Preventive Effect of Perinatal Oral Probiotic Supplementation (POPS) on Neonatal Jaundice

Study Overview
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Brief Summary
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This is a randomized double-blind placebo-controlled parallel group superiority clinical trial among 94 pregnant women (47 in each group) to investigate the effect of maternal perinatal probiotic supplementation on neonatal jaundice, breast milk microbiome, maternal stool, and infant fecal microbiome. Vivomixx®-probiotic product will be used as treatment and placebo as a control.

Detailed Description
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Neonatal jaundice is a yellowish discoloration of the skin and sclera because of over-concentration of circulating unconjugated bilirubin (hyperbilirubinemia) in the body. It can lead the baby to severe complications including death. Intestinal flora modulation by probiotics administration to the mother may tackle this problem. Therefore, investigators designed a randomized double-blind placebo-controlled parallel group superiority clinical trial among 94 pregnant women (47 in each group). Eligible pregnant women will be recruited voluntarily at 28-36 weeks of gestation and allocated randomly to either the probiotic group (Vivomixx®) or placebo group (maltose-containing unit) which are phenotypically similar. Participants will take one sachet of the product per day starting from 36 weeks of gestation until the end of first week of postpartum. Biological samples (maternal stool, breast milk, and neonatal faeces) will be collected at different time points. Additionally, neonatal transcutaneous bilirubin will be measured on the second and seventh day of life using a Drager Meter (a transcutaneous bilirubinometer). The microbial DNA will be extracted from biological samples using commercial kits and metagenomics sequencing will be employed and will be correlated with bilirubin level using appropriate statistical methods. This study will be conducted based on the Helsinki Declaration and International Council for Harmonization Requirements for Pharmaceuticals for Human Use (ICH) Guideline for Good Clinical Practice (GCP) standards. Ethical approval is obtained from the Joint Chinese University of Hong Kong and New Territories East Cluster (CUHK-NTEC) Clinical Research Ethics Committee, Hong Kong with reference number: 2023.100-T. Written informed consent will be obtained from each participant during enrolment.

Official Title
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Preventive Effect of Perinatal Oral Probiotic Supplementation (POPS) on Neonatal Jaundice: A Randomized Double-Blind Placebo-Controlled Parallel-Group Superiority Clinical Trial

Conditions
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Neonatal Jaundice, Microtia, Pregnancy Related

Intervention / Treatment
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* Dietary Supplement: Vivomixx®
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All pregnant women aged 18-45 years old. Gestational age of 28-34 weeks Normal singleton pregnancy Exclusion Criteria: Foetal abnormality Mothers with antibiotic medication during the allocation Couples with glucose 6-phosphate dehydrogenase enzyme deficiency Couples with known rhesus or haemolytic disease history Plan of place of birth at other hospitals other than Prince of Wales Hospital known breast disorder or any contraindication for breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Probiotics<br>Vivomixx® is a multi-strain probiotics product. | Dietary Supplement: Vivomixx®<br>* The probiotic group participants will receive 1 sachet of probiotic product daily from 36weeks of gestation up to 7th day of postpartum while placebo groups will 1 sachet placebo prepared with the same colour, taste, and packaging with Vivomixx® daily for the same duration of probiotic groups. Vivomixx® is a non-genetically modified (GMO), gluten-free, high potency microbiotic food supplement, containing eight strains (Streptococcus thermophilus DSM24731® / NCIMB 30438, Bifidobacterium breve DSM24732® / NCIMB 30441, Bifidobacterium longum DSM24736® / NCIMB 30435, Bifidobacterium infantis DSM24737® / NCIMB 30436*, Lactobacillus acidophilus DSM24735® / NCIMB 30442, Lactobacillus plantarum DSM24730® / NCIMB 30437, Lactobacillus paracasei DSM24733® / NCIMB 30439, Lactobacillus delbrueckii subsp. bulgaricus DSM24734® / NCIMB 30440) of live bacteria (450 billion bacteria per sachet).<br>|
| Placebo Comparator: Placebo<br>Maltose-containing placebo product | Dietary Supplement: Placebo<br>* A maltose- containing product with a similar phenotype with Vivomixx®.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neonatal Jaundice | Investigators will measure the transcutaneous bilirubin level on the second and seventh day of life and plot the record on the nomograph. The record above the 95th percentile will be taken as considerable jaundice and then the physician in charge will declare the diagnosis by clinical evaluation and total serum bilirubin measurement if needed. The outcome will be classified as jaundiced or non-jaundice. | 1 week since birth | 
| Transcutaneous bilirubin level | Infant's skin bilirubin level on the chest measured using a non-invasive devise called Drager meter. It will be measured in milligram per decilitre. | 1 week of life (after birth) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Preterm birth | This will be measured using the gestational age at birth | within two days of birth | 
| Number of participants with Initiation of labor | Spontaneous initiation of induction of labour | within two days of birth | 
| Mode of birth checklist | Spontaneous vaginal delivery, assisted birth or cesarean section | within two days of birth | 
| Birth weight | Weight of the baby at birth in grams | within two days of birth | 
| Apgar scores | First and fifth-minute Apgar scores of babies | within two days of birth | 
| Breast milk microbiome profile | Breast milk samples will be collected, bacterial DNA collected and meta-genomic sequencing will be carried out. | From birth seventh day of postpartum | 
| Stool microbiome profile | maternal and infant stool samples will be collected, bacterial DNA collected and meta-genomic sequencing will be carried out. | From birth seventh day of postpartum |