Two new observational studies by scientists in New Zealand provide conflicting evidence on the potential link between early childhood exposure to antibiotics and the risk of developing obesity.
In one of the studies, both of which appeared this week in JAMA Network Open, researchers found that children who received multiple courses of antibiotics during the first 4 years of life were more likely to have a higher body mass index (BMI) score than those who received no antibiotics. In addition, children who received more than nine antibiotic prescriptions by age 4 were more than twice as likely to be obese.
In the other study, which looked at antibiotic use during the first 2 years of life, researchers also found a small association between antibiotic use and obesity risk by age 4. But when the researchers conducted further analysis in siblings and twins with different outcomes, they found no link between antibiotic exposure and obesity, leading them to conclude that antibiotics are unlikely to be a major contributor to childhood obesity, and that other, unmeasurable factors may be at work.
The two studies are in line with other observational studies on the potential association between early antibiotic use and obesity risk in children, a theory based on research showing that antibiotics alter the still-developing gut microbiome of young children in ways that could lead to weight gain. These studies have produced mixed results, with some finding an association and others finding none.
Sorting out confounding effect
In the first study, researchers with the University of Auckland and Harvard Medical School measured the weight and height of more than 5,000 children in New Zealand at 54 months of age, then obtained community pharmacy antibiotic dispensing data for the children. They looked at whether or not the children had any antibiotic exposure by age 4, the age of first exposure, and how many prescriptions they received.
Of the 5,128 children analyzed, 95% had received an antibiotic by age 4, and 9% had obesity by 54 months. The analysis, which controlled for familial, lifestyle, and economic factors, found that the BMI score for children who received at least four antibiotic prescriptions was higher than for those who hadn't been exposed, and it increased with the number of prescriptions the children received. The risk for obesity increased as well. Compared with no exposure, children who received more than nine antibiotic prescriptions had more than double the risk of being obese (adjusted odds ratio [aOR], 2.41; 95% confidence interval [CI], 1.07 to 5.41).
The analysis also found an increase in BMI associated with receipt of two or more antibiotic prescriptions during pregnancy, and that antibiotic exposure during the first years of life was associated with higher BMI compared with no exposure.
"The study findings suggest that repeated antibiotic exposure may be a potentially modifiable risk factor for childhood obesity," the authors of the study write.
In the second study, another team of researchers from the University of Auckland, along with colleagues from Dunedin School of Medicine in New Zealand and Uppsala University in Sweden, looked at antibiotic exposure during pregnancy and the first 2 years of life among 132,000 mothers and 151,000 children in New Zealand. The study, one of the largest undertaken on the topic, included a large cohort of twins and siblings, some of whom had discordant outcomes (ie, one with obesity and one without).
"This allowed us to control for a lot of unmeasured and unmeasurable confounding factors, such as genetics (largely), diet, ethnicity, household, stress, sleep patterns, etc.," corresponding author Wayne Cutfield, MD, of the University of Auckland's Liggins Institute, said in an email. "These are all corrected for, notably, with twins."
Antibiotic use was common among mothers and children, with at least one course of antibiotics dispensed to 35.7% of mothers during pregnancy and 82.3% of children during the first 2 years of life. Nearly 16% of children were identified as obese. As with the first study, the results showed that both prenatal and early childhood exposure to antibiotics were independently associated with increased BMI and obesity at age 4 in a dose-dependent manner.
Across the entire study population, antibiotic exposure during pregnancy yielded a small but increased risk of obesity in children (aOR, 1.06; 95% CI, 1.04 to 1.07), as did antibiotic exposure during the first 2 years of life (aOR, 1.04; 95% CI, 1.04 to 1.05). For children's exposure to antibiotics, the findings were similar among all siblings (aOR, 1.04; 95% CI, 1.03 to 1.05) and twins (aOR, 1.05; 95% CI, 1.02 to 1.09).
But when Cutfield and his colleagues analyzed 6,249 siblings and 522 twins with different outcomes, these associations disappeared. Among the siblings, there were no associations between antibiotic use and odds of obesity for maternal exposure (aOR, 0.95; 95% CI, 0.90 to 1.00) or children's exposure (aOR, 1.02; 95% CI, 0.99 to 1.04). The aOR for children’s antibiotic exposure among the twins was 0.91 (95% CI, 0.81 to 1.02).
"This initially surprised me, as I was expecting to see a stronger relationship between antibiotic exposure and obesity when background confounding noise was reduced," Cutfield said.
The inability to control for unmeasured family variables, Cutfield explained, likely explains why they found an association between antibiotic exposure and obesity risk in the wider population—and why other studies have found a link between the two.
"The weak, dose-related effect of early childhood antibiotics with obesity is probably due to unmeasured/unmeasurable confounding effects, which is always a problem with association studies," he said. "There are many association studies in the past in which associations have not been borne out when tested in RCTs [randomized controlled trials]."
A multifactorial problem
In an editorial that accompanies the two studies, Meghan Azad, PhD, of the University of Manitoba and Arthur Owora, DrPH, of Indiana University write that childhood obesity results from a number of different factors—environmental, socioeconomic, genetic—and that antibiotic exposure is "neither necessary nor sufficient as a cause."
But they argue that it can't be overlooked, since antibiotics have been used in food-producing animals to promote growth and weight gain, and animal and human studies have documented how antibiotic-induced disruptions of the gut microbiome are linked with metabolism and weight gain.
"These 2 studies 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," they write.
And though it's unclear whether efforts to reduce unnecessary antibiotic prescribing in children will have an impact on childhood obesity, they say, those efforts are still important.
"From a public health perspective, antibiotic stewardship is an urgent priority, regardless of its potential role in obesity prevention," they write.
See also:
Jan 22 JAMA Netw Open first study
Jan 22 JAMA Netw Open second study
Jan 22 JAMA Netw Open editorial
