performance After Oocyte Warming
Oocyte recovery rates and performance after warming are impacted by the patient’s age at cryopreservation, the method of cryopreservation (vitrification versus slow-freeze), as well as the individual ART center’s success rates. Survival rates are approximately 85–95% for vitrified oocytes, with younger oocytes surviving more readily than those harvested at an older age [2, 4, 41, 42]. Each center’s individual success rates may differ, but in general, there is an approximate 4–7% live birth rate per warmed vitrified oocyte and 2% per thawed slow-freeze oocyte [6, 8, 43]. Many recent studies have reported comparable outcomes from cryopreserved oocytes through the vitrification method versus using fresh oocytes [2, 42, 44, 45]. However, a recent retrospective analysis of data from 2013 to 2015 from the Society for Assisted Reproductive Technology (SART) revealed that the live birth rate from fresh donor oocytes was 11.4% higher than that from frozen donor oocytes [46]. This finding is unlikely to impact a patient’s interest in oocyte cryopreservation, as she may have personal or medical reasons for delaying pregnancy, and using her own fresh oocytes may not be an option. Furthermore, patients may prefer to try ART with their own genetic material than using fresh donor oocytes, especially when choosing the former does not preclude the latter. Nevertheless, there are physical changes happening in oocyte by cryopreservation, some of which are irreversible (such as zona hardening) and may help explain some of the discrepancies in outcome.
There have been several tools designed to assist providers in counseling patients regarding an optimal number of oocytes to attain for cryopreservation [41, 44]. To use these tools, a discussion of the patient’s goals is involved. This discussion should query a patient’s acceptable percentage risk of not having a live birth at a later date and how many children they ultimately desire. In 2013, a Gallup poll revealed 47% of women aged 30–49 desired two children total and 25% desired three children [47]. This can help guide the patient and the practitioner to decide how many oocyte cryopreservation cycles will be necessary to obtain a reasonable number of oocytes to approach the patient’s goals or to have a discussion regarding how realistic the patient’s expectations are. These tools are also created based upon particular programs’ success rates and vary in whether they account for embryo euploidy, etc. Providers need to take these factors into account when using these tools for assistance in counseling patients.
27.6 Discussion on Feasibility of Oocyte Cryopreservation in Young Patients and Future Prospects
As discussed previously, oocyte cryopreservation is becoming a widely available option for women desiring an attempt to achieve pregnancy at a later date, regardless of their reasoning. A criticism of oocyte cryopreservation is that the numbers of women returning to use their vitrified oocytes thus far are comparatively few, but as oocyte cryopreservation is a relatively new technology, these numbers may increase over time. A study of 1468 women who underwent oocyte cryopreservation for a reason other than cancer from 2007 to 2015 revealed that 9.3% of the patients had returned to use their oocytes, at an average of 2.1 years later [4]. Most of these women had vitrified oocytes due to age, whereas 12% had a medical condition other than cancer for which they cryopreserved oocytes in advance [4]. Most of the women were single at time of oocyte cryopreservation, and half returning to use their oocytes had since found a partner [4]. The other half of the women returning used donor sperm when using their oocytes [4]. Reasons for not returning might include natural pregnancy or the decision to not pursue pregnancy at all.
Despite the relatively low numbers of women returning to use their cryopreserved oocytes, a study of 201 women who underwent oocyte cryopreservation from 2012 to 2016 revealed that most of the women (89%) reported they were happy that they underwent fertility preservation, even if they were to never come back to use the oocytes [48]. Most of the women felt that oocyte cryopreservation provided them with increased control over their reproductive planning (88%) [48]. Regret was noted in 16% of the women who had undergone oocyte cryopreservation, and this feeling was linked to a perception of lower adequacy of information, less emotional support during the process, and if they had fewer than ten oocytes retrieved [48]. This highlights the need for robust pretreatment counseling, including realistic expectations for the treatment and for the possibility of the need for additional procedures in the future (needing additional cycles for a greater total number of oocytes, undergoing oocyte warming and embryo transfer in the future). Patients can also be referred to additional resources for emotional and mental support during the process.
After proper counseling, oocyte cryopreservation can be a useful treatment for women hoping to have a chance for a pregnancy at a later date. As oocyte cryopreservation becomes more prevalent, continued follow-up of patients and whether or not they eventually use their cryopreserved oocytes will be an area for research. Additional advocacy is warranted to help women with the financial aspect of the treatment, as cost is often a barrier to those who are interested and well-informed, regardless of their motive for oocyte cryopreservation. It is our hope that women who wish to become mothers who have not yet found the right partner or who have been diagnosed with a devastating illness will be able to have a practical chance to realize that dream.
