Artificial womb: a paradigm shift for saving extremely premature infants

To the Editor: Approximately 15 million preterm babies, i.e., those delivered at <37 weeks of gestational age (GA), are born globally every year, and of them, 0.4% are extremely premature infants (EPIs), i.e., those delivered at <28 weeks of GA.^[1] Iterations of neonatal care have significantly extended the viability of preterm babies. However, improved viability is accompanied by an increased risk of unreversed injuries, such as bronchopulmonary dysplasia and intraventricular hemorrhage. Therefore, a more physiological simulating in utero status is needed to protect EPIs' immature organs during the transitional period and ensure that they develop in the same manner that they would have in the womb.

A new extracorporeal membrane oxygenation-based technology called artificial womb (AW) designed for EPIs is characterized by five components: extracorporeal circulation, maintenance of fetal circulation, fluid-filled lungs, vascular access entirely or partly through the umbilical vessels, and a specialized environment for organs under development.^[2] Another term, artificial placenta (AP), was confused with AW in former studies. Since the term "womb" has a more abundant meaning than "placenta," we use AW instead of AP in this article. Broadly speaking, AW continues the "full pregnancy" outside the human body, completely replacing the female womb. Narrowly speaking, the technology is referred to as "partial pregnancy," which only serves as an advanced incubator in the later trimester and is the main focus of our review.

Several studies have demonstrated that the AW system can potentially improve the outcomes of preterm infants. Different animal models have been used to further explore the feasibility of the AW system, including sheep, goats, pigs, and dogs. However, there were many differences between animal models of the AW system and EPIs [Supplementary Table 1, http://links.lww.com/CM9/B604]. The remaining questions should be comprehensively evaluated before translating these results to human subjects.

Importantly, a womb can perform multiple physiological functions, but gas exchange is the primary function of the current AW system. Therefore, we also explored additional potential application scenarios of AW [Figure 1] to minimize the preterm-related complications.

Figure 1.

Role of AW as an advanced incubator. AW: Artificial womb.

EPIs often receive mechanical ventilation (MV), a major contributor to bronchopulmonary dysplasia. Only 2 h of MV of the extremely preterm saccular-stage lung can cause considerable injury to the bronchioles and lung parenchyma. One study proved that AW lamb lungs showed significantly higher average and maximum compliance, manifested less necrosis and total injuries than MV lungs, and demonstrated higher area fractions of alveolar tips double-positive for both α-actin and platelet-derived growth factor receptor-α.^[3] The aforesaid evidence confirmed that AW could prevent lung injuries relative to MV and maintain the lung's development, thereby facilitating transition to MV. This is probably because AW allows the normal glottic resistance required for the maintenance of normal airway pressure and lung growth. Furthermore, intratracheal perfluorocarbons are believed to better promote normal lung development than crystalloids or amniotic fluid with tracheal occlusion during AW support.

In addition to altered lung development, EPIs are more likely to suffer from neurological disabilities such as intracranial hemorrhage (ICH) and white matter injury. Multifactorial contributors may lead to this condition, including hypoxia-ischemia, MV, inflammation, and hemodynamic instability. The AW system helps maintain relatively normal intrauterine growth, preventing the morbidity of brain injury caused by infections or other hazards out of the womb. The AW group showed better performance in white matter myelination as fractional anisotropy values, which increased with GA and was most reduced in the cerebral peduncles of MV lambs vs. age-matched controls or AP-supported lambs. However, it is worth noting that high-pressure ventilation in MV groups can increase intrathoracic pressure and impede venous drainage from the brain, leading to a higher possibility of venous hypertension and ICH,^[4] while in AW system using the jugular vein for cannulation appears to decrease cerebral blood flow. Moreover, the use of heparin in the AW system may increase the risk of clinically significant cerebral hemorrhage, although no cases of ICH were observed during the experiment. Whether these results can be applied to human fetuses remains under discussion.

EPIs are most susceptible to hypothermia and dehydration shortly after birth, and the drop in core body temperature can have serious negative effects on their developing organs. EPIs are more like cold-blooded animals as they lack the ability to regulate their body temperature. Furthermore, they have very thin skin and lack sufficient subcutaneous fat to insulate against heat loss, which leads to their vulnerability to heat and water loss. The current incubators required that the infants be wrapped in a plastic bag with a cap covering the head, as well as the using of radiant heaters and exothermic mattresses to prevent rapid heat loss and preserve the body temperature. However, it is difficult to accurately adjust the temperature (both higher and lower core temperatures have negative effects), and automatic monitoring is lacking. The use of radiant heaters can result in insensible perspiration, leading to episodes of hypothermia and dehydration. To reduce the risk of hypothermia, dehydration, and skin injuries, some published AW studies immersed the fetus in a sterile and warm liquid environment (synthetic amniotic fluid). The ideal amniotic fluid is thermoregulated, continuously circulated, and filtered. For example, Alan's AW system created a sterile environment termed "Biobag" using a polyethylene film and ports for continuous amniotic fluid inflow and outflow, allowing the fetal lamb to be maintained on circuit for up to 4 weeks.^[5] This sterile fluid submersion can isolate the fetus from sound, mechanical injury, and infection. It is also believed that a liquid environment can effectively prevent limb adhesion and related malformation.

The immature gastrointestinal tract of EPIs results in many nutrition-related complications, especially feeding intolerance and necrotizing enterocolitis (NEC). NEC inhibits the use of the enteral feeding route; therefore, they are supported initially with total parenteral nutrition (TPN). Nonetheless, a lack of enteral feeding can lead to intestinal atrophy, bacterial translocation, and sepsis. AW might provide another way to supply nutrition. Although most studies of the AW system chose TPN to supply nutrition, the fluid environment allows the fetus to swallow amniotic fluid, promoting development of the digestive tract. Most current studies have used a simple electrolyte solution, but amniotic fluid contains many trophic factors and other components that may be beneficial to the fetus. To develop an optimal "amniotic fluid" for optimal fetal growth and development, Baumgarten et al^[6] designed a model of continuous amniotic fluid exchange around a fetal rabbit. Monitoring of fetal development and timely adjustment of the nutrient concentration during the medical practice are of great significance, including checking blood glucose daily, calculating weight gain, or checking insulin-like growth factor (IGF)-1 and IGF binding protein, which can also be treated as an indicator of fetal growth in the management of nutrition.^[7] Indeed, it is desirable that advancements in AW could lead to breakthroughs toward fetal metabolism.

The foresaid evidence strongly suggests that AW is a multifunctional complex comprising of many technologies. In terms of monitoring function, AW has unparalleled superiority over current infant incubators. First, the translucent polyethylene film and open sealable side of AW enable manipulation and monitoring of fetal parameters such as temperature and pressure regulation. Poor visualization of fetal anatomy, due to factors such as fetal position and maternal obesity, can lead to misjudgments, but AW solves this challenge by allowing for visualized and automatic evaluations. In addition, a single-use closed sterile fluid system was developed, which may reduce infection rates and noise levels by reducing direct contact with the external environment. Increasing the fluid exchange rate and injecting antibiotics daily may help clear contaminants. In the future, more wearable devices based on flexible technology could be applied to automatically record the physiological parameters of EPIs such as body temperature, electrocardiogram data, and electroencephalogram data. AW can also reduce invasive maternal examinations and surgeries, which may lead to procedure-related miscarriages and a higher risk of vertical transmission.

Increasing survivability for preterm infants has aroused interest in studying AW using extremely premature lamb models, which combine expertise in the fields of cardiology, gynecology, biology, physics, and computer and simulation modeling. Its implications for research into fetology and fetal interventions are exciting and may lead to a paradigm shift in the clinical practice of neonatology in the future. Whether AW can be an integral part of the neonatal intensive care unit depends on its long-term benefits and risks. Medicine has focused on the beginning and end stages of pregnancy, and the focus on the essential time inside a woman's body has been reduced. However, many researchers have emphasized that the ultimate goal of AW research is not to push back the GA limit but to eliminate the damage and improve the prognosis of EPIs. We are more likely to view AW as an advanced incubator that is more consistent with fetal physiology playing the role of the womb at the final stages of gestation. Further clinical trials are required in primates before their use in humans. Although no clinical translation has been achieved, further development of AW technology will provide an opportunity to improve the quality of life for EPIs.

Conflicts of interest

None.