On September 19-20, 2023, the U.S. Food and Drug Administration's Pediatric Advisory Committee held a two-day independent advisory meeting to discuss how to better evaluate the safety and effectiveness of artificial uterus technology. The quality of life of premature mothers and infants and the patient's right to choose are central issues in ethical discussions.

Members at the meeting said that based on current animal data, the technology is not yet ready for human trials. "Studies in more animal models may be needed to ensure the safety of this technology and fill gaps."

On September 19-20, 2023, the Pediatric Advisory Committee of the U.S. Food and Drug Administration (FDA) held a two-day independent advisory meeting to discuss how to better evaluate the safety and effectiveness of Artificial Womb Technology (AWT). The committee is composed of FDA officials, doctors, members of the pharmaceutical industry, and patient representatives. Topics at the meeting included the limitations of current animal data for this technology and the ethical difficulties of conducting human trials. Plans for future human trials have not been disclosed as of this discussion.

Currently, artificial womb technology is aimed at saving the lives of extremely premature babies. Extremely premature babies, those born before 28 weeks, have a very low survival rate.

According to a 2022 study in the Journal of the American Medical Association (JAMA) involving 10,877 babies, the survival rate of premature infants at 28 weeks of gestation was 94%, about half of premature infants at 23 weeks of gestation survived, and only 10% at 22 weeks of gestation. According to the Centers for Disease Control and Prevention (CDC) report, the rate of premature birth increased by 4% between 2020 and 2021. China defines premature babies as live babies born before 37 weeks of gestation, accounting for about 7% of the number of newborns. Premature birth has become the leading cause of neonatal death.

The artificial womb can simulate the environment of the womb, allowing premature babies to continue to develop and survive the dangerous period. Several research groups around the world are developing artificial wombs. The "BioBag" system (BioBag) developed by the Children's Hospital of Philadelphia (CHOP) research group led by Dr. Alan Flake is currently the closest to human experiments.

On September 14, the CHOP case was mentioned in an article titled "Human trials of artificial wombs may start soon" in Nature magazine. 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 fluid that encases the fetus and provides oxygen and nutrients through tubes. In 2017, the system kept one lamb alive for four weeks. The team then 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." FDA Veterinary Medical Officer Annabelle Crusan said fetal sheep are the most commonly used animals for neonatal research because their weight and organs are comparable to the size of human fetuses. But sheep and humans grow at different rates. The growth rate of primate fetuses is most similar to that of human fetuses, but the fetuses are small, making it difficult to insert intravenous tubes to connect them to machines.

Pigs are another option, they are similar in size to human fetuses but their blood flows differently. A team at the Hospital for Sick Children in Toronto, Canada, led by Dr. Mike Seed, used pigs for research, but has not yet succeeded in keeping pig fetuses alive for more than one day. Dr. Alan Flake said his team had tried pig models but declined to elaborate on the experimental data.

"How do we replicate the human intrauterine environment in terms of growth and nutrition?" asked Christine Gleason, a professor of pediatrics at the University of Washington. "I think there needs to be more understanding in animal studies of things that we may have overlooked." Participants also said that based on current animal data, this technology is not yet ready for human experiments.

"Studies in more animal models may be needed to ensure the safety of this technology and fill gaps." Annabelle Crusan commented.

Experts have previously said that testing the device on humans would be very difficult. First, researchers need to predict extreme preterm birth in advance and obtain informed consent from pregnant women during a very brief window. Second, the impact of artificial wombs on the long-term development of babies is unclear.

“It’s not like we’re extending the lives of older people by doing research on heart disease or dementia,” said Bill Hay, chief medical officer of Astarte Medical, a Pennsylvania-based precision medicine company. “This is the beginning of a child’s life that everyone hopes will be a long and healthy life.”

Ethical issues in in vitro embryo development

Mark Mercurio, a professor of pediatrics and biomedical ethics at Yale University in the United States, raised various ethical questions that need to be answered before conducting clinical trials at the FDA meeting. 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 which fetuses are most at risk, and thus whether the technique is suitable.

"It is critical to identify the target population, and it cannot be based solely on gestational age. Other factors will also affect fetal survival." Mark Mercurio said, "In the future we may be asked by parents, can I use this technology for my child? We need to prepare an ethically defensible answer."

Professor Mark Mercurio has called for a national conference where experts can discuss all the ethical issues inherent in artificial wombs - including what to call patients placed inside the technology, since they are neither quite fetuses nor quite babies.

It is understood that in the American context, the definition of fetus is an important part of the discussion of reproductive ethics. Take the topic of abortion, which is often embroiled in bipartisan politics in the United States. Anti-abortion advocates argue that a fetus is a person at the moment of fertilization and that killing innocent people through abortion is immoral. Pro-choice abortion rights defenders emphasize the bodily autonomy of pregnant women. Even though a fetus is a person at the moment of fertilization, a woman's bodily autonomy—her right to decide what can happen in and on her body—means that it is morally acceptable to remove the fetus from her body.

In an effort to strike a balance between a woman's bodily autonomy and the moral status of her fetus, abortion legislation in many countries uses fetal "viability" (the fetus's ability 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 overrides the woman's bodily autonomy when the fetus becomes capable of independent survival. For example, UK abortion laws only allow abortion until 24 weeks of development, which is currently the earliest stage of development that a fetus can survive with the help of medical devices. If artificial wombs appear, this standard may change, which will trigger more ethical and legal debates.

In the above-mentioned FDA meeting, the quality of life of premature mothers and infants and the patient's right to choose were central issues in ethical discussions. Committee members agreed that the ultimate goal should not only be survival but also the child's ultimate quality of life. Charleta Guillory, a professor of pediatrics at Baylor University in the United States, pointed out that the rate of premature babies is high among black patients and called for the emphasis on long-term care in the face of health disparities. Committee members also recommended that researchers monitor for several possible adverse events, including failure to grow, infection, and maternal and infant mortality.

Charleta Guillory also noted the importance of involving a neutral third party in obtaining consent from patients: "We need a better assessment system through which patients can participate in decision-making." Patient-family representative Gianna McMillan spoke of her experience when having to choose between experimental and standard treatments for her child's malignant brain tumor. Providing easily understood information, opportunities for multiple inquiries, access to third parties and ongoing emotional support will all be critical, she said.

"I don't want people to think that because preterm birth is a complex issue and parents are in a difficult situation, they can't make a well-thought-out decision," said Gianna McMillan.

References:

1. PediatricAdvisoryCommitteeMeetingAnnouncement, https://www.fda.gov/advisory-committees/advisory-committee-calendar/pediatric-advisory-committee-meeting-announcement-09192023

2. Artificialwombs,afteryearsindevelopment,reachFDAreviewforhumantrials, https://www.statnews.com/2023/09/19/fda-studies-artificial-womb-technology/

3. Artificialwombsustainsprematurebabylambsforweeks, https://www.statnews.com/2017/04/25/mechanical-womb-premature-infant/

4. ArtificialWombsWillChangeAbortionRightsForever, https://www.wired.com/story/ectogenesis-reproductive-health-abortion/