The goal of this international multicentre prospective observational cohort study with a
      nested case-control study is to test some automated fetal heart functional parameters in
      healthy babies compared to those affected by a congenital heart condition.

      The main questions it aims to answer are:

        -  If there is a significant difference between the two populations of infants

        -  Whether these parameters could significantly improve the predictive value of actual
           cardiovascular profile score to predict hydrops Participants will be offered two
           automated cardiac function assessments between 27+6 and 29+6 gestational weeks and
           between 34+6 and 36+6 weeks of gestation. Functional parameters will be compared between
           the two study groups and evaluated over time.

Automated Fetal Cardiac Function in Babies Affected by Heart Diseases

Congenital Heart Defect

Cardiac Function

Investigation Plan

      Participating patients will be offered a fetal cardiac function echocardiography between 27+6
      and 29+6 weeks of gestation and another between 34+6 and 36+6 weeks.

      At the stage patients will come in to carry out fetal cardiac function echocardiography they
      will already know whether the baby is affected by congenital heart disease since malformation
      screening is carried out between 18 and 20 gestational weeks and will have already been
      undertaken. In the remote case of detecting an undiagnosed fetal malformation during one of
      the research scans, patients will be reassured, and appointments arranged at Maternal and
      Fetal medicine (MFM) clinic for further consultation along with notification of to their own
      treating doctor.

      Every participant will be assigned a study number following recruiting order of
      participation. De-identification will be undertaken at image acquisition by the doctors prior
      to image review by the engineers. Researchers will access an online patients' form system,
      collect the assigned patients' number and add the necessary outcomes information. Ultrasound
      images will be saved locally in the ultrasound machine by the same assigned patient's study
      number and uploaded to a specific Microsoft (OneDrive) folder created in Sydney. This data
      will be stored for a minimum of 5 years after publication, then the data record will be
      securely destroyed in accordance with the University of New South Wales (UNSW) Records
      Disposal processes.

      The research ultrasound scans will be performed by a trained sonographer using either a
      clinical ultrasound system or a research ultrasound system that is Therapeutic Goods
      Administration (TGA) approved for research imaging. The machine used clinically is made by
      one of the common commercial manufacturers (in this case General Electric E10) and is an
      identical model to that used in the Department of Maternal and Fetal Medicine. The machine
      used for research porpoises is called Vantage 256 and it is manufactured by a private company
      in the United States (Verasonics). It uses the same fundamental electronic circuitry and
      transducer design as conventional commercial machines, and in fact uses the same transducers
      as the commercial machines. However, the way that the ultrasound is delivered differs.
      Instead of transmitting beams as used in conventional ultrasound machines, Verasonics scans
      the area of interest by unfocused waves, allowing high quality images with a limited number
      of compounded plane-waves, and reduced acquisition time.

      Women will be placed in a semi-recumbent position, as standard for pregnancy ultrasounds.
      After routine biometry, the research fetal cardiac function ultrasound will be carried out.

      Each fetal cardiac function examination will include the following parameters:

        1. Fetal biometric parameters (biparietal diameter, head circumference, abdominal
           circumference, femur diaphysis length)

        2. Standard fetal Doppler parameters (umbilical artery, medial cerebral artery, ductus
           venosus)

        3. Fetal cardiac heart rate

        4. Presence of pericardial effusion or hydrops

        5. Cardiac morphometry - all measurements carried out at the end of diastole, with the
           exception of atrial dimensions measured in systole (at their maximum extension)

             -  Heart/thorax area measurement

             -  4 heart chambers measurements (apical/basal 4-chambers view in 2D)

             -  Atrial and ventricular areas (apical/basal 4-chambers view in 2D)

             -  Ventricular and atrial sphericity calculation

             -  Inter-ventricular septum and myocardial walls thickness measurement (transversal
                4-chambers view in 2D or M-mode)

        6. Cardiac contractility

             -  Spatio-temporal image correlation (STIC) M-Mode stroke volume, ejection fraction
                and shortening fraction

             -  Automated STIC Mitral Annular Plane Systolic Excursion (MAPSE), Tricuspid Annular
                Plane Systolic Excursion (TAPSE), Septal Annular Plane Systolic Excursion (SAPSE)

             -  Automated Pulsed Wave Doppler (PWD) Left and Right modified myocardial performance
                index (Mod-MPI)

        7. Atrioventricular valves' function evaluation

             -  Cine-loop evaluation of correct opening and closing

             -  Anterograde Colour Doppler without regurgitation

             -  Pulsed Doppler evaluation of flow velocity (monophasic or biphasic)

             -  Left and right E/A ratio calculation

             -  If any regurgitation: peak velocity and duration quantified

        8. Aorta outflow evaluation

             -  Aorta artery measurement (at the level of valvular ring in systole)

             -  Aortic flow evaluation (Colour Doppler evaluation of systolic peak velocity)

        9. Pulmonary outflow evaluation

             -  Pulmonary artery measurement (at the level of valvular ring in systole)

             -  Pulmonary flow evaluation (Colour Doppler evaluation of systolic peak velocity)

       10. V-sign evaluation

             -  Confirmation of anterograde flow in the entire length of the arteries

             -  Pulsatility index of aortic isthmus and ductus arteriosus

      All fetal morphometric and functional cardiac parameters will be normalised to Z-score by
      gestational age where possible. Fetal cardiac volumes and 2D images with inadequate quality
      due to fetal movements, presence of acoustic shadows of fetal ribs or spine, and maternal
      breathing will be excluded. If hydrops develops, cardiovascular profile score will be added
      to the routine cardiac function exploration.

      The study population will be followed up until delivery and discharge of both mother and
      neonate. Patients' information will be collected anonymously. Each patient's history will be
      evaluated and information about previous pregnancies (maternal or fetal diseases during
      pregnancy) and outcomes (type of delivery, maternal and neonatal conditions at birth,
      long-term outcome of the pregnancy) will be collected. Furthermore, investigators plan to
      collect information about the current pregnancy (maternal and fetal observations during
      pregnancy) and outcomes (type of delivery, maternal and neonatal conditions at birth and up
      to hospital discharge of both).

      Study Procedure Risks

      There is no increased risk related to participating in this study. The study uses
      conventional ultrasound machinery as used in routine fetal evaluation, with no alteration in
      power output (as defined by Thermal Index or Mechanical Index). The Verasonics research
      ultrasound system is also comparable to conventional ultrasounds in terms of risks.

      Approximately 20-30 minutes scan duration is anticipated for acquisition of the necessary
      research data which is in keeping with standard ultrasound examinations, and the As Low As
      Reasonably Achievable (ALARA) principle conventionally applied in fetal imaging.

      Sample Size Calculation

      The primary outcome of the study is the difference in the mean of automated fetal functional
      cardiac parameters between CHD cases and controls. This will be analysed using a two-sample
      t-test.

      To estimate the sample size, the most commonly applied fetal functional parameter was used,
      specifically the left ventricle MPI (LV-MPI) as a proxy of all the automated fetal cardiac
      parameters.

      Due to the rarity of congenital heart disease, the sample size calculation was performed
      based on recruiting two controls for each case. Pooled across cases with isolated pulmonary
      valve stenosis (n = 16) and controls (n = 48), a previous work observed a standard deviation
      of 0.098 in LV-MPI measurements. Using this observed pooled Standard Deviation (SD), a total
      sample of 381 pregnancies (127 CHD + 254 controls) with completed measurements is required to
      achieve at least 80% power to detect a difference of 0.03 in mean LV-MPI, with a two-sided
      type I error rate of 5%.

      Investigators acknowledge that some pilot data may be required to evaluate the limited number
      of pathological cases and therefore some approximations are necessary e.g. for standard
      deviation within the population. For this reason, investigators have aimed to recruit a
      larger number of participants (approximately 30%), 165 CHD and 330 Controls, allowing also
      for some patient exclusions due to patient drop out, difficulties in scanning due to fetal
      movements etc, and incomplete data sets.

      The aim would be to recruit sufficient cases to be able to estimate if there is significant
      difference in terms of fetal cardiac function parameters between affected and not affected
      fetuses to inform further research.

      Data Analysis Plan

      Raw (radio-frequency) ultrasound data generated using the Verasonics will allow the
      researchers to analyse the signal/image processing that takes place prior to display,
      enabling refinement of this imaging technique.

      Image analysis will be carried out first manually through optical evaluation and then through
      the use of mathematical algorithms which will recognise and analyse only high-quality images.
      This could be a limitation because automatically only high-quality images will be included
      (which is not representative of real clinical work) but also guarantees that parameters are
      collected only from almost perfect research material (showing true differences if they
      exist).

      Ultrasound images will be analysed and cardiac function parameters interpreted by South
      Eastern Sydney Local Health District (SESLHD)/UNSW researchers based at the Royal Hospital
      for Women (RHW), Randwick. Images will be analysed by a team of fetal medicine doctors at
      Royal Hospital for Women and UNSW engineers to assure that algorithms are correctly applied
      to calculate fetal cardiac function parameters.

      Comparisons of interest between cases and controls in baseline characteristics will be
      performed using two-sample t-tests, Wilcoxon rank-sum tests or Pearson Chi-squared tests, as
      appropriate.

      Secondary outcomes comparing cases and controls at a single time point will be analysed in a
      similar way to the primary outcome, subject to checks of assumptions. Analyses of changes in
      fetal function parameters over time (i.e. between the 27+6-29+6 and 34+6-36+6 week scans),
      and the comparison of these changes between cases and controls will employ generalised linear
      mixed models, as appropriate for the parameter.

      Logistic regression will be used to estimate the association between fetal cardiac parameters
      and the incidence of hydrops. Receiver-operating-characteristics-curve analysis will be
      carried out to assess functional cardiac parameters compared to the routinely used
      cardiovascular profile score to predict cardiac failure in fetuses with congenital heart
      disease.

      Statistical analysis will be performed using SPSS version 22.0 (SPSS Inc., Chicago, Illinois
      (IL), USA).

      For those cases without complete data acquisition (i.e. intending but not undertaking a
      second scan), analysis will take place for only the isolated value and not for any temporal
      change. Their single gestational data set of ultrasound measurements will still be included
      in analysis but excluded from any analysis of sequential change.

      Data Safety and Monitoring Board

      To assure high quality data collection, images will be collected at each participating centre
      by experienced fetal medicine doctors who have practiced fetal medicine for over 10 years.
      Each image will be stored securely. Data will be anonymised and monitored by researchers at
      SESLHD/UNSW. Researchers at UNSW will also review and complete data collection in case of
      missing data.

      Our team from RHW will supervise and guarantee the quality of the data. Each participating
      centre will have a site researcher, a fetal cardiologist who will discuss and sign consent
      form, collect ultrasound images and relevant patients' data. The data collected will be
      uploaded and securely stored onto the UNSW platform.

      Once ethical approval for each overseas center will be granted, UNSW team will download data
      from all centers, merge the information in a unique database and analyze them with the help
      of a statistician. UNSW team will be responsible for images analysis and data analysis. All
      the participants will then collaborate in drafting manuscripts for publication.

      Outcome data will be accessed only by authorised researchers using an encrypted code for data
      protection. Final drafts for publication will be reviewed by all the authors from each
      research site.

      Dissemination of results and publication policy

      Results of the study will be published in peer-reviewed scientific journals, presentations at
      conferences or other professional forums. In any publication, patient privacy will be
      protected and presented in a de-identified manner.

Automated fetal cardiac function evaluation

Automated Fetal Cardiac Function Parameters in Congenital Heart Disease

Measure the difference in the mean absolute numerical value for PWD-MPI (expressed to 2 decimal places) between fetuses with CHD overall compared to healthy fetuses and then by subgroups of different CHDs.

Difference in absolute values for each of STIC Tricuspid, Mitral and Septal Annular Plane Systolic Excursion between fetuses with CHD overall compared to healthy fetuses and then by subgroups of different CHDs.

Difference in variation of the mean absolute value for PWD-MPI over time between fetuses with CHD overall compared to healthy fetuses and then by subgroups of different CHDs.

Difference in variation of absolute values for each of STIC Tricuspid, Mitral and Septal Annular Plane Systolic Excursion between fetuses with CHD overall compared to healthy fetuses and then by subgroups of different CHDs.

Consultant in Obstetrics and Gynaecology

Difference in predictive values between Modified and Classical Cardiovascular Profile Score. Minimum score value is 0, Maximum score value is 12. Higher score means a better outcome.

Difference in predictive values between Modified and Classical Cardiovascular Profile Score. Minimum score value is 0, Maximum score value is 14. Higher score means a better outcome.

Automated Fetal Cardiac Function in Babies Affected by Heart Diseases

About this trial

Study ID

Status

Type

Placebo

Accepting

Trial Timing

What is this trial about?

What are the participation requirements?

Locations

Location

Status