Preterm Infant Gut (PINGU) - a Norwegian Multi Centre Study
Condition: Mixed Flora; Infection
Study type: Observational [Patient Registry]

Summary: 
      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: 
      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.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Preterm infants hospitalized in 6 Norwegian NICUs; divided in one group extremely preterm
        infants receiving probiotics and one group moderate preterm infants not receiving
        antibiotics. A group of helathy infants from the post-natal ward will also be included
      
Biospecimen description: 
      Fecal samples for bacterial DNA analyses
    
Keywords: Gut microbiome; Necrotizing enterocolitis; Antibiotics