Successful use of an artificial placenta to support extremely preterm ovine fetuses at the border of viability
Successful use of an artificial placenta to support extremely preterm ovine fetuses at the border of viability
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DOI：
10.1016/j.ajog.2019.03.001
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发表时间：
2019-07-01
影响因子：
9.8
通讯作者：
Kemp, Matthew W.
中科院分区：
文献类型：
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作者：
Usuda, Haruo;Watanabe, Shimpei;Kemp, Matthew W.
背景：离体子宫环境疗法是一个实验性的生命支持平台，旨在降低生存能力边界出生的极早产儿（21e24周妊娠）的发病率和死亡的风险。为了避免功能不成熟的肺部，该平台通过连接到脐带血管的膜氧气进行气体交换，并将胎儿浸入人造羊水的保护性浴中。我们和其他人已经证明了在早产晚期胎儿的体内子宫环境疗法延长生存的可行性。但是，目前尚无证据表明这种平台的使用可以支持极端的胎儿，最终的转化目标是这种性质的治疗目标：该研究的目的是使用我们的离体子宫环境疗法平台来支持600-700 g/95天的健康维护，以使胎儿的健康年龄为600-700 g/95天（等于人类的胎儿24周）。主要结果指标如下：（1）维持关键生理变量； （2）缺乏感染； （3）缺乏脑损伤； （4）在子宫控制中匹配的未录取年龄的生长和心血管功能模式。研究：8岁母羊的Singleton胎儿在妊娠95天（术语，150天）进行了手术分娩。胎儿适应了体内子宫环境疗法，并通过对关键生理变量进行实时监测维持120小时。定期收集脐动脉血液样本，以评估血液数据，差异计数，炎症和微生物负荷以排除感染。脑损伤通过安乐死后总体解剖学和组织病理学方法评估。在100天的妊娠时对9只怀孕的动物安乐死，以允许对现年后的比较分析。通过方差分析测试了数据的平均差异。结果：8个离体子宫环境组胎儿中的七个（87.5％）完成了120小时的治疗，关键参数维持在正常的生理范围内。与对照组相比，在最终体重，冠状长度和体重归量归化的肺和脑体重没有明显的群体间差异（第05页）。血液学参数没有生物学上的显着差异（肿瘤坏死因子-A和单核细胞趋化蛋白1）的血液学参数（总或差异白细胞计数和血浆浓度）（p> .05）。所有外子宫环境动物的每日血液培养物对有氧和厌氧生长均为阴性。对照和离体子宫环境动物之间的空域巩固没有差异，并且T细胞标记CD3染色阳性的肺细胞数量没有增加。与对照组相比，白介素1，白介素-6，白介素-8，肿瘤坏死因子-A和单核细胞趋化因子蛋白1 mRNA表达没有增加。未观察到脑室内出血的病例，仅在1个离体子宫环境胎儿中发现白质损伤。结论：几十年来，在生存能力边界出生的极端早产群的结果几乎没有改善。在本研究中，我们报告了人造胎盘技术的使用首次支持稳定的生长正常状态以120小时的稳定状态支持极端早产的卵子胎儿（相当于人类妊娠24周）。通过额外的细化，本研究产生的数据可能会为改善极早产的治疗选择提供信息。
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.