r FERTILITY AND STERILITY

Vol. 53, No.4, April 1990

Copyright © 1990 The American Fertility Society

Printed on acid·free paper in U.S.A.

A protocol for satisfying the ethical issues raised by oocyte donation: the free, anonymous, and fertile donors

Rene Frydman, M.D.*t:j: HelEme Letur-Konirsch, M.D.* Dominique de Ziegler, M.D.*

Monique Bydlowski, M.D. t Anne Raoul-Duval, M.D.*t Jacqueline Selva, M.D.§

Universite of Paris·Sud, Hopital Antoine Beclere; Institute National pour la Science et la Recherche Medicale, Clamart, France; and Hopital de Bicetre, Le Kremlin·Bicetre, France

A new protocol was developed to provide participants of our oocyte donation program with oocytes donated by donors who were not financially rewarded, were anonymous, and fertile. Each participant provided an oocyte donor selected among fertile friends or family members. The retrieved oocytes were anonymously exchanged between phenotypically matched donor-recipient pairs. In the first 30 months of activity, we obtained 111 embryos suitable for transfer or cryopreservation from 52 retrievals, and 40 embryo transfers (ETs) were performed. Recipients received oral Estradiol-valerate and vaginal micronized progesterone. Fifteen embryos were transferred fresh in 8 ETs conducted after donorrecipient synchronization. This resulted in four pregnancies, all ongoing (ongoing pregnancy rate 50% per transfer). Of the 96 cryopreserved embryos, 82 were thawed for ET, and 45 surviving embryos were transferred in 32 ETs. This resulted in eight pregnancies, with six ongoing or delivered (ongoing pregnancy rate 19% per transfer). The overall ongoing pregnancy rate of 25 % per transfer indicates that our approach is a viable method for obtaining donated oocytes while respecting the ethical guidelines that recommend that donation of human gametes should be free, and from anonymous and fertile donors. Furthermore, guaranteeing anonymous oocyte donation had practical importance because, for many volunteer donors, it played a crucial role in their decision to donate. Fertil Steril53:666, 1990

Oocyte donation programs have allowed young women without functioning ovaries or the inability to use their oocytes because of genetic or other reasons, to become pregnant through in vitro fertilization (IVF) of donated oocytes. 1- 3 Access to this recent medical procedure is, however, limited because of the great scarcity of oocytes available for donation. Sources of donated oocytes have in-

Received August 2, 1989; revised and accepted December 21, 1989. * Universite of Paris· Sud, Hopital Antoine Beclere. t Institut National pour la Science et la Recherche Medicale. Reprint requests: Rene Frydman, M.D., Hopital Antoine Beclere, Materniw, 157, rue de la Porte de Trivaux, Clamart 92141 1 Clamart, France. § Hopital de Bicetre, Le Kremlin·Bicetre, 94270, France.

*

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eluded infertile4,5 or fertile 6 women, who were known6 ,7 or unknown 2,5,7 to the recipient, and who received8 or did not receive monetary compensation. 4 ,5 Despite the possible personal preferences of individual candidates who volunteer to donate 00cytes to a relative or friend, ethic committees in the United States9 and France 10 discourage either the nonanonymous or the financially rewarded exchange of human gametes. Furthermore, we believe that assuring anonymous donation of oocytes would limit the risk of possible tension in the future between the participating parties, Le., the donor and recipient couples and the resulting children. To satisfy these ethical considerations, we developed an original protocol to obtain oocytes that were freely donated from anonymous and fer-

Fertility and Sterility

tile donors. Weare reporting results obtained after the first 40 embryo transfers (ETs) performed during the first 30 months of activity of our oocyte donation program.

Table 1

Population Characteristics (Recipient)

With absent or inactive ovaries Age Diagnosis Ovarian dysgenesis

32.1 ± 4.9·

(XO)

MATERIALS AND METHODS Population Characteristics Donors

Each recipient of our oocyte donation program provided an oocyte donor selected among fertile friends or family members. All oocyte donors were required to be 38 years old and have at least one live child. Each oocyte donor was genetically screened by an interview with a geneticist and a blood karyotype. Phenotypes and blood types of donors were recorded. Each prospective donor gave her written consent after receiving a thorough explanation of the planned procedure and a description of its potential risks. Verbal consent of spouses of oocyte donors was also obtained. The spouse's consent was considered a part of the elements that enabled the medical team, including the participating psychologist, to determine that the donor's decision was taken in harmony, rather than as a result of undue pressure. A formal written permission from the husband was, however, not requested. The age of the oocyte donors was 31 ± 2.7 years (mean ± SD). Sixty percent were sisters of the recipient, whereas 20% were relatives, and the remaining 20% were friends. Recipients

Thirty-two women had 40 transfers of embryos obtained with donated oocytes. All the recipients were 2 embryos were obtained. Embryo Transfers

Forty ETs took place in recipients of our program, including 8 transfers offresh embryos and 32 transfers of cryopreserved embryos. Results appear in Table 3. Fifteen embryos were transferred fresh (8 transfers) resulting in 4 pregnancies, all ongoing (~ third trimester). The ongoing pregnancy rate for fresh ETs was 50% whereas the implantation rate was 26% for embryos transferred after thawing; 82 cryopreserved embryos yielded 45 embryos suitable for transfer indicating an embryo survival rate of 55%. The implantation rate per embryo transferred was 18% and the pregnancy rate per transfer for cryopreserved embryos was 25%. The ongoing pregnancy rate per transfer was 50% and 19% after transfers of fresh and cryopreserved embryos, respectively. Of the 111 utilizable embryos obtained from 52 retrievals, 15 embryos were transferred fresh and 96 were cryopreserved. At the time of this report 82 embryos were thawed, whereas 14 embryos remained cryopreserved for future transfers scheduled in five egg donation recipients.

After Establishment of Pregnancy (All Patients)

Oral E 2-valerate was increased to 8 mg/d when pregnancy was documented by a positive {j-hCG titer on the 11th day after ET. Progesterone was supplied by 250-mg intramuscular injections of hydroxyprogesterone caproate three times a week (P Retard; Schering Pharmaceuticals) and vaginal micronized-P (600 mg/d). Hormone replacement was continued until placental production of E2 and P was documented by observing rising levels of serum E2 and P despite a constant hormone supply. In all cases, this occurred 8 weeks after ET at the latest. RESULTS Oocyte Retrievals

Fifty-two retrievals were performed in 48 oocyte donors. Results appear in Table 2. These retrievals provided 111 utilizable embryos, i.e., embryos that were suitable for either tran'sfer or cryopreservati9n. In 13 cases (25%), an oocyte retrieval took place but no utilizable embryos were obtained. In

Vol. 53, No.4, April 1990

DISCUSSION

The scarcity of oocyte donors is a crucial problem for most oocyte donation programs. Donated oocytes have been obtained from women participating in regular IVF programs. 4,5 Asking infertile women who undergo IVF to donate some of their Table 3

Outcome of Embryo Transfers Transfers of fresh embryos

Number of transfers Number of embryos thawed Number of embryos transferred (implantation rate/embryo transferred) " Pregnancies (rate/transfer)" Ongoing pregnancies (rate/transfer)"

Transfers of crypreserved embryos

Total

32

40

82

82

15 (27)

45 (18)

60 (20)

4 (50)

8 (25)

12 (30)

4 (50)

6 (19)

10 (25)

8

" Values in parentheses are percents.

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oocyte raises, however, serious ethical questions as pregnancy may develop in the recipient and not in the donor. 1 Moreover, as cryopreservation of human embryos became available, donation of extra oocytes by IVF patients is even more questionable because it proportionally decreases the overall chances for that patient to become pregnant. Voluntary donation of oocyte by women undergoing tubal ligation is another potential source of donated oocytes. Unfortunately, the necessity for hormonal treatment before harvesting fertilizable oocytes is considered as an excessive burden by most women. Therefore, it is unrealistic to expect that voluntary donation of oocytes by women undergoing tubal ligation could provide a sufficient source of donated oocytes unless monetary compensation is provided. This latter possibility was not retained in our program as financial reward for donation of human gametes is not recommended in France and other countries. 9 ,lo Because of the difficulty in finding anonymously donated oocytes, several programs have requested that their participants provide an oocyte donor selected among friends or family members. Whereas this approach offers the advantage of an altruistic motivation of the donor, it unfortunately implies a nonanonymous exchange of gametes, which is also strongly discouraged by ethic committees.9 ,lo In contrast, our approach in which donated 00cytes were anonymously exchanged between phenotypically matched volunteer donor-recipient pairs provided a reliable source of oocytes from anonymous and fertile donors who were not financially rewarded. This approach satisfies all of the essential requirements formulated by ethical committees on human gamete donation. Furthermore, it was our impression that offering anonymous oocyte donation was crucial for many volunteer donors when they took their decision to donate. Our results showing an overall ongoing pregnancy rate of 25% per transfer are similar to published dataY,-17 Therefore, our results indicate that the strategy proposed for obtaining donated oocytes is viable. It remains true, however, that finding a person who volunteers for oocyte donation is difficult. This is particularly problematic for women who wish to undertake a second attempt at IVF through oocyte donation. Thirty-two recipients of our program who did not become pregnant after their embryo replacement needed to find another donor for a new ,attempt. Some women, therefore, prefer participating in a oocyte donation program in which

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one to two oocytes are donated by couples undergoing IVF .18 We also noted that, in rare occasions «5%), donors and recipients preferred that 00cytes be donated nonanonymously. As this is not offered at our institution, these individuals were referred to other institutions in Paris. 15,18 Cryopreservation of embryos offers obvious advantages that facilitate the cross-exchange of donated oocytes between anonymously matched donor-recipient pairs. Our results indicated, however, that cryopreservation carried an excessive toll on embryos as 45% of cryopreserved embryos obtained from donated oocytes did not survive the thawing process. The post-thawing survival rate of 55% was not different from that observed with cryopreserved embryos originating from our regular IVF program. 19 This indicates that the oocyte's origin (fertile donors or infertile IVF patients) does not influence the embryo resistance to the freezingthawing process. The excessive loss of embryos through cryopreservation led us recently to attempt, whenever possible, to synchronize donors and recipients for fresh ETs. Although the number of fresh ETs performed after donor-recipient synchronization is still small (8 transfers), we obtained encouraging results with an ongoing pregnancy rate of 50% per transfer. If confirmed, the observation of a higher implantation rate after transfers of fresh embryos (26% per embryo transferred) than after transfers of cryopreserved embryo (18% per embryo transferred) suggests that cryopreservation may result in an even larger loss of potential pregnancies than estimated by the post-thawing survival rate. The practical implantation of this observation is that donor-recipient synchronization should be attempted whenever possible for a more efficient use of donated oocytes. The excellent pregnancy rate after our protocol for donorrecipient synchronization (50% per transfer) is in agreement with the observation of others14 that it is not necessary to duplicate the preovulatory rise of serum E2 to achieve optimal receptivity of the endometrium. Thirteen oocyte retrievals (26%) performed in fertile donors did not yield any utilizable embryos (Table 3), which represents an unexpectedly high finding. The poor characteristics of either fresh or cryopreserved sperm may explain some but not all of these cases. We think that another explanation resides in some degree of insufficient motivation from a few donors leading to treatment deviations which in turn may have been responsible for sev-

Fertility and Sterility

eral cases of poor IVF outcome. Decreased donor motivation was particularly problematic when a recipient had her ET before the oocyte retrieval was performed in her donor. After we made this observation, it became a standard policy in our program that the oocyte retrieval in a donor should always preceed the ET of her recipient. Since this policy was implemented, 14 oocyte retrievals were performed and only 1 did not provide at least one utilizable embryo. One of the requirements imposed on women volunteering for oocyte donation by us but not by otherss is that they had at least one child. The exact impact of an oocyte retrieval on the further ability to conceive is unknown as this procedure is normally performed in infertile women. Whereas it is unlikely that infertility will result from laparoscopic or ultrasound-guided aspiration of oocytes, it would be impossible to rule out that multiple ovarian punctures played a role if infertility occurred in the future. Our requirement that volunteer donors had at least one child is in agreement with the ethical considerations formulated by The American Fertility Society stating that "utmost care must be exercised in using donors who do not have the necessity of having an accompanying procedure.,,9 The recent report of occasional infectious complications from transvaginal oocyte retrievals 20 reinforced our decision to request that volunteer oocyte donors should have at least one child. Excluding nulligravida from volunteer oocyte donation is also recommended by the French ethic committee, advising that all donation of human gametes should be from fertile donors only.1O The French ethic committee and the national sperm bank (Centre d'Etude et de Conservation du Sperme) justify this requirement by a fear of childsearching conducts or of psychological disturbances if an individual volunteering for gamete donation will ultimately become childless. 10 Besides its primary objective of providing participants of our egg donation program with donated oocyte of anonymous origin, our method offered also the advantage of equalizing the chances of pregnancy between all egg donation recipients. It was indeed our policy to guarantee that all recipients whose donor had an oocyte retrieval will have an ET despite individual differences in the quality of avarian response to hMG. Guaranteeing equal chances to all participants of our program greatly dE(creased the stress level in both donors and recipients.

Vol. 53, No.4, April 1990

Our results indicated that the proposed strategy for obtaining donated oocytes, i.e., the anonymous exchange of voluntarily donated oocytes between phenotypically matched donor-recipient pairs, is a viable approach for an oocyte donation program. This approach offers the advantage of respecting all major requirements formulated by ethic committees. We think, therefore, that our results are justifying the efforts required for organizing the anonymous exchange of donated oocytes between participants of our program. Moreover, we observed that offering the guarantee to individuals who consider volunteering for oocyte donation that their gametes would be anonymously attributed was a factor that often played a crucial role when they agreed to donate. Acknowledgments. We thank C. Cornel, M.D. for his assistance in gathering the clinical data and J. Taieb, M.D. for the biochemical collaboration. Mrs. M. Volante, Ms. G. Gallo, V. Pietri are similarly acknowledged for their technical assistance for IVF and cryopreservation under the direction of J. Testart, Ph.D. Expert secretarial help of Ms. V. Martel and S. Borie was greatly appreciated.

REFERENCES 1. Lutjen P, TrounsonA, LeetonJ, FindlayJ, 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 2. Navot D, Laufer N, Kopolovic J, Rabinowitz R, Birkenfeld A, Granat M, Margalioth E, Schenker J: Artificially induced endometrial cycles and establishment of pregnancies in the absence of ovaries. N Engl J Med 314:806, 1986 3. Rosenwaks Z, Veeck LL, Liu H-C: Pregnancy following transfer of in vitro fertilized donated oocytes. Fertil Steril 45:417, 1986 4. Leeton J, Harman J: Attitudes toward egg donation ofthirty-four infertile women who donated during their in vitro fertilization treatment. J In Vitro Fert Embryo Transfer 3: 374,1986 5. Rosenwaks Z: Donor eggs: their application in modern reproductive technologies. Fertil Steril47:895, 1987 6. Leeton J, Chan LK, Trounson A, Harman J: Pregnancy established in an infertile patient after transfer of an embryo fertilized in vitro where the oocyte was donated by the sister of the recipient. J In Vitro Fert Embryo Transfer 3:379, 1986 7. Leeton J, Caro C, Howlett D, Harman J: The search for donor eggs: a problem of supply and demand. Clin Reprod FertiI4:337,1986 8. Kennard EAD, Collins RL, Blankstein J, Schover LR, Kanoti G, Reiss J, Quigley MM: A program for matched, anonymous oocyte donation. Fertil Steril51:655, 1989 9. The Ethics Committee of The American Fertility Society: Donor egg in in vitro fertilization. Ethical considerations of

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A protocol for satisfying the ethical issues raised by oocyte donation: the free, anonymous, and fertile donors.

A new protocol was developed to provide participants of our oocyte donation program with oocytes donated by donors who were not financially rewarded, ...
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