[REV. MED. CLIN.

CONDES - 2021; 32(6) 699-706]

REVISTA MÉDICA CLÍNICA LAS CONDES

[Link]

The artificial placenta: sci-fi or reality?

La placenta artificial: ¿ciencia ficción o realidad?

Haruo Usudaa,b, Erin L Feea, Tsukasa Takahashia,b, Yuki Takahashia,b, Sean Cartera, John P Newnhama,e, Matthew W Kempa,b,c,d,e .

a
Division of Obstetrics and Gynaecology, The University of Western Australia, Perth, Western Australia, Australia.
b
Centre for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan.
c
School of Veterinary and Life Sciences, Murdoch University, Perth, Western Australia, Australia.
d
Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
e
Women and Infants Research Foundation, King Edward Memorial Hospital, Perth, Western Australia, Australia.

INFORMACIÓN RESUMEN
DEL ARTÍCULO Una placenta artificial es una plataforma de soporte vital para bebés prematuros o que tuvieron menos
de 37 semanas de gestación completa. Aunque existe la posibilidad de utilizar esta plataforma para la
Historia del
reparación intraoperatoria de anomalías congénitas (p. ej., hernia diafragmática congénita) en bebés
Artículo:
Recibido: 31 08 2021. prematuros tardíos, o para el estudio del desarrollo fetal, el objetivo principal de esta tecnología es
Aceptado: 15 10 2021. actualmente el tratamiento de bebés extremadamente prematuros, o aquellos nacidos durante el período
peri-viable entre las 21-24 semanas de gestación completa.
Palabras clave:
Placenta Artificial;
Prematuro; Feto; Los bebés que nacen en este período peri-viable, generalmente tienen malos resultados debido a la
Oxigenador; Cordero. necesidad de ventilar mecánicamente sus pulmones extremadamente inmaduros, a menudo a altas
presiones máximas. Las plataformas de soporte vital basadas en placenta artificial están diseñadas para
Key words: evitar la necesidad de ventilar como un medio para facilitar el intercambio de gases y así evitar lesiones
Atificial Placenta; en el pulmón prematuro inmaduro. En cambio, el intercambio de gases altamente eficiente y fácilmente
Preterm; Fetus;
Oxygenator; Lamb. regulado se realiza mediante dispositivos de intercambio de gases conectados a la vasculatura fetal.
Dependiendo de la forma del sistema utilizado, se han probado diseños de circuitos venoso-venosos y
arterio-venosos, con los prototipos arterio-venosos más recientes que utilizan el corazón fetal, en lugar de
una bomba externa, para generar la presión del circuito.

A pesar de tener la apariencia de un concepto futurista, el trabajo de desarrollar una placenta artificial
se ha llevado a cabo de forma intermitente desde al menos finales de los años 50. El hecho de que la
tecnología aún no haya entrado en servicio clínico, a pesar de que han pasado más de 60 años, refleja los
desafíos técnicos que rodean el desarrollo y uso de la placenta artificial. Esta demora en la introducción
también refleja el panorama cambiante de la atención neonatal y, en particular, los avances en la
ventilación mecánica y los modos de soporte respiratorio no invasivo, como la presión positiva continua
en las vías respiratorias, la introducción de esteroides prenatales y la disponibilidad de terapia con
surfactante exógeno.

Autor para correspondencia

Correo electrónico: kemma@[Link]

[Link]
e-ISSN: 2531-0186/ ISSN: 0716-8640/© 2019 Revista Médica Clínica Las Condes.
Este es un artículo Open Access bajo la licencia CC BY-NC-ND
([Link]

699
 [REV. MED. CLIN. CONDES - 2021; 32(6) 699-706]

Como tal, es razonable argumentar que el grupo demográfico objetivo para la tecnología de placenta
artificial ha cambiado significativamente desde que comenzó su desarrollo. Los bebés que antes se
consideraban peri-viables y probables candidatos para la terapia con placenta artificial (es decir, los
que nacieron antes de las 28 semanas de gestación) ahora tienen tasas mucho mejores de supervivencia
libre de enfermedad con la tecnología disponible en la actualidad. El grupo demográfico con los peores
resultados, y los posibles candidatos para la terapia de placenta artificial contemporánea, son aquellos
nacidos de embarazos significativamente comprometidos (por ejemplo, infección intrauterina, sepsis,
preeclampsia severa, insuficiencia placentaria severa) a las 21-24 semanas de gestación y con un
peso de aprox. 300 gramos.

Este artículo proporcionará una revisión del historial de desarrollo de la placenta artificial, un resumen
de la situación actual y concluirá discutiendo los desafíos restantes que deberán abordarse antes de
que esta tecnología pueda introducirse en la práctica clínica.

SUMMARY
An artificial placenta is a life support platform for babies born preterm, or prior to 37 weeks’ completed
gestation. Although there is potential to use this platform for the intraoperative repair of congenital
abnormalities (e.g. congenital diaphragmatic hernia) in late preterm babies, or for the study of fetal
development, the primary target for this technology is currently treatment of extremely preterm
infants, or those delivered during the peri-viable period between 21-24 weeks’ completed gestation.

Babies born in this peri-viable period generally have poor outcomes due to the need to mechanically
ventilate their extremely immature lungs – often at high peak pressures. Artificial placenta-based
life support platforms are designed to obviate the need to ventilate as a means of facilitating gas
exchange, and thus avoid injury to the immature preterm lung. Instead, highly efficient, and easily
regulated gas exchange is performed by gas-exchange devices connected to the fetal vasculature.
Depending on the form of the system used, venous-venous and arterio-venous circuit designs have
been trialled, with the more recent arterio-venous prototypes using the fetal heart, rather than an
external pump, to generate circuit pressure.

Despite having the appearance of a futuristic concept, work to develop an artificial placenta has been
undertaken intermittently since at least the late 1950s. That the technology is yet to enter clinical
service, despite 60-plus years of work, reflects the technical challenges surrounding the development
and use of the artificial placenta. This delay in introduction also reflects the changing neonatal care
landscape, and notably advances in mechanical ventilation and non-invasive respiratory support
modes such as continuous positive airway pressure, the introduction of antenatal steroids, and the
availability of exogenous surfactant therapy.

As such, it is reasonable to argue that the target demographic for artificial placenta technology
has changed significantly since development first began. Babies once considered peri-viable and a
probable candidate for artificial placenta therapy (i.e. those born below 28 weeks’ gestation) now have
much improved rates of disease-free survival using currently available technology. The demographic
with the poorest outcomes, and the likely candidates for contemporary artificial placenta therapy,
are those born from significantly compromised pregnancies (e.g. intrauterine infection, sepsis, severe
pre-eclampsia, severe placental insufficiency) at 21-24 weeks’ gestation and weighing as little as
300 grams.

This paper will provide a review of the development history of the artificial placenta, a summary of
the current state-of-play, and conclude by discussing the remaining challenges that will need to be
addressed before this technology might be introduced to clinical practice.

700
 [The artificial placenta: sci-fi or reality? - Usuda, H et al.]

PRETERM BIRTH AND THE NEED FOR AN ARTIFICIAL remained unchanged over the past several decades13. Setting
PLACENTA aside the inherently high-risk nature of these cases, one may
Preterm birth (PTB), being born before 37 weeks of completed argue that an explanation for this distinct lack of improvement
gestation, is a leading cause of early childhood death, and is lies in the fact that key obstetric and neonatal interventions are
implicated in over one million deaths each year1-3. Worldwide, broadly focussed on the provision and support of pulmonary
it is estimated that over 15 million babies are born premature respiration in the preterm infant. Mechanical ventilation, a key
each year, with the highest rates of prematurity and associated development, is quite clearly targeted at supporting pulmo-
morbidity and mortality correlating strongly with socio-eco- nary gas exchange. Setting aside the cardiovascular stability
nomic disadvantage. As such, parts of Asia, Sub-Saharan Africa, benefits associated with antenatal steroid administration, the
and regions in the United States report preterm birth rates above primary target of these drugs is precocious functional matura-
13% of their total delivery populations. Conversely, Scandinavian tion (increased surfactant production, alveolar development,
countries, with highly developed and well-financed public health septal thinning) of the preterm lung. And although it is increas-
systems, report some of the lowest rates of prematurity, around ingly clear that surfactant components play a host of distinct roles
4-5%4,5. PTB is a complex syndrome, and although its sizable (including immune-modulation and protection from infection)
health-burden is clearly appreciated6, the aetiology of prema- the key benefit derived from exogenous surfactant therapy is an
turity is incompletely understood. Infection (notably in early, immediate improvement in pulmonary compliance facilitating
high-risk preterm deliveries)7,8, inflammation, placental patholo- improved gas exchange at lower ventilation pressures and thus
gies2,3,9, environmental insults (smoking, alcohol consumption)10, greater protection from injury to the lung and to cardiovascular
and a previous history of preterm labour3 are all implicated in disruption.
increasing the risk for delivering a baby preterm. Understand-
ably, unpacking these often-interrelated factors and the role(s) A number of investigators have argued that these therapeutic
that they play in increasing the risk of preterm delivery is difficult. interventions have reached an efficacy threshold when applied
Our incomplete understanding of these processes continues to to peri-viable, extremely preterm infants born 21-24 weeks’
hamper our ability to devise effective treatments and to diagnose gestation14-16. The primary reason for this assertion is that, at this
mothers at risk of preterm delivery so as to facilitate timely and extreme gestational age, the fetal lung is highly immature from
effective interventions. a structural and functional perspective. At 21-24 weeks’ gesta-
tion the fetal lung is transitioning from the canalicular to the
We are now starting to make improvements, via public health saccular phase of development. From a histological perspective,
initiatives, in our ability to identify women at risk and deliver the lung is characterised by the presence of respiratory bron-
interventions to lower the rate of preterm birth11. In contrast, chioles, and lacks extensively formed terminal alveolar sacs that
our ability to care for preterm infants has steadily improved begin to develop after 36 weeks’ gestation in the human. The
over the past fifty to sixty years12. Indeed, preterm babies once transitional canalicular / saccular lung enables limited perfusion
viewed as being unsuitable for resuscitation and unable to survive of the gas exchange surfaces which are in turn extremely limited
(or surviving only with significant, life-long disability) are now in surface area. A lack of pulmonary surfactant, combined with
routinely discharged with few or no overt injuries relating to their comparably thick septal walls combine to result in a lung that is
preterm birth and subsequent treatment. Given the highly inte- highly non-compliant and ill-suited to function as a gas exchange
grated nature of modern medicine, it is difficult to isolate the organ. It is perhaps no surprise then, that therapies (ventilation,
specific factors that underpin these improvements. However, antenatal steroids, surfactant) that require at least some degree
three key pieces of technology, namely, mechanical ventilation of functional lung maturation to be efficacious have failed to
(and advances in safety and efficacy therein), the introduction deliver the same significant improvements in outcomes that are
of antenatal steroid therapy, and the introduction of exogenous now routinely observed in older preterm babies13.
surfactant therapy based around the post-natal application of
porcine- or bovine-surfactant preparations are clearly linked to One approach to this problem is to view the extremely preterm
improved outcomes. Together with broader improvements in infant not as a small baby, but as (at least from anatomical and
obstetric and neonatal care, these technologies have contributed physiological perspectives) a fetus, and in doing so attempt to
to significant improvements in both overall survival and in the devise a treatment modality that recognises and takes advantage
disease-free discharge rates of preterm infants. of these characteristics.
At a most simple level, the concept of the artificial placenta for
Despite the availability of an increasingly large and effective extremely preterm infants is based around the aim of obviating
array of these and other preterm therapeutics, there remains a the need to use the immature lung for gas exchange. Instead,
small rump of extremely preterm infants for whom key outcome gas exchange is performed by oxygen / carbon dioxide exchange
measures (survival, disease-free at discharge) have stubbornly devices attached to the fetal circulation. Although not exclu-

701
 [REV. MED. CLIN. CONDES - 2021; 32(6) 699-706]

sively the case, a significant number of studies in this area have A subsequent report, again by Zapol and colleagues, reinforced
sought to replicate the in utero environment more fully, and have the need for artificial placenta-based systems to carefully repli-
devised a variety of means by which the developing fetus may be cate native fetal physiological conditions. In an elegant series
submerged in a bath of artificial amniotic fluid – protecting the of contrast angiography studies, it was demonstrated that the
fetus from the risks (skin tears / abrasions / dehydration) associ- ductus arteriosus rapidly responded to increases in arterial PaO2
ated with the external environment and promoting an environ- by constricting. Indeed, an increase in PaO2 from 13-20 mmHg
ment able to support normal lung maturation, including fluid to 40-60 mmHg saw nearly complete conversion of fetal circu-
swallowing/breathing reflexes. latory distribution to a newborn configuration, consistent with
marked occlusion of the ductus arteriosus. Most interestingly,
This mini-review will provide an overview of the developmental and of additional importance in the management of fetuses
history of the artificial placenta, discuss contemporary devel- on an artificial placenta platform, the authors also showed that
opments in the field over the past decade, and then move to a a return of PaO2 to normal low levels (i.e. 13-20 mmHg) was
final discussion of the challenges that remain to be overcome accompanied by a rapid return of a fetal circulatory configu-
before this technology could reasonably be considered for clin- ration and dilation of the ductus arteriosus. Similarly, neither
ical application. metabolic nor respiratory acidosis altered ductal patency21.
This study in particular highlights the potential of the artifi-
cial placenta platform to serve as a means by which to dissect
DEVELOPMENTAL HISTORY OF THE ARTIFICIAL and study questions relating to fundamental fetal physiology,
PLACENTA anatomy and development.
Initial studies to explore the potential to support preterm
infants using non-pulmonary gas exchange were likely inspired The next significant advances in the field came from studies
by pioneering work undertaken by Dr John Gibbon in the field undertaken in Japan and South Korea between 1989 and 2002.
of cardiac bypass surgery. Dr Gibbon’s work, beginning in the Kuwabara and colleges at the University of Tokyo reported the
mid-1930s with a report of the successful provision of artificial findings of a nine-animal study using goat fetuses between 112-
lung and heart support to a cat with a deliberately occluded and 136-days’ gestational age (term is approximately 148 days’
pulmonary artery, and culminating with the successful repair gestation). In this model, fetuses were submerged in a bath of
of a large atrial septal defect and left-to-right shunt in an 18 artificial amniotic fluid with catheters introduced to the umbil-
year-old girl hospitalised with recurrent right ventricular failure, ical arteries and veins. The artificial placenta itself consisted of
is rightly regarded as one of the most important advances in an arterial reservoir, roller pump, membranous oxygenator and
medicine17. heat exchanger. Six animals were successfully catheterised and
were maintained in good physiological condition for an average
In 1958, a group of researchers at the Karolinska Institute repre- period of 146,5±15 hours. The longest successful experiment
sented by Westin, Nyberg and Enhöring reported a technique for was 231,18 hours in a 123-day gestational age fetus weighing
the perfusion of peri-viable human fetuses weighing 375g, for 1,95kg. The primary cause of death in successfully catheterised
periods of up to 12 hours. A number of proof-of-principle animal animals was reported as being progressive circulatory depres-
studies rapidly followed this landmark study; Lawn and McCance sion and cardiac failure22. A follow-up paper by Kuwabara and
in Cambridge reported using pig fetuses at 60-70 days’ gesta- Unno reported additional and highly impressive advances in the
tion on an artificial placenta device18. Callaghan and colleagues development of their platform. Using two goat fetuses (120d
in Canada used late-preterm sheep fetuses to execute short gestation, 1,6kg weight and 128d gestation, 2,4kg weight), the
(~40 minute) pulmonary bypass protocols, followed by successful authors reported a successful artificial placenta maintenance
recovery and extended (> 6 month) survival19. period of 494 and 542 hours, respectively. In addition, both
fetuses were successfully adapted from the artificial placenta
Some of the most important early work in the field was that onto pulmonary respiration and ventilated for an additional
undertaken by Zapol and colleagues. Writing in the journal 704 and 169 hours, respectively – an achievement that remains
Science, Zapol et al. reported the successful maintenance of a a landmark success in the field23. Interestingly, the authors
male preterm lamb fetus (125 days gestational age, 3,05kg) for a reported that they were unable to wean the goat fetuses off
period of 55 hours prior to the experiment concluding as a result assisted ventilation. The cause(s) of this remain unclear, but
of acute cardiac failure. Analyses revealed progressive anaemia, may relate to iatrogenic injury deriving from the constant use
but with well controlled lactate, pH and pCO2 values. Cultures of pancuronium bromide to immobilise the animals during
of both fetal blood and the artificial amniotic bath in which the the experimental period. Additional studies in sheep by Sakata
animal was submerged demonstrated the presence of klebsiella and colleagues explored the use of centrifugal, high-flow
and aerobacter species20. pumps synchronised to the fetal heart; Pak and colleagues

702
 [The artificial placenta: sci-fi or reality? - Usuda, H et al.]

also performed a number of experiments with fetal goats at further Canadian-Australian group have begun late-term artificial
120-130d, achieving survival periods of around 24 hours using placenta experiments using pig fetuses26.
a roller-pump driven system24.
The University of Michigan group has worked for a number of years
Taken together, these studies demonstrated an incremental to develop what might now be described as a ‘ventilation-assist’
improvement in both survival times and significant advances in artificial placenta model using a venous-venous return system,
the quality of the maintenance (i.e. stability of key physiolog- driven by an external pump. In the latest iterations of this work,
ical variables within normal ranges, absence of life-threatening the fetus is maintained in room air. In contrast, work undertaken
infection) able to be achieved with artificial placenta tech- in Philadelphia, and by the Japanese-Australian consortium, is
nology. Critically, in the case of the work by Callaghan et al., and based around studies employing an arterio-venous system, with
by Unno and colleagues, this work clearly demonstrated that it the fetus submerged in an artificial amniotic fluid bath and the
was possible to maintain a fetus on an artificial placenta plat- circuit pressurised by the fetal heart. Given the significant differ-
form for an extended period of time and then successfully adapt ences in these approaches, and in their potential utilisation, it is
it to pulmonary gas exchange – a fundamental requirement for useful to discuss them separately.
the clinical translation of any such life support platform.

PUMP-DRIVEN VENOUS-VENOUS RETURN SYSTEMS

CONTEMPORARY DEVELOPMENTS – 2010 ONWARDS Work published in 2012 by the team at the University of Mich-
The past decade has seen a rapid upswing in both the number of igan under Dr Mychaliska reported the use of a venous-ve-
studies being published in the field of artificial placenta devel- nous return system to maintain late gestation preterm (130
opment, and the amount of interest shown by the scientific and days’ gestation) fetuses. The artificial placenta design was
lay media in the potential application of this technology in a based around a peristaltic roller pump-driven system that
clinical environment. Despite this, and the promising advances takes fetal blood from the right jugular vein, passes it through
that have occurred of late, there still remains a sizable body of a gas exchange device (0,5m2 hollow fibre oxygenator) before
development work to be done before an artificial placenta could returning it to an umbilical vein. In these studies, fetuses were
conceivably used in an attempt to treat an extremely preterm maintained in an amniotic fluid bath for up to 24 hours, with
infant. five out of nine animals surviving their treatments27. In a subse-
quent study that perhaps highlights one potential application
Efforts to develop an artificial placenta have evolved into two of the system under development, the investigators reported
distinct model systems, demarcated broadly by three factors: using a similar but non-immersion system to explore the use
i) the orientation of the fetal catheterisation being either an of their artificial placenta platform to rescue late preterm (130
arterio-venous system employing the umbilical vessels, or a days’ gestation) lambs from ventilatory failure. Animals were
venous-venous system employing a cervical vessel (generally first ventilated for approximately one hour before the lung was
a fetal jugular vein) and an umbilical vein; ii) the use of either deliberately filled with amniotic fluid and the animal trans-
the fetal heart (in arterio-venous systems) or an external pump ferred to artificial placenta support. Six out of seven animals
(in venous-venous systems) to pressurise the external gas survived a 70-hour procedure. PaCO2 and PaO2 were maintained
exchange circuit; and iii) either the submersion of the fetus within normal ranges and all animals were free of intraventric-
in a bath of artificial amniotic fluid (in arterio-venous systems ular haemorrhage28. In a follow-up study published in 2015,
dependent on maintenance of umbilical patency) or the main- the authors reported the use of more preterm lambs (110-120
tenance of fetuses in a dry-air system with the lung artificially days’ gestation) to test the performance of their apparatus over
fluid-filled and occluded to establish the pressure necessary for a seven-day treatment period. Four out of nine animals survived
normal pulmonary development to occur. their seven-day protocols, with a further animal surviving six
days29. More recently, the same group has demonstrated prom-
Much of the contemporary work in the field is derived from the ising results from a comparative study of lung injury between
efforts of three research groups. Two are based in the United animals either adapted to mechanical ventilation for 48 hours
States, one at the University of Michigan and a second at the Chil- or venous-venous artificial placenta therapy incorporating a
dren’s Hospital of Philadelphia. The third is a Japanese-Australian perflurocarbon-flooded lung for approximately seven days.
collaboration between researchers at the Women and Infants As might be expected, animals in the artificial placenta group
Research Foundation (Perth, Western Australia) and Tohoku had lower lung injury scores than those exposed to mechan-
University (Sendai, Miyagi Prefecture, Japan). More recently, a ical ventilation30. Additional investigations regarding splenic
group in the Netherlands have announced their intention to and gastrointestinal development have also returned promising
rapidly develop a clinic-ready artificial placenta platform25, and a results31,32.

703
 [REV. MED. CLIN. CONDES - 2021; 32(6) 699-706]

FETAL HEART-DRIVEN ARTERIO-VENOUS RETURN the findings of a number of years of iterative development work
SYSTEMS culminating in an arterio-venous artificial placenta platform.
One of the most important advances in arterio-venous system Commencing with late preterm sheep fetuses (125-140 days’
development came from work published by Reoma and gestation), Partridge and colleagues first described an initial
colleagues, again at the University of Michigan. Using very late system based around carotid artery and jugular vein catheterisa-
preterm fetuses (140 days’ gestation) animals had catheters tion with lambs submerged in an open amniotic fluid bath. Lamb
placed into umbilical vessels and were commenced on arte- survival time was limited to between 23 and 108 hours due, in
rio-venous artificial placenta therapy lasting for a maximum of keeping with earlier reports by Miura et al., to sepsis and cath-
four hours in an immersion-based system. The authors reported eter positioning. A follow-up set of studies using slightly more
that the major limitation of this approach was high cannula immature lambs (120-132 days’ gestation) reported a significant
resistance and progressively deteriorating flow through the arti- improvement in survival time (an average 346±93 hours) but
ficial placenta circuit33. At around the same time the Michigan with continued challenges in relation to microbial colonisation.
group moved to report their initial findings with a pump-as- The Philadelphia apparatus subsequently went through a series
sisted venous-venous return system, Drs Miura and Matsuda at of further adaptations (a carotid artery – umbilical vein circuit
Tohoku University reported the findings of their work with a new, orientation followed by an umbilical artery – umbilical vein circuit
low-priming volume artificial placenta system. Advancing the orientation) and the implementation of a closed bag system to
work of Remoa and colleagues, Miura and colleagues incorpo- house the fetus, with catheters externalised via a sealed port.
rated a low-resistance, high-performance membranous oxygen- Using a mature umbilical artery – umbilical vein circuit design,
ator that allowed for a 40% reduction in circuit priming volume. the investigators reported successful maintenance of normal
Using preterm lambs (120-130 days’ gestation) animals were physiological parameters and absence of infection in fetuses as
maintained for an average of 18 hours34. In a further important young as 105 days’ gestation for a period of up to four weeks39.
advance, the same group hypothesised that the use of a parallel- More recent work by the same group has sought to address a
ised circuit would allow a further reduction in circuit resistance, significant gap in the literature, namely how fetal organ systems
additionally reduce stress on the fetal heart, and achieve longer develop under the influence of artificial placenta therapy – with a
periods of healthy fetal maintenance. In this study, again using particular focus on the brain40,41.
preterm lambs, survival was extended out to an average of 60,4
hours – a sizable advance over earlier work35. Additional studies,
undertaken collaboratively with researchers at the Women and FUTURE CHALLENGES AND CONCLUSIONS
Infants Research Foundation in Western Australia, explored As outlined above, the artificial placenta field has a long and iter-
adapting progressively premature (115 days’ gestation) fetal ative development history that is seemingly in contrast with the
sheep to the parallelised pumpless system, and the inflamma- novel, somewhat futuristic manner in which it is frequently viewed
tory and microbial impacts deriving from the use of an open bath today. Significant technical challenges and an evolving obstetric
system36,37. Subsequent work by the same group, led by Dr Usuda, and neonatal care landscape have combined to greatly delay the
then incorporated progressively reduced priming volumes into clinical translation of what, in the late 1950s, likely seemed to be
their system and demonstrated stable, infection-free fetal main- an imminent and much welcome advance in the care of extremely
tenance for a period of one week38. Having achieved an extended preterm infants. Today, some 60 years later, although progress
(336 hr) period of artificial placenta maintenance using their plat- towards the clinical translation of an artificial placenta for extremely
form (Dr Usuda, personal communication), the most recent focus preterm infants in certainly accelerating, significant technical and
of this group’s work has been on modifying its artificial placenta ethical hurdles remain to be overcome before one might expect
platform to support extremely preterm ovine fetuses (95 days’ to see an artificial placenta used to support an extremely preterm
gestation) and similarly aged extremely preterm fetuses compro- fetus. Perhaps paramount amongst challenges these is the relative
mised by intrauterine inflammation, similar to that commonly lack of data to inform the maintenance of compromised, extremely
seen in periviable human preterm deliveries15,16. One key finding preterm fetuses (as would be expected in a peri-viable delivery)
of this work – which highlights the importance of model selec- on artificial placenta platforms. Although ontologically, the sheep
tion - is that the maintenance of compromised fetuses is signifi- lung at 110d may broadly align with the developmental status of
cantly more challenging, and that their growth parameters are a 24-week human fetus, a 110d sheep fetus is also in the region of
inferior, relative to gestational age-matched fetuses from healthy 3-4 times the body weight, with a far greater circulatory volume,
or uncompromised pregnancies. and likely with significantly better cardiac compensation capabilities.

A significant body of work has been undertaken over the same Although the primary focus of artificial placenta development
period by a group at the Children’s Hospital of Philadelphia. A has been as a therapy for extremely preterm infants in lieu of
landmark study published by Dr Flake’s group in 2017 reported ventilation, there is additionally good potential for using artificial

704
 [The artificial placenta: sci-fi or reality? - Usuda, H et al.]

placenta technology as a modality for rescuing neonates suffering for this purpose may be gained from the adaptation of heart-lung
respiratory failure, or as a tool for the intraoperative support of bypass technology, from which the artificial placenta paradigm is
neonates undergoing surgery to repair congenital abnormalities. itself derived. Hill reported that, by 1953, Dr Gibbon’s heart-lung
Indeed, work undertaken by the Michigan group highlights this machine had achieved a success rate of 78% in experimental trials
particular application very effectively. With the recent availability before it was introduced to treat patients (i.e. those with massive
of platforms of maintaining extremely preterm fetuses in good pulmonary embolism otherwise undergoing Trendelenberg opera-
health, there is now also the potential to meaningfully deploy this tions) with extremely limited chances of survival41. Today, extremely
technology for the study of fetal development absent maternal preterm fetuses at gestations as early as 23 weeks’ gestation have a
and placenta input. >60% chance of survival in some jurisdictions with currently avail-
able ventilator technology and advanced neonatal care. Thus, it is
However, discussions around when one might introduce the artifi- quite reasonable to conclude that although the artificial placenta
cial placenta as a replacement for ventilation support in extremely has come a long way, there remains a very great deal of work to be
preterm infants remain a contentious topic. Perhaps the best guid- done before one could responsibly advocate for its clinical applica-
ance in when we might eventually consider applying this therapy tion in even the most preterm of babies.

Declaración de conflicto de interés

The authors report no conflict of interest.

REFERENCIAS BIBLIOGRÁFICAS

1. Lawn JE, Davidge R, Paul VK, von Xylander S, de Graft Johnson J, Costello 12. Jobe AH, Goldenberg RL. Antenatal corticosteroids: an assessment of
A, et al. Born too soon: care for the preterm baby. Reproductive health. anticipated benefits and potential risks. American journal of obstetrics
2013;10 Suppl 1(Suppl 1):S5. doi: 10.1186/1742-4755-10-S1-S5. and gynecology. 2018;219(1):62-74.
2. Blencowe H, Cousens S, Chou D, Oestergaard M, Say L, Moller AB, 13. Stoll BJ, Hansen NI, Bell EF, Walsh MC, Carlo WA, Shankaran S, et al.
et al. Born too soon: the global epidemiology of 15 million preterm Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm
births. Reproductive health. 2013;10 Suppl 1(Suppl 1):S2. doi: Neonates, 1993-2012. Jama. 2015;314(10):1039-51.
10.1186/1742-4755-10-S1-S2. 14. Usuda H, Watanabe S, Miura Y, Saito M, Musk GC, Rittenschober-
3. Romero R, Dey SK, Fisher SJ. Preterm labor: one syndrome, many causes. Bohm J, et al. Successful maintenance of key physiological parameters
Science. 2014;345(6198):760-5. doi: 10.1126/science.1251816. in preterm lambs treated with ex vivo uterine environment therapy
4. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and for a period of 1 week. American journal of obstetrics and gynecology.
causes of preterm birth. Lancet. 2008;371(9606):75-84. doi: 2017;217(4):457.e1-.e13.
10.1016/S0140-6736(08)60074-4. 15. Usuda H, Watanabe S, Saito M, Sato S, Musk GC, Fee ME, et al.
5. Harrison MS, Goldenberg RL. Global burden of prematurity. Seminars Successful use of an artificial placenta to support extremely preterm
in fetal & neonatal medicine. 2016;21(2):74-9. doi: 10.1016/j. ovine fetuses at the border of viability. American journal of obstetrics
siny.2015.12.007. and gynecology. 2019;221(1):69.e1-.e17.
6. Frey HA, Klebanoff MA. The epidemiology, etiology, and costs of preterm 16. Usuda H, Watanabe S, Saito M, Ikeda H, Koshinami S, Sato S, et al.
birth. Seminars in fetal & neonatal medicine. 2016;21(2):68-73. doi: Successful use of an artificial placenta-based life support system to
10.1016/[Link].2015.12.011. treat extremely preterm ovine fetuses compromised by intrauterine
7. Kemp MW. Preterm birth, intrauterine infection, and fetal inflammation. American journal of obstetrics and gynecology.
inflammation. Front Immunol. 2014;5:574. doi: 10.3389/ 2020;223(5):755.e1-.e20.
fimmu.2014.00574. 17. Hill JD. John H. Gibbon, Jr. Part I. The development of the first
8. Kemp MW, Saito M, Newnham JP, Nitsos I, Okamura K, Kallapur successful heart-lung machine. The Annals of thoracic surgery.
SG. Preterm birth, infection, and inflammation advances from 1982;34(3):337-41.
the study of animal models. Reprod Sci. 2010;17(7):619-28. doi: 18. Lawn L, McCance RA. Ventures with an artificial placenta - I. Principles
10.1177/1933719110373148. and preliminary results. Proceedings of the Royal Society of London
9. Lawn JE, Davidge R, Paul VK, von Xylander S, de Graft Johnson J, Series B Biological Sciences. 1962;155(961):500-9.
Costello A, et al. Born too soon: care for the preterm baby. Reproductive 19. Callaghan JC, Maynes EA, Hug HR. STUDIES ON LAMBS OF THE
health. 2013;10 Suppl 1:S5. DEVELOPMENT OF AN ARTIFICIAL PLACENTA. REVIEW OF NINE LONG-
10. Newnham JP, Kemp MW, White SW, Arrese CA, Hart RJ, Keelan JA. TERM SURVIVORS OF EXTRACORPOREAL CIRCULATION MAINTAINED IN
Applying Precision Public Health to Prevent Preterm Birth. Front Public A FLUID MEDIUM. Can J Surg. 1965;8:208-13.
Health. 2017;5:66. 20. Zapol WM, Kolobow T, Pierce JE, Vurek GG, Bowman RL. Artificial
11. Newnham JP, White SW, Meharry S, Lee HS, Pedretti MK, Arrese CA, et Placenta: Two Days of Total Extrauterine Support of the Isolated
al. Reducing preterm birth by a statewide multifaceted program: an Premature Lamb Fetus. Science. 1969;166(3905):617-8.
implementation study. American journal of obstetrics and gynecology. 21. Zapol WM, Kolobow T, Doppman J, Pierce JE. Response of ductus
2017;216(5):434-42. arteriosus and pulmonary blood flow to blood oxygen tension in

705
 [REV. MED. CLIN. CONDES - 2021; 32(6) 699-706]

immersed lamb fetuses perfused through an artificial placenta. J 2017;217(4):457.e1-.e13.

Thorac Cardiovasc Surg. 1971;61(6):891-903. 39. Partridge EA, Davey MG, Hornick MA, McGovern PE, Mejaddam AY,
22. Kuwabara Y, Okai T, Kozuma S, Unno N, Akiba K, Shinozuka N, et al. Vrecenak JD, et al. An extra-uterine system to physiologically support
Artificial placenta: long-term extrauterine incubation of isolated goat the extreme premature lamb. Nat Commun. 2017;8:15112.
fetuses. Artif Organs. 1989;13(6):527-31. 40. McGovern PE, Hornick MA, Mejaddam AY, Lawrence K, Schupper AJ,
23. Unno N, Kuwabara Y, Okai T, Kido K, Nakayama H, Kikuchi A, et al. Rossidis AC, et al. Neurologic outcomes of the premature lamb in
Development of an Artificial Placenta: Survival of Isolated Goat an extrauterine environment for neonatal development. Journal of
Fetuses for Three Weeks with Umbilical Arteriovenous Extracorporeal Pediatric Surgery. 2020;55(10):2115-23.
Membrane Oxygenation. Artificial Organs. 1993;17(12):996-1003. 41. McGovern PE, Lawrence K, Baumgarten H, Rossidis AC, Mejaddam AY,
24. Pak SC, Song CH, So GY, Jang CH, Lee KH, Kim JY. Extrauterine incubation Licht DJ, et al. Ex Utero Extracorporeal Support as a Model for Fetal
of fetal goats applying the extracorporeal membrane oxygenation via Hypoxia and Brain Dysmaturity. Ann Thorac Surg. 2020;109(3):810-9.
umbilical artery and vein. J Korean Med Sci. 2002;17(5):663-8. 42. Gibbon JH, Hill JD. Part I. The Development of the First Successful Heart-
25. Zimmer K. Artificial Wombs are Science Fiction: But Artificial Placentas Lung Machine. The Annals of Thoracic Surgery. 1982;34(3):337-41.
are on the Horizon. IEEE Spectrum. 2021;58(4):22-9.
26. Charest-Pekeski AJ, Sheta A, Taniguchi L, McVey MJ, Floh A, Sun L, et
al. Achieving sustained extrauterine life: Challenges of an artificial
placenta in fetal pigs as a model of the preterm human fetus. Physiol
Rep. 2021;9(5):e14742.
27. Gray BW, El-Sabbagh A, Rojas-Pena A, Kim AC, Gadepali S,
Koch KL, et al. Development of an artificial placenta IV: 24 hour
venovenous extracorporeal life support in premature lambs. Asaio j.
2012;58(2):148-54.
28. Gray BW, El-Sabbagh A, Zakem SJ, Koch KL, Rojas-Pena A, Owens
GE, et al. Development of an artificial placenta V: 70h veno-venous
extracorporeal life support after ventilatory failure in premature
lambs. Journal of Pediatric Surgery. 2013;48(1):145-53.
29. Bryner B, Gray B, Perkins E, Davis R, Hoffman H, Barks J, et al. An
extracorporeal artificial placenta supports extremely premature
lambs for 1week. Journal of Pediatric Surgery. 2015;50(1):44-9.
30. Coughlin MA, Werner NL, Church JT, Perkins EM, Bryner BS, Barks JD,
et al. An Artificial Placenta Protects Against Lung Injury and Promotes
Continued Lung Development in Extremely Premature Lambs. Asaio j.
2019;65(7):690-7.
31. McLeod JS, Church JT, Yerramilli P, Coughlin MA, Perkins EM, Rabah
R, et al. Gastrointestinal mucosal development and injury in
premature lambs supported by the artificial placenta. J Pediatr Surg.
2018;53(6):1240-5.
32. Gharib A, Komaki A, Manoochehri Khoshinani H, Saidijam M, Barkley
V, Sarihi A, et al. Intrahippocampal 5-HT1A receptor antagonist
inhibits the improving effect of low-frequency stimulation on memory
impairment in kindled rats. Brain Res Bull. 2019;148:109-17.
33. Reoma JL, Rojas A, Kim AC, Khouri JS, Boothman E, Brown K, et al.
Development of an artificial placenta I: pumpless arterio-venous
extracorporeal life support in a neonatal sheep model. J Pediatr Surg.
2009;44(1):53-9.
34. Miura Y, Matsuda T, Funakubo A, Watanabe S, Kitanishi R, Saito
M, et al. Novel modification of an artificial placenta: pumpless
arteriovenous extracorporeal life support in a premature lamb model.
Pediatric research. 2012;72(5):490-4.
35. Miura Y, Matsuda T, Usuda H, Watanabe S, Kitanishi R, Saito M, et
al. A Parallelized Pumpless Artificial Placenta System Significantly
Prolonged Survival Time in a Preterm Lamb Model. Artificial organs.
2016;40(5):E61-E8.
36. Miura Y, Saito M, Usuda H, Woodward E, Rittenschober-Böhm J,
Kannan PS, et al. Ex-Vivo Uterine Environment (EVE) Therapy Induced
Limited Fetal Inflammation in a Premature Lamb Model. PLoS One.
2015;10(10):e0140701.
37. Miura Y, Usuda H, Watanabe S, Woodward E, Saito M, Musk GC, et
al. Stable Control of Physiological Parameters, But Not Infection, in
Preterm Lambs Maintained on Ex Vivo Uterine Environment Therapy.
Artificial organs. 2017;41(10):959-68.
38. Usuda H, Watanabe S, Miura Y, Saito M, Musk GC, Rittenschober-
Böhm J, et al. Successful maintenance of key physiological parameters
in preterm lambs treated with ex vivo uterine environment therapy
for a period of 1 week. American journal of obstetrics and gynecology.

706