(CSPOT48) Comparative Risk of Neurodevelopmental Disorders Between Children Exposed to β-lactam and non-β-lactam Antibiotics During Gestation: An Emulated Target Trial

Background: Use of antibiotics during pregnancy has been linked to attention deficit hyperactive disorder (ADHD) and autism spectrum disorder (ASD) in children. However, a paucity of information on the association between prenatal exposure to antibiotics and other cognitive and behavioral disorders exists.

Objectives: The objective of this study was to compare the risk of neurodevelopmental disorders (NDDs) between children exposed to β-lactam and non-β-lactam antibiotics during gestation.

Methods: This retrospective cohort study utilized administrative claims data and followed the framework of target trial emulation. The study included pregnant women between the ages of 12 and 55 years and dispensed at least one antibiotic during pregnancy between 2012 and 2022. NDDs, including ADHD, ASD, intellectual disability, learning difficulty, speech and language disorder (SLD), behavioral disorder (BD), and developmental coordination disorder (DCD), were assessed as the primary outcome. Three types of target trials, defined by the exposure window of early (≤ 20 weeks), late (>20 weeks), and entire pregnancy, were performed to compare the incidence of NDDs between β-lactam and non-β-lactam antibiotics. Cox Proportional Hazard regression analyses were conducted using propensity score matching to adjust for confounding variables including demographic characteristics, maternal comorbidities, and comedication use. To further address confounding and bias, a series of sensitivity analyses were performed, including dose response, alternative definitions of exposure and outcomes, and alternative propensity score methods.

Results: Of the 14,409 livebirths included in the study, 11.5% and 10.4% were prenatally exposed to β-lactam and non-β-lactam antibiotics, respectively. A total of 2,482 children were diagnosed with at least one NDD, 13.9% and 11.9% of which were prenatally exposed to β-lactam and non-β-lactam antibiotics, respectively. While there was no increased risk of NDDs in children exposed to β-lactam as compared to those exposed to non-β-lactam antibiotics during the entire and early pregnancy periods , an increased risk was observed for NDDs as a composite outcome (HR: 1.46; 95% CI: 1.12 - 1.89) and SLD (HR: 1.65; 95% CI: 1.21 - 2.25) in late pregnancy period. Sensitivity studies yielded results similar to the primary analyses.

Conclusions: Maternal exposure to β-lactam antibiotics during late pregnancy was found to be associated with an increased risk of SLD in childhood as compared to exposure to non-β-lactam antibiotics. However, further investigation is needed to establish a direct causal relationship between maternal use of β-lactam antibiotics during pregnancy and the development of NDDs in children .