MICA: A Non-invasive Ultrasound-guided High Intensity Focused Ultrasound system for placental and fetal vascular ablation

Lead Research Organisation: Imperial College London
Department Name: Dept of Surgery and Cancer


Twin-Twin Transfusion Syndrome (TTTS) affects 10-15% of identical twins who share a placenta. This may need treatment that is high risk for around 400-600 babies every year in the UK. In TTTS, blood moves from one twin to the other through abnormal blood vessel connections in the placenta called anastomoses, which directly link the blood supplies of the twins. These anastomoses may cause one twin to get less blood and amniotic fluid and the other twin too much blood and amniotic fluid. TTTS is the biggest cause of premature birth, death or disability in identical twin pregnancies.
TTTS can be seen with a specialist ultrasound scan. Women who have severe TTTS have the worst outcomes, and are recommended to have a treatment which can divide the twins' placenta by blocking the abnormal blood vessel connections that cause TTTS. At the moment this is done using a technique called fetoscopic laser, a surgical procedure where a 2-4 mm wide instrument is placed into the womb so it can reach the placenta. As the laser must be put inside the womb, this treatment is risky and can cause miscarriage, bleeding or infection in the womb, or leakage of fluid from the womb which can affect the twins' development. This is why fetoscopic laser is only used in serious cases; the risks are too high to for it to be used in cases that are not as serious.
In the UK about 100-150 women per year have severe TTTS diagnosed before 18 weeks. Even though they need treatment, fetoscopic laser cannot be used because the risks are too high and instruments too big. This is a group of women whose babies have the worst outcomes of all those diagnosed with TTTS, but we have no good, safe treatments for them.
Our research group works with High Intensity Focused Ultrasound (HIFU), which uses very powerful ultrasound waves that can block blood vessels in the placenta without needing to make a hole in the womb. As HIFU does not require invasive surgery to be done, we could use it to treat severe TTTS in pregnancies below 18 weeks. So far, we have tested this treatment in pregnant sheep, which share similarities to human pregnancies. Based on these experiments HIFU seems to be work well and is a safe way to block placental blood vessels.
At Queen Charlotte's and Chelsea Hospital, London, we will work with experts in HIFU from the Institute of Cancer Research, London, international fetal medicine experts, pregnancy support groups and patient volunteers with experience of TTTS to design a clinical study. We will offer around 13 women and babies diagnosed with TTTS before 18 weeks the HIFU treatment as part of a carefully designed study. In this very early stage study look primarily at whether the technique is safe for mothers and babies and if we can stop blood flowing through the abnormal vessels connecting the two halves of the placenta. If HIFU is safe and effective, it would prevent the need for riskier laser treatment when these pregnancies reach 18 weeks and will most likely lead on to further, larger clinical trials.
As part of this study, we will build a special ultrasound guided HIFU system that combines the best available ultrasound imaging of the babies and placental blood vessels with a HIFU system specially designed to direct the treatment to exactly the right area in the placenta. We will also design a special computer program to control the whole system. Fixing the abnormal placental blood vessels without harming the mother or the babies is difficult. The experiments we have done in sheep has shown us some of the problems that might happen. There are no places to buy a HIFU system that makes good enough pictures or allows accurate treatment of the abnormal blood vessels. Therefore we need to build a one to use in this study. The HIFU system we build may also be used in the future for treating other problems that can happen in pregnancy or for cancer treatment, where it could block the blood vessels that feed tumours.

Technical Summary

Approximately 4000 identical (monochorionic diamniotic-MCDA) twin pairs are born in the UK every year. Twin-Twin Transfusion Syndrome (TTTS) affects 10-15% of MCDA twin pregnancies in which it is a leading cause of mortality, premature delivery and morbidity. Fetoscopic laser ablation of placental vascular connections is an invasive procedure performed after 18 weeks gestation, with risks of preterm rupture of membranes or labour/miscarriage, infection and maternal complications. Hence management of TTTS is expectant, with monitoring for severe fetal compromise and intervention when the potential benefits exceed the associated risks of invasive treatment. Development of non-invasive alternatives would reduce these risks, allowing earlier treatment or treatment in less severe TTTS. High Intensity Focused Ultrasound (HIFU) is a licensed non-invasive therapeutic technique. It uses precisely aimed ultrasound beams generated using external sources to produce sharply delineated areas of ablation without damage to adjacent tissue. Our team has successfully demonstrated the use of ultrasound-guided HIFU to target, and selectively ablate, placental vessels in sheep, a recognised model of fetal physiology. The HIFU procedure was well tolerated without significant short or long term adverse effects (Shaw Sci Trans Med 2016).

We will translate non-invasive HIFU vascular ablation into a first-in-human clinical trial by constructing a prototype ultrasound guided HIFU system and user interface, customised to ablate placental vasculature. This will be informed by market research involving interventional fetal medicine practitioners and patient-public groups, accessed through UK based patient support groups (TAMBA and MBF). Using advice from this advisory group and patient support organisations, we will conduct a Phase 1a safety/efficacy study of early gestation TTTS treatment with HIFU where other therapeutic modalities are severely limited.

Planned Impact

This project is a first in human, phase 1a study of noninvasive placental surgery to treat twin-twin transfusion syndrome (TTTS). To achieve this, we will fabricate and test customised ultrasound guided HIFU (USgHIFU) equipment. The current treatment for TTTS, fetoscopic laser, involves invasive intrauterine surgery and occlusion, under direct vision, of blood vessels on the surface of the placenta that communicate between the twins' circulations (known as arterio-venous anastomoses-AVAs). Fetoscopic laser, though it has been shown to occlude the AVAs which cause TTTS, has procedure related risks of fetal death, miscarriage, rupture of membranes, haemorrhage and infection.

If non invasive ablation of blood vessels using USgHIFU were successful, this would represent a paradigm shift in the treatment of the condition. In the UK, 400-600 pairs of twins are treated invasively annually, of whom several hundred die or suffer neurodevelopmental sequalae such as cerebral palsy, as a result of the condition or the treatment. The latter is associated with lifetime care costs of several million pounds per survivor and there are personal, social and economic costs associated with loss of a pregnancy or a child. It is likely that USgHIFU would be associated with none of the complications associated with invasive interventions. Furthermore, early gestation prophylactic treatment for TTTS could for the first time be entertained. A major distinction between HIFU and fetoscopic laser is that deep placental vascular anastomoses would be targeted and ablated, and retreatment would be feasible as many times as was considered appropriate. This could have major implications for the management of TTTS worldwide where an estimated several tens of thousands of monochorionic twins are treated invasively every year and many complications of the procedure and the condition occur. It is axiomatic of the level of interest in this area that our first published description of the sheep studies was immediately accepted for publication in the high impact US journal Science Translational Medicine in July 2016 and presentations of this work in the last 12 months has led to at least 2 prizes at World Conferences.

Quite apart from TTTS, the imaging and targeting of small calibre vessels within the uterus will have an application in fetal vascular conditions such as twin reversed arterial perfusion sequence (TRAP), a condition with approximately 30% healthy co-twin loss rate untreated, and fetal tumours such as teratoma (sacro-coccygeal, cervical). These are usually associated with a feeding blood vessel and often fatal to the fetus or neonate. The vessels are not amenable to ablation through conventional invasive means due to the potential for damage of local structures: nerves, bladder, bowel. Non invasive ablation of the feeding vessel is likely to stop the fetal tumour growing and could lead to its involution.

Beyond fetal medicine, vascular imaging and high precision targeting of blood vessels will represent a major step forward for HIFU therapy, which is still technology that is the preserve of a relatively limited group of superspecialists. Bringing imaging and targeting technology to oncology and surgical therapists will realise the potential of HIFU to treat vascular abnormalities and devascularise malignant and benign tumours where conventional treatments are associated with a high risk of life-threatening haemorrhage and hence often not attempted.

The technique is translatable to lower resource settings where fetal intervention is currently precluded, given the level of expertise required for invasive fetal interventions and neonatal/obstetric services required because of the risk of fetal/maternal complications. This depends on whether the imaging and HIFU source & targeting aspects can be integrated and made 'user friendly' in a cost effective package, a prerequisite of this first in human Phase 1a study.


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Description Working with UK twin support groups TAMBA and Multiple Birth Foundation to disseminate information about the study to parents, the public and professionals through newsletters, meetings and their websites 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact We have started to raise the profile of the study as we are actively recruiting to the placental mapping study currently underway, and wish to publicize the planned human HIFU studies intended to start in the next grant year.
Year(s) Of Engagement Activity 2019