Version May 2024
INTRODUCTION — While there are many reasons why a person may wish to delay childbearing, female patients' ability to become parents or create their desired family size may be limited by age-related fertility decline (eg, as women age, fecundity/fertility decreases and the risk of an aneuploid pregnancy increases). Fertility preservation for nonmedical indications is the process of cryopreserving oocytes and/or embryos prior to age-related loss of fecundity and increased risk of embryo aneuploidy. Given the predictable age-related fertility decline and trend toward delayed childbearing, some patients choose to preserve their fertility with oocyte or embryo cryopreservation.
This topic will review the candidates, protocols, and fertility preservation options available to patients, as well as outcomes. Related content on fertility preservation for patients undergoing cytotoxic treatment and all available cryopreservation techniques is presented in separate reviews.
●(See "Fertility preservation: Cryopreservation options".)
In this topic, when discussing study results, we will use the terms "woman/en" or "patient(s)" as they are used in the studies presented. However, we encourage the reader to consider the specific counseling and treatment needs of transgender and gender expansive individuals.
BACKGROUND
Trend toward delayed childbearing — Population-based birth statistics demonstrate a consistent increase in the proportion of females choosing to delay childbearing until later in their reproductive years [1]. This desire for later childbearing can conflict with age-related decline in female fertility. As the trends of delayed childbearing and awareness of the age-related decline in female fertility have increased, development of and demand for fertility preservation for deferred childbearing for nonmedical indications has grown and is considered part of an individual's reproductive autonomy by at least one national medical society [2-7]. As such, the percentage of cycles for fertility preservation in the United States rose from 5 percent in 2017 to nearly 7 percent by 2019 [8].
Societal trends are likely to support the continued development and greater use of oocyte cryopreservation to reduce the impact of female infertility due to advancing age. In some cases the cost of the procedure is covered by employers, although the ethics of this policy has been debated [9].
Age-related decline in fertility — The influence of female age on fertility has been clearly established by a number of observational studies, which have consistently demonstrated a decline in pregnancy rates with advancing maternal age. This decline begins as early as age 32 [10], and by age 45 years, as many as 99 percent of women are infertile [11]. Furthermore, cycles that result in pregnancy among older women are less likely to progress to live births because of higher rates of aneuploidy, miscarriage, and stillbirth in this population (figure 1 and figure 2). These relationships are further illustrated by outcome data from clinics performing in vitro fertilization (table 1 and figure 3). (See "Effects of advanced maternal age on pregnancy".)
Age-related female fertility decline results from reduced numbers of available oocytes and decline in oocyte quality:
●Oocyte loss – The progressive loss of oocytes that occurs from fetal life until menopause is one of the defining features of the age-related decline in female fertility. The oocyte pool peaks while the female fetus is in utero, reaching approximately six to seven million oocytes at 20 weeks of gestation. Subsequently, progressive atresia occurs so that the number of remaining oocytes is approximately one to two million at birth and 200,000 to 400,000 at the onset of puberty [12]. During the reproductive years, there is continued atresia, which occurs at an accelerated rate after the age of 37 in normal women [13]. The average age of menopause is approximately 51 years with some variation globally [14-17].
●Oocyte quality – As the number of oocytes declines over time, the quality of oocytes also declines and eventually reaches a critical threshold below which pregnancy is no longer possible. The decrease in quality primarily refers to an increased prevalence of oocytes that yield aneuploid embryos, largely due to dysfunction of the meiotic spindle [18]. Errors in meiotic segregation result in higher rates of chromosomally abnormal embryos, translating into higher rates of miscarriage and lower chances of pregnancy. It is estimated that the prevalence of aneuploid oocytes approaches 99 percent after the age of 45 [19,20].
Males do not experience the same predictable age-related decline in fertility as females. While male fertility can be impacted by age, the decline occurs much later in life [21]. Thus, sperm preservation is not typically performed for concerns of advancing age. The impact of advancing paternal age on pregnancy is discussed separately. (See "Effect of advanced paternal age on fertility and pregnancy".)
Role of crypreservation for assisted reproductive technology — Cryopreservation of oocytes or embryos does not avoid or prevent infertility. Rather, cryopreservation is a tool that provides oocytes or embryos for future use for patients who do in fact have infertility when conception is attempted.
As the age-related decline in fertility is primarily related to the oocyte and not the uterus, cryopreserving oocytes or embryos at a young maternal age may be a strategy to avoid infertility in female patients who plan to delay childbearing. In a sense, oocyte cryopreservation allows patients to serve as their own "egg donor" in the future, should they need, by cryopreserving oocytes at their current younger age. The patient's age at the time of oocyte retrieval, and not the age of the patient/uterus at the time of embryo transfer, predicts the likelihood of pregnancy and live birth.
●(See 'Approach by age group' below.)
●(See "Evaluation and management of infertility in females of advancing age".)
●(See "Effects of advanced maternal age on pregnancy".)
WHO IS A CANDIDATE?
Patient counseling — There is no single factor or set of absolute criteria that determine who is a good candidate for planned fertility preservation [7]. The main factors for consideration are patient age, markers of ovarian reserve, family-building goals, and the anticipated age at the time of likely childbearing. Patients considering oocyte cryopreservation as a method of fertility preservation should be informed of the probability of pregnancy should they need to use these oocytes in the future and, furthermore, that there is no guarantee of pregnancy or live birth [22]. Counseling patients about the benefits, risks, and costs (including insurance coverage if applicable) of oocyte cryopreservation to protect against female infertility due to advancing age is complex and should be done by a specialist with fellowship training in reproductive endocrinology and infertility.
Within the group of variables considered for patient selection, the patient's age is one of the main guiding factors. Female patients who are older at the time of oocyte cryopreservation should expect to have a lower probability of live birth in the future than those who are younger due to rising oocyte aneuploidy rates with advancing age. The highest probability of live birth following oocyte cryopreservation occurs for females ≤35 years of age [23]. In addition to age, assessment of markers of ovarian reserve, including anti-müllerian hormone (AMH) concentration, antral follicle count, and day 3 follicle-stimulating hormone (FSH) and estradiol (E2) concentration, can help guide counseling and manage expectations of oocyte yield and success rates. Counseling about oocyte cryopreservation is likely best focused on women between 30 to 37 years old (age group as per the authors), in younger individuals known to have a diminished oocyte pool, and patients with a family history of premature menopause (ie, premature ovarian insufficiency). (See 'Patient age' below and 'Markers of ovarian reserve' below.)
Patient age
Approach by age group — Extensive experience with oocyte donation has demonstrated that reproductive aging is primarily related to the "age" of the oocyte and is influenced little, if at all, by the "age" of the uterus. Thus, the ability of a person's uterus to successfully host a pregnancy is mostly maintained despite advancing maternal age. As a result, the probability of pregnancy when using donor oocytes is determined by the oocyte donor's age at the time of donation rather than the age of the recipient (figure 3) [24-26].
●Age <30 years – We counsel individuals under the age of 30 that planned fertility preservation may be of lower utility for them as there is an increased probability that cryopreserved oocytes or embryos will never be used to achieve a pregnancy. Generally, these patients will eventually conceive without using the cryopreserved oocytes [27]. Ultimately, the decision to proceed with planned oocyte cryopreservation is based on conversations with the patient about the risks and benefits of the procedure. Factors that are considered include the anticipated duration of delay to family building, the ideal number of children desired, and any known potential barriers to natural conception in the future (endometriosis, tubal factor, polycystic ovary syndrome [PCOS]). In general, the patient should have autonomy to make an informed decision regarding this reproductive choice.
Planned fertility preservation does benefit younger patients with specific medical issues, including diminished ovarian reserve; family history of premature ovarian insufficiency; and carriers for genetic breast cancer syndromes, such as BRCA gene mutations [28]. Additionally, lesbian individuals or couples may opt to cryopreserve oocytes or embryos at younger ages, as ART may be part of their family-building plan (eg, reciprocal IVF).
●Age 30 to 37 years – Patients in this age range are generally considered ideal candidates for planned fertility preservation as they are the most likely to have good quality oocytes to freeze while also having a relatively high probability of utilizing their frozen eggs [27]. Live birth rates of 50 to 69 percent have been reported for patients using eggs frozen before age 35 years [23,29,30]. (See 'Probability of live birth' below.)
●Age 38 to 45 years – Older patients with good ovarian reserve may respond well to ovarian stimulation and yield enough oocytes to have a reasonable chance of future live birth. However, these patients are counseled about increased chances of inadequate ovarian response to stimulation, increased risk of age-related aneuploidy, and decreased live birth rates compared with younger patients. The older patients are, the more eggs required to achieve the certain likelihood of live birth, as compared with younger patients [31]. In some settings, the patient may undergo multiple stimulation cycles to obtain an adequate number of eggs. (See 'Probability of live birth' below.)
•A study of 182 patients with infertility who froze supernumerary oocytes reported a live birth rate of 22 percent (4 out of 18) for subjects ages 41 to 43 years [32]. While this rate is lower than for younger patients, live birth was still achieved by nearly one-quarter of patients with an identified fertility challenge, although the number of study participants was very low.
•In a 2022 study including 543 patients who froze oocytes between 27 to 44 years of age (median age of 38.3 years), live birth rates stratified by patient age at the time of oocyte cryopreservation were 51 percent for those <38 years, 31 percent for individuals 38 to 41 years, and 22 percent for patients ≥41 years [33]. Importantly, among those patients who elected preimplantation genetic testing on the embryos created from their thawed oocytes, 17 percent had no embryos to biopsy due to suboptimal embryo development and 46 percent had no euploid embryos to transfer. Older age was associated with higher risk of no embryos to biopsy and lower chance of having at least one euploid embryo.
●Age ≥46 years – Patients ≥46 years old are generally not candidates for planned fertility preservation because of significantly reduced ovarian reserve. Some centers discourage female patients >43 years old from cryopreserving their own eggs because the rates of pregnancy and subsequent live birth are extremely low [34]. While there are no absolute upper or lower age limits, successful ovarian cryopreservation after the age of 45 is unlikely. (See 'Maximum age for fertility preservation' below.)
Ideal age — In the authors' practices, the ideal age to pursue fertility preservation procedures is typically between 30 and 37 because patients in this age group are the most likely to have good quality oocytes to freeze while also having a relatively high probability of utilizing their frozen eggs [27,33]. However, these procedures can also be considered at younger and older ages depending on factors such as ovarian reserve markers and planned age of childbearing. (See 'Approach by age group' above.)
Maximum age for fertility preservation — The maximum age for attempting oocyte cryopreservation may be as high as 45 years based on a study that evaluated the success of in vitro fertilization (IVF) in female subjects >44 years old. In this study, IVF yielded live births up to the age of 45 years, but success was limited to those patients producing >5 oocytes in response to ovarian stimulation [35]. Although pregnancy rates for patients 46 and 47 years of age were 17 and 9 percent, respectively, none of these pregnancies resulted in a live birth. Thus, it may be reasonable to consider oocyte cryopreservation for fertility preservation up to age 45 years as long as the patient is thoroughly counseled about the low probability of success.
Markers of ovarian reserve — In addition to age, assessment of markers of ovarian reserve, including AMH concentration, antral follicle count, and day 3 FSH and E2 concentrations, can help guide counseling. These measurements taken together can help the clinician counsel patients on the relative quantity of their oocytes and a predicted egg number at the time of retrieval. However, care should be taken to emphasize to patients that none of these markers are a "fertility test." Indeed, only attempting to conceive can demonstrate whether a patient is infertile or not. Patients should also know that the best marker of egg quality is chronologic age, and, therefore, age at the time of the procedure remains one of the most critical points of counseling. Generally speaking, however, a cycle day 2 or 3 FSH >10 international units/L, E2 >80 pg/mL, or AMH <1 ng/mL portends a poorer prognosis in terms of oocyte yield at the time of retrieval and failure to conceive in those undergoing IVF [36,37].
●(See "Female infertility: Evaluation", section on 'Assessment of ovarian reserve'.)
Planned age of childbearing — An additional factor for consideration is the length of time the patient wishes to delay childbearing. The probability of a naturally conceived pregnancy at that specific time in the future (eg, the patient's age in two years, five years, etc) is weighed against the probability of a live birth resulting from oocyte cryopreservation. The longer the interval of expected delay and, in turn, the older the patient's age, the more beneficial oocyte cryopreservation is likely to be. By contrast, oocyte preservation is not advised for planned pregnancy intervals of less than one year unless the patient anticipates using the frozen eggs to become pregnant with siblings in the future.
ESTABLISHED OPTIONS FOR FERTILITY PRESERVATION — For patients who are approaching advanced reproductive age (typically defined as 35 years) but are not ready to become pregnant or are not in the position to have a child, established fertility preservation options include embryo and oocyte cryopreservation.
Embryo cryopreservation — Embryo cryopreservation is a proven method of fertility preservation. Since the first human pregnancy following the transfer of cryopreserved embryos was described in 1983 [38], embryo cryopreservation has become a routine part of in vitro fertilization (IVF). Briefly, embryo cryopreservation follows a standard IVF procedure that typically involves controlled ovarian hyperstimulation and oocyte retrieval. Following retrieval, oocytes are then fertilized with sperm in the laboratory. The sperm can be provided by a participating male partner or by a non-identified or directed sperm donor [39]. The resulting embryos are cryopreserved and can be stored until the patient is ready to attempt to conceive. There is no known time limit for the duration of embryo storage; live birth has been reported following transfer of embryos that had been cryopreserved nearly 20 years earlier [40]. Details of both IVF and cryopreservation are presented separately. (See "In vitro fertilization: Procedure", section on 'Cryopreservation' and "Fertility preservation: Cryopreservation options", section on 'Embryo'.)
Oocyte cryopreservation — Although technically more challenging to perform than embryo cryopreservation, oocyte cryopreservation through vitrification is an established method of fertility preservation.
●Advantage of reproductive autonomy – This option may be appealing to patients who do not wish to create embryos or do not want to use donor sperm. Moreover, it allows for patients to maintain reproductive autonomy; they can choose to use the oocytes with a future partner or with donor sperm. In the United States in 2019, over 3000 transfers were performed of fresh embryos that were created using previously frozen eggs [8]. Nearly 47 percent of such transfers resulted in a live birth.
●Technique – The initial IVF cycle and oocyte retrieval are the same as for embryo cryopreservation. However, retrieved mature oocytes are not fertilized but go directly to vitrification and storage. With the advent of vitrification, oocyte cryopreservation has become much more successful in achieving pregnancies as compared with the older technology, slow freezing [41,42]. (See "Fertility preservation: Cryopreservation options", section on 'Oocytes'.)
●Live birth rate – A retrospective single-institution study reported on 543 patients who collectively underwent 800 oocyte cryopreservation cycles (median patient age 38.3 years; median time between the first cryopreservation and thaw 4.2 years), 605 thaws, and 436 oocyte transfers [33]. Eighty percent of thawed oocytes survived. Based on the data below, we advise oocyte cryopreservation be performed prior to age 38 if possible. While patients over age 38 may elect to preserve oocytes, they should be counseled on the higher likelihood of no live birth resulting from their oocytes.
•Live birth rates per transfer were 55 percent for euploid embryos and 31 percent for non-biopsied embryos.
•Final live birth rate (FLBR) per patient was 39 percent and comparable to that of age-matched in vitro fertilization cycles. The FLBR was >50 percent for patients aged <38 years at time of cryopreservation and for those who were able to thaw ≥20 metaphase II oocytes.
Combined oocyte and embryo cryopreservation — Some programs offer patients the option of cryopreserving both oocytes and embryos (with a designated male partner or sperm donor) in a single IVF cycle. For example, a patient may choose to cryopreserve 50 percent of oocytes and to fertilize the other 50 percent with sperm to cryopreserve embryos. If patients separate from a designated male partner, they can use their oocytes. If patients continue with the designated male partner, they can use the embryos. If patients whose embryos were created with donor sperm find a male partner, they can use the oocytes rather than the embryos generated with the donor sperm. This approach, however, results in lower numbers of each (oocytes and embryos) and is potentially best suited to patients with higher ovarian reserve and more oocytes expected to be retrieved.
CHOOSING BETWEEN EMBRYO OR OOCYTE CRYOPRESERVATION — Beyond live birth rates, factors that influence the choice of procedure include the need for a sperm donor at the time of the procedure, ability to perform preimplantation morphology assessment and genetic testing, and cost. Live birth rates are mainly driven by the age of the patient at the time of oocyte retrieval and thus are similar on a per-cycle basis between the two treatments. (See 'Probability of live birth' below.)
●Embryo cryopreservation – The need for sperm to create embryos is the main limitation of this approach; not all patients have a partner or desired sperm donor and may not wish to use a non-directed donor. Embryo cryopreservation also provides the patient with more information about the reproductive competency of the eggs and resultant embryos. While oocytes generally look identical under the microscope and are not typically assigned quality "grades," embryo morphology can vary quite a bit, and the embryo "grade" is somewhat predictive of pregnancy rates [43].
•Option of preimplantation genetic testing – While aneuploidy screening is not yet available for unfertilized oocytes, it is commonly performed on embryos (preimplantation genetic testing). Since aneuploidy is one of the most frequent causes of failed embryo implantation, testing for aneuploidy at the time of cryopreservation offers more information about the future chance of pregnancy [44,45]. However, this should not be mistaken with an increase in success. The reproductive potential of the patient's oocytes is the same whether they are fertilized at the time of oocyte retrieval or later, although more eggs may be lost during the thaw process if frozen oocytes are used, which will reduce the number of embryos available for transfer [46]. Thus, preimplantation genetic testing may be of greater benefit to older patients seeking fertility preservation with embryo cryopreservation as oocytes frozen at older ages may lead to false reassurance for patients due to the higher rates of aneuploidy.
-(See "Preimplantation genetic testing".)
•Potential legal consideration – If a patient and the partner providing sperm share legal ownership of the resulting embryos, they would both need to agree to transfer of the embryos (which may be years in the future). If a couple separates, a patient may not legally be able to use the embryos. (See 'Probability of live birth' below.)
●Oocyte cryopreservation – Oocyte cryopreservation preserves the reproductive autonomy of the patient. Since the oocytes will not be fertilized until a future date, oocyte cryopreservation avoids the need for a sperm donor at the time of the oocyte retrieval procedure. A majority of patients who seek oocyte cryopreservation state that they are doing so because they have not yet found a suitable partner [47]. As such, preserving oocytes allows patients the flexibility to have a child with a future partner. The percentage of oocytes that subsequently fertilize normally and divide to become an embryo suitable for transfer remains to be determined. However, long-term cryopreservation of oocytes has not been shown to increase embryonic aneuploidy when oocytes are thawed and fertilized many years later [48]. (See 'Aneuploidy' below and 'Probability of live birth' below.)
THE PROCESS
Ovarian stimulation — The goal of controlled ovarian stimulation is to stimulate development of multiple ovarian follicles, which will ultimately be retrieved as multiple mature oocytes for cryopreservation. Multifollicular development is achieved by exposure to follicle-stimulating hormone (FSH) levels beyond the normal physiologic threshold. In addition, controlled ovarian stimulation also requires supraphysiologic levels of luteinizing hormone to aid on oocyte maturation and an agent to prevent premature ovulation, either a gonadotropin-releasing hormone (GnRH) agonist or antagonist. In certain circumstances, adjuvant agents, such as selective estrogen receptor modulators, can be used to enhance response to stimulation. However, these treatments are not first line in ovarian stimulation protocols. (See "In vitro fertilization: Procedure", section on 'Ovarian stimulation'.)
Types of ovarian stimulation protocols — Long protocols refer to those in which a medication is started in the menstrual cycle that precedes the in vitro fertilization cycle. Short protocols refer to those in which stimulation medications are started at the time of the natural menstrual cycle and are more commonly used in current practice because they require less time and fewer injections. (See "In vitro fertilization: Procedure", section on 'Ovarian stimulation'.)
Briefly, commonly used protocols include the following:
●GnRH agonist (long) protocol – In these protocols, a GnRH agonist (eg, leuprolide acetate) is administered for approximately two weeks or until downregulation of the pituitary gland is complete, which is signaled by a withdrawal bleed. Exogenous recombinant FSH, human menopausal gonadotropins (hMG), or a combination of both is then initiated to stimulate follicle growth. When ovarian follicles are judged to be mature (generally signaled by at least two follicles 18 mm in size), a trigger (human chorionic gonadotropin [hCG]) is administered to induce the final maturation and release of the oocytes. (See "In vitro fertilization: Procedure", section on 'Ovarian stimulation protocols'.)
●GnRH agonist flare (short) protocol – GnRH agonists can also be used in conjunction with ovarian stimulation so that the initial agonist effect of the GnRH agonist on the pituitary gland can be used for ovarian stimulation. This so-called "flare" protocol can be started with spontaneous menstruation or after pretreatment with birth control pills. It is often combined with the maximum dose of FSH and/or hMG since this protocol is typically used in patients with diminished ovarian reserve. As with the GnRH agonist (long) protocol, a final trigger shot of hCG is administered when the ovarian follicles are judged to be mature. (See "In vitro fertilization: Procedure", section on 'Ovarian stimulation protocols'.)
●GnRH antagonist (short) protocol – In this protocol, ovarian stimulation is started either with the menstrual cycle or with a period of pretreatment with birth control pills. As in the previously described protocols, FSH, hMG, or a combination of both is used to stimulate multifollicular development. GnRH antagonists result in more rapid pituitary desensitization than GnRH agonists. GnRH antagonists are generally started when the lead follicle reaches 14 mm, when the follicles are at risk of premature ovulation. These injections are all continued until the administration of a trigger shot. Of note, with this protocol, the clinician can elect to use a GnRH agonist to trigger final follicle development to reduce the risk of ovarian hyperstimulation syndrome. Estrogen priming in the luteal phase can also be used in patients with diminished ovarian reserve or with a prior history of asynchronous growth of the follicle cohort. Estrogen may be administered orally or transdermally in the luteal phase, followed by gonadotropin started in the early follicular phase. (See "In vitro fertilization: Procedure", section on 'Ovarian stimulation protocols'.)
Detailed information regarding protocol selection and follicle aspiration is reviewed separately.
●(See "In vitro fertilization: Procedure", section on 'Ovarian stimulation'.)
●(See "In vitro fertilization: Procedure", section on 'Oocyte retrieval'.)
Oocyte retrieval/follicle aspiration — Upon completion of ovarian stimulation, the final step of the process is a minor surgical procedure in which ovarian follicles are aspirated and oocytes are retrieved. Oocyte retrieval is typically achieved through transvaginal ultrasound-guided needle aspiration of follicles; transabdominal retrieval is less commonly performed. This is performed 34 to 36 hours after trigger administration and under some type of analgesia/anesthesia, most commonly intravenous propofol with monitored anesthesia care. The needle is advanced into each follicle, and gentle suction is used to aspirate the follicular fluid and the egg. Complications from this procedure may include bleeding, infection, or injury to organs near the ovaries, but such complications are exceedingly uncommon (<1 percent). (See "In vitro fertilization: Procedure", section on 'Oocyte retrieval'.)
Embryo creation — For those patients who desire embryo cryopreservation, oocytes are fertilized with partner or donor sperm. After fertilization is confirmed, embryo development may be monitored for three to five days, at which time optimally developing embryos are frozen (cryopreserved). If desired, embryo biopsy for preimplantation genetic testing can be performed prior to freezing. Protocols vary by practice and geographic region. The process is discussed in greater detail elsewhere.
●(See "Preimplantation genetic testing".)
●(See "In vitro fertilization: Procedure", section on 'Embryo management'.)
OUTCOMES — Procedure risks, live birth rates, and obstetric risks specific to in vitro fertilization (IVF) for planned fertility preservation are discussed here. Immediate and long-term outcomes from IVF procedures are presented in related topics.
●(See "Assisted reproductive technology: Pregnancy and maternal outcomes".)
Procedure risks — The main risk of oocyte or embryo cryopreservation is ovarian hyperstimulation syndrome. The risks associated with oocyte retrieval include bleeding, pain, and infection, although complications from this procedure are generally low. (See "In vitro fertilization: Procedure", section on 'Oocyte retrieval'.)
While not a procedure-related risk, there is a chance that the number of oocytes retrieved is low. In this situation, the patient may be counseled to pursue multiple cycles of oocyte or embryo cryopreservation in order to ensure a reasonable probability of pregnancy, according to patient preference. Finally, all patients should be counseled that there is no guarantee of pregnancy or live birth with cryopreservation of oocytes or embryos.
Probability of live birth — Live birth rate is mainly impacted by the age of the patient at the time of oocyte retrieval; the older the patient is at the time of oocyte cryopreservation (with or without embryo creation), the lower the probability of live birth in the future because of age-related decline in oocyte quality. (See 'Age-related decline in fertility' above.)
●Embryo cryopreservation – In the United States in 2019, live birth rates in cycles using frozen-thawed embryos ranged from approximately 48 percent for women less than age 35 years to 39 percent for women ages 41 to 42 years and 33 percent for patients age 42 years and older [49].
•Impact of oocyte age at the time of freezing – The performance of a cryopreserved embryo is related to the age of the female when the embryo was frozen, not the age of the patient when the embryo was thawed and transferred. Thus, the number of embryos transferred after thawing is based on the age at time of embryo created. For example, a patient who cryopreserved multiple embryos at 34 years of age and plans a transfer at 42 years of age could expect to have a single embryo thawed and achieve both a high pregnancy rate and low risk of multiple gestation.
•Impact of preimplantation genetic testing – Some couples may opt for preimplantation genetic testing on the embryos that will be cryopreserved. Since aneuploidy is believed to be one of the most common age-associated factors to cause embryo implantation failure, cryopreservation of euploid embryos should theoretically result in high live birth rates regardless of the age of the female at the time of cryopreservation. In a retrospective cohort of 4429 women who underwent up to three consecutive frozen euploid single-embryo transfers, the live birth rates after the first, second, and third FE-SET were 64.8, 54.4, and 54.1 percent per transfer, respectively. The cumulative live birth rate after up to three consecutive FE-SET was 92.6 percent [50].
●Oocyte cryopreservation – A few studies have reported on live birth rates following planned fertility preservation:
•In a study of 1468 women who underwent oocyte vitrification for planned fertility preservation (mainly due to advancing age), 137 women (9 percent) returned to use their oocytes [29]. Resultant live birth rates per patient ranged from 50 percent (patients ≤35 years of age) to 23 percent (patients ≥36 years of age). This study reported increased live birth rates with increasing numbers of frozen oocytes thawed, with the highest live birth rates seen in women ≤35 with 15 oocytes (85 percent live birth rate).
•In a study including over 5200 women who underwent planned oocyte preservation, cumulative live birth rates per patient ranged from 68.8 percent to 25.5 percent for women ≤35 years and >35 years, respectively [30].
•In a study of infertile couples, 182 warming cycles of supernumerary vitrified oocytes resulted in significantly lower clinical pregnancy rates per transfer with increasing maternal age, from 48.6 percent (17/35) for age ≤34 years down to 22.0 percent (4/18) for ages 41 to 43 years [32]. However, it is of note that oocytes derived from infertile women may perform differently than oocytes of those who are not infertile.
●Tools for estimating live birth – Various tools are available to help clinicians and patients understand the relationship between age, number of oocytes retrieved, and probability of achieving a live birth. One such example is available online [51]. One available online calculator, which has not been externally validated, predicts that, if 10 oocytes are cryopreserved for women 30 and 37 years of age, the probability of achieving one live birth using thawed oocytes is 69 and 50 percent, respectively [31]. (See 'Age-related decline in fertility' above.)
Obstetric risks — Risks specific to oocyte cryopreservation for delayed childbearing are discussed here. Potential risks associated with ovarian stimulation, IVF, and pregnancy are reviewed separately.
●(See "Assisted reproductive technology: Pregnancy and maternal outcomes".)
Aneuploidy — Karyotype evaluation of frozen-thawed oocytes has shown no increase in the number of abnormal or stray chromosomes compared with fresh oocytes [52], and fluorescence in situ hybridization has shown the incidence of aneuploid embryos is no different for embryos resulting from frozen oocytes and those resulting from fresh oocytes [53]. Similarly, studies of preimplantation genetic testing of embryos from cryopreserved oocytes have reported no increase in embryonic aneuploidy when compared with embryos from fresh oocytes [48,54]. Furthermore, there have been no reports of an increased incidence of aneuploidies among live births reported from frozen and thawed oocytes. (See "Genetic testing", section on 'Cytogenetic testing and FISH'.)
Chromosomal abnormalities are of particular concern due to the fragility of the meiotic spindle. Because chromosomes segregate along the spindle apparatus during meiosis, proper functioning is essential to avoid embryonic aneuploidy. Although oocyte cooling can disrupt the spindle [55,56], studies have consistently shown that the spindle reforms after thawing. These studies used a computer-assisted polarization microscopy system (polyscope) to analyze the meiotic spindle of oocytes without affecting their viability [57]. With use of this device, spindle repolymerization has been observed to occur at similar rates in both slow-frozen and vitrified oocytes, and normal spindle configuration was seen in similar proportions of frozen-thawed oocytes and controls [58].
Congenital anomalies — There have been no reports of an increased incidence of congenital anomalies or other adverse outcomes among live births resulting from frozen and thawed oocytes [59-62]. The largest review of perinatal outcomes after oocyte cryopreservation analyzed outcomes in 936 live births from cryopreserved oocytes and found that the rate of congenital abnormalities (1.3 percent) was not increased compared with the rate of congenital abnormalities in spontaneously conceived infants [59].
Other data include:
●A study of 50 children born after autologous oocyte vitrification/warming showed no differences in birth weight or birth defects when compared with children born from patients undergoing IVF with fresh oocytes [63].
●Additionally, a follow-up study of 116 children born from previously vitrified oocytes and followed up to the age of six showed no differences in mental or physical development when compared with naturally conceived children [64].
The risk of congenital anomalies after all types of assisted reproductive technology is reviewed separately. (See "Assisted reproductive technology: Infant and child outcomes".)
Obstetric and childhood outcomes — Advancing maternal age remains the most significant driver of adverse obstetric outcomes (figure 4). Although pregnancy outcomes in patients of advanced maternal age are associated with increased rates of complications (eg, pregnancy-induced hypertension, gestational diabetes), the majority of pregnancies in females <50 years of age have good outcomes in the absence of underlying maternal medical conditions. (See "Effects of advanced maternal age on pregnancy".)
●Embryo cryopreservation – Obstetric outcomes in pregnancies resulting from cryopreserved embryos are similar to those resulting from fresh embryos with respect to gestational age at delivery, perinatal mortality, and rates of major congenital malformations [65,66]. However, pregnancies resulted from cryopreserved embryos do have higher rates of morbidly adherent placenta, large for gestational age infant, and preeclampsia [67,68]. Patients who choose to cryopreserve oocytes should be counseled regarding the risks associated with an IVF-derived pregnancy should they ever use their oocytes.
●Oocyte cryopreservation – While there are few large case series of pregnancy and childhood outcomes following successful oocyte cryopreservation performed for fertility preservation, there does not appear to be an increased risk with oocyte cryopreservation compared with other fertility treatments, but available data are limited. In one series of over 1000 live births following the use of thawed oocytes to achieve pregnancy, the obstetric and newborn outcomes were similar to those observed in live births derived from the use of fresh oocytes [69].
Obstetric and childhood outcomes after all types of assisted reproductive technology is reviewed elsewhere. (See "Assisted reproductive technology: Pregnancy and maternal outcomes".)
Satisfaction or regret — Since the American Society of Reproductive Medicine determined in 2012 that oocyte cryopreservation should no longer be categorized as an experimental technology, small studies have attempted to identify long-term emotional outcomes following use of this technology [47,70,71]. A retrospective cohort survey study of 201 women who underwent planned oocyte preservation between 2012 and 2016 reported the following [72]:
●Satisfaction – Separate from decision regret, 88 percent noted feelings of increased control over their reproductive planning, and 89 percent stated they would be happy with the decision even if the frozen eggs were never used.
●Decision regret – Based on answers to the validated Decision Regret Scale, 51 percent had no decision regret, 33 percent reported mild regret, and 16 percent experienced moderate to severe decision regret.
●Risk factors for decision regret – Increasing regret was associated with decreased numbers of preserved oocytes, perceived adequacy of information at the time of decision making, and patient-estimated probability of achieving a live birth (increased information and higher perceived odds of having a live birth were associated with reduced decision regret).
•Women who froze ≤10 oocytes had a fourfold increase in risk of regret compared with women who froze >10 oocytes in an age-adjusted logistic regression model.
•Approximately 6 percent of women anticipated an unrealistically high live birth rate of 100 percent.
As nearly one-half of patients in the study above expressed some level of regret, the authors' counseling process includes discussions addressing decision regret, anticipated oocyte count based on the patient's anti-müllerian hormone testing and antral follicle count, and realistic expectations of the potential live birth rate from the procedure based on the patient's age at the time of freezing. Patients are advised that risk of regret is higher, and chance of live birth is lower, in patients who freeze <10 oocytes; in some cases, multiple cycles may be beneficial to improve the overall oocyte yield.
LOGISTICS AND COST — Patients who are considering fertility preservation should first have a detailed consultation with a reproductive endocrinologist to address the issues discussed above. Potential candidates will generally undergo baseline ovarian reserve testing (eg, anti-müllerian hormone [AMH], day 3 serum follicle-stimulating hormone and estradiol levels and antral follicle count) prior to initiating treatment. The processes of embryo and oocyte cryopreservation are identical to that of in vitro fertilization (IVF) up until the time of the oocyte retrieval. As of 2020, in the United States, the cost of embryo and oocyte cryopreservation procedures is comparable to that of IVF. A single cycle, including monitoring visits, surgical, anesthesia, and embryology costs, can total approximately USD $12,000 [73]. Medications cost an additional USD $1000 to $5000 depending on the dose and amount needed. Annual storage fees are approximately USD $400 per year.
Mathematical decision tree modeling has been performed to help patients understand if oocyte cryopreservation for deferred reproduction is a cost-effective model. One model reported that oocyte cryopreservation at age 35 years in a patient who does not plan to reproduce until age 40 increases the odds of live birth from 42 to 62 percent and decreases the cost per live birth from USD $55,060 to $39,946 should a patient need assisted reproduction at age 40 [74].
Discussions of ethical issues of nonmedical fertility preservation and cost coverage are discussed elsewhere [75].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Female infertility".)
RESOURCES FOR PATIENTS AND CLINICIANS
●Society for Assisted Reproductive Technology (SART) – Provides free access to information for patients and clinicians.
●European Society of Human Reproduction and Embryology (ESHRE) – A clinician-oriented site that requires membership.
SUMMARY AND RECOMMENDATIONS
●Procedure rationale – Females who delay childbearing may face age-related infertility by the time they desire to become pregnant. Thus, patients who wish to delay childbearing may consider methods of planned fertility preservation, including embryo and oocyte cryopreservation. (See 'Background' above.)
●Impact of biologic age – Reproductive aging is primarily related to the "age" of the oocyte and is influenced very little, if at all, by the "age" of the uterus. Age-related female fertility decline results from reduced numbers of available oocytes and decline in oocyte quality with increasing age. (See 'Age-related decline in fertility' above.)
●Live birth rates – Live birth rates ranging from approximately 25 to over 50 percent have been reported following embryo and oocyte cryopreservation for nonmedical indications. Likelihood of success drops with increasing patient age at the time of oocyte retrieval. (See 'Probability of live birth' above.)
●General approach by age – While the clinical plan is individualized to each patient, the authors take the general following approach based on patient age (see 'Approach by age group' above):
•Age ≤30 years – We counsel these patients that planned fertility preservation may be of lower utility under the age of 30 because there is an increased probability that cryopreserved oocytes or embryos will never be used to achieve a pregnancy. (See 'Approach by age group' above.)
•Age 30 to 37 years – Patients in this age range are generally considered ideal candidates for planned fertility preservation as they are the most likely to have good quality oocytes to freeze while also having a relatively high probability of utilizing their frozen eggs. (See 'Ideal age' above.)
•Age 38 to 45 years – Older patients with good ovarian reserve may respond well to ovarian stimulation and yield enough oocytes to have a reasonable chance of future live birth. However, these patients are counseled about increased chances of inadequate ovarian response to stimulation, increased risk of age-related aneuploidy, and decreased live birth rates compared with younger patients. (See 'Approach by age group' above.)
•Age ≥46 years – Patients ≥46 years old are generally not candidates for planned fertility preservation because of significantly reduced ovarian reserve. Successful live birth resulting from planned oocyte cryopreservation after the age of 45 years is unlikely. (See 'Maximum age for fertility preservation' above.)
●Options for fertility preservation – Established fertility preservation options include embryo and oocyte cryopreservation. (See 'Established options for fertility preservation' above.)
•Embryo cryopreservation is a well-established technique that has been used for decades with in vitro fertilization (IVF). The major limiting factor is the need for the use of sperm, which makes it applicable only for female patients who have a participating male partner or those who are interested in using donor sperm. (See 'Embryo cryopreservation' above.)
•Oocyte cryopreservation is an effective means of fertility preservation for patients who do not have a participating male partner, who do not wish to use donor sperm, or do not wish to create embryos. (See 'Oocyte cryopreservation' above.)
•Combined oocyte and embryo cryopreservation – Some fertility programs offer patients the option of cryopreserving both oocytes and embryos (with a designated male partner or sperm donor) in a single IVF cycle. The patient can decide at a future date whether or not to use the existing embryos or create new embryos with a male partner or donor sperm. (See 'Combined oocyte and embryo cryopreservation' above.)
●Risks – Despite the use of controlled ovarian stimulation protocols, the main risk of oocyte or embryo cryopreservation is ovarian hyperstimulation syndrome. The risks associated with oocyte retrieval include bleeding, pain, and infection, although complications from this procedure are generally low. (See 'Ovarian stimulation' above and 'Procedure risks' above.)
●Obstetric and childhood outcomes – Advancing maternal age remains the most significant driver of adverse obstetric outcomes. Childhood outcomes from embryo and oocyte cryopreservation appear to be similar with other reproductive technologies, but there is a greater body of data for embryo cryopreservation compared with oocyte cryopreservation. (See 'Obstetric and childhood outcomes' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Richard Paulson, MD, who contributed to an earlier version of this topic review.
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