Efficacy of Multiple Strain Probiotics Reduces the Neurobehavioral Disorder in Premature Very Low Birth Weight Infants

Study Overview
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Brief Summary
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The management protocols, clinical practices, equipment, infrastructure, and key personnel in NICU are unchanged during the study period. The data collected by each center are transmitted to the office of the principal investigator (Dr Lin) at China Medical University Hospital. Primary outcome is death or attention deficit and hyperactivity disorder (ADHD) and ASD.

Detailed Description
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Over the years, preterm very low birth weight (PVLBW) infants (<32 weeks gestation) have better survival rates and improved outcomes. Nonetheless, It is of concern that there are increased risk of psychiatric problems reported in PVLBW infants, 11.5% to 31% of them are reported to be at increased risk of attention deficit and hyperactivity disorder (ADHD) and 25 % of them would develop autism spectrum disorder (ASD). Many VLBWs experience rapid vaginal or Caesarean births that increased relative risk of developing ASD and possibly ADHD when compared to vaginal delivery. Further, PVLBW infants often experience delays in enteral feeding, and many receive little or no mother's own milk, use of antibiotics, invasive procedures and maternal separation can contribute to dysbiosis and dysbiosis in early life may prone to develop ASD and ADHD There is growing body of evidence demonstrates that gut microbiota is involved in communication, and may impact brain development and modulate behavior. Evidences have showed that there were increased intestinal permeability, altered gut microbiota and activity in autism and ADHD. Studies have demonstrated that early postnatal phase of microbial development is a primer for future health. Giving all the evidence, it is reasonable to speculate that probiotics could reduce the ASD and ADHD in preterm VLBW infants. From Aug 1, 2017 to June 30, 2020, a prospective, double blind, randomized, controlled trial will be conducted in five NICUs at Taiwan. The study protocol will be approved by the institutional review board of each hospital. Preterm infants ≧ 23 weeks and ≦ 32 weeks gestational age and birth weight below 1500 gm and who survive to NICU are eligible for the trial. They will be assigned randomly to either group A: multiple strian probiotics or group B: control group received 1 mL of a 5% glucose solution. Study is continuous until preterm infants grow up to 4 months postnatal age. The management protocols, clinical practices, equipment, infrastructure, and key personnel in NICU are unchanged during the study period. The data collected by each center are transmitted to the office of the principal investigator (Dr Lin) at China Medical University Hospital. Primary outcome is death or attention deficit and hyperactivity disorder (ADHD) and ASD. Mortality is defined as death prior to discharge. Secondary outcomes are NEC ≧ stage 2, sepsis, severe (grade 3-4) IVH, BPD, alteration of liver function, and adverse effects or intolerance and neurodevelopment impairment. Objection of the first two years is to enroll cases, ASD and ADHD will be assessed by two independent neurologists at third year of life; no examiner is aware of treatment assigned to any infant.

Official Title
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Efficacy of Multiple Strain Probiotics Reduces the Neurobehavioral Disorder in Premature Very Low Birth Weight Infants

Conditions
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Very Low Birth Weight Infants

Intervention / Treatment
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* Other: Mixture probiotics
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Preterm infants ≧ 23 weeks and ≦ 32 weeks gestational age. Birth weight below 1500 gm and who survive to NICU. Exclusion Criteria: Severe asphyxia (stage III) Fetal chromosomal anomalies Cyanotic congenital heart disease Congenital intestinal atresia Gastroschisis Omphalocele Active upper gastric intestinal bleeding Lacking/refused of parental consent Early onset sepsis (before the third day of life) Liver failure (aspartate aminotransferase, alanine aminotransferase, glutamyl transferase, direct bilirubin serum values 3-fold higher than reference range) Fasted for >3 weeks.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mixture probiotics<br>The probiotic contain 1 ×10^9 CFU/1 capsule of mixture probiotics, taking 1 probiotic capsule for up to 4 months after birth. | Other: Mixture probiotics<br>* The mixture probiotics capsule<br>|
| Placebo Comparator: Placebo<br>Taking 1 placebo capsule for up to 4 months after birth. | Other: Placebo<br>* The placebo contains the same excipient ingredients but without the live bacteria.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence rate of death or ADHD and ASD |  | Two years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence rate of NEC ≧ stage 2, sepsis, severe (grade 3-4) IVH, BPD, liver function and adverse effects or intolerance and neurodevelopment impairment. |  | Two years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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probiotics, neuropsychiatric disorder, very low birth weight infants, attention deficit and hyperactivity disorder (ADHD), autism spectrum disorder (ASD)