It sounds like the plot of a bad science fiction movie: human babies taken from their mothers’ wombs and raised in fluid-filled capsules.
Yet that’s exactly what scientists at the Children’s Hospital of Philadelphia (CHOP) in Pennsylvania are proposing to do for babies at extreme risk of preterm birth.
They are developing what they call an “artificial uterus” or, more precisely, an extrauterine environment for the development of the newborn (Extend).
Extend is not intended to grow a fetus from conception to birth, which would be impossible even if it were attempted. It is intended to increase the survival rate of extremely premature babies, who face a host of potential health effects throughout their lives.
A normal healthy pregnancy lasts about 40 weeks and a baby is considered fully developed at 37 weeks. However, sometimes pregnancy complications arise which can result in the baby having to be born early.
Fortunately, thanks to the enormous advances in neonatal medicine in recent decades, most premature babies survive and are discharged with few complications. The most recent data show that even 30% of babies born at 22 weeks gestation survive if they receive intensive care.
“Honestly, babies at 28 weeks and even 27 weeks are generally doing very well,” says Stephanie Kukora, a neonatologist at Mercy Children’s Hospital in Kansas City.
“It is actually babies born between 22 and 23 weeks who have such severe outcomes that we are not sure that the quality of life they achieve will be acceptable.”
Risks of premature babies
Babies born at the peak of viability often face serious health problems.
They weigh less than 900 grams at birth. Their critical organs, such as the heart, lungs, digestive organs and brain, have not yet developed enough to sustain them alive without intensive medical care.
Among the most common short-term complications is necrotizing enterocolitis (NEC), a serious condition in which tissues in the intestine become inflamed and begin to die.
Babies this age are also very prone to infections, sepsis and septic shock, a potentially life-threatening drop in blood pressure that can damage the lungs, kidneys, liver and other organs.
Long-term problems that can affect extremely premature babies include cerebral palsy, moderate to severe learning difficulties, vision and hearing problems, and asthma.
How to help them?
The idea of artificial wombs and placentas is to ensure that the lungs do not come into play.
Today, even the very technology designed to save babies’ lives (oxygen and ventilation) can damage their fragile lungs.
“At that early gestational age, the lungs are still developing and should be filled with fluid,” says George Mychaliska, MD, professor of surgery, obstetrics and gynecology at the University of Michigan C.S. Mott Children’s Hospital.
“But when they are born very prematurely, we put an endotracheal tube in their trachea and we put air and oxygen at high tension and pressure into their lungs. It is well documented that this causes injury.”
Over time, the injuries lead to scarring of the lungs and a condition known as bronchopulmonary dysplasia, or chronic lung disease. Children often leave the hospital requiring long-term oxygen and mechanical ventilation for the rest of their lives.
Ventilation can also increase the risk of retinal blindness. The blood vessels that feed the retina of the eye are not fully formed until near birth.
Too much oxygen can trigger the growth of new, abnormal blood vessels, which can eventually lead to retinal detachment.
By removing the lungs from the equation, the new technology would allow the fetus to continue developing in a safe environment until the baby is ready to take its first breath.
There are 3 main groups working on this.
All three are inspired by an existing therapy called extracorporeal membrane oxygenation (ECMO), a type of artificial life support that can help a person whose lungs and heart are not working properly.
In ECMO, blood is pumped out of the patient’s body to a machine that removes carbon dioxide and adds oxygen. The oxygenated blood is then returned to the body’s tissues.
This method allows blood to bypass the heart and lungs, allowing these organs to rest and heal. Although ECMO can be used in older babies, it is not suitable for extremely premature babies. All three teams are trying to miniaturize and adapt the technology.
However, there are subtle differences between the various devices in development.
The alternatives
Scientists at the Children’s Hospital of Philadelphia, led by fetal surgeon Alan Flake, plan to immerse premature babies in fluid-filled capsules designed to mimic the amniotic fluid in the womb.
Surgeons would then connect tiny blood vessels in the baby’s umbilical cord to an ECMO-like device. Blood is pumped through the system using the fetus’s heart, just as in nature.
In 2017, Flake and his colleagues took eight premature lambs of a gestational age equivalent to that of human fetuses between 23 and 24 weeks and kept them alive for four weeks using the artificial womb.
During this time, the lambs appeared to develop normally and even produced wool.
Meanwhile, George Mychaliska’s team at the University of Michigan is developing what they call an artificial placenta.
Instead of submerging the entire fetus in liquid, they plan to use breathing tubes to fill the baby’s lungs with a specially developed liquid. Their system drains blood from the heart through the jugular vein, similar to traditional Ecmo machines, but returns oxygenated blood through the umbilical vein.
Premature lambs kept on the machine survived 16 days before being safely transferred to mechanical ventilation.
“I wanted a platform that would be accessible to most babies and could be used in neonatal intensive care units,” Mychaliska explains.
“The technology is not intended to replace the many functions of the placenta. It focuses on gas exchange and maintaining fetal blood pressure, heart rate and circulation while premature organs are protected and continue to develop.”
In a recent trial of the artificial placenta, premature lambs kept on the machine survived 16 days before being safely transferred to mechanical ventilation. During this time, their lungs, brains and other organs continued to develop well.
The third group, a team from Australia and Japan, is developing an artificial womb called ex vivo uterine environment therapy (EVE). Its goal is to treat more premature and sick fetuses than the other two groups.
“We’ve reached a point where we can take a 500-gram fetus and maintain it in what I would describe as a normal physiological state for two weeks,” says Matt Kemp, a professor of obstetrics and gynecology at the National University of Singapore, who heads Eve.
“It’s a pretty amazing achievement, but on the other hand, the growth of these fetuses is abnormal.”
Most trials using placentas or artificial wombs are conducted on lamb fetuses that are otherwise healthy and would have reached full gestation if they had not been terminated.
The problem is that extremely premature babies are often born early due to health complications of the mother or the fetus itself. Therefore, it is more complicated to treat them.
“In the only experiment we’ve done with fairly compromised fetuses, those animals are much more difficult to treat,” Kemp says.
“We think it’s pretty clear that a very small fetus doesn’t have the ability to direct its own growth in a normal way,” he explains.
“Their growth is much more complicated and their blood pressure and flow are much, much more difficult to keep normal. So we are making progress, but we still have a lot of things to figure out.”
Still under investigation
When will we see artificial placentas and wombs in hospitals?
CHOP is probably the center furthest along in the development process. The team has just applied to the U.S. Federal Drug Administration for permission to begin human trials of Extend.
Mychaliska, for his part, hopes to move on to human clinical trials in about three to four years, after his team has further miniaturized their system so it can work with the tiny blood vessels of a human newborn.
However, Kemp still believes there are fundamental gaps in our understanding of how fetuses grow in artificial wombs that need to be filled before moving on to trials.
“We think it’s pretty clear that a very small fetus doesn’t have the capacity to direct its own growth in a normal way, and that’s exacerbated when it’s sick,” Kemp said.
“We are trying to figure out how the placenta is involved in normal growth processes. That is what we are working on. It is a rather big task, to put it mildly.”
Question of ethics
There are also ethical considerations. In a recent article, Stephanie Kukora argues that there are subtle differences between different technologies that create unique ethical challenges.
For example, because the artificial wombs used by EVE and CHOP teams require the placement of a cannula in the umbilical cord, babies must be transferred immediately from the mother to the device because the umbilical artery closes quickly after birth.
Therefore, mothers who could have given birth vaginally would have to undergo an early Caesarean section.
“When you do a C-section so early, you can’t do it as you would when the baby is fully developed,” says Kukora.
“It involves an incision that goes through the muscular layer of the uterus, and that can affect future pregnancies, which means whether they can carry a full pregnancy or have a vaginal birth.”
There are more risks associated with this procedure compared to a vaginal birth, raising issues regarding informed consent.
“I think one of the most important things is how we approach prospective parents about doing this trial,” Kukora said.
“We can imagine parents facing “a really sad situation, that they have just been counselled about the poor results at 22 weeks, and they might be really excited about something new even though it hasn’t been tried. Parents will do anything for their children.”
Another problem with immediately transferring a baby to the Extend system is that there is no opportunity to assess how he or she would have fared with conventional therapy.
“There is not much data available, other than gestational age, to decide who gets Extend because the baby has not yet been born and we don’t know how it is,” Mychaliska explains.
This could mean that babies who would otherwise have done well with traditional therapies could be treated with a new, unproven technology, the risks of which are much less quantified.
However, Mychaliska believes the Extend would be beneficial for more premature babies, 22-23 weeks gestational age, who are known to suffer high mortality and morbidity.
By draining blood from the jugular vein instead of the umbilical artery, doctors have more time to place the babies into Mychaliska’s artificial placenta.
This allows specialists to “risk stratify” babies after birth, with the aim of ensuring that only the sickest are transferred to treatment with this method.
Babies could also be treated with conventional therapy first and then transferred to the artificial placenta if they do not develop well. Unlike the other two technologies, mothers can also give birth vaginally.
Whichever technology makes it into trials first, the first participants are likely to be babies born before 24 weeks who have a very low chance of surviving with a good outcome using conventional treatment.
“I believe that technology will revolutionize the field of prematurity and that the artificial placenta and Extend will complement each other in clinical practice,” says Mychaliska.
“But it is also not without potential risks that need to be evaluated in an initial safety trial. I believe that the initial application of this technology should be in babies with little chance of survival, and then expanded to more premature babies once we determine the risks and efficacy of this technology.”
If successful, all three technologies will offer much-needed lifeline to parents who unexpectedly go into premature labor.
This article was originally published on BBC Future. Can lRead the English version here.
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