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The availability of computer-controlled artificial hearts, kidneys, and lungs, as well as the possibility of implanting human embryos in ex vivo uterus models or an artificial endometrium, presents new perspectives for creating an artificial uterus. Survival rates have also improved, with fetuses surviving from as early as 24 weeks of gestation. These advances bring new opportunities for complete or partial ectogenesis through the creation of an artificial womb, one that could sustain the growth and development of fetuses outside of the human body.
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Ann. N.Y. Acad. Sci. ISSN 0077-8923
ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
Issue: Reproductive Science
The artificial womb
Carlo Bulletti,1Antonio Palagiano,2Caterina Pace,2Angelica Cerni,3Andrea Borini,4
and Dominique de Ziegler5
1Physiopathology of Reproduction Unit, Cervesi’s General Hospital in Cattolica, Cattolica, Italy. 2University of Naples, Naples,
Italy. 3University of Bologna, Bologna, Italy. 4Tecnobios Procreazione, Forl`
ı, Italy. 5Hopital Baudeloque, Groupe Hopitalier
Cochien, Paris, France
Address for correspondence: Carlo Bulletti, MD, Fisiopatologia della Riproduzione, Ospedale Cervesi di Cattolica (Rimini), Via
Beethoven, 2-47841, Cattolica, Italy. Email: bulletticarlo@libero.it
The availability of computer-controlled artificial hearts, kidneys, and lungs, as well as the possibility of implanting
human embryos in ex vivo uterus models or an artificial endometrium, presents new perspectives for creating an
artificial uterus. Survival rates have also improved, with fetuses surviving from as early as 24 weeks of gestat ion. These
advances bring new opportunities for complete or partial ectogenesis through the creation of an artificial womb, one
that could sustain the growth and development of fetuses outside of the human body.
Keywords: womb; artificial uterus; ectogenesis; embryo implantation; fetal surgery; assisted reproductive technology
Introduction
The mastery of in vitro fertilization and improve-
ments in the survival of premature infants have
opened new opportunities for ectogenesis, the im-
plantation and full development of fetuses in vitro.
Here, ectogenesis denotes the availability of an arti-
ficial uterus capable of fostering the development of
embryos to viability.
An artificial uterus could assist women with dam-
aged or diseased uteri by allowing them to conceive
and carry infants, despite an inability to do so on
their own. A second possibility is that an artificial
uterus could serve as an incubator for preterm ba-
bies, specifically those who are delivered before ap-
proximately 24 weeks of gestation—the minimum
for viability with current incubators. The develop-
ment of such an incubator could provide a break-
through for reducing fetal mortality and morbidity
that stems from prematurity.
Artificial wombs,” as they are currently con-
ceived, would function by connecting to an extra-
corporeal supply of maternal blood or replacement
fluids. The artificial womb would supply nutrients
and oxygen to an incubated fetus and would be ca-
pable of disposing of waste materials. This would,
therefore, necessitate an artificial placenta for medi-
ating the necessary exchanges between fetal circula-
tion and the system that would replace the maternal
flow.
The first attempts to support the implantation of
human embryos outside of the human body were
conducted in 1982 in Bologna, Italy, and continued
at Mount Sinai Hospital in New York City in 1983;
the first results were published in 1986.1The pro-
gram of ex vivo human uteri maintained through
extracorporeal perfusion led to different sets of ex-
periments targeted at clarifying uterine physiology
and pathophysiology.1–6 The report of the first hu-
man embryo implantation in an ex vivo, isolated,
extracorporeally perfused uterus occurred in 1989,
stirring comments and bringing ethical concerns
to attention, including those voiced by the editor
of the journal Fertility and Sterility.4Ultimately,
the experimental program conducted in Italy was
stopped because of the ethical issues raised and the
strong and vociferous opposition from the polit-
ical community.4Further studies were conducted
using the ex vivo model, however, not for study-
ing embryo implantation. Rather, these studies in-
vestigated various pharmacological effects on uter-
ine physiology. These included, for example, a set
doi: 10.1111/j.1749-6632.2011.05999.x
124 Ann. N.Y. Acad. Sci. 1221 (2011) 124–128 c
2011 New York Academy of Sciences.
Bulletti et al. Ectogenesis
Figure 1. The artificial endometrium obtained in vitro from
epithelial cells placed on a bed of matrigel.
of studies documenting the existence of a direct
vagina-to-uterus transport called the “first uterine
pass effect.” This work details some important char-
acteristics of the uterus, including the unexpectedly
high levels of vaginally delivered hormones such as
progesterone.5,6
The technology of ex vivo perfusion in human
uteri was helpful in learning to imitate mechanisms
governing human uterine receptivity and embryo
implantation. Today, however, more advanced tech-
nologies are available and make possible the notion
that an artificial uterus could support fetal devel-
opment, at least for part of the pregnancy. Once
perfected, however, an artificial womb would al-
low for the possibility to continue or initiate fetal
development outside of the mother’s body.
The artificial endometrium
Hung-Ching Liu, a researcher at Cornell Univer-
sity in New York, prepared a co-culture system that
combined epithelial and stromal cells—a model re-
ported as being the first step toward an artificial
uterus.8Importantly, these experiments were not
extended beyond the 6-day limit for embryo re-
search enacted in the United States. As illustrated in
Figure 1, several studies have employed artificial en-
dometrium models and reported their responses to
steroid hormones in various contexts.9–12 In these
co-culture systems, epithelial and stromal cells were
layered on matrigel supports. This permits epithe-
lial cells to exhibit spontaneous orientation and
promising viability, allowing the development of
new models for studying maternal–embryo inter-
actions. Relatedly, in Japan in 1996, Kuwabara9re-
ported attempts at preserving a developing goat for
three weeks in an incubator that reproduced the
uterus and placenta, together with amniotic fluid
and blood supply. Similar attempts at developing an
artificial womb took place concomitantly.
The artificial placenta
Placenta preservation through extracorporeal per-
fusion has been attempted in the past to study hor-
mone metabolism and the respective fetal and ma-
ternal contributions to various pathophysiological
issues.7For example, it has been demonstrated that
the human placenta can still supply nutrients and
dispose of waste products when connected to an ar-
tificial uterus.6–19 However several attempts at uter-
ine transplantation have taken place, but all were
unsuccessful.46,47 Placentation, or the passage of nu-
trients via the placenta, under these conditions re-
mains an unresolved issue, in particular because of
immunosuppressive therapies. It is possible that the
placenta may offer immune protection to the fe-
tus by passing antibodies such as immunoglobulin
(IgG).17
Following the premature removal of the fetus
from the maternal uterus, the three umbilical cord
vessels could remain open by inhibiting their phys-
iological occlusion, for example, through heparin
flushing, placement of a stent, or by creating an
arterial bypass that sustains exchanges between ma-
ternal and fetal blood.20–23 Areservoirofmater-
nal blood could therefore support placental phys-
iology, provide nutrients for the fetus, and assure
the removal of waste. Yet another option, where
the artificial uterus and placenta would be directly
connected to the maternal circulation, has been
considered.24,25
Notably, the use of artificial “suppliers” and “dis-
posers” has the advantage of allowing the fetus to
develop in a separate environment where it is ex-
cluded from the possible deleterious effects of ma-
ternal disease, or from exposure to pollutants, al-
cohol, or drugs.24,27–29 Furthermore, independent
systems could not bear the risk of an immune reac-
tion in the maternal system against the fetus because
of insufficient gestational immune tolerance.
Additionally, waste disposal could also be
achieved by dialysis. Oxygenation of the embryo or
fetus has been achieved with extracorporeal mem-
brane oxygenation (ECMO), a validated technique
that has successfully allowed the development of a
goat fetus for up to 237 hours in an amniotic tank.30
Ann. N.Y. Acad. Sci. 1221 (2011) 124–128 c
2011 New York Academy of Sciences. 125
Ectogenesis Bulletti et al.
Current techniques are problematic, however, for
providing proper nutrition. Total parenteral nu-
trition, as studied in infants suffering from severe
short bowel syndrome, offers a 5-year survival of
approximately 20%.30–32
Another potential application of ectogenesis is
the possibility of xenopregnancy. Interspecific preg-
nancies (sometimes called interspecies pregnancies
or xenopregnancy) involve an embryo or fetus and
a uterine carrier belonging to a different species.
Immunologically speaking, letting a fetus develop
in a carrier of a different species is the equivalent
of xenografts compared to allografts. Such an ap-
proach would put a higher demand on the gesta-
tional immune tolerance system to avoid immune
rejection of the fetus. Furthermore, interspecific ges-
tation would encounter issues linked to the different
types of placentation that characterize each species.
For example, the most invasive hemochorial placen-
tation that characterizes humans implies a profound
down-regulation of the maternal immune response.
Conversely, the endotheliochorial type of placen-
tation characteristic of cats and dogs, and those
characteristic of pigs, ruminants, and whales, does
not allow for true contact between maternal blood
and the fetal chorion. Hence, interspecific pregnan-
cies could bear the risk of generating inappropriate
interactions between the fetal trophoblast and the
endometrium of the mother.
In the case of an embryo from a Bactrian camel
transferred to the uterus of a Dromedary, pregnan-
cies can be carried to term with no other interven-
tion beyond the embryo transfer.47 The ability of
one species to survive inside the uterus of another
is often unidirectional—pregnancies are not neces-
sarily successful in the inverse situation. For exam-
ple, horse embryos survive in the donkey uterus, but
donkey embryos perish in the uterus of an untreated
mare.48 Deer mouse embryos survive in the uterus
of the white-footed mouse, but reciprocal transfers
invariably fail. Ethical concerns are not considered
here but would certainly arise if the development of
human embryos were to be attempted in the uteri
of other species.
The incubator
Although no technology currently exists for sup-
porting the development of embryos from concep-
tion to viability, the importance of developing such
technologies is now recognized. For example, new
technologies have allowed our group to propose the
computer-controlled sequence of two artificial kid-
neys: one provides the balanced fluid content of
synthetic amniotic sacs, while the other permits the
proper perfusion of the umbilical vessel with filtered
blood coming from a reservoir of maternal blood.
An artificial lung and heart and a temperature-
controlled cabinet complete the system.1–6 To re -
place placental function, an artificial placenta,
or other filtering system capable of supporting
nutrition, would be incorporated.
Discussion
In 2005, the French biologist Henri Atlan predicted
in a book, L’Ut´
erus Artificiel, that within 100 years,
artificial reproductive technology would master the
in vitro development of the human fetus. These ap-
proaches would offer the possibility of fertilizing
oocytes and growing the resulting embryo to via-
bility. This could also lead to treatments for certain
anomalies in utero rather than after birth.32,33
Understanding the anatomical characteristics of
the fetal–maternal interaction began several cen-
turies ago—as shown in the famous drawing of an
opened uterus with fetus in situ,The Fetus in the
Womb, by Leonardo da Vinci—and the possibility
of incubating a human fetus with an artificial appa-
ratus has been a dream for many years. Interestingly,
in 1932, Aldous Huxley wrote of a sort of artificial
placenta in the novel, Brave New World,describ-
ing problems that later would be experienced by
researchers attempting to develop an artificial pla-
centa. It was not until the late 1950s, however, that
actual efforts commenced for the development of
the clinically applicable artificial placenta system.
Initial attempts to develop artificial placentas
were abandoned in the mid-1980s. At the same
time, however, continuous positive airway pressure
(CPAP) systems and intermittent mandatory ven-
tilation (IMV) using a mechanical ventilator were
introduced to treat respiratory distress syndrome
in premature newborns.37–40 These new methods
dramatically improved the prognosis of markedly
premature newborns. More recently, a new system
called extrauterine fetal incubation (EUFI), which
used cannulation of the umbilical vein and artery
that were connected to the circuit, was tested on a
baby goat that was ultimately extracted by cesarean
section at 148 days of pregnancy.40–44
126 Ann. N.Y. Acad. Sci. 1221 (2011) 124–128 c
2011 New York Academy of Sciences.
Bulletti et al. Ectogenesis
In contrast to the pessimistic view of the feasi-
bility of partial or complete ectogenesis, we believe
that the following lines of research provide evidence
to suggest that improving technology may advance
this goal: our model of extracorporeal perfusion of
the human uterus that allows for embryo implan-
tation that is operational for up to 52 hours;1–6 the
achievements of Hung-Ching Liu at Cornell Uni-
versity, permitting the development of an artificial
human uterus using endometrial cells grown over a
uterus-shaped scaffolding (the scaffolding dissolves
as cells grow and form novel uterine tissue);8and
the experiments conducted by Yoshinori Kuwabara
of Juntendo University supporting developing goats
with an artificial placenta and uterus.9Though no
experiments have yet been conducted on human
fetuses brought to term, experiments on previable
goat fetuses have resulted in maintenance of life for
several weeks outside the uterus.14,15 However, is-
sues related to nutrition and hormonal stability in
these models remain.
In our view, liquid ventilation constitutes the
next important step in the treatments of prema-
ture infants. In 1989, the first human studies of-
fering liquid ventilation to infants, with no chance
for survival through conventional therapy, were
performed.14,17–45 The results were promising and
larger trials are now under way. Recently, a fluoro-
carbon liquid was developed that has the capacity to
carry a large amount of dissolved oxygen and car-
bon dioxide.17–45 By inserting liquid into the lung,
Shaffer and his colleagues argue, the lung sacs can
be expanded at a much lower pressure. Thus, the
development of liquid breathing could serve as an
intermediate stage between the womb and breathing
in open air.
In conclusion, we foresee that partial
ectogenesis—the growth and development of
fetuses between 14 and 35 weeks of pregnancy—is
withinreachgivenourcurrentknowledgeand
existing technical tools.
Conflicts of interest
The authors declare no conflicts of interest.
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... Perspectives regarding the AU AU or artificial womb stands for an extracorporeal support and supplementation with all appropriate nutrients and oxygen for fetal development to imitate a female intrauterine environment [44]. The first successful ex vivo human embryo implantation, specifically into a surgicallyremoved human uterus, was conducted in 1988 by Bulletti and colleagues who presented an artificially perfused uterus. ...
... Such matters could severely challenge the field of bioethics. Along with ethical issues, the potential implication of AU would also challenge the known 14-day limit for human embryos, exposing further conflicts regarding the legacy because embryos could be implanted and grow for more than 14 days into artificial wombs [44]. The media reported Dr. Hung-Ching Liu's first attempt to grow a human embryo on a scaffold incorporated with endometrial tissue for 10 days and was claimed to be a successful implantation (Hung-Ching Liu, unpublished observations). ...
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Technofeminisms are dealing with new sets of challenges directly related to the possibilities opened by transhumanism. Among the huge list of possible technological advances, we direct our interest towards reproductive technologies, in particular ectogenesis (foetus pregnancy and growth outside a human womb). Although some authors defend the benefits of this technology for the advancement of gender equality, we want to suggest a radically different scenario: the studies on ectogenesis will not liberate women—once they are not ‘limited’ by the duties of childbirth (and care)—nor blur gender differences according to evolutionary requests, but they can rather reinforce the current male gendered dominance. A study of the situated nature of existing studies and experiments on ectogenesis, as well as a study of the current clashes between the possibilities offered by technology and the more probable biased outcomes will offer us a sound background to think about the limits of technological transformation that are directly related to social pressures, rather than to a “natural or rational outcome” in relation to such technologies. Despite the fact that from a biotechnological perspective embryos have been created without fertilisation by sperm nuclei, consequently eliminating the need of males for reproductive purposes, more intense efforts are being invested into extra womb pregnancy. Biotechnologies, and especially those related to reproductive tasks, are being gendered biased, following a tendency also present into AI and robotics industries and researches (where assistant roles are always ruled by ‘female characters’). At some point, the lemma of xenofeminists of “Gender abolitionism” can become true…but could this abolition to imply the emergence of a neutral gender which true essence was a male reference (for example at bodily level)? Under such scenario, the dilution of females under an over-dominating male-society, thanks to technology, would create a specific scenario: males would not need women for reproducing new human beings. Could it mean the end of the existence of females (as humans able to be pregnant and to give birth), or even a definitive undervaluation of female’s ancient roles in favor of a new male prototype?
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The development of assisted reproductive technology (ART) through four decades has led to offer the ultimate treatment for nearly all forms of infertility. The only remaining factor of childlessness however that still eludes ART and its routine variants are the absolute uterine infertility factors, for which the only option is an experimental approach, uterus transplantation. Progresses has been made over the past few years, and more are underway for simplifying the process notably for simplifying the uterus extraction step performed in the uterus donor. Furthermore, as the technique is being better mastered, the original indications for uterus transplantation, the congenital or acquired absence of the uterus, are now widened to also include incurable uterine fibrosis, or Asherman's syndrome. The ART-related practicalities of uterus transplantation, ovarian stimulation and uterine priming are being discussed in the present review.
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Science Fiction (Sci-Fi) brings several examples of modifications made in the human body, each having different goals in mind-it may be either improving or compromising intellectual, physical, or psychological abilities. Lately, with consistent advancements in the Health field, mostly brought about by e-Health startups and the interdisciplinary combination of Biology, Medicine, Computer Science, and Engineering, many of the modifications seen in big screens became a reality, albeit from a weak signal point of view and not yet mainstream solutions to Health issues. Aiming to define the scope of this research, as Sci-Fi works are abundant and take the form of movies, animes, mangas, and books, filtering all of those would be a herculean job. Hence, for this paper, only movies and animes were assessed, according to precepts established in the Methodology section. Taking our society's progress into consideration, the aims of this work are twofold: (i) knowing to what extent there has already been real scientific progress with regard to science fiction scenarios and predictions of human body transformations; (ii) understanding the repercussions of humans undergoing such modifications applied to several fields, such as Economics, Sociology and Ethics, pinpointing scenarios that should be discussed in preparation for future changes.
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Cambridge Core - Medico-Legal, Bioethics and Health Law - Regulating Assisted Reproductive Technologies - by Amel Alghrani
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Science Fiction (Sci-Fi) brings several examples of modifications made in the human body, each having different goals in mind—it may be either improving or compromising intellectual, physical, or psychological abilities. Lately, with consistent advancements in the Health field, mostly brought about by e-Health startups and the interdisciplinary combination of Biology, Medicine, Computer Science, and Engineering, many of the modifications seen in big screens became a reality, albeit from a weak signal point of view and not yet mainstream solutions to Health issues. Aiming to define the scope of this research, as Sci-Fi works are abundant and take the form of movies, animes, mangas, and books, filtering all of those would be a herculean job. Hence, for this paper, only movies and animes were assessed, according to precepts established in the Methodology section. Taking our society’s progress into consideration, the aims of this work are twofold: (i) knowing to what extent there has already been real scientific progress with regard to science fiction scenarios and predictions of human body transformations; (ii) understanding the repercussions of humans undergoing such modifications applied to several fields, such as Economics, Sociology and Ethics, pinpointing scenarios that should be discussed in preparation for future changes.
Article
Science Fiction (Sci-Fi) brings several examples of modifications made in the human body, each having different goals in mind — it may be either improving or compromising intellectual, physical, or psychological abilities. Lately, with consistent advancements in the Health field, mostly brought about by e-Health startups and the interdisciplinary combination of Biology, Medicine, Computer Science, and Engineering, many of the modifications seen in big screens became a reality, albeit from a weak signal point of view and not yet mainstream solutions to Health issues. Aiming to define the scope of this research, as Sci-Fi works are abundant and take the form of movies, animes, mangas, and books, filtering all of those would be a herculean job. Hence, for this paper, only movies and animes were assessed, according to precepts established in the Methodology section. Taking our society’s progress into consideration, the aims of this work are twofold: (i) knowing to what extent there has already been real scientific progress with regard to science fiction scenarios and predictions of human body transformations; (ii) understanding the repercussions of humans undergoing such modifications applied to several fields, such as Economics, Sociology and Ethics, pinpointing scenarios that should be discussed in preparation for future changes.
Chapter
Vor Kurzem ging eine Schockwelle um die Welt. Chinesische Wissenschaftler berichteten von der erstmaligen Erzeugung genetisch modifizierter menschlicher Embryos mittels einer neuen Gentechnologie und entfachten damit eine hitzige Kontroverse. Einige sind der Meinung, derlei Experimente müssten ein Ende haben, während andere dafür plädieren, die humane Genmodifikation mit Volldampf voranzutreiben, um Erkrankungen vorzubeugen oder gar verbesserte Designerbabys zu erschaffen. Als Vollblutwissenschaftler fand ich mich zwischen den beiden Polen wieder. Überzeugt davon, dass die Öffentlichkeit sehr viel mehr über diesen Präzedenzfall in der Wissenschafts- und Kulturgeschichte erfahren sollte, fasste ich den Entschluss, meine Kenntnisse mithilfe dieses Buches an Sie weiterzugeben.
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In the paper, the authors present legal and bioethical issues related to the fertilization outside the human body, particularly, to the producing and applying an artificial womb for this purpose. Considering these issues appears to be necessary to create proper legislation that will provide a legal basis for the given issue.
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R. HALLGRENTHEFIRSTINTERESTof this group inthe development of an artificial placentalwas to provide a nmeans of testing the long-term use of an oxygenator in an unanesthe-tized animal in a readily controlled state.Secondly, the possibility was considered ofsupporting the newborn child in respiratorvdistress syndrome with oxygenated blood de-livered into the umbilical vein on a long-termbasis.2In 1958, Westin3 studied seven previablehuman fetuses which he kept alive between 5and 12 hours by perfusion of the umbilicalvein, in association with hypothermia. Inchoosing the lambas the experimental animal,we were guided by the
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To investigate endocrine responses of isolated premature goat fetuses during long-term extrauterine incubation with umbilical arteriovenous extracorporeal membrane oxygenation (A-V ECMO), we conducted experiments in seven goat fetuses (95-134 days gestation). The fetuses were cannulated from the umbilical vessels, and their blood-gas exchange was totally supported by A-V ECMO, while they were maintained in an isothermal incubator containing artificial amniotic fluid. The survival period was between 84 and 190 h. At 24-h intervals, fetal blood samples were collected, and plasma concentrations of catecholamines, ACTH, and cortisol were determined. After 24 h of incubation, fetal circulatory and respiratory variables remained stable, until evident circulatory failure occurred before their deaths. A similar pattern was observed in temporal changes in plasma concentrations of catecholamines, ACTH, and cortisol. Plasma levels were high during the initial 24 h of incubation, subsequently decreased, and then increased before death. Hormone levels during stable periods were equivalent to or slightly higher than values for fetuses in utero. These results suggest that conditions during the stable period of long-term extracorporeal fetal incubation are not highly stressful for the isolated fetuses.
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The apparatus consists essentially of a gas exchanger and a small dialyzer. Satisfactory oxygenation of the blood has been achieved and foetuses have been kept alive and active at 38 degrees C for 7 h after they have been removed from the uterus. The circulation both inside and outside the body is maintained by the foetal heart, and drop counters are used to record the blood flow in the umbilical arteries and vein. The venous and arterial pressures in the umbilical cord can be varied independently, and records are shown of the effects of doing so upon the blood flow through the vessels. An electrocardiogram enables continuous records to be kept of the foetal heart, and temporary failures of the circulation have been shown to cause reversible disorders of rhythm and conduction.
Article
THE perfusion of the isolated fœtus allows aspects of fœtal metabolism to be investigated in the absence of placental transfer or synthesis of metabolites. A future extension of this technique may find application in the management and treatment of the premature or hypoxic human infant.
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Previously, this group reported on a system of extrauterine incubation of a goat fetus, in which the fetus is surrounded by artificial amniotic fluid and connected to the circuit with an ECMO (extracorporeal membrane ox-ygenator) by the umbilical arteries and veins. The following is a summary of recent progress using an improved method of catheterization and a new system that included a dialyzer within the circuit. Nine goat fetuses were used in this experiment. Six goats were successfully incubated; the duration of their incubation was 146.5 ± 61.3 h (mean ± SD). The longest one was 236 h. Slowly progressive circulatory depression was thought to be the main cause of fetal death. Marked tendencies to bleeding and water retention were not observed in any cases. Stable serum electrolyte levels were maintained.