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Original Investigation | Journal Club

Association of Cesarean Delivery and Formula Supplementation With the Intestinal Microbiome of 6-Week-Old Infants

Juliette C. Madan, MD, MS1,2; Anne G. Hoen, PhD2,3,4; Sara N. Lundgren, BA3; Shohreh F. Farzan, PhD2,3; Kathryn L. Cottingham, PhD2,5; Hilary G. Morrison, PhD6; Mitchell L. Sogin, PhD6; Hongzhe Li, PhD7; Jason H. Moore, PhD4,8; Margaret R. Karagas, PhD2,3,9
[+] Author Affiliations
1Division of Neonatology, Department of Pediatrics, Children’s Hospital at Dartmouth, Lebanon, New Hampshire
2Children’s Environmental Health and Disease Prevention Research Center at Dartmouth, Hanover, New Hampshire
3Department of Epidemiology, The Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
4Computational Genetics Laboratory, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
5Department of Biological Sciences, Dartmouth College, Hanover, New Hampshire
6Josephine Bay Paul Center, Marine Biological Laboratory, Woods Hole, Massachusetts
7Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia
8Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia
9Center for Molecular Epidemiology, The Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
JAMA Pediatr. 2016;170(3):212-219. doi:10.1001/jamapediatrics.2015.3732.
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Importance  The intestinal microbiome plays a critical role in infant development, and delivery mode and feeding method (breast milk vs formula) are determinants of its composition. However, the importance of delivery mode beyond the first days of life is unknown, and studies of associations between infant feeding and microbiome composition have been generally limited to comparisons between exclusively breastfed and formula-fed infants, with little consideration given to combination feeding of both breast milk and formula.

Objective  To examine the associations of delivery mode and feeding method with infant intestinal microbiome composition at approximately 6 weeks of life.

Design, Setting, and Participants  Prospective observational study of 102 infants followed up as part of a US pregnancy cohort study.

Exposures  Delivery mode was abstracted from delivery medical records, and feeding method prior to the time of stool collection was ascertained through detailed questionnaires.

Main Outcomes and Measures  Stool microbiome composition was characterized using next-generation sequencing of the 16S rRNA gene.

Results  There were 102 infants (mean gestational age, 39.7 weeks; range, 37.1-41.9 weeks) included in this study, of whom 70 were delivered vaginally and 32 by cesarean delivery. In the first 6 weeks of life, 70 were exclusively breastfed, 26 received combination feeding, and 6 were exclusively formula fed. We identified independent associations between microbial community composition and both delivery mode (P < .001; Q < .001) and feeding method (P = .01; Q < .001). Differences in microbial community composition between vaginally delivered infants and infants delivered by cesarean birth were equivalent to or significantly larger than those between feeding groups (P = .003). Bacterial communities associated with combination feeding were more similar to those associated with exclusive formula feeding than exclusive breastfeeding (P = .002). We identified 6 individual bacterial genera that were differentially abundant between delivery mode and feeding groups.

Conclusions and Relevance  The infant intestinal microbiome at approximately 6 weeks of age is significantly associated with both delivery mode and feeding method, and the supplementation of breast milk feeding with formula is associated with a microbiome composition that resembles that of infants who are exclusively formula fed. These results may inform feeding choices and shed light on the mechanisms behind the lifelong health consequences of delivery and infant feeding modalities.

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Figure 1.
Principal Coordinate Plots Comparing Microbial Community Composition Between Delivery Mode and Feeding Method Groups

Principal coordinate plots within groups for delivery mode (A) and feeding method (B). UniFrac is a distance metric used for comparing biological communities that incorporates information on the phylogenetic relatedness of community members. Individual participants are represented by points marked according to delivery mode (A) or feeding method (B) and are plotted on the first 2 principal coordinates with permutational multivariate analysis of variance using distance matrices P values indicated. Lines are drawn from each point to its group centroid. In A, P < .001; Q < .001. In B, the P and Q values are as follows: exclusively breasfed vs combination fed (P = .02; Q = .04), combination fed vs exclusively formula fed (P = .52; Q = .52), and exclusively breastfed vs exclusively formula fed (P = .04; Q = .04). Q values indicate significance of differences after adjusting for multiple comparisons by controlling the false discovery rate for selected comparisons.

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Figure 2.
Comparison of UniFrac Distances of Microbial Community Composition Between Delivery Mode and Feeding Method Groups

Mean pairwise UniFrac distances within groups for delivery mode (A), feeding method (B), and between groups (C). UniFrac is a distance metric used for comparing biological communities that incorporates information on the phylogenetic relatedness of community members. Bar height is proportional to mean pairwise UniFrac distance within (A and B) or between (C) groups, with error bars indicating SEM. Throughout, Q values indicate significance of differences after adjusting for multiple comparisons by controlling the false discovery rate for selected comparisons.

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Figure 3.
Associations Between Individual Genus Abundance and Delivery Mode and Feeding Method

Positive coefficients indicate independent associations with vaginal delivery (A) or breast milk exposure (B-D) after controlling for the other. Point colors correspond to adjusted P values of >.10 (light gray), ≤.10, >.05 (dark gray), ≤.05, >.01 (orange), and ≤.01 (blue). Circles are sized according to relative log-ratio–transformed abundance. The bold labels indicate genera that were significantly differentially abundant after controlling for the false discovery rate at a significance level of Q = .10. Note differences in the axis scales.

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