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Observational Study
. 2020 Sep 1;3(9):e2018119.
doi: 10.1001/jamanetworkopen.2020.18119.

Assessment of Neonatal Intensive Care Unit Practices and Preterm Newborn Gut Microbiota and 2-Year Neurodevelopmental Outcomes

Jean-Christophe Rozé  1 , Pierre-Yves Ancel  2   3 , Laetitia Marchand-Martin  2 , Clotilde Rousseau  4   5   6 , Emmanuel Montassier  7 , Céline Monot  8 , Karine Le Roux  8 , Marine Butin  9 , Matthieu Resche-Rigon  10 , Julio Aires  4   5 , Josef Neu  11 , Patricia Lepage  8 , Marie-José Butel  4   5 ; EPIFLORE Study Group
Affiliations
Observational Study

Assessment of Neonatal Intensive Care Unit Practices and Preterm Newborn Gut Microbiota and 2-Year Neurodevelopmental Outcomes

Jean-Christophe Rozé et al. JAMA Netw Open. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Rozé reports receiving grants from the French National Agency for Research and the Nestec Research Center during the conduct of the study. Dr Rousseau reports receiving grants from the Nestec Research Center and the French National Agency for Research during the conduct of the study. Dr Neu is the principal investigator of a phase 3 multicenter trial of a microbial agent being studied by Infant Bacterial Therapeutics for the prevention of neonatal necrotizing enterocolitis and improvement of feeding tolerance in preterm infants. Dr Butel reports receiving grants from the French National Agency for Research and the Nestec Research Center during the conduct of the study, as well as consulting fees from Danone and grants from Biostime Institute for Nutrition and Care and Mead Johnson outside of the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Composition of the 5 Identified Microbiota Clusters
Mean composition of each cluster is represented at phylum (A), genus (B), and operational taxonomic unit levels (C). The sixth cluster, constituted by newborns in whom no amplification could be performed owing to a low bacterial load, is not represented by definition.
Figure 2.
Figure 2.. Repartition of Gestational Age and Microbiota Cluster in 18 Neonatal Intensives Care Units (NICUs) Enrolling More Than 10 Preterm Newborns
Among 577 preterm newborns enrolled in the EPIFLORE study, 544 were hospitalized from 18 NICUs enrolling more than 10 preterm newborns each. Difference in gut microbiota composition among NICUs is not only dependent of gestational age (A). As an example, more than 60% of newborns hospitalized in NICU C belonged to clusters 4, 5, or 6 (B) and were considered immature, although more than 60% of them had a gestational age of more than 26 weeks. Conversely, less than 20% of the newborns of NICUs K stratified into clusters 4, 5, or 6, while 50% of them have a gestational age less than 27 weeks.
Figure 3.
Figure 3.. Repartition of Microbiota Clusters According to Gestational Age and 2-Year Outcome
Two-year-outcome is defined by death or Ages and Stages questionnaire (ASQ) score less than 185 at 2 years of age (A, C, and E) and by death or cerebral palsy (B, D, and F) (result after multiple imputation). Percentages are weighted to take into account the differences in survey design between gestational age groups.
See this image and copyright information in PMC

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