Brain Probiotic and LC-PUFA Intervention for Optimum Early Life
- Conditions
- Child DevelopmentHealth BehaviorMaternal ExposureInfant Development
- Interventions
- Dietary Supplement: Placebo probiotics and control LC-PUFA (120 mg DHA)Dietary Supplement: Probiotics and LC-PUFA (480 mg DHA)Behavioral: Psychosocial stimulation and healthy eating education
- Registration Number
- NCT03851120
- Lead Sponsor
- Indonesia University
- Brief Summary
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.
- 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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- Female
- Target Recruitment
- 314
Each pregnant woman must meet all of the following criteria to be enrolled in this study:
- 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
Each pregnant women meeting any of the following criteria will be excluded from the study:
- 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
- Having history of previous gestational diabetes or been diagnosed to have gestational diabetes
- Having history of type 1 and type 2 diabetes
- Severe anemia
Inclusion Criteria for Follow-up at 24 months:
- Child age above 24 months from the BRAVE intervention project
- 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:
- Child being hospitalized during the study/data collection
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Control Placebo probiotics and control LC-PUFA (120 mg DHA) 150 pregnant women will be given placebo probiotics and 240 mg DHA, psychosocial stimulation, and healthy eating education Intervention Probiotics and LC-PUFA (480 mg DHA) 150 pregnant women will be given Probiotics and 480 mg DHA, psychosocial stimulation, and healthy eating education Intervention Psychosocial stimulation and healthy eating education 150 pregnant women will be given Probiotics and 480 mg DHA, psychosocial stimulation, and healthy eating education Control Psychosocial stimulation and healthy eating education 150 pregnant women will be given placebo probiotics and 240 mg DHA, psychosocial stimulation, and healthy eating education
- Primary Outcome Measures
Name Time Method Total brain volume 1 year measured in parenchymal and cortical regions
Fetal brain development 1 year Myelination index
Child cognitive at 4 months of age 1 year Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III); a higher score indicates better performance
Brain function at 4 months of age 1 year Brainstem Evoked Response Audiometry (BERA)
Eye tracking tasks at 6 months of age 1 year Visual paired comparison memory task and Infant Orienting with Attention task at 4 months of age
Child cognitive at 6 months of age 1 year Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III); a higher score indicates better performance
- Secondary Outcome Measures
Name Time Method Child nutritional status 6 months Change in weight-for-length z score
Quality of interaction with parents 1 year Maternal involvement using HOME inventory questionnaires
Maternal blood micronutrient & macronutrient status 1 year Zinc, iron, folate, omega-3 blood level
Maternal History of COVID-19 during follow-up 2 years Frequency of COVID-19 case during the follow-up period
Birth weight 4 month Baby weighing scale
Child's Growth 6 months Change in weight-for-age z-score
Mother Body weight 1 year Mother's body weight
Incidence of gestational diabetes 1 year Based on blood glucose assessment
Mother depression scale 1 year Mother's Depression Test; a lower score indicates better performance
Child's linear growth 6 months Change in Length-for-age z-score
Head circumference 25 months Change in Head-circumference-for-age
Mother's dietary quality 1 year actual dietary intake, dietary pattern and quality
Incidence of pre-eclampsia 1 year Diagnosed by physician
Incidence of preterm birth 4 month Gestational age
Maternal fecal microbiota composition 1 year Microbiota composition by S16rRNA analysis
Child fecal microbiota composition 4 months Microbiota composition by S16rRNA analysis
Maternal omega-3 level in breast milk at 4 months of age 1 year Omega-3 level assessment using Gas Chromatography-Mass Spectrometry
Human milk oligosaccharides at 6 months of age 1 year 2-FL HMO assessment in breast milk
Post-partum weight retention 1 year Monthly changes in maternal weight
Maternal weight circumference 1 year Post-partum monthly changes in weight circumference
Maternal glucagon-like peptide-1 (GLP-1) profile 1 year GLP-1 assessment using enzyme-linked immunosorbent assay
Maternal peptide-YY (PYY) profile 1 year PYY assessment using enzyme-linked immunosorbent assay
Mid-Upper Arm Circumference 25 months Change in Mid-Upper Arm Circumference
Toddler Height 25 months Toddler height measurement
Mother Fat Percentage 1 year Mother's fat percentage
Maternal fecal short chain fatty acids (SCFAs) 1 year SCFAs analysis using Gas Chromatography-Mass Spectrometry
Child fecal short chain fatty acids 1 year SCFAs analysis using Gas Chromatography-Mass Spectrometry
Gestational weight gain 1 year Changes in maternal height throughout pregnancy period
Toddler Body Weight 25 months Toddler weighing scale
Maternal Occurrence of COVID-19 during intervention period 1 year Frequency of COVID-19 case during the intervention period
Mother Depression Test 1 year Mother depression score
Mother Quality of Life 1 year Mother quality of life score
Child cognitive at 25-28 months of age 1 year Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III); a higher score indicates better performance
Mother Height 1 year Mother's height
Eye tracking tasks at 25-28 months of age 1 year Visual paired comparison memory task and Infant Orienting with Attention task at 24 months of age
Trial Locations
- Locations (1)
Human Nutrition Research Center, Indonesian Medical Education Research Institute; and Department of Nutrition, Faculty of Medicine, Universitas Indonesia
🇮🇩Jakarta Pusat, DKI Jakarta, Indonesia