title: Ex-Vivo Uterine Environment (EVE) Therapy Induced Limited Fetal Inflammation in a Premature Lamb Model.
abstract: BACKGROUND
  Ex-vivo uterine environment (EVE) therapy uses an artificial placenta to provide gas exchange and nutrient delivery to a fetus submerged in an amniotic fluid bath. Development of EVE may allow us to treat very premature neonates without mechanical ventilation. Meanwhile, elevations in fetal inflammation are associated with adverse neonatal outcomes. In the present study, we analysed fetal survival, inflammation and pulmonary maturation in preterm lambs maintained on EVE therapy using a parallelised umbilical circuit system with a low priming volume.
  
  
  METHODS
  Ewes underwent surgical delivery at 115 days of gestation (term is 150 days), and fetuses were transferred to EVE therapy (EVE group; n = 5). Physiological parameters were continuously monitored; fetal blood samples were intermittently obtained to assess wellbeing and targeted to reference range values for 2 days. Age-matched animals (Control group; n = 6) were surgically delivered at 117 days of gestation. Fetal blood and tissue samples were analysed and compared between the two groups.
  
  
  RESULTS
  Fetal survival time in the EVE group was 27.0 ± 15.5 (group mean ± SD) hours. Only one fetus completed the pre-determined study period with optimal physiological parameters, while the other 4 animals demonstrated physiological deterioration or death prior to the pre-determined study end point. Significant elevations (p<0.05) in: i) inflammatory proteins in fetal plasma; ii) selected cytokine/chemokine mRNA expression levels in fetal tissues; and iii) histological inflammatory score in fetal lung, were observed in the EVE group compared to the Control group. There was no significant difference (p>0.05) in surfactant protein mRNA expression level between the two groups.
  
  
  CONCLUSIONS
  In this study, we achieved limited fetal survival using EVE therapy. Despite this, EVE therapy only induced a modest fetal inflammatory response and did not promote lung maturation. These data provide additional insight into markers of treatment efficacy for the assessment of future studies.
authors.affiliation: School of Women's and Infants' Health, The University of Western Australia, Crawley, Western Australia, Australia; Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Miyagi, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Miura
authors.affiliation: Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Miyagi, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Saito
authors.affiliation: Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Miyagi, Japan.
authors.forename: Haruo
authors.initials: H
authors.lastname: Usuda
authors.affiliation: School of Women's and Infants' Health, The University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Woodward
authors.affiliation: School of Women's and Infants' Health, The University of Western Australia, Crawley, Western Australia, Australia; Division of Neonatology, Pediatric Intensive Care and Neuropediatrics, Medical University of Vienna, Vienna, Austria.
authors.forename: Judith
authors.initials: J
authors.lastname: Rittenschober-Böhm
authors.affiliation: Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Paranthaman S
authors.initials: PS
authors.lastname: Kannan
authors.affiliation: School of Veterinary and Life Sciences, Murdoch University, Murdoch, Western Australia, Australia; Animal Care Services, The University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Gabrielle C
authors.initials: GC
authors.lastname: Musk
authors.affiliation: Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Miyagi, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Matsuda
authors.affiliation: School of Women's and Infants' Health, The University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: John P
authors.initials: JP
authors.lastname: Newnham
authors.affiliation: School of Women's and Infants' Health, The University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Kemp
mesh_terms: D000818:Animals; D001187:Artificial Organs; D004195:Disease Models, Animal; D005260:Female; D005315:Fetal Diseases / Q000473:pathology / Q000628:therapy*; D007249:Inflammation / Q000473:pathology / Q000628:therapy; D010920:Placenta; D011247:Pregnancy; D047928:Premature Birth / Q000473:pathology / Q000628:therapy*; D012756:Sheep