A new study suggests repeated antibiotic use in early childhood is linked to a host of chronic conditions in children.
The study, published this week in the Journal of Infectious Diseases, found that antibiotic exposure before age 2 years was positively associated with asthma, food allergy, hay fever, and intellectual disability, with stronger associations observed following multiple antibiotic courses. The findings were confirmed in a sibling-matched analysis.
The findings add to a growing body of evidence that early exposure to antibiotics—which are the most commonly prescribed medication in young children and frequently overused—is associated with increased risk of childhood-onset diseases and neurodevelopmental conditions. Other studies have found links to a higher risk of obesity. The hypothesis is that these conditions may be occurring because of the way antibiotics disrupt the gut microbiome, which is still in development in infants.
The study authors say the results highlight the need to limit unnecessary antibiotic use in young children.
"Antibiotics play a critical role in combatting bacterial infections, but physicians should be judicious when prescribing antibiotics to children under 2, as frequent use may affect long-term health outcomes," lead study author Daniel Horton, MD, of the Rutgers Institute for Health, Health Care Policy, and Aging Research, said in a university press release.
Large study factors in many variables
For the study, Horton and his colleagues at Rutgers examined electronic health record data from the United Kingdom's Clinical Practice Research Datalink, which contains records on medications and clinical diagnoses in UK primary care settings, from 1987 through 2020. The primary exposure was prescriptions to antibiotics within 2 years of birth. The primary outcome was asthma/allergic conditions, autoimmune diseases, and neurodevelopmental/psychiatric conditions in children ages 27 months to 12 years.
While previous studies have found that antibiotic exposure during the first 2 years of life is linked to development of some of these conditions, the authors note that those studies have had a variety of limitations. Some have involved small populations. Others have been unable to account for other factors that might explain the observed associations, such as the underlying infections that led to antibiotic use.
For this study, the researchers examined data on more than 1 million children and evaluated a range of potential variables that could bias the results. They also compared exposures and outcomes in siblings from the same mother.
"Through careful consideration of various potential confounders, including family history, maternal antibiotic exposure, infections, perinatal factors, and healthcare utilization, as well as through sibling-matched analyses, we controlled for many measured and unmeasured confounders often overlooked in observational studies of long-term effects of antibiotics," Horton and his colleagues wrote.
'Mounting evidence' of long-term harms
Of the 1,091,499 children included in the study, 685,665 (62.8%) were exposed to antibiotics from birth to age 2.
Compared with no antibiotic exposure, any antibiotic exposure was associated with a higher risk for asthma (adjusted hazard ratio [aHR], 1.24; 95% confidence interval [CI], 1.22 to 1.26), food allergy (aHR, 1.33; 95% CI, 1.26 to 1.40), and, to a lesser extent, allergic rhinitis (aHR, 1.06; 95% CI, 1.03 to 1.10). The results were similar in the sibling-matched analysis.
The relationship was even stronger in the dose-response analysis. Receipt of multiple antibiotic courses (5 or more vs 1 to 2 courses) was associated with asthma (aHR, 1.52; 95% CI, 1.49 to 1.55), food allergy (aHR, 1.53; 95% CI, 1.42 to 1.64), and allergic rhinitis (aHR, 1.18; 95% CI, 1.13 to 1.23).
Antibiotics play a critical role in combatting bacterial infections, but physicians should be judicious when prescribing antibiotics to children under 2, as frequent use may affect long-term health outcomes.
Although there was no association between any antibiotic use and risk of intellectual disability, there was a dose-dependent association when comparing 5-plus with 1 to 2 antibiotic courses (aHR, 1.73; 95% CI, 1.49 to 2.01). That association was stronger in the sibling-matched analysis (aHR, 2.79; 95% CI, 1.87 to 4.18).
No association was observed between early antibiotic exposure and autoimmune diseases (celiac disease, inflammatory bowel disease, juvenile idiopathic arthritis, type 1 diabetes) or other neurodevelopmental/psychiatric conditions, including autism, attention-deficit/hyperactivity disorder (ADHD), or anxiety.
"Despite important benefits of antibiotics, this study contributes to mounting evidence for long-term harms from early-life antibiotic exposure, underscoring the need for judicious antibiotic use in infancy and early childhood," the authors wrote.
A vulnerable period for the developing microbiome
Although the study is observational and doesn't prove that early antibiotic exposure caused conditions, the research is based on the hypothesis that microbiome disruption is a key factor in the development of an array of pediatric conditions. The hypothesis stems from experiments that study co-author Martin Blaser, MD, and others have conducted in mice that show early exposure to antibiotics—with no other variables involved—changes microbial diversity in ways that can produce long-term effects.
Blaser, who directs the Center for Advanced Biotechnology and Medicine at Rutgers, was also involved in a smaller 2020 study that involved more than 14,000 children in Minnesota's Olmsted County. Like the present study, that study also found early antibiotic use was associated with increased risk of childhood-onset asthma and hay fever. It also found associations with atopic dermatitis, obesity, celiac disease, and ADHD.
Blaser says investigating early exposure to antibiotics is important, because that's when the infant microbiome is developing and most vulnerable to disruption. "The first 3 years of life is when the microbiome is most dynamic," he said in an interview.
At same time, those early years are when infants are developing their immunity, metabolism, and cognition.
"All these physiologic systems are not fully formed at birth, but they develop in the early years of life," he added. "But what we now know is that the microbiome is the partner of the host in this development…and the microbiome is affecting the host in ways that determine what the trajectory is going to be."
...what we now know is that the microbiome is the partner of the host in this development…and the microbiome is affecting the host in ways that determine what the trajectory is going to be.
While more research is needed to confirm the associations and understand the potential mechanisms, Blaser says there's already some evidence that antibiotic stewardship could play a role in reducing children's risk of developing these conditions. He cited a 2020 study conducted in British Columbia that found that a reduction in asthma incidence in young children from 2000 through 2014 was associated with decreased antibiotic use in children in their first year of life.
"The general mantra with the overuse of antibiotics is 'this may not help, but it won't hurt,' " he said. "But that's why we're doing studies like this. We're now providing evidence supporting the hypothesis that they do hurt, and the risks are cumulative."
