Contrast-enhanced ultrasound reveals real-time spatial changes in vascular perfusion during early implantation in the macaque uterus

Abstract

Objective To use contrast enhanced ultrasound (CEU) to quantify blood flow in the macaque uterus during early pregnancy. Design Prospective nonhuman primate study. Setting National Primate Research Center. Animals Naturally cycling female rhesus macaques (Macaca mulatta). Interventions Female macaques were mated on days 11–14 of the cycle. Females were then imaged by CEU and Doppler ultrasound (DUS) once every 3 days from day 21 through day 39 of the fertile cycle. Main Outcome Measures Visualization and quantification of uterine vascular perfusion. Results CEU identified the primary placental disc and underlying vessels ~2 days earlier than DUS was able to observe endometrial thickening. CEU revealed spatial differences in vascular perfusion between the endometrium, myometrium, and the endometrial-myometrial (junctional) zone. Myometrium displayed the highest rate of blood flow (>10 mL/min/g tissue). There was less blood flow in the endometrium and junctional zone (<3 mL/min/g). A brief fall in progesterone was observed during early implantation, which was correlated with reduced blood flow to all three uterine compartments, but did not reduce flow to the placenta. Conclusions CEU provides a sensitive, non-invasive method to assess vascular perfusion of the uterus during embryo implantation in macaques. We propose CEU as a new diagnostic tool to monitor vascular changes associated with early pregnancy in women.

Modeling Cyclosporine A Inhibition of the Distribution of a P-Glycoprotein PET Ligand, 11C-Verapamil, into the Maternal Brain and Fetal Liver of the Pregnant Nonhuman Primate: Impact of Tissue Blood Flow and Site of Inhibition

“…This limitation may also affect the accurate determination of placental blood flow. Nonetheless, our estimates of placental blood flow were comparable to placental perfusion rates obtained by contrast-enhanced ultrasound in pregnant macaques (15). …”

“…Because of the limited resolution of the MR images obtained in the current study, it was not possible to identify both primary and secondary disks on these images. Therefore, placental blood flow was estimated after a manual adjustment of 15 O-water radioactivity in the placenta by a factor of 2, based on the fact that primary and secondary disks are of similar size and perfusion level (15). …”

Quantitative assessment of placental perfusion by contrast-enhanced ultrasound in macaques and human subjects

“…15 In addition, CE-US has been used in early pregnancy implantation studies in the Rhesus macaque 16 but not later in gestation. Importantly, Keator and colleagues demonstrated no adverse effect on pregnancy outcome at full term following early CE-US use in their small sample cohort of three animals.…”

Non-invasive evaluation of placental blood flow: lessons from animal models

“…Examination of placentas by electron microscopy showed no evidence of ultrastructure damage to microvilli syncytiotrophoblast and indicated that the use of CEU does not results in placental structural damage and may offer a safe clinical tool (Roberts et al 2016). Studies in macaques and rats also suggest that CEU is safe (Keator et al 2011, Roberts et al 2016, without significant effects either on foetal circulation (Schmiedl et al 1998) or on foetal weight (Arthuis et al 2013). One study, however, suggests that it may affect placenta.…”

“…Using Japanese macaques, CEU imaging after a micro-bubble burst demonstrated that the rate of perfusion increases with advancing gestation in the 2nd trimester of pregnancy (Roberts et al 2016). In macaques during early pregnancy, CEU and Doppler were combined to calculate blood flow in a manually identified ROI and subsequently quantify volume (mL/100 mL), flow rate (s-1) and blood flow (mL/min/g) (Keator et al 2011). Finally, in rats, CEU has been used for quantitative analysis of placental perfusion through the visualisation of the central arterial canal (Zhou et al 2013) and to compare uteroplacental perfusion between controls and a rat model of PE (Yan et al 2014).…”