Haruo Usuda1, Shimpei Watanabe2, Masatoshi Saito3, Shinichi Sato2, Gabrielle C Musk4, Ms Erin Fee5, Sean Carter5, Yusaku Kumagai2, Tsukasa Takahashi2, Mr Shinichi Kawamura6, Takushi Hanita2, Shigeo Kure2, Nobuo Yaegashi2, John P Newnham7, Matthew W Kemp8. 1. Division of Obstetrics and Gynecology, University of Western Australia, Crawley, Western Australia, Australia; Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Miyagi, Japan. Electronic address: haruo.usuda@uwa.edu.au. 2. Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Miyagi, Japan. 3. Division of Obstetrics and Gynecology, University of Western Australia, Crawley, Western Australia, Australia; Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Miyagi, Japan. 4. Division of Obstetrics and Gynecology, University of Western Australia, Crawley, Western Australia, Australia; Animal Care Services, University of Western Australia, Crawley, Western Australia, Australia. 5. Division of Obstetrics and Gynecology, University of Western Australia, Crawley, Western Australia, Australia. 6. Nipro Corporation, Osaka, Japan. 7. Division of Obstetrics and Gynecology, University of Western Australia, Crawley, Western Australia, Australia; School of Veterinary and Life Sciences, Murdoch University, Western Australia, Australia. 8. Division of Obstetrics and Gynecology, University of Western Australia, Crawley, Western Australia, Australia; Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Miyagi, Japan; School of Veterinary and Life Sciences, Murdoch University, Western Australia, Australia.
Abstract
BACKGROUND: Ex vivo uterine environment 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 ex vivo uterine environment therapy 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. OBJECTIVE: The objective of the study was to use our ex vivo uterine environment therapy platform to support the healthy maintenance of 600-700 g/95 days gestational age (equivalent to 24 weeks of human gestation) sheep fetuses. Primary outcome measures were as follows: (1) maintenance of key physiological variables; (2) absence of infection; (3) absence of brain injury; and (4) growth and cardiovascular function patterns matching that of noninstrumented, age-matched in utero controls. STUDY DESIGN: Singleton fetuses from 8 ewes underwent surgical delivery at 95 days' gestation (term, 150 days). Fetuses were adapted to ex vivo uterine environment therapy and maintained for 120 hours 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 euthanized at 100 days' gestation to allow comparative postmortem analyses. Data were tested for mean differences with an analysis of variance. RESULTS: Seven of 8 ex vivo uterine environment group fetuses (87.5%) completed 120 hours of therapy with key parameters maintained in a normal physiological range. There were no significant intergroup differences (P > .05) in final weight, crown-rump length, and body weight-normalized lung and brain weights at euthanasia compared with controls. There were no biologically significant differences in hematological parameters (total or differential leucocyte counts and plasma concentration of tumor necrosis factor-α and monocyte chemoattractant protein 1) (P > .05). Daily blood cultures were negative for aerobic and anaerobic growth in all ex vivo uterine environment animals. There was no difference in airspace consolidation between control and ex vivo uterine environment 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-1, interleukin-6, interleukin-8, tumor necrosis factor-α, and monocyte chemoattractant protein 1 mRNA expression in lung tissues compared with the control group. No cases of intraventricular hemorrhage were observed, and white matter injury was identified in only 1 ex vivo uterine environment fetus. CONCLUSION: 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 hours. With additional refinement, the data generated by this study may inform a treatment option to improve outcomes for extremely preterm infants.
BACKGROUND: Ex vivo uterine environment 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 ex vivo uterine environment therapy 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. OBJECTIVE: The objective of the study was to use our ex vivo uterine environment therapy platform to support the healthy maintenance of 600-700 g/95 days gestational age (equivalent to 24 weeks of human gestation) sheep fetuses. Primary outcome measures were as follows: (1) maintenance of key physiological variables; (2) absence of infection; (3) absence of brain injury; and (4) growth and cardiovascular function patterns matching that of noninstrumented, age-matched in utero controls. STUDY DESIGN: Singleton fetuses from 8 ewes underwent surgical delivery at 95 days' gestation (term, 150 days). Fetuses were adapted to ex vivo uterine environment therapy and maintained for 120 hours 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 euthanized at 100 days' gestation to allow comparative postmortem analyses. Data were tested for mean differences with an analysis of variance. RESULTS: Seven of 8 ex vivo uterine environment group fetuses (87.5%) completed 120 hours of therapy with key parameters maintained in a normal physiological range. There were no significant intergroup differences (P > .05) in final weight, crown-rump length, and body weight-normalized lung and brain weights at euthanasia compared with controls. There were no biologically significant differences in hematological parameters (total or differential leucocyte counts and plasma concentration of tumor necrosis factor-α and monocyte chemoattractant protein 1) (P > .05). Daily blood cultures were negative for aerobic and anaerobic growth in all ex vivo uterine environment animals. There was no difference in airspace consolidation between control and ex vivo uterine environment 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-1, interleukin-6, interleukin-8, tumor necrosis factor-α, and monocyte chemoattractant protein 1 mRNA expression in lung tissues compared with the control group. No cases of intraventricular hemorrhage were observed, and white matter injury was identified in only 1 ex vivo uterine environment fetus. CONCLUSION: 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 hours. With additional refinement, the data generated by this study may inform a treatment option to improve outcomes for extremely preterm infants.
Authors: Alex J Charest-Pekeski; Ayman Sheta; Luiza Taniguchi; Mark J McVey; Alejandro Floh; Liqun Sun; Tanroop Aujla; Steven K S Cho; Jiaqi Ren; Lynn Crawford-Lean; Celeste Foreman; Jessie Mei Lim; Brahmdeep S Saini; Marvin Estrada; Anson Lam; Jaques Belik; Dariusz Mroczek; Megan Quinn; Stacey L Holman; Jack R T Darby; Mike Seed; Janna L Morrison; Christoph Haller Journal: Physiol Rep Date: 2021-03
Authors: E J Verweij; Lien De Proost; Judith O E H van Laar; Lily Frank; Sylvia A Obermann-Borstn; Marijn J Vermeulen; Sophie van Baalen; M Beatrijs van der Hout-van der Jagt; Elselijn Kingma Journal: Front Pediatr Date: 2021-12-08 Impact factor: 3.418