Assessment of Neonatal Intensive Care Unit Practices and Preterm Newborn Gut Microbiota and 2-Year Neurodevelopmental Outcomes
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Updated: Dec 8, 2025
Assessment and Evaluation of the High Risk Neonate: The NICU Network Neurobehavioral Scale
Published on: August 25, 2014
Jean-Christophe Rozé1, Pierre-Yves Ancel2,3, Laetitia Marchand-Martin2
1Neonatal Department, INSERM-CHU Clinical Investigation Center 1413, et UMR- INRA 1280, Physiologie des Adaptations Nutritionnelles, Nantes University Hospital, Nantes, France.
Insights
Neonatal intensive care unit (NICU) practices influence gut microbiota in very preterm infants. Specific microbiota compositions are linked to adverse long-term neurodevelopmental outcomes at two years.
Area of Science:
- Neonatology
- Microbiology
- Developmental Pediatrics
Background:
- Gut microbiota in very preterm newborns is highly variable and often dysbiotic.
- While short-term health associations are known, the link between gut microbiota and long-term infant outcomes is unclear.
Purpose of the Study:
- To examine associations between neonatal intensive care unit (NICU) practices, gut microbiota composition, and infant outcomes at two years of age.
Main Methods:
- Prospective observational cohort study (EPIFLORE) of preterm infants (<32 weeks gestational age).
- Stool samples analyzed via 16S rRNA gene sequencing during the fourth week after birth.
- Two-year outcomes assessed for death or neurodevelopmental delay using the Ages and Stages Questionnaire.
Main Results:
- Gut microbiota clustered into distinct groups, with some associated with lower gestational age.
- NICU practices like ventilation, sedation, and enteral nutrition volume significantly impacted microbiota composition.
- Specific microbiota clusters (Enterococcus, Staphylococcus-dominant) were associated with increased risk of nonoptimal two-year outcomes.
Conclusions:
- Gut microbiota composition in very preterm infants at four weeks is associated with NICU care strategies.
- Microbiota profiles correlate with neurodevelopmental outcomes at two years.
- Gut microbiota may serve as a noninvasive biomarker for infant immaturity and long-term prognosis.
Importance:
In very preterm newborns, gut microbiota is highly variable with major dysbiosis. Its association with short-term health is widely studied, but the association with long-term outcomes remains unknown.
Objective:
To investigate in preterm newborns the associations among practice strategies in neonatal intensive care units (NICUs), gut microbiota, and outcomes at 2 years.
Design, Setting, And Participants:
EPIFLORE is a prospective observational cohort study that includes a stool sample collection during the fourth week after birth. Preterm newborns of less than 32 weeks of gestational age (GA) born in 2011 were included from 24 NICUs as part of the French nationwide population-based cohort, EPIPAGE 2. Data were collected from May 2011 to December 2011 and analyzed from September 2016 to December 2018.
Exposures:
Eight NICU strategies concerning sedation, ventilation, skin-to-skin practice, antibiotherapy, ductus arteriosus, and breastfeeding were assessed. A NICU was considered favorable to a practice if the percentage of that practice in the NICU was more than the expected percentage.
Main Outcomes And Measures:
Gut microbiota was analyzed by 16S ribosomal RNA gene sequencing and characterized by a clustering-based method. The 2-year outcome was defined by death or neurodevelopmental delay using a Global Ages and Stages questionnaire score.
Results:
Of 577 newborns included in the study, the mean (SD) GA was 28.3 (2.0) weeks, and 303 (52.5%) were male. Collected gut microbiota was grouped into 5 discrete clusters. A sixth cluster included nonamplifiable samples owing to low bacterial load. Cluster 4 (driven by Enterococcus [n = 63]), cluster 5 (driven by Staphylococcus [n = 52]), and cluster 6 (n = 93) were significantly associated with lower mean (SD) GA (26.7 [1.8] weeks and 26.8 [1.9] weeks, respectively) and cluster 3 (driven by Escherichia/Shigella [n = 61]) with higher mean (SD) GA (29.4 [1.6] weeks; P = .001). Cluster 3 was considered the reference. After adjustment for confounders, no assisted ventilation at day 1 was associated with a decreased risk of belonging to cluster 5 or cluster 6 (adjusted odds ratio [AOR], 0.21 [95% CI, 0.06-0.78] and 0.19 [95% CI, 0.06-0.62], respectively) when sedation (AOR, 10.55 [95% CI, 2.28-48.87] and 4.62 [1.32-16.18], respectively) and low volume of enteral nutrition (AOR, 10.48 [95% CI, 2.48-44.29] and 7.28 [95% CI, 2.03-26.18], respectively) was associated with an increased risk. Skin-to-skin practice was associated with a decreased risk of being in cluster 5 (AOR, 0.14 [95% CI, 0.04-0.48]). Moreover, clusters 4, 5, 6 were significantly associated with 2-year nonoptimal outcome (AOR, 6.17 [95% CI, 1.46-26.0]; AOR, 4.53 [95% CI, 1.02-20.1]; and AOR, 5.42 [95% CI, 1.36-21.6], respectively).
Conclusions And Relevance:
Gut microbiota of very preterm newborns at week 4 is associated with NICU practices and 2-year outcomes. Microbiota could be a noninvasive biomarker of immaturity.
