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The first human birth from a frozen oocyte was reported in 1986.1 Nearly 3 decades later, mature oocyte cryopreservation has emerged as a meaningful technology to preserve reproductive potential in women of reproductive age. In 2013, the American Society for Reproductive Medicine (ASRM) removed the “experimental” label from egg freezing but cautioned that more data on safety and efficacy were needed prior to widespread adoption of the technique.2
In this Update, we present the current protocols for oocyte cryopreservation, how we arrived at them, and the questions regarding outcomes that still remain. In addition, we discuss the ethical dilemmas egg freezing presents, according to the varying rhetoric within the media and our own profession. Finally, we consider what preliminary data suggest as to the live-birth rate using frozen eggs from women of varying ages and what the costs are associated with using oocyte cryopreservation as the approach to fertility treatment.
Vitrification and slow freezing: How did we get here and how effective are they?
Fertility preservation is a rapidly advancing area of reproductive medicine. Cryopreservation is the cooling of cells to subzero temperatures to halt biologic activity and preserve the cells for future use. Clinically, oocyte cryopreservation requires a patient to undergo in vitro fertilization (IVF). After egg retrieval, the oocytes are cryopreserved for use at a later time.
The prefix “cryo” originated from the Greek word “kryos,” meaning icy cold or frost. Cryopreservation is not a new science. In 1776, the Italian priest and scientist Lazzaro Spallanzani reported that sperm became motionless when cooled by snow. A pivotal discovery in the field came in 1949, when Christopher Polge, an English scientist, showed that glycerol, a permeating solute, could provide protection to cells at low temperatures.3 Progress in sperm cryopreservation advanced quickly, partly due to the ease of observing sperm motility as a marker of postthaw function.4
The ongoing evolution of cryopreservation science led to landmark achievements, including the first birth using human cryopreserved sperm in the 1950s, and the first human birth after embryo thaw in 1983. Since that time cryopreservation has become a cornerstone in the field of reproductive medicine.
Initial problems encountered with egg freezing
Although the first birth after thaw of a human oocyte occurred in 1986, oocyte cryopreservation was fraught with technical difficulties. Oocytes (vs sperm and embryos) proved challenging to successfully cryopreserve. The problem lay in the damage caused by water crystals forming ice and rising concentrations of intracellular solutes as cells were cooled to freezing temperatures.5 The large size and high water content of the human oocyte made it particularly vulnerable to the detrimental effects of freezing. In addition, freeze−thaw hardening of the zone pellucida led to decreased postthaw fertilization. The delicate meiotic spindle within the oocyte was prone to injury from ice crystals.6
Use of cryoprotectants, such as ethylene glycol, glycerol, and dimethylsulfoxide (DMSO), can prevent ice crystal formation, but high concentrations are theoretically toxic. The fine balance between protection and toxicity led to the development of diverse egg freezing protocols using various types and concentrations of cryoprotectants. Inconsistent results and lack of reproducibility among labs, together with concerns about postthaw oocyte function and safety, slowed the progression of oocyte freezing. By the end of the 1980s, clinical oocyte cryopreservation had been effectively halted and the field was confined to small groups of researchers who continued laboratory experiments with limited success.5
In 1997, clinical work with frozen oocytes resumed with a Bologna team reporting postthawing oocyte survival rates of up to 80% using propanediol as the primary cryoprotectant, and viable pregnancies with the use of intracytoplasmic sperm injection (ICSI) for fertilization.7,8 Since the late 1990s, further modifications in freezing technologies have resulted in greater success. And currently, both slow freezing and vitrification methods are used to preserve oocytes.
Slow freezing
Slow freezing involves a low rate of oocyte temperature decline with a simultaneous gradual increase in the concentration of cryoprotectants. As the metabolic activity of the oocyte decreases, the concentration of cryoprotectant can be increased to prevent ice crystal formation. Once solidification of the oocyte is achieved, the oocyte can be exposed to freezing at colder temperatures. Results of a meta-analysis of 26 studies revealed that, compared with using fresh oocytes, eggs thawed after slow-freezing yielded significantly lower rates of fertilization (61.0% [1,346/2,217] vs 76.7% [2,788/3,637]), clinical pregnancy rate per transfer (27.1% [95/351] vs 68.5% [272/397]), and live birth per transfer (21.6% [76/351] vs 32.4% [24/72]).9
Vitrification
Vitrification involves the rapid cooling of cells to extremely low temperatures. During vitrification, oocytes are exposed to high concentrations of cryoprotectants and, after a short equilibration time, rapidly cooled. The rate of cooling is dramatic, up to 20,000°C per minute—so fast that ice does not have time to form and a glass-like state is achieved within the oocyte. Studies suggest that the use of vitrification improves oocyte survival and function compared with slow freezing.9-11 A prospective randomized controlled trial comparing frozen/thawed with vitrified/warmed oocytes demonstrated superior oocyte function in the vitrification group, with higher oocyte survival (81% for vitrification/warming vs 67% for slow freezing/thawing); higher rates of fertilization, cleavage, and embryo morphology; as well as higher clinical pregnancy rates (38% for vitrified/warmed vs 13% for frozen/thawed).10
The Practice Committee of ASRM published a guideline for mature cryopreservation in 2013.2 The committee reviewed the literature on efficacy and safety of mature oocyte cryopreservation. Although data are limited, studies comparing outcomes of IVF using cryopreserved versus fresh oocytes, including four randomized controlled trials and a meta-analysis, provide evidence that previously vitrified/thawed eggs result in similar fertilization and pregnancy rates as IVF/ICSI with fresh oocytes. Similar to data from fresh IVF cycles, decreased success with oocyte vitrification is seen in women with advanced age, and delivery rates, not unexpectedly, are inversely correlated with maternal age.12
Safety outcomes data are limited but reassuring
Two major factors limit our current understanding of egg cryopreservation outcomes. First, many women who have cryopreserved their eggs have not yet used them and, second, babies born after use of cryopreserved oocytes have not reached ages in which safety of the technique can be fully evaluated. Despite this important gap in our knowledge, to date, results of studies examining safety outcomes of the procedure have been reassuring.
For instance, chromosomal analysis via fluorescence in-situ hybridization of embryos created with thawed oocytes versus controls revealed no difference in the incidence of chromosomal abnormalities, decreasing concerns about damage to the oocyte spindle secondary to freezing.13
Data from a review of 900 live births resulting from embryos created from thawed oocytes frozen via the slow freeze technique revealed no increase in the risk of congenital anomalies.14 Similarly, no increased risk of congenital anomalies or difference in birth weights was noted in a study of 200 live births after transfers with embryos derived from vitrified oocytes compared with fresh oocytes.15
In a study of 954 clinical pregnancies occurring in 855 couples with cryopreserved oocytes after assisted reproductive technology, the outcomes of 197 pregnancies from frozen/thawed oocytes were compared with 757 obtained from fresh sibling oocyte cycles. A significantly higher rate of spontaneous abortions at 12 weeks or less was observed in the frozen/thawed oocyte group. No statistically significant differences were noted in gestational age at delivery or in the incidence of major congenital anomalies at birth, but mean birth weights were significantly lower in fresh oocyte pregnancies. Interestingly, in the group of 63 women who had pregnancies derived from both fresh and thawed oocytes, no differences were noted in the abortion rate or mean birth weight.16
