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Original Investigation |

Association of Early-Life Antibiotic Use and Protective Effects of Breastfeeding Role of the Intestinal Microbiota

Katri Korpela, PhD1; Anne Salonen, PhD1; Lauri J. Virta, MD2; Riina A. Kekkonen, PhD3; Willem M. de Vos, PhD1,4
[+] Author Affiliations
1Immunobiology Research Programme, Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland
2Research Department, Social Insurance Institution, Turku, Finland
3Research and Development, Valio Ltd, Helsinki, Finland
4Laboratory of Microbiology, Wageningen University, Wageningen, the Netherlands
JAMA Pediatr. 2016;170(8):750-757. doi:10.1001/jamapediatrics.2016.0585.
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Importance  Long duration of breastfeeding is known to reduce the frequency of infections and the risk of overweight, both of which are prevalent health problems among children, but the mechanisms are unclear.

Objectives  To test whether early-life antibiotic use in children prevents the beneficial long-term effects of breastfeeding on weight development and lifetime antibiotic use, and to investigate whether the duration of breastfeeding is associated with long-term microbiota development.

Design, Setting, and Participants  Retrospective cohort study, conducted from June 2015 to December 2015, of the association between the duration of breastfeeding and lifetime antibiotic use by children as well as body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) z score in a cohort of 226 healthy children aged 2 to 6 years attending day care at the study area in northern Finland and participating in a probiotic trial from October 1, 2009, through April 30, 2010. Fecal microbiota composition analysis was performed in a subcohort of 42 of these children.

Exposures  Duration of breastfeeding and the number of different antibiotic courses purchased for the child.

Main Outcomes and Measures  The BMI z score, lifetime antibiotic use after weaning, and fecal microbiota composition.

Results  A total of 226 children (mean [SD] age, 55 [1.4] months; 54% male) were included in the study. Among the 113 children with no antibiotics before weaning, each month of breastfeeding decreased the mean number of postweaning antibiotic courses by 5% (95% CI, 2% to 8%; P = .001) and mean BMI z scores by 0.08 unit (95% CI, 0.04 to 0.11; P < .001). Among the 113 early-life antibiotic users, the effect of breastfeeding on postweaning antibiotic use was borderline significant (estimated 4% decrease per month; 95% CI, 0% to 7%; P = .04) and the effect on BMI z score disappeared (estimated 1% increase; 95% CI, −3% to 5%; P = .50). In the subcohort of 42 children with fecal microbiota composition analysis, the children with short breastfeeding duration (0-6 months) and no early-life antibiotic use or with long breastfeeding duration (8-16 months) and early-life use of antibiotics had a significantly lower abundance of Bifidobacterium (by 55%; 95% CI, 43% to 87%; P = .006; and 39%, 95% CI, 30% to 68%; P < .001, respectively) and Akkermansia (by 71%; 95% CI, 28% to 87%; P = .008; and 69%; 95% CI, 22% to 90%; P = .02, respectively) compared with those with long duration of breastfeeding and no early-life antibiotics.

Conclusions and Relevance  Antibiotic use in a child during breastfeeding may weaken the beneficial effects of long breastfeeding duration. The results suggest that particularly the long-term metabolic benefits of breastfeeding are conveyed by the intestinal microbiota.

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Figure 1.
Lifetime Antibiotic Use in Relation to Duration of Breastfeeding

Lifetime antibiotic use in relation to the duration of breastfeeding in 113 children with and 113 children without antibiotic use during breastfeeding or within 4 months after weaning. Shaded areas indicate the 95% confidence interval of each trend line.

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Figure 2.
Body Mass Index (BMI) z Score in Relation to Duration of Breastfeeding

The BMI (calculated as weight in kilograms divided by height in meters squared) z score at ages 2 to 6 years in relation to the duration of breastfeeding in 113 children with and 113 children without antibiotic use during breastfeeding or within 4 months after weaning. Shaded areas indicate the 95% confidence interval of each trend line.

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Figure 3.
Global Intestinal Microbiota Composition in the Subcohort of 42 Children With Fecal Microbiota Composition Analysis

A, Principal coordinates analysis of the intestinal microbiota with Bray-Curtis dissimilarity, categorized by the duration of breastfeeding (short, 0-6 months; long, 8-16 months) and antibiotic use during breastfeeding or shortly after weaning (no early-life antibiotic use, AB−; early-life antibiotic use, AB+). Each circle is the microbiota of a child and the number in each circle indicates the age (in years) of the child at the time of fecal sample collection. B, Box and whisker plot of Actinobacteria to Firmicutes relative abundance ratio by group. For the taxa, the unit is the number of DNA sequencing reads assigned to that taxon relative to the total number of reads for the sample; the ratio is therefore computed as the following: (Actinobacteria reads/total reads)/(Firmicutes reads/total reads). The horizontal line in the middle of each box indicates median; top and bottom borders of each box, 75th and 25th percentiles, respectively; whiskers above and below each box, maximally 1.5 times the length of the box; and points beyond the whiskers, outliers beyond 1.5 times the length of the box.

aP < .001.

bP < .01.

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Figure 4.
Differences in Abundance of the Intestinal Microbiota Associated With Breastfeeding and Antibiotic Use

Significant differences between the mean relative abundance of the indicated genera (phyla shown at the top of panels) in the group with long breastfeeding duration (8-16 months) with early-life antibiotic use (long/AB+) and the group with short breastfeeding duration (0-6 months) and no early-life antibiotic use (short/AB−) compared with the group with long breastfeeding duration and no early-life antibiotic use (long/AB−). Error bars indicate standard error.

aFalse discovery rate–corrected P < .10, based on negative binomial models.

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