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.
Key words
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Article info
Publication history
Published online: March 07, 2019
Accepted:
March 4,
2019
Received in revised form:
February 26,
2019
Received:
December 7,
2018
Footnotes
The funders of this work had no role in study design, in the collection, analysis or interpretation of data, in the writing of the report, or in the decision to submit the article for publication.
This work was supported by grants from the Channel 7 Telethon Trust, the Department of Health, Government of Western Australia (to Dr Kemp) and an in-kind donation from Nipro Corporation, Osaka, Japan. Dr Kemp is supported by the Women and Infants Research Foundation and the National Health and Medical Research Council (grants GNT1049148 and GNT1162572).
The authors report no conflict of interest.
Cite this article as: Usuda H, Watanabe S, Saito M, et al. Successful use of an artificial placenta to support extremely preterm ovine fetuses at the border of viability. Am J Obstet Gynecol 2019;221:69.e1-17.
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- ReplyAmerican Journal of Obstetrics & GynecologyVol. 221Issue 4
- PreviewWe thank Drs Sahoo and Gulla for their commentary on our recent publication1 that described the preclinical development of an artificial placenta for extremely preterm infants. As discussed in our submission, an abbreviated study period was selected because of a lack of performance data for extremely preterm fetuses that are supported via an artificial placenta-based platform; moreover, there are good data to show that a significant percentage of morbidity and death occurs acutely after extreme preterm birth,2 hence the duration of the studies undertaken.
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- Artificial placenta: Miles to go before I sleep…American Journal of Obstetrics & GynecologyVol. 221Issue 4
- PreviewFirst of all, we would like to congratulate the authors for this adventurous novel piece of research.1 With advancement in technology and better medical care the survival of premature infants has improved drastically over the last few decades. However, the survival of micro preemies in the periviable period (22–25 weeks) and the associated long-term morbidities have not changed meaningfully. Hence, prevention of spontaneous prematurity is a real challenge and requires scientific breakthrough in the form of artificial placenta.
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