Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000443594
Ethics application status
Approved
Date submitted
27/03/2024
Date registered
10/04/2024
Date last updated
4/08/2024
Date data sharing statement initially provided
10/04/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Investigation of Foetal Auditory Abilities - Effects on Brain Activity
Scientific title
Investigation of Foetal Auditory Abilities to Perceive Music - Effects on Brain Activity
Secondary ID [1] 311834 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
auditory perception 333364 0
pregnancy 333365 0
Condition category
Condition code
Reproductive Health and Childbirth 330050 330050 0 0
Normal pregnancy
Neurological 330051 330051 0 0
Studies of the normal brain and nervous system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The research project will investigate foetal auditory abilities to perceive and process music in two separate study sets that either measure foetal heart rate (studies 1a & 1b, described separately) or foetal brain activity (studies 2a & 2b, present registration form).
All studies will take place at Waikato Hospital and every participant will only take part in one of the study sets. Both study sets have two experiments which are separated by a five minute break in between to minimise carry over effects of foetal heart rate and brain activity responses between studies. One of the experiments investigates musical timbre perception by using audio files of three different instruments (clarinet, trumpet, violin) while the other experiment investigates foetal harmony perception using audio files of major and minor chords that are played by a piano. Studies 2a and 2b play the stimuli intermixed without silence blocks in between them.
The presentation of the stimuli is controlled by a computer program written for the studies that ensures randomisation of all stimuli and counterbalancing across participants. The stimuli are delivered via a loudspeaker (Marshall Acton III Bluetooth Speaker) that is placed above the maternal abdomen.
The total time of auditory stimulation will be 16.5 minutes for the brain activity studies including short periods of silence in between each individual stimulus in every experiment.

Experimental conditions
Study 2a - musical timbre
timbres: clarinet, trumpet, violin (audio files)
trials: nine trials per timbre with 3.492 sec sound (tone: C4 = 261.63 Hz) and 26.508 sec silence (30 sec per trial)
sound pressure level: 95 dB

Study 2b - chords
chords: C-, G-, and D-major & a-, e-, and d-minor, all played by a piano (audio files)
trials: four trials per individual chord (= 12 per category) with 1.327 sec sound (chord) and 28.673 sec silence (30 sec per trial)
sound pressure level: 95 dB


An individual study session will be between 54-67 min long and includes the following:
One member of the research team will greet the mother-to-be and her whaanau or friends at the meeting point in front of the hospital and will bring her to the sonography unit where the studies will take place. They will then be taken through the participant information sheet and informed consent form. The participant information sheet includes an explanation of the purpose of the studies, explains the safety of the stimuli and methods used, has a brief description of the experimental procedure, and informs about what will be done to ensure the anonymity and the safety of the collected data. All explanations will be done in a clear, easy to understand language, and every participant will be asked for questions or concerns. Afterwards, the mothers-to-be will be asked to sign two copies of the informed consent sheet of which one of them will be given to the participant to keep for her records and one of them will be kept by the researchers.
After written informed consent, the participant will be brought to the sonography room where every member of the research team present will be introduced and her or his role in the session will be explained. Next, the woman will lie down in a comfortable position on her back and routine foetal check-ups will be performed by a qualified and registered diagnostic medical sonographer with a current annual practicing certificate from the New Zealand Medical Radiation Technologists Board in Wellington. These check-ups will include measurements of the foetal bi-parietal diameter, head circumference, abdominal circumference, and femur length to estimate foetal weight and gestational age (GA). Furthermore, foetal heart rate (HR) as well as single deepest pocket of amniotic fluid will be recorded.
The experimental procedure will then be explained in more detail and exemplary stimuli will be played to give the mothers-to-be an idea of what their babies will hear during the experiments. Each participant will be explicitly asked if she has any questions or concerns, and each will be reminded that the procedure can be stopped in case she feels uncomfortable or wants to withdraw. Neither of them must be justified. Then, the mother-to-be will be asked if she agrees to proceed with the procedure. If she does, she will be reminded to remain silent during the experiments and to lie as still as possible to ensure a high quality of the collected data throughout the experimental parts. Next, the research team will identify foetal position as well as foetal behavioural state (after Nijhuis et al., 1982) using 2D-ultrasound.
To access fronto-temporal brain activity in studies 2a and 2b a particular position of the foetus will be required. The near-infrared light of fNIRS penetrates up to 5 cm into the maternal abdomen (Araki & Nashimoto, 1992) and if the foetal head is not within this range, the participant will be asked to be taken for a short walk or to drink a glass of water to stimulate foetal repositioning. Otherwise, the experimental procedure cannot be continued, and the women will be asked to return a few days later if she is still interested in participating. If the foetus is in an appropriate position, the fNIRS probe and the loudspeaker will be put into place, headphones will be given to the mother-to-be and her company and the experiments will start.
After the completion of both experiments, the mothers-to-be will be asked if they have heard any of the stimuli or if they felt any foetal movement during the session. Everyone will be thanked for participating, debriefed, and given the opportunity to ask further questions or to comment about the studies. Every participant will be given $ 30 vouchers in recognition of travel costs and to show appreciation of taking part in the studies as well as a debrief form that summarises the studies in easy to understand language. The debrief form also includes the contact details of the primary investigators and two recommendations for further reading if the mothers-to-be have any further interest in pregnancy, foetal, and early development in general.


References
Araki, R., & Nashimoto, I. (1992). Near-infrared imaging in vivo (II): 2-dimensional visualization of tissue oxygenation state. In T. K. Goldstick, M. McCabe & D. J. Maguire (Eds.), Oxygen Transport to Tissue XIII (pp. 173-178). Springer. https://doi.org/10.1007/978-1-4615-3404-4_20
Nijhuis, J. G., Prechtl, H. F. R., Martin, C. B., & Bots, R. S. G. M. (1982). Are there behavioural states in the human fetus?. Early Human Development, 6(2), 177-195. https://doi.org/10.1016/0378-3782(82)90106-2
Intervention code [1] 328289 0
Diagnosis / Prognosis
Comparator / control treatment
The three different timbres (clarinet, trumpet, violin) as well as the different chords (major vs. minor) will be compared to each other. The timbre and chord category that is played first will serve as the comparator. The order of the stimuli and of the experiments is counterbalanced across participants and controlled by a computer program.
Furthermore, the foetal responses during the experimental blocks will be contrasted to blocks without auditory stimulation and complete silence. These blocks are the two baseline periods of the experiments which are two minutes each.
Control group
Active

Outcomes
Primary outcome [1] 337811 0
foetal brain activity
Timepoint [1] 337811 0
Foetal brain activity will be continuously measured for the 67 minute experimental session, with activity measured for 13.5 min during the timbre experiment, 12 min during the chord experiment, during the baseline periods of both experiments (2 min each) and the break in between them (5 min).
Secondary outcome [1] 433374 0
foetal movement
Timepoint [1] 433374 0
The 2D-ultrasound will be continuously used from the routine foetal check-ups at the beginning (approx. 5-10 min), during the baseline periods of both experiments (2 min each), the experiments themselves (25.5 min), and the break in between them (5 min). In sum, the 2D-ultrasound will be used for approximately 39.5-44.5 min in the brain activity studies.

Eligibility
Key inclusion criteria
All participants will be volunteers which will be selected based on the following inclusion criteria:
• maternal age: 18-42 years old
• singleton pregnancy
• gestational age is between 35 weeks + 0 days – 36 weeks +6 days
• no pregnancy complications
• healthy mother and healthy foetus
• age-appropriate foetal development: abdominal circumference above the 5th
percentile, estimated foetal weight greater than or equal to 10th percentile, and single
deepest pocket greater than or equal to 2 cm (Ministry of
Health, 2019)
• foetal HR is within the normal range: 120-160 bpm (Von Steinburg et al., 2013)


References
Ministry of Health. (2019, December 13). New Zealand Obstetric Ultrasound Guidelines. https://www.health.govt.nz/system/files/documents/publications/new-zealand-obstetric-ultrasound-guidelines-2019-dec19.pdf)
Von Steinburg, S. P., Boulesteix, A. L., Lederer, C., Grunow, S., Schiermeier, S., Hatzmann, W., Schneider, K. T., & Daumer, M. (2013). What is the “normal” fetal heart rate? PeerJ, 1:e82. https://doi.org/10.7717/peerj.82
Minimum age
18 Years
Maximum age
42 Years
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Women will be excluded if they meet one or more of the following exclusion criteria:
• multifetal pregnancy
• gestational age is < 35 weeks or >37 weeks
• pregnancy complications which affect foetal HR, auditory, neuronal, or general foetal
development
• maternal health issues which put either the mother-to-be or the foetus at risk or which
affect foetal cardiac, auditory, neuronal, or its general development
• foetal abnormalities or health issues which affect foetal HR, auditory, neuronal, or its
general development (e. g. Down syndrome)
• the foetus is small for gestational age: abdominal circumference < 5th percentile,
estimated foetal weight < 10th percentile, and single deepest pocket < 2 cm (Ministry
of Health, 2019)
• the foetal HR is not within the normal range: <120/ >160 bpm (Von Steinburg et al.,
2013)


References
Ministry of Health. (2019, December 13). New Zealand Obstetric Ultrasound Guidelines. https://www.health.govt.nz/system/files/documents/publications/new-zealand-obstetric-ultrasound-guidelines-2019-dec19.pdf)
Von Steinburg, S. P., Boulesteix, A. L., Lederer, C., Grunow, S., Schiermeier, S., Hatzmann, W., Schneider, K. T., & Daumer, M. (2013). What is the “normal” fetal heart rate? PeerJ, 1:e82. https://doi.org/10.7717/peerj.82

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation via computer program.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by a computer software.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Other design features
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis
Based on a probability of 1 – ß = .80, an a-value of a = .05 and a theoretical correlation of Rho = .50 between repeated measurements, a priori calculation using G.Power 3.1.3 (Faul et al., 2009) yielded in a sample size of N = 87 for 10 trials per timbre and N = 72 for 12 trials per chord category for studies 2a and 2b, respectively. Previous fNIRS studies with newborns reported an attrition of approximately 40 % (for review, see Lloyd-Fox et al., 2010) while foetal neuroimaging studies sometimes had to exclude 50 % of their participants (e. g. Jardri et al., 2008). Because no one has used fNIRS for foetal research before, sample size estimation will be based on a conservative attrition rate of 50 % and 131 women will be collected for the fNIRS studies.
Please note that the final estimated sample size for both set of studies was oriented on the estimations for the experiment where a larger number of participants was needed to find a small effect of f = .1 which was the timbre experiment.


References
Faul, F., Erdfelder, E., Buchner, A., & Lang, A. G. (2009). Statistical power analyses using G* Power 3.1: Tests for correlation and regression analyses. Behavior Research Methods, 41(4), 1149-1160. https://doi.org/10.3758/BRM.41.4.1149
Lecanuet, J. P., Granier-Deferre, C., Jacquet, A. Y., & Busnel, M. C. (1992). Decelerative cardiac responsiveness to acoustical stimulation in the near term fetus. Quarterly Journal of Experimental Psychology: Section B, 44(3-4), 279-303.
Lecanuet, J. P., Graniere-Deferre, C., Jacquet, A. Y., & DeCasper, A. J. (2000). Fetal discrimination of low-pitched musical notes. Developmental Psychobiology: The Journal of the International Society for Developmental Psychobiology, 36(1), 29-39. https://doi.org/10.1002/(SICI)1098-2302(200001)36:1<29::AID-DEV4>3.0.CO;2-J
Lloyd-Fox, S., Blasi, A., & Elwell, C. E. (2010). Illuminating the developing brain: The past, present and future of functional near infrared spectroscopy. Neuroscience & Biobehavioral Reviews, 34(3), 269-284. https://doi.org/10.1016/j.neubiorev.2009.07.008

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/01/2025
Actual
Date of last participant enrolment
Anticipated
31/01/2026
Actual
Date of last data collection
Anticipated
31/01/2026
Actual
Sample size
Target
131
Accrual to date
Final
Recruitment outside Australia
Country [1] 26221 0
New Zealand
State/province [1] 26221 0
Waikato

Funding & Sponsors
Funding source category [1] 316178 0
University
Name [1] 316178 0
University of Waikato
Country [1] 316178 0
New Zealand
Primary sponsor type
University
Name
University of Waikato
Address
Country
New Zealand
Secondary sponsor category [1] 318360 0
None
Name [1] 318360 0
Address [1] 318360 0
Country [1] 318360 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 315000 0
Southern Health and Disability Ethics Committee
Ethics committee address [1] 315000 0
Ethics committee country [1] 315000 0
New Zealand
Date submitted for ethics approval [1] 315000 0
17/11/2023
Approval date [1] 315000 0
26/01/2024
Ethics approval number [1] 315000 0
19197

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 133378 0
Prof Vincent M. Reid
Address 133378 0
The University of Waikato, Gate 1 Knighton Road, Hamilton East, 3240, Hamilton
Country 133378 0
New Zealand
Phone 133378 0
+64 78379593
Fax 133378 0
Email 133378 0
[email protected]
Contact person for public queries
Name 133379 0
Vincent M. Reid
Address 133379 0
The University of Waikato, Gate 1 Knighton Road, Hamilton East, 3240, Hamilton
Country 133379 0
New Zealand
Phone 133379 0
+64 78379593
Fax 133379 0
Email 133379 0
[email protected]
Contact person for scientific queries
Name 133380 0
Vincent M. Reid
Address 133380 0
The University of Waikato, Gate 1 Knighton Road, Hamilton East, 3240, Hamilton
Country 133380 0
New Zealand
Phone 133380 0
+64 78379593
Fax 133380 0
Email 133380 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
21987Study protocol    387580-(Uploaded-27-03-2024-09-16-38)-Study-related document.pdf
21988Informed consent form    387580-(Uploaded-27-03-2024-09-16-49)-Study-related document.pdf



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.