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More than 13 million children are born preterm annually. Prematurity-related mortality accounts for 0.9 million deaths worldwide. The majority of those affected are Extremely Preterm Infants (gestational age less than 28 weeks). Immaturity causes organ failure and specific morbidities like germinal matrix hemorrhage, bronchopulmonary dysplasia, and necrotizing enterocolitis. Artificial womb and placenta technologies address these issues. As a bridge-to-life technology, they provide a liquid environment to allow organ maturation under more physiological conditions. The proposed artificial womb can adapt to fetal growth. Volume adjustment is achieved by removing fluid from the interspace between an inner and outer chamber. Results of the in vitro tests showed a temperature constancy of 36.8°C ± 0.3°C without pressure loss over 7 days. The volume of the inner sac was variable between 3.6 and 7.0 L. We designed a filtration and disinfection system for this particular purpose. This system has proven strong disinfection capabilities, effective filtering of metabolic waste, and the ability to avoid phospholipid washout. The presented artificial womb has sufficient volume variability to adapt to the physiologic growth of an extremely preterm neonate over a 4-week period. We regard this as an important step in the development of this bridge-to-life technology.
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Órgãos Artificiais , Lactente Extremamente Prematuro , Humanos , Recém-Nascido , Feminino , Gravidez , Desinfecção , Idade GestacionalRESUMO
Artificial Amnion and Placenta Technology (AAPT)-sometimes referred to as 'Artificial Womb Technology'-could provide an extracorporeal alternative to bodily gestations, allowing a fetus delivered prematurely from the human uterus to continue development while maintaining fetal physiology. As AAPT moves nearer to being used in humans, important ethical and legal questions remain unanswered. In this paper, we explore how the death of the entity sustained by AAPT would be characterized in law. This question matters, as legal ambiguity in this area has the potential to compound uncertainty and the suffering of newly bereaved parent(s). We first identify the existing criteria used to delineate the legal characterization of death, which occurs before birth or during the immediate neonatal period in England and Wales. We then demonstrate that attempting to apply these in the context of AAPT gives rise to a number of challenges, which make it impossible to reach a definitive conclusion as to the nature of death in AAPT using the current legal framework. In doing so, we demonstrate that the current legal framework in England and Wales may be unable to adequately capture the situation of an entity being sustained by AAPT.
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To improve care for extremely premature infants, the development of an extrauterine environment for newborn development is being researched, known as Artificial Placenta and Artificial Womb (APAW) technology. APAW facilitates extended development in a liquid-filled incubator with oxygen and nutrient supply through an oxygenator connected to the umbilical vessels. This setup is intended to provide the optimal environment for further development, allowing further lung maturation by delaying gas exposure to oxygen. This innovative treatment necessitates interventions in obstetric procedures to transfer an infant from the native to an artificial womb, while preventing fetal-to-neonatal transition. In this narrative review we analyze relevant fetal physiology literature, provide an overview of insights from APAW studies, and identify considerations for the obstetric procedure from the native uterus to an APAW system. Lastly, this review provides suggestions to improve sterility, fetal and maternal well-being, and the prevention of neonatal transition.
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Ectogenesis technology would make it possible to support the complete gestational development of a human being outside the female body. Proponents argue that this technology offers a welcome opportunity to expand reproductive options for those unable or unwilling to gestate. However, by completely bypassing pregnancy, the use of ectogenesis prevents the formation of gestational family ties. Consequently, it has faced criticism for perpetuating a patriarchal view of the family that undermines the moral significance of gestation. The concern is that the introduction of this technology might result in the loss of reproductive autonomy for those who desire to experience pregnancy, as they face pressures to opt for ectogenesis instead. Existing accounts of family values define parents' rights to rear a child, but they fail to establish a right to gestate that can protect an individual's interest in bearing a child. To provide a more comprehensive account of family values, I argue that pregnancy involves a unique quality of intimacy and can make distinct contributions to one's flourishing. Based on this premise, I defend a fundamental moral right to gestate that can help safeguard the option of pregnancy for those who desire it. In conclusion, I consider how a prospective gestator need not provide optimal conditions for fetal development in the way that ectogenesis promises in order for their choice of pregnancy to be justified.
Assuntos
Ectogênese , Humanos , Feminino , Gravidez , Ectogênese/ética , Autonomia Pessoal , Desenvolvimento Fetal , Pais , Direitos Sexuais e Reprodutivos/ética , Princípios MoraisRESUMO
BACKGROUND: Research into Artificial Placenta and Artificial Womb (APAW) technology for extremely premature infants (born < 28 weeks of gestation) is currently being conducted in animal studies and shows promising results. Because of the unprecedented nature of a potential treatment and the high-risk and low incidence of occurrence, translation to the human condition is a complex task. Consequently, the obstetric procedure, the act of transferring the infant from the pregnant woman to the APAW system, has not yet been established for human patients. The use of simulation-based user-centered development allows for a safe environment in which protocols and devices can be conceptualized and tested. Our aim is to use participatory design principles in a simulation context, to gain and integrate the user perspectives in the early design phase of a protocol for this novel procedure. METHODS: Simulation protocols and prototypes were developed using an iterative participatory design approach; usability testing, including general and task-specific feedback, was obtained from participants with clinical expertise from a range of disciplines. The procedure made use of fetal and maternal manikins and included animations and protocol task cards. RESULTS: Physical simulation with the active participation of clinicians led to the diffusion of tacit knowledge and an iteratively formed shared understanding of the requirements and values that needed to be implemented in the procedure. At each sequel, participant input was translated into simulation protocols and design adjustments. CONCLUSION: This work demonstrates that simulation-based participatory design can aid in shaping the future of clinical procedure and product development and rehearsing future implementation with healthcare professionals.
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Outcomes for extremely low gestational age newborns (ELGANs), defined as <28 weeks estimated gestational age (EGA), remain disproportionately poor. A radical paradigm shift in the treatment of prematurity is to recreate the fetal environment with extracorporeal support and provide an environment for organ maturation using an extracorporeal VV-ECLS artificial placenta (AP) or an AV-ECLS artificial womb (AW). In this article, we will review clinical indications, current approaches in development, ongoing challenges, remaining milestones and ethical considerations prior to clinical translation.
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Órgãos Artificiais , Oxigenação por Membrana Extracorpórea , Gravidez , Feminino , Recém-Nascido , Humanos , Placenta , Recém-Nascido Prematuro , ÚteroRESUMO
OBJECTIVE: To describe the development of an artificial placenta (AP) system in sheep with learning curve and main bottlenecks to allow survival up to one week. METHODS: A total of 28 fetal sheep were transferred to an AP system at 110-115 days of gestation. The survival goal in the AP system was increased progressively in three consecutive study groups: 1-3 h (n = 8), 4-24 h (n = 10) and 48-168 h (n = 10). Duration of cannulation procedure, technical complications, pH, lactate, extracorporeal circulation (EC) circuit flows, fetal heart rate, and outcomes across experiments were compared. RESULTS: There was a progressive reduction in cannulation complications (75%, 50% and 0%, p = 0.004), improvement in initial pH (7.20 ± 0.06, 7.31 ± 0.04 and 7.33 ± 0.02, p = 0.161), and increment in the rate of experiments reaching survival goal (25%, 70% and 80%, p = 0.045). In the first two groups, cannulation accidents, air bubbles in the extracorporeal circuit, and thrombotic complications were the most common cause of AP system failure. CONCLUSIONS: Achieving a reproducible experimental setting for an AP system is extremely challenging, time- and effort-consuming, and requires a highly multidisciplinary team. As a result of the learning curve, we achieved reproducible transition and survival up to 7 days. Extended survival requires improving instrumentation with custom-designed devices.
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The microbiome in the female reproductive tract plays an essential role in immune modulation and reproductive health. However, various microbes become established during pregnancy, the balance of which plays a crucial role in embryonic development and healthy births. The contribution of disturbances in the microbiome profile to embryo health is poorly understood. A better understanding of the relationship between reproductive outcomes and the vaginal microbiota is needed to optimize the chances of healthy births. In this regards, microbiome dysbiosis refers to conditions in which the pathways of communication and balance within the normal microbiome are imbalanced due to the intrusion of pathogenic microorganisms into the reproductive system. This review summarizes the current state of knowledge on the natural human microbiome, with a focus on the natural uterine microbiome, mother-to-child transmission, dysbiosis, and the pattern of microbial change in pregnancy and parturition, and reviews the effects of artificial uterus probiotics during pregnancy. These effects can be studied in the sterile environment of an artificial uterus, and microbes with potential probiotic activity can be studied as a possible therapeutic approach. The artificial uterus is a technological device or biobag used as an incubator, allowing extracorporeal pregnancy. Establishing beneficial microbial communities within the artificial womb using probiotic species could modulate the immune system of both the fetus and the mother. The artificial womb could be used to select the best strains of probiotic species to fight infection with specific pathogens. Questions about the interactions and stability of the most appropriate probiotics, as well as dosage and duration of treatment, need to be answered before probiotics can be a clinical treatment in human pregnancy.
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Disbiose , Microbiota , Gravidez , Feminino , Humanos , Transmissão Vertical de Doenças Infecciosas , Útero , VaginaRESUMO
Since the early 1980's, with the clinical advent of in vitro fertilization resulting in so-called "test tube babies," a wide array of ethical considerations and concerns regarding artificial womb technology (AWT) have been described. Recent breakthroughs in the development of extracorporeal neonatal life support by means of AWT have reinitiated ethical interest about this topic with a sense of urgency. Most of the recent ethical literature on the topic, however, pertains not to the more imminent scenario of a physiologically improved method of neonatal care through AWT, but instead to the remote scenario of "complete ectogenesis" that imagines human gestation occurring entirely outside of the womb. This scoping review of the ethical literature on AWT spans from more abstract concerns about complete ectogenesis to more immediate concerns about the soon-to-be-expected clinical life support of what we term the fetal neonate or fetonate. Within an organizing framework of different stages of human gestational development, from conception to the viable premature infant, we discuss both already identified and newly emerging ethical considerations and concerns regarding AWT and the care of the fetonate.
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Recém-Nascido Prematuro , Útero , Recém-Nascido , Feminino , Lactente , Humanos , Feto , TecnologiaRESUMO
Increasing numbers of research teams are investigating the feasibility of developing artificial amnion and placenta technology (AAPT), commonly referred to as "artificial womb technology". This technology, aimed at supporting ex vivo gestation, has not yet been tested in humans, but it has been stated that we are closer to clinical application than ever before as breakthroughs in animal studies demonstrate good proof of principle. With these proof-of-concept models, further dissemination of AAPT as a research modality is expected. In this review article, we consider the ethical implications of the most imminent anticipated applications for AAPT. We focus specifically on the specific ethical complications regarding the improvements this technology may offer to conventional neonatal intensive care, its potential utility in facilitating prenatal interventions, and some of the broader socio-legal implications such as the debates about abortion access and reproductive and gestational choices. We discuss translational and societal questions when it comes to designing and developing this technology, like commitments to value-sensitive design, along with an examination of the legal and moral status of the entity gestating ex utero, which will be relevant for how it ought to be treated in the context of these various applications. From these perspectives, this review identifies the ethical questions that we believe to be most pressing in the development and potential introduction of AAPT, with due attention to their manifestation as translational and legal issues.
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Despite significant advances in the treatment of prematurity, premature birth results in significant mortality and morbidity. In particular, extremely low gestational age newborns (ELGANs) defined as <28 weeks estimated gestational age (EGA) suffer from disproportionate mortality and morbidity. A radical paradigm shift in the treatment of prematurity is to recreate fetal physiology using an extracorporeal VV-ECLS artificial placenta (AP) or an AV-ECLS artificial womb (AW). Over the past 15 years, tremendous advances have been made in the laboratory confirming long-term support and organ protection and ongoing development. The major milestones to clinical application are miniaturization, anticoagulation, clinical risk stratification, specialized critical care protocols, a regulatory path and a strategy and platform to translate technology to the bedside. Currently, several groups are addressing the remaining milestones for clinical translation.
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Órgãos Artificiais , Oxigenação por Membrana Extracorpórea , Doenças do Prematuro , Nascimento Prematuro , Gravidez , Feminino , Recém-Nascido , Humanos , Lactente , Oxigenação por Membrana Extracorpórea/métodos , Placenta , Idade Gestacional , Nascimento Prematuro/prevenção & controleRESUMO
Artificial wombs are already in development that have the potential to radically alter how we perceive the developing fetus and the role of pregnancy in society. That this technology would allow greater visibility of gestation than ever before also highlights the risk that artificial wombs will be used to further restrict women's reproductive liberty and access to abortion. This article uses Paul Lauritzen's theory of "visual bioethics" to explore the ethical significance of images of the developing fetus and how artificial wombs might best be visually designed and integrated into society.
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Aborto Induzido , Bioética , Feminino , Humanos , Princípios Morais , Percepção , Gravidez , ÚteroRESUMO
The purpose of this article is to reflect on the changes that the implementation of artificial wombs would bring to society, the family, and the concept of motherhood and fatherhood through the lens of two recent books: Helen Sedgwick's The Growing Season and Rebecca Ann Smith's Baby X. Each of the two novels, set in a near future, follows the work of a scientist who develops artificial womb technology. Significantly, both women experience concerns about the technology and its long-term effects that make both of them leave their laboratories and rethink the technology they invented, while considering its many ethical implications. Both novels can be seen as feminist revisionary rewritings of Aldous Huxley's Brave New World, rejecting the vision of rows of mass-produced, anonymous babies in artificial wombs, stressing instead the closeness of the parents to their offspring. They nevertheless critically evaluate not only the many potential benefits for women of ectogenetic technology but also the possible disadvantages and pitfalls.
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Ectogênese , Útero , Feminino , Humanos , Princípios Morais , Pais , Gravidez , TecnologiaRESUMO
Despite advances in clinical care and modest improvement in mortality rates for extreme prematurity, morbidity remains a significant challenge. The ideal environment to support prematurity would be fluidic and rely on natural fetal circulation to mimic the natural fetal amniotic environment, yet such an environment has been unsuccessful in long-term support until recently. Our group has succeeded in developing such a support system to foster fetal growth in the premature lamb model that shows promise for clinical translation. Here, we describe the EXTrauterine Environment for Neonatal Development (EXTEND) from its conception onwards, review published literature on fetal development and support of the premature lamb model in EXTEND, and discuss future applications.
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Nascimento Prematuro , Âmnio , Animais , Feminino , Desenvolvimento Fetal , Feto , Humanos , Pulmão , OvinosRESUMO
This paper argues that uterine transplants are a potentially dangerous distraction from the development of alternative methods of providing reproductive options for women with absolute uterine factor infertility (AUFI). We consider two alternatives in particular: the bioengineering of wombs using stem cells (which would carry fewer risks than uterine transplants) and ectogenesis (which would not require surgical intervention for either the prospective mother with AUFI or a womb donor). Whether biologically or mechanically engineered, these womb replacements could provide a way for women to have children, including genetically related offspring for those who would value this possibility. Most importantly, this alternative would avoid the challenge of sourcing wombs for transplant, a practice that we argue would likely be exploitative and unethical. Continued research into bioengineering and ectogenesis will therefore remain morally important despite the recent development of uterine transplantation, even if the procedure reaches routine clinical application.
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Ectogênese , Infertilidade Feminina , Criança , Feminino , Humanos , Infertilidade Feminina/cirurgia , Estudos Prospectivos , Reprodução , Útero/transplanteRESUMO
Despite improvements in survival over the past few decades, pulmonary immaturity and the use of mechanical ventilation have stunted reduction in short- and long-term morbidities for infants at the borderline of viability (22-24 weeks of gestation). It has long been suspected that the use of an artificial womb or artificial placenta to preserve native fetal physiology and maintain fluid- rather than air-filled lungs would help to improve outcomes for these infants. As such, several institutions have ongoing efforts to develop this technology, bringing the field of neonatology within sight of clinical trials. Prior to use in humans, several important ethical issues should be considered and discussed, including the moral status of these patients and the term used to describe them, whether neonate, fetus, or another term entirely. These determinations will guide when it is appropriate to use the technology and when it is permissible to withdraw this support, as well as how to ascribe parental rights and the legal status of these patients.
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Neonatologia , Placenta , Feminino , Feto , Humanos , Lactente , Recém-Nascido , Gravidez , Tecnologia , ÚteroRESUMO
Extreme prematurity remains an unsolved problem and is the leading cause of pediatric mortality and morbidity in developed countries. The extreme premature infant is physiologically a fetus, and current supportive measures in our NICUs are for the most part non-physiologic. In order to improve morbidity and mortality in this population, we have developed the Extra-uterine environment for newborn development (EXTEND) system which seeks to mimic as closely as possible the environment of the womb. The primary components of EXTEND include a sterile fluid environment, a pumpless arteriovenous extracorporeal oxygenator circuit, and vascular access via umbilical arterial and venous vessels. While supported on the EXTEND system, premature fetal lambs grow and develop normally for up to 4 weeks. Fetal physiology is maintained, and detailed organ system analysis supports normal development. This article summarizes current progress in the development of EXTEND, the pathway for human translation, ethical considerations related to EXTEND, and anticipated clinical applications of this potentially paradigm changing technology. LEVEL OF EVIDENCE: IV.
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Doenças do Prematuro , Recém-Nascido Prematuro , Animais , Animais Recém-Nascidos , Criança , Feminino , Feto , Humanos , Recém-Nascido , Ovinos , ÚteroRESUMO
In this paper we present an initial roadmap for the ethical development and eventual implementation of artificial amniotic sac and placenta technology in clinical practice. We consider four elements of attention: (1) framing and societal dialogue; (2) value sensitive design, (3) research ethics and (4) ethical and legal research resulting in the development of an adequate moral and legal framework. Attention to all elements is a necessary requirement for ethically responsible development of this technology. The first element concerns the importance of framing and societal dialogue. This should involve all relevant stakeholders as well as the general public. We also identify the need to consider carefully the use of terminology and how this influences the understanding of the technology. Second, we elaborate on value sensitive design: the technology should be designed based upon the principles and values that emerge in the first step: societal dialogue. Third, research ethics deserves attention: for proceeding with first-in-human research with the technology, the process of recruiting and counseling eventual study participants and assuring their informed consent deserves careful attention. Fourth, ethical and legal research should concern the status of the subject in the AAPT. An eventual robust moral and legal framework for developing and implementing the technology in a research setting should combine all previous elements. With this roadmap, we emphasize the importance of stakeholder engagement throughout the process of developing and implementing the technology; this will contribute to ethically and responsibly innovating health care.
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Over 50 years ago, visionary researchers began work on an extracorporeal artificial placenta to support premature infants. Despite rudimentary technology and incomplete understanding of fetal physiology, these pioneering scientists laid the foundation for future work. The research was episodic, as medical advances improved outcomes of premature infants and extracorporeal life support (ECLS) was introduced for the treatment of term and near-term infants with respiratory or cardiac failure. Despite ongoing medical advances, extremely premature infants continue to suffer a disproportionate burden of mortality and morbidity due to organ immaturity and unintended iatrogenic consequences of medical treatment. With advancing technology and innovative approaches, there has been a resurgence of interest in developing an artificial placenta to further diminish the mortality and morbidity of prematurity. Two related but distinct platforms have emerged to support premature infants by recreating fetal physiology: a system based on arteriovenous (AV) ECLS and one based on veno-venous (VV) ECLS. The AV-ECLS approach utilizes only the umbilical vessels for cannulation. It requires immediate transition of the infant at the time of birth to a fluid-filled artificial womb to prevent umbilical vessel spasm and avoid gas ventilation. In contradistinction, the VV-ECLS approach utilizes the umbilical vein and the internal jugular vein. It would be applied after birth to infants failing maximal medical therapy or preemptively if risk stratified for high mortality and morbidity. Animal studies are promising, demonstrating prolonged support and ongoing organ development in both systems. The milestones for clinical translation are currently being evaluated.
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BACKGROUND: Breakthroughs in animal studies make the topic of human application of ectogenesis for medical and non-medical purposes more relevant than ever before. While current data do not yet demonstrate a reasonable expectation of clinical benefit soon, several groups are investigating the feasibility of artificial uteri for extracorporeal human gestation. MAIN TEXT: This paper offers the first comprehensive and up to date discussion of the most important pros and cons of human ectogenesis in light of clinical application, along with an examination of crucial ethical (and legal) issues that continued research into, and the clinical translation of, ectogenesis gives rise to. The expected benefits include advancing prenatal medicine, improving neonatal intensive care, and providing a novel pathway towards biological parenthood. This comes with important future challenges. Prior to human application, important questions have to be considered concerning translational research, experimental use of human fetuses and appropriate safety testing. Key questions are identified regarding risks to ectogenesis' subjects, and the physical impact on the pregnant person when transfer from the uterus to the artificial womb is required. Critical issues concerning proportionality have to be considered, also in terms of equity of access, relative to the envisaged application of ectogenesis. The advent of ectogenesis also comes with crucial issues surrounding abortion, extended fetal viability and moral status of the fetus. CONCLUSIONS: The development of human ectogenesis will have numerous implications for clinical practice. Prior to human testing, close consideration should be given to whether (and how) ectogenesis can be introduced as a continuation of existing neonatal care, with due attention to both safety risks to the fetus and pressures on pregnant persons to undergo experimental and/or invasive procedures. Equally important is the societal debate about the acceptable applications of ectogenesis and how access to these usages should be prioritized. It should be anticipated that clinical availability of ectogenesis, possibly first as a way to save extremely premature fetuses, may spark demand for non-medical purposes, like avoiding physical and social burdens of pregnancy.