Recent Developments in Fertility Research

Is Egg Freezing Ready for Prime Time?

Is egg freezing ready for prime time?Dr. Jain believes this technology has arrived and appears to be safe. Dr. Fritz says no, not yet, for several reasons.

Yes. This technology has arrived and appears to be safe.

John Jain, MD

John Jain, MD

The portal to successful oocyte cryopreservation (egg freezing) has recently opened, a technological advance that provides both fertile and infertile women an opportunity to safeguard fertility. The technology can be used to preserve fertility in women who wish to delay pregnancy to pursue educational and professional goals, and in women diagnosed with cancer who face therapies that will destroy their ovarian function. Oocyte cryopreservation can also be used by those undergoing IVF who, for ethical or religious reasons, wish to avoid freezing embryos.

Aging eggs chiefly to blame for decline in age-related fertility.

It’s now well established that oocyte aging and not uterine factors is the primary cause of the age-related decline in reproductive function.1 Thus, the strategy of freezing eggs seems an obvious extension of assisted reproduction technology. Studies of cryopreservation have shown that eggs do not deteriorate during long-term storage at the temperature of liquid nitrogen (-196 C).2 Therefore, a young woman may undergo oocyte cryopreservation and then act as her own egg donor at a time when she is ready for reproduction, perhaps as long as 10 or 20 years later, without concern for diminished endometrial receptivity over time.3

However, unlike frozen embryos, which are a standard part of IVF practice and represented by more than 150,000 births worldwide, consistent and acceptable pregnancy rates using frozen eggs have been elusive.4 Approximately 150 births have occurred in the 20 years since Chen reported the first birth after oocyte cryopreservation in 1986.5

The technical difficulties of oocyte cryopreservation have been related to three things:

  1. High water content and intracellular ice crystal formation upon freezing;
  2. Hardening of the zona pellucida during cryopreservation, and thus difficulty with subsequent fertilization; and
  3. The relatively large size of the cell, and thus an unfavorable surface-to-volume ratio for equilibration of solutes.

These roadblocks have been gradually overcome by the use of cryoprotectants, ICSI for fertilization, and the replacement of sodium in freezing media with an osmolyte like choline.6 The net effect has been a substantial increase in oocyte survival and viability after cryo-preservation.

A recent meta-analysis by Oktay and colleagues reported a live birth rate per transfer of 28.4% following oocyte cryopreservation, a rate comparable to cryopreserved embryos.8 More recently, investigators from several countries have reported pregnancy rates above 35% from cryopreserved oocytes, similar to the 37.5% rate derived from fresh oocytes. Many studies also report multiple gestations following oocyte cryopreservation, suggesting that the technology is robust.

Alternatives to oocyte cryopreservation have many limitations. The current recommendation for single women to cryopreserve embryos derived from donor sperm introduces many personal challenges, such as paternity issues related to nonanonymous sperm donation, the disposition of embryos should that woman marry, and in the case of anonymous sperm donation, the emotional discomfort of not knowing who fathered the child. In addition, frozen embryos are associated with lower pregnancy rates than fresh ones. Other techniques to preserve oocytes using ovarian cortex cryopreservation or in vitro maturation are still in their infancy. There’s even been a recent report describing residual cancer cells in ovarian cortex harvested from a patient with leukemia.

Safety questions remain

A number of questions relating to the safety of cryopreserved oocytes remain. The number of established pregnancies and deliveries derived from cryopreserved oocytes is limited. Despite concern that oocyte cryopreservation may induce damage to the meiotic spindle that could lead to chromosomal aneuploidy or other karyotypic abnormalities, no increase in the number of abnormal or stray chromosomes in thawed, previously cryopreserved oocytes has been observed.10 The incidence of chromosomal abnormalities in human embryos obtained from frozen oocytes was no different from noncryopreserved controls using fluorescence in situ hybridization.

Key Points

  • Our role should be to empower our patient’s decision-making process and provide evidence-based data.
  • A woman under age 25 who freezes her eggs today is more than twice as likely to succeed with IVF 10 years later using fresh eggs rather than frozen.

Other studies of children conceived from cryopreserved oocytes failed to show any increase in congenital or karyotypic abnormalities, or intellectual or developmental deficits.12,13 Perhaps more reassuring is the long history of embryo cryopreservation, the track record of more than 150,000 births cited earlier. The incidence of fetal developmental complications or the threat of obstetric and perinatal problems is no different among children conceived from frozen embryos versus fresh or conceived spontaneously.14 However, the number of live births following egg freezing is still too small to draw any reliable conclusion on these anomalies.

Is withholding egg freezing sexist?

The consistency and reproducibility of good pregnancy rates and perinatal outcomes from many international centers—even though based on small sample sizes—suggest that women can now be offered oocyte cryopreservation. Our role as reproductive specialists should be to empower our patient’s decision-making process through counseling and to provide evidence-based data. To withhold oocyte cryopreservation is sexist. After all, men have long-enjoyed the option of freezing sperm; why should the standards be different for women? Although the process of oocyte cryopreservation is more involved than sperm cryopreservation, there are abundant data to indicate that the procedures involved are extremely safe and do not carry long-term risks. We have to recognize the autonomy of the patient and not be overly paternalistic. We should trust that our patients better understand the value of cryopreserving their genetic legacy and the complex interplay of emotional, professional, and personal factors that contribute to the decision.

To assure patient protection, centers offering oocyte cryopreservation should first establish their own success rates under an Institutional Review Board (IRB)-approved protocol. Results should be reported using the same high standards established by the Society for Assisted Reproductive Technologies (SART), and each patient should be thoroughly counseled on the risks, benefits, and alternatives of oocyte cryopreservation. Based on such feasibility trials, each center should provide evidence-based guidelines for egg freezing, such as age of inclusion, anticipated pregnancy rates, and the number of oocytes needed for each pregnancy attempt. Clinicians should also share real-time information comparing that center’s results to domestic and global success rates with their patients. Continuing to conduct a program of oocyte cryopreservation under IRB oversight as recommended by the American Society for Reproductive Medicine assures fair disclosure and should be followed until it is considered standard practice.15 That decision will most likely take many years and hundreds or thousands of births to realize. Many women do not have the luxury of time.

The patient must bear the high costs of oocyte cryopreservation. Once again, she is the most qualified person to determine her financial priorities. For some, a chance to conceive a genetically-related child supersedes all other material choices. To avoid financially exploiting patients, centers offering oocyte cryopreservation should disclose all costs involved, including the costs of ovarian hyperstimulation, oocyte retrieval and cryopreservation, oocyte storage, and embryo transfer prior to commencing the cycle.

FERTILITY WILL DECLINE with age. Oocyte cryopreservation offers a chance to safeguard fertility. Consistent and reproducible results from many international centers suggest that this technology has arrived and does not appear to be unsafe. Withholding oocyte cryopreservation from women faced with imminent loss of ovarian function is sexist, paternalistic, and inappropriate. Responsibly offering the technology in an evidence-based, transparent manner under the guidance of an IRB empowers patients to make an informed decision.

REFERENCES

  • Maroulis GB. Effect of aging on fertility and pregnancy. Semin Reprod Endocrinol. 1991;9:165-175.
  • Machtinger R, Dor J, Levron J, et al. The effect of prolonged cryopreservation on embryo survival.Gynecol Endocrinol. 2002;16:293-298.
  • Paulson RJ, Hatch IE, Lobo RA, et al. Cumulative conception and live birth rates after oocyte donation: implications regarding endometrial receptivity. Hum Reprod. 1997;12:835-839.
  • Tucker MJ, Shipley S, Liebermann J. Conventional technologies for cryopreservation of human oocytes and embryos. Methods Mol Biol. 2004;254:325-344.
  • Chen C. Pregnancy after human oocyte cryo-preservation. Lancet. 1986;1:884-886.

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