REVIEW ARTICLE

https://doi.org/10.5005/jp-journals-10009-1963
Donald School Journal of Ultrasound in Obstetrics and Gynecology
Volume 17 | Issue 1 | Year 2023

Infants at the Limits of Viability: Medical and Ethical Aspects

Milan Stanojevic

University Hospital Sveti Duh, Zagreb, Croatia; Department of Obstetrics and Gynecology, School of Medicine, Neonatal Unit, University of Zagreb, Zagreb, Croatia

Corresponding Author: Milan Stanojevic, University Hospital Sveti Duh, Zagreb, Croatia; Department of Obstetrics and Gynecology, School of Medicine, Neonatal Unit, University of Zagreb, Zagreb, Croatia, Phone: +385913712110, e-mail: milan.stanojevic@optinet.hr

Received on: 15 January 2023; Accepted on: 10 February 2023; Published on: 14 April 2023

ABSTRACT

The AWT is investigated on animal models only, but even in the research model, microgravity and gravity (G), age, thermoregulation, and oxygenation (GATO) hypotheses have not been mentioned or considered, although they might be important for the development of the fetus at early gestations. It might be advisable to change the way of thinking and find the reasons pro and contra of microgravity use in AWT research, which may improve care for fetuses born at the lower limits of viability.

How to cite this article: Stanojevic M. Infants at the Limits of Viability: Medical and Ethical Aspects. Donald School J Ultrasound Obstet Gynecol 2023;17(1):79-87.

Source of support: Nil

Conflict of interest: Dr. Milan Stanojevic is associated as the Executive Editor of this journal and this manuscript was subjected to this journal’s standard review procedures, with this peer review handled independently of this Executive Editor and his research group.

Keywords: Artificial uterus, Limits of viability, Microgravity, Outcome, Prematurity, Treatment.

This paper was presented at the symposium ZAGREB-New York Ethical and Perinatal Dialogue (1^st International Symposium When does human life begin? Ethics, law, and professionalism in reproductive medicine; and Fetal neurology: from short to the long-term follow-up - how to proceed? Multi-center results on the clinical use of KANET), held on 8–9 October 2022 in Zagreb, Croatia.

INTRODUCTION

There is a continuity of intrauterine to extrauterine life. With the existing level of knowledge and technical possibilities, extrauterine survival above 50% without major morbidity in some developed countries is possible at 22 gestational week (GW), while anecdotal survival has been described even at 21 GW + 4 days.¹^,² The possibility of extending the survival of the smallest premature infants has been challenging for many decades. Physicians have often been sharing information on the survival of the tinniest male and female premature infants, which had been considered a miracle for the public and a sensation for medical professionals.³^,⁴ A different way of thinking concerning the treatment of tiny premature infants appeared about 70 years ago, known as the AU project. The first article on the topic of the AU, which can be found on the PubMed entitled “The artificial uterus,” is unfortunately not available online,⁵ while it is known that the project and the patent by the same author on AU have been submitted in the United States of America in 1954.⁶ As the author of the patent stated in his application, “One of the objects of this invention is to provide an AU which will sustain an unborn fetus in a condition similar to that of the human uterus.”⁵^,⁶ Almost 70 years ago and recently, treating extreme prematurity remains a difficult medical issue due to many iatrogenic injuries, which can hardly be avoided by using existing modes of therapy, including the modern way of thinking, sophisticated technology, and drugs.⁷^,⁸ Recent technological advancements may enable the translation of experimental models of the artificial uterus and the artificial womb (AW) to clinical practice raising many technical, medical, and ethical dilemmas.⁸^-¹² In vitro fertilization (IVF) was, among other factors, connected with the possibility of selecting and culturing the embryo outside the uterus.¹³^,¹⁴ It means that there was enough knowledge and skills to nurture the embryo ex utero before its implantation and formation of the placenta.⁸^-¹³ Replacement of the placenta and uterus after embryo implantation in terms of clinical application is still used only in animal models, with many unsolved issues.⁸^-¹⁴ But due to the development of AU and AW projects, also known as artificial amnion and placenta technology (AAPT), the paradigm of neonatal intensive care of infants may be changing due to the appearing possibility of so-called “ectogenesis”—that is, partial or complete maturation of a developing embryo or fetus outside the human body.¹⁵^,¹⁶

The prematurity rate is increasing in the world, with the prevalence of prematurity in some African countries approaching 18%, while in some European countries, it is only 5%.¹⁷ The absolute number of premature babies in the world per year is estimated to be 15.1 million, of which only 1% belong to the group below 28 weeks of gestation.¹⁷ Survival of premature infants is gestational age and birthweight related, but the wealth of the country and the availability of neonatal intensive care units (NICU) are also important factors.¹⁷ Delivery before 28 GW and lack of NICUs are decreasing the probability of infants surviving to only 5%.¹⁷ Neonatal intensive care is available for only 1% of all premature babies born per year in the world who need it.¹⁷ Good results of the survival of tiny and immature infants are improving in developed countries, but survival without major morbidity is still stagnant.¹⁸^-²¹ From the historical point of view, limits of viability changed in the last 150 years for many medical, economic, ethical, and other reasons from 32 to 22 weeks of gestation, but always related to already born infants.¹⁸^-²¹

The aim is to present medical and ethical issues connected with the treatment of neonates born at the limits of viability, briefly discussing the future development of new treatment possibilities for those infants outside the human body called “ectogenesis,” which is still practiced only on animal models.¹⁵^,²²

THE EXISTING DEFINITION OF THE LIMITS OF VIABILITY WITH FUTURE CHALLENGES

Nowadays, viability is considered a survival outside the uterus using medical knowledge and available technical possibilities to nurture the newborn infant outside the uterus. Currently, the World Health Organization sets a lower limit of viability at 22 weeks of gestation and/or birthweight of 500 gm and/or 25 cm of birth length.²³^,²⁴ That definition is used for the national perinatal statistics, while for the international comparisons between the countries, the criteria are 28 GW and/or birthweight of more or equal to 1000 gm.²³^,²⁴ The 10th revision of the International Classification of Diseases describes the perinatal period as starting at 22 completed weeks.²³ The concept of viability is variable, sometimes meaning the gestational age, weight, or length at which the smallest known infant survived, while sometimes meaning the stage at which a specified percentage of infants survived with the assistance of given technological and other therapeutic means.²³^,²⁴ According to the American College of Obstetricians and Gynecologists, previable birth is defined as delivery after 20 + 0/7 to 25 + 6/7 weeks of gestation, at which families and healthcare teams are faced with complex and ethically challenging decisions.²⁵

Limits of viability are sometimes defined as certain gestational age or birthweight at which infant survival to discharge is above 50%.²⁶^,²⁷ At the beginning of the 20th century, an important statement was made concerning the definition of the limits of viability, saying that using gestational age and body measures should be avoided because it could encourage withholding life-saving support to infants believed to be unviable.²⁷

Technological and therapeutic resources essential for the survival of infants at the limits of viability are not available equally in the world, so viability involves social and economic issues as well.²⁶^,²⁷ Sometimes, to be viable means to be discharged alive from the hospital regardless of the length of stay and the quality of life, which is important for the survivors, their parents, and society.²⁶^,²⁷ The universal definition of the limit of viability is probably not possible because of its variability from one individual to the other, from one setting to another, and from one community to the other.²⁶^,²⁷ Therefore, it should be described statistically as a survival curve for specific gestation or birthweight for a particular institution or other location for the specified period.²⁸ Human viability, defined as gestational age at which the chance of survival is 50%, is currently set at approximately 24–25 weeks in most developed countries, although there are NICUs where they could be set at 22–23 GW, with better survival of infant girls.²⁹ From the point of view of healthcare professionals involved in intensive care of those infants, viable infants are those whom most clinicians would treat, while nonviable are those whom most clinicians would not treat, and those in between are the so-called gray zone.²⁹^,³⁰ This subjective definition could be different in developed and in developing countries, within developed countries, or even in different NICUs in the same country.

Brain development at the limits of viability is very vulnerable and susceptible to damage, with many unknown developmental facts like consciousness, which is used to define limits of viability as the period of life when brain development has achieved a minimum level of consciousness.²⁷ But it is a big question of how to define consciousness and whether should issue of consciousness and brain development be included in the definition of the limit of viability or should it be treated as the development of any other organ or system in the human fetus.³¹

Previously mentioned facts show that the definition of the limits of viability is very complicated and confusing and that a precise and universal meaning of viability scientifically has not been produced yet due to the complexity of the problem and lack of knowledge.²⁷ Improved care for immature prematurely born infants resulted in better survival of the infants at the limits of viability, which was the reason to shift the resuscitation limit from 23 towards the gestational age of 22 weeks, resulting in better survival of infants born at 22 GW.³²

SURVIVAL AT THE LIMITS OF VIABILITY FROM THE HISTORICAL POINT OF VIEW AND RECENTLY

According to the data from the literature, the survival of infants with low birthweight changed from 1800 gm in the 1900s to a birthweight of 700 gm in the 2000s.²⁷ As shown in Figure 1, in the 30 years in Sweden, survival of infants at the limits of viability changed considerably, with 50% of survival for the infants born at 25 weeks of gestation achieved at the end of the 1980s, in the next decade in the middle 1990s survival of 50% has been reached for infants at 24 GW, in the middle of 2000s it was reached for infants at 23 GW and for 22 weeks of gestation babies 50% survival was reached in 2010s.¹

Fig. 1: Neonatal survival of extremely preterm, live-born infants at 22–26 completed weeks’ gestation in Sweden between 1985 and 2016 by gestational age and year of birth. Data are from the Swedish Birth Registry (1985–2000), the Extremely Preterm Infants in Sweden Study (EXPRESS) (2004–2007), and the Swedish Neonatal Quality Register (SNQ) (2008–2016). Data from the EXPRESS and SNQ are based on infants who were admitted to the neonatal unit¹

The dotted line is set at 50%, and where it crosses the timeline and gestational age survival lines (orthogonal lines of the same color as the gestational age lines), it shows a 50% survival rate at a certain period).

If we look at the data from developing countries, then in one center in the 10 years (from 2005 to 2014), the survival rate of infants with a birth weight of <1500 gm was only 18%, while no survivors were found in the group below 750 gm at birth.¹⁸ In Ghana, the mortality rate of extremely preterm infants (below 26 weeks of gestation) in the period from 2011 to 2015 was 80.2% (survival to discharge was 19.8%), while for the infants of gestational age from 26 to 27 weeks it was 68.9% (survival to discharge was 31.1%).³³ In another study from Ghana, 22.0% of babies below 28 weeks of gestation survived till discharge in the 10 years from 2010 to 2019.³⁴ In a recently published Ethiopian study (covering the period from 2014 to 2017) mortality rate of premature infants above 28 weeks of gestation was 50.8%.³⁵ In the study of the literature on the mortality rates at the limits of viability in developed and developing countries, it was concluded that the mortality rates ranged from 4 to 46% in developed countries and 0.2–64.4% in developing countries, meaning that they remain high in developing and in developed countries.²⁸

SHORT AND LONG-TERM OUTCOMES OF INFANTS AT THE LIMITS OF VIABILITY

In developed countries limit of viability has reached 22 GW in the last decade, while some improvement has been achieved in developing countries; however, infants below 28 GW have not been included even in the national perinatal statistics because their survival, even with the availability of the neonatal intensive care is sporadic in developing world.³⁶ The time for developing countries to reach the same chance of neonatal survival as in 2012 for newborn babies in high-income countries, based on the average annual rate of reduction from 2000–12, was 110 years for sub-Saharan Africa, and a little less in other nondeveloped countries, which is discouraging.³⁷ Statistics for infants below 28 GW are almost lacking in developing countries, while in developed countries, it is important to have reliable data on the short and long-term outcomes of the infants at the limits of viability.³⁸ Based on reliable data on short and long-term outcomes of the infants born at the limits of viability, the observed adverse outcomes were postnatal growth restriction and increased prevalence of cardiovascular diseases in adulthood, raising many medical, legal, and ethical questions.¹⁹^,³⁹^-⁴¹ Availability of such data is very important for parent counseling, although the parents should be informed that we are sharing with them statistical data, not data that are related to the situation of their premature baby.³⁹ While counseling the parents, it is important to increase the knowledge of parents on the concept of the quality of life without major disability and which health problems may arise in adulthood if their infant is born at the limit of viability.⁴²^,³⁹ Besides that, parents should be informed about the statistics of NICU in which they plan to give birth to their infant because this information may influence their decision-making process based on informed consent.⁴³^,⁴⁴ In a recently published Swedish study, they concluded that the Swedish proactive approach to care at the border of viability has not resulted in an increased proportion of functional impairment among survivors.¹

In the review of literature on the neurodevelopmental outcome of infants at the limits of viability, the rates of surviving unimpaired or minimally impaired were 6–20% for live-born infants at ≤25 GW and <5% for infants born at 22 and 23 GW.¹⁹ Figure 2 shows that in different studies from three developed countries (United States of America, Sweden, and the United Kingdom), the data on the mild, moderate, and severe disabilities are very similar, and they are dependent on gestational age.⁴⁴^-⁴⁷ With decreasing, the gestational age number of infants with disabilities is increasing.⁴⁴^-⁴⁷ Long-term disabilities like intellectual disability (appearing in 5–36% of survivors), cerebral palsy (appearing in 9–18% of survivors), blindness (appearing in 0.7–9% of survivors), and deafness (appearing in 2–4% of survivors) occurring later in the life of the infants at the limits of viability are influencing their quality of life.¹⁹ Milder degrees of disability involving cognition, behavior, and learning are increasingly recognized among older preterm children, teens, and young adults.¹⁹ Besides neurodevelopmental disability, there is also the problem of postnatal growth restriction affecting at least in the first 12 years of life weight, height, and particularly head growth, with significant growth delay observed in 20% of children throughout the whole period of 12 years having smaller head circumference compared to their term-born counterparts.⁴⁰

Fig. 2: The spectrum of disability among surviving extremely preterm infants (NICHD, National Institute of Child Health and Human Development; NRN, Neonatal Research; EXPRESS, Extremely Preterm Infants in Sweden Study; the EPICure acronym of the study determining survival rates and long-term health, developmental, educational and psychological outcomes across the life span following birth at 25 GW or less in the whole of the United Kingdom and Ireland)⁴⁴^,⁴⁷

ETHICAL ISSUES CONNECTED WITH EXISTING CARE FOR INFANTS AT THE LIMITS OF VIABILITY IN THE DEVELOPED WORLD

Threatened preterm labor at the limits of viability is always raising many ethical issues connected with the treatment of the mother and the baby:³⁶^,⁴¹^,⁴⁶^,⁴⁸

To continue the pregnancy or to terminate it.
To give corticosteroids or not.
To give antibiotics to the pregnant women or not.
To resuscitate and treat the baby or not.
How to prevent short and long-term morbidity.

Maternal indications were the reason to terminate the pregnancy at the average gestational age of 24 weeks and 3 days in one/1,000 pregnancies in the 10 years, with an overall perinatal mortality of 99.4%.⁴⁸ Some obstetric factors during the delivery of infants at the limits of viability influenced their outcome in the following way:⁴⁶

Delivery by cesarean section lowered the risk of death on the 1st day of life but not later.
Prenatal use of corticosteroids decreased the risk of death in the first 365 days of life.
Vaginal breach delivery increased the risk of mental developmental delay.

In many countries or institutions, guidelines for the intervention at the limits of viability are not available, but if they are, then often-used categories are “futile,” “gray zone,” and “beneficial” based on completed gestational age in weeks and/or rarely on certain birthweight categories which may be misleading and different in various countries.⁴⁹ As emphasized before, it is questionable to use the gestational age as the criterion for the definition of viability, which should be more thoroughly discussed from the ethical point of view because this may prevent practitioners from an active approach in infants in whom it might be beneficial.⁴⁹ If some decision like life-sustaining treatment is to be made, then prognostic information should be as precise as possible, which may be almost impossible due to many obstacles like how to accurately define severe disability.⁴⁹^,⁵⁰ This may prevent professionals from producing precise guidelines for the care of infants at the limits of viability because they are based on imprecise data.⁴⁹^,⁵⁰ These data express the inability of healthcare professionals to make precise, accurate, and practically applicable guidelines from an ethical point of view, while the situation is even worse when trying to perceive the decisions from the parental point of view.⁵⁰ For doctors, it is always very important to give information that is empathetic, sincere, and as accurate as possible and not influenced by medical provider beliefs (nondirective counseling).³⁸ That kind of counseling or decision-making is not easy at all because it is connected with many dilemmas—do we try to save these babies knowing that our procedures are likely to be unsuccessful, or do we provide just comfort care for them with the consciousness that we may allow some babies to die who might have been saved.⁵¹ Proposed by Brunckhorst et al., 10 suggestions for the doctors caring for babies at the limits of viability seem practically applicable, accurate, and to the point:⁵¹

Accept that there is a “gray zone” during which decisions are not black and white.
Do not place too much emphasis on gestational age.
Dying is generally not in an infant’s best interest.
Impairment does not necessarily equal poor quality of life.
Just because the train has left the station doesn’t mean you can’t get off.
Respect powerful emotions.
Be aware of the self-fulfilling prophecies.
Time lag likely skews all outcome data.
Statistics can be both confused and confusing.
Never abandon parents.

Although it is expected from medical professionals to be objective and to make counseling without emotions, sometimes it is not likely to be achieved. On the other hand, the parents are using probabilities and medical data, which are not the main decision-making tool, because emotions like fear, concern, regret, hope, quality of life, and personalized and individualized approach are essential.⁵²

Counseling the parents of infants at the limits of viability is a demanding and complex issue that has not been well covered by the education of the trainees in neonatology. Only 7% of trainees in neonatology in Europe have got some education, while most of them were not even aware of the mortality data and rarely shared specific information on the long-term outcome.⁵³^,⁵⁴

DEVELOPMENT OF THE CARE FOR INFANTS AT THE LIMITS OF VIABILITY

The development of medicine and perinatal care enabled better outcomes for infants at the limits of viability.²⁹^,⁵⁵^-⁵⁷ Survival of infants at the limits of viability has been influenced by some antenatal procedures like the use of corticosteroids and magnesium sulfate.⁵⁵^-⁵⁷ Postnatal procedures and drugs like oxygen use, mechanical ventilation, exogenous surfactant, targeted oxygen therapy, prophylactic methylxanthines, and some other procedures like postnatal corticosteroid use in the first week of life, ethamsylate versus placebo for prevention of morbidity and mortality in preterm or very low birth weight infants, volume expansion versus no treatment, gelatin versus fresh frozen plasma for prevention of morbidity and mortality in very preterm infants, prophylactic indomethacin versus placebo for preventing mortality and morbidity in preterm infants proved to be effective based on evidence in improving the outcome of infants at the limits of viability.⁵⁵ The historical perspective of the therapeutic modalities for the care of infants at the limits of viability in developed countries is shown in Table 1.²⁹

**Table 1:** Historical perspective of the therapeutic modalities for the care of infants at the limits of viability in developed countries²⁹
Treatment method	Year of development
CPAP*, mechanical ventilation	1980s
Exogenous surfactant	The early 1990s
Antenatal steroids	The mid/late 1990s
Avoiding postnatal steroids	The early 2000s
Targeted oxygen therapy	Mid-2000s

*CPAP, continuous positive airway pressure

As Albert Einstein said—”We cannot solve our problems with the same thinking we used when we created them,”⁵⁸ if applying it to the treatment of infants at the limits of viability, probably something should be changed in our way of thinking considering the care for those tiny infants. There are at least two reasons to make some changes—the first is that the limit of viability has been shifting towards 20 GW and beyond, and the second is that up to now, the intrauterine environment has been only partly considered in the care of the infants at the limits of viability because microgravity as possibly an important environmental factor has not been taken under consideration at all.

THE ENVIRONMENTAL HYPOTHESIS OF INTRAUTERINE LIFE: THE ROLE OF MICROGRAVITY

Intrauterine and extrauterine environments are different, with possibly significant repercussions on the development of muscle fibers.⁵⁹^-⁶⁵ According to the “Baby Astronaut” or gravity (G), age, thermoregulation, and oxygenation (GATO) hypothesis, which is trying to explain the synergistic effect of environments different in G on motor system adaptation, the development of the human individual is characterized by three different strategies influencing the adaptation of motor fibers to environmental circumstances.⁵⁹^-⁶⁵

The first strategy is the so-called fetal microgravity strategy which is characterized by microgravity (G < 1) in an intrauterine environment and is characterized by enhancing the development of fast muscle fibers and phasic movements of the fetus to survive in heating, strongly hypoxic, although normal for the fetus, immersion in amniotic fluid.⁵⁹^-⁶⁵ The amount of amniotic fluid can influence the development of fetal bones.⁵⁹^-⁶⁵ In the first part of gestation, the human fetus develops under conditions similar to neutral floating and has an apparent weight that is approximately 5% of its actual weight.⁵⁹^-⁶⁵ During the last trimester of gestation, the fetus overgrows the intrauterine cavity, and its apparent body weight is 60–80% of its actual weight.⁵⁹^-⁶⁵ Polyhydramnios can reduce the apparent weight of the fetus to 10–20% of its actual weight with the reduction of the mechanical stress on fetal bones, affecting their development and ossification.⁵⁹^-⁶⁵

The second adaptation strategy is called gravitation/Earth or GE strategy, characterized by the postnatal environment and it could be compared with the astronaut landing on the Earth.⁵⁹^-⁶⁵ The environmental condition characterizing this strategy is lower, but still normal temperature, normoxia, 1G gravitation, and healthy maturation of slow muscle fibers.⁵⁹^-⁶⁵ The process of parturition can be considered equivalent to a cosmonaut’s/astronaut’s transition from microgravitation back to Earth gravitation (G = 1) during landing.⁵⁹^-⁶⁵

During the third so-called slow and Jupiter (the most massive planet and the only planet with G > 1 in the solar system) strategy, the motor system undergoes a second profound remodeling in older people during healthy aging that results in further domination of slow muscle fibers and slowing down motor unit activity, simulating the condition of hypergravitation (G > 1).⁵⁹^-⁶⁵

The GATO hypothesis implies that specific sensory conditions may substitute for each other owing to their synergistic action on the motor system.⁵⁹^-⁶⁵ According to the GATO hypothesis, heating and hypoxia may be considered as “promicrogravity” factors, while cold and hyperoxia—as “progravity” ones.⁵⁹^-⁶⁵

If considering the intrauterine environment as very important for the development and survival of human fetuses as the gestational age is decreasing, then it could be speculated that producing microgravity conditions ex utero would be beneficial for the fetuses-neonates born at the limits of viability. Technically it is not known how to produce microgravity ex utero, but if medical science is capable of IVF, which is a landmark not only in the reproductive sciences but also in the history of mankind’s technological evolution, then producing microgravity for the treatment of immature fetuses outside the uterus might challenging research project.⁶⁶ For this reason, it can be expected that future development of the care for fetuses-infants at the limits of viability would move the boundaries and the definition of the limits of viability toward lower gestations and birth weights. At the moment, it seems like speculation, but in such a dynamically changing world, it could become a reality in several decades or even earlier.

ECTOGESTATIVE TECHNOLOGIES: ARE THEY READY FOR CLINICAL USE IN HUMANS?

As has been pointed out in the introduction, ectogenesis is defined as the partial or complete maturation of a developing embryo or fetus outside the human body.¹⁵^,¹⁶ Up to now, several terms have been used to describe the technique, like AWT, which includes AAPT.¹⁵^,¹⁶ Theoretically, ectogenesis is possible in transplanted or bioengineered uteri, but in most of the recent animal studies, relatively simple sterile, either pump-driven or pumpless containers for the fetus have been used.¹⁵^,¹⁶ Both pump-driven (venovenous) systems use a pump to control the drainage of blood to an oxygenator, and pumpless (arteriovenous) models use the fetus’ heart to pump the fetal blood from the umbilical arteries mimicking circulation as it occurs in the intact fetal umbilical-placental unit.¹⁵^,¹⁶ The most popular in the recent investigation is the pumpless (arteriovenous) model, which was developed in 2017 and the other in 2019.⁶⁶^-⁶⁸ An important aim of artificial womb technology (AWT) research is the improvement of survival of extremely premature infants who cannot survive by application of currently available means of neonatal intensive care.⁶⁷^,⁶⁸ This is one point of view on ectogenesis as a possible improvement or conceivably replacement of neonatal intensive care for infants at the limits of viability.

In some papers, complete ectogenesis in humans is considered an alternative for surrogacy or uterus transplantation, for advanced prenatal therapy, the remedy of gender inequity, and a method of treatment enabling termination of pregnancy without terminating the life of the fetus; however, it is probably too early to use ectogenesis for those purposes because of many yet unsolved issues.⁶⁷^,⁶⁸ Either partial or complete ectogenesis probably will not be translated into clinical practice in humans in the nearest future due to many unsolved ethical, technical, and societal issues, mainly due to unknown neurodevelopmental and growth risks of the exposed babies.⁶⁷^,⁶⁸ Considering the mothers whose fetuses have been transferred to ectogenetic incubators, it should be pointed out that the mother’s physical well-being and principle of autonomy should still be respected, regardless of the fact that her fetus is raised outside her body.⁶⁷^,⁶⁸

The concept of microgravity has not been mentioned and considered as important for the development and well-being of the fetus nurtured in an ectogenetic incubator either in animal models or theoretically for application in humans.⁶⁷^,⁶⁸ Maybe the GATO hypothesis is not considered important in the development of the embryo and the fetus; however, it would be prudent to make a theoretical basis for the investigation of this unknown field of human development.

CONCLUSION

The plateau of the survival of infants at the limits of viability at the gestations between 22 and 25 weeks of gestation has been reached in some developed countries, which could be considered a big achievement of medical science from a historical perspective. Data are confirming that antenatal corticosteroid use at a gestational age of 22–25 GW increased significantly from 78.8 to 85.0% in <1 decade and that some quality improvement measures resulted in the decrease of any intracranial hemorrhage and severe intracranial hemorrhage within the first week of life.⁶⁹^-⁷² A meta-analysis confirmed almost unavoidable mild to severe intraventricular hemorrhage and white matter injury in some infants at the limits of viability influenced their neurodevelopmental outcome (the risk of cerebral palsy, motor, cognitive, hearing, and visual impairments).⁷² The total proportion of neonates born at the limits of viability given early empirical ampicillin and gentamicin and those with negative cultures who were treated with antibiotics for >3 days also decreased, while those with no antibiotic use increased.⁷³ The proportion of infants who were mechanically ventilated and the median days of ventilator support decreased.⁷⁴ Hypothermia on neonatal intensive care unit admission decreased in premature infants born at the limits of viability as well as the mortality, necrotizing enterocolitis, severe and surgical retinopathy of prematurity, and bacteremia after the 3rd day of life.⁶⁹ Changing the paradigm of the therapeutic approach to the treatment of infants at the limits of viability resulted in better survival with fewer unfavorable outcomes. As the gestational age of limits of viability is decreasing toward lower gestations which are not taken under consideration in actual definitions of the limits of viability, maybe the paradigm of the treatment options for those infants should be shifted towards AWT for better survival with less undesirable outcomes.⁶⁷^,⁶⁸ The AWT is investigated on animal models only, but even in the research model, microgravity and GATO hypotheses have not been mentioned or considered, although they might be important for the development of the fetus at early gestations. It might be advisable to change the way of thinking and find the reasons pro and contra of microgravity use in AWT research, which may improve care for fetuses born at the lower limits of viability.

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