Neonatal antibiotic exposure impairs child growth during the first six years of life by perturbing intestinal microbial colonization

Newborn infants are highly susceptible to bacterial infections, leading to frequent antibiotic use in neonatal units. While short-term effects of neonatal antibiotic treatment on the gut microbiome are known, the long-term consequences remain unclear. Given the established link between the gut microbiome and various health outcomes, including growth, obesity, and metabolic disease, there is a hypothesis that neonatal antibiotic exposure might have a lasting impact on child development. Previous studies have shown associations between early-life antibiotic exposure and decreased growth in the first year, and later antibiotic use and increased risk of obesity. This study aimed to investigate the long-term association between antibiotic exposure during and after the neonatal period and childhood growth up to six years of age in a large, unselected cohort. The researchers hypothesized that early-life antibiotic treatment disrupts the natural gut microbial colonization process and thereby affects childhood growth trajectories. The study’s importance lies in understanding potential long-term health implications of a common neonatal practice. The findings could inform clinical guidelines and practices surrounding antibiotic use in newborns and contribute to a deeper understanding of the complex interplay between the microbiome and child health.

The literature review section of this paper highlights existing research on the impact of antibiotic exposure in early life on various health outcomes. Studies have shown links between early-life antibiotic use and altered gut microbiome composition in the first few weeks of life, but the longer-term consequences have been less understood. The review mentions studies that reported associations between early-life antibiotic exposure and decreased growth in the first year of life and between antibiotic exposure later in childhood and an increased risk of obesity and overweight. However, the long-term effects on growth beyond the first year of life remained largely unknown. This research gap underscores the need for a longitudinal study that examines the prolonged impact of neonatal antibiotic exposure on growth trajectories.

This study utilized a two-cohort approach, investigating the impact of antibiotic exposure on growth and gut microbiota. The first cohort, the Southwestern Finland Birth Cohort (SFBC), comprised 12,422 full-term children born between 2008 and 2010. Data on neonatal antibiotic exposure (within 14 days of life), child growth parameters (weight, height, BMI Z-scores), and antibiotic use during the first six years of life were collected from hospital records and national registries. The second cohort, the German PEACHES cohort, provided an independent data set to validate the findings. In this cohort, 535 children were studied, and analysis focused on the first five years of life. Both cohorts utilized hierarchical linear mixed models for repeated measures to analyze the association between antibiotic exposure and growth, controlling for potential confounders like gestational age, birth weight, maternal BMI, and mode of delivery. To investigate the mechanisms linking antibiotic exposure and growth, a subset of infants from the SFBC participated in a clinical trial investigating the impact of maternal probiotic supplementation. Fecal samples were collected at 1, 6, 12, and 24 months of age, and 16S rRNA gene sequencing and metagenomics were performed to analyze the gut microbiome composition. Furthermore, a fecal microbiota transplant (FMT) experiment in germ-free mice was conducted using samples from antibiotic-exposed and non-exposed infants to examine the causal role of the altered gut microbiome in growth impairment. The statistical analyses used included linear mixed models, principal coordinate analysis (PCoA), and various microbiome analysis techniques.

The study revealed a sex-specific effect of neonatal antibiotic exposure on growth. In boys, neonatal antibiotic exposure was associated with significantly lower weight and height Z-scores throughout the first six years of life compared to non-exposed boys. This association held true even after adjusting for potential confounders. In contrast, no significant association was observed between neonatal antibiotic exposure and growth in girls. The findings from the independent PEACHES cohort largely corroborated these results, showing a similar pattern of growth reduction in boys following neonatal antibiotic treatment. Interestingly, antibiotic use after the neonatal period but during the first six years of life showed a different effect – it was associated with significantly higher BMI Z-scores in both boys and girls throughout the study period. Microbiome analysis revealed that neonatal antibiotic exposure led to significant alterations in the gut microbiome composition, particularly a decreased abundance and diversity of Bifidobacterium at 2 years of age. The FMT experiment using samples from antibiotic-exposed infants demonstrated a significant growth impairment in male, but not female, germ-free mice, suggesting a causal link between the altered gut microbiome and growth retardation.

The findings of this study provide strong evidence for a long-term impact of neonatal antibiotic exposure on childhood growth, particularly in boys. The sex-specific effect suggests potential hormonal or other biological mechanisms that interact with the gut microbiome. The observed reduction in Bifidobacterium abundance after neonatal antibiotic exposure is consistent with other studies and highlights the importance of this bacterial genus for healthy development. The FMT experiment supports a causal role of the altered gut microbiome in the observed growth impairment. The contrasting effect of antibiotic use after the neonatal period (increased BMI) suggests a complex interplay between the timing of antibiotic exposure, the developing gut microbiome, and growth trajectories. The study's limitations highlight the need for larger studies to confirm these findings, explore potential confounding factors, and investigate the underlying mechanisms in greater depth. This study underscores the importance of considering the potential long-term effects of neonatal antibiotic treatment on child health and exploring strategies for minimizing unnecessary antibiotic use in newborns.

This study demonstrates a significant association between neonatal antibiotic exposure and reduced growth in boys during the first six years of life, linked to alterations in the gut microbiome. Later antibiotic use was associated with increased BMI. The sex-specific impact and the mechanistic evidence from FMT experiments highlight the need for judicious antibiotic use in neonates and further research into the complex interplay between the gut microbiome and growth.

The study acknowledges several limitations, including the observational nature of the design, which does not establish direct causality. The reliance on antibiotic purchase data rather than direct medical records for later antibiotic use might underestimate actual exposure. The sample size for the microbiome and FMT experiments was relatively small, limiting the generalizability of these findings. Further research is needed to explore potential confounding factors and fully elucidate the underlying mechanisms involved.