On September 19-20, 2023, the U.S. Food and Drug Administration's Pediatric Advisory Committee convened a two-day meeting of independent advisors to discuss how to better evaluate the safety and efficacy of artificial uterine technology. The quality of life of preterm mothers and babies and the right of patients to choose are central to ethical discussions.
Participants said that based on current animal data, the technology is not ready for human experimentation.
On September 19-20, 2023, the U.S. Food and Drug Administration's (FDA) Pediatric Advisory Committee convened a two-day meeting of independent advisors to discuss how to better evaluate the safety and efficacy of Artificial Womb Technology (AWT). The committee is made up of FDA officials, physicians, pharmaceutical professionals and patient representatives. Topics included the limitations of current animal data for the technology and the ethical difficulties of conducting human trials. Scenarios for future human trials have not been disclosed in this discussion.
Currently, artificial womb technology is designed to save the lives of extremely premature babies. Extremely preterm infants, i.e. babies born less than 28 weeks old, have a low survival rate.
According to a 2022 study of 10,877 infants in the Journal of the American Medical Association (JAMA), the survival rate for discharging preterm infants at 28 weeks of gestation was 94%, and about half of premature babies at 23 weeks' gestation survived, compared with only 10% by 22 weeks' gestation. According to the Centers for Disease Control and Prevention (CDC), the rate of preterm birth increased by 4% between 2020 and 2021. In China, preterm infants are defined as live births born before 37 weeks' gestational age, accounting for about 7% of the number of newborns. Preterm birth has become the leading cause of neonatal mortality.
The artificial womb mimics the uterine environment in which premature babies continue to develop and thus survive the dangerous period. There are several research groups around the world developing artificial uteruses, and the BioBag system developed by the research team at Children's Hospital of Philadelphia (CHOP), led by Dr. Alan Flake, is currently the closest to human experiments.
The CHOP case was mentioned in a September 14 article in Nature titled "Human trials of artificial wombs may begin soon." CHOP researchers are seeking approval for their first human clinical trial, which is why the FDA convened an independent advisory meeting.
A "biobag" is a bag filled with sterile liquid that wraps the fetus and provides oxygen and nutrients through a tube. In 2017, the system kept a lamb alive for four weeks. After that, the team tested their device on pigs and turned the research into a well-funded startup called Vitara Biomedical, which has raised more than $100 million.
The artificial uterus "biobag" developed by CHOP kept a premature lamb alive for four weeks. Image source: Nature
Limitations of animal experimental data
Recently, Dr. Alan Flake admitted that "there is no perfect animal model." Annabelle Crusan, an FDA veterinary medical officer, said fetal sheep are the most commonly used animals for neonatal studies because they weigh and have organs comparable to the size of a human fetus. But sheep and humans differ in their growth rates. Primate fetuses grow at the rate most similar to human fetuses, but fetuses are small and therefore difficult to insert into an intravenous tube to connect to a machine.
Pigs are another option, they are similar in size to human fetuses, but they have different ways of blood flow. A team at The Hospital for Sick Children, led by Dr. Mike Seed, used pigs for research, but it has not succeeded in surviving pig fetuses for more than a day. Dr. Alan Flake said his team had tried pig models but declined to elaborate on the experimental data.
"How should we replicate the human intrauterine environment in terms of growth and nutrition?" Christine Gleason, a professor of pediatrics at the University of Washington, asked, "I think there is a need to learn more about things in animal studies that we might have overlooked." Participants also said that based on current animal data, the technology is not ready for human experimentation.
"Studies in more animal models may be needed to ensure the safety of the technique and fill in the gaps." Annabelle Crusan commented.
Experts have previously said that testing the device in humans will be very difficult. First, researchers need to predict extreme preterm birth in advance and obtain informed consent from pregnant women during a very short window. Second, the effect of artificial uteruses on the long-term development of babies is unclear.
"It's not like we extend the lives of older adults by doing research on heart disease or dementia," said Bill Hay, chief medical officer of Astarte Medical, a precision medicine company based in Pennsylvania. ”
Ethical issues in vitro embryonic development
Mark Mercurio, a professor of pediatrics and biomedical ethics at Yale University, asked the FDA meeting a variety of ethical questions that need to be answered before conducting clinical trials. He noted that preterm survival data vary between countries and even between different academic centers in the United States. Researchers will have to decide which survival data to consider using to find out which fetal risk is highest and thus decide whether the technique is suitable.
"Identifying the target demographic is critical, and it can't just be based on gestational age. Other factors can also affect fetal survival. "In the future, we may be asked by parents, can we use this technology for my child?" We need to prepare an ethically defensible answer. ”
Professor Mark Mercurio called for a national conference where experts could discuss all the ethical issues inherent in artificial wombs – including how to address patients placed within the technology, as they are neither exactly fetus nor exactly babies.
It is understood that in the American context, the definition of fetus is an important part of the discussion of fertility ethics. In the case of abortion, which is often embroiled in bipartisan politics in the United States, anti-abortion advocates argue that fetuses are human when they are fertilized, and that it is immoral to kill innocent people through abortion. Abortion rights defenders who support the right to choose emphasize the bodily autonomy of pregnant women. Even if a fetus is a person at the moment of fertilization, a woman's bodily autonomy—her right to decide what can happen within her body, on her body—means that it is morally acceptable to remove the fetus from her body.
To strike a balance between a woman's bodily autonomy and the moral status of the fetus, abortion legislation in many countries uses fetal "viability" (the ability of the fetus to survive outside the womb, including with the help of medical devices) as a measure of the moral acceptability of abortion. Under the laws of many places where abortion is permitted, the fetus's right to life will override a woman's bodily autonomy when it becomes able to survive independently. For example, abortion laws in the UK only allow abortion until 24 weeks of fetal development, which is currently the earliest developmental stage at which a fetus can survive with the help of medical devices. If artificial wombs appear, this standard may change, which will lead to more ethical and legal debates.
At these FDA meetings, the quality of life of preterm mothers and babies and the right of patients to choose were central ethical discussions. Committee members agreed that the ultimate goal should be not only survival, but also the child's eventual quality of life. Charleta Guillory, a professor of pediatrics at Baylor University in the United States, noted the high rate of premature babies born in black patients and called for a focus on long-term care in the face of health disparities. Committee members also recommended that researchers monitor several possible adverse events, including growth failure, infection, and maternal and infant mortality.
Charleta Guillory also noted the importance of involving neutral third parties to obtain consent from patients: "We need a better assessment system through which patients can participate in decision-making. Patient-family representative Gianna McMillan spoke about her experience when she had to choose experimental and standard treatments for her child's malignant brain tumor. Providing easy-to-understand information, opportunities for multiple inquiries, access from third parties and ongoing emotional support will all be critical, she said.
"I don't want people to feel that because preterm birth is complicated and parents are in a difficult situation, they can't make a deliberate decision." Gianna McMillan said.
Bibliography:
1. Pediatric Advisory Committee Meeting Announcement，https://www.fda.gov/advisory-committees/advisory-committee-calendar/pediatric-advisory-committee-meeting-announcement-09192023
2. Artificial wombs, after years in development, reach FDA review for human trials，https://www.statnews.com/2023/09/19/fda-studies-artificial-womb-technology/
3. Artificial womb sustains premature baby lambs for weeks，https://www.statnews.com/2017/04/25/mechanical-womb-premature-infant/
4. Artificial Wombs Will Change Abortion Rights Forever，https://www.wired.com/story/ectogenesis-reproductive-health-abortion/