Introduction


It is impossible to discuss the topic of stem cell research without considering the singular contribution of women, as one of the most vital ingredients in this technology is the egg or oocyte from the woman. As well, issues raised by embryonic stem cell research highlight concerns that are profound, divisive, and troubling.

In this supplement, we present issues concerning informed consent, medical and psychological risks, compensation for donors, and other ethical concerns related to egg donation both for assisted reproduction purposes and for stem cell research.

One critical question relevant to both assisted reproduction technologies such as in vitro fertilization (IVF) and for somatic cell nuclear transfer (SCNT) is who is providing the human oocytes (see Module 4) .















What do we know about egg donation?


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In the US, oocyte or egg donation has a relatively short history. Egg donation was transformed into a commercial market after 1978 when IVF was proven to be successful in producing the first test tube baby, and in 1990, when it became acceptable to use donated eggs to treat age-related infertility. Today, infertile women, even those over age 40, who are both physically able to bear a child and financially capable of spending large sums of money for egg donors have led to a surge in demand that has yet to abate.



The competition for “attractive and desirable eggs” with a good “pedigree” has set off a bidding war for donors. We currently find sophisticated ads for egg donors in fashionable magazines and in newspapers, especially those at leading colleges and universities. Women whose eggs have been used previously to produce children via IVF are even in greater demand and are paid even higher fees.


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The ad to the right was posted on bulletin boards at Columbia University’s campus. For women struggling with the high cost of tuition, the money offered as compensation could be a significant financial help and thus could be an inducement to go through the intense ovarian stimulation process and the procedure to obtain the oocytes.



While helping others to achieve their dream of having a child can be deeply gratifying, and even a life-altering experience, the ads for egg donors focus heavily on the large sums of money that the donors will receive. This inevitably creates a strong financial incentive for women who might not be otherwise inclined to donate, and who might not fully weigh the risks involved (see risks described below). Some other countries, for example, Canada, Israel, United Kingdom, and Belgium do not allow paid egg donation on the grounds that “a non-patient should not be converted into a patient for monetary gain” (Schneider 2008).


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Is it morally correct to seek human eggs for science?


Starting in 1997, when the world learned about the power of somatic cell nuclear transfer (SCNT) technology (Wilmut, Schnieke et al. 1997), a need arose to obtain ova (eggs) and, hence, to find ways to encourage healthy young women to donate their eggs for science.

Eggs do not have to be obtained from paid donors. Many of the eggs used in SCNT experiments are left over from IVF procedures, that is, they are eggs in excess of clinical need. But a major challenge facing stem cell researchers is the procurement of eggs from “non-medical” donors, that is, from those women who are dedicating their eggs for purposes that are neither medical nor reproductive, i.e., they are donating for science.

Donating eggs is not a benign medical procedure. Women must be given ovulation-stimulation hormones. These hormones are associated with short-term risks including Ovarian Hyperstimulation Syndrome (OHSS). There also are acute dangers from anesthesia, infection, and bleeding; some medical complications could endanger a young woman’s future fertility (Norsigian 2005; Schneider 2008). In addition, there are potential longer-term risks of ovarian or other cancers. Yet, not allowing women to donate eggs would be inappropriately controlling and would breach the bioethical principle of autonomy and self-determination.

Especially given the risk, complete information should be provided to the prospective donors during the informed consent process. This information should be understandable and thorough in order to ensure that the potential donors are fully aware of the risks and benefits of the donation procedure.
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The five basic steps of in vitro fertilization (IVF)


The National Institutes of Health (NIH) web site (The National Library of Medicine (NLM) - Medline Plus) summarizes essential steps of IVF that are adapted here.

Step 1: Stimulation, also called super ovulation
Would-be donors are screened extensively for known risk factors – medical, psychological, and genetic – before they might be accepted as donors.

Medications are given to the selected woman to boost her egg production. Normally, a woman produces one egg per month. Fertility drugs stimulate the ovaries to produce anywhere from 10-20 eggs. During this step, the woman will have regular transvaginal ultrasounds to examine the status of the ovaries and blood tests to check hormone levels.

Step 2: Egg retrieval
When it is judged that the eggs are ready for retrieval, a minor surgery, called follicular aspiration, is performed to remove the eggs from the woman’s ovaries. Follicular aspiration is normally performed as an outpatient procedure in the doctor’s office. The woman is given anesthesia so she does not feel pain during the procedure. Using ultrasound images as a guide, the health care professional inserts a thin needle through the vagina and into the ovary and sacs (follicles) containing the eggs. The needle is connected to a suction device, which gently pulls the eggs and fluid out of each follicle, one at a time. This procedure is then repeated for the other ovary. The woman may have some cramping after the surgery, but it usually goes away within a day. In rare cases, a pelvic laparoscopy may be needed to remove the eggs.

Note: If the process is only to harvest eggs for donation, the procedure ends here.


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Figure 3: Procuring Oocytes from the Ovary

Step 3: Insemination and Fertilization
The quality of the retrieved eggs is evaluated according to several key morphological criteria; eggs with chromosomal abnormalities, for example, are not used in IVF and are set aside (some may be used later for non-reproductive research purposes). To create an embryo, the man’s sperm is placed together with the best quality eggs in an environmentally controlled chamber. The mixing of the sperm and egg is called insemination. The sperm usually enters (fertilizes) an egg a few hours after insemination. If the doctor thinks the chance of fertilization is poor, the laboratory staff may inject the sperm directly into the egg. This is called intracytoplasmic sperm injection (ICSI). Many fertility programs routinely do ICSI on some of the eggs even if everything appears normal.

Step 4: Embryo culture
As the fertilized egg divides, it becomes an embryo. Laboratory staff will regularly check the embryo to make sure it is dividing properly and retains good morphology.

Pre-implantation Genetic Diagnosis

If there is a high risk of passing a genetic (hereditary) disorder to a child, pre-implantation genetic diagnosis (PGD) may be performed. The procedure is done about 3-4 days after fertilization when the embryo is composed of eight cells. Laboratory scientists remove a single cell from each embryo and screen the genetic material from the retrieved cell for specific genetic disorders. Amazingly, removing one of these cells does not impair embryo development.


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According to the American Society for Reproductive Medicine, PGD can help parents decide which embryos to implant that decrease the chance of passing on a genetic disorder (e.g., cystic fibrosis, Huntington’s disease) to a child. The technique is ethically controversial as some embryos will be discarded and is not offered at all fertility centers.

If the purpose is to obtain stem cells, the early embryo is placed in a Petri dish and allowed to develop until reaching the blastocyst stage at day 5/6. At that point stem cells are harvested from the inner cell mass of the blastocyst.


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Blastocysts: Closed and Open (Images courtesy Wellcome Library)



Step 5: Embryo transfer if pregnancy is the goal
Embryos that have been developing in the Petri dish are placed into the woman’s uterus 3 - 5 days after egg retrieval and fertilization. The procedure is done in the doctor’s office while the woman is awake. The doctor inserts a thin tube (catheter) containing usually one or two embryos into the woman’s vagina, through the cervix, and up into the uterus. If an embryo sticks to (implants) in the lining of the uterus and grows, pregnancy results.

In the early stages of IVF, when a successful pregnancy was less likely, several pre-embryos were transferred into the woman leading to triplets, quadruplets, or more. Deciding on the exact number of embryos transferred is a complex issue that depends on many factors.
In current practice usually two embryos are implanted. If the woman is older, the number may be increased to improve the likelihood of a successful pregnancy. Unused embryos may be frozen and donated or implanted at a later date.

In contrast to what happens in the course of in vitro fertilization, Figure 4 below illustrates what happens in a natural pregnancy. Immediately after fertilization takes place in the distal (end) of one of the fallopian tubes, the zygote travels toward the uterus where it will implant.

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From Zygote to Blastula

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Risks of egg donation


Egg donation requires a significant physical, emotional, financial, as well as time commitment. Stress and depression are common, as are a range of mild to serious, short- to longer-term symptoms and reactions.

Table 1. Medical and psychological risks of oocyte (egg) donation, as a function of the stage of the donation process

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References for Table 1: nih.gov Updated: 2/10/2010. Accessed February 24, 2011; Institute of Medicine, 2007; (Girolami, Scandellari et al. 2007; Kramer, Schneider et al. 2009; Zivi, Simon et al. 2010)

Expand your knowledge in bioethics


The source of stem cells influences their therapeutic potential, with stem cells derived from early-stage embryos remaining the most versatile. Somatic cell nuclear transfer (SCNT) requires women to donate eggs, which involves injection of ovulation-inducing hormones and egg retrieval through laparoscopy or transvaginal needle aspiration. The following review and responses examines risk of OHSS resulting from oocyte donation. See Vol 11 Issue 9 of the American Journal of Bioethics and the subsequent open peer commentaries to read opposing views on the ethics of this procedure.

The case of Jessica Wing: Fatal colon cancer in a young egg donor


Jessica Wing, a healthy, fit young woman, underwent three egg retrieval cycles in her early-mid twenties. At the age of 29, she inexplicably developed metastatic colon cancer. She died two years later. DNA testing of her tissue later revealed no genetic predisposition to colon cancer. Her mother, Jennifer Schneider, MD, PhD, published her daughter’s case; she believes that Jessica’s egg donation cycles and her colon cancer may be related (Schneider 2008). A similar case was reported in England (Ahuja and Simons 1998).

Dr. Schneider investigated informed consent procedures and medical follow-up for egg donors. She discovered that women are not fully informed of the potential for most risks, including longer-term risks, considerably because risk data were then, and still are, minimal. Yet many medical experts continue to believe that long term risks exist, particularly of cancer, and would likely be proven if donors were followed systematically for a long enough period of time (Althuis, Moghissi et al. 2005; Pearson 2006; Schneider 2008). As of now, there is no universal donor registry, therefore no pooled, detailed information about donor status pre- and post-procedure, and no long-term follow-up of the health status of egg donors.

Importantly, in appearances before congressional committees, Dr. Schneider strongly advocated for more comprehensive informed consent, mandated donor registries, and long-term donor health follow up, ideas the Institute of Medicine and National Research Council of the National Academy also support in principle. She further suggested that the CDC expand its currently insufficient donor documentation efforts, and undertake universal donor registration and follow-up:

See the CDC's National Action Plan for the Prevention, Detection, and Management of Infertility.

Dr. Schneider, who approves of IVF and egg donation, also believes warnings about risks should appear as part of the informed consent process as well as the ads for oocyte donors. Commercial profits of the fertility industry should be tapped to help fund the registries and increased surveillance. Finally, surplus eggs should be shared efficiently by consenting donors and patients to offset any reduction in donated eggs that might follow from more accurate informed consent.

Source: Schneider 2008


Creating registries of women who have donated their eggs will not be accomplished easily. Fertility clinics have a conflict of interest. They have neither the money to follow donors for years nor the motivation to find out the results of possible medical problems that might discourage egg donation. In addition, many women would resist being added to a registry that would entail periodic long-term (10-15 years) follow-up calls or letters. Because of the expense of carrying out a comprehensive survey, this is something the government would have to undertake.

Assisted reproductive clincs


In 2008, there were approximately 470 IVF clinics in the United States. And as of 2008, the Society for Assisted Reproductive Technology (SART) lists 400 of these ART clinics as members. It is likely 100% of them advertise. Given published data on number of cycles of egg donation (see Schneider 2008), approximately 100,000 young American women have donated or sold their eggs to fertility clinics, as of about 2008. Few would have received enough information for them to make an informed decision. Most would not have understood that there is a huge difference between being told, “We don't know of any significant long-term risks” and “There are no significant long-term risks.”

Source: Schneider 2008

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Should donors be compensated for their eggs to be used for research purposes?


Stem cell research leaders in California and Massachusetts, in order to avoid potential coercion, made the decision that egg donors for research would NOT be compensated. As a consequence, no women volunteered to become egg donors for research. The process and procedures are too extensive and time consuming and include risks and discomforts that preclude that volunteers would do this for purely altruistic reasons according to most women.

New York State decides to pay women to donate eggs for research

The New York State Stem Cell Initiative Ethics Committee, noting the experience of California and Massachusetts, voted to allow egg donors for research to be compensated at the same rate as for fertility donation. Thus, as of June 2009, the Empire State Stem Cell Board of New York State decided that it would be permissible for researchers to spend up to $10,000 in public funds to compensate each woman willing to donate her eggs for embryonic stem cell research. This was believed to be the first time a US state allowed state research money to be used for this purpose. Women donating eggs for fertility procedures routinely are paid comparable amounts, and often much more. Without compensation for the time and effort involved, women almost never voluntarily donate their eggs. An egg shortage has an inhibiting effect on stem cell research. The Empire State Stem Cell Board’s ethics and finance committees voted to approve compensation, but some bioethicists or individuals opposed to embryonic stem cell research remain concerned that this compensation will commodify the human body, and potentially be exploitative of women, particularly those in financial need. The concern remains that many women are not made fully aware of the potential risks of egg donation.

Researchers point out that some scientific questions can only be answered using human eggs. Given egg shortages, sometimes they will try to use poor-quality eggs discarded after in vitro fertilization; this has yielded some results, but no stem cells, as of June 2009. Many scientists are in favor of compensating women donors for research donation, but some institutions prohibit this payment (e.g., in New York City: Rockefeller University, Cornell University, and the Sloan-Kettering Institute).

States that permit women to be paid for egg donation for research it is believed will lead in stem cell science, a strong scientific and economic incentive.

Source: "New York State Allows Payment for Egg Donations for Research" (The New York Times, June 26, 2009).

It is likely that commercial stem cell facilities may in the future have funds to compensate non-reproductive egg donors, but most universities and scientific labs are not likely to offer compensation. In all cases, payment should be relatively modest to avoid coercion. Compensation should be based on the number of hours involved, which some estimate to be about one hundred hours, at $40 per hour, totaling approximately $4,000.

Thought question


What is your opinion about compensation? Do you favor the decision of California and Massachusetts or New York State? What reasons can you give to support your opinion? Expand your Bioethical Knowledge on compensation - download The American Journal of Bioethics "Contractual Duties in Research, Surrogacy, and Stem Cell Donation".

The American Society for Reproductive Medicine (2000) has concluded that financial compensation for egg donors for reproductive purposes is ethically appropriate and should be based on time, inconvenience, as well as the physical and emotional demands of the donation process. While there is no consensus on the precise payment donors should receive, payments above $10,000 are considered inappropriate. In practice, this guidance is hardly observed; genetically desirable and “proven” donors (those whose eggs have resulted in successful pregnancies) are often recruited independently and paid far more.

While we use the term egg “donation,” a more appropriate term might be egg “market.” Unlike many other countries, the US has chosen a laissez faire approach to egg donation, allowing market forces to rule – whatever the market will bear. While there may be guidelines, there are no regulations. The costs associated with egg donation have also risen partly as a result of profit-taking.

This commercialization of egg donation has created an environment in which exploitation has become acceptable. Even with the guidelines that have been suggested, policing is non-existent and sanctions have never been levied against violators (Sauer 2001).
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What issues are of particular concern regarding egg donation?


Issues of concern with egg donation range from minor to profound including the number of discomforts as well as physical and psychological risks associated with the donation process. The specific concerns range from common and minor to the risk of death, which fortunately is rare but still must be considered.

We now must ask, does the current standard informed consent procedure for egg donors really make these prospective donors fully aware of the potential medical risks they face from hormones and surgeries? If not, what should be done to improve the consent process?

Inadequacies of informed consent


The Informed Consent process regarding IVF and egg donation, as stated repeatedly, often is inadequate. It emphasizes the benefits of egg donation and underestimates and under-informs about the discomforts and serious risks involved.

Pre-screening of potential donors is very extensive – to prevent the participation of medically or psychologically vulnerable women, but also to prevent donation by women who might pass along genetically-linked diseases. As noted above, there are very real risks to women donors that include adverse reactions to the fertility drugs used in the procedure; adverse events related to the surgical extraction of the eggs, such as perforation of the ovary or adjacent tissues; adverse sequelae of the retrieval procedure, such as infection from the surgery, or possibly even sterility, although this would be a very rare complication.

As mentioned above, more research must be undertaken to identify potential long-term consequences of the drugs used in egg donor procurement as there have been neither follow-up of donors, nor epidemiological surveys (Norsigian 2005; Schneider 2008). Cancer risk is one issue that requires further analysis (Schneider 2008).

It is possible that there is a difference in women who undergo ovarian stimulation only to harvest eggs for research purposes as compared to women who have embryos implanted in their uteri and go on to have a full term pregnancy. Not having a pregnancy after ovarian stimulation may increase the risk of adverse events such as cancer, although there are minimal data about this (Schneider 2008).

How often can a woman donate eggs?


The lavish compensation may prompt many young women to donate eggs multiple times, to the limit of what is allowed And the concern is that the more stimulation procedures, the greater the risk. If there is no limit where they donate, their risk may be increased. Given the medical risks, reputable fertility clinics generally limit the total number of cycles in which an egg donor may participate. In South Korea, for example, in the aftermath of the Dr. Hwang, Woo-Suk scandal (see Supplement 3 - The Cloning Scandal of Hwang Woo-Suk) because he coerced his female laboratory staff to be repeat egg donors – medically approved female donors now can donate oocytes only 3 times during their lifetime, and the interval between donations should be longer than 6 months (Jung 2010). Donation and consent practices in the US and internationally do vary widely, despite the efforts of professional medical fertility associations to standardize procedures.
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Other serious ethical concerns


  • Commodification of human life: Of great concern is the commodification of human life --that body parts can be bought and sold – often with significant sums of money changing hands. Should eggs be a marketplace item? Seeing eggs as a commercial product yields to a slippery slope on the way to viewing human beings as more universally harvest-able for tissues in an open marketplace. This is beyond the traditional morally and medically sanctioned purposes such as voluntary and altruistic blood and organ donation.
  • Concepts of identity: Serious concerns also are raised that egg donation can impact personal identity and cause psychological issues. Pre-consent screening of potential donors is intended to prevent medically and psychologically vulnerable women from becoming egg donors. Some who undergo the process, however, may be faced with psychological issues later, particularly if their own health or reproductive potential might be compromised.
  • Women not selected as donors also may face risks to their psychological self-image; follow-up has been suggested for this population (Zweifel, Biaggio et al. 2009).

Thought questions

  • Should women have any rights over the embryos created for reproductive purposes that are now in excess of clinical need and that they now might like to donate for research rather than have the embryos discarded?
  • Would the donors have any rights over the blastocysts created for research if the technology is commercialized?
  • Currently, egg donors have no such rights.


Comparisons between sperm donors, who have been around for decades longer than egg donors, show that women donors bear much greater medical and psychological risks, and, accordingly, are compensated far more. Yet, sperm donors can be compensated very well (see the ad below from a Columbia University publication advertising compensation of $1200/month). And of course, it is much easier for men to donate their gametes, and to donate frequently, with little or no known risk.

Thought questions about sperm donation




(Image Source: Columbia Spectator, Classifieds February 9, 2011)
  • Egg donation is ever more widespread and highly compensated in fertility medicine and science. Sperm donation thus far is not as relevant to stem cell science. How might this reflect on societal roles and contributions of men and women?
  • Men donating sperm are exposed to minimal risk compared to women donating eggs. While men are paid much less per donation, given the very low medical risks and their ability to donate frequently, in one year they can earn a lot of money. Does this disparity raise any gender-based issues?
  • Will couples care, and worry, now and in the future, if the woman partner has been an egg donor? Will there be an equal worry if the male partner has been a sperm donor?

Case Study


“Jennalee Ryan is a San Antonio, Texas, entrepreneur who recognized a market opportunity. If she could persuade a young woman in college to sell her eggs, and get sperm from a man with an advanced degree, and both of them had cute baby pictures, she could hire a fertility lab to make embryos, which she could then sell at $2,500 apiece. Like houses built on speculation, these embryos were created in the hope that buyers would show up. Ms. Ryan is the developer, hiring the subcontractors and marketing the product.

No one has done this with embryos before. Is there anything to worry about? Not according to John Robertson, as quoted in the Washington Post. “I know some people say: ‘This is shocking. Embryos made to order.’ But if you step back a little bit, you realize that people are already choosing sperm and egg donors in separate transactions. Combining them doesn't pose any new major ethical problems.”

Question: Do you agree or disagree - that Ms. Ryan’s proposed enterprise is little different from the IVF and other fertility procedures society now widely accepts?

Source: Murray, Thomas. (2007).Embryo Sales: Been (Nearly) There, Done (Almost) That.


What is the ethical imperative?


As a society, we need to ask “Is it right to seek human eggs for scientific purposes?” There are arguments for and against as surely you can now appreciate.

In a discussion on women’s rights and the status of women, the ethical questions associated with egg donation for stem cell research and somatic cell nuclear transfer loom large. Definitive answers are not available; therefore, we need to be guided by the Ethical Imperative.

In research and medicine, our actions should be guided not by what we can do, but rather what we should do.

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References

  • Ahuja, K. K. and E. G. Simons (1998). "Cancer of the colon in an egg donor: policy repercussions for donor recruitment." Hum Reprod 13(1): 227-231.
  • Althuis, M. D., K. S. Moghissi, et al. (2005). "Uterine cancer after use of clomiphene citrate to induce ovulation." Am J Epidemiol 161(7): 607-615.
  • Girolami, A., R. Scandellari, et al. (2007). "Arterial thrombosis in young women after ovarian stimulation: case report and review of the literature." J Thromb Thrombolysis 24(2): 169-174.
  • Jung, K. W. (2010). "Regulation of human stem cell research in South Korea." Stem Cell Rev 6(3): 340-344.
  • Kramer, W., J. Schneider, et al. (2009). "US oocyte donors: a retrospective study of medical and psychosocial issues." Hum Reprod 24(12): 3144-3149.
  • Norsigian, J. (2005). "Egg donation dangers: additional demand for eggs leads to additional risks." Genewatch 18(5): 6-8, 16.
  • Pearson, H. (2006). "Health effects of egg donation may take decades to emerge." Nature 442(7103): 607-608.
  • Sauer, M. V. (2001). "Egg donor solicitation: problems exist, but do abuses?" Am J Bioeth 1(4): 1-2.
  • Schneider, J. (2008). "Fatal colon cancer in a young egg donor: a physician mother's call for follow-up and research on the long-term risks of ovarian stimulation." Fertil Steril 90(5): 2016 e2011-2015.
  • Society for Assisted Reproductive Technologists. Clinic Summary Report: All SART Member Clinics. 2005.
  • Wilmut, I., A. E. Schnieke, et al. (1997). "Viable offspring derived from fetal and adult mammalian cells." Nature 385(6619): 810-813.
  • Zivi, E., A. Simon, et al. (2010). "Ovarian hyperstimulation syndrome: definition, incidence, and classification." Semin Reprod Med 28(6): 441-447.
  • Zweifel, J. E., B. Biaggio, et al. (2009). "Follow-up assessment of excluded oocyte donor candidates." J Obstet Gynaecol Res 35(2): 320-325.


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