Achieving sustained extrauterine life: Challenges of an artificial placenta in fetal pigs as a model of the preterm human fetus

Abstract

Artificial placenta (AP) technology aims to maintain fetal circulation, while promoting the physiologic development of organs. Recent reports of experiments performed in sheep indicate the intrauterine environment can be recreated through the cannulation of umbilical vessels, replacement of the placenta with a low‐resistance membrane oxygenator, and incubation of the fetus in fluid. However, it remains to be seen whether animal fetuses similar in size to the extremely preterm human infant that have been proposed as a potential target for this technology can be supported in this way. Preterm Yucatan miniature piglets are similar in size to extremely preterm human infants and share similar umbilical cord anatomy, raising the possibility to serve as a good model to investigate the AP. To characterize fetal cardiovascular physiology, the carotid artery (n = 24) was cannulated in utero and umbilical vein (UV) and umbilical artery were sampled. Fetal UV flow was measured by MRI (n = 16). Piglets were delivered at 98 ± 4 days gestation (term = 115 days), cannulated, and supported on the AP (n = 12) for 684 ± 228 min (range 195–3077 min). UV flow was subphysiologic (p = .002), while heart rate was elevated on the AP compared with in utero controls (p = .0007). We observed an inverse relationship between heart rate and UV flow (r2 = .4527; p < .001) with progressive right ventricular enlargement that was associated with reduced contractility and ultimately hydrops and circulatory collapse. We attribute this to excessive afterload imposed by supraphysiologic circuit resistance and augmented sympathetic activity. We conclude that short‐term support of the preterm piglet on the AP is feasible, although we have not been able to attain normal fetal physiology. In the future, we propose to investigate the feasibility of an AP circuit that incorporates a centrifugal pump in our miniature pig model.

Advantages of a Centrifugal Pump in the Development of a Swine Model of an Artificial Placenta

“…The results presented in this report are comprised from fetal pigs studied in utero and while maintained using a pumped AP circuit and of our previously published ndings using a pumpless AP system 27 . Fetal Large White Landrace pigs were studied in utero at 98, 106, and 112 days GA (n = 24 ) and Yucatan miniature pigs at 107 ± 3 days (n = 16), providing reference physiologic data regarding heart rate (HR), blood pressure, blood gases, electrolytes, lactate and glucose concentrations, and UV ow 27 . Fetal Yucatan miniature pigs (n =13) were maintained using an umbilical arteriovenous AP circuit consisting of a centrifugal pump and oxygenator and using a pumpless AP circuit (n = 12) 27 .…”

“…Fetal Large White Landrace pigs were studied in utero at 98, 106, and 112 days GA (n = 24 ) and Yucatan miniature pigs at 107 ± 3 days (n = 16), providing reference physiologic data regarding heart rate (HR), blood pressure, blood gases, electrolytes, lactate and glucose concentrations, and UV ow 27 . Fetal Yucatan miniature pigs (n =13) were maintained using an umbilical arteriovenous AP circuit consisting of a centrifugal pump and oxygenator and using a pumpless AP circuit (n = 12) 27 . We included AP subjects that survived on the system for a minimum of 3 hours.…”

“…In utero fetal weight and UV ow were measured in sixteen fetuses from 4 pregnant Yucatan pigs (n = 4; gestational age 107 ± 3 days GA) as previously described using a 3 Tesla magnetic resonance imaging (MRI) system 27 .…”

“…In addition, fetal sheep possess two umbilical arteries (UA) and two umbilical veins (UV). This may allow a more stable transition to the AP circuit using one pair of UA and UV while maintaining native gas exchange via the placenta using the other pair of umbilical vessels, thus minimizing the cessation of oxygenation from the mother 27,28 . By contrast, human and pig fetuses usually have one UV and two UAs, which may represent a more technically challenging approach to the initiation of AP support.…”

“…We hypothesized that the addition of a pump might improve the hemodynamics of our animals on the circuit by reducing afterload through the generation of negative pressure downstream of the umbilical arterial cannulas, thereby improving venous return and cardiac output. Herein, we sought to investigate the hemodynamics of a pumped AP system, comparing our ndings to those obtained using the pumpless circuit 27 .…”