Prophylactic Probiotics to Extremely Low Birth Weight Prematures

Phase 2

Completed

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

Interventions: Dietary Supplement: Placebo
Dietary Supplement: Lactobacillus reuteri

Registration Number: NCT01603368

Lead Sponsor: Ostergotland County Council, Sweden

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 134

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	The same oil drops as the active study product but without Lactobacillus reuteri
Lactobacillus reuteri	Lactobacillus reuteri	Lactobacillus reuteri DSM 17938, 125 million bacteria/day

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
Sepsis	Birth to gw 36+0	Blood culture positive sepsis
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.
Weight Gain (SD)	At gestational week 36+0	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
Bronchopulmonary Dysplasia	Gw 36+0	Need of oxygen or CPAP/ventilator at gw 36+0
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
Number of Stools	Recorded over the first four weeks
Head Circumference Growth (SD)	At gestational week 36+0	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.
Length Gain (SD)	At gestational week 36+0	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