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Posted on January 24, 2020 at 11:12 AM

by Craig Klugman, Ph.D.

Last week, NPR reported on a new pre-publication article published in the journal Human Reproduction (HR). The study was conducted in Mexico where 81 women received in vivo assisted reproduction (a cycle of ovarian stimulation followed by artificial insemination—introduction of sperm into her body). After several days, researchers used the patented Previvo Genetics1 lavage device to wash the embryos out her uterus. Twenty of these women also underwent a (second) more traditional in vitro fertilization (IVF) cycle and all embryos were tested for “euploidy rates” (having the correct number of chromosomes) and morphology (shape and appearance of the cells).

Some previous studies have suggested changes in embryos as a result of IVF techniques, while others have shown no changes. In this case, the goal was to prove the efficacy of the Previvo tool as a “minimally invasive technique”.

On the surface, this article may seem to report a novel technique that could benefit people trying to have a baby through assisted reproductive technologies. As a bioethicist and clinical research ethicist, I saw several moral red flags around protecting the subjects, the buying and selling of embryos, the production of embryos for research, the scientific claims, and financial entanglements. I was also interested in this article for a personal reason, the lead author,

Santiago Munné, is a geneticist who used to work with my mom in a New Jersey infertility clinic.

The Study
In traditional IVF, oocytes (eggs) are removed from the female by the use of a long needle inserted through the vagina, and then into the abdominal space while the woman is under twilight anesthesia. The egg is fertilized by a sperm in a petri dish (also known as in vitro fertilization). At this point, the embryo could be subject to genetic testing if desired, to make sure it does not carry any inheritable diseases. In the novel approach used in the study, after stimulating the ovaries, sperm is introduced through the cervix to fertilize the eggs and fertilization takes place in the body (also known as in vivo fertilization). The Previvo tool then washes the embryo from the uterus, where it can be frozen and stored for future fertility, be available for genetic testing, or transferred into the uterus of another woman. In the words of bioethicist Laurie Zoloth at the University of Chicago who was interviewed for an NPR story, the researchers treated female subjects as “petri dishes” where fertilization could occur.

In another possible use of this technology, the study authors suggest shared maternity. For example, a female-female couple may both wish to be part of the pregnancy experience. One could provide the egg and environment for conception and the other could gestate the embryo and give birth. If this idea sounds farfetched, it is already being done: A December 2019 BBC article reported on two moms who did something similar, sharing in the reproduction of their son—one fertilized the egg and the other gestated it to birth.

Funding for this study was provided by Previvo Genetics LLC, a company that was founded by John E. Buster with his brother, Steven K. The company has addresses in San Jose, California and Parker, Colorado. The company’s website says that their lavage system is not FDA approved and is thus only available via Investigational Use, such as in a study. This particular study was conducted at Punta Mita hospital, about an hour north of Puerto Vallarta, on the Pacific coast of Mexico. This small hospital only opened in 2017 and features a fertility clinic. The hospital website is in English and encourages “medical tourism”, the idea of going to another country where the medical care is cheaper and where procedures may be available that are not approved back home. On the website, you can explore their executive health care services as well as the many local resorts where you can stay. In bioethics, medical tourism is viewed as suspicious since it is usually only available to people with wealth, which excludes most of the local population. The clinic’s participation in this study raises the question of whether they are situating themselves as a center for fertility tourism, using local woman to provide eggs and their bodies for fertilization to wealthy foreigners.

Brief History
In 1978, Louise Brown of the U.K. was the first “test tube” baby ever born. The first American baby born through artificial reproductive technology was Elizabeth Jordan Carr in December 1981 in Virginia. Soon thereafter, brothers Richard and Randolph Seed founded F.G.R. (Fertility and Genetics Research, Inc.), a Chicago firm that sought to commercialize artificial reproduction in humans, using a lavage (washing) technique that the brothers has used in breeding cattle since the 1970s. Richard was an inventor who would propose a human cloning business in 1998 and Randolph was a surgeon. In the early 1980s, F.G.R. gave $400,000 (about $1.25 million in 2020 dollars) to UCLA and its lead reproductive scientist, John E. Buster to develop the system.

In 1982, Buster ran The Ovum Transfer Project at Harbor-UCLA Medical Center; the first effort to take an egg from one woman and use it to create an embryo that another woman would carry. Buster and his team recruited fifteen subjects who were paid an average of $200 (approximately $553 in 2020 dollars) for their eggs. Subjects underwent ovarian stimulation and were then inseminated in vivo with sperm from a couple seeking to have a child. Five days after fertilization, a catheter was inserted through the subject’s uterus that permitted injection of 60 ccs of a nutrient fluid. The wash and the embryo (which has not yet attached to the uterine wall) would be collected by a second catheter and deposited into a lab dish. The embryo was then transferred to the womb of the female member of the couple who would gestate and raise the baby. Neither egg donors nor gestational mothers knew the other’s identity. The process was successful in recovering an embryo from the donor 44% of the time. Of the five transfers recipients, only 2 women carried a pregnancy to birth. (the first birth was announced in a JAMA article).  In one case, the donor became pregnant and then reportedly lost the pregnancy. The new system uses a single device to perform this lavage procedure.

Even during this early effort, there was concern about the ethics of this technique and the commodification of human reproduction. An article in The New York Times in 1984 was specifically concerned with how the female donors were recruited, paid, and treated during this procedure. Today, egg donation is common with over 10,000 babies born from them each year.

A 2014 article that reported using Previvo to lavage mouse embryos from a silicone uterus model. The Previvo device was first introduced at the 2014 meeting of the American Society of Reproductive Medicine and is covered under at least 9 patents.*

Protecting Human Subjects
Researchers recruited female subjects from an existing list of potential oocyte donors registered at a fertility center in Mexico. Presumably, a woman would join the list with the aim of providing an egg for people who wish to have a baby. Sperm donors were recruited through advertisements and gave consent for preservation, quarantine and fertilization of any resulting embryos. All donors gave written informed consent to be part of the study, a standard part of any research study. The process of informed consent is an exercise of autonomy. (freedom to make your own medical choices) Subjects are required to be told the risks, benefits, steps of the procedure, and alternative treatments. The potential subject must have freedom to give permission or to walk away. Risks must be minimized and the benefits of the study must outweigh the risks. The protocol, informed consent documents, and plans for protecting subjects must be reviewed by an institutional review board (IRB-a human subjects review committee) before the study can begin.

The Mexican study was approved by two IRBs: One through the Ministry of Health of the State of Nayarit (Mexico) and a second through the for-profit Western IRB (owned by Copernicus Group, a company that earns over $70 million per year)). . Zeke Emmanuel suggests that they are just as good as any other IRB. Trudo Lemmons and Carl Elliott have suggested that such companies have an inherent conflict of interest since their very existence is based on approving research protocols (who will pay them again if their protocol is not approved?). Did these IRBs know about the 1982 trials on this technique in humans? We do not have a record of the deliberations of these IRBs, nor how much WIRB was paid. Such transparency should become a standard for reporting on research.

Galia Oron is an associate editor of the journal and researcher at Tel Aviv University and Rabin Medical Center. In an editorial that accompanied the 2019 research study publication, Oron provided a principlist analysis that expressed concern as to whether the amount of money female subjects were paid was so high, that they would participate in the study just for the cash. In other words, were the potential subjects coerced by the money into giving their consent. Female subjects were paid $1,400 to participate in the experiment. While this would be far less than a woman would be paid for her eggs in the United States ($5000-$10,000, or 26-52 days’ worth of salary), for the women in Mexico, the money was equal to working 71 days.2 The study does not report the compensation given to male sperm donors.

Researchers are supposed to minimize potential harm to a subject both physical and psychological. Of the 81 study subjects, 20 were selected to undergo a second round of in vitro fertilization, where the mature eggs are removed using a needle, a technique that is more invasive than the lavage. Stimulation of the ovaries is not a risk-free procedure. Some side effects are temporary such as bloating and nausea but in some cases the process can effect future fertility, is associated with certain cancers, and can be life threatening. Having 20 women exposed to this risk twice seems an unnecessary harm to them.

While the informed consent documents used in this study have not been released, a 1983 People magazine articlediscussed parts of the consent form used in that early study. Subjects (the egg donors) waived all parental rights and agreed to abstain from intercourse to ensure that the sperm were those of the father donating the sperm and raising the child. Consent forms also included a clause requiring the subject to agree to “menstrual extraction or abortion” if they became pregnant. That means if the embryo did not wash out but instead implanted in the donor’s uterus, the subject was required to undergo an abortion. This clause probably also existed in the more recent trial since the HR report stated that the lavage failed to remove the embryo in 11 cycles, requiring subjects to undergo an abortion.

It is doubtful that a researcher could enforce a requirement to abort an embryo in the United States, even if a woman had sign a consent document. Abortion is one of the most contentious issues in America. Morally, some people in the U.S. and throughout the world, believe that abortion is murder because, in their worldview, life begins at conception. Buster acknowledged this in several interviews he gave in the 1980s. Other people believe an embryo is a grouping of cells that has the potential to become a human being, but until birth is part of a woman’s body. These second group accept abortion because it is a woman’s choice as to what to do with her body. Other people fall along a spectrum between these two ends. In recent years, many states have passed laws to ban all abortions, while others have expanded abortion rights. Several cases about abortion are currently sitting before the U.S. Supreme Court.

The study also touches on the abortion debate in creating human embryos solely for the purpose of research. The embryos were created to be harvested, tested, and then destroyed after the genetic tests. The Dickey-Wicker Amendment prohibits the use of federal funds on research that creates embryos strictly for research purposes. Since this study was funded solely by Previvo Genetics, a private company, that ban would not be an issue. The FDA permits research on embryos but those have to be created using specific guidelines, approvals, and consent processes. However, there are several states  (AR, IN, LA, MI, ND, SD) that have more restrictive bans so finding a study site could be tricky. In public health ethics, analysis of a policy includes efficacy, which asks does this scientifically work and is this approach culturally, socially, and politically feasible. Given the controversy around abortion and the creation of embryos for research, this study does not pass the feasibility test.

Ethics Dumping in Mexico
Research is often conducted outside of the country of the sponsors and researchers for good reasons. Sometimes they are looking at diseases that are uncommon in the U.S., and sometimes the cost of the study is less. Looking at the compensation for the female subjects alone, the study would have cost 3.5 times more for subject payments in the U.S.  Other times, research is done elsewhere because U.S. law would prohibit that study from being done here. In the case of creating embryos for research purposes, Mexican federal law permits creating embryos for infertility when that information cannot be gained in other ways, a situation that is more muddled in the U.S.

Similar to medical tourism though, the act of a researcher or sponsor based in a high income country conducting a study in a middle or low income country may also be due to “ethics dumping” which is when a study cannot ethically be done in the high income country. By moving the research to another nation where laws, regulations and traditions are different, researchers can conduct the study. Governments may even welcome the money provided by the study in terms of creating temporary local jobs, staying in local hotels, eating in local restaurants, and permit fees. A 2019 study published in the journal BMC Medical Ethics reported that half of Mexican IRB members believe that ethics dumping occurs in their country. The survey showed concerns that research tourism takes advantage of local populations by offering high rates of payments to subjects that are hard to turn down. Often, being in a research study means a subject gains access to free medical care and transportation to hospitals. Most of the subjects in this study were women from Puerto Vallarta, a city with a high rate of poverty. While the risks of the study is born by these poor women, all of the benefit goes to the high income patients who will use this procedure in the future (if it works). In some countries, cultural norms emphasize individual sacrificing for the community ,meaning people might be more likely to volunteer for research. Patient safety and protection of autonomy may not be as strong as in the U.S.

Thus, choosing the study site in Mexico may have been because of the lower cost, but also might have been because the location allowed researchers to avoid laws, regulations, and ethical norms that exist in the U.S. For purposes of testing medical devices and drugs, it also means the research avoids being under the jurisdiction of the Food & Drug Administration, which has many regulatory requirements for clinical trials.

This study also points to a disturbing trend in research tourism where U.S. companies and academics bring studies overseas. For example, look at the recent study in Colombia that charged $1 million of people to try an unproven anti-aging treatment. Studies in these farflung locales are cheaper, may have fewer regulations, have less oversight, and there are fewer questions. Research tourism, however, is a colonialist enterprise, using people in low and middle income countries to provide benefits for those in high income countries.

Publishing Controversial Research
The editor of Human Reproduction was the lead author of another editorial that accompanied the study manuscript. Editor E.B. Lambalk and colleagues explains why the editors decided to publish an article that raises so many ethical questions. In short, they felt that since the study met scientific standards and underwent ethics review, that it should be published: “This study contributes with new knowledge on the biology of reproduction that is expected to be of interest among the scientific community”. However, the editors may not have had all of the information they needed in making this determination. Four of the 11 authors in the HR study published on some of the results in a New Zealand medical journal in April 2019.

The issue of whether to publish ethically questionable research is important. On the one hand, as the editors explain, scientific information is valuable and helpful in progress that may be able to help patients. On the other hand, publishing studies that have ethical concerns can be saying “Sorry, not sorry” to future researchers that even if the methods are concerning, editors will look the other way if the results are significant.

Another publication concern is the many conflicts of interests held by the study authors. In the HR article, there are 14 authors who claim 11 institutional affiliations (often each author has more than one affiliation). Of the 11 affiliates, six are private companies, four are university departments, and one is Previvo Genetics. Three of the authors are from Punta Mita Hospital fertility center and are the only ones located at the test site. One author is from Spain but works (and owns companies) in the U.S., and the others are U.S.-based. The Previvo authors include a senior marketing manager, the director of science, and Buster. Ideally, authors should not stand to gain financially from their participation in a study. Otherwise, the desire for a positive outcome (and images of future sales and high stock values) could cloud their objective judgement. Revealing a conflict, as the authors did here, is the minimum that a person can do, but best would be to avoid the conflict in the first place.

This study raises a number of ethical questions regarding financial entanglements, handling of embryos created just for research, abortion, ethics dumping, medical tourism, avoiding regulations and scrutiny, and most importantly, protecting human research subjects. As a bioethicist, I ask myself whether the study could have been done differently. Perhaps instead of creating embryos for this purpose, couples who undergo ovarian stimulation to create their families could be offered the option of traditional (needle) harvesting or the experimental technique, a study design that removes concerns over the status of creating embryos for research. However, a couple who has just spent tens of thousands of dollars for a cycle and only has a few eggs might be unwilling to gamble their reproductive success on an experiment. Instead of having twenty subjects undergo two stimulation cycles, another twenty subjects could have been enrolled as controls. The manuscript could have listed more information on why the work was done in Mexico instead of the company’s home country and how much they paid for a private IRB company to review their protocol. In some journals, editors are asking authors what work they did on the study and in writing the article, which leads to all of the authors having done work on the research. More complete conflict of interest forms could be scrutinized as part of manuscript review and be made public. More careful attention, detail, and transparency could have improved the optics of ethics in this work. I served on my institution’s IRB for nearly 6 years and worked with many IRBs for a decade before that. As this study stands, there are simply too many ethical questions raised in this research to justify its having been approved and published.

1 U.S. Patent  US9498252B2, US20140378754A1, US20140378751A1, US20140378752A1, US9561257B2, US20140378750A1, US20170224379A1, EP3578122A1, US20160151090A1

2 At $1400, the amount was far less than a woman in the US would be paid for her eggs, which is $5,000-$10,000. The average woman in the U.S. earned about $42,000 a year in 2017 and the U.S. government calculates there are 221 workdays in a year, meaning a woman, on average, earns $190 per day. An egg donor in the US would thus be paid between 26 days ($5000) and 52 days ($10,000) salary for her egg. Remember that in 1982 donors were paid $200 (approximately $553 in 2020 dollars).

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