Ethical aspects of modern reproductive medicine and research

Petra De Sutter, MD PhD Dept Reproductive Medicine Ethics Committee University Hospital Ghent

Reproductive medicine and research

• • – – – – – – – – Assisted reproductive technologies: Intrauterine insemination In vitro fertilization / intracytoplasmic sperm injection Gamete and embryo donation Cryopreservation of gametes, gonads and embryos Preimplantation genetic diagnosis / screening Designer babies, sex selection Surrogacy Multiple pregnancies – – – Reproductive medicine research (embryonic) stem cell research (artificial gametes) Artificial oocyte activation / parthenogenesis Somatic cell nuclear transfer (cloning)

Age limits for treatment ?

Own oocytes Donor oocytes

Pregnancy after IVF and IUI as a function of female age

40 35 30 Pregnancy rate per cycle 25 20 15 10 5 0 < 30 30 - 35 36 - 38 39 - 40 41 - 42 Age > 42 IVF IUI

Pregnancy and miscarriage after IVF/ICSI as a function of female age

40 35 30 Pregnancy 25 rate per cycle 20 15 10 5 0 < 30 30 - 35 36 - 38 39 - 40 41 - 42 > 42 Female age Pregnancy Miscarriage

Patient autonomy Societal interests Clinicians autonomy

Multiple pregnancies following ART: blessing or curse?

Twins and Triplets: England and Wales and France 1970-1998

Twins Triplets Blondel & Kaminski 2002. Semin Perinatol 26:239-49.

Multiple Pregnancy and Prematurity

UK (Scotland) UK (Northern Ireland) Sweden Netherlands Italy Ireland Germany (9 Bundeslander) France (Perinatal survey) Finland Denmark Belgium (Flanders) Austria Singleton births Multiple births 0 10 20 30 40 50 Percent < 37 Weeks 60 Blondel et al 2006. BJOG 113:528-35.

70 80

Maternal Morbidity

Multiple (n=44,674) vs singleton pregnancy (n=165,188) RR (95% CI) Pre-eclampsia Gestational diabetes 2.8 (2.7-2.9) 1.1 (1.9-1.2)

Myocardial infarction Heart failure Venous thromboembolism Pulmonary oedema 3.7 (2.3-5.8) 12.9 (2.7-62.3) 2.7 (2.0-3.5) 7.1 (4.5-11.3)

Post partum haemorrhage Caesarean delivery Hysterectomy 1.9 (1.8-1.9) 2.2 (2.1-2.2) 2.3 (1.7-3.2) Walker et al, BJOG, 2004

Single embryo transfer

50 45 40 35 15 10 5 0 30 25 20

Introduction of eSET Proof of concept

3,0

Funding

2,5 34,4 2,0 1,4 8,9 1,5 1,0 0,5 1995 1996 1997 1998 Multiple PR 1999 2000 OPR/transfer 2001 2002 2003 embryos/transfer 2004 0,0

BELGIAN FUNDING REGULATION

•Six IVF/ICSI cycles (= oocyte harvests) funded in a life-time •1187€ per cycle for laboratory costs ( gamete procurement and handling ) •Including cryocycles •Up to the age of 43 years

Linked to a rational transfer strategy

≤ 36 years

1st trial ever or 1st trial after previous IVF/ICSI-delivery: always one fresh embryo; 2nd trial: one embryo if of sufficient quality; two if of insufficient quality; ≥3rd trial: maximum 2 embryos.

>36 - ≤39 years

1st and 2nd trial: maximum 2 embryos; ≥3rd trials: maximum 3 embryos.

> 39 years

No maximum number of embryos to transfer is dictated

CRYOCYCLES: 1 or 2 embryos

● Unmarried persons and gays and lesbians have interests in having and rearing children.

● There is no persuasive evidence that children raised by single parents or by gays and lesbians are harmed or disadvantaged by that fact alone.

● Programs should treat all requests for assisted reproduction equally without regard to marital status or sexual orientation.

The instrumentalisation / commercialism of reproductive medicine …

• "Donation" of eggs generate between $2,000 and $50,000 per donation, as ironic as that may seem. Men "donate" sperm for an average of $200 per transaction. Since no governmental or medical regulation covers these "donations" there are no hard facts as to the total outlay for eggs and sperm. Researchers estimate that the figure is nearly $18 billion, citing that one researcher paid $1.5 million for eggs in one year.

• The IRS reports that doctors of fertility medicine average adjusted income (after deducting expenses) of $9 million per year, with a gross income of over $20 million each.

1. Financial compensation of women donating oocytes for infertility therapy or for research is justified on ethical grounds.

2. Compensation should be structured to acknowledge the time, inconvenience, and discomfort associated with screening, ovarian stimulation, and oocyte retrieval. Compensation should not vary according to the planned use of the oocytes, the number or quality of oocytes retrieved, the number or outcome of prior donation cycles, or the donor’s ethnic or other personal characteristics.

3. Total payments to donors in excess of $5,000 require justification and sums above $10,000 are not appropriate.

4. To discourage inappropriate decisions to donate oocytes, programs should adopt effective information disclosure and counseling processes. Donors independently recruited by prospective oocyte recipients or agencies should undergo the same disclosure and counseling process as donors recruited by the program.

5. Oocyte-sharing programs should formulate and disclose clear policies on the eligibility criteria for participants and on how oocytes will be allocated, especially if a low number of oocytes or oocytes of varying quality are produced.

6. Treating physicians owe the same duties to oocyte donors as to any other patients. Programs should ensure equitable and fair provision of services to donors.

7. Programs should adopt and disclose policies regarding coverage of an oocyte donor’s medical costs should she experience complications from the procedure.

Preimplantation genetic diagnosis

Preimplantation genetic diagnosis

SCNT (therapeutical cloning) and stem cel technology

Ethical concerns regarding cloning

Cloning / stem cell research

• • • • Ethical concerns are often clouded by subjectivity, emotion, and perspective In animals? – Cloning members of an endangered species is generally regarded as positive, whereas attempting to clone an extinct mammoth from preserved tissue is regarded as negative (interferes with nature).

– Cloning pets might be seen as unethical (knowing that strays crowd shelters) In the human? – Ethical objections to cloning < this is not a normal way to have a baby, exact duplicates?. – the U.S. House of Representatives voted on July 31, 2001 to outlaw human cloning for any reason (impeding other types of medical research, thus introducing a different bioethical dilemma).

“Reproductive cloning" (to create a baby) versus "therapeutic cloning" (to create embryonic stem cells that are genetically identical to the individual who donated the nucleus).

– Does therapeutic cloning violate the rights of early-stage embryos ?

– Does banning this research violate the rights of people who might benefit from embryonic stem cell therapy?

As far as reproductive cloning is concerned, many motives have been proposed, from the frankly selfish (the elderly millionaire vainly seeking immortality) to the apparently acceptable (the couple seeking a replacement for a dead child, or a fully compatible donor for a dying child, or the attempt to perpetuate some extraordinary artistic or intellectual talent). Considerations of instrumentalization and eugenics render any such acts ethically unacceptable. In addition, since these techniques entail increased potential risks, safety considerations constitute another ethical objection. In the light of these considerations, any attempt to produce a genetically identical human individual by nuclear substitution from a human adult or child cell (“reproductive cloning”) should be prohibited.

The ethical objections against cloning also rule out any attempt to make genetically identical embryos for clinical use in assisted reproduction, either by embryo splitting or by nuclear transfer from an existing embryo, however understandable.

Multiple cloning is a fortiori unacceptable. In any case, its demands on egg donors and surrogate mothers would be outwith the realms of practicality at the present time.

ART law in Belgium 2007

• • • FORBIDDEN: sexing, reproductive cloning, commercial donation Separate law on research on embryos (11-05-2003) – federal commission – – – – – Not regulated: surrogacy, ethically controversial situations ( single women, homosexual couples ) vulnerable psychosocial situations, male age In all of these cases: -> psychosocial evaluation -> ethical commissions

“Embryo law”

Federal Commission for Medical and Scientific Research on Embryos

In Vitro

Act relating to research on embryos in vitro

(11 May 2003)

• The Commission is composed of: – 4 MDs – 4 PhDs – 2 Legal experts – 4 Experts in ethical questions

and social sciences

• and their substitutes (# 14) • • • •

Centralise all information related to research projects on embryos in vitro To licence research projects on embryos in vitro

Recommendations to the Parliament and Senate Inform application of law to local ethical committees

www.health.fgov.be/embryo www.embryos.be

Research on embryos in vitro is allowed when

• • • • • •

Therapeutic objective Based on the most recent scientific knowledge Performed in an accredited laboratory from - a University Centre for Reproductive Medicine - a Centre for Medical Genetics Directed by MD or PhD During the first 14 days of embryo development No alternative method as effective to obtain the information

It is not allowed

• • • • • • •

To implant human embryos into animals To create chimaeras or hybrids To replace human embryos subjected to reseach except … To use embryos, gametes and embryonic stem cells for commercial purposes To do ‘eugenetic’ research To do sex selection except to prevent sex-linked genetic diseases Reproductive cloning

Comments

• Some pathological conditions can only be diagnosed by (because human oocytes are not readily available): – Hamster ovum penetration assay – Hamster zona binding assay – Mouse oocyte activation test • Reproductive cloning – May be an option for many azoospermic men to have genetically own offspring – Sperm donation in Islam unacceptable: reproductive cloning unofficially accepted option as soon a technically possible

Belgian Advisory Committee on Bioethics and cloning Consensus The analysis of these arguments led all the members of the Committee to the conclusion that, regardless of any other consideration, it is out of the question at present to contemplate reproductive human cloning. In effect, in view of the scientific, technical and ethical uncertainties surrounding the technique of reproductive human cloning, an outright ban on any attempt to carry out cloning of this type in the near future is to be recommended. All the members of the Committee would like the psychological, philosophical, medical and ethical studies on this subject to be developed in greater depth, in order to help citizens form an enlightened opinion of the phenomenon of cloning. All the members of the Committee also agree that if a human clone was to be born - even if it was due to an illegal act - he would still be a full human being and none of the arguments put forward could challenge his dignity as a human.

Belgian Advisory Committee on Bioethics and cloning POSITION A : consider the above-mentioned prohibition to be a moratorium -> Knowledge as regards the possibilities and implications of reproductive human cloning from the biological, psychological, social and ethical points of view is so limited at present that no sound argument in favour of the definitive prohibition of any form of reproductive human cloning can be put forward.

-> concepts such as "human dignity", "uniqueness", "identity", "determinism" and "instrumentalization" were used without an in-depth analysis and without a comparison with their application in other spheres of human behaviour.

POSITION B: prohibit cloning < with the current state of knowledge, representations and social relations and in view of : the problems raised concerning construction of the clone's identity; the disruption of the relationship between genetic identity and phenotypic identity, especially through the identity of appearance that reproductive human cloning would introduce the problems of intergenerational relationships to which it could give rise the problem of the social and, conversely, the self-perception of the clone the instrumentalization logic to be found in the hypotheses in which the use of this technique is envisaged, it would be wise to prohibit cloning.

POSITION C: prohibit and penalize as a crime

TNX