Compensating human subjects providing oocytes for stem cell research: 9-year experience and outcomes

Abstract

Purpose

Human oocytes are arguably one of the most important cell types in humans, yet they are one of the least investigated cells. Because oocytes are limited in number, the use of high-quality oocytes is almost entirely in reproduction. Furthermore, regulatory hurdles for research on gametes and regulations on funding related to research on gametes present significant obstacles to research and the advancement of reproductive treatments. Here we report the outcomes of the largest compensated oocyte donation program for research in the USA to date, and probably worldwide.

Methods

Women who participated in oocyte donation for research between 2008 and 2017 were contacted in a phone interview and completed a standardized questionnaire.

Results

Of 114 participants, 98 oocyte donors completed donation, donating 1787 mature MII oocytes and a total of 86 skin biopsies. Complication rate, including minor complications, of oocyte donation was 8/98, or 8.1%, for which two involved follow-up. Fifty-seven donors answered questions about their experience. Participants were incentivized primarily by money and a desire to help others and reported an overall favorable experience. Most, but not all, human subjects recalled that they had donated for research, and approximately half recalled that their oocytes were being used specifically for stem cell research.

Conclusions

Compensated oocyte donation provides a reliable path to obtaining high-quality oocytes for research and is reviewed favorably by oocyte donors. The continuation of programs that offer compensation for oocyte donation is invaluable to continued progress and advancements in stem cell research and human embryology, and for the advancement of novel reproductive treatments.

Introduction

Oocyte donation for the treatment of infertility is an established part of clinical practice at most centers performing assisted reproduction. In the USA, oocyte donors are routinely compensated for their participation, typically at a rate of between $5000 and $10,000 for each completed cycle. The payment of donors for services rendered has been the standard of practice in the USA since its inception in 1984, but from the beginning, the appropriateness of providing remuneration to participants has been questioned [28].

Oocyte donation for the specific purpose of providing gametes for stem cell research is controversial, and the payment of donors for stem cell research is even more divisive. In 1996, the Congress passed the Dickey-Wicker Amendment, which was signed into law by President Clinton. This act prohibited the use of federal funds for the creation of human embryos for research purposes or for research in which human embryos would be destroyed [6], but the law did not ban the research itself. This amendment was a response to the “Report of the Human Embryo Research Panel” written by the National Institutes of Health (NIH), which provided guidelines regarding the use of embryos for research and stated that “there must be no purchase or sale of gametes or embryos used in research” [24]. During the Bush presidency, further prohibitions were placed on the use of federal funds necessary to develop new stem cell lines as well as subsidies needed to continue studies of most established cell lines. President Obama revoked this ban and allowed the use of federal funds for the study of new stem cell lines from embryos obtained from IVF cycles, as long as informed consent for stem cell derivation was provided. However, this did not include funding for the creation of stem cell lines themselves, or the manipulation of either oocytes or embryos, let alone their generation. Notably, these policies apply only to federal funds and do not dictate guidelines if private underwriting is involved. However, the competition for federal funding at most Universities commands the prioritization of even private funds to projects eligible for NIH funding. Therefore, restrictions on federal funding have effects far beyond the NIH and remain a major impediment to innovation in the area of human reproduction.

Other non-federal agencies have participated in similar discussions. The California Institute for Regenerative Medicine cannot accept for stem cell research remaining oocytes that were donated during a compensated reproductive donor cycle as California law prohibits compensation of egg donors for research [19]. The National Academy of Sciences (NAS) wrote that gamete donors to research should not be compensated except for time and travel expenses [11]. NAS also called for the establishment of Embryonic Stem Cell Research Committees (ESCRO) in order to oversee all issues related to research involving stem cells within individual institutions. The International Society for Stem Cell Research (ISSR), in response to the restrictive position of the NAS, recommended that compensation be determined by individual ESCROs [14], a policy that was adopted by the State of New York [2, 26]. Importantly, the American College of Obstetrics and Gynecology (ACOG) [8] and the American Society for Reproductive Medicine (ASRM) [22] have both endorsed reasonable payment of donors participating in research.

Individuals opposed to compensation cite several reasons for concern. First, they fear that donation involving financial enticements may unduly influence participants who need to also consider the physical and psychological risks associated with donating [10]. Second, they are concerned that oocytes and embryos will be viewed as commodities that may be opening bought and sold within an open mercantile marketplace [9]. Finally, young women of low income may be targeted and exploited for their gametes. On the contrary, supporters of compensation believe that oocyte donors should be provided compensation regardless of the intended use of the gametes, since at the same time, inconvenience and risks are involved [29]. Additionally, in other research areas, volunteers are commonly compensated for their time, effort, and discomfort.

Due to the current stringent guidelines, the majority of stem cell research is being performed with oocytes altruistically obtained from non-paid donors. Oocyte donation requires that participants undergo injectable medication, frequent blood work and ultrasound monitoring, and an oocyte retrieval procedure over the course of approximately 2 weeks. Given the time commitment and invasive nature of procuring oocytes, many women are unwilling to donate without compensation. Several investigators have highlighted the challenge in recruiting donors in this manner, noting that women generally appear unwilling to donate eggs altruistically. A research program at Harvard University attempted to recruit non-compensated oocyte donors for years, but of the 79 women who met enrollment criteria, only one was willing to participate [7]. On reflection, the absence of financial compensation appeared to be the major reason for their unwillingness to participate. In a survey conducted by Columbia University of oocyte donors, only 2% of respondents indicated that they would donate for research purposes without payment [16]. Both of these studies demonstrated that the majority of oocyte donors believe that compensation should be provided regardless of whether or not the resulting oocytes are used for research or assisted reproduction. Furthermore, hesitation to participate in stem cell research project versus providing eggs for reproductive purposes to an infertile woman was not a significant issue.

In 2009, in New York, the Empire State Stem Cell Board was created as an ESCRO according to the guidelines set forth by NAS. The Empire State Stem Cell Board decided to allow reasonable compensation of oocyte donors for research (Board) in accordance with the ACOG and ASRM recommendations. As a result, the Columbia University Medical Center, in conjunction with The New York Stem Cell Foundation Research Institute, recruited over 100 oocyte donors to participate in stem cell research offering equivalent compensation to that paid to donors undergoing conventional fertility treatment. We report our experience over the 9-year experience including participant demographic information, cycle outcomes, participant follow-up experience, and resultant research accomplishments achieved from the oocytes procured.

Materials and methods

This is a retrospective longitudinal review and follow-up survey of all women who participated in the oocyte donor program for stem cell research at Columbia University between October 2008 and April 2017. Oocyte donation for research was approved by the Columbia University IRB and filed under protocol AAAI1347. During that time, women who presented to donate oocytes for reproductive purposes were also alerted to their eligibility to provide gametes for research. There was no specific recruitment effort made to target women to specifically donate for research purposes. Women were offered participation if they met criteria for donation for reproductive purposes and there was no current recipient match, or women who did not meet criteria to donate for reproductive purposes based on genetic carrier screening or pertinent family history of inheritable diseases. Participants underwent standard screening protocols required of all oocyte donors. This included a psychological examination by a mental health care professional, a complete physical exam including gynecologic examination and ovarian reserve testing, and sexually transmitted disease screening including hepatitis B and C, HIV, gonorrhea, chlamydia, and syphilis screening. Once approved for oocyte donation, participants underwent counseling session that included information as to the purpose of oocyte donation for research, what the oocytes would be used for, the risks and benefits of donation, and process of oocyte stimulation, retrieval, and skin biopsy with a physician. After counseling, IRB approved consents were signed. Screening was in accord to the published standards of ASRM [1, 3].

Donors were treated with standard ovarian stimulation protocols utilized for all donors. This included ovarian stimulation with exogenous gonadotropins, trigger of ovulation (primarily with a GnRH agonist trigger, or with an hCG trigger), and subsequent oocyte aspiration under intravenous sedation. Additionally, participants were asked to undergo a 2-mm skin punch biopsy at time of retrieval to harvest fibroblast cells for stem cell generation. Eighty-five participants—all of those who were asked—agreed to do so.

Compensation of $8000 was provided for full participation in this study, which was the identical rate paid for the woman donating oocytes for reproductive purposes. Payment was rendered following aspiration of the oocytes. Subjects who began the protocol, but who did not complete it, were reimbursed $500 for undergoing the screening portion, $2500 for the hormone suppression and egg recruitment portion. The additional $5000 was received for completing the egg collection portion of the study. Supplemental health insurance was provided for all participants to cover any incidental medical expenses related to the procedure.

A total of 114 participants were screened for participation in the donor stem cell program. Demographic data including age, ethnicity, religious affiliation, education level, parity, sexual orientation, and history of prior oocyte donation was reviewed. Most subjects were Caucasian (53.9%), were identified as Christian (69.0%), were nulliparous (92.8%), had not previously donated oocytes (71.7%), and held a college degree or higher (79.5%) (Table 1). There was one participant who underwent two stimulation cycles to donate to research, and 28.3% of participants that had undergone prior oocyte donation to another couple.

Table 1.

Demographics

Age	26 (IQR 24–28)
BMI	22.1 (IQR 20.6–23.8)
Religious identification	Christian 69.0% None 16.7% Agnostic 7.1% Jewish 2.4% Muslim 2.4% Buddhist 1.2% Jehovah’s Witness 1.2%
Ethnicity	Hispanic 33.7% Caucasian 53.9% Asian 5.6% African American 6.8%
Highest education level	High school/GED 8.4% Some college 12.1% College 61.4% Graduate 18.1%
Sexual orientation	Heterosexual 94% Homosexual 3.6% Bisexual 2.4%
Prior oocyte donation	Yes 28.3% No 71.7%

All donors underwent ovarian reserve screening at the time of initial consultation including antral follicle count (AFC), anti-mullerian hormone (AMH) level, and basic physical examination. Cycle outcomes, including days of stimulation, peak estradiol (E2), number of oocytes retrieved, and complication rates, were analyzed.

Phone call survey addressing participant experience was attempted for each woman that completed a cycle through retrieval. The calls were completed using standardized questions as seen in Table 2. Calls were attempted a maximum of three times for each participant, and a call back number was provided.

Table 2.

Survey questions to donors

1. Please rate your overall experience: 1–10 (1 poor, 10 outstanding). 2. Would you consider donating again or recommending program to a friend? 3. Was donating eggs a rewarding experience? 4. Do you have any regrets about donating? 5. Any issue with skin biopsy? 6. What is your understanding of what the eggs retrieved were used for? 7. Reason/incentive for donating. 8. Anything you would change about the experience?

Results

Of the 114 participants, 98 (86.0%) participants completed a cycle through retrieval. The primary reason for cancelation was a poor response to ovarian stimulation as determined by cycle day 6 ultrasound, which occurred in 13/16 canceled events. Additionally, a hyper-response, based on cycle day 6 ultrasound and E2 levels, occurred in 2/16 cycles. These cycles were canceled at the discretion of the physician. Additionally, 1 cycle was not initiated secondary to an enlarged ovarian cyst. Median days of ovarian stimulation was 10 (IQR 10–10.25 days), peak E2 was 2127.5 pg/mL (IQR 1351–3534 pg/mL), and median number of oocytes retrieved was 20 (IQR 15–26). A total of 1787 mature MII oocytes were procured. Additionally, 86 skin biopsies were performed to harvest fibroblast cells. Immature oocytes were not utilized for research, and all donors who completed a cycle through retrieval were included for various research protocols.

The complication rate, including minor complications, was 8.1% (Table 3). Symptoms of mild ovarian hyperstimulation (OHSS), including complaints of bloating, weight gain, and nausea, were the most common noted. A total of 6/98 (6.1%) participants returned to the office for evaluation of OHSS by a physician, which included ultrasound evaluation for free fluid and physical exam. No patients required medical intervention or hospitalization for OHSS. One woman experienced an infected skin biopsy site and required management with antibiotics. There was one participant who was sent to the hospital for evaluation of persistent lower abdominal pain and underwent diagnostic laparoscopy within 48 h of the retrieval with no resultant torsion/injury or pathology noted. Her symptoms resolved spontaneously and the etiology for her complaints remain unclear.

Table 3.

Cycle results

Antral follicle count	20 (IQR 16–22)
AMH	2.65 (IQR 2.0–3.5)
Peak E2	2127 (IQR 1351–3534)
Cycle type	Lupron 9.1 Antagonist 90.9%
Days of stimulation	10 (IQR 10–10.25)
No. oocytes retrieved	20 (IQR 15–26)
Complication rate	Overall 8/98 (8.1%) • 6 mild/mod OHSS, no hospitalizations • 1 entrapped ovary/laparoscopy for rule out torsion • 1 skin biopsy infection

A phone interview and follow-up was attempted for participants that completed a cycle through retrieval using a standardized questionnaire. Survey response rate was 57/98 (58.1%). Most reported they would donate again/recommend the program to a friend 52/57 (91.2%), found the experience rewarding 55/57 (96.5%), and had no regrets about donating 53/57 (93.0%). Women reported that their primary incentive to donate was financial 27/57 (47.4%), for advancement of science 2/57 (3.5%), to help others 15/57 (26.3%), or both for financial reasons and to help others 13/57 (22.8%). Four out of 57 (7.0%) reported a complaint in regard to skin punch biopsy (one infection, three local skin scarring). Interestingly, despite extensive face-to-face time obtaining consents by one of the principal investigators (MVS), most, but not all, human subjects recalled that they had donated for research (50/57; 87.7%); of these, only 23/50 (46.0%) recalled that their oocytes were being used specifically for stem cell research. In overall experience rating (1: worst—10: best), women reported a favorable experience with a median score of 9 (IQR 8–10). The range of response was 1–10; of the three participants that rated their overall experience less than 5, one was canceled due to poor ovarian response, and the remaining two participants required follow-up for minor complications. Suggestions on how to change the experience included more flexible times for injections and monitoring, One participant wanted more information on what was done with the oocytes, and one more information about the skin biopsy.

Discussion

The importance of human oocytes for stem cell research cannot be overstated. At conception, we are endowed with the genome that determines much of our health as adults. The potential for reproductive treatments to improve human health and prevent disease is enormous. For instance, it should be possible to prevent the transmission of mitochondrial disease to the next generation through genome transfer [25] and prevent inherited disease through gene editing [20]. Despite the potential, such research is stifled by numerous obstacles, including laws that impose limitations to research or its funding. The research presented here was performed despite these challenges. Interestingly, while laws restricting stem cell research may in part be motivated by religious concerns, more than 75% of oocyte donors in this study identified with a religion, with 69 percent identifying as Christian. Notably, the mandate to improve human health is a central part of many faiths.

In 2011, Hyun released a position paper arguing for the compensation of egg donors in order to further science, noting the success of stem cell research generated from oocytes procured in this manner [13]. Our paid oocyte donor program for research is the largest currently reported in the USA. Another active research program is currently ongoing in the state of Oregon. Because availability of human oocytes remains a significant rate-limiting factor for research progress, it is critical to promote awareness, as well as emphasize the importance of maintaining these programs.

While the advantage of procuring human oocytes for stem cell research is clear, the ethical implications of utilizing the services of paid oocyte donor remain controversial. An oocyte donor for stem cell research undergoes the same treatment as an oocyte donor in the reproductive setting, but the aim of the donation is to advance medical knowledge rather than to establish a pregnancy. Compensation is provided for the time and effort of donors; however, some are concerned about undue inducement of woman to donate. Undue inducement is a specific threat to autonomous decision-making in that volunteers may become so distracted by a high offer of compensation that they fail to fully comprehend the risks involved in ovarian stimulation and egg aspiration. However, in the USA, men are usually compensated for sperm donations, and research subjects are commonly compensated when they undergo invasive procedures, such as bronchoscopy or endoscopy. We and others believe that it is inconsistent to compensate subjects for undergoing certain invasive procedures but not others or to allow compensation for egg donation for reproductive purposes but not for research [29]. Although undue inducement is a concern related to oocyte donation in general, compensation for women donating to another couple has been accepted in the field of reproduction, and the right of donors to set their own level of reimbursement protected by law [17]. In our program at Columbia University, women underwent the same psychological assessment and thorough counseling prior to being accepted into the program, whether they participated in reproductive donation, or in research. This was done in order to ensure that participants clearly understood the risks of donation and in order to minimize the chance of undue inducement. Additionally, the program remained under the guidance and oversight of both an Internal Review Board and a medical center ethics committee.

Given that the time commitment and risks assumed by research donors are identical to those donating oocytes for reproductive purposes, our program opted to compensate all human subjects the same amount of money as women paid to be egg donors in the fertility program. Congruent to what has been published [7, 16], most women in our program would not donate altruistically and were largely incentivized through compensation for their time. Reviewing the follow-up survey, it was apparent that monetary compensation remained the biggest incentive for donors to participate in the program (70.2%): with 47.4% citing financial reasons alone and additional 22.8% of responders reporting for both financial reasons and to help others.

Follow-up of our research donors’ experience strongly suggests that women had a favorable experience. When asked about recommendations for change, the most common suggestion was offering more flexible times to come in for monitoring/injections.

In a 9-year time period, over 1500 mature MII oocytes were procured and utilized for stem cell research in the Egli research lab at the New York Stem Cell Foundation Research Institute and at Columbia University. Oocytes were allocated to research projects according to their specific needs. The majority of oocytes were used to establish protocols for reprogramming of somatic cell nuclear transfer (270 for [23], and 423 for [34], 73 to [25], 66 to [4], and 175 to [33], and 110 to [27]). Remaining oocytes are part of unpublished projects. Thus far, key advancements have been made using these oocytes in work including patient-specific stem cells by somatic cell nuclear transfer [15, 34], as a method for the replacement of mitochondria in human oocytes [25, 33], in the derivation of haploid human pluripotent stem cells [27], and in the reprogramming of human somatic cells to pluripotent cells from patients with diabetes [23, 34]. Furthermore, fundamental new biology was discovered in human oocytes: the finding that chromosome segregation errors in early preimplantation development are DNA replication dependent and occur independent of transcription [4, 18]. These studies have also led to a conceptual advance in cell biology: that cell cycle progression is tied to cell identity through a cell type-specific DNA replication program [5]. Currently, work including genetic studies in haploid stem cells and continued work with mitochondrial replacement techniques is ongoing using oocytes obtained through this program. It is important to note that the MII oocytes were not fertilized with a sperm to create an embryo capable of producing a live birth. All oocytes were used for the creation of stem cells or parthenogenetic blastocysts.

To our knowledge, this is the largest cohort of paid oocyte donors assembled for research in the USA. Historically, just one program was able to procure a comparable number of oocytes, although this program ceased in the wake of a research misconduct case [30], and nothing is known about the experience of the egg donors. Other research programs involving compensation for oocyte donation are currently ongoing at the Oregon Health and Science University, as well as at Newcastle University in the UK. These programs have made important contributions in the area of mitochondrial replacement [12, 32], and nuclear transfer [21, 31]. A survey of the experience of oocyte donors is not currently available for these programs.

Overall, our donors underwent successful cycles and their efforts have provided significant research material and unique and novel scientific insight. One main limitation of the study was our survey response rate. Unfortunately, we were not able to contact all participants for the follow-up survey. We operate in a large metropolitan area and the population at large is highly mobile and transient in nature. Some of our contact numbers were disconnected or no longer in use, and many women did not answer their phones or never did call back despite repeated efforts to gain their response to the survey. Additionally, of those participants that we were able to contact for the survey, only 46% recalled that they were donating oocytes specifically to stem cell research despite meeting with a physician for counseling and consent forms for participation. Perhaps this is partly due to the prolonged length of time for follow-up from time of participation to survey for many of the participants. An additional limitation of the study is that we do not have data on the total number of times a participant has donated oocytes to other programs, in New York or elsewhere, after participating with us.

Reproducibility of the oocyte donation program is not without challenges; firstly, federal funding cannot currently be utilized for oocyte donation cycles, for compensation of researchers performing the experiments, or for the cell lines derived through this work. Submissions to the National Institutes of Health (NIH) registry of human embryonic stem cell lines eligible for federal funding were not accepted. This decision was regardless whether the dividing egg was developmentally competent and was also applied to parthenogenetic stem cell lines and haploid stem cell lines. The reason why limitations in NIH funding apply to cells that never involved an embryo is because the Dickey-Wicker amendment designates any dividing egg or gamete as an embryo, even though it is not. The decision was also regardless of the fact that donors of the gametes had provided informed consent to perform these experiments. Success of our program also is reliant on the collaboration between a large, academic-affiliated reproductive endocrinology clinic with a research laboratory. This partnership was key in coordinating oocyte donor stimulations and retrievals with the availability of physicians as well as the research colleagues who transported the oocytes to the research laboratory. Commonly, clinical embryologists would also work alongside researchers to help with oocyte handling on the day of oocytes retrieval.

Conclusion

A successful donor oocyte program for research can be achieved using paid participants with a good gamete yield and minimal complications. Participants largely found donating oocytes for research to be rewarding, were incentivized primarily by money and a desire to help others, and reported an overall favorable experience. Despite concerted efforts to provide meaningful information regarding the nature of the research during the obtainment of informed consent, when asked later to recall how their gametes were utilized, it appeared that donors retained only a partial understanding of the nature of the research. Procurement of oocytes continues to be a rate-limiting step in stem cell research, and therefore the continuance of programs that offer compensation is invaluable to continued progress and advancements in stem cell research.

Compliance with ethical standards

Oocyte donation for research skin biopsy donation, and conducting this survey was approved by the Columbia University IRB and filed under protocol AAAI1347.