In our retrospectivestudy of a large cohort of children born in a community with high prevalence of obesity, we found that those exposed to antibiotics in the neonatal period were more likely to be obese at five years of age compared with those who were not exposed. To the best of our knowledge, this is the first study to report an association between neonatal exposure to penicillin-based and aminoglycoside antibiotics and obesity in early childhood.
Our finding is consistent with other studies, which showed a similar association between antibiotic exposure in childhood and increased risk of obesity.(4, 11, 13, 17, 18, 20, 22) For example, like our study, where the risk of obesity at 5 years increased by 37% among the antibiotic exposed neonates, Scott et al. found that early exposure to antibiotics increased the odds of childhood obesity at 4 years by 21%. In contrast, some other studies have reported a negative association between early antibiotic exposure and childhood obesity.(18–20, 23) It is, however, important to note that the methodology of these studies differ from ours, which might explain the inconsistent findings. For example, Rogawaski et al. and Gerber et al. extracted their antibiotic exposure variable from the prescription database(19), caregiver verbal report and prescription data.(18) There was no means of validating whether the medication was dispensed from the pharmacy, that caregiver recall was accurate, or that medication was taken by the infant as prescribed. Misclassification bias could then probably explain the lack of association. Our study tried to minimize this bias by utilizing data from administered antibiotics with standardized weight-based dosing and duration of treatment.
Increased exposure to antibiotics through longer or multiple courses is thought to lead to more pronounced alterations in the gut microbiome and potentially more effects on the metabolic pathways. Previous studies(4, 16) have demonstrated a dose-dependent association between antibiotic use and childhood obesity when utilizing data with multiple antibiotic exposures over a prolonged time throughout childhood. However, we did not find a significant difference between the incidence of obesity between infants exposed for less than or equal to 72 hours versus greater than 72 hours, suggesting that mere exposure, regardless of duration and dose, is impactful in the neonatal period. However, the effect we found in our study may also be limited to the timing of antibiotic exposure in our cohort as animal models suggest that earlier exposure may lead to more significant alterations.(24) The risk of developing obesity with antibiotic exposure in the first month of life emphasizes that the neonatal microbiome is a dynamic environment that is extremely inducible by external factors like antibiotics.1819,20
This emphasis on exposure timing is fundamental. For instance, some studies(13, 14) found a positive association in children exposed to antibiotics before 6 months of life. Scott et al. found increasing risk of obesity as duration of exposure shortens from 2 years to 1 year to < 6 months.(4) Others, like Block et al., reported a marginal association between antibiotic exposure in infants exposed under 24 months of age and being overweight or obese at five years of age.(11) It is important to highlight that in the population we studied, antibiotic exposure was generally in the first few days, if not first hours, of life. By focusing solely on the neonatal period, we were able to explore the effects of antibiotic exposure on the formative period of gut microbiome development and confirm that alterations at this time may have been impactful on the future weight trajectories of the children included in the study. Hence, neonatal antibiotic exposure is a modifiable risk factor for obesity in our population and judicious use of antibiotics at this time may have critical importance in preventing childhood obesity.
In our study, the association between antibiotic exposure and childhood obesity remained significant after controlling for covariates, some of which include maternal comorbidities and feeding practices. We found that maternal obesity and maternal gestational diabetes were significantly associated with childhood obesity at 5 years. This association is intuitive as maternal genetic or environmental predispositions that led to the maternal comorbidities can easily influence weight trajectories in their offspring. Additionally, in our study, unadjusted analysis showed association between feeding practices and childhood obesity; the variable was removed in the stepwise multivariate analysis model due to non-significance at 0.05 significance level. This finding is inconsistent with previous studies, which suggested that breastfeeding is an important early contributor to gut microbiota.(17, 18) These studies surmised that antibiotic exposure may attenuate the beneficial effect of breastfeeding. Since only 7.4% of our study population were exclusively breast fed, that conclusion is difficult to ascertain from our study population.
The initial development and maturation of the neonatal microbiome is closely related to the maternal microbiome which is influenced by diet, infection, antibiotic use, and a host of other factors. During the perinatal period, there is transfer of the maternal microbiota, especially from vaginal fluid and gastrointestinal tract to the gut of the neonate during vaginal delivery, forming the core of the neonatal gut microbiome. Infants born via cesarian section are colonized by skin bacteria(25). Delivery route was not significantly related to child obesity status in our bivariate analysis and was not included in our final model. The non-inclusion of delivery route as a confounder in our model is a potential limitation.
Strengths of this study includes a large sample size and the retrospective cohort design, which provides a means of estimating risk, as opposed to a cross-sectional or case-control design. Additionally, the direct extraction of our primary independent variable (antibiotic exposure) from the administered medication section of the electronic medical record reduced misclassification bias, added to the exposure classification's validity, and improved our ability to detect a true effect. We also included multiple covariates (including variables previously established as risk factors or based on biologic plausibility) in our analysis. This helped us to account for their possible effect on our outcome variable, obesity at five years.
Some of the potential limitations of this study include the lack of exploration of additional antibiotic use after the neonatal period and failure to evaluate the potential effect of such exposure on the outcome variable. Selection bias, which is peculiar to many retrospective studies, may have influenced our result. Therefore, we tried to strengthen our design by adopting a retrospective cohort design which provides a higher level of evidence for the association between early antibiotic exposure and obesity compared to the case control approach employed by Azad et. Al(26), which was lacking in precision of the effect size (wide confidence interval), albeit statistically significant. Although we adjusted for many potential confounding variables, variables such as GBS IAP and race or ethnicity had poor documentation, which may have impacted our findings.