Egg banking in the United States: current status of commercially available cryopreserved oocytes

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1 Egg banking in the United States: current status of commercially available cryopreserved oocytes Alexander M. Quaas, M.D., Ph.D., Alexander Melamed, M.D., M.P.H., Karine Chung, M.D., Kristin A. Bendikson, M.D., and Richard J. Paulson, M.D. Department of Reproductive Endocrinology, Keck School of Medicine, University of Southern California, Los Angeles, California Objective: To estimate the current availability of donor cryopreserved oocytes and to describe the emerging phenomenon of commercial egg banks (s) in the United States. Design: Cross-sectional survey of s. Setting: , telephone, and fax survey of all scientific directors, conducted April Patient(s): None. Intervention(s): None. Main Outcome Measure(s): Number and location of s in the United States, years in existence, number of donors, number of available oocytes, level of donor anonymity, donor screening, cost of oocytes to recipients, freezing/thawing technique, pregnancy statistics. Result(s): Seven s were identified and surveyed (response rate: 100%). The s used three distinct operational models, had been in existence for a median of 2 years (range: 1 to 8 years), with a median 21.5 (range: 6 to 100) donors and 120 (range: 20 to 1,000) currently available oocytes. The median recommended minimum number of eggs to obtain was six (range: four to seven), at an estimated mean cost per oocyte of $2,225 (range: $1,500 to $2,500). An estimated 3,130 oocytes from 294 donors are currently stored for future use. Of these s, 6 (86%) of 7 use vitrification as cryopreservation method. To date, 8,780 frozen donor oocytes from s have been used for in vitro fertilization, resulting in 602 pregnancies. Pregnancy rates per oocyte, available for 5 (71%) of 7 s, were 532 (7.5%) of 7,080 for s using vitrification and 70 (10%) of 700 for the single using slow freezing as cryopreservation method. Conclusion(s): Frozen donor eggs are currently widely available in the United States. Three different operational models are currently used, resulting in more than 600 pregnancies from oocytes obtained at s. The majority of s use vitrification as cryopreservation technique. (Fertil Steril Ò 2013;99: Ó2013 by American Society for Reproductive Medicine.) Key Words: Commercial oocyte banking, oocyte cryopreservation, oocyte donation Discuss: You can discuss this article with its authors and with other ASRM members at fertstertforum.com/quassam-oocyte-banking-cryopreservation/ Use your smartphone to scan this QR code and connect to the discussion forum for this article now.* * Download a free QR code scanner by searching for QR scanner in your smartphone s app store or app marketplace. There has been much debate in the reproductive endocrinology community and in the United States general public regarding the current status and clinical applicability of oocyte cryopreservation. Whereas sperm and embryo freezing has been used with good pregnancy success rates for a long enough time to gain widespread acceptance, oocyte freezing still suffers from being labeled experimental (1, 2). This label stems from the fact that in the first two decades after the first pregnancy from a cryopreserved oocyte (3), technical difficulties specific to the oocyte (4) resulted in poor oocyte survival and low clinical pregnancy rates (5). Received June 26, 2012; revised October 8, 2012; accepted October 29, 2012; published online November 29, A.M.Q. has nothing to disclose. A.M. has nothing to disclose. K.C. has nothing to disclose. K.A.B. has nothing to disclose. R.J.P. has nothing to disclose. Presented at the 68th annual meeting of the American Society for Reproductive Medicine; October 20 24, 2012; San Diego, CA. Reprint requests: Alexander M. Quaas, M.D., Ph.D., 2020 Zonal Avenue, IRD 534, Los Angeles, CA ( alexander.quaas@med.usc.edu). Fertility and Sterility Vol. 99, No. 3, March 1, /$36.00 Copyright 2013 American Society for Reproductive Medicine, Published by Elsevier Inc. Recent advances in the field of oocyte cryopreservation include the use of sodium-depleted freezing media (6 9), the breakthrough discovery that intracytoplasmic sperm injection (ICSI) can overcome cryopreservationinduced hardening of the zona pellucida (10 12), and the advent of rapid freezing, called vitrification (13, 14). Together, they have led to improved efficiency of oocyte freezing and put the experimental label into question (15). Concomitant with the evolution of oocyte cryopreservation, the use of oocyte donation has evolved rapidly to become an integral tool in assisted reproductive technology (ART). Shortly after the first reported human VOL. 99 NO. 3 / MARCH 1,

2 pregnancies with this technique nearly 30 years ago (16, 17), it was observed that the pregnancy rates with oocyte donation appeared to be independent of the age of the recipient (18, 19). Thus, the utility of this type of fertility therapy to circumvent the age-related decline in fertility was quickly appreciated. According to the 2009 Centers for Disease Control and Prevention (CDC) report (20), there were 17,697 cycles of oocyte donation reported to the Society for Assisted Reproductive Technology (SART) registry for the calendar year 2009, representing approximately 12% of all ART cycles that year. Improved methods for oocyte preservation and demand for donor oocytes have led to the emergence of a new phenomenon in the United States and worldwide: commercial egg banks (s), entities able to provide cryopreserved oocytes to intended recipients of egg donation. In 2007, Akin et al. (21) first reported their initial experience with a donor egg bank and predicted that s would change the landscape of donor egg IVF. They estimated at the time that about 200 children had been born from frozen oocytes worldwide, a number that reportedly increased to over 900 in 2009 (22). In 2010, it was estimated that oocyte cryopreservation was offered in over half of all ART clinics in the United States, suggesting a growing acceptance for the technology (23). However the extent to which oocytes are specifically obtained from donors for egg banking has not been studied. We have estimated the current commercial availability of cryopreserved oocytes and describe the emerging phenomenon of s in the United States. MATERIALS AND METHODS This study was approved by the University of Southern California institutional review board. Commercial egg banks (s) were identified with following methods. First, an Internet search was conducted using the search terms egg bank, oocyte bank, cryopreserved oocytes, frozen oocytes, and frozen oocyte donation as well as related synonyms, using the search engines Google and Bing. Second, a survey was sent to the s identified through the Internet search to ask the scientific directors to name any other known s. Finally, selected ART clinic laboratory directors and practice directors across the United States were asked to list known s. After identification of the s, each 's scientific director was contacted at least twice during the month of April 2012 by telephone, FAX, or to request completion of a 32- question survey. All surveys were conducted anonymously. The first part of the survey contained information about the practice and the year of its foundation. The second part of the survey elicited information on the number of donors, level of donor anonymity, number of eggs in storage, freezing and thawing technique, cost per egg to the intended recipient, minimum purchase number, potential guarantees regarding survival or fertilization, recommendations for purchased number of eggs, recommendations for thawing technique, provision of thawing instructions and media, number of clinical pregnancies (defined as detection of one or more gestational sacs during transvaginal ultrasound scan 3 weeks after embryo transfer), legal concerns, and donor screening. Scientific directors were surveyed on the specifics of psychological screening, ovarian reserve testing, and genetic screening (single gene disorder testing, karyotyping, and/or fragile X testing). The survey data on s were then analyzed using chi-square and Fisher's exact tests (for categorical variables). P<.05 was considered statistically significant. Statistical analysis was performed using SAS, version 9.2 (SAS Institute, Inc.). RESULTS Seven s were identified and surveyed. The response rate was 100%. We identified three operational models (Fig. 1): [1] servicing a single in vitro fertilization (IVF) center (one FIGURE 1 Single Affiliated ART clinic ART clinic A ART clinic I ART clinic A ART clinic B ART clinic H ART clinic C ART clinic C ART clinic B ART clinic G ART clinic D ART clinic F ART clinic E Operational models for commercial egg banks (s). (A) providing cryopreserved oocytes exclusively to single affiliated ART clinic. (B) providing cryopreserved oocytes to network of affiliated clinics. (C) providing cryopreserved oocytes to any interested ART clinic. 828 VOL. 99 NO. 3 / MARCH 1, 2013

3 Fertility and Sterility TABLE 1 Characteristics of the seven identified commercial egg banks in the United States. Freezing technique Years in existence donors used to date currently available oocytes oocytes recommended 1 Vitrification Vitrification Vitrification Vitrification Vitrification , Vitrification Slow freeze ); [2] affiliated with a network of IVF centers (four s); and [3] shipping cryopreserved oocytes to any IVF facility (two s). Six (86%) out of seven s reported using vitrification as the cryopreservation method, and one used slow freezing. The geographic distribution of the seven s within the United States was as follows: Southwest (3), Northwest (1), Midwest (1), South (1), Mid-Atlantic (1). The s had been in existence for a median of 2 years (range: 1 8 years), and had a median of 21.5 donors (range: 6 100) with a median of 250 oocytes (range: 100 1,000) currently available (Table 1). The median recommended minimum number of eggs to obtain was 6 (range: 4 7), at an estimated mean cost per oocyte of $2,225 (range $1,500 to $2,500). Three of the seven s provided limited guarantees to the patient once a clinic had been trained to receive cryopreserved oocytes. Examples of such guarantees were the presence of intact cell membranes of surviving oocytes before ICSI or the development of at least two blastocysts from a batch of oocytes. On the basis of the survey information, an estimated total of 3,130 oocytes from 294 donors are currently stored for future use. Donor screening practices in the identified s are shown in Table 2. All s performed psychological, medical, and genetic screening, ovarian reserve testing with day- 3 serum estradiol/follicle-stimulating hormone (FSH) and antral follicle count estimation, and routine cystic fibrosis (CF) carrier screening. Most also performed antim ullerian hormone (AMH) testing and routine fragile-x carrier testing. Routine karyotyping was only performed by two of the s. All s provide high levels of information on the donor if requested, but do not provide the identity unless the recipient's country's legislation mandates it. Pregnancy outcome data were available for five of the seven s. The remaining two s stated that they did not have pregnancy information available. As of April 26, 2012, 8,780 frozen donor oocytes from s have been used for IVF, resulting in 602 clinical pregnancies. The overall reported pregnancy rate per oocyte (number of clinical pregnancies per eggs obtained) was 602 (7.7%) out of 7,780 for the five s with available data. The pregnancy rate per oocyte was 532 (7.5%) out of 7,080 for the s using vitrification and 70 (10%) out of 700 for the single using slow freezing as the cryopreservation method (Table 3). TABLE 2 Routine donor screening in the identified commercial egg banks. Psychological/medical screening, genetic counseling E2/FSH testing AMH testing AFC testing Routine karyotyping Routine CF carrier testing Routine fragile X carrier testing 1 O O O O O O O 2 O O O O O O 3 O O O O O 4 O O O O O O 5 O O O O O 6 O O O O O 7 O O O O O Note: AFC ¼ antral follicle count; AMH ¼ antim ullerian hormone; CF ¼ cystic fibrosis; E 2 ¼ estradiol; FSH ¼ follicle-stimulating hormone. VOL. 99 NO. 3 / MARCH 1,

4 TABLE 3 Estimated clinical pregnancy rates per number of dispensed cryopreserved oocytes according to commercial egg banks and cryopreservation method. cryopreserved donor oocytes obtained from clinical pregnancies conceived from cryopreserved donor oocytes from Clinical pregnancy rate per oocyte ( pregnancies/ oocytes obtained 3 100) 1 1,000 a NA NA 2 1, % % 4 NA NA NA 5 5, % % % Technique Vitrification 7, % Slow freezing % Total 8,780 (7,780 included in pregnancy analysis) % Note: ¼ commercial egg bank; NA ¼ data not available. a Number not included in overall pregnancy analysis because pregnancy number not available. DISCUSSION Frozen donor eggs are currently widely available in the United States. Three different operational models for s were identified. A may be linked to a single ART center, at which the oocyte thawing/warming, fertilization, and embryo transfer is undertaken. The advantage of this model is the familiarity with the embryology unit; however, it may limit access to the to a smaller pool of potential recipients. An extension of this model is the linkage of a network of ART clinics to a given. Two s provide cryopreserved donor oocytes to patients from any interested ART clinic. This allows the most widespread access to the oocytes at a, but requires repeated assistance with thawing/warming/handling of the oocytes to a large number of ART clinics. It is possible that the practice model affects success rates, but our study was not designed to assess this. An estimated 3,130 oocytes from 294 donors are currently stored in s. All s indicated that they were expanding their donor database, with an increasing rate of retrievals per week. The s affiliated with a particular network signaled that they are intending to expand to ART clinics outside their network. Donor screening practices in the identified s were consistent with American Society for Reproductive Medicine (ASRM) guidelines for gamete donation (24). All s provide high levels of information on the donor if requested. Identity is not released unless the recipient is from a country such as Australia where local legislation mandates the release of donor identity (three out of seven clinics indicated that they provided oocytes to recipients and ART practices outside of the United States). There have been more than 600 pregnancies from oocytes obtained at s. Since the discovery of vitrification as an alternative to slow freezing (25), research on the optimal cryopreservation method of oocytes is ongoing (26). The majority of s reported using vitrification. The reported pregnancy rate per oocyte in the using slow freezing was 10%, and 7.5% in the s using vitrification. Pregnancy rates were calculated as the percentage of all oocytes obtained from a resulting in clinical pregnancy. We did not have information from the clinics receiving oocytes regarding oocyte survival, fertilization rates, or the number of embryos transferred. In addition, our study design did not control for the many variables that could affect pregnancy rates, so it would be premature and not scientifically valid to conclude that slow freezing is superior to vitrification in the setting of a. The pregnancy rates in our study compare favorably with the estimated pregnancy rates using nondonor cryopreserved oocytes of 2% per oocyte for slow freezing and 4% per oocyte for vitrification (2). Success rates of oocyte cryopreservation are thought to be in part operator dependent, especially for vitrification, which requires specialized skills in loading, cooling, and unloading of cryoprotective agents (27). There may be greater familiarity with slow freezing on the part of the IVF programs receiving the oocytes; however, s are an emerging phenomenon, and thus the success rates would be expected to fluctuate for some time. Nevertheless, reported success rates in our study are quite high and compare favorably with the findings by Patrizio et al. (28, 29) in fresh ART cycles, where only approximately 5% of fresh nondonor oocytes result in live births. Advances in molecular methods of oocyte selection may help improve this number for both fresh and frozen oocytes (30). A recent randomized controlled trial by Cobo et al. (31) compared the use of cryobanked vitrified oocytes with fresh oocytes in 600 patients enrolled in an ovum donation program, and the ongoing pregnancy rates were comparable in patients randomized to frozen oocytes with those randomized to fresh oocytes. With respect to our findings regarding pregnancy rates, we do recognize that the major weakness of our study lies in the self-reporting of analyzed data, even though we did attempt to encourage accurate reporting by emphasizing that thestudydatawouldremainanonymous. The potential advantages of s include wider availability of and quicker access to (cryobanked) donor oocytes, eliminating waiting lists and making ovum donation programs 830 VOL. 99 NO. 3 / MARCH 1, 2013

5 Fertility and Sterility more efficient. Additionally, the longer quarantine period during oocyte cryostorage may make oocyte donation safer, permitting more extensive donor infectious disease screening. Finally, the widespread availability of frozen donor oocytes may lead to a decrease in the large number of stored frozen embryos in ART laboratories. Currently donor oocytes from s represent only a minority of donor egg IVF cycles: according to our data, 8,780 oocytes were obtained from s, mostly in batches of six oocytes. This represents approximately 1,500 transfer cycles using frozen donor oocytes from s since the introduction of the first in In comparison, in 2009 alone, 17,697 cycles of oocyte donation were reported to the SART registry (20). With the establishment of more s, their impact on overall egg donation cycles is likely to increase. The establishment of an egg bank presents many logistical challenges. In addition to the laboratory personnel, s employ a large number of additional staff members, including legal experts, recruiters, compliance officers, and marketing specialists. Familiarity with the relevant bureaucracy and legal regulations is required. Uncertainty exists about the use of language. Several scientific directors reported that after discussions with legal experts, the terms purchase, buy, and sell in connection with cryopreserved oocytes were replaced by the terms acquire, obtain, use, reserve, or secure. This stems from the existing legal environment in some states where selling eggs is illegal, but donor egg services are permitted. The wording therefore seeks to represent that IVF treatment in which donor eggs are used is merely facilitated. To our knowledge, no regulations exist on the number of times that a donor's oocytes are used within a certain geographic region, raising long-term concerns about consanguity. Uncertainties about and variations in regional laws in different states and countries, paired with the ability to ship cryopreserved oocytes anywhere, result in uncharted legal and ethical territory (32). As s become part of the landscape of donor egg IVF (21), it is crucial to intensify research on oocyte cryopreservation techniques, establish guidelines for commercial egg banking, and provide ethical and legal guidance for this promising new phenomenon. REFERENCES 1. Practice Committee of the Society for Assisted Reproductive Technology and Practice Committee of the American Society for Reproductive Medicine. Essential elements of informed consent for elective oocyte cryopreservation: a Practice Committee opinion. Fertil Steril 2007;88: Practice Committee of the Society for Assisted Reproductive Technology and Practice Committee of the American Society for Reproductive Medicine. 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