Feeding; Difficult, Newborn, Growth Failure, Necrotizing Enterocolitis, Sepsis
Conditions
Keywords
Probiotics, Lactobacillus reuteri, Prematures, Enteral feeding, Motility, Necrotizing enterocolitis, Sepsis, Weight
Brief summary
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
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.
Interventions
DIETARY_SUPPLEMENTLactobacillus reuteri
Oil drops with Lactobacillus reuteri DSM 17938, 125 million bacteria=0.2 ml per day
DIETARY_SUPPLEMENTPlacebo
Oil drops without Lactobacillus reuteri
Sponsors
BioGaia AB
Ekhaga Foundation, Sweden
Medical Research Council of Southeast Sweden
University Hospital, Linkoeping
The Swedish Research Council
The Swedish Society of Medicine
Ostergotland County Council, Sweden
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
1 Days to 3 Days
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Establish Full Enteral Feeds | Birth to gestational week 36+0 | The age of the infants in days when the infant receive 150 ml/kg/day via enteral feeding for the first time. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. | Birth to gw 36+0 | Specifies the number of full days the child has lived. |
| Weight Gain (SD) | At 14th day of life | 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. |
| Mortality | Birth to gw 36+0 | — |
| Necrotizing Enterocolitis | Birth to gw 36+0 | Bell´s criteria II-III |
| Days With Halted Feeding Due to Food Intolerance | Birth to gestational week 36 | 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. |
| Bronchopulmonary Dysplasia | Gw 36+0 | Need of oxygen or CPAP/ventilator at gw 36+0 |
| Length Gain (SD) | At 14th day of life | 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. |
| Head Circumference Growth (SD) | At 14th day of life | 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. |
| Neurological Development | At 2 years corrected age | Bayleys´s test by psychologist |
| Neurological Development Impairment | At 2 years corrected age | 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 |
| Sepsis | Birth to gw 36+0 | Blood culture positive sepsis |
Countries
Sweden
Participant flow
Recruitment details
Extremely preterm infants with a birth weight \<1000 g were recruited within 72 hours after birth in two level 3 NICUs .
Pre-assignment details
Inclusion should be completed to allow first dose of study product to be administered within 72 hours from birth.
Participants by arm
| Arm | Count |
|---|---|
| Probiotic Lactobacillus reuteri | 68 |
| Placebo | 66 |
| Total | 134 |
Baseline characteristics
| Characteristic | Placebo | Total | Probiotic |
|---|---|---|---|
| Age, Continuous | 25.5 age in postmenstrual weeks at birth STANDARD_DEVIATION 1.3 | 25.5 age in postmenstrual weeks at birth STANDARD_DEVIATION 1.2 | 25.5 age in postmenstrual weeks at birth STANDARD_DEVIATION 1.2 |
| Birth weight | 740 gram STANDARD_DEVIATION 148 | 735 gram STANDARD_DEVIATION 138 | 731 gram STANDARD_DEVIATION 129 |
| Sex: Female, Male Female | 24 Participants | 60 Participants | 36 Participants |
| Sex: Female, Male Male | 42 Participants | 74 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 68 | 5 / 66 |
| other Total, other adverse events | 0 / 68 | 0 / 66 |
| serious Total, serious adverse events | 55 / 68 | 52 / 66 |
Outcome results
Primary
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.
Time frame: Birth to gestational week 36+0
Population: Six infants - Four allocated to receive L. reuteri and two allocated to the placebo group died before reaching full enteral feeding and were not included in the analyses.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lactobacillus Reuteri | Time to Establish Full Enteral Feeds | 15 days |
| Placebo | Time to Establish Full Enteral Feeds | 15 days |
Secondary
Bronchopulmonary Dysplasia
Need of oxygen or CPAP/ventilator at gw 36+0
Time frame: Gw 36+0
Population: Only patients surviving to gestational week 36+0 could be assessed for the diagnosis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lactobacillus Reuteri | Bronchopulmonary Dysplasia | 40 participants |
| Placebo | Bronchopulmonary Dysplasia | 39 participants |
Secondary
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.
Time frame: Birth to gestational week 36
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lactobacillus Reuteri | Days With Halted Feeding Due to Food Intolerance | 5.5 days |
| Placebo | Days With Halted Feeding Due to Food Intolerance | 6 days |
Secondary
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.
Time frame: At 28th day of life
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lactobacillus Reuteri | Head Circumference Growth (SD) | -1.21 change in standard deviations | Standard Deviation 0.85 |
| Placebo | Head Circumference Growth (SD) | -1.73 change in standard deviations | Standard Deviation 0.91 |
p-value: =0.001t-test, 2 sided
Secondary
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.
Time frame: At gestational week 36+0
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lactobacillus Reuteri | Head Circumference Growth (SD) | -0.57 change in standard deviations | Standard Deviation 1.29 |
| Placebo | Head Circumference Growth (SD) | -0.79 change in standard deviations | Standard Deviation 1.24 |
Secondary
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.
Time frame: At 14th day of life
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lactobacillus Reuteri | Head Circumference Growth (SD) | -0.92 change in standard deviations | Standard Deviation 0.56 |
| Placebo | Head Circumference Growth (SD) | -1.11 change in standard deviations | Standard Deviation 0.82 |
Secondary
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.
Time frame: At 28th day of life
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lactobacillus Reuteri | Length Gain (SD) | -1.67 change in standard deviations | Standard Deviation 1.47 |
| Placebo | Length Gain (SD) | -1.96 change in standard deviations | Standard Deviation 1.28 |
Secondary
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.
Time frame: At gestational week 36+0
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lactobacillus Reuteri | Length Gain (SD) | -1.44 change in standard deviations | Standard Deviation 1.65 |
| Placebo | Length Gain (SD) | -1.34 change in standard deviations | Standard Deviation 1.52 |
Secondary
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.
Time frame: At 14th day of life
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lactobacillus Reuteri | Length Gain (SD) | -1.02 change in standard deviations | Standard Deviation 1 |
| Placebo | Length Gain (SD) | -1.20 change in standard deviations | Standard Deviation 1.01 |
Secondary
Mortality
Time frame: Birth to gw 36+0
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lactobacillus Reuteri | Mortality | 5 participants |
| Placebo | Mortality | 5 participants |
Secondary
Necrotizing Enterocolitis
Bell´s criteria II-III
Time frame: Birth to gw 36+0
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lactobacillus Reuteri | Necrotizing Enterocolitis | 7 participants |
| Placebo | Necrotizing Enterocolitis | 8 participants |
Secondary
Neurological Development
Bayleys´s test by psychologist
Time frame: At 2 years corrected age
Secondary
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
Time frame: At 2 years corrected age
Secondary
Number of Stools
Time frame: Recorded over the first four weeks
Population: Only infants with complete records of stools during the first four weeks are included
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Lactobacillus Reuteri | Number of Stools | 69.6 number of stools |
| Placebo | Number of Stools | 69.9 number of stools |
Secondary
Sepsis
Blood culture positive sepsis
Time frame: Birth to gw 36+0
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lactobacillus Reuteri | Sepsis | 25 participants |
| Placebo | Sepsis | 23 participants |
Secondary
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.
Time frame: Birth to gw 36+0
Secondary
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.
Time frame: At 14th day of life
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lactobacillus Reuteri | Weight Gain (SD) | -0.88 change in standard deviations | Standard Deviation 0.81 |
| Placebo | Weight Gain (SD) | -0.88 change in standard deviations | Standard Deviation 0.81 |
Secondary
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.
Time frame: At 28th day of life
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lactobacillus Reuteri | Weight Gain (SD) | -1.14 change in standard deviations | Standard Deviation 1.07 |
| Placebo | Weight Gain (SD) | -1.25 change in standard deviations | Standard Deviation 0.95 |
Secondary
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.
Time frame: At gestational week 36+0
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lactobacillus Reuteri | Weight Gain (SD) | -0.40 change in standard deviations | Standard Deviation 1.3 |
| Placebo | Weight Gain (SD) | -0.24 change in standard deviations | Standard Deviation 1.1 |