INTRODUCTION — Oocyte (egg) donation is an integral part of modern assisted reproductive care and is associated with the highest success rates. Originally offered to women with primary ovarian insufficiency (premature ovarian failure) or those who had genetic diseases who did not want to transmit the gene defect to their offspring, donated oocytes are now used by women with many reproductive disorders and commonly by women in later reproductive years [1,2]. Approximately 25,000 attempts at pregnancy using in vitro fertilization (IVF) with donated oocytes or embryos are initiated annually in the United States [3].

Oocyte donation is, at present, the only effective therapy for the treatment of infertility in women with ovarian failure and for the vast majority of women of advanced reproductive age. Details of the IVF procedure are discussed in detail elsewhere. (See "In vitro fertilization: Overview of clinical issues and questions".)

HISTORICAL OVERVIEW — The first pregnancies from oocyte and embryo donation were reported in women in 1983 [2,4,5]. Recipients had normal ovarian hormonal secretion, and the natural cycles of the donor and recipients were synchronized.

Soon thereafter, a successful pregnancy was achieved in a woman with ovarian failure, who required estrogen and progesterone to prepare the endometrium to receive the ovum [6]. Estrogen and progesterone were administered in a manner that mimicked the natural ovulatory cycle prior to conception and were continued through the first trimester to support the developing pregnancy.

During the next few years, refinements in oocyte donation continued, and efficacy improved [7-10]. The refinements included:

●Collection of oocytes from the donor using a transvaginal, ultrasound-guided needle aspiration technique instead of laparoscopy or uterine lavage.

●Administration of gonadotropin-releasing hormone (GnRH) agonists or antagonists to the donor and recipient (in women with ovarian function) to facilitate synchronization of the donor's cycle with that of the recipient.

●Recruitment of younger aged donors to enhance the quality and quantity of oocytes obtained.

●Better techniques for embryo culture and cryopreservation, which allows better embryo selection and the possibility for multiple transfers from any single oocyte donation.

A major breakthrough occurred in 1989 when oocyte donation was used to address the problem of age-related infertility [11-13]. Today, birth rates exceeding 50 percent per embryo transfer are typically reported in women in their 40s and 50s [1,14], suggesting that the decreased fecundity and increased pregnancy wastage associated with aging was due to problems with the ovary (oocyte) rather than the uterus (figure 1).

Current trends — In an analysis of United States donor oocyte cycle data from the years 2000 to 2010, reported by US Centers for Disease Control and Prevention (CDC) and the National Assisted Reproductive Technology Surveillance System (NASS), there was an increase in the annual number of donor oocyte cycles from 10,801 to 18,306 and an overall increase in good outcomes [15]. Specific findings included the following:

●An increase in the proportion of cycles using frozen rather than fresh embryos (26 to 40 percent)

●An increase in the percentage of single embryo rather than multiple embryo transfers (0.8 to 14.5 percent)

●An increase in good perinatal outcomes, defined as a singleton live-born infant delivered at 37 weeks or later and weighing 2500 g or more (18.5 to 24.4 percent)

●Transfer of an embryo at day 5 and single embryo transfer were associated with good perinatal outcomes

●Tubal or uterine factor infertility were associated with a decreased chance of good outcome

●Patient age (recipient) was not associated with the likelihood of good perinatal outcome

INDICATIONS — Oocyte donation has been used to achieve pregnancy by women with many reproductive disorders [1]. The American Society of Reproductive Medicine has endorsed the following indications:

●Primary ovarian insufficiency (premature ovarian failure) or gonadal dysgenesis

●Avoidance of genetic disease transmission

●Diminished or absent ovarian function

●Persistent poor oocyte quality during assisted reproductive technologies (ART)

●Advanced reproductive age (>40 years)

Presently, perimenopausal and menopausal women and women who have failed traditional approaches to fertility represent the majority of women treated (figure 2) [16].

Special considerations

Turner syndrome — Women with Turner syndrome are potential candidates for in vitro fertilization (IVF) with donor oocytes. However, these women, who often have cardiovascular anomalies, have a high rate of cardiovascular mortality during pregnancy due to aortic dissection. Therefore, before attempting to become pregnant, women with Turner syndrome should undergo a complete medical evaluation, with particular attention paid to cardiovascular and renal function, as recommended by the American Society of Reproductive Medicine [17]. (See "Management of Turner syndrome in adults", section on 'Management of fertility and pregnancy'.)

Advanced reproductive age — As noted above, the majority of women undergoing IVF with donor oocytes are women of advanced reproductive age, a population at higher risk for pregnancy complications, particularly in the setting of multiple gestation [18]. The American Society of Reproductive Medicine recommends that in order to minimize multiple gestation rates, while maintaining high pregnancy rates in recipients where high-quality blastocysts are used, a single embryo transfer should be considered [19].

Cancer survivors — Improvements in the treatments of pediatric and adult cancers has resulted in increased survival rates for many women with malignancies. However, the use of chemotherapy and radiotherapy may have detrimental effects on ovarian function, leading to impairment or even complete loss of reproductive capacity. As a result, cancer survivors have often used donor oocytes to achieve pregnancy. Patients receiving high doses of pelvic radiation (9 Gy and greater) are at particular risk for developing ovarian insufficiency and endometrial injury. However, a comparative analysis of 142 cancer survivors undergoing oocyte donation failed to demonstrate differences in pregnancy outcomes when compared with patients of similar age receiving oocyte donation treatment [20]. However, embryo transfers were performed only in women with an endometrial thickness greater than 5 mm on ultrasound following the use of prescribed estrogen. The authors cautioned that patients with endometrial atrophy or fibrosis secondary to radiation damage may not be candidates.

Cancer survivors have higher risk of pregnancy complications, including anthracycline-induced cardiomyopathy. Like patients with Turner's syndrome, these patients would probably benefit from maternal-fetal medicine consultation prior to conception. (See "Overview of infertility and pregnancy outcome in cancer survivors".)

Advanced paternal age — Oocyte donation is most frequently used to address infertility due to advanced female reproductive age. Not surprisingly, male partners of women undergoing oocyte donation are in a similar age group (over the age 40 or 50 years). Advanced paternal age may be associated with a decline in semen parameters (volume, motility, morphology) [21], infertility, increased spontaneous abortion, and offspring abnormalities [22,23].

Although pregnancy outcomes remain favorable for oocyte donation, women over the age of 45 years appear to have a small but significant decrease in embryo implantation, clinical pregnancy, and live-birth rates compared with younger cohorts, which might be partially influenced by the sperm from their older partners [24,25]. In an analysis of over 1000 oocyte donation cycles adjusted for female recipient age, having a male partner over age 50 years was associated with a decrease in blastocyst formation and live-birth rates, and an increased rate of pregnancy loss [26].

DONOR SELECTION — Matching a donor to a recipient is usually based upon phenotypic similarities between the women. Oocyte donors have usually been recruited in the community and traditionally been unknown to the recipient. In most metropolitan areas, oocyte donors are paid, with payments varying from USD $2500 to 10,000. Outside the United States, however, remuneration is frowned upon and is illegal in many places [27].

Occasionally, women offer to donate oocytes for a recipient known to them [28]. Other known donors are siblings [29] and, more rarely, daughters who have provided oocytes for their postmenopausal, remarried mothers [30,31].

Importance of donor age — Most donor programs seek 21- to 34-year-old women [32]. Some centers also prefer to use donors of proven fertility [33]. This preference is based upon the premise that women who have not been pregnant may be infertile.

The importance of donor age on live birth rates was reported in a population-based retrospective cohort study of all women (n = 1,490) using donated oocytes over a six-year period in Victoria, Australia [34]. The cumulative live birth rates for recipients with donors aged 30 to 34, 35 to 37, 38 to 40, and >41 years was 43, 34, 23, and 5 percent, respectively. No significant effect of the recipient's age was seen on live birth rates. Ideally, women seeking pregnancy with donor oocytes should choose women under the age of 35 years.

Screening — The screening of donors at most centers and recommended by the American Society for Reproductive Medicine includes assessment of physical and mental health and risk for infectious diseases.

In 2005, the US Food and Drug Administration (FDA) became responsible for regulating infectious disease testing of all oocyte donors. Serological tests for syphilis, hepatitis B core antibody and surface antigen and hepatitis C, and human immunodeficiency virus type 1 (HIV-1)/type 2 (HIV-2) infections are required [32,35]. Tests must be performed in a laboratory using tests that are FDA-approved for donor screening. Additionally, under the new guidelines, the physical exam and serum and cervical samples for gonorrhea and chlamydia must be performed within 30 days of oocyte retrieval. False-positive results exclude donor participation and retests or confirmatory status tests are not allowed to overturn false-positive results. Written documentation of eligibility for donation is now required to meet the FDA regulation.

Although currently declining in the number of reported outbreaks in the Americas, the Caribbean, and the Pacific, the Zika virus is transmitted to humans via the bite of an infected Aedes mosquito but also via sexual contact, blood products, and organ or tissue transplantation. To avoid possible transmission of Zika virus infection, the FDA has issued donor deferral recommendations for hematopoietic stem cells, solid organs/tissues, and donor gametes [36]. Living donors with Zika virus infection or relevant epidemiologic exposure (residence in or travel to an area where mosquito-borne transmission of Zika virus infection has been reported, or unprotected sexual contact with a person who meets these criteria) should be considered ineligible for oocyte donation for six months. (See "Zika virus infection: An overview", section on 'Blood/tissue donation'.)

Rh testing is also done, and the couple and donor commonly are Rh matched. Specific genetic testing is performed for patients and donors at risk for genetic illness, such as cystic fibrosis and spinal muscular atrophy in Caucasians, sickle cell trait in Blacks, and hemoglobinopathies in Asians.

CURRENT APPROACH — Oocyte donation is typically accomplished by synchronizing the menstrual cycle of the infertile woman with an ovarian-stimulated cycle of a donor (figure 3).

Donor

Protocol — The donor undergoes the following procedures:

●Ovarian stimulation with gonadotropins followed by monitoring of the follicular response. The latter is usually accomplished by serial measurements of serum estradiol and frequent transvaginal ultrasonography of the ovaries. The exact stimulation protocol may vary from center to center. In general, there has been a shift to protocols that are associated with a lower risk of ovarian hyperstimulation syndrome (OHSS). (See "Prevention of ovarian hyperstimulation syndrome".)

●Oocyte recovery is performed by transvaginal, ultrasound-guided needle aspiration (figure 4). Oocytes are then fertilized in vitro by sperm provided by the recipient (ie, husband, partner, or sperm bank). In the case of "shared egg donation," retrieved oocytes are usually divided equally among the parties in order to produce enough embryos for transfer (one to two embryos per transfer) to each of the recipients. (See "Overview of ovulation induction", section on 'Multiple gestation'.)

Procedural risks and complications — Women should be informed that there is a risk, albeit low, of potential complications when donating oocytes. The risk of complications (approximately 1 percent) in the donor is similar to that of infertile women who undergo the same procedure, and includes anesthetic accidents, hemorrhage, infection, and development of OHSS [37,38].

●In a retrospective study of 587 donors undergoing 973 cycles of controlled ovarian hyperstimulation and 886 oocyte retrievals, the rate of serious complications (OHSS, ovarian torsion, infections, ruptured ovarian cyst) was 6 in 886 (0.7 percent) [39]. The incidence of other complications serious enough to seek medical attention (mild to moderate OHSS, ovarian cysts, intraabdominal bleeding, hematoma) was 8.5 percent. The cycle cancellation rate was 9 percent.

●Similar rates and types of complications were seen in a second report of 1917 oocyte donors [40].

●Potential risk of the donor developing OHSS may be reduced by measuring antral follicle counts (AFC) and serum anti-müllerian hormone (AMH) [41,42]; lower gonadotropin doses should be chosen for donors with high serum AMH concentrations or AFC. Further safeguards now include the use of gonadotropin-releasing antagonists rather than agonists for downregulating the pituitary prior to stimulating the ovaries. In addition, a gonadotropin-releasing hormone (GnRH) agonist can be used to trigger ovulation instead of human chorionic gonadotropin (hCG) in cycles where there is concern for OHSS. The "Lupron trigger" protocol has reduced OHSS to under 1 percent of stimulated cycles [43]. Dopamine agonists prescribed at the time of, or soon after, ovulatory hCG administration appears to reduce the rate of moderate and severe OHSS cases. (See "Prevention of ovarian hyperstimulation syndrome".)

Recipient — The cycle of the recipient is synchronized with that of the donor by estrogen-progestin therapy, usually given as micronized estradiol orally and progesterone vaginally [44]. Other popular formulations and routes of delivery include transdermal estradiol and intramuscular progesterone. A retrospective review of over 8000 patients saw no difference in success rates when prescribing oral or transdermal estradiol, regardless of whether a fixed or variable dose was used [45]. All recipients received micronized vaginal progesterone as capsules or gels.

An alternative approach is to give the recipient a fixed dose of micronized estradiol (2 to 6 mg/day) to maintain a constant state of readiness for transfer [46]. This approach has been popular in areas where donor availability is limited, or when the source of gametes depends upon the sporadic donation of oocytes from infertile women undergoing in vitro fertilization (IVF). Progesterone is added to the recipient's hormone regimen before embryo transfer.

The approach is slightly different for women with primary ovarian insufficiency and those with regular ovulatory cycles:

●For recipient women with primary ovarian insufficiency, endometrial preparation is achieved by prescribing estradiol followed by progesterone at an appropriate time to ensure endometrial receptivity is achieved when embryos are ready to be transferred.

●For recipient women with regular ovulatory cycles, a GnRH analog (agonist or antagonist) is used to suppress ovarian activity. The woman is then treated with sequential estradiol followed by progesterone to establish endometrial receptivity [47].

A meta-analysis of 22 trials concluded that the different regimens for hormone replacement are associated with similar pregnancy rates [48]. Minimal risks to the mother or child are posed by the use of any of these medications, and untoward side effects are rare.

Procedural risks and complications — Reported complications in recipients include a tuboovarian abscess after embryo transfer, ectopic pregnancies, chromosomal abnormalities in offspring, and third trimester maternal deaths secondary to vascular accidents such as cerebral or aortic aneurysm rupture [49-51]. These complications are not unique to oocyte donation; they also occur in women undergoing IVF, as well as spontaneous pregnancies.

Disclosure — There has been considerable controversy over whether offspring should be informed about the facts of their conception, with arguments for both disclosure and nondisclosure. The Ethics Committee of the American Society for Reproductive Medicine supports disclosure and has made suggestions for assisted reproductive technology (ART) programs and sperm banks [52].

PREGNANCY AND OBSTETRICAL OUTCOMES

Pregnancy rates — Considering the high rate of success of viable intrauterine pregnancy using oocyte donation, it is reasonable to assume that the majority of women will eventually deliver babies. Life-table analysis of 500 consecutive cycles of oocyte donation performed in the early 1990s demonstrated more than one-half of all the recipients achieved a viable pregnancy by the third embryo transfer regardless of age or diagnosis (figure 1 and figure 5) [53].

Today, with national birth rates at 50 to 60 percent per embryo transfer, it is reasonable to assume that success may be obtained in 75 to 90 percent of patients given similar opportunity for multiple attempts [54].

Obese women — Obesity is associated with a number of adverse reproductive outcomes, including infertility, an increased risk of miscarriage, and a decreased conception rate when undergoing in vitro fertilization (IVF) with autologous oocytes. However, the chance of conceiving when undergoing IVF with donor oocytes may be no different in obese and normal-weight women. This was illustrated in a meta-analysis of six studies that included 4758 women undergoing IVF with donor oocytes [55]. There were no associations between obesity (body mass index [BMI] >30 kg/m²) and pregnancy rates, miscarriage, or live-birth rates. There was significant heterogeneity among studies for clinical pregnancy rates, with one report showing a beneficial effect of obesity on pregnancy rates. However, when the meta-analysis was performed either with or without the study showing a benefit of obesity, the conclusion was the same: Obesity was not associated with adverse reproductive outcomes.

Gestational hypertension — Gestational hypertension occurs more frequently in women with donor oocyte pregnancies compared with IVF with autologous oocyte pregnancies [56-61]. It was initially thought that the older age of the women undergoing donor oocyte might explain some of the increase [56,59]. However, in several studies of age-matched groups of pregnant women who had undergone IVF with either donor or autologous oocytes, an excess risk of gestational hypertension and preeclampsia was still observed [57,58,60-62]. One possible mechanism for the increase in risk is that foreign antigens on trophoblastic tissue could trigger an autoimmune response in the mother.

Evidence of immune-modulated vasculitis affecting the decidua, placental bed, and spiral arteries has been described as commonplace in recipient pregnancies [63]. The exaggerated rates of pregnancy-related hypertensive disorders and observed fetal growth restriction, particularly in women over the age of 45 years, may be a result of maladaptation in the normal immunological response to pregnancy [64].

Pregnancy outcome — Despite the apparent increase in hypertensive problems associated with pregnancy following oocyte donation, the outcomes are generally very good. Nevertheless, most of the recipients are older than 35 years and should be considered to have high-risk pregnancies [18]. In addition, multiple gestations are very common (over 23 percent of pregnancies), further complicating obstetric care. Therefore, it remains important to emphasize to all recipients, particularly women of advanced reproductive age (>40 years), the value of a single embryo transfer in an effort to lower the risk of multiple gestation.

Outcomes continue to be relatively good in women over the age of 45 to 50 years [65,66]. One study of 101 consecutive pregnancies in women ages 50 to 59 years reported the following [66]:

●Singleton births occurred in 74, twins in 24, triplets in three pregnancies.

●The average birth weight was 3029, 2362, and 1357 g for singletons, twins, and triplets, respectively.

●The average delivery time was at 37, 35, and 30 weeks for singletons, twins, and triplets, respectively.

●Antenatal complications occurred in 40 women, but rates were similar to those seen in a younger cohort of recipients also undergoing egg donation. Complications included hypertensive disorders of pregnancy (23 percent); gestational diabetes (4 percent); preterm rupture of membranes or preterm labor (9 percent); and abnormal placentation (2 percent).

●Because of the advanced maternal age, high rate of multiple gestation, and risk of gestational hypertension, most women were delivered by cesarean section (81 and 100 percent of singletons and multiples, respectively).

●There was one maternal death thought to be secondary to an acute myocardial infarction and one cesarean hysterectomy for placenta accreta.

ALTERNATIVE SOURCES OF DONOR OOCYTES — The current approach to obtaining donor oocytes from stimulated ovaries is associated with the potential risks and significant costs (see 'Procedural risks and complications' above). In 1991, pregnancy in a functionally agonadal woman was reported using immature oocytes obtained from surgically excised ovaries [67]. Others have successfully retrieved oocytes from natural cycles, maturing and fertilizing the eggs in vitro using culture media enriched with follicular fluid [68]. Several pregnancies resulted using these oocytes donated from unstimulated ovaries.

Other possibilities that have been investigated include:

●Live births in mice have occurred following the transplantation of cryopreserved autologous ovaries [69].

●The ability to retrieve immature oocytes from mouse embryos and culture them in vitro for purposes of oocyte donation to recipient animals has been demonstrated [70]. Oocytes procured from electively aborted fetuses could be similarly used as a source of donor eggs [71].

●Cadaver ovaries donated for medical use, similar to other organ grafts, have also been suggested as a source [72].

The use of either fetal oocytes or cadaver ovaries raises important ethical issues, which would need to be resolved before considering such an approach.

Cryopreservation of oocytes and egg banks — Vast improvements in cryopreservation of oocytes have occurred in recent years, which make possible the banking of eggs. Successful oocyte freezing and thawing has simplified the current approach to egg donation using freshly harvested gametes since it obviates the need for synchronization of recipients, which can be a time-consuming and costly process. Furthermore, meeting US Food and Drug Administration (FDA) requirements for the testing of donors within a 30-day window prior to egg retrieval is easier to manage since donors do not need to be synchronized to the recipients. Following cryopreservation, eggs may be stored locally and shipped to distant locations when needed. Thus, eggs, still considered to be in short supply, can be maximally resourced. Finally, reducing the cryopreservation of large numbers of supernumerary embryos produced through conventional in vitro fertilization (IVF) methodology would lessen ethical concerns over the disposition of unused embryos that often result from donor egg cycles. This approach has demonstrated success in several series reports [73,74].

Cryopreserved donor oocytes are now available and are increasingly used for assisted reproduction cycles. A survey of American clinics reported that commercial egg banks (CEBs) were the most commonly used resource using primarily vitrification and allocating approximately six eggs per recipient. In this survey, pregnancy rates were similar to those reported using traditional methodology but at a lower cost to recipients and with less need to freeze supernumerary embryos.

Although a minority of the 17,697 cycles of oocyte donation reported to the Society for Assisted Reproductive Technology (SART) in 2009 used eggs from a frozen egg bank (believed to be approximately 1500 cycles), the early reports of success will likely result in more widespread acceptance and use. However, there are important concerns about the role of CEBs in assisted reproductive technology (ART) because the industry remains unregulated and critics have focused on the perception of buying and selling human eggs and the commodification of reproductive tissue [75]. (See "Cryopreservation options for fertility preservation", section on 'Oocytes' and "Fertility preservation for deferred childbearing for nonmedical indications", section on 'Oocyte cryopreservation'.)

Cryopreserved versus fresh oocytes — Although the survey of CEBs reported similar pregnancy rates for cryopreserved and fresh donor oocyte cycles [75], this was not observed in a second study of 11,000 oocyte donation cycles, of which 20 percent used cryopreserved oocytes [76]. The live-birth rate per transfer for cryopreserved oocyte cycles was lower than fresh oocyte cycles (47 versus 56 percent, respectively). Although the live-birth rate for cryopreserved oocytes was lower in this report, the efficiency and lower cost of cryopreserved donor oocytes make it a reasonable and attractive option. Of note, the second study was based upon 2013, not 2015, data from the SART; it is anticipated that outcomes with cryopreserved oocytes will improve over time.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Female infertility".)

SUMMARY

Oocyte (egg) donation is an important part of modern assisted reproductive care. Originally offered only to women with primary ovarian insufficiency (premature ovarian failure) or those who had genetic diseases who did not want to transmit the gene defect to their offspring, donated oocytes are now also used for women with a variety of reproductive disorders as well as for postmenopausal women. (See 'Introduction' above.)

Approximately 25,000 attempts at pregnancy using in vitro fertilization (IVF) with donated oocytes or embryos are initiated annually in the United States. (See 'Current trends' above.)

Indications for undergoing IVF with donor oocytes include (see 'Indications' above):

●Primary ovarian insufficiency (premature ovarian failure) or gonadal dysgenesis

●Avoidance of genetic disease transmission

●Declining or absent ovarian function

●Persistent poor oocyte quality during assisted reproductive technologies (ART)

●Advanced reproductive age (>40 years)

Oocyte donation is typically accomplished by synchronizing the menstrual cycle of the recipient with a stimulated cycle of the woman who is donating her oocytes (figure 3). (See 'Current approach' above.)

Conception rates are high with this technology, and pregnancy outcomes are good. Rates of gestational hypertension are higher in women undergoing in vitro fertilization (IVF) with donor oocytes when compared with those using autologous oocytes. The mechanism for this difference remains unknown. (See 'Pregnancy outcome' above and 'Gestational hypertension' above.)