한빛사논문
Ahhyung Choi, postdoctoral research fellow1,2, Hyesung Lee, research professor1,3, Han Eol Jeong, postdoctoral research fellow1,3, Seo-Young Lee, professor4,5, Jun Soo Kwon, professor6,7,8, Jung Yeol Han, professor9, Young June Choe, associate professor10, Ju-Young Shin, associate professor1,3,11
1School of Pharmacy, Sungkyunkwan University, Suwon, South Korea
2Harvard-MIT Center for Regulatory Science, Harvard Medical School, Boston, MA, USA
3Department of Biohealth Regulatory Science, Sungkyunkwan University, Suwon, South Korea
4Department of Neurology, College of Medicine, Kangwon National University, Chuncheon, South Korea
5Interdisciplinary Graduate Program in Medical Bigdata Convergence, Kangwon National University, Chuncheon, South Korea
6Department of Psychiatry, Seoul National University College of Medicine, Seoul, South Korea
7Department of Brain and Cognitive Sciences, Seoul National University College of Natural Sciences, Seoul, South Korea
8Institute of Human Behavioral Medicine, Seoul National University Medical Research Center, Seoul, South Korea
9Korean Mothersafe Counselling Center, Department of Obstetrics and Gynecology, Inje University Ilsan Paik Hospital, Goyang, South Korea
10Department of Pediatrics, Korea University Anam Hospital, Korea University College of Medicine, Seoul, South Korea
11Department of Clinical Research Design & Evaluation, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, South Korea
AC and HL contributed equally to the paper as joint first authors.
Correspondence to: J-Y Shin
Abstract
Objective: To evaluate the association between antibiotic use during pregnancy or early infancy and the risk of neurodevelopmental disorders in children.
Design: Nationwide population based cohort study and sibling analysis.
Setting: Korea's National Health Insurance Service mother-child linked database, 2008-21.
Participants: All children live born between 2009 and 2020, followed up until 2021 to compare those with and without antibiotic exposure during pregnancy or early infancy (first six months of life).
Main outcomes measures: Autism spectrum disorder, intellectual disorder, language disorder, and epilepsy in children. After 1:1 propensity score matching based on many potential confounders, hazard ratios with 95% confidence interval were estimated using Cox proportional hazard models. A sibling analysis additionally accounted for unmeasured familial factors.
Results: After propensity score matching, 1 961 744 children were identified for the pregnancy analysis and 1 609 774 children were identified for the early infancy analysis. Although antibiotic exposure during pregnancy was associated with increased risks of all four neurodevelopmental disorders in the overall cohort, these estimates were attenuated towards the null in the sibling analyses (hazard ratio for autism spectrum disorder 1.06, 95% confidence interval 1.01 to 1.12; intellectual disorder 1.00, 0.93 to 1.07; language disorder 1.05, 1.02 to 1.09; and epilepsy 1.03, 0.98 to 1.08). Likewise, no association was observed between antibiotic exposure during early infancy and autism spectrum disorder (hazard ratio 1.00, 0.96 to 1.03), intellectual disorder (1.07, 0.98 to 1.15), and language disorder (1.04, 1.00 to 1.08) in the sibling analyses; however, a small increased risk of epilepsy was observed (1.13, 1.09 to 1.18). The results generally remained consistent across several subgroup and sensitivity analyses, except for slightly elevated risks observed among children who used antibiotics during very early life and those who used antibiotics for more than 15 days.
Conclusions: In this large cohort study, antibiotic exposure during pregnancy or early infancy was not associated with an increased risk of autism spectrum disorder, intellectual disorder, or language disorder in children. However, elevated risks were observed in several subgroups such as children using antibiotics during very early life and those with long term antibiotic use, which warrants attention and further investigation. Moreover, antibiotic use during infancy was modestly associated with epilepsy, even after control for indications and familial factors. When prescribing antibiotics to pregnant women and infants, clinicians should carefully balance the benefits of use against potential risks.
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