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On September 19, US Food and Drug Administration advisors met to discuss how to move research on artificial wombs from animals into humans. These medical devices are designed to give extremely premature infants a bit more time to develop in a womblike environment before entering the outside world. They have been tested with hundreds of lambs (and some piglets), but animal models can’t fully predict how the technology will work for humans.
“The most challenging question to answer is how much unknown is acceptable,” said An Massaro, FDA’s lead neonatologist in the Office of Pediatric Therapeutics, at the committee meeting. That’s a question regulators will have to grapple with as this research moves out of the lab and into first-in-human trials.
What is an artificial womb?
An artificial womb is an experimental medical device intended to provide a womblike environment for extremely premature infants. In most of the technologies, the infant would float in a clear “biobag,” surrounded by fluid. The idea is that preemies could spend a few weeks continuing to develop in this device after birth, so that “when they’re transitioned from the device, they’re more capable of surviving and having fewer complications with conventional treatment,” says George Mychaliska, a pediatric surgeon at the University of Michigan.
One of the main limiting factors for survival in extremely premature babies is lung development. Rather than breathing air, babies in an artificial womb would have their lungs filled with lab-made amniotic fluid, that mimics the amniotic fluid they would have hadjust like they would in utero. Neonatologists would insert tubes into blood vessels in the umbilical cord so that the infant’s blood could cycle through an artificial lung to pick up oxygen.
The device closest to being ready to be tested in humans, called the EXTrauterine Environment for Newborn Development, or EXTEND, encases the baby in a container filled with lab-made amniotic fluid. It was invented by Alan Flake and Marcus Davey at the Children’s Hospital of Philadelphia and is being developed by Vitara Biomedical.
Other researchers are working on artificial wombs too, though they’re a bit farther behind. Scientists in Australia and Japan are developing a system very similar to EXTEND. In Europe, the Perinatal Life Support project is working on its own technology. And in Canada, researchers have been testing their version of an artificial womb on piglets. Researchers at the University of Michigan are working on similar technology intended to be used within preemies for whom conventional therapies aren’t likely to work. Rather than floating in fluid, the infants would only have their lungs filled. It’s a system that could be used in existing ICUs with relatively few modifications, so “we believe that that has more clinical applicability,” says Mychaliska,who is leading the project.
When will this technology be tested in humans?
The technology used in the EXTEND system has been tested on lamb fetuses, about 300 so far, with good results. The lambs can survive and develop inside the sack for three or even four weeks.
To move forward with human testing, the company needs an investigational device exemption from the FDA. At a meeting in June, Flake said Vitara might be ready to request that exemption in September or October. But at the September advisory committee meeting, when Flake was directly asked how far the technology had advanced he declined to answer. He said he could discuss timing with the advisory committee during the portion of the meeting that was closed to the public. To greenlight a trial, FDA officials need to be convinced that babies who try EXTEND are likely to benefit from the system, and that they’ll fare at least as well as babies who receive the current standard of care.
What would the first human tests look like?
The procedure requires a carefully choreographed transfer. First, the baby must be delivered via cesarean section and immediately have tubes inserted into the umbilical cord before being transferred into the fluid-filled container.
The technology would likely be used first on infants born at 22 or 23 weeks who don’t have many other options. “You don’t want to put an infant on this device who would otherwise do well with conventional therapy,” Mychaliska says. At 22 weeks gestation, babies are tiny, often weighing less than a pound. And their lungs are still developing. When researchers looked at babies born between 2013 and 2018, survival among those who were resuscitated at 22 weeks was 30%. That number rose to nearly 56% at 23 weeks. And babies born at that stage who do survive have an increased risk of neurodevelopmental problems, cerebral palsy, mobility problems, hearing impairments, and other disabilities.
Selecting the right participants will be tricky. Some experts argue that gestational age shouldn’t be the only criteria. One complicating factor is that prognosis varies widely from center to center, and it’s improving as hospitals learn how best to treat these preemies. At the University of Iowa Stead Family Children’s Hospital, for example, survival rates are much higher than average: 64% for babies born at 22 weeks. They’ve even managed to keep a handful of infants born at 21 weeks alive. “These babies are not a hopeless case. They very much can survive. They very much can thrive if you are managing them appropriately,” says Brady Thomas, a neonatologist at Stead. “Are you really going to make that much of a bigger impact by adding in this technology, and what risks might exist to those patients as you’re starting to trial it?”
Prognosis also varies widely from baby to baby depending on a variety of factors. “The girls do better than the boys. The bigger ones do better than the smaller ones,” says Mark Mercurio, a neonatologist and pediatric bioethicist at the Yale School of Medicine. So “how bad does the prognosis with current therapy need to be to justify use of an artificial womb?” That’s a question Mercurio would like to see answered.
What are the risks?
One ever-present concern in the tiniest babies is brain bleeds. “That’s due to a number of factors—a combination of their brain immaturity, and in part associated with the treatment that we provide,” Mychaliska says. Babies in an artificial womb would need to be on a blood thinner to prevent clots from forming where the tubes enter the body. “I believe that places a premature infant at very high risk for brain bleeding,” he says.
And it’s not just about the baby. To be eligible for EXTEND, infants must be delivered via cesarean section, which puts the pregnant person at higher risk for infection and bleeding. Delivery via a C-section can also have an impact on future pregnancies.
So if it works, could babies be grown entirely outside the womb?
Not anytime soon. Maybe not ever. In a paper published in 2022, Flake and his colleagues called this scenario “a technically and developmentally naive, yet sensationally speculative, pipe dream.” The problem is twofold. First, fetal development is a carefully choreographed process that relies on chemical communication between the pregnant parent’s body and the fetus. Even if researchers understood all the factors that contribute to fetal development—and they don’t—there’s no guarantee they could recreate those conditions.
The second issue is size. The artificial womb systems being developed require doctors to insert a small tube into the infant’s umbilical cord to deliver oxygenated blood. The smaller the umbilical cord, the more difficult this becomes.
What are the ethical concerns?
In the near term, there are concerns about how to ensure that researchers are obtaining proper informed consent from parents who may be desperate to save their babies. “This is an issue that comes up with lots of last-chance therapies,” says Vardit Ravitsky, a bioethicist and president of the Hastings Center, a bioethics research institute.
If the artificial wombs work, more significant questions will come up. When these devices are used to save infants born too soon, “this is obviously potentially a wonderful technology,” Ravitsky says. But as with any technology, other uses might arise. Imagine that a woman wants to terminate a pregnancy at 21 or 22 weeks and this technology is available. How would that impact a woman’s right to choose whether to carry a pregnancy to term? “When we say that a woman has the right to terminate, do we mean the right to physically separate from the fetus? Or do we mean the right not to become a biological mother?” Ravitsky asks.
With the technology at an early stage, that situation might seem far-fetched, but it’s worth thinking about the implications now. Elizabeth Chloe Romanis, who studies health-care law and bioethics at Durham University in the UK, argued at the advisory meeting that “an entity undergoing gestation outside the body is a unique human entity,” one that might have different needs and require different protections.
The advent of an artificial womb raises all kinds of questions, Ravitsky says: “What’s a fetus, what’s a baby, what’s a newborn, what’s birth, what’s viability?” These questions have ethical implications, but also legal ones. “If we don’t start thinking about it, now we’re going to have lots of blind spots,” she says.
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