Probiotics and the Neurodevelopment in the Premature Infant <32 Weeks Gestational Age and <1500g

Study Overview
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Brief Summary
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Unicentric, quasi-experimental, cohort study to evaluate the effect of combining two probiotics (Bifidobacterium bifidum NCDO 2203 and Lactobacillus acidophilus NCDO 1748) in the neurodevelopment of preterm neonates below 32 weeks' gestation and a birthweight under 1,500 g. This probiotic combination has shown to be safe and beneficial in premature neonates in the prevention of NEC. The investigators hypothesised that this mixture would contribute to better neurodevelopmental outcomes of preterm neonates when assessed at 24 months corrected age. Additionally, neurodevelopment improved would be more relevant at 6 years of age, together with a better pattern of neuronal plasticity biomarkers. Secondarily, this mixture of probiotics could reduce NEC, LOS, intraventricular haemorrhage and neonatal mortality in accordance with previous studies.

Official Title
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Probiotics and the Neurodevelopment in the Premature Infant <32 Weeks Gestational Age and <1500g

Conditions
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Infant, Newborn, Diseases, Infant Development

Intervention / Treatment
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* Dietary Supplement: Infloran® -Berne, Switzerland- (Bifidobacterium bifidum NCDO 2203 and Lactobacillus acidophilus NCDO 1748


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Premature infants under 32 weeks gestational age and less than 1500g birthweight. Born at BCNatal Hospital Clínic between years 2014-2019. Exclusion Criteria: All neonates presenting with suspected congenital anomalies, inborn errors of metabolism, or genetic defects were excluded. Infants with a suspected syndrome, or who have suffered events beyond the neonatal period, not related to prematurity, that could entail impairment in neurodevelopment (severe cranioencephalic trauma, oncological process, meningitis, or exposure to toxic substances)

Ages Eligible for Study
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Maximum Age: 32 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: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Sequential study with consecutive recruitment with a washout period of 12 months between groups
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bifidobacterium bifidum NCDO 2203 and Lactobacillus acidophilus NCDO 1748<br>Daily dose of 6x109 UFC Infloran® -Berne, Switzerland- (Bifidobacterium bifidum NCDO 2203 and Lactobacillus acidophilus NCDO 1748) from 7 days of life until reaching a postmenstrual age of 34 weeks or discharge | Dietary Supplement: Infloran® -Berne, Switzerland- (Bifidobacterium bifidum NCDO 2203 and Lactobacillus acidophilus NCDO 1748<br> <br> |
| No Intervention: Control<br>Untreated control group | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Degree of neurodevelopment at 24 months corrected age | Normal neurodevelopment will be considered when no muscle tone changes, no impaired fine or gross motor coordination, Bayley scale score between above 84, no behaviour disorders or visual disability. | 24 months | 
| Degree of neurodevelopment at 24 months corrected age | Mild impairment will be considered if any of the following: muscle tone changes, impaired fine or gross motor coordination, Bayley scale score between 71-84, moderate behaviour disorders or mild visual disability. | 24 months | 
| Degree of neurodevelopment at 24 months corrected age | Moderate impairment will be diagnosed when suffering from any of the following: spastic diplegia, hemiplegia, seizures (non-febrile), Bayley scores between 50-70, severe behaviour disorders, moderate visual disability or mild-moderate hypoacusis. | 24 months | 
| Degree of neurodevelopment at 24 months corrected age | Severe impairment will be attributed to subjects with any of the following: spastic quadriplegia, choreoathetosis, ataxia, Bayley score <50, blindness or severe hypoacusis | 24 months | 
| Degree of neurodevelopment at 6 years of age | Wechsler Intelligence Scale for Children - Fifth edition. Ranges from below 69 to above 130. Scores from 90-109 indicate average, above it indicates above average and below, below average performance. | 6 years | 
| Degree of neurodevelopment at 6 years of age | Child behaviour checklist 6-18 years of age. 113 items about behaviour and social competence scored from 0 absent to 2 occurs often | 6 years | 
| Degree of neurodevelopment at 6 years of age | Behavior Rating Inventory of Executive Function, Second Edition (BRIEF2). Parent/teacher self reporting form. | 6 years | 
| Neuroplasticity biomarkers and intestinal permeability | NeuN, Doublecortin, GFAP, GDNF, Ki67, Nrf2, BDNF, NGF, neurotrophin-1 (NT-1), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), DYRK1A, HIF1α, S100B i GSK3B. IL1B, IL6, IL8, IL10, IL12, TNF- α | 6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of necrotising enterocolitis | cases fulfilling the stage II or above of the modified Bell's Criteria | 40 weeks | 
| Mortality | Proportion of dead participants before discharge | 40 weeks | 
| Incidence of late onset sepsis | positive blood culture beyond 72 hours of life | 40 weeks | 
| Incidence of Intraventricular haemorrhage | Grade I-IV | 40 weeks | 
| Intensive care length of stay | Days of intensive care | 40 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prematurity, Probiotics, Bifidobacterium bifidum, Lactobacillus acidophilus, Neurodevelopment, Late-onset sepsis