Prophylactic Probiotics to Extremely Low Birth Weight Prematures

Study Overview
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Brief Summary
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Mortality and incidence of severe complications is still high among extremely premature infants. Common causes of severe complications in this population are poor nutrition, necrotizing enterocolitis, and severe infections. Feeding intolerance is also a common problem resulting in prolonged need for intravenous lines and poor nutrition. The aim of the study is to evaluate whether supplementation with the probiotic bacterium Lactobacillus reuteri DSM 17938 daily to premature infants with extremely low birth weight increases feeding tolerance to breast milk and thereby improves nutrition, increases growth and reduces serious complications and mortality in this population. Beyond this, possible mechanisms underlying these effects will be analyzed in stool, breast milk and blood samples.

Detailed Description
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RATIONALE Mortality and incidence of severe complications is still high among extremely premature infants. Common causes of severe complications in this population are poor nutrition, necrotizing enterocolitis (NEC), and severe infections. Feeding intolerance is also a common problem resulting in prolonged need for intravenous lines and poor nutrition. There is scientific evidence that dietary supplements with probiotics may have an effect on these manifestations. Lactobacillus reuteri is a well studied probiotic bacterium that has been tested in several clinical studies in premature infants and older children, and the results of these studies and animal studies suggest that this bacterium may also have an effect on growth and mortality in extremely premature infants. Lactobacillus reuteri reduces colonization with pathogenic microbes, stimulates gastric and intestinal motility and shortens hospital stay in moderately premature infants. In animal models, L. reuteri also induces anti-inflammatory immune responses, reduces the symptoms of inflammatory bowel disease and the incidence of NEC. Administration of L. reuteri also improves the intestinal barrier both in human studies in children and in animal studies. Dietary supplements of L. reuteri to extremely premature infants may therefore improve feeding tolerance and nutrition and reduce the incidence of severe complications in this population. HYPOTHESIS Premature infants with extremely low birth weight receiving daily supplements of Lactobacillus reuteri DSM 17938 will reach full enteral feeding faster compared with children receiving placebo. STUDY DESIGN This study will be conducted as a prospective multi-center double blind placebo-controlled study in neonatal intensive care units in Sweden. In total 134 neonates with extremely low birth weight (<1000g) and gestational age <28+0 weeks will be randomized to receive either dietary supplements of Lactobacillus reuteri or placebo. Study product will be identical to the active and placebo group besides the addition of Lactobacillus reuteri (1.25 x 100 million bacteria=0.2 ml oil drops per day) in the active group. The supplementation will commence within 1-3 days after birth and will be given daily until gestational week 36+0. The infants will be followed until gestational week 36+0 and data on feeding tolerance, nutrition, growth, infections, NEC, bronchopulmonary dysplasia, death, and potential confounders will be entered in an individual study protocol. Stool, breast milk, and blood samples will be collected for analyses of possible underlying mechanisms. A 2-year follow up including examination by pediatrician, growth parameters, questionnaire and psychology testing (Bayley´s test) will be performed.

Official Title
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Prophylactic Probiotics to Extremely Low Birth Weight Prematures

Conditions
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Feeding; Difficult, Newborn, Growth Failure, Necrotizing Enterocolitis, Sepsis

Intervention / Treatment
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* Dietary Supplement: Lactobacillus reuteri
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Birth weight < 1000 g Gestational age: v23+0-V27 +6. Age < 72 hours at inclusion. Signed informed consent by parents. Exclusion Criteria: Fatal or complex congenital malformation at inclusion time. Chromosomal defect at inclusion time. No realistic hope of survival at inclusion time. Gastrointestinal malformation at inclusion time. Participation in another study which aims to influence nutrition, growth, feeding tolerance or necrotizing enterocolitis.

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 3 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Lactobacillus reuteri<br>Lactobacillus reuteri DSM 17938, 125 million bacteria/day | Dietary Supplement: Lactobacillus reuteri<br>* Oil drops with Lactobacillus reuteri DSM 17938, 125 million bacteria=0.2 ml per day<br>|
| Placebo Comparator: Placebo<br>The same oil drops as the active study product but without Lactobacillus reuteri | Dietary Supplement: Placebo<br>* Oil drops without Lactobacillus reuteri<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Establish Full Enteral Feeds | The age of the infants in days when the infant receive 150 ml/kg/day via enteral feeding for the first time. | Birth to gestational week 36+0 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Days With Halted Feeding Due to Food Intolerance | Episode with food intolerance. Retention volume> food volume given the last 2 hours (retention checked routinely every 4 hours) and/or clinical signs consistent with necrotizing enterocolitis (reduced general condition and inflated abdomen). The number of such events will also be indicated. | Birth to gestational week 36 | 
| Number of Stools |  | Recorded over the first four weeks | 
| Time Until Birth Weight is Regained. Specifies the Number of Full Days the Child Has Lived. | Specifies the number of full days the child has lived. | Birth to gw 36+0 | 
| Weight Gain (SD) | In this analysis, the difference in standard deviation score (delta z-scores) for weight, height and head circumference at birth and 14 and 28 days and gestational week 36+0 will be calculated. At gestational week 36+0 also absolute values will be analyzed. A positive delta z-score indicates faster growth than the growth chart would predict. | At 14th day of life | 
| Mortality |  | Birth to gw 36+0 | 
| Necrotizing Enterocolitis | Bell´s criteria II-III | Birth to gw 36+0 | 
| Sepsis | Blood culture positive sepsis | Birth to gw 36+0 | 
| Bronchopulmonary Dysplasia | Need of oxygen or CPAP/ventilator at gw 36+0 | Gw 36+0 | 
| Weight Gain (SD) | In this analysis, the difference in standard deviation score (delta z-scores) for weight, height and head circumference at birth and 14 and 28 days and gestational week 36+0 will be calculated. At gestational week 36+0 also absolute values will be analyzed. A positive delta z-score indicates faster growth than the growth chart would predict. | At 28th day of life | 
| Weight Gain (SD) | In this analysis, the difference in standard deviation score (delta z-scores) for weight, height and head circumference at birth and 14 and 28 days and gestational week 36+0 will be calculated. At gestational week 36+0 also absolute values will be analyzed. A positive delta z-score indicates faster growth than the growth chart would predict. | At gestational week 36+0 | 
| Length Gain (SD) | In this analysis, the difference in standard deviation score (delta z-scores) for weight, height and head circumference at birth and 14 and 28 days and gestational week 36+0 will be calculated. At gestational week 36+0 also absolute values will be analyzed. A positive delta z-score indicates faster growth than the growth chart would predict. | At 14th day of life | 
| Length Gain (SD) | In this analysis, the difference in standard deviation score (delta z-scores) for weight, height and head circumference at birth and 14 and 28 days and gestational week 36+0 will be calculated. At gestational week 36+0 also absolute values will be analyzed. A positive delta z-score indicates faster growth than the growth chart would predict. | At 28th day of life | 
| Length Gain (SD) | In this analysis, the difference in standard deviation score (delta z-scores) for weight, height and head circumference at birth and 14 and 28 days and gestational week 36+0 will be calculated. At gestational week 36+0 also absolute values will be analyzed. A positive delta z-score indicates faster growth than the growth chart would predict. | At gestational week 36+0 | 
| Head Circumference Growth (SD) | In this analysis, the difference in standard deviation score (delta z-scores) for weight, height and head circumference at birth and 14 and 28 days and gestational week 36+0 will be calculated. At gestational week 36+0 also absolute values will be analyzed. A positive delta z-score indicates faster growth than the growth chart would predict. | At 14th day of life | 
| Head Circumference Growth (SD) | In this analysis, the difference in standard deviation score (delta z-scores) for weight, height and head circumference at birth and 14 and 28 days and gestational week 36+0 will be calculated. At gestational week 36+0 also absolute values will be analyzed. A positive delta z-score indicates faster growth than the growth chart would predict. | At 28th day of life | 
| Head Circumference Growth (SD) | In this analysis, the difference in standard deviation score (delta z-scores) for weight, height and head circumference at birth and 14 and 28 days and gestational week 36+0 will be calculated. At gestational week 36+0 also absolute values will be analyzed. A positive delta z-score indicates faster growth than the growth chart would predict. | At gestational week 36+0 | 
| Neurological Development | Bayleys´s test by psychologist | At 2 years corrected age | 
| Neurological Development Impairment | A composite of several outcomes: impaired cognition at the Bayleys´test, cerebral palsy, blindness and deafness, divided into normal, mild, moderate and severe. Mild -1SD to -2SD, Moderate <-2D to 3 SD and Severe <3SD | At 2 years corrected age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Probiotics, Lactobacillus reuteri, Prematures, Enteral feeding, Motility, Necrotizing enterocolitis, Sepsis, Weight