They are developing what they refer to as an “artificial womb”, or extra-uterine environment for newborn development (Extend) to be precise. Extend is not intended to grow a foetus from conception to birth – that would be impossible even if it was desirable. Instead, it is intended to help boost the survival rate of extremely premature infants, who face a plethora of possible health effects throughout their lives.
It sounds like a plot straight out of a bad science fiction movie – human babies taken from their mothers’ wombs and grown inside fluid-filled pods instead. Yet that is exactly what scientists at the Children’s Hospital of Philadelphia (CHOP) in Pennsylvania in the US propose doing for infants at risk of extreme prematurity.
A typical healthy pregnancy lasts around 40 weeks, with babies considered full term at 37 weeks. However sometimes complications occur in pregnancy that may result in a baby having to be delivered early.
Luckily, thanks to huge advances in neonatal medicine over the last few decades, most premature infants survive and are discharged with few complications. The most recent data shows that even 30% of 22-week-gestation patients survive if given intensive care.
Babies born on the cusp of viability often face severe health challenges. These infants weigh less than 2lb (900g) at birth, and critical organs such as the heart, the lungs, the digestive organs, and the brain are not yet developed enough to keep the baby alive without intensive medical care.
Short-term complications which frequently arise include necrotising enterocolitis (NEC), a serious illness in which tissues in the intestine (gut) become inflamed and start to die. Infants of this age are also very prone to infection, sepsis and septic shock – a life-threatening drop in blood pressure that can damage the lungs, kidneys, liver and other organs.
Long-term conditions that can impact newborns born very early include asthma, cerebral palsy, mild to severe learning disabilities, and trouble with vision and hearing.
The goal of artificial placentas and wombs is to completely eliminate the lungs from the equation.
Even ventilator and oxygen support systems, which are meant to save the lives of the kids, might damage their developing lungs.
“At that early gestational age, the lungs are still developing and should be filled with fluid,” explains George Mychaliska, an obstetrics and gynaecology professor at Michigan University’s C. S. Mott Children’s Hospital.
“However, we insert an endotracheal tube into their trachea and force air and oxygen under extreme pressure and tension into their lungs when babies are born really preterm.
Over time the injuries lead to scarring of the lungs and a condition known as bronchopulmonary dysplasia, or chronic lung disease. Children often leave hospital needing long-term oxygen support and require mechanical ventilation for the rest of their lives. Ventilation can also raise the risk of retinal blindness. The blood vessels that feed the eye’s retina aren’t fully formed until close to birth. Too much oxygen can trigger the growth of new, abnormal blood vessels, which can ultimately lead to retinal detachment.
The idea behind artificial wombs and placentas is to take the lungs out of the equation all together, allowing time for the foetus to continue developing in a safe environment until the baby is ready to take its first breath.
There are three major groups working on the technology. All three are inspired by an existing therapy known as extracorporeal membrane oxygenation (Ecmo), which is a sort of mechanical life support that can aid people whose lungs and hearts aren’t working properly. Ecmo involves pumping blood outside of the patient’s body to a machine that eliminates CO2 and adds oxygen. The oxygenated blood is subsequently returned to tissues in the body.
This approach allows the blood to “bypass” the heart and lungs, giving them time to rest and mend. Ecmo can be used on older babies, although it is not appropriate for extremely preterm infants. All three teams are working to miniaturise and adapt the technology.
However, there are subtle differences between the different devices in development.
Scientists at CHOP, led by foetal surgeon Alan Flake, plan to submerge premature babies in fluid-filled pods designed to mimic the amniotic fluid of the womb. Surgeons would then connect the tiny blood vessels of the baby’s umbilical cord to an Ecmo-like device. The blood is pumped around the system using the foetal heart, just like in nature.
In 2017, Flake and his colleagues took eight premature lambs of an equivalent gestational age to 23-to-24-week-old human foetuses and kept them alive for four weeks using the artificial womb. During this time the lambs seemed to develop normally, even growing wool.
George Mychaliska’s team at the University of Michigan, on the other hand, are developing what they call an artificial placenta. Rather than submerging the whole foetus in fluid, they plan on using breathing tubes to fill the lungs of the infant with a specially developed fluid. Their system drains blood from the heart via the jugular vein, similar to traditional Ecmo machines, but returns oxygenated blood via the umbilical vein.
Premature lambs maintained on the machine survived for 16 days before being safely transferred to mechanical ventilation. “I wanted a platform that’s readily available to most babies, and that could be used in existing neonatal intensive-care units,” says Mychaliska.
“The technology isn’t intended to replace the myriad functions of the placenta. It’s focusing on gas exchange and maintaining blood pressure, heart rate and foetal circulation while the premature organs are protected and continue developing.”
In a recent trial of the artificial placenta, premature lambs maintained on the machine survived for 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 (Eve) therapy. It is aimed at treating more premature and sick foetuses than the other two groups.
“In the one experiment that we’ve done with quite compromised foetuses, those animals are much more difficult to manage,” says Kemp.
We think that it’s pretty clear that a very small foetus doesn’t have the ability to direct its own growth in a normal fashion.
“Their growth is far worse, and maintaining normal blood pressure and flow is much more challenging. So, while we’re making good progress, we still have a lot of things to work out.
So, how soon will we be seeing artificial placentas and wombs in hospitals? CHOP is arguably the furthest in the development pipeline. The team has applied to the Federal Drug Administration (FDA) for approval to commence human studies with Extend. Mychaliska, on the other hand, wants to begin human clinical trials in three or four years, when his team has further miniaturised their device to accommodate the tiny blood arteries of a human neonate.
However, Kemp still thinks there are fundamental gaps in our knowledge of how foetuses grow in artificial wombs that need filling in before we move to trials.
“We think that it’s pretty clear that a very small foetus doesn’t have the ability to direct its own growth in a normal fashion, and that’s exacerbated when it is sick,” says Kemp.
“So we’re attempting to understand the role of the placenta in promoting those normal growth processes. This is where we’re at currently. To put it plainly, that is a daunting task.”
There are also ethical considerations. Stephanie Kukora argues in a recent study that the diverse technologies provide new ethical issues due to small distinctions. For example, because both the EVE and CHOP teams’ artificial wombs need the insertion of a cannula into the umbilical cord, newborns must be moved from the mother to the device as soon as possible because the umbilical artery closes shortly after birth. Mothers who could have delivered vaginally would have to undergo an early Caesarean surgery.
“When you have a Caesarean section that early, they can’t do it the way that they do it at term,” says Kukora.
“It involves an incision that goes through the muscular layer of the uterus, and that can have an impact on future pregnancies, such as whether they can go to term and whether they can be delivered vaginally. “There are more risks associated with this procedure compared to a vaginal birth, which raises issues to do with informed consent.
“I think that one of the biggest ones is how we will approach expectant parents about doing this trial,” Kukora explains.
“You can image a parent who is in this incredibly sad circumstance, who has just been counselled about the dismal results at 22 weeks, and who is quite excited for something new, even if it is untested. Parents will go to any length to protect their infant.”
Babies who would normally have done well on established medicines could be treated on a new experimental technique, the hazards of which are far less quantifiable.
Another disadvantage of instantly shifting a kid to the Extend system is that there is no opportunity to evaluate how that baby would have performed on traditional therapy. “You don’t have a lot of data apart from the gestational age to decide who goes on the Extend system – because the baby’s not born yet, so you don’t know how they’re doing,” says Mychaliska.
This may mean that babies who would otherwise have done well on traditional therapies could be treated on a new untested technology, whose risks are much less quantified. However, Mychaliska believes Extend would be beneficial for the most premature infants at 22-23 weeks gestational age, who are known to suffer high mortality and morbidity.
Because it drains blood from the jugular vein rather than the umbilical artery, surgeons have more time to deliver newborns using Mychaliska’s artificial placenta. This enables clinicians to “risk stratify” kids after delivery, ensuring that only the sickest children are transferred to the trial’s therapy arm. Infants might also be treated with conventional medicine initially, then moved to an artificial placenta if they did not respond adequately. Unlike the other two technologies, mothers can deliver their kids vaginally.
Whichever technique enters trials first, the first participants are likely to be babies delivered before 24 weeks who have a very low probability of survival with a positive outcome using traditional care.
“I think the technology will revolutionise the field of prematurity, and the artificial placenta and Extend approaches will be complimentary in clinical practice,” says Mychaliska.
“But it is not without potential risks, which must be assessed during an initial safety trial.” I believe that the initial application of this technique should be on kids with a low likelihood of survival, and then expanded to include more premature children after the hazards and efficacy of this technology are determined.”
If effective, these three technologies will provide a much-needed ray of hope to parents who unexpectedly go into premature labour.
