Oocyte donation in infertility treatment

Abstract

Most women have a strong desire to experience pregnancy and motherhood. Even though most women would prefer to bear children with their own genetic characteristics, unfortunately, premature or incipient ovarian failure for various reasons sometimes makes it impossible. Oocyte donation (OD) was developed to help such women. Since its introduction in 1984 (1) it has been a highly successful method of treating women unable to conceive with their own oocytes. In 1995, we presented our first experience of oocyte donation treatment in Finland (2). Since then the program has expanded and women are also coming from other Nordic countries to receive treatment, because oocyte donation is forbidden in Sweden and Norway. This review considers practical and ethical aspects involved in oocyte donation treatment and also provides follow-up data on our oocyte donation program in 1992–1999. Oocyte donation was originally introduced for women with ovarian failure of various etiologies (Table I). Primary ovarian failure is often seen in women with X-chromosomal abnormalities or an FSH-receptor defect (3). Premature ovarian failure (POF) occurs in about 1% of women under 40 years of age and often no obvious cause can be found (4). Frequently, certain autoimmune conditions may occur at the same time. An increased risk of developing POF has been identified in fragile X premutation carriers (5, 6). An important group of patients who benefit from oocyte donation are those who have had their ovaries removed because of endometriosis or neoplasia. Even in cases with a malign ovarian disease, e.g. epithelial carcinomas of stage IA and IB, dysgerminoma, teratoma and granulosa cell tumors, conservative surgery with preservation of the uterus may be justified (7). In addition, oocyte donation offers a treatment option for women whose ovaries have been destroyed by chemotherapy or radiation therapy for malignancies, including Hodgkin’s disease or leukemia. An essential precondition for treatment of this patient group is, of course, that the disease is cured and that the uterus will respond adequately to hormone replacement therapy. Since 1990 a large proportion of women utilizing oocyte donation have been those who are poor responders to conventional ovarian stimulation or who have experienced multiple failures in earlier in vitro fertilization (IVF) attempts (8). Many of these patients are premenopausal women with hormonal profiles signifying diminished ovarian reserve. Oocyte donation may also be a valuable tool in improving pregnancy success in situations where poor oocyte quality or oocyte abnormality is suspected (9). Structural chromosomal aberrations, specifically translocations, may cause recurrent miscarriage, and may be an indication for oocyte donation (10). Treatment with donated oocytes has also been utilized to avoid transmission of inheritable disorders that may result in significant morbidity and potential mortality in the offspring (11). It is to be hoped that many such women will be able to use their own gametes in the future, thanks to ongoing progress in the field of preimplantation genetic diagnosis (12). Oocyte donation has also been used to treat infertility in women of advanced reproductive age (13, 14). Increasingly, women choose to defer reproduction to later decades of life and a growing number of women aged 40–50 years of age desire pregnancy by this method. Careful medical examination of the recipient is performed before oocyte donation treatment. Recipients need prenatal counseling and a thorough pre-pregnancy evaluation to ensure general health and to exclude any contraindication for pregnancy. Medical screening is particularly important if the recipient has survived cancer therapy or is of advanced reproductive age. Advanced age of the woman is associated with increases in the incidence of cardiovascular disease, hypertension, diabetes mellitus, and breast cancer. These medical conditions may be exacerbated by and further complicated by pregnancy. Women with Turner’s syndrome require investigation by an internist or cardiologist because of a possible risk of aortic dissection or other cardiac or renal anomaly before oocyte donation treatment (15, 16). Tests for thyroid and liver function, and glucose intolerance, are also recommended for these women. A major challenge in oocyte donation programs is to find adequate numbers of women willing to donate their eggs. Donated oocytes have been recovered from infertile women undergoing IVF themselves (egg sharing) and from fertile women – either known or anonymous to the recipient – who are willing to donate oocytes. Which type of oocyte donor is the most preferable is a matter of debate (17). The practice varies widely in different countries. In Denmark and Israel, egg sharing between an IVF-patient and an oocyte recipient is the only form of donation allowed by law (18, 19). If both women share the cost of the IVF cycle, it may, of course, enable some couples to pursue IVF who might not otherwise afford this therapy. In Finland, most infertile couples prefer to fertilize all recovered oocytes and cryopreserve the resulting surplus embryos for possible future use. Most Finnish oocyte donors are healthy, fertile women who express an altruistic desire to help another women as motivation for participation. They are not paid for their contribution. The anonymous donors are matched to infertile couples as regards phenotypic characteristics such as height, and hair and eye color. Known donors are frequently either family members or close friends. Guidelines and minimum requirements for oocyte donation programs have been worked out both in America and in Europe to ensure safety and good practice for donors and recipients (20, 21). The anonymous oocyte donor should be younger than 36 years of age to avoid trisomy in the fetuses, screened for sexually transmitted diseases, such as syphilis, hepatitis B and C, and human immunodeficiency virus (HIV), and screened for risk factors as regards transmission of a genetic disease. Psychological counseling should be offered to all donors. In the case of a known oocyte donor, there are special psychological considerations. It is important to explore the nature of the arrangement, to ensure that the donor’s participation is her own voluntary decision, and to discuss the potential effects of the treatment on the relationship between the donor and the recipient in the future. If the recipient has POF of unknown etiology and she receives eggs from her sister, it may be wise to exclude the presence of Fragile X premutation in the family before treatment (5, 6). The donor undergoes ovarian stimulation with gonadotropins to achieve multifollicular growth. Until recently the treatment has been performed by using a gonadotropin-releasing hormone (GnRH) agonist according to a long protocol. However, a GnRH antagonist may be better for the donor, requiring shorter treatment and having fewer side-effects (22). Synchronization of menstrual cycles between the donor and the recipient is essential for successful outcome of the treatment. The endometrium of the recipient is prepared using hormone replacement therapy. The dosage of estrogen and the length of the artificial follicular phase may vary considerably without affecting outcome in the recipients. Estradiol has been administered either in an increasing stepwise manner or as a fixed dose of 4–6 mg daily. In a study published in 1991, Navot et al. (23) observed no difference in implantation rates between short (5–10 days) and long (21–45 days) estrogen-priming. Later, Remohi et al. (24) concluded that unopposed estradiol may be administered for at least 65 days without having any negative consequences on endometrial receptivity. However, at least two weeks of estrogen administration before progesterone initiation may be recommendable, as a shortened follicular phase in the recipient may increase the spontaneous miscarriage rate (23). In the cycling recipient the most widely accepted protocol involves the use of GnRH agonist to suppress ovarian function (25, 26). Estrogen therapy is initiated about 5 days before gonadotropin treatment of the donor is started. The recipient usually starts taking progesterone either on the day of egg collection from the donor, or the day before. Progesterone can be administered either by intramuscular injections or vaginally. The transvaginal route of administration results in serum progesterone concentrations 6–10 times lower than found after intramuscular administration (27, 28). However, because of the ‘uterine first pass effect’, tissue concentrations of progesterone in endometrial samples are up to ten times higher in patients receiving vaginal progesterone (28). The great success experienced using estradiol and progesterone in oocyte donation treatments has led to similar pharmacologic applications for timing transfers of cryopreserved embryos in cycling patients. The success rate after oocyte donation is among the highest reported for any assisted reproduction technique. Most centers report pregnancy rates of 25–50% per embryo transfer. After four embryo replacements the pregnancy rate increases to 88–95% and the live birth rate reaches 86–88% (29, 30). Most authorities believe that the success of oocyte donation results from the use of high quality oocytes from young donors (23, 31). In a world survey of oocyte donation (>4400 cycles), the pregnancy rate per embryo transfer was significantly higher when oocytes were derived from healthy volunteers compared with surplus oocytes from IVF (29% versus 18%) (32). At our Infertility Clinic in Helsinki, almost all donated oocytes have been collected from healthy fertile women. In 1992–1999, 284 healthy donors participated in the oocyte donation program. The mean age of the donors was 30 years (range 21–39 years) and most of them were recruited through advertisements in newspapers. The specific indications for treatment in oocyte recipients are shown in Table II. The mean age of the recipients was 35 (range 21–48). They used estradiol valerate at 4–6 mg/day, and vaginally administered progesterone, 600 mg/day, was started on the day of oocyte collection from the donor. If pregnancy was confirmed, hormone replacement therapy was continued until 12 weeks of gestation. In 1992–1999, the clinical pregnancy rate/fresh embryo transfer was 31.5% (104/330). On average, only 1.9 embryos were transferred at a time. With frozen/thawed embryos the clinical pregnancy rate was 21.9% (53/242) per embryo transfer. The cumulative delivery rate is shown in Fig. 1. Twelve women have delivered twice. The spontaneous miscarriage rate was 22.9% (36/157), similar to that reported by other clinics (33, 34). Oocyte donation outcome at the Family Federation of Finland, Infertility Clinic, Helsinki, Finland, in 1992–1999. Cumulative delivery rate after one, two, three and four treatments (fresh and frozen-thawed embryo transfers included). Oocyte donation is associated with similar success rates regardless of the indication for treatment, including repeatedly failed IVF attempts or severe endometriosis (29-31). However, some interesting observations as regards exceptional treatment outcome have been made. At an early stage it was noticed that pregnancy rates were higher in agonadal and postmenopausal women than in women with normal menstrual cycles. It was suggested that amenorrhea or a rest period from repeated menstrual cycles allows the endometrium to recover an ability for implantation consistent with that of young women (35). We found higher pregnancy rates in women with primary ovarian failure than in those with secondary ovarian failure (36). Similar results have also been published by other investigators (37, 38). Women with Turner’s syndrome have had similar (16, 39) or lower pregnancy rates (40) than other POF patients. They appear to have an unusually high frequency of biochemical pregnancies and early miscarriages (16). The reason for this is not clear. It has been suggested that this is connected to some inherent abnormality in the endometrium (39, 40), but low blood flow in a hypoplastic uterus may be another explanation (16). Impaired OD pregnancy rates have been observed in patients with a malignant disease after chemotherapy and/or radiotherapy (38). We have treated 12 recipients with a malignant disease (Table II). Six of these women have delivered healthy infants. Several authors have analyzed the outcome of oocyte donation according to the age of the recipient. It has repeatedly been shown that the success rate is not dependent on the recipient’s age and that uterine receptivity can be extended for 10–20 years beyond the natural menopause. Women at the age of 40–50 years achieve pregnancies in 25–50% of embryo transfers if they use young women’s oocytes (13, 23, 31, 41). These achievements led to the conclusion that the reason for the decline in female fertility with age is aging oocytes rather than uterine aging (42). Although the effect of aging oocytes on declining fertility with age is generally accepted, there may also, perhaps, be a minor decline in uterine receptivity with age. Although the measure of success of assisted reproduction programs is the establishment of pregnancies, the ultimate goal is the delivery of a healthy child. Oocyte recipients often differ from other infertility patients as regards their medical history and endocrinological background. Advanced age of the mother will increase the risk of obstetric complications such as diabetes and hypertension. The embryo is immunologically foreign to the mother, which may have implications as to how the pregnancy proceeds. The obstetric and perinatal outcome of OD pregnancies is mostly favorable. However, in many studies a high frequency of some specific complications has been noted. First trimester bleeding is common and occurs in 12–53% of OD pregnancies (34, 43, 44). As early as in 1989, Serhal and Craft noted a high incidence of preeclampsia in oocyte recipients (31). Later studies have confirmed an increased risk of pregnancy-induced hypertension (PIH), which occurs in 20–33% of OD pregnancies (43-45). In our study, the incidence of PIH was 31% in oocyte recipients and 14% in IVF patients (44). Furthermore, this complication is seen in both young and older recipients and cannot be explained solely by a high incidence of multiple gestation or primiparity. It seems to be an inherent problem associated with this procedure. It may have to do with immunological factors and one proposed explanation is that there is inadequate immunoprotection of the fetoplacental unit in oocyte recipients (46). The cesarean section rate is high, exceeding 50%, among recipients of donated oocytes. The obstetric risks involved with this treatment make it evident that this patient population requires careful monitoring throughout gestation. In particular, women with some specific medical risks, such as those with Turner’s syndrome, need to be followed up with great care. We send all women with Turner’s syndrome for cardiologic assessment, including echocardiography, before treatment. This examination may be repeated during gestation, if necessary. Disturbances in carbohydrate metabolism and thyroid function are common in these subjects and a glucose tolerance test during pregnancy is recommended (47). Nevertheless, our experience with oocyte donation treatment in women with Turner’s syndrome is very positive. The overall incidence of complications is similar to that in our oocyte recipients in general. To avoid complications brought about by twin pregnancy we always transfer only one embryo at a time in these patients, even when we transfer frozen-thawed embryos. The perinatal outcome after oocyte donation treatment is favorable (Table III). The incidence of congenital malformation appears to be similar to that in the general population. In a comparison between OD and IVF infants we found no difference in birth-weight, or the incidence of prematurity and growth retardation (IUGR) between the two groups (44). However, as in conventional IVF (48), there is a dramatic increase in perinatal complications in connection with multiple pregnancies. Of all OD pregnancies, 15–39% are multi-fetal gestations. The incidence of preterm labor, and low birth-weight (<2500 g) and IUGR among the infants is twice as high in twins compared with singletons and three times as high in triplets compared with singletons (34, 44). Nowadays, when cryopreservation of excess embryos can successfully be performed, it is possible, and our obligation, to try to avoid multiple pregnancies by reducing the number of embryos transferred. The outcome of OD treatment is dependent on the age of the donor. If the donor is young, embryo quality is good, and the recipient already has some medical disorder increasing the risk of obstetric complications, elective replacement of only one embryo at a time should be considered (49). In all published follow-up studies of children born after oocyte donation treatment, the growth, development, and health of these children have been reported to be within normal ranges (50-53). In our questionnaire study regarding health and development of all 59 OD children born between 1992–1996, every child was healthy at the time of the study (53). No cases of neurological, hearing or visual disorders were reported. There has been concern raised about potential negative psychological consequences of gamete donation on the child. The most common of these concerns is the practice of keeping information about the genetic origin secret from the child. It is thought to have an adverse impact on the quality of parent-child relationships and to cause identity problems in the children. Findings suggestive of an association between secrecy about genetic parentage and negative outcomes for children have come from research on adoption. A further concern expressed is whether parents may feel less positively toward a ‘non-genetic’ than a ‘genetic’ child. However, investigations performed among families with children conceived by gamete donation have demonstrated that such fears are not justified. In a current study by Golombok et al. (54), family function in 21 oocyte donation families was investigated and compared with that in donor insemination families, adoptive families and conventional IVF families. Only one child in the OD group had been told of its manner of conception. All the children were younger than 10 years. Interestingly, greater psychological well-being among mothers and fathers was demonstrated in OD families than in those with a genetically related child. Furthermore, the families did not differ as regards the quality of parenting or the psychological adjustment of the child. This is perhaps not surprising. A strong desire to have children and a strong commitment to parenthood may outweigh any negative effects coming from the missing genetic tie between the parents and the child (54). Compared with adopted children, children born after oocyte donation do not have to experience the loss of an existing parent; nor do they need to create relationships with new family members. However, children born after oocyte donation are still young and more follow-up studies will be needed to be able to evaluate the well-being of these children. Oocyte donation is technically not a difficult procedure. However, the ethical aspects surrounding the treatment need consideration. Opinions as regards anonymity, secrecy, age limits of recipients, and compensation for donors vary worldwide. Oocyte donation is practiced in many parts of the world, but relatively few countries have legislation addressing this treatment. In Europe, there are four countries in which oocyte donation is forbidden by legislation (Austria, Germany, Norway and Sweden) and four countries in which the law specifically permits the use of donor oocytes in fertility treatment or to avoid genetic diseases (Denmark, France, Spain and the United Kingdom) (55, 56). In most European countries, for example in France, anonymity of the donor is preserved, and the donor cannot be a member of the recipient family. In Finland and The Netherlands, the infertile couple may also use oocytes from a known donor. Because of the great shortage of anonymously donated oocytes, leading to long waiting times for treatment, many choose to have a known donor (for example a sister or a friend). In 1999, at the Infertility Clinic at the Family Federation of Finland, Helsinki, 35% of all donors were known to the recipient (unpublished data). Some couples would not even accept an anonymous donor as they wanted to have as much genetic and medical information about the donor as possible. Open arrangements between sisters may also be thought of as a kind of equitable sharing of genetic heritage from the mother. If the donor is known, most recipients intend to inform the child of his or her origin at some future date (57). In anonymous oocyte donation, 20–70% of the parents plan to tell the child (53, 57, 58). This means that OD families are in general more open than donor insemination families, where 10–52% of the parents intend to inform their child (59-62). Another difficult ethical question concerns the child’s right to have identifying information about the donor. At our clinic, only 12% of the OD recipients think that the child should have such information (53). In the UK, there is central record keeping of donors, but providing information about the donor’s identity is prohibited. According to Swedish law, a child born after donor insemination should have access to such identifying information (56). In most countries non-identifying information is given by the medical team according to the regulations in each country. In anonymous donation we have told the recipient couple of the donor’s age, height, weight, and hair and eye color. We have also told the donor about the recipient’s pregnancy test result. Age limits for oocyte recipients is another matter of debate. Nowadays, many women choose to pursue educational and professional goals and postpone childbearing until these needs are met. In Western societies, there are also increased numbers of divorces and second marriages. This means that many women are in the perimenopause when they want to begin a family. As the success rate of assisted reproduction methods is low in women over the age of 40 years, the opportunity to use donated oocytes serves these women well. But what age limit should we use? Is it right to offer treatment to women up to the age of 60 years, as has been done at some centers (13, 41)? In most European countries, the practice of oocyte donation is limited to women under 45 (61). An important factor regarding why pregnancies in women of advanced age should be avoided is the risk of obstetric complications. For aging parents, bringing up children might also become problematic at some point. A strict upper age limit is very difficult to define, but if the woman is healthy we think that oocyte donation treatment could be considered up to age of 50–55 years (49). Most international ethics committees state that gamete donors should not be reimbursed for their contribution. According to the laws in Denmark, France, Israel, Spain and the UK, the donation should be altruistic. No money or other benefits should be given for donation. Reasonable compensation for expenses is, however, appropriate. In some countries, particularly the United States, oocyte donors are generously rewarded. For many American egg donors, money appears to be a clear motivating factor for donating (63). Compensation averages US $2000–3000 per treatment cycle. At our clinic in Helsinki the donors receive only a small amount to help cover their expenses (FIM 500; about US $80). One concern related to oocyte donation treatment is the possible risk involved in ovarian stimulation of the donors. Currently, new methods are being developed aiming at milder stimulation protocols, collection of immature oocytes, and maturation in vitro (64-66). These techniques would make the treatment easier and more convenient for the donors, and reduce the costs. Another option would be to preserve fertility in women known to be at risk of POF because of genetic reasons, chemotherapy or radiotherapy. Biopsied ovarian tissue could be cryopreserved. Primordial follicles are tolerant to freezing and thawing, in contrast to metaphase II oocytes (67, 68). Later on, fertility could be re-established by maturing oocytes in vitro from the cryopreserved tissue or by replantation of the biopsy. Replantation of ovarian tissue has already led to live offspring in mice (69) and sheep (70). Recently, cryopreserved human ovarian tissue has been transplanted in mice and follicle development has been confirmed in the transplanted tissue (71). Continued research is needed to bring these methods forward to clinical practice. Oocyte donation has become a highly successful treatment modality for thousands of women previously regarded as hopelessly infertile. It represents a very special type of infertility treatment. The pregnancy is unique, because it starts from an embryo which is genetically and immunologically foreign to the mother. Involvement of a third person, the oocyte donor, makes oocyte donation ethically and psychologically much more complicated than conventional IVF. Couples contemplating this treatment need to have extensive counseling about the many psychological and medical issues involved in the process. However, fifteen years of experience with oocyte donation has shown that it is an excellent treatment option for couples who desire a child but cannot be helped by other techniques. The success rate after oocyte donation is at least as good as after standard IVF. An increased risk of obstetric complications has been noted in these pregnancies and the oocyte recipients need thorough antepartum and intrapartum care. Mostly, perinatal outcome is excellent, and if complications occur, they are usually related to multiple pregnancies. In follow-up studies, children born after oocyte donation treatment have been younger than 10 years. Their medical health and socio-emotional development appear to be within normal ranges. The authors wish to thank Dr. Nicholas Bolton for revising the language of the manuscript.