Oocyte Donation: State of the Art doc

Unfortunately, this method, known as ‘‘ovum transfer,’’ was inefficient 3.Attempts to enhance the efficiency of the process by administering fertilitymedications to the donors were unsucce

Oocyte Donation: State of the Art

Anne Z Steiner and Richard J Paulson

Division of Reproductive Endocrinology and Infertility, Department of Obstetricsand Gynecology, Women’s and Children’s Hospital, Keck School of Medicine,University of Southern California, Los Angeles, California, U.S.A

INTRODUCTION

Oocyte donation is now an integral part of the armamentarium of the tility specialist At its inception, it was intended as therapy for women withpremature ovarian failure, or those with heritable genetic defects However,

infer-as experience accumulated, oocyte donation infer-as a treatment hinfer-as beenextended to women with a variety of defects in oocyte production or func-tion The largest group of women now undergoing treatment with oocytedonation consists of those with age-related decline in fertility Additionally,techniques learned from oocyte donation, including endometrial prep-aration and embryo-endometrial synchrony, have been applied to otherinfertility treatments, including frozen embryo transfer and in vitro matu-ration of immature oocytes

HISTORY

The first successful human oocyte donation was reported in 1983 At thetime of ovulation, a fertile donor was inseminated with the recipientpartner’s sperm Uterine lavage was performed on the fifth day after theluteinizing hormone (LH) peak The recovered embryo was then transferred

to the uterus of the infertile patient After several attempts, a pregnancy wassuccessfully initiated and a singleton birth at term was achieved (1,2)

381

Unfortunately, this method, known as ‘‘ovum transfer,’’ was inefficient (3).Attempts to enhance the efficiency of the process by administering fertilitymedications to the donors were unsuccessful and led to retained pregnancies

preg-INDICATIONS

Oocyte donation is a therapy which allows women to conceive when theirown oocytes are either not capable of producing a pregnancy or carry a heri-table defect that the patient does not want to pass on to their children.Common indications for oocyte donation thus include premature ovarianfailure secondary to chemotherapy in healthy cancer survivors (10), follicle-stimulating hormone (FSH) receptor defects (11), or other causes Patientswith gonadal dysgenesis are also appropriate candidates for oocyte donation.Those with Turner’s syndrome may conceive; this group may be at somerisk of obstetrical complications (12) Oocyte donation is also indicated inthe cases of poor oocyte quality inferred by multiple failed cycles of con-ventional IVF or in women of advanced reproductive age with associateddiminished ovarian reserve Other patients may choose oocyte donation in

an attempt to avoid passing heritable genetic diseases to their children,although pre-implantation genetic diagnosis is increasingly being applied

retrospective series do not demonstrate a major effect of donor age on nancy success (13–18) However, retrospective series suffer from selectionbias; older donors may indeed have been chosen for inclusion because oftheir prior good track record Some studies have confirmed that olderdonors may be less likely to produce a clinical pregnancy (19–21) Althoughprior fertility in a donor does not appear to play a role (19,21), previous suc-cessful cycles may improve the prognosis in subsequent ones (15).

preg-Recipient Age

Recipient age per se does not appear to decrease the probability of pregnancysuccess with oocyte donation Indeed, it was the observation that the age ofthe uterus does not influence the probability of the initiation of pregnancythat led to the conclusion that the age-related decline in human fertilitywas primarily due to the age of the oocyte (22–27) Supporting this conten-tion were physiological observations that uterine blood flow does not appear

to decrease with age (28) and that the endometrial response to exogenoussteroids also does not appear to diminish with age (29) It is not yet defini-tively established whether pregnancy success after the age of 50 remainsunaltered In our experience (30,31), no decline has been observed However,

an analysis of data derived from the national registry suggested a modestdecline in live birth rates after 50 years of age (32)

Maternal Factors

The specific indication for oocyte donation does not appear to influence thesuccess of the procedure (15,27,32) However, uterine pathology, such asAsherman’s syndrome or previous radiation therapy, may negatively impactuterine receptivity (33) Analogously, uterine fibroids or other endometriallesions are thought to interfere in embryo implantation, regardless ofwhether or not oocyte donation is used (34) It should be noted that the inci-dence of uterine pathology increases with the chronological age of therecipient Therefore, older recipients may require more careful screeningfor these factors Hydrosalpinges in recipients also appear to negativelyimpact embryo implantation (35), and thus we recommend imaging of thefallopian tubes in all potential recipients Obesity in recipients does notappear to impact pregnancy rates (36,37); one report suggested an increase

in miscarriage rates (38) Endometriosis in recipients does not negativelyimpact embryo implantation (39) Pinopod expression, a marker of uterinereceptivity, appears to be the same in recipients with endometriosis as inthose without the disease (36)

Repetitive Cycles

Lack of success in one or more cycles does not negatively impact the come in subsequent cycles, and pregnancy rates appear to remain unaltered

out-on a per cycle basis (32) as lout-ong as the recipient has a normal uterine cavityand normal endometrial development was verified However, in one series,patients who conceived during their first cycle of oocyte donation were morelikely to conceive in subsequent cycles (40).

Cycle fecundability also appears to be unaltered by the number ofcycles that the donor has undergone The donor response to gonadotropintherapy and pregnancy rates do not differ by the interval between donationcycles or the cycle rank (41,42) Donor complications are uncommon and donot appear related to the number of stimulation cycles Nevertheless, theAmerican Society for Reproductive Medicine (ASRM) recommends that

an individual limit the number of donor cycles to no more than six (43)

SCREENING OF DONORS

The ASRM publishes and periodically updates its guidelines for donorscreening (44) Screening guidelines include a personal and sexual history,with the intent of excluding those women at high risk for HIV, other sexu-ally transmitted disease, transmissible spongiform encephalopathy (44), orrecent confirmed or suspected West Nile virus infection (45) Serum screen-ing for syphilis, hepatitis B and C, HIV-1, and HIV-2, as well as cervicalcultures for Neisseria Gonorrhoea and Chlamydia, is recommended (44).Psychological screening should include family, sexual, substance use,psychiatric history, information on educational background, assessment ofstability, motivation to donate, life stressors and coping skills, and interper-sonal relationships The counselor should confirm that the donor has beeninformed of the medical treatment, discuss the psychological risks of oocytedonation, and evaluate for signs of coercion (46)

Genetic screening should include a history with a specific focus on anymajor Mendelian disorders, major malformations due to multifactorialcauses, or known karyotypic abnormalities in the potential donors or inany of their first-degree relatives (47) A screening test for cystic fibrosis isrecommended for all donors A heterozygote may be included as a donor

if the recipient is aware and the recipient’s partner tests negative (48) cific ethnic groups known to be at high risk for carrying certain recessivegenes should undergo additional screening tests (47)

Spe-SCREENING OF RECIPIENTS

As with donors, the ASRM periodically updates its guidelines for the ing of recipients (44) Routine screening includes a medical and reproductivehistory, physical exam, and standard preconception testing and counseling.These include blood type and Rh factor, rubella and varicella titers (withvaccination if not immune) along with infectious disease screening Recipients

screen-should undergo counseling regarding the potential psychological tions of becoming parents as a result of oocyte donation (46).

implica-The uterus should be examined by ultrasound and the cavity evaluatedand pathology corrected prior to embryo transfer (36) Evaluation of theendometrial cavity can be achieved by saline-injection sonography (49), hys-teroscopy, or hysterosalpingography (HSG) The advantage of the HSG lies

in its ability to visualize the fallopian tubes and thus detect the presence ofhydrosalpinges All hydrosalpinges should be removed, as these have beenshown to decrease implantation rates and increase the risk of infection aswell as ectopic pregnancy in recipients of oocyte donation (50,51) If salpin-gectomy is not possible, interruption of the oviduct in a location proximal tothe uterotubal junction also appears to prevent reflux of hydrosalpingealfluid and thus to mitigate the adverse effects of the hydrosalpinx (52) As

a special group, patients with Turner’s syndrome should undergo diography because they are thought to have as high as a 2% risk of aorticrupture or dissection with a risk of death during pregnancy (12)

echocar-The screening of partners of recipients of oocyte donation shouldinclude a semen analysis, blood type and Rh screen, and a genetic screenalong with infectious disease screening for syphilis, hepatitis B and C,cytomegalovirus antibody, and HIV Screening should also include psycho-logical counseling

PRACTICE CYCLE

When oocyte donation first began, all recipients underwent practice cycles

to ensure an adequate response of the recipient’s endometrium to exogenoussteroids Although this practice has recently become somewhat controversial

in that some programs feel that it is not necessary, our program continues torely on the information the cycle provides In a practice cycle, recipientsundergo a regimen of exogenous estrogen and progesterone, which isidentical to the actual recipient cycle Our practice utilizes the regimendepicted in Table 1 Endometrial thickness is noted at the beginning ofthe cycle and prior to the initiation of progesterone On the seventh day

of progesterone administration, endometrial thickness is again documentedand the recipient undergoes a practice embryo transfer as well as endome-trial biopsy We have found that ultrasound measurement of endometrialthickness does not always correlate with biopsy findings (54) The biopsymay the document a lack of adequate estrogen priming or out-of-phaseendometrium (55) Practice cycles also provide additional information onpatient’s ability to comply with the hormone therapy protocol In one largestudy, 5.8% of women had difficulty in following the instructions (54) Arecent report has suggested that local injury to the endometrium duringnon-transfer cycles may improve subsequent implantation rates duringIVF, although the mechanism is not clear (56)

In contrast, programs that no longer require endometrial biopsies rely

on information from studies indicating that an in-phase endometrial biopsydoes not predict pregnancy (57) and an out-of-phase biopsy does not neces-sarily predict failure (58) Pregnancy rates in one small study did not differwhether a biopsy was or was not performed (57) It has also been arguedthat measurement of the endometrial thickness may be a better predictor

of outcome (58) and one study did find that it correlates with biopsy (59)

OVARIAN STIMULATION

Oocyte donors undergo controlled ovarian hyperstimulation in a mannersimilar to that of conventional IVF The most common method is theso-called ‘‘long protocol,’’ which relies on pre-stimulation pituitary down-regulation using GnRH agonists in daily intermittent or depot formulations.More recently, short protocols using GnRH antagonist during the late fol-licular phase of the stimulation cycle have been utilized Studies comparingagonists and antagonists have not shown a significant difference in preg-nancy rates achieved with protocols using agonists or antagonists (60,61)

As with conventional IVF, the use of antagonists appears to reduce theamount of gonadotropins required and the duration of treatment (60,62).When utilizing antagonists, gonadotropin dosage may need to be adjusted

to prevent a potential decline in estradiol levels, which has been correlatedwith decreased pregnancy and implantation rates (63) Others have advo-cated adding recombinant LH to recombinant FSH protocols, when startingantagonists, as a strategy to increase oocyte yield and improve pregnancyrates (64)

In agonist cycles, controlled ovarian hyperstimulation follows itary downregulation in the standard fashion as per conventional IVF usingrecombinant or purified gonadotropins The addition of recombinant LH

pitu-to recombinant FSH in donors on agonists with an LH value of less than

Table 1 Standard Estrogen and Progesterone Replacement Regimen

Micronized estradiol(oral administration)

Micronizedprogesterone(vaginal administration)Days 1–4 1 mg BID

1 IU/L during downregulation may increase the number of mature oocytesand the implantation rate (65) Dosages are individualized based on donorcharacteristics For example, non-hirsute fertile women with polycystic-appearing ovaries may require fewer ampoules to meet criteria for oocyteretrieval compared to donors without polycystic-appearing ovaries; fertiliza-tion rates tend to be similar (66) During the stimulation phase, serum estradiollevels on day 5 (67) and at peak (68) have been reported to correlate withthe number of oocytes as well as with the implantation rate.

In our practice, donors are most commonly prescribed an overlappingregimen of oral contraceptives and GnRH agonists in a long protocol Oralcontraceptives are begun one week before the initiation of leuprolide acetate.Both medications are continued for one week, and the oral contraceptivesare then stopped, whereas leuprolide is continued Oral contraceptives allowfor coordination of recipient and donor cycles Donors are evaluatedapproximately one week after cessation of oral contraceptives prior to stimu-lation to confirm downregulation by ultrasound evaluation of the ovariesand endometrium and by measurement of serum estradiol Stimulation isthen performed using human menopausal gonadotropins alone or in con-junction with recombinant FSH

Donor cycles require vigilance on the part of the nursing staff Onestudy showed that despite thorough and repetitive instructions, 2% ofdonors were found to have difficulties adhering to the protocol and 7%become pregnant after stimulation, despite instructions to use barrier meth-ods of contraception (69) We now advise donors to abstain from intercoursefrom the onset of stimulation until the following menses In addition, donorsare given a prescription for oral contraceptives to initiate with menses.DONOR SAFETY

Serious complications of oocyte donation are relatively rare Less than 1%

of donors have events requiring hospitalization or emergent interventionduring or following aspiration as a result of any cause, including severeovarian hyperstimulation syndrome (OHSS), reactions to anesthesia, orintra-abdominal bleeding (70) Severe OHSS is uncommon (71); however,mild forms should be anticipated as a majority of donors experienceabdominal discomfort and bloating to some extent The symptoms usuallyresolve by the time of menstrual flow As the severity of OHSS is correlatedwith estradiol levels on the day of human chorionic gonadotropin, oversti-mulation of donors should be avoided (72) Other general principles in theprevention and management of OHSS apply in donors as in infertilitypatients with the significant advantage that donors do not become pregnantand thus avoid pregnancy-related exacerbation of OHSS (73) Additionalintravenous fluid and/or albumin may be administered at the time of follicleaspiration (74) In our practice, donors are evaluated in our office two days

after follicle aspiration If necessary, additional intravenous fluids (1000–

2000 mL of normal saline) may be administered Rarely, paracentesis may

be required (75) A small retrospective study showed that ‘‘coasting’’ in

an attempt to prevent OHSS does not affect pregnancy rates unless coastinglasts for more than four days (76)

Little is known about the effect of oocyte donation on future healthand fertility However, in a study of eight donors who each underwent 4

to 12 cycles, laparoscopy confirmed no pelvic pathology except minimalendometriosis in one patient (77)

ENDOMETRIAL PREPARATION

The goal of endometrial preparation is to prepare the uterine cavity forimplantation and to synchronize endometrial progress with embryo devel-opment In general, preparation of the recipient endometrium with estrogenand progesterone occurs in fashion identical to the recipient practice cycle(Table 1) Women with ovarian failure can initiate a cycle at any time,whereas those with residual ovarian function should undergo pituitarydownregulation with agonists to avoid untimely uterine bleeding associatedwith fluctuating steroid levels Additionally, premature progesterone pro-duction by the recipients’ ovaries can disrupt synchrony between embryosand endometrium Using agonist therapy allows coordination of the oocytedonor and recipient and prevents ovulation, but does not appear to affectimplantation rates (78) One study (79) suggested that downregulation inthe recipient with residual function may not always be necessary In thattrial, 4 mg of oral estradiol daily starting on cycle day 1 suppressed ovu-lation (as determined by serum progesterone levels) until day 14 of the cycle

in 97% of patients Unfortunately, this regimen limits the flexibility for chronization with donor stimulation in fresh cycles and is thus primarilyused in frozen-thawed embryo transfer cycles

syn-Ever since Navot et al showed that in-phase endometrium could beobtained with a variable estrogen and progesterone regimen, designed tomimic the natural cycle (80), variations on this combination have been used

To date, no study has demonstrated that a better endometrial environmentcan be generated by any other means In other words, although many otherbiochemical substances are involved in the actual implantation process, theirproduction is secondary to the steroid stimulation of the endometrial cells.Estrogen stimulation can be achieved by a variety of regimens utilizingdifferent routes of administration as well as different duration of adminis-tration Estrogen may be delivered via an oral, transdermal, or vaginal route

in a fixed or variable regimen Oral or transdermal estradiol is most monly used In one study comparing a transdermal 0.1 mg patch to 6 mg

com-of oral estradiol daily, less com-of a delay in glandular histology was noteddespite lower serum estradiol levels (81)

Estradiol therapy can be provided in a fixed or variable regimen withcomparable efficacy (82) Although fixed regimens using 1 mg of estradiol aday appear to be ineffective (82), fixed regimens using 4 or 8 mg/day with-out downregulation have been used to achieve an endometrial thicknessgreater than 6 mm in an average of seven days with good pregnancy rates.Navot et al found that such small administration of fixed dosage estradiolcompared favorably to a longer variable regimen (83); however, others havenoted higher miscarriage rates with such short duration of estradiol therapy(84) In contrast, prolonged duration of estradiol therapy does not appear tohave a negative impact (83,85).

Serum estradiol measurements during estradiol therapy appear to beunnecessary (27,86) However, multiple studies have shown that mid-cyclethickness correlates with pregnancy success (36,85,87) Although pregnan-cies occur in patients with a thinner endometrium measurement (88,89), itappears that endometrial thickness of
7 mm offers superior results Thepresence of a multilayer endometrial echo complex may (90) or may notmatter (91)

In patients who cannot achieve an adequate endometrial thicknesswith oral or transdermal estradiol alone, vaginal estradiol may be used.The vaginal route of steroid administration results in high endometrialtissue levels and these appear to increase the endometrial thickness(85,92) Low-dose aspirin (81 mg/day) has also been reported to increasethe endometrial thickness (93) A combination of pentoxifylline 800 mgand tocopherol (Vitamin E) 1000 IU for nine months prior to hormonetherapy has also been reported as therapy to enhance endometrial respon-siveness in some women (94)

Following adequate estrogen priming of the endometrium, it is gesterone that prepares the endometrium for implantation However,progesterone cannot act in the absence of adequate priming Thus, an endo-metrial biopsy taken during a practice cycle, which shows no progestationaleffect has, in our experience, generally been reflective of inadequate estrogenpriming rather than inadequate progesterone delivery to the endometrium.This effect may be observed in women after long episodes of amenorrhea,such as that occurs in agonadal women in the absence of estrogen stimu-lation, or after prolonged hormonal replacement with combination ofestrogen and progesterone replacement in which menstrual sloughing doesnot take place It is tempting to speculate that prolonged continuous pro-gesterone stimulation of the endometrium produces a profound downregu-lation of estrogen receptors and that these may require priming prior toattaining an appropriate response

pro-To achieve luteinization of the endometrium, progesterone is startedeither on the day of oocyte retrieval or one day prior Progesterone may

be administered by the intramuscular or vaginal route, but progesteronedelivery modes are more complex than those of estradiol The reasons for

this are (i) much larger quantities of progesterone are necessary to achieveluteinization in the endometrium and (ii) progesterone is susceptible to

metabolism by 5a-reductase in the skin, making transdermal delivery even

more impractical due to the large size of the patch that would be required

In addition, oral progesterone is ineffective because it is rapidly lized The advantages of the intramuscular route include higher serum pro-gesterone levels and emotionally reassuring sense that the progesterone hasbeen delivered to the body of the recipient Many programs in the UnitedStates still utilize this mode of delivery with a dose of 50 to 100 mg daily.Even lower doses of 25 to 50 mg/day results in luteal phase serum levels

metabo-of progesterone, a secretory endometrium, and good pregnancy rates (95).Supra-physiological doses of intramuscular progesterone do not appear tohave an adverse effect on the maturation process (83), but doses lower thanthe standard result may have a negative impact (96)

Vaginal progesterone has generally been formulated in three ways:capsules containing micronized progesterone powder, a silastic ring thatgradually releases progesterone, and a cream formulation When comparedwith intramuscular administration of progesterone, vaginal micronizedprogesterone results in lower serum levels, but higher endometrial levels

of progesterone Its administration results in similar histological findings(97,98) For this reason, we have all but abandoned the intramuscularroute, reserving it only for those patients who dislike the use of vaginalsuppositories Results from Europe on the use of a vaginal ring releasing

10 to 20 nmol/L of progesterone for 90 days have been favorable (99)

In the United States, Crinone1, formulated as a cream, and administeredvaginally twice daily, has been shown to result in in-phase biopsies (100)and pregnancy rates similar to those achieved with intramuscular proge-sterone (101)

EMBRYO TRANSFER

Embryo transfer is performed in the same manner as in conventional IVF.Pregnancies have been reported after transfer of embryos at any stage indevelopment and after zygote intrafallopian transfer and tubal embryotransfer In general, the recipient starts progesterone the day of or day prior

to oocyte retrieval (102,103) As with conventional IVF cycles, the use oftransabdominal ultrasound guidance during transcervical embryo transferappears to improve the pregnancy and implantation rates (104)

Embryos derived from oocytes donated by young oocyte donors havevery good implantation potential Therefore, it is reasonable to limit thenumber of embryos that are transferred at one time Recent studies havereported that the transfer of two versus three embryos results in similarpregnancy and implantation rates and a lower triplet and multiple rate

(14,105) Transfer of one embryo resulted in a slight decrease in pregnancyrate, but the probability of twins was greatly reduced (106).

PREGNANCY OUTCOMES

Live birth rates after oocyte donation have risen consistently, with pregnancyrates from fresh embryos being higher than those from cryopreserved ones(Fig 1) (107) Pregnancy loss after visualization of fetal heart motion has beenreported to occur in 5.7% of singleton pregnancies after oocyte donation (108)

In the setting of multiple gestation, the probability of absorption of one or moreembryos is 19% to 28% (108,109) The risk of fetal loss appears to correlate withthe number of gestational sacs Although patients with multiple gestations aremore likely to have bleeding, their miscarriage rates (loss of all gestational sacs)does not appear to be increased (109) Most losses occur prior to the ninthweek; thus selective reduction is generally delayed until after this time.Pregnancies after oocyte donation appear to be associated with higherrates of pregnancy-induced hypertension, when recipients are compared toage-matched controls (110,111) (Table 2) It is not clear whether theincreased incidence of pre-eclampsia is due to underlying disease or second-ary to the oocyte donation itself Serhal and Craft proposed that it may bedue to inadequate immunoprotection of the fetoplacental unit (116) As isthe case with all assisted reproduction, oocyte donation is associated withhigher rates of multiple gestation, but pre-term delivery rates (at least forsingleton gestations) do not appear to be significantly higher than those

of the general population Deliveries of multiples and even singletons mostcommonly occur via cesarean section (Table 2)

Figure 1 Percentage of transfers resulting in live births after oocyte donation by year.Source: From Ref 107