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Key Points Twin-twin transfusion syndrome (TTTS) is a rare condition where placental blood vessels are abnormally distributed, leading to an imbalance in the blood exchange between twins.Current interventions are high-risk, invasive, and can lead to complications, including miscarriage and very preterm delivery.This interim report, by Professor Christoph Lees, MD, FRCOG, describes an ongoing clinical trial in the UK that is investigating focused ultrasound as a noninvasive solution for this condition. Figure 1: The team (left to right) that undertook the first TTTS treatment in November 2021 are Nma Ofili (lead midwife, Imperial College Healthcare NHS Trust), Richard Symonds-Tayler (Institute for Cancer Research), Professor Christoph Lees & Dr. Caroline Shaw (Imperial College London), Dr. Ian Rivens (Institute for Cancer Research) and Dr. Sana Usman (Imperial College Healthcare NHS Trust) Twin-twin transfusion syndrome (TTTS) is a rare, serious, prenatal condition that can affect identical twins and multiples. In this syndrome, blood vessels are distributed abnormally within the placenta, leading to an imbalance in the blood exchange between twins. One twin, called the donor twin, gives away more blood than it receives and can suffer organ failure and even death. The other twin, the recipient twin, receives too much blood and is susceptible to overworking of the heart, heart failure, and death. The diagnosis of TTTS is usually made upon routine prenatal ultrasound scans. Once identified, more advanced ultrasound techniques can be used to grade the severity of TTTS. Depending on the severity of the disease, physicians will decide the proper treatment path, which might include early delivery of the twins, if they are of appropriate gestational age, or surgical intervention for the most severe cases if birth is not an option. It is estimated that approximately 15% of cases require invasive intervention. Current interventions include amnioreduction and laser fetal surgery. Both procedures are high-risk, invasive, and can lead to complications including miscarriage, premature rupture of the membranes, and very preterm delivery. Ultrasound-guided high intensity focused ultrasound (HIFU) has been proposed as a noninvasive method of treatment for TTTS, potentially providing a safer therapeutic option. HIFU for TTTS The early research for HIFU and TTTS was pioneered by Prof. Gail ter Haar from the Institute of Cancer Research, Prof. Dino Giussani from the University of Cambridge, and Prof. Christoph Lees from Imperial College London. Preclinical Research By 2017, Caroline Shaw, PhD, of the Physiology Department at the University of Cambridge had established that it was possible to noninvasively occlude placental vessels using HIFU in a preclinical model. This work was performed under the supervision of Prof. Giussani. Prof. ter Haar and colleagues also performed preclinical laboratory studies, where they established feasibility, safety, and proof of principle of this technique. Researchers overcame a technical challenge by using a special Doppler setting with state-of-the-art Canon ultrasound equipment. This produced high sensitivity, low flow vascular imaging; for the first time, it was possible to see with precision the tiny vessels that crossed between the two placental circulations. The next step was establishing the clinical need, which was accomplished by conducting surveys and holding focus groups with individuals from two leading patient support groups, Twins trust and The Multiple Births Foundation. First-in-Human Clinical Trial Figure 2: Ultrasound (US) evidence of the technical efficacy of the US-guided HIFU procedure. (A) Before US-guided HIFU, there was bidirectional blood flow within the placental vessel. (B) After US-guided HIFU, no flow was detected. In 2017, having established the feasibility, unmet clinical need, and safety of the technique in preclinical studies, the research group led by Prof. Lees was awarded just under £2M in funding from the Medical Research Council for a phase 1 clinical trial. The Focused Ultrasound Foundation is also funding a portion of this study. The funding enabled the team to build and test the equipment and recruit women with early TTTS throughout the UK to the study. Unfortunately, due to the COVID-19 pandemic, the start of the study was delayed until October 2021. Since that time, the group has enrolled and treated five women with early onset TTTS (Figure 1). In all cases, there has been successful and safe ablation of the targeted placental vessels. The TTTS was severe at the time of treatment, so it is too early to speculate on clinical efficacy. However, some women have reached close to term with healthy twins; in others, the underlying disease has led to very preterm delivery. This trial is not assessing efficacy, but the researchers have seen signs of clinical efficacy in some of the women treated. Technical efficacy has been demonstrated by Doppler imaging of the ablated portion of the blood vessel targeted (Figure 2). The goal is to complete study enrollment by the end of 2022, which would mean recruiting another four to eight participants within that timeframe. Significance This clinical trial is ground-breaking, because it could lead to the first noninvasive treatment option for TTTS. HIFU could substantially decrease the treatment risk for this condition, as no entry into the intrauterine space is needed. The Focused Ultrasound Foundation would like to thank Prof. Lees and Dr. Shaw for providing this interim report on the clinical trial. Prof. Lees wishes to thank Dr. Ian Rivens and Dr. Richard Symonds-Tayler for being available at short notice for treatments and Prof. ter Haar for her continued contributions to the field of focused ultrasound.