Preterm Infant Gut (PINGU) - a Norwegian Multi Centre Study

Study Overview
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Brief Summary
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Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality among infants in the neonatal intensive care unit (NICU). It has been postulated that abnormal colonization of the preterm gut, or an unfavorable balance between gut bacteria may contribute to the development of NEC. Recent clinical randomized studies and meta-analysis have shown that proactive colonization of probiotic bacteria reduce the frequency of NEC. Based on this evidence, in April 2014 all Norwegian NICUs started routinely administration of probiotics to all extremely premature neonates susceptible to NEC (gestational age <28 weeks/birth weight <1000g). The current project is investigating the gut microbiome in patients receiving probiotics and compare the the gut microbiome with moderate premature infants not receiving probiotics. In addition, we are including a control of healthy full-term infants. Samples containing feces from participants will be analyzed by state of the art whole-genome sequencing techniques. Bacterial diversity will be analysed with bioinformatic tools. Study hypotheses: Probiotics given to extremely preterm infants will change the biodiversity of the gut microflora. Antibiotics given to these patients may influence the gut microflora also in infants receiving probiotics. In particular use of vancomycin may change the gut flora. After cessation of probiotic prophylaxis the gut flora of infants receiving probiotics will gradually resemble the gut flora of infants not receiving probiotics. A cross-contamination of probiotic bacteria between patients treated with probiotics and patients not treated with antibiotics may occur.

Detailed Description
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Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality among infants in the neonatal intensive care unit (NICU). Prematurity is the most important risk factor for NEC. The pathogenesis of NEC remains unclear, and prevention and treatment strategies are limited. It has been postulated that abnormal colonization of the preterm gut, or an unfavorable balance between gut bacteria, is significant in the pathogenesis of NEC. Recent clinical randomized studies and meta-analysis have shown that proactive colonization of probiotic bacteria reduce the frequency of NEC. Based on this evidence, in April 2014 all Norwegian NICUs started routinely administration of probiotics to all extremely premature neonates susceptible to NEC (gestational age (GA) <28 weeks/birth birth weight (BW) <1000 g). The current project is investigating the gut microbiome in patients receiving probiotics and compare the the gut microbiome with moderate premature infants not receiving probiotics. In addition, we are including a control of healthy full-term infants. Samples containing feces from participants will be analyzed by state of the art whole-genome sequencing techniques. Bacterial diversity and taxonomy will be analysed using bioinformatic tools Inclusion criteria: Preterm infants 24-27 weeks gestation/ birth weight < 1000 g receiving probiotics Preterm infants 28-31 weeks gestation/BW 1000-1500 g not receiving probiotics Healthy term infants Exclusion criteria Preterm infants < 24 weeks gestation Preterm infants < 32 weeks with severe lethal complication/poor prognosis around 1 week of age Infants with severe congenital malformations Fecal samples will be obtained: 1 week of age 4 weeks of age 4 months corrected age 12 months corrected age Study hypotheses: Probiotics given to extremely preterm infants will change the biodiversity of the gut microflora. Antibiotics given to these patients may influence the gut microflora also in infants receiving probiotics. In particular use of vancomycin may change the gut flora. After cessation of probiotic prophylaxis the gut flora of infants receiving probiotics will gradually resemble the gut flora of infants not receiving probiotics. A cross-contamination of probiotic bacteria between patients treated with probiotics and patients not treated with antibiotics may occur. This is an explorative study. No formal sample size assessment is possible. Sequencing costs will be substantial. We will limit the number of participants to 26 x 2 preterm infants and 10 control healthy infants. Six Norwegian Neonatal Intensive care units wil participate in the study.

Official Title
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Gut Microbiome Study in Preterm Infants - a Norwegian Multi Centre Study

Conditions
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Mixed Flora; Infection

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Preterm infants with gestational age 24-27 weeks/birth weight < 1000 g, treated with probiotics (target number 26) Preterm infants with gestational age 29-31 weeks/birth weight 1000-1500 g, not treated with probiotics (target number 26) Term infants (target number 10) Exclusion Criteria: Extremely preterm infants with gestational age below 24 weeks Preterm infants (24-31 weeks) with life threatening complications during 1 week of age Infants with congenital malformations

Ages Eligible for Study
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Minimum Age: 1 Hour
Maximum Age: 12 Months

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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Probiotics<br>Preterm infants given probiotics: GA 24-27 weeks/Birth weight < 1000 g Preterm infants not given probiotics: GA 28-31 weeks/Birth weight 1000-1500 g Full-term infants not given probiotics (control) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess gut microbiome composition (meta genome sequencing) of preterm infants receiving probiotics versus preterm infants not receiving probiotics | Stools samples from preterm infants and term infants (control) | 4 time points: 7 days of age, 4 weeks of age, 4 months corrected age and 12 months corrected age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Impact of antibiotic exposure on gut microbiome | Stool samples from preterm and term infants | 4 time points: 7 days of age, 4 weeks of age, 4 months corrected age and 12 months corrected age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gut microbiome, Necrotizing enterocolitis, Antibiotics