MODERN METHODS Luigi Mastroianni, Jr.
ETHICAL ISSUES Bernard M. Dickens
The medical management of infertility has involved increasingly complex treatment methods. Most of these reproductive technologies employ manipulations of the gametes: sperm and eggs. Most of the newer methods are offshoots of in vitro fertilization systems, although older techniques such as artificial insemination still play an important role.
Artificial insemination has been practiced for more than a century. When done using the husband's semen, it is clinically useful in the management of conditions such as penetration failure, premature ejaculation, and retrograde ejaculation into the bladder. Artificial insemination using a specimen other than the husband's (donor insemination) also has evolved as an acceptable treatment for infertility. Donor insemination is utilized mainly in cases in which the spermatozoa are absent or severely compromised in number and quality.
The donor, who usually is anonymous and is identified only by a third party, is thoroughly screened for general health, genetic abnormalities, and sexually transmitted diseases such as HIV infection. Other characteristics are considered as well. Detailed pretreatment counseling is critical and should include an in-depth discussion with both partners of the acceptability of using a donor. The ethical issues to be considered should include whether the offspring will be informed of the method of conception and the safeguards in place to ensure the long-term availability of genetic information if it becomes medically important in the future. Donor insemination has been extended to single women and lesbian couples in many centers.
Techniques have evolved to concentrate and wash the spermatozoa from the ejaculate so that they can be safely inserted directly into the uterus. Intrauterine insemination (IUI) commonly is combined with the induction of ovulation with gonadotropins, which allows precise timing of the insemination and the development of several egg-containing follicles. This increase in the number of ovulations improves the success rate. Gonadotropin superovulation combined with intrauterine insemination has proved useful in the management of male infertility as well as unexplained infertility. It has also contributed significantly to an epidemic of multiple pregnancies that are associated with increased prematurity and newborn morbidity. Although the incidence of high multiple pregnancies can be reduced by careful clinical management, it cannot be eliminated completely. For this reason, the approach is gradually being replaced by in vitro fertilization procedures in which the number of embryos transferred into the uterus is more easily controlled.
In Vitro Fertilization/Embryo Transfer
Normal reproduction requires a properly functioning fallopian tube. The fallopian tube captures the egg from the ovulating ovarian follicle, transports it to a point well within its lumen for fertilization, and retains and nurtures the newly dividing embryo for three days, after which, at the eight- to 16-cell stage, it is delivered into the uterus. After approximately three additional days the embryo attaches to the uterine lining (endometrium) in the process of implantation.
Much of the early information on fertilization was derived from observations in marine forms, mainly the sea urchin. The first mammalian in vitro fertilization was carried out in the rabbit in 1952 by M. C. Chang, but it was not until 1980 that Robert Edwards and Patrick Steptoe reported the first successful pregnancy after the in vitro fertilization (IVF) of human eggs. Until their experiment there was reluctance to transfer in vitro fertilized human embryos back into the uterus out of concern that they were abnormal. There is now firm evidence that there is no increased risk of congenital or genetic abnormalities in children born after IVF and embryo transfer.
Multiple ovulations are induced with gonadotropins, follicle-stimulating hormone (FSH) to produce larger number of follicles, and human chorionic gonadotropin (hCG) or luteinizing hormone (LH) to finalize the development of the follicle and egg. The eggs are easily recovered by means of a transvaginal ultrasound probe to facilitate direct aspiration from the mature follicles. Spermatozoa that have been appropriately conditioned are then added to the culture system containing the eggs, initiating the fertilization process.
Within 24 hours, a spermatozoon has penetrated the egg and its nucleus has formed a pronucleus. The nucleus of the egg also forms a pronucleus. The two pronuclei then join, completing the initial phases of fertilization. Within hours there is a first cell division, followed by other cell divisions. Usually on the third day after fertilization embryos are selected for transfer into the uterus. The transfer is carried out with a fine, flexible catheter placed into the uterine cavity transcervically. In the early phases of the development of IVF, it was common to transfer multiple embryos in the hope that at least one would implant. As the quality of the cultured embryos has improved, multiple embryo transfer with its attendant complication of multiple pregnancies has become unnecessary. In some countries the number of embryos transferred is regulated to no more than two, and this is now standard practice in many U.S. centers.
Initially IVF was used solely in patients with damaged, nonfunctioning fallopian tubes. As it became clear that fertilization could be enhanced by using in vitro techniques, IVF became clinically applicable for couples with impaired sperm number or motility. As laboratory and clinical methods have evolved, additional techniques for managing fertilization have been developed that enhance male fertilization potential.
IVF and Male Fertility Potential
In 1992 Gianpierro Palermo, A. Van Steirteghem, and colleagues reported pregnancies after the mechanical injection of sperm directly into the cytoplasm of the egg. This procedure–intracytoplasmic sperm injection (ICSI)–has been applied to clinical situations in which there are a limited number of spermatozoa or in which the spermatozoa are functionally impaired. The egg is held firmly in place under the microscope. A single spermatozoon is aspirated into a fine catheter, and the catheter is inserted directly through the zona pellucida, the protein egg coat, past the egg membrane and into the cytoplasm, where it is released. Thus, the necessity for the spermatozoon to traverse these barriers by normal mechanisms is eliminated. Groups with the most experience with ICSI have reported a slightly increased incidence of genetic abnormalities.
Men with congenital absence of the vas deferens, which transports spermatozoa from the testes, fail to release sperm in the ejaculate. In these cases the epididymis, the storage reservoir of spermatozoa proximal to the vas, contains spermatozoa. These spermatozoa can be aspirated for in vitro fertilization through the use of ICSI. Spermatozoa have also been recovered directly from the testes and used successfully for ICSI. Men with congenital absence of the vas have been shown to be carriers of the cystic fibrosis gene. Pregnancies that might not have been possible otherwise can be produced with ICSI, and although the incidence of abnormalities is increased over that of the general population, the increase is small. Fortunately, when the embryo that is transferred is abnormal, it is destined not to proceed through pregnancy. Generally, grossly abnormal embryos fail to implant or do not develop normally, aborting early in the pregnancy. To address these issues further, techniques for genetic evaluation of the embryo have been developed.
Preimplantation Genetic Diagnosis
As laboratory techniques for in vitro culture of embryos have been refined, systems have been developed to analyze the genetic characteristics of a single cell for preimplantation genetic diagnosis (PGD). PGD involves the removal of a cell from a dividing embryo by micromanipulation for genetic analysis, using probes to identify and assess the normality of individual chromosomes. Only embryos that are deemed genetically normal are transferred into the uterus, and the remainder are discarded. These techniques are particularly useful in couples who are carriers for certain genetic diseases, such as Tay-Sachs disease. This approach is also useful clinically in women over age 35, who are at a greater risk for having a baby with Down's syndrome. Transferring only normal embryos could result in an increased pregnancy rate after in vitro fertilization. The downside is that because the technique involves the removal of a cell from the embryo, there is the possibility that the embryo will be injured, impairing further development. PGD allows the determination of the sex of the embryo, and some have suggested that it be used for prenatal sex selection. This would be clinically applicable in cases in which there is a sex-linked genetic defect that would be present only in an embryo of a given sex (e.g., hemophilia).
The techniques of IVF result in the recovery of numerous oocytes that are then available for fertilization. In contrast to semen, which is readily frozen and stored, techniques for freezing eggs have encountered difficulties. The freezing and storage of embryos, however, is technically feasible and practical. Embryo freezing is most successful when it is carried out at the pronuclear stage shortly after the development of the male and female pronuclei. Freezing of embryos that are not transferred in the treatment cycle allows the opportunity for additional pregnancies without another cycle of stimulation and ovum recovery.
Although offering a significant advantage in terms of the pregnancy rate per couple, the eventual use or disposal of freeze-stored embryos is a matter for careful consideration. In its guidelines, the Ethics Committee of the American Society for Reproductive Medicine strongly recommends that the decision on freezing and eventual disposition of unused embryos be made in advance, after a thorough consultation with both partners. The couple may elect to allow their stored embryos to be used for research. A preliminary decision is also made in advance about the disposition of the frozen embryos in the event of a divorce or the death of one partner. From time to time legal issues arise in this regard that must be resolved in court.
Research utilizing human embryos is controversial. Policies vary from one country to the next. In the United Kingdom research is deemed permissible up to the fourteenth day of development but not beyond that time. This matter is receiving increasing attention as methods are developed to identify and culture embryonal stem cells to provide future treatment options for a number of diseases.
The use of an egg donated by another woman is the female counterpart to the use of donor semen for male infertility. The differences, however, are significant. Although small, there are risks associated with the procedures employed to recover the ova. The ovaries can overrespond to the gonadotropin hormones, causing hyperstimulation, a serious medical condition. Rare deaths have been reported from hyperstimulation because of coagulation problems and pulmonary emboli. Infection after ovum recovery, although rare, has been reported.
Ovum donors usually are recruited from among young women, often college or graduate students. Some programs allow a differential in the payment scale when a woman undergoing IVF is willing to release some of her recovered oocytes for the use of an infertile woman who is unable to produce eggs. Obviously, the ethical and social issues surrounding ovum donation are far more complicated than is the case for semen donation. The Ethics Committee of the American Society for Reproductive Medicine has established guidelines for the compensation of ovum donors and has suggested that a woman be paid reasonably for her time and effort.
Recipients of donated eggs are usually women who are unable to produce their own eggs. Ovum donation has been used in postmenopausal women who wish to extend their reproductive life span. Extreme examples include pregnancies in women over age 60, which have been reported in at least three countries. The risk to the mother in those circumstances is not insignificant, and the social and ethical issues surrounding such treatment require careful consideration. Donated embryos genetically unrelated to the couple have also been used.
The development of reproductive technologies has occurred at a breathtaking rate. The net result has been increased opportunity for reproductive choice. These techniques have provided an increased likelihood of pregnancy among women in their late reproductive years. They have allowed men with subfertility or even complete absence of spermatozoa in their ejaculate to establish a pregnancy by using their own genetic material. Concomitant with these dramatic developments has been an increasing concern over ethical issues, and societal norms have been strained. As basic mechanisms of reproductive functions are analyzed and demystified, there will be continued clinical and laboratory innovation not only in the management of infertility but in the development of systems to prevent pregnancy as well.
Dohle, G. R., D. J. Halley, J. O. Van Hemel, A. M. van Den Ouwel, M. H. Pieters, R. F. Weber, and L. C. Govaerts. 2002. "Genetic Risk Factors in Infertile Men with Severe Oligozoospermia and Azoospermia." Human Reproduction 17: 13–26.
Ethics Committee of the American Society for Reproductive Medicine. 2000. "Financial Incentives in Recruitment of Oocyte Donors." Fertility and Sterility 74: 216–220.
Guzick, D. S., S. A. Carson, C. Coutifaris, J. W. Overstreet, P. Factor-Litvak, M. P. Steinkampf, J. A. Hill, L. Mastroianni, J. E. Buster, S. T. Nakajima, D. L. Vogel, and R. E. Canfield. 1999. "Efficacy of Superovulation and Intrauterine Insemination in the Treatment of Infertility." New England Journal of Medicine 340: 177–183.
Patrizio P., and L. G. Leonard. 2000. "Mutations of the Cystic Fibrosis Gene and Congenital Absence of the Vas Deferens." In The Genetics of Male Infertility: Results and Problems in Cell Differentiation, ed. K. McElreavy. Berlin and Heidelberg: Springer-Verlag.
Luigi Mastroianni, Jr.
Reproductive technologies–the manipulation and exchange of gametes (i.e., sperm and ova) and human embryos–were developed to overcome the natural infertility that frustrates individuals' intentions to parent children. The development and application of these technologies raised heated ethical debates at the turn of the twenty-first century. Some condemn these technologies as "unnatural," although many other applications of medical science intended to overcome natural failures in health, such as organ failure or susceptibility to infection, are not ethically condemned.
Ethicists do not agree on the moral status that human embryos deserve. Those who consider them to have high intrinsic worth, as actual or potential human beings, oppose the deliberate wastage of embryos that accompanies the development and application of reproductive technologies. Those who accord embryos respect, but at a lower level than born people or fetuses, assert that embryos may be employed, and their wastage may be responsibly planned, in efforts to assist reproduction. The ethical expectation of tolerance of plurality–that is, the acceptance of different ethical approaches–requires that individuals not be compelled to act against their conscience, and that they not be barred from acting as their conscientious convictions allow, unless there is demonstrable evidence that their actions cause pain to others. Scientists widely accept, for instance, that embryos may ethically be used and be let perish in reproductive research up to fourteen days from their creation, when the "primitive streak," the origin of the brain, appears.
Reproductive technologies include drug treatments to assist fertility and natural conception. Hormonal stimulation of women's ovulation raises ethical concerns because it may result in hyperstimulation and the natural conception of a high number of embryos in the same reproductive cycle. Pregnancies of four or more fetuses usually jeopardize the health of the mother, and endanger the survival of their fetuses or born children, due, for instance, to low birth weight. Triplet and even twin pregnancies can also present risks. One medical response to high multiple pregnancies is to use techniques that reduce the number of embryos or fetuses growing in utero; these techniques raise ethical concerns related to abortion.
People who adhere to religious convictions approach reproductive technologies differently. Some raise few ethical objections, seeing the procedures as expressions of divinely inspired human resourcefulness and proper human collaboration in creation. However, there is considerable religious condemnation of the prospect of human reproduction by cloning. Cloning is the production, by non-sexual means, of a genetically identical cellular structure (a "twin") such as an embryo, from a pre-existing structure. The religious objection to it is that induced human cloning is unnatural, and a human assumption of divine authority to create human life. The Roman Catholic tradition is very conservative regarding almost all reproductive technologies and rejects any procedure perceived as unnatural. Roman Catholic ethics may allow transfer of ova into a woman's reproductive system for natural fertilization there by her husband. The Islamic tradition rejects all gamete and embryo transfer, because of the strong emphasis on the integrity of genetic lineage, but accepts many technologies that equip women to bear their husbands' children. As a secular, pluralistic approach to human behavior, the observance of ethics requires tolerance of diverse opinions about the many forms of consensual reproduction.
Gamete and Embryo Donation and Use
Ethical respect for individuals' self-determination or autonomy requires that gamete and embryo donors give their informed consent. Donors may be required to remain anonymous to recipients, since personal contact may raise concerns about payments, unethical commerce, and treating reproductive materials as marketable commodities. Similar concerns arise when clinics purchase gametes and embryos and pass costs on to recipients the donors do not know. When couples have surplus embryos or gametes from their own in vitro fertilization (IVF) treatment, they may donate an embryo or gamete to another couple. If IVF clinics refuse to accept applicants if they will not agree to donate surplus gametes or embryos, they raise issues around the patient-donors' freedom of choice, and clinic operators' conflict of interest. If treatment is unsuccessful, childless donors may face the knowledge that strangers may bear and rear their children when they cannot. If a couple ends IVF treatment because they have separated, one may veto the other's consent to embryo donation. Patients are always ethically entitled to withdraw consent that has been elicited by excessive pressure.
Use of gametes and embryos, by couples themselves or by the recipients of donation, depends on these materials satisfying genetic and other criteria. Ethicists disagree over precisely which characteristics make gametes and embryos unsuitable for use. Gross genetic abnormality, determined by pre-implantation genetic diagnosis (PGD), will clearly negate use, as will racial incompatibility with possible recipients. Mild genetic abnormalities, such as to genetically-inherited but manageable disabilities, may not be an ethical basis of rejection, and some legal systems and ethics codes prohibit decision making on the sole basis of an embryo's sex. Ethical advantages of PGD are that it reduces the incidence of elective abortion due to negatively perceived embryonic or fetal characteristics, and may provide support for initiating pregnancies women would otherwise decline.
Eligibility for Assisted-Reproduction Services
The characteristics that make couples and individuals ineligible to receive technological assistance to become parents are often ethically contentious, since they may reflect negative stereotypes of poor parents that lack evidence, and may violate principles of nondiscrimination. Social justice is denied when low family income excludes couples from access to high-cost assisted reproduction. Couples may also be ineligible for reproductive assistance when one parent has a disability. Denial of assistance to applicants with physical disabilities may be unethical even when disabling conditions may be genetically transmitted, and raises issues of negative eugenics concerning whether conditions such as congenital deafness and short stature truly are disabilities. Negative eugenics is the practice of restricting people considered unfit to transmit their genetic characteristics from having children, which became discredited by association with coercive Nazi practices. Mental impairment may more easily justify ethical denial of assistance, on the grounds that prospective children's interests would be violated, but this claim also requires demonstrated evidence. Ethicists assert that applicants' unmarried status and partnership in same-sex relationships are decreasingly defensible ethical grounds to deny technologically assisted reproductive services, since evidence shows that children brought up in homes of such parents are not significantly different from children reared in more conventional homes.
Since advanced paternal age is not a natural barrier to parenthood, ethicists sometimes question whether age should be a bar to assisted reproduction. Post-menopausal pregnancy is often opposed on grounds that aging mothers are a disadvantage to children, although many children are successfully raised by grandparents. Assisted reproduction in cases of premature menopause raises fewer ethical objections. There is also an ethical debate around assisting widows to conceive children by their deceased husbands, since some consider recovery of sperm while the men are unconscious, dying, or deceased without their clearly given prior consent ethically objectionable.
A surrogate mother is a woman who agrees in advance to gestate a child or children for surrender upon birth to others who requested this service. Such women provide authentic prenatal mothering, whether they are also genetic mothers or receive embryos created by IVF from other women's ova. Ethical concerns around surrogate motherhood include how women are engaged for this role, and whether their consent is adequately informed, freely given, and not unduly induced. Both commercial recruitment and pressuring family members or friends to render unpaid services raise ethical concerns.
If the experience of human life is considered inherently beneficial, it may be ethically unobjectionable to create a new human life. Some may claim, however, that inappropriate reproductive assistance causes births that violate the interests of particular families, communities, or societies. Human reproductive cloning may ethically be opposed, for instance, with the argument that its safety has not yet been established in animal studies. Objection relies on political or macro-ethical claims, however, which address community-wide interests, rather than micro-ethics, meaning the ethics of individual physician–patient relationships, since within those relationships patients may ethically be assisted to bear children at known risk of adverse health consequences.
Communities are increasingly recognizing the ethical entitlement of children born of gamete and embryo donation to know about their genetic origins. The anticipated growth of genetically based diagnosis, prognosis, and treatment is likely to reinforce claims to this knowledge, particularly as therapeutic drugs begin to be designed to fit the particular features of patients' genetic inheritance. Ethicists differ on how much children should be entitled to learn. At one end of the spectrum are those who argue that information of children's biological parents' genetic deficits and predispositions to illness should be available, so that children may benefit from accessible treatments and be able to avoid diets, lifestyles and, for instance, environments that trigger inherited predispositions to illness. At the other extreme are those who claim that, notwithstanding confidentiality, children have a right to know the personal identities, circumstances and family background of those whose genes they have inherited, and the right to meet them if the children wish and practically can. The ethical basis of this claim is that individuals should not become parents unless they are willing to be responsible to their children. However, social parenthood, meaning accepting continuing responsibility for the welfare and rearing of children, is now distinguishable from medically assisted biological parenthood. Children conceived in casual, perhaps single-instance sexual encounters may not have enforceable claims to know who their fathers are, and it is not ethically established that children of artificial, planned conception have superior rights to those born of natural, unplanned conception.
Department of Health and Social Security (U.K.). 1984. Report of the Warnock Committee of Inquiry into Human Fertilisation and Embryology. London: Her Majesty's Stationery Office, Cmnd. 9314.
Golombok, Susan, R. Cook, A. Bish, and C. Murray. 1995. "Families Created by the New Reproductive Technologies: Quality of Parenting and Social and Emotional Development of the Children." Child Development 66: 285–298.
Harris, John, and Soren Holm, eds. 1998. The Future of Human Reproduction. Oxford: Clarendon Press.
Royal Commission on New Reproductive Technologies. 1993. Final Report: Proceed With Care. Ottawa: Minister of Government Services, Canada.
Serour, Gamal, and Bernard Dickens. "Assisted Reproduction Developments in the Islamic World." International Journal of Gynecology and Obstetrics 74: 187–193.
Bernard M. Dickens