Clinical trial NCT02197468: Preterm Infant Gut (PINGU) - a Norwegian Multi Centre Study
Official title: Gut Microbiome Study in Preterm Infants - a Norwegian Multi Centre Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Mixed Flora; Infection
Keywords: Gut microbiome
Necrotizing enterocolitis
Antibiotics
Lead sponsor: University Hospital of North Norway
Sponsor class: OTHER
Collaborators: name: University of Tromso
name: Oslo University Hospital
name: Ullevaal University Hospital
name: St. Olavs Hospital
name: Haukeland University Hospital
name: Helse Stavanger HF
First posted: 2014-07-22
Enrollment: 60
Sex: ALL
Minimum age (years): 1
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
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

Brief 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.

Eligibility criteria: 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

Primary outcomes:
measure: To assess gut microbiome composition (meta genome sequencing) of preterm infants receiving probiotics versus preterm infants not receiving probiotics
timeFrame: 4 time points: 7 days of age, 4 weeks of age, 4 months corrected age and 12 months corrected age
Secondary outcomes:
measure: Impact of antibiotic exposure on gut microbiome
timeFrame: 4 time points: 7 days of age, 4 weeks of age, 4 months corrected age and 12 months corrected age
Other outcomes:
measure: Cross contamination of probiotic bacteria in a NICU
timeFrame: 7 days of age and 4 weeks of age
Locations:
city: Bergen
country: Norway
facility: Haukeland Universtiy Hospital
city: Oslo
country: Norway
facility: Oslo University Hospital, Rikshospitalet
city: Oslo
country: Norway
facility: Oslo University Hospital, Ullevaal
city: Oslo
country: Norway
facility: Ahus University Hospital
city: Stavanger
country: Norway
facility: Stavanger University Hospital
city: Tromsø
country: Norway
facility: University Hospital of North Norway
city: Trondheim
country: Norway
facility: St Olavs Hospital, Trondheim University Hospital
Study officials:
affiliation: University Hospital of North Norway
name: Claus Klingenberg, MD.phD.Prof.
role: STUDY_CHAIR
affiliation: University Hospital of North-Noway
name: Eirin Esaiassen, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Berrington JE, Stewart CJ, Cummings SP, Embleton ND. The neonatal bowel microbiome in health and infection. Curr Opin Infect Dis. 2014 Jun;27(3):236-43. doi: 10.1097/QCO.0000000000000061.
citation: Stewart CJ, Marrs EC, Magorrian S, Nelson A, Lanyon C, Perry JD, Embleton ND, Cummings SP, Berrington JE. The preterm gut microbiota: changes associated with necrotizing enterocolitis and infection. Acta Paediatr. 2012 Nov;101(11):1121-7. doi: 10.1111/j.1651-2227.2012.02801.x. Epub 2012 Aug 31.
citation: Esaiassen E, Hjerde E, Cavanagh JP, Pedersen T, Andresen JH, Rettedal SI, Stoen R, Nakstad B, Willassen NP, Klingenberg C. Effects of Probiotic Supplementation on the Gut Microbiota and Antibiotic Resistome Development in Preterm Infants. Front Pediatr. 2018 Nov 16;6:347. doi: 10.3389/fped.2018.00347. eCollection 2018.