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

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.

Study Overview

• Status: Withdrawn
• Conditions: Very Low Birth Weight Infants
• Intervention / Treatment: Other: Mixture probiotics; Other: Placebo

Detailed Description

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.

• Study Type: Interventional
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Taiwan
  • Taichung, Taiwan, 404
    • Department of Pediatrics, Children Hospital, China Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Mixture probiotics; 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; The mixture probiotics capsule
Placebo Comparator: Placebo; Taking 1 placebo capsule for up to 4 months after birth.	Other: Placebo; The placebo contains the same excipient ingredients but without the live bacteria.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: China Medical University Hospital

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): June 14, 2018
• Primary Completion (Anticipated): June 30, 2020
• Study Completion (Anticipated): June 30, 2021

Study Registration Dates

• First Submitted: February 27, 2019
• First Submitted That Met QC Criteria: February 27, 2019
• First Posted (Actual): March 1, 2019

Study Record Updates

• Last Update Posted (Actual): March 21, 2022
• Last Update Submitted That Met QC Criteria: March 7, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: probiotics; very low birth weight infants; autism spectrum disorder (ASD); neuropsychiatric disorder; attention deficit and hyperactivity disorder (ADHD)
• Additional Relevant MeSH Terms: Body Weight; Birth Weight
• Other Study ID Numbers: CMUH106-REC2-102

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data for all primary and secondary outcome measures will be made available.
• IPD Sharing Time Frame: Data will be available within 6 months of study completion.
• IPD Sharing Access Criteria: Data access requests will be reviewed by an external Independent Review Panel. Requestors will be required to sign a Data Access Agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

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