Antibiotics administered to children younger than 2 are associated with several ongoing illnesses or conditions ranging from allergies to obesity

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In a retrospective case study, Mayo Clinic researchers have found that antibiotics administered to children younger than 2 are associated with several ongoing illnesses or conditions, ranging from allergies to obesity.

The findings appear in Mayo Clinic Proceedings.

Using health record data from the Rochester Epidemiology Project, a population-based research collaboration in Minnesota and Wisconsin, researchers analyzed data from over 14,500 children.

About 70% of the children had received at least one treatment with antibiotics for illness before age 2. Children receiving multiple antibiotic treatments were more likely to have multiple illnesses or conditions later in childhood.

Types and frequency of illness varied depending on age, type of medication, dose and number of doses. There also were some differences between boys and girls.

Conditions associated with early use of antibiotics included asthma, allergic rhinitis, weight issues and obesity, food allergies, attention deficit hyperactivity disorder, celiac disease, and atopic dermatitis.

The authors speculate that even though antibiotics may only transiently affect the microbiome, the collection of microbes in the body, this may have long-term health consequences.

“We want to emphasize that this study shows association ― not causation ― of these conditions,” says Nathan LeBrasseur, Ph.D., a researcher at Mayo Clinic’s Robert and Arlene Kogod Center on Aging and the study’s senior author.

“These findings offer the opportunity to target future research to determine more reliable and safer approaches to timing, dosing and types of antibiotics for children in this age group.”

While recent data show an increase in some of the childhood conditions involved in the study, experts are not sure why. Other than the issue of multidrug resistance, antibiotics have been presumed safe by most pediatricians.

Researchers also say the ultimate goal is to provide practical guidelines for physicians on the safest way to use antibiotics early in life.

Other coauthors of the study are Zaira Aversa, M.D., Ph.D., first author; Elizabeth Atkinson; Marissa Schafer, Ph.D.; Regan Theiler, M.D., Ph.D.; and Walter Rocca, M.D. ― all of Mayo Clinic ― and Martin Blaser, M.D., of Rutgers University.


Interest in the microbiome and its role in the developmental origins of obesity has increased substantially in the past decade, prompting multiple studies on early-life antibiotic exposures and childhood obesity.

In addition to 20 previous studies on this topic, reviewed recently by Baron et al,1 there are 2 new reports using prescription records to assess antibiotic exposures in New Zealand: a prospective cohort study of 5128 children by Chelimo et al2 and a retrospective national study of 284 211 mothers and children by Leong et al.3 Both studies found dose-dependent associations between early antibiotic exposure (prenatally or during the first 1-2 years of life) and body mass index or obesity at age 4 to 5 years.

However, when Leong et al3 restricted their analysis to siblings and twins, they found no significant association, suggesting that the association between antibiotics and obesity may be due to unmeasured confounding factors that are shared within families.

Although sibling comparisons have become popular in observational epidemiology for studying associations that are likely confounded by familial factors (eg, genetics, socioeconomic factors, home environment, and family lifestyle), they remain subject to bias from nonshared confounders and measurement error.4

In this case, as Leong et al3 acknowledge, it is possible that transmission of the unexposed sibling’s microbiome could have “repaired” the antibiotic-induced dysbiosis in the exposed sibling. Bias can also occur in sibling studies through carry-over or contagion effects, whereby the exposure or outcome of 1 sibling affects the exposure or outcome of the other.5

This is possible if an infection requiring antibiotic treatment (or an obesogenic microbiome) is transmitted between siblings. These potential biases should be considered alongside the authors’ interpretation that the antibiotic-obesity association is entirely explained by unmeasured familial confounders.

It is noteworthy that although the cohort study by Chelimo et al2 was smaller than that by Leong et al,3 the authors were able to control for many familial, lifestyle, and socioeconomic factors that were not available in the larger database study by Leong et al.3 These factors included diet, sleep, and television watching and maternal weight, education, and relationship status.

Furthermore, 2 factors known to disrupt the infant microbiome – cesarean delivery and short breastfeeding duration—were assessed and found to be associated with higher body mass index later in childhood, supporting a role for the early microbiome in obesity development.

It is also important to acknowledge that childhood obesity results from multifactorial influences; thus, antibiotic exposure is neither necessary nor sufficient as a cause. However, its potential role cannot be ignored given the mounting evidence from livestock farming, animal experiments, and human studies6 showing that antibiotics may cause changes in the gut microbiome that are associated with metabolism and weight gain.

These 2 studies2,3 contribute new data and highlight potential limitations to a growing body of evidence suggesting that antibiotics (among multiple other factors) may contribute to the development of childhood obesity, particularly when repeated exposures occur during the first year of life, a critical time for metabolic programming.

From a public health perspective, antibiotic stewardship is an urgent priority,7 regardless of its potential role in obesity prevention. It remains unclear whether antibiotics causally influence obesity development in humans and whether particular antibiotic types or time windows of exposure are especially detrimental.

These nuances are important to understand because, although the associations appear to be modest, they could be meaningful at the population level. However, further observational studies are unlikely to definitively answer these questions.

It would be unethical to randomly assign infants to receive antibiotics; however, it should be feasible, as Chelimo et al2 suggest, to study whether randomized interventions to reduce overprescribing of antibiotics have an additional benefit of reducing the incidence of childhood obesity.

Meanwhile, both antibiotic stewardship programs and childhood obesity prevention programs are clearly needed, although it remains to be seen whether and how these initiatives might converge.

References

  1. Baron  R, Taye  M, Besseling-van der Vaart  I,  et al; SAWANTI Working Group.  The relationship of prenatal and infant antibiotic xposure with childhood overweight and obesity: a systematic review  [published online November 18].  J Dev Orig Health Dis. doi:10.1017/S2040174419000722PubMedGoogle Scholar
  2. Chelimo  C, Camargo  CA  Jr, Morton  SMB, Grant  CC.  Association of repeated antibiotic exposure up to age 4 years with body mass at age 4.5 years.  JAMA Netw Open. 2020;3(1):e1917577. doi:10.1001/jamanetworkopen.2019.17577
    ArticleGoogle Scholar
  3. Leong  KSW, McLay  J, Derraik  JGB,  et al.  Associations of prenatal and childhood antibiotic exposure with obesity at age 4 years.  JAMA Netw Open. 2020;3(1):e1919681. doi:10.1001/jamanetworkopen.2019.19681
    ArticleGoogle Scholar
  4. Frisell  T, Öberg  S, Kuja-Halkola  R, Sjölander  A.  Sibling comparison designs: bias from non-shared confounders and measurement error.  Epidemiology. 2012;23(5):713-720. doi:10.1097/EDE.0b013e31825fa230PubMedGoogle ScholarCrossref
  5. Sjölander  A, Frisell  T, Kuja-Halkola  R, Öberg  S, Zetterqvist  J.  Carryover effects in sibling comparison designs.  Epidemiology. 2016;27(6):852-858. doi:10.1097/EDE.0000000000000541PubMedGoogle ScholarCrossref
  6. Azad  MB, Moossavi  S, Owora  A, Sepehri  S.  Early-life antibiotic exposure, gut microbiota development, and predisposition to obesity.  Nestle Nutr Inst Workshop Ser. 2017;88:67-79. doi:10.1159/000455216PubMedGoogle ScholarCrossref
  7. Araujo da Silva  AR, Albernaz de Almeida Dias  DC, Marques  AF,  et al.  Role of antimicrobial stewardship programmes in children: a systematic review.  J Hosp Infect. 2018;99(2):117-123. doi:10.1016/j.jhin.2017.08.003PubMedGoogle ScholarCrossref

Original Research: Open access.
Association of Infant Antibiotic Exposure With Childhood Health Outcomes” by Nathan LeBrasseur et al. Mayo Clinic Proceedings

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