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Successful use of an artificial placenta-based life support system to treat extremely preterm ovine fetuses compromised by intrauterine inflammation

Usuda, H., Watanabe, S., Saito, M., Ikeda, H., Koshinami, S., Sato, S., Musk, G.C., Fee, E., Carter, S., Kumagai, Y., Takahashi, T., Takahashi, Y., Kawamura, S., Hanita, T., Kure, S., Yaegashi, N., Newnham, J.P. and Kemp, M.W. (2020) Successful use of an artificial placenta-based life support system to treat extremely preterm ovine fetuses compromised by intrauterine inflammation. American Journal of Obstetrics and Gynecology, 223 (5). 755.e1-755.e20.

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Ex-vivo uterine environment (EVE) therapy is an experimental intensive care strategy for extremely preterm infants born between 21 and 24 weeks of gestation. Gas exchange is performed by membranous oxygenators connected by catheters to the umbilical vessels. The fetus is submerged in a bath of synthetic amniotic fluid. The lungs remain fluid-filled and pulmonary respiration does not occur. Intrauterine inflammation is strongly associated with extremely early preterm birth and fetal injury. Presently, there are no data of which we are aware to show that artificial placenta-based systems can be used to support extremely preterm fetuses compromised by exposure to intrauterine inflammation.

To evaluate the ability of our EVE therapy platform to support extremely preterm ovine fetuses (95 d gestational age; approximately equivalent to 24 weeks of human gestation) exposed to intrauterine inflammation for a period of 120 hours, the following primary endpoints were chosen: i) maintenance of key physiological variables within normal ranges; ii) absence of infection and inflammation; iii) absence of brain injury; and iv) gross fetal growth and cardiovascular function matching that of age-matched in utero controls.

[Study Design]
Ten ewes with singleton pregnancies were each given a single intraamniotic injection of 10 mg E.coli lipopolysaccharides (LPS) under ultrasound guidance 48h before undergoing surgical delivery for adaptation to EVE therapy at 95d gestation (term=150d). Fetuses were adapted to EVE therapy and maintained for 120h with constant monitoring of key vital parameters (EVE Group) before being euthanised at 100d equivalent gestational age. Umbilical artery blood samples were regularly collected to assess blood gas data, differential counts, biochemical parameters, inflammatory markers and microbial load to exclude infection. Ultrasound was conducted at 48 h after intraamniotic LPS (before surgery) to confirm fetal viability and at the conclusion of the experiments (before euthanasia) to evaluate cardiac function. Brain injury was evaluated by gross anatomical and histopathological investigations. Eight singleton pregnant control animals were similarly exposed to intraamniotic LPS at 93d gestation and were euthanized at 100 d gestation to allow comparative post-mortem analyses (Control Group). Bio-banked samples from age-matched saline-treated animals served as an additional comparison group. Successful instillation of LPS into the amniotic fluid exposure was confirmed by amniotic fluid analysis at the time of administration, and by analyzing cytokine levels in fetal plasma and amniotic fluid. Data were tested for mean differences with ANOVA.

Six out of eight LPS Control Group (75%) and eight out of ten EVE Group fetuses (80%) successfully completed their protocols. Six of eight EVE Group fetuses required dexamethasone phosphate treatment to manage profound refractory hypotension. Weight and crown rump length was reduced in EVE Group fetuses at euthanasia compared to LPS Control Group fetuses (p<0.05). There were no biologically significant differences in cardiac ultrasound measurement, differential leucocyte counts (p>0.05), plasma tumour necrosis factor α (TNF-α), monocyte chemoattractant protein-1 (MCP-1) concentrations (p>0.05), or liver function tests between groups. Daily blood cultures were negative for aerobic and anaerobic growth in all EVE Group animals. No cases of intraventricular haemorrhage were observed. White matter injury was identified in three of six LPS Control Group fetuses and three of eight EVE Group fetuses.

We report the use of an artificial placenta-based system to support extremely preterm lambs compromised by exposure to intrauterine inflammation. Our data highlight key challenges (refractory hypotension, growth restriction and white matter injury) to be overcome in the development and use of artificial placenta technology for extremely early preterm infants. As such challenges appear largely absent from studies based on healthy pregnancies, additional experiments of this nature using clinically relevant model systems are essential for further development of this technology and its eventual clinical application.

Item Type: Journal Article
Murdoch Affiliation(s): School of Veterinary and Life Sciences
Publisher: Mosby Inc
Copyright: © 2020 Elsevier Inc.
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