Yes. This technology has arrived and appears to be safe.
John Jain, MD
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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 (-196C).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.7
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.9
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.11
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
1. Maroulis GB. Effect of aging on fertility and pregnancy. Semin ReprodEndocrinol. 1991;9:165-175.
2. Machtinger R, Dor J, Levron J, et al. The effect of prolonged cryopreservation on embryo survival. Gynecol Endocrinol. 2002;16:293-298.
3. 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.
4. Tucker MJ, Shipley S, Liebermann J. Conventional technologies for cryopreservation of human oocytes and embryos. Methods Mol Biol. 2004;254:325-344.
5. Chen C. Pregnancy after human oocyte cryo-preservation. Lancet. 1986;1:884-886.
6. Boldt J, Cline D, McLaughlin D. Human oocyte cryopreservation as an adjunct to IVF-embryo transfer cycles. Hum Reprod. 2003;18:1250-1255.
7. Jain JK, Francis MM, Bayrak A, et al. Pregnancy outcome after cryopreservation of all oocytes from a single ovulatory cohort:
a prospective trial. Fertil Steril. 2005;84(suppl 1):S350.
8. Oktay K, Cil AP, Veeck L, et al. Comparative efficiency of IVF between frozen-thawed and fresh oocytes: a meta-analysis.
Fertil Steril. 2005;84(suppl 1):S37.
9. Meirow D, Levron J, Eldar-Geva T, et al. Ovarian tissue storing for fertility preservation in clinical practice: successful
pregnancy, technology and risk assessment. Fertil Steril. 2005;84(suppl 1):S2.
10. Gook DA, Osborn SM, Bourne H, et al. Fertilization of human oocytes following cryopreservation: normal karyotypes and
absence of stray chromosomes. Hum Reprod. 1994;9:684-691.
11. Cobo A, Rubio C, Gerli S, et al. Use of fluorescence in situ hybridization to assess the chromosomal status of embryos
obtained from cryopreserved oocytes. Fertil Steril. 2001;75:354-360.
12. Porcu E, Fabbri R, Seracchioli R, et al. Obstetric, perinatal outcome and follow up of children conceived from cryopreserved
oocytes. Fertil Steril. 2000;74(suppl 1):S48.
13. Winslow KL, Yang D, Blohm PL, et al. Oocyte cryopreservation: a three year follow-up of sixteen births. Fertil Steril. 2001;76(suppl 1):S120-S121.
14. Wennerholm UB, Hamburger L, Nilsson L, et al. Obstetric and perinatal outcome of children conceived from cryopreserved
embryos. Hum Reprod. 1997;12:1819-1825.
15. Practice Committee of the American Society for Reproductive Medicine. Ovarian tissue and oocyte cryopreservation. Fertil Steril. 2004;82:993-998.
No, not yet; for several reasons.
Marc A. Fritz, MD
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In 2004, the American Society for Reproductive Medicine (ASRM) Practice Committee concluded that oocyte cryopreservation must
be considered investigational, should not be offered or marketed as a means to defer reproductive aging in young healthy women,
and should proceed only with the approval and oversight of a prop-erly constituted institutional review board (IRB), even
when offered to women with malignancies and other illnesses requiring imminent treatment that may cause ovarian failure.1 Why?
FIRST AND FOREMOST, the total number of documented live births resulting from frozen human oocytes worldwide is quite small—approximately 200.
Obviously, the experience of any one center, even those at the forefront of this developing technology, is even more limited.
Certainly, we can expect that results will vary with age at the time of oocyte harvest and with other factors, but available
data are not yet sufficient to permit any meaningful analysis. Consequently, it's simply not yet possible to offer any valid
estimate of the likelihood for success with in vitro fertilization (IVF) using frozen oocytes. Without such information women
cannot make an informed decision about whether treatment can meet their needs and expectations.
Since it is inappropriate to represent results achieved with standard IVF at other centers as one's own, it is certainly also
in-appropriate to suggest that the results achieved with oocyte cryopreservation in a small number of pioneering centers accurately
predict outcomes for a center that has no significant experience with the technology. If results of standard IVF vary significantly
among centers, as they clearly do, results with egg freezing surely will also.
SECOND, we don't yet know what methodology will produce the best results with oocyte cryopreservation, because the technology is
still evolving. Published data suggest that the technology and results are improving, but once again, the collected experience
with any one method remains limited. Emerging evidence suggests that vitrification might yield better results than more traditional
"slow freeze" methods for oocyte cryo-preservation. However, the total number of documented live births resulting from IVF
using previously vitrified eggs is less than 50 worldwide—hardly a sufficient basis for estimating the likelihood of success
for an individual woman.
The evidence doesn't validate the underlying assumption
READER RESPONSE FORM
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THIRD, the great promise of egg freezing is that the technology can offer women who freeze their eggs when they are young the opportunity
to preserve their fertility at its peak and thus to avoid the otherwise inevitable decline in fertility associated with aging.
Here's the underlying premise for that promise: that undergoing IVF later on, using eggs frozen now, will substantially improve
the odds of achieving a successful pregnancy for women who must delay childbearing until their latter reproductive years.
However, current evidence does not validate that assumption.
It's certainly true that the likelihood of achieving a successful pregnancy declines steadily with increasing age and is generally
poor for women in their late reproductive years. However, it is neither reasonable nor appropriate to compare the results
of IVF using frozen eggs to the natural cycle fecundity of older women receiving no treatment. Rather, to accurately judge
the current value of the technology, the results of IVF in older women using eggs frozen at a younger age must be compared
to those of IVF at the same or similar age using fresh oocytes.
Currently, the collected results of IVF using cryopreserved oocytes for women of all ages, most of whom have been young, indicate
that fertilization rates, implantation rates, clinical pregnancy rates, and live birth rates all are sub-stantially lower
than those of IVF using freshly harvested oocytes. Although results have varied among centers, and with different methods
for egg freezing, the overall live birth rate for IVF using frozen eggs currently is no greater than approximately 20% per
transfer.
For comparison, the 2005 Assisted Reproductive Technology Report, published by the Society for Assisted Reproductive Technology,
indicates that the national average live birth rate per transfer for IVF using fresh oocytes was 43.3% for women under 35,
35.8% for those ages 35 to 37, 25.4% for ages 38 to 40, and 14.9% for women ages 41 to 42.2 Based on those data, a woman under age 35 who freezes her eggs today would have a better prognosis for success with IVF
at age 40 using freshly harvested oocytes than using her frozen oocytes. 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 using her frozen eggs.
The difference is greater still if one also considers the pregnancies likely to result from later transfer of frozen surplus
embryos derived from fresh IVF cycles. We also can't forget that the large majority of young women who might consider egg
freezing today can reasonably expect to conceive without treatment and would never need their frozen oocytes.
What about egg freezing before cancer tx that might cause ovarian failure?
In contrast to young healthy women, there are fewer options for women recently diagnosed with malignancies and other illnesses
that require treatment that seriously threatens their fertility. With early diagnosis and recent advances in treatment, an
increasing number of such women are surviving their illnesses. If the treatment plan for the illness offers the opportunity,
it is entirely reasonable to offer such women the opportunity to freeze their eggs to preserve the chance to conceive their
own biological children in case treatment results in ovarian failure. Although the prognosis for success with later IVF using
the frozen eggs may be modest, it is still better than having no prognosis, or no option other than oocyte donation. However,
even in these difficult circumstances, any program prepared to offer oocyte cryopreservation should proceed only with the
formal approval and continuing oversight of a properly constituted IRB, because the technology itself still must be considered
investigational.1
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IT SEEMS LIKELY that further advances in technology will establish oocyte cryo-preservation as a reliable and effective means to preserve
fertility and to defer the otherwise inevitable age-related decline in fertility for women whose circumstances force them
to delay childbearing. However, that time has not yet arrived. Currently, the technology simply cannot deliver on that promise.
The ASRM Practice Committee is acutely aware of the interest and controversy that surrounds the technology and its published
opinion, is carefully monitoring progress in the field, and is fully prepared to reconsider and revise its published opinion
when that is warranted.
REFERENCES
1. Practice Committee of the American Society for Reproductive Medicine. Ovarian tissue and oocyte cryopreservation. Fertil Steril. 2004;82:993-998.
2. http://www.sartcorsonline.com/rptCSR_PublicMultYear.aspx?ClinicPKID=0.
