Successful use of an artificial placenta to support extremely preterm ovine fetuses at the border of viability

Abstract Background Ex-vivo uterine environment (EVE) therapy is an experimental life support platform designed to reduce the risk of morbidity and mortality for extremely preterm infants born at the border of viability (21-24 weeks gestation). To spare the functionally immature lung, this platform performs gas exchange via a membranous oxygenator connected to the umbilical vessels, and the fetus is submerged in a protective bath of artificial amniotic fluid. We and others have demonstrated the feasibility of extended survival with EVE therapy in late preterm fetuses; however, there is presently no evidence to show that the use of such a platform can support extremely preterm fetuses, the eventual translational target for therapy of this nature. Objectives To use our EVE therapy platform to support the healthy maintenance of 600-700 g / 95 d gestational age (equivalent to 24 weeks of human gestation) sheep fetuses. Primary outcome measures were: i) maintenance of key physiological variables; ii) absence of infection; iii) absence of brain injury; and iv) growth and cardiovascular function patterns matching that of non-instrumented, age-matched in utero controls. Study Design Singleton fetuses from eight ewes underwent surgical delivery at 95 d gestation (term=150 d). Fetuses were adapted to EVE therapy and maintained for 120 h with real-time monitoring of key physiological variables. Umbilical artery blood samples were regularly collected to assess blood gas data, differential counts, inflammation and microbial load to exclude infection. Brain injury was evaluated by gross anatomical and histopathological approaches after euthanasia. Nine pregnant control animals were euthanised at 100 d gestation to allow comparative post-mortem analyses. Data were tested for mean differences with ANOVA . Results Seven of eight EVE group fetuses (87.5%) completed 120 h of therapy with key parameters maintained in a normal physiological range. There were no significant inter-group differences (p>0.05) in final weight, crown rump length and body-weight normalized lung and brain weights at euthanasia compared to controls. There were no biologically significant differences in hematological parameters (total or differential leucocyte counts and plasma concentration of TNF-α and MCP-1) (p>0.05). Daily blood cultures were negative for aerobic and anaerobic growth in all EVE animals. There was no difference in airspace consolidation between control and EVE animals, and there was no increase in the number of lung cells staining positive for the T-cell marker CD3. There were no increases in interleukin (IL)-1, 6, 8, TNF-α and MCP-1 mRNA expression in lung tissues compared to the Control group. No cases of intraventricular haemorrhage were observed, and white matter injury was identified only in one EVE fetus. Conclusions For several decades there has been little improvement in outcomes of extremely preterm infants born at the border of viability. In the present study, we report the use of artificial placenta technology to support, for the first time, extremely preterm ovine fetuses (equivalent to 24 weeks of human gestation) in a stable, growth-normal state for 120 h. With additional refinement, the data generated by this study may inform a treatment option to improve outcomes for extremely preterm infants.