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

Haruo Usuda, Shimpei Watanabe, Masatoshi Saito, Shinichi Sato, Gabrielle C. Musk, Erin Fee, Sean Carter, Yusaku Kumagai, Tsukasa Takahashi, Shinichi Kawamura, Takushi Hanita, Shigeo Kure, Nobuo Yaegashi, John P. Newnham, Matthew W. Kemp

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 (21e24 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 weightnormalized 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-a 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 interleukin1, interleukin-6, interleukin-8, tumor necrosis factor-a, 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 preterminfants 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.

Original languageEnglish
Article numberARTN 69.e1-17
Number of pages17
JournalAmerican Journal of Obstetrics and Gynecology
Volume222
Issue number1
DOIs
Publication statusPublished - Jul 2019

Cite this

Usuda, Haruo ; Watanabe, Shimpei ; Saito, Masatoshi ; Sato, Shinichi ; Musk, Gabrielle C. ; Fee, Erin ; Carter, Sean ; Kumagai, Yusaku ; Takahashi, Tsukasa ; Kawamura, Shinichi ; Hanita, Takushi ; Kure, Shigeo ; Yaegashi, Nobuo ; Newnham, John P. ; Kemp, Matthew W. / Successful use of an artificial placenta to support extremely preterm ovine fetuses at the border of viability. In: American Journal of Obstetrics and Gynecology. 2019 ; Vol. 222, No. 1.
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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 (21e24 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 weightnormalized 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-a 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 interleukin1, interleukin-6, interleukin-8, tumor necrosis factor-a, 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 preterminfants 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.",
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author = "Haruo Usuda and Shimpei Watanabe and Masatoshi Saito and Shinichi Sato and Musk, {Gabrielle C.} and Erin Fee and Sean Carter and Yusaku Kumagai and Tsukasa Takahashi and Shinichi Kawamura and Takushi Hanita and Shigeo Kure and Nobuo Yaegashi and Newnham, {John P.} and Kemp, {Matthew W.}",
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Usuda, H, Watanabe, S, Saito, M, Sato, S, Musk, GC, Fee, E, Carter, S, Kumagai, Y, Takahashi, T, Kawamura, S, Hanita, T, Kure, S, Yaegashi, N, Newnham, JP & Kemp, MW 2019, 'Successful use of an artificial placenta to support extremely preterm ovine fetuses at the border of viability' American Journal of Obstetrics and Gynecology, vol. 222, no. 1, ARTN 69.e1-17. https://doi.org/10.1016/j.ajog.2019.03.001

Successful use of an artificial placenta to support extremely preterm ovine fetuses at the border of viability. / Usuda, Haruo; Watanabe, Shimpei; Saito, Masatoshi; Sato, Shinichi; Musk, Gabrielle C.; Fee, Erin; Carter, Sean; Kumagai, Yusaku; Takahashi, Tsukasa; Kawamura, Shinichi; Hanita, Takushi; Kure, Shigeo; Yaegashi, Nobuo; Newnham, John P.; Kemp, Matthew W.

In: American Journal of Obstetrics and Gynecology, Vol. 222, No. 1, ARTN 69.e1-17, 07.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Successful use of an artificial placenta to support extremely preterm ovine fetuses at the border of viability

AU - Usuda, Haruo

AU - Watanabe, Shimpei

AU - Saito, Masatoshi

AU - Sato, Shinichi

AU - Musk, Gabrielle C.

AU - Fee, Erin

AU - Carter, Sean

AU - Kumagai, Yusaku

AU - Takahashi, Tsukasa

AU - Kawamura, Shinichi

AU - Hanita, Takushi

AU - Kure, Shigeo

AU - Yaegashi, Nobuo

AU - Newnham, John P.

AU - Kemp, Matthew W.

PY - 2019/7

Y1 - 2019/7

N2 - 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 (21e24 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 weightnormalized 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-a 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 interleukin1, interleukin-6, interleukin-8, tumor necrosis factor-a, 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 preterminfants 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.

AB - 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 (21e24 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 weightnormalized 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-a 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 interleukin1, interleukin-6, interleukin-8, tumor necrosis factor-a, 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 preterminfants 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.

KW - artificial placenta

KW - extremely preterm infants

KW - ex vivo uterine environment therapy

KW - fetal brain injury

KW - fetal inflammatory responses

KW - LOW-BIRTH-WEIGHT

KW - MYOCARDIAL PERFORMANCE INDEX

KW - LOW-DOSE HYDROCORTISONE

KW - PERINATAL WHITE-MATTER

KW - CEREBRAL-BLOOD-FLOW

KW - NEURODEVELOPMENTAL OUTCOMES

KW - BRONCHOPULMONARY DYSPLASIA

KW - FETAL

KW - GROWTH

KW - HYPOTENSION

U2 - 10.1016/j.ajog.2019.03.001

DO - 10.1016/j.ajog.2019.03.001

M3 - Article

VL - 222

JO - American Journal of Obstetrics & Gynecology

JF - American Journal of Obstetrics & Gynecology

SN - 0002-9378

IS - 1

M1 - ARTN 69.e1-17

ER -