Abstract
Every year many women worldwide are diagnosed with cancer. More than 90% of cancer patients undergo invasive cancer therapy, such as chemo- and radiotherapy [1]. Most chemotherapy regimens include the alkylating agent cyclophosphamide, which is known to cause a significant loss in ovarian follicle reserve, and may result in infertility and early menopause. The irreversible destruction of germ cells after using both radio and chemotherapy is due to a direct apoptotic effect on oocytes [2]. On the other hand, advances in oncological treatments and better screening programs have significantly improved the life expectancy thus increasing the population of young cancer survivors. Therefore, protection against iatrogenic infertility caused by cancer therapies is considered indispensable to allow patients to have a chance to conceive in the future and to have their own genetic offspring.
Introduction
This book is primarily about prevention; its emphasis is on interventions that can be done at the time of cancer diagnosis – modifications of treatment and techniques for storing gametes, tissues or embryos for future use. By contrast, this chapter explores options open to cancer survivors after treatment has been completed. If preventive treatment was successful, either through medical interventions such as using less gonadotoxic regimens, fertility-sparing surgery, oophoropexy or gonadoprotective adjuncts like GnRH agonists, normal fertility has been preserved. Other survivors may be able to conceive using the gametes, embryos or tissue that was obtained and cryopreserved before their gonadotoxic treatment(s). However, in some cases, fertility preservation may not have been possible before treatment or, alternatively, the cryopreserved gametes, embryos or tissue may not have resulted in a successful pregnancy. This chapter provides insight into the fertility management of cancer survivors with compromised or absent ovarian function, who do not have cryopreserved gametes, embryos, or ovarian tissue.
Before cancer survivors embark on achieving a pregnancy, their general health, uterine function, chance of cancer recurrence and, finally, prognosis for long-term survival must be assessed by their physicians. Since these concerns are common to all cancer survivors trying to achieve pregnancy – whether achieved in the natural cycle, through assisted reproductive technology (ART) or through third-party reproduction like oocyte donation (or donor egg, DE) – they will be discussed together in the first part of this chapter.
The second part of this chapter focuses on situations in which cancer has resulted in reduced fertility or has markedly shortened the reproductive window due to diminished ovarian reserve. In situations where ovarian function persists but is attenuated, the use of ARTs may enable patients to achieve a pregnancy before there is further decline in ovarian function. For some cancer survivors, specific treatment modifications may be indicated.
The third section of this chapter explores situations in which fertility preservation has failed, was not possible or was not the appropriate option for a given individual. We emphasize here that DE is not always considered by patients to be the last resort. For a variety of reasons that we will discuss later, some women may choose DE as the best reproductive choice in a difficult situation.
Evaluating the Cancer Survivor for Pregnancy
We begin with the evaluation of the cancer survivor who desires to become pregnant. A flow chart of cancer survivor screening is shown in Figure 21.1.
Figure 21.1 Screening of the cancer survivor for pregnancy (spontaneous, assisted reproductive technology [ART] or oocyte donation). MFM, Maternal Fetal Medicine
Prognosis
Before any evaluations are performed, the treating oncologist should determine the prospective mother’s prognosis. Has she been disease-free for a sufficient period of time? Is her prognosis for cure generally good? Would pregnancy increase her risk of cancer recurrence? Kavic and Sauer have suggested that in some cases, particularly those in which the cancer is considered to be in remission but is not cured, a second opinion from an independent oncologist may be helpful [1]. Nevertheless, it must be recognized that patients and their physicians may choose to proceed with achieving a pregnancy despite a poor prognosis, or even in cases where pregnancy may increase the risk of cancer recurrence. However, this decision should not be made without a thorough discussion and fully informed consent by all parties involved.
Chronic Health Problems
Seventy-five percent of childhood cancer survivors will have at least one chronic health problem. Cardiotoxicity from anthracyclines or mediastinal irradiation is common. Nephrotoxicity may result from ifosfamide and cis-platinum chemotherapy, radiotherapy, surgery or immunotherapy. Finally, 1 in 25 survivors of childhood cancer will develop a second primary cancer [2]. Thus, a cancer survivor contemplating parenthood should be evaluated for organ-system damage and counseled about any risks to herself and the fetus during pregnancy. When indicated, prior to conception she should consult with the obstetrician who will care for her during pregnancy. She should also be made aware of any significant health risks that might affect her ability to raise a child to adulthood.
Time Interval between Treatment and Pregnancy
Depending on the nature of the cancer and the type of gonadotoxic treatment used, oncologists may recommend that cancer survivors wait at least 1 year before attempting pregnancy [3]. This interval gives the oncologist time to evaluate for recurrence. Furthermore, it may minimize the toxic effects of chemotherapy on a developing fetus. Experimental studies in animals have supported concerns about the risk to the fetus from exposure to chemotherapeutic agents. For example, mice that were exposed to chemotherapy three weeks before conception had high malformation rates, and malformation rates remained 10-fold higher than the control group for conception up to nine weeks after exposure [4]. In humans, pregnancy outcomes reported in women exposed to potentially mutagenic therapies are reassuring; however, these pregnancies often occurred many years after exposure [5, 6]. Although a wait of at least a year is generally recommended, a safe time interval from chemotherapy to pregnancy has not been determined. These risks to pregnancy after the completion of chemotherapy may be related to its sustained effects on developing oocytes rather than on the fetus. These risks may not be relevant to pregnancies conceived with oocytes collected prior to exposure or with donated gametes. Younger women with good ovarian reserve may wish to wait longer than the minimum 1–2 years to achieve pregnancy.
Breast cancer survivors, by contrast, are usually advised to wait two years after completing chemotherapy before attempting pregnancy. Breast oncologists make this recommendation primarily because of the high rate of recurrence in the first years after diagnosis and not necessarily because of the effects of treatment on pregnancy outcome. The recommended time interval may be different depending on the age of the patient, estrogen receptor status and stage of disease – with longer intervals recommended for younger patients and those with more advanced stage disease. Disease-free breast cancer survivors who conceive more than two years after finishing treatment do not appear to be at any increased risk of recurrence as compared to those who do not become pregnant following treatment [3].
This imposed delay causes concern for many women – they are aware of the higher risk of premature ovarian failure and the reduced chance for pregnancy as time passes. We can help to ease their anxiety by providing information and support, evaluating their ovarian reserve with anti-Müllerian hormone (AMH) measurements or antral follicle counts (AFCs) and recommending that treatment be delayed only in cases in which it is deemed appropriate to do so.
Uterine Evaluation
If a cancer survivor does not become pregnant in the first few months of attempting conception, she should have a uterine cavity evaluation – a hysterogram or sono-hysterogram – to rule out adhesions, intraluminal pathology or a significant septum. Such an evaluation is especially critical for women who have had pelvic or total body irradiation.
Pelvic irradiation often results in damage to the uterine musculature and vasculature. Childhood radiation, in particular, may result in poor uterine growth during puberty. Smaller uterine volumes may diminish implantation rates, cause preterm labor or result in second-trimester loss or placental abnormalities such as reduced placental perfusion leading to intra-uterine growth retardation (IUGR) or placenta accreta, increta or percreta [7]. A tripling of spontaneous miscarriage and a 10-fold increase in low birth weight infants have been reported in patients who had received pelvic radiation therapy (RT) as compared to the general population [8].
These risks are affected by the dose of RT delivered to the uterus and by the temporal association with puberty. For example, there is a linear correlation between the size of the uterus, the response to hormone treatment and the age at which RT was administered [8]. Some investigators have emphasized that many reported pregnancies after pelvic radiation are delivered prematurely and do not result in the delivery of a healthy child [9].
Although the adult uterus is less sensitive to the effects of radiation, adult cancer survivors who received RT to the pelvis should delay pregnancy for at least a year following RT; it has been suggested that pregnancies that occur <1 year after RT have a higher rate of low birth weight babies and miscarriages [10]. (For a more detailed discussion of the effects of pelvic radiation on uterine function, see Chapter 3.)
Use of a Gestational Carrier
In individuals for whom a pregnancy is contraindicated, that is, where carrying a pregnancy poses a significant risk to the mother or child, a gestational carrier may be considered. If ovarian function is sufficient and there is no medical contraindication to ovarian stimulation or retrieval, the patient’s own oocytes can be retrieved and fertilized for transfer into a hormonally synchronized gestational carrier. In cases of low or absent ovarian reserve, or where there are contraindications to ovarian stimulation, oocytes from a donor can be fertilized and transferred to the carrier. Fresh embryos may be transferred when the cycles have been synchronized in the same manner as that used for oocyte donation (see subsequently), or the embryos may be cryopreserved for transfer into the carrier during a later cycle. Screening and testing for infectious agents and risk factors from all gamete providers are clearly delineated and mandated by the United States Food and Drug Administration (FDA) and may reduce risk to the gestational carrier. Some US states such as New York have additional regulations that supersede the federal regulations. Finally, psychological and legal counsel for all parties should be obtained before proceeding with a gestational carrier pregnancy.
ART in Cancer Survivors
Testing Ovarian Function
Ovarian reserve, a measure of the quantity of oocytes remaining in the ovary, can be performed most accurately with a blood test for AMH and/or an ultrasound to count the antral follicles. Both correlate directly to the number of oocytes retrieved following ovarian stimulation; however, they do not indicate oocyte quality. It can be useful to test ovarian reserve before initiating fertility treatment in cancer survivors since gonadotoxic treatments frequently reduce the primordial follicle pool and effectively “age” the ovary. Diminished ovarian reserve, even in young women, may already have been present before gonadotoxic treatments [11] and will almost certainly be further diminished after therapy. Early follicular phase follicle stimulating hormone (FSH) and estradiol (E2), inhibin B, AFC, AMH and response to ovarian stimulation (in addition to other measures) have all been utilized to estimate ovarian reserve and indirectly assess the chance for pregnancy. While AMH and AFC have been the most accurate and consistent measures of response to stimulation, caution must be exercised in interpreting results, especially in individuals who use hormonal contraception or who have recently undergone ovarian stimulation or chemotherapy (within 6–9 months).
Patients who have received chemotherapy have been shown to have diminished ovarian reserve with abnormal elevations in FSH as well as lower AMH, inhibin B and AFC [12, 13]. Additionally, embryos created after cancer treatment have lower implantation rates compared to embryos from similar-aged women who have never undergone chemotherapy [14–16].
None of the current tests, either alone or in combination, can predict with certainty whether a pregnancy will be achieved. Therefore, a cancer survivor who maintains some follicles and ovarian function should be given a chance to attempt conception without utilizing her cryopreserved tissue – as long as she is advised of her estimated prognosis in doing so. By contrast, a patient who exhibits extremely high FSH levels, very low inhibin or AMH levels, or has a negligible AFC, may wish to discuss oocyte donation or other reproductive alternatives. If she has cryopreserved eggs or embryos, she should be encouraged to use them if attempts at stimulation are predicted to be futile.
Ovarian Stimulation
The physician treating a cancer survivor who wishes to have children will want to keep one central principle in mind: if the patient was treated with gonadotoxic agents or pelvic RT, no matter what her present age or ovarian function, she is likely to have reduced ovarian function earlier than her age would suggest. Therefore, as soon as she is ready, she should be encouraged to attempt conception. If she is not successful within 6 months, a thorough evaluation and intervention should be undertaken. Finally, strategies to achieve pregnancy in the shortest time frame possible are reasonable, if not imperative, in this population. Storing additional gametes or embryos is also encouraged, as many patients would like to have more than a single child.
For these reasons, we should recommend ART for the infertile cancer survivor who fails to conceive a pregnancy after a limited trial of natural cycle and timed intercourse or ovulation induction and intrauterine insemination (IUI). In vitro fertilization (IVF) offers the greatest chance for pregnancy in the shortest time interval. This is especially important in women with estrogen-sensitive tumors in order to minimize their exposure to multiple courses of ovarian stimulation.
For women who stored gametes or embryos before gonadotoxic treatments, the following caveats are equally important: when ovarian function still exists and they are prepared to become pregnant, they should be encouraged to attempt conception as soon as possible. It should be emphasized that having frozen oocytes and embryos does not guarantee pregnancy success. Rather, their use should be considered as the last option should the women become sterile. Given that frozen ovarian tissue and/or eggs and embryos may lead to a false sense of security in terms of reproductive potential, women who may still have a chance to conceive should be discouraged from delaying childbearing. In general, and especially if the patient is considering having more than one child, consideration should be given to maintaining the cryopreserved eggs or embryos in reserve. If the patient has reasonable ovarian function and a normal fertility evaluation, she should attempt to conceive a pregnancy first in a natural cycle with timed intercourse. If she is unsuccessful after 3–6 months or if there is tubal occlusion or male factor, ART would be the best option. The patient gives herself the best chance of fulfilling her reproductive desires by retaining her frozen gametes or embryos until either her last attempt at pregnancy or her ovaries fail.
Patients with a history of cancer (not known to be hormonally sensitive) may be stimulated with gonadotropins in the same way as patients who are not cancer survivors. The main difference will be a generally lower response to gonadotropin stimulation – and accompanying lower implantation and pregnancy rates – as compared to either age-matched controls with infertility or cancer patients before chemotherapy [15, 16].
Women who received chemotherapy for a variety of cancers had significantly lower AMH levels and fewer oocytes retrieved as compared to age-matched patients undergoing fertility preservation before cancer treatment. Additionally, in one study, the implantation rate for 36-year-old patients who had previously undergone chemotherapy was only 7.9%, significantly lower than that expected for the infertile population in the same age group [17]. In a separate study, when a group of patients who had received local treatments for their cancer was compared to a group who had received systemic therapies, response to stimulation was significantly better in the patients who had received local treatment only. Additionally, the study suggested that the pregnancy rate in patients who had received systemic chemotherapy was lower than in women who had received only local treatments [15].
Finally, these results suggest that a liberal embryo transfer policy should be applied to patients undergoing ovarian stimulation and embryo transfer subsequent to chemotherapy. Patients should be counseled that their chances for pregnancy as well as the rate of multiple gestation, even with an increased number of embryos transferred, will be lower as compared to other infertile patients of the same age. Extended embryo culture to the blastocyst stage and genetic testing of embryos may not be possible for patients with few oocytes or embryos and may lower the likelihood of achieving pregnancy by excluding potentially viable embryos due to false positive errors. Documentation of this counseling should be placed in the patient’s record, and the reason for exceeding the clinic’s transfer guidelines should also be noted.
As in any other IVF cycle, additional embryos can be cryopreserved. There is no reason to believe that good-quality cryopreserved embryos will not have reasonable survival rates; however, there is no specific data regarding outcomes with cryopreserved embryos in cancer survivors.
Ovarian Stimulation for Hormonally Sensitive Cancers
Standard ovarian stimulation for ART results in high levels of circulating estrogen – potentially 10-fold higher than peak levels seen in unstimulated spontaneous cycles. Breast and endometrial cancer survivors, as well as survivors of other estrogen-sensitive cancers, and their doctors should be aware of the impact of high E2 levels on the risk of recurrence. Because of this theoretical risk, stimulation regimens that utilize estrogen-receptor modulators, such as tamoxifen or agents that suppress E2 synthesis (aromatase inhibitors), have been utilized and may be preferable to conventional stimulation protocols.
Several alternative methods of ovarian stimulation have been described. These use estrogen receptor modulators or aromatase inhibitors, either alone or in combination with gonadotropins, in an effort to stimulate multifollicular development while reducing or avoiding high serum E2 levels. Most protocols have been developed and studied in the context of stimulating newly diagnosed breast cancer patients for fertility preservation. However, the protocols may have application in cancer survivors as well.
In a randomized controlled trial, our group compared tamoxifen, tamoxifen in combination with FSH or letrozole in combination with FSH to stimulate follicle development (Figure 21.2). The highest number of total and mature oocytes was obtained in the letrozole/FSH group (11 ± 1.2 and 8.5 ± 1.6, respectively) compared to either the tamoxifen/FSH group (6.9 ± 1.1 and 5.1 ± 1.1, respectively) or the tamoxifen-alone group (1.7 ± 0.3 and 1.5 ± 0.3, respectively). Despite high peak estrogen levels in the tamoxifen, tamoxifen/FSH and letrozole/FSH groups (419 ± 39 pg/ml, 1,182 ± 271 pg/ml and 405 ± 45 pg/ml, respectively), cancer recurrence rates were not different between groups after a mean follow-up of 554 ± 31 days [18]. The timing of final oocyte maturation with human chorionic gonadotropin (hCG) in tamoxifen or letrozole stimulation cycles is similar to protocols using clomiphene citrate: oocyte maturity is typically reached when the lead follicles are approximately 20 mm [19]. Additionally, when patients with breast cancer underwent ovarian stimulation for fertility preservation using letrozole and gonadotropins at our institution, there was no difference in disease-free survival compared to patients who elected to proceed directly to adjuvant treatments without ovarian stimulation [16]. Randomized studies with modifications to the above protocols are currently underway at our institution and others in an effort to further improve ovarian response and confirm safety. At this time, we can reassure patients with a history of estrogen-sensitive tumors that ovarian stimulation, using protocols that modulate the estrogen receptor or the ovarian hormonal response, do not appear to increase short-term recurrence. Further studies need to be performed to confirm and extend these findings.
Patients who are concerned about ovarian stimulation, either with or without modification, may express interest in natural cycle IVF. The success rates for these cycles are relatively low. Patients should be counseled about the possibility of cycle cancellation due to premature ovulation, failure to retrieve an oocyte or lack of an embryo to transfer. Moreover, the reduced viability of oocytes in patients who have undergone chemotherapy renders natural cycle IVF in this population a questionable option.
Another option, which has demonstrated some success in polycystic ovary (PCO)-like patients, is retrieval of immature oocytes after hCG with or without a truncated course of gonadotropin stimulation [20]. This field is reviewed in detail in Chapter 36. The significantly reduced developmental potential of embryos derived from in vitro matured oocytes (manifested in lower implantation rates and higher miscarriage rates), the need to transfer excess embryos in an attempt to maintain acceptable pregnancy rates and the requirement for prolonged hormone replacement in these women limit the present applicability of this approach for the cancer survivor [21].
As treatments for cancer improve and survival extends, more women of reproductive age who have been exposed to potentially gonadotoxic therapy will present to their physicians desiring pregnancy. Many of these women will achieve a pregnancy naturally without medical assistance. However, for others, fertility potential will be reduced. In general, women who have been treated with gonadotoxic therapy will experience diminished ovarian reserve and menopause at earlier ages than their peers.
Women with ovarian function but diminished ovarian reserve can safely undergo ART and can be reassured that, so far, recurrence rates are no different when compared to women who elected not to attempt pregnancy. Stimulation with standard protocols for IVF or novel protocols in patients with hormonally sensitive tumors can be undertaken. However, the success rates in cancer survivors who received systemic chemotherapy or pelvic RT are not equivalent to their age-matched peers who do not have a history of cancer treatment. Despite recent advances, some will not achieve pregnancy with their own gametes. Some will choose to pursue adoption or child-free living. Others may choose to pursue pregnancy through oocyte donation.
Oocyte Donation in Cancer Survivors
Egg donation is not suitable for everyone due to moral, religious or emotional reasons. For others, DE is a reasonable and effective way to have children. For over a third of a century, oocyte donation has been successfully utilized to overcome infertility due to disorders of female gametes [22–24]. In the United States, for example, in 2015, 53% of 2,228 recipients achieved a live birth from the transfer of a single fresh embryo derived from an oocyte donor [25]. The success rates are much higher – approaching 100% – if recipients undergo multiple attempts [26].
In addition, some young women recently diagnosed with cancer will be carriers of cancer predisposition genes. Hereditary breast cancer syndromes (BrCa 1 and 2), familial adenomatous polyposis, multiple endocrine neoplasia syndromes, retinoblastoma and Lynch syndrome are only a few examples [27, 28]. Without doubt, as we begin to understand the biology of cancer, there will be more in the future. We have already seen that some of these young people will wish to have children who are not carriers [29–32]. Technology – PGT-M with transfer of unaffected embryos only, or prenatal diagnosis with termination of affected fetuses – offers one set of solutions. However, these are added interventions into what is already very high tech, high stress reproduction. Both procedures carry risks and, when the gene is dominant, half of the embryos or fetuses so conceived will be carriers. Thus, for example, everything else being equal, a young woman recently diagnosed with cancer, carrying a BrCa gene and wishing to have a non-affected child will find that the probability of conceiving a child from cryopreserved gametes or embryos will be half that of a recently diagnosed cancer patient who is not a carrier. In this group of patients, additional back-to-back stimulations and retrievals before starting gonadotoxic chemotherapies is warranted. Some recently diagnosed cancer patients who carry predisposition genes will see DE as a simpler solution: a proven, highly successful way to build a family and, at the same time, eliminate a deleterious gene.
The young cancer patient faces physical and emotional ordeals, as well as a daunting array of difficult choices to make in an extremely short amount of time. Sometimes a plan for oocyte donation (or adoption or child-free living) is a better option than attempting fertility preservation. It is our hope that this chapter will help the advisors – oncologists, reproductive endocrinologists, psychologists and others – to support not only the patient who chooses to pursue fertility preservation but also the one who chooses to decline it.
To this end, we believe that it is important to discuss oocyte donation from the outset, and at times even in some detail, along with the options for fertility preservation. All in all, a full discussion represents a hopeful message about available reproductive options.
Clinical Practice of Oocyte Donation
Although in the future, the majority of oocyte donation cycles may be performed using cryopreserved oocytes [33] in a manner analogous to sperm donation, today many cycles are still being performed using fresh oocytes fertilized by the partner’s sperm and transferred to a hormonally synchronized recipient. Thus, the mechanics of oocyte donation require several steps: recruiting suitable donors, obtaining informed consent from donors and recipients, and phenotypic matching of donors with recipients. The process involves ovarian stimulation of the donor, retrieving her oocytes and fertilizing them with the recipient partner’s sperm. Simultaneously, hormonal preparation of the recipient’s endometrium is done in a manner which synchronizes endometrial development with development of the embryo (Table 21.1). Vitrified oocytes can be thawed and fertilized one day following the natural cycle LH surge of a recipient or at a predetermined time in a hormonally prepared programmed cycle.
Table 21.1 Mechanics of oocyte donation
| Donor | Recipient |
|---|---|
| Recruitment and screening | Screening |
| • Medical/infectious disease | • Medical |
| • Psychological | • Psychological/psycho-education |
| • Genetic | • Genetic screening of partner |
| • Informed consent | • Informed consent |
| Matching | Matching |
| • Ovarian stimulation | • Preparation/synchronization of endometrium |
| • Retrieval of oocytes | • Fertilization |
| • Transfer |
Recruitment of Donors
Third-party reproduction is one of the most ethically complex aspects of reproductive healthcare. Even societies with generally similar values legislate donor recruitment very differently [34]. Thus, some countries have mandated anonymity (Spain, France, Belgium, Denmark), while others have mandated that donors be identifiable to their genetic offspring (UK, Sweden, Austria, Switzerland, the Netherlands, Canada, New Zealand and the Australian state of Victoria) [35].
Some countries do not allow monetary compensation (UK) or strictly regulate it (in France donors can be compensated for documented expenses), while others have looser regulations (Spain allows a small monetary compensation and expenses) [35]. In others, compensation is unregulated (United States and India), although it may be loosely limited by professional guidelines [36].
Some countries (Italy and Germany) do not allow oocyte donation at all. In others, oocyte donation is legal but so strictly regulated as to make it impractical (China’s “double blind” regulations, for example, have essentially eliminated oocyte donation in that country).
In general, these national regulations meet the needs of their respective societies. However, differences in policy have fostered trans-border reproductive care [37, 38]. Not only do recipients travel for oocyte donation services, but centers also actively recruit donors across national borders [39, 40]. Not surprisingly, more prosperous countries generally recruit from less prosperous ones. For some donors, the small stipend, the travel, the meals and the hotel stay are enticing, if not undue inducement.
In 2005, European IVF centers performed 11,475 oocyte donation cycles, or 3% of the 418,111 IVF cycles done in Europe that year [41]. By contrast, in the same year, US IVF centers performed 134,260 IVF cycles of which 16,161 or 12% were oocyte donation cycles [42]. In 2015, 19,988 cycles of ART in the United States utilized donated oocytes (www.sartcorsonline.com/rptCSR_PublicMultYear.aspx?reportingYear=2015). This difference is striking. The explanations are various but include cultural differences, the lack of universal insurance coverage for infertility in the United States, the significant compensation paid to US donors, the predominance of anonymity in US gamete donation and, most significantly, much less US government regulation.
Specifically, US law allows both anonymous and known donation, and the American Society for Reproductive Medicine (ASRM) guidelines suggest that both are acceptable [36, 43]. Compensation is not legislated. While current guidelines no longer include recommended compensation ranges for oocyte donors, they do advise that each clinic “establish a level of compensation that minimizes the possibility of undue inducement of donors and the suggestion that payment is for the oocytes themselves.” Additionally, the guidelines go on to state that: “Payment also should reflect the amount of time expended and the burdens of the procedures performed. Thus, a woman who withdraws for medical or other reasons should be paid a portion of the fee appropriate to the time and effort she contributed. To protect the donor’s right to withdraw, oocyte recipients must accept the risk that a donor will change her mind. In no circumstances should payment be conditioned on successful retrieval of oocytes or number of oocytes retrieved.”
Anonymous versus Known Donation
At the present time, most oocyte donation worldwide is anonymous. However, family and known donation is the best choice for some recipients. This may be especially true for some cancer survivors. A sister, cousin or friend may derive great satisfaction from donating to a survivor. For the recipient, the opportunity to have a child who is genetically related to her family (a sister or cousin donation) or the kindness of the gift can also make it a desirable choice.
However, family and known donation also carries a greater risk of coercion or may lead to complicated family dynamics, particularly when the recipient is a cancer survivor. Thus, we recommend psychological screening of all involved parties – prospective donor, recipient and their respective partners – before proceeding with known donation [36, 44].
Infectious Disease Screening of Donors
By law, donors in the United States must be screened for infectious disease risks and tested for exposure to specific infectious diseases according to detailed FDA guidelines [36, 45]. While the risk of infectious disease transmission is remote, FDA regulations have provided a standard of care for this aspect of the donor-screening process.
Genetic Screening
By contrast, genetic testing of US donors is not legally mandated. The appropriate professional society sets the standard of care: ASRM recommends that all donors be tested according to ethnicity- and population-based guidelines published at the time of donation by the American Congress of Obstetricians and Gynecologists and the American College of Medical Genetics (www.acog.org and www.acmg.net/). According to ASRM guidelines, donors and their first-degree relatives should be free of Mendelian disorders, major malformations of complex causes, significant familial diseases with a known genetic component and mental retardation of undocumented etiology [36].
The field of genetics is progressing rapidly, and recommended screening tests change very quickly. The American College of Medical Genetics has published excellent guidelines regarding ethnicity- and population-based genetic screening (www.acmg.net). Of course, the absence of legal mandates does not decrease a physician’s responsibility to act in the best interests of the donor, the recipient parents and the potential child. It should be noted that gamete donor screening is not the same as preconceptual testing in women attempting pregnancy. The testing of young, often unmarried oocyte donors and the dissemination of information so acquired carry different ethical, medical and psychological implications than those same tests in prospective parents. If possible, a genetic counselor should advise every prospective oocyte donor before testing. Ideally, it should also be a genetic counselor who conveys the test results and their often complex implications [46].
In our practice, a genetic counselor meets with the prospective donor at her initial visit. Over more than a decade, we have seen that a battery of tests does not substitute for a professional genetic counselor. A good genetic counselor will identify issues that are detectable only through careful, directed history or, in some cases, observation of physical characteristics [46–48]. Genetic health issues may be mild in the donor herself or her family but may be of variable penetrance and may have serious consequences for potential offspring.
Our current practice is to screen all donors with an extensive, non-ethnicity–based panel for 281 genetically inheritable diseases, hemoglobin electrophoresis and thalassemia, and perform a chromosome analysis. In addition to screening the donor, we routinely test the male partner of the recipient with the same extensive panel. If the male partner is found to be a carrier, additional testing of the donor may be indicated, and the recipient family should be counseled about the findings.
Finally, we need to advise recipients not only of the genetic evaluation findings, but also of their limits. Only a relatively small number of genetic diseases are amenable to detection through either history or testing. Birth defects are common in the population at large – 3–4% of all births – and most of these defects are not related to a specific gene mutation and are therefore not screenable [46].
We see meticulous genetic screening and counseling as part of our ethical responsibility to the families who come to us, to the donors and to the donor-conceived persons who may result from our care.
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