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Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
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3

Potential Clinical Implications of IVG

Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
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This chapter covers a panel discussion that anchored the workshop in the potential real-life impacts of IVG on stakeholders and society, moderated by Susan Crockin, a senior scholar at the O’Neil Institute for National and Global Health Law at Georgetown Law and private practice lawyer in ART law. The panelists, Andrea Braverman (Thomas Jefferson University) and Katherine Kraschel (Yale Law School), discussed the potential impacts of IVG on the infertility and LGBTQIA1 communities, respectively. Throughout the workshop, several speakers acknowledged the need to include voices from the disability community. Panelist Joel Michael Reynolds, a philosopher at Georgetown, was unable to attend the workshop but had planned to address the potential impacts of IVG through the lens of disability and reproductive justice.

STAKEHOLDERS AND SOCIETY

Crockin began by saying that “the science is extraordinary, but the impact we have to keep front and center.” Panelists addressed these potential impacts in a number of areas.

IVG and the Infertility Community

As a health psychologist who focuses on infertility and third-party reproduction,2 Braverman shared her perspective on what IVG could

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1 LGBTQIA is an abbreviation for lesbian, gay, bisexual, transgender, queer and/or questioning, intersex, and asexual persons. This umbrella term and its variants, including LGBTQ and LGBT, are often used to encompass the diversity of the community.

2 According to the American Society for Reproductive Medicine, third-party reproduction is using donated eggs, sperm, or embryos to enable an infertile individual or couple to become parents.

Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
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mean for people struggling with fertility or for whom traditional family building is not an option. She began by emphasizing that the desire to have genetic offspring is strong, so infertility can have psychosocial effects. In fact, a study revealed that people experiencing infertility have similar levels of anxiety, depression, and distress as people with heart disease and cancer (Domar et al., 1993). Furthermore, the quality of life impacts are similar globally and cross-culturally. Many of Dr. Braverman’s patients have very different ideas of family but are united by desiring genetic offspring. IVG could be life altering for these individuals, allowing them to build the family of their dreams, Braverman said.

Braverman highlighted the potential impacts of IVG if it were to be used clinically for this patient population. It might remove or reduce age limitation barriers, she continued, noting that this could be “as exciting as birth control” for allowing people to control their family building. She also raised concerns about the potential consequences of doing so: “if we are breaking age barriers just because we can, should we?” IVG may also eliminate the need for donor gametes. Third-party reproduction has changed drastically in recent years with the advent of direct-to-consumer genetic testing. In the past, some families would try to identify the nongenetic parent as the donor, and the donor-conceived child would not be informed. Now, everyone can access their genetics, and donors can often be easily identified. IVG would avert these issues by removing the need for a donor entirely, Braverman said.

Braverman noted the potential for anxiety among patients using a new ART. Research has shown that patients often do not consider their ART-related anxiety until after achieving a pregnancy and actively parenting, when they step back and ask what these technologies mean for their children and their families. Intended parents’ concerns need to be considered, she said.

IVG and the LGBTQ Community

Kraschel focused on the effects of IVG on the LGBTQ community. She began by emphasizing that the queer community is not a monolith and discussions within it about the value of offspring that are genetically connected to both intended parents are nuanced. The virtue of IVG depends on one’s vision for an ideal world for LGBTQ families, she said. Is it a world of “formal equality and assimilation” wherein same-sex couples can have children “just like” their opposite-sex couple counterparts, Kraschel asked, “or is it a world of radicalization and tearing down entrenched value systems” that privilege traditional notions of family? A third vision is a hybrid of these options that is most concerned with individual reproductive choice; “LGBTQ families are formed however the

Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
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intended parents desire and are socially respected and legally protected regardless of their genesis.”

Assuming that LGBTQ people have reproductive autonomy, IVG would offer more choices in family building, Kraschel said. It could enable transgender people to produce gametes that align with their gender identity, allowing them to avoid pausing gender-affirming therapy and experiencing gender dysphoria. Same-sex couples could create children who are genetically related to both intended parents. Third-party reproduction could largely be replaced, eliminating the need for sperm and egg donors. In the vision for the future wherein formal equality is the goal, IVG would allow LGBTQ couples to have genetic offspring in a way that many desire. Given how courts have historically recognized genetics as supreme in determining familial relationships, enabling queer couples to form genetic families provides critical legal protection, Kraschel said.

However, some within the LGBTQ community hold the belief that the goal ought to be to radicalize ideas of family formation, Kraschel continued, noting that queer access to ART has torn down patriarchal notions about family building and parentage, in part, by normalizing third-party reproduction. Over time, this has catalyzed a shift away from genetic essentialism. To the extent that IVG could replace third-party donation, valid concerns arise that it may reify the valuation of genetic ties, Kraschel said. In the current climate in the United States of rights retraction,3 reprivileging genetic connections could harm existing and prospective LGBTQ families formed without these ties. Examples of such action have already occurred: over the objections of the non-gestational, nongenetic parent, a court in Oklahoma recently granted a sperm donor parental rights over a child that was born into and raised by a lesbian-coupled family. Tension may occur between families who have already been formed and intended parents who wish to use IVG, Kraschel commented.

In any discussion of fertility care, access and cost must be addressed. Kraschel speculated that IVG might make in vitro fertilization (IVF) less expensive because it avoids the most cost-prohibitive part of the process, ovulation induction and egg retrieval. If so, it could improve access for intended queer parents in a way that is laudable, Kraschel concluded.

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3 Kraschel referenced the Supreme Court’s decision to overturn Roe v. Wade in 2022, which eliminated the constitutional right to abortion and federal standards on abortion access.

Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
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Panel Discussion

Discerning Between Desire and Social Pressure

Ogbogu opened the conversation by asking Braverman about research distinguishing between an individual’s desire and social pressure to have genetically related children. “The literature does not have as much insight as we would like,” Braverman began, noting how difficult it would be to design a study to discern the relative contribution of these factors. “What leads us as an adult to say this is what I want” is hard to tease apart, encompassing the values of a person’s culture, their desire, social pressure, and the character of the family unit. However, Braverman was struck that the same desire exists cross-culturally, implying that it may be independent of cultural context. With that said, there are individual differences within the same culture; not everyone wants to have children, she said. Braverman concluded that patients she sees who are experiencing infertility are united by a strong desire for genetic offspring that is not mitigated by offering other options for family formation.

Considering Potential IVG Users

Henry (Hank) Greely (Stanford University) asked the panelists to estimate how many people would want to use IVG if it were available, noting that he could not find any figures in the literature. Although no panelists could provide a number, they offered their perspectives on the demographic makeup of potential users.

Crockin commented that she would expect that most fertility patients who currently use donors would be thrilled to have this as an option. This group encompasses many LGBTQ couples who would no longer have to deal with third-party reproduction. Although this development could be beneficial to LGBTQ families for legal and psychosocial reasons, Crockin shared her concern that the advent of IVG could undermine the work performed to expand legal definitions of family and reify genetic essentialism.

Kraschel reframed the conversation around replacing the current donor market with in vitro–derived gametes. She shared that most sperm donation users are single or queer-coupled women. When considering the gamete market space, she urged regulators to think about the type of families or prospective families on which this regulation and barriers to access would be operating. Exceptionalizing the parenting decision to use a certain type of genetic material could put constraints on historically marginalized families, including queer and single-parent families, she concluded.

Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
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From the audience, Hugh Taylor of Yale University added that the market of who would be interested in IVG likely goes far beyond those who rely on third-party reproduction: “Who would want to undergo an IVF retrieval if they did not have to?” He said that it can be a burdensome and traumatic procedure. If clinicians could ensure safety and the treatment was affordable, he suggested that IVG could largely replace this component of IVF.

Patient Perspectives

Cyranoski asked the panelists to reflect on whether patients have a growing awareness of IVG or an emerging desire to use it. “[IVG] is not the buzz among the patient community,” Braverman said. Even if patients are aware of IVG, they are not interested in options that are not available. Kraschel agreed, saying that IVG might be fodder for intellectual conversation but not yet a topic of focus at support groups for intended parents.

Impact of Gamete Donation

Paula Amato of Oregon Health and Science University asked Braverman to discuss the impact of using nonidentified versus directed donation4 on donor-conceived children and their families. Despite no comparison studies, follow-up studies have been done for both groups, Braverman said. Issues come up around either choice, and outcomes ultimately rely on the health of the family. Families using directed donation need to address all facets of the process ahead of time for the well-being of the family and the donor-conceived child, Dr. Braverman continued; among other concerns, families who use nonidentified donation must consider the possibility that the child could have 50 or more genetic half siblings and weigh how the donor will react if contacted. She said that the fertility community is still wrestling with how to deal with the implications of nonidentified donation. With IVG as a choice, people may choose this path so that they do not have to burden their children with these considerations, Braverman commented. Such practical implications, rather than valuing personal genetics, may influence their choice to use IVG.

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4 According to the American Society for Reproductive Medicine, directed and nonidentified donation involve a donor who is or is not known to the intended family, respectively. Dr. Amato refers to directed donation by immediate family members.

Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
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Conservative Perspectives

Matthew Krisiloff of Conception Bioscience, a for-profit company developing IVG, asked the panelists to reflect on the impact of IVG in parts of society that operate on a more conservative or traditional outlook around family building. Kraschel responded that opposition will likely be strong given the current political climate. Some people believe that anything outside of coital reproduction is morally objectionable, she said, and they would likely be further upset by IVG. Kraschel also shared her concerns that regulation for IVG could be used as an entry point to further certain agendas: given an opportunity to limit choices in the IVG context, it could be used to limit reproductive choices more broadly.

Equity and Access in the LGBTQ Community

Ogbogu asked Kraschel to give her perspective on how those within the LGBTQ community experience cost and access pressures differently. Status quo access to existing ART is stratified by income within the LGBTQ community, Kraschel said, noting that “paying $1,000 for a vial of sperm is a greater financial burden for some than for others.” Given that members of minoritized groups tend to have lower socioeconomic status, racial disparities exist in access to ART. There are also complicated, and yet to be understood, social and cultural differences in terms of who accesses fertility care, with Black and Latinx people less likely to undergo ART even with a diagnosis of infertility. Cost is not the only contributor to these different patterns of access to and use of fertility care; however, it is certainly one of them, Kraschel said.

Kraschel shared two potential paths for conversations about access within the United States. States can question whether money ought to be spent on helping people become genetic parents. However, for states with existing private insurance mandates (see Figure 3-1), the question would revolve around whether coverage ought to be extended to all people; 14 states mandate that private insurance cover fertility care, and a few of these encompass the LGBTQ community (e.g., Maine). The Appropriations Committee in the Connecticut Legislature recently considered a bill that would mandate that Medicaid include fertility care inclusive of queer parents and single parents, Kraschel said, ultimately allowing many more intended parents to be covered.

Policy Structures for Family Building

Building from Kraschel’s points that IVG may impose heteronormative values around family formation, Mathews highlighted how policy can encourage different kinds of family building, noting that states vary in

Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
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FIGURE 3-1 Infertility coverage by state in the United States in April 2023.
SOURCES: Presented by Amato, April 19, 2023. Reprinted, with permission, from RESOLVE: The National Infertility Association.

what types of services they support, for example fertility care mandates versus supporting adoption costs. Mathews asked panelists to reflect on the interplay between the kinds of families people want to build and the policy structures that facilitate family building. These two elements are inextricable, Braverman responded, noting that although people may differ in how they would like to create their families, all individuals want agency to make these choices free from legal or social concerns. People want to tell their children their stories of origin, she said, which involve how parents came to make their choices. Braverman concluded that “it is not just laws but community and culture too” that impact these decisions.

Crockin directly addressed the example of adoption support versus fertility mandates. Although mandates are not growing among states, private industry (e.g., Google and Facebook) is supporting genetic parenthood by enacting policies for fertility preservation. Coupled with direct-to-consumer genetics and donor identity issues, these pieces seem to be emphasizing the “importance of genetics to us all,” Crockin commented, “and IVG takes us one step closer.” These actions could have unintended ripple effects that must be considered, she concluded.

Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×

POTENTIAL CLINICAL IMPLICATIONS OF IVG

Practicing physicians Amato and Gamal Serour (Al Azhar University in Egypt) discussed how IVG could potentially impact fertility care and intersect with current ART methods. They also highlighted how its application might differ between countries according to political, cultural, and religious contexts if it were ever practiced. This session was moderated by Hugh Taylor, a practicing reproductive endocrinologist and professor at Yale University, who opened by noting the breakneck pace at which the field is moving, concluding that “it’s not a matter of if this will be available for clinical practice but just a matter of when.”

Clinical Considerations

Paula Amato provided a “clinician on the ground perspective [for] if IVG ever came to fruition,” discussing trends in ART, potential users, and how IVG could impact clinical practice.

Trends in ART

Approximately one in six people experience infertility globally (WHO, 2023). As a result, “every fertility clinic, at least in the United States, [is] super busy,” shared Amato. According to the Society for Assisted Reproductive Technology, the number of ART cycles performed has increased substantially over the last decade to over 300,000 per year in the United States. Babies born via ART now represent 2 percent of all U.S. births, approaching nearly 100,000 babies each year (SART, 2023).

These numbers likely underestimate the U.S. demand, Amato said, as only those with resources or in states with insurance mandates have access to ART. Only 20 states have fertility coverage mandates, 14 of which cover IVF, producing major access disparities.

How ART is practiced has also changed over the last decade. Clinicians are performing far more cycles with frozen than fresh embryo transfers (CDC, 2022), which Amato suspected is due to PGT and embryo banking. The number of cycles using frozen donor eggs or donor embryos has also increased (CDC, 2022), which Amato said were used by women who cannot use their own eggs in mainly heterosexual couples or for men in same-sex couples or choosing to parent independently. See Figure 3-2 for trends in egg or embryo source from 2011 to 2020.

Potential Users for IVG

Amato discussed the potential users and clinical indications for IVG, with a focus on those affected by infertility. The largest group would likely

Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
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FIGURE 3-2 2020 National ART summary—number of ART cycles by egg or embryo source, United States, 2011–2020.
SOURCES: Presented by Amato, April 19, 2023. Centers for Disease Control and Prevention, February 21, 2023.

be those5 of advanced maternal age or with primary ovarian insufficiency,6 said Amato. Men with infertility issues, including azoospermia,7 may also use IVG. IVG would also allow same-sex couples to have a child that is genetically related to both parents (see the section on IVG and the LGBTQ Community).

IVG could also enable solo and multiplex parenting, said Amato. In theory, it could allow a single person to reproduce with themselves, either using two in vitro–derived gametes or one in vitro–derived and one native gamete. The offspring of solo IVG would not be a clone because the combination of alleles for each gamete would be different from the parental

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5 Amato used terms within the gender binary for simplicity but acknowledged that not all people who have testes are men and not all people with ovaries are women.

6 Primary ovarian insufficiency occurs when ovaries stop functioning properly, including regularly releasing eggs, before age 40. In addition to genetic causes, it can be spontaneous or medically induced due to chemotherapy, gender-affirming therapy, or surgery.

7 One of the leading causes of male infertility, azoospermia is the complete absence of sperm in the ejaculate. Azoospermia can have idiopathic, genetic, or medically induced causes.

Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×

source. However, Amato would expect a high incidence of homozygosity and potential for recessive diseases. IVG could also facilitate multiplex parenting, yielding a baby with more than two genetic parents. Amato provided the example of four people who wanted to have a child together: they could generate two embryos, derive gametes from the embryos, and then create a child using those gametes. The resulting baby would be their genetic grandchild. Amato emphasized that these paths to parenting are “theoretic possibilities.”

Potential Impacts of IVG on Clinical Practice

Beyond extending who could potentially conceive a genetically related child, IVG would likely change how reproductive medicine is practiced. Amato discussed the current state of clinical practice of ART, including IVF, third-party reproduction, surrogacy, and PGT, before outlining the potential impacts of IVG on these practices.

IVF

In IVF, egg fertilization occurs in vitro. People endure weeks of hormone injections, frequent clinic visits, and surgery to collect mature eggs from their ovaries. Then, eggs are inseminated with sperm, embryos are created and cultured, and the embryos are implanted into the uterus through the cervix. Amato described the side effects of this arduous process, the most common of which include soreness, mild bruising at the injection site, nausea, mood swings, fatigue, abdominal bloating, and discomfort. More serious complications, including surgical risks (e.g., bleeding, infection, bowel or vessel injury) and ovarian hyperstimulation syndrome,8 are rare and have decreased as practitioners have become more adept at preventing them, Amato said. If IVG were available clinically, Amato said that in IVG, the egg retrieval process would no longer be necessary and instead occur “in a petri dish.” Furthermore, IVG could significantly decrease the morbidity and rare mortality associated with IVF, she said.

Third-Party Reproduction, Surrogacy, and ART

With the help of ART, more women are having children in their 40s, Amato said. Although IVF is highly successful, the rates of live birth decrease precipitously with egg age (Figure 3-3). However, the percentage of live births reported with donor eggs remains consistent across patient

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8 According to the Mayo Clinic, ovarian hyperstimulation syndrome causes the ovaries to swell and become painful in response to excess hormones.

Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
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FIGURE 3-3 2020 National ART summary—percentage of embryo transfers that resulted in live-birth delivery by patient age and egg/embryo source, United States, 2020.
SOURCES: Presented by Amato, April 19, 2023. Centers for Disease Control and Prevention, February 21, 2023.

age, indicating that the age of the uterus does not have as great of an impact on success (CDC, 2022). Therefore, if women are willing to use a donated egg, they can carry pregnancies into advanced age.

Irrespective of egg source, “pregnancy is risky, and it becomes riskier as you get older,” Amato said. Advanced maternal age is associated with increased risks for spontaneous miscarriage, preterm delivery, gestational diabetes, preeclampsia, stillbirth, cesarean delivery, postpartum hemorrhage, low birth weight, prematurity, and neonatal intensive care unit admission. Some of these risks can be circumvented if a patient is willing and able to use gestational surrogacy. However, surrogacy requires lots of resources and raises many ethical issues, Amato stated.

If ever available clinically, Dr. Amato would expect that IVG would significantly reduce demand for third-party egg and sperm donors; those of advanced maternal age, same-sex couples, and single individuals rely on these donors. IVG would enable the first two categories to have genetically related children without donation. Gestational carriers would still be needed, particularly for male same-sex couples, at least until artificial wombs become a reality, Amato said.

Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×

PGT

PGT9 is used to evaluate embryos before transfer to the uterus. In the United States, about 30 percent of ART cycles employ PGT (CDC, 2022), with numbers likely higher for older women, shared Amato. The most-used PGT assesses aneuploidy in embryos (PGT-A), allowing clinicians to select embryos without chromosomal abnormalities. PGT-M is used to test for monogenic diseases, particularly if the parents are known carriers. The third and most controversial form, PGT-P, provides risk scores for developing certain polygenic diseases. Amato shared that its utility and validity are unclear, with many ethical issues to consider, especially if people were to use it to select for nonmedical traits. Despite questions about its efficacy, nearly half of U.S. respondents in a recent survey indicated that they would use PGT-P to increase educational attainment for their child (Meyer et al., 2023).

PGT-P is limited in scope by the availability of oocytes and embryos, but IVG could facilitate broader use by generating hundreds, if not thousands, of embryos. Amato shared how combining IVG, PGT-P, and genome editing may result in in vitro eugenics, the conscious shaping of the human genome through selection, fears that have been raised for a few decades.

Nonreproductive IVG

Amato touched on nonclinical uses for IVG, including for research purposes. For example, reprotoxicity of drugs on fertility and embryonic development could be assayed more easily with a greatly expanded supply of oocytes and embryos. IVG could also have implications for regenerative medicine, including therapeutic cloning to generate ESCs, an area that would also be controversial.10

Looking Toward Potential Clinical Use: Ethical Issues and Regulatory Oversight

Amato foreshadowed workshop discussions concerning ethical issues, regulatory barriers, and a potential time line for clinical use. Serour echoed and expanded on many of these concerns during his presentation.

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9 PGT involves taking a few cells from the trophoblast of the blastocyst at about 5–6 days postfertilization and sending them to a laboratory for genetic analysis.

10 Therapeutic cloning involves creating a human embryo in the laboratory and destroying it to obtain embryonic stem cells for research; U.S. federal funds cannot be used for this purpose.

Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×

Ethical Concerns

Amato raised several ethical issues, noting that upcoming sessions would be devoted to discussing them in more detail, so she simply listed them to start the conversation. As a clinician, Amato emphasized that the most important ethical issue is safety for future children, especially considering the potential for germline genetic and epigenetic modifications that can be transmitted across generations. Other ethical issues included (1) the “slippery slope” of disease prevention versus enhancement; (2) eugenics; (3) commodification of human reproduction; (4) creation and destruction of embryos; and (5) access disparities, particularly related to cost.

Regulatory Barriers

Amato outlined two major U.S. regulatory barriers to bringing IVG to the clinic: the Dickey-Wicker Amendment and the appropriations rider. The amendment prohibits federal funding of human embryo research, requiring those studying IVG in humans to seek funding from nongovernmental organizations. The rider bars the Food and Drug Administration (FDA) from using any of its budget to consider any application for a clinical trial “in which a human embryo is intentionally created or modified to include a heritable genetic modification”; whether FDA considers IVG to do so is up for discussion, Amato said.

Potential Time Line

Several forecasters, including Metaculus, predict that the field is about 10 years away from a baby conceived via IVG, and Amato agreed this time line seemed reasonable. In closing, Amato shared a quote from C. Palacios-Gonzalez, “If impractically high precautionary thresholds were decisive, we would not have vaccines, nor IVF, nor any other advance.” Balancing progress with patient autonomy and safety will be needed, Amato said, and a wide societal discussion about what is ethical and acceptable, as in the workshop.

Considering the Global Context for IVG

Serour shared clinical considerations for potential future practice of IVG with a focus on how different societal, religious, and cultural contexts influence clinical application of ART.

Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×

The Cycle of Denial and Acceptance

Serour shared that ART developments are often initially met with condemnation and concern, followed by rigorous ethical, religious, and legal debates. “The possibilities of designer conception or an ideal race have tainted most of these innovative successes,” he said, and this public fear may lead to temporary roadblocks to clinical practice. However, most ARTs eventually achieve public acceptance and are conducted routinely with the appropriate regulations and oversight. Serour posited that IVG will likely take the same path to acceptance.

The Influence of Societal Context on IVG Application

If ever used clinically, IVG would be applied differently in different cultures. Serour explained that “medical ethics are based on the moral, religious, cultural, and philosophical ideals and principles of the society in which they are practiced. It is therefore not surprising to find what is ethical in the application of [IVG] in one society may not be ethical in another society.” Despite likely clinical applications that could be acceptable by most societies and cultures (i.e., treating infertility in heterosexual couples or preventing the transmission of heritable diseases), Serour suspected that many applications would be controversial and might not be accepted in all societies. For example, posthumously creating in vitro–derived gametes for a bereaved spouse would likely not be allowed in all jurisdictions.11 Some societies may not allow same-sex couples, couples with a trans partner, or unmarried individuals to use IVG to create a genetically related child. Finally, employing IVG for eugenic applications would likely be condemned in most if not all societies, Serour said.

Global Scientific and Ethical Concerns

Serour shared his scientific and ethical concerns through a global perspective. He called for scientific, ethical, legislative, jurisprudential, regulatory, and social implications to be discussed with broader societal engagement and noted that the workshop was useful to begin that conversation. Echoing Amato, he expressed that the main scientific concern for IVG is the health of the future child. From a global perspective, Serour also said that failures in professional self-regulation could lead to a chilling effect on scientific research given fractured international regulations. Before IVG is available clinically, global standards for governance and

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11 Some countries have laws requiring marriage certificates to perform ART. Given that marriage certificates are invalid upon death or divorce, posthumous IVG would likely be prohibited in those countries.

Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×

oversight will need to be developed that are conscious of the potential impacts on the fertility industry.

Serour urged the global community to consider how to address issues of human dignity, potential harm, global equity, safety of the child, equality, justice, nondiscrimination, and respect for cultural diversity and pluralism relating. IVG may increase existing disparities in access to reproductive health care between high-income and low-income countries; the latter tend to have weaker health care systems and smaller health care budgets, he said. In addition to equity and access, Serour reemphasized that IVG will need to be applied with respect for different cultural contexts, noting that “what can be applied in one society cannot be applied in another.”

Panel Discussion

Cost Considerations for IVG

Ogbogu offered comments, concerns, and a question about the potential cost, pricing, and access to IVG. Because of the significant financial investments necessary to advance this technology, Ogbogu said it is likely that industry will develop it for clinical application. Whoever does so sets the price, he said, and pricing for treatments in the United States often “makes no sense and is anchored on no sense of reality.” With all that in mind, Ogbogu asked the panelists to reflect on why clinicians seem to assume the price will be or could be affordable.

Taylor said that this is the “million-dollar question.” If the cost is high, it could increase existing disparities in reproductive medicine; if it is lower, it could increase access. The cost of U.S. infertility care is high at least in part due to the limited number of ART centers and reproductive endocrinologists. Increasing providers could drive cost down, Taylor said. He also noted that how IVG develops will impact its price. If a single company develops and patents it, that would be a “tremendous disservice.” Taylor expressed his hope that IVG could be widely adopted and competitive with fewer limitations to access.

Traditionally, new technology is more expensive when it first becomes available and then becomes cheaper, Amato said, positing that IVG will likely take a similar path. However, cost of an ART is not the only issue when it comes to access; insurance coverage, work policies, and family leave would all need to be considered, Amato said.

When considering cost of IVG, Serour said, it needs to be compared to the cost of alternative ARTs. Serour noted that IVF is still expensive for many U.S. citizens and used only by a fraction of the patients who might benefit from it. The cost of all options needs to be weighed with the potential for complications posed by each treatment, he concluded.

Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×

A Field-Wide Concern

Clark said that cost concerns are not unique to IVG, sharing that the whole stem cell therapy community is grappling with this issue. The recent FDA-approved treatment that involves gene editing for sickle cell disease is priced at 2 million dollars, and Clark assumed that the price for IVG would be similar.

Commercialization of IVG

The panelists followed a similar line of thought when addressing questions from Mathews about access and structural inequities. First, Mathews asked whose values are driving the advancement of IVG, noting that it will be shaped by the sphere in which it is developed, whether it is scientifical/medical or commercial. Mathews was pleased that so many speakers discussed access and equity and how IVG could exacerbate inequities in reproductive medicine and asked the panelists what concrete steps the field can take to attend to such concerns.

The panelists acknowledged that they do not have complete answers to those questions and hoped more answers would be illuminated through workshop conversations. Taylor said that “we ought to look to avoid” the traditional pathway of big pharmaceutical companies patenting a treatment and charging millions of dollars because no one else can offer it. Public funding rather than relying on commercialization for advancement may ensure more equitable pricing, he concluded. Amato then used the expense of the somatic gene therapy mentioned by Clark as an example of what can happen when research is driven into commercial spaces due to controversy.

Polygenic Risk Screening

A participant posited that the applicability of polygenic risk screening, a form of PGT, could be linked with IVG. It is only available to those using ART, who may have few, if any, embryos to choose among. Using IVG to generate embryos could increase the potential feasibility and marketability of embryo screening, he said, transforming the potential patient population to everyone. The participant then asked the clinicians to reflect on the possibility of increased interest and application of polygenic embryo screening.

Taylor referenced the poll Amato presented to assert that many people would want to use polygenic screening if it were affordable and accessible. If these technologies are not prohibitively expensive, he could envision a time when people choose to use IVG for genetic screening rather than infertility. Amato and Serour both said that polygenic risk screening is very

Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×

controversial and not validated. However, Amato agreed that its utility increases with the number of embryos, noting that IVG could enable creating hundreds of embryos.

Crockin commented that the clinical conversations at the workshop began with discussions about helping patients struggling with fertility and quickly slipped into conversations about creating mass embryos and choosing the “best” one. Given the charged political environment in the United States, she expressed fears about how IVG could be perceived. She then asked whether being strategic and careful about verbiage around IVG is on the radar screen for clinicians and leadership at professional society organizations, such as the American Society for Reproductive Medicine. Taylor agreed that IVG needs to be properly described, giving appropriate background and context. However, if clinicians do not discuss all the possibilities, it would not be possible to develop appropriate regulations and guidelines for their use and oversight, he said.

Limits of U.S. Funding/Oversight

Several participants highlighted issues relating to the lack of U.S. government funding for research that involves creating human embryos. Clark said that validating the quality and safety of IVG will require making embryos for research purposes. Because the National Institutes of Health (NIH) cannot fund this research, Clark said, the technological development may move to regions that are more permissive and lack regulatory frameworks that require transparency.

Removing Age Barriers

Taylor asked his fellow panelists how they would rethink pregnancy safety if age barriers were removed by using IVG. He questioned how that would affect prenatal care, labor and delivery, birth, and child-rearing. Serour stated that clinics are already facing this quandary with the advent of embryo cryopreservation. In his clinic in Egypt, patients are provided with evidence-based information about the risks involved in pregnancy at advanced maternal ages, but the choice is left to them. Amato agreed that U.S. clinics also face this issue, particularly as egg donation enables people to become pregnant at more advanced ages; most U.S. clinics have age limits for pregnancy, usually 55. However, people can have children at any age if they are willing and able to use a surrogate. Amato has not seen a lot of demand over 50 with egg donation but speculated that this could change if IVG were available. It is important to consider the familial and societal implications if having a child is no longer as tethered to age, she concluded.

Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×

BREAKOUT GROUP DISCUSSION

A breakout group moderated by Amrita Pande (University of Cape Town, South Africa) discussed the “Impact of IVG on the Fertility Enterprise.” The group discussed the potential effects on this burgeoning industry, were it ever used clinically. Key points from participants in the breakout group discussion were reported to workshop attendees by the rapporteur, Pande.

Lessons Learned from the Cost and Price of IVF

Pande began by acknowledging the complexities of cost and pricing. Costs per cycle for IVF have not depreciated over the years, but the cost per baby has decreased as it has become more efficient and more successful. One participant argued that the costs of IVF are not so different from other treatments in the United States, and the true access barrier is insurance coverage. He noted that pushes have been made to increase mandates for insurance coverage. Participants discussed models of IVF coverage in other countries, including Canada, where many states cover the first cycle, and Spain, which covers up to three cycles. Public coverage is often restricted to public hospitals and can have long waiting lists, so that patients end up resorting to more expensive private care.

The Cost of Fertility Care

Some participants suggested that IVG could have lower costs, or at least lower opportunity costs, compared to IVF because (1) IVG may not involve drugs, injections, hospital visits, or third-party reproduction; and (2) the potential for risks and pain could be lower. However, some participants were concerned that motivation would be insufficient to lower pricing, based on the history of pricing for other reproductive technologies.

Whether the cost of IVG might fall after an initial period could be dependent on the prevalence of add-ons associated with fertility services, such as preimplantation embryo screening or heritable genome editing, several participants speculated. Many were concerned that practices such as trait selection or even pressure for the use of heritable genome editing could increase if IVG were ever clinically practiced.

Potential Mass Production of Embryos

Several participants disagreed about the likelihood that large numbers of human embryos would be produced from in vitro–derived gametes if ever available clinically. Some thought that this would not be necessary

Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×

if screening could occur at the in vitro–derived gamete stage. Several participants did not expect that excess embryos would add considerably to the potential cost of IVF, but many were concerned about the potential ethical implications, particularly when combined with prenatal selection. Participants discussed the underlying potential for eugenics inherent in embryo screening technologies and the potential implications for disability by routinely using them. Several participants acknowledged that including voices from a broad range of communities in these conversations is crucial.

Reproductive Tourism

Several participants suggested that even if the United States were to become a leader in IVG, it would not be a hub for reproductive medicine services unless it were to reduce costs and offer package deals with gestational surrogacy services. Those who need surrogates would likely still want to go to cheaper hubs, a participant shared, and might be willing to move across the globe for these services.

Engaging the Public on IVG12

Participants discussed the timing and structuring of public consultations and dialogues. Some participants felt that these discussions could wait until scientists have come closer to establishing safety and efficacy. Others emphasized that public engagement is critical at every step of development, including shaping the research agenda, and thus it will be important that these discussions not wait. Participants considered how to ensure diverse voices are included and who could best facilitate these discussions.

During the report-out, multiple attendees shared perspectives on the many potential goals of public engagement. Saskia Hendriks of NIH shared how different goals yield different strategies for public engagement, so it is important to clearly identify the mission. Clark said that many scientists reduce public engagement to informing the public, but inviting the public to inform research is crucial. Alana Cattapan of the University of Waterloo, Canada, discussed how conversations with the public can often bring people to the table who already identify as stakeholders, but new technology, such as IVG, could affect everyone. She noted the importance of finding ways to invite people to the table who might not self-identify as stakeholders.

__________________

12 For an in-depth discussion of public and community engagement on reproductive advances, please see Chapter 8.

Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
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Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
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Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
Page 33
Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
Page 34
Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
Page 35
Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
Page 36
Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
Page 37
Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
Page 38
Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
Page 39
Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
Page 40
Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
Page 41
Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
Page 42
Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
Page 43
Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
Page 44
Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
Page 45
Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
Page 46
Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
Page 47
Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
Page 48
Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
Page 49
Suggested Citation:"3 Potential Clinical Implications of IVG." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
Page 50
Next: 4 Social, Ethical, and Legal Considerations Raised by IVG »
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Current assisted reproductive technologies such as in vitro fertilization (IVF) do not enable all prospective parents to have genetically related children. The National Academies Board on Health Sciences Policy hosted a workshop in April 2023 to explore the development of in vitro-derived human eggs and sperm from pluripotent stem cells through a process known as in vitro gametogenesis (IVG). Speakers emphasized the impacts of the potential biotechnology on research and reproductive medicine should clinical IVG ever be approved, along with the many social, ethical, legal, and technical considerations its development raises. This proceedings document summarizes workshop discussions.

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