Brain Probiotic and LC-PUFA Intervention for Optimum Early Life (BRAVE)

Promotion of Maternal Gut Microbiota and Psychological Stimulation on Child Cognitive Development at 6 Months of Age

Probiotics is suggested to play several roles in promoting health, including alleviating disease symptoms, protection against atopic disease, and modulating the immune system by improving the beneficial gut microbiota colonization. The discovery of the gut microbiota-brain axis suggested that there is a reciprocal influence between the brain and the gut through a constant communication. This bi-directional axis enables signals to be transferred from brain to influence sensory, motor, and secretory modalities of the GI tract, also permits signal from the gut to influence brain function. The establishment of intestinal microbiota during early neurodevelopmental period suggests the colonization and maturation of gut microbiota may influence brain development. Several studies have shown there is an association between shifts in the gut microbiota composition in children with neurodevelopmental disorders. This study aims to investigate how maternal probiotic + LC-PUFA supported with government program supplements, healthy eating, and psychosocial stimulation could affect fetal brain development and later child brain functions and cognitive development. Intervention would be delivered to pregnant women for 9 months, starting at the end of second trimester of gestational period.

Study Overview

• Status: Active, not recruiting
• Conditions: Child Development; Health Behavior; Infant Development; Maternal Exposure
• Intervention / Treatment: Dietary supplement: Probiotics and LC-PUFA (480 mg DHA); Behavioral: Psychosocial stimulation and healthy eating education; Dietary supplement: Placebo probiotics and control LC-PUFA (120 mg DHA)

Detailed Description

Health and well-being at all ages is one of the goal set in the Sustainable Development Goals. Starting as early as possible has been considered to be an effective strategy for better investation in achieving healthy population. Therefore, the prevention and promotion of health and well being is starting to target population at younger age, starting as early as possible. Accordingly, the early life period of individuals has been considered as a critical period, especially in terms of the brain and cognitive development. The phases of brain development starts very early, starting from the fetal development in the uterus. The development process extends from early in the beginning of fetal development and lasted to the end, finishing last. The brain undergoes a period of rapid growth during the last trimester of fetal life and the first 2 years of childhood. Therefore, quality of pregnancy as well as quality of early life is important to the fetal brain development as well as later child brain function and cognitive development. In line with that notion, there are many studies suggesting that gut microbiota could affect CNS development through several ways, i.e. alteration of microbial composition, activation of immune system, changes in signaling via neural pathways, affecting tryptophan metabolism, modulating gut hormonal response and affecting hormonal signaling pathway, and releasing metabolites that could stimulate sympathetic nervous system. In particular, these studies have found bi-directional communication between the brain and the gut microbiota, referred to as the microbiota-gut-brain axis. The animal study showed that the gut microbiota regulates the development and function of the brain. Unfortunately, the study on human was still lacking.

This study is a randomized clinical trial (RCT) and placebo parallel controlled study, followed by a follow-up study at 2 years old. The research will be conducted in eight public hospitals / health care facilities in Indonesia, Jakarta.

In light of COVID-19 outbreak, if face-to-face activities are permitted by (1) national government (Indonesian Ministry of Health), (2) local government (DKI Jakarta), (3) the university, (4) Data Safety Monitoring Board, and (5) by consent of the subject, then the activities need to be strictly adjusted with the COVID-19 prevention measures for both personnel and subjects. All personnel and subjects who will be involved in the activities are required to fill out the COVID-19 symptom screening form prior to the visit.

Some adjustments for the project field implementation have been conducted during the outbreak, including:

1. Following Good Clinical Practice, for the safety of the subjects and all the team members, we are now ensuring that the subjects gain benefits from their involvement in the BRAVE project by implementing routine COVID-19 screening, providing adequate PPE for the fieldworkers, and educating them about the prevention measures.
2. Supplement delivery: Because we could not visit to the houses anymore due to staff restriction regulations, the bottles of the supplement are delivered using online motorcycle taxi services, and this includes the weighing scale for monthly monitoring. We have also developed a protocol to ensure the safety of supplement bottle transfer from the research personnel to the motorcycle taxi driver, and from the driver to the mothers, including safe distancing and disinfection procedures. We will also educate, provide a thermometer for self-temperature screening and provide the disinfectant to the mothers.
3. Outcome assessment: As per March 19, MRI assessment and blood sample collection remained implemented at a non-COVID-19 referral hospital and laboratory, with strict safety procedures for the subjects and personnel. For mothers who do not feel comfortable visiting the hospital/laboratory, they are free to refuse these procedures.
4. Compliance: Online system to promote and assess compliance. To maintain the quality, we cross-check mothers' activities by online assessment, interactive short message service (sms), and phone calls.
5. New Subject Recruitment are less priority right now or potentially stop for the time being until the situation is getting better.

• Study Type: Interventional
• Enrollment (Actual): 314
• Phase: Phase 2

Contacts and Locations

Study Locations

• Indonesia
  • DKI Jakarta
    • Jakarta Pusat, DKI Jakarta, Indonesia, 13420
      • Human Nutrition Research Center, Indonesian Medical Education Research Institute; and Department of Nutrition, Faculty of Medicine, Universitas Indonesia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

Each pregnant woman must meet all of the following criteria to be enrolled in this study:

1. Indonesian pregnant women in the 2nd trimester of gestational period 2. healthy pregnancy (as measured by hemoglobin level, pregnancy status, pregnancy history) 3. Having a normal blood pressure 4. Planning to stay in the study area until the child is 6 months old 5. Willing to sign informed consent 5. Having a legally acceptable representative who is capable to understand the informed consent document and providing consent on the subject's behalf

Exclusion Criteria:

Each pregnant women meeting any of the following criteria will be excluded from the study:

1. Having foreign objects in the body due to trauma, artificial heart value, metal objects or ferromagnetic (plate, screw, clip, prosthetic), and electronic device (pacemaker, cochlear implant, insulin pump), and being claustrophobic
2. Having history of previous gestational diabetes or been diagnosed to have gestational diabetes
3. Having history of type 1 and type 2 diabetes
4. Severe anemia

Inclusion Criteria for Follow-up at 24 months:

1. Child age above 24 months from the BRAVE intervention project
2. Having a legally acceptable representative who is capable to understand the informed consent document and providing consent on the subject's behalf

Exclusion Criteria for Follow-up at 24 months:

1. Child being hospitalized during the study/data collection

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention; 150 pregnant women will be given Probiotics and 480 mg DHA, psychosocial stimulation, and healthy eating education	Dietary supplement: Probiotics and LC-PUFA (480 mg DHA); Probiotics and LC-PUFA (480 mg DHA); Behavioral: Psychosocial stimulation and healthy eating education; Psychosocial stimulation and healthy eating education
Placebo Comparator: Control; 150 pregnant women will be given placebo probiotics and 240 mg DHA, psychosocial stimulation, and healthy eating education	Behavioral: Psychosocial stimulation and healthy eating education; Psychosocial stimulation and healthy eating education; Dietary supplement: Placebo probiotics and control LC-PUFA (120 mg DHA); Placebo probiotics and control LC-PUFA (120 mg DHA)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total brain volume	measured in parenchymal and cortical regions	1 year
Fetal brain development	Myelination index	1 year
Child cognitive at 4 months of age	Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III); a higher score indicates better performance	1 year
Brain function at 4 months of age	Brainstem Evoked Response Audiometry (BERA)	1 year
Eye tracking tasks at 6 months of age	Visual paired comparison memory task and Infant Orienting with Attention task at 4 months of age	1 year
Child cognitive at 6 months of age	Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III); a higher score indicates better performance	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mother depression scale	Mother's Depression Test; a lower score indicates better performance	1 year
Birth weight	Baby weighing scale	4 month
Child's Growth	Change in weight-for-age z-score	6 months
Child's linear growth	Change in Length-for-age z-score	6 months
Head circumference	Change in Head-circumference-for-age	6 months
Child nutritional status	Change in weight-for-length z score	6 months
Quality of interaction with parents	Maternal involvement using HOME inventory questionnaires	1 year
Maternal blood micronutrient & macronutrient status	Zinc, iron, folate, omega-3 blood level	1 year
Incidence of gestational diabetes	Based on blood glucose assessment	1 year
Incidence of pre-eclampsia	Diagnosed by physician	1 year
Incidence of preterm birth	Gestational age	4 month
Mother's dietary quality	actual dietary intake, dietary pattern and quality	1 year
Maternal fecal microbiota composition	Microbiota composition by S16rRNA analysis	1 year
Child fecal microbiota composition	Microbiota composition by S16rRNA analysis	4 months
Maternal omega-3 level in breast milk at 4 months of age	Omega-3 level assessment using Gas Chromatography-Mass Spectrometry	1 year
Human milk oligosaccharides at 6 months of age	2-FL HMO assessment in breast milk	1 year
Maternal glucagon-like peptide-1 (GLP-1) profile	GLP-1 assessment using enzyme-linked immunosorbent assay	1 year
Maternal peptide-YY (PYY) profile	PYY assessment using enzyme-linked immunosorbent assay	1 year
Maternal fecal short chain fatty acids (SCFAs)	SCFAs analysis using Gas Chromatography-Mass Spectrometry	1 year
Child fecal short chain fatty acids	SCFAs analysis using Gas Chromatography-Mass Spectrometry	1 year
Post-partum weight retention	Monthly changes in maternal weight	1 year
Maternal weight circumference	Post-partum monthly changes in weight circumference	1 year
Gestational weight gain	Changes in maternal height throughout pregnancy period	1 year
Head circumference	Change in Head-circumference-for-age	25 months
Mid-Upper Arm Circumference	Change in Mid-Upper Arm Circumference	25 months
Toddler Body Weight	Toddler weighing scale	25 months
Toddler Height	Toddler height measurement	25 months
Mother Body weight	Mother's body weight	1 year
Mother Depression Test	Mother depression score	1 year
Mother Quality of Life	Mother quality of life score	1 year
Maternal History of COVID-19 during follow-up	Frequency of COVID-19 case during the follow-up period	2 years
Maternal Occurrence of COVID-19 during intervention period	Frequency of COVID-19 case during the intervention period	1 year
Child cognitive at 25-28 months of age	Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III); a higher score indicates better performance	1 year
Eye tracking tasks at 25-28 months of age	Visual paired comparison memory task and Infant Orienting with Attention task at 24 months of age	1 year
Mother Height	Mother's height	1 year
Mother Fat Percentage	Mother's fat percentage	1 year

Collaborators and Investigators

• Sponsor: Indonesia University
• Collaborators: Grand Challenges Canada

Publications and helpful links

General Publications

• Sheridan PO, Bindels LB, Saulnier DM, Reid G, Nova E, Holmgren K, O'Toole PW, Bunn J, Delzenne N, Scott KP. Can prebiotics and probiotics improve therapeutic outcomes for undernourished individuals? Gut Microbes. 2014 Jan-Feb;5(1):74-82. doi: 10.4161/gmic.27252. Epub 2013 Dec 16.
• Sharon G, Sampson TR, Geschwind DH, Mazmanian SK. The Central Nervous System and the Gut Microbiome. Cell. 2016 Nov 3;167(4):915-932. doi: 10.1016/j.cell.2016.10.027.
• Naaktgeboren, C. Effect of maternal probiotic exposure during pregnancy and lactation on the mother and infant. International Journal of Probiotics and Prebiotics 5: 113-124, 2010
• Ramakrishnan, U. A review of the benefits of nutrients supplements during pregnancy: from iron -folic-acid to long-chain polyunsaturated fatty acids to probiotics. Annales Nestle (English Ed): 29-40, 2010

Study record dates

Study Major Dates

• Study Start (Actual): October 31, 2019
• Primary Completion (Anticipated): August 31, 2022
• Study Completion (Anticipated): August 31, 2024

Study Registration Dates

• First Submitted: February 19, 2019
• First Submitted That Met QC Criteria: February 20, 2019
• First Posted (Actual): February 22, 2019

Study Record Updates

• Last Update Posted (Actual): July 7, 2022
• Last Update Submitted That Met QC Criteria: July 4, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Other Study ID Numbers: BRAVE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No