Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA.
Department of Pathology, Oregon Health and Science University, Portland, OR 97239, USA.
Hum Reprod. 2017 Dec 1;32(12):2382-2393. doi: 10.1093/humrep/dex301.
Does the use of a vascular contrast agent facilitate earlier detection of maternal flow to the placental intervillous space (IVS) in the first trimester of pregnancy?
Microvascular filling of the IVS was demonstrated by contrast-enhanced ultrasound from 6 weeks of gestation onwards, earlier than previously believed.
During placental establishment and remodeling of maternal spiral arteries, endovascular trophoblast cells invade and accumulate in the lumen of these vessels to form 'trophoblast plugs'. Prior evidence from morphological and Doppler ultrasound studies has been conflicting as to whether the spiral arteries are completely plugged, preventing maternal blood flow to the IVS until late in the first trimester.
STUDY DESIGN, SIZE, DURATION: Uteroplacental flow was examined across the first trimester in human subjects given an intravenous infusion of lipid-shelled octofluoropropane microbubbles with ultrasound measurement of destruction and replenishment kinetics. We also performed a comprehensive histopathological correlation using two separately archived uteroplacental tissue collections to evaluate the degree of spiral artery plugging and evaluate remodeling of the upstream myometrial radial and arcurate arteries.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Pregnant women (n = 34) were recruited in the first trimester (range: 6+3 to 13+6 weeks gestation) for contrast-enhanced ultrasound studies with destruction-replenishment analysis of signal intensity for assessment of microvascular flux rate. Histological samples from archived in situ (Boyd Collection, n = 11) and fresh first, second, and third trimester decidual and post-hysterectomy uterine specimens (n = 16) were evaluated by immunohistochemistry (using markers of epithelial, endothelial and T-cells, as well as cell adhesion and proliferation) and ultrastructural analysis.
Contrast agent entry into the IVS was visualized as early as 6+3 weeks of gestation with some variability in microvascular flux rate noted in the 6-7+6 week samples. Spiral artery plug canalization was observed from 7 weeks with progressive disintegration thereafter. Of note, microvascular flux rate did not progressively increase until 13 weeks, which suggests that resistance to maternal flow in the early placenta may be mediated more proximally by myometrial radial arteries that begin remodeling at the end of the first trimester.
Gestational age was determined by crown-rump length measurements obtained by transvaginal ultrasound on the day of contrast-enhanced imaging studies, which may explain the variability in the earliest gestational age samples due to the margin of error in this type of measurement.
Our comprehensive in situ histological analysis, in combination with the use of an in vivo imaging modality that has the sensitivity to permit visualization of microvascular filling, has allowed us to reveal new evidence in support of increasing blood flow to the IVS from 6 weeks of gestation. Histologic review suggested the mechanism may be blood flow through capillary-sized channels that form through the loosely cohesive 'plugs' by 7 weeks gestation. However, spiral artery remodeling on its own did not appear to explain why there is significantly more blood flow at 13 weeks gestation. Histologic studies suggest it may be related to radial artery remodeling, which begins at the end of the first trimester.
STUDY FUNDING/COMPETING INTEREST(S): This project was supported by the Oregon Health and Science University Knight Cardiovascular Institute, Center for Developmental Health and the Struble Foundation. There are no competing interests.
血管对比剂的使用是否有助于在妊娠早期更早地检测到胎盘绒毛间隙（IVS）的母体血流？
使用对比增强超声从 6 周妊娠开始显示 IVS 的微血管充盈，早于以前的认为。
在胎盘建立和母体螺旋动脉重塑过程中，血管内滋养细胞侵入并积聚在这些血管的管腔中，形成“滋养细胞栓子”。先前来自形态学和多普勒超声研究的证据相互矛盾，关于螺旋动脉是否完全阻塞，阻止母体血流进入 IVS 直到妊娠早期后期。
研究设计、大小和持续时间：对人类受试者进行了整个妊娠早期的子宫胎盘血流检查，方法是静脉内输注脂质壳八氟丙烷微泡，并进行超声破坏和补充动力学测量。我们还使用两个单独存档的子宫胎盘组织收集进行了全面的组织病理学相关性评估，以评估螺旋动脉堵塞的程度，并评估上游子宫肌层放射状和弓形动脉的重塑。
参与者/材料、设置和方法：招募了妊娠早期（范围：6+3 至 13+6 周妊娠）的孕妇进行对比增强超声研究，使用信号强度的破坏-补充分析评估微血管通量率。使用上皮、内皮和 T 细胞以及细胞粘附和增殖的标志物，对存档原位（Boyd 收集，n=11）和新鲜第一、第二和第三孕期蜕膜和子宫切除术子宫标本（n=16）的组织样本进行免疫组织化学和超微结构分析。
早在 6+3 周妊娠时就可以看到对比剂进入 IVS，在 6-7+6 周的样本中观察到微血流率的一些变化。从 7 周开始观察到螺旋动脉堵塞管腔，此后逐渐解体。值得注意的是，直到 13 周，微血流率才逐渐增加，这表明早期胎盘的母体血流阻力可能更靠近子宫肌层的放射状动脉，这些动脉在妊娠早期结束时开始重塑。
妊娠年龄通过经阴道超声测量的头臀长在对比增强成像研究当天确定，这可能解释了最早妊娠年龄样本的可变性，因为这种测量类型存在误差幅度。
我们的综合原位组织学分析，结合使用能够敏感地允许观察微血管充盈的体内成像方式，使我们能够提供新的证据支持从 6 周妊娠开始向 IVS 增加血流。组织学回顾表明，该机制可能是通过松散结合的“栓子”形成毛细血管大小的通道的血流，在 7 周妊娠时形成。然而，单独的螺旋动脉重塑似乎并不能解释为什么在 13 周妊娠时会有更多的血流。组织学研究表明，这可能与始于妊娠早期结束的放射状动脉重塑有关。
研究资金/竞争利益：该项目由俄勒冈健康与科学大学奈特心血管研究所、发育健康中心和斯特鲁布基金会支持。没有竞争利益。
