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.
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.
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).
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.
Your institute does not have access to this article
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
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.
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.
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.
Cox LM, Blaser MJ. Antibiotics in early life and obesity. Nat Rev Endocrinol. 2015;11:182–90.
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.
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.
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.
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.
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.
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.
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.
Falagas ME, Kompoti M. Obesity and infection. Lancet Infect Dis. 2006;6:438–46.
Huttunen R, Syrjanen J. Obesity and the risk and outcome of infection. Int J Obes (Lond). 2013;37:333–40.
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.
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.
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.
Greenland S, Robins JM. Identifiability, exchangeability, and epidemiological confounding. Int J Epidemiol. 1986;15:413–19.
VanderWeele TJ. Mediation analysis: a practitioner’s guide. Ann Rev Public Health. 2016;37:17–32.
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.
MacKinnon DP, Fairchild AJ, Fritz MS. Mediation analysis. Annu Rev Psychol. 2007;58:593–614.
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.
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.
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.
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.
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.
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.
Malaty HM, Graham DY. Importance of childhood socioeconomic status on the current prevalence of Helicobacter pylori infection. Gut. 1994;35:742–45.
VanderWeele T, Vansteelandt S. Mediation analysis with multiple mediators. Epidemiol Methods. 2014;2:95–115.
VanderWeele T. Explanation in causal inference: methods for mediation and interaction, Oxford University Press, 2015.
VanderWeele TJ, Ding P. Sensitivity analysis in observational research: introducing the E-value. Ann Intern Med. 2017;167:268–74.
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.
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.
Albert RH. Diagnosis and treatment of acute bronchitis. Am Fam Physician. 2010;82:1345–50.
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.
Richiardi L, Bellocco R, Zugna D. Mediation analysis in epidemiology: methods, interpretation and bias. Int J Epidemiol. 2013;42:1511–9.
Davies HTO, Crombie IK, Tavakoli M. When can odds ratios mislead? BMJ. 1998;316:989–91.
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.
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.
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.
Chow J, Tang H, Mazmanian SK. Pathobionts of the gastrointestinal microbiota and inflammatory disease. Curr Opin Immunol. 2011;23:473–80.
Bücker R, Schumann M, Amasheh S, Schulzke J-D. Claudins in intestinal function and disease. In Current Topics in Membranes. 2010;10:195–227.
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.
Chantry CJ, Howard CR, Auinger P. Full breastfeeding duration and associated decrease in respiratory tract infection in US children. Pediatrics. 2006;117:425–32.
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.
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.
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.
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 for data acquisition for this research was supported by the MU-Child Health Research Institute through the Lead J. Sears Grant Award.
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
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 (2022). https://doi.org/10.1038/s41366-022-01155-7