Association Between Exposure to Antibiotics During Pregnancy or Early Infancy and Risk of Autism Spectrum Disorder, Intellectual Disorder, Language Disorder, and Epilepsy in Children: Population Based Cohort Study

초록

The prevalence of neurodevelopmental disorders is increasing, creating long-term challenges for affected children, their families, and society. Some studies suggest a link among antibiotic use, gut microbiota disturbances, and neurodevelopmental disorders, but these findings are often limited by confounding factors such as the underlying reason for antibiotic use and genetic predisposition. This study investigates whether antibiotic exposure during pregnancy or early infancy increases the risk of children developing autism spectrum disorder, language disorder, intellectual disorder, or epilepsy, while controlling for potential confounders. This nationwide retrospective cohort study analyzed mother-child pairs in South Korea from 2008 to 2021 using data from the National Health Insurance Service. Two cohorts were constructed: a pregnancy cohort and an infant cohort. The pregnancy cohort included mothers who were or were not exposed to antibiotics during pregnancy, excluding those with children having chromosomal abnormalities and those who took antibiotics one month before but not during pregnancy. The infant cohort included infants who were or were not exposed to antibiotics in early infancy, excluding those with chromosomal abnormalities, those who died within 6 months, and those diagnosed with neurodevelopmental disorders in the first 6 months. Outcomes were defined as diagnosis codes for autism spectrum disorder, intellectual disability, language disorder, or epilepsy in the child’s medical records. Confounding variables—including demographics, clinical indications for antibiotic use, maternal and obstetric conditions, lifestyle factors (eg, smoking status, body mass index), and familial factors—were controlled using propensity score matching, sibling control analysis, and subgroup analysis. The final population included 3,665,246 children in the pregnancy cohort and 3,944,731 children in the infant cohort. In both cohorts, antibiotic exposure was initially associated with higher hazards ratios for all neurodevelopmental disorders, whether exposure occurred during pregnancy or in early infancy. For the pregnancy cohort, hazards ratios ranged from 1.08 to 1.17 for autism spectrum disorder, intellectual disability, language disorder, and epilepsy. For the infant cohort, hazards ratios ranged from 1.04 to 1.27. However, sibling analysis showed no substantial association between antibiotic exposure and neurodevelopmental disorders, except for epilepsy, which had a slightly increased hazards ratio of 1.13 (95% CI, 1.09–1.18) in the exposed group of the infant cohort. Subgroup analysis indicated a slightly higher risk of neurodevelopmental disorders among infants exposed to antibiotics within the first 2 months of life or for longer than 15 days, with hazards ratios ranging from 1.13 to 1.36, even after sibling analysis. Overall, after accounting for familial confounders through sibling analysis, there was no significant association between antibiotic exposure during pregnancy or early infancy and the risk of autism spectrum disorder, language disorder, or intellectual disability. The risk of epilepsy was slightly higher in infants exposed to antibiotics. Subgroup analysis also indicated a slightly increased risk of all four neurodevelopmental disorders with antibiotic use very early in life or for longer than 15 days. The study's strengths include a large sample size, long follow-up, and control for many confounders. Limitations include indirect measurements of antibiotic use and infection severity, which could result in misclassification. The authors recommend further research on antibiotic exposure before 2 months of age, for longer than 15 days, and the potential link to epilepsy.