Developing a non-invasive treatment for twin-twin transfusion syndrome using high intensity focused ultrasound in an animal model

Abstract

High Intensity Focused Ultrasound (HIFU) is a non-invasive, non-ionising technology which can selectively occlude blood vessels. In Twin-Twin Transfusion Syndrome (TTTS), anastomotic placental vessels in a shared placenta allow uneven blood distribution between the twins. Despite advances in prenatal and neonatal care, TTTS remains the leading cause of death and disability in twins. Invasive fetoscopic laser can divide anastomoses, with risks of miscarriage, placental haemorrhage, extreme prematurity or second trimester rupture of membranes. Fetoscopic laser has undergone improvements in technology and therapeutic protocols over two decades, but it still does not consistently improve survival or decrease severe neurological morbidity in surviving twins. Hence, it is only used in severe cases, where benefits outweigh risks, and over 16-18 weeks gestation, after chorion and amnion fusion. This represents an unmet clinical need, which could be addressed by ultrasound-guided HIFU (USgHIFU). Selective occlusion of placental vessels using HIFU has not been described. Ultrasound identification of placental vascular anastomoses in humans is described, but is not in routine clinical use. Therefore, we tested the efficacy and safety of using USgHIFU as a non-invasive method of placental vascular occlusion in the pregnant sheep. An iterative study design in six animal groups was used. Treatment protocols for ultrasound guidance and HIFU delivery were developed in three animal groups. The efficacy and rates of associated direct and indirect iatrogenic harm of each version of the protocol was tested in another three animal groups, using invasive and non-invasive measures. Overall, transdermal USgHIFU occluded 97% of target placental vessels in the most developed treatment protocol. This persisted for 21 days and showed evidence of permanent vessel occlusion by fibrosis obliterans. This was achieved without significant adverse events, although maternal skin (2%), uterine (1%) and fetal skin burns (1%) were observed. There were no long term effects (up to 21 d) of the technique based on assessment of maternal and fetal cardiovascular, metabolic, endocrine and obstetric outcomes, or evidence of fetal compromise. This study is proof of principle that USgHIFU can be used to occlude placental vessels in the pregnant sheep. There is a low rate of direct iatrogenic harm and no evidence of indirect harm associated with the technique. As such, this supports the concept of future translational studies to develop USgHIFU as a treatment for TTTS in humans.