Bench to Bedside | April/May 2017

Researchers Recreate Womb Experience to Transform Care of Premature Infants

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Every child begins life in a paradise built of biological wonders. The umbilical cord tethering the fetus to her mother’s placenta not only enables the exchange of blood gases in place of breathing air, but it also permits her to float and rotate within the warm incubating amniotic fluid while it delivers her every nutritional need as she grows ready for independent life.

Babies born too soon suffer from the paradise lost. About 30,000 per year are critically preterm — younger than 26 weeks. The most fragile preemies who have any hope of being viable, born at only 22 or 23 weeks, face immense struggles in their first hours and days of life. One of the biggest threats is their fragile, underdeveloped lungs, which are not prepared to take in and out the dry air around them. Extremely premature infants who do survive encounter a 90 percent risk of morbidity and face lifelong, complex medical issues.

“Just looking at [extremely premature infants], it is immediately clear that they shouldn’t be here yet. They’re not ready,” said Emily Partridge, MD, a fellow in the Center for Fetal Research at Children’s Hospital of Philadelphia. “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.”

This desire spurred a multidisciplinary team at CHOP to use their ingenuity, innovation, and perseverance to create a unique, fluid-filled environment that mimics as closely as possible how a fetus experiences life in the womb. The system, which only has been tested in animal studies, could one day transform care for extremely premature babies by giving them a precious few weeks to develop their lungs and other organs.

“These infants have an urgent need for a bridge between the mother’s womb and the outside world,” said study leader and senior author Alan Flake, MD, a fetal surgeon and director of the Center for Fetal Research at CHOP and a professor of Surgery and Obstetrics and Gynecology at the Perelman School of Medicine at the University of Pennsylvania. “If we can develop an extra-uterine system to support growth and organ maturation for only a few weeks, we can dramatically improve outcomes for extremely premature babies.”

The sealed, sterile system is insulated from variations in temperature, pressure, and light, and particularly from hazardous infections. While the idea may at first have sounded more like science fiction than reality, the study team persistently pursued it for more than four years. Many technological revisions to the incubator system and physiologic monitoring of the fetus were necessary to best recapitulate fetal physiology. The study team recently described findings from their inception pilot study through the evolution of four rounds of prototypes in preclinical studies of the device in the journal Nature Communications.

The study team tested the most recent prototype on eight fetal lambs, which have similar prenatal lung development to humans, for up to 28 days, and they remained healthy. Vital signs, blood flow, fetal blood gases, and other parameters were continuously monitored 24/7, which required a continuous attentive presence by team members for the duration of the study.

“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,” Dr. Partridge said. “It is an awe-inspiring sight every time.”

The device started as a glass incubator tank combined with monitoring devices, and it has become more sophisticated as each prototype advanced. The current preclinical model uses a meticulously designed fluid-filled container that is custom made to fit each fetus and support it as if it were being carried in the uterus. A continuous amniotic fluid exchange system developed by CHOP fetal physiologist Marcus Davey, PhD, supplies nutrients and growth factors that are produced in the laboratory. Dr. Davey also is an assistant professor in the department of Surgery at Penn.

The fetus’ heart pumps blood via the umbilical cord into a low-resistance external oxygenator that substitutes for the mother’s placenta in exchanging oxygen and carbon dioxide. The system does not rely on an external pump to drive circulation because even gentle artificial pressure can fatally overload an underdeveloped heart, and there is no ventilator because immature lungs are not ready to do their work of breathing in atmospheric oxygen.

“We have innovated a circuit in which the flow of blood is entirely driven by the fetus, which is what a fetus does in utero,” Dr. Partridge said. “It perfuses its own placenta, and it regulates that perfusion in a way that we think probably can’t be improved upon. Nature usually has a reason for its design. So rather than trying to impose something artificial, what we have striven to do at every turn is to recapitulate the normal physiology of a fetus.”

In order to allow the fetus to establish and maintain a normal circulatory pattern, one of the team’s main challenges was to find a way to preserve as much of the fetus’ native umbilical cord as possible and then to place cannulas as a gateway from the body’s own blood vessels to the oxygenator’s circuit. The cannulas, which are short pieces of tubing, pass into the umbilical arteries and vein and then connect to the circuit that directs the blood flow to the oxygenator. Once that cannulation is complete and the fetus is stable, then they can cut the umbilical cord and move the fetus into the system’s fluid-filled enclosure.

Dr. Flake stresses that the team does not aim to extend fetuses’ viability to an earlier period than the current mark of 23 weeks. Before that point, limitations of physical size and physiologic monitoring would impose unacceptably high risks. However, he added, “This system is potentially far superior to what hospitals can currently do for a 23-week-old baby born at the cusp of viability. This could establish a new standard of care for this subset of extremely premature infants.”

The system also is not intended to support an infant until full-term at 40 weeks. Its purpose is to stabilize the critical period when a very premature infant is most at risk until she reaches 28 or 29 weeks, when there is an improved chance of survival and good outcomes as she transitions to the care of a traditional neonatal intensive care unit. If more research shows that the animal studies could translate into clinical care, Dr. Flake envisions that in a decade or so the system could be a feasible way to bridge the time from womb to the outside world to reduce mortality and disability for extremely premature babies.

Attempting to recreate the womb experience has been an extraordinary research effort that presented huge engineering and circulatory challenges, but it also has been one of the most rewarding endeavors for Dr. Flake’s laboratory team.

“Having the opportunity to work on a project that I had thought about for years, ever since seeing sick babies in the NICU, was really the realization of a dream,” Dr. Partridge said. “And it has required a pretty heroic effort on the part of the team to make this happen … But 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.”

Read more about the development of this womb-like system in our 2014 Annual Report. See the current press release. And watch a related video.


www.research.chop.edu

Produced by The Children’s Hospital of Philadelphia Research Institute.

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