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Trial registered on ANZCTR


Registration number
ACTRN12624000954527
Ethics application status
Approved
Date submitted
18/07/2024
Date registered
6/08/2024
Date last updated
6/08/2024
Date data sharing statement initially provided
6/08/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
The CUTE Project - CUT umbilical cord milking to prevent Encephalopathy in infants with prenatal drug exposure
Scientific title
CUT umbilical cord milking to prevent Encephalopathy in infants with prenatal drug exposure
Secondary ID [1] 312557 0
2023/PID02555
Universal Trial Number (UTN)
Trial acronym
CUTE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Prenatal opioid exposure 334453 0
Inflammation in neonate 334465 0
Condition category
Condition code
Reproductive Health and Childbirth 331073 331073 0 0
Fetal medicine and complications of pregnancy
Reproductive Health and Childbirth 331074 331074 0 0
Childbirth and postnatal care
Mental Health 331075 331075 0 0
Addiction
Inflammatory and Immune System 331159 331159 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Umbilical cord milking (UCM) - 32 opioid-using mothers will be randomly assigned to receive umbilical cord milking or standard cord clamping in the 2 weeks prior to birth. The Research Midwife/PI will be responsible for ensuring that the correct cord clamping technique is employed through notation on hospital records. An information sheet and video will be provided to all staff involved. Formal training will not be provided unless requested by staff. Note that this is a variation of normal cord clamping procedures, and does not disrupt the birth process.

Infants randomized to the UCM condition will have their umbilical cord clamped 20-30 cm from their body within 30-60 seconds of birth. The cord will then be cut, leaving the long section attached to the infant. This section of the cord will be squeezed slowly (‘milked’) towards the infant once or twice to push the blood within inside the infant’s body. The cord is then clamped closer to the infant and care proceeds as usual. Once each cord is milked, it will be measured (cut end to infant umbilicus).

Standard (or immediate) cord clamping refers to clamping of the cord within 15-60 seconds of birth (WHO).
Intervention code [1] 329071 0
Treatment: Other
Comparator / control treatment
16 pregnant women with no history of substance use across pregnancy will be recruited. No UCM will be administered to control participants, they will receive standard cord clamping. Standard (or immediate) cord clamping refers to clamping of the cord within 15-60 seconds of birth (WHO).

There is no control group receiving UCM in this design for two reasons: 1) obstetric and midwife staff conclude it would be difficult to recruit otherwise healthy pregnant women to receive UCM; 2) there would be a ceiling effect in these infants where UCM would not noticeably improve outcomes. Nonetheless, the control group is essential to provide a baseline reading across all measures while controlling for all external factors (e.g., socio-economic status) and to indicate a direction of change for the measures to be gathered i.e. whether infant inflammatory cytokines are higher or lower compared to controls, and whether the UCM normalises these values.
Control group
Active

Outcomes
Primary outcome [1] 338836 0
Change in inflammatory markers in blood, saliva and placental samples. Inflammatory markers assessed as a composite primary outcome.

Markers of interest: FGF basic, Eotaxin, G-CSF, GM-CSF, IFN-?, IL-1ß, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17A, IP-10, MCP-1 (MCAF), MIP-1a, MIP-1ß, PDGF-BB, RANTES, TNF-a, VEGF, DRD2, CXCL1, CCL2, TLR4, NLRP3, SERT, TPH1, IDO.
Timepoint [1] 338836 0
Maternal blood collected = Antenatal (~32 weeks)
Infant and cord blood collected = At birth and postnatal (during heel-prick)
Saliva collected = Postnatal (2-3 days post-birth)
Placental biopsies = At birth
All of these samples will be analysed at a later date. Inflammatory markers assessed as a composite primary outcome.
Primary outcome [2] 338845 0
Presence of inflammatory gut microbiota. Samples assessed as a composite primary outcome.
Timepoint [2] 338845 0
Maternal stool = antenatal (~32 weeks gestation)
Infant stool = Postnatal (2-3 days post-birth), 3-months postnatal
Samples analysed at a later date.
Secondary outcome [1] 437662 0
Frequency of abnormal scores on neuro-behavioural assessment (GMA)
Timepoint [1] 437662 0
3-months postnatal
Secondary outcome [2] 437663 0
Mean brain volume and frequency of abnormalities in white and grey matter structure. This will be assessed as a composite outcome.
Timepoint [2] 437663 0
Within first 2 weeks of birth
Secondary outcome [3] 437664 0
Rate of physical growth
Timepoint [3] 437664 0
Birth weight, length and head circumference measured at birth, at weekly medical appointments 1-8 weeks post-birth, and 3-months.
Secondary outcome [4] 438195 0
Cognitive, emotion and motor development at 3 months
Timepoint [4] 438195 0
3-months = GMA video to be submitted by participant

Eligibility
Key inclusion criteria
Opioid-using mothers-
1) 18-35 yrs, healthy weight (BMI 25-29.9; Australian Institute of Health and Welfare, 2023)
2) Singleton pregnancy
3) Willingness and ability to give written informed consent prior to birth
4) Willingness to participate in and comply with the study
5) Use of opiates (heroin, methadone, buprenorphine, codeine, oxycodone, fentanyl, tramadol, pethidine) during pregnancy as confirmed via self-report and/or maternal and neonatal urine toxicology

Non opioid-using mothers-
1-4 as above
5) No use of substances (e.g. opiates) during pregnancy as confirmed via self-report and/or maternal and neonatal urine toxicology

Infant-
1) Born at >39-41 weeks of gestation (or, if gestation unknown, an estimated birthweight of greater than or equal to 2.5 kg)
Minimum age
0 Years
Maximum age
35 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Maternal-
HIV positive status, diabetes
Complications with pregnancy (e.g. gestational diabetes, pre-eclampsia, chorioamnionitis)
Chromosomal, inflammatory or autoimmune disorders with or without medication
Use of any anti-inflammatory or steroid medications
Consent unable to be obtained before birth (e.g., insufficient time, precipitous labour, cognitive impairment, inebriation)
Patients with a history of a psychological illness or condition such as to interfere with the patient's ability to understand the requirements of the study

Infant-
Non-vigorous status at birth
Major congenital or chromosomal anomalies
Auto-immune or infectious diseases
Admission to NICU or requiring ventilatory support

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation randomised on RedCap server by project manager.
Allocation only revealed to CPI and project manager.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by Excel
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Other
Other design features
Opioid-using mothers randomly allocated to umbilical-cord milking (UCM) or standard cord clamping (SCC) conditions. Simple randomisation via RedCap secure platform using a randomisation table created by Excel.
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
30/08/2024
Actual
Date of last participant enrolment
Anticipated
30/08/2025
Actual
Date of last data collection
Anticipated
30/11/2025
Actual
Sample size
Target
96
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 26812 0
Liverpool Hospital - Liverpool
Recruitment postcode(s) [1] 42863 0
2170 - Liverpool

Funding & Sponsors
Funding source category [1] 316983 0
Charities/Societies/Foundations
Name [1] 316983 0
The Ross Trust Foundation
Country [1] 316983 0
Australia
Primary sponsor type
Individual
Name
Dr Ju Lee Oei
Address
Country
Australia
Secondary sponsor category [1] 319233 0
None
Name [1] 319233 0
Address [1] 319233 0
Country [1] 319233 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 315737 0
South Western Sydney Local Health District Human Research Ethics Committee
Ethics committee address [1] 315737 0
https://www.swslhd.health.nsw.gov.au/ethics/
Ethics committee country [1] 315737 0
Australia
Date submitted for ethics approval [1] 315737 0
02/10/2023
Approval date [1] 315737 0
20/12/2023
Ethics approval number [1] 315737 0
2023/ETH02217

Summary
Brief summary
The CUTE Project seeks to determine whether prenatal opioid exposure increases inflammation in neonates. The CUTE Project also seeks to determine whether umbilical cord milking (UCM) reduces inflammation in infants with prenatal opioid exposure, and whether it improves their postnatal developmental outcomes. UCM involves supplying the baby with the blood from their umbilical cord. 48 pregnant women will be recruited: 32 with histories of opioid use during pregnancy, and 16 without. At birth, half the opioid-exposed babies will be randomly assigned to receive UCM. Placenta, blood and saliva samples from all babies, and blood samples from all mothers, will be collected to assess immune functioning. Maternal and infant stool samples will also be collected to assess gut health. Urine from mothers and infants, and meconium, will be collected for toxicology analyses. Brain development will be measured through MRI scans of exposed babies, and behavioural testing of all babies.

Compared to non-drug exposed controls, we hypothesise prenatal opioid exposure (POE) will be associated with systemic inflammation evident as increased proinflammatory markers in mother and infant blood and saliva. We hypothesise that both mother and infant with show evidence of gut dysbiosis. We hypothesise that infants with POE will have reduced brain volume and white matter density, and poorer cognitive, emotion and motor development at 3 months of age. Finally, we hypothesise that these measures will be inter-related, where infants with greater evidence of inflammation will have poorer outcomes on the MRI and 3-month follow-up. We hypothesise that UCM will reduce evidence of inflammation in the days following birth and that this will be related to improved outcomes at 3-month follow-up.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 135654 0
Dr Ju Lee Oei
Address 135654 0
Department of Newborn Care Royal Hospital for Women Level 1 Barker Street Randwick NSW 2031
Country 135654 0
Australia
Phone 135654 0
+61 409228005
Fax 135654 0
Email 135654 0
[email protected]
Contact person for public queries
Name 135655 0
Ju Lee Oei
Address 135655 0
Department of Newborn Care Royal Hospital for Women Level 1 Barker Street Randwick NSW 2031
Country 135655 0
Australia
Phone 135655 0
+61 409228005
Fax 135655 0
Email 135655 0
[email protected]
Contact person for scientific queries
Name 135656 0
Ju Lee Oei
Address 135656 0
Department of Newborn Care Royal Hospital for Women Level 1 Barker Street Randwick NSW 2031
Country 135656 0
Australia
Phone 135656 0
+61 409228005
Fax 135656 0
Email 135656 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?




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.