Prenatal and Early Childhood Exposure to Antibiotics or Gastric Acid Inhibitors and Increased Risk of Epilepsy: A Nationwide Population-Based Study

Abstract

Over 10 million children in the world have epilepsy, with an unknown cause in half of the cases. The gut microbiome has been associated with various neurological disorders, and certain drugs greatly disturb the microbiome. Our aim was to study the association of prenatal and childhood exposure (before the age of two) to antibiotics, proton pump inhibitors (PPIs) and histamine-2 receptor antagonists, and the risk of childhood epilepsy. Using population-based registers, we included all live singleton births in Sweden from 2006 to 2017. Exposure was considered prescription(s) to antibiotics, proton pump inhibitors, or H2-receptor antagonists (separately). Multivariable Cox regression was used to calculate hazard ratios and 95% confidence intervals. 708,903 mother-child dyads were included, and 0.5% of children had an epilepsy diagnosis. Average follow-up was 3.8 years (IQR 1-6). Prenatal exposure to antibiotics (aHR 1.09, 95% CI 1.01-1.18) and PPIs (aHR 1.38, 95% CI 1.17-1.65) were associated with an increased risk of epilepsy. Exposure to antibiotics (1.11, 95% CI 1.02-1.21), PPIs (3.40, 95% CI 2.47-4.68) and H2RAs (1.65, 95% CI 1.03-2.64) before the age of two was associated with an increased risk of epilepsy after the age of two. Dose response analysis showed that one prescription of antibiotics in pregnancy or early life was not associated with an increased risk of epilepsy, while one prescription of PPIs in pregnancy or early life had an association. To conclude, our results support the hypothesis that microbiome modulating drugs are associated with an increased risk of epilepsy. This needs to be further validated in other studies, ideally including indications for drug use.

Figure 1

Results from multivariable Cox regression, showing adjusted hazard ratios (aHR) with 95% confidence intervals (CI).

Figure 2

Unadjusted cumulative incidence for prenatal (a) antibiotics, (b) proton pump inhibitors (PPIs) and (c) H2RAs and the risk of epilepsy at any time during the study period. Early life (d) antibiotics, (e) PPIs and (f) H2RAs and the incidence of epilepsy after the age of two.

Figure 3

Dose response analysis for antibiotics and proton pump inhibitors (PPIs), both during pregnancy and in early life (before the age of two). Hazard ratios (aHR) and 95% confidence intervals (CI) calculated using multivariable Cox regression adjusted for in pregnancy exposure (maternal age, maternal BMI, parity, country of birth, delivery mode, sex of child, preterm status, tobacco usage, maternal epilepsy, maternal diabetes, maternal hyperthyroidism, Apgar score at 5 minutes, small for gestational age) and early life exposure (maternal age, maternal BMI, parity, delivery mode, sex of child, preterm status, tobacco usage, maternal epilepsy, maternal diabetes, Apgar score at 5 minutes, small for gestational age).