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Oocyte donation: insights gleaned and future challenges
Oocyte donation: insights gleaned and future challenges Alexis P. Melnick, M.D. and Zev Rosenwaks, M.D. The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medical College, New York, New York
With the first successful report of an IVF pregnancy achieved via donor oocytes in 1984, the applications of assisted reproductive technology (ART) were further expanded to include women unable to conceive with their own oocytes. Today, oocyte donation makes up an increasingly large percentage of all ART cycles worldwide. Oocyte donation presents several unique challenges to clinicians as two separate interests, those of the donor and those of the recipient, must be represented. These challenges include successful preparation of the endometrium in donor oocyte recipients, the synchronization of donor/recipient cycles, and the optimization of ovarian stimulation while maximizing donor safety. Facing these challenges has not only allowed for the creation of successful donor egg programs but has also provided insights into many aspects of ART. Much of what we know about the window of implantation, frozen ET procedures, triggering of oocyte maturation, and fertility preservation has been learned through experience and investigations with donor egg cycles. Not only has oocyte donation, through its optimization and wide use, provided new treatment opportunities for patients, it has also become a critical scientific tool to study many aspects of menstrual cycle dynamics and implantation. Concomitantly, with its increased efficiency, it has also raised several clinical and ethical challenges. (Fertil SterilÒ 2018;110:988–93. Ó2018 by American Society for Reproductive Medicine.) Key Words: Oocyte donation, synchronization, endometrial preparation, donor safety Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertilityand-sterility/posts/39243-27050
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n 1984, 6 years after the birth of the first human IVF baby, Lutjen et al. reported the first successful donor oocyte IVF pregnancy in a 25-year-old with a history of primary ovarian insufficiency (1, 2). This report, which represented the pinnacle of efforts by several groups worldwide, illustrated another successful application of assisted reproductive technology (ART). Women unable to conceive using autologous oocytes, either due to premature cessation of ovarian function or repetitive IVF failures, were now able to use ART to successfully achieve pregnancies. Today, oocyte donation cycles account for nearly 10% of all ART cycles in the United States, with live birth rates upwards of 50% per cycle (3).
The journey from those early reports of egg donor pregnancies to today's large and successful egg donor programs has presented numerous clinical challenges, including the successful preparation of the endometrium in donor oocyte recipients, the synchronization of donor/recipient cycles, and the optimization of ovarian stimulation for donors in order to strike a balance between oocyte yield and safety. The insights gleaned from this experience have allowed for success not only in donor oocyte programs but also for ART as a whole. Because factors affecting the ovary (donor) are separate and distinct from endometrial events in the recipient, this clinical paradigm has served as a critical tool to study both ovarian and endometrial factors
Received September 26, 2018; accepted September 27, 2018. A.P.M. has nothing to disclose. Z.R. has nothing to disclose. Correspondence: Zev Rosenwaks, M.D., The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine of Weill Cornell Medical College, 1305 York Avenue, New York, New York 10021 (E-mail: [email protected]). Fertility and Sterility® Vol. 110, No. 6, November 2018 0015-0282/$36.00 Copyright ©2018 Published by Elsevier Inc. on behalf of the American Society for Reproductive Medicine https://doi.org/10.1016/j.fertnstert.2018.09.021 988
contributing to implantation. Furthermore, our current ability to use donated oocytes so efficiently brings with it a host of new opportunities and challenges.
ENDOMETRIAL PREPARATION FOR RECIPIENTS Successful implantation of a fertilized oocyte depends on two key factors: a receptive endometrium and the synchronization of embryonic and endometrial development. In the natural menstrual cycle, this process relies on the precise coordination of ovarian steroid production, the timing of ovulation, and tubal transport of oocyte and embryo. Studies of human fallopian transport demonstrated that the oocyte arrives in the endometrial cavity 4–5 days after the LH surge and is still floating freely 6 days postsurge, suggesting that in vivo human oocyte transport provides adequate time for fertilization and simultaneous embryo and endometrial development (4, 5). VOL. 110 NO. 6 / NOVEMBER 2018
Fertility and Sterility® This allows for the arrival of an implantation-competent embryo to a receptive endometrium.
DONOR-RECIPIENT SYNCHRONIZATION Early work with donor oocytes sought to mimic this complex series of in vivo events. Buster et al., with their nonsurgical transfer procedures, attempted to synchronize donor and recipient ovulation within two days of the LH surge (6–8). Oocyte donors were inseminated with recipient partner's sperm, and donor uterus lavage and embryo recovery were performed 5 days after the LH surge. Of five fertilized oocytes recovered and transferred, two pregnancies were achieved; in both successful pregnancies, donor and recipient LH surges were synchronized (6). Later work in the natural cycle using IVF of donor oocytes sought to enhance efficiency by allowing for retrieval and fertilization of multiple oocytes. Early endeavors at donor/recipient synchronization demonstrated that transfer of 4- to 6-cellstage donor embryos on days 17–19 of a recipient's cycle led to implantation and pregnancy. However, when embryos were transferred on day 20 or beyond, no pregnancies were achieved. In these cases, all recipients were monitored for at least one cycle before transfer with daily serum E2 and LH measurements as well as luteal phase endometrial biopsies to confirm adequate endometrial development. This early work helped to elucidate the window of implantation and the optimal timing of ET (9). Early protocols therefore aimed for transfer of a 2- to 16-cell embryo to a day 17–19 endometrium. Of 21 transfers performed during this window, eight (38%) pregnancies were achieved (9, 10). Despite these early successes, synchronization of donor and recipient in the natural cycle presented a unique challenge for clinicians, given the need for precise coordination of recipient LH surge and donor oocyte retrieval. However, before the availability of GnRH agonists and the routine and efficient use of embryo cryopreservation, this was the only option for ovulatory recipients. Natural cycle synchronization cycles, while not used routinely today, set the stage for our understanding of the optimal timing of ET and have influenced many of the protocols currently used in ART. Natural frozen embryo cycles, for example, use the knowledge gleaned from this early work, for both autologous and donor ETs. Given the efficiency of embryo vitrification, in our donor oocyte program an increasingly large percentage of embryos are cryopreserved at the blastocyst stage. For ovulatory recipients, these embryos are replaced 5 days after the serum-defined LH surge, optimizing donor/recipient synchronization and allowing the recipient to avoid exogenous hormone replacement. We have also extrapolated these data for the use of vitrified donor oocytes in ovulatory recipients: frozen oocytes are thawed 1 day post–LH surge, with ET occurring on day 3 for 3-day-old embryos and 5 days later for blastocysts.
THE ROLE OF ESTROGEN AND P SUPPLEMENTATION As with the study of the natural cycle in donor recipients, investigation of estrogen and P replacement cycles also proVOL. 110 NO. 6 / NOVEMBER 2018
vided us with a wealth of information about the window of implantation and the maintenance of pregnancy in the absence of ovarian function. The first successful IVF donor pregnancy was achieved with oral estradiol valerate and vaginal P supplementation. Once a pregnancy was confirmed, the patient was switched from vaginal to IM P for pregnancy maintenance. Steroids were withdrawn in the second trimester (1). This initial protocol was modified by several groups worldwide using different methods of estrogen and P delivery at varying concentrations and durations, with the goals of mimicking the normal menstrual cycle and allowing for implantation and maintenance of early pregnancy. During the early days of oocyte donation, the importance of P for implantation and the maintenance of early pregnancy was well established. However, less was known about the role of estrogens. Csapo et al. showed that P replacement during the first 50 days of gestation in women undergoing luteectomy allowed for continuation of pregnancy; E2 alone was unable to do so (11). Studies in nonhuman primates demonstrated a likely facilitatory role of estrogen. Pregnancy in oophorectomized rhesus monkeys was established and maintained with supplementation of P alone (12). Given these findings, early replacement protocols attempted to minimize the dosage of replaced E2. The first ovarian failure recipient at Norfolk, for example, was treated with P injections only, with estrogen levels maintained between 10 and 30 pg/mL during the luteal phase. Although initially positive and appropriately increasing, hCG levels dropped to 0 by week 6 of pregnancy. From this experience, we learned that while facilitatory in nonhuman primates, estrogen clearly plays an obligatory role in human gestation. In a subsequent cycle, the patient was treated with E2 during both the follicular and luteal phases, with levels maintained at 100–300 pg/ mL. Pregnancy was achieved, and steroid doses were kept fixed, allowing for the assessment of endogenous placental steroid production. Estrogen levels were noted to rise during the eighth week of gestation, and withdrawal of estrogen supplementation by the end of the first trimester did not compromise pregnancy outcome (9, 13, 14). Similarly, Lutjen et al. demonstrated early increases in placental steroid production with successful withdrawal of hormone supplementation beginning as early as cycle day 38 of pregnancy (15). From this early work, it was apparent that while estrogen supplementation in the human ovarian failure patient was required for implantation and early pregnancy maintenance, less estrogen was needed, and for a shorter duration, than had been previously used. Furthermore, this work provided an in vivo model for the luteoplacental shift, revealing that this shift occurs much earlier than previously thought (14). In contrast to estrogen, the obligatory role of P for implantation had been firmly established during the early evolution of oocyte donation. However, the ideal P replacement protocol was not clearly known. Early work on P replacement showed that adequate levels could be achieved with a variety of delivery methods. In our initial experience, recipients were monitored during two mock replacement cycles before transfer, with P supplementation beginning on cycle day 15. Endometrial biopsies were performed on days 20–22 and again on 989
VIEWS AND REVIEWS days 26–27. Interestingly, early midluteal biopsies demonstrated glandular/stromal asynchrony with glandular architecture characteristic of day 18 endometrium, although late luteal biopsies demonstrated a characteristic day 25–26 appearance. The observed early glandular lag did not appear to affect implantation (9), although it highlighted the differences between natural and replacement cycles. In the natural cycle, P elevation begins gradually on day 14, allowing for earlier development of endometrial glands, whereas in the replacement cycles, P intake was begun 1–2 days later at a higher fixed dose, thus leading to an apparent glandular lag. As a result, replacement protocols were adjusted, with P starting at a lower dose in an attempt to mimic the natural cycle. At our center, P is started at 25 mg IM (0.5 mL) once adequate endometrial thickness is achieved. After the first night of P, the dose is increased to 50 mg IM (1 mL) nightly. ET occurs after 6 days of P supplementation. The early studies of recipient replacement cycles play an increasingly important role in all of ART. The realization that exogenous hormone regimens could successfully prime an endometrium for implantation in the recipient population led to their use for frozen-thawed ETs (FETs). Today's programmed FET protocols are based on this early work, highlighting its importance as FETs make up a growing proportion of all ETs performed. Given the efficiency of oocyte vitrification and the increasing use of frozen oocytes, synchronization has become much simpler in both natural and programmed cycles. Thus, efforts made to achieve synchronization in early egg donation studies laid the groundwork for much of today's ART practices.
DONOR SELECTION AND STIMULATION Unlike ART procedures using autologous oocytes, donor oocyte cycles must represent two separate interests: those of the donor and those of the recipient. In the early days of oocyte donation, before routine donor compensation, most donated oocytes were provided by IVF patients who agreed to donate excess oocytes or by patients' sisters. Today, the majority of donated oocytes come from anonymous donors. Whereas recipients obtain a clear benefit from oocyte donation, the donors' benefits—which may include financial compensation or a perceived sense of altruism—are less tangible. Furthermore, unlike sperm donors, egg donors undergo complex and invasive medical procedures each time they donate. As such, every effort should be made to ensure that donor safety remains the top priority of a donor oocyte program. Careful and critical analyses of egg donation treatment protocols along with their medical consequences have led to several modifications of donor stimulation and retrieval practices (protocols), which have been generally applied to all IVF treatment cycles. The majority of studies on complication rates in donors undergoing controlled ovarian hyperstimulation and oocyte retrieval report low rates of major complications, often lower than those reported in the general IVF population. For example, 2008 data from our center examining 587 donors undergoing 973 cycles demonstrated an overall rate of serious complications, including ovarian hyperstimulation syndrome 990
(OHSS), ovarian torsion, infection, and ruptured ovarian cyst of 0.7% (16). While these rates are low, it must be emphasized that any complication in a patient undergoing a procedure for which she does not derive a direct health benefit should be viewed as one complication too many. This viewpoint has led to several of the protocol modifications used today. Antibiotic prophylaxis, for example, now routinely given to all donors at the time of retrieval, was started after a pelvic infection rate of 0.4% (two hospital admissions in 526 cases) was deemed unacceptably high. It had been assumed that donors at risk for infection—those with a history of endometriosis or pelvic inflammatory disease, for example—would have already been excluded from donating and therefore antibiotic prophylaxis was unnecessary. However, after the observed infection incidence in two donors, as of August 2003, all donors now receive prophylactic antibiotics at the time of retrieval. This change in practice has reduced our infection rate to zero (17).
REDUCING THE RISK OF OHSS OHSS, like infection, is a rare complication among oocyte donors but one with potentially catastrophic implications. By virtue of being selected to donate, egg donors represent a population of women with an increased risk of OHSS: young with good ovarian reserve. Furthermore, because donor oocytes are often divided between more than one recipient, donors are often stimulated more aggressively to maximize oocyte yield. Over the years, several strategies have been successfully employed to reduce OHSS risk, including the use of sliding-scale hCG doses for the ovulatory trigger and the administration of dopamine agonists. However, it is the use of GnRH agonists for triggering final oocyte maturation that has brought us closest to achieving OHSS-free stimulation in oocyte donation cycles. In contrast to the prolonged luteotrophic effects of hCG, the endogenous LH surge elicited by the GnRH agonist trigger has a short half-life leading to early luteolysis. Several large retrospective and smaller prospective studies have demonstrated a significantly decreased risk of OHSS in donors without compromising recipient pregnancy rates (18–20). At our center, a randomized controlled trial in which donors were randomized to receive hCG, leuprolide acetate, or leuprolide acetate with low-dose hCG (dual trigger) was terminated early due to preliminary data showing significant symptomatic benefit for donors receiving leuprolide or dual triggers as compared with those receiving full-dose hCG, with no change in pregnancy outcomes among the three groups. All donor stimulation protocols at our center are GnRH antagonist based, and the vast majority of donors receive either pure leuprolide or a combination of leuprolide and low-dose (1,500 IU) hCG triggers. One of the concerns with the use of GnRH agonist triggers is that a small subset of patients fails to respond with an adequate LH surge. This is particularly concerning for fresh donor cycles in which two recipients have undergone endometrial preparation in anticipation of an ET. As such, understanding which patients are at risk for failed response to agonist triggers is of paramount importance to avoid the emotional consequences of a recipient's cancelled cycle. A VOL. 110 NO. 6 / NOVEMBER 2018
Fertility and Sterility® 2015 retrospective study from our center sought to identify risk factors for suboptimal response to GnRH agonist triggers. The patients studied received either leuprolide alone or a dual trigger with low-dose hCG, and 31.8% of included cycles were donor cycles. Suboptimal response was defined as a serum LH level of <15 mIU/mL 8–12 hours post-trigger. This cutoff was selected based on poor clinical outcomes associated with LH levels <12–15 mIU/mL in prior studies. Suboptimal LH responses were found in patients who were younger, had lower body mass indexes (BMIs), lower baseline gonadotropin levels, and lower LH levels on the day of trigger, and were more likely to be long-term oral contraceptive pill (OCP) users compared with those who responded appropriately to the agonist trigger. These findings implicate downregulation of the hypothalamic-pituitary axis as the primary cause for failed response. Interestingly, oocyte donors were found to be more likely to have an inadequate response; however, this was not surprising, given that 12.6% of all donor cycles took place in the context of long-term OCP use (21). Using this profile of a nonresponder has allowed us to select patients for whom GnRH agonist triggers are appropriate. Donors with no risk factors typically receive leuprolide triggers, whereas those deemed to be at some risk of nonresponse receive dual GnRH agonist and low-dose hCG triggers. We also try to minimize long-term OCP use before donor cycles whenever possible. These data have allowed for efficient use of GnRH agonist triggers among the donor population. Donors are at a lower risk of OHSS and, more importantly, feel better at the end of their cycles while cycle cancellation rates for failed trigger are low. While donor safety is of the utmost importance in an oocyte donation cycle, maximizing donor convenience is also crucial. In addition to the physical obligation, the decision to donate eggs brings with it a tremendous time commitment. Complete donor screening takes several hours, and while cycling, donors are required to be present for monitoring on a near-daily basis. As such, every effort should be made to ensure that the donor cycle fits as seamlessly into day-today life as possible. Vitrification, which has allowed for the freezing and thawing of oocytes with incredible efficiency, has given us tremendous freedom in scheduling donor cycles. An abundance of data have confirmed that vitrified oocytes are comparable to fresh in terms of fertilization, embryo development, pregnancy rates, and birth outcomes. The ability to freeze a donor's oocytes upfront negates the need for donorrecipient synchronization and allows donors to cycle according to their schedule. Furthermore, oocyte vitrification has proved essential amidst recent Zika concerns. If not for the ability to cycle without synchronization, many of our donors would have had to wait 6 months after Zika travel to cycle in order to comply with Food and Drug Administration regulations.
THE UNIQUE MODEL OF OOCYTE DONATION While oocyte donation represents a subset of all ART procedures performed, the oocyte donation model has provided us with a tremendous knowledge base applicable to all aspects of ART. An early review of oocyte donation foreshadowed this role, describing the use of donor eggs as not only theraVOL. 110 NO. 6 / NOVEMBER 2018
peutic but diagnostic as well. Donated oocytes were used for testing sperm-oocyte interaction in couples with a history of unexplained infertility and prior IVF failure (9). This allowed for identification of the true etiology of the infertility. Although oocyte donation is not routinely used today as a diagnostic technique, its study offers a wealth of information to patients undergoing all types of ART. The oocyte donation model is unique because it removes the oocyte as a variable affecting reproductive outcomes. As such, other factors affecting ART success can be studied. Moreover, cycles in which donor oocytes are split between two recipients allow for a clean analysis of various factors affecting implantation. Given the complexity of the implantation process, a model that can elucidate specific factors involved in endometrial receptivity and successful embryo implantation is invaluable. While the impact of age on oocyte quality was well established early on, less was known about its effect on uterine receptivity. Poor implantation in older women was attributed to diminished oocyte quality and higher aneuploidy rates. Comparing oocyte recipients of various ages, however, has provided us with a great deal of information about the impact of age on uterine receptivity. A few early studies, including one published by our group in 1999, demonstrated a deleterious effect of age on both implantation and miscarriage rates (22). A subsequent multivariate retrospective analysis of over 17,000 oocyte donation cycles in the United States showed that while implantation, clinical pregnancy, and delivery rates remained stable among recipients age 25 through the late 40s, rates began to decline at age 48, with a steep decline after age 50. Furthermore, an association between increasing recipient age and higher miscarriage rates was demonstrated (23). A 2005 study of over 3,000 oocyte donation cycles showed significantly lower implantation and pregnancy rates from age 45 onward, with an even sharper decline after age 50. An increased incidence of miscarriages in older recipients was also shown (24). These data demonstrate a clear alteration in uterine receptivity in older women, which may be a function of altered uterine blood flow, changes in endometrial steroid receptor concentrations, stromal angiosclerosis, and subepithelial extracellular matrix deposition, processes seen in other animal species (25, 26). The donor oocyte model has also proved invaluable to studies of endometriosis. Several retrospective studies have demonstrated that oocytes donated from women without endometriosis and split between recipients with and without endometriosis lead to similar reproductive outcomes (27–29). This suggests that it is the oocyte, not the endometrium, that leads to diminished success with ART in patients with endometriosis. A subsequent prospective study confirming these results compared three groups: [1] donors/recipients without endometriosis, [2] donors with endometriosis donating to recipients without the disease, and [3] donors without endometriosis donating to recipients with the disease. Lower pregnancy rates per transfer were observed in the second group, confirming that embryos derived from oocytes of women with endometriosis had diminished implantation potential (30). Findings such as these would be difficult to obtain without the study of donor oocytes. However, these studies must be interpreted with caution. 991
VIEWS AND REVIEWS The oocyte donation model has also provided us with insights into lifestyle factors and their impact on reproductive outcomes. Obesity is clearly associated with diminished fertility and poor reproductive outcomes in all modes of conception. However, the mechanism by which increasing BMI affects outcome—whether it is at the level of oocyte, endometrium, or both—is not as clear. Several studies of oocyte recipients have shown decreasing pregnancy rates with increasing BMI. In these cases, oocyte donors all had normal BMI, a clear demonstration of the impact of obesity at the uterine level (31–33). Conversely, a recent study of 235 oocyte donation cycles assessed the association between donor BMI and pregnancy outcomes. After adjusting for recipient BMI, this group showed that increasing oocyte donor BMI is associated with a reduction in clinical pregnancy and live birth rate, suggesting an effect of BMI at the oocyte level (34). Cigarette smoking, another lifestyle factor known to impact fertility, has also been examined through the donor egg model. A 2007 study of 785 oocyte donation cycles over a 3-year period showed that heavy smoking (>10 cigarettes per day) led to a significantly lower pregnancy rate. The study controlled for father and donor smoking status, patient age, BMI, duration of endometrial priming, and number of good-quality embryos transferred (35). While smoking is known to affect ovarian function, its impact at the level of the uterus has been less understood. These data suggest an impact at the endometrial level that can be used when counseling not only recipients, but all fertility patients. Oocyte donation has greatly contributed to our current application of fertility preservation outcomes. With the advent and subsequent wide adoption of vitrification, a large number of women have pursued elective egg freezing. While many have frozen, fewer have returned to use their oocytes. As such, there is a dearth of data available to counsel our fertility preservation patients about outcomes post-thaw. However, given the role that vitrification now plays in most donor oocyte programs worldwide, what we know about frozen eggs can be extrapolated to our elective fertility preservation patients. Oocyte donation has also broadened our current knowledge of obstetric management of women with Turner syndrome. Given that only 5%–10% of Turner syndrome patients will achieve natural pregnancies, the reproductive possibilities for these women have been greatly expanded by oocyte donation. Pregnancy rates after oocyte donation in women with Turner syndrome are equivalent to those of other recipients, suggesting no impact of the syndrome on uterine receptivity. However, women with Turner syndrome have high rates of congenital cardiovascular malformations and predisposition to aortic root dilatation, a known risk factor for aortic dissection. In 2003, Karnis et al. reported that the risk of death from aortic dissection during pregnancy is at least 2% in Turner patients. They also noted that only about 50% of women with Turner syndrome in the United States underwent cardiac examination before beginning fertility treatment (36). These findings led to specific guidelines for screening and management of patients with Turner syndrome both before and during pregnancy (37). Further studies of Turner syndrome patients after oocyte donation and their 992
maternal outcomes will allow us to continue to make recommendations to optimize the health of these recipients.
FUTURE CHALLENGES Oocyte donation has greatly enhanced our ability to treat infertility. As the application of this technology has increased, so have the clinical challenges that we face in day-to-day practice. While oocyte donor recipients have traditionally been women with pathologic conditions—poor oocyte quality, diminished ovarian reserve, primary ovarian insufficiency— today, an increasing number of recipients are either perimenopausal or even menopausal, which raises the question, at what age do we stop? The reported successes of donor egg pregnancies for women in their 50s and 60s suggest that with the proper hormone priming, any woman with a uterus can achieve pregnancy. However, it is well established that the risk of pregnancy-related complications increases with maternal age. This risk is compounded by the increased risk of hypertensive disorders conferred by donor egg pregnancies. In several series, recipients over the age of 50 have been found to have higher rates of gestational diabetes, cesarean section, and gestational hypertension (38–40). The effect on children born to mothers of advanced reproductive age conceived via oocyte donation is also not well defined. Furthermore, concerns related to longevity and the ability to raise a child into adulthood are at the center of the age debate. Several expert groups recommend against providing donor oocytes to women over 55 years of age (41). Some clinics have strict age cutoffs, while others evaluate women on a case-by-case basis. Clearly, all prospective recipients of advanced reproductive age must undergo thorough medical screening and counseling about the medical risks of pregnancy by a maternal-fetal medicine specialist. Additionally, every attempt should be made to avoid multiple gestation in this population, with single ET as the standard of care. But once these two conditions are met, is it enough? And at what age do we say that it is not? Furthermore, what do we do with the patient with cryopreserved supernumerary embryos who may fall outside of our age cutoff? Does the risk of being another 2–3 years older trump the importance of having a biological sibling for a child who may not have his or her parents into adulthood? Of the many challenges surrounding egg donation, the age limits set for recipients are likely to continue to be the most challenging.
CONCLUSIONS Since its inception, egg donation has become one of the mainstays of ART treatment. It has not only enabled successful outcomes in women who otherwise would have been sterile, it has also become an important tool to study various aspects of human reproduction. Lessons learned from egg donation have been applied to many areas of ART.
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Moomjy M, Cholst I, Mangieri R, Rosenwaks Z. Oocyte donation: insights into implantation. Fertil Steril 1999;71:15–21. Toner JP, Grainger DA, Frazier LM. Clinical outcomes among recipients of donated eggs: an analysis of the U.S. national experience, 1996–1998. Fertil Steril 2002;78:1038–45. Soares SR, Troncoso C, Bosch E, Serra V, Simon C, Remohi J, et al. Age and uterine receptiveness: predicting the outcome of oocyte donation cycles. J Clin Endocrinol Metab 2005;90:4399–404. Gruninger B, Schoon HA, Schoon D, Menger S, Klug E. Incidence and morphology of endometrial angiopathies in mares in relationship to age and parity. J Comp Pathol 1998;119:293–309. Hsueh AJ, Erickson GF, Lu KH. Changes in uterine estrogen receptor and morphology in aging female rats. Biol Reprod 1979;21:793–800. Bodri D, Colodron M, Vidal R, Galindo A, Durban M, Coll O. Prognostic factors in oocyte donation: an analysis through egg-sharing recipient pairs showing a discordant outcome. Fertil Steril 2007;88:1548–53. Garcia-Velasco JA, Isaza V, Caligara C, Pellicer A, Remohi J, Simon C. Factors that determine discordant outcome from shared oocytes. Fertil Steril 2003; 80:54–60. Hauzman EE, Garcia-Velasco JA, Pellicer A. Oocyte donation and endometriosis: what are the lessons? Semin Reprod Med 2013;31:173–7. n C. Implantation in endoPellicer A, Oliveira N, Gutierrez A, Remohí J, Simo metriosis: lessons learned from IVF and oocyte donation. In: Spinola PY, Coutinho EM, editors. Progress in Endometriosis. Casterton-Hill, United Kingdom: Parthenon Publishing Group; 1994:177–83. Bellver J, Melo MA, Bosch E, Serra V, Remohi J, Pellicer A. Obesity and poor reproductive outcome: the potential role of the endometrium. Fertil Steril 2007;88:446–51. Bellver J, Pellicer A, Garcia-Velasco JA, Ballesteros A, Remohi J, Meseguer M. Obesity reduces uterine receptivity: clinical experience from 9,587 first cycles of ovum donation with normal weight donors. Fertil Steril 2013;100:1050–8. Dessolle L, Darai E, Cornet D, Rouzier R, Coutant C, Mandelbaum J, et al. Determinants of pregnancy rate in the donor oocyte model: a multivariate analysis of 450 frozen-thawed embryo transfers. Hum Reprod 2009;24: 3082–9. Cardozo ER, Karmon AE, Gold J, Petrozza JC, Styer AK. Reproductive outcomes in oocyte donation cycles are associated with donor BMI. Hum Reprod 2016;31:385–92. Soares SR, Simon C, Remohi J, Pellicer A. Cigarette smoking affects uterine receptiveness. Hum Reprod 2007;22:543–7. Karnis MF, Zimon AE, Lalwani SI, Timmreck LS, Klipstein S, Reindollar RH. Risk of death in pregnancy achieved through oocyte donation in patients with Turner syndrome: a national survey. Fertil Steril 2003;80:498–501. Practice Committee of the American Society for Reproductive Medicine. Increased maternal cardiovascular mortality associated with pregnancy in women with Turner syndrome. Fertil Steril 2012;97:282–4. Sauer MV, Paulson RJ, Lobo RA. Oocyte donation to women of advanced reproductive age: pregnancy results and obstetrical outcomes in patients 45 years and older. Hum Reprod 1996;11:2540–3. Kort DH, Gosselin J, Choi JM, Thornton MH, Cleary-Goldman J, Sauer MV. Pregnancy after age 50: defining risks for mother and child. Am J Perinatol 2012;29:245–50. Vincent-Rohfritsch A, Le Ray C, Anselem O, Cabrol D, Goffinet F. [Pregnancy in women aged 43 years or older: maternal and perinatal risks]. J Gynecol Obstet Biol Reprod (Paris) 2012;41:468–75. Oocyte or embryo donation to women of advanced reproductive age: an Ethics Committee opinion. Fertil Steril 2016;106:e3–7.
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With the first successful report of an IVF pregnancy achieved via donor oocytes in 1984, the applications of assisted reproductive technology (ART) were further expanded to include women unable to conceive with their own oocytes. Today, oocyte donation makes up an increasingly large percentage of all ART cycles worldwide. Oocyte donation presents several unique challenges to clinicians as two separate interests, those of the donor and those of the recipient, must be represented. These challenges include successful preparation of the endometrium in donor oocyte recipients, the synchronization of donor/recipient cycles, and the optimization of ovarian stimulation while maximizing donor safety. Facing these challenges has not only allowed for the creation of successful donor egg programs but has also provided insights into many aspects of ART. Much of what we know about the window of implantation, frozen ET procedures, triggering of oocyte maturation, and fertility preservation has been learned through experience and investigations with donor egg cycles. Not only has oocyte donation, through its optimization and wide use, provided new treatment opportunities for patients, it has also become a critical scientific tool to study many aspects of menstrual cycle dynamics and implantation. Concomitantly, with its increased efficiency, it has also raised several clinical and ethical challenges. (Fertil SterilÒ 2018;110:988–93. Ó2018 by American Society for Reproductive Medicine.) Key Words: Oocyte donation, synchronization, endometrial preparation, donor safety Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertilityand-sterility/posts/39243-27050
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n 1984, 6 years after the birth of the first human IVF baby, Lutjen et al. reported the first successful donor oocyte IVF pregnancy in a 25-year-old with a history of primary ovarian insufficiency (1, 2). This report, which represented the pinnacle of efforts by several groups worldwide, illustrated another successful application of assisted reproductive technology (ART). Women unable to conceive using autologous oocytes, either due to premature cessation of ovarian function or repetitive IVF failures, were now able to use ART to successfully achieve pregnancies. Today, oocyte donation cycles account for nearly 10% of all ART cycles in the United States, with live birth rates upwards of 50% per cycle (3).
The journey from those early reports of egg donor pregnancies to today's large and successful egg donor programs has presented numerous clinical challenges, including the successful preparation of the endometrium in donor oocyte recipients, the synchronization of donor/recipient cycles, and the optimization of ovarian stimulation for donors in order to strike a balance between oocyte yield and safety. The insights gleaned from this experience have allowed for success not only in donor oocyte programs but also for ART as a whole. Because factors affecting the ovary (donor) are separate and distinct from endometrial events in the recipient, this clinical paradigm has served as a critical tool to study both ovarian and endometrial factors
Received September 26, 2018; accepted September 27, 2018. A.P.M. has nothing to disclose. Z.R. has nothing to disclose. Correspondence: Zev Rosenwaks, M.D., The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine of Weill Cornell Medical College, 1305 York Avenue, New York, New York 10021 (E-mail: [email protected]). Fertility and Sterility® Vol. 110, No. 6, November 2018 0015-0282/$36.00 Copyright ©2018 Published by Elsevier Inc. on behalf of the American Society for Reproductive Medicine https://doi.org/10.1016/j.fertnstert.2018.09.021 988
contributing to implantation. Furthermore, our current ability to use donated oocytes so efficiently brings with it a host of new opportunities and challenges.
ENDOMETRIAL PREPARATION FOR RECIPIENTS Successful implantation of a fertilized oocyte depends on two key factors: a receptive endometrium and the synchronization of embryonic and endometrial development. In the natural menstrual cycle, this process relies on the precise coordination of ovarian steroid production, the timing of ovulation, and tubal transport of oocyte and embryo. Studies of human fallopian transport demonstrated that the oocyte arrives in the endometrial cavity 4–5 days after the LH surge and is still floating freely 6 days postsurge, suggesting that in vivo human oocyte transport provides adequate time for fertilization and simultaneous embryo and endometrial development (4, 5). VOL. 110 NO. 6 / NOVEMBER 2018
Fertility and Sterility® This allows for the arrival of an implantation-competent embryo to a receptive endometrium.
DONOR-RECIPIENT SYNCHRONIZATION Early work with donor oocytes sought to mimic this complex series of in vivo events. Buster et al., with their nonsurgical transfer procedures, attempted to synchronize donor and recipient ovulation within two days of the LH surge (6–8). Oocyte donors were inseminated with recipient partner's sperm, and donor uterus lavage and embryo recovery were performed 5 days after the LH surge. Of five fertilized oocytes recovered and transferred, two pregnancies were achieved; in both successful pregnancies, donor and recipient LH surges were synchronized (6). Later work in the natural cycle using IVF of donor oocytes sought to enhance efficiency by allowing for retrieval and fertilization of multiple oocytes. Early endeavors at donor/recipient synchronization demonstrated that transfer of 4- to 6-cellstage donor embryos on days 17–19 of a recipient's cycle led to implantation and pregnancy. However, when embryos were transferred on day 20 or beyond, no pregnancies were achieved. In these cases, all recipients were monitored for at least one cycle before transfer with daily serum E2 and LH measurements as well as luteal phase endometrial biopsies to confirm adequate endometrial development. This early work helped to elucidate the window of implantation and the optimal timing of ET (9). Early protocols therefore aimed for transfer of a 2- to 16-cell embryo to a day 17–19 endometrium. Of 21 transfers performed during this window, eight (38%) pregnancies were achieved (9, 10). Despite these early successes, synchronization of donor and recipient in the natural cycle presented a unique challenge for clinicians, given the need for precise coordination of recipient LH surge and donor oocyte retrieval. However, before the availability of GnRH agonists and the routine and efficient use of embryo cryopreservation, this was the only option for ovulatory recipients. Natural cycle synchronization cycles, while not used routinely today, set the stage for our understanding of the optimal timing of ET and have influenced many of the protocols currently used in ART. Natural frozen embryo cycles, for example, use the knowledge gleaned from this early work, for both autologous and donor ETs. Given the efficiency of embryo vitrification, in our donor oocyte program an increasingly large percentage of embryos are cryopreserved at the blastocyst stage. For ovulatory recipients, these embryos are replaced 5 days after the serum-defined LH surge, optimizing donor/recipient synchronization and allowing the recipient to avoid exogenous hormone replacement. We have also extrapolated these data for the use of vitrified donor oocytes in ovulatory recipients: frozen oocytes are thawed 1 day post–LH surge, with ET occurring on day 3 for 3-day-old embryos and 5 days later for blastocysts.
THE ROLE OF ESTROGEN AND P SUPPLEMENTATION As with the study of the natural cycle in donor recipients, investigation of estrogen and P replacement cycles also proVOL. 110 NO. 6 / NOVEMBER 2018
vided us with a wealth of information about the window of implantation and the maintenance of pregnancy in the absence of ovarian function. The first successful IVF donor pregnancy was achieved with oral estradiol valerate and vaginal P supplementation. Once a pregnancy was confirmed, the patient was switched from vaginal to IM P for pregnancy maintenance. Steroids were withdrawn in the second trimester (1). This initial protocol was modified by several groups worldwide using different methods of estrogen and P delivery at varying concentrations and durations, with the goals of mimicking the normal menstrual cycle and allowing for implantation and maintenance of early pregnancy. During the early days of oocyte donation, the importance of P for implantation and the maintenance of early pregnancy was well established. However, less was known about the role of estrogens. Csapo et al. showed that P replacement during the first 50 days of gestation in women undergoing luteectomy allowed for continuation of pregnancy; E2 alone was unable to do so (11). Studies in nonhuman primates demonstrated a likely facilitatory role of estrogen. Pregnancy in oophorectomized rhesus monkeys was established and maintained with supplementation of P alone (12). Given these findings, early replacement protocols attempted to minimize the dosage of replaced E2. The first ovarian failure recipient at Norfolk, for example, was treated with P injections only, with estrogen levels maintained between 10 and 30 pg/mL during the luteal phase. Although initially positive and appropriately increasing, hCG levels dropped to 0 by week 6 of pregnancy. From this experience, we learned that while facilitatory in nonhuman primates, estrogen clearly plays an obligatory role in human gestation. In a subsequent cycle, the patient was treated with E2 during both the follicular and luteal phases, with levels maintained at 100–300 pg/ mL. Pregnancy was achieved, and steroid doses were kept fixed, allowing for the assessment of endogenous placental steroid production. Estrogen levels were noted to rise during the eighth week of gestation, and withdrawal of estrogen supplementation by the end of the first trimester did not compromise pregnancy outcome (9, 13, 14). Similarly, Lutjen et al. demonstrated early increases in placental steroid production with successful withdrawal of hormone supplementation beginning as early as cycle day 38 of pregnancy (15). From this early work, it was apparent that while estrogen supplementation in the human ovarian failure patient was required for implantation and early pregnancy maintenance, less estrogen was needed, and for a shorter duration, than had been previously used. Furthermore, this work provided an in vivo model for the luteoplacental shift, revealing that this shift occurs much earlier than previously thought (14). In contrast to estrogen, the obligatory role of P for implantation had been firmly established during the early evolution of oocyte donation. However, the ideal P replacement protocol was not clearly known. Early work on P replacement showed that adequate levels could be achieved with a variety of delivery methods. In our initial experience, recipients were monitored during two mock replacement cycles before transfer, with P supplementation beginning on cycle day 15. Endometrial biopsies were performed on days 20–22 and again on 989
VIEWS AND REVIEWS days 26–27. Interestingly, early midluteal biopsies demonstrated glandular/stromal asynchrony with glandular architecture characteristic of day 18 endometrium, although late luteal biopsies demonstrated a characteristic day 25–26 appearance. The observed early glandular lag did not appear to affect implantation (9), although it highlighted the differences between natural and replacement cycles. In the natural cycle, P elevation begins gradually on day 14, allowing for earlier development of endometrial glands, whereas in the replacement cycles, P intake was begun 1–2 days later at a higher fixed dose, thus leading to an apparent glandular lag. As a result, replacement protocols were adjusted, with P starting at a lower dose in an attempt to mimic the natural cycle. At our center, P is started at 25 mg IM (0.5 mL) once adequate endometrial thickness is achieved. After the first night of P, the dose is increased to 50 mg IM (1 mL) nightly. ET occurs after 6 days of P supplementation. The early studies of recipient replacement cycles play an increasingly important role in all of ART. The realization that exogenous hormone regimens could successfully prime an endometrium for implantation in the recipient population led to their use for frozen-thawed ETs (FETs). Today's programmed FET protocols are based on this early work, highlighting its importance as FETs make up a growing proportion of all ETs performed. Given the efficiency of oocyte vitrification and the increasing use of frozen oocytes, synchronization has become much simpler in both natural and programmed cycles. Thus, efforts made to achieve synchronization in early egg donation studies laid the groundwork for much of today's ART practices.
DONOR SELECTION AND STIMULATION Unlike ART procedures using autologous oocytes, donor oocyte cycles must represent two separate interests: those of the donor and those of the recipient. In the early days of oocyte donation, before routine donor compensation, most donated oocytes were provided by IVF patients who agreed to donate excess oocytes or by patients' sisters. Today, the majority of donated oocytes come from anonymous donors. Whereas recipients obtain a clear benefit from oocyte donation, the donors' benefits—which may include financial compensation or a perceived sense of altruism—are less tangible. Furthermore, unlike sperm donors, egg donors undergo complex and invasive medical procedures each time they donate. As such, every effort should be made to ensure that donor safety remains the top priority of a donor oocyte program. Careful and critical analyses of egg donation treatment protocols along with their medical consequences have led to several modifications of donor stimulation and retrieval practices (protocols), which have been generally applied to all IVF treatment cycles. The majority of studies on complication rates in donors undergoing controlled ovarian hyperstimulation and oocyte retrieval report low rates of major complications, often lower than those reported in the general IVF population. For example, 2008 data from our center examining 587 donors undergoing 973 cycles demonstrated an overall rate of serious complications, including ovarian hyperstimulation syndrome 990
(OHSS), ovarian torsion, infection, and ruptured ovarian cyst of 0.7% (16). While these rates are low, it must be emphasized that any complication in a patient undergoing a procedure for which she does not derive a direct health benefit should be viewed as one complication too many. This viewpoint has led to several of the protocol modifications used today. Antibiotic prophylaxis, for example, now routinely given to all donors at the time of retrieval, was started after a pelvic infection rate of 0.4% (two hospital admissions in 526 cases) was deemed unacceptably high. It had been assumed that donors at risk for infection—those with a history of endometriosis or pelvic inflammatory disease, for example—would have already been excluded from donating and therefore antibiotic prophylaxis was unnecessary. However, after the observed infection incidence in two donors, as of August 2003, all donors now receive prophylactic antibiotics at the time of retrieval. This change in practice has reduced our infection rate to zero (17).
REDUCING THE RISK OF OHSS OHSS, like infection, is a rare complication among oocyte donors but one with potentially catastrophic implications. By virtue of being selected to donate, egg donors represent a population of women with an increased risk of OHSS: young with good ovarian reserve. Furthermore, because donor oocytes are often divided between more than one recipient, donors are often stimulated more aggressively to maximize oocyte yield. Over the years, several strategies have been successfully employed to reduce OHSS risk, including the use of sliding-scale hCG doses for the ovulatory trigger and the administration of dopamine agonists. However, it is the use of GnRH agonists for triggering final oocyte maturation that has brought us closest to achieving OHSS-free stimulation in oocyte donation cycles. In contrast to the prolonged luteotrophic effects of hCG, the endogenous LH surge elicited by the GnRH agonist trigger has a short half-life leading to early luteolysis. Several large retrospective and smaller prospective studies have demonstrated a significantly decreased risk of OHSS in donors without compromising recipient pregnancy rates (18–20). At our center, a randomized controlled trial in which donors were randomized to receive hCG, leuprolide acetate, or leuprolide acetate with low-dose hCG (dual trigger) was terminated early due to preliminary data showing significant symptomatic benefit for donors receiving leuprolide or dual triggers as compared with those receiving full-dose hCG, with no change in pregnancy outcomes among the three groups. All donor stimulation protocols at our center are GnRH antagonist based, and the vast majority of donors receive either pure leuprolide or a combination of leuprolide and low-dose (1,500 IU) hCG triggers. One of the concerns with the use of GnRH agonist triggers is that a small subset of patients fails to respond with an adequate LH surge. This is particularly concerning for fresh donor cycles in which two recipients have undergone endometrial preparation in anticipation of an ET. As such, understanding which patients are at risk for failed response to agonist triggers is of paramount importance to avoid the emotional consequences of a recipient's cancelled cycle. A VOL. 110 NO. 6 / NOVEMBER 2018
Fertility and Sterility® 2015 retrospective study from our center sought to identify risk factors for suboptimal response to GnRH agonist triggers. The patients studied received either leuprolide alone or a dual trigger with low-dose hCG, and 31.8% of included cycles were donor cycles. Suboptimal response was defined as a serum LH level of <15 mIU/mL 8–12 hours post-trigger. This cutoff was selected based on poor clinical outcomes associated with LH levels <12–15 mIU/mL in prior studies. Suboptimal LH responses were found in patients who were younger, had lower body mass indexes (BMIs), lower baseline gonadotropin levels, and lower LH levels on the day of trigger, and were more likely to be long-term oral contraceptive pill (OCP) users compared with those who responded appropriately to the agonist trigger. These findings implicate downregulation of the hypothalamic-pituitary axis as the primary cause for failed response. Interestingly, oocyte donors were found to be more likely to have an inadequate response; however, this was not surprising, given that 12.6% of all donor cycles took place in the context of long-term OCP use (21). Using this profile of a nonresponder has allowed us to select patients for whom GnRH agonist triggers are appropriate. Donors with no risk factors typically receive leuprolide triggers, whereas those deemed to be at some risk of nonresponse receive dual GnRH agonist and low-dose hCG triggers. We also try to minimize long-term OCP use before donor cycles whenever possible. These data have allowed for efficient use of GnRH agonist triggers among the donor population. Donors are at a lower risk of OHSS and, more importantly, feel better at the end of their cycles while cycle cancellation rates for failed trigger are low. While donor safety is of the utmost importance in an oocyte donation cycle, maximizing donor convenience is also crucial. In addition to the physical obligation, the decision to donate eggs brings with it a tremendous time commitment. Complete donor screening takes several hours, and while cycling, donors are required to be present for monitoring on a near-daily basis. As such, every effort should be made to ensure that the donor cycle fits as seamlessly into day-today life as possible. Vitrification, which has allowed for the freezing and thawing of oocytes with incredible efficiency, has given us tremendous freedom in scheduling donor cycles. An abundance of data have confirmed that vitrified oocytes are comparable to fresh in terms of fertilization, embryo development, pregnancy rates, and birth outcomes. The ability to freeze a donor's oocytes upfront negates the need for donorrecipient synchronization and allows donors to cycle according to their schedule. Furthermore, oocyte vitrification has proved essential amidst recent Zika concerns. If not for the ability to cycle without synchronization, many of our donors would have had to wait 6 months after Zika travel to cycle in order to comply with Food and Drug Administration regulations.
THE UNIQUE MODEL OF OOCYTE DONATION While oocyte donation represents a subset of all ART procedures performed, the oocyte donation model has provided us with a tremendous knowledge base applicable to all aspects of ART. An early review of oocyte donation foreshadowed this role, describing the use of donor eggs as not only theraVOL. 110 NO. 6 / NOVEMBER 2018
peutic but diagnostic as well. Donated oocytes were used for testing sperm-oocyte interaction in couples with a history of unexplained infertility and prior IVF failure (9). This allowed for identification of the true etiology of the infertility. Although oocyte donation is not routinely used today as a diagnostic technique, its study offers a wealth of information to patients undergoing all types of ART. The oocyte donation model is unique because it removes the oocyte as a variable affecting reproductive outcomes. As such, other factors affecting ART success can be studied. Moreover, cycles in which donor oocytes are split between two recipients allow for a clean analysis of various factors affecting implantation. Given the complexity of the implantation process, a model that can elucidate specific factors involved in endometrial receptivity and successful embryo implantation is invaluable. While the impact of age on oocyte quality was well established early on, less was known about its effect on uterine receptivity. Poor implantation in older women was attributed to diminished oocyte quality and higher aneuploidy rates. Comparing oocyte recipients of various ages, however, has provided us with a great deal of information about the impact of age on uterine receptivity. A few early studies, including one published by our group in 1999, demonstrated a deleterious effect of age on both implantation and miscarriage rates (22). A subsequent multivariate retrospective analysis of over 17,000 oocyte donation cycles in the United States showed that while implantation, clinical pregnancy, and delivery rates remained stable among recipients age 25 through the late 40s, rates began to decline at age 48, with a steep decline after age 50. Furthermore, an association between increasing recipient age and higher miscarriage rates was demonstrated (23). A 2005 study of over 3,000 oocyte donation cycles showed significantly lower implantation and pregnancy rates from age 45 onward, with an even sharper decline after age 50. An increased incidence of miscarriages in older recipients was also shown (24). These data demonstrate a clear alteration in uterine receptivity in older women, which may be a function of altered uterine blood flow, changes in endometrial steroid receptor concentrations, stromal angiosclerosis, and subepithelial extracellular matrix deposition, processes seen in other animal species (25, 26). The donor oocyte model has also proved invaluable to studies of endometriosis. Several retrospective studies have demonstrated that oocytes donated from women without endometriosis and split between recipients with and without endometriosis lead to similar reproductive outcomes (27–29). This suggests that it is the oocyte, not the endometrium, that leads to diminished success with ART in patients with endometriosis. A subsequent prospective study confirming these results compared three groups: [1] donors/recipients without endometriosis, [2] donors with endometriosis donating to recipients without the disease, and [3] donors without endometriosis donating to recipients with the disease. Lower pregnancy rates per transfer were observed in the second group, confirming that embryos derived from oocytes of women with endometriosis had diminished implantation potential (30). Findings such as these would be difficult to obtain without the study of donor oocytes. However, these studies must be interpreted with caution. 991
VIEWS AND REVIEWS The oocyte donation model has also provided us with insights into lifestyle factors and their impact on reproductive outcomes. Obesity is clearly associated with diminished fertility and poor reproductive outcomes in all modes of conception. However, the mechanism by which increasing BMI affects outcome—whether it is at the level of oocyte, endometrium, or both—is not as clear. Several studies of oocyte recipients have shown decreasing pregnancy rates with increasing BMI. In these cases, oocyte donors all had normal BMI, a clear demonstration of the impact of obesity at the uterine level (31–33). Conversely, a recent study of 235 oocyte donation cycles assessed the association between donor BMI and pregnancy outcomes. After adjusting for recipient BMI, this group showed that increasing oocyte donor BMI is associated with a reduction in clinical pregnancy and live birth rate, suggesting an effect of BMI at the oocyte level (34). Cigarette smoking, another lifestyle factor known to impact fertility, has also been examined through the donor egg model. A 2007 study of 785 oocyte donation cycles over a 3-year period showed that heavy smoking (>10 cigarettes per day) led to a significantly lower pregnancy rate. The study controlled for father and donor smoking status, patient age, BMI, duration of endometrial priming, and number of good-quality embryos transferred (35). While smoking is known to affect ovarian function, its impact at the level of the uterus has been less understood. These data suggest an impact at the endometrial level that can be used when counseling not only recipients, but all fertility patients. Oocyte donation has greatly contributed to our current application of fertility preservation outcomes. With the advent and subsequent wide adoption of vitrification, a large number of women have pursued elective egg freezing. While many have frozen, fewer have returned to use their oocytes. As such, there is a dearth of data available to counsel our fertility preservation patients about outcomes post-thaw. However, given the role that vitrification now plays in most donor oocyte programs worldwide, what we know about frozen eggs can be extrapolated to our elective fertility preservation patients. Oocyte donation has also broadened our current knowledge of obstetric management of women with Turner syndrome. Given that only 5%–10% of Turner syndrome patients will achieve natural pregnancies, the reproductive possibilities for these women have been greatly expanded by oocyte donation. Pregnancy rates after oocyte donation in women with Turner syndrome are equivalent to those of other recipients, suggesting no impact of the syndrome on uterine receptivity. However, women with Turner syndrome have high rates of congenital cardiovascular malformations and predisposition to aortic root dilatation, a known risk factor for aortic dissection. In 2003, Karnis et al. reported that the risk of death from aortic dissection during pregnancy is at least 2% in Turner patients. They also noted that only about 50% of women with Turner syndrome in the United States underwent cardiac examination before beginning fertility treatment (36). These findings led to specific guidelines for screening and management of patients with Turner syndrome both before and during pregnancy (37). Further studies of Turner syndrome patients after oocyte donation and their 992
maternal outcomes will allow us to continue to make recommendations to optimize the health of these recipients.
FUTURE CHALLENGES Oocyte donation has greatly enhanced our ability to treat infertility. As the application of this technology has increased, so have the clinical challenges that we face in day-to-day practice. While oocyte donor recipients have traditionally been women with pathologic conditions—poor oocyte quality, diminished ovarian reserve, primary ovarian insufficiency— today, an increasing number of recipients are either perimenopausal or even menopausal, which raises the question, at what age do we stop? The reported successes of donor egg pregnancies for women in their 50s and 60s suggest that with the proper hormone priming, any woman with a uterus can achieve pregnancy. However, it is well established that the risk of pregnancy-related complications increases with maternal age. This risk is compounded by the increased risk of hypertensive disorders conferred by donor egg pregnancies. In several series, recipients over the age of 50 have been found to have higher rates of gestational diabetes, cesarean section, and gestational hypertension (38–40). The effect on children born to mothers of advanced reproductive age conceived via oocyte donation is also not well defined. Furthermore, concerns related to longevity and the ability to raise a child into adulthood are at the center of the age debate. Several expert groups recommend against providing donor oocytes to women over 55 years of age (41). Some clinics have strict age cutoffs, while others evaluate women on a case-by-case basis. Clearly, all prospective recipients of advanced reproductive age must undergo thorough medical screening and counseling about the medical risks of pregnancy by a maternal-fetal medicine specialist. Additionally, every attempt should be made to avoid multiple gestation in this population, with single ET as the standard of care. But once these two conditions are met, is it enough? And at what age do we say that it is not? Furthermore, what do we do with the patient with cryopreserved supernumerary embryos who may fall outside of our age cutoff? Does the risk of being another 2–3 years older trump the importance of having a biological sibling for a child who may not have his or her parents into adulthood? Of the many challenges surrounding egg donation, the age limits set for recipients are likely to continue to be the most challenging.
CONCLUSIONS Since its inception, egg donation has become one of the mainstays of ART treatment. It has not only enabled successful outcomes in women who otherwise would have been sterile, it has also become an important tool to study various aspects of human reproduction. Lessons learned from egg donation have been applied to many areas of ART.
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