A program for matched, anonymous oocyte donation

FERTILITY AND STERILITY

Vol. 51, No.4, April1989

Printed in U.S.A.

Copyright" 1989 The American Fertility Society

A program for matched, anonymous oocyte donation Elizabeth A. D. Kennard, M.D.*t Robert L. Collins, M.D.* JosefBlankstein, M.D.* Leslie R. Schover, Ph.D.+

George Kanoti, S.T.D.§ Joann Reiss, R.N.C.* Martin M. Quigley, M.D.*II

Cleveland Clinic Foundation, Cleveland, Ohio

The authors' program for matched, anonymous oocyte donation has resulted in two successful pregnancies among the first eight oocyte recipients. All oocyte recipients to date have had ovarian failure or absence with premature ovarian failure the most common cause. All recipients were cycled on a program of incremental oral micronized estradiol and intramuscular progesterone-in-oil. Thirteen candidates for oocyte donation were screened to obtain 8 donors. One donor candidate was excluded because of her medical history. The psychological screening of 2 of the other donor candidates (who subsequently did not complete the donation cycle) revealed a primary motive of financial gain. In general, the psychological profiles of donor candidates revealed a high incidence of troubled families and either reproductive loss or loss of a parent. Ovarian stimulation of the donors followed our standard in vitro fertilization protocol. The recipients' exogenous steroid replacement continued until days 97 and 101, respectively, of the two gestations. Both pregnancies resulted in the delivery of normal singleton males-the first at 40 weeks, the second at 35 weeks. Fertil Steril51:655, 1989

The first successful pregnancy established in an agonadal woman through the use of donated oocytes was reported in 1984. 1 Since then, successful pregnancies have resulted from oocytes donated either by patients undergoing in vitro fertilization (IVF) or by donors who know the patient and volunteer to undergo ovarian stimulation. 2- 9 A woman may require donated oocytes to achieve pregnancy for several reasons including gonadal dysgenesis, ovarian destruction or removal, premature ovarian failure, or to avoid transmission of significant genetic diseases. For most of these women, donor oocytes represent the only method for them to ever Received September 7, 1988; revised and accepted December 20,1988. * Department of Gynecology. t Present address: Department of Obstetrics and Gynecology, Cleveland Metropolitan General Hospital, Cleveland, Ohio. :j: Center for Sexual Function. § Department of Bioethics. II Reprint requests: Martin M. Quigley, M.D., Department of Gynecology, Cleveland Clinic Foundation, One Clinic Center, Cleveland, Ohio 44195. Vol. 51, No.4, April1989

become pregnant .. This is especially true since the availability of cryopreservation has diminished the number of excess IVF embryos previously available for donation. We have developed a program of anonymous, matched oocyte donation. This program is analogous to our sperm donor insemination program, in that the physical characteristics of the recipients and donors are matched and anonymity of the involved parties is maintained.

MATERIALS AND METHODS Donor Selection and Screening

The media announcement of this program 10 resulted in over 500 telephone calls from potential donors. Women who express interest in becoming an oocyte donor are offered a preliminary interview conducted by a staff physician to explain the program and to note physical characteristics such as height, weight, eye and hair color, national origin, and blood type. A photograph of the potential doKennard et al.

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nor is obtained and she is placed on a waiting list. The only absolute requirements for consideration as a donor are: general good health, age 18 through 35, and normal menstrual cycles. The donor is recalled when she is matched with a specific recipient. She is mailed a 26-page questionnaire concerning family history, personal health habits, and medical history as well as a standardized psychological screening test. A complete history and physical exam then is performed by a staff gynecologist not directly affiliated with the donor program. During this visit, serologic testing for syphilis, human immunodeficiency virus (HIV), hepatitis B, and cytomegalovirus is performed. Cervical cultures for herpes, gonorrhea, and chlamydia are also obtained. Where indicated, testing for sickle-cell trait or Tay-Sachs disease is performed. The medical questionnaire is reviewed by the examining physician and, if the patient appears to be an appropriate candidate for donation, informed consent is obtained by one of the authors (R.L.C., M.M.Q.). If the donor is married, informed consent also is obtained from her husband. Following her medical screening, the prospective donor has an interview with a doctoral-level clinical psychologist (L.R.S.) for 45 to 60 minutes. The interview is semistructured and assesses the potential donor's motivation for participating, positive and negative expectations about oocyte donation, support or disapproval of spouse, family, or friends, current sources of life stress and satisfaction, previous participation in medical research, and expected impact of oocyte donation on the current sexual relationship. Also assessed is any history of emotional traumas related to childbearing, sexual trauma, and psychiatric disorders or substance abuse. The prospective donor's career history, history of intimate relationships, family history of psychiatric disorders or substance abuse, and risk factors for HIV infection, also are elicited. Before this interview, each woman completes the SCL90R, a self-report psychological inventory that assesses global psychological distress (global symptom index, GSI). A number of subscales also are obtained, including scores for somatization, anxiety, depression, paranoia, hostility, and psychosis. The total number of symptoms checked (positive symptom total) and the average level of severity of symptoms (positive symptom distress index) also are scored. After reviewing the interview and questionnaire data, the psychologist rates each potential donor as 1 = ideal candidate; 2 = acceptable, but with some reservations, or 3 = unacceptable. Following the psychological testing, the prospec656

Kennard et al.

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tive donor has an interview with a member of the Department of Bioethics to confirm knowledge of the risks and benefits, lack of coercion, and adequacy of informed consent. A weekly meeting is held with the members of all involved departments and data from psychological and medical testing is presented for review. The decision to accept a donor into the program and beg-in active stimulation for oocyte retrieval is made in this forum. Recipient Preparation and Management

Potential recipients have their diagnosis confirmed by karyotype, serum hormone levels, or review of medical records as appropriate. These women undergo an initial interview and examination. Physical characteristics are recorded and details of the program are explained. Their husbands have a routine semen analysis performed to confirm sufficient sperm for fertilization in vitro. Once a couple has decided to proceed with the program, estradiol (E 2 ) and progesterone (P) replacement is begun. Steroid replacement for the recipient patients is first assessed using a "mock cycle." Endometrial biopsies are obtained to verify adequate secretory changes in the endometrium. Patients are given oral micronized E 2 (Estrace, Mead Johnson, Evansville, IN) in incremental doses and intramuscular (IM) P-in-oil (Lilly, Indianapolis, IN) as outlined in Figure 1. Endometrial biopsies are performed on days 24 and 30 of the mock cycle (which are days 20 and 26 from the start of E 2 replacement). All patients thus far have demonstrated adequate endometrial changes by the second biopsy and have not required any further adjustment of hormone replacement. Once adequate endometrial development has been conFertility and Sterility

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firmed, informed consent is obtained from both the recipient and her husband. While waiting for screening of the donor and cycle synchronization, patients are maintained on oral micronized E 2 as shown in Figure 1, with medroxyprogesterone acetate (MPA, Provera, Upjohn, Kalamazoo, MI) 10 mg/day on days 15 through 28 substituted for the P-in-oil. The matched donor then is screened as above, and the donor's stimulation cycle is begun after synchronization of menstrual cycles by varying the length of the recipient's E 2 replacement. If the donor happens to be using oral contraceptives (OCs) before the stimulation cycle, shortening or lengthening the time of OC administration also can be used to aid in synchronization. The ovarian stimulation of the donor follows our standard IVF protocol and is detailed elsewhere. 11 Oocyte aspiration is performed with vaginal ultrasound guidance. 12 During the replacement cycle, the recipient is given oral micronized E 2 and IM P-in-oil in doses outlined in Figure 2. In order to complete the synchronization of the donor's and recipient's cycles, the number of days of 2 mg/day E 2 can be extended to lengthen the recipient's cycle or the E 2 replacement regimen can be shortened to as few as 6 days of6 mg/day E 2 to shorten the recipient's cycle. All obtained oocytes are inseminated with therecipient's husband's sperm. With a goal of placing three (maximum four) embryos in the recipient's uterus, the following are our current recommendations to the patients: if six or more oocytes have normally fertilized (two pronuclei), four are cultured and all that cleave are transferred, while the Vol. 51, No.4, April1989

remaining embryos are frozen at the pronuclear stage. If pronuclear freezing is not chosen and five or more embryos have cleaved, three are transferred and the remaining embryos are frozen. As shown in Figure 2, embryo placement is performed on the fourth day of P replacement. Embryos are transferred at the 2-cell to 4-cell stage. Fourteen days after the placement of embryos, a qualitative serum human chorionic gonadotropin (hCG) test is obtained. If positive, the patient continues the daily 50 mg IM P-in-oil and 4 mg oral micronized E 2 until biweekly serum E 2 and P levels demonstrate evidence of the luteal-placental shift. A decrease in the exogenous hormones to a dose of 50% then is prescribed and if the E 2 and P levels continue to increase, the exogenous hormones are discontinued altogether. If the serum hCG is negative at 14 days after replacement, the recipient is instructed to stop the E 2 and P-in-oil and expect menses. RESULTS

Thus far, 23 recipients have been identified and screened. Eight have completed nine replacement cycles (One patient underwent a second replacement of frozen embryos obtained in the first cycle). Of the remaining 15 patients, 14 are awaiting donor matching and screening and 1 patient withdrew because of the development of autoimmune eighth nerve deafness that resulted in severe acute hearing loss. In the 8 patients who have completed cycles, 5 have premature ovarian failure, and 1 each has gonadal dysgenesis, prior chemotherapy, and bilateral oophorectomy for severe endometriosis. The recipients treated to date ranged in age from 23 to 31 years. As described elsewhere/3 a characteristic finding of the endometrial biopsies obtained on day 24 of the "mock" cycle (day 20 of E 2 replacement) is glandular-stromal disparity, with the glands being retarded (day 16 to 17) when compared with the stroma (day 19 to 20). The biopsies from day 30 (day 26 of hormone replacement) were interpreted as day 26 or 27 by all reviewers. There were no detectable differences in the biopsies of the two women who subsequently became pregnant. For the eight recipients, 13 potential donors were screened. They ranged in age from 19 to 34 years. Five did not become oocyte donors: 1 withdrew before the initiation of ovarian stimulation; 2 were noncompliant with the medication and/or monitoring protocol and their participation was discontinued; 1 potential donor was excluded for a history Kennard et al.

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of pseudotumor cerebri; and 1 was excluded because of a rating of "3" on the psychological evaluation. Of the 13 donor candidates, the psychologist rated 5 women as "1"; 7 as "2"; and one as "3". The latter candidate was going through a bitter divorce and lawsuit, and had an unsupportive partner. The four other women who did not complete the donation procedure all were rated as "2". The SCL-90 was not helpful in selecting candidates because the women clearly wanted to minimize psychological symptoms. The GSI scores were below the mean for a healthy community sample of women. The mean standardized (T) score for the normative group is 50, whereas our donor candidates' T-scores ranged from 30 to 58 (mean, 41.67). This picture of psychological well-being was often in stark contrast to the degree of life stress and anxiety or depression found from the clinical interview. A number of donor candidates reported histories of family trauma or reproductive trauma that could have influenced their decision to volunteer for oocyte donation. Four had become pregnant while unmarried (30.7%); two had had abortions; three had partners who refused to have children; one had recently located her sister who had been given up for adoption as an infant; and one brought her sister, who had given up a baby for adoption, to the interview. We also found a history of disrupted families, with five women who had a parent who died (38.5%) and three who came from divorced families. Three women had a history of incest or rape and three had a parent or sibling who abused drugs or alcohol. Financial gain was not an apparent motive for six of the eight donors who eventually participated. Of the four donors who did not participate because of nonmedical reasons, three stated that financial gain was their primary motive. The following are summaries of the first two pregnancies: Patient 1 is a 22-year-old married caucasian woman who was originally referred with 5 months of secondary amenorrhea. Menarche was at age 14 with regular menses until age 19. She had 2 months of amenorrhea and was placed on OCs. She took OCs for 3 years and reported no problems. She discontinued the OCs and had three spontaneous menses followed by 5 months of amenorrhea, hot flashes, and vaginal dryness. Serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) both were markedly elevated in the postmenopausal range. Repeat determinations also 658

Kennard et al. Matched, anonymous oocyte donation

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were elevated. Her karyotype was 46,XX. She was begun on estrogen replacement therapy and had two withdrawal menses followed by 4 months of amenorrhea. She was seen at this time for followup and found to be 24 weeks pregnant. Ultrasound was obtained, verified gestational age, and diagnosed anencephaly. She underwent prostaglandin induction and delivery. Three months postpartum, her serum gonadotropins again were elevated, with an LH of 69.9 and FSH of 59.9. She was begun on standard estrogen and MP A hormone replacement until entered into our donor program. She underwent a "mock" stimulation cycle (Fig. 1). The first endometrial biopsy was interpreted as day 17 and the second biopsy as day 26. In the actual treatment cycle, she received 2 mg/ day E 2 for 3 days, starting on cycle day 2, then 4 mg/day for 3 days and finally 6 mg/day for 6 days. The next day (the day after the donor received hCG), she began 4 mg/day E 2 and 50 mg/day P-inoil. Three embryos (a 2-cell, a 3-cell, and a 4-cell) were placed in the uterus on the fourth day of the 4 mg/day E 2 and P regimen. Two other embryos are cryopreserved for an additional attempt at pregnancy. Ultrasound confirmed a singleton, normal appearing fetus, with normal growth patterns. Serum alpha-fetoprotein was normal at 16 weeks. She received E 2 and P until the 11th week of gestation. Her serum hormone levels during early pregnancy are shown in Figure 3. She delivered a 7 lb 3 oz male at 40 weeks. Patient 2 is a 22-year-old woman who originally sought care at the age of 19 for primary amenorrhea and absence of secondary sexual characteristics. Serum gonadotropins were measured and found to be in the postmenopausal range, karyotype was 46,XX, and laparoscopy revealed streak gonads. She was placed on hormone replacement therapy and had withdrawal menses. The laparosFertility and Sterility

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Figure 4 Serum hormone levels of Patient 2 measured from day 14 after placement of embryos. She also was mai~ta~ned on 4 mg E 2 and 50 mg P-in-oil daily until she was hosp1tal~zed f~r intractable nausea and vomiting from day 66 to 77. Dunng th1s interval, she was maintained on four 0.1-gm E2 patches (changed every 3! days) as well as injectable P-in-oil. Her st~n­ dard hormone replacement was resumed on day 78 and co.ntH~­ ued until day 94 when daily doses of 2 mg E 2 and 25 mg ~-m-oll were prescribed. On day 101, all hormone supplementatiOn was discontinued.

copy was repeated by a second physician and confirmed streak gonads. She continued hormone replacement until referred to our donor program. She underwent a mock stimulation cycle and her two endometrial biopsies were interpreted as days 16 and 27, respectively. In the actual treatment cycle, she received 4 mg/ day E 2 for 4 days, starting on cycle day 2, then 6 mg/day for 6 days. The next day (the day after the donor received hCG) she began 4 mg/day E2 and 50 mg/day P-in-oil. Two 2-cell embryos were placed in the uterus on the fourth day of the 4 mg/day E2 and P regimen. A single intrauterine pregnancy was documented by ultrasound 4 weeks after replacement. Her pregnancy was complicated by protracted nausea and vomiting and suspected acute cholecystitis. Ultrasound of the abdomen and gallbladder was negative for cholelithiasis. Because of inability to ingest oral medications, the patient was changed from oral E 2to four simultaneous 0.1 gm E 2patches (Estraderm, CIBA, Summit, NJ). The patches were changed every 3! days. After resolution of her nausea, vomiting, and abdominal pain, the oral E2 was resumed. She continued exogenous hormone therapy through the 14th week of pregnancy because biweekly E 2 and P levels failed to demonstrate a luteal-placental shift before that time. Figure 4 shows her early pregnancy serum hormone levels. She.delivered a 2381 g male at 35 weeks. DISCUSSION

Several previously reported successful pregnancies have resulted from donated oocytes. In all of Vol. 51, No.4, April1989

the cases, oocytes were obtained either from patients undergoing IVF, or from donors known to the patient. With the availability of cryopreservation and reports of successful pregnancies from frozen embryos, 14 patients undergoing IVF today seldom voluntarily donate their oocytes. Even if oocytes are available, matching the physical characteristics of donor and recipient is almost impossible, since it is unlikely that a matching recipient will have her endometrium correctly primed to receive embryos. The only alternative is to cryopreserve the embryos obtained from donated oocytes and replace them when the recipient is prepared. Although it will not allow matching of physical characteristics, a program that allows oocyte donation between a known donor and recipient will allow synchronization of cycles and omits the need to cryopreserve any obtained embryos. However, donation of semen by relatives or friends is a widely discouraged practice 15 because of potential psychosocial complications associated with the use of a known donor/ 6 and there is no reason that donated oocytes should be regarded differently. Therefore, we reason that the best possible source of donated. oocytes is an anonymous, volunteer donor. She then is matched to the physical characteristics of the recipient, and their menstrual cycles are synchronized to avoid the need for cryopreservation. Our oocyte donation proposal underwent over a year and a half of review before final approval. The proposal initially was presented to the Institutional Review Board (IRB). Their decision was that the program was "innovative therapy" and not research. The principle review of the proposal was conducted by our Institutional Ethics Committee. Before final approval, because of concerns regarding the possibilities of financial coercion and subjecting a normal volunteer to some risk for nodirect benefit to herself, the IRB was requested to review and approve the program before its institution. The informed consent documents* executed by both the donor (and her husband if she is married) as well as the recipient and her husband have been IRB-approved and conform to the applicable Federal guidelines for human research informed consent documents. 17 Our program emphasizes lengthy physical and psychological screening for the donors. Great care is taken to ensure that donors do not have unrealistic expectations or motives and that they have been appropriately informed before giving their consent to donation. *Available on request from the author (M.M.Q.). Kennard et al.

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The psychological interviews suggest that many volunteers for oocyte donation grew up in troubled families and experienced loss of a parent or personal or family reproductive losses. Pregnancies were aborted, given up for adoption, or never conceived due to a partner's refusal to have children. In addition, financial gain as a primary motive seems to be a negative prognostic indicator for compliance with the program. After evaluating this group of potential donors, we switched our screening psychological questionnaire from the SCL-90R to the Minnesota Multiphasic Personality Inventory (MMPI) because it was designed to identify people who try to mask psychological distress. Other researchers have also found the MMPI useful in selecting women to participate in an alternate type of oocyte donation, ovum transfer. 18 The American Fertility Society recommends that oocyte donors not be reimbursed for their oocytes.19 Our donors are therefore only given financial consideration for the direct and indirect costs of their participation. Donors receive $50.00 for each day they receive injections and/or have blood drawn, $100.00 for each day they have an ultrasound exam, blood drawn, and injections, and $350.00 for the day of the aspiration procedure. This consideration is within the guidelines approved by the IRB for participation in research projects. Transfer of donated, fertilized in vitro, oocytes to women unable to provide their own oocytes resulted in a 25% continuing pregnancy rate. This is a slightly higher pregnancy rate than in our regular IVF program. Endometrial biopsies performed during "mock cycles" revealed a consistent early luteal defect that resolved in all recipients by the second biopsy. It is quite possible that the recipient endometrium, although lagging initially, is eventually better prepared for successful implantation than in normal IVF, since it has not been exposed to the excessive hormonal manipulation necessary to stimulate multiple ovarian follicles.

REFERENCES 1. Lutjen PJ, Trounson A, Leeton JF, Findlay J, Wood C, Renou P: The establishment and maintenance of pregnancy using in vitro fertilization and embryo donation in a patient with primary ovarian failure. Nature 307:174, 1984

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2. Feichtinger W, Kemeter P: Pregnancy after total ovariectomy achieved by ovum donation. Lancet 2:722, 1985 3. Navot D, Laufer N, Kopolivic J, Rabinowitz R, Birkenfeld A, Lewin A, Granat M, Margalioth EJ, Schenker JG: Artificially induced endometrial cycles and establishment of pregnancies in the absence of ovaries. N Engl J Med 314: 806,1986 4. Rosenwaks Z, Veeck LL, Liu H-C: Pregnancy following transfer of in vitro fertilized donated oocytes. Fertil Steril 45:417, 1986 5. Chan CLK, Cameron IT, Findlay JK, Healy D, Leeton JF, Lutjen PJ, Renou PM, Rogers PA, Trounson AO, Wood EC: Oocyte donation and in vitro fertilization for hypergonadotropic hypogonadism: clinical state of the art. Obstet Gynecol Surv 42:350, 1987 6. Serhal PF, Craft 1: Simplified treatment for ovum donation. Lancet 1:687, 1987 7. Asch R, Balmaceda J, Ord T, Borrero C, Cefalu E, Gastaldi C, Rojas F: Oocyte donation and gamete intrafallopian transfer as treatment for premature ovarian failure. Lancet 1:687,1987 8. Yovich JL, Blackledge DG, Richardson P A, Edirisinghe WR, Matson PL, Turner SR, Draper R: PROST for ovum donation. Lancet 1:1209, 1987 9. Correy JF, Leeton JF, Watkins RA, Bradfield GF, Garner S, Watson S: Donor oocyte pregnancy with transfer of deep-frozen embryo. Fertil Steril49:534, 1988 10. Clinic in Ohio starts egg donor plan. New York Times 136: 47,201:10 (National Edition), July 15, 1987 11. Quigley MM, Sokoloski JE, Richards SI: Timing hu~an chorionic gonadotropin administration by days of estradiol rise. Fertil Steril44:791, 1985 12. Seifer DB, Collins RL, Paushter DM, George CR, Quigley MM: Follicular aspiration: a comparison of an ultrasonic endovaginal transducer with fixed needle guide and other retrieval methods. Fertil Steril 49:462, 1988 13. Rosenwaks Z: Donor eggs: their application in modern reproductive technologies. Fertil Steril47:895, 1987 14. Trounson AO, Mohr L: Human pregnancy following cryopreservation, thawing and transfer of an 8-cell embryo. Nature 305:707, 1983 15. Curie-Cohen M, Luttrell L, Shapiro S: Current practice of artificial insemination by donor in the United States. N Engl J Med 300:585, 1979 16. Joyce DN: Recruitment, selection and matching of donors. In Artificial Insemination: Proceedings of the Fourth Study Group of the Royal College of Obstetricians and Gynecologists, Edited by M Brudenell, A McLaren, R Short, M Symonds. London, Royal College of Obstetricians and Gynecologists, 1976, p 62 17. US Department of Health and Human Services: Protection of human subjects. 45 Code of Federal Regulations 46, March 8, 1983 18. Martin DJ: MMPI profiles of ovum transfer donors and recipients. Presented at the annual meeting of the American Psychological Association, Anaheim, California. September4, 1983 19. Ethics Committee of the American Fertility Society: Donor eggs in in vitro fertilization. In Ethical Considerations of the New Reproductive Technologies. Fertil Steril (Suppl) 46:42S, 1986

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