Recreating the Womb: New Hope for Premature Babies

Recreating the Womb: New Hope for Premature Babies

Emily Partridge, MD: I think that most physicians who remember their first encounter in the NICU with a critically low birth weight premature infant, they’re fascinatingly resilient. At the same time, they present a real clinical conundrum. Just looking at them, it is immediately clear that they shouldn’t be here yet; they’re not ready.

Kevin Dysart, MD: The first health challenge the very preterm babies face is actually surviving, being born very preterm. Amongst those that survive, the challenges really are some of the things we all take very much for granted: walking, talking, seeing, hearing, and developing along the normal path.

Marcus Davey, PhD: Many of the infants that are born preterm once they leave the hospital can be institutionalized. Many of the infants have cerebral palsy.

Alan Flake, MD: In the United States, about 1 percent of all infants are considered significantly premature. And so, the frequency of prematurity has increased significantly in the last two or three decades. So, the problem isn’t going away.

Marcus Davey, PhD: So, some of the terms we use when talking about preterm infants is mortality, which means death, and morbidity, which means sickness. So, if we take a look at mortality of the infants born at 24 weeks, it’s around about 50 percent. Now, those infants that do survive the early neonatal period, they are normally around about 90 percent morbidity. So the majority of those infants born at 24 weeks have some sort of illness, and most of the time that is due to lung immaturity.

Kevin Dysart, MD: When babies are born at 23 and 24 weeks, they’re really not ready to breathe. They are being cared for with tools that are the best we can provide, and they provide a great benefit compared to 50 years ago. But compared to where we would like to be, we’re still not close.

Emily Partridge, MD: Our system is really a recreation of the environment that a fetus normally resides in.

Marcus Davey, PhD: So, many research groups have been trying to develop a system like this since the 1950s; however, they’ve met with limited success. So, we went back to the literature, and we had a look at what other people had tried, and we sort of transitioned our line of thought to let’s not treat this as a newborn baby, let’s actually treat this as a fetus.

Alan Flake, MD: We chose the lamb, an animal model for a number of reasons. Most of what we know about human fetal development is from the lamb. So, all of the physiologic research over the past 50, 60 years that have told us about the fetal circulation, about developmental events, most of it has been from the lamb. The system — it works by two major components. The first one is a circulatory system that goes through an oxygenator. So, it’s a connection through the umbilical cord vessels that allows blood to flow out of the fetus through the oxygenator back into the fetus. It exchanges gas like the placenta does. And then the other component is a fluid environment that surrounds the fetus and allows the fetus to swallow and breathe amniotic fluid like it’s supposed to during development.

Our lambs receive everything that they receive in their mothers’ womb in a very physiologic way. So, they mature normally; they grow normally.

Emily Partridge, MD: We have reported in our manuscript the support of these fetuses for up to four weeks, which is far in excess of the experience of other researchers.

Marcus Davey, PhD: So, Thomas Edison said to be an inventor, all you need is an imagination and a pile of junk. And essentially, that is the story of this system.

Emily Partridge, MD: For the first few generations, we used a lot of supplies from plumbing/piping, beer stores. We did not have grants at the time. So, it really required a bit of innovation to create the first prototype really from nothing.

Alan Flake, MD: And so, they gathered up some used items from the ECMO program and went on eBay and Home Depot and came up with a primitive fishbowl system. And with all of that, I was convinced that we could do some pilot experiments and they worked amazingly well.

Marcus Davey, PhD: One thing the project has taught me is never give up. You’ve got to keep going, keep going until it works.

Emily Partridge, MD: We believe that the animal data that we have reported in this manuscript really supports translating our system into a clinical therapy for human babies.  

Marcus Davey, PhD: In the future, we envision a system that will be in the NICU, and it will look pretty much like a traditional incubator. It will have a lid that we’ll be able to move up and down, and inside that heated warm chamber will be the infant.

Emily Partridge, MD: It is a hugely important point that we do not intend to challenge the currently accepted standard for a viable infant. The challenging age that we’re trying to offset is that 23- to 24-week baby who is faced with such a challenge of adapting to life outside of the uterus on dry land. So, our intention would not be to support them on our system until they were a chubby 40-week gestation babe. The idea is to bridge the rough patch when they’re really struggling and carry them through to a point when they can do OK.

Kevin Dysart, MD: Nobody is looking to extend the limits of viability with this set of care techniques. I think we’re just simply trying to provide a different set, a different model that has … is clearly revolutionary.

Alan Flake, MD: If it’s as successful as we think it can be, ultimately, the majority of pregnancies that are predicted at a risk for extreme prematurity would be delivered early onto our system, rather than being delivered premature onto a ventilator. With that, we would have normal physiologic development and avoid essentially all of the major risks of prematurity. And that would translate into, you know, a huge impact on pediatric health.

We’re in the process of interacting with the FDA. So, it’s not inconceivable that, you know, we could be talking about a clinical trial one to two years from now.

Emily Partridge, MD: It never fails to strike me what a miracle it is to see this fetus that is clearly not ready to be born enclosed in this fluid space — breathing, swallowing, swimming, dreaming — with complete detachment from the placenta and from mom. It is an awe-inspiring sight. This certainly is a project that would have sounded more like science fiction than a reality, but over three years of really doggedly pursuing it and refusing to accept setbacks and limitations, it has become a very real therapeutic tool.

Marcus Davey, PhD: We had this kind of sort of cool group of people where we could really approach this from different angles and apply all of our skill sets together to move forward and succeed.

Emily Partridge, MD: It has been nothing but a privilege to do this work because of the potential that it represents. These infants are desperate for solutions and for innovation.

Recreating the Womb: Q&A with the Researchers

Alan Flake, MD:  This is a system that we developed for supporting an extreme premature infant in a very physiologic way outside of the mother’s womb.  

Marcus Davey, PhD: We tried to develop the system to mimic all aspects of normal fetal life.  It is a fluidic incubator. So, the infant is reimmersed in an artificial amniotic fluid. And the infant will survive inside the bio-bag with the oxygenator on the outside for a period of up to three to four weeks.

Emily Partridge, MD: So, we have reported in our manuscript the support of these fetuses for up to four weeks, which is far in excess of the experience of other researchers. So, this really has surpassed our reasonable expectations and really is looking like a hugely promising therapy. This is to say that we believe that the animal data that we have reported in this manuscript really supports translating our system into a clinical therapy for human babies.

How does the system work? 

Alan Flake, MD: The system works by two major components. The first one is a circulatory system that goes through an oxygenator. An oxygenator is a device that was originally developed for applications like cardiopulmonary bypass operations, where you have to stop the heart and you pump blood through a device that allows gas exchange like the lungs do.

Emily Partridge, MD: This is a device in which blood flows and carbon dioxide is removed and oxygen is added to that blood. The other component is recreating the womb itself, and that’s really the fluid environment which we have recreated with a soft bag-like structure. It’s meant in some ways to swaddle and keep the fetus supported physically, the way that it would be in the uterus.  

Marcus Davey, PhD: The amniotic fluid we make in the laboratory is designed to mimic the normal electrolyte composition of amniotic fluid. And it’s essentially water with several different salts added to it. We make gallons of it. We make about I think it’s more than 300 gallons per day. It’s quite a production process.

When might this technology be available to human babies?

Alan Flake, MD: We’re in the process of interacting with the FDA. So, it’s not inconceivable that we could be talking about a clinical trial one to two years from now.  

Marcus Davey, PhD: We envision the unit will look pretty much like a traditional incubator. It will have a lid, and inside that warmed environment will be the baby inside the bio-bag. We’ll have amniotic fluid next door to the incubator, which will be pumped through the bio-bag and then leave the bio-bag on the other side.

Alan Flake, MD: Well, parents would see a lot more than they see during a normal pregnancy. We’ll have a dark field camera within the unit, so that they actually look at their fetus in real-time. See their fetus move and breathe and swallow and do all the things that fetuses do. There also be a ultrasound unit, and that’s really how we’ll do physical examinations on the fetus, and so we can’t touch the baby like you can a preterm infant. We will do ultrasound and look at its physiologic well-being at least once or twice a day.

How long would a baby be on this system?

Emily Partridge, MD: The challenging age that we’re trying to offset is that 23- to 24-week baby who is faced with such a challenge of adapting to life outside of the uterus on dry land, breathing air when they’re not supposed to be there yet. So, our intention would not be to support them on our system until they were a chubby 40-week gestation babe. So, the idea is to bridge the rough patch when they’re really struggling and carry them through to a point when they can do OK.    

Alan Flake, MD: With each week of advancing gestation, the morbidity and the mortality progressively decrease. And so, once you get a 23-weeker out to 27 weeks, most of the risk related to prematurity is gone. And you can anticipate that that child would have a much better outcome than one that was delivered 23 weeks.

Could the new system be used to support even younger premature babies?

So, I think any new technology introduces new ethical dilemmas. And I think perhaps the greatest dilemma will be how early to extend this technology, whether to extend it beyond what’s currently the limit of viability, which is around 23 weeks.  And I, at this point in time, would be very worried about doing that. First of all, there are mechanical limitations to what we can do. So, as you get earlier in gestation, fetal blood pressure is lower, fetal blood vessels are smaller, fetal blood flow is much lower. And so you reach mechanical limits as to what will support the circuit.

The other major thing is that there are very important developmental events going on during that … the earlier you get, the more important normal development really is. And I think as we go earlier, we’re very likely to see deficits that only the mother and the placenta can provide that are extremely important in early development in the fetus and become much less important after 22, 23, 24 weeks.  Those are the main reasons I think we’re very likely to inflict other morbidities and harm if we go earlier.

Kevin Dysart, MD: Nobody is looking to extend the limits of viability with this set of care techniques. I think we’re just simply trying to provide a different set, a different model that has … is clearly revolutionary and would frameshift things in an important way.

How common is premature birth?

Alan Flake, MD: In the United States, about 1 percent of all infants are considered significantly premature. There are about 30,000 infants a year born in the United States that would be considered candidates for — in our system. And if you look at the actual numbers of children that are born and have morbidity related to prematurity, that number has gone up; it hasn’t gone down over the past decade. And the reason is is that we’re saving many more extreme premature infants now than used to survive. So, the problem isn’t going away, and it won’t go away in the foreseeable future.

What are the health effects of prematurity?

Kevin Dysart, MD: The babies who are born at 23-24 weeks weigh as much as this bottle of water. This bottle of water contains about 500 milliliters, which are about 500 grams. If you think about somebody fitting in your hand, you start to get an appreciation for how small they are, how fragile they are.

Marcus Davey, PhD: So, some of the terms we use when talking about preterm infants is mortality which means death, and morbidity which means sickness. So, if we take a look at mortality of the infants born at 24 weeks, it’s around about 50 percent. Now, those infants that do survive the early neonatal period, they are normally around about 90 percent morbidity. So, the majority of those infants born at 24 weeks have some sort of illness, and most of the time that is due to lung immaturity.

So, when you’re a fetus, you get the oxygen from your mom. The mother breathes the oxygen in, it travels through her bloodstream to the uterus, then through the placenta, via the umbilical vessels and ultimately to the baby.

Kevin Dysart, MD: The lungs themselves aren’t doing anything until that moment where you hear babies cry and take that first breath. That’s the moment where they’re really functioning for the first time.

Marcus Davey PhD: When these infants are born, they don’t really have great capacity to get the oxygen in and to get the carbon dioxide out. Their lungs are very stiff. And so, clinically what we can do is, we can provide additional support for these infants in the way of mechanical ventilation and supplemental oxygen.  Now, we know that these two therapies, although beneficial, can actually be detrimental to the infant’s lungs in the long term.

Kevin Dysart, MD: Exposure to oxygen, exposure to being breathed for, creates an injury to the lung that we call bronchopulmonary dysplasia, which simply means that the lungs and airways develop in a different way because of that abnormal stimulation. They are being cared for with tools that are the best we can provide, and they provide a great benefit compared to 50 years ago. But, the best outcomes we’re able to create right now are still not nearly the same as they would have been if the pregnancy had continued.

What are the financial costs of prematurity?

Marcus Davey, PhD: So, the cost of care of preterm infants in the United States is many tens of billions of dollars a year. And that’s just for looking after the kids while they’re in the hospital.

Alan Flake, MD: That doesn’t even take into account the costs that are much harder to get a handle on, and those are the ongoing costs of lung disease, neurologic problems, intestinal disorders, blindness, all of the things that severe prematurity is associated with.

Marcus Davey, PhD: We don’t know the absolute long-term care cost of preterm infants. Many of the infants that are born preterm, once they leave the hospital can be institutionalized. That also costs many, many millions of dollars for the lifetime of the individual to care for them.

Alan Flake, MD: So half of our children in nursing homes from neurologic injury, for instance with cerebral palsy, are related to prematurity. So, it’s really a devastating disease if you want to look at it that way. It should eradicate many of the late costs of the morbidity related to prematurity if it’s successful.

Have research teams tried to create something like this before?

Marcus Davey, PhD: So, many research groups have been trying to develop a system like this since the 1950s. Many groups have attempted to develop the system; however, they’ve met with limited success.

Alan Flake, MD: One of the main differences in what we’ve done versus some of the previous attempts that failed, is that we’ve been able to do this without introducing a pump into the circuit.

Emily Partridge, MD: So, where the previous groups used large circuits with pumps that were forcing the blood through at a certain rate and inducing heart failure, we have instead innovated a circuit in which the flow of blood is entirely driven by the fetus, which is what a fetus does in utero.

Marcus Davey, PhD: And so, we are able to cannulate the umbilical vessels, connect up to the oxygenator. In that way, or in that situation, the baby’s heart is doing the pumping, the blood is pumped out through the umbilical arteries to the oxygenator and then returns to the umbilical vein and back to the baby carrying oxygen from the oxygenator.

Alan Flake, MD: Every step has been directed toward normality. Every obstacle that we’ve encountered, we’ve been able to overcome by turning to Mother Nature; it’s a normal physiology and trying to replicate it. And that’s the beauty of this system.

How was the new system invented?

Emily Partridge, MD: I think that most physicians who remember their first encounter in the NICU with a critically low birth weight premature infant, they’re fascinatingly resilient. At the same time, they present a real clinical conundrum.  Just looking at them, it is immediately clear that they shouldn’t be here yet; they’re not ready. And, I had many compelling encounters with those patients over the course of my training. All of which really led to the idea that we should be able to do better for them.

Marcus Davey, PhD: The system has undergone significant modifications since we started this project around about four years ago. We first started with a simple plastic tank. It was something that I took from the lab. I took it home, started to drill holes in the side of it, and sort of glued things together. And that was really prototype one.

Emily Partridge, MD: We did not have grants at the time. So, it really required a bit of innovation to create the first prototype really from nothing.

Marcus Davey, PhD: So, Thomas Edison said to be an inventor, all you need is an imagination and a pile of junk. And essentially, that is the story of this system. Sometimes we ended up going to Home Depot, we ended up going to Lowe’s, and to Michael’s, and we would bring these objects back to the lab and sort of glue them and melt them all together. As we moved on generating through the prototypes, we’ve acquired a little bit of additional funding, which has helped us to refine the prototypes and finally get to prototype three and four, which is the bio-bag. The bio-bag has been, you know, a huge step forward for the project.

Emily Partridge, MD: It never fails to strike me what a miracle it is to see this fetus that is clearly not ready to be born enclosed in this fluid space — breathing, swallowing, swimming, dreaming — with complete detachment from the placenta and from mom. It is an awe-inspiring sight.

Marcus Davey, PhD: What I would say to people that would want to sort of take on an endeavor like this is just don’t give up. You’ve got to keep going, keep going until it works.