Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Pediatrics

Infections and antibiotic use in early life, and obesity in early childhood: a mediation analysis

International Journal of Obesity volume 46, pages 1608–1614 (2022)Cite this article

Subjects

Abstract

Background/objective

Literature shows a positive association between antibiotics and obesity in childhood, but fails to account for confounding by indication. We evaluate the direct effect of infection on obesity and the indirect effect mediated by antibiotics by performing a mediation analysis of the infection-obesity association.

Methods

A Medicaid cohort of children age 2–14 years old between 2015–2019 (n = 61,330) is used to perform mediation analysis of infections and antibiotic use in the first year of life, and obesity in childhood in Missouri, U.S.A.

Results

An additional infection increases the risk of obesity in childhood (aIRR = 1.050, p < 0.001); however, mediation by antibiotic use is clinically and statistically insignificant. If the number of infections is not considered in the analysis, then antibiotic use as a risk factor for obesity is overstated (aIRR = 1.037 vs. 1.013 p < 0.001).

Conclusions

The number of infections exhibits a significant relationship with obesity and is a stronger risk factor for obesity than antibiotic use. In particular, a greater number of bronchitis, otitis media, and upper respiratory infections in the first year of life are associated with a significant increased risk of obesity in childhood. We find only weak evidence that an additional antibiotics claim increases the risk of obesity in childhood and this risk may not be clinically meaningful. Further research is needed to explore the association between early childhood infections, especially in the first 6 months of life, and obesity including the biological mechanism and environmental factor of early life infections associated with obesity.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Directed Acyclic Graph of Mediation Model and Simple Model for Childhood Obesity.

Similar content being viewed by others

Data availability

These data are not publicly available, but the deidentified cohort was acquired with permission from the Missouri Department of Social Services, through partnership with the Center for Health Policy at the University of Missouri. Due to confidentiality agreements, supporting data can only be made available to bona fide researchers subject to a non-disclosure agreement. Details of the data and how to request access are available through the Center for Health Policy at the University of Missouri in partnership with the Missouri Department of Social Services where the data reside.

References

  1. Rasmussen SH, Shrestha S, Bjerregaard LG, Angquist LH, Baker JL, Jess T, et al. Antibiotic exposure in early life and childhood overweight and obesity: A systematic review and meta-analysis. Diabetes Obes Metab. 2018;20:1508–14.

    Article  Google Scholar 

  2. Aghaali M, Hashemi-Nazari SS. Association between early antibiotic exposure and risk of childhood weight gain and obesity: a systematic review and meta-analysis. J Pediatr Endocrinol Metab. 2019;32:439–45.

    Article  Google Scholar 

  3. Cox LM, Blaser MJ. Antibiotics in early life and obesity. Nat Rev Endocrinol. 2015;11:182–90.

    Article  Google Scholar 

  4. Mikkelsen KH, Allin KH, Knop FK. Effect of antibiotics on gut microbiota, glucose metabolism and body weight regulation: a review of the literature. Diabetes Obes Metab. 2016;18:444–53.

    Article  CAS  Google Scholar 

  5. Miller SA, Wu RKS, Oremus M. The association between antibiotic use in infancy and childhood overweight or obesity: a systematic review and meta-analysis. Obes Rev. 2018;19:1463–75.

    Article  CAS  Google Scholar 

  6. Shao X, Ding X, Wang B, Li L, An X, Yao Q, et al. Antibiotic exposure in early life increases risk of childhood obesity: a systematic review and meta-analysis. Front Endocrinol (Lausanne). 2017;8:170.

    Article  Google Scholar 

  7. Li D-K, Chen H, Ferber J, Odouli R. Infection and antibiotic use in infancy and risk of childhood obesity: a longitudinal birth cohort study. Lancet Diabetes Endocrinol. 2017;5:18–25.

    Article  Google Scholar 

  8. Cox LM, Yamanishi S, Sohn J, Alekseyenko AV, Leung JM, Cho I, et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell. 2014;158:705–21.

    Article  CAS  Google Scholar 

  9. Wang J, Li F, Wei H, Lian ZX, Sun R, Tian Z. Respiratory influenza virus infection induces intestinal immune injury via microbiota-mediated Th17 cell-dependent inflammation. J Exp Med. 2014;211:2397–410.

    Article  CAS  Google Scholar 

  10. Ha CW, Lam YY, Holmes AJ. Mechanistic links between gut microbial community dynamics, microbial functions and metabolic health. World J Gastroenterol. 2014;20:16498–517.

    Article  CAS  Google Scholar 

  11. Falagas ME, Kompoti M. Obesity and infection. Lancet Infect Dis. 2006;6:438–46.

    Article  Google Scholar 

  12. Huttunen R, Syrjanen J. Obesity and the risk and outcome of infection. Int J Obes (Lond). 2013;37:333–40.

    Article  CAS  Google Scholar 

  13. Prins-van Ginkel AC, Wijga AH, Bruijning-Verhagen PCJ, Brunekreef B, Gehring U, van der Hoek W, et al. Early childhood infections and body mass index in adolescence. Int J Obes (Lond). 2021;45:1143–51.

    Article  Google Scholar 

  14. Partap U, Allcock SH, Parker E, Gurdasani D, Young EH, Sandhu MS. Association between early life antibiotic use and childhood overweight and obesity: a narrative review. Glob Health Epidemiol Genom. 2018;3:e18.

    Article  Google Scholar 

  15. Block JP, Bailey LC, Gillman MW, Lunsford D, Daley MF, Eneli I, et al. Early antibiotic exposure and weight outcomes in young children. Pediatrics. 2018;142:1–12.

  16. Greenland S, Robins JM. Identifiability, exchangeability, and epidemiological confounding. Int J Epidemiol. 1986;15:413–19.

    Article  CAS  Google Scholar 

  17. VanderWeele TJ. Mediation analysis: a practitioner’s guide. Ann Rev Public Health. 2016;37:17–32.

    Article  Google Scholar 

  18. Valeri L, VanderWeele TJ. Mediation analysis allowing for exposure–mediator interactions and causal interpretation: theoretical assumptions and implementation with SAS and SPSS macros. Psychol Methods. 2013;18:137.

    Article  Google Scholar 

  19. MacKinnon DP, Fairchild AJ, Fritz MS. Mediation analysis. Annu Rev Psychol. 2007;58:593–614.

    Article  Google Scholar 

  20. Burgner DP, Sabin MA, Magnussen CG, Cheung M, Kähönen M, Lehtimäki T, et al. Infection-related hospitalization in childhood and adult metabolic outcomes. Pediatrics. 2015;136:e554–62.

  21. Liu RS, Burgner DP, Sabin MA, Magnussen CG, Cheung M, Hutri-Kähönen N, et al. Childhood infections, socioeconomic status, and adult cardiometabolic risk. Pediatrics. 2016;137:1–9.

  22. Dowd JB, Zajacova A, Aiello A. Early origins of health disparities: burden of infection, health, and socioeconomic status in U.S. children. Soc Sci Med. 2009;68:699–707.

    Article  Google Scholar 

  23. Scott FI, Horton DB, Mamtani R, Haynes K, Goldberg DS, Lee DY, et al. Administration of antibiotics to children before age 2 years increases risk for childhood obesity. Gastroenterology. 2016;151:120–9.

    Article  CAS  Google Scholar 

  24. Azad MB, Bridgman SL, Becker AB, Kozyrskyj AL. Infant antibiotic exposure and the development of childhood overweight and central adiposity. Int J Obes (Lond). 2014;38:1290–8.

    Article  CAS  Google Scholar 

  25. Miller JE, Hammond GC, Strunk T, Moore HC, Leonard H, Carter KW, et al. Association of gestational age and growth measures at birth with infection-related admissions to hospital throughout childhood: a population-based, data-linkage study from Western Australia. Lancet Infect Dis. 2016;16:952–61.

    Article  Google Scholar 

  26. Malaty HM, Graham DY. Importance of childhood socioeconomic status on the current prevalence of Helicobacter pylori infection. Gut. 1994;35:742–45.

  27. VanderWeele T, Vansteelandt S. Mediation analysis with multiple mediators. Epidemiol Methods. 2014;2:95–115.

    Article  CAS  Google Scholar 

  28. VanderWeele T. Explanation in causal inference: methods for mediation and interaction, Oxford University Press, 2015.

  29. VanderWeele TJ, Ding P. Sensitivity analysis in observational research: introducing the E-value. Ann Intern Med. 2017;167:268–74.

    Article  Google Scholar 

  30. Emsley R, Liu H. PARAMED: Stata module to perform causal mediation analysis using parametric regression models. 2013. https://econpapers.repec.org/software/bocbocode/S457581.htm.

  31. Shi B, Choirat C, Coull BA, VanderWeele TJ, Valeri L. Cmaverse: a suite of functions for reproducible causal mediation analyses. Epidemiology. 2021;32:e20–2.

    Article  Google Scholar 

  32. Albert RH. Diagnosis and treatment of acute bronchitis. Am Fam Physician. 2010;82:1345–50.

  33. Saari A, Virta LJ, Sankilampi U, Dunkel L, Saxen H. Antibiotic exposure in infancy and risk of being overweight in the first 24 months of life. Pediatrics. 2015;135:617–26.

    Article  Google Scholar 

  34. Richiardi L, Bellocco R, Zugna D. Mediation analysis in epidemiology: methods, interpretation and bias. Int J Epidemiol. 2013;42:1511–9.

    Article  Google Scholar 

  35. Davies HTO, Crombie IK, Tavakoli M. When can odds ratios mislead? BMJ. 1998;316:989–91.

    Article  CAS  Google Scholar 

  36. Kinlaw AC, Stürmer T, Lund JL, Pedersen L, Kappelman MD, Daniels JL et al. Trends in antibiotic use by birth season and birth year. Pediatrics. 2017;140:1–12.

  37. Islam S, Mannix MK, Breuer RK, Hassinger AB. Guideline adherence and antibiotic utilization by community pediatricians, private urgent care centers, and a pediatric emergency department. Clin Pediatr (Phila). 2020;59:21–30.

    Article  Google Scholar 

  38. Kerr CA, Grice DM, Tran CD, Bauer DC, Li D, Hendry P, et al. Early life events influence whole-of-life metabolic health via gut microflora and gut permeability. Crit Rev Microbiol. 2015;41:326–40.

    Article  CAS  Google Scholar 

  39. Chow J, Tang H, Mazmanian SK. Pathobionts of the gastrointestinal microbiota and inflammatory disease. Curr Opin Immunol. 2011;23:473–80.

    Article  CAS  Google Scholar 

  40. Bücker R, Schumann M, Amasheh S, Schulzke J-D. Claudins in intestinal function and disease. In Current Topics in Membranes. 2010;10:195–227.

  41. Vallianou N, Dalamaga M, Stratigou T, Karampela I, Tsigalou C. Do antibiotics cause obesity through long-term alterations in the gut microbiome? A review of current evidence. Curr Obes Rep. 2021;10:1–19.

  42. Chantry CJ, Howard CR, Auinger P. Full breastfeeding duration and associated decrease in respiratory tract infection in US children. Pediatrics. 2006;117:425–32.

    Article  Google Scholar 

  43. Arenz S, Ruckerl R, Koletzko B, von Kries R. Breast-feeding and childhood obesity-a systematic review. Int J Obes Relat Metab Disord. 2004;28:1247–56.

    Article  CAS  Google Scholar 

  44. Yan J, Liu L, Zhu Y, Huang G, Wang PP. The association between breastfeeding and childhood obesity: a meta-analysis. BMC Pub Health. 2014;14:1–11.

  45. Haneuse S, VanderWeele TJ, Arterburn D. Using the E-value to assess the potential effect of unmeasured confounding in observational studies. JAMA. 2019;321:602–3.

    Article  Google Scholar 

Download references

Acknowledgements

We thank the Center for Health Policy for providing tremendous support in requesting, accessing, and approval of the use of this data from the Missouri Department of Social Services. We also thank participants at the MU-Collaborative Health Researchers Interdisciplinary Seminar Series for valuable feedback.

Funding

Funding for data acquisition for this research was supported by the MU-Child Health Research Institute through the Lead J. Sears Grant Award.

Author information

Authors and Affiliations

  1. Department of Child Health, Child Health Research Institute, University of Missouri, COLUMBIA, MO, USA

    Adrienne M. Ohler

  2. Department of Family and Community Medicine, University of Missouri, Columbia, MO, USA

    Amy Braddock

Authors
  1. Adrienne M. Ohler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amy Braddock
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AMO conceived of the hypothesis and carried out the data acquisition, analysis, generation of figures and tables, and initial manuscript. AM provided clinical expertise, literature search, interpretation of findings, and manuscript editing. All authors were involved in writing the paper and had final approval of the submitted and published versions.

Corresponding authors

Correspondence to Adrienne M. Ohler or Amy Braddock.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ohler, A.M., Braddock, A. Infections and antibiotic use in early life, and obesity in early childhood: a mediation analysis. Int J Obes 46, 1608–1614 (2022). https://doi.org/10.1038/s41366-022-01155-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41366-022-01155-7

Search

Advanced search

Quick links