Evaluation of Sulfur Hexafluoride-Enhanced Ultrasound in Assessing Placental Vascularization in Fetal Growth Restriction and Non-Restriction Pregnancies

The primary objective of this study is to compare **placental contrast ultrasound** in patients undergoing medical termination of pregnancy between gestational ages 16 weeks and 38 weeks + 6 days. The comparison is made between two groups: those with **fetal growth restriction** and those without. This objective is clinically relevant as it aims to enhance the understanding of placental vascularization differences in cases of fetal growth restriction, potentially informing future diagnostic and therapeutic strategies.

Secondary objectives include: - Describing the placental vascularization parameters measured by enhanced contrast ultrasound (ECUS) for all patients. - Describing the parameters for quantifying vascularization at different gestational ages using ECUS. - Studying the associations between ECUS data and placental histological data. - Establishing a biological collection of placentas to study the consequences of using **sulfur hexafluoride** in the placenta.

The clinical trial focuses on a population of **adult women** aged 18 years and older, specifically those experiencing **fetal growth restriction**. The study includes participants with a gestational age ranging from 16 weeks to 38 weeks and 6 days, all of whom have a singleton pregnancy. Participants are selected based on their request for a medical termination of pregnancy, which must be formally accepted by the Centre Pluridisciplinaire de Diagnostic Prénatal (CPDPN) of the CHRU de Nancy. The trial population is exclusively female, with no male participants involved. The study does not provide information on the total number of participants, as this data was not disclosed by the sponsor. The trial involves a vulnerable population, given the medical and ethical considerations surrounding the termination of pregnancy. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the contribution of **contrast-enhanced ultrasound** (CES) in the study of fetal-placental circulation, specifically focusing on **fetal growth restriction**. This trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The trial is expected to commence on May 1, 2024, and conclude by May 2, 2028, with the duration of participant involvement varying based on individual circumstances but generally aligning with the gestational period specified in the inclusion criteria.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, gestational age, and pregnancy status. The primary inclusion criteria include adult women aged 18 years or older, with a gestational age between 16 weeks and 38 weeks plus 6 days, and a singleton pregnancy. The screening visit will also involve the assessment of fetal growth restriction, defined by an estimated fetal weight below the 3rd percentile. Following the inclusion visit, participants will attend follow-up visits where the primary endpoint, the comparison of placental contrast ultrasound parameters, will be assessed. Secondary endpoints include the measurement of perfusion kinetics of the contrast agent and the association between vascularization parameters and placental histology data.

The end-of-study visit will mark the conclusion of the participant's involvement, during which final assessments and data collection will occur. The expected length of participant involvement is contingent upon the gestational age at the time of inclusion and the progression of the pregnancy. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The investigational product, SonoVue, containing **sulfur hexafluoride**, will be administered via intravenous infusion, with a maximum daily dose of 4.8 ml. The trial is categorized as non-low intervention, with the investigational product being used in a manner consistent with its marketing authorization, albeit in a pregnant population.

The clinical trial involves the use of **SonoVue**, a pharmaceutical product formulated as a **powder and solvent for dispersion for injection**. The active substance in this experimental medication is **sulfur hexafluoride**, a chemical compound. SonoVue is administered via **intravenous infusion**. The dosage is set at a maximum of 4.8 milliliters per day, with the total dose not exceeding 4.8 milliliters. The treatment period is limited to a single day. The product is not a pediatric formulation and is not classified as an orphan drug. The pharmaceutical form is specifically designed for dispersion for injection, ensuring optimal delivery of the active substance.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are mentioned. The focus is solely on the administration of SonoVue to evaluate its efficacy in the context of the trial's objectives. Participant compliance with the dosing schedule is crucial and will be monitored throughout the trial to ensure adherence to the protocol. The trial aims to assess the contribution of contrast-enhanced ultrasound in the study of fetal-placental circulation, specifically comparing outcomes between groups with and without fetal growth restriction.

Efficacy in this clinical trial will be assessed through the primary endpoint of comparing placental contrast ultrasound parameters between two groups defined by fetal weight percentiles, specifically focusing on cases of **Severe IntraUterine Growth Restriction (IUGR)**, which is characterized by a fetal weight below the 3rd percentile for gestational age. Secondary endpoints include the measurement of perfusion kinetics of the contrast agent in Contrast-Enhanced Ultrasound (ECUS) on the fetal side, utilizing semi-quantitative analysis parameters obtained with VueBox software. Additionally, the trial will explore the association between ECUS vascularization parameters and placental histology data, including macro- and microscopic indices based on the Amsterdam Standardized Analysis Criteria. This involves evaluating placental weight, cord length, and the presence of macroscopic and histological lesions. Furthermore, placental samples will be obtained to study the deposition of sulfur hexafluoride using electronic microscopy. These assessments will provide comprehensive insights into the efficacy of the intervention in the context of fetal-placental circulation studies.